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PHASE I/II STUDY OF INTERFERON-GAMMA AND eC-DI'FLUOROMETHYLORNITHINE (DFMO) FOR'THE TREATMENT OF METASTATIC MALIGNANT MELANOMA,GASTROINTESTINAL CARCINOMAS AND HYPERNEPHRORA IN CONVENTIONALLY PRETREATED PATIENTS. W. Zeller, H. Garbrecht and D.K. Hossfeld

RADIOSENSITIZATION BY HYPERTHERHIA: P R O F I L E S AND TUMOR R E S P O N S E M. Molls. H . 3 . F e l d m a n n , W. B a u m h o e r , H. A n n w e i l e r , H. Sack

It is well known from previous studies that gastrointestinal carcinomas, malignant melanoma and hypernephroma are tumors which poorly respond to conventional chemotherapy. In a Phase I/II study in conventionally pretreated patients with these malignomas a combination of oC-difluoromethylornithine, an irreversible enzymeactivated inhibitor of ornithine decarboxylase, and Interferon-gamma was given over a period of three months. DFMO was taken perorally in a constant dose, the dose of IFN-y, which was injected subcutaneously, was duplicated every four weeks. Of six patients with hypernephroma, one presented with partial response, in three patients the disease could be stabilized, two patients showed progressive disease. Of six patients with malignant melanoma in only one case stable disease could be achieved, all other patients did not respond. In all four patients with gastrointestinal carcinoma the growth of tumor could not be altered by therapy. During the treatment period of three months, natural-killer-eellassays, Interleukin 2 assays and the determination of IFN-y serum levels were performed every two weeks. NK-cell activity raised to high values in the first weeks of treatment, falling to nearly pretreatment levels in the following weeks. Significant relations between NK-cell values and tumor response could not be observed. A b t e i l u n g Onkologie und Hfimatologie, Universit@tskrankenhaus Eppendorf, Martinistr. 52, D-2000 Hamburg 20

THERMAL

Hyperthermia o~ superficial, h a l { - d e e p and deep located tumors was p e r f o r m e d w i t h the 8 S D - 1 0 0 0 d e v i c e , In 28 p a t i e n t s w e t r e a t e d 31 tumors, Hypertbermia was g i v e n i m m e d i a t e l y after irradiation, in m o s t c a s e s t w i c e per week. In 50Z of the tumors the r a d i a t i o n doses were low (18-38 Gy) due t o p r e v i o u s treatment. Temperature measurements at several tumor sites r e v e a l e d d i f f e r e n c e s o{ about 3e C per tumor, In 55~ of the t u m o r s the equivalent time at 42,5 e C r a n g e d f r o m 100 to 400 m i n ( s u m m a r i z i n g the heat d o s e s o~ all treatments per tumor). W h e n the heat d o s e was less the n u m b e r of t u m o r r e g r e s s i o n s was comparatively low (37Z versus 7~Z), Complete response (CR) occurred in 26Z, partial r e s p o n s e in &1Z. M o s t i m p r e s s i n g was the CR of a l a r g e (5• cm2) p a r a v e r t e b r a l melanoma after 46 Gy plus 15 h y p e r t h e r m i c treatments, A s t e r n a l m e t a s t a s i s o~ a b r e a s t carcinoma disappeared alter 20 Gy plus hyperthermia as proven by histology. Regressions w e r e also o b s e r v e d in l y m p h oode m e t a s t a s e s of head and neck c a r c i n o m a s and in pelvic tumors of the r e c t u m , As s e v e r e side effects could be avoided we c o n s i d e r the c o m b i n a t i o n of r a d i o t h e r a p y plus h y p e r t h e r m i a to be a safe t r e a t m e n t m o d a l i t y . W i t h r e g a r d to palliation it is of g r e a t i n t e r e s t that even after low radiation doses plus hyperthermia tumor regressions can be obtained, Radiologisches Zentrum, Universitatsklinikum, 4300 Essen I

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I/5-M 002 INHIBITION dE CARCINOGEN-INDUCED DNA AMPLIFICATION BY ETHANOL, ETHACRIDINE OR

LOCAL RADIOTHERAPY AND MICROWAVE HYPERTHERMIA FOR SUPERFICIAL CHESTWALL RECURRENCES.

HYPERTHERMIA

A. B ~ r k l e

a n d H. zur H a u s e n .

Amplification of D N A is recognized as an important mechanism in t h e d e v e l o p m e n t of cytotoxic drug resistance. We are using a SV40-transformed Chinese Hamster cell line (CO 60) in c o n j u n c t i o n with quantitative DNA slot blot hybridization as a model system for DNA amplification. This cell line amplifies integrated viral DNA sequences as a response to treatment with a variety of carcinogens (e.g. M N N G , an a l k y l a t i n g agent) as w e l l a s t o t r a n s i e n t a r r e s t of DNA replication with metabolic inhibitors (e.g. hydroxyurea, MTX, mA M S A ) . In an attempt to elucidate the mechanism(s) of DNA amplification, we found that ethanol or ethaes (an i n t e r c a lative non-mutagenic compound) at nontoxic concentrations block MNNG- or gammaray induced amplification substantially. Both drugs alone do not induce any amplification detectable with our assay at the concentrations we used. Furthermore, hyperthermia can reduce amplification drastically, The m e c h a n i s m s of i n h i b i t i o n of a m p l i f i c a t i o n by these treatments is currently under investigation. Our results m a y s h o w a w a y to u n c o u p l e i n d u c t i o n o f a n important tumor cell resistance mechanism from the cytotoxieity of drugs or irradiation. Institut f~r Virusforschung, DKFZ, Im N e u e n h e i m e r F e l d 280, D - H e i d e l b e r g 1

M. H. Seegeuschmiedt (1), R. Saner (1), L.W. Brady (2). Recurrent superficial chestwall malignancies from carcinoma of the breast produce significant morbidity and impairment of quality of life and are usually difficult to manage after multiple surgical procedures, aggressive radiation therapy and/or chemotherapy. Here combined radiotherapy and local hyperthermia is an additional therapeutic alternative for improvement of local control. Sofar 26 patients with 44 treatment sites (applicator fields) have been treated at Hahnemann University, Philadelphia for superficial chestwatl recurreucies. In all cases radiotherapy (15 - 50 Gy, 2x/week, 1.5 - 2" Gy/fraction) was combined with local microwave hyperthermia (2x/week, 2 - 12 total treatments @ 41~ - 44~ for 45 - 60 minutes). A 915 MHz microwave system and a fiberoptic thermometry unit with 24 measure points were employed. Complete response (CR) at 1 month follow- up was 22/44 (50%), and l g / 4 4 (41%) achieved partial response (PR), overall response rate was 40/44 (91%); those patients who achieved complete response were either longterm respouders without local evidence of disease at 12 month (18/22 = 82%) or suffered death due to systemic disease without local recurrence (4/22 = 18%). Recurrences were observed in 6/18 (33%) partial responders. No change (NC) or even progression of disease (PD) under treatment was seen in only 4/44 (9%) sites. Due to intensive pre-treatment overall complication rate (blisters, thermal burns or subcutaneous necrosis or ulcers) was relatively high, 15/44 (34%). Initial complete response rate at I month was depending upon minimal tumor temperature (> 41~ achieved per site and hyperthermia treatment, on the applied total radiation dose (> 30 Gy) and on the initial size of the tumor lesion (< 5 era 0). Complications occured at high maximum temperatures in tumor or in normal tissue (> 45~ Median follow-up is 12.4 months. (1) Strahlentherapeutische Uuiversitatsklinik Erlangen-Niirnberg, FRG (2) Hahnemann University, Dep. Radiation Oucology, Philadelphia, USA.

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BIOCHEMICAL DRUG TARGETING DEOXYCOFORMYCIN AS A SELECTIVE DRUG FOR CHRONIC LYMPHOID NEOPLASMS A.D. Ho, R. Kuse, R. Willemze, R. Zittoun and P. Stryckmans for the EORTC leukemia study group

LECTIN-MEDIATED DRUG-TARGETING 2X9 CULTUP~ED H U M ~ TUMOR CELLS S. Gabius, G.A. Nagel, H.-J. Scb2noll, H.-J. Gabius

Knowledge of the vital role of adenosine deamlnase (ADA) in lymphocytes and their precursors has led to the pharmacological use of enzyme inhlbitors for the specific treatment of lymphoid neoplasms. Deoxycoformycin (DCF, Pentostatin) is a tight binding inhibitor of

ADA. In v i t r o e x p e r i m e n t s s u g g e s t t h a t t h i s drug i s s p e c i a l l y a c t i v e in lymphoma c e l l s o f t h e T c e l l type, In a p r o s p e c t i v e m u l t i c e n t e r phase tI t r i a l o f t h e EORTC, t h e a c t i v i t y of t h i s drug i s i n v e s t i g a t e d in c h r o n i c T c e l l neoplasms. Eleven p a t i e n t s with S6zary syndrome, 6 p a t i e n t s with T-eLL and 2 p a t i e n t s with Tprolymphocytic leukemia (PLL) are p r e s e n t l y e v a l u a b l e for r e s p o n s e and t o x i c i t y , Four o f the 11 p a t i e n t s with S4zary syndrome, 3 o f t h e 6 p a t i e n t s with T-eLL and 1 o f t h e 2 p a t i e n t s with T-PLL achieved a p a r t i a l r e m i s s i o n . Major toxicity included nausea, transient skin rash and infections. ~ematological toxicity was rare, indicating the selective activity against lymphoid cells. Simultaneous investigations of the biochemical sequelae of DCF treatment showed that clinical response correlated with inhibition of S-adenosyl-homocysteine (SA8) hydrolase in the leukemic cells of the patients. As inhibition of SAH-hydrolase causes a shift in the ratio of S-Adenosyl methionine and SAH (methylation index), suppression of methylatlon might be the ultimate molecular mechanism leading to cell death. No correlations could be established between clinical response and membrane phenotype o f t h e leukemic c e l l s . Thus s t u d i e s of the enzyme profiles and biochemical changes in lymphoid neoplasms p r o v i d e s an avenue for s e l e c t i v e

Human tumor cell lines offer a tool to investigate, whether endogenous membrane carbohydrate-binding proteins (leetins) of tumor cells may contribute to an improvement of clinical management of tikmors by serving in a selective lectin-mediated uptake of ~erapeutically active conjugates of a synthetic neoglyeoprotein and a cytotoxie drug. To infer presence of membrane lectins and their sugar specificities for human colon carcinoma, melanom~ aJqd e~Lbryonal carcinoma lines, fluorescent neoglycoproteins %~re employed. Efficient fluorescent labeling that exhibited a characteristic pattern for each cell line correlated with extent of lectin-mediated, sugar-specific uptake of drug-neoglycoprotein conjugates, as consistently measured by the significant exerted growth inhibition of the different, covalently linked cytotoxic drugs, namely etoposide, cis-Pt, FuDr and MTX upon intracellular release. Two different neoglyeoproteins, reacting with independently targeted membrane lectins~ were shown to be useful in a model for combination chemotherapy. Affinity chron~tography on supports of immobilized carbohydrates results in purification of the respective membrane lectins as an initial step to characterize their biological fur~ction and to a lectin-based drug targeting. ~Lbt. H~matologie-Onkologie der Medizinischen Universit&tsklinik, Rok~rt-Koch-StraBe 40, D-3400 G6ttingen

chemotherapy. Universit~t Heidelberg, Inhere Medizin ur~ Poliklinik V, Rospitalstr.3, 6900 Heidelberg

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EVALUATION OF (131-J)~MIBG UPTAKE AND R E L E A S E IN A NEUROBLASTOMA CELL CULTURE SYSTE~I AND ITS CLINICAL IMPORTANCE V.Paffenholz, H.Hoffecker, E,Gusettis, U.Ebener, B.Kornhuber

DRUG TARGETING WITH LIPOSOMES IN CANCER T H E R A P Y H. Stricker

A n e u r o b ! a s t o m a cell line established from a bone marrow puncture of a patient in stage IV disease was cloned, c h a r a c t e r i z e d and grown as a model system to elaborate data of clinical relevancy in n e u r o b l a s t o m a treatment like c e l l - d r u g - i n t e r a c t i o n s and the mode of uptake conditions for storage and release of mlBG in n s u r o b l a s t o m a tissues. The incubation of n e u r o b ! a s t o m a cells with labelled mlBG starts with a fast increase in cell-bound r a d i o a c t i v i t y giving a maximum level of uptake four hours after the addition of the drug. Variation of cell culture conditions only results in minor changes of uptake whereas previous incubation of the c e l l s w i t h low concentrations of c h e m o t h e r a p e u t i c agents as recommended in the NB-85 protocol greatly affects the uptake of mlBG in neuroblastoma cells. The removal of mlBG from culture medium results in a dramatic loss of cell-bound radioactivity whereas the replacement of labelled by unlabelled drug prevents a fast release maintaining a high level of cell-associated mlBG, The clinical r e l e v a n c y of the data gives rise to the following considerations: Therapeutical application of mlBG to patients in phases of chemotherapeutic t r e a t m e n t may reduce the level of radioactivity taken up; the exposure time obviously can be prolonged .if high levels of extracellu!ar miBG are kept up, Zentrum dsr Kinderheilkunde, 6000 Frankfurt 70

Universit~tskiinik,

The intratumoral application (direct targeting) of large liposomes (x = 500 nm) having specific lipid composition results in a defined local depot effect with a slow drug release. In the case of MTX, results with animals show a significant reduction in tumor growth and very low blood levels. Such a depot effect would also be desireable with TNF, although there are still problemes of encapsulation. The i.v. application of large liposomes leads to a rapid clearance and accumulation at the macrophages of RES (passiv targeting[. Encapsulated immunostimulatlng agencies such as MDP-derivatives and ~ - I F N cause an increased activation of macrophages and probably allow the therapy of the micrometastases. Essential factors are the lipid composition and the localisation of the~IFN molecules within or on the liposomes. Sm~ll cytostatics- or TNFcontaining liposomes (x = i00 nm) wlth c o v a l e n t l y bonded antibodies on their surface allow an active targetinng. A therapy of livermicrometastases could be possible after i.v. a p p l i c a t i o n if the rates of the interaction with cupffercells and cancer-cells could be influenced by the properties of the MAB-liposomes. Applied s.c., such liposomes cumulate w i t h i n lymphnodes and allow therapy of relevant metastases. Important factors are the properties of the llposomes and the stability of the covalent linkage in biological fluids. Institut f~r Pharmazeutische Technologie und Biopharmazie, Universit~t Heidelberg, Im Neuenhelmet Feld 366, 6900 H e i d e l b e r g

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REGIONAL HEMIBODY CHEMOTHERAPY FOR METASTATIC MELANOMA H.Voigt. K.R. Aigner, K~H. Link, H. Walther, H. Mdller Results of isolated limb perfusion for metastatic melanoma suggest distinct dose-response correlations with tumoricidal properties of several antineoplastic agents. These experiences prompted the idea to pilot the effects of a high-dose chemotherapeutic regimen confined to one regional compartment for targeted tumor therapy. Practically, this goal appeared to be achievable by expanding the perfused area and simultaneously detoxifying systemic drug levels of the non-perfueed compartment. Methods: For this approach the abdominal aorta and v.cava are catheterized above the pelvic bifurcation and connected with an extracorporal circuit including a venous hemofilter for drug filtration (Lower Hemibody Chemotherapy). For chemotherapy of the upper hemibody compartment another catheter is placed into the aorta with its tip within the aortic arc. Interventional chemotherapy was completed at 6 w by cross-over exchange of the perfused compartments. Drug regimen was: Mitomycin C 40 MG/L-PAM 100 MG (37.5~C - 39.5~C) at flow rates 150 - 200 mi/min for 1 h. Results: Out of 10 hemibody perfusions performed so far, 3 pts. (F=2,M=I; median age 41 y) had had heavily pretreated disseminated melanoma refractory to any other treatment modality, but having an expected life span of at least 6 m. Main sites of metastases were skin, soft-tissue, lymph nodes, and lungs. At 3 w in all cases P.R. could be assessed revealing impressive tumor regreseions within the perfused comparO~ent lasting for a median duration of 8 w. In this pilot series toxicity was moderate due to soft-tissue leakage and subsequent myelosuppression being reversible without interventional care. In all cases improvement of performance status could be obtained indicating promising palliative properties in widely spread disease stages. melanoma research project H. Voigt D-2358 Ka!tenkirchen, Postbox D~8223 Trostberg, Dept. Surgical Oncologg FRG

GROWTH DYNAMICS OF MALIGNANT MELANOMA E Paul,

KD Sch6tterl,

A Henkelmann,

RH B6deker

Photooatamnestic studies have shown that the development of m a l i g n a n t m e l a n o m a s may last for m a n y years. However, since determination of t h e t i m e of g r o w t h of l u n g m e t a s t a s e s from malignant melanoma had shown tumor doubling t i m e s t h a t v a r i e d b e t w e e n 9 a n d 298 days, it was d o u b t e d w h e t h e r p h o t o c a t a m n e s t i c a l l y d o c u mented protracted tumor growth was representat i v e for all m e l a n o m a s . Therefore, the m e a n a g e s w e r e d e t e r m i n e d in a major g r o u p of p a t i e n t s w i t h t u m o r s of equal levels a n d t h i c k n e s s to f i n d o u t t h e periods in w h i c h i n i t i a l , thin, low-level melanomas d e v e l o p to a d v a n c e d t u m o r s of g r e a t thicknesses a n d h i g h levels. It was s h o w n t h a t the p e r i o d s were similar w i t h r e g a r d to b o t h l e v e l a n d t u m o r thickness a n d t h a t the m e a n p e r i o d s of t i m e development from i n i t i a l i n v a s i v e to a d v a n c e d S S M or NM w e r e a b o u t I0 y e a r s . E x t e n s i o n i n t o t h e d e r m i s seems to o c c u r in a r e g u l a r manner, for it takes 2-3 y e a r s for the m e l a n o m a s to proceed f r o m one l e v e l or t u m o r t h i c k n e s s o a t e g o r y to t h e n e x t one. It w a s t h e r e f o r e c o n c l u d e d t h a t p h o t o c a t a m n e s tically documented findings are quite representative and that melanomas generally develop over many years, so that early detection s h o u l d b e p o s s i b l e in a n y case. Zentrum fur Dermatologie und Andrologie Hautklinik - der Justus-Liebig-Universit~t Giessen, D-6300 Giessen, FR-Germany.

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HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS BONE MARROW SUPPORT tN A D V A N C E D M A L I G N A N T M E L A NOMA. R. Seitz, H. K6ppler, K . - H . PflQger, and K. Havemann

C H R O M O S O M E I N S T A B I L I T Y IN P A T I E N T S W I T H CUTANEOUS MALIGNANT MELANOMA M.Roser ~ , M~ I , A.Boehm I , M.Oldig i , U.Schmidt-Preuss ~ , A.Rahman 2 , E.Breitbart 3 , H. W . R G d i g e r *

Eight patients with advanced malignant melanoma were treated with high dose chemotherapy: melphalan 80 mg/m z and BCNU 800 mg/m 2 i.v. In all patients auto!ogous bone marrow preservation was performed prior to therapy. Bone marrow was stored for 48 h in a refrigerator at 10~ and reinfused 48 h post therapy. Three patients had a complete response (OR), one a partial response and 4 patients no response. Two patients with CR died 4 and 5 months post therapy. One had a i n t e r s t i t i a l pneumonitis and one patient died from unknown cause. The third patient is in unmainrained CR 11 months post therapy. Major side effects were severe nausea/vomiting and mild mucositis. All patients had a complete hematologic recovery with normal leukocytes after 3 weeks. Two patients had prolonged thrombocytopenia (4 and 6 weeks). No treatment related death was seen. High dose chemotherapy with autologeus bone marrow support may be useful in advanced malignant melanoma. Zentrum for tnnere Medizin, A b t . H~matologie/Onkologie/lmmunologie, Philipps-Universit~t, Baldinger Stra6e, D-3550 Marburg

C h r o m o s o m e i n s t a b i l i t y is o b s e r v e d in s e v e r a l i n h e r i t e d s y n d r o m e s as B l o o m s y n d r o m e , F a n c o n i anemia, Cockayne syndrome, Xeroderma pigmentos u m and A t a x i a t e l a n g i e c t a s i a , p a t i e n t s of w h i c h h a v e in c o m m o n an i n c r e a s e d c a n c e r i n c i d e n c e . H e r e w e r e p o r t an e n h a n c e d s p o n t a n e o u s and uv-induced chromosome instability which was a s s e s s e d b y d e t e r m i n a t i o n of m i c r o n u c l e i (MN) in c u l t u r e d f i b r o b l a s t s f r o m 28 p a t i e n t s with sporadic cutaneous malignant melanoma ( C M M ) and 16 p a t i e n t s w i t h f a m i l i a l CMM. 44 h e a l t h y p r o b a n d s and 77 p a t i e n t s w i t h l u n g c a n c e r s e r v e d as c o n t r o l s . 500 c e l l s w e r e e v a l u a t e d p e r i n d i v i d u a l test. S p o n t a n e o u s M N p e r 500 c e l l s w e r e 4.0 in c o n t r o l s , 8.4 in s p o r a d i c c a s e s w i t h CMM, 1 7 . 4 in f a m i l i a l C M M a n d 4.5 in l u n g c a n c e r p a t i e n t s . We c o n c l u d e that a l a r g e p r o p o r t i o n of C M M p a t i e n t s , in p a r t i c u l a r f a m i l i a l c a s e s m i g h t be g e n e t i c a l l y c a n c e r p r o n e in c o n n e c t i o n with chromosome instability. A r b e i t s g r u p p e T o x i k o g e n e t i k , O r d i n a r i a t f~r A r b e i t s m e d i z i n I , A b t e i l u n g f~r B l u t g e r i n n u n g s st6rungen der Chirurgischen Klinik ~ , Hautk l i n i k s der U n i v e r s i t ~ t H a m b u r g , A d o l p h S c h S n f e l d e r s t r a ~ e 5, 2 0 0 0 H a m b u r g 76

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SLOCKROTATION - A METHOD OF IRRADiAtING HEAD AND NECK CANCER Technique and preliminary el[nice} experience Z. Lapukin% K. Mi]ller-Sievers: B, Kober

DECREASE IN SIZE AND DYSFUNCTION OF THE THYROID FOLLOWING MANTLE RADIOTHERAPY FOR HODGKIN'S DISEASE

Since Sept. 86 we are using a new technique in irradiating head and neck cancer - the blockrotaUon. This technique can be apptied~ if the patient can be so positioned, that his cervical mye[an becomes straight over the whole length of the radlation field, This is achieved by means of a from us developed device,which allows far an axaet posiLioning of the sheulder-gurtle combined with a Palyfo~m-headcast. The method of adjusting the eervica{ column, radiation planning, optimization of isodose distribution through variation of field width, bbck width and possibiy addition of a do,sat fixed fletd will be described. During irradiation the axis of rotation is put into the middle of the myeLon and is then constantly blocked out, which means, that a homogeneous dose of 5Q Gy (80 %-Isedase) can be delivered to the ~erget volume, whereas the maximal dose to the ce~'vlcal medulla is ~imited to 25 Gy. As of August 31~ 1987~ 2t patients- 42~8 ~ of those referred for radiation of the head and neck region - could be positioned in this way. An analysis of acute radiation reactions of mueosa] tissues and skin shows a t'eductton of toxicity compared to own patients previously irradiated with common technique. At fa~|ow-up median observation time 7 months - we noticed two cases of radiogenic hypothyreosis~ requiring horman substitution. We interpret this as a bio]ogica| sign, confirming dosis homogeneity throughout the neck region. Further~ lymphedema of the facial and arytenoid region was commonly seen~ reducing spontanously during the observation time. Radiation fibrosis of skin was not seen~ teducing the risque of wound healing complications at later operation. To time we have seen no radiogenic myelopathy, t7/21 patients had an evaloable tumotparameter at onset of radiation. 14 of these were treated concomitantly with cis-DDP-radiosensitization. 9/17 (52,9%) reached a complete remission, 8/17 (47,t ~) a partial remlssian. No response or disease progression we['e oct seen. 4 patients (25,5 %) died intercurrently wiU~ partial remission, one patient developed a T~-recurrence locally after 8 months. The other patients are s~:ill in remission. ~ patients were treated postoperatively~ None of those has

recurred. We will present the results of an up-date evaluation as of February, 29, 1988.

Chr. Kr6nke, Chr. Reiners, St. M~ller, W. Sauerwein 47 patients were treated for Hodgkin's disease by mantle radiotherapy receiving a mean dose of 35,8 Gy ( 22 to 44 Gy ) in the thyroid. At the time of therapy the patients aged 16 to 60 years, average 31 years, wherby 16 patients were younger than 31 years. Nobody had a thyroid disease. 0,6 to 14 years after radiotherapy we ex~minded the thyroids by echography and hormone determinations. The echography was performed with a real-time-Toshibaultrasonoscope using a 5 MHz transducer. According to Brunn et. el. we evaluated the volume. There was a negative correlation (r=-0,603) between time after radiotherapy and thyroid volume amounted to 4,6 g ( 2~7 to 7~9 g), 10 of 12 patients had a volume smaller than the average of a healthy control population. Simultaneously there was a negative correlation between thyroid volume and basal TSH ( r=-0,605; p= 0,002) as well as with stimulated TSH (by 200 ~g Protirelin i.v.; r=-0,587; p= 0~0011). One patient showed overt hypothyroidism while 7 additional cases showed overstimulation with elevated TSN after Protirelin as a sig~ of latent hypothyroidism. We conclude that decrease in thyroid size and (latent) hypothyroidism may be late effect not unco~aon after radiotherapy of 36 Gy. Abteilung f ~ Nuklearmedizin, Universit~t -Gesamthochschule- Essen, Hufelsndstr. 55, D-4300 Essen

Z.Lapuk~cs, 5trahlenLherapie, St~idt.Kl~niken, Grafeastr. 9, 6100 Darmstadt, BRD

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BIOANALYTICAL INVESTIGATIONS ON EXPERIMENTAL NEUTRON CAPTURE THERAPY WITH COLD NEUTRONS IN JOLICH W. Porschen, A. Kollmar and L.E, Feinendegen

ADVANTAGES AND L I M I T A T I O N S OF RADIOTHERAPY I N THE TREATMENT OF MULTIPLE MYELOMA

Neutron Capture Therapy (N.C.T.) with thermal Neutrons and suitable Bl0-Compounds permits the successful treatment of brain tumors via the reaction BIO (n, u) Li7. During the past the effects of new organic boron lOamino acid analogs were analysed by irradiation of solid tumors (EO771), transplanted on the hind leg of mice (C57 BI/6j), at the reactor Merlin in J~lich (Porschen e t a l . , Hadiat. Environ. Biophy. (1987) 26, 209-218). Now, the new external neutron laboratory ELLA at the reactor Dido (23 MW) with a cold Source (20 k) and Ni 5acoated neutron guide tubes goes into operation and a universal irradiation facility (EKN) may be used also for biological and bioanalytical experiments. The measurement of neutron flux density (7 x 107 - 2 x i0" n/cm z sec) and gan~a dosimetry demonstrated the high quality of this cold neutron beam (E~O.005 eV). This facility was used for the analysis of boron I0 in tumor slices and in blood of mice after the injection of boron I0 Hatanaka-SS compound (Na4 H22 laBs4 SS; Callery, P.A. 16024) using the solid state detector Kodak-Path~ LR-II5 (6~m, Kodak 505.5066). The beam of Cold Neutrons with very low background of fast Neutrons in the new LabOratory ELLA is a powerful instrument for Boron lO-Detection and pictorial representation of Bl0-distribution. Nuclear Research Center J~lich, P.O. Box 19 13 D-5170 JQlich, F.R.-Germany

I.A.

Adamietz,

C. S c h 6 b e r ,

R. S c h u l t e ,

D.

Unverferth,

D~ Peest, Kh. Renner We reviewed 70 cases of multiple myeloma treated with chemotherapy end additional radiotherapy. Following indications for irradiation were found: pain(55%), bone lesion(36%), neurological symptoms or extramedullary manifestation(6%), fractures(l%). A total of 238 radiation sites were analysed. Criteria for local remission were pain relief and/or x-ray. In patients treated primarily with chemotherapy end irradiation (n=23) the response rate was 87% with complete or partial remission for 31.8 (12-51) months. In all cases of raditherapy started at secondary progression or later (n=47) the response rate was only 37% with CR+PR for 24~ (1-51) months. The local control of repeatedly irradiated sites was achieved by the first treatment in 96%, after the second one in 57% and in none of cases after the third one. Total dose > 35 Gy prolonged significantly the remission period. The remission was 17.7 (1-45) months by progression in the irradiated area and 14.7 (1-51) months by relapse beyond the treated site. Local remission of multiple myeloma can be improved by early started combined therapy procedure. The total radiation dose should be > 35 Gy. Repeated irradiations of the same sites with lower doses give worse results.

Zentrum Radiologie IV Strahleotherapie und spezielle Onkologie, Medizinische Hochschule Hannover, KonstantyGutschow-Str. 8, D-3000 Hannover 61

$5

1/P-GM 005 Abstract Frankfurt

for

1/P-GM 007 den

am M a i n ,

19.

Deutsehen

28.

Feb.

his

KrebskongreB, 5.

M~rz

1988

C A R C I N O M A O F THE S T O M A C H F O L L O W I N G I R R A D I A T I O N FOR M A L I G N A N T G A S T R I C L Y M P H O M A / N E U R O S A R C O M A P.K. Schfifer~, U. Loos a n d D. G e r h a r t z _ _ G a s t r i c a n a p l a s t i c c a r c i n o m a d e v e l o p e d in two p a t i e n t s f o l l o w i n g r a d i a t i o n t h e r a p y for lymphosarkoma and neurosarcoma, respectively. The f i r s t p a t i e n t , a 6 3 - y e a r - o l d man, u n d e r w e n t an e x p l o r a t o r y l a p a r a t o m y in 1967. I n f i l t r a t e s of a l y m p h o s a r e o m a w e r e f o u n d in the s t o m a c h w i t h l y m p h n o d e s in the o m e n t u m a n d a l o n g the aorta. No r e s e c t i o n was p e r f o r m e d , o n l y t i s s u e s p e c i m e n s w e r e t a k e n from the situs. P o s t o p e r a t i v e l y , the p a t i e n t w a s t r e a t e d b y r a d i o t h e r a p y to a d o s e of 60 G y to the u p p e r a b d o m e n . 6 1/2 y e a r s later he d e v e l o p e d an a n a p l a s t i c c a r c i n o m a of the s t o m a c h w h i c h was p a l l i a t i v e l y resected.

In the s e c o n d p a t i e n t , a 3 4 - y e a r - o l d female, a p a r t i a l g a s t r e c t o m y was p e r f o r m e d in 1965 d u e to a n e u r o s a r c o m a o f the stomach. A f t e r w a r d s , she r e c e i v e d a r a d i a t i o n t h e r a p y to a d o s e of 40 Gy. 14 years later she d e v e l o p e d an a n a p l a s t i c unr e s e c t a b l e g a s t r i c cancer. T h e s e c a s e r e p o r t s m i g h t be e x c e p t i o n a l , as g a s t r i c c a n c e r as s e c o n d a r y m a l i g n a n c y is a r a r e event. In our two p a t i e n t s the d i s e a s e s c a n b e r e l a t e d to the p r e c e d i n g i n t e n s i v e r a d i a t i o n t h e r a p y of the s a m e a n a t o m i c region. Thus, c a n c e r of the s t o m a c h m a y be a n o t h e r c o m plication of a "successful" aggressive managem e n t of m a l i g n a n t t u m o r a n d n e e d s s p e c i a l a f t e r care. Gastroenterologisehe Praxis and Medizinische Universit~tsklinik Bonn, M ~ n s t e r s t r a B e 18, D - 5 3 0 0 B o n n I

RADIOTHERAPY IN ESTHESIONEUROBLASTOHA - CASE~REPORT E. Eising, R. PStter, A. Nasz~ly, Th. Deitmer* Esthesioneuroblastoma, a rarely presented tumor, is according to few data from literature knol~n to be bast treated in small tumors with either surgery or radiotherapy and combined modality treatment in large tumors. The small number of case reports on the value of chemotherapy reveals some limited effectiveness. A case report stressing the effectiveness of definitive radiotherapy in a locally advanced tumor is put forward. A 65 year old man presented with an inoperable mass extending throughout most of the facial Part of the skull. Ten years before he had been treated for a parasellar, inooerable mass by definitive radiotherapy up to 60 Gy from two opposing temporal fields. He suffered from a vision loss on the right eye after surgical exploration, There was no evidence of disease until 1985, when tumor growth involving the nasal cavity, the paranasal sinuses, the left orbita and the skin resulted in epistaxis, nasal obstruction~ exephthalmus and vision reduction (left eye). A surgical procedure did not appear to be useful. Because of pretreatment by radiotherapy and vision lass a polychemotherapy (CYVADIC) was started and after two cycles a slight reduction of tumor mass was noticed. Six weeks later a massive regrowth uncured. The salvage radiotherapy led to a quick response and after treating up to 65 Gy in 7 weeks ~ith shrinking field technique (pretreatmant volume) a clinically complete remission was impressive. The old man died 9 months later with no ev~idence of disease. The treatment of choice for esthesisnauroblastoma is surgery and/or radiotherapy depending on tumor stage. In very advanced tumors the value of adjuvant chemotherapy has not been clearly established yet. Rad{ologische Klinik u. Klinik der Hals-, Nasen- und Ohrenheilkunde~ Albert-Schweitzsr-StraBa 33~ D-4400 MOnster

1/P-GM 006

1/P-GM 008

NEUTRONTHERAPIE FOR ADENOID CYSTIC CARCINOMA -INOPERABLE TUMORS, RESIDUAL TUMORS, RECURRENCES-

High C o n t r a s t Images for V e r i f i c a t i o n and D o c u m e n t a t i o n of T r e a t m e n t Fields During Teletherapy H.L. Kronholz~ J. SchOtz~ H.D. BSttchar

R. POtter, A. Nasz~ly, R. Hemprieh , W. HSver U. Haverkamp.

Before the irradiation procedure begins~ it is necessary to check the field position ~ith respect to the proposed patient irradiation region. For this purpose, field definition images are obtained and compared with images obtained during simulation. Any necessary corrections can than be performed. The field definition image is obtained using a double exposure technique. To be of use, the image quality obtained must approach that of diagnostic x-ray image quality. However, a diagnostic type film with a fluorescent screen cannot be used because of the high energy of the incident photons. Instead a diagnostic type Film with a metal screen is employed. In the metal screen photons are converted into electrons.The back plate of the screen serves to back-scatter electrons, ~hich have passed through the film back into the film. The screen may be of either copper or steel although steel has the advantage of being more robust.A lead screen however, is unsuitable as it interacts strongly with low-energy photons, which have been scattered in the patient, rather than with the non-scattered high-energy photons, producing low contrast images. In our experience, production of a field verification image leads to an improved reproduceability and a clearer definition of the irradiation field. In addition, the production of these special images on a routine basis, has motivated our technical personel to become more actively involved in the treatment process. For the purpose of documenting the final treatment field posit/on, a different less sensitive film using the same metal screen is positioned under the patient during the whole of the irradiation process.

,

9 patients were treated ~ith fast neutron therapy (DT, 14 MeV) in this institute for adenoid cystic carcinomas of typical localisations (parohis, paranasal sinus, orbita, external auditory canal). Complete or expressed partial local control was obtained in 7 of these patients. Treatment planning based on CT and MR is demonstrated ans aspects of indication and dosage are discussed in this paper. Fast neutron therapy is indicated for this histology and pattern of spread because of high local recurrence rate for phobone-telebherapy. Department of Radiology, Umiversity Clinics M~nster, Albert-Sch~eitzer-Str. 33, 4400 N~nster, FRG * Clinic of Oral Surgery, University Clinics MOnster~ ** Institute of Nuclear Medicine, DKFZ Heidelberg.

Klinik und Poliklinik for Strahlentherapie-Radioonkologie Albert-Schweitzer-StraBe 33, D-4400 MOnster

$6 1/P-GM 009

1/P-GM 011

DEFINITION OF REPAIR AND ISOEFFECTIVE DOSAGE FOR HYPERFRACTIONED RADIOTHERAPY ACCORDING TO THE ALPHA/BETA MODEL FOR A SQUAMOUS CARCINORA OF THE HEAD-AND-NECK REGION ~. ~agner, ~. G~hde, H.D. B ~ t t c h e r

POSTOPERATIVE

[he squamoua carcinoma line Os ~as transplanted to nude mice and established in 15 passages. This uss a primary floor of the mouth carcinoma unpretreated at the date of transplantation. Isoeffective dosage uas determined according to ~ithers alpha/beta model for single treatment and hyperfractinotion. Values uere first determined experimentally, and then calculated. Therefore the gro#th delay assay :~as used. Single doses and isoeffective hyperfractionation (3 therapies/day) ~as ascertained ~hich gave the best fit . Resting upon these dates other especially smalier values uieh are clinically interesting, ~ere calculated. Then some calculated dates ~ere exa:~ined experimentally again to confirm the accuracy of the linear-quadratic model for the squamous cell carcinoma Os. Radiotherapy ~as performend without clamps under anesthesia ~ith a telecobalt instrument. The influence of reoxygenation is thus included in the determination of repair effects.

RADIOTHERAPY OF SALIVARY GLAND TUMORS

G. Scardilll, V. Budach, T. Polyzoides, H.J. Feldmann H. Sack .

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From 1972 to 1987, 47 malignant salivary gland tumors were treated in the department of radiotherapy at Essen University. 25 male and 22 female patients with a median age of 66 (14 to 84) years were treated for stage I-II (15) and stage III-IV (32) tumors. The distribution according to the histologies included 19 undifferentiated carcinomas, 9 squamous cell-, 9 adenoid cystic-, 2 adeno-, 3 mucoepidermoid-, I aeinic cell carcinomas and 4 malignant mixed cell tumors. All patients were irradiated postoperatively using 60-Co, 137-Cs or electrons of adequate energies. As basic techniques ipsilateral portals, a wedge pair of portals or, if extension to the midline occurs, parallel opposed fields were used. The target-doses were 50-65Gy and 40-50Gy for the lymphatic drainage with fractions of 3-5 x 2-3.0 Gy weekly, depending on the postoperative status and tumor stage. Of 47 patients, 30 are alive and 17 are dead. The 4year relapse free survival was 85% for stage I-II and 30% for stage III-IV patients, respectively. The corresponding 5- and lO-year survival rates were 94.5% vs. 35% and 75% vs. 22.5%, respectively. The median survival time was II years for stage I-II and 5 years for stage III-IV patients after radiation therapy. These data compare well to the published results from the literature (I) i. Cancer of the Salivary Glands. in: Radiation Oncology, Principle and Practise ed. C.A. Perez, L.W. Brady, J.B. Lippincott Co. 1987, pp. 513-526.

Department of Radiology, University Clinics MQnster A/bert-Sch~eitzer-StraBe 35, 4400 MOnster, FRG

Dept. for Radiation Oncology, Hufelandstr. 55, D-4300 Essen-I

University of Essen,

I/P-GM 010

1/P-GM 012

THE RADIOSENSITIVITY OF OSIEOSARCOMAS ON NUDE MICE. A COMPARATIVE STUDY OF TREATMENT WITH FAST NEUTRONS

RADIOTHERAPY FOR SQUAMOUS CELL CARCINOMAS OF THE OROPHARYMX

AND 60C0. H.D. B~ttcher, W. Wagner, W. G~hde, A. H~rle

W. Budaoh, V. Badach, W. Sauerwein

M. Balla, S. Dinges,

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The osteosarcoma cell line Ha was transplanted to nude mice; radiotherapy was applied in the 4th passage. The tumor had been defined histological]y as a paresteal osteosarcoma. The treatment was given ~ith single irradiations as varying dosage. 6O While Co therapy foiled to produce adequate therapeutic effect, neutron therapy resulted in dose-dependent growth delay. Then RBE values for neutron therapy were calculated for single doses using the regro~th delay assay. RBE values for osteosareomas Ma ~ere compared with those for squamous carcinoma. These dates contradict the opinion of many authors about the complete radioresistance of osteosareomas.

From 1977 - 1987, 69 patients with squamous cell carcinoma of the oropharyngeal region were treated in the department of radiotherapy at Essen University. The median age of 49 male end 20 female patients was 58 (43-86) years. According to the UICC-classification, iO patients were attributed to stages I and II, 30 patients to stage III and 29 to stage IV. Postoperative or primary irradiation was used in 53 and 16 cases respectively. Treatment volume included the primary and regional lymph nodes using parallel opposed portals of 60 Co or 5,7 MeV photons. The total doses to the primary was 66 - 70 Gy and 50 Gy for the lymphatic drainage without surgery. Postoperatively 50 - 60 Gy were administered depending on the extension of surgery. The fractionation schedule was 4-5x 2-2.5 Gy weekly. The median interval to recurrence was )102 me for stage l-II, 52 me for stage III and 12 me for stage IV patients. The 5-year survival rats (Eap!an + Meier) was 90% for stages l-II, 48 % for stage III and 20% for stage IV. Dept. for Radiation Oncology, University of Esaen Hufelandstr. 55, D-4300 Essen 1

Department of Radiology, University Clinics MOnster, Albert-Sch#eitzer-StroOe 33, 4400 MUnster, FRG

$7

I/P-GM 013

1/P-GM 015

PATTERN OF INTRINSIC RADIORESISTANCE FOR HUMAN XENOGRAFTED SOFT TISSUE SARCOMAS V. Budach, M. Stuschke, W. Budach, M. BamSerg, H.Sack ........................................................

HAS C l S P L A T I N A R A D I O S E N S I T I Z I N G EFFEKT? M. B a d e n h e u e r , M. M o i l s , M. B a n ) b e r g , W,U. ler, N. Z a m b o g l o u

From 1984 to 1987, 37 human soft tissue sarcomas (STS) were successfully xenografted into nude athymic mice. Grading 2 and 3 tumors preferentially grew in this model (36/37 biopsies). All tumors were characterized by a panel of investigations to determine speciesand tumor- identity during continuous passage in mice. By gel-electrophoresis, 6 of 8 STS xenografts showed a human lactic-dehydrogenase isozyme pattern and glucose-6-phosphate-dehydrogenase band. Four of these tumors were karyotyped and displayed a human chromosomal pattern. 4 sarcomas each were euploid and aneuploid. The volume doubling times (VDT) ranged from 2.9 to 16.0 days and they were neither correlated to the histopathological grading nor to the DNA-index of the tumors. Xenografts in passages 3 to 28 at groups of I0 to 12 animals were used for each of the four 60-Co single dose and two 5.8 MeV neutron dose levels. Acute hypoxemia was induced by clamping the tumorhed. Endpoint of the radiation experiments was the specific growth delay as this allows a better comparison of of different proliferating tumors. In terms of VDT', the range was 0.25 and 0.35 for 2 "resistant" when compared to 3.35 and 3.80 for 2 "sensitive STS at a dose level of 20Gy hypoxic. For neutrons, a range of 1.3 to 4.5 VDT's was observed. Surprisingly, radioresistance was accompanied by a loss of the LDH 1-2 isozymes for 3 tumors. These data reflect a considerable range of intrinsic radioresponsiveness for human STS and point to the need of pretherapeutic radiobiological data resulting in more individualised treatment policies. Intrinsic radioresistance seems to be one factor contributing to a lower tumor control probability in exceeding the limits of normal tissue tolerance. Dept. for Radiation Oncology, University of Essen, Hufelandstr. 55, D-4300 Essen 1

CHROMOSOME

ABERRATIONS

IN BONE M A R R O W CELLS 9 HOl-

AS DNA is the target for radiation and 9or cisplatin one Can speculate that the combination o{ both agents increases c h r o m o s o m a l damage. which ginally leads t o an i n c r e a s e o{ cell

death.

We h a v e

studied

the

?requency

og

chromosome a b e r r a t i o n s (breaks, rings, dicentrics, gaps) in bone m a r r o w cells of mice. I n the c o m b i n a t i o n e x p e r i m e n t s (cisplatin dose: 9 mg/kg,

radiation

9rom

dose

• 0.25,

at 1,

Chromatid

&, 2,

or

3, 3,

breaks

9requency o9 when cisplatin

re

dose:

e99ect curves)

I hour

1.5

Gy;

doses

taken

cisplatin was given

2 , 1, 0 . 2 5 h o u r s be{ore, and 4, 5 hours agter irradiation.

numerically

dominated.

aberrations was was applicated at

agter irradiation.

]'he

supraadditive 2 hours bego-

Ne o b t a i n e d

59Z a n d 58Z a b e r r a n t metaphases versus a calculated level of a d d i t i v i t y 09 48Z. The value at 2 hours begore i r r a d i a t i o n w a s s i g n i { i c a n t

with p< 0.05. Thus the r a d i o s e n s i t i z i n g e99ect o? cisplatin only seen within a very narrow time interval was rather weak. We conclude that it is q u e s t i o n a b l e w h e t h e r in clinical situations the combination 09 cisplatin and radiation leads to a s u p r a a d d i t i v e amount os chromosom~l damage and cell death either in normal tissues or in tumors. Radiologisches 2entrum, g n i v e r s i t ~ t s k l i n i k u m , D-4300

Essen

1/P-GM014

1/P-GM016

RADIOCHEMOTHERAPY IN A D V A N C E D HEAD ~& NECK C3hNCER: CONTINUOUS INFUSIONAL CISPLATIN AND O N C E O R T W I C E D A I L Y IRRADIATION. J.Karstens, H. Malt, G. Schl~ndorff, J. A m m o n

IS 1 3 1 - I - M E T A I O D O B E N Z Y L G U A N E D I N E TREATMENT AN ADEQUATE THERAPY FOR CHILDHOOD NEUROBLASTOMA ? D. S c h w a b e , F.D. M a u l a n d B. K o r n h u b e r

C i s p l a t i n (cP) has a p p a r e n t r a d i a t i o n e n h a n c e m e n t c h a r a c t e r i s t i c s . W e a d m i n i s t e r e d cP a s continuous infusion (ci) b e c a u s e optimal timing of cP and radiotherapy (RT) is n o t k n o w n and cP as ci results in p r o l o n g e d p l a s m a l e v e l s of u n b o u n d active cP. In a f i r s t p r o t o c o l 20 p t s w i t h a d v a n c e d h e a d & n e c k c a n c e r entered a feasibility study using once daily R T a n d t h r e e c y c l e s cP (15-20 m g / q m / 2 4 hrs d u r i n g 1 2 0 h r s ; w e e k 1,4,7). 17 p t s c o m p l e t e d this regimen and are evaluable for toxicity and response. Toxicity is a c c e p t a b l e . CR o c c u r e d in 12 and PR in 4 pts. If e a r l y t u m o r regrowth within the first 3 months is e x c l u d e d , C R w a s o b s e r v e d in i0 p t s ; 8 p t s remained free of locoregional relapse wfth a m e d i a n d u r a t i o n of 2 7 * ( 4 - 4 5 + ) m o n t h s . In a second protocol pts were treated with twice d a i l y R T (C.C.Wang et al.,Cancer 55:2100,1985) a n d cP as c i in w e e k 1,4. P r e l i m i n a r y e x p e r i e n c e in 7 p t s is e n c o u r a g i n g . C o n c l u s i o n s : c P as c i a n d o n c e o r t w i c e d a i l y R T is f e a s i b l e in p t s w i t h a d v a n c e d head and n e c k c a n cer; r e m i s s i o n rates as w e l l as l o c a l c o n t r o l rates may be enhanced when combining RT and cP.

M e t a i o d o b e n z y l g u a n e d i n e (MIBG) t h e r a p y m a k e s use of the s p e c i f i c a c c u m u l a t i o n of the r a d i o p h a r m a c o n b y n e u r o b l a s t o m a tissues. S i n c e 1984 we t r e a t e d 15 c h i l d r e n w i t h MIBG. T h e y e i t h e r experienced relapse after conventional therapy or were refractory. One p a t i e n t was t r e a t e d p r i o r to any o t h e r therapy. The initial d i a g n o s i s was NB s t a g e IV in ten p a t i e n t s and NB stage III in five patients. C a t e c h o l a m i n e s w e r e e l e v a t e d in 13 cases. M I B G w i t h a s p e c i fic a c t i v i t y of 30 m C i / m g or h i g h e r was used. 48 to 417 mCi per course of t h e r a p y w e r e given. The c u m u l a t i v e a c t i v i t y v a r i e d f r o m I00 to 926 mCi w h i c h was d e l i v e r e d in one to six courses. 13 of the 15 p a t i e n t s h a d an u p t a k e in their tumor lesions. The tumor doses w e r e c a l c u l a t e d to r a n g e from 23 to 253 G y c u m u l a tively. C l i n i c a l r e s p o n s e s h o w e d a m i x e d p a t tern. T w i c e a CR of stage IV was achieved. PR was seen in s e v e n patients. Two of them are n o w in CCR a f t e r a d d i t i o n a l t h e r a p y for 25 a n d 28 m o n t h s after MIBG. One SD and four N R w e r e seen. It can be s e e n that M I B G is a h i g h l y e f f i c i e n t agent in a d e q u a t e l y s e l e c t e d cases but it will not cure any p a t i e n t f r o m d i s s e m i n a t e d NB if not a d d i t i o n a l t h e r a p y is p r o v i ded. Dept. of P e d i a t r i c H a e m a t o l o g y a n d Oncology, Johann Wolfgang Goethe Universit~t, Theodor Stern Kai 7, D 6000 F r a n k f u r t 71, G e r m a n y

Abt. S t r a h l e n t h e r a 2 i e u n d Abt. H a l s - , N a s e n - , Ohrenheilkunde und plastische Kopf- und Halschirurgie, Mad. F a k u l t [ t , K l i n i k u m R W T H Aachen, D-51 A a c h e n , Pauwelsstr.

$8 1/P-GM017

1/P-GM 019

RESULTS AND SIDE EFFECTS OF COMBINED MODALITY TREATMENT: A PROPOSAL OF A DATA BASE H. Sack, W. S a u e r w e i n , H,G. S c h m i t t , R. H e r r -

TUMORRESPONSE-ADAPTEDSEQUENTIAL CHEMOTHERAPYOF SMALL CELL LUNGC~NCER. A RANDOMIZEDSTUDY .'2 R. Zschaber-,iF. Thies , U. Gatzemeler , G. Koschel3, D.K. Hossfeld-

mann

With the help of the Bundespostministerium a "fact" data base with information concerning combinations chemotherapy and r a d i a t i o n therapy i s d e m o n s t r a t e d , Without special knowledge, information c a n be o b t a i n e d u s i n g BTX and n o r mal German language ("computer-friendly"). The d a t e is s t o r e d on a c o m p u t e r of the U n i v e r s i t y Clinic E s s e n (IBM &341). The d i f f e r e n t " d o c u ments" (each d o c u m e n t is o n e c a s e , o n e e v e n t ) are c o l l e c t e d by the c o o p e r s t i o n of m a n y collegues. The goal of the u t i l i z a t i o n o f this modern communication and i n f o r m a t i o n s y s t e m is to p r o v i d e b e t t e r s e c u r i t y of t h e r a p y for the cancer patient. Once the s u c c e s s of s u c h a system is established, t h e n a p e r p e t u a l and continually up-dated s y s t e m s h o u l d be e s t a b lished. The primary c o s t o~ t h i s s y s t e m is the collection and c o r r e c t i o n of the d a t a , using p e o p l e of m a n y m e d i c a l d i s c i p l i n e s , and not the development of the c o m p u t e r system. This system should be operable within one

year. Universit~ts-Strahlenklinik,

D-4300

Between Jan, 1984 and Dec. 1985 151 p a t i e n t s with ~CLC were randomized t o r e c e i v e 2 e i t h e r c i s p l a t i n (80 mg/m-, d 1) + etoposide (170 ~g/m i . v . , d 1 - 3) [ A ] or cyclop~osphamide (1000 mg/m i . v . , d I) + etaposide (170 mg/ m i . v . , d 1 - 3) q. 3 weeks. 70 patients had limited, 81 patients had extensive disease. Complete responders received irradiation to the primary tumor site (45 Gy) and prophylactic brain irradiation (30 Gy). Poor responders (< partial remission progressive disease) to 2 initial Cycles or later failures wer~ crossed over. Salvage regime~ consisted of ADM, 60 mg/m i.v. + Eldisine 3 mg/m i.v.q. 3 weeks. A total of 30 CR (= 19,8 %) and 73 PR (= 48.3 %) were seen lasting 14.06 + m. and 5.58 + m, respectively. CR, PR and non-responders survive 19,99 + m., 10.89 + m,, 9.43 + m,, respectively. We found that A and B are equally effective in inducing CR and PR in both limited and extensive disease, the survival time of ED-petients being significantly better after A. The number of CR is disappointingly low. The possiblereasons for this are discussed.

1Abteilung Onkologie und H~matologie, Universit~tskrenkenhaus Eppendorf, Martinistr. 52, D-20OO Hamburg 20

Essen

2pneumologisch-Onkologische Abteilung, Krsnkenhaus Gro6hansdorf, W0hrendamm 80, D-2070 GroBhsnsdorf 3Lungenabteitung, Allgemeines Krankenhaus Harburg, EiBendorfer Pferdeweg 52, D-2180 Hamburg 90

1/P-GMOl8

I/P-GM 020

COMBINATION RADIATION THERAPY (RT) AND CHEMO-

PHASE-II-STUDY WITH ETOPOSIDE (E) / VINCRISTrNE (V) IN EXTENSIVE DISEASE SMALL CELL LUNG CANCER (SCLC). D.Valle6, J.v.Pawel, M.Freund, H.-J.Schmoll and H.Wilke

THERAPY (CT): A S I M P L I F I E D COMPUTED COLLECTION OF SIDE EFFECTS AND RESULTS.

N. S a u e r w e i n ,

H, Sack,

E. E n g h o f e r ,

P. O r i n g s

In recent y e a r s , the i n d i c a t i o n s f o r combination t r e a t m e n t o f cancer w i t h combined CT and RT have i n c r e a s e d . E v e n if the c o l l e c t e d exp e r i e n c e of such t r e a t m e n t is p u b l i s h e d , t h e r e is a l o n g l a g - p e r i o d b e f o r e this i n f o r m a t i o n is s i r e n w i d e d i s s e m i n a t i o n . Unusual complicat i o n s and u n u s u a l l y g o o d r e s u l t s are f r e q u e n t ly not a p p r e c i a t e d . It is p o s s i b l e t h a t o v e r a long t i m e period, the s a m e m i s t a k e s are made. At a m e e t i n g of M e d i c a l and R a d i a t i o n O n c o l o -

gists

(Bad Homburg v . d . H . ,

June,

1987)

a con-

census was reached that a s y s t e m s h o u l d be established to solve this prob!em. Such a system s h o u l d be s i m p l e to use, b a s e d on simp l e s p o k e n v o c a b u l a r y , r a t h e r t h a n an e l e c t r o nic language, and open to all clinicians. Using s y s t e m s c u r r e n t l y a v a i l a b l e at the U n i versity of Essen. in cooperation with many collegues from other German-speaking areas, a solution for this problem is p r o p o s e d . An electronic data b a s e c a n be e s t a b l i s h e d on a main-frame c o m p u t e r (IBM 4341). This d a t a can

be

accessed

from all

o v e r Germany,

using

BTX.

Much d a t a w o u l d be a v a i l a b l e , i.e.: c o m p l i c a t i o n of CT or RT or the c o m b i n a t i o n t r e a t m e n t , results of such t r e a t m e n t , n e w s t u d i e s u n d e r way, etc. The s u c c e s s of this p r o j e c t r e q u i r e s the active i n p u t of m a n y c l i n i c i a n s . If t h i s proposed solution finds much interest, then for the f i r s t t i m e an a c c u r a t e a n d u p - t o - d a t e communication and i n f o r m a t i o n s y s t e m w o u l d be a v a i l a b l e for e a c h p r a c t i c i n g o n c o l o g i s t . Universit~ts-Strahlenklinik, O-4300 Essen

Etoposide and Vincristine are very active drugs in small cell lung cancer without overlapping organ t o x i c i t i e s . At present cytostatic treatment in extensive disease SCLC is done usually with p a l l i a t i v e intentions, especially in elderly patients. Therefore combinations without severe subjective side effects are needed. Etoposide/Vincristine might f u l f i l l these c r i t e r i a . Since 4/87 twenty-seven pts. with extensive disease SCLC have entered this ongoing t r i a l with E/V. D_.osageand s~edule: E 200mg/m2 i . v . d 1,2,3; V 2~. i . v . d I and 8; q d ~8 x 6. Vincristine was withdrawn in case of peripheral neurotoxicity WHO grade I. E l i q i b i l i t y c r i t e r i a : Histologically proven extensive dis. SCLC; measurable disease ; a g ~ 7 5 yrs.; Karnofsky PSv-~50%; no prior chemo-/radiotherapy; no severe comorbidities. Patient characteristics: male 21; female 6; age 65 yrs. (48-75); Karnofsky PS 75% (50-100). Results: 21 pts are evaluable for response (~2 courses); T t o ~ a r l y ; I lost to follow up; I early death. CR 5(24%); CR+PR 14(67%)~ NC 5; P 2. Remission duration and survival time too early. Toxicity(WH0 grade): 23 pts. are evaluable for toxicity(;~T-c-ourse); 3 t o o early; lear~ l y death. Leukocytes 2~ 3~ 4~ thrombocytes 2~ 3~ nausea/vomiting 2~ fever/infection 3~ peripheral neurotoxicity I~ 2~176 2~ reversible in all cases), I irreversible paresis of n. recurrens; stomatitis 2~ No treatment related letal t o x i c i t i e s occurred. Conclusions: Etoposide/Vincristine in this schedule can be ~nistered without severe subjective t o x i c i t i e s . Dose escalation of E might be done in pts. without severe myelotoxicity during the I. course. CR+PRrates with E/V seemtobeas good as objective response rates being achieved with 3-drug-regimens. Krankenhaus biekholzen, Am Bahnberg 5, 3201Diekholzen

SP

1/P-GM021

1/P-GM 023

PILOT STUDY WITH CARBOPLATIN(C)/ETOPOSIDE(E)/VINCRISTINE (V) IN EXTENSIVE DISEASE SMALL CELL LUNG CANCER (SCLC). J.Krause, H.Fabel, W.Achterrath, H.-J.Schmoll, H.Link, H. Poliwoda and H.Wilke

HIGH DOSE FOLINIC ACID (HDFA}/5-FLUOROURACIL(5-FU) AS SECOND LINE TREATMENT IN ETOPOSlDE/ADRIAMYCIN/CISPLATIN (s PRETREATEDPATIENTS WIIH ADVANCEDGASTRIC CANCER M. Stahl, Ch. SchSber, N.-J. Schmell, H. Poliwoda, P. Preusser and H. Wilke

A p i l o t study was carried out with Carboplatin/Etoposide/ Vincristine in pts. with extensive disease SCLC to determine the recommended dose f o r phase I I studies. In a d d i t i on, f i r s t data on antineoplastic a c t i v i t y were ascertained. Dosage and schedule: C 300mg/m~ i . v . d I; V 2mg i . v . d 1,8 were g i v e n - ~ - f ~ d o s e s ; E with a starting dose of 120 mg/m2 i . v . d 1,2,3. With t h i s dose 12 pts should be t r e a ted because of the dose l i m i t i n g myelotoxicity being reDom ted in other phase 11 studies using similar doses of C/E. I f no i n t o l e r a b l e t o x i c i t y occurred in 12 p t s . , f u r t h e r escalation of E (140mg/m2 and 160mg/mz d 1,2,3) was planned. Intolerable t o x i c i t y was defined as leukopenia WHO 4~ , thrombocytopenia 30 and nephrotoxicity 2~ . V was withdrawn in case of peripheral neuropathia I ~ 21 pts. have entered this t r i a l . 3 pts. are too early t o evaluate. 12 pts. were treated with E 120mg/m~ and 6 pts: with 140~/m ~ in combination with C/V. E was not escalated to 160mg/m2 because of 30% of leukopenia WHO 4~ with E 140 mg/m2, 18 pts. are evaluable for response and t o x i c i t y ~ I courses(2-6)). Other t o x i c i t i e s than myelosuppression: nausea/vomiting 2 ~ I~(45%), 2~ (22%)(reversible in a l l cases); alopezia 3~ No other t o x i c i t i e s occurred. A CR rate of 11% and an overall response rate of 72% was achieved. Conclusions: In t h i s regimen Etoposide in combination with ~ o p ~ - 3 O O m g / m 2 d I cannot be escalated to doses higher than 140mg/m2 d 1,2,3 without an increased r i s k of severe t o x i c i t y . Abt. Pulmonologie und H~matologie/Onkologie, Medizinische Hochschule Hannover, Konstanty-Gutschow-StraBe 8, 3000 Hannover 61

EAP has shown to be effective in gastric cancer. 5-FU is an active drug in gastric cancer and not cross-resistant to Etoposide, Adriamycin or Cisplatin. Therefore the efficacy of HDFA/5-FU in pts with gastric cancer refractory to or relapsing after EAP is investigated. So far 13 pts have entered this ongoing t r i a l . Dosage and schedule: Folinic acid 300 mg/mz i . v . I0 min. i n f . followed 40 min. l a t e r by 5-FU 500-600 mg/m~ bolus, day I - 3, q d 22 - 28, max. 6 cycles. Patient characteristics: Ma|e 7; female 6; mean age 54 years (34 L 59); mean Karnofsky-PS 70% (50%-90%); refractory to EAP 8 pts; NC during EAP 3 pts; relapse a f t e r EAP pts. Evaluable for response and t o x i c i t y ( 2 cycles) 11 pts; 2 pts too early to evaluate. Results: No change 10/11 lasting 6+ - 18+ weeks (mean 13+ weeks~, P 1/11. Toxicity (WHO grade): Leucopenia ~ (2)~ ~ (3), ~ ( I ) , ~ ( I ) ; anemia ~ (6), ~ (2); nausea/ vomiting ~ (2), ~ (2); stomatitis/mucositis ~I (5), ~ ( I ) , ~ (2); diarrhea ~ (2), ~ (2); alopecia ~ (2), ~ (I). Conclusion: HDFA/5-FU seems to have some a c t i v i t y in h e a v i i y pretreated patients with advanced gastric cancer. Inclusion of HDFA/5-FU in f i r s t l i n e regimen could be promising. Abteilung H~matologie/Onkologie, Medizinische Hochschule Hannover Konstanty-Gutschow-StraBe 8, 3000 Hannever 61

1/P.GM 022

1/P.GM 024

HIGH-DOSE FOLINIC ACID (HDFA)/ 5-FLUOROURACIL (FU) PLUS DIPYRIDAMOL (DP) IN PATIENTS WITH GASTROINTESTINAL CARCINOMA REFRACTORYTO OR RELAPSING AFER HDFA/FU: H.-J.Schmoll, H.Wilke, Ch.SchSber, M.Stahl, H.Poliwoda.

COMBINED CARBO-PLATIN-RADIOTHERAPY IN PATIENTS WITH A D V A N CED SQUAMOUS CARCINOMA OF THE HEAD AND N E C K AN ANALYSIS O F ACUTE EFFECTS ON TUMOUR AND NORMAL TISSUE

Experimental and early c l i n i c a l data suggest that DP is able to enhance the antitumor a c t i v i t y of 5-FU by increasing the i n t r a c e l l u l a r half-time o f ~dUMPand blocking thymidine salvage. In this ongoing t r i a l 17 pts. with colorectal (13) and gastric cancer(4) refractory to or relapsing a f t e r HDFA/FU = VP-16 were treated with the following protocol: FA 300 mg/m2 10 min. i . v . - i n f . , 40 min. l a ~ e r ~ b o m~/m~ 15 min. i . v . - i n f . , d I - 3 , and DP 2 x 75 mg p.o, d 0-4, q d 22-29. Pts. with gastric carcinoma pretreated with HDFA/FU/VP-16 received addit i o n a l l y VP-16 120 mg/mz d I-3 . Pat.-characteristics: 12 male, 5 female; age 55 (35-72) years; Karnofsky PS 70% (60-90); progression during p r i mary treatment : 10 p t s . ; early relapses: 7 pts. Toxicity (WHO-grade) of 40 evaluable cycles in 17 pts.: nausea~omiting I ~ 2~ leucocytes I ~ 2~ 3~ mucositis I ~ 3~ diarrhea I ~ 2~ alopecia I ~ angina pectoris 2 pts.. Dose escalation of 5-FU to 550 mg/m= was only possible in 3 pts. due to increased g a s t r o - i n t e s t i n a l t o x i c i t y . Results in 15 evaluable pts. (2 pts. too e a r l y ) : resists.(10): 2 MR, 5 NC, 3 P; relapsing p t s . ( 5 ) : I PR, 2 MR, 2 NC. Conclusion: Dipyridamol given o r a l l y in this dose in com~ i t h HDFA/FU enhances s l i g h t l y the bone marrowand mucosa t o x i c i t y and possibly the cardiac t o x i c i t y . The minimal but d e f i n i t i v e a c t i v i t y even in pts. refractory to the same regimen without DP indicates a potent i a l role of DP for a f u r t h e r enhanced antitumor a c t i v i ty of HDFA/FU in colorectal or gastric cancer. However, the optimal dose and schedule of DP s t i l l has to be i n vestigated. 1 Abtlg. H~matologie/Onkologie,Medizinische Hochschui~ Hannover, 3000 Hannover 61

Between September and October 1987, 15 patients with advanced squamous carcinoma of the head and neck underwent a combined treatment regimen with Carbo-platin and irradiation in a pilot-study designed to evaluate dose tolerance and early tumour response. Patients were separated into 3 groups which received 60 mg/m 2, 70 mg/m 2 and 80 mg/m 2 of Carbo-platin on day 1-5 and 28-32, respectively. Radiotherapy was administered up to a target absorbed dose of 70 Gy, 5 x 2 Gy/week, in a shrinking field technique. 12 males and 3 females with a mean age of 55 years (36-72) and a Karnofsky-lndex of 80% (60-100) were treated. 9 tumours were located in the oral cavity (5 x T3,4 X T4), 4 in the oropharynx (3 x T3, 1 x T4), and one each in the epipharynx (T4) and larynx (T4). The lymph node status was N1 in one and N2 in the remaining c a s e s ( U I C C , 1987). Myelotoxic - or septic reactions were not observed, an well as nausea, nephro- and ototoxicity or alopecia. Mucositls (WHO II-III) was registered in 12 patients. The study is being continued with increasing doses of Carbo-Platin. Early remission quality w i l l b e analysed.

H.Pape, W.Achterrath, R.Marafiotti, Th.Sqhnabel, G.Schmi ~

Klinik f~r Strahlenhherapie, Universit~t D~sseldorf, MoorenstraSe 5, D-4000 Dusseldorf I

SIO 1/P-GM 025

1/P-GM 027

TREATMENT OF METASTIC SOFT TISSUE SARCOMASBY ADRIAMYCIN AND DTIC AS FIRST LINE AND IFOSPHAMIDE AS SALVAGE THERAPY H.J. Weh, D. Wingberg, M. Heller, M, Dietel and D.K. Hossfeld

ADJUVANT CHEMOTHERAPYIN HIGH GRADESOFTTISSUE SARCOMAS M. Westerhausen, R. Fuchs, H. Frhr, v. Andrian-Werburg, H.-B. Makoski and H. J. Knieriem The 5-year-survival of patients with high grade soft tissue sarcomas (STS) is approx. 30-60 %. The majority of patients died of lung metastases. In our own series of metastatic disease 32/53 pts (60 %) have had pulmonary metastases. High grade sarcomas (G3) showed in 73 % distant metastases compared with 18 % for low grade STS. Encouraging previous adjuvant chemotherapy with CYVADIC led us set up a multimodality treatment in 1984. After radical surgery or a conservative operation followed by irradiation (65 Gy) an adjuvant chemotherapy using ADM 50 mg/m~ dI + Ifo 5 g/m~/d~ + Mesnawas given after wound healing every 4 weeks for a total of 6 cycles. Twenty four patients received this regimen. 17/24 had a concomitant radiotherapy. Because of previous radical surgery 7/24 received only chemotherapy. After a median follow-up of 37 mos 8/24 (33 %) developed distant metastases, in two cases starting from local recurrences. Compared with untreated controls with a metastatic rate up to 70 % there might be a benefit for adjuvantly treated patients. According to the literature the value of adjuvant chemotherapy is controversial. Based on a prospective randomized study ROSENBERG(NCI-Bethesda) and GHERLINZONI (Bologna) reported for adjuvantly treated pts with sarcomas at extremities a significant benefit for both DSF and overall survival. On the contrary six other clinical trials failed to show any advantage. Most of them included all localizations of STS. This might be one reason for the different results. Summarizing the actual data there might be a benefit for pts with high grade STS located in limbs with a size of > 5 cm which are locally adequately treated. For patients who meet this criteria an adjuvant chemotherapy is recommendable. It should be a challenge for a cooperative prospective randomized t r i a l . II.Med.Klinik, St. Johannes-Hospital, An der Abtei 7-11, D-r Duisburg II

Between 1982 and 1986 we have treated 40 patients with metastic soft tissue sarcomas with a combination ~f Adriamycin (ADR) 60 mg/m /day 1 and DTIC 400 mg/m~/dey 1 + 2 given every 4 weeks. If a response was noted after two cycles of this regimen, it was continued until progressive disease developed. In patients with primary resistance to ADR/DTIC or progressive disease after an initial reBponse chemotherapy was switched to ifosphamids 2,5 g/m~/day 1-5 every 4 weeks. Patients' characteristics were: 22 women, 18 men, mean age 47 (19-76) years. Leiomyosarcome. malignant fibrous histiocytoma and neurogenic sarcoma were the most frequent histelogic entities. ADR/DTIC treatment led to CR in 3 patients (= 8 %) with a remission duration of 8+, 12, 42+ months. PR was achieved in 13 patients (= 32 %) with a median duration of 4 months. 11 patients had stable and 13 patients progressive disease. 8 (= 36 %) of the 22 patients treated by Ifosphsmide obtained e PR with a median duration of 3 months. We conclude that ADR/DTIC is an effective regimen in soft tissue sarcomas, but Ifosphsmide should be included in future first line protocols. Abteilung Onkologie und H~matologie, Universit~tskrankenheus Eppendorf, Martinistr. 52, D-2000 Hamburg 20

1/P-GM 026

1/P-GM 028

EPtRUBICIN/IFQSFAMtDE CQMBINATIQN CHEMQTRERAPu

EFFECTSOF POLARORGANICC C ~ P ~ ONPROLIFERATIONAN) DIFFERENTIATION OFA CLONALRATF~ABDOMYOSARC(M~CELLLINE IN VITRO. C.-D. Gerharz, H. Gabbert, R. Engers, C. Luley

IN REFRACTORY S O L I D TUMORS - A PHASE-II-STUDY J. K6nner,W. Hoffmann,M. Kress,F. Migeod, B. Wsidmann and S. Seeber (*) A combination of epirubicin (35 mg/m days 1+Z) and ifosfamide (1.8 - 2.5 g/m days 1-5)was given to 48 patients ~ith refractory breast cancer (n=lS),metamtatic sarcomas (n=14) and other solid tumors (n=lg).Due to extensive prior therapy,the ifosfamide dose had to be adapted to the individual hematologic situation. Out of a total of 45 evaluable patients, 4 complete and 13 partial responses were registred. Additional 14 patients experienced minor responses or a no change status of clinical significance. The complete responses were seen in metastatic sarcomas (2)~ abdominal mesmthelioma (I) and Merkel cell tumor (1).The median duration of all responses was 6,7 months. Toxicity usa in general mild and closely related to previous therapy. In summary the combination of epirubicin and ifosfamide has shown promising activity st a low toxicity. The best results will be achieved by an individualized dose schedule with dose increments for both drugs in patients without prior treatment and dose reductions in compromised clinical situations.

Medizinische Klimik llI,Zentrum fur Innate Medizin,St~dt. Krankenhaus,D-5090 Leverkusem (*) Supported by "Aktion Kampf dem Westdeutsehes ~umorzentrum,Essen

Krebs",

The observationthat cancer cells havenot necessarily lost all the genesthat control proliferation and differentiation stimulated attempts to i ~ differentiation in various types of ~ as an alternative to standardcytotoxic chemotherapy.Hoaever,sarcomas received less attention, partly becausecell type-specific markers of differentiation are not easily available in most sarcomacell lines. Wereport on differentiation induction in a clonal rat rhabdomyosarcomacell line, composedof proliferating mona-aclearcells which fuse to form terminally differentiated postmitotic ,~otube-like giant cells. The effects of N,N-dimethylf~de (DFF), N-mo~thylfonrr amide (NM:), dioxane, dimathylsulfoxide (DYe0), sodiumbutyrate ($8), and hexaBethylene-bisacetamide(FI~iA) were assessedin vitro. 14~ereas OMSO,IM~A, ~M:, and SB failed to induce differentiation, D~F and dioxane provedto be effective inducers of differentiation. The tumor cells were moreregularly arrangedand showedsigns of contact inhibition. The ~ l e a r tumor cells developedultrastructural features of rhabdomyogenicdifferentiation such as irregJlar bundlesof thick and thin myofilarents never observedin the ~ l e a r cells of treated cultures. The numberof terminally differentiated posbnitotic myotube-like giant cells and the creatine kinase activity as biochemical markerof differentiation showedstatistically significant increases. In addition, exposureto ~ causedan increase in doubling time and a decreasein the saturation density and cloning efficiency. In contrast, dioxaneaffected neither the saturation density nor the cloning efficiency. Our results showthat somepolar compoundsare effective as differentiation inducers in our clonal rhabdomyosarcoma cell line. The failure of DN60, FV~A, ~F, and SB, which are knownto be potent inducers of differentiation in several other in vitro systems, suggeststhat the different polar coBpoondsmay act via distinct mechanis~snot necessarily ~ecessible in ~ tumor. Patholngisches Institut der JohannesGutenberg-Universit~t, Langenbeckstr. l, D-6500Mainz, FRG

SI1

1/pIGM 029

1/P-GM 031

POSITRON E M I S S I O N T O M O G R A P H Y (PET) OF LIVER METASTASES WITH F-18-URACIL. L.G. Strauss, J.H. Clorius, M.E. Helm, U. R~th, P. Schlag, F. Helus, F. 0berdorfer, H. 0stertag, G. Wolber, G. v a n K a i c k

CHILDHOOD LYMPHOBLASTIC LEUKEMIA OF B-CELL TYPE: R E S U L T S O F S T U D I E S B - A L L B F M 81 A N D 83 H.J.Feickert, S.Mueller-Weihrich, G. H e n z e , J. H o f f m a n n and H. R i e h m In s t u d i e s B - A L L B F M 81 a n d 83 f o r t y - s i x children with confirmed B-ALL were treated according to a especially designed protocol between April 1981 a n d O c t o b e r 1986. T h e r a p y c o n s i s t e d of 6-8 blocks of multidrug chemotherapy applied in alternating sequence following a pre-phase of cytoreductive treatment with cyclophosphamide and prednisone. In e a c h b l o c k t r e a t m e n t ( i n c l u ding ADR, ARA-C, MTX, CP and DEXA) was given during d a y 1 t h r o u g h 5 f o l l o w e d b y n i n e d a y s of rest. A f t e r b l o c k 1 a l l pts, of s t u d y B - A L L B F M 83 received an Omaya reservoir for subsequent intrathecal c h e m o t h e r a p y (dose a d j u s t e d accord i n g to a g e a n d i n i t i a l C N S i n v o l v e m e n t ) . R a d i o therapy to the C N S w a s g i v e n in t h e f i r s t s t u d y after b l o c k 2 a n d in t h e l a s t s t u d y a f t e r completion of c h e m o t h e r a p y a b o u t 12 w e e k s after diagnosis. Forty-three pts. (93.5%) entered comlete remission. N i n e t e e n pts. (41.3%) rel a p s e d all w i t h i n 12 m o n t h s ( B - A L L B F M 81: 3 x BM, 6 x CNS, I x B M / C N S ; B - A L L B F M 83: 7 x BM, 2 x BM/CNS). Two deaths were therapy-related. Currently, 25 pts. a r e in C C R (54.3%), eventf r e e s u r v i v a l is e s t i m a t e d t o b e 50% (SD = 0.07) at a m e d i a n d u r a t i o n o f t h e s t u d i e s of 60 and 30 m o n t h s . F a c t o r s f o r p r o g n o s i s w e r e l i v e r s i z e and percentage of blast cells at diagnosis. These studies a r e the f i r s t c l o s e d trials in which significant cure rates for childhood B-ALL have been achieved,

Thirteen patients with liver metastases from colorectal tumors were examined in an ongoing study, in order to assess tumor uptake of F-18 labeled fluorouracil. N-13glutamate and O-15 labeled water were also used in selected patients to assess tumor metabolism and perfusion. Serial transversal s c a n s (3 s l i c e s s i m u l t a n e o u s l y ) w e r e o b t a i n e d at 5 min intervals for a total of 30 min. Late images were acquired 2 hours after i.v. injection of the F-18 labeled fluorouracil, to evaluate metabolic turnover. The reconstructed cross sections were quantitatively evaluated using a region-of-interest technique. T h e g l u t a m a t e a n d f l u o r o u r a c i l u p t a k e o f metastases was expressed as percent of tracer concentration i n n o r m a l l i v e r parench~rma as w e l l as d i f f e r e n t i a l a b s o r p t i o n r a t i o s . Furthermore, we were able to compare the tracer concentrations in two patients, who were examined after intravenous and intraarterial i n j e c t i o n o f t h e c y t o s t a t i c agent. A significant correlation was noted between relative glutamate and fluorouracil accumulation in the metastases after intravenous tracer injection. Our preliminary results indicate, that the uptake of the cytostatic agent may depend on tumor metabolism. Multiple tracer studies may be used to select individual treatment protocols.

Kinderk!inik der Medizinischen Hochschule Hannovet, Konstanty-Gutschow-Str.8, D-3000 Hannover

1/P-GM 032

I/P-GM 030 1s

der Deutschen Krebsgesellschaft

vom 2 9 , F e b r u a r

big

5.M~rz

1988 in

e.V

Frank{urt/Main

TREATMENT OF HIGH RISK NONSEMINOMATOUS TESTICULAR CANCER (NSTC) WITH CISPLATINUM, IFOSFAMIDE, AND BLEOMYCIN ( P I B )

U. Wandl. G. S c h u m a c h e r , K. GOnzel, N. N i e d e r l e , M. E. S c h e u l e n , K. H 6 f f k e n and C . G . Schmidt In p a t i e n t s (pts) w i t h NSTC, r e m i s s i o n r a t e s and survival correlate with p r i m a r y t u m o r burden. Prognosis has t u r n e d out to be very p o o r in the a d v a n c e d s t a g e s II C ( r e t r o p e r i t o n e a l t u m o r m a s s (RTM) > 5 cm), IV C (lung m e t a s t a s e s (LM) < 10 gem and RTM > 5 cm), and IV D (tM > t 0 c c m and RTN > 5 cm), r e s p e c t i v e l y . In a c l i n i c a l p h a s e II study, 28 pts w i t h s t a g e TiC. IVC and IVD NSTC without prior cytostatic treatment received PIB every three weeks: c i s p l a t i n u m , ~0 m g / m / day, 1+5; now,

d. 2-&; bleomycin. 14/28 pts

ifosfamide, 5 . 0 0 0 mg/m / d a y , d. 30 mg/dav, d. 1+8+15. Up t o (50Z) are free of disease (NED).

T h r e e pts u n d e r w e n t c o m p l e t e r e m o v a l of r e s i d u a l d i s e a s e e i t h e r by r e t r o p e r i t o n e a l l y m p h a d e n e c t o m y (NED 7+, 17+ mth.) or by t h o r a c o t o m y (NED 10+ mth.). Remission duration is in the r a n g e of ~-20 mth. (median 9 mth.). P a r t i a l r e m i s s i o n (PR)

was

achieved

in

another

10

pts,

two

of

them

are still on s c h e d u l e and i m p r o v i n g . Five pts are in s t a b l e PR. M a i n side e f f e c t s w e r e m y e l o suppression, a l o p e c i a , and n a u s e a and v o m i t i n g . Ifosfamide induced psychoses w e r e seen in two pts. Reversible r e t i n a l h e m o r r h a g e s o c c u r e d in three thrombocytopenic pts. One pt d i e d of a bleomycin induced pulmonary fibrosis, another one of septicaemia. These preliminary results are r a t h e r p r o m i s i n g . H o w e v e r , due to the t o x i city, the PIB r e g i m e n s h o u l d be c o n s i d e r e d o n l y in c o n t r o l l e d c l i n i c a l trials. I n n e r e U n i v e r s i t f i t s k l i n i k und P o l i k l i n i k (Tumorforschung). Westdeutsches Tumorzentrum, H u f e l a n d s t r . 55, D - 4 3 0 0 E s s e n I

BIOLOGICAL CHARA~STICS ;~D T4ERAPYRESPONSEFOR ACLTE L~4PEOBIASTIC (ALL) OF INFANCYIN FIVE C/INSECUTI-VEALIrBFMSTUDIES 1970-83. P. Bucsky, J. Ritter, R. Dopfer, H. Schmid and H. Riehm Age and treatmentare importantprognosticfactors in childhoodALL. In studies ALIz-BFM70/76/79/81/83initial clinical findings, l!a~ohlsst characteristics, therapyr e - - e , relapserate and sites in 42 infant patients 50x109/i (ccmpl.gr.: 18%). C~S diseaseat diagnosishas been observedin 12 pts. (29%; in compl, gr. 2,4%), 9 of then with an initialblast cell count >50x10~/I. Th/I~-eight infants (90%) achieveda completeremission,17 pts. (40%) are in continouos complete remission(CCR; compl,gr.: 75%). Four infants (10%) failed to respoude to therapy, 3 of them <6 mtha. (compl. gr. 1,6%). In 8 infants toxic death occured (in stud~ ALS-B~M 83 only in one patient). Eighteeninfants (42~) relapsed (compl.gr. 20%), most often isolatedbone marrow and CNS relapses have occured (8 and 5 pts., respectively). Detailed immunophenotypingdata were available for 12 of 15 infantsin study ALL-BFM 83. In 6 infants (50%) 0-AI,f. with cASLa negativelenkEic cells, Lu one infant AUL with blast cells negative for both cALI~ and TdT have bsen diagnosed, whereas in the compl, gr. for the trial 83 (461pts.), 7 pts. with 0-ALL, 2 pts. with AUL could he observed (3%). Two of the 15 infant pts. (13%)showed a poor response for an initialone week therapyby prednisolen (5,7% in the cenpl, gr.). Two infants (13%) and two pts. in the compl, gr. (0,5%) presentedblast cells with both lymphoid and myeloidmarkers. Neither pre-B, nor B-ALL could be diagnosed in infants in study ALL-BFM 83. Cyto~eneticdata were not evaluatedfor this study. Characteristics of infant ALL suggest, that clinicallyless favorable and phenotypicallymore undifferentiatedsubtypes of childhoodALL are more ccamon in infants
S12 1 / P - G M 033

1/P-GM 035

HIGH DOSE AR~-C IN C O M B I N A T I O N WITH MITOXANTRONE (HAM) IN THE T R E A T M E N T OF CHILDHOOD AML J. Ritter, U. Creutzig, and G. Schellong for the AML-BFM Study Group

PRIMARY EWING'S SARCOMA OF BONE; UPDATED RESULTS OF THE GPO COOPERATIVE EWING'S SARCOMA STUDIES (CESS) 81186 H. JOrgens*+, UB. Graubner, St. MOt!er-Weihrich, J. Ritter, M. Pfreundschuh, R. Sauer, HJ, Schmoll, Ch. Urban, PA. Vo0te, P. Weinel, H. Winkler, and U. GBbel* The CPO CESS 81 trial with ~ nine-week cycles of 4drug chemotherapy (vincristine, actinomycin D, cyclophosphamide, adriamycin = VACA) and local control following two cycles of chemotherapy with surgery and/ or radiation has resulted in a Kaplan-Meier estimated disease-free survival rate of 5 1 % (+- 6 %) after 6 years (51/93 patients (pts.) disease-free). Tumor volume and hlstotogic response to primary chemotherapy were identified as most significant factors influencing prognosis. As a consequence the treatment regimen of the follow-up trial CESS 86 was stratified according to risk of relapse. Standard risk pts. (extremity tumors <100 ml tumor volume) continued to receive VACA chemotherapy. In high risk pts. (extremity tumors >100 e l , central t u morsJ conventional dose cyclophosphamide was replaced by high dose ifosfamide (3 g/rag/d, days t+2) with masna uroprotection ( V A I A ) . Local therapy was now administered following week 9. Pts. with radiation were randomised for either conventional fractionation or accelerated split-course hyperfractionation. The study was piloted from Feb. to Dec. 85, 27/37 pts. were disease-free on Nov, 1, 87, The ongoing trial was started on Jan. 86. On Nov. 1, 87, 63/66 lOtS. were disease-free. According to Kaplan-Meier life-table analysis pts. with large tumors who received VAIA instead of VACA chemotherapy had a significantly improved disease-free survival. The toxicity of both regimens was comparable. +Supported by BMFT grant no. 01 ZP 063 5 and Deutsche Krebshilfe f. H~matologie und *U niversR~itskinderklinik. Abt. Onkologie, Moorenstr, 5, D-/$000 D0sseldorf

Twenty-one children with refractory AML were treated using the combination of high-dose cytosine arabinoside and m i t o x a n t r o n e . All children were initially treated according to protocol AML-BFM-83. 3/8 children with refractory AML and 6/13 children with bone marrow relapse during or after m a i n t e n a n c e therapy achieved complete remission (43%). Three children ( 1 4 % ) d i e d in bone m a r r o w aplasia, whereas two children did not respond. Five of the nine responding children have been in complete remission for 4-20 months, two of them after bone m a r r o w transplantation. 24 children with ~ML in remission received HAM as early intensification treatment during the ~i!o~-~hase of ~tudy ~ L - 3 F M 87~ Three cht!dren (12,5%) died in bone m a r r o w aplasia. Bone m a r r o w recovery time and toxicity of the HAM therapy weze co~parablc in the two groups of children. Our data show that HAM has a high antileukemic activity in refractory AML. A significant number of toxic deaths, however, occurred both in refractory leukemia and children in remission. Universit~ts-Kinderklinik, Str.33, D-4400 M ~ n s t e r

Albert-Schweitzer-

1/P-GM 034 DISEASE- AND THERAPY- RELATED DEFECTS OF CELLULAR IMMUNITY IN ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) U.Ebener*, H.-J. Rehagel and B.Kornhuber In 32 children with ALL included in the ALL-BFM 81/83 studies and in 21 normal children serced as controls we analysed the distribution pattern of lymphocyte subsets in peripheral blood (PB) and Iymphocyte function in PB and bone marrow (BM). Based on the reactivity with commercial monoclonal antibodies (cMAB) the cases were classified as 22 cALL, 2 T-cell ALL and 1 case of 0-ALL missing diagnosis in 7 cases 03FM 81). Surface markers were tested by ir~aaunofluorescence technique using a panel of cMAB and proliferative response was measured after in-vitro stimulation with PHA, ConA, PWM and OKT3. The experiments were performed at time of diagnosis, during and after chemo-radio-therapy. At diagnosis: The percentage as well as the total number of T-cells proportional decrease of T4 + and T8+ ceils leads to a normal T4/T8ratio- are markedly decreased in PB of all i0 patients. In BM atl patients show strongly decreased spontaneous and mitogen-lnduced proliferation. The degree of impairment of lymphocyte function and the number of leukemic blasts does not correlate in BM as welt as in PB. On therapy: At the end of induction therapy we fred only in 1 out of 5 patients decreased mitogen-induced proliferation in PB and in all 5 patients an increase of proliferation rates in BM, but also lower than in healthy controls. T-cells show restitution to normal range. B-eells are now markedly reduced. During the first month of maintenance therapy a higher percentage of patients (4/7) show impaired lymphocyte functions (PB) and the number as well as the degree of impairment increases with duration of maintenance therapy. Long-term chemotherapy has a long-lasting immunosuppressive effect: in one case we s impaired cellular immtmity after 30 month off therapy. The results show, that a short-term intensive chemotherapy has a lower immunosuppressive effect than a long-term lower-dosed chemotherapy. *) supported by "Stiftang Volkswagenwerk" 9 Center of Pediatrics, Department of Hematology and Oncology, University Hospital, 6000 FrankfurffMain

1/P-GM036 TREATNEMTOF CHROIICNYELOIDLEUKENIA(CNL) IN CHILDROODWITH ALPHA-IMTERFERON(IFI) AS MOMQTHERAPY OR IN COMBINATION WITHEYDROXIUREA

Ten patients with CML have been treated with IFN. Four children had a juvenile and six an adult Ph+ C~L, Age of onset of juvenile CML was 3/12- 3 years (median: I 1/12 years). Children with adult type of CHL have been fallen sick at am age of 2 9/12 -14 B/12 with a median of g 2/12 years. Duration of illness at the start of IfN-therapy was 3/12 - 3 years (medlan: I 1/12 years) in the group with ~uvenile CNL. Children with adult CML had a duration of illness between 0 month and 8 2/!2 years (medla~ 2 5/12). Moste~atients have been treated with Myleran~9, Pori-Nethol ~, Thioguanln ~, Rydroxiurea, Etritinat or the BFM-AML therapy-protocol. At the tlme of enrol~ent in the study group all patients have been ~n the chronic phase of CML. The Individual IFN dosage and therapy scheme of each patient was determined using the induction kinetics of (2t-bl)-ollgo (A) synthetase activity in perlphera! blood mononuolear cells. IFN was ~iven as native or recomblned alphe-IFNgn i.=. in dosages of 5-30xi0 u/kg 2 or 3 times a week. The duration BT IFN therapy leads from 1 month to 23 month (median: g ~onths), 7 out o~ g patients (77~) have responded to tFN therapy, 2 patients (23~) (i juvenile, 1 adult CML) ere non remponders. In one patient with juvenile CML the duration of observatiom is toe short to be evaluated. 2 o~ the 7 respomders are in complete remission under IFN therapy (normal size of liver and spleen, normalisation of hemat0gram, normalisati0n of the alkallne phosphatase in leucocytes, normallsztlon of bone marrow smear end the bone marrow cells). In patients with a s t a n d s t i l l of illness in a partial remission over 5 month, further IFN-tberapy has been comblned with Rydroxiurea in a doaage 0f 30 - 50mg/kg, Thereby 2 out of 3 patients with adult CHL reached complete remission, though before IFN-therapy with hydroxlurea alone, ~o hematologlcal re=isslon could he reache~. 2 patients have been excluded from the study after 3 and 6 montho (I mf prei~mlnarles for bone marrow transplantation and 1 because of progression of osteomyelosclermsls of which he died at last). Patients tolerated native and recomblned IF~ allke. An expression of antibodies against used IF~s couldn't be observed. The above mentioned observations lead to the conclusion that alpha-IFN could bring a complete remission to some of CML petlents. Patients with ~n insufficient respond to Hydroxiurea or IFR-therapy could be treated sucessfully with a combined therapy of IFN and Hydrox[urea. Gereln V. I, A. Krause-ErnstI, E, Lmdemann2, H. JOrgens3, T. Rath&, Rister 5, Ertel 6, B. Kornhuber I 1 Unlvermlt~ta-Kinderkllnik, Frankfurt am Main, 2 Zentrum f~r Therapeutlscha Biochemla der Unlverslt~t Frankfurt, 3 Universit~tsKinderklinik DgsseldorF, 4 Unlverslt~ts-Kinderk1[mlk M~nster, 5 gnlveralt~ts-KinderkIinlk Kiel, B Kindmrkllnik Stuttgart

S13

1/P-GM 037 LIVERAFFECTIONS ARISING FRON CRV IN PATIENTS WITH CYIOSTATIC THERAPY (ALL-BFN 79, ALL-BFH 81)

G, Maurer, V. Gere~n, B. Kornh~ber oF Th~s retrospective study was carried out with study-patients Frankfurt to proove the following: I. Amount of CMV seroposltve patients at the time of entering the ALL-BFM-7g and ALL-BFM 81 study. 2. Frequency and time of CMV reactlvatlon. 3. Amount of patients who underwent a seroconversion during cytostatlc therapy, ~. Amount o~ severe liver affections, which were correlated to a manifest CMV ~ngectlon. The study ~ncluded 3B patients of BFM-7g and the f i r s t 24 patients of BFM-81 study. (the remaining 19 patients of BFM-81 study were out of question because of passive immunlsation against CHV). Out of 62 cases are 33 ~ and 29 ~, at the age between I month - 15 8/12 years. At the time of ALL-dlagnos~s 4g patients [87g) have been CRV seronegative, 7 patients (13~) CMV seroposltlve. In 6 patients (10%) the i n l t i a l CMV antibody test haven't been carried out, CMV-reactlvatlon during ALL-therapy could be recognized in a11 CHV positive patients. 6 out of these patients had an increase of transam~nases. A seroconversion was observed in 13 out of ig patients (27~) which could be compatible to s CMV-hepatltls. Pathologlcml hepatic alterations due to CMV appeared ~n i n i t i a l l y seropes~tlve patients usually in the intensive part of ALL-therapy and oecured again in the continous therapy. Patients with seroconversion got their CMV-hepatlt~s during contlnous therapy. In all patients with an increase of transamlnases in correlatlon to CMV IgM antibody progress an interruption of zytostatlc therapy was necessary. Zentrum der Kinderhnilkunde , der Johann Wolfgang yen Geethe-gniverslt~t Theodor-Stern-Kal 7, 6000 Frankfurt am Main 70.

1/P-GM 039 COMBINED CH~THERAPY(CI') WITH ADRI~,IYCIN~BLEC~CIN,VINCRISTIN,ETOPOSIDEAN~ PRED~SONE(.aJ3OEP) DOES NOT INDUCE GONADAL DYSFUNCTION IN MAL~ PATIENTS WITH HODGKIN'S DIS. G. Lautenschl~ger, P.S~ Mitrou, Th. Klippstein, F. Walther Gonadal dysfunction and increased risk of developing second malignancies are frequent late complications in HD patients treated with CT or CT+RT. Their frequency is signific~itly lower with ABV~ thmn with MOPP. A B ~ treatment is complicated by severe Gl-toxicity. We present preliminary results with a regimen which do not contain either alkylating agents or DTIC. Patients: 13 pts. with stage IIA to IlIA and adverse prognostic factors were entered in the study. The median age of the 8 males and 5 females was 35 yrs.. Histology was nodular sclerosis(7/13) or mixed cellularity(5/]3). 12 pts. were previously u:itreated and ] in first relapse. Treatment: ABOEP: ADM 25 mg/m 2 i.v., BLM I0 mg/m 2 i.v., VCR 2 mg i.v. days I+8, E I00 mg/m ~ i.v. days I-4, PDN 40 mg/m ~ p.o. days I-8. All.pts. received at least 4 cycles of CT followed by EFrr~diation with 30-36 Gy. Results: 12 pts. entered CRand I PR after 4 cycles of ABOEP. All pts. were in CR after CT+RT. The median follow up is 13 mo. with all pts. remaining in CR. ToxicityL WHO-grade 3 or 4 toxicity was observed in 2~ for Hb, 18% for WBC, 25 for platelets, 16~ for GI, and 2% of mucositis of the ABOEP-courses. Pneumonia occured in I pt.. Gonadal function: In a control group of pts. treated with C-MOPP+RTor C-MOPP/ABVD alls pts. had azoospermia with high F-SH and I~ levels I tb 10 yrs. after discontinuation of treatment. 2 pts. treated withABOEP and pelvic irradiation had also azoospermia. 3 pts. treated with 4-6 cycles of ABOEP without pelvic irradiation had a normal spermiogra~n or asthenospermia with normal FSH- and LHlevels 3 to 6 months after discontinuation of treatment. In conclusion, from the preliminary results it appears that ABOEP is an effective combination with low toxicity, which does not cause infertility in young men. Division of Haemat~logy/Oncology, Dept. of Internal Med., J.W. Goethe University, Frankfurt/bl.

1/P-GM 038

1/P-GM 040

B-CLL IN EARLY PHASE RESPONDS TO RECOMBINANT ALRHA-2b INTERFERON THERAPY AS DETERMINED IN A PILOT STUDY R. Schlag, H.W.L.Ziegler, D. F l i e g e r , W.Hill and E. Thiel

ADVANCED HODGKIN'S DISEASE (HD) - ANALYSIS OF PATIENTS WHO FAILED TO PRIMARY TREATMENT R.Fuchs, M. LGffler, M. Pfreundschuh, V. Diehl German Hodqkin Study Group

Recombinant alpha i n t e r f e r o n (rlFNa) has been reported to be a c t i v e in low grade lymphomas in many studies, but some r e p o r t s of small numbers of p a t i e n t s with CLL suggested t h a t QLL is poorly responsive to rIFNa. These p a t i e n t s , however, had r a t h e r advanced disease and were e x t e n s i v e l y p r e t r e a t e d . We, t h e r e f o r e , asked whether b i o logic response m o d i f i e r (BRM) treatment would be more e f f i c i e n t in the e a r l y phase of the disease when the B - c e l l clone is s t i l l under c o n t r o l . Since l i f e expectancy has been demonstrated to be shortened in CLL of lower age, we decided to t r e a t 10 p a t i e n t s (6M, 4F) less than 60 years old (median age 50) in e a r l y c l i n i c a l stages (RAI 0-2) a f t e r informed consent with INTRON A (Essex P'harma) (5xi0 I . U . s . c . three times a week). Immunophenotyping of CLL-celIs revealed surface IgM only. In a l l cases an o b j e c t i v e response as measured by the decrease of c i r c u l a t i n g lymphoma c e l l s by f l o w cytometry was observed w i t h i n 4-6 weeks a f t e r s t a r t i n g treatment. 9 o f 10 pat i e n t s f i n d in continuous p a r t i a l remission 6 to 12 months a f t e r s t a r t of therapy. C r i t e r i ~ f o r response were decrease in WBC (median values 36,0x10 / i before and 26,5 x10 / I a f t e r 9 t h e r a p y ) , decrease in9B~-cells (median values 15,4xi0 / l before and 3,95xi0 / I a f t e r therapy), increase in granulocytes and decrease in bone marrow i n f i l t r a t i o n in 2 of 5 sequential biopsies i n v e s t i g a t e d . Self treatment in o u t p a t i e n t form was accomplished in every case due to minimal side e f f e c t s . Paracetamol to avoid " f l u l i k e symptoms" was no longer required than f o r three weeks. These r e s u l t s underline t h a t BRM such as IFN may be e f f e c t L v e in e a r l y phase of disease with low tumoral burden in s p i t e o f treatment f a i l u r e s in progressed disease.

In a multicenter study 230 pts with advanced HD ( I I I B; IV) were treated with an alternating schedule COPPx3 / ABVDx3. After restaging pts with CR were randomized to further chemotherapy (COPPxl/ABVDxl) or to additional radiotherapy. Up to now 137 pts were evaluable for response. 49/137 failed to have freedom from progression, Regarding the actual status pts could be divided in four groups as seen at the table: CR Alive with tu. Dead Lost (n=12) (n=16) (n=17) (n=4) Sex r a t i o m:w 9:3 9:7 13:4 4:0 Age/median 34 26 37 28 Risk factors * 6 8 8 3 Treatment delay 7 15 16 1 Dose reduction 2 6 8 1 Therapy stopped by pt 5 5 4 4 *mediastinal mass; massive spleen involv,; extranodal l~s.

Fifteen pts had relapse a f t e r primary CR. 5/15 died. Three of these f i v e pts stopped therapy themselves. 5/15 had progressive disease. 5/15 achieved secondary CR. Analysis of relapse pattern revealed nodal recurrences in 3/5 pts with CR. Comparing the group with secondary CR with pts who f a i l e d to salvage therapy two d i f f e r e n t types of relapse could be distinguished: Low risk relapse with favorable prognosis: Nodal relapse z 5 cm i n size; relapse stage I, I I ; no r i s k factors; no B-symptoms, High r i s k relapse with poor prognosis: I f one or more of the following c r i t e r i a are present: B-symptoms; relapse stage I I I , IV; f a s t growing lymphomas; bulky disease >5 cm, r i s k factors including ESR > 50 mm f o r A- and >30 mm f o r B-symptomatic pts and 3 or more involved lymphatic areas. These high r i s k pts are candidates f o r aggressive chemotherapy followed by bone marrow transplantation.

S14

1/P-GM 041

1/P-GM 043

LOW-DOSE CYTOSINE ARABINOSIDE IN THE TREATMENT OF CML BLAST CRISIS R. Donhuijsen-Ant, R. Fuchs and M. Westerhausen

SODIUM BUTYRATE INHIBITS PHOSPHOINOSITIDE-TURNOVER AND CELL PROLIFERATION IN COLO 320 COLON CARCINOMA CELLS.

In 1983 Castaigne et al suggested the c a p a b i l i t y of low-dose cytosine arabinoside (L-D Are-C) to induce c e l l u l a r d i f f e r e n t i a t i o n in AML. 1985 Di Raimondo et al reported the f i r s t results of L-D Ara-C in CML with b l a s t i c transformation (7 p t s ) . Only in one case they observed a return to the chronic phase lasting for 15 weeks. We treated 5 pts (2 , 3 , 24-59 years) with L-D Ara-C, 2x20 mg sc d a i l y . Therapy was stopped when reaching a mild pancytopenia, In one case we reached a stable control of the disease for 19 months. The mean survival time a f t e r the onset of blastic tranformation was 2 months (I-19 months). Low-dose Ara-C may be an useful p a l l i a t i v e therapy in patients with contraindications to a more aggressive therapy. L i t e r a t u r e : CASTAIGNE, S., DANIEL, M.T., TILLY, H., HERAIT, P. and DEGO, L. (1983) Does treatment with Ara-C in low dosage cause d i f f e r e n t i a t i o n of leukemic cells? Blood 62, 85-86 DI RAIMONDO, F., MILONE, G., GUGLIELMO, P., CACCIOLA, E., GIUSTOLISI, R. (1985) Treatment of CML blast c r i s i s with low dose Ara-C. B r i t i s h Journal of Hematology 60, 773-774 Med. K l i n i k I I , St.Johannes-Hospital, An der Abtei 7-11, D-4100 Duisburg I I

Reinhord Kopp und Andreas P f e i f f e r Activation of the phosphoinositide system and the subsequent phospholipose C-dependent formation of the second messengers diecylglycerol (bAG) and inositol trisphosphate (IP3) may play a fundamental role in

malignant transformation and growth regulation of tumor cells. To investigate t h i s suspected association we measured

after

phosphoinasitide

turnover

in

Cola

320 cells

treatment

with sodium butyrote in comparison to cells. Sodium butyrate is known to inhibit

untreated proliferation and to induce differentiation in several malignant cell lines. Methods: Phosphoinositlde turnover was measured by short term ~P-incorporation i n t o phospholipids separated by t h i n layer chromatography, Phospholipids were quantitoted by measurement of phosphorus. Results: Sodium butyrate decreased cell proliferation by 40% odd 80% a f t e r treatment for 6 days with 2 and 4

mM, respectively. turnover shewed

Measurements of significant a

phosphoinositide inhibition of ~2P-incorporation i n t o phosphotidic acid (-40%) and phosphatidyl inositol 4,5-bisphosphate (PIP2) (-48% with 2 mM butyrate, p< 0.01). Turnover of phosphotidyl

ieositol was also decreased while the total mass of this lipid was increased. Conclusion: The parallel inhibition of cell proliferation and phosphoinositide turnover by sodium butyrote, in particular of PIP% the precursor of the second messengers IP3 and DAG, supports the hypothesis that this system is of importance for cell proliferation in malignant colonic cells. We also suggest a novel mechanism of action of sodium butyrate which may involve o modulation of phospholipid kinases. Supported by the Wilhelm Sonder-Stiftung. Medizinische

Klinik II, Klinikum Gro~hodern, Universit~t

M0nchen, Marchioninistr.lS,

8000 M0nchen 70.

1/P-GM 042

1/P-GM 044

5 - F L U O R O U R A C I L + M I T O M Y C I N - C F O R T R E A T M E N T OF E X O C R I N E P A N C R E A T I C C A R C I N O M A (PA CA) U. Klapdor, R. Klapdor, M. Hit s chmann and A. Gut ho ff

5-FO PLUS FOLINIC ACID IN COLORECTAL CANCER A PHASE-II-STUDY F. MigeodTW. H o f f m a n n , B . Weidmann,S. Seeber ( * )

In c o n t i n u a t i o n of p r e v i o u s e x p e r i m e n t a l a n d clinical studies w i t h 5 - F U + M - C we e v a l u a t e d the t r e a t m e n t e f f i c a c y of 5 - F U + M - C in 14 p a t i e n t s s u f f e r i n g from h i s t o l o g i c a l l y p r o v e n paca. T r e a t m e n t : lO 0 0 m g / m 5-FU day I-5 and 7 m g / m 2 M-C day I and 2 , e v e r y 6 w e e k s . C l i n i c a l signs,b.w., s e r u m CA 19-9 and C E A , U S and CT were controlled during follow-up simultaneously,tumor disease was c l a s s i f i e d a c c o r d i n g T N M - s t a g e and grading. M a i n p a r a m e t e r s : tumor r e s p o n s e and survival(after d i a g n o s i s and ( ) b e g i n n i n g of chemotherap#). R e s u l t s : C o m p a r e d to 6 u n t r e a t e d p a t i e n t s w i t h d e c r e a s i n g b . w . , i n c r e a s i n g tumor m a r k e r s and tum o r masses in U S / C T , t h e 14 t r e a t e d p a t i e n t s sqlow e d the f o l l o w i n g r e s u l t s : n = 5 : b . w . l ,CA 19-9 and /or CEA ~,tumor m a s s e s in U S / C T ~, s u r v i v a l 4-10.5 2-6, m e d i a n = 4 ) m o n t h s ;n=1 :b.w. I ,US/CT !, transier~ 2 . h m . ) s l i g h t I of CA 1 9 - 9 + C E A , s u r v i v a l 15(6) n~ n=4:b.w.I ,tumor m a s s e s in U S / C T u n c h a n g e d or s l i g h t l y ~ for 6-11 m.+ s i g n i f i c a n t I of CA 19-9/ CEA ( < 5 0 % of the initial v a l u e s ) , s u r v i v a l 9-29 ( 8 - 2 8 , m e d i a n = 1 3 ) m . ;n:1:b.w.l ,PR in US/CT, ~ of CA 19-9/CEA ( < 5 0 % of the initial values),survivalm12(>11)m; n = 3 tumors did not secret CA or C E A . U S / C T s h o w e d a SD in 2 p a t i e n t s for 4 m. and a PD in I p a t i e n t ( s u r v i v a l 16/17 and 11 m. r e s p . ) . S u m m a r y : 1 ) C o m b i n a t i o n t h e r a p y w i t h 5-FU~ M-C may induce SD and PR in pace p a t i e n t s . 2 ) S D in U S / C T a c c o m p a n i e d by t r a n s i e n t d e c r e a s e of e l e v a t e d tumor m a r k e r s seem to be of b e n e f i t fom p a c e p a t i e n t s . 3 ) C A 19-9 a n d / o r CEA s e e m to reflect t h e r a p e u t i c a l effects more s e n s i t i v e than the i m a g i n g methods.

There is a number enhanced therapeutic (FUra) when combined

M e d i z i n i s c h e K e r n k l i n i k u n d Poliklinik, Univ e r s i t ~ t s k r a n k e n h a u s Eppendorf, M a r t i n i s t r . 5 2 D - 2 0 0 0 H a m b u r g 20, FRG

te In

of reports describing activity of 5-fluorouracil with 5-formyltetrahydrofola-

(dl-CF) the

present

phase-ll-study

20 p a t i e n t s

with

metastatic eolorectal cancer were entered into a first line chemotherapeutica! protocol consisting of high dose dl-CF (200 mg/m2/day x 5)i.v.push directly followed by 340 m g / m 2 / F U r a / d a y x 5 i.v. push. This far a response rate of 45% (1 CR, 8 PR) was achieved and minor responses or no change were registered in another 30% of the patients lowering the rate of primary therapeutic failures down to 25%. Median time till progression was 8.5 months, median survival has not been reached. Toxic effects included stomatitis, diarrhea and nausea. Hematoxic effects were negligible.

Medizinische Klinik Ill,Zentrum f. Innere Medizin~ St~dt. K r s n k e n h a u s , D-5090 Leverkusen ( * ) S u p p o r t e d by "Aktion Kampf dem K r e b s " , Westdeutsches Tumorzentrum, Essen

$15 1/P-GM 045

1/P-GM 047

DISEASE ORIENTED PHASE II STUDY W I T H CISPLATIN (P), E T O P O S I D E (E), A N D 5FU (F)=PEF IN A D V A N CED S Q U A M O U S CELL C A R C I N O M A OF THE ESOPHAGUS Preusser, P., W i l k e , H., A c h t e r r a t h , W., Pirchef, W., M e y e r , J., Blum, M., Lenaz, L., B ~ n te, H. U n i v e r s i t y Hospitals MHnster, Hannover, Bristol Myers N e w York

CYTOTOXIC DRUG SAFETY CABINETS J.W. B~nning

~i~-E-i%-F?i~%-7~%%-j~:~-~q-g~%-jg~7~-~:

sponse rates, s u g g e s t i n g t h a t E is a c t i v e in esophageal c a n c e r . T h e r e f o r e a d i s e a s e o r i ented p h a s e II s t u d y w i t h P E F in s q u a m o u s c e l l cancer of the esophagus was started June 1986: 20 pts (19 e x t e n s i v e , 1 l o c o r e g i o n a l d i s e a s e ace. MSKCC-criteria) are evaluable for response a n d t o x i c i t y up to now. 17 pts s u r g i c a l l y staged, m e a n age 57 yrs, all m a l e r m e a n p e r formance status W H O grade II (I-II). Response, response duration, and toxicity w e r e assessed acc. ~ W H O - c l a s s i f i c a t i o n . Treatment: P 50 m g / m ~, i.v.. on d a y s 1+72 E 120 m g / m z, i.v., on d a y s 3-~, F 5 0 ~ m g / m , i.v., on d a y s 3-5, every 4 weeks. 81 (mean 4 per pt) courses were given. O n e p t w i t h N C a n d o n e p t w i t h PD underwent r a d i a t i o n and were, t h e r e f o r e , excluded from survival calculation. Overall resDonse r a t e w a s 65% (95% c o n f i d e n c e l i m i t s 448~%), 3 (15%) CR, I0 (50%) PR. 7 of I0 s t a b l e PRs w e r e p a t h o l o g i c a l l y confirmed as pPRs. They w e r e ~isease free aTter surgery. They received 2 further courses of CT pes{.operalively. M e d i a n progress free i n t e r v a l for p t s w i t h PR a n d N E D a ~ t e r s u r g e r y h a s not y e t B e e n reached (5~-15 ~ month~], ~ e d i a n survival of all pts is 12 m o n t h s (3 -15 m o n t h s ) . Pts w i t h CR or PR and N E D h a v e a m e d i a n s u r v i v a l t i m e of 15 m o n t h s , p t s w i t h NC of 9 m o n t h s . L e u c o eytopenia and t h r e m b o c v t o p e n i a of W H O - g r a d e III w e r e observed in 35% and 10%, respectively; of W H O - g r a d e IV in t w o pts. A l o p e c i a of grade III occured in 55%. No other toxicity of grade III and IV w a s o b s e r v e d . T h e d a t a of %his study suggest that the activity of PEF in extensive d i s e a s e is c o m m a r a b l e ~o t h a t of P / E / F / A D M in l o c o - r e g i o n a l d i s e a s e . PEF is an active and safe r e g i m e n for t r e a t m e n t of esophageal cancer. It i n c r e a s e s o p e r a b i l i t y in pts w i t h e x t e n s i v e d i s e a s e . U p d a t e d r e s u l t s will be presented. Intern. Onkologie in der C h i r u r g i s c h e n J u n g e b l o d t p l a t z I, D-4400 MHnster

On principle, cytotoxic drugs mean a risk to health. Therefore it is necessary to protect the personnel handling them from the influence of cytotoxic drugs. The method of protection may consist in personal p r o t e c t i v e equipment, but better in technical p r e v e n t i v e measures; this means: cytotoxic drug safety cabinets. The essential criteria for construction are: an a i r f l o w system based on a HEPA filter, defined quantities of intake and exhaust air, - clearly outlined access openings for the operator, a clean working area. The national and international standards do not contain any requirement how to construct and to test cytot0xic drug safety cabinets, But as it was necessary to establish a testing procedure, the Industrial Injuries Insurance Institute for Health and W e l f a r e Services laid down testing principles of "Cytotoxic Drug Safety Cabinets" depending on DIN 12950 (German Standards Institute) respectively NSF Standard # 49 (National Sanitation Foundation). After a test period, s t a n d a r d i z a t i o n will be proposed to the German Standards Institute. -

-

-

B e r u f s g e n o s s e n s c h a f t fur G e s u n d h e i t s d i e n s t und Wohlfahrtspflege, P a p p e l a l l e e 35/37, D-2000 H a m b u r g 76 (German title:

Zytostatika-Werkb~nke)

Klinik,

1/P-GM 046

1/P-GM048

C O N C E R N FOR THE P R O B A B I L I T Y O F M I S S I N G AN IMPORTANT T H E R A P E U T I C I M P R O V E M E N T IN R A N D O M I Z E D CLINICAL TRIALS. D. Messerer, H. Ansari, ~. A y d e m i r

POSTINFLAMMATORY HYPERPIGMENTATION AS SIDE EFFECT OF THE TREATMENT WITH 5-FLUOROURACIL (5-FU) AND HIGH DOSE FOLINIC ACID C. Gropp end G. E~ler

10 years have elapsed since F r e i m a n et al. ree x a m i n e d 71 "negative" trials to determine whether the i n v e s t i g a t o r s had studied large e n o u g h samples to give a high p r o b a b i l i t y (> 0.90) of d e t e c t i n g a 25 per cent or 50 per cent therapeutic improvement in the response (NEJM 299, 690, 1978). 67 of the trials had a greater than 10 per cent risk of m i s s i n g a true 25 per cent t h e r a p e u t i c improvement, and w i t h the same risk, 50 of the trials could have m i s s e d a 50 per cent improvement.

In the lest years the combination of 5-fluorouracil with high dose folinic acid was investigated as a new concept for the treatment of patients with some gastrointestinal tumors. Several studies have shown higher response rates but also increased side effects (stomatitis, leucopenia, thrombocytopenia~ diarrhoea) especially in colorectal carcinomas. In our study 40 patients with gastrointestinal tumors received 5-FU (500 mg/m2/d by intravenous infusion for a period of 3 hours) and folinic acid (100 mg/m2/d by iv bolus) for 5 consecutive days, with a 21-day interval between courses. Beside mild stomatitis and diarrhoea 90~ of the patients did show a mild to severe postinflammatory hyparpigmentation along the route of intravenous infusion. Postinflammatory hyperpigmentation usually developed after two to three treatment courses, was painless and allowed further infusions into the same veins. Postinflammatory hyperpigmentation is e rare side effect of the treatment with 5-FU alone but is markedly increased by the concomitant use of high dose folinic acid. The diagnosis of p o s t i n f l a m m a t o r y hyDerpigmentation was proven histologically by biopsy.

Since 1978 r a n d o m i z e d clinical trials have inc r e a s i n g l y become accepted as the most effective way of d e t e r m i n i n g the e f f i c a c y of a new therapy. Did the a t t e n t i o n m e a n w h i l e increase c o n c e r n i n g the p r o b a b i l i t y of m i s s i n g an i m p o r t a n t therap e u t i c i m p r o v e m e n t b e c a u s e of small sample sizes in the p l a n n i n g of clinical trials? R e c e n t publications (1986,87) in journals of high repute in h e m a t o l o g y and oncologic u r o l o g y were analysed. Our analysis indicates that there are still too m a n y of the therapies labelled as "no d i f f e r e n t from control" in trials using i n a d e q u a t e samples have not r e c e i v e d a fair test. Two thirds of the "negative" u r o l o g i c trials had a greater than 20 per cent risk of m i s s i n g a true 50 per cent therapeutic improvement. Less "negative" hematologic trials could have m i s s i n g such a striking improvement. B i o m e t r i s c h e s Z e n t r u m fHr T h e r a p i e s t u d i e n Pettenkoferstr. 35, 8000 M ~ n c h e n 2

GmbH

Abt. for H ~ m a t o l o g i e / O n k o l o g i a / I m m u n o l o g i e St~dt. Krankenhaus, Reckenberger Str. 19, D-4830 GOtersloh

am

$16

1/P-GM 051

1/P-GM 049 ANAPHYLACTIC REACTION DUE TO ETOPOSIDE Le B l a n c S , H a r s t r i c k A , W i l k e E , S g h m o l l P o l l w o d a H.

H.-J.,

INVESTIGATIONSONTHE ACUTETUBULARANDGLOMERULAR TOXICITYOF CARBOPLATIN U_~_~_etz-~urschel*E.Ku~chel,U. Kach~l-Fischer N, Niederle

Anaphylactlc r e a c t i o n s u n d e r the t r e a t m e n t w i t h e t o p o s l d e are e x t r e m l y r a r e ( O ' D w y e r Ca T r R e p , 1 9 8 4 ) . W e r e p o r t o n a n a n a p h y l a c t i c r e a c t i o n to e t o p o s i d e i n a 46 old p a t i e n t w i t h a r e t r o p e r i t o n e a l m a s s o f t e s t i c u l a r c a n c e r . I n the h i s t o r y o f t h i s p a t i e n t w a s no e v e n t of a l l e r g i c r e a c tion.He was treated with cisplatin,etoposlde, bleomycin and vlncrlstine.After a total dose a p p r o x . 5 m g o f e t o p o s i d e the p a t i e n t d e v e l o p e d respiratory distress,generalized urticaria, tachycardia and hypotension.After discontinuat i o n o f the i n f u s i o n a n d f l u i d s u b s t i t u t i o n the symptoms resolved spontaneously after a few minutes.The chemotherapy was subsquently continued with omission of etoposide.Since all o t h e r d r u g s w e r e k e p t w i t h o u t c h a n g e i n the therapy without another reaction this anaphyl a x i s m u s t c l e a r l y be attributed to e t o p o s i d e . E t o p o s l d e is a s u b s t a n c e o f l o w m o l e c u l a r w e i g h t a n d m a y act as a h a p t e n or a n t i g e n p r o d u c i n g a type I a l l e r g i c r e a c t i o n in s u s c e p t i b l e individuals.Though t h i s s e e m s to be v e r y r a r e , physicians treating patients with etoposlde s h o u l d be a w a r e of the p o s s i b i l i t y o f s e v e r e a l l e r g i c r e a c t i o n to e t o p o s i d e . Abt. H ~ m a t o l o g i e / o n k o l o g i e ~ed. Hochschule Hannover Konstanty Gutschow Str.8,3OOOHannover

Carboplatin (eis-diamLno-cyclobutanedicarboxylataplatinum II) is a new platinum a~alogue that has been found in phase I-If trials to he lass nephrotoxic than ois-platirmm but equally affective~During a phass-Ii study we evaluated the potential nephrotoxic effects of carboplatin in 6 patients (pts) with small cell lung cancer. Carboplatln (300 mg/m2 iv, day I) was administered with prehydration together with etoposide (escalating doses; 100 - 140 mg/m2 iv, days I-3) and vincrlstine (1,Stag,iv, days 1,8,15 and 21). PeDal function was studied i~y the fallowing parameters on days 1 -3.8 and 28 - 31 : oreatinip~ clearance; analysis of urinary enzj-m~ r (lactate dahydro~enase = LDH, ~lanine amirmpeptidase=AAP,gamms-glutamyltransferaae = GGT); total urinary protein output; measurement of albumlne, IgG and alpha-l-mioro~lobulin excretion. During the first treatment o~urse oreatinine clearance decreased in 3/6 pte from 120e25 ml/min to 81e53 ml/mln. Pathaloglcal enzymuria of LDH o ~ r e d in 4/6 pts (1383 675 to 4001 9 5049 mU/g cr~tinlne), of AAP in 4/6 pts (2161 ~ 1481 to 4425 • 3203 mU/g Cr~tird.ne) and of in 6/6 pte(3235 ~ 1832 to 10319 ~ 5572 m~/g czeatlnina). Alb%minuria was detected in 4/6 pts (0,34 • 0,56 ~g/dl to 3,45 • 3,49 ng/dl), Ig G was excreted in abrmrmal quantities in 4/6 pte (0 • 0 to 0,49 ~ 0,85 mg/dl), alphs-l-microglobulln excretion was pathological in 4/6 pts (8 • 8 to 1,45 • 0,94 m~/dl). Th~se findings are o0nsistent with a combined glom~ralar and tnbular injury ~aased by carboplatin.Whether these ~i~ings represent a zevarei~l@ acute damage or persistent i~r~airment of ~nal f~nction is subject of ongoing investigations. 9 kbt. far Nieren- and Hochdruckkranke, Medizinische Klinik dee Universltataklinikums und Innate Klinik ur~ Poliklinik (T~morforsch~), Weatdeutschea Tumsrzentrum Hufel~ndstr~ 55. D-4300 Eeeen, FRG

1/P-GM 050

1/P-GM 052

MASSIVE OVERDOSAGE OF CYCLOPHOSPHANIDE IN A PATIENT WITH STAGE IV MALIGNANT TERATOMA R.Zimmermann, A.Neubauer, R.Schwerdtfeger, W.Siegert, D.Huhn

C A R D I O T O X I C I T Y OF 5 - F L U O R O U R A C I L IN C O M B I N A T I O N WITH HIGH-DOSE FOLINIC ACID Ch. SchGber, E.Papageorgiou~ M.Stahl, H . W i l k e , H . P o l i w o d a and H . J . S c h m o l l

A 28 year old man was t r e a t e d f o r high r i s k t e r a t o c a r c i noma according t o the A I O - p i l o t - p r o t o e o l (Schmoll et a l . ) which consists of c i s p l a t i n 3 x 50 mg/m2, VP 16 3 x 170 mg/m2,Bleomycin 30 mg/m2 and V i n c r i s t i n 2 x 1.4 mg/m2 alternated with Ifosfamid 5 g/m2 as 24 hour infusion, Bleomycin 30 mg/m2 and V i n o r i s t i n 2 x 1.4 mg/m2. Erroneously the p a t i e n t received cyclophosphamide (CY) instead o f ifosfamid in the second cycle. When the mistake was discovered and CY was stopped, the patient had received 6.5 g CY w i t h i n 21 hours (=100 mg/kg). A d d i t i o n a l l y 7 doses MESNA (1.5 g/m2 q 6 hours) were given. The p a t i e n t was r e f e r r e d t o our BNT unit f o r f u r t h e r supportive care, which included s e l e c t i v e gut decontamination, a l l o p u r i n o t and reverse i s o l a t i o n . Observed side e f f e c t s were: Vomit i n g (WHO IV) day 0 - 3, granulccytopenia (WHO IV) day 8 - 11 and anemia (WHO I I t ) , which required transfusion of 4 units of packed red blood c e l l s . On day 11 we diagnosed fever of unknown o r i g i n and started a n t i b i o t i c t r e a t ment. From day 12 the granulocyte count increased r a p i d l y to normal levels on day 15. There was no f u r t h e r t o x i c i t y observed. I t is important t o note, t h a t therapy could be completed according t o protocol without delay. There are other reports showing t h a t administration of CY 60 mg/kg as 1 hour infusion on each of two days results in profound but short granulocytopeoia. It is noteworthy, that the dose of i00 mg/kg given as 24 hour continuous infusion produces no more severe toxicity. This observation of reversible myelotoxicity is important, because CY is a widely used component of immunosuppressive and myeloa b l a t i v e therapy in bone marrow t r a n s p l a n t a t i o n . Klinikum Rudolf Virchow der FU, Standort Charlettenburg, Med. K l i n i k und P o l i k l i n i k m.S. HGmatologie und Onkotogie Spandauer Damm 130, D-IOOO Berlin 19.

C a r d i o t o x i c i t y of 5 - F l u o r o u r a c i l (FU) is a rare event r e s u l t i n g in a n g i n a pectoris, arrhythmias, seldom in c o n g e s t i v e h e a r t f a i l u r e and myocardial infarction ( 3 cases ).In the l i t e r a t u r e the i n c i d e n c e is 2,6% (22/1312) in FU-monotherapy with an increased risk in patients with positive cardiovascular history, amounting 13,6% in pts. receiving polychemotherapy including anthracyclines or cis-p!atinum.To our k n o w l e d g e there was only one report in the literature in 609 pts. r e c e i v i n g v a r i o u s r e g i m e n s of f o l i n i c acid (FA) and FU. In our series of 172 pts. with colorectal or gastric cancer there was no recorded c a r d i a c e v e n t in I00 pts. receiving 200 m g / m z FA and 2 5 - 4 0 m g / k g F U i v - b o l u s d a y 1 and n o n e in 34 pts r e c e i v i n g 500 m g / m 2 i v - b o l u s a f t e r 300 m g / m 2 FA d a y 1 - 3 . I n 38 pts. with FU dose increased to 600 mg/m z i myocardial infarction and severe angina pectoris was o b s e r v e d . { l pt. pretreated with anthracyclines and c i s - p l a t i n ) . A t the h i g h e s t d o s e level with 700 rag/= FU 1/5 pts. suffered from myocardial infarction, 1/5 f r o m a n g i n a p e c t o r i s and 1/5 from s e v e r e a r r h y t h m i a s , b o t h r e s o l v i n g b y dose reduction.Neither the mechanism of the cardiotoxicity of FU n o r the role of FA are known. F r o m t h e s e d a t a a c o r r e l a t i o n to d o s a g e and s c h e d u l e s e e m s to be o b v i o u s . F o r further trials with high-dose FA/FU combinations cardiotoxicity has to be c a r e f u l l y monitored, particularly with h i g h e r d o s e s of FU School Hannover, FRG, Dept. of Hema-tology and Oncelogy

SI7

1/P-GM 053

UP-GM 055

LONG TEP~M TOXICITY AFTER CURATIVE POLYCHEMOTgERAPY OF NONSEMINOMATOUS TESTICULAR GEP@[ CELL TL~IOR (NSGCT). Ch__,Clemm, _R.Hartenstein ,* W.Mair, H.Lauter, W.Wilmanns

NEUROPHYSIOLOGICAL EXAMINATIONS TO THE RISK OF CISPLATIN-INDUCED NEUROPATHYIN TUMORPATIENTS

101 patients (Pts) with NSGCT were followed up after they received sucessful therapy with cisplatin from ~979-~986. Chemotherapy consisted of 4 cycles PVB (cisplatin, vinblastine,bleomycin) in 62 pts (group I), g pts with intensified 4 drug chemotherapy (group II) and 31 pts with additional treatment or pretreatment (group III). All I0~ pts were observed for more than I I/2 years, 68 pts more than 3 years, 26 pts more than 5 years. I.) Paresthesia was observed in 64% of the pts with areilexia in 42% of group I during the first year, mild paresthesia in 36% with areflexia persisting in only 9% after 5 years. Groups II and III showed paresthesia and areflexia in 80% of the pts during the first year, 35% persisting after 5 years. 2.) The Raynaud phenomenon was observed in about 30% of all 3 groups, remaining constant over a period of 5 years. 3.) Lung toxicity of clinical relevance ocurred in only 6%, but these patients had a Bleomycin dose exceeding 400mg. Radiological signs of up to 30% declined after the first year to 10% after 3 years~ 4.) Mild serum ereatinine elevation was consistant in about 25% of the pts in groups I and II and in 40% of group III over a 5 year period. 5.) Bone marrow toxicity showed only mild thrombopenia in app, 20% of the pts. 6.) Impairment of fertility measured by FSH elevation showed reversibility in more than 50% of the pts after 2 years, but spermiogram analysis was not possible due to loss of ejaculation in most of the pts. Since most of the side effects observed are not completely reversible, it is important to exclude chronic side effects through dose limitation or elimination of specific drugs and perhaps reconsidering the necessity of secondary l~n~phadenec tomy. Med.Klinik IIl~ K!inikum GroBhadern der Univ.MHnchen, D-8000 MOnehen 70 und *Iv.Med.Abtlg. des St~dt. Krankenhauses M[inohen-Harlaching, D-8000 MHnchen 90.

65 patients with advanced cancer of various o r i g i n underwent a neurolegic-electrophysiologic examination at d i f f e r e n t stages of therapy with c i s p l a t i n . The cumulative dose > 600 mg of c i s p l a t i n led to moderate neuropathy of the axenal type in 60 % of patients with ovarian carcinoma (n=23). Patients with head and neck tumors and lung cancer (n=29) showed already p r i o r to therapy in about 60 % signs of a demyelinisating neuropathy obvious due to alcoholism, malnutrition or malabsorption-syndroms in t h i s group. C i s p l a t i n led to a rapid progress of the neurological d e f i c i t at e a r l i e r stages of treatment, in some cases with severe peripheral neuropathies. Comparison of d i f f e r e n t forms of application (bolus-infusion versus 120 h longtime-infusion) revealed no s i g n i f i c a n t differences respect to n e u r o t o x i c i t y . Whereas the development of peripheral neuropathies by higher doses of c i s p l a t i n showed some steadiness there is no c o r r e l a t i o n between neurotoxicity and the response of the tumors to chemotherapy. As a conclusion i t seems to be of practical use to divide patients in those of low and high r i s k for a c i s p l a t i n therapy by an i n i t i a l neurologic examination. For patients with preexisting neuropathies cisplatinum containing chemotherapy should be given very cautiously. On the other hand patients with an i n i t i a l intact peripheral nervous system have only a minimal r i s k f o r a persisting c i s p l a t i n induced neuropathy.

1/P-GM 054

1/P-GM 056

R. Pasdi~ M. Heine~ S. ~ a u % O. ~

....................

Besides G ~ a~d gOT elevati~s d r a g DllC-tberaW several cases of B~d f~ri s ~ followingDIIC therapyhave been re~orted. ~mress a toxic as ~ as an allergic etioloEyhas b~m dismss~, ~e could 0hseve e ~ for atcmic etiologf ( ~ et ai. P ~ t ~ s~_rology 32, 273, 1985). We t/~efc~e tried to elucidate~ether

p~sible a~avating fact.s m~nt be re~n~hle for the mmifestation of DTIC hepatot~dcity aqd ~ y the Budd r ~ . 120 Sprague l~ley ~ats were treatet as follows: I. : 4,5 n~ DIIC~g hw a)iov., b)i.p., e)into the portal vein. 2. : 200 mg DTIC/kg bw a)i.v., b)i.p., e)into the Vxial ~/n. 3.: 4,5 mg DI!C/kg h~~ after exposure of DYIC to the s~ecto_,nof smiight

for 2 rain.,documntati~ of toxic decay paints by s~ctme~y. 4.: 4,~g DnC/kg ~ (a) a ~ Z00 mg mTC/kg b~ (b) after 4 ~ k s of a liq~d diet emtsJrfing 50 g e ~ l

per liter.

C~Z (U/l) msasxsl before ~ d ~re day after D~IC a~olication ~

the

following decreases: la)-76*;ib)-64*; ic)-231"; 2a)-85"; 2b)-154", 2c)-165; 3)-22; 4a)-43"; 4b)-172; (* = signif, for p = 0.05). GPr (U/I) ~ t s did not show a ~ sigrdfic~mt increases in group 1 and 2, ~hereas his~a)lo~f:of the liver (day 5) did shay necrosis of

single h~atoc~es.~C exposure to smlight did not came aiterati~ns in C4E ~r ~ f nmasmamnts a~d he~tic histologf. After p~etrestsmnt of tPe animgls with ethanol, the followingdecreases of CHE a~1 increases of GPr were obeeved: O ~ (U/l) 4a)-43"; 4b)-172; GFf (U/l) 4a)+5; 4b)+26" (* = signif, for p = O.05).Histologicemmdmtioo of the liver did not signs of DTIC be~totc~=idty. ~ exmni~_iom of blood/~med in all grotps a ckee depenlmt decrease of i ~ a~d t h r ~ . results ~ t e a p ~ h l y dose dep~x~nt ~p~imm~t of liver function after D]XC tre~m~nt ~ t i v e of the a p ~ t i o n m~e. E~posure to s,~ight d/d not ~ be~tic t~dcity, V0et~'eam~nt of tbe rats with ethanol sears to increase suscept/b/lity for DIIC hspstot~xicity. ~refore a possible role of bepstic e~mgTe

ir/~tia~ ( e s p y

microsomsl a ~ )

in DZ[C !~ato~icity

be discussed since DI[C is trarsfonmd in the l i ~ ~ to its active metabelites~ II. ~ Klinik ur~ Pathologisdes Instimt, ~ der thiversitatF e i d ~ , ~modor - Kutzer - Ufer, 6830

E. Koletzki I , R. Fuchs 2, M. Westerhausen 2 and B. Leven I

1Neurologische K l i n i k , St~dtische Kliniken Duisburg, Zu 2 den Rehwiesen 9, D-4100 Duisburg l Med. K l i n i k I I , St. ~ohannes-Hospital, An der Abtei 7-11, D-4100 Duisburg II

COLONIC MUCOSAL NONSULPHATED BILE ACID C0NCENTRATIONS CORRELATE WITH CANCER LOCALIZATIONS IN CHRONIC INFLAMM= ATORY BOWEL DISEASE. W. Kurtz, S. GOldOtuna, A. Hellstern. I. Rieger, U. Leuschner

Some b i l e acids, in p a r t i c u l a r secondary b i l e acids, have been shown to be (co)carcinogenic. In u l c e r a t i v e c o l i t i s , colonic carcinomas arise in the d i s t a l colon, in Crohn~s disease they are less frequent and are l o c a l i z e d more proximally. We, therefore, analysed b i l e acids in colonic mucosal biopsies from cecum to rectum by glass c a p i l l a r y g a s - l i q u i d chromatography in 7 patients with u l c e r a t i v e c o l i t i s and 7 patients with Crohn's disease. Results. In u l c e r a t i v e c o l i t i s , concentrations of non= sulphated b i l e acids r i s e s i g n i f i c a n t l y from cecum to rectum from 38,63 + 11,40 SEM ng/mg to 58,08 + 7,92 ng/ mg, b i l e acid sulphate esters drop s i g n i f i c a n t l y from 104,96 ~ 19,09 ng/mg to 33,64 + 10,41 ng/mg. In Crohn~s disease, nonsulphated mocosalbile acids drop signific= antly from cecum to rectum from 66,50 + 13,05 ng/mg to 40,20 + 5,54 ng/mg with no significant--change in bile acid s~lphate esters.In both diseases, toxic lithocholic acid is the main mucosel bile acid, Conclusions. In both types of chronic inflammatory bowel disease, mucosal nonsulphated bile acid concentrations are highest in the regions where the carcinoma rate is highest. This points to the possibility of a pathogenetic role of these bile acids, in particular lithocholic acid, in colonic carcinogenesis. Dept. of Gastroenterology, Center of Internal Medicine, University Clinics, Theodor-Stern-Kai 7, 0-6000 Frankfurt/Main

S18

1/P-GM 059

1/P-GM 057 O. SCHEIBE, Surgical Division, Bi~rgerhospital Stuttgart-Feuerbach,

LIVER METASTASESOF COLORECTALCANCERXENOGRAFT IN NUDE MICE (CHEMOTHERAPYWITH CLINICALLY ACTIVE DRUGS) F. S a f i , S. K i r s t e i n , R. Roscher, R. B i t t n e r , H.G. Beget

TNM versus DUKES in colon carcinoma It is demonstrated by contrasting the staging according to TNM and DUKES that a classification in terms of lymph node involvement is not possible in the DUKES system. Here, perieolic lymph node metastases, metastases of a named vascular trunk and those designated as "collecting lymph nodes" by DUKES cannot be distinguished either in C1 or C2 tumors. However, the lymph node involvement of pericolic lymph nodes has a very much more favorable prognosis compared to lymph node involvement on a named vascular trunk. Even DUKES D involvement does not atJow any dilferentiation of the lymph node involvement. In contrast to this) the TNM system shows a clear, short description of findings with interdisciplinary and international comprehensibility which is above all reconstruetabte in terms of spreading of the lesions,

Literatum reference: UICC, TNM classification of malignant tumors (UICC TNM Klassifikation maligner Tumoren). Fourth, completely revised edition,

Springer,

Berlin

- Heidelberg

- New

York

- Paris

10 l i v e r metastases of colorectal cancer s e r i a l l y heterotransplanted in nude mice (NMRl-nu/nu) have been tested f o r t h e i r response to chemotherapeutic agents (5 FU, FUDR Mitomycin C). Each tumor originated in a d i f f e r e n t p a t i e n t . Following l i v e r metastases resection during pumpimplantation procedure, pieces of tumor tissues were p r i m a r i l y xenotransplanted subcutaneously to c o l l e c t i v e s of 4-6 weeks old nude mice. The inoculated animals (n=208) were then divided into groups of six animals. Results: ~ o f tumor growth a f t e r xenOtransplantation was 84%. The treatment was i n i t i a t e d when the implants were well established, showing a:constant increase of t h e i r i n i t i a l mass (median time of tumor growth 46 day). 85% of established tumors were treated. The animals were given dosage of the drugs s i m i l a r to those administered c l i n i c a l l y . Until now the results can be exactly demonstrated in 6 tumors. In three tumors FUDR was c l e a r l y more e f f e c t i v e than 5 FU. Two other tumors were equally sensitive to 5 FU, FUDR and Mitomycin C. The treatment with 5 FU against the sixth tumor produced a s t a t s t i c a l l y s i g n i f i c a n t delay in tumor growth compared to FUDR and Mitomycin C. Human tumors heterotransplanted in nude mice could be a possible p r e d i c t i v e model for screening a n t i neoplastic drugs in regional therapy of l i v e r metastases of colorectal carcinoma.

Department of General Surgery, University of Ulm, Steinh~velstraBe 9, D-7900 Ulm.

-

Tokyo 1987.

1/P-GM 058 PROQNOSTIC ~ACTORS IN PATIENTS WITH C t ~ T I ~ L Y STONACHCARCINON~. P.Hermanek and I.GuFgenmoos-Holzmann.

1/P-GM 060 R~SECTED

EARLY POSTOPERATIVE THERAPEUTICAL CONTROLOF CARCINOMAOF THE PANCREASBY PERIOPERATIVE DETERMINATION OF CA 19-9 F. Safi, R. Roscher, R. Bittner,H.G. Beger

The age-corrected S year survival rate of patients foliowznR curative surgical removal of a stomach carcino~m is today about 5o~, surgical mortality excluded. When patients are subdivided accordin~ to the new UICC stage grouping (4th ed.) the 5 year survival rates r a ~ e f ~ m 9o% for sta~e I to 0% for stage IV. The UICC sta~e system considers exclusively the anatomical extent of disease. But other factors, including treatment ~rocedures, come into play in the cancer patient's prognosis. We therefore investiRated the extent to wi~ich other prognostic factors could be of possible influence within each of the different UICC stages, Cox's multivariate analysis was used. In the proRT~ostically very favourable stage I, there is an additional influence from co-morbidity. In stage IlIA the extent of the proximal margin of clearance and the number of involved lymp.h nodes show an independent influence on ~rognosis. There were significantly better results obtained~en in early carcinoma and in advanced intestinal type carcinoma there was a margin of clearance of more than 2.5 cm, as measured on the non-stretched fresh resection specimen~ corresponding to aDproximately 4-5 cm in situ, and when in the case of diffuse t)roe carcinoma t - ~ was a margin of S cm (8-1o cm in situ). In stage IIIB the n~mber of involved lym.~h n o e ~ d sex are additional inde~endent prognostic factors. The aim of such investigations is to exDand the existin~ "stages", which relate only to anatomical extent, into "prognostic groups" by taking other prognostic factors and treatment procedures into s~sideration.

~he CA 19-9 value in the serum reflects the quantity of ~ancreatic cancer tissue in the body. After removal of tumor tissue a quick normalisation of the markers is to be expected in the serum. Patients and Methods: 120 patients with adenocarcinomaof t-Fg~pancreas ~ n treated in our clinic, 36 patients s underwent partial duodenopancreatectomyand 84 patients a p a l l i a t i v bypass operation or an exploratory laparotomy. Histological diagnosis of the tumor as well as a lymph node staging has been established in all patients intraoperatively, Tumor staging has been performed according to the classification of UICC '87.CA 19-9 has been estimated in all patients preoperatively and on day I, 3, 6, 9, and 12 postoperatively (normal value of CA 19-9 amountedto < 37 U/ml). ~esults: After curative resection of pancreatic cancer in ~tage I-patients (n=6), the preoperatively raised antigen values decreasedto normal, whereas no serum concentration below 37 U/ml could be observed in patients with involved lymph nodes who underwent palliative partial duodenopancreatectomy (n=30) or bypass operation (n=84). According to this fact, the median survival rate of stage I-patients amountedto 29 months, of stage I l l - and IV-patients and patients with inoperable tumors to 8 months only. Conclusion: Already in the early postoperative course of cUrativelyresected patients CA 19-9 shows special signiFicance concerning radicality and prognosis of the surgical intervention. In addition, the necessity of an immediate adjuvant therapy can be derived.

Abteil~mg fNr Klinische Pathologie in der Chirurgischen Universit~tsklinik, ~ximiliansplatz, D 8S2o Erlan~en.

Department of General Surgery, University of Ulm, Steinh~velstra~e 9, D-7900 Ulm.

S19 I/P-GM06I

1/P-GM 063

LONG-TERM SURVIVAL AFTER SURGERY FOR GASTROINTESTINAL CANCER - TRUE IMPROVEMENT OR E F F E C T OF PATIENT SELECTION?

EFFICA~ OF S~DUNfI~IL M I ~ 0 T R D ~ E AND 5-FLLDROUP~CILL ~ N G - ~ INFL~ION ON SYNC4RON~JS AND FETAC~LRO~DL~~EAST~SES IN COLON C~NCER U. Plene<, J. Aqagnou, E.q.%BorP~rdt

P,J.Hermanek

jun.,

E,-A.8urkhardt

and

F.P.Gall

The f o l l o w - u p of p a t i e n t s o p e r a t e d on for c a r c i n o m a s of the s t o m a c h , c o l o n a n d r e c t u m has s h o w n a highly significant improvement of l o n g - t e r m s u r v i v a l in r e c e n t y e a r s . For s t o m a c h c a n c e r the overall 5-year survival rates (actuarial method) including postoperative mortality raised from 21 • 3 % in the y e a r s 1 9 6 9 - 7 7 to 31 • 4 Z in the y e a r s 1 9 7 8 - 8 5 . The r e s p e c t i v e f i g u r e s for c o l o n i c c a n c e r are 48 + 5 Z ( 1 9 6 9 - 7 7 ) a n d 65 + 5 ( 1 9 7 8 - 8 5 ) and for ? e c t a l c a n c e r 42 + 4 Z ~ 1 9 6 9 77) and 58 + 4 Z ( 1 9 7 8 - 8 5 ) . The p o s s i b l e r e a s o n s for our i m p r o v e d r e s u l t s are a r e d u c e d o p e r a t i v e m o r t a l i t y , a more sophisticated surgical technique with extended lymph node-dissection, a more radical surgical approach w i t h r e s e c t i o n of i n f i l t r a t e d neighboured structures and a c o n s e q u e n t follow-up programe. The a n a l y s i s of our r e s u l t s s h o w e d t h a t s e l e c t i o n c r i t e r i a are not r e s p o n s i b l e for the imp r o v e m e n t o b s e r v e d . We c o n c l u d e t h i s f r o m the f a c t s t h a t no s h i f t c o u l d be s e e n in the d i s t r i b u t i o n of t u m o r s t a g e s a n d t h a t the i m p r o v e m e n t of p r o g n o s i s ~as s e e n in all c u r a b l e t u m o r

stages. Chirurgische Universit~tsklinik Maximiliansplatz

Erlangen

8520 E r l a n g e n

Sequential use of methotrem3te (MIX) and 5-Fluoreuracil (5-FU) n~y result in syner~Lstie turretcell kill. Recent studies have shc~n an increasi[~ overall response rate in colon cancer patients with t]~eapplication of a high-dose of MTX/5-FU in the sequence, compared to the con~only accepted response rate of 153A~~ with 5-FU treatment alone. In. vitro data suggested a superior synergistic effect with longer time intervals for the sequence M]X/5-FU. 36 patients with a median age of 64,5 years (reng~ 46-77 years) entered the study so far. 8 were pretreated by radiation and / or chemotherapy. Cf the 33 cur~ntly evaluable patients 15 presen~d with s ~ r m h ~ metastases (Lncluding 2 patients with inoperable extended masses) an~ 18 with metachronousmetastases. ~he treatment cgnsisted of MfX 75 mg/m~ i.v. bolus injection, fo~lowed bY MIX 50 mg/m~ as a 24 hour infusion and h e ~ m%er 1000 n~/m 5-FU as a 6 hour infusion, teuonvorin rescue 10 r~/m ~Tasgiven to all patients every 6 hours for eight doses after finishipg 5-FU. The first two treatment cycles were repeated every two weeks, then followed by three weeks s until proE~eesien. A miniof three treatment cycles was required for evaluation of ~por~e usL~g standard criteria. - Of the 33 ctmrently evaluable patients 27,3% achieved a ~artial r~spen~e (PR) and 48~5% had stable disease (NC),24,~/~ showed a progressive disease. ~]e response rates in patient with metachronous metastases (PR 27,8%, NC 50%) were not significantlydifferent from those in patients with synchronous metastases (PR 26,7~, NC 46,7%). Median duration of response (PR + NC) is 8,2+~onth~. P~dian survival is 16,7+ months, but only 3,8 months for nor~esponders. In patient with synsh~onous metastases median ~ i v a l time is 13,9+ months compared with 19,3+ months in patients ~ t h metachronousmetastasea. Toxicity is extre~/[ymild, especially stc~etitis, hairless, %~iting or si~gificant myelosuppressionwas not observed. ~her~ was only a mild nausea in about 12% of the patients. This data from an orgo~r~ study is very promising. Regardir~ the efficacy of the treatment especially in patients ~ith s}~chrenousmetastases the r~sults are c~perable to the beet response rates reported from the r~w 5-~mJ/ieuesvor~]eombs therapy. Compared with this regimen ~@LXIb-FUcan be a4mi~J~stredin a shorter time and is definitely leas e x ~ i % ~ Abteilang F/eatologie/O~
1/P-GM 062

1/P-GM 064

GASTRIC CARCINOMA IN YOUNG ADULTS: COMPARATIVE CLINICOPATHOLOGICAL AND IMMUNOHISTOCHEMICAL STUDIES ON SURGICAL CASES IN GERMANY AND JAPAN H. Ire I, H, Yokozaki I, E. Tahara I, Ch. Wittekind 2 and H.-J. Meyer 3

GASTRIC CANCER: CORRELATION OF GROWTH-FRACTION~ CLASSIFICATION AND TUMORSTADIUM. H. N e k a r d a , J. G e r d e s , H. S t e i n , J. L a n g e a n d U. Fink ............................................... According to o u r r e c e n t l y p u b l i s h e d d a t a of ~ h e different growth behavior for gastric carcinoma (Verh.Dtsch.Ges.Path 70, 231, 1 9 8 6 ) , w e a r e looking for the best correlation b e t w e e n the practiced classifications (WHO, L a u r ~ n ; M i n g , B o r r m a n n ) , the l y m p h o n o d a l stadium (UICC) a n d the i m m u n h i s t o l o g i c a ! determinated growthf r a c t i o n (GF), u s i n g t h e M C A K i - 6 7 a n d t h e APAAP-Methode (J.Histochem. Cytochem. 32, 219, 1 9 8 4 } i n s p e c i m e n s of t h e p r i m a r y t u m o r of g a s t r i c c a n c e r (n=50) a n d m e t a s t a s i s ( n = 1 6 ) . Using the Laur&n-ciassifikation we found the best correlation b e t w e e n the h i s t o l o g i c a l f i n d i n g s a n d the GF. T h e m e d i a n G F w a s 60 % in the i n t e s t i n a l t y p e , 20 % i n t h e d i f f u s e t y p e a n d 40 % in t h e m i x e d t y p e . T h e v a l u e s r a n g e b e t w e e n 20 % a n d 80 % i n t h e g r o u p of i n t e s t i n a l type. The WHO-classification gives not any useless correlation to the GF. T h e M i n g - a n d t h e Borrmann-classification shows a slight but not practicabei correlation to t h e G F. T h e G F in t h e l y m p h n o d e s of t h e i n t e s t i n a l t y p e h a s in a l l c a s e s t h e s a m e v a l u e . In c o n t r a s t the G F is m u c h h i g h e r in t h e p o s i t i v e l y m p h n o d e s comparing to the p r i m a r y t u m o r in t h e d i f f u s e t y p e . O n l y in the g r o u p of t h e i n t e s t i n a l type higher GF were correlated to a a d v a n c e d l y m p h o n o d a l stadium. In c o n c l u s i o n , we b e l i e v e , t h a t d e t e r m i n a t i o n of the i n d u v i d u a l G F i n c o n < e x t to t h e L a u r @ n classification can be a prognostic parameter for advanced gastric cancer in the intestinal type a n d m i x e d t y p e b u t n o t in t h e d i f f u s e t y p e ~

A comparison of clinicopathological and im~mnohistochemieal findings was performed on surgically resected gastric cancers, aged 30 years or younger, the cases comprising 32 in Hiroshima/Japan (J) an 8 in Hannover/Germany (G). The frequency was 2.9% (J) and 0.9% (G) in all the surgical cases, respectively. Male to female ratio was 2.2:1 (J) and ~.7:1 (G). 7 (J) and 2 (G) cases were early gastric cancer and free from metastases. The majority of the tumors showed histologically undifferentiated or signetring cell carcinoma, number of cases being 26 (J) and 5 (G), respectively. Mucinous adenocarcinoma was detected in 2 (J) and in I (G) cases, and tubular adenocarcinoma in 4 (J) and in I (G) cases. Careinoid was noted in one German case. In~nnnohistochemically~ a variety of endocrine cells were detected with a different density in 22 (68.8%) out of 32 Japanese cases. Of these, 5 cases were endocrine cell carcinoma (ECC) after Tahara (1987) and the tumor cells demonstrated irmnunoreactivities for several peptides including gastrin, somatostatin, caleitonin, glicentin an glucagon. Three ECC contained three peptides, synchronously. Conclusions: The frequency of the gastric carcinoma in young adults was significantly higher ((0.01) in Japan than in Germany, probably due to the early clinical diagnosis. Neuroendoerine differentiation appeared to be one of the properties of gastric carcinoma in young adults. I) Department of Pathology, Hireshima University School of Medicine I-2-3 Kasumi,Minamiku,734 Hiroshima, Japan 2) Pathologisches Institut; 3) Klinik f~r Abdominal-und Transplantationschirurgie, Medizinische Hochsehule Hannover, Konstanty-Gutschow-Str. 8, 3000 Hannover 61

Chirurgische Klinik, Rechts der ismaningerstr. 22, 8 0 0 0 M ~ n c h e n

Isar, 80.

$20

1/P-GM 065

1/P-GM 067

THE HOSPITAL FOLLOW UP OF GASTROINTESTINAL TUMORS BY THE ATTENDING SURGEON. A REPORT OF 480 CASES OF GASTROINTESTINAL TUMORS. D.PLck, B.Korinth,A.Ourtius-Hartung,M.Heidrich H.Reinl,M.Schwan,P.Werres,R.Wolkersdorfer

Factors influencing anastomotic recurrence OF COLONCARCINOMA - CLINICAL INVESTIGATIONS E. Gross, F.W. Eigler

Following guideloines are discussed: I. Sex and age of patients,distribution of the tumors,microscopical and biological stage. 2. Results of diagnostic examinations. 3. Analysis of patients compliance. 4. Number of tumor reeidives. 5. Therapy of tumor recidives. 6. Life expectation in dependence of the biological stage of tumor. The benefit of this type of follow up: The patient saves time,because the control lasts only two days. A direct reaction regarding a sargieal problem is possible. The confidence of the patient is supported. The patient is highly motivated. He is closely bind to his hospital. D.PIOK, Surgical Department,Augusta-Hospital, 4000 DGsseldorf 30 Chief of service: B.KORINTH

The q u a n t i t a t i v e significance of various mechanisms causing anastomotic recurrence is s t i l l subject to controversy. A C l i n i c a l i n v e s t i g a t i o n on 290 patients operated on f o r colon carcinoma between 1972 and 1981 should reveal wether anastomotic recurrence and other local recurrence might have d i f f e r e n t o r i g i n s . The development of anastomotic recurrence and other local was analysed by l i f e table method related to various tumour c h a r a c t e r i s t i c s l i k e Duke Stage tumour s i t e grading and mucinous content. Results: Anastomotic recurrence occurred in 10.7 % and ~ c a l recurrence in 12.8 %. Staging and grading influence the rate of anastomotic recurrence but not the rate of local recurrence. Anastomotic recurrence developed predominantly at the hepatic and splenic flexures and at the rectosigmoidal j u n c t i o n . Mucinous carcinomas did not show any d i f f e r e n t rate of anastomotic or other local recurrens. Conclusion: The most l i k e l y explan ation f o r these findings is a d i f f e r e n t o r i g i n of both sorts of recurrences. The influence of tumour stage on the incidence of other local recurrences Ls well explained by tumour been l e f t back in large tumours. In opposite free tumour cells within the bowel lumen may be l e f t back in any tumours stage. This explainsthe missing c o r r e l a t i o n between grading and anastomotic recurrence caused by tumour-cell implantation. The influence of l o c a l i z a t i o n on anastomot i c recurrence is obv/ous for thedegree~necessary manipulation being dependent o n the primary s i t e of the tumour. [L~p. of General Surgery University Hospital Essen

1/P-GM 066

1/P-GM 068

NOT PREOPERATIVE, BUT POSTOPERATIVE IRRADIATION SEEMS TO IMPROVE THE RESULTS AFTER

IMPROVEDRESDLTSOF HLTRASODNDIN THE PRE-OPERATIVE STAGING OF GASTRICCARCINOMAWITH A MODIFIEDTECHNIQUE H.Milbradt, J.Jhhne, H.J.Meyer, P.Reimer

CURATIVE RESECTION OF PRIMARY RECTUM CARCINOMA. 5 YR RESULTS OF THE ESSEN/OFFENBACH RECTUM-CA-STUDY W~NIEBEL, U.SCHULZ, M.RIED, J.ERHARD, E.GROSS, G.BL6CHER, H.NIER, H.HALAMA, E.SCHERER,

G. Zeller F.W.EIGLER The 5 yr results of a prospective rectum carcinoma study are now available, in which 142 resected patients were treated with various X-ray therapies (preoperative X-ray N = 46: 25 Gy/2,5 weeks; postoperative X-ray N = 30: 50 Gy/6 weeks; pre- and postoperative x-ray N = 1 8 : 2 x 2 5 Gy; Control N = 48). Results: i. The best 5 yr survival rate of 75 + 7 % was achieved in the study-arm "control" plus

curative resection. 2. After postoperative ~-ray therapy plus curative surgery we found a survival rate of 70 + 10 %. This is also very high figure considering that in this group only patients with a pT~/PT4-stage are collected. 3. Neither the grading nor the pT-classification but the site of the tumor had a significant influence on the outcome. Conclusion: Regarding the good results obtained with surgery alone, preoperative X-ray therapy can not be recommended generally. In patients with the tumor lying at the lower level of the rectum and an increased risk of recurrence, postoperative irradiation seems to be indicated. university of Essen, City Hospital of Offenbach,

Hospital "Lutherhaus"

Essen-Steele

In the staging of gastric carcinoma uItrasound is an established method, but the results in detecting extraluminal spread of the tumour are not satisfying. We therefore examined 100 patiens by ultrasound, 55 in a conventional manner, 45 after fiIiing the stomach with water. The results in both groups were comparedwith the histological TNM stage. The primary tumor was seen in the I. and 2. group in 60% resp. 85%, but the exakt T-classification was even after f i l l i n g the stomach with water not definable. Lymphnode involvement was detectable in 30% resp. 64%. In patients with N2 and N3 (MI UICC 1987) the results showed a better correlation with the histological staging than in the N1 region. Intraabdominal organ metastases could be found irrespectivly of the method in 75% of the histologically proven cases.

Filling the stomach with fluid improves the results of ultrasound in the preoperative staging in patients with gastric carcinoma. Local resectability can not be determined and exptorative laparatomycan%be avoided for exact staging. Medizinische Hochschule Hannover, Abteilung for Diagnostische Radiologie I Konstanty-Gutschow-StraBe 8 D-3000 Hannover 61

$21

1/P-GM069

1/P-GM 071

CHEMOTHERAPY OF M E T A S T A S I Z E D COLO-RECTAL CARCINOMA WITH 5-FLUOROURACIL (5-FU) AND FOLINIC ACID (FA) W I T H OR W I T H O U T ADDITIONAL VP-16: A COMPARATIVE ANALYSIS OF THREE CONSECUTIVE STUDIES W. Hiddemann I, P. Preusser 2, H.J. Pielken I, H.J. Wilke3,D. Urbanitzl,R. Hense 1 L. B a l l e i s e n 4, D. Kamanabroo5, J. van de Loo 1 Dpts. of Int. Med. 1 and Surg.2~ Univ. of M~nster, Hangover ~, Ev. Krhs. Hamm ~, St~dt. Krhs. Dortmund u In 3 consecutive studies 64 pts. with metastasized colo-rectal carcinomas were treated with one of the following drug combinations: I. FFFA 200 m g / m 2 followed by 5-FU 370-400 m g / m 2 d 1-5 (n=24); 2. FFE-FA 200 m g / m 2 followed after 1 hr by 5-FU 600 m g / m 2 and VP-16 200-240 m g / m 2 d 1 and 2 plus VP-16 alone on d 3 (n=23); FEFFA 300 mg/m 2 followed by VP-16 120 m g / m 2 and 5-Eu 500-600 m g / m 2 d 1-3 (n=17). Eligibility criteria included progressive metastatic disease prior to therapy and measurable m a l i g n a n t lesions for the m o n i t o r i n g of response. The following results emerged from these consecutive studies: FP complete remissions (CR)=2, partial remissions (PR)=7, stable disease=no change (NC)=7, progress (PG) =8; FFE: CR and PR=0, NC=I6, PG=7; FEE: PR=5, NC=5, PG=7. These data indicate that the FF and FEF regimens p r o v i d e d effective p a l l i a t i v e therapy in 16 of 24 (67%) and 12 of 17 (70%) pts. and are therefore of similar antitumor activity while FFE was substantially inferior. Hence, the addition of VP-16 obviously failed to increase the antitumor efficacy of the FF combination but was hampered with a higher rate of p r e d o m i n a n t l y hematologic sideeffects. Prof. Dr. W. Hiddemann, Med. U n i v . - K l i n i k Abt. A, A l b e r t - S c h w e i t z e r - S t r a s s e 33,D-4400 Minster

CHRONIC

P~NCREATITIS

- A PREDISPOSITION

FOR THE

DEVELOPNFNT OF PANCREATIC CANCER?

U. Sulkowski I, J. Meyer',

G. Edel 2 and H. B~nte I

The role of chronic pancreatitis as a predisposing factor for the development of pancreatic carcinoma has been discussed controversely in the literature for decades. Except, a special hereditary form without aminoaoiduria (Ann. Intern. Med. 68, 88-96,1968) an influence of chronic pancreatitis has been denied. In a clinical case-control-study we matched 299 patients treated for pancreatic cancer at our institution with 518 controls. The latter were selected according to age, sex, year of admission and primary disease. A history of chronic pancreatitis could be evaluated in 2o cancer (6.7%), but only two control patients (0.4%). To rule out obstructive pancreatitis on the basis of pancreatic cancer, a diagnosis of "chronic pancreatitis" was only regarded relevant, if made at least two years before the detection of cancer. The association was statistically significant at p ~ o . o 5 in both sexes. Moreover, male cancer patients w i t h a history of chronic pancreatitis were significantly younger than those without (p~:o.1), giving rise to the idea of chronic pancreatitis acting as a promoting factor in carcinogenesis. In addition,we are going to present results from the histologic work-up of our tumours showing different stages of carcinogenesis in chronic pancreatitis which may be able give a proof of our view. IKlinik f~r Allgeameinchirurgie der Z ~ M~nster, Jungeblodtplatz I, D-44oo M~nster; 2pathologisches Institut der ~ U , Domagkstra~e 17/M~nster

1/P-GM 070

1/P-GM 072

RESULT OF TRANSANAL ENDOSCOPIC MICROSURGERY IN ADENOMAS AND EARLY CARCINOMASOF THE RECTUM G__~_BueB, K. KipfmUller, D. Hack, Th. dungin_ger

SURGICAL MANAGEMENT OF PULMONARY METASTASES: PROGNOSTIC FACTORS AND RESULTS. H. Dienemann~ L. Sunder-.Plassmann, Wt. Cappeller, Wo Wyrwich

Sessile adenomas are predominantly localized in the rectum and lower sigma. Surgical removal is indicated, but often implicates invasive surgical procedure. Using conventional transanal surgical techniques only the lower rectum can be reached, a d d i t i o n a l l y charged with high recurrence rates. The new technique combines endoscopic view of the rectum under gas i n s u f f l a t i o n via a stereoscopic telescope with conventional surgical preparation and suturing. Andenomas can be excised in mucosectomy technique or f u l l thickness e x c i s i o n , whereas small carcinomas should be excised in the technique of f u l l thickness excision with a s u f f i c i e n t border of healthy bowel w a l l . In case of carcinoma in the sacral c a v i t y we can remove the r e t r o r e c t a l f a t up to the fascia of Waldeyer including regional lymph nodes. A f t e r operation on 116 patients we have one intraoperat i v e complication, three postoperative healing problems of the suture and a r e c i d i v e rate in local excised adenomas of 3 %. H o s p i t a l i s a t i o n is shorter than a f t e r conventional surgery, there is a short r e h a b i l i t a t i o n period without postoperative local pain. Transanal endoscopic microsurgery therefore is the most defensive surgical technique f o r removal of rectum polyps. From June 1983 t i l l May 1987 we did operate on 116 pat i e n t s . 91 t u b u l o v i l l o u s adenomas, 18 pT1, and 6 pT2 carcinomas could be removed t o t a l l y . A l l 10 patients with pT1 carcinomas and only local excision are tumorfree a f t e r a f o l l o w up period of 19.6 months (median). Ergebnisse der Transanalen Endoskopischen Mikrochirurgie bei Adenomen und frUhen Karzinomen des Rektums.

Oncological conditions for resection of putmomary metastases include radically resected or resectable primary tumor and absence of extrapulmonary metastases. Nevertheless, the effect of surgical management of metastatic lesions to the tungs are difficult to establish~ as control groups are lacking for etNcal reasons. Therefore we tried to identify the prognostic criteria for long term survival of those patients who had prolonged survival following exploration of their metastases. RESULTS: 248 tung resections were performed in 198 patients between 1978 and 1986 with a mortality below 1%. 3-year survival rate ranges from 35 to 80%. The prognosis is mainly determined by the histology of the primary tumor. It is most favourable in testicuiar and breast carcinoma, when patients respond to chemotherapy or hormonal therapy. The prognosis is worst in patients with malignant melanoma. Furthermore the prognosis seems to correlate with the tumor volume; the more lung parenchyma is being preserved, the better the survival. The prognosis seems to be independent of the number and the location of metastases (unilateral vs, bilateral) and of the tumor-free interval (time interval between resection of primary tumor and detection of metastases). CONCLUSION: Within every tumor entity some patients seem to benefit from the operation whereas others do not, yet it remains difficult to predict the individual outcome. But regarding the low perioperative mortality it seems justified to operate on all patients with secondaries to the lungs who fulfill the oncologic criteria.

K l i n i k und P o l i k l i n i k f ~ r Allgemein und Abdominalchirurgie, Universit~tsklinikum Mainz, LangenbeckstraBe 1 D-6500 Mainz i

Chirurgische Klinik und Poliklinik der Universitfit MiJnchen, Klinikum GroBhadern, Marchioninistr. 15, 8000 MOnchen 70.

S22

1/P-GM 073

1/P-GM075

SURGERY OF COLORECTAL CARCINOMA STAGNATION OR PROGRESS? E. HagmOller, H . - D . Saeger and M. Sauer

T - C e l l D e p e n d a n t S c r e e n i n g Systela to Detect Colon Carcinoma.

From 1973 to 1986, 26611 patients were operated on f o r the f i r s t time f o r colorectal carcinoma at o u r hospital. All patients were r e g i s t e r e d systematically and the early and long-term postoperative results were analysed. Progress could be attained in major points: I. The hospital lethality could be markedly reduced (1973-1977:12.9 %; 1978-1982:6.9 % and since 1983: 3.~, %). The lethality is less than 3 % f o r elective o p e r a tions. 2. The postoperative complications were also reduced ( e . g . rate of anastomosis insufficiency: 3 %). 3. The long-term followup shows a significant improvement of the global actuarial f i v e - y e a r s u r v i v a l (n = 1231 patients; 1973-1976:44.1%; 1977-1978:45.4 %; 1979-1980:52.4 %), b u t the rate o f c u r a t i v e s u r v i v a l also increased signiflcantly frQm (}0.! % to 70~ %. 4. In recent years, c o n t i n e n c e - p r e s e r v i n g methods (deep a n t e r i o r resect!on, transanal tumor resection) have been carried out to a g r e a t e r e x t e n t than rectal e x t i r p a t i o n s . The f i v e - y e a r actuarial s u r v i v a l s f o r the resection treatment (66,6 %} were markedly h i g h e r than in rectal e x t i r p a t i o n (48.6 %). In the comparison of the two operation g r o u p s , there were no differences f o r degree of d i f f e r e n t i a t i o n , tumor stage or age of the patients.

k.H.Link,

K.H.Muhrer,

Ch. Gisa, a n d H . G . B e g e r .

Chir.l~

U n i v e r s i t y U l m (K.H.L. a n d H . G . B . , Head:Prof. H.G.Beger) a n d D e p t . G e n . Surg., U n i v e r s i t y G i e s s e n ( K o H . M a n d Ch.G., H e a d t P r o f . K . S c h w e m m l e ) . A h u m a n c o l o r e c t a l c a r c i n o m a cell l i n e N N G 6 4 / 8 @ w a s e s t a b l i s h e d and w e l l c h a r a c t e r ized. T h e cells w e r e u s e d as a n t i g e n s o u r c e in an e l e c t r o p h e r e s i s m o b i l i t y t e s t (EMT) w h e r e T - c e l l r e a c t i v i t y o f b l o o d from %estpersons was d e t e r m i n e d by a n d i n d i r e c t i n d i c a t o r syst~l. T e s t p a t i e n t s s h o w e d the f o l l o w i n g r e a c t i o n s ( p o s i t i v e / t o t a l t e s t e d (in%) ): H e a l t h y c o n t r o l s .............. 1/18" Inflammatory large bowel disease ~/19 Colon adenomas - tubulous O/ 8 Colon adenomas - villous 8/ 9 Large bowel carcinoma 20/21 pther malignancies . . . . . . . . 0/ 8

(6) (21) (O) (89) (95) (O)

T h i s n e w l y m o d i f i e d EMT, by u s i n g e c e l l l i n e i n s t e a d of t u m o r % i s s u e e x t r a c t s as a n t i g e n sou/-ce, s e e m s to be h i E h l y s e n s i t i v e in d e t e c t i n g c o l o n c a r c i n o m a a n d v i l l o u s adenoma. C u r r e n t l y w e are w o r k i n g on a b i o l o g i c a l l y m o r e r e l e v a n t system i n d i c a t i n g a n t i g e n effector cell reactions.

C h i r u r g l s c h e Klinik am Klinikum Mannheim d e r U n i v e r sit/~t Heidelberg, T h e o d o r - K u t z e r - U f e r , D-6800 Mannheim

1/P-GM 074

1/P-GM076

I N T R A O P E R A T I V E D E L I N E A T I O N OF B O R D E R S FOR R E S E C T I O N OF RECTAL C A R C I N O M A B,HINDRINGER, H , J , S E I B The incidence of local tumor reccurence after anterior rectum resektion for c a r c i n o m a appears closely related to the d i s t a n c e of the line of resection from the tumor. In general, the surgeon is primarily responsible for the decision of the resection limits to be established. On use of the stapler technique, the tissue ring, as well, is a c c r u e d into the estimation, To assess the r e l i a b i l i t y of these estimations, the s u r g i c a l specimens from i00 of the 262 rectum resections performed for adenocarcinoma between August I, 1984 and November 30, 1986, for comparison of the surgeon's appriasal with the m e a s u r e m e n t s of the pathologist. Since 90% of the i n t e r v e n t i o n s were p e r f o r m e d by 8 surgeons, a substantial degree of experience can be assumed. The intraoperatively chosen d i s t a n c e from the tumor averaged 5.22!2.1icm, well within the prerequisite limits. Standardized measurements by the pathologist, however, demonstrated errors in 95% of the estimations; in 22% the magnitude of which ranged between 2-3cm. Consequently, the critical m a r g i n of s a f e t y m a y not have been achieved. Even the a d d i t i o n of the tissue thickness (1,Scm) of the ring does not assure a d e q u a t e distance: in 87% the h e i g h t of the donut in the c i r c u m f e r e n c e v a r i e s and can show differences of up to 12mm. Accordingly, with respect to m i n i m i z i n g local tumor recurrence, on-site monitoring by the pathologist of the limits of resection chosen by the s u r g e o n w o u l d seem warranted. First Department of Surgery, N E U P E R L A C H City Hospital, Munich, F,R,G.

GASTROINTESTINAL CARCINOIDS D I A G N O S T I C AND F U N C T I O N A L ASPECTS U. F i n k e n and J. Vogel C a r c i n o i d s are o o t e n t i a l l y m a l i g n a n t n e o o l a s m s of the d i s s e m i n a t e d e n d o c r i n e cell system. T h e y may occur in any part of the g a s t r o - i n t e s t i n a l tract. 33 c a r c i n o i d tumors in f o r e q u t , m i d q u t and endgut l o c a l i s a t i o n were e x a m i n e d for the f r e q u e n c y of various d i f f e r e n t i a t i o n p a t t e r n s , P r o d u c t i o n of m u c o u s s u b s t a n c e s and i m m u n o r e a c t i v i t y for IO d i f f e r e n t amine and m e D t i d e hormones. C o n v e n t i o nal silver staining m e t h o d s w e r e c o m o a r e d with s o - c a l l e d n e u r o e n d o c r i n e markers. More than 2/3 of the tumors could be c l a s s i f i e d into the group of m i x e d d i f f e r e n t i a t i o n , w i t h a p r e v a l e n c e of solid and adenoid structures. ~'Chromogranin" s h o w e d m o s t intensive r e a c t i o n s in m i d g u t c a r c i n o i d s , a p p a r e n t l y r e l a t e d to solid and/or a d e n o i d d i f f e r e n t i a t i o n . w h e r e a s for "Neur o n - s p e c i f i c E n o l a s e ' , t h e r e was a t e n d e n c y of increasing r e a c t i v i t y seen t o w a r d s the distal parts of the intestine. The c o m b i n e d aDplication of b o t h e n d o c r i n e m a r k e r s turned out to be m o r e useful in the d i a g n o s t i c s of c a r c i n o i d s than silver staining m e t h o d s a c c o r d i n g to G r i m e l i u s and M a s s o n - H a m D e r l . The D < o d u c t i o n of hormonal s u b s t a n c e s ~
$23

1/P-GM077 VALUE OF RADIOGRAPIIY AND ENDOSCOPY FOR DIAGNOSIS OF LOCAL RECURRENCE OF GASTRIC CANCER E.H.J.Eeller~ H.H.S,child~,,,,U.E.DUI1 Within the scope of foll0w-up of operated tumor patients the value of endoscopy and radiography for diagnosis of local recurrence of gastric cancer should be reviewed. In the Chirurgische Universit~tsklinik Mainz(director at this time: F.K[immerle)1010 patients with gastric cancer were treated.46 of them had a recurrence following potential curative first resection.70% of the curatively treated had a close-meshed follow-up examination.50% of the recurrences were manifested within 12 months,80% in 24 months.4 of 46 were operated curatively,20 palliatively secondly. Altogether 33 patients were relaparotomised.The other cases were verified by the cause of death:4 had a dissiminated and 42 a local recurrence. A radiological examination was done of 29 patients,endoscopical in 37 and both in 25 patients. In 18 cases endoscopy was completed by a histological examination. Radiologically 23 of 29 were right p o s i t i v e ( 7 9 ~ six were false n e g a t i v e ( 2 0 % ) ( s e n s i t i v i t y 77,2, specificity 66,6%).Endoscopy was right positive in 23 of 33(69%) and five times false negative (13%)(sensitlvity 91,6%,specificity lO0%).Radiography and endoscopy corresponded in 58%,radiography was false negative in 5 cases compared with endoscopy while endoscopy was false negative in 2 cases in comparison to radiography. Macroscopical and microscopical findings were in agreement in 72%.Three times the biopsy was false negative and only once the macroscopical report. Corzequently for diagnosis of local recurrence of gastric cancer endoscopy is recommended. Ohirurg. Abtlg. Allg.Krhs.Heidberg Tangstedter Landstr.400, D-2ooo IIamburg 62

1/P-GM 079 PARTIAL GASTRECTOvtY, A LOGICAL TREATMENT FOR GASTRIC CAb~ER LIXDE:R O._P..ATIVE ASPECTS ? B. Husemann, E.-A. Burkhardt For patient's somatic comfort the proximal stomach remnat after gastric resection is of high relevance. However, is partial gastrectomy, infact a curative surgicaJ treatment for a carcinoma of the middle and lower third of the stomach, this question will be answered using the pregnosis and the rate of local recurrence (n=7O0,RO, 1969-1985, 2 years fol}owup). Of high importance seems the distance between and resection mating in correlation to LAUREN's eJsssification: local recurrence for the diffuse type totally 19,6%~ over 41 mm 1:[%, below 44 %, for the intestinaJ ceil type totally 14,2 %, over 21 mm 18 %~ below 18% . The prognosis correlates directly: 5 year-survival rate (stage pNO,RO) for the diffuse type over 41 mm 85% i 7, below 43%•

results have the following consequence: The gastric carcinema localized in the (middle or) distal third can be treated by partial gastrectomy~ if the safety margins are sufficient, a situation what is possible in most of the intestinal ceil type. For dif[use type the clearance must be checked very carefully. Mostly a total gastrectamy is necessary.

Ch}rurgische Universit~ts-Klinik , 8520 EHangen

1/P-GM 078

1/P-GM 080

DORSAL SPONDYLODESIS USING BONE CEMENT Ch. Eggers, D. Wolter, B. Huchting

BILIODIGESTIVE OF OBSTRUCTIVE

The spine is the predominant l o c a t i o n of bone metastases, Mainly the lower t h o r a c i c and the lumbar spine is a f f e c t e d . A f t e r a f a i l u r e of r a d i a t i o n or chemotherapy the s u r g i c a l therapy g e n e r a l l y was a decompression of the spinal cord by a laminectomy. This r e g u l a r l y caused an increase in spine i n s t a b i l i t y . So i t was obvious to combine the laminectomy with a spine s t a b i l i z i n g operat i v e procedure. By f i l l i n g the o s t e o l y s i s with bone cement a load c a r r y i n g f i x a t i o n of the metal implants can be achieved, The surgical procedure s t a r t s with a laminectomy in the level of the tumor-affected v e r t e brae. Then the tumor c a r r y i n g v e r t e b r a l bodies and one body c r a n i a l l y and caudally are d r i ! i e d through the pedicles under x - r a y c o n t r o l and f i l l e d with bone cement, A special syringe is used f o r t h i s . Then t r a n s p e d i c u l a r screws are put in and remain u n t i l the cement is hardened, A f t e r polymerisation these screws are r e moved. In the r e s u l t i n g threads the p l a t e screws can be app!iedo Between 1982 and 1987 we performed 44 dorsal spondylodeses procedures at the lower t h o r a c i c and lumbar spine using.bone cement. The mean time o f p o s t o p e r a t i v e s u r v i v a l was 12,8 months in 21 investgated p a t i e n t s . The advantage of the method was the simple and gentle approach from dorsal and the easy p o s s i b i l i t y of decompression o f the spinal cord. In a l l cases f u l l weight c a r r y i n g s t a b i l i t y was achieved, A f t e r the oper a t i o n adjuvant therapy corresponding to the type o f tumor was applied. Abteilung f . U n f a l l - , Wiederherstellungs- und Handc h i r u r g i e - Allgem. Krankenhaus St. Georg LohmOhlenstr. 5, D-2000 Hamburg I

for the

intestinal cell type over or below 20 mm 68-72%. These

ANASTOMOSIS SURGICAL TREATMENT JAUNDICE IN BILIARY AND PANCREATIC CANCER -

J,Schmidt Obstructive jaundice caused by biliary and pancreatic cancer is an acute life-threatening situation. The present study from %he department of surgery of the district hospital of Detmold is a retrospective review of 55 cases of obstructive jaundice in those malignancies, treated in a 12-year period with a hiliodlgestire anastomosis with attention to clinical features, diagnostic problems and surgical therapy. 14 patients had a biliary malignancy and 41 patients had a pancreatic malignancy. The bile flow was surgically reconstructed with choledoeho-duodenostomy in 46 cases, with choledocho-jejunostomy in 4 cases and with hepatlco-jejunostomie in 5 cases, 20% of patients died postoperatively within 30 days. 70.9% died because of their basic disease in mean 6 1 months after surgical treatment. Pancreatic malignancies had a slight longer survival-rate than biliary malignancies - 6,7 to 4.6 months~ 9.1% of patients live at this time, in mean 18.8 months with %his c h o l a n g i o - e n t e r o s t o m y According to our results we emphasize the biliodigesrive anastomosis as a convenient method for surgical treatment of obstructive jaundice in hillcry and pancreatic cancer in advanced stages.

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1/P-GMO81

1/P-GM 083

WHICH RECONSTRUCTION AFTER TOTAL GASTRECTOMY? - WELL-BEING AS AN ENDPOINT IN A RANDOMIZED CLINICAL TRIAL (RCT) FOR GASTRIC CANCER

CHRONIC ATROPHIC GASTRITIS AS A P R E C U R S O R F O R GASTRIC CARCINOMA - AN EPIDEMIOLOGIC STUDY K, Kayser, H.U. Burkhardt, H. Kattan, R. Meier, W. Sehmid

THERAPY

....

H. TROIDL~ J. KUSCHE, EYPASCH and U. MAUL

K.-H.

VESTWEBER,

E.

After total gastrectomy a reconstruction of the digestive tract by esophago-jejunostomy (EJ) was compared with the formation of a gastric pouch according to Hunt-Ls~rence-Rodine (HLR). Besides conventional variables like mortality or complication rate~ patient's well-being ~as chosen as endpoint. In a RCT 58 patients ~ere included (18 EJ; 20 HLR) until no~. For measuring patient's wellbeing a score-system was developed (14 points: best 0 points: worst) comprising disease specific and socio-personal variables. 1 y after operation 15/38 (39%) patients were alive. Until I/2 y after operation hunger and appetite ~ere strongly reduced, the food intake was < 1/2 of preoperative values and body weight decreased by 7kg on average. Patients dying within 1 y after total gastrectomy suffered an irreversible loss of well-being (scoring ca. 7 points). Patients surviving this period regained well-being and exceeded preoperative values especially after HLR. Patients ~ell-being turned out to be a useful objective t o evaluate operation procedures of otherwise similar outcome criteria (morlality~ complication rate, etc.) II. Chirurgischer Lehrstuhl der Universit~t zu K~In, Chirurg. Klinik K~in-Merheim, Ostmerheimer Strasse 200, D-5000 K~In 91

A p o p u l a t i o n - b a s e d study of histological proven chronic atrophic gastritis was performed in the district of North-Baden for the years 1971-1980. All patients w i t h gastroscopie biopsies sent to the Pathological Institutes of the district were analyzed for the morphological findings and for developing a gastric carcinoma. The following results were obtained: Biopsy specimens of the stomach were taken out from 41.995 males and 26.712 females. An increasing frequency of the gastroscopies was n o t e d with 2.467 gastroscopied patients in 1971 and in 13.887 patients in 1980. The predominant part of the biopsies was taken from the antrum (62%) and from the corpus (28.5%). Ulcerous lesions were found in 8.6%, a chronic gastritis in 80.6%, and a chronic atrophic gastritis in 29.0% of the patients which was located in the corpus in 28.1% and in the antrum in 69.9%.1.303 patients (810 males and 439 females) developed a gastric carcinoma afterwards. A chronic atrophic gastritis was observed in 345 patients (26.5%) in this case being located in the corpus in 30.9% and in the antrum in 61.9%. The data indicate that the chronic atrophic gastritis of the corpus m u c o s a (type A) is associated w i t h a higher risk for developing a stomach carcinoma opposite to the chronic atrophic gastritis of the antrum (type B). Thoraxklinik Heidelberg-Rohrbach, ~ 6 9 0 0 Heidelberg

Amalienstr.

5,

1/P-GM082

1/P-GM 084

LARGE BOWEL CANCER PROMOTION BY THE INHIBITION OF POLYAMINE DEGRADATION: CLINICAL ASPECTS OF AN ANIMAL MODEL J. KUSCHE and R. MENNIGEN

Clinical symptoms in patients with partial or ton tel gastric resection after stomach cancer.

Mucosal hyperproliferat~on~ as observed in ulcerative colitis or polyps is regarded to promote large bo~el cancer. Polyamines, ho~ever~ - a key substance of ~hich is putrescina - are known to stimulate ceil proliferation. There~ fore an enzyme like the intestinal diamine oxidase (DAO) which catabolizes putrescine, was suggested to terminate mueosal gro~th~ but its inhibition probably should enhance tumor development in the large bo~el. This was tested in male Fisher-344-raLs (n=30) treated with a treshold dose of the carcinogen azoxymethane which produced by itself no tumor ~ithin I y. If, however~ the specific DAO inhibitor aminoguanidine (AG) ~as added~ 10/15 animals produced large bowel tumors (p = 0.00003). AG by itself is not toxic and does not produce any tumor. During mueosal hyperproliferation the DAO activitiy ~as statistically significant reduced in the large bowel mucosa of rats. This result w a s confirmed also in large bo~el cancer patients. Because aminoguanidine ~as recently proposed by Wieland to prevent diabetic vascular disorders the animal model may be suitable to rule out substances being DAO inhibitors and therefore large bo~el cancer pramotors. Espe~ cially long term intake of these drugs should be avoided.

In an on-going prospectively planned study started in January 1987 we tried to evaluate problems in the aftercare of patients with gastric carcinoma. Ue can actually (11/87) oversee the documented data of 146 gastrectomized patients. According to palliatively or potentially curative planned total or subtotal gaatrectomy and according to the surgical reconstruction the following criteria have been observed: nutritional status, food indigestions, loss of weight before and after surgery and in a delay of 1, 2, 3, 4 years, serum iron, recall-antigenactivity~ OKT 4-8, evidence of reflux-esophagitis and anastomositis as well as gastric pain, dysphagia and other subjective syndrome related to gsstrectomy. Our previous results show that total gastrectomy is associated with a higher loss of weight, a higher incidence of anaemia and meteorism than partial gastrectomy. The frequence of dumping-syndrome, reflux-esophegitis, impaired nutrition and recall-antigen-activity differs significantly between the different groups. 90% of the gastrectomized patients complained about food indigestions such as: intolerance of milk (42,5%), of fried meat (37,5%), of fatty food (30%) and fruit (28,6%).

If. Chirurg. LehrstuhI Universit@t zu Chirurg~ Klinik, Ostmerheimer Strasse D~5000 KSln 91

K~ln~

200~

Severin,

Klinik

M.~ B. Scholz~

Bergisch

Land

H. D e l b r O c k

56 Wuppertal-Ronsdorf

$25

1/P-GM 085

1/P-GM 087

COMBINED TREATMENT IN ANAL CANCZR H. Denecke, R. Roloff

SEPARATION OF TUMOR CELLS FROM DISSOCIATED HUMAN COLON TUMOR TISSUE W. Kemmner and R. Brossmer

Tumor~ of tlle anus are radiosensitive. Combination of r~d~cal sur'gical treatment witll radio-chemotherapy seems reasonable and was examined in a prospective study. 31 patients were treated by radio-chemotherapy since 1982 ~54-70 years old, squameous carcinoma: n-24, basal o i d ca.; n=7). Chemotherapy was applied during day I-5 (Mitomycine C I0 m~/m~ 5• 1,000 m~ 5-Eu/m'), r a d i a t i o n therapy was given by single doses of 200 mGy up to 40 Sy. Radica~ abdomlno-perineal excise.on was performed in 13 p a t l e n t s , local scar excision was done in 3. In 15 pmtients no surgery was done. In 8 patients of the ap,excision group, no tumor was found in the specimen. In 5 patients, res~dua| ~umor had s t i l ! been present a f t e r radio-chemotherapy. In %~e 10cal excisio~ group, in a l l 3 cases %he excised soar tissue showed no ev~de~ue of tumor, The response to radio-chemotherapy showed no dependency for the preoperative h i s t o l o g i c a l c l a s s ~ f i cation ( i . e. basaloid, squameous carcinoma) nor of t~e primary ~umor s~age ( i . e, T2, T3 or T4), According ~o our f i n d i n g s , b e t t e r r e s u l t s of treatment are ach%eved wlZh radio-chemotherapy than with surgery or radiatlor} a10ne. However, there remains a challenge for one t ~ i r d of the patieflbs, We need mo~'e exper'iellce mHd more exdm~nations to d i f f e r e o t ~ a t e between possible prognostic factors. Chirurg. uT)d R~dlu!og. U)IiversiL~tskllnik M~uche~1, K|Inlkum Gro61~adern, Marchlonlnls~r. 15, D-800 M~nc~en 70

For biochemical characterization of tumor cell~ in particular of cell surface parameters, one needs tumor cell preparations devoid of other cell types. By enzymatical and mechanical dissociation of human colon tumor tissue directly obtained from the surgeon, a singlecell suspension could be produced of high cell yield and viability (J.Cancer Res.Clin. 0ncoi.,113, (1987) 400). Analysis of GiemsaWright stained cytofuge preparations of such suspensions revealed the presence of lymphocytes, monocytes and granulocytes in addition to 6 0 - 70% tumor cells. A murine antibody (HEAl25) directed against epithelial cells of the human intestine has been isolated by G. Moldenhauer (DKFZ, Heidelberg). By use of this antibody coupled to magnetic beads (DYNAL, Oslo) it was possible to separate tumor cells from the suspension of dissociated colon tumor tissue. After incubation with these beads about 50% of the tumor cells were bound and could thus be separated. Studies with established lines, a colon carcinoma line (HT-29) and a lymphoma line (Eb) showed that 96% of colon cells but only 9% lymphoma cells were bound to the beads, and that binding could be prevented by co-incubation with antibody HEA-125. Institut fGr Biochemie II der Universit~t Heidelberg, Im Neuenheimer Feld 328, D~6900 Heidelberg

1/P-GM 086 FOLINIC ACID/5-FLUOROURACIL IN PRETREATED PATIENTS WITH FAR ADVANCEDCOLORECTALCARCINOMA A.Schalhorn, J.Lerner, K.Possinger, W.Wilmanns F o l i n i c a c i d / 5 - f l u o r o u r a c i l (FA/FU) is a new approach in the treatment of metastatic colorectal carcinoma with remission rates (RR) of about 30% in untreated patients (pts). We report on our experiences with FA/FU in heavily pretreated pts with advanced colorectal carcinoma. Patients: All pts were pretreated, and FA/FU was 2nd, 3r , ] ~ 4th line therapy in 2, 6, and 8 pts, respectively, of a t o t a l of 16 pts. Tumor burden was substantial in a l l pts, 6 pts with l i v e r metastases only, and lO pts with m u l t i p l e sites of and/or extrahepatie metastases only. Treatment: Pts received FA 80 mg/mz in a 20-hour {IV) i n f u ~ o w e d by 5-FU 400 mg/m2 IV bolus d a i l y for three consecutive days. Then they received FA 80 mg/m2 in a l-hour IV infusion followed by 5-FU 400 mg/m IV bolus weekly. Results; In t h i s small series of pts the results were a s ~ w s : 0 CR, 2/16 PR, 9/16 (=56%) stable disease (SD), and 5/16 (=31%) progressive disease. In pts with PR and SD, median time u n t i l progress was 5.5 months, and median survival time f o r a l l pts was 8.3 months (mean: I0.8 months) from s t a r t of FA/FU. T o x i c i t y ; In 259 treatment cycles t o x i c i t y was assessed~ng to WHO c r i t e r i a . Over a l l , t o x i c i t y was minimal, with grade I l l mucositis and/or diarrhea in 0.4% and 3.5%, respecively, and leucopenia grade I l l or IV a f t e r 1.6% of treatment cycles. There was no case of thrombopenia grade I l l or IV. This treatment modality of combining f o l i n i c acid and 5 - f l u o r o r u a c i l bears some important advantages: Due to i t s low t o x i c i t y , FA/FU can be safely administered even to heavily pretreated pts, and in approximately two thirds of these pts t h i s therapy prevents a f u r t h e r progress of the disease f o r a median of 8.3 months. With support by DFG grant Scha 299/2-I Med.Klinik I11, Klinikum GroF~hadern, Ludwig-MaximiliansUniversit~t, Marchioninistr. 15, 8000 MUnchen 70

1/P.GM088 P n o g n o s t i e ~ac~ons and Clinical Classification for Liven Metastases oZ Colorectal Carcinoma G. M e y e n L E . 0evermann, F.W. Schildbe~g A world-wide accepted classification of liver metastases is of urgent necessity. The lack of it is responsible for the p r a s e n t d i f i L e u l t y o~ assessing the effioiacy of a treatment and its limit in relation to untreated historical controls as w e l l as for the difZiculty of comparing one therapy with another. 77 patients with untreated liver metastases from colorectal carcinoma were attached to the different stages of the Classification of Lausanne (1984), of Gennari (1984))and of the International Staging System (ISS, 1984)'. All classifications showed statistical difZerences of the probability of survival between the staes but ISS was the best discriminating system p=0,O01). The penoent hepatic replacement p=O, O04~), additional sxtrahepatic tumor (p=O, O04)), symptomatic metastases (p=O,006)) and some laboratory parameters seem to b e g o o d p~ognostic factors. C o n c l u s i o n j T h e effectivity os therapeutic procedures and ths therapeutic limits have to be measured in future under consideration of a clinical classification.

l

K l i n i k f ~ Chirurgi~ de~ Medizinischen ~ i versit~t ZGbeck, Ratzeburgen Allee 160, D-2400 Lfibeck

$26 1/P-GM 089

1/P-GM 091

LARGE BOWEL TUMORS AND POLYAMINE METABOLISM IN PATIENTS: A NEW APPROACH FOR RISK GROUP I D E N I I FICATION. R. Mennigen, J . Kusehe~ H. Sommer

N U M B E R ~ R E G I O N A L DISTRIBUTION: SIZE AND METASTATIC INVOLVEMENT OF P E R I G A S T R I C LYMPH NODES IN GASTRIC CANCER. F. Borchard, B. Lohe , A. Mester, and K. Thon.

Diamine oxidase (DAO) is the enzyme which is responsible for the oxidative degradation of putreseine, the central substance of the polyamine metabolism. This enzyme occurs ~ith high activity in the intestinal mueosa and is a very sensitive marker of mucosal integrity. From experiments in rats, ~e suggest, that it has a protective and antiproliferative function in the mueos8. Therefore it man our aim, to study the DAO in patients suffering from large bowel cancer, polyps or having no pathological process of this organ, In 44 patients the DAO activity ~ a s measured i n 55 examinations. In 11 examinations no disease of the large bowel, in 29 examinations adenocarcinomas and in 15 examinations polyps ~ere found. Cancer patients had a DAO activity in the non affected mueosa (11 nmol/min.g) mhich ~as significantly lomer (2 tailed p = 0.0017) t h a n in patients ~ith polyps (37.7 nmol/min*g). The greatest differences, hoNever, had been found between non a f f e c t e d m u c o s a and c a n c e r tissue (I.8 nmoi/min.g; 2 tailed p = 0.O000) and betmeen non affected mucosa and polyps (18,3 nmol/min.g; 2 tailed p = O.0034). We c o n c l u d e , that a u t o n o m o u s g r o w t h o f t h e mucosa is connected ~ith a reduction o f DAn a c t i vity, But also in the not affected mucosa o f these patients alterations o f t h e enzyme ~ e r e observed ~hieh may be a ne~ approach for the definition of risk groups.

Among the factors of p r o m i n e n t p r o g n o s t i c significance is the m e t a s t a t i c involvement of lymph nodes. The number of lymph nodes w h i c h can be prepared is dependant on the extent of lymphadenectomy and standardized pathologic preparation techniques. Since the former factor depends on therapeutic a i m s , w e d e c i d e d to investigate the number, regional distribution, and metastatic involvement of perigastric lymph nodes in total gastrectomy (n=56), and the size dis t r i b u t i o n of normal and m e t a s t a t i c lymph nodes (n=15).The japanese c l a s s i f i c a t i o n of l y m ~ n o des was used, but the position 3 was subd2vided into left (3a) and right (3b) p a r t s . P e r i g a s t r i c lymph nodes and adipose tissue were investigated by serial s e c t i o n i n g . O n the mean 29,1 perigastric lymph nodes per stomach could be found (range 7-61 ).There are two lymphocentra in the p e r i g a s t r i c lymph nodes, e.g. the left lesser c u r v a t u r e ( m e a n : t 1 , 0 nodes)and the right greater curvatur (mean:4,4 nodes)~ W i t h severe lymph node involvement the number of lymph nodes was slightly increased, p r o b a b l y to persistence or d e v e l o p m e n t of v e r y small nodes. As for the size, 56,6 % of the nodes without m e t a s t a s i s were smaller than 3 ram and 13,3 % even smaller than I mm. In m e t a s t a t i c spread the size d i s t r i b u t i o n was only slightly shifted to higher size classes, except for the greatest n o d ~ w h i c h contained m o s t l y m e t a s t a t i c deposits~:In lower size classes partial nodal involvement prevailed.

Chirurg. K61n 91

Klinik,

Ostmerheimerstr.

200,

5000

Pathologisches Institut und Chirurgische Klinik A der Universit~t, M o o r e n s t r a B e 5, 4 D H s s e l d o r f

1/P-GM 090

17P-GM 092

FOLLOW-UP IN RECURRENT CANCER OF THE RECTUM: DIAGNOSIS AND OUTCOME OF SECOND LOOK SURGERY Th. Zoedler,R.Hesterberg, M . K l e i n , u . S e h m i d t

FACTORS1NFLUENCING TREATMENT OF LOCAL RECURRENCE AFTER SURGERY FOR COLO-RECTAL CANCER

This retrospective study deals with the data of 38 patients treated with recurrent cancer of the rectum between 1979 and 1984.0ut of these 38 patients 9 recurreneies were detected on account of pathological findings during follow-up examlnations.These patients were asymptomatic. 6 Of them had a potentially curative reoperation 20 out of 38 patients presented with symptoms on occasion of check-up e x a m i n a t i o n s . 0 n l y 8 of them had a curative second look surgery. In 9 patients,who did not participate in followup,only palliative reoperations were possible. Patients with curative reoperation survived 21 months on average whereas those with a palliative r e o p e r a t i o n h a d a mean survival of 12 months. Survival without therapy was 6 months only.3 patients survived up to now.These 3 patients have been followed up regularely.

This clinical investigation was based on lg3 patients, who developed recurrent cancer of the colon and rectum after intended curative resection. The prognosis after diagnosis of recurrent cancer mainly depends on the stage of the disease indicated by the localisation of the recurrence, the kind of t r e a t m e n t , which could be performed and whether the patient was symptomatic or not. Only in g0% of tumor-relaps another resection was possible. " C u r a t i v e " r e - r e s e c t i o n showed a 5-year-survival-time of 28% and for pure suture line recurrence even of g6%. For palliative resection this rate was 10% and for surgical procedures without resection of the tumor it was 6%. Recurrence in asymptomatic patients found by systematic follow-up was resectable in 60% with a 5-year-survival of 26% while for symptomatic patients these rates were 36% and 8%.

The value of follow -up in eoloreetal cancer has been questioned due to poor results of second laparatomy. In addition it was said that most patients p r e s e n t e d with symptoms when recurrence was d e t e c t e d o ( O , K r o n b e r g , T h e o r . S u r g . 1 , 4 0 - 4 6 , 1 9 8 6 ) . 0 u r results demonstrate,that early d e t e c t i o n of asymptomatic patients w i t h recurrent cancer of the rectum can be achieved by a careful follow-up.Those patients have a higher chance of a curative second look surgery. K l i n i k f~r Allgemeine und Unfallohirurgie der m e d i z i n i s c h e n E i n r i e h t u n g e n der UniversltNt DUsseldorf,Moorenstr.5,D-4000 D ~ s s e l d o r f

V.Lange, G.Meyer, F.W.Schildberg

Co__nclusionsL" Systematic follow-up after resection of colarectal cancer in creases the rate of resectable recurrence and survival time, The relapsed cancer should be resected whenever possible because of extended survival. Except in disseminated disease surgery should be undertaken for there is a lack of alternative t r e a t m e n t procedures. Klinik Ifir Chirurgie der MUL, Ratzeburger Allee 160, 2#00 L~ibeck, West-Germany

$27 1/P-GM 093

1/P-GM 095

PATHOHISTOLOGICAL AND IMMUNOHISTOCHEMICAL INVESTIGATIONS OF C~DIA CARCINOMA AS A SEPARATE ENTITY OF GASTRIC CARCINOMA: G.Heidl, P.Langhans*, l.Awlasewicz*, V.Krieg, E.Grundmann

ADEQUATE SECONDAHY THERAPY IN RECURRENT PAPILLA/Tf CARCINOMA - A 22 YEARS CLINICAL STUDY REPORT Th.H61ting, H.Meybier, H.Buhr, P.Georgi .........................................................

According to the l i t e r a t u r e gastric cardia carcinoma must be considered an e n t i t y of i t s own. For this reason, a t o t a l of 900 operative specimens and biopsies of gastric carcinomas were examined using classical h i s t o pathological and immunohistochemical techniques. Signif i c a n t differences were detected with regard to sex dist r i b u t i o n (male : female = 4,2, resp. 1,45; p<0.0005), d i s t r i b u t i o n of carcinoma types according to Borrmann (p<0.0005), as well as histopathologic c l a s s i f i c a t i o n according to the WHO (p< 0.0005), MING (p<0.005) and LAUREN ( p < 0.001). Cardia carcinoma more frequently shows types I and I I according to Borrmann, d i f f e r e n t i a t e d carcinoma according to WHO, the expansive type according to MING, and the i n t e s t i n a l type according to LAUREN. Because of the early onset of complaints, operations are performed early so that the stage of i n f i l t r a t i o n on average w i l l not be as advanced as in gastric carcinoma below the cardia (p<0.005). Immunohistochemical investigations have shown that tumor cells positive for alpha~-anti-chymotrypsin in cardia carcinoma occur in a high4r amount than in antral or pyloric carcinoma, respectively (p <0.05). PD.Dr. Gerhard Heidl, Gerhard-Domagk I n s t i t u t fur Pathologie der Westf~lischen Wilhelms-Universit~t, Domagkstr. 17, D-4400 MUnster *) Chirurgische U n i v e r s i t ~ t s - K l i n i k , Jungeblodtplatz I , D-4000 MUnster

[_n__t_re_duc_t_ion:Despite of favourable prognosis of papillary thyroid carcinoma in cases of t~mour recurrence the evaluation of prognostic parameters and of adequate treatment modalities continuous to be controversial. In a retrospective study the incidence of recurrence and the results of a combined therapy have been analysed. M__at_eri_a!_a~_d__m_e_t_h_od_si_ 155 pat ients suffering from papi llary thyroid carcinoma were treated between 1964-1986. Recurrencies were observed in 27~, 26~ of these patients died due to their turnouts. The analysis comprehenses the prognostic value of age, sex, staging-results, extension of s%trgical therapy, postoperative radio iodine therapy as well as kind and efficeney of secondary treatment. _H_es_u!ts: - Follow up studies (median 8 years, 0.5-22 y) showed 10 local recurrencies, 15 lymph node and 8 distant metastases. Age at the time of diagnosis and primary tvmour stage were the most important prognostic factors, Differences in the extent of primary surgery had no influence on mortality in intrathyroidal turnouts without lymph node metastases. Prognosis of local recarrencies (mortality 60~) and lymph node metastases (80~ cured) was significantly different. Regarding the type of retreatmeat radio iodine therapy was curative in 87~ (mostly regional metastases) while 69% of patients with surgical or combined therapy had further reeurrencies or died. Conclusions: Age at the time of diagnosis and primary tabour stage are important for recurrent disease. In patients with recurrent lymph node metastases and a positive radio iodine scan survival results were satisfactory after secondary radio iodine therapy while the prognosis of local recurrencies was limited even with combined therapy. Chirurgische Universit~tsklinik, Abteilang Neuenheimer Feld II0, sqo0 Heidelberg, FRG

2. I. I,

1/P-GM 094

1/P.GM096

ENZYME ACTIVITY OF DE NOVO AND SALVAGE PATHWAYS FOR PURINE NUCLEOTIDE SYNTHESIS IN TWO HUMAN COLON CARCINOMA GROWN IN NUDE MICE AND ~FURINE LIVER. P.Dias Wickr amanayake, N. O. Klein

COMBINED MODALITY TREATMENT OF HEPATOMA A CASE REPORT H. M u e l l e r , H. W a l t h e r , K.R. A i g n e r Dept. of Surgery, KKH T r o s t b e r g , S i e g e r t h o e h e D-8223 Trostberg

The enzyme actLvities of the de novo and salvage pathways for pnrine nucleotide synthesis were compared in two human colon adeno carcinoma of different proliferations rates and in marine liver.Assays were worked out for measuring the activity of adenine phosphoribosyltransferase (APRT) hypoxanthine phosphoribosyltransferase(HPRT) and guanin phosphoribosyltransferase(GPRT)and also amidotransferase activity using tissue extracts.MichaelisMenten kinetics (Km)were calculated for these enzymes. The reciprocal plots for phosphoribosylpyrophosphat(PRPP) were calculated for APRT activity in both colon carcinomas and liver and found a PRPP concentration of 25 uM and was not inhibited by excess of PRPP.HPRT and GPRT in both carcinoma and liver were saturated at a concentration of 65 uM PRPP.The Km value of 2,2 uMfor APRT and 5 nM for HPRT and GPRT show two orders of magnitude higher affinities for PRPP than the rate limiting enzyme amidophosphoribsyltransferas of de novo synthesis for which the Km ranges from 300-800 uM in two colon carcinomas and liver. Enz[me activity (nmo]Jh/m$ protein) de novo salvage pathways Tissues Ami!otransferas APRT GPRT HPRT Colon CaI 23 • 1,5 861-+13 2311+28 915-+6 Colon CaII 19+0,7 840-+9 2375+16 740+11 Liver 21+1,6 548+11 1316+14 418-+5 High capacity of salvage enzyme activity may explain the insufficient inhibiting of de novo synthesis with most cytostatic drugs resulting in poor therapeutic effects.A rational basis for cancer treatment has to combine drugs which inhibit de novo and salvage pathways to gain better therapeutic results in cancer chemotherapy. Medizinische Universititsklinik I,Joseph-Stelzmann-Str~9 D-5000 K61n 41

im

1

H e p a t o m a s u s u a l l y are d i a g n o s e d in a p r o g r e s s e d s t a g e w h e r e c h a n c e s for c u r a t i v e m a j o r l i v e r res e c t i o n are poor. D e v e l o p m e n t of d i f f e r e n t c h e m o e m b o l i z a t i o a techn i q u e s has d e f i n i t e l y c h a n g e d p r o g n o s i s and prol o n g e d life e x p e c t a n c y of h e p a t o m a p a t i e n t s . Nonreseetable tumors after chemoembolization f r e q u e n t l y turn out to be r e s e c t a b l e again. S i n c e s y s t e m i c c h e m o t h e r a p y for h e p a t o m a s u s u a l l y a f f e c t s q u a l i t y of life m o r e than the tumors r e s i s t a n c e we tried a n e w m e t h o d of a o r t a l h i g h dose c h e m o t h e r a p y w i t h c e n t r a l v e n o u s d r u g f i l t r a t i o n in a p a t i e n t h a v i n g no more viable hepatic arteries after ehemoembolis a t i o n for i n t r a a r t e r i a l access. M e t a s t a s e s w e r e supplied by secondary capillarisation. A 1 4 - y e a r old p a t i e n t w i t h e x t e n s i v e l i v e r enl a r g e m e n t from h e p a t o m a in b o t h lobes had combination treatment chemoembolization, resection and i.a. infusion. D i s e a s e free i n t e r v a l was two years. T h e n r e c u r r e n c e was t r e a t e d w i t h ADM 80 mg a o r t i c i n f u s i o n and d r u g f i l t r a t i o n in two courses. C o m p l e t e r e m i s s i o n o c c u r e d . T o t a l f o l l o w up is three y e a r s the A F P - c o u r s e is d e m o n strated.

$28 1/P-GM 097

1/P-GM 099

INFLUENCE OF AGE ON CLINICAL COURSE AND PROGNOSIS OF PATIENTS WITH COLORECTAL CANCER E. M o z d z a n o ~ s k i , L. Hoffmann

SCREENING FOR COLOREL-~ALCANCER OF INHOSPITAL PATIENTS. D. Wdrdehof f

From 1978 to 1980 263 patients with colorectal cancer were treated in the general hospital Barmbek. ll6 mere evaluable for this retrospective study: 22 ~ere younger than 50, 94 older than 70 years. Clinical courses of both groups ~ere compared ~ihh the following results: stages Dukes A B1 + B2 C

+ C2

DI X preoperative i leus preoperative perforation coecal logalisatiom Hb <9 g/dl curative operation palliative operation postoperative mortality uncorrected 5 y. survival rate 5 y. surv. rate curative op. medium duration of survival (pall. o p . )

< 49 y. 14Z 32~

> 70 y.

27%

39N

27%

27% 9% 18% 4% 18% 14%

5% 9~ 68% 23% 9% 36% 57% 12 mo.

26~

33%

62% 26% 20% 53% 17 mo.

Age i s not the single predominating prognostic factor. Prognosis i s primarily correlated ~ i . t h tumor stage and operability. The ~orse overall 5 years survival rate of the older patients is caused by indirect (partially) age-related facfiors: frequency of emergency operations for Jleus/perforation, comorbidity, p o s t o p e r a t i v e mortality, palliative surgery.

A PROSPECTIVE STUDY

Today theadenoma-carcinoma-sequence in the colo-rectum is accepted. With the spread of colonoscopy the diagnostic - and therapeutic - approach to the colon has become easy. The examination of stool with occult blood test is a simple and effective method for screening, but testing is not enough practised. Therefore over two years all patients in an internal department were invited to perform a fecal occult blood test(Hemocult) in the first days of stay. 74,2%(3494 from 4707) admitted patients could be evaluated. One half of the missedtests are caused b y t o o short stay or dangerous illness, the other(12,5%) are forgotten or refused inspite of repeated invitings. 195 patients had a positive test, 94 had a examination with c~lonoscopy, i01 were not explored, 55 because of missingtherapeuticconsequences, 36 because of known bleeding sources in the UGI-tract, only ii because refusing colonoscopy. 94 patients could be examined, 27 carcinomas were detected, 57 polyps in 36 patients(5 adenomas with severe atypia) were endoscopically removed. Theresults demonstrate: I) the motivation of patients as for testing as for examination seems easier in the clinic. 2) a great ntmlber of findings could bedetected and treated. Webelieve that clinical testing cancomplete ambulant screening and improve the rate of earlyrecognised colorectal tumors. Internal department of hospital St. Michael, KOhlweinstr. 103, D-6620 Vdlklingen

Onkologische Abteilung, Allgemines Krankenhaus Barmbek, RObenkamp 148, D2000 Hamburg 60

1/P-GM 098

1/P-GM 100

GASTRIC CANCER - CORRELATION BETWEEN AGE AND PROGNOSIS L. Braun

INTRAOPERATIVE DELINEATION OF BORDERS FOR RESECTION OF RECTAL CARCINOMA B.HINDRINGER, H . J , S E I B The incidence of local tumor reccure~ce after anterior rectum resektion for carcinoma appears closely related to the distance of the line of resection from the tumor, In general, the surgeon is primarily responsible for the decision of the resection limits to be established. On use of the stapler technique, the tissue ring, as well, is accrued into the estimation. To assess the reliability of these estimations, the surgical specimens from 100 of the 262 rectum resections performed for adenocarcinoma between August i, 1984 and November 30, 1986, for comparison of the surgeon's appriasal with the measurements of the pathologist. Since 90% of the interventions were performed by 8 surgeons, a substantial degree of experience can be assumed. The intraoperatively chosen distance from the tumor averaged 5.22• well within the prerequisite limits. Standardized m e a s u r e m e n t s by the pathologist, however, demonstrated errors in 95% of the estimations; in 22% the magnitude of which ranged between 2-3cm. Consequently, the critical margin of safety may not have been achieved. Even the addition of the tissue thickness (l,Scm) of the ring does not assure adequate distance: in 87% the height of the donut ih the circumference varies and can show differences of up to 12mm. Accordingly, with respect to m i n i m i z i n g local tumor recurrence, on-slte monitoring by the oathologist of the limits of resection chosen oy the surgeon w o u l d seem warranted.

Between 1974 - 1987 4o3 patients with gastric cancer have been treated operatively. Correlations between age, sex, tumor stage, operability, operative mortality, postoperative complication rate, and prognosis are analyzed.Postoperative mortality and complications, percentage of female patients, advanced tumors, and inoperability increase significantly with age. The fate of all patients was followed closely. 239 patients were operated upon between 1974 and 1981, their follow-up ranges between 5 and 13 years. The total 5-year-survival rate for this group is 13.0 %. The prognosis gets worth with increasing age due to a higher postoperative mortality and death rate according to age related diseases. There was no difference in number of local recidives or metastases. Tab.1 Age Postop Postop Inopera- Palliative 5-Y-Sur Morta. Compli. bility Surgery rival

31-4o 41-5o 51-6o 61-7o 71-8o 81-% 91-Ioo

o o 4.8 8.2 18.8 41.5 33.3

5o.o 31.6 23.8 3o.3 34.9 41.5 66.7

o 15.8 2o.6 15.6 14.8 14.6 33.3

o Io.5 17.5 2o.5 2o.I 36.6 o

Ioo.o 46.2 15.2 11.1 6.0 o o

total

14.6

33.3

15.9

2o.6

13.o

Chirurgische Abteilung des Kreiskrankenhauses RSntgenstr. 18 D 493o Detmold

l. Chlr.Abteilung 8t&dt,Krh. MOnchen-NEUPERLACH, O s k a r - M a r l a - G r a f - R i n q 51 8000 M~nchen 83

$29

1/P-GM 101 GROWTH DYNAMICS

E Paul,

1/P-GM103 OF MALIGNANT MELANOMA

KD SchStterl,

A Henkelmann,

RH B6deker

Photocatamnestic studies have shown that the development of m a l i g n a n t m e l a n o m a s may last for m a n y years. However, since determination of the t i m e of g r o w t h of l u n g m e t a s t a s e s from malignant m e l a n o m a had s h o w n tumor doubling t i m e s t h a t v a r i e d b e t w e e n 9 a n d 298 days, it was d o u b t e d w h e t h e r p h o t o c a t a m n e s t i c a l l y d o c u m e n t e d p r o t r a c t e d t u m o r g r o w t h was r e p r e s e n t a tive for all m e l a n o m a s . Therefore, the m e a n a g e s w e r e d e t e r m i n e d in a major g r o u p of p a t i e n t s w i t h t u m o r s of equal levels a n d t h i c k n e s s to f i n d out the periods in w h i c h i n i t i a l , thin, low-level melanomas d e v e l o p to a d v a n c e d t u m o r s of g r e a t thicknesses a n d h i g h levels. It was s h o w n t h a t the p e r i o d s were similar w i t h r e g a r d to b o t h l e v e l a n d t u m o r thickness a n d t h a t the m e a n p e r i o d s of t i m e development from i n i t i a l i n v a s i v e to a d v a n c e d S S M or NM w e r e a b o u t I0 years. E x t e n s i o n into the d e r m i s seems to o c c u r in a r e g u l a r manner, for it takes 2-3 y e a r s for the m e l a n o m a s to proceed f r o m one l e v e l or t u m o r t h i c k n e s s e a t e g o r y to the n e x t one. It was t h e r e f o r e c o n c l u d e d t h a t p h o t o c a t a m n e s tieally d o c u m e n t e d f i n d i n g s are q u i t e repres e n t a t i v e a n d that m e l a n o m a s g e n e r a l l y d e v e l o p over many years, so that early detection s h o u l d be p o s s i b l e in a n y case.

3 1 - P S P E C T R O S C O P Y IN A M A L I G N A N T M E L A N O M A LYMPHNODE METASTASIS I.C. K i r i c u t a , H . H ~ t z i n g e r , R . BiHmm, H.K.

Beyer

T h e M a l i g n a n t M e l a n o m a is a h e t e r o g e n o u s t u m o r r e g a r d i n g the m i c r o e n v i r o n m e n t a l c o n d i t i o n s . T o o b t a i n s o m e i n f o r m a t i o n a b o u t the v a s c u l a r i t y o f the M M - l y m p h n o d e m e t a s t a s i s w e p e r f o r m e d an DSA-study. Also we used MR Imaging and 31-P S p e c t r o s c o p y to o b t a i n i n f o r m a t i o n a b o u t the p a t h o l o g i c a l a n a t o m y and In V i v o b i o c h e m i s t r y o f this t u m o r . T h e d i m e n s i o n s and l o c a l i s a t i o n s p e r m i t t e d the use of the s u r f a c e coil m e t h o d . T h e t u m o r s p e c t r u m is c h a r a c t e r i z e d b y the p r e s e n c e of s i g n a l s c o r r e s p o n d i n g to P M E , P i , P C r and~-~-~-ATP. The c a l c u l a t e d i n t r a t u m o r a l p H is 7. 3985. D i s p i t e of a h i g h d e g r e e of v a s c u l a r i t y of the tumor, t h i s p H v a l u e is c o n s i s t e n t w i t h a low o x y g e n a t i o n r e s p e c t i v l y l a r g e a r e a s of n e c r o s i s . T h e a r t e r i a l v e n o u s s h u n t s d e m o n s t r a t e d b y the D S A - s t u d y m a y a c c o u n t for this c o n t r o v e r s i a l f i n d i n g : a h i g h d e g r e e of v a s c u l a r i t y vs. a l c a l i n e status. Per

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1/P-GM 102 IN SITU DETECTION OF ~ L A ~ D ~ MEASUR~S

Bochum,

1/P-GM104 By F L U O R E S ~

W. Imhmann* and E. Paul+ Att6~pts to d e t e r g e melanc~as in situ have been han~2e_red primarily by the non-availability of suitab]e techniques and, of course, by the ignorance about the molecular reactions involved in forming this type of cancer. Here we report cn a non-invasive and nondestructive fluorescence measure2nent using a natural] v occurring chrcmophore which e~hibits a fluorescence band at about 475 nm if excited with a monochrcmatic wave~ length at 366 nm. By using an ontical multi-channel analyzer (OMAJ, the fluorescence snectra can be recorded in a millisecond range. The results show that at the edge of the malignancy the fluorescence intensity is considerable higher than in healthy tissue, while no fluorescence could be detected yet in the flat tumor re~ion. In the case of a mole (naevus cell naevus), the increase in fluorescence intensity at the rim couldn't be observed. in the mole region the intensity measured was about 20'% of healthy tissue. It is, thus, nossible to use this method for an in situ detection of melanomas and, thus, for distinguishing between them and moles. This avoids an unnecessary surgery. Furthermore, the extent of the malignancy can be determined by scanninq the tumor a n d . its surroundings. *Institut ffir Biophysik und +Hautklinik der Universit~t, Leihgesterner Weg 217, D~.6300 Giessen

EXPLORATORY STATISTICS OF MELANOMA GROWTH PATTERN O. Leder, H. Kurz and H. Wokalek Tumour thickness as a decisive diagnostic a t t r i b u t e is dependent from the growth pattern of melanomas in h o r i z o n t a l or v e r t i c a l d i r e c t i o n . Ackerman's unifying concept (Hum. Pathol. I I , 1980), t h a t a l l melanomas i n i t i a l l y grow h o r i z o n t a l l y makes comprehensible the amount of intermediate forms between the d i f f e r e n t classes (LM, LMM, SSM, NMM, ALM). For a more q u a n t i t a t i v e approach to understanding the d i f f i c u l t i e s in d i s c r i m i n a t i n g melanoma types by t h e i r growth pattern, a r e c l a s s i f i c a t i o n of tumours (1976-79) o f the U n i v e r s i t ~ t s - H a u t k l i n i k Freiburg wa~ c a r r i e d out without consideration o f e l a s t o s i s , l o c a l i z a t i o n , and previous diagnosis. The table c l e a r l y shows, t h a t the d i f f e r e n t i a t i o n by growth pattern alone has i t s l i m i t a t i o n s . Especially LMM and SSM present d i f f i c u l t i e s in d i f f e r e n t i a t i o n , i f e l a s t o s i s and l o c a l i z a t i o n are not considered. In a d d i t i o n , NMM on one side, and LMM or SSM on the other may not be d i s t i n g u i s h e d in every case as i t is ~o be expected assuming a h o r i z o n t a l growth phase even in NMM. Table: Concordance o f c l i n i c o - p a t h o l o g i c a l diagnosis (CPD) and three c l a s s i f i c a t o r y runs (by one o f us). CI: concordance o f f i r s t run and CPD; C2 and C3: concordance o f two c l a s s i f i c a t i o n s ( i n c l u d i n g CPD). NC: not c l a s s i f i e d . LM

LMM

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1/P-GM 105

1/P-GM 107

MELANOMA AND ACTINIC DAMAGE OF THE H. Kurz, O. Leder and K. Martay

SK!N

CLONAL EXPRF~SlON OF ~JLTIPLE TUMOR ANTIGENS IN MELANOMA DETECTED WITH CYTOLYTIC T LYMPHOCYTE (CTL) CLONES A.Knuth,T.Wolfel,E.Klehmann,K.-H.Meyer zum Buschenfelde

The r o l e o f a c t i n i c damage in the development o f cutaneous malignant melanoma is regarded controversely. The-question cannot be decided without an o b j e c t i v e m e a s u r e ~ f r a d i a t i o n exposure a t the tumour s i t e . Therefore, an automated s t e r e o l o g i c a l q u a n t i f i c a t i o n of a c t i n i c e l a s t o s i s in the skin around the tumour was performed ( l i n e a r a n a l y s i s , c f . Acta Stereol 6, 1987). For t h i s r e t r o s p e c t i v e study, 166 p a t i e n t s with l e n t i g o maligna melanoma or s u p e r f i c i a l spreading melanoma (years 1975-79, U n i v e r s i t ~ t s - H a u t k l i n i k Freiburg) were i n v e s t i g a t e d . They were grouped on sex, age and tumour s i t e (sun-exposed (sx): head, ~eck, forearm, leg ~ 32% surface, non-exposed (nx): truthS, upper arm, thigh ~ 68% surface). Number o f cases (n) and mean values f o r volume f r a c t i o n e l a s t o s i s (V), as a p a r t of the e x p l o r a t o r y s t a t i s t i c s employed, are given in the contingency t a b l e s below. They demonstrate, that only f o r women over 40 tumour incidence may be corre.latEd with r a d i a t i o n damage, r a t h e r than with amount o f skin surface involved. For men and f o r younger women the tumour incidence remains the same and i s not r e l a t e d to e l a s t o s i s . For comparison, spinaliomas from 21 patients ( s e l e o t e ~ a t random from year 1980) showed no sex preference, more than 95% of them ~ere located in exposed regions, and a l l had marked e l a s t o s i s (V=62.7 vs. 32.8 in melanomas). I t may be concluded t h a t , in c o n t r a s t to spinaliomas, l i g h t exposure alone cannot account f o r the observed melanoma d i s t r i b u t i o n , l e a s t in younger p a t i e n t s , age >4__00

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Tumor specific antigens in human cancer have not been defined, yet. The ~lOst compelling evidence for their existence comes from serological studies defining such antigens with autologous serum antibodies in malignant melanoma and a few other cancers (L.J.Old, Cancer 41: 361, 1981). In continuation of earlier studies with autologous CTL clones against malignant melanoma (A.Knuth, PNAS 81: 3511, 1984) we pursued this approach to define tumor antigens on human melanoma by autologous T lymphocytes clones. Melanoma cell lines were cloned at limiting dilutions and cocultured with autologous peripheral lymphocytes in vitro. Stimulated T lymphoblasts were propagated in rIL2 (BIOGF_N) and cloned in the presence of irradiated autologous tumor cells and feeder cells. CTL clones with specificity for autologous melanoma target cells but not other autologous or allogeneic targets were isolated in two melanoma systems (AV and MZ-3). All CTL clones tested were T3+, T4-, T8 +. The cytolytic activity was blocked by monoclonal antibodies specific for HLA class I, T8, and T3. In the AV melanoma system tumor cell clones were identified that had lost t/le expression of single antigens after immunoselection experiments with specific autologous CTL clones. Other autologous CTL clones and allogeneic CTL clones specific for the AV allotype still recognized i~unoselected AV tumor cell clones. At least three distinctive antigens recognized by autolog0us CTL clones were identified on single melanoma clones by this approach. We speculate that immunoselection pressure on tumor cells in rive may contribute to tumor progression and metastasis. i. Medizinische Klinik und Poliklinik, Joh.GutenbergUniversit~t, LangenbeckstraSe i, D-6500 Mainz, FRO

1/P-GM106

1/P-GM108

T R E A T M E N T OF M E L A N O M A BY ISOLATED H Y P E R T H E R M I C PERFUSION THERAPY WITH MELPHALAN U. Loos~ E. Musoh, H _ ~ R a u s e h e e k e r ~ a n d B. R ~

REGIONAL HEMIBODY CHEMOTHERAPY FOR METASTATIC MELANOMA H.Voigt, K.R. Aiqner, K.H. Link, H. W a l t h e r r H , Mdller Results of isolated limb perfusion for metastatic melanoma suggest distinct dose-response correlations with tumoricidal properties of several antineop!astic agents. These experiences prompted the idea to pilot the effects of a high-dose chemotherapeutic regimen confined to one regional compartment for targeted tumor therapy. Practically, this goal appeared to be achievable by expanding the perfused area and simultaneously detoxifying systemic drug levels of the non-perfused compartment. Methods: For this approach the abdominal aorta and v.cava are catheterized above the pelvic bifurcation and connected with an extracorpqral circuit including a venous hemofilter for drug filtration (Lower Hemibody Chemotherapy). For chemotherapy of the upper hemibody compartment another catheter is placed into the aorta with its tip within the aortic arc. Interventional chemotherapy was completed at 6 w by cross-over exchange of the perfused compartments. Drug regimen was: Mitomycin C 40 MG/L-PAM 100 MG (37.5~C - 39.5~ at flow rates 150 - 200 ml/min for ! h. Results: Out of 10 hemibody perfusions performed so far. 3 pts. (F:2,M:!; median age 41 y) had had heavily pretreated disseminated melanoma refractory to any other treatment modality, but having an expected life span of at least 6 m. Main sites of metastases were skin. soft-tissue, lymph nodes, and lungs. At 3 w in all cases P.R. could be assessed revealing impressive tumor regressions within the perfused compartment lasting for a median duration of 8 w. In this pilot series toxicity was moderate due to soft-tissue leakage and subsequent myelosuppression being reversible without interventional care. In all cases improvement of performance status could be obtained indicating promising palliative properties in widely spread disease stages.

In m a l i g n a n t m e l a n o m a of the limb the combination of h y p e r t h e r m l a and m e l p h a l a n (: Lp h e n y l a l a n i n e mustard) seems to be more effective than the single therapeutic moda!ities. We studied the kinetics of the drug in hyperthermie regional perfusion in twelve patients suffering from m e l a n o m a of the upper or lower extremity. High perfusate c o n c e n t r a t i o n s of m e l p h a l a n were reached with levels b e t w e e n 6 474 and 28 835 ng/ml after the onset of the perfusion (mean temperature 40 - 41 oC). The elimination halflife was 27 minutes c o m p a r e d to 53 minutes without applying hyperthermia, on the average (J. Pharmacol. Exp. Thor. 237, 583, 1986). The resulting m e l p h a l a n c o n c e n t r a t i o n s at the end of the I h o u r - p e r f u s i o n a m o u n t e d to about one fourth of the starting values. H y d r o l y s i s into the inactive dihydroxy d e r i v a t i v e of melphalan played a minor role and could be n e g l e c t e d (only 2.8 % of the m e l p h a l a n was c o n v e r t e d into the d i h y d r o x y product). Thus, regional m e l p h a l a n p e r f u s i o n in combination with h y p e r t h e r m i a has the advantage of high local drug concentrations with an increased chemical r e a c t i v i t y of the a l k y l a t i n g drug as was shown by its a c c e l e r a t e d turn-over. There was no significant loss due to h y d r o l y s i s into dihydroxy melphalan. M e d i z i n i s c h e und C h i r u r g i s c h e Klinik der U n i v e r s i t ~ t e n Bonn und G6ttingen, S i g m u n d - F r e u d - S t r a ~ e 25, D-5300 Bonn I

melanoma research project H. Voigt D-2358 Kaltenkirchen, Postbox D-8223 Trostberg, Dept. Surgical Oncology FRO

$31 1/P-GM 109 PHASE II-STUDY:INTERFERON ALPHA 2b-TREATMENT IN ADVANCED MALIGNANT MELANOMA F.Hartmann,P.v.Wussow,B.Block and H.Deicher

1/P-GMlll FIRST EXPERIENCE WITH THE NEW METAL COMPLEX BUDOTITAN~ (BDT) IN A P H A S E I C L I N I C A L T R I A L M . E , H e l m - , H. F l e e h t n e r , B.K. Keppler ~

T o x i c i t y o f t h e I F N - t r e a t m e n t c o n s i s t e d of f e v e r in a l l 41 p a t i e n t s , f a t i g u e in 1 8 , a p a t h y in 7, nausea in 6 , h e a d a c h e in 6 , m y a l g i a in 6 , E E G - a l t e r a t i o n s in 5 , i n a p p e t e n c e / w e i g h t l o s s in 4 , d y s pnea in I and l o c a l i n f l a m m a t i o n in 4 p a t i e n t s . L e u k o p e n i a o f L 3 0 0 0 / p l was o b s e r v e d in 7 p a t i e n t s , In one case t h r o m b o c y t o p e n i a ( 9 5 . 0 0 0 ) o c c u r e d . M i l d i n c r e a s e in GOT was seen in 6 cases w i t h o u t l i v e r m e t a s t a s e s . I t is i m p o r t a n t t o m e n t i o n two p a t i e n t s w i t h p s o r i a s i s who e x p e r i e n c e d an e x a c e r b a t i o n w i t h i n 4 weeks a f t e r i n i t i a t i o n oftherapy,requesting cortison-therapy. We c o n c l u d e t h a t I F N - ~ a t dose s c h e d u l e used i n duces in a b o u t 20% o f p a t i e n t s o b j e c t i v e remiss i o n s in m a l i g n a n t melanoma. I n t r a l e s i o n a l IFN administration may l e a d t o a h i g h e r a n t i t u m o r a l activity in t h e i n j e c t e d l e s i o n . Abt.fOr Immunologie,MHH,3OO0 Hannover 61

The new antitumor-active transition metal complex Diethoxybis (l-phenylbutane-l,3-dionato) titanium (IV) (BDT) h a s d e m o n s t r a t e d antitumor activity in s e v e r a l e x p e r i m e n t a l tumor models. The cytotoxic a c t i v i t y o f B D T in the A M M N i n d u ced autochthonous eolorectal carcinoma in t h e rat appeared especially promising. In the p r e c l i n i c a l toxicity studies liver toxic i t y , b u t no m y e l o s u p p r e s s i o n or n e p h r o t o x i c i t y was observed. In a p h a s e I s t u d y p a t i e n t s with histologically confirmed malignant t u m o r s no l o n g e r a m e n a b l e to s t a r d a r d treatments w e r e t r e a t e d w i t h B D T to determine the maximum tolerated single and rep e a t e d d o s e . T h e s t a r t i n g d o s e w a s c h o s e n as i / i 0 of t h e a c u t e L D I 0 in r a t s . T h r e e p a t i e n t s w e r e t r e a t e d at e a c h n o n t o x i c dose level. Dose escalation was performed with initial dose inc r e m e n t s o f i00 %, s u b s e q u e n t 50 % as l o n g as no t o x i c i t y w a s o b s e r v e d a n d 25 % in t h e c a s e of m i l d t o x i c i t y . Safety laboratory controls and pharmacokinetic studies were performed during treatments. S i n g l e d o s e l e v e l s of 1 , 2 , 4 a n d 6 mg/kg b o d y w e i g h t as s h o r t i.v. i n f u s i o n c o u l d be g i v e n w i t h o u t t o x i c i t y . A t a d o s e of 9 mg/kg a reversible i m p a i r m e n t of t h e g u s t a t o r y sense was observed, at 1 4 m g / k g a m o d e r a t e inc r e a s e of l i v e r e n z y m e s a n d L D H w a s s e e n . T w o of the three patients receiving 21mg/kg developed a dose limiting nephrotoxicity. The repeated dose application of 1 0 0 m g / m ~ t w i c e a w e e k f o r a 4 week period (800mg/m ~ total) was well tolerated and f~rther dose escalation is p l a n n e d , Det a i l s of t h e p h a r m a c o k i n e t i c s t u d i e s w i l l be p r e sented. 1 Onkol. Zentrum, D-6800 Mannheim 2 Anorgan.-Chem. Institut, Univ. Heidelberg

1/P-GMllO

1/P-GM112

MELANOMA-FOLLOW-UP-STUDIES, BASIS OF A MODERATERADICAL TREATMENT SPECIFIC TO STAGE. H. Drepper, B, Bie6, E.B.BrScker, A. Grootens, M.Ktein, G. Padberg, A. Peters, H. Wiebelt

DRUG SENSITIVITY PATTERN OF HUMAN LEUKEMIA SPECIMENS B. Lathan, I. T~bben, M. Z i b u l l a , V. Diehl

In a phase I f - s t u d y 34 p a t i e n t s w i t h h i s t o l o g i c a l l y p r o v e n m e t a s t a t i c melanoma were t r e a t e d w i t h I F N ~ 2 b 10 M i o . U g i v e n s . c . t h r i c e w e e k l y . A l l p a t i e n t s were in s t a g e I I I and showed pro~ g r e s s i v e d i s e a s e b e f o r e e n t e r i n g t h e s t u d y . l n 33 e v a l u a b l e p a t i e n t s ( I p a t . t r e a t e d < I m o n t h ) 3CR (9%;]ung,lung/lymph node,skin/lymph node),3PR (9%;2xlung/skin,lymph n o d e s ) , 9 S D ( 2 7 % ) , a n d 18PD (55%) were o b s e r v e d . The median d u r a t i o n of t h e objective r e m i s s i o n s were 6months r a n g i n g f r o m I t o 1 9 m o n t h s . T h e SD l a s t e d between 3 and 14 months (median 6 m o n t h s ) . In a d d i t i o n , 7 patients w i t h n o n - r e s e c t a b l e s k i n m e t a s t a s e s were t r e a t e d w i t h 10 Mio. U IFN~ 2b a d m i n i s t e r e d i n t r a l e s i o n a l l y t h r i c e w e e k l y . Of t h e 7 i n j e c t e d s k i n l e s i o n s one c o m p l e t e l y d i s a p p e a r e d ( I C R ) , 4 s h r i n k more t h e n 50% ( ~ P R ) , w h i l e 2 l e s i o n s p r o g r e s s e d .

T-he- follow-up of 384 patients with primary melanoma of the C l i n i c Hornheide submitted to a prophylactic lymph-nodedissection from January 1,197o to December 31,1982 and 370 patients of the C l i n i c of Dermatology of the University of MOnster, whehadn't been submitted to a prophylactic lymph-node-dissection from January 1, 1974 to December 31, 1982, showed, when s t r a t i f y i n g the c o l l e c t i v e s into groups of equal r i s k a better prognosis only f o r men with a tumor thickness of >1,5-3 mm submitted to lymph-node-dissection, This difference is independent of l o c a l i s a t i o n and s i g n i f i c a n t with regard to s u r v i v a l rate both in the f i v e - y e a r as well as in the eight-year comparison (p=o,o074). In another group it became apparent under the same conditions that men with primary melanoma of 1,5-3 mm thickness had a better prognosis after an excision of the primary tumor with a width of 5 cm than with a width of < 3 cm. The results need further investigation, #roposals of therapie: Primary melanoma with thickness o,75-1,5 mm: excision with a margin of 3 cm, thickness of >1,5 mm: minimalwidth of the excision 3 cm. In men with a thickness of the primary tumor of 1,5-4 mm: width of excision 5 cm plus lymph-node-dissection. The moderate radical therapy requires frequent controls in the follow up, combined with the use of modern imaging diagnostics (f.e.sonography), since in case of metastasizing size and number of metastases determine the future prognosis.

T r e a t m e n t of a c u t e leukemia (AL) i s m a j o r l y based upon m u l t i d r u g r e g i m e n s . While t o x i c e f f e c t s of a c y t o s t a t i c drug a r e u n a v o i d a b l e , the t h e r a p e u t i c e f f i c a c y a g a i n s t an individual p a t i e n t s malignancy i s not known. Assays f o r p r e d i c t i o n of c h e m o s e n s i t i v l t y are l i m i t e d by t h e i r i n a b i l i t y e i t h e r to s u c c e s s f u l l y t e s t a s u f f i c i e n t p e r c e n t a g e of l e u k e m i a s or t o d i s t i n g u i s h benign c e l l s from leukemic b l a s t s . To overcome these l i m i t a t i o n s we have modified a d i f f e r e n t i a l s t a i n i n g c y t o t o x i c i t y (DISC) a s s a y to t e s t 13 from August '87 u n t i l October '87 o b t a i n e d AL specimens (10 AML, 3 ALL). A f t e r a 4 day drug i n c u b a t i o n , c e l l s were stained with f a s t g r e e n / n i g r o s i n , cytocent r i f u g e d and c o u n t e r s t a i n e d a c c o r d i n g to the method of Pappenheim. The number of v i a b l e malignant c e l l s was determined and the percent tumor c e l l s u r v i v a l in r e l a t i o n to an untreated c o n t r o l was c a l c u l a t e d . Of the 13 specimens, 12 (92%) were e v a l u a b l e f o r drug s e n s i t i v i t y information. U t i l i z i n g at l e a s t 3 d i f f e r e n t drug c o n c e n t r a t i o n s a dose response e f f e c t was noticed for a l l a c t i v e compounds. The ehemosens i t i v i t y p a t t e r n for the AL specimens resembled the c l i n i c a l experience w i t h for instance AraC, d a u n o b l a s t i n , or m i t o x a n t r o n e b e i n g a c t i v e and bleomycin being inactive. To date p r e l i m i nary c l i n i c a l c o r r e l a t i o n s (CR vs. p r o g r e s s ) a r e a v a i l a b l e f o r 8 of the 12 e v a l u a b l e AL s p e c i m e n s . The DiSC a s s a y seems to be a r a p i d and f e a s i b l e in v i t r o method f o r chemosens i t i v i t y t e s t i n g of AL.

Fschklinik Hornheide, Oorbaumstr. 300, 4400 MOnster Medizinische U n i v e r s i t ~ t s k l i n i k I, Stelzmann-Str.9, D-5000 Kbln 41

Joseph-

$32

1/P-GMll5

1/P-GM113 IN

VITRO STRUCTURE ACTIVITY RELATIONSHIP OF ANTHRACYCLINES D. Hoffmann, H . G . Berscheldp P. Hermentinp

H.H.

Sediacek~

H.P.

Kraemer

In the present investigation the In vitro c y t o t o x i c activity as d e t e r m i n e d in the clonogenic assay after short ( I h) and c o n t i n u ous incubation against L1210 Ieukemla and human colon tumor cells (Colon %, HT 29] was examined for several natural and semisynthetic a n t h r a c y c I i n e s and was quantitatively related to the partition coefficient and O N A - b i n d i n g affinity of the compounds. Ana]ysis os equitations in w h i c h cytotoxicity against L1210 (lh incubation) was paraboilcaliy related to the partitlon coefficient and/or DNA-binding a f f i n i t y revealed that the activity of the compounds was almost exclusively re]ated %o the partition coefficient. This correIation was o n l y slightly improved by additional c o n s i d e r a t l o D o f DNA-blnding affinity. On the other hand cytotoxic activity after continuous incubation seems to be partially related to both i[pophiiiclty and D N A - b i n d i n g a f f i n i t y of the compounds. In this case the c o r r e l a t i o n between activity and 1 1 p o p h i I i c R t y ( R = 0 . 5 3 ) was significantly improved by further c o n s i d e r a t i o n of DNA-binding affinity (R=0.90). S i m i l a r results were also obtained for human colon tumor ceils a~though the corresponding oorreiation

ooefficients indicating

generai]y

were

of

lower

value

that o y t o t o x i c ac~ivity of anthraoycI ines against resistant ceils may be determined by further parameters. Dr. D. Hoffmann, Research L a b o r a t o r i e s 8ehringwerke AG, 3550 Marburg, FRG

of

S E Q U E N T I A L I M M U N O H I S T O C H E M I C A L S T U D I E S OF A M E T H A F I B R O S A R C O M A A F T E R T R E A T M E N T WITH HYPERTHERMIA P . P e s c h k e L E _ . ~ H a h n , H ~ J . H a c k e r and W . J . L o r e n z The antigenic and p r o g r e s s i v e l y g r o w i n g 3 - m e t h y l c h o l a n t h r e n e induced f i b r o s a r c o m a (Meth A) can be locally c o n t r o l l e d in intact B A L B / c mice by h y p e r t h e r m i a alone, but not in i m m u n o s u p p r e s s e d animals (Alfieri et al., Cancer Res. 41, 1301, 1981). In order to u n d e r stand b e t t e r the r e l a t i o n s h i p b e t w e e n heats e n s i t i v i t y and the i m m u n e r e s p o n s e of the host, h i s t o m o r p h o l o g i c a l b e h a v i o r and s t r u c t u r e - f u n c t i o n r e l a t i o n s h i p s of host and tumor cells were c h a r a c t e r i z e d . I s o g e n i c B A L B / c male mice were i n o c u l a t e d i.d. w i t h single cell s u s p e n s i o n of Meth A. Local Tumor H y p e r t h e r m i a (LTH) was g i v e n by immersion of the tumor b e a r i n g leg in a c i r c u l a t i n g water bath for 35 min at 43.5 + 0.1~ F r o m 4 hours to 12 days after treatment, tumors were excised and p r e p a r e d for c o n v e n t i o n a l histology. F o l l o w i n g LTH the number of n e c r o t i c cells increased rapidly, such that by 24 hours the center of tumor c o n s i s t i n g of necrotic tissue e x c l u s i v e l y . D u r i n g the p r o c e s s of tumor resorption m a r k e d i n f i l t r a t i o n and a c c u m u l a t i o n of i n f l a m m a t o r y cells were observed. Nond a m a g e d , normal appearing tumor cells at the t u m o r / n o r m a l t i s s u e m a r g i n d i s a p p e a r within a few days after treatment. Studies are now in p r o g r e s s using specific i m m u n o h i s t o c h e m i c a l t e c h n i q u e s to c h a r a c t e r i z e the t o p o h i s t o l o gical d i s t r i b u t i o n of f u n c t i o n a l l y d e f i n e d Tcell s u b s e t s d u r i n g the c o u r s e of a s i n g l e local h y p e r t h e r m i c treatment. G e r m a n C a n c e r R e s e a r c h Center, Im N e u e n h e i m e r F e l d 280, D - 6 9 0 0 H e i d e l b e r g

1/P-GM 114

1/P-GM 116

COLLATERAL SENSITIVITY TO METHOTREXATE & LEUCOVORIN BUT NOT TO M E T H O T R E X A T E At.ONE IN THE PRESENCE OF PLEIOTROPIC DRUG RESISTANCE s D~ S o l l , ~ W~ O ~ , and C.Go S c h m i d t C o l l a t e r a l sensitivity is a rare phenomenon a s with pleiotropic resistance. While sociated this mechanism Of drug resistance encompasses many amphiphilie substances, sensitivity tu antimetabolites and alkylating agents Or ionizing irradiation remains unchanged. In c o n trast to SUCh absence of cross-resistance, col~ lateral s e n s i t i v i t y implies that cells expressing, e.g., the multidrug resistant ( ' m d r ' ) phenotype are more sensitive to certain treatments than the sensitive parental line. This has been documented in a subline LI21e/EID of L1210 murine leukemia selected for resistance to e t o p o s i d e at !0 pg/m], in tissue culture. So {ar~ the subline L 1 2 1 0 / E I O has been shown to display collateral sensitivity to bleomycin, reduced ambient temperature (3r ~ C) and the combination of m i t o m y c i n C with c y c l o s p o r i n A~ We now report that in L1210/EIO cells selected for high resistance to etoposide and c~oss-resistant to anthracyclines and vinca-alka].oids sensitivity to m e t h o t r e • (continuous exposure over 72 hours) remains unchanged. If, however, m e t h o t r e • is present together with l e u c o v o r i n in a 1:1 molar ratio, survival of t_121O/E10 cells is reduced 10 t o 2H-fold marc than survival of L1210 cells. We conclude, that a d i f f e r e n t i a l rescue by ],eucovorin offers a new stategy to o v e r c o m e p l e i o t r o p i c drug resistance.

REGIONAL HYPERTHE~IA O%HT)CO~4~INEDWITH SYSTH~ICCFEMO~Y FOR DEEP-SEATEDTUMORS:RESULTSOF A PHASE-I STUDY

Supported

by SFB 102 of t h e

DFG

Inhere U n i v e r s i t ~ t s k l i n i k und P o l i k l i n i k (Tumor{orschung), W e s t d e u t s c h e s Tumorzentrum, Hufelandstr. 55, 0--#300 Essen 1

R.Issels, H.Riess: H.Sauer, M.Wadepohl, H.Cramer and W.Wilmanns Frea July 86 to September87, a total of 23 patients with deep-seated t~ors of the pelvic (18/23) and abdceina] {5/23) region has been treated (104 = total number of t r e a t e r s ) on a pilot protocol involving regional hyperthermia (f~T). Hyperthermia was ccmbined with systemic chemotherapy (XT). Before entering this study, the patients showedprogressive disease under' conventional treatment protocols. The patients (15 sarccmas, 7 colorectal-ca, 1 terato-ca) received I to 12 ~HT sessions (mean 4.5) combinedwith XT (e.g, ifosfamide, etoposide, cisplatin, 5-fluorouracil, vindesine, 4'-epirubicine). In all pelvic (92/104) and abdominal (12/104) RHT treatments detailed t h ~ l mapping of ttmor and normal tissue temperatures has been performed. In -- 50% of pelvic treatments, tumor temperatures > 42.5% could be achieved but only in 8% of abdominal treatments. Acute toxicity related to RHTconsisted primarily of pain within the applicator (48%) and/or systemic stress (38%) during ~ treatments. The following con~31icatioas ~ere observed: bacterial centeTdnation (asymptcmatic) of RHT catheter (14/104), infection (16/104), haemorrhage (2/104), thrcmbosis (2/104), and hae~aturia (I/104). ~bltidrug chemotherapy given by i .v. infusion simultaneously with ~T showed no substantial increase of com~ systemic side effects. Furthermore, we achieved a ccrr#lete/pantial response in 3/I out of 8 evaluable patients treated with more than 6 RHT-XT. From these clinical data we conclude that a.) the ~A syst~ is a regional heating device with potential for deep-seated tumors of the pelvic region, b.) the combination with systemic chemotherapy was well tolerated by the patients and c.) a phase-ll stuc[y should be performed. Ibis work was supported by Grant M 12/86/Wi 1 from the Deutsche Krebshilfe. Medizinische Klinik 111, Klinikum Gre~adern, Ludwig-MaximiliansUniversit~t, D~8000MJnchen 70

S 33 1/P-GM 117

1/P-GM 119

ISOLATED HYPERTHERMIC PERFUSION OF TUMOR BEARING HIND LIMBS OF RATS. K. Nagel, U. LUcke, C. Seip, B. SchUrle, W. I s s e l h a r d , M. GUnther

RAPID DETECTION OF M U L T I D R U G ~ R ~ S I S T A N C E BY D O X O R U B I C I N AND RHODAMINE 123 Th. Effert and M. Volm Multidrug-resistance (MDR) is c h a r a c t e r i s i z e d by c r o s s - r e s i s t a n c e of tumor cells to many s t r u c t u r a l l y and functionally unrelated drugs. In attempts to develop a simple and rapid assay for MDR we have investigated doxorubicinresistant S 180 (S 180 DOX), colchicineresistant CHO (CHOCOL) and cytosinearabinoside-resistant L 1210 cell lines (L 1210-AraC). S 180 DOX and CHO-COL express the M D R - p h e n o t y p e while L 1210-AraC does not. With a s h o r t - t e r m assay we measured inhibition of incorporation of radioactive nucleic acid p r e c u r s o r s into tumor cells after addition of doxorubicin and rhodamine 123 (R 123) and established that S 180-DOX and CHO-COL cells are resistant and L 1210-AraC cells are collaterally sensitive to the tested agents. Because R 123 is a f l u o r e s c e n t - m i t o c h o n d r i a l dye, its accumulation in cells can be observed under the fluorescence microscope. At intervals of two minutes all R 123-stained and nonstained cells of the same viewfield were counted. Dead cells were excluded by propidiumiodide-counterstaining. S 180-DOX and CHOL-COL cells need more time to accumulate R 123 than their sensitive parental cell lines: they are thus resistant to R 123. L 1210-AraC cells need less time: the cells are c o l l a t e r a l l y sensitive. In both assays the detected resistance correspond to the expression of MDR. These assays are adequate tools for the rapid detection of MDR. German Cancer Research Center, Dept. Exp. Pathol., Im Neuenheimer Peld 280, D-6900 Heidelberg, 1

Although the technic o f i s o l a t e d limb perfusion in humans has been employed in cancer chemotherapy f o r several years, experimental studies using t h i s approach on tumor bearing small animals are not a v a i l a b l e . Theref o r e we studied the e f f e c t i v e n e s s o f the perfusion in nude r a t s with Yoshida sarcoma on t h e i r hind limbs. 68 male, homocygote ( r n u / r n u ) , 180 - 250 g nude r a t s with subcutaneous Yoshida sarcomas on the r i g h t limb and volumes o f 0.55 + 0.23 ml were used to compare the tumor growth cur~es, the s u r v i v a l and the causes o f death. There were 23 animals without treatment (group A), 20 r a t s t r e a t e d with melphalan, 0.5 mg/kg body weight and dactinomycin 0.0075 mg/kg body weight i . p . ( g r o u p B) and 25 animals, hyperthermic perfused with the same drugs f o r one hour, group C (muscle temper a t u r e 41.5 ~ C). A l l tumors o f the untreated animals showed an exponential tumor growing. The delay o f growth in group B was 3.95, in group C 11.8 days on an average. There was no s i g n i f i c a n t d i f f e r e n c e in mean and median s u r v i v a l o f the r a t s in group A and B (x : 16 + 4.28, m = 16 days group A, # = 19.2 + 5.58, m = 19 days group B), but the perfused_animals ITved s i g n i f i c a n t l y longer with an s u r v i v a l o f x 41 + 70, m = 22 days. All untreated animals died by metastases, 14 in group B, 8 in group C r e s p e c t i v e l y . Other cause o f death was pneumonia. 6 nude r a t s o f group C were f r e e o f tumor. Conclusion: The regional a p p l i c a t i o n o f melphalan and dactinomycin in combination with hyperthermic i s o l a t e d perfusion is much more e f f e c t i v e in the treatment of nude rats with Yoshida sarcoma bearing hind limbs than a systemic treatment with the same substances. Die i s o l i e r t e hypertherme Z y t o s t a t i k a p e r f u s i o n von Nacktratten mit Yoshidasarkomen der hinteren Extremit~t. CMrurgische U n i v . - K l i n i k Mainz Langenbeckstrage I , D-6500 Mainz I

1/P-GM 118

1/P-GM120

INTRINSIC M U L T I D R U G RESISTANCE IN HUMAN LUNG C A R C I N O M A XENOGRAFTS" M. Volm, M. Bak, B. Lathan and J. Mattern Y6s r e s l s t a n c e "of a panel of 8 human epidermoid lung cancer xenografts grown in nude mice were investigated. As expected, the tumor lines responded d i f f e r e n t l y to cytostatic drugs. When the effects of vincristine on the 8 tumor lines were c o r r e l a t e d with the effect of actinomycin D, a close relationship could be found (r=0.96). The tumors exhibited a similar pattern of cross resistance as observed in m u l t i d r u g - r e s i s t a n t cell lines. Whereas the resistance in the resistant tumor cells can p a r t i a l l y be overcome by the addition of verapamil, the response of the sensitive tumor cells cannot be s u b s t a n t i a l l y influenced. The resistant lung tumor cells express a glyeoprotein of Mrl70kg. Monoclonal antibody 265/F4 to this g l y c o p r o t e i n was detected immunohistochem~cally by using streptavidinb i o t i n - p e r o x i d a s e - c o m p l e x method. In contrast no or weak immunoreactivity could be seen on the d r u g - s e n s i t i v e lung carcinoma cells. To d e t e r m i n e whether multidrug genes were expressed in the lung tumors we used the probe pDR 7.8 kd LEco R1 fragment cloned into PUC 19 gift from J.M.Croop, Cambridge, U.S.A.]. The level of expression could be correlated with the degree of drug resistance. G e n e - a m p l i f i cation may at least be p a r t i a l l y responsible for the intrinsic resistance observed in human lung xenografts. German Cancer Research Center, Dept. Exp. Pathol., Im N e u e n h e i m e r Feld 2 8 0 , D-6900 Heidelberg 1

A C Q U I R E D RESISTANCE TO V I N C R I S T I N E IN A HUMAN LUNG CARCINOMA XENOGRAFT LINE J. Mattern, M. Bak, B. Lathan and M. Volm The development of resistance to chemotherapy is a major problem in the treatment of cancer. Tumours which are initially responsive to chem o t h e r a p y can develop resistance during treatment with cytotoxic agents. In the present study the in vivo development of resistance to vineristine in a human epidermoid lung carcinoma xenograft line growing in nude mice has been examined. Treatment of img/kg vincristine as a single dose in each in vivo passage in nude mice resulted in a rapid reduction in tumour responsiveness to this drug. Cross resistance studies with different antineoplastic drugs revealed a similar general pattern of drug resistance to the drugs a c t i n o m y c i n D and adriamycin as is observed in multidrug-resistant cell lines. Using the MAB 265/F4, the membrane protein P-glycoprotein (M r 170 000) could be detected in the resistant subline. The induced resistant subline was characterized in terms of the time course of its production, the degree of induced resistance, the growth rate and stability of the phenotype. German Cancer Research Center, Dept. Exp. Pathol., Im N e u e n h e i m e r Feld 280, 6900 Heidelberg 1

$34 1/P-GM 121

1/P-GM123

IN UITRO INDUCTION AND ~RPHOLOBICAL CHAR~TERI-

CARRIER MEDIATED ACTION OF PLATINUM COMPLEXES ON ESTROGEN RECEPTOR POSITIVE TUMORS E. von A n g e r e r , N. Knebel, J. K a r l , R. Gust, M. R. Schneider H. Sch6nenberqer

ZATIDN OF CHEMORESISTANI TUMOR CELLS M. Dietel, H, Arps, X. Stblting, and A, N i e n d o r f

One m a j o r p r o b l e m in c h e m o t h e r a p y a r e m a l i g n a n t tumors which p r i m a r i l y are c h e m o e e n s l t i v e but a f t e r o n e or two t h e r a p e u t i c a l a p p r o a c h e s b e c a m e r e s i s t a n t to t h e a n t i n e o p l a s t i c d r u g s applied. The r e s i s t a n t cell c l o n e s are t h o s e m h i c h limit patients' li~e. To ffurther u n d e r s t a n d the proc e s s off c r e a t i n g c h e m o r e s i s t a n c e me simulated this m e c h a n i s m in vitro. E x p e r i m e n t s : Six cell lines d e r i v e d ~ r o m p r i m a r g human malignomas were selected under the criter i u m of c h e m o s e n s i t i v i t g . T h i s w a s d e t e r m i n e d in a monolager proliferation assag showing a dec r e a s e off cell g r o w t h bg > 5 0 ~ w h e n i n c u b a t e d for 3 d a g s in the p r e s e n c e of O . S ug/ml c i s - p l a tin~ O . O S ug/ml m e t o t h r e x a t and 0 . 0 5 ug/ml a d r i blastin, r e s p e c t i v e l y ( c o n c e n t r a t i o n s c o r r e s p o n d to t h o s e a c h i e v a b l e in vivo), Subsequently, the cells were i n c u b a t e d in s l o m l g i n c r e a s i n g d r u g c o n c e n t r a t i o n s Eor S months. At the b e g i n n i n g and end of the incubation period cell growth, DNA-content, c ~ t o s k e l e t e l proteins, and t u m o r associated antlgens (TAA) were determined by scanning cgtophotometrg as mall as lightand electrode microscopical immunocytochemistro, Results: Four cell lines d e v e l o p e d r e s i s t a n c e to all 3 c g t o s t a t i c s up to the 15 E o l d m u l t i p l i c a t i o n of the p r i m a r g c o n c e n t r a t i o n , In t h e p r e s e n c e of the d r u g s the c e l l s proliferated rapidlg ~ i t h a cell d o u b l i n g t i m e o~ approx. 2~h, O u t i n g the d e v e l o p m e n t off c h e m o r e s i s t a n c e m o r phological characterization revealed several d i s t u r b a n c e s of cgtoskeletal proteins and TAA, The n u c l e a r DNA c o n t e n t v a r i e d onlg slightlg, Discussion: The r e s u l t s s h o m s d that the c r e a t i o n of c h e m o r s s i s t a n t cell c l o n e s is p o s s i b l e in vitro s i m u l a t i n g the in vivo situation. In our ser i e s this appeared r a t h e r f r e q u e n t l g (in ~ o u t of 5 cell lines). D u r i n g this p r o c e s s m o r p h o l o ical c h a n g e s appeared concerning the distribuion oE o g t o s k e l a t p r o t e i n s a n d t u m o r a s s o c i a t e d antigens.

The aim of these i n v e s t i g a t i o n s is the d e v e l opment of p l a t i n u m complexes t h a t e x e r t a spec i f i c a c t i o n on mammary and p r o s t a t i c c a r c i n o mas. To reach t h i s g o a l , complexes w i t h high binding affinity for estrogen r e c e p t o r and c y t o s t a t i c a c t i v i t y were s y n t h e s i z e d . . T w o d i f f e r e n t types of l i g a n d s were used f o r comp l e x a t i o n . P l a t i n u m complexes w i t h s u b s t i t u t e d diphenylethylenediamines possess moderate binding affinity f o r the e s t r o g e n r e c e p t o r , but s t r o n g e n d o c r i n e a c t i v i t y . The growth of hormone-dependent experimental mammary and prostatic tumors was ~ t r o n g l y inhibited. In the second c l a s s of compounds the c i s - d i a m i n o d i c h l o r o - p l a t i n u m group i s l i n k e d by a spacer group to a substit,uted 2-phenylindole as homing d e v i c e f o r the e s t r o g e n r e c e p t o r . These s t r u c t u r e s e x h i b i t high b i n d i n g a f f i n i t i e s for the e s t r o g e n r e c e p t o r and a s e l e c t i v e c y t o s t a tic action on tumors containing estrogen r e c e p t o r s l i k e t r a n s p l a n t e d MXT mammary tumors of the mouse. I n s t i t u t fur Pharmazie, Univ. Regensburg, U n i v e r s i t ~ t s s t r . 31, D-8400 Regensburg

g

Institute of Pathologg, U n i v e r s i t g of Hamburg, Martinistr, 52, D - ~ O O O H a m b u r g 20, FRG,

1/P-GM122

1/P-GM 124

THE EFFECTS OF M I S O N I D A Z 3 L g ON G L U T A T H I O N E C O N T E N T IN N O R M A L TISSUES AND T U N O U R P. TAHULEVICIUS, A. R OCKZR, C. STREFFER

STRUCTURE-ACTIVITY-STUDIES AND EVALUATION OF MAMMARY TUMOR INHIBITING ACTIVITY~OF NEW AROMATASE INHIBITORS OF THE AMINOGLUTETHIMIDE(AG)~TYPE R. Hartmann~ C. Batzl, H. SchUnenberger

There is e v i d e n c e that t~e i n t r a c e l l u l a r GSH levels are r e l a t e d to the degree of hypoxic r a d i o s e n s i t i z a t i o n of t u m o u r s by n i t r o i m i d a zoles both in vitro and in vivo. Thus several t u m o u r cell lines with low GSH levels exhibit higher s e n s i t i z a t i o n e n h a n c e m e n t ratios. In the present study we have e x a m i n e d the extent of GSH d e p l e t i o n in an a d e n o c a r c i n o m a transp l a n t e d i n t o the h i n d l e g s of C57 B! m a l e m i c e e i t h e r by M I S O a l o n e (I m g / g ) 2 h p o s t a p p l i c a t i o n or in c o m b i n a t i o n with local hyp e r t h e r m i a by m e a n s of ultrasound for 30 6in at 4 3 ~ g i v e n 30 m i n a f t e r i n j e c t i o n of sensitizer and the GSH levels d e t e r m i n e d i h later. The resa!ts show that M I S O leads to a significant l o w e r i n g of the GSH content (from 265 ~g/g in controls to 144 ~g/g) and this can be fucther d e c r e a s e d to about 70 pg/g using c o m b i n e d treatment. By contrast, there is little i n f o r m a t i o n available of the effects of s e n s i t i z e r s on the GSH levels in n o r m a l tissues in vivo. if they too can be decreased, this could greatly affect the degree of r a d i o s e n s i t i z a t i o s in such tissues. N e h a v e l o o k e d at the l e v e l s of G S H in the l i v e r and b r a i n of n o r m a l m i c e up to 4 h p o s t - a p p l i c a t i o n of MISO given as above. It c o u l d be s h o w n t h a t the G S H l e v e l s w e r ~ not m a r k e d l y altered in the brain over this period but were l o w e r e d about 2-fold in the l i v e r a f t e r 1 h and r e t u r n i n g to n e a r n o r m a l levels after 4 h. In s u m m a r y , it appears that s e n s i t i z e r s can affect b i o c h e m i c a l s y s t e m s in both t u m o u r s and n o r m a l tissue. Inst. f~r Med. Strahlenbiologie, Univ.-Klinikum Hufelandstr. 55, 4300 Essen 1

The aromatase i n h i b i t o r AG has shown benefit in the treatment of disseminated: hormone-dependent breast cancer. But AG is not an optimal drug, for i t also i n h i b i t s the enzyme desmolase and shows strong CNSdepressive a c t i v i t y . This is why stronger inhibitors of aromatase exhibiting less inhibition of desmolase and a weaker CNS-depressive a c t i v i t y than AG are required. For that purpose structurally modified derivatives of AG and cyclohexylaniline were synthesized and tested for t h e i r i n h i b i t o r y potency towards human placental aromatase and bovine adrenal desmolase. Only in the case of an elongation of the 3-ethyl group of AG more active compounds were found. "The most active derivative ~- the cyclohexyl compound showed a 123-fold stronger. Inh~b~tlon of aromatase and a markedly decreased i n h i b i t i o n of desmolase compared to AG. The new compound showed also a stronger i n h i b i tion of the plasma E2 concentration of PMSG-primed SDrats (0,3 mg/kg: 52 % inhibn; AG, I mg/kg: 28 %) and the testosterone stimulated tumor growth of ovariectomized rats bearing DMBA-induced mammary tumors. 9

%

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Tested for i t s CNS-depressive a c t i v i t y this compound showed no a c t i v i t y in the rotarod test and the m o t i l i t y test - even in very high doses. Being a stronger and more selective i n h i b i t o r of the estrogen biosynthesis than AG, the new cyclohexyl compound might be a better candidate for the treatment of hormone-dependent breast cancer. I n s t i t u t fur Pharmazie, Universit~t Regensburg, Universit~tsstr. 31:D-8400 Regensburg

$35 1/P-GM 125

1/P-GM 127

CAPILLARY PERMEABILITY IN CNS METASTASIS: A PHARMACOKINETIC APPROACH TOWARDS CHEMOTHERAPY P,C.Warnke, F , A l e s c h , D . R . G r o o t h u i s and C.B.Ostertag

P H A R M A C O K Z N E T I C S AND T I S S U E D I S T R I B U T I O N OF T H I A Z O L I D I N Y L AND P E R H Y D R O T H I A Z I N Y L - E T H Y L - N MUSTARD-PHOSPHORODIAMIDE-ESTER G. Voelcker, L.Bielicki, K.M[ller and H.-J.Hohorst

Whereas numerous k i n d s of s y s t e m i c cancer can be i n f l u e n c e d e f f e c t i v e l y by chemotherapy, therapeutic efficacy for cerebral metastasis of the i d e n t i c a l tumor is o f t e n l a c k i n g because of the p a r t i a l l y intact blood-brain barrier. Using a two-compartment model and a q u a n t i t a t i v e CT-method the b l o o d - t o - b r a i n t r a n s f e r r a t e (K1) and the t i s s u e - t o - b l o o d t r a n s f e r r a t e (k2) f o r i o d i n a t e d w a t e r - s o l u b l e compounds was measured in 6 p a t i e n t s b e a r i n g CNS m e t a s t a s i s . K l - v a l u e s were r a n g i n g from 0.02 - 0.08 ml/lOOg/ min (normal brain:O.O017~O.O012 ml/1OOg/min) thus d e m o n s t r a t i n g p h y s i o l o g i c a l h e t e r o g e n e i t y of c e r e b r a l m e t a s t a s i s ~Iso seen by k 2 - v a l u e s between 0.17 - 0.9 min. The data were then used t o c a l c u l a t e time x c o n c e n t r a t i o n i n t e g r a l s f o r small w a t e r - s o l u b l e c y t o s t a t i c s as w e l l as e x t r a c t i o n f r a c t i o n s , So a r a t i o n a l basis f o r chemotherapy could be p r o v i d e d t o s e l e c t p a t i e n t s f o r an " i n d i v i d u a l i z e d " chemotherapy a c c o r d i n g t o the p h y s i o l o g i c a l p r o p e r t i e s of t h e i r tumor and the p h y s i c o - c h e m i c a l c h a r a c t e r i s t i c s of i n d i v i d u a l d r u g s . The method may be u s e f u l t o p r e v e n t i n e f f i c i e n t time consuming chemotherapy regimens and to a v o i d unnecessary n e u r o t o x i c i t y .

P e r h y d r o t h i a z i n y l - p h o s p h a m i d e - e s t e r s were developed as detoxified prodrugs of a c t i v a t e d cyclop h o s p h a m i d e (4-OH-CP + Aldophosphamide) a high specific suicide inaetivator of DNA p o l y m e r a s e ~ holoenzyme. From the compounds synthesized two derivatives N S C - 6 1 3 0 6 0 and N S C - 6 1 2 5 6 7 were choosen for further d e v e l o p m e n t b e c a u s e of their slow h y d r o l y s i s (tl/2 3 and 24 hl and their small d i s s o c i a t i o n constant (10 -4 and 10 -6 M) which both guarantee steady state c o n c e n t r a t i o n s of 4-OH-CP in the affinity range of the exonuclease subsite of DNA p o l y m e r a s e ~ h o l o e n z y m e but below that of exonucleases. Pharmacokinetics, tissue d i s t r i b u t i o n and cell uptake of these c y t o s t a t i c s with low toxicity (LD 50 for acute toxicity in mice > 4 mmol/kg) but high activity against a number of murine tumors, solid tumors in rats and human xenografts in nu/nu mice were investigated: After i. v. injection N S C - 6 1 3 0 6 0 and NSC-612567 were elim i n a t e d rapidly from the blood c o m p a r t m e n t of mice (ti/2=8 min) and a c c u m u l a t e d in the tissue compartment. F l u o r o m e t r i c d e t e r m i n a t i o n s of both the compounds in 100000g supernatants of tissue homogenates d e m o n s t r a t e d blood brain barrier p e r m e a b i l i t y to t h i a z o l i d i n y l - and p e r h y d r o t h i a zinyl-phosphamide-esters. F u r t h e r m o r e it was found in in vitro studies that 14C N S C - 6 1 3 0 6 0 is a c t i v e l y taken up into EAT cells.

Neurochirurgische Universit~tsklinik, Homburg/Saar, Fed. Rep. of Germany.

D-6650

Zentrum der B i o l o g i s c h e n Chemie, A b t e i l u n g Zellchemie der U n i v e r s i t ~ t Frankfurt, T h e o d o r - S t e r n - K a i 7, D-6000 F r a n k f u r t / M 70

1/P-GM 126

2/10-M 001

LOW TOXIC C A N C E R C H E M O T H E R A P Y BY SUICIDE INACTIV A T I O N OF D N A P O L Y M E R A S E ~ HOLOENZYME: FIRST RESULTS WITH T H I A Z O L I D I N Y L - AND P E R H Y D R O T H I A Z I N Y L ETHYL-N-MUSTARD-PHOSPHORODIAMIDE-ESTER H.-J.Hohorst, L.Bielicki, K.MHIIer and G.Voelcker

HOOGKIN'S DISEASE AFTER THERAPY: AUTOPSYRESULTS. B. G~nther and K. Donhuijsen

T h i a z o l i d i n y l - and P e r h y d r o t h i a z i n y l - e t h y l - N m u s t a r d - p h o s p h o r e d i a m i d e - e s t e r s were synthesized. R a t i o n a l e for the design was to eliminate overall toxicity and non specific c y t o t o x i c i t y and to u n f o l d c y t o s t a t i c specificity based on suicide i n a c t i v a t i o n of D N A - p o l y m e r a s e ~ holoenzyme. Acute and subacute toxicities of these new drugs are very low. R e g i m e n curative on mice P388 leukemia showed no blood leucopenia. P r o l o n g e d daily a p p l i c a t i o n s for three weeks of doses curative for P388 leukemia and P815 m a s t o zytoma showed no toxic m a n i f e s t a t i o n s e.g. no significant body w e i g h t loss, alopecia or urotoxicity. High activity was found in various h u m a n xenograft tumors on thymus aplastic mice. In the clonogenic stem cell assay doses of perhydrothiazinyl-phosphamide-ester (H4) effective on various human tumor cell lines were nontoxic against human bone m a r r o w cells (CFU-C). These findings suggest that the new drugs are p r o m i s i n g c a n d i d a t e s for the d e v e l o p m e n t of low toxic cancer chemotherapy. M o r e o v e r they may be valuable tools for the e l u c i d a t i o n of the biochemical and p h a r m a c o l o g i c a l basis of this concept. Zentrum der B i o l o g i s c h e n Chemie, A b t e i l u n g Zellchemie der U n i v e r s i t ~ t Frankfurt, T h e o d o r - S t e r n Kai 7, D-6000 Frankfurt/M. 70.

Autopsy findings of 84 pts. with Hodgkin's disease (HD) out of the period 1975 - 1987 were reviewed. The overall median age was 44 years (range 15 - 84). 79 pts. received radiation therapy and/or chemotherapy, 58 of them in combined form. 21 of 79 pts, (27 %) had no postmortem evidence of HD. 34 pts. (43 %) had widespread HD with pronounced manifestation. H i s t o l o g i c a l l y the LD subtype was the most frequent at autopsy whereas NS and MC subtypes predominated on diagnostic biopsies. Discreete h i s t o l o gical rest i n f i l t r a t e s of HD could be detected in 15 pts. 45 pts. (57 %) showed serious side effects of therapy: pulmonary f i b r o s i s (20 p t s . ) , bone marrow depletion followed by bleedings or sepsis (12 p t s . ) , second malignancies (7 p t s . ) , p e r i c a r d i t i s constrictiva (3 p t s . ) , and in one case a necrotic c o l i t i s , an Opsi syndrome and a radiation induced myocardial i n f a r c t i o n . The cause of death was independent of HD ~n two pts. only (bronchiogenic Ca; myocardial infarction). Our results exhibit that nearly the half of.the pts. died in relationship to side effects of therapy) Even i f the series may be a negative selection the question w i l l arise wether the i n t e n s i t y Of therapy is reducible or mere individual therapeutic modalities are possible without diminishing the remission rates markedly.

Universit~tsinstitut fur Pathologie (Dir, Prof. Dr, L.-D. Leder), HufelandstraBe 55,-D-4300 Essen I

$36 2/10-M002

2/11-0 002

C A R C I N O M A OF THE STOMACH FOLLOWING IRRADIATION FOR M A L I G N A N T GASTRIC L Y M P H O M A / N E U R O S A R C O M A P.K. Sch&fer, U. Lees and D. Gerhartz

MEASUREMENT OF METABOLISM IN GLIOMAS BY PET AND MR SPECTROSCOPY: NEW ASPECTS FOR MANAGEMENT OF THERAPY d, Jeske, K, Herholz, W. Heindel, W. D. Heiss

Gastric anaplastic carcinoma d e v e l o p e d in two patients following radiation t h e r a p y f o r l y m p h o s a r k o m a and neurosarcoma, respectively. The first patient, a 63-year-old man, u n d e r w e n t an exploratory laparatomy in 1967. Infiltrates of a lymphosarcoma were found in the stomach with lymph nodes in the omentum and along the aorta. No resection was performed, only tissue specimens were taken from the situs. Postoperatively, the patient was treated by radiotherapy to a dose of 60 Gy to the upper abdomen. 6 I/Z years later he developed an anaplastic c a r c i n o m a of the stomach which was p a l l i a t i v e l y resected. In the second patient, a 34-year-old female, a partial g a s t r e o t o m y was performed in 1965 due to a n e u r o s a r c o m a of the stomach. Afterwards, she received a radiation therapy to a dose of 40 Gy. 14 years later she d e v e l o p e d an a n a p l a s t i c unresectable gastric cancer. These case reports might be exceptional, as gastric cancer as secondary m a l i g n a n c y is a rare event. In our two patients the diseases can be related to the preceding intensive radiation therapy of the same anatomic region. Thus, cancer of the stomach may be another comp l i c a t i o n of a "successful" aggressive management of m a l i g n a n t tumor and needs special after-

Gliomas are usually heterogeneous and tend to become more malignant in the course of their development. Grading is quite difficult because of the heterogeneity and because of the fact that only parts of the tumor can be examined histologically, Surgical specimens of recurrent gliomas are often not available. Non-invasive measurement of tumor glucose metabolism with 1 8 F - 2 - f l u o r o - d e s o x y g l u c o s e (FDG) and positroneemission-tomography (PET) has been shown to be useful to evaluate tumor malignancy, A correlation between histological tumor grade and glucose consumption was found in 20 glioma patients in accordance with recent literature reports (DICHIRO G, Invest Radiol 22: 360-37T, 1986). Tumor metabolism may even better predict prognosis than the histological classification (PATRONAS NJ at al., J Neurosurg 62: 816-822, 1985). Preliminary experience with image-guided localized spectroscopy of the brain demonstrated elevated phosphomonoester peaks and reduced phosphocreatina concentration in brain tumors. The usefulness of these metabolic examinations for planning the radio- and chemotherapy is demonstrated in clinical cases. U n i v e r s i t ~ t s - N e r v e n k l i n i k und Max-PlanckInstitut for neur01sgische F0rschung J0seph-Stelzmann-Str. 9 D - 5000 K61n 41

care. G a s t r o e n t e r o l o g i s c h e Praxis und M e d i z i n i s c h e U n i v e r s i t ~ t s k l i n i k M ~ n s t e r s t r a ~ e IS, D-5300 Bonn I

Bonn,

2/11-0 001 MATHEMATICAL MODELFOR THE KINETCS OF 18F RADIOACTIVITY IN TUMOURS,AS MONITOREDBY POSITI~ONEMISSION TOMOGRAPHY, AFTERBRIEF INFUSION OF 5-18F-URACIL R.E. Port, L.G. Strauss____,J.H. Clorius Uptake and retention of 18F in l i v e r metastases of colerectal cancer after systemic and loco-regional infusion of 5-18F-uracil has been visualized by positron emission tomography (PET). Since this method measures total radioa c t i v i t y , regardless of metabolic transformations, a mathematical model has been developed s p l i t t i n g up total r a d i o a c t i v i t y k i n e t i c s into k i n e t i c s of unchanged f l u o rouracil (FU) and k i n e t i c s of FU metabolites. The model requires information on a r t e r i a l FU plasma levels as a p r e r e q u i s i t e . Tumour r a d i o a c t i v i t y k i n e t i c s are described by four parameters: the d i s t r i b u t i o n a l clearance f o r unchanged FU between plasma and tumour, a global kM and vmax describing the o v e r - a l l concentration dependence of metabolic conversions of FU, and a global d i s t r i b u t i o n a l clearance f o r FU metabolites. The model has been implemented using a commercially a v a i l a b l e extended least squares modelling program package (MKMODEL, by N. Holford (Elsevier, Cambridge 1987). I t has been tested using r a d i o a c t i v i t y data from l i v e r metastases, with simulation of a r t e r i a l FU plasma levels by a conventional non-linear two-compartment model, assuming t y pical values of pharmacokinetic constants as derived from a separate study of systemic FU pharmacokinetics. The two d i s t r i b u t i o n a l clearance parameters are e s t i mated consistently with varying value combinations of the two metabolic parameters. These in turn (kM and vmax) are highly correlated with each other and cannot be estimated simultaneously. I t is hoped that analyses of t h i s kind w i l l f i n a l l y help in the early recognition of non-responsive tumours, as well as serve as a basis f o r a better understanding of the role of "local pharmacokinetics" in cancer chemotherapy. German Cancer Research Center, P.O. Box i01 494, D-6900 Heidelberg i

2/11-0 003 N O N I N V A S I V E M O N I T O R I N G OF T U M O R T H E R A P Y RESPONSE TO C H E M O T H E R A P Y BY MEANS OF IN V I V O ~*P M R - S P E C T R O S C O P Y USING A WHOLE BODY M R - S Y S T E M W. Semmler, G. Gademann, P. Bachert-Baumann, F. G~ckel, H.-J. Zabel, G. v. Kaick ~*p M R - s p e c t r o s c o p y (MRS) can m o n i t o r in vivo and n o n i n v a s i v e l y the cell m e t a b o l i s m and opens a new m o d a l i t y of following up in tumor patients under chemotherapy. A total of eight patients with superficial tumors were examined. ~ P M R - s p e c t r a were obtained during infusion of chemotherapeutics and/or w i t h i n the first hours and up to eight months after onset of therapy. M R - s p e c t r o s c o p y was p e r f o r m e d with a 1.5 Tesla M R - i m a g e r using surface coils. Pulse sequences were optimized to receive signals p r e f e r e n t i a l l y from tumor tissue and to minimize c o n t a m i n a t i o n of surface layers. Quantitative assessment of MRspectra was p e r f o r m e d using a least square fit procedure. In addition to MRS, tumor response was m o n i t o r e d by MRI in all patients. In case of positive tumor response, an increase of PCr-PI ratio and PCr-PI sum is observed in long term follow up. As early as one day after onset of therapy, MR spectral parameters of tumor tissue change, whereas no clinical signs of tumor response are observed. A common feature of tumor tissue is the increased pH value when compared to h e a l t h y tissue. A c c o r d i n g to our observations, MRS is capable to m o n i t o r tumor response already within the first days after onset of therapy and may have the potential to optimize cancer therapy. Deutsches Krebsforschungszentrum, Institut f~r Nuklearmedizin, Im N e u e n h e i m e r Feld 280, D6900 H e i d e l b e r g

$37 2/11-0 004

2/11-0 006

C R I T I C A L E V A L U A T I O N OF THE SO-CALLED FOSSEL-TEST K.P.Sohalk, H.R~terjans, J.P.Kaltwasser, H.Said ~ T H a d j , L. S t a f f e n b e r g e r

S U C C E S S F U L L TUMOR DIAGNOSIS BY !i~IMUNOSCiNTIGRAPHY (IS) USING T E C H N E T I U M - 9 9 m LABELED MON0CLONAL ANTI-CEA ANTIBODIES (MAB) R.P. Baum, M. Lorenz, M. Platz, G. HSr In most of the nearly g00 immunoseintigraphic studies performed during the last 3 yrs by our group, 1-131 or !n-111 labeled MAB were used. However, both r a d i o n u c l i d e s are not ideal. Recently, a new technique for labeling MAB with Tc-99m was described by Schwarz et al. providing the opportunity to use an ideal radionuelide for IS. The aim of the present study was to determine the diagnostic sensitivity, specificity and accuracy of IS with Tc-99m labeled MAB BW 431/26 (Behringwerke,Marburg) in patients with proven or suspected C E A - p r o d u c i m g tumors. 20 patients (age 32-76 yr) with different malignant tumors or recurrences (colorectal 14, lung 2, breast 2, c-cell carcinoma 2) were examined after i.v. injection of 1,11 GBq Tc-99m bound to 2 mg of Anti-CEA MAB BW 431/26. Labeling efficiency was controlled by paper chromatography before injection (96%). Planar scintigraphy and ECT was performed 6-12 and 18-26 h p.i. Resu•q a positive scintigraphic contrast was detected in 19/ 20 patients ( sensitivity 95%). In many patients tumor lesions could be detected which were not known before ( e.g., abdominal lymph node metastases)and could be confirmed surgically or in the follow-up. The specificity was more than 90% and in many cases excellent tumor contrast was seen. From the first clinical results we conclude that IS with Tc-99m labeled MAB is easy to perform (with lower radiation exposure to the patient), sensitive and specific, and therefore could be of great value in the earlier tumor localization of CEA-producing tumors or recurrences. Abt. Nuklearmedizin, Universit~tskliniken, D-6000 F r a n k f u r t / N a i n 70

One year ago a new specific test for the detection of cancer was p r e s e n t e d (Fossel et aI.N.E. J . M e d . 3 1 3 : 1 3 6 9 - 1 3 7 6 ) . The authors d e s c r i b e d a new method to m e a s u r e the line width of lipoproteins in plasma by N M R - s p e c t r o s c o p y . Their results showed a significant decrease of the line width in plasma of patients with cancer c o m p a r e d to normals. The present study gives the results of a cooperative investigation of our instituts to prove the reliability of the so-called Fossel test. We investigated60 samples, including 7 healthy persons, 11 p r e g n a n t women, 9 patients with non m a l i g n a n t and 33 patients with m a l i g n a n t disease w i t h o u t any tumor treatment. Blood samples were drawn after an overnight fasting and EDTA plasma was stored at 4~ N M R - s p e c t r o s c o p y was performed by an AM S p e c t r o m e t e r B r u k e r by using deuteriumoxide and water s u p p r e s s i o n by a decoupling power of 9 L. The m e a n line width was found 38.85~6.56 Hz for healthy and 37.0s for patients with non m a l i g n a n t diseases. Patients with cancer and other m a l i g n a n t h e m a t o l o g i c a l diseases showed a mean of 36.69-7.7 Hz. Only in p r e g n a n c y a sig9 i f i c a n t decrease of the line width (mean 31.72 -5.7 Hz) was observed. In contrast to Fossel et el. no d i f f e r e n c e between normals and patients with cancer could be found. The wide range of the line width did not allow any discrimination between healthy, non m a l i g n a n t and m a l i g n a n t disease. Abt. H~matologie, Zentrum der Inneren M e d i z i n und Institut fir B i o p h y s i k a l i s c h e Chemie der J . W . G o e t h e U n i v e r s i t i t , T h . S t e r n Kai 7,6 F r a n k f u r t

2/11-0 005 MRT - DETECTION OF BONE NARROW I~P/OLVEItENT BY IL%LIGNANTLYMPHOMA F. Gfickel, H. D6hner*, W. Knauf*, A. D. Ho*, W. Semmler, G. v. Kaick Bone marrow involvement by systemic neoplastic diseases is presently confirmed by biopsies taken from the posterior iliac crest. This small sample, however, is not representative for the total bone marrow. MRT allows a good visualisation of extensive parts of the hone marrow by sagittal and frontal slices. A relatively high amount of fatty tissue leads to a high signal intensity of bone marrow in Tl-weighted images. Infiltration of the bone marrow by neoplastic tissue results in a decrease of the signal intensity in these regions. In a prospective NRT study, both, normal volunteers (n=lO) and patients with Hodkin and Non-Hodgkin lymphomas (n=31) were examined (lumbar spine, pelvis and proximal femura). A biopsy from the posterior iliac crest was taken in all patients. About one half of the patients showed in MR-images diffuse or patchy areas of decreased signal intensity in the regions of the bone marrow, while the bone marrow of the volunteers showed an almost homogeneous pattern with high signal intensity. Our findings observed by MRT in bone marrow of these patients corresponds with pathological results obtained from crest biopsies. In order to improve the diagnostic accuracy, a quantitative evaluation of the signal intensities in selected ROIs, referring to a standard was used. This method allows to correct variations of the signal intensity due to technical reasons. As our results show, this leads to a better differentiation of border-line cases. MRT has the advantage to detect localised lesions outside of the iliac crest. In cases of negative crest biopsies, but suspicious areas in MR-images, biopsies could he directed to these lesions. Deutsches Kreh~crschm~szentrum, Institut f~ir} A ~ k l ~ z i n , Im Neuenheimer Feld 280 D-6900 Heidelberg; *Med. Klinik und Poliklinik V, Univexsit~t Heidelberg, Hospitalstra~e 3

2/11-0 007 IN VIVO IMAGING OF HODGKIN'S LYMPHOMAWITH MONOCLONAL ANTIBODIES BY IMML~-~OSCINTIGRAPHY. M. Pfreundschuh, L. Da Costa, P. Carde, L. Manil, J . - D . Lumbroso, B. C a i l l o u , C. Parment i e r , J . - C . S a c c a v i n i , and V. Diehl The Hodgkin- and Reed-Sternberg (H&RS) c e l l s a s s o c i a t e d monoclonal a n t i b o d y ( m o a b ) HRS-1 was l a b e l e d w i t h r a d i o a c t i v e i o d i n e and i n j e c ted into 6 p a t i e n t s ( p t s . ) w i t h Hodgkin's lymphoma (HD). Doses of the m o a b H R S - I ranged from 0.5.mg to 2 mg. In 5 p t s . HRS-1 was l a b e led w i t h !3~I for l i n e a r immunoscintigraphy. A ~@b a g a i n s t a l p h a - f e t o p r o t e i n l a b e l e d w i t h was used as a c o n t r o l . 4/5 p t s . had a positive scan (nodal, s p l e n i c and h e p a t i c i n v o l v e m e n t ) , the r e s u l t s in 1 p t . were equivoIn the 6th p t . HRS-I was l a b e l e d w i t h f o r t o m o s c i n t i g r a p h y . Although the tomosc i n t i g r a m was performed a f t e r e f f e c t i v e chemotherapy, images of bony d i s e a s e were demonstrated. No s i d e e f f e c t s were observed in any p a t i e n t . These p r e l i m i n a r y r e s u l t s demonstrate that immunoscintigraphy w i t h the r a d i o l a b e l e d HRS-1 i s l e a s a b l e and i n f o r m t i v e in HD. The r e a l c l i n i c a l s i g n i f i c a n c e and the s p e c i f i c i t y of t h i s procedure must be d e f i n e d in a l a r g e r s e r i e s of p a t i e n t s . M o d i f i c a t i o n s of the t e c h niques such as the use of Fab or F(abt)~ f r a g ments should f u r t h e r improve the r e s u l t g .

~

M e d i z i n i s c h e K l i n i k I der U n i v e r s i t ~ t zu Kbln, J o s e f - S t e i z m a n n - S t r . 9 , D-5000 K61n 41.

$38 2/11-0 008

2/11-O 010

CL ]:NII2AI., ~31I}]NIFICANCE OF f'~ADIOIMMI.~NOSCINTqGRAPH~
IMMUNOCYTOCHEMICAL IDENTIFYING OF NEUROBLASTOMA MINIMAL RESIDUAL DISEASE IN BONE MARROW FROM PATIENTS DURING OR AFTER THERAPY USING A PANEL OF MONOCLONAL ANTIBODIES E,S.Gussetis,U.Ebener,S.Wehner and B.Konlhuber

In rec:ent year~s ~7~ever'al ~luthors r e p o r t e d h i g h d i a g n o s t i c s e n s i t i v i t i e s I':H:R I S w i t h m e n o c l o n a l antibc~d:i,es (I"IABs) dir'ected a g a i n s t C;li!i'.Aand CA 19---9 ir'l p~i~tier'Its w i t h g a s t r e i n t e s t i n a l mallgru;:Y,., mas, Ther'e-fore w e e v a l u a t e d t h e c l i n i c a l s i g n i fic:ar'u:;:e cH: R I S by r'etcosTiective a n a l y s i s o 4 : 7 4 s t u d i e s w h i c h had b e e n per.~oi"med in our d e p a r t m e n t b e t w e e n 1 / 1 9 8 6 and 3/1987, All s t u d i e s were validated by surgical al",d h i s t o i o g i c a l f i r'u:;li n g s ( i n c i ,, i mlm.,e~cichemi s t : l " y i r"~ :[3 i::ase!~i~) CT-,,,scar.ls,~ and c:lir'licai '{:cf,l, ll:;l~""ul:* e4: a t ] . e a s t 6 mervM-~s~ F"c,s i t l v e results o.f RtS w e r e d i v : i , d e d irrl=o de.~:i, n i t : i v e and equivocal accor'ding to sc::i i~t:~ q r a p h i c : c:or'H;,r'ast~ Oi ai]nesi s T'I::> EV* TN FP FN Sens, (%)

I::"r"i m,, ]"Limef

18

t::~e c u vq" e r",i:::y

1,5 33 66

Metastasis Tet al

I,2

0

','5

5 :L (86 )

'7

IO

3

3

6 0 (88)

I0 29

ii 21

2 5

14 21

*=equiw~cal ~=value in Four" o'f t h e 8&~ p o s i t i v e t h e da't:e e,{: e x a m i n a t i o n ,

O

58(75) 5 7 (82} ~i

<) S o n ( T P + E V ) lesions w e ~ e unkr'~ewn a t l,,,lewever~ t h e r ' a p e u t i c a l

~::)17!!i; 14 e F ~:? C}Y' a ~t I"~ i r'~ t':)r7], y C)I"~e C &~s e ,, (]i,,ll" r'*~'~..... su]'L!.'.:i irld:i, cate, that: at'. pr"e!sent, st.a't.e eml::)lewr, er'lt e,{ F,':]' ~.:i~ !;~hot{ld b e r'~!~H~vt.F'Jc, t e d tf.) patq. er3tf.'4 I ~ i t h inc:c~r~clusiwii~ eut.c:oms, o4* c : l i n i c : a i r ' e u t i r * e . A d d i t i e , hal diag|!ic.!s'tic in~fermat, ier~ is4 r a r e l y ~:4ained b y RIS,, C e I"rC: ], t4 ,qliJ

/}ef:lh~;,.

o4: N u c l e a r '

Med:i, c i r ~ e

and

Surger"y,~

Aac:he!r'x ,, I:::'at4we],~!;f;'t:,r ,, ,! D-5100 (~r

Univ.

Immunoalkaline Phosphatase staining by the APAAP technique has been used to recognise tumor involvement of bone marrow from eleven cases of Neuroblastoma during or after therapy.In all cases aspirated marrow cells were labelled by ten well characterized menoclonaI antibodies,which specificly bind ceils of neural crest origin (J.T.Kemshead et al.Lancet j 12,1983).Eaeh monoclonat antibody raised against neural tissue has shown strong reaction with four human neuroblastoma cell lines (established in our laboratory) but not to normal marrow ceils or malignant hemopoiede cell lines,as well as,with fresh leukemia cells.To insure optimal binding of minor cells,careful titration of each monoclonal antibody was conducted on normal marrow samples contaminated with one percent neuroblastoma cells.One cell per 100.000 cells could be detected with the APAAP method. Eleven children with bone marrow involvement at diagnosis were included in this study.The fact that at least thirty percent of minor bone marrow involvement occurs in patients apparently in CR, led us perform immunophenotyping of bone marrow cells at various times of disease during or after therapy. In 7/11 children 2-25 percent neumblastoma cells were identified whereas bone marrow biopsies and aspirates in three patients of them were classified as normal. Our study demonstrates that immunological staining may detect neuroblastoma cells which are not yet recognisable by traditionM cytological or histological criteria.Now such ceils should be fully characterized in their cytological aspect and membrane marker expression in order to investigate whether the presence of such cells precedies clinical relapse. Center of Pediatrics,Hematology-Oncology Div. University of Frai~furt,Theodor-Stem-Kai 7,6,~'anks

el:

,~ [::'l':~('.~

2/11-0 009

2/11-O 011

THE IMPACT OF IMMUNOSCINTIGRAPI~" ON THE OPERATIVE TREATMENT OF RECURRENT COLORECTAL CANCER - LIMITATIONS OF A NEW DIAGNOSTIC METHOD Th. H61ting, P . Schlag,M. Steinb~cher, U, Kretzschmar ~P.Georgi

DEYECTI(IN OF MALIGNANT CELLS VIA I ~ S T R Y AND FINE ARCHITECTURE OF CELL NUClei USING H I ~ RESOLUTION LMAGE ANALYSIS U. Gu_nzer*, I. Baumann*, M. Klink*, H. Harms**, H.M. Aus** V. ter Meulen**, P. Schauer***

IntEod_~tion:

Interpretation of morphology from individual cells or in tissue sections is still the most reliable procedure of discrLminating malignm~t or non-malignant disorders. ~he world-wide clinical acceptance enjoyed by such methods has not been achieved by eit21er flow cytometry or image .processing systems up to now. However, progress in pattern recognition provides autc~ated analyses even of blast cells from peripheral blood or of tissue cells staining positive for cell markers. ~ and me,hods: From 20.000 blast cells of air-ch-ied Pappe.nheim and Wittekind stained blood smears 32 features were extracted from both the nucleus and the cytoplasm using high-resolution, single-focus, ~llticolor ~nalyses adapted to the human visual color syst~a and frcm breast cancer tissue sections stained for estrogene receptors using a multi-focus modality. The imag~ analysis system combined a ZEISS Axiomat microscope, attached to a Sony T V co/~ra and an EYCOM 3 system for data acquisition, a PDP 11/23 prozessor for controlling microscope and camera, a VAX 11/750 cc~puter to run the algorithms and a Cc~tal vision-one system for two color output. ~ts: Cell features from blast cells of ostec~yelofibrosis it, blast crisis (QMS-BC)mathematically differed significantly from those in uncomplicated O~S and CML. Cells from T-ALL could be separated frc~a Non-T-ALL cells by using and analyzing no~nal Rornanowski-Giemsa stains including Wittekind's stain with purified Azure B/Eosin Y. Blast cells could not be determined with size and shape analyses as was possible with fine architecture of bot~ the nucleus and the c~coplasm. Subtle multi-fceal color s/aalyses in tissue sections of breast ce~ncer s ~ i m e n s revealed proper discrimination of estrogene receptor (P~/Pmethod) positive and negative cells. Med.Klin.*& Inst.Virol.** Univ. ~irzburg; Inst.Pathol.*** Univ. C~Sttingen

The

development"

of

radiolabeled

monoclonal

antibodies h a s offered a new potentially specific diagnostic parameter for tumor localisation in recurrent colorectal cancer. However, since some studies showed a high incidence of false results a controversy about the benefit of this procedure arouse. Material and methods: From 1985-1987 the immunoscintigraphy was administered to 29 patients where after curative resection suspicion of recurrence arouse because of patological findings in conventional restaging. The second-look operation which was performed in all cases revealed in 12 coses intrahepatic, in 9 cases intra- and extrahepatic metastases and in 7 cases local recurrent disease, Analyses of comparison of preoperative conventional re-stating results versus i~unoscintigraphy in relation to surgical exploration are presented. _Res_ul_ts: In proof or exclusion of intrahepatic lesions conventional methods had a sensitivity of 71% versus 52~ of im~unoscintigraphy (specifity 75~ vs i00%). In ext r~lhepatic lesions conventional procedures had a sensitivity of 7~ vs 25% of immunoscint ig~aphy (specifity 9 2 g vs S 2 % ) . Conclusions: At the present the value of radioimmunoscintigraphy must be regarded critically as an additative diagnostic tool for early detection of metastatic or recurrent colorectal cancer. There is still a high rate of errors especially in regard to e• tumor Iocalisation. Chiru~gische Universit~tskiinik, Abteilung Neuenheimer Feld II0, 6s Heidelberg, FRG

2. I. I., Im

$39 2/11-0012

2/12-M 002

BONE ~[ARROW SCINTIGRAPh~ (BMS) AND MAGNETIC RESONANCE TOMOGRAPHY (MRT) IN PLASMOCYTOMA J. Ruhlmann (I), A. Bockisch (I), W. Dewes (2), U. Loos (3), A. Hotze (I), B.J. Biersaok (I)

C O M B I N A T I O N C H E M O T H E R A P Y OF M E T H Y L N I T R O S O U R E A (MNU)-INDUCED RAT MAMMARY CARCINOMA WITH HEXADECYLPHOSPHOCHOLINE AND TAMOXIFEN. C. M u s c h i o l , M.R. B e r g e r , H.J. Eibl, D. Schmfihl

BMS employs the phagocytic capacity of the RES for small albumin colloids in the detection of marrow involvement and/or destruction. As a relatively new imaging method ~ T also allows to visualize the bone marrow. We have undertaken a prospective study in 15 pts. with proven plasmocytoma comparing ths results of both BMS and NET. Method: a--~BNS was performed using 740MBq Tc-99m-labeled nanocolloid (particle size <3Onm). Whole body scans were obtained 30 min. past injection on a LFOV gamma camera. The scans were evaluated as follows: Presence or absence of RES-extension (RE), cold lesions (el), hot spot (HS), complete destruction (CD), normal activity pattern (N). b) MRT was performed on a Philips Gyroscan with a field strength of 1.5T. T] as well as T2 weighted tomograms of pelvis and femoral region were recorded and evaluated visually as follows: diffuse involvement (DI), remnant of yellow marrow (YM), focal involvement (FI). complete destruction (CD), normal (N). ReFemur: BMS RE 13 CL 6 HS I GD I N I sults: MET DI 13 YM 6 FI I GD I N I Pelvis: /?MS CL 3 GD I N 11 F~T FI 5 GD I N 11 These results indicate that femoral RES-extension as seen on BMS is primarily due to diffuse tumorous involvement proved by MRT, and cold lesions of the femoral RES on BMS correspond to residual yellow marrow. In contrast, focal tumor involvement of the pelvis as seen on MET appeared as cold lesion on BMS. Thus BMS will be helpful in the follow up of plasmocytoma, may reduce the number of biopsies, and allows - if necessary - scan-guided biopsy. Dept. Nucl. Ned. (I), Dept. Radiol. (2), Dept. Int. Ned. (3); Univ. 5300 Bonn, Venusberg, W. Germany

Hexadecylphosphocholine (HPC) is a n i n t e r e s t i n g n e w a n t i n e o p l a s t i c a g e n t w h i c h h a s b e e n f o u n d to be especially active against chemically induced p r i m a r y r a t m a m m a r y c a r c i n o m a (Berger e t a l . , J . C a n c e r Res. C l i n . O n c o l . Iii, $24, 1986). In an investigation on potentially useful combinations H P C (I) and t a m o x i f e n (tam; II) w e r e a d m i n i s t e r e d a l o n e a n d in two c o m b i n a t i o n s , w h i c h w h e r e b a s e d on a m o l a r r a t i o o f H P C v e r s u s T a m of 2 : 1 (III) a n d 1:2 (IV). A d d i t i o n a l to the h i g h e s t d o s a g e s (a) of H P C (77 ~ m o l / k g ) , T a m (16 ~ m o l / kg) a n d t h o s e o f t h e c o m b i n a t i o n s , two log. s p a c e d lower d o s a g e s {factor = 1.5; b, c) w e r e s e l e c t e d to o b t a i n a d o s e - r e s p o n s e r e l a t i o n s h i p in all four t r e a t m e n t arms. T r e a t m e n t w a s adm i n i s t e r e d t o g r o u p s of 13 r a t s b e a r i n g o v e r t MNU-induced autochthonous mammary carcinoma and w a s m a i n t a i n e d o v e r five w e e k s . T r e a t m e n t results at week 6 in terms of T/C% and % mortality w e r e as f o l l o w s . Ia: 1.1-17, b: 9.4-0, c: 32.3-0; IIa: 123-46, b: 55-53, c: 7 8 . 8 - 2 3 ; IIIa: 2 3 . 5 - 3 1 , b: 5 3 . 4 - 4 6 , c: 1 4 . 8 - 3 8 ; IV: 55-33, b: 2 4 . 2 - 5 3 , c: 5 9 . 3 - 4 6 ; Control: 100-15. T h e s e r e s u l t s i n d i c a t e n o i n c r e a s e in t h e r a peutic efficacy of HPC when Tam was coadministered; o n the c o n t r a r y , a d e c r e a s e d a n t i c a n c e r a c t i v i t y and a n i n c r e a s e d m o r t a l i t y w a s obs e r v e d . T h e c o m b i n a t i o n of H P C and T a m s h o u l d be used therefore with precaution and cannot b e r e c o m m e n d e d for c l i n i c a l p r a c t i c e on the b a s i s of the m o d e l u s e d . I n s t i t u t e of T o x i c o l o g y and C h e m o t h e r a p y , D E F Z , Im N e u e n h e i m e r F e l d 280, 6900 H e i d e l b e r g , F.R.G.

2/12-M 001

2/12-M 003

HEXADECYLPHOSPHOCHOLINE (D 18506),A NEW PHOSPHOLIPID WITH HIGHLY SELECTIVE ANTITUMORACTIVITY d. Stekar*, P. Hilgard*, J. Engel*, W. Schumacher*, H. Eibl**, C. Unger*** D 18506, a new phospholipid, was selected f o r experimental studies, because i t is easily s p l i t by phosphoIlpases C/D and t h i s enzymatic reaction is considered to be important for the antitumor a c t i v i t y ( I ) . In v i t r o D 18506 was only moderately active against clonogenic L1210 ceils but inact i v e against 4 other rodent and human cell lines. Correspondingly, D 18506 was ineffective in vivo against P388, L1210 and B-16 melanoma of mice. Likewise, neither the DScarcinosarcoma nor the AHI3r tumor of rats responded to a variety of D 18506 dose schedules. However, in agreement with MUSCHIOL et al. (2) we found substantial antitumor a c t i v i t y in autochthonous methylnitrosourea-induced rat mammary tumors. Furthermore, using the DMBA-induced mammary carcinoma of the SD rat and a 5-week daily oral t r e a t ment regimen, we achieved a dose dependent suppression of the tumor growth over the period of therapy. Treatment with D 18506 in optimal therapeutic doses was well tolerated and no overt toxic symptoms were observed. Cyclophosphamide, administered at a maximally tolerated dose, was considerably less active than D 18506 in the DMBAtumor. In marked contrast to the classical cytostatics, t r e a t ment with D 18506 was not followed by bone marrow suppression. On the basis of the data presented and the favourable toxicology of the compound, c l i n i c a l t r i a l s with oral D 18506 have been i n i t i a t e d . (I) Eibl, H., Unger, C. Proc. I s t Int.Symp.Ether kipids, G~ttingen 1986. (2) Muschiol, C., Berger, M.R., Schm~hl, D. Proc. Ist Int. Symp. Ether Lipids, GOttingen 1986. Asta Pharma AG D-4800 Bieiefeld 14 ( * ) ; Max-Plancki n s t i t u t , D-3400 G~ttingen ( * * ) ; University Hospital, D-3400 GSttingen (***)

KLKYLPHOSPHOCHOLINES AND ALKYL-GLYCER0PHOSPHOCHOLINES AS SUBSTRATES FOR PHOSPHOLIPASE C J. K~ttlng, E.A.M Fleer, C. Unger and H. Elbl Alkyli~hospho~holines

antineoplastic

agents.

are a new

(AI-PC)

They

are derived

class

from

of

~Lkyl-

~lycer0~h0spho~holines (AI-GPC) with the knowledge

that

substrate

(PLC,

E.C.

earlier results were obtained wlth PLC

from

properties

for ~hospholipase

Q

3.1.4.3) are required for toxicity. These bacterial were

not

purlfled

since PLC's from

available.

Therefore,

mammalian we

have

requirements with those from

antibodies

antibodies for

partially

against

PLC

of

against

the bacterial

antibodies are now used for instance

purification

of

the

their

bacterial

PLC.

cereus

are

B.

crossreactlve with the rat liver enzyme, These

tissues

cytosollc PLC from rat liver to compare

substrate Since

sources

we have raised

enzyme

in rabbits.

different liver

purposes, enzyme

and

determination of PLC in liver and in cell homogenates of different neoplastic cell lines. The result should allow a description of the relation between PLC

concentration

in cells and their sensitivity for Al-PC or AI-GPC. M.P.I. f~r Biophyslkallsche Chemic, D-3400 G~ttingen

$40 2/12-M 004

2/12-M 006

ETHERLIPIDS IN THE TOPICAL TREATMENT OF SKIN METASTASES C.Unger, H.-W.von Heyden, A.Breiser, G.A.Nagel,

H.Elbl

AlkylI~hospho~,holines (AI-PC) represent a new class o f antineoplastlc agents.

Hexadecylphosphochollne as

representative

is applied in

of

alkyl-glycer01s tases.

AI-PC

for

a

topical treatment of

mixture

a of

skin

metas-

Breast cancer patients suffering from

severe

skin invasion were treated with etherliplds twice daily. All

patients had a history of

extensive

(chemotherapy/radlatlon/surgery). patients,

a

change,

(i-6 months), (5

2-12

progressive

effects

occurred.

months), months)

disease.

simultaneously slde

pretreat-ment

a

of

group

complete remission was observed for

individuals remission

In

one person showed a

slx patients and five

person

dryness,

partial

suffered

treatment.

reddening

(no

stable

Three of the six stable

received hormonal mlld

were

15

three

from

patients As

and

local itching

Systemic side effects were not detected, Skin

biopsies

taken from invaded and normal skin revealed

moderate

increase

in

formation

without affecting the normal skin

of

a

collagen

fibers

architecture.

There-

fore, topically applied etherllplds may represent a safe and effective treatment of skin metastases, Zsntrum

Innere

Medlzln,

Abt.

H~matologle/0nkologle,

DIFFERENTIAL SENSITIVITY OF NORMALHUMANBONEMARROWPROGENITOR CE~LS AND HUMANLYMPHOMACELL LINES TO CYTOTOXIC ETHER LIPIDS AND THEIR ROLE FOR PURGING LYMPHOMAMARROW AUTOGRAFTS. W. E. Berdel, S. Okamoto. A. Reichert, A. C. Olson, E. F. Winton, W. R. Vg_~er. genitors can be eliminated from simulated remission bone marrows (BM) by incubation with ether lipide under conditions that spare normal BM progenitor cells. To assess the a p p l i c a b i l i t y of ether lipids for purging of lymphoma cells from autografts for the treatment of nonHodgkin's lymphomas (NHL), we have compared the sensitivi t y of human lymphoma cell line progenitors (Li-A, lymphoblastoid, G. Roos, Sweden) and normal human BM progenitor cells in a CFU-assay. Li-A cells and cells of BM from 6 healthy donors were incubated for 4 and 18 hrs with O, 25, 50 and 75 ug/ml, ET-18-OCH3 (ET) and combinations of ET with the lipoidal amine CP-46,665 (CP) at CP:ET concentrations of 5:25, 10:50 and 15:75 ~g/ml in RPMI 1640 medium with 10% serum. After incubation, cells were washed and cultured in methylcellulose (37~ 5% CO2, high humidity) for 14 days with PHA-LCM (BM cells) or for 10 days without stimulators (Li-A). Incubation with ET for 4 hrs up to a dose of 50 ~g/ml did not suppress clonogenicity of normal BM progenitors or the distribution of the types of progenitors (GM-clusters, CFU-GM, BFU-E, CFU-E, CFU-GEMM)while this condition led to an approx, l - l o g reduction of clonogenic Li-A c e l l s . However, higher concentrations of ET, the combinations of ET and CP and longer incubation periods led to increased k i l l i n g of Li-A progenitors, but also to a more variable t o x i c i t y for normal BM progenitors. Cryopreservation f u r t h e r decreased the clonogenicity of both Li-A and BM cells without adding to the difference in s e n s i t i v i t y . Thus, ether l i p i d s seem to be promising as purging agents for autologous bone marrow transplantation in NHL. DFG Be 822/2-4, Be 822/3-i, NIH CA 29850-04 AI. Emory University, Atlanta, GA, USA.

Robert-Kocb-Str, 40, D-3400 GSttlngen

2n2.M cos

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SHORT- AND LONG-TERM T O L E R A B I L I T Y STUDY OF THE TRIOETHER PHOSPHOLIPID ANALOGUE ILMOFOSINE IN CANCER PATIENTS M.E. Helm ~, H.A~ Neu~ann 2 , W.E. B~rdel 3 , M. 5 F r o m m ~ R~ Andreesen ~, W. Quei~er ~ , D. B o o m e r s D U. Bicker and D.B.J, Herrmann

POSTOPERATIVE VACCINATION WITH AUTOLOGOUS TUMOR CELLS MODIFIED BY NEWCASTLE DISEASE VIRUS: ANTIMETASTATIC EFFECTS AND ANALYSIS OF IMMUNE T CELL ACTIVATION P. yon Hoegen, H.-J. Schild, R. Heicappell and V.

Ilmofoeine ( l - h e x a d e c y l m e r c a p t o - 2 - m e t h o x y m e t h y l r a c - g l y c e r o - 3 - p h o s p h o c h o l i n e , BM 41.440) a new thioether p h o s p h o l i p i d derivative was evaluated in a m u l t i c e n t e r phase I study in 34 patients (pts) with refractory cancers. The objectives were (I) determination of the m a x i m u m - t o l e r a t e d dose of a single or multiple oral a d m i n i s t r a t i o n of Ilmofosine for one day, and (2) definition of the d o s e - l i m i t i n g tocicities according to the WHO grading. Pts were orally treated with doses ranging from 0.5 to'7.0 mg/kg body weight (bw). Three different formulations were tested: soft gelatine capsule, film tablet and coated film tablet. The m a x i m u m - t o l e r a t e d dose (MTD) was 5 mg/kg bw. The limiting side effects were nausea and vomiting. There was no evidence for systemic toxieities like nephro-, neuro-, h e p a t o t o x i c i t y or h e m a t o l o g i c a l side effects~ In the long-term tolerability study Ilmofosine was administered on a daily oral schedule for at least 8 weeks. So far, 44 pts have entered this trial on dose levels ranging from i00 to 400 mg/day. At present, 29 pts are evaluable for tolerability. The median d u r a t i o n of therapy in these pts was 5 weeks (range: i to 50 weeks). The limiting sideeffects also were nausea and vomiting. The MTD was 200 mg/day. Results of p h a r m a c o k i n e t i c investigations p e r f o r m e d in parallel will be pro ~ sented. i Onkol. Zentrmm, D-6800 Mannheim 2~St.-~osef-Hospital, D-4630 Boch~m 1 3 I. Med. Klinik, Techn. Univ., D-8000 M ~ n c h e n 4 Med. Univ.-Klinik, D-7800 Freiburg 5 Boehrinqer Mennheim, D-6800 Mannheim

W e have developed an active specific inununotherapy (ASI) protocol for postoperative treatment of micrometastases using the highly metastatic murine tumor model ESb. The ESb lymphoma growth in syngeneic DBA/2 mice whereby as few as ten tumor cells are able to kill the host. Specific "vaccination" against the tumor was achieved by modification of the tumor cells with Newcastle Disease Virus (NDV), a low pathogenic chicken paramyxovirus; 2.5x107 irradiated ESb tumor cells were modified with 160 hemagglutinating units of NDV. The effect of this modification on T cell-mediated tumor specific immune responses was investigated both in vivo and in vitro. Immunization with modified tumor cells led to an increased lysis of u n modified tumor cells by splenic T cells as measured in vitro without generating a virus-specific immune response. Detailed analysis of the T cell compartment revealed an increased maturation of cytolytic and helper T cell precursors. Taking into account the augmented recruitment of T cells and increased production of lymphokines we estimated an overall increase of specific anti-tumor immunity by a factor of 25 in vitro and 250 after vaccination with modified tumor cells. The therapeutic benefit of this protocol was assessed by its influence on the growth of micrometastases after the removal of the primary tumor. While removal of locally growing ESb tumors by surgery alone had no curative effect and the animals died of disseminated disease, the combination of surgery with "tumor vaccination" led to about 80% surviving animals. These mice were free of micrometastases and had a long lasting systemic immunity. Institut fEir Immunologic und Genetik, Deutsches Krebsforschungszentrum, Postfacb 101949. D-6900 Heidelberg

$41 2/13-M 002

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INFLUENCE OF DIFFERENT CYTOKINES AND OKT3 ANTIBODIES ON LAK-CELL INDUCTION IN VITRO E.Weidmann, L.Bergmann, P.S. Mitrou, D. Hoelzer

IMMUNOTOXIN THERAPYIN ADVANCEDMALIGNANTMELANOMA

Interleukin-2 [IL-2) activates in vivo and in vitro lymphocytes with cytolytic activity to neoplastic cells ( L y m p h o k i n e - A c t i v a t e d KillerCells = LAK-cells). These LAK-cells can discriminate between malignant and benign cells and lyse autologous, heterologous and allogenetic tumor cells and cell lines. We present in vitro results of lymphocyte differentiation to LAK-cells with IL-2 with or withuot other cytokines (TNF, y-IFN, IL-l) or mitogenic OKT3 antibody. Results: ]. Surface marker analysis with monoclonal antibodies d e m o n s t r a t e d an increased expression of CD2,CD3 and CD4 antigenes on peripheral lymphocytes incubated with IL-2 for 3 to 2] days. Surprisingly, the IL-2 receptor (Tac) was not expressed on these cells. In addition the CD4+Leul8 + subset (helper-inducer cells) increased substantially. 2. LAK-cell activity was p r e d o m i n a n t l y found in T-cell subpepulations. 3. Addition of y-IFN, IL-] or TNF to peripheral lymphocytes and optimal concentrations of IL-2 may partially enhance the LAK-cell activity. 4. A u g m e n t a t i o n of cytotoxic activity could not be observed in combination of IL-2 with OKT3 antibody in short-term-cultures, but suppression of cytelysis by this combination was detected in long-term-cultures

Division of Haematology, Department of Internal Medicine, J.W. Goethe University, Frankfurt/M, FRG

B. Block, P. v. Wussow, L. Spitler and H. Deicher Seven patients with metastatic malignant melanoma were treated with a murine monoclonal (anti-melanoma) antibody recognizing an surface 220 KD antigen on melanoma cells coupled to the highly purified A chain of the ricin toxin (Xoma, California). They received 5 i . v . 30 minute-infusions with a dose of 0,4 mg/kg body weight over a period of 8 days. All patients failed previous chemotherapy and/or IFN- -therapy and showed progressive disease before entering the study. The treatment was accompanied with tolerable t o x i c i t y . The side effects consisted of weight gain (up to 10% of body weight), edema, mild drop in serum albumin and serum calcium, fever and fatigue. All symptoms disappeared within one week after the last immunotoxin infusion. Neither severe allergic reactions nor thrombocytopenia were observed. However, a l l seven patients developed both anti-toxin and anti-murine-antibodies 3 weeks after the last IT-infusion. All seven patients were evaluable for tumor response. No CR or PR was seen; one patient experienced a minimal response with shrinkage of l i v e r metastases (12 months +). One mixed response was observed with disappearence of skin metastases, whereas intraabdominal lymph nodes progressed slowly. We conclude that the iv~unotoxin at the dose schedule used can be safely administered. Although the clinical effects in the patients studied are not encouriging the data from a single course ot therapy indicate that the immunotoxin has some antitumoral a c t i v i t y . We hope to improve the therapeutic efficacy by repeating treatment courses with IT. Abteilung Immunologie, Medizinische Hochschule Hannover, Konstanty-Gutschow-StraGe 8, D-3000 Hannover 61

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THE HUMANLYMPHOKINE-ACTIVATEDKILLER PHENOMENON: REGULATION OF PROGENITORAND EFFECTORFUNCTIONS J. Atzpodien, S. Gulati, D. Wisniewski, C. Shimazaki, C. BUhrer, S. Oz, K. Welte, H. Link, H. Poliwoda, and B. Clarkson

immunotherapy

Recently, a new approach to cancer immunotherapy has been described employing the adoptive transfer of autologous patient-derived lymphokine-activated k i l l e r (LAK) c e i l s . LAK cel!s for c l i n i c a l use are commonly generated via incubation with i n t e r l e u k i n - 2 (IL-2) of unseparated peripheral blood mononuclear c e l l s (PBMC). In our laboratory, substantial LAK-like i . e . , MHC-unrestricted, k i l l i n g acti v i t y against various human tumors could be induced in highly p u r i f i e d PBMC-derived c e l l subpopulations. When compared to unseparated PBMC, p u r i f i e d natural k i l l e r iNK) c e l l s were more than t e n - f o l d enriched f o r non-speci f i c c y t o t o x i c i t y against NK-sensitive targets on day O, and acquired optimal LAK c y t o t o x i c i t y a f t e r 5-day stimulation with IL-2. However, no s i g n i f i c a n t difference in per c e l l c y t o l y t i c a c t i v i t y against LAK-sensitive targets was noted when p u r i f i e d NK c e l l s were stimulated with IL-2 in the absence or presence of T c e l l s and/or monocytes. In contrast, the t o t a l LAK c y t o t o x i c i t y ( i . e . , percent c y t o t o x i c i t y x percent cell recovery) generated in IL-2-NK c e l l cultures was s u b s t a n t i a l l y (two-fold, f o u r - f o l d , and eleven-fold) enhanced when NK c e l l s were co-incubated with equal numbers of monocytes, T c e l l s , and T c e l l s plus monocytes, respectively. While no sign i f i c a n t LAK t o x i c i t y could be induced in IL-2 cultures that were depleted of NK c e l l s on day O, removal of this c e l l subset a f t e r 5-day stimulation with IL-2 resulted in an up to 60% abrogation of LAK a c t i v i t y , In summary, our results suggest that T c e l l s and monocytes regulate the generation and contribute to the functional a c t i v i t y of human lymphokine-activated k i l l e r c e l l s . Memorial S1oan-Kettering Cancer Center, New York, NY 10021, and Medizinische Hochschule, D-3000 Hannover 61

in Bladder Cancer with KLH

Autor: C. Jurincic, K.F. Klippel

U.Engelmann,J.Gasch, ...............

First observations by O l s s o n / B o s t o n / U S A indicated a significant reduction in tumor r e c u r r e n c e rate in patients with b l a d d e r cancer treated with 5 mg KLH s.c. In a r a n d o m pilot study 21 pts. received after I mg KLH s.c. m o n t h l y K L H - i n s t i l l a t i o n s for 10 mg, The versus group received m o n t h l y instillations of m i t o m y c i n (MMC). After the m e a n follow up of 20.7 (18.3) m o n t h three out of 21 in the K L H - g r o u p and 9 out of 23had tumor recurrence. In a single drug prospective study KLH w i t h given in a same regimen in 171 patients with the mean follow up of about 38 month. The recurrence rate in this group is calculated at 2? %, A down grading of the recurrences was seen in 57 %. In contrast to c y t o s t a t i c drugs and i n s t i l l a t i o n regimens K L H - t h e r a p y does not implicate the p r o d u c t i o n of cytostatic drugresistant tumor cell c l o n e s ~ p o l l u t i o n of anm e t a b o l i z e d mutagenic, carcinogenic, cVtostati~ drugs can be avoided. May be a combinea treatment w i t h cytostatic drug i n s t i l l a t i o n increases effectiveness. A l l g e m e i n e s Krankenhaus, Dept. D-3100 ~elle, Siemensplatz 4

Urology,

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AUGMENTATION OF HOST ANTI-TUMOR MECHANISMS IN RODENTS BY LOW-DOSE MAFOSFAMIDE T. Reissmann, R. voegeli and P. Hilgard

EXPRESSION IN E.COLI AND PURIFICATION OF I N S U L I N - L I K E G R O W T H F A C T O R S I AND II (IGF-I AND -II)

M,H___um~3~ Cyclophosphamide in nontoxic doses has been shown to be c u r a t i v e in c e r t a i n experimental animal tumors, e.g. the L5222 myeloid leukemia o f BDIX r a t s ( I ) and the MOPC-315 plasmocytoma o f Balb/c mice ( 2 ) , rendering these animals r e s i s t a n t against a new challenge with tumor c e l l s . Treatment of the L5222 and MOPC-315 tumors with mafosfamide (Asta Z 7554), a s t a b i l i z e d d e r i v a t i v e of the a c t i v e m e t a b o l i t e of cyclophosphamide, gave a s i m i l a r response p a t t e r n but the e f f e c t i v e dose-range was considerably broader. By in v i t r o - c l o n i n g we have obtained sublines of the L5222 leukemia with d i f f e r e n t in v i v o - s e n s i t i v i t i e s t o low doses of mafosfamide which were not due to d i f f e r e n t s u s c e p t i b i l i t i e s in v i t r o to the c y t o t o x i c a c t i v i t y of the drug. Transfer o f spleen c e l l s of animals immune against the L5222 leukemia did not r e s u l t in resistance of the r e c i pients against tumor challenge unless they were t r e a t e d with a high immunosuppressive dose (100 mg/kg) of c y c l o phosphamide p r i o r to the implantation of the spleen cells. Our r e s u l t s suggest t h a t mafosfamide in low doses enhances host antitumor immunity, p o s s i b l y by i n h i b i t i n g host suppressor mechanisms. ( I ) H i l g a r d , P., Pohl, J., Stekar, J . , Voegeli, R., Cancer Treat. Rev. 12, 155 - 162 (1985) (2) Mokyr, M.B., Hengst, J.C., Dray, S., Cancer Res. 42, 974 - 979 (1982) ASTA PHARMA AG, Artur-Ladebeck-StraBe 128 - 152, D-4800 B i e l e f e l d 14

Hz H~rbstt ~ H~...St#i~. . . . . . . .

The i n s u l i n - l i k e growth f a ~ t o r s I and II (IGF-I or II, Somatomedin C and A) appear to be variably expressed in d e v e l o p i n g and m a l i g n a n t t i s s u e s and they may be involved in a u t o c r i n e r e g u l a t i o n of tumor growth. In order to o b t a i n unlimited amounts of IGF proteins to be e m p l o y e d in immunoassays and for the p r e p a r a t i o n of m o n o c l o n a l a n t i b o d i e s w e h a v e s y n t h e sized g e n e s e n c o d i n g both IGF-I and -II p o l y peptides. F o l l o w i n g a s s e m b l y of 16 and 17 o l i gonucleotides~ respectively~ the g e n e s were subcloned into p A T H expression vectors and s e q u e n c e d subsequently. Induction of protein e x p r e s s i o n in E.ooli by t r y p t o p h a n d e p l e t i o n in the p r e s e n c e of indoleacrylic acid yielded fusion proteins c o n s i s t i n g of the N-terminal p o r t i o n of E.coli trpE p o l y p e p t i d e and IGF-I or -II. T h e s e p r o t e i n s were p u r i f i e d with C8 rev e r s e d - p h a s e high p e r f o r m a n c e liquid c h r o m a t o graphy. Due to the very hydrophobic c h a r a c t e r i s t i c s of the trpE p o l y p e p t i d e f u s i o n proteins eluted in the last peak of the c h r e m a t o g r a m m e using a g r a d i e n t s y s t e m of 4 to 22% 2 - p r o p a n o l for 30 m i n u t e s with 60% of formic acid as solvent. P u r i t y was at least 95% as s h o w n by SDS-PAGE. Bound to p l a s t i c s u r f a c e s by drying these f u s i o n p r o t e i n s are c u r r e n t l y used for the p r e p a r a t i o n s of immunological reagents. Institut fQr Pathologie~ K l i n i k u m Steglitz, Freie Universit~t Berlin, Hindenburgdamm 30, D - I O 0 0 B e r l i n 45

Supported by Bundesministerium f o r Forschung und Technol o g i e , Bonn (No. 038719)

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LET THE FLY TELL YOU WHY CELLS BECOME MALIGNANT E. G a t e f f

INSULIN-LIKE GROWTH FACTOR I BiNDiNG SITES IN NON SMALL CELL AND SMALL CELL LUNG CANCER CELL LINES M. Rotsch, U. Worsch, G. Jaques, M. Maasberg~ K. Havemann

The f r u i t f l y genome contains about 15 independent tumorsuppressor genes each o f which s p e c i f y during normal development a d i f f e r e n t i a t i o n step in one o f the f o l l o w ing f o u r a d u l t primordial c e l l - t y p e s in the l a r v a : the a d u l t o p t i c neuroblasts in the b r a i n , the imaginal discs, the primordial blood c e l l s in the hematopoietic organs and the male and female gonial c e l l s ( G a t e f f , 1982; In "Advances in Cancer Research" 37, 33-69). Recessive mutations in these tumorsuppressing genes cause the development o f l e t h a l tumors in the above c e l l s and t i s s u e s . One o f the genes has been cloned (Mechler e t . a l . , 1985, The ENBO Journal 4, 1551-1557. I t s molecular analysis revealed 10 exons coding f o r two p r o t e i n s . The absence o f the smaller p r o t e i n is responsible f o r the malignant t r a n s f o r m a t i o n o f the a d u l t o p t i c neuroblasts and the imaginal disc c e l l s (Jacob e t . a l . , 1987, Cell 5_00, 215-225; Opper e t . a l . , 1987, Oncogene I , 91-96). Four f u r t h e r genes are p r e s e n t l y being clon-ed. The molecular and c e l l - b i o l o g i c a l analysis o f these genes should reveal t h e i r f u n c t i o n in normal d i f f e r e n t i a t i o n and at the same time shad l i g h t on the i n i t i a l step in malignant t r a n s formation when the gene is in the n o n f u n c t i o n a l , mutated s t a t e . The recessive tumorsuppressor genes o f the f r u i t f l y represent an e x c e l l e n t animal modell system to study the primary event leading to malignant t r a n s f o r m a t i o n . I n s t i t u t f u r Genetik, Johannes Gutenberg-Universit~t; S a a r s t r . 21, D-6500 Mainz.

Insulin-like growth factor t (IGF-I), a 70 aminoacid polypeptide with structural homology to tGF H (6t%) and insulin (49%) stimulates the proliferation of tumor cell in vivo and in vitro. IGF I has been shown to be mitogenic for a variety of cultured cells. This effect is mediated by high affinity ligand binding for specific surface receptors. The autocrine growth hypothesis proposes that carcinoma cells produce and secrete their own proliferation factors, which interact with specific receptors on their cell sL;rface. We and others have established a large number of continuously growing cell lines derived from non small cell and small cell lung carcinoma. In this study we examined the IGF I binding sites in several lung carcinoma cell lines. Displacement experiments with IGF I demonstrated competition of labelled tGF I (1251-1GF I) with unlabetled IGF Io The binding parameters for IGF I (Bmax and K D) were determined by scatchard blot analysis. Nonspecific binding was calculated from the differences between samples with or without and excess of uniabelled IGF I. The dissociation constants (KD) are similar for both non small cell and small cell lines. The amount of maximally bound IGF I (Bronx) ranges from 110 fmol/mg protein to 1230 fmol/mg protein. There were no characteristic differences between non small cell and small cell lines. Besides binding sites for IGF I we found expression and secretion of immunoreactive IGF I in the lung cancer cell lines tested. Furthermore~ addition of a recombinant human IGF I analog has a mitogenic effect. We conclude that IGF I fnay function as an autocrine growth factor in human lung cancer.

Zentrum for Innere Medizin, Abteilung H~matologie/Onkologic/Immunologic, Baldingerstral3e, D-3550 Marburg

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2/16-0 001

URINARY CYTOLOGY - THE DIAGNOSTIC VALUE OF SAMPLING PROCEDURE AND PREPARATION, CYIOFLUOROMEIRu SCANNING ELECTRON MICROSCOPY AND DETERMINATION OF NUCLEAR ORGANIZING REGIONS (NOR) J.R~schoff~A.Bittinger~A.PeemSller~B.UlshSfer Urine cytology has become a sensitive method for -~ detecting tumors of the urinary tract. The diagnostic efficacy of conventional lightmicroscopy was analyzed in a prospective study with special reference to sampling and preparation of the urine. Bladder washings were obtained at cystoscopy or by uretheral catheter from p a t i e n t s ~ t h tumorous and nontumorous urinary tract disease. Immediately after collecting the third washing 5 ml were cytocentrifuged. After air drying,~xation with B~hms fixative the slides were stained with Giemsa and PAS-Giemsa. In case of occult c a r c ~ o mas cytometry,scanning electron microscopy and determination of NOR was performed. 680 bladder washout specimens were examined c~ologically of which 112 gave a positive result. Out of these 84 had a histologically proved urinary tract tumor: 71 bladder, 7 ureter or pyelon 4 prostate and 2 renal cell carcinomas. 45 were grade I, 19 grade II, 7 grade III bladder carcinomas and 5 papillomas. The accuracy of the cytological diagnoses in grade II and grade III tumors was 97.2% vs. 89.8% in grade I carcinomas including papillomas. These fairly high p e r c e ~ a ges significantly decreased when spontaneous urine was examined.(Parallel examination of spontaneous and washout specimens was done in 50 eases). Finally the usefullness of cytometry, scanning electron microscopy and determination of NOR on urinary cytologic specimens will b e d e m o n s t r a t e d in those cases with positive cytology without histologically proven carcinoma so far.

MOLECULARANALYSIS OF TNF-ALPHA AND IFN-GAMMAACTION ON HUMANCARCINOMAAND LEUKEMIACELL LINES C. SchlUter, K. Pfizenmaier, K., and M. Kr~nke

In order to delineate the molecular mechanisms of Tumor Necrosis Factor (TNF) and interferon-gamma (IFN-gamma) mediated i n h i b i t i o n of tumor cell growth, we have begun to investigate the effects of the two cytokines on the expression of genes encoding proteins with known regulatory functions for cell growth and d i f f e r e n t i a t i o n . We have used the human breast cancer c e l l lines CLRISO0, HTB26, BT20, and MCF7, because t h e i r p r o l i f e r a t i o n is d i f f e r e n t l y influenced by these cytokines. These phenot y p i c responses are reflected at the gene l e v e l , where IFN-gamma and TNF d i f f e r e n t i a l l y modulate the expression of several proto-oncogenes including myco Ha-ras, r a f , erb-B, sis and fos. In addition, we studied the r e l a t i o n of TNF and IFN-gamma to other growth promoting or inh i b i t i n g factors. For example, both epidermal growth factor (EGF) and estrogen antagonize TNF-alpha and IFNgamma action. On the other hand, TNF-alpha induces the gene coding for IFN-beta2 (BSF-2, IL-6), which supposedly plays an important role in c e l l growth control. Taken together, from the available data a picture is emerging, i n d i c a t i n g rather complex i n t e r a c t i o n s of TNF, IFN, and other growth factors p o s i t i v e l y and negatively i n t e r f e r ing at several levels with tumor c e l l p r o l i f e r a t i o n and differentiation. Klinische Arbeitsgruppe "BRWTI", Max-Planek-Gesellschaft, Medizinische K l i n i k der Universit~t G~ttingen, GoBlerstr. I0 d, D-3400 G~ttingen

Zentrum f. Pathologie der Philipps-Universit~t Marburg, BaldingerstraBe, D-3550 Marburg

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The Value of MRI c o n c e r n i n g the Diagnosis of B l a d d e r Neoplasm B a y e r , K . - H . , H 6 t z i n g e r , H.:

RECOMBINANT HUMANTUMORNECROSIS FACTOR (rhuTNF) IN THE TREATMENT OF PATIENTS WITH ADVANCEDMALIGNANCIES. T.Moritz, N.Niederle, E.Kurschel, D.May, R.Osieka, E.Schl ick, C.G.Schmidt

The s u r v i v a l t i m e of p a t i e n t s w i t h b l a d d e r c a r c i n o m a d e s p e n d s on t h e h i s t o l o g i c a l g r a d i n g and t h e e x t e n t of t h e t u m o r a t t h e t i m e of the d e f i n i t e diagnosis. T h e r e f o r e , t h e c l i n i c a l s t a g i n g is of g r e a t value. Besides of t h e m e t h o d s , w h i c h a r e r o u t i n e l y used, s u c h as e y s t o s copy, s u p r a p u b i e u l t r a s o u n d as well as e n d o v e s i c a l u l t r a sound, MRI has t h e c h a n c e to r e p l a c e in p a r t t h e o t h e r m e t h o d s b e c a u s e of t h e b e t t e r s o f t tissue c o n t r a s t resolution and t h e m u l t i p l a n e s f a c i l i t y of MRI. We i n v e s t i g a t e d 120 p a t i e n t s w i t h b l a d d e r c a r n i n o m a by MRI, p a r t l y also by CT. In all c a s e s t h e e x t e n t of t h e t u m o r h a s b e e n p r o v e n by s u r g e r y . We f o u n d t h a t t h e b l a d d e r t u m o r c a n be well s e p a r a t e d f r o m t h e n o r m a l b l a d d e r wall. H o w e v e r , t h e r e a r e d i f f i c u l t i e s c o n c e r n i n g the d i f f e r e n t i a t i o n b e t w e e n o e d e m a , i n f l a m m a t i o n and t u m o r . The d i s t i n c t i o n b e t w e e n different non-wail exceeding tumors infiltration grades w a s d i f f i c u l t too, w h i l e p e r i v e s i e a l i n f i l t r a t i o n c a n be p r o v e d in a high p e r c e n t a g e . F u r t h e r m o r e we c h e c k e d t h e u s e of g a d o l i n i u m - D T P A as an M R - c o n t r a s t a g e n t in t h e b l a d d e r t u m o r s , In 20 p a t i e n t s w i t h b l a d d e r t u m o r we instilled via t h e u r e t h r a g a d o l i n i u m - D T P A d i l u t e d by a q u a d e s t . O u r r e s u l t s s h o w e d t h a t w i t h this m o d i f i c a t i o n T l - w e i g h ted i m a g e s w e r e s u f f i c i e n t for t h e diagnosis. MRI has d i f f i c u l t i e s c o n c e r n i n g t h e d i a g n o s i s of l y m p h node m e t a s t a s i s . In this r e s p e c t our r e s u l t s d i d n ' t show any a d v a n t a g e s in c o m p a r i s o n with CT. It m a y be possible t h a t t h e a p p l i c a t i o n of oral c o n t r a s t a g e n t s m a y i m p r o v e t h e s e n s i t i v i t y in this r e s p e c t . F i r s t r e s u l t s will be d e m o n s t r a t e d . R u h r - U n i v . B o c h u m , A m H o l g e s k a m p r i n g 40, D 4 6 9 0 H e r n e 1

A phase-I study with rhuTNF (Knoll AG, Ludwigshafen, FRG) was conducted in patients with advanced malignancies r e s i s t a n t to standard therapy. Study objectives were to determine the maximal t o l e r a t e d dose and to evaluate drug t o x i c i t y including organ s p e c i f i t y , time course, predict a b i l i t y and r e v e r s i b i l i t y . TNF was administered as test dose (single i . v . infusion l a s t i n g 15 minutes, TNF solved in 50 ml 5% human albumin ) followed by d a i l y i . v . infusions f o r 5 days, q 3 weeks. Dosage was increased in c o horts of 4 patients from 0,04 to 0,28 mg/m2. By November 1987, 16 patients ( 7 large bowel carcinoma, 3 hypernephroma, 2 chronic myeloid leucemia, I malignant melanoma, I fibrosarcoma, I rhabdomyosarcoma, I malignant lymphoma ) were treated. Main side effects were c h i l l s and fever ( maximum 40,2~ median 38,5~ 16/16 ), vomiting (6/16), back pain (5/16) and hypotension (4/16). Acute side effects could be diminished by indometacine or paracetamol application p r i o r to TNF and a l l were comp l e t e l y reversible within 8 hours. TNF treatment was followed by regular checks of tumor parameters and laboratory values including pharmacokinetics ( plasma half time 16-18 min.), kidney function tests and determination of oncogen expression. So f a r , no d e f i n i t e antitumor effect could be established, although a marked decrease in tumor parameters ( e.g. CEA, excretory l i v e r enzymes ) was noted in three patients. The maximal t o l e r a t e d dose without indometacine pretreatment is in the range of 0,20 mg/m2 . Innere U n i v e r s i t a e t s k l i n i k und P o l i k l i n i k (Tumorforschung ), Hufelandstr. 55, D-4300 Essen

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TUMOR NECROSIS FACTORALPHAADMINISTERED I.M. OR INTRATUMORAL IN PATIENTSWITH ADVANCEDCANCER H.H. Bartsch, K. Pfizenmaier, W.Rauscbnin9 and G.A.Nagel

RESISTANCE TO T U M O R NECROSIS FACTOR: INVESTIGATIONS ON POSSIBLE MECHANISMS.

Recombinant Tumor Necrosis Factor-alpha (TNF-alpha) exerts growth and immuneregulatory effects on normal and malignant cells. To define the potential role as antitumor substance we investigate the effect of systemic and local application of TNF-alpha in pts with advanced cancer, Thirty pts were included into a phase I protocol using recombinant TNF-alpha 3x weekly i,m. at doses from 5 ug/m2 to 150 ug/m=. Five additional pts were treated with 50 ug/m= to 150 ug/m= TNF-alpha intralesional. Time of treatment varied between 1 week (2 pts at MTD) and 28 weeks. In 5/30 pts stable disease with max. duration of 28 weeks was noted. To the time of this report 1 patient treated with 150 ug/m~ TNF-alpha intralesional demonstrated a dramatic response of the local tumor mass and the respective serological tumor parameters. The toxi c i t y of i.m. and i , t . TNF-alpha therapy was comparable with main side effects of such as c h i l l s , fever and l o cal inflammation. These symptoms were clearly dose related. Anorexia and vomoting were more frequently at doses above I00 ug/m~. The MTD of TNF-alpha i.m. in this study was 150 ug/m due to local t o x i c i t y . Although there was a slight decrease of systolic blood pressure in pts treated at doses above 75 ug/m: we did not recognize any severe cardiac, pulmonary, renal or l i v e r toxi c i t y , The monitoring of hematologic parameters revealed a dose dependent decrease of leucocytes and platelets. There was no evidence for cumulative t o x i c i t y , We conclude from our data that recombinant TNF-alpha can be administered safely by i.m, application to a dose of 150 ug/m~. Further studies need to prove the potential role of local and/or systemic TNF-alpha therapy in various human malignancies. Abteilung H~matologie/Onkologie, Zentrum Innere Medizin der Universit~t, Robert-Koch-Str. 40, D-3400 GSttingen

B. Genth, H. Kirchner, T. Steinmetz, Schaadt, P . Seheurich, A. Lindemann, Raueh, V. D i e h l , and M. Pfreundsehuh

M. F.

In order to g a i n i n s i g h t i n t o p o s s i b l e mechanisms of r e s i s t a n c e to tumor necrosis factor (TNF), we i n v e s t i g a t e d p a i r s of c l o n e s of the human c e l l l i n e s ME 180 (cervical cancer) and B T - 2 0 (breast carcinoma) which were s e l e c t e d for high sensitivity and r e s i s t a n c e to TNF. Sublcones were made r e s i s t a n t to TNF by g r a d u a l l y i n c r e a s i n g the TNF c o n c e n t r a t i o n in the c u l t u re medium. R e s i s t a n t c l o n e s continue to be r e s i s t a n t in the absence of TNF a f t e r more than one year and 50 p a s s a g e s . No d i f f e r e n ces could be shown in the number and a f f i n i t y of TNF r e c e p t o r s between the s e n s i t i v e and r e s i s t a n t c l o n e s . SDS-PAGE of l y s t a e s of the r e s i s t a n t and sensitive clones showed i d e n t i c a l bands. There was i d e n t i c a l s e n s i t i v i t y to c y t o t o x i c drugs such as a c t i nomyein D and to interferon-ganmaa. No messenger RNA could be d e t e c t e d in e i t h e r subc l o n e . The growth p a t t e r n of TNF r e s i s t a n t and TNF s e n s i t i v e ME 180 in nude mice was i d e n t i c a l . As tumors grown in nude mice der i v e d from the s e n s i t i v e and resistant c l o n e s responded e q u a l l y w e l l to an i n t r a t u moral i n j e c t i o n of TNF, we conclude t h a t d i f f e r e n t mechanisms a r e r e s p o n s i b l e for s e n s i t i v i t y and r e s i s t a n c e to the c y t o t o x i e e f f e c t s of TNF in v i t r o and in v i v o . Medizinische K l i n i k I der U n i v e r s i t A t zu K01n, J o s e f - S t e l z m a n n - S t r . 9, 5000 K01n 41

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PHASE-I-TRIAL OF INTRAVENOUS 24-HOUR INFUSION OF TUMOR NECROSIS FACTOR (TNF) IN PATIENTS WITH METASTASING ADENOCARCINOMAS

OF TUMOR NECROSIS FACTOR ALPHA ON TUMORBLOOD FLOW A N D H Y P E R T ~ M I C T R F A T M ~ F. Kallinowski, R. Moehle, C. Schaefer, P. Vaupel w

U. R~th, B. Wiedenmann, B. Sch61e, E. Schlick, L. T h e i l mann, and B. Kommerell To determine side effects and maximum tolerated dose ( M T D ) , a total of 8 patients with advanced metastatic adenocarcinomas were treated in a phase-l-study by continuous 2qhour infusions of recombinant human t u m ~ necrosis factor (TNF-d~). Patients received q0-400 tug/m TNF once or twice weekly for 2q hours by continuous 24-hour infusions. The scheduled treatment period was two months. The toxicity observed resembled that reported for interferons and included fever, chills, fatigue, headaches, myalgias, thrombocytopenia, prostration and malaise. Of the 8 patients, 6 patients showed tumor progression and one patient sustained in a nochange situation for over two months of treatment A . Minor response was seen in one patient with a colorectal carcinoma and liver metastases. To reduce side effects, patients were treated with paracetamol (4) or indometacin (4). Higher MTDs were observed in patients treated with indometacin. No detectable plasma T N F - ~ levels and T N F - & antibodies were measured under therapy (plasma TNF-O~100 n g / m l ) . We conclude that TNF appears to have some antineoplastic action in patients with adenocarcinomas. Despite v e r y low plasma TNF-O~ levels, we observed considerable dose limiting toxicity. MTDs were reached at very different TNF-04 concentrations, suggesting variable individual susceptibility to TNF-o~. In addition our results also suggest an antineoplastic activity of TNF-O(. Medizinische Universit~tsklinik, Bergheimer Str. 58, D-6900 Heidelberg

Effects of recombinant human tumor necrosis factor(rhTNF- ~) were evaluated using DS-carcinosarcoma, a moderately rhTNF-~ sensitive rat tumor, grown subcutaneously in the hind foot dorsum, rhTNF-~(6.6.103 U/~g protein, KNOLL AG, Ludwigshafen, FRG) was injected into the tail vein (I mg/kg). T u m o r b l o o d flow (TBF) was measured using the 85-Krypton clearance technique (Vaupel et al., Pfl~gers Arch. 369: 193, 1977). Upon acute application of r h T N F - ~ T B F was decreased up to 70% within 2 hrs, the reduction being sustained for more than 2 hrs. Hyperthermia (HT) was achieved by immersing the foot into a saline bath (43~ 30 min). Tumors were treated every 3rd day up to day 20 starting 5 days after implantation (tumor wet weights around 0.6 g). HT was given 2-4 hrs after rhTNF-~application. Untreated tumors served as controls. Tumor volume was determined by caliber measurements. HT retarded tumor volume growth only slightly. Upon rhTNF- kgiven alone tumor growth was reduced significantly (2p~ 0.05). However, regrowth started during the continued rhTNF-~therapy after the 3rd treatment. A pronounced tumor regression was observed during the combined therapy. In this group, regrowth occurred in about 30% of the tumors after the cessation of treatment. In conclusion, the combined therapy with rhTNF-~may be beneficial, since rhTNF-~ and hyperthermia at temperatures > 42~ can both significantly decrease TBF. Abtlg. Angewandte Physiologic, Universit~t Mainz, Saarstrasse 21, D-6500 Mainz, FRG w Radiation Medicine, Mass. General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA

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C O M B I N E D T H E R A P Y OF X E N O G R A F T S OF H U M A N COLORECTAL AND PANCREATIC CARCINOMA WITH MITOMYCIN-C A N D R T N F - ~ R . K l a p d o r ~ N . F r a n k e and M . B a h l o

Untersuchungen

B a s i n g on e x p e r i m e n t a l studies in n u d e mice i ~ d i c a t i n g that M-C as w e l l as r T N F - ~ are able to induce s i g n i f i c a n t g r o w t h i n h i b i t i o n of xen o t r a n s p l a n t s of g.i. and pa e a ( K l a p d o r et al. D i g . D i s . S c i . 3 1 , 1 9 8 6 , 1 1 3 6 and 1137) as well as on s t u d i e s r e p o r t i n g on s y n e r g i s t i c effects of e.g. r e c o m b i n a n t IL2 in c o m b i n a t i o n w i t h M - C ~ i g o et a l . T r e a t . R e p . 7 1 , 1 9 8 7 , 5 6 7 ) w e p e r f o r m e d the f o l l o w i n g e x p e r i m e n t s . I n n u - n u B a l b - C m i c e b e a r i n g x e n o t r a n s p l a n t s of h u m a n tumors of the c o l o n ( N . O . 8 5 ) a n d the p a n c r e a s ( H . K . 8 4 ) w e compared the a n t i - t u m o r effects of M - C ( 2 . 4 m g / k g / d , 3 times in I w e e k i n t e r v a l s ( M e d a c ) ) , r T N F - ~ ( 0 . 8 m g / k g / d for 21 d ( K n o l l ) ) a n d a c o m b i n a t i o n of b o t h d r u g s ( 2 . 4 + 0 . 8 ) . I n a f u r t h e r trial we s t a ~ ted t r e a t m e n t w i t h these d r u g s / d r u g combinatiaa i m m e d i a t e l y a f t e r s . c . t r a n s p l a n t a t i o n of 2 x 2 m m tumor s l i c e s ( C R c a , H . S z . 8 5 ) . I n a d d i t i o n to tumor g r o w t h serum CEA and CA 19-9 and b o d y w e ~ were m e a s u r e d . T h e r e s u l t s d e m o n s t r a t e that the c o m b i n a t i o n of r T N F - m + M-C was s i g n i f i c a n t l y more e f f e c t i v e t h a n r T N F - ~ and M-C alone in studies on e s t a b l i s h e d tumors r e s u l t i n g in S D ( N . O . 8 5 ) a n d P R ( H . K . 8 4 ) . I n the a d j u v a n t trial c o m b i n a t i o n of r T N F - ~ +M-C r e s u l t e d in total i n h i b i t i o n of tumor g r o w t h d u r i n g the treatment period. In a d d i t i o n , c o m b i n a t i o n of b o t h drugs r e s u l t e d in more rapid a n t i - t u m o r e f f e c ~ but also in more toxic effects (loss of b . w . o f about 2 0 % ) t h a n r T N F - ~ and M-C a l o n e . Sum m a r i z i n g the r e s u l t s s u p p o r t the c o n c e p t that c o m b i n a t i o n s of c y t o s t a t i c s and c y t o k i n e s might be of value f o r t r e a t m e n t of g.i. and pa c~ucer. Medizinische Kernklinik und Poliklinik, M a r t i ~ i s t r . 52, D - 2 O O O H a m b u r g 20

~ber die W i r k u n g von T ~ o r n e k r o -

sefaktor

auf M e g a k a r y o z y t e n v o r l i u f e r z e l l e n , B . V ~ i k e r s , A . G a n s e r r J . G r e h e r , C.Carlo Stella, D.Hoelzer A b t . f . H ~ m a t o l o g i e , Z e n t r u m d.Inneren Medizin, U n i v e r s i t ~ t F r a n k f u r t , D - ~ 0 0 0 Frankfurt am Main; *Dipartimento di M e d i c i n a Interna,Universit~ di Pavia,I-27100 P a v i a , I t a l i a T u m o r n e k r o s e f a k t o r , z y t o t o x i s c h fdr v e r s c h i e d e n e T u m o r z e l l p o p u l a t i o n e n induziert h i m a t o p o e t i s c h e W a e h s t u m s f a k t o r e n (CSF's),hema~t abet auch himatopoetische S t a m m z e l l e n . D i e Wirkung dieses Zytokins auf die n o r m a l e Megakaryopoese ist b i s h e r nicht g e k l i r t . W i r haben den Effekt rekombinantel humanen T u m o r n e k r e s e f a k t o r s (rh-T~$F-~ auf das W a c h s t u m normaler megakaryozytirer Vorl~uferzellen (CFU-Mk) in einem klonalen M e t h y l z e l l u l o s e Assay u n t e r s u c h t . B e i inkubation mit Zugabe v o n IE - 300E/ml r h - T N F - ~ zu Ficoll separierten K n o c h e n m a r k z e l l e n k o n n t e n wit eine d o s i s a b h i n g ige Henm~ung der CFU-Mk feststellen. Die 50%-ige He~mung lag bei 10E/ml,die 100%-ige H e m m u n g bei 300E/ml T N F - ~ . E i n e in p a r a l l e l ~ d u r c h g e f ~ h r t e n E x p e r i m e n t e n v o r g e n o m m e n e Entfernung akzessorischer Zellen (Makrophagen und T-Lymphozyten) hatte nur geringen EinfluB auf die Hem~ung der CFU-M~ durch T N F - ~ . N a c h k o m b i n i e r t e r E n t f e r n u n g der Y-Zellen und M o n o z y t e n lag die 50% H e m m u n g bei 30E~ml,die 100% Hemmung war konstant bei 300E/ml T N F - ~ .Die dOsisabhingige Hemmung der M e g a k a r y o z y t e n v o r l ~ u f e r z e l l e n durch T u m o r n e k r o sefaktor ist nicht durch akzessorisehe Zellen v e r m i t t e l t , d e r F a k t o r scheint direkt auf die ~ e g a k a r y o z y t ~ r e n Stam~zellen zu wirken.

UKE, G e f ~ r d e r t dutch die DFG

(Projekt-Nr.GA 333/I-I)

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TUMORNECROSIS FACTORAND LYMPHOTOXINGENE EXPRESSION IN HUMANTUMORCELLS G. Hensel, C. SchlUter, P. Scheurich, K. Pfizenmaier, and M. Kr~nke

A C T I V A T I O N OF H U ~ N MONOCYTE AND N A T U R A L K I L L E R CELL MEDIATED T U M O R - C E L L LYSIS BY A D I A L Y S A B L E FACTOR FROM H U M A N - L E U K O C Y T E EXTRACTS.

Based on t h e i r c y t o t o x i c and other d i r e c t effects on tumor c e l l s in v i t r o and in vivo, Tumor Necrosis Factor (TNF) and lymphotoxin (LT) may contribute to the host's immune response against development of cancer. We here demonstrate that 8 of 16 tumor c e l l lines of various tissue o r i g i n c o n s t i t u t i v e l y express e i t h e r TNF or LT mRNA. From the remaining 8 cell l i n e s , 5 could be induced by PMA, L P S , CHX or cytokines to accumulate TNF or LT mRNA. While LT mRNA expression seemed to be generally r e s t r i c t e d to lymphoid c e l l s , TNF mRNA was found not only in neoplastic hematopoietic c e l l s , but also in c e l l lines derived from s o l i d tumors. Unlike LT, TNF gene expression appears to be controlled predominantly at a t r a n s l a t i o n a l or p o s t - t r a n s l a t i o n a l l e v e l , since most of the c e l l lines containing TNF mRNA did not release TNF protein i n t o the supernatants. All of the tumor c e l l s capable of LT mRNA expression proved r e s i s t a n t to the c y t o t o x i c effects of TNF. in contrast, neither TNF mRNA synthesis nor TNF secretion is necessarily associated with a TNF-resistant phenotype. Since TNF is implicated in pathologic syndroms l i k e cachexia, hypercalciemia, and, furthermore, e x h i b i t s potent angiogenic a c t i v i t y , our findings strongly suggest possible roles of TNF in the pathogenesis of cancer. Klinische Arbeitsgruppe "BRWTI", Max-Planck-Gesellschaft, Medizinische K l i n i k der Universit~t G~ttingen, GoBlerstr. I0 d, D-3400 G~ttingen

K.H.Hamprecht,

W.V6tsch

and F.A.Anderer

D i a l y s a b l e human leukocyte extract c o n t a i n e d a natural killer (NK) c y t o t o x i c i t y - s t i m u l a t i n g factor, CySF-LI, which could be enriched by ion exchange chromatography. In vivo application of CySF-LI after tumor challenge induced reduction of tumor take incidence and tumor development in mice. In vitro tests showed that N K - c y t o t o x i c i t y of human peripheral blood m o n o n u c l e a r celIs(PBMC) against human K 5 6 2 or HT29 tumor cells was strongly enhanced after 72 h p r e - i n c u b a t i o n with the factor. The C y S F - L 1 - s p e c i f i c stimulation of PBMC required the presence of monocytes. The cytotoxic effector cells activated during p r e - i n c u b a t i o n of PBMC with CySF-LI were identified as monocytes and as NK cells p r e s e n t in the fraction of large granular lymphocytes (LGL). Selective cell depletion studies with L G L - c o n t a i n i n g subpopulations (free of monocytes) indicated, that the activated NX cells express CD16 (Leu 11) and CD8 (T8) markers and the majority of them also the Leu7 marker. Analysis of the changes of surface marker expresssion of human PBMC during p r e - i n c u b a t i o n w i t h CYsF-L1 revealed an e f f i c i e n t stimulation of CD8 and TfR (trans ferrin receptor) expression, partly in c o n j u n c t i o n with d i m i n i s h e d e x p r e s s i o n of CD4 (T4). Criteria of m o l e c u l a r size and b i o l o g i c a l specificity indicate that the factor is different from interleukin 2 and interferons. Friedrich-~liescher-Laboratorium der Max-Planck-Gesellsch. Spemannstrasse 37-39, 7400 T~bingen

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2/17-M 002

A NEW REGULATORY ROLE FOR t N T E R L E U K t N - 2 : IMMUNOREGULATIONOF HEMATOPOIESIS St. E. G. Burdach1,2 N. Zessack1 and k J. Levitt2

IS THERE ANY B E N E F I T OF AGGRESSIVE ARTIFICIAL NUTRITION IN END-STAGE CANCER PATIENTS? K.H. Vcstweber, Cl. Bode, B. Viell, H. Troidl

We established a receptor-specific model of the regulatory interaction between T cells and hematopoietic progenitors and defined cellular and molecular mechanims of hematopoietic immunoregulation by the lymphokine cascade. IL2 receptors (p55) were induced on immunopurified T cells by triggering the antigen receptor complex. Recombinant DNA-derived IL2 inhibited growth of eady erythroid and myeloid progenitors in the presence but not in the absence of p55 positive T celts. IL2-induced inhibition of erythropoiesis or myelopoiesis in the presence of p55 positive T cells was abrogated by addition of p55 blocking monoclonal antibody. T cell supernatant generated in the presence of IL2 from p55 positive T cells also inhibited erythroid and myeloid progenitor growth, IL2 induced release of 190+60 U/m[ interferon-? (IF7) but <10 U/m] tumor necrosis factors (TNFs) c~ and ~ from p55 positive T cells. Treatment of T cell supernatant with IF7 monoclonai antibody abrogated >95% of IL2-induced inhibition of erythropoiesis but only 60% of ]L2-induced inhibition of myelopoiesis, Treatment of T ceil supernatant with TNF antibodies had no significant effect on progenitor growth. Northern analysis of T cell m-RNA utilizing a full length cDNA probe for IF7 revealed IL2 induction of IF? mRNA in p55 positive but not in p55 negative T cells. Preincubation of T ceils with a blocking antibody for the receptor of Lymphocyte Function Antigen3 (LFA-3) before triggering the antigen receptor complex partially abrogated tL2-induced release of IF? and IL2-induced inhibition of erythropoiesis but not myelopoiesis. We conclude: (1) [L2 induces a receptor-specific inhibition of hematopoiesis, (2) IL2-induced inhibition of hematopoiesis is mediated by sequential lymphokinetarget cell interactions, (3) the LFA-3 receptor participates in regulation of hematopoiesis by tL2. The data suggests that the regulatory role of IL2 extends beyond governance of the immune system itself.

In a prospective trial 25 patients sus from incurable tumors were fed via tubes (fine-needle-catheter-jejunostomy, percutaneous-cndoscopic-gastrostomy/duodenostomy) with I5oo - 20oo kcal / day with fluid formula diets. Diagnoses were: 8 esophagus-ca.; 6 pancreatic-ca.; 6 stomachca. and 5 miscellaneous. Nutritional support was given in median during I6 days (range: I - 62,) in hospital and during 52 days (range: o - 520) at home, KARNOFSKY~PerformanceStatus (KPS) and SPtTZERS Quality of Life-Index (QL) was assessed weekly, Before nutritional therapy the KPS was in median 4o (range: 20 - 5o) and QL 3 (range: 2 - 4) respectively indicating a pronounced depression of quality of life in these sick patients. Within the first three weeks of artificial nutritional support the indices were significantly improved by KPS fo 6o (range: 4o - 70) and QL 6 (range: 4 ~ 8) respectively (KPS: p=o.oooi; QL: p:o.ooo3), They remained at these levels for several weeks and dropped significantly 2 - 3 weeks before the patients died. tn conclusion it could be shown that there is a measurable improvement of quality of life in these patients. It should be discussed whether this effect is related only to the nutritional therapy. Chirurgische Klinik K~ln - Merheim, II. Chirurgischer Lehrstuhl der Universit~lt zu K~ln, Ostmerheimer Stral3e 200, D - 5ooo K~ln 9r

1Abt. for P~idiatrische HAmatologie/Onkologie der Universit~.t D0sseldorf, D-4000 D0ssetdorf I, FRG and 2Hematology Division, Stanford University Medical Center, Stanford, CA, USA.

2/17-M O01

2/17-M003

~UALITY OF LIFE AFTER GASTRECTOMY: PREVALENCEOF 50MATIC F'ACr0Rs S, Fiedler, H. Denecke

QUALITY OF LIFE (QL) OF PATIENTS WITH SMALL CELL LUNG CANCER UNDER TREATMENT: RESULTS FROM A MULTICENTRE RANDOMIZED CLINICAL TRIAL H,Flechtner, R.Holle, M.E.Heim, K.Hans, B.Mosthaf, K.Havemann

The consequences of the t o t a l or subtotal resection of the stomach are considerable for q u a l i t y of l i f e , e s p e c i a l l y for cancer patients. The aim of the study was to show for which patients and to which extent the q u a l i t y of l i f e may be improved by surgery, by possible psychatric care or by social r e h a b i l i t a t i o n . Prospectivel y , we examined the tumor evaluation (e, g. stage ~ recurrence), other somatic factors (weight, problems of n u t r i t i o n , v i t a l i t y , concomitant diseases), psychologic factors ( p e r s o n a l i t y , stress, emotional condition~ s t r a t e g i e s ) as well as social f a c t o r s . Examinations were done preop, and Dostop. a f t e r 3, 6, 9, 12 and 18 months. After at least 12 months postop, we survey Z5 patients (gastreczcmy: n=18, subtotal resection: n=7). Z# % of nhe patlen~s died afLer 12 months. 15 patients reacted on tDe diagnosis "cancer" with " s i g n i f i c a n t " and "strong" depressions. In the poszop, course, 2/3 of the patients over'cdme Li~is ~egaLive en~uLio~al s l a t e ~ generally due to physical s ~ a b i l l z a t i o n ; 5 patients did not: somatogenic (recurrence, problem of n u t r l t i o n ) n=2, psychogenic n=2, pSychosoClaI1y conditioned n=t). 8 patients r~du~ed on Ll~e diagnosis "cancer" in a r e l a t i v e l y calm way: only one of t h i s group showed negatlve psychic reaction a f t e r 12 months. Generally, tile physical s t a b i I i z a t l o n preceded the psycnlc s t a b i l i z a t i o n , SO that the somatic r e s u l t of treatment (recurrence, functional remuiL) proved to be the most Important f a c t o r . After 12 me~ths, in 85 % the somatic anO psycI~c s i t u a t i o n was correspondlng. A "bad" q u a l i t y of l i f e was psychogenic or due ~o psyc~osocia! conditions in 15 % (3/2U). After subtotal resection the physical recover), was s i g n i f l c a n t l y better than a f t e r gastrectomy. Chirurgtsche Unlversi%a~skl~nlk M~ncnen, Klinikum Gro~hadern, Marcniontnlstr. 15, D-8000 MOnc~dn 70

334 patients with SCLC were randomized to receive ifosfamide/etoposide and cyclofosfamide/ doxorubicin/vincristin either in a fixed alternating or in a response oriented schedule. A representative subsample of 195 pat. took part in a QL assessment study. Pat, were asked to complete a QL questionnaire before each treatment cycle. The questionnaire was a modified German version of a prevalidated instrument developed by the EORTC QL study group, consisting of 36 items concerning different physical and psychological aspects of QL. Additionally physicians rated pat. performance status, psychological distress, pain and appetite. Side effects were recorded according to WHO criteria, Factor and item analysis confirmed the construction of the different scales in accordance with the prevalidation study. Results: Scales for fatigue/malaise, physical status and disease related symptoms are highly significant prognostic factors (p 0.0001) for survival and very well comparable with Karnofsky performance scale and tumor stage, No differences in QL were detected between treat ment arms, Patients showed a significant increase on all QL scales during cycles 1-3 without any further amelioration in cycles 4-6, Physicians ratings were basically in accordance with data from QL scales but were unable to detect slighter changes. Onkologisches Zentrum, Klinikum Mannheim Postfach 23, 6800 Mannheim ]

$47 2/17-M 004

2/17-M006

INFLUENCE OF PHASE I EARLY CLINICAL TRIALS ON THE QUALITY OF LIFE OF CANCER PATIENTS. A PROSPECTIVE CONTROLLED PILOT STUDY. W. E. Berdel, H. Knopf, M. Fromm, H. D. Schick, R. Busch, U. Fink, A. Sellschopp, and J. Rastetter

LIFE QUALITY OF 67 PATIENTS WITH BONE METASTASES OF BREAST CANCER AFTER HORMONAL AND CYTOTOXIC TREATMENT K.Rieche and C. Mathuis

A non-randomized, prospective, two-arm p i l o t study was conducted to assess the impact of clinical phase I t r i a l s with new cytotoxic drugs on the quality of l i f e (QOL) of cancer patients, comparing a lO-item linear analog self-assessment (LASA) and Karnofsky performance scale (KPS) of 18 patients treated in phase I protocols versus 8 patients treated with standard/low efficacy cytotoxic or endocrine 1-2 drug regimens. There was neither a significant negative influence of treatment in phase I protocols on LASA and KPS at the times before, during and after study nor on changes (ALASA,AKPS) occurring with treatment. On the contrary, there was a slight positive influence of treatment within phase I protocols on self-assessed social a c t i v i t y (A LASA) and on A KPS when the groups were compared throughout the complete observation period. In addition, within the total study populatfon there was a significant positive influence of overall anticancer medication on psychological and social aspects of LASA as indicated by feeling of well being, mood, level of a c t i v i t y and level of anxiety. KPS and questions regarding appetite within LASA furthermore correlated with prognosis as measured by survival time, and intraindividual response comparison revealed the dominance of a differentiated, reliable response type among our patients. DFG Be 822/2-4 and 822/3-1. Klinikum rechts der T s a r , Technische Universit~t, Ismaninger S t r .

22, D-8000 M{inchen 80, FRG.

2/17-M005 RELIEF

M e t a s t a t i c cancer w l t h osseous m e t a s t a s e s (OM) e n c o m p a s s e s a h e t e r o g e n o u s group of patients (pts) . B r e a s t c a n c e r (BC) Dis w i t h O M s h o u l d be a n a l y s e d as a d i s t i n c t s u b g r o u p b e c a u s e a wide range of systemic forms of therapy is available. Radiation treatment is usually initiated for two reasons: i) retief of pain and l i ) return of function for weight bearing

bones. AS t h e r e is a p a u c i t y of s u f f i c i e n t data invest!gating pain relief, a p r o s p e c t i v e study w a s initiated to evaluate the degree and duration of pain relief with specla{ emphasis on t h e p r o m p t n e s s o f p a i n r e l i e f . 55 c o n s e e u tire p t s (92 m e t a s t a t i c sites) were evaluated

Using different m e a s u r e s of pain and narcotic m e d i c a t i o n b a s e d on p a i n and n a r c o t l c s c o r e s developed by the Radiation Treatment O n t o l o g y G r o u p ( C a n c e r 58,pp29), P t s w e r e i r r a d i a t e d w l t h conventional (76 sites) or unconventional ( = t w o or t h r e e f r a c t i o n s per day) f r a c t i o nation (16 s i t e s ) . Sufficient pain relief was observed in a l m o s t every patient. Furthermore promptness of pain relief within the first days after the start of radiotherapy was docum e n t e d . To r e c o g n i z e differences between these two groups, curves of pain relief wiil be described by random-coefficient-regression (RCR) m o d e l s . C o n c l u s i o n : d a t a of this prospective study underline the high degree of pain relief achieved b y RT I n p t s w i t h OM f r o m BC. Abt. Strahlentherapie und Abt. Medizinische StatistIk und Ookumentatlon, Mad. Fakult{t,

R W T H Aachen,

hormonal

and

cytotoxic

treatment

proved

2/P-GM 001

BREAST CANCER AND BONE METASTASES: A PROSPECTIVE STUDY ANALYSING PAIN ACHIEVED BY RADIOTHERAPY. A.Rheln,J.H.Karstens,W.Meyers,J.Ammon

Kllnlkum

Combined

to be an effective management of extensive bone metastases in breast c a n c ~ ~ p e c i a l l y when patients (pats.) had relapsed after p r i ~ therapy. In a nonrandomised study 67 pats.with bone metastases of breast cancer were treated with either aminoglutethimids (AG) or tamoxifen (TAM) in combination with a polychemotherapy regimen such as CUE, FAG or AV. Twenty five of the 26 pats. who had relapsed after prior therapy received AG plus chemotherapy (CT), as a regimen containing adr~amycin. In the study 62 pats. responded to management with C,PR or NC (36 pats, with C+PR), Parameters for the evaluation of life quality were the Karnofsky index (KI), diminution of pain, r ~ mobilisation of formerly bedridden pats., and response duration, Fourteen out of 15 pats. with KI below 50 % responded to simultaneous combination of AG and CT within 21 and 60 (median 37) days. The duration of responses in this group was median 17.7 months and did not differ from that obtained in the group of pats, with KI above 50 % (17.1 mos.). Although the improvement of the performance status occurred sooner in the AG+CT group, the duration of responses overall was shorter (median 15.8 mos.) than in pats.of the TAM+CT group (median 21,6 mos.)However, t h e e were more pats, in the AG+CT group with prior treatment, In conclusion we recommend a combination of hormonal and cytotoxic treatment for ~ tensive bone metastases based on individual considerations of the patients' general condition and prognosis. Abteilung N ~ m a t o l o g i e / O n k o l o g i e am St. JosefHospital, Buerer Str. 47, D-465 Gelsenkirchen

D-51

Aachen,

Pauwelsstr,

DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF DNA PLOIDY IN SQUAMOUS CELL CARCINOMAS OF THE ORAL CAVITY. J. Hemmer, J. Kreidler, St. Haase

Aneuploidy determined by flow cytometry has turned out to be the most universal tumor marker. Also in primary squamous cell carcinomas of the oral cavity aneuploid cell lines are found in about 50 % of all cases studied. This incidence is much lower than reviewed for nearly all other solid tumors. The reason might be that carcinomas of the head and neck region are recognized in a relatively early stage of growth, i.e. before expression of aneuploid cell lines has occured. Indeed, in primary squamous cell carcinomas of the oral cavity tumor age and rate of aneuploidy is significantly correlated. Furthermore, the frequency of aneuploid tumors increase with decreasing tumor differentiation. Additionally, there are some indications for prognostic relevance of cytokinetic data derived by flow cytometry: the risk of lymph node involvement seems to be much lower in patients with low proliferating diploid tumors than in patients with rapid proliferating diploid or aneuploid primary tumors. It is evident that flow cytometry has developed to a powerfull diagnostic and prognostic tool in clinical oncology. Abt. Mund-, Kiefer- und Cesichtschirurgie der Universit~t Ulm im Bundeswehrkrankenhaus, Oberer Eselsberg 40, D-7900 Ulm

S 48

2/P-GM 002

2/P-GM 004

EXPERIENCES WITH A NEW PERFUSED CAPILLARY CLONING SYSTEM H. Wei~er, B. Lathan, R. Schnabel, P. Langer, V. Diehl

MANAGEMENTOF PATIENTS WITH CARCINOMAOF UNKNOWNPRIMARY: THE RECOGNITION OF PROGNOSTICALLYDIFFERENT SUBGROUPSAND THEIR INPUT ON TREATMENTREPORTS

Systems f o r in v i t r o drug s e n s i t i v i t y t e s t i n g are l i m i t e d by t h e i r i n a b i l i t y to t e s t drug combinations and to provide pharmakokinetic f l e x i b i l i t y for dose variations of the i n v e s t i gated drugs. We h a v e t h e r e f o r e developed the p e r f u s e d c a p i l l a r y c l o n i n g s y s t e m , which circumvents these l i m i t a t i o n s . I t allows the growth of human tumor c e l l c o l o n i e s in s o f t agar w i t h i n s p e c i a l porous g l a s c a p i l l a r i e s (Schott Glaswerke, Mainz) which are p e r f u s e d with fresh medium with or without the addition of antitumor drugs. Of 26 d i f f e r e n t types of c a p i l l a r i e s best cloning e f f i c i e n c y (CE) was found w i t h i n those c a p i l l a r y tubes c o n s i s t i n g of membranes w i t h pore s i z e s between 8 and 16nm. The chemical m o d i f i c a t i o n of the c a p i l l a r y s u r f a c e had another important impact on CE. Best CE was obtained in c a p i l l a r i e s modified with quaternary amonium base or with amino groups.For MDA231 human breast cancer c e l l s a linear r e l a t i o n of number of seeded c e l l s and number of c u l t i v a t e d c o l o n i e s was d e m o n s t r a t e d f o r c e l l concentrations between 500 and 6000 c e l l s / m l . Having shown the f e a s i b i l i t y for growing tumor cell colonies with the perfused capillary cloning system, d r u g experiments w e r e performed. MDA-231 c e l l s showed a g o o d dose response effect with adriamycin when the drug was given into the perfusion medium at d i f f e r e n t concent r a t i o n s , ranging from 0,0004 to 4,0 ~g/ml.

Chr. Sch~ber 2, H.-J. Schmoll 2, Kh. Rennet 1

I.

Medizinische U n i v e r s i t ~ t s k l i n i k I, Stelzmann-Str.9, D-5000 Kbln 41

Joseph-

Wildfang I

R. RathmannI

C. Tamme2, G. H~bner 2

156 patients with carcinoma of unknown primary (CUP-syndrom) were reviewed r e t r o s p e c t i v e l y from 1977 - 1987. The median age was 57 years, male 63 %, female 37 %. The histology showed 76 (49 %) adenocarcinoma (ACUP), 25 (16

%) undifferentiated carcinoma (UCUP), 15 patients (9 %) squamous cell carcinoma (SQCUP), 25 patients (16 %) various histologies including extragonadal germ cell tumor, 16 patients (lO %) malignant but unclassified. The survival rate was markedly different with respect to the extend of disease and the presenting site of the metastases. We subdivided the patients into 4 groups: group I: primary localized, non-lymphonodalmanifestation, 40 patients (26 %); group I I : primary lymphonodal manifestation, 26 patients (17 %); group I l l : primarily disseminated disease, 68 patients (43 %); group IV: primarily fatal prognosis, 22 patients (14 %). Group I and II received radiotherapy and/or surgery, group I l l chemotherapy and group IV only palliative care inclusive palliative radiotherapy. The preliminary evaluation of median survival in 87/156 patients is 6 months and stratefied by group:f3 months (group I ) , 20 months (group I I ) , 6 months (group I l l ) and l month (group IV). The type of histology had no impact on survival. From these data we conclude that in patients with CUP-syndrom the localization and extend of the metastases are the main prognostic factors. For reports on treatment results in CUPsyndrom patients i t is mandatory to s t r a t i f y the patients into these prognostic different subgroups. Furthermore, therapeutic implications arise from this knowledge and w i l l be explained in detail. Department of Radiotherapy, Medical School Hannoverl Dpt. of Medical Oncology, Konstanty-Gutschow-StraBe 8, D-3000 Hannover 61

2/P-GM 003

2/P-GM 005

DNA FLOW CYTOMETRY OF FEMALE BREAST CANCER IN CORRELATION WITH LYMPH NODE STATUS AND CLINICAL FOLLOW UP,

DNA-histogram and recurrence in carcinoma of the breast R.E. Herzog, R. Seufert, U. Weisgerber, F. Casper Universit~ts-FrauenkliniK Mainz, FRG Direktor: Prof. Dr. V. Friedberg

M. Nekarda, M. Albrecht, H. Baisch, E. Goepel, The prognosis of breast cancer pts. is highly correlated with lymph node status and tumor dissimination. To proove the impact of flow cytometry on predicting the recurrance or survival in breast cancer pts. we analysed the results from breast cancer pts. with primary tumors who were treated between 1978 and 1983. In parafin embedded breast cancer tissue the proportion of tumor cells in S-phase of the cell cycle and the content of DNA was determined and correlated to the ER status, the histological grading, the axillary lymph node status, and the probability of desease free and overall survival. Data are presented as histograms. The proportion of cells corresponding to DNA synthesis (S-phase) and G2-pase were calculated by the use of a planimetric method. The degree of DNA aneup!oidy was given by the DNA-Indax (DI), defined as the proportion of DNA in the aneuploid tumor Gl-eells to the DNA content of the diploid cells in the sample. Pts. with aneuploid tumors (DI 1-2) seem to have a worse prognosis than pts. with diploid tumors (DI i or 2), Aneuploidy may be associated with other negative prognostic factors in pta. with primary breast cancer and may reflect the aggressiveness of the tumor. The ploidy status may be taken in consideration for individualisation in post operative treatment. Zentrum fNr Frauenheilkunde und Geburtshilfe, Universit~tsklinikum Frankfurt Theodor-Stern-Kai 7, D - 6000 Frankfurt/M 70

Histological gradings is becoming increasingly important in organ-retaining therapy. As some of the c y t o i o g i c a l c r i t e r i a concern the c e l l nucleus and can be determined by DNA-measurement, the r e l a t i o n s h i p between DNA-histogram and frequency of recurrent carcinomas was i n v e s t i gated in 168 women. A t o t a l of 100 s i n g l e - c e l l cytophotometic measurements from each carcinoma were evaluated a f t e r Acriflavin-Feulgen staining of the c e l l nucleus. An i n d i v i d u a l d i p l o i d standard was used f o r each carcinoma and was compared to the c l i n i c a l course over 44 months. Correlation with the h i s t o l o g i c a l typing of the carcinoma could not be obtained from the DNA-histogram. Likewise, lymph nodes and d i s t a n t metastases could only p a r t i a l l y he d e t e r m i n e d . . In contrast, a clear c o r r e l a t i o n between DNA-histogram and rate of recurrence was found. Furthermore, more informations is obtained by evaluating the pioidy ]evei in the DNA-histogram in addition to the scatering of the i n d i v i d u a l values. While 90 % of the patients with emploid DNA-histogram were free of cancer a f t e r 44 months, t h i s was true f o r only 50 % of the aneuploid DNA-histograms. The poorest prognosis was seen in those carcinomas with a wide scattering in the DNAhistograms. Only 20 % of these patients were recurrence at the end of the observation period. Thus, the UNA-histograms is one of the most informative prognostig factors in the evaluations of the course of breast cancer.

$49

2/P.GM 006

2/P-GM008

BONE MARROWBIOPSY (JAMSHIDI NEEDLE) REVISITED. I I : COMPLICATIONS UN THE BASIS OF 7000 BIOPSIES J.Anagnou, H.J.Avenarius, H.Dietrich, R.Eisert, M.Freund, H.Kirchner,S.Le Blanc, B.Metzner and H.Poliwoda

Comparison of DNA flow cytometric results, prognostic parameters and follow up data in primary breast cancer. G.E.Feichter r M~Kaufmann r U.Abel~ K.Goerttler.

On the 15th anniversary of Jamshidi's introduction of the new bone marrow biopsy needle device as routine into the c l i n i c , a reappraisal is in order. Data concerning the complications of this procedure are surprisingly scanty. Between February 1977 and December 1986 approximately 7000 biopsies a f t e r the Jamshidi technique have been performed on in- and outpatients at this i n s t i t u t i o n . Registries of biopsies were reviewed and the operators and assistant technicians were interviewed; the obtained information was used to attempt to define an incidence figure for complications. The overall morbidity was n e g l i g i b l e ; however, occasionally grave complications occured: In 3 cases the needle had broken und i t must be removed s u r g i c a l l y ; further the needles were bent in several cases. These complications were most probably due to some rocking and sculling during the procedure. In 3 cases large retroperitoneal haematoma developed post biopsy which was s u r g i c a l l y treated. In 4 cases collaps without sequelae due e i t h e r to reaction to local anaesthesia or to poor physical condition of very i l l , f e b r i l e patients was observed. In 15 cases small haematoma developed which led only to local discomfort for several days. In 3 instances the needle penetrated the posterior i l i a c crest, in another case improper placement of the needle in the spinal canal without i n j u r y occured. In no case was observed local skin i n f e c t i o n , osteomyelitis or nerve damage. In patients with compromised coagulation p o t e n t i a l , especially in those with thombocytopenias no serious hemorrhagic complications were observed. We conclude that the procedure is safe; patients with polycythaemia vera and severe thrombocytosis should be monitored c a r e f u l l y for bleeding. Abt. Haem./Onkol. Department Innere Medizin, Medizinische Hochschule Hannover, Konstanty-Gutschow-StraBe B.

The DNA-Index (DI, DNA-ploidy) and the percentage of cells in the S-phase have been measured in 30o m a m m a r y carcinomas using one parameter DNA-flow cytometry. The data have been compared with the histologic grade, the stage, free interval and receptor content, r e c u r r e n c e with the overall survival time. Both, D! and percentage of cells in the S-phase (SPF) revealed a significant correlation with the histologic grade after Bloom and Richardson (p
2/P-GM 007

2/P-GM 009

BONE MARROWBIOPSY (JAMSHIDI) REVISITED. I : INDICATIONS, SUCCES RATE, QUALITY OF TREPHINE SPECIMENSAND OTHER CHARACTERISTICS ON THE BASIS OF 7000 BIUPSIES J. Anagnou, H.J, Avenarius, H. Dietrich, R. Eisert, M. Freund, H. Kirchner, S. Le Blanc, B.Metzner, H.Poliwoda

Cervical !ymph node metastases of unknown primary

The findings from this study are based on 7000 consecutive biopsies among in-and outpatients performed by the House 3 t a f f in the last decade (2/1977-12/ 1986) in the Div. of Haematology/Oncology of a u n i v e r s i t y 1200- bed hospital. MAJOR INDICATIONS (%): NHL 26.63, Myelomas IZ.58, Acute Leukaemias 6.84, HD 6.1b ,CML 6.09, Suspected not Confirmed Systemic Haematological Disease 5.64, Unknown Indication 4.45, Metastatic Solid Tumors 4.00, Polycythaemia Vera 3.00, Thyroid Cancer 3.00, Anaemias 3.00, Other M y e l o p r o l i f e r a t i v e Diseases 3.00, CLL 3.00, Vasculitis 2.71, Leuko-, Thrombocytopenias 2.70, Other Conditions 8.28. SUCCESRATE: In 94% of the cases a core biopsy could be obtained ; however, 2.37% of a l l biopsies were very small (1-3 mm) and 13.33% not representative. Bone marrow could not be aspirated in 4.44% of the cases. Succes rate seems to depend among other factors on the operator. Although higher mean succes rates have been reported our succes rate seems us to approximate more closely to a r e a l i s t i c succes rate f o r routine biopsies performed by the House Staff. BIOPSY-LENGTH: In 70% of the biopsies the length lay between I0 and 20 mm: LENGTH (up to .. mm) 5 i0 ~ 20 25 30 35 BIOPSIES(%) 17.17 22.11 21.32 24.98 5.37 6.00 2.05 BIOPSY-QUALITY~ I t was strongly dependent on the length: Length 5 I0 15 20 z5 30 35 mm Very good % 20.01 56.75 7 3 . 3 ~ . 5 2 89.47 92.3~ Good % 12.72 13.97 11.11 8.22 7.00 9.53 7.70 Inadequate% 67.27 29.28 15.55 10./5 7.48 1.00 0.00 Abteilung H~matologie/Onkologie, Department Innere Medizin, Medizinische Hochschule Hannover, Konstanty-Gutschow-StraBe 8, 3000 Hannover 61

Pathologisches Institut, Institut f~r Vergleichende und Experimentelle Pathologie, Frauenklinik der Universit~t und Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 22o-221, D-69oo Heidelberg I.

J.Dunst!~ M.Weidenbecher2~. R.Sauer 1 Strahlenklinik Iund Hals-Nasen-Ohren-Klinik~ t~t Erlangen-NOrnberg

Universi-

32 patients with cervical lymph node metastases of unknown primary have been treated from January 1978 to August 1986. Most patients had advanced disease (ND-metastases) of squamous cell carcinoma or anaplastic carcinoma. Melanomas were excluded. Treatment consisted of surgery plus radiotherapy or irradiation alone. In irradiated patients, the target volume included the entire neck, hypopharynx, base of the tongue and nasopharynx. The total dose was at least 50Gy in patients treated with curative intent. The survival rate for the entire group is 70% after three years and 52% after 5 years. The best results were achieved in patients with excisional biopsy or neck dissection and postoperative irradiation with more than 50Gy: 16 out of 20 patients in this subgroup are alive with no evidence of disease and the 5-year-survival rate is 80% in this group. On the other hand, the prognosis in patients with irradiation alone was poor: no patient survived longer than four years. After completed therapy, two primary tumors were detected. Both were situated in the head and neck area outside the former radiation fields. The data confirm that the prognosis of patients with isolated cervical lymph node metastases of unknown origin is relatively good as compared to other metastases of un~known primaries, if they recieve adequate locoregional treatment. Combined modality approach (surgery and curative irradiation) offers the best results and can be considered as treatment of choice.

$50 2/P-GM 012

2/P-GM 010 F L O W CYTOMETRIC HEAD AND NECK

DNA ANALYSIS

R. Fietkau, E. Langer, Herbst, R. Hoh, R. Sauer

FOR TUMOURS

OF THE

MULTI-CENTER

AND

INTERDISCIPLINARY

DOCUMENTATION

AND D A T A A N A L Y S I S IN O N C O L O G Y A - H ~ r l e r P. W u i s m a n H.

Ire,

P.

Bilek,

M.

D N A - i n d e x and p r o l i f e r a t i o n rate (percentage of S-phase-cells) of 52 head and neck tumours and 8 lymphnode metastases in the cervical region were analyzed before any tumour treatment d e p e n d i n g upon tumour stage (chemotherapy, surgery or radiotherapy) by flow cytometry. 35 of these tumours were aneuploid, 24 tumours were diploid. The p e r c e n t a g e of aneuploid tumours was n e a r l y e q u a l l y d i s t r i b u t e d in all primary tumour stages (38-54%). In contrast the number of a n e u p l o i d tumours increased with more advanced disease (lymphatic involvement: N0=43%; N~=72% a n e u p l o i d tumours). The p e r c e n t a g e of S-p~ase-cells was greater in aneuploid tumours (median 18.6%) compared to diploid tumeurs (mean 10.4%). Complete response was achieved with primary treatment in 32 tumours. Aneuploid tumours d e v e l o p e d more often (69%) and earlier (median 5 months) recurrences than diploid tumours (54%; median Ii months). Regional recurrences w e r e m a i n l y observed in aneuploid tumours, w h e r e a s diploid tumours demonstrated only local recurrences. For recurrent aneuploid tumours a higher rate of S-phase-cells (mean 21.7%) than for those w i t h o u t recurrences (mean 18%) was seen. For diploid tumours no such difference was observed. The p r o g n o s t i c value of these results will be discussed. Strahlentherapeutische Klinik, Institut Pathologie und Hals-Nasen-0hren-Klinik U n i v e r s i t ~ t Erlangen.

f~r der

Progress in treatment of tumors depends on a coo p e r a t i v e i n t e r d i s c i p l i n a r y group of o n c o l o g i s t s and a w e l l o r g a n i z e d f o l l o w - u p , b a s e d on an careful d o c u m e n t a t i o n of interesting data. All the i n t e g r a t e d d i s c i p l i n e s of the team s h o u l d participate a c t i v e in treatment and e v a l u a t i o n of r e s u l t s as w e l l and b r i n g in t h e i r s p e c i f i c knowledge and s c i e n t i f i c questions. Optimal a c c u r a c y of d a t a c o l l e c t i o n and d o c u m e n t a t i o n for the combined a n a l y s i s w i l l be achieved, when a l l p a r t i c i p a n t s have the same chance and right to i n v e s t i g a t e the data on their own. Data coll e c t i o n and a n a l y s i s in o n l y one d o m i n a t i n g i n s t i t u t i o n w i l l d e c r e a s e the i n t e r e s t of the other participants and frustrate them scientifically. The modern f a c i l i t i e s of data a n a l y s i s on p o w e r f u l and n o n - e x p e n s i v e m i c r o c o m p u t e r s e n a b l e a l l the m e m b e r s of s u c h a t e a m a n d the t r i a l g r o u p s to i m p r o v e t h e i r w o r k by c h e c k i n g the individual p a t i e n t course. F o r this p u r p o s e a w e l l adapted c l i n i c a l data m a n a g e m e n t system is n e e d e d , w h i c h a l l o w s the d o c t o r to c u s t o m i z e data organization according to his own requests without being a p r o g r a m m e r or needing permanent a s s i s t a n c e of i n f o r m a t i c p e o p l e . On the o t h e r hand data transfer to other institutions and to mainframe systems s h o u l d be prepared and e a s i l y performed. The c l i n i c a l data management system MEDLOG d e v e l o p p e d for the decumentation of m u l t i - c e n t e r i n v e s t i g a t i o n in r h e u m a t i c d i s e a s e s and based on a time-oriented databank structure has a l l the f e a t u r e s n e e d e d for d o c u m e n t a t i o n , r e t r i e v a l and statistical a n a l y s i s of patients data in c o o p e r a t i v e cancer therapy. Orthop~dische Universit~ts-Klinik,

MUnster

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TUMOR FOLLOW-UP SCHEDULES: E M P I R I C A L CONTENT AND EVALUATION D, Hoelzel, H. Sauer, J.C. de Waal Tumor follow-up schedules become more and more known and define standards for follow-up examination. They give instructions about adequate diagnostic tests, the frequency of administration, the duration of follow-up and the group of the patients for which the schedule is suitable. Therefore they are a very concise summary of empirical facts about the c h a r a c t e r i s t i c s of diagnostic test, the typical p a t t e r n of p r o g r e s s i o n and the clinical course of the diseases. The p o s s i b i l i t i e s of an a priori evaluation will be d i s c u s s e d for breast cancer and malignes melanoma. Empirical and theoretical results show that about 0.4% positive scintigraphies can be e x p e c t e d with common follow-up schedules for breast cancer and that about 3% of all progressions are confined to the liver. The c o m p a r i s o n to the incidence of second m a l i g n o m a during follow-up gives another measure of efficacy. Refinements seem to be necessary at least in direction of r i s k - a d a p t e d schedules. Further questions have to be answered about adm i n i s t r a t i o n of the schedules, the compliance of the patients and physicians, the improvement of quality of life or life e x p e c t a n c y due to early detection of p r o g r e s s i o n etc. These empirical data are necessary for a scientific basis of the strategies. In contrast to the introduction of the early cancer detection programs, the evaluation of the follow-up schedules must be defined at least now with the propagation of the standards for follow-up examinations.

PSYCHOSOCIAL COUNSELINGOF FAMILIES WITH CANCER-SICK CHILDREN AND ADOLESCENTS. B. Grabisch, M. Noeker, F. Petermann, and U. Bode

ISB / Klinikum GroBhadern, D-8000 M~nchen 70

Marchioninistr.

15,

In a retrospective study of 30 families of children with cancer f i v e d i f f e r e n t modes of disease appraisal were established: cancer was seen as challenge, probat i o n , misfortune, f a t e , or punishment. The d i f f e r e n t kinds of appraisal influence the coping s t y l e of pat i e n t s and t h e i r families. Using half-structured i n t e r views f o r evaluation a program of psychosocial counseling was developed. I t was based on the coping model of Lazarus and intended to f a c i l i t a t e appropiate coping behavior of the families. This program was used f o r a prospective study of 35 f a m i l i e s , of which a c h i l d was diagnosed and treated for cancer at the Children s Hospital. The content analysis of a l l counseling protocols resulted in a system of categories, which allowed prospective deter~,~ination of a p o s i t i v e coping behavior in certain families. I t is assumed that p o s i t i v e coping behavior is enhanced by the p a t i e n t s b e l i e f of being able to a c t i v e l y influence the course and sequelae of his disease. The level of medical information correlates with the q u a l i t y of coping behavior as well. Uninformed families tend to create p r i v a t e fantasies about the o r i g i n of t h e i r c h i l d s cancer. Often they feel g u i l t y and thus punished by the disease. A r e l a t i o n s h i p between the kind of childhood cancer, i t s c l i n i c a l prognosis, and the p a t i e n t s coping behavior can be observed. U n i v . - K i n d e r k l i n i k , Adenauerallee 119, 53 Bonn 1, FRG

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STUDIES ON THE C A R C I N O G E N I C POTENTIAL OF AUTOM O B I L E E X H A U S T P A R T I C U L A T E S F R O M GASOLINEPOWERED ENGINES W ~ H a d n a g y and N.H. See__mgyer

"IF YOU WANT TO GET AN ANSWER;YOU FIRST HAVE TO ASK QUESTIONS!" M I S S E D QUESTIONS IN TAKING PATIENTS HISTORY IS A CONTRIBUTION TO THE RESEARCH ON BREAST CANCER: NOT AS UNCONVENTIONAL AS IT MAY LOOK. WRITTEN BY MEDICAL DOCTOR CONCERNED HERSELF. U. H a s s e n s t e i n

Previous studies have shown, that extract of p a r t i c u l a t e m a t t e r from g a s o l i n e engine exhaust affects the spindle apparatus and produces numerical c h r o m o s o m e a b e r r a t i o n s (Hadnagy and Seem&yer, M u t a g e n e s i s , I, 445-448, 1986; Seemayer et al., Sci. Total Environ., 61, I07-115~ 1987). Since genomic imbalances may be involved in carcinogenesis, a further p a r t i c u l a t e extract from gasoline engine exhaust has been tested on cytotoxic, m u t a g e n i c and c a r c i n o g e n i c activities using rodent and human tissue culture cells. C y t o t o x i c i t y is shown by a p r o n o u n c e d r e d u c t i o n of p l a t i n g e f f i c i e n c y after treatment of Chinese hamster lung cells V79. M u t a g e n i c i t y is d e m o n s t r a t e d by a d o s e - d e p e n d e n t induction of sister chromatid exchanges in human lymphocyte cultures. Cell division studies on V79 cells revealed spindle d i s t u r b a n c e s as indicated by the o c c u r r e n c e of abnormal m i t o t i c figures at the m e t a p h a s e stage and an increased m i t o t i c index. In contrast to our first study for this sample no induction of numerical chromosome alterations could be d e t e c t e d suggesting an irreversible d a m a g e of the m i t o t i c spindle. However, the cell t r a n s f o r m a t i o n assay using SV-40 virus infected Syrian hamster kidney cells showed a s i g n i f i c a n t l y increased t r a n s f o r m a t i o n rate in a d o s e - d e p e n d e n t manner. A c c o r d i n g to our previous studies and data p r e s e n t e d here, results strongly suggest that p a r t i c u l a t e m a t t e r from gasoline engine exhaust have a c a r c i n o g e n i c potential. M e d i z i n i s c h e s Institut f~r U m w e l t h y g i e n e an der Universit[t, Gurlittstr. 53, D-4000 D [ s s e l d o r f

Beethevenstr.

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C A R C I N O G E N I C AND M U T A G E N I C EFFECTS OF A I R B O R N E P A R T I C U L A T E S ON HUMAN AND R O D E N T TISSUE CULTURE CELLS: A C O M P A R A T I V E STUDY F R O M A HIGHLY I N D U S T R I A L I Z E D REGION OVER A PERIOD OF 12 YEARS (1975 -1987) N.H~ Seemayer, W. H a d n a g y and R. Tomingas

NON-MEDICAL PRACTITIONERS AND CANCER - SUBJECTIVE DISEASE CONCEPTIONSAND THERAPEUTICSOF NON-REGISTERED HEALERS R. Alting

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E p i d e m i o l o g i c a ! studies reveal a higher incidence of lung cancer in industrialized areas. A i r b o r n e p a r t i c u l a t e m a t t e r from h e a v i l y ind u s t r i a l i z e d regions contains m o r e than 600 m o s t l y organic substances, among them known carcinogens and mutagens. Chronic inhalation of a great v a r i e t y of air p o l l u t a n t s raises serious problems about health effects in humans particu l a r l y of r e s p i r a t o r y carcinogenesis. In this study 24 samples of airborne p a r t i c u l a t e m a t t e r c o l l e c t e d b e t w e e n 1975 and 1987 in the RhineR u h r - r e g i o n were extracted by organic solvents and analyzed for m u t a g e n i c and c a r c i n o g e n i c effects on rodent and human tissue culture cells, M u t a g e n i c i t y of samples was e v a l u a t e d by induction of "sister chromatid exchanges" in human lymphocyte cultures, while c a r c i n o g e n i c i t y was d e t e r m i n e d by "enhancement" of m a l i g n a n t cell transformation. Results demonstrate, that airborne p a r t i c u l a t e s collected between 1975 1987 contain chemical compounds with strong m u t a g e n i c and c a r c i n o g e n i c activity. C o n c e r n i n g human cancer risk by airborne particules we have to regard a r e s p i r a t o r y v o l u m e of 12-14 m 3 of air per day in c o m p a r i s o n to c a r c i n o g e n i c and m u t a g e n i c e f f e c t s 3 d e m o n s t r a b l e with particulates from 0.2-0.5 m of air. Therefore, a lung cancer risk in humans m u s t be considered. M e d i z i n i s c h e s Institut f[r U m w e l t h y g i e n e an der Universit~t, Gurlittstr. 53, D-40OO D~sseldorf, FRG

In BOA-report Nr.44 of 9.Sept.1987 it is mentioned that there are 30.000 wommen with breast cancer among the 268.700 new cancer patients per year. Cancer therapy has made much progress~ but we have to state,that research in general still does not start befor the stage of overt m a n i f e s t a t i o n of illness.An inquiry bougth about that the patients history is restricted to general items.There is a lack of systematic and methodical research concerning individual factors of possible importance etlologically.This artical aims at this point and the anthor suggests to look at the following anamnestic factors in patients with breast cancer in order to validate them wing todays possibilities of computer assisted statistical amalysis: Conditions of l i f e / s t r e s s - f a c t o r s / p a r t n e r relat i o b s h i p / s e x u a l i t y / n u t r i t i o n / p a s s i v smoking/ sleeping costoms/use of d e o d o r a n t s / h o r m o n e s t h e " p i l l " / e n v i r e n m e n t a l f a c t o r s / s p o r t s / t h e use of security belts/patients conception concerning etiology~This cataloque is far from beging complet,bat only asking questions like these ~ d looking closer to different aspeczts of every day life, imdividual risk factors for breast cancer may be discovered and prevention may become a ohamcs. 2

D

- 7600 Offenburg

A l l the p o l i t i c a l e f f o r t s of the last few years to a l t e r the legal statutes governing non-medical p r a c t i t i o n e r s have f a i l e d . Prior to a further discussion on t h i s level i t seemed to be important to obtain information on the internal structure of t h i s "paramedical" sector. For t h i s purpose non-medical p r a c t i t i o n e r s in an urban area and two bordering rural d i s t r i c t s were questioned as to t h e i r conceptual and p r a c t i c a l dealings with cancer. This was effected on the basis of semistandardised, problem-centred recorded interviews. There followed a contextually sensitive a n a l y t i c a l evaluation of the content. The refusal rate was 40%, Approximately half the respondents assessed the control a t t r i b u t i o n as high, i . e . they implied that they considered cancer to be highly c o n t r o l l a b l e , susceptible to treatment whether in the prophylactic or in the therapeutic f i e l d . This u n r e a l i s t i c optimism is due i n t e r a l i a to a conviction that a multitude of diagnostic and therapeutic procedures are available to the nonmedical p r a c t i t i o n e r which are greatly superior to those of the o f f i c i a l medical system. Such unconventional methods as are used by the non-medical p r a c t i t i o n e r Will be portrayed in d e t a i l . One c h a r a c t e r i s t i c feature of almost a l l procedures was the magic element. I t is assumed that the a f f e c t i v e emotional level of magic thinking and acting complies with the cancer patientrs experience of threat and danger. The disquieting f a c t o r is the presence of strongly i r r a t i o n a l elements which have led to a p a r t l y absurd mimicry of s c i e n t i f i c medicine. Reiner A l t i n g , Blumenstrasse 6, D 6900 HeLdelberg

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THERAPY-INDUCED LEUKEMIAAND PRELEUKEMIA U. Heyll, C. Aul, A. Heyll, W. Schneider

THE GERmaN CANCER INFOrmaTION SERVICE (KREBSINFORMATIONSDIENST, KID) - A TELEPHONE SERVICE LINKING RESEARCH, MEDICAL CARE WITH THE PUBLIC. Hilke Stamatiadis-Smidt, Deutsches Krebsforschungszentrum, Heidelberg, BRD, and Almuth Sellschopp, Institut f~r Psychotherapie und Medizinische Psychologie, Klinikum Rechts der Isar, M~nchen, BRD.

Myelodysplasia and acute myeloblastic leukemia may occur as late complications after cytotoxic chemotherapy or radiotherapy. Alkylating agents, procarbazine and nitrosoureas have been most frequently associated with the developmentof secondary leukemia, which is different from de novo AML with respect to morphology, chromosomestudies and prognosis. From 1975-1987 26 cases of secondary AML (n=11) and Myelodysplasia (n=15) have been diagnosed at the University of DOsseldorf. 14 patients had received chemotherapy alone, 5 patients radiotherapy alone and 7 patients a combinedtreatment for the following diseases : Hodgkin~s disease n=5, multiple myeloman=4, NHL n=3, solid tumors n=13 and rheumatoid a r t h r i t i s n=1. Alkyiating agents (cyclophosphamide,dihydroxybusulfan) had been administered in 18 cases. The intervall betweentreatment of the primary disease and onset of the hematological disorder ranged from 9 months to 31 years (median 7 years). The overall incidence of leukemia in patients with Hodgkin's disease treatedwith polychemotherapyand radiotherapy (n=307) was 1,6%. In contrast to de novo AML prognosis of secondary AML was found to be extremely poor with a median survival time of 6 weeks. Only I of 6 patients who were treated with aggressive polychemotherapyafter diagnosis of secondary AML achieved complete remission (duration 13 months). Our findings emphasizethe leukemic risk which is associated with antineoplastic treatment and may be of relevance for long-time survivors amongthese patients.

KID, a German nationwide telephone cancer information service, promoted and financed for a 3year-pilot phase by the German Federal Ministry of Youth, Family, Women and Health, has been established at the Deutsches Krebsforschungszentrum (German Cancer Research Center) and the Tumour-Center Heidelberg/Mannheim. It is in full operation since July 1986. Its aim is to serve as a link between the scientist, the physician and the public. Anybody can dial the KID number in order to get information about cancer research diagnosis, therapy and prevention, information about institutions , groups, addresses etc., anon~naously and according to the caller's individual needs. The data about the acceptance, the subjects of inquiries, the type of information and services needed by the German population etc. for the period of two years will be presented.

~d.

DER DEUTSCHE KREBSINFORMATIONSDIENST, KID EIN TELEFONDIENST ALS BINDEGLIED ZWISCHEN FORSCHUNG, MEDIZINISCHER VERSORGUNG UND DEM BURGER. Hilke Stamatiadis-SmidttM.A. , Deutsches Krebsf0rschungszentrum, Heidelberg, BRD, und Dr. Almuth Sellschopp, Institut fHr Psychotherapie und Medizinische Psychologie, Klinikum Rechts der Isar, M~nchen, BRD

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CANCER SOCIO-ECONOMIC FACTORS AND CAUSE OF DEATH IN THE ELDERLY - AN AUTOPSY STUDY K. Kayser~ C. Barth, H. BOIzebruck, H.F. Otto

INTRAOPERATIVE, INTRAPERITONEAL CHEMOTHERAPY IN ADVANCED GYNECOLOGIC MALIGNOMAS A, Werner, D, Krebs, U, Bode ~ Considering t h a t in g y n e c o l o g i c c a r c i n o m a s c e l l s and c e l l u lar tumor p a r t s can be l e f t in t h e abdominal space leading to an i n c r e a s e d g r o w t h of r e c u r r e n c e s due to a change in the cell k i n e t i c situation, 19 p a t i e n t s with an a d v a n c e d gynecologic tumor w e r e t r e a t e d locally with 15 mg m i t o mycin or 30 mg (~0 mg) m i t o x a n t r o n e dissolved in 1000 mg saline b e f o r e the operation was c o m p l e t e d . In i# p a t i e n t s assessed up to now, a NED s t a t e was a c h i e v e d g t i m e s , while t h e r e was a p a r t i a l remission in 2 c a s e s and a SD s i t u a t i o n in one. In two women t h e r e was progression. In t h e group with r e c u r e n t t r e a t m e n t (5 women), a f u r t h e r progressive course was observed in # p a t i e n t s . In one c a s e t h e r e was a p a r t i a l remission. With m i t o x a n t r o n e serum l e v e l s b e t w e e n 10-60 n g / m l the s i d e - e f f e c t s of the i n t r a o p e r a t i v e and i n t r a p e r i t o n e a l t h e r a p y with c y t o s t a t i c s w e r e g e n e r a l l y a c c e p t a b l e . Given the observed courses of the disease, a c o n t i n u a t i o n of the i n t r a p e r i t o n e a I t h e r a p y form a i m e d a g a i n s t postoperat i v e residual and a g g r e s s i v e l y growing t u m o r c e l l s would appear to be justifiable.

K l i n i k A Universit~t DUsseldorf, Moorenstr. 5 0-4000 DOsseldorf

Socio-economic factors, chronic diseases, and cause of death were analyzed in autopsied patients of 70 years or older. Data include chronic diseases as hypertonia, diabetes mellitus, various chronic infectious diseases, and various malignancies. Socio-economic factors include profession, domicile, consultations of the house physicians, nutrition, and medicamenration. The following results were obtained: 994 patients could be included in the study (492 males, 502 females). 202 patients suffered from hypertonia, 126 patients from diabetes mellitus, 11% from hepatopathia, nephropathia, and chronic infectious lung diseases. A malignant tumour was diagnosed in 230 patients, however, only 74 patients died from a malignan, cy (cause of death). Majority of patients:died from a cardiogenie shock (432 cases), coronary heart disease (193 cases), and from respiratory insufficiency (80 cases). Multi-morbidity was found in 811 patients (82%). A m a l i g n a n t tumour was seen less frequently in patients w i t h occupations of high physical a c t i v i t ~ with longtime consultations of the house physician, and w i t h additional chronic inflammatory diseases. The data indicate that chronic inflammatory diseases m a y protect the patients against cancer to a certain amount. The socio-eeonomic ,significance of the study wi~be discussed. T h o r a x k l i n i k Heidelberg-Rohrbach, D-6900 Heidelberg

Amalienstr. 5,

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Universit/its-Frauen5300 gonn-Venusberg

und

Universit/its-Kinderklinik

,

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THE INVOLVEMENT OF APPENDIX, PELVIC AND PARAAORTAL LYMPH NODES IN OPERABLE OVARIAN CANCER.

TUMOR-ASSOCIATED AND GENERAL CELLULAR IMMUNITY IN OVARIAN CANCER PATIENTS S.Janke~ P.Mallmann and D.Krebs

A.Storz, M.Geppert, and W.E. Simon 31 patients with ovarian malignancy underwent pelvic lymphadenectomy and sampling biopsy of paraaortal lymph nodes combined with total hysterectomy bilateral salpingo-oophorectomy, omentectomy, appendectomy and, if necessary, tumor debulking. Staging was performed according to the FIGO recommendations, No involvement of lymph nodes or appendix was detectable in the tt~ patients with stage IA-IIB disease. 9 of the 17 patients with stage III disease were appendectomized. In 3 of these patients microscopic tumor involvement of appendix was detected. Pelvic lymph node involvement was demonstrated in 11 of the 17 patients (65 %). Only patients with positiv pelvic lymph nodes had aortic lymph node involvement (8 patients, ~7 %). With respect to histologic grade of the stage III malignancies only in the 2 grade t tumor patients lymph nodes were not involved. AII tumors with lymph node invoIvement were serous papillary cystadenocarcinomas or undifferentiated carcinomas, No positiv lymph nodes were detected in the g tumors histologically classified as endometroid or mucinous.

Based upon our observations we suggest the relevance of pelvic, paraaortal lymphadenectomy, and appendectomy in stage III ovarian cancer. The effectiveness of lymphadenectomy in stage I or II ovarian cancer needs further evaluation, particularly in grade I tumors. Universitgts-Frauenklinik, Schleichstraf~e g) D 7g00 T~Jbingen

There are a l o t of h i s t o l o g i c a l and biochemical parameters known to be of prognostic value in ovarian cancer patients. I t was the aim of our study to determine, i f the f u r t h e r use of immunological parameters could be helpful f o r the d e f i n i t i o n of high r i s k groups. In 51 patients with ovarian cancer stages FIGO I l l and IV and 10 age matched c o n t r o l l s the following immunological parameters were determined and correlated with the c l i n i c a l course of disease: leucocyte migration i n h i b i t i o n t e s t (LMI-test) against d i f f e r e n t preparations tumor tissue and recall antigens and the d i s t r i b u t i o n of lymphocyte subsets by means of monoclonal antibodies ( t o t a l T c e l l s , T helper/ inducer c e l l s , T suppressor/cytotoxic c e l l s and natural k i l l e r c e l l s ) . In 21% of a l l patients tested a tumorassociated c e l l u l a r immunity in the meaning of reaction in the LMl-test could be observed, whereas in 31 of a l l patients an enhancement was demonstrable. Considering the c l i n i c a l l course of disease we found s i g n i f i c a n t differences. In patients, c l i n i c a l l s c l a s s i f i e d as no evident of disease (NED 6 month a f t e r primary therapy the percentage of patients with a reaction in the LMI-test was 45%, whereas in patients with no change or progression a reaction could only be observed in 13 resp. 25%. Compared to the age matched control group and to the c l i n i c a l course of disease we found no differneces in the percentage of lymphocyte subsets. These results show, that in ovarian cancer patients I. the general c e l l u a l r immunity ( r e a c t i v i t y in the LMI-test against recall antigens and percentage of lymphocyte subsets) is only s l i g h t l y altered and 2. a tumor-associated c e l l u l a r immunity can be demonstrated in the LMl-test which can be set in r e l a t i o n to the c l i n i c a l course of disease and seems to be of prognostic value. Universit~ts-Frauenklinik Bonn, D-5300 Bonn-Venusberg

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TUMORASSOCIATED CELLULAR IMMUNITY IN GYNECOLOGIC CANCER PATIENTS UNDERAN IMMUNETHERAPYWITH THYMUSHORMONES P.Mallmann and D.Krebs

PHASE II TRIAL OF CARBOPLATIN IN ADVANCED OVARIAN CANCER J. Pohl, H.G. Meerpohl, A. P f t e i d e r e r Between 10/1984 a n d ' 1 0 / 1 9 8 7 , 30 p a t i e n t s ( p t s / ~ were t r e a t e d with c a r b o p l a t i n (CBDCA,JM8, c i s - d i a m m i n e 1,1-cyclobutane dieaboxylate platinum II) a cisplatin a n a l o g u e in a p h a s e ti t r i a l . P a t i e n t c h a r a c t e r i s t i c : median age 59 ( r a n g e 38-72), median p e r f o r m a n ce s t a t u s : WHO g r a d e I I , p r i o r c h e m o t h e r a p y : PC/PAC/ CHAP: 24 p t s . , t h e r a p y without DDP 6 p t s . , p e r c u t a neous c o b a l t i r r a d i a t i o n and c h e m o t h e r a p y : 7 p t s . , only c h e m o t h e r a p y (1-5 s u b s t a n c e s ) : 23 p t s . . Drug dosage used was 400 m g / m 2 i . v , Cyeles were r e p e a t e d every 4 weeks without h i g h - v o l u m e f l u i d h y d r a t a t i o n . Pts. who h a d more t h a n 6 weeks between c o u r s e s will go off s t u d y . Response is as follows:8 p t s . h a d p r o g r e s s i v e d i s e a s e a f t e r one cycle and died within 3 months, In the r e m a i n i n g 22 p t s . , 3 p t s . with CR, 2 p t s . with PR and 6 p t s . with s t a b i l i s a t i o n of d i s c ase (NC) were o b s e r v e d . l l p t s . who r e c e i v e d more t h a n 2 cycles showed no r e s p o n s e (PD). Overall r e s p o n s e r a t e : 23% (3 CR, 2 PR), p r i o r a l k a l a t o r s (6 p t s . ) 50?0 (1 CR, 2 PR), p r i o r c i s p t a t i n , r e l a p s e d (20 p t s . ) 13%, p r i o r e i s p t a t i n , r e s i s t a n t (4 p t s . ) 0%.Toxicities: M y e t o s u p p r e s s i o n is d o s e - l i m i t i n g and its s e v e r i t y is r e l a t e d to p r i o r t h e r a p y . In 116 cycles (median 4 c y c les (1-13) Haemoglobin (WHO Grade I I I - I V ) oceured in 6%, Leukocytes (WHO Grade I I I - t V ) in 11%, P l a t e l e t s WHO Grade I I I - I V ) in 25%. Nausea and vomiting were l e s s s e v e r e as shown by t r e a t m e n t with c i s p l a t i n b u t were also o b s e r v e d 85% (WHO Grade I I ) . No s i g n i f i c a n t ototoxicity or n e u r o t o x i c i t y h a s been o b s e r v e d . Renal impairment: blood u r e a c r e a t i n i n e >1.25 was seen in 9 p t s . . Reduction of dosage were performed in 21 of 116 cycles. Conclusion: e a r b o p l a t i n as second line d r u g h a s some a c t i v i t y in o v a r i a n c a n c e r p t s . r e f r a c t o r y to s t a n d a r d dose c i s p l a t i n but h a s a l s o dose l i m i t i n g h a e m a t o l o g i cal t o x i c i t i e s . Universit~ t s - F r a u e n k l i n i k F r e i b u r g H u g s t e t t e r s t r a s s e ,55, D-7800 F r e i b u r g

In some gynecologic tumor patients with disseminated disease changes of tumorassociated and general c e l l u l a r immunity in the meaning of an in v i t r o demonstrable enhancement against tumor tissue in the leucocyte migration i n h i b i t i o n t e s t (LMI-test) and a reduction of t o t a l T - c e l l s , especially T-helper/inducer c e l l s can be observed, which correlates well with the c l i n i c a l course of disease. For an immunerestaurative therapy we used thymushormones, which are known to lead to an enhanced d i f f e r e n t i a t i o n of unspecific T - c e l l s , to a prolonged T~ c e l l r e a c t i v i t y and to an induction of c y t o t o x i c e f f e c t o r c e i l s . Immunotherapy was done in combination with chemoor hormonal therapy in 18 patients with disseminated breast, 11 with ovarian, 4 with corpus and 2 with cervical cancer. The following parameters of c e l l u l a r immunity were determined before and every 3 months during therapy: LMIt e s t against d i f f e r e n t preparations of tumor tissue and r e c a l l antigens and percentage of d i f f e r e n t lymphocyte subsets by means of monoclonal antibodies ( t o t a l T, T helper/inducer, T suppressor/ c y t o t o x i c and natural k i l l e r c e l l s ) . Immunotherapy was done only in patients with Thelper c e l l d e f i c i t and a lack of r e a c t i v i t y resp. an enhancement against tumor tissue in the LMI-test. The percentage of T-helper c e l l s increased from 24% before to 47% a f t e r immunotherapy. The percentage of the other lymphocyte subsets remained unchanged. Before therapy none of the patients showed a reaction in the LMI-test, a f t e r immunotherap a reaction was demonstrable in about 17% of a l l patients, further the percentage of patients with an enhancement against tumor tissue decreased from 70% to 42%. These results show, that under combined immunotheapy changes of immunological parameters can be f i n d , which j u s t i f y f u r t h e r examinations in c o n t r o l l e d t r i a l s . Universlt~ts-Frauenklinik Bonn, D-5300 Bonn-Venusberg

S54

2/P-GM

026

2/P-GM028

INTRAOPERATIVE, ]NTRAPERtTONEAL CHEMOTHERAPY IN ADVANCED GYNECOLOGIC MALIGNOMAS A. Werner, D. Krebs, U. Bode* Considering that in gyneco!ogic carcinomas cells and cellular tumor parts can be Ieft in the abdomina! space [eading to an increased growth of recurrences due to a change in the cell kinetic situation, I9 patients with an advanced gynecologic tumor were treated bcaIly w h h [5 mg mitomycin or 30 mg (40 rag) mitoxantrone dissolved in I000 mg saKne be[ore the operation was completed. In lr patients assessed up to now, a NED state was achieved # tim~s, while there was a partiM remission in 2 cases and a SD situation in one. In two women there was progression. In the group with recurent treatment (5 women), a further progressive course was observed in ~ patients. In one Case there was a partial remission.

With the

mitoxantrone

serum

levels

between

I0-60

ng/ml

side-effects of the intraoperative and intraper[toneal

therapy with cytostatics were generally acceptable. Given the observed courses of the disease, a continuation of the intraperitoneaI therapy form aimed against postoperative residual and aggressively growing appear to be justifiable.

Universit~ts-Frauen5300 Bonn-Venusberg

umd

tumor

ceils would

Universit~ts-Kinderkiinik*

,

VAGINAL ULTRASOUND: A NEW METHOD TO ASSESS THE ENDOMETRIAL CANCER F. Degenhardt, S. BOhmer, 3. Hilfrioh and M. Maero~li ...................................... A noninvBsiVe assessment of the endametrium was not possible until recent improvements of ultrasound technolog V became available~ Using s 5 MHz vaginal ultrasound probe with a frontal screen of 2~a degrees we examined menopausal women prior to curettage because of vaginal bleedlng. Thickness and structure of the endometrium as well as the demarcation of endometrium / mvometrium were assessed. In particular, the existence of areas with a hvperdensa echo or no clear demarcation of the myometrium and the appearance of "spiral structures" were interpreted as abnormal. These observations correlated well with the histological findings and the diagnosis of endometrial cancer. Comparing the ultrasound with the histology it was found, however, that a carcinoma of the endometrium was only detected by ultrasound if the thickness of the mucoaa was greater than ~ mm. Frauenklinik der Medizinischen Hochsehule Hannaver im O s t s t s d t k r e n k e n h a u s (Direktor: Prof. Dr. 3. Schneider), Podblelskistr. 38o, D-3aoo Hannaver 51

2/P-GM

027

RADIOII~UNODETECTION (RID) WITH CA 12-5 ANTIBODIES IN THE FOLLOW-UP OF OVARIAN CARCINOMA - A PROSPECTIVE STUDY. A. Beckisch*, J. Br~kelmann+, P. 0ehr*, D. Krebs +, H.J.Biersack* 21 patients with metastasizing ovarian carcinoma were investigated by RID during and after chemotherapy. The aim of the study was to evaluate RID as a diagnostic tool in the detection of metastases. The thyroid was blocked with iodine and gastric uptake of free radioiodine was reduced by oral application of pc- tassium perchlorate. 131I-labelled (74 MBq) Whole antiCA 12.5 antibody INACIS II (Isotopen Diagnostik CIS) diluted in 1OO ml of physiological NaC1 solution was given by infusion within 30 min. Planar images (ventral and dorsal views) of the pelvis, abdomen, thorax, and head were obtained at 72 and 120 h. In 5 out of 7 cases with suspected (clinical investigation, ultrascnography, and X-ray CT) abdominal metastases RID gave positive results. The last two cases are currently under further clinical investigation. RID proved to be a valuable tool for the detection of intraabdeminal metastases. It also clearly demonstrated a histologically proven metastasis of the vagina. Yet it failed to mark a supraclavicular metastasis in a patient who had intraabdominal metastases proven by RID as well as X-ray CT. As the specificity of the method is very high, a positive finding is helpful for the eneological surgeon. This work was supported by a grant of the Bundesministerium f~r Arbsit und Sozialordnung. Inst. f. klin. u. exp. Nuklearmsdizin (*) und Frauenklinik (+), Univ. Bonn, Venusberg, 5300 Bonn, Germany

2/P-GM029 SECOND-LOOK LAPAROTOMY IN ADVANCEDEPITHELIAL OVARIAN CANCER N. Golz, R. Kiekenap, H. Mast Department of Obstretic and Gynocology St.Bernward hospital, HILDESHEIM, FRG From 1980 to 1985 64 womenwith advanced e p i t h e l i a l ovarian cancer were treated at the St. Bernward hospltal, Hildesheim. The primary managementinvolved an exploratory l aparotomy to reduce the rumor. So 31 (48,4%) patients got a laparotomy without any residual tumor, 6 (9,4%) with smaler than 2 cm and 27 (42,2%) with residual desease of more than 2 cm in diameter. Courses of chemotherapywith clsplatlnum 50mg/sqm, dexorubicln 50mg/sqm and cyclophosphamlde500mg/sqm every 2B days followed. After 6 courses a second Iook-operatlon was planned to estimate the remission. 43 (67%) patients were controlled by second look-laparotemy. In 20 cases no histological or cytological evidence of tumor (NED) and in I i cases a reduction of tumor of more than 60% (PR) was diagnosed. This included four following cycles of chemotherapy. 12 patients showed no change (NC) or tumorprogresslon (P). Here, a stop of chemotherapyor second-llne chemotherapywas erformed. hese 43 second look-laparotomles had only a small amount of operative complications. These data indicate that the second look- laparotomy Is required in the treatment of advancedovarian cancer by Bgresslve chemotherapyto indicate the response or to save the patients this severe andunnecessary suffering i f there is no response of chemotherapy.

~

$55 2/P-GM 030

2/P-GM 032

INVASIVE CARCINOMA OF THE CERVIX IN WOMEN UNDER 40 YEARS OF AGE P. Schefdel, D. Pfeiffer, W. Meier, H. H e p p

I N C I D E N C E O F S E C O N D A R Y N E O P L A S M S IN G Y N E C O L O G I C PATIENTS WITH REGARD TO PREVIOUS THERAPY A.Hettenbach,D.Edel,and H.Schleich

There is considerable evidence that patients with cervical cancer under the age of 35 may carry a worse prognosis than cancer at this site in older women (Ward et aL Brit Med. J. 290 (1985) 1301). In order to identify high risk groups among the 1032 invasive carcinomas that have been treated from 1975 to 1985 at our department, primary radically operated patients (n = 268) were evaluated retrospectively. Statistically significant differences in grading, lymph node status and treatment modatities (e. g. adjuvant radiotherapy)could not be detected, comparing the young age group with the older patients. 5 year survival however in Nl-patients over 40 years was 62 %, compared to 38 % in yoonger patients. Although statistically not significant (0.783) with increasing numbers tbs difference may become important. Prospective trials in these patients were started in 1986 and preliminary results indicate a raise of

In a t o t a l of 4408 g y n e c o l o g i c t u m o r p a t i e n t s , b e t w e e n 1970 and 1985 in a f t e r c a r e , 147 m e t a c h r o n i c s e c o n d a r y a n d 11 m e t a c h r o n i c t e r t i a r y neoplasms were diagnosed. Since a longterm l o n g i t u d ~ n a l o b s e r v a t i o n o f the p a t i e n t s to a g r e a t e x t e n t w a s i m p o s s i b l e w e c a l c u l a t e d acc. to S C H O E N B E R G a n d M Y E R S the p a t i e n t ' s r i s k to contract another neoplasm. The calculation was c a r r i e d o u t by a c c u m u l a t i n g the o b s e r v a t i o n y e a r s w i t h r e g a r d to the r e g i s t r a t e d s e c o n d a r y n e o p l a s m s of c o r r e s p o n d i n g a g e g r o u p s . T h e c a l c ulated incidence was compared with cancer regi s t e r s o f H a m b u r g and S a a r l a n d . Our calculations revealed that patients operated on c o l l m u c a , do n o t b e a r an i n c r e a s e d r i s k of another neoplasm. For irradiated patients, however, t h i s r i s k s e e m s to b e i n c r e a s e d i n p a r t i c u l a r for n e o p l a s m s in a d j a c e n t o r g a n s ( calc. r i s k of c o l o n c a . : 0 . 0 0 0 4 2 5 ; found: 0 . 0 0 0 7 3 4 ). Patients suffering from a corpusca, bear about the t w o f o l d r i s k o f a s e c o n d n e o p l a s m . F o r e m o s t the r i s k of b r e a s t c a , is c l e a r l y h i g h e r t h a n expected after additional irradiation (calc.: 0 . 0 0 2 6 6 ; found: 0 . 0 0 5 3 3 ). For women with a history of ovaryca, after chemo t h e r a p y t h e r e w a s an i n c r e a s e d r i s k o f b l a d d e r ca. ( calc.: 0 . 0 0 0 3 9 ; found: 0 . 0 0 2 9 6 ). P a t i e n t s w i t h a h i s t o r y of b r e a s t c a , o b v i o u s l y b e a r a v e r y h i g h r i s k to f a l l ill w i t h g e n i t a l n e o p l a s m s in p a r t i c u l a r w i t h c o r p u s c a . (calc.: 0 . 0 0 1 1 4 ; found: 0 . 0 2 5 9 4 ) .

undifferentiated

squamous

cell c a r c i n o m a s

in y o u n g

women

with r a p i d clinical p r o g r e s s i o n . T h e p l a c e o f c h e m o t h e r a p y these patients is c u r r e n t l y i n v e s t i g a t e d .

in

5 year-survival (n = 54) in cervical carcinomas and lymph node metastases 100

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Frauenklinik im Klinikum GroBhadern, Ludwig-Maximilians-Uni-

Univ.-Frauenklinik am Klinikum Mannheim, Theodor-Kutzer-Ufer, D-6800 Mannheim I

versitfit, MarchioninistraBe I5, 8000 MQnchen 70 2/P-GM 031

2/P-GM033

COMBINATION-CHEMOTHERAPYFOR MALIGNANT GERM CELL TUMORS OF THE OVARY: THE UFK FREIBURG EXPERIENCE H,G. Meerpohl, D, Sehwerer end A. P f l e i d e r e r

D N A - F L O W C Y T O M ~ T R Y - R E S U L T S AS P R O G N O S T I C F A C T O R S IN ~ V . ~ N C E D OVAR!~=N C ~ C E R OF D I F F E R E N T HISTOLOGIC TYPES AND THEIR INELUENCE ON SURVIVAL W. K~hn, M. K a u f m a n n , G . E . F e i c h t e r , H. H. Rummel, D. Heber!ing, H. S e h m i d

In recent years our understanding of malignant germ cell tumors has improved. With the advent of combination chemotherapy treatment results started to become more promising. Sixteen patients with malignant germ cell tumors who received combination chemotherapy between 10/81 and 5/87 ware reported. The histological diagnosis was confirmed in all pts, and tumors were classified into one of the following categories: dysgerminoma (8), endodermal sinus tumor (5) and immature teratema (5). The extent of disease was staged using the FIGO classification for ovarian tumors: stage I a - I c (6), stage II a - Ii c (2), stage III (2), recurrent disease (6). The following chemotherapy regimens were used: PV8 (Cisplatinum, Vinblastine, Bleomycin) in 8 pts (3-6 courses), VAC (Vincristine, Actinomycin, Cyclephosphamide) in 5 pts (5-6 courses), or other cisplatin containing regimens in 3 pts (PC, PAC, P Hexs) At the present time 12/16 patients (75 %) remain diseasefree for 6 - 67 months (26 months median follow up). One patient is alive with progressive disease (4Qmonths) and 3 patients have died after 28, 38 and 58 months. Drug induced toxicity was moderate. Nausea, vomiting and alopecia were universal. There were no drug related deaths. In conclusion: it appears, based on available data, that the majority of patients with malignant ovarian germ cell tumors have the chance of cure using a conservative surgical approach combined with a short effective combination chemotherapy. Univerit~ts-Prauenklinik der Albert-Ludwigs-Universit~t Hugstetterstr. 55 D 7800 Freiburg

140 o v a r i a n c a n c e r s and b o r d e r l i n e tumors all s t a g e s F I G O I I I / I V u n d e r w e n t s u r g e r y and p o s t o p e r a t i v e c h e m o t h e r a p y at the U n i v e r s i t y W o m e n ' s H o s p i t a l H e i d e l b e r g . F r o m all t u m o r s c o m p l e t e kin e t i c r e s u l t s like D N A - s t e m l i n e and S - p h a s e - f r a c tion established by DNA-flow-cytometry,are availa b l e . T h e o b s e r v a t i o n time was f r o m 12 to 72 m o n t h s . The r e s u l t s w e r e r e l a t e d to the o v e r a l l s u r v i v a l time ( K a p l a n - M e i e r estimate). 1.Met a s t a s i s i n g g r a n u l o s a cell tumors, b o r d e r l i n e tum o r s a n d s e r o u s c a r c i n o m a s w i t h a h i g h c o n t e n t of psa!mmoma b o d i e s h a d a b e t t e r p r o g n o s i s t h a n serous c a r c i n o m a s w i t h a low c o n t e n t of p s a m m o m a b o d i e s , e n d o m e t r i o i d or m u t i n o u s carcinomas. 2 . M o s t o f the a b o v e m e n t i o n e d tumors had a d i p l o i d D N A - s t e m l i n e a n d an S - p h a s e f r a c t i o n b e l o w 4%. 3 . D N A - p l o i d y is an e f f e c t i v e and s t a t i s t i c a l l y s i g n i f i c a n t p r o g n o s t i c factor. T u m o r s w h i c h are D N A - d i p l o i d h a v e a b e t t e r p r o g n o s i s than a n e u p l o i d ones. 4 . S - p h a s e - f r a c t i o n is a p r o g n o s tic f a c k o r of h i g h e s t v a l u e . T u m o r s w i t h an Sp h a s e - f r a c t i o n of l e s s t h a n 4% h a v e a b e t t e r p r o g n o s i s t h a n t u m o r s with an S - p h a s e - f r a c t i o n of 4 - 10%, o r of m o r e than 10%. T h e r e s u l t s show that these newly introduced prognostic crit e r i a a r e m o r e r e l e v a n t than light m i c r o s c o p i c f i n d i n g s (cytologic, h i s t o l o g i c ) . In c o m b i n a t i o n w i t h t h e h i s t o l o g i c ~ h a r a c t e r i s t i c s they a l l o w an individual prognosis.They therefore should b e i n c l u d e d in c l i n i c a l m a n a g e m e n t of a d v a n c e d ovarian cancer. U n i v e r s i t [ t s - F r a u e n k l i n i k H e i d e l b e r g , VoBstr. 9 D-6900 Heidelberg

$56

2/P-GM 034

2/P-GM 036

VINDESINE MONOTHERAPY IN PATIENTS WITH RELAPSE OF CARCINOMA OF THE CERVIX UTERI - A PHASE II TRIAL H. Mssrogli, J. Hilfrioh, E. Sohwarzenau, H.J. L~ek, F. Degenherdt und W. Mauffels .........

SECOND-LOOK OPERATION FOR OVARIAN C A N C E R : PREDICTIVE VALUE OF CA 125 ANTIGEN H. Cartier, G. Crombach, M. Kaufmann, R. Kreienberg, P. Schmidt-Rhode

Chemotherapy of squemous cell carcinoma of the cervix has been not very encouraging. Single reports from the literature indicate, that Vindesine might be effective in cervical cancer. To examine the therapeutic affect of Vindesine, 31 patients with relapse of squamous cell carcinoma of the cervix between 1983 sod 1987 were treated with 3 mg/m 2 Vindesine (Eldssine R) iv (bolus) in a ? to Io days interval. Treatment evaluation was performed after 5 to 8 injections. All patients were pretreated with surgery and/or radiotherapy.

The purpose of this study was to determine the predictive value of C A 125 antigen levels at the time of second-look operation regarding the presence or absence of intraperitoneal tumor. 5 institutions (Universit~its-Frauenkliniken Wi~rzburg, K6ln, Heidelberg, Mainz, Marburg} participated in this retrospective study and provided the data of 111 patients. Evaluated were the serum levels o f C A 125 and the clinical tumor situation before second-look operation, the intraoperative tumor situs and survival data. CA 12S levels equal or above 65 U / e l were defined as positive. The results are summarized in the table.

Results: There was a response rate of 38,7 % with CR 9,7 % (3/31), PR 6,5 % (2/31) and 'stable disease' of 22,6 % (7/31). Residual 19 patients (61,3 %) had progressive disease. Remarkably is the duration of tumor remission especially in patients with CR (51+, 49+ and 18 months). Duration of PR was 5 and 9 months and for 'stable disease' from 4 to 12 months.

Preoperative C A 125 Clinical

In conclusion, Vindesine man induce in a small percentage long lasting remissions in recurrences of cervical cancer. The overall response rate of 38,7 % and low toxicity of Vindesine allows its use as salvage therapy or in combination with other cytostatic drugs for cervical cancer. Frauenklinik der Medizinisehsn Hoehsohule Hannover im Oststadtkrenkenhaus (Direktor: Prof. Dr. J. Schneider), Podhielskistr. 38o, O-3ooo Hannover 51

nag. pos. neg. pos.

Tu-neg. Tu-neg, Tu-pos. T U-DOS.

n pat. and intraoperative situs Tumor Tumor Tumor Total macrosc, microsc, only free 51 82 13 18 3 2 1 11 11 15 15 -

The data clearly demonstrate that elevated CA 125 levels are a strong predictor of intraperitoneal disease and suggest that diagnostic second-look operations may not be required in these patients, Conversely, a negative C A 125 level was not predictive of the intraperitoneal tumor status (45% with rumor, 55% tumor free). Thus patients with negative C A 125 levels may or may not be free of tumor and second-look procedures are therefore mandatory. Of prognostic significance are the CA 125 levels insofar as only a part of the C A 125 negative patients demonstrated long term survival dependent on the intraoperative tumor status,

Gynecological Tumor Marker Group (GTMG) c/o H. Caffier, Universit~ts-Frauenklinik Wiirzburg, Josef-Schneider-Str. 4, D-8700 Wiir zburg

2/P-GM 037

2/P-GM035 INTRAPERITONEAL CHEMOTHERAPY SALVAGE THERAPY OF REGURRENT GANGER - A PILOT STUDY J. Hilfrich, E. Sohwarzenau, H. Eorter.ie~TJ. Preis and H.

WITH MITOXANTRONE AS ASGITES IN OVARIAN H.J. L~ek, I. Seh~nborn, Wagner

Recurrent ascites is one of the major slinical problems in patients with relapses of ovarian cancer. Mitoxentrone has been shown to cause in vitro oytotoxic effects on ovarian cell lines. In addition, Mitoxentrone showed s slow peritoneal clearance with a marked pharmacologic advantage. 17 patients with recurrent sscites because of relapsed ovarian cancer were treated. All patients had previously received at least one mostly Cisplatln containing systemic chemotherapy. Immediately before ip Nitoxantrone infusion, the abdominal cavity was drained as completely as possible and washed out with st least twice 1.51 o,9 % sal~ne (37 ~ ) vie a peritoneal catheter. 25 or 3o mg/m ~ Hito• (Novantren ~) was diluted in 1.51 to 2.ol o,9 % saline (37~ infused rapidly end remained ip for 24 hours before drainage. The response rate was 9/17 patients (52,9 %) with reduction of aaoites~ 5 patients with complete reduction after the first infusion; 2 patients after the second infusion. 2 more patients showed partial reduction. The duration of reduction was 4 to 8 months, however, in general, solid tumor masses in the abdominal cavity progressed during that time. 5/17 patients (29,4 %) showed no response after 3 infusions at maximum (4 weeks interval) and 3 patients are not yet evsluable. Side effects were mild. The results indicate that intraperitoneal infusion of Mitoxantrone can reduce recurrent ascites in ovarian cancer which has s remarkable palliative effect even in progressive disease. Frauenklinik der Medizinisohen Hochschule Hannover im Oststadtkraokenhaus (Direktor: Prof. Dr. J. Schneider), Podbialskistr. 3 8 % D-3ooo Hsnnover 51

RESECTION GUIDED BY ANTIBODIES (JODINIZED) REGAJ - A SURGICAL PROCEDURE TO DETECT M I N O R RESIDUES OF OVARIAN CANCER E.M.Paterok, W.J~ger, N . L a n g / N . F e i s t e l , F.Wolf Treatment of o v a r i a n carcinoma is based on the assumption that the surgical removal of t~mour must be total - as far as possible - so that chemotherapy has the chance to destroy remaining cancer cells. For further survival improvement we are looking for a m e t h o d to detect recurrent disease so early that it can be completly resacred. CA-125, an o v a r i a n cancer associated glycoprotein, is defined by the immunological reaction with the murine antibody OC-125. The injection of iodine-labelled OC-125 leads to high r a d i o a c t i v i t y in the cancer r e s i d u e s , w h e r e as normal tissue accumulates only sparse amounts. During laparotomy we were searching foci w i t h high r a d i o a c t i v i t y by a newly d e v e l o p e d hand held s c i n t i l l a t i o n probe. We have performed that surgical procedure, called REGAJ, in 15 patients after complete primary chemotherapy. 7 women showed an increase of CA-125 serum level by postoperative screening. In all patients immunos c i n t i g r a p h y using 131-iodine labelled OC-125 was performed up to ten days before REGAJ. Three times detected REGAJ vital tumour cells during second-look laparotomy, although CA-125 analysis, immunoscintigram and CT did not suspect cancer residues! This new diagnostic procedure renders possible removing tumour when only - or not even - CA-125 levels indicate progressive disease. U n i v e r s i t ~ t s - F r a u e n k l i n i k / Institut fur Nuklearm e d i z i n der UniversitY@, D-8520 Erlangen

$57

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VARIOUS LASER TECHNIQUES IN EXPERIMENTAL TUMOR SURGERY (LEWIS-LOUNG-CARZINOMA) WallwienerD., Morawski A., Klinger U., Book M., Bastert G.

INCREASING CA 125 AS A PREDICTOR OF RECURRENCE tN OVARIAN CANCER PATIENTS W. Meier, P. Stieber*, A. Fateh-Moghadam*, D. Pfeiffer, W. Eiermann

The autors present a comparison of various laser techniques as used in oneologcal surgery in experiments on animals, The studyinclades: CO:2-Laser~exeision, vaporization and combination of both, as welt as Nd:YAG Laser "non-touch" and "in-touch" techniques of operation an Nd;YAG laser by means of sapphire tips. We studied the rate of local reeurrencies, dissemination and the rate of survival after different Iaser treatment. In addition the results were compared with those of conventionalsurgieal methods. Laser-Forschungsabteitung der Universit~its-Fraue~klinik, D-6650 Homburg/Saar

CA 125 is a well-established tumor marker for epithelial ovarian carcinomas. In patients with elevated tumor marker levels, CA 125 correlates wet! with response to primary therapy. At the time of second look operation 70 patients have been investigated. In 27 of 51 patients with negative tumor marker persistent disease could be demonstrated at least microscopically. There were no false positive CA 125 values, in all of the 19 patients with elevated levels residual tumor was found. Therefore it can be calculated that CA 125 if elevated does predict tumor persistence. In our present study we followed 160 patients with ovarian carcinomas. 67 patients could be identified with temporary negative CA 125 and consecutively increasing tumor marker levels during follow-up, in some cases years after initial treatment. In 24 of these patients recurrent disease was not detectable by simultaneous clinical and radiological investigations. All of these 24 patients developed recurrence 2 to 7 months after the rise of CA t25 (median lead time 3,6 months). Due to these findings second line chemotherapy beginning at the time of increasing CA 125 should be considered, Frauenklinik und Institut fQr Klinische Chemie* im Klinikum GroBhadern der Ludwig-Maximilians-Universit&t, MarchioninistraBe 15, 8000 MOnchen 70

2/P-GM 039

2/P-GM 041

LASER IN GYNECOLOGICAL ONCOLOGY CO:2-LASER, Nd:YAG-LASER -

CA 125 PLASMA CONCENTRATION AND SECO~q) LOOK OPERATION IN OVARIAN CANCER PATIENTS German Gynecologic Tumour Marker Grou~ (GTMG)

Morawski A., WallwienerD., Bastert G. Laser-Forschungsabteilung, Universit fits-Frauenklinik, D-6650 Homburg/Saar In this paper the authors present the possibilities of the use of various laser techniques in gynecological oncology. In the Department of Obstetrics and Gynecology of the University of Saarland, the laser surgery is used first of all for p a l l i a t i v e t r e a t m e n t of: breast cancer, cancer of the vulva; it is used as well for the t r e a t m e n t of local recurreneies of the afore-mentioned neoplasms, Our clinical experience permitted the working out of indications for the application of various laser techniques (CO:2-Laser, Nd:YAG Laser- "non-touch", "In-touch") depending on the situs, The introduction of the sapphire tip made also possible the intraabdominat application of the laser for the palliative reduction of the tumor mass. We present the reliminsry results of the t r e a t m e n t and the advantages of this a l t e r n a t i v e surgical method. Laser-Forsehungsabteilung der Universitfits-Frauenklinik D-6650 Homburg/Saar

The present evaluation investigates the predictive value of the CA 125 plasma concentration in relation to the findings of the second lock !aparotomy~ data of 111 patients with primary epithelial ovarian carcinoma of stages II-IV (FIGO),who underwent restaging laparotomy,were evaluated.In 85 CaSeS the surgery was performed as diagnostic procedure,in 26 cases of persistent disease as therapeutical intervention.41 of the 111 patients were found to have residual tumour during operation macroscopicallywith ranging CA 125 levels between 5- 500 U/ml.In nearly 50 % of these cases CA 125 values above 65 U/ml were measured. In further 19 cases tumour was demonstrable by microscopical examination.0nly 1 of these 19 had an abnormal CA 125 titer.Of the remai ning 51 patients,who were microscopically diagnosed to be tumour-free,in all cases the the antigen concentration was below 65 U/ml, Regarding only the 85 patlents,who underwent diagnostic second look operation,3 cases had abnormal CA 125 values and microscopically evidence of tumour.In the other 82 patients, demonstrating normal antigen levels,13 (16%) had macroscopica!ly residual tumcur and 18 (22%) microscopically positive evidence of tumour.Summarizing these data the diagnostic second look operation was accompanied in 38~ by falsely negative marker concentration.The survival curves of the patients in relation to the findings during second look procedure and in relation to the marker values will be demonstrated. For authora:P,Schmidt-Rhode pep. of Obstet.&Gynecol.,Univ. Marburg,FRG

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2/P-GM 044

IMMUNOLO(}ICAL MONITORING I~PRIMARY BREAST CA~R]ER PATIENTS BY ANALYSIS OF BONE MARROW ASPIRATES G. Forell~ M. Untch, ~. Harbeck, W. Eiermann ..........................................................

THE INVOLVEMENT OF APPENDIX, PELVIC AND PARAAORTAL LYMPH NODES IN OPERABLE OVARIAN CANCER.

Recent studies have shown that tumor cells in bone marrow aspirates can be detected in about one-thlrd of primary breast cancer patients (Redding et al.~ 1984; Untch, Harbeck, Eiermmnn, 198g), In this study, the cellular immune reaction of bone marrow was examined, since this is one of the prime sites for metastasis in breast cancer, Bone marrow was aspirated from 20 patients at the time of primary therapy at six sites (2x sternum, 2x iliacal crest left and 2x right), At the same time, blood samples were taken for parallel examination, Three normal patients served as controls. The samples were separated over a Ficell-Hypaque gradient (d= 1.077), and the mononuelear concentrate was incubated with monoclon~l antibodies and analysed by flow cytometry (FACS Analyser). In all 20 breast cancer patients, in addition to a CD4/CD8 inversion in the bone marrow and peripheral blood, a markedly increased percentage of transferrin-receptor positive cells was found. In three of the 20 patien%s~ tumor cells were detected in the bone marrow (by immunocytechemical staining with anti-ERA and anti-Cytekeratin). In contrast to all the other patients, these three patients also displayed a significantly increased percentage of interleukin-2 posiglve cells. The presence of activated T-cells in the bone marrow might be due to an immune reaction against cancerous cells which is restricted to the marrow only. In view of our observations, further studies are needed to examine the question of tumor cell inactivation in the bone marrow based on immmunologlcal factors,

A.Storz, M.Geppert, and W.E. Simon 3I patients with ovarian malignancy underwent pelvic lymphadenectomy and sampfing biopsy of paraaortal lymph nodes

combined with total hysterectomy bilateral salpingo-oophorectomy~ omentectomy~ appendectomy and, if necessary, tumor debulking. Staging was performed according to the FIGO recommendations. N o involvement of lymph nodes or appendix was detectable in the 14 patients with stage IA-IIB disease. 9 of the 17 patients with stage HI disease were appendectomized. In 3 of these patients microscopic tumor involvement of appendix was detected. Pelvic lymph node inv6ivemenV was demonstrated in II of the 17 patients (65 %). Only patients with posi~iv pelvic lymph nodes had aortic lymph node involvement (g patients,

#? %).

With respect to histologic grade of the stage Iti malignancies only in the 2 grade I tumor patients lymph nodes were not involved. All tumors with lymph node involvement were serous papillary cystadenocarcinomas or undifferentiated carcinomas. N o positiv lymph nodes were detected in the # tumors histotogkalty classifiedas endometroid or mutinous. Based upon our observations w e suggest the relevance of pelvic, paraaortal lymphadenectomy, and appendectomy in stage Ill ovarian cancer. The effectiveness of lymphadenectomy in stage I or It ovarian cancer needs further evaluation, particularly in grade I tumors.

Universit~its-Frauenklinik, Schleichstral~e #, D 7400 Ttibingen

Department of Gynecology and Obstetrics~ Klinikum Grosshadern, LMU M~nchen.

2/P-GM043 TREATMENT OF ADENOCARCINOMA G.E. U m b a c h , D. B a c k e s h o f f , H.G. B e n d e r

2/P-GM 045 OF THE ENDOMETRIUM H.G. S c h n ~ r c h ,

W e r e t r o s p e c t i v e l y a n a l y z e d the c l i n i c a l o u t c o m e of i01 p a t i e n t s w i t h e n d o m e t r i a l c a r c i n o m a t r e a t e d at o u r i n s t i t u t i o n . D i s t r i b u t i o n a c c o r d i n g to F I G O - s t a g e w a s as f o l l o w i n g ( p a t i e n t n u m b e r s in p a r e n t h e s e s ) : I (65), II (20), Ill (8), IV (8). The o v e r a l l 5y e a r - s u r v i v a l w a s 69%. T h e e s t i m a t e d s u r v i v a l durations correlated with decreasing FIGOs t a g e and i n c r e a s i n g h i s t o l o g i c d i f f e r e n t i a tion. O p e r a t i v e p r o c e d u r e s w e r e p e r f o r m e d in 78 p a t i e n t s . T h i r t y - o n e of t h o s e 78 p a t i e n t s received additional intravaginal brachyt h e r a p y , w h i c h c o n s i s t e d of r a d i u m i n s e r t i o n s in 22 c a s e s a n d h i g h - d o s e r a t e a f t e r l o a d i n g t h e r a p y in 9 cases. S e v e n t e e n p a t i e n t s presenting high operative risks received b r a c h y t h e r a p y only. P r o g e s t i n s o n l y w e r e a d m i n i s t e r e d in 2 p a t i e n t s w h e r e a s 4 p a t i e n t s r e c e i v e d no a n t i t u m o r t r e a t m e n t . All o b s e r v e d 6 v a g i n a l r e c u r r e n c e s in o p e r a t e d p a t i e n t s were FIGO-stages I and had shown myometrial i n v a s i o n . F i v e of t h e s e 6 v a g i n a l r e c u r r e n c e s o c c u r e d in p a t i e n t s t h a t r e c e i v e d n e i t h e r i n t r a o p e r a t i v e p r o p h y l a x i s ( r i n s i n g the v a g i n a w i t h a l c o h o l u n d s u t u r i n g the c e r v i x ) n o r a d d i t i o n a l i n t r a v a g i n a l b r a c h y t h e r a p y . Surv i v a l in p a t i e n t s w i t h v a g i n a l r e c u r r e n c e s was s h o r t e r t h a n in p a t i e n t s w i t h o u t v a g i n a l recurrences. Intravaginal brachytherapy and p o s s i b l y i n t r a o p e r a t i v e p r o p h y l a x i s are e f f e c ~ tire m o d a l i t i e s in d e c r e a s i n g the i n c i d e n c e of v a g i n a l r e c u r r e n c e s in e n d o m e t r i a l c a n c e r . Universit~ts-Frauenklinik, 4000 D ~ s s e l d o r f

Moorenstrasse

5, D-

NEW ASPECTS FOR STAGING CARCINOMAOF CERVIX UTERI BY TRANSRECTAL ENDOSONOGRAPHICDIAGNOSTICS G. Th. Rutt, G. Bastert Up to now staging of cervix carcinoma is based on c l i n i c a l palpation in the f i r s t l i n e . The correct c l i n i c a l staging is of high importance for therapeutic management and result. In the meantime the c l i n i c a l staging can be o b j e c t i f i e d by transrectal ultrasound better than by other techniques, for example computertomography. By endosonography i t is possible to d i f f e r e n t i a t e between stage la and Ib, because cervical and endocervical located tumors can be recognized and measured. This technique also alows the d i f f e r e n t i a tion between stage Ib and l l b , by sonographic evaluation of the proximal part of parametrium. We are also able to stage l l b versus l l l b in most of the cases, by ultrasound diagnosis of the d i s t a l part of parametrium. Furthermore, now i t is possible to d i f f e r e n t i a t e between stage Ib, l l a and l l l a by detailed diagnosis of the vagina, to estimate the vaginal i n f i l t r a t i o n of tumor. Last not least by transrectal sonography i n f i l t r a t i o n s of bladder and rectum can be demonstrated f o r diagnosis of CC IV. Especially in this case in contrary to any other technique, we are a b l e now to detect early i n f i l t r a t i o n s of muscularis of bladder or rectum, which also leads :to the diagnosis of CC lV. For a l l these stages representative examples w i l l be demonstrated. Comparisons of transrectal endosonography to computertomography and, as f a r as a v a i l a b l e , histology w i l l follow. Universit~ts-Frauenklinik, D-6650 Homburg/Saar

$59

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BIOCHEMICAL CHARACTERIZATION OF THE MUCINE LIKE TUMOR

SIDEEFFECTS OF AGGRESSIVE CHEMOTHERAPY IN THE TREATMENT OF ADVANCED OVARIAN CANCER BY PAC/PEC REGIMEN

ASSOZIATED ANTIGEN TAG 12 M. Werner (a. G.), S. Kaul (a. G.), G. Bastert Monoclonal antibody (MAb) 12 H 12 defines a high molecul a r weight glycoprotein of 2000 kD termed TAG 12. The antigen is expressed in more than 90 % of breast carcinomas and 60 % of ovarian carcinomas. TAG 12 is secreted by a l l positive tumors. Evaluation of TAG 12 by competition EIA in sera of patients with breast and ovarian cancer showed similar s e n s i t i v i t y and s p e c i f i c i t y as CA 15-3. For production of second generation Ab and f u r t h e r characterization TAG 12 was p u r i f i e d from cytosol of T47D mammary carcinoma cells by a combination of FPLC with superose 6 g e l f i l t r a t i o n and 12 H 12 a f f i n i t y chromotography. Immunization of BALB/c mice with highly p u r i f i e d antigen yielded a series of second generation Ab including 7 A g. In binding assays of a f f i n i t y pure TAG 12 with Lentil Lectin, Con A, WGA, PNA and Anguilla, binding of 7 A 9 was blocked by WGA and PNA, whereas binding of 12 H 12 was not i n h i b i t e d , suggesting the involvment of terminal N-acetyl-D-neuraminic acid and/or N-acetyl-glucosamine residues in the antigenic s i t e of 7 A 9. Both, 12 H 12 and 7 A 9 a n t i g e n i c i t y was sensitive to neuraminidase, proteinase K,~C-chymotrypsin and trypsin but not hyaluronidase and chondroitinase ABC as analized by ELISA and Western b l o t t i n g . The results indicate that protein is d i r e c t l y part of the antibody binding sites and TAG 12 is a mucine-like glycoprotein. MAb 12 H 12 and 7 A 9 were used to develop a new sandwich ELISA for the serological analysis of TAG 12. Universit~ts-Frauenklinik, D-6650 Homburg/Soar

Golz, N., K i e k e n a p , R , Mast, H. Department of Obstetric and Gynecology St. Bernward-hospital, Hildesheim, FRG Since 1981 the advanced ovarian cancer is treated according to the PAt-combination at the St. Bernwardhospital (cisplatinum 50 mg/sqm, doxorubicin 50 mg/ sqm and cyclophosphamide 500 mg/sqm every 28 days). Last year doxorubiein was replaced by the less cardiotoxic 4-epirubicin, 470 courses of chemotherapy was adminestered in 64 patients. As sideeffeet in 40 women (57,8%) myelosuppression (anaemia 30,4%, leucopenia 23,]%, thrombopenia 4,3%) was diagnosed and in some cases a chemotherapy course was to displace. Two patients developed a left ventricular enlargement and one a pericardia] effusion. There of two was treated and in one case the doxorubicin was discontinued~ 4 patient showed ototoxicity. One time cisplatinum was discontinued. 3 women got a deep vein thrombosis of the leg, but chemotherapy was continued with oral anticoagulants. In these cases the routinely second-look-laparotomy was not accepted. 3 times neurotoxicity was diagnosed, there of 2 was reversible. The PAC/PEC chemotherapy showed a remission quota of 47,8%, diagnosed by second-look-laparotomy. In sumnary, according to the good remission quota of nearly 50% of aggressive chemotherapy with this regimen the most reversible side effects are to accept, but a very good control of the treated patients is necessary~

2/P-GM 047

2/P-GM 049

THERAPEUTIC E F F E C T O F 1-131 OC 125 M O N O C L O N A L A N T I B O D I E S ON A D I S S E M I N A T E D P E R I T O N E A L C A R C I N O S I S OF A H U M A N O V A R I A N C A R C I N O M A IN N U D E MICE

ETOPOSIDE IN CISPLATIN-REFRACTORYOVARIANCANCER

R.Senekowitsch, H . K r i e q e l , H.W.

:) Univ.-FrauenklinikG6ttingen ~) Univ.-FrauenklinikFreiburg ~) Dept. AnticancerRes. Bristol-Hyers,FRG

P.Schmid, Pabst

S. M 6 1 1 e n s t ~ d t ,

For radioimmunotherapy t u m o r u p t a k e of M A B S is o f t e n to low to a c h i e v e r a d i a t i o n a b s o r b e d d o s e s h i g h e n o u g h to d e s t r o y all t u m o r tissue. In the p r e s e n t s t u d y a t t e m p t s w e r e u n d e r t a k e n to i n c r e a s e the u p t a k e of 1-131 OC 125 M A b inJ e c t e d e i t h e r as i n t a c t M A b or as F ( a b ' ) 2 f r a g m e n t s on a d i s s e m i n a t e d h u m a n o v a r i a n c a r c i n o m a d e p e n d i n g on the r o u t e of a d m i n i s t r a t i o n (i.v.,i.p.). A f t e r i n j e c t i o n of 1 m i l l i o n of h u m a n o v a r i a n c a r c i n o m a cells 90% of the animals developed a peritoneal carcinosis with a s c i t e s in 20%. For b i o d i s t r i b u t i o n studies the a n i m a l s w e r e i n j e c t e d w i t h 1.85 M B q i n t a c t M A b or F ( a b ' ) 2 - f r a g m e n t s e i t h e r i.v. or i.p.. A s i g n i f i c a n t h i g h e r u p t a k e in t u m o r t i s s u e w a s f o u n d a f t e r i.p. a d m i n i s t r a t i o n in a n i m a l s w i t h o u t ascites. A f t e r a s c i t e s d e v e l o p m e n t the i.p. i n j e c t i o n r e s u l t e d in a d e c r e a s e of t u m o r uptake, b e c a u s e m o s t a c t i v i t y was b o u n d to t u m o r c e l l s in the ascites. A p e r i t o n e a l !arage before i.p.injection again increased a c t i v i t y u p t a k e b y the t u m o r tissue. F o r stud i e s on r a d i o i m m u n o t h e r a p y an a c t i v i t y of 34 M B q w a s t h e r f o r e i n j e c t e d b y the i.p.route. The a s c i t e s d e v e l o p m e n t as w e l l as the t u m o r m a s s e s w e r e f o u n d s i g n i f i c a n t e l y r e d u c e d for the t r e a t e d a n i m a l s c o m p a r e d to the controls. Nuklearmedizinische K l i n i k und P o l i k l i n i k tsar der Technischen Universit~t M~nchen, Ismaningerstra~e 22, 8000 M ~ n c h e n 80

r.d.

K~hnle, H~; Meerpohl, H.G.~; Achterrath,~; Phhl, jz; R6ben,SI; Alfug, S~; Pfleiderer,k2; Kuhn, W.I

Etoposide (E) is neither cross resistantwith Oisplatin (P) nor with Oyclo-phosphamide(c) in animaltumours. In 1981 we initiateda phase II study with Etoposide(E) in patientswith epithelial ovarianDancerrefractory to our standard regimen (PC)with Cisplatin (60-100mg/m2) and oyclophospha~ide(600-i000mg/m2). ~e started E uith 150 cg/m2 LV. d I-3 q 4 N and escalatedit up to 220 cg/mz d i-3 dependingon individualtoxicity.After 3 cycles most of the the patients changed to the oral form (280-320mg/mz d i-3). At the end of 1986 131 pat94 e~tered the study and 123 patients have been evaluatedfor toxicity and Iii roy response. Of 62 patients mith primary resistance12 had CR (19 %), I0 (16 %} PR, 12 (19 X} NOand 28 (40 X) PD. Of 49 patients relapsing after a CRwith PC7 (14 %} had a OR, 9 (18 %) a PR, 14 (29 X) NOand 19 (39 I) PK Therewas neither a strong correlationbetweenresponsetoi.linetherapyand response to E nor betceen responseto E and performancestatusor tumourvolume or grade. Toxicity (N~O):Almpecia grd 3 : 65 X, leucopeniagrd 3 + 4 (15 X) thrombopeniagrd 3 + 4:10 X, anemia grd ~ + 4:4 X ecesis grd h 20 %. Toxicity is manageblebecause the myelo toxicity is not cumulative. In conclusion,E has provenan effectiveagent in ovarian cancer. Updated results uill be presented.

$60 2/P-GM 050

2/P-GM 052

CARBOPLATIN IN ADVANCED BREAST CANCER H.-E. Wander, G.A. Nagel m

KIRSTEN-RAS ONCOGENE MUTATIONS ASSOCIATED WITH METASTATIC PROGRESSIONOF HUMAN BREASTCANCER. CF Rochlitz, GK Scott, EA Liu, R Herrmann, H Smith, CC Benz. Univemitv of California San Francisco: Freie Universitaet Berlin. Transforming oncogenes have been Identified in a variety of human tumors including breast carcinoma, and recently a role of the Ki-ras oncogene has been established in colonic carcinomas and edenocarcinoma of the tung. We studied three breast cancer effusion specimens (two pleural effusions and one escitic effusion) obtained during a six month interval from a patient with progressive disease. All specimens had similar marker chromosomes (monoclonal) but only the final specimen (#3) produced immortalized tumor cell tines in vitro (2/2 trials). Unlike specimens #1 and #2, however, effusion #3 and its derived cell lines were all found to contain a transforming gene detected by DNA transfection into NIH-3T3 ceils and tumorigenesis in nude mice. The transforming gene was identified and sequenced as the Ki-ras oncogene with a codon 12 (Gly----> Val) mutation. The presence or absence of this mutation in all the patient's specimens was verified using in vitro amplification by polymerase chain reaction (PCR) and probing with synthetic oligomera. The Ki-ras mutation was found oniy in effusion specimen #3 and the cell lines derived from it, suggesting that the mutation occurred at a late stage in the progression of the malignancy. This finding correlates with the patient's clinical course which rapidly progressed to death after pleural effusion #3 occurred. To test the hypothesis that Ki-ras activation occurs at a late stage in the malignant progression of breast cancer, we are using the PCR technique to detect Ki-ras mutations in primary and metastatic breast cancer samples. DNA sequences (110 bp) surrounding Ki-ras codons 12, 13, and 61 are amplified in vitro (xl06) and probed on slot-blots with 32p-labelled synthetic oligomers (20-mers) specific for the wildtype sequence and 20 possible non-conservative single base mutations. Primary tumor samples (45) are being compared with lymph node metastases (5), malignant pleural effusions (6), and established breast cancer cell lines (4). The results of these studies will be discussed at the meeting.

A p i l o t study was c a r r i e d out to evaluate the e f f i c a c y and s a f e t y o f c a r b o p l a t i n (JM 8), in progressive~breast cancer. Seven p a t i e n t s received e a r b o p l a t i n 400 mg/m" intravenously day 1 on an o u t p a t i e n t basis every three weeks. No a d d i t i o n a l hydration was applied. A t o t a l 19 courses were administered. Results courses s i t e s o f metastases pretreatment CR 3 soft tissue hormonal (HT) PR 1 soft tissue 5 s o f t tissue/bone HT NC 1 bone HT+idarubicin (7 month) 3 soft t./bone/pulm.-pleur.HT+idarubicin (Ix) 3 s o f t t./pulm, adjuv. CMF (12x) + HT +

VAC (4x) 3 bone HT Main side e f f e c t s : i n f e c t i o n (WHO 2): Ix alopecia (WHO I ) : Ix nausea/vomiting, exhaustion (marked > course I I , WHO I - 3 ) a l l pts. Platelets: course I II III day 0 7 14 21 28 35 42 63 mean value 257 228 120 139 190 92 122 III n 7 2 3 5 4 7 6 6 Conclusion Carboplatin is e f f e c t i v e in the treatment o f advanced breast cancer. Therapy is l i m i t e d by decrease of p l a t e l e t s and increased nausea/vomiting, loss o f a p p e t i t e and exhaustion. The schedule used seems to be p r a c t i c a b l e on an o u t p a t i e n t basis. Carboplatin merits f u r t h e r e v a l u a t i o n alone and in combination with other c y t o t o x i c agents in f i r s t and second l i n e therapy. H~m.-Onkol. Praxis, Nikolausberger Weg 36, D-3400 Goettingen Dep. of Med., Univ. Goettingen, D-3400 Goettingen

2/P-GM 051

2/P-GM 053

CARBOPLATIN (CBDCA) IN PATIENTS WITH ADVANCED OVARIAN CANCER: RESULTS OF TWO PHASE I I STUDIES H.G,MEERPOHL

RECOMBINANT HUMAN G R A N U L O C Y T E - M A C R O P H A G E COLONYSTIMULATING FACTOR (rhGM-CSF) IN PATIENTS WITH M Y E L O D Y S P L A S T I C SYNDROMES - A P H A S E - I / I I - T R I A L A. Ganser, J. Greher, B. V~ikers, F. Walther, D. Hoelzer

Carbeplatin (CBDCA)is c u r r e n t l y being proposed as a possible a l t e r n a t i v e drug t o c i s p l a t i n in the treatment o f advanced ovarian cancer. From 10/1984 - 6/1986 56 e l i g i b l e p a t i e n t s with advanced disease (stage I l l / I V ) have entered two d i f f e r e n t phase I I t r i a l s . The f o l l o wing questions were asked: Can c a r b e p l a t i n replace ~ i e p l a t i n in the established f r o n t l i n e combinationregimen CP ( t r i a l 1)? Is there any evidence f o r remaining a c t i v i t y o f c a r b o p l a t i n in p a t i e n t s r e f r a c t o r y or r e l a p s i n g from frenttine-chemotherapy ( t r i a l 2) ? In t r i a l 1 the regimen consisted o f 6 courses o f 200-400 mg/m2 c a r b o p l a t i n i v . d 1 in combination with 600 mg/m2 C i v . d 1, The cycles were repeated every 28 days. Of 32 pts e l i g i b l e and evaluabIe f o r t o x i c i t y 25 pts only were evaluable f o r response. A l l pts were p r e v i o u s l y untreated: 4 CR and 10 PR were seen, 6 pts had NC and 5 PD were observed. The CR/PR r a t e was 14/25 (56 %) Response was reassessed by SLO in 11/14 c l i n i c a l responders, Median time t o relapse: 15,6 months. Median time to s u r v i v a l : 19.2 months. In t r i a l 2 o f 24 pts entered the study 23 pts were analysed. S t a r t i n g dose o f carbsp l a t i n : 400 mg/m2 i , v . d, 1 (22 pts) and 200 mg/m2 i . v , d, 1 (1 p t ) , Previous therapy: chemotherapy without CDDP: 5, chemotherapy i n c l u d i n g CDDP: 18. C l i n i c a l response: 2 CR, 2 PR, 6 $0, 11 PD and 2 NED. CR/PR r a t e : 4/21 (19 %). The duration o f c l i n i c a l CR were 11 and 8 months. Median s u r v i v a l time: 194 days. Conclusions: Our data suggest t h a t 350/600 mg/m2 may be the optimal dose schedule o f CBDCA/C in p r e v i o u s l y untreated pts at the cost o f acceptable t o x i c i t y . CBDCA may also be s u i t a b l e in r e f r a c t o r y and r e l a p s i n g pts but there i s less remaining a c t i v i t y in CDDP p r e t r e a t e d p a t i e n t s . This suggests t h a t there i s nearly a complete crassr e s i s t a n c e between c a r b a p l a t i n and c i s p l a t i n in those heavily CDDP p r s t r e a t e d pts. Carboplatin in der Behandlung f e r t g e s c h r i t t e n e r O v a r i a l karzinome, Ergebnisse von zwei Phase t I - S t u d i e n .

In preclinical studies rhGM-CSF increases peripheral blood neutrophil and platelet counts in a dose dependent manner and can induce differentiation in leukemic cell lines. It therefore was the aim of this still on-going study to investiqate the toxicity of rhGM-CSF and its effect on h e m a t o p o i e s i s in patients with m y e l o d y s p l a s t i c syndromes, rhGM-CSF (Behringwerke/Immunex) was a d m i n i s t e r e d i.v. daily by continuous infusion on days I-7(14) and 22-28 in increasing dosages from 15-150 pg/m ~. Up to now 10 patients have been entered into the study: 3 with refractory anemia, 5 with refractory anemia and excess of blasts, and 2 with chronic m y e l o - m o n o c y t i c leukemia. An increase in leukocyte counts was observed in 9 out of the 10 patients being dosedependent and ranoing between 130% and 1800%. Major side effects were lower back pain after push injection but not at slow continuous infusion, fever in two, mild increase in the serum creatinine in two. Two patients w i t h CMML experienced an increase in neutrophil but also blast cell counts which reversed upon termination of rhGM-CSF infusion. Patients whose blast cell population is stimulated by treatment w i t h rhGM-CSF are now enrolled into a combined r h G M - C S F / l o w - d o s e ara-C trial. Abteilung fHr Himatologie, Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang GoetheUniversit~t, T h e o d o r - S t e r n - K a i 7, D-6000 Frankfurt 70

$61

2/P-GM 054

2/P-GM056

CELLS ~ITH ~ETI{OVIRUS VECTORS~ Pierre Laneuville~ Axel A, Fauser and John E. Dick. Retroviral vectorscontainingthe selectablebacterialgene for G418 resistance (neo} mere used to demonstrategene transfer into primaryhuman bone marrow pr0genit~rcells. In an attemptto obtainp0pulatiensof cellsmhere a high prep0rtimnof ceils~ere expressin8the hem @eriewe ~ade severel i~purtant modificationsto earlierprocedures. Normaldonor bone earr0~cells were infected with amphotropic replication defective neo virus by cocultivation with PA317-~2cells for ~4 hours. Infectionwas performed with and without growth factors supplied by supereatantsof the bladder cells carcinoma cell line5~37. Cellswere subsequently exposed to high concentrations of ~41B IS mg/ml) for 4~ hours in liquidculture tm select for 8418 resistantceils. Cellswere plated in semi-s01idmethyeellulomein the absence and presence ef increosingdnsesof SdlS to ~enerateday I~ CF~-BM ond BFU-E survival curves. The froctionof B418 resistantCF~-GMand BFU-E with G41S preselectinn increased 3-fold and approached IOOX, Addition of 56S7 conditioned medium had the effect of increasing the yield of GdlSR-CFU ~-3-fsld. Theseresults demonstratethat retrovirusvectorscan be successfully used to transferne~ genes at high efficiency into relatively undifferentiated progenitor cells in the humanblood-forming system. Division of Bemat~Iogy, Royal Victoria Hospital, McSill University, Montreal, Quebec and Divisionof Medical Benefits, SickChildren'sHospital, University of Tnrnnb~ Ontario,Canada.

2/P-GM055 HUMAN BONE MARROW STROMAL CELLS GROWTH OF HUMAN TUMOR CELLS E . - S . S t r o b e l , K.J~ B r o s s , H . H . terhalt~r, G.W. L~hr

T h e i n v e s t i g a t i o n o f o n c o g e n e e x p r e s s i o n at the level of individual cells requires the a v a i l a b i l i t y of m o n o c l o n a l a n t i b o d i e s d e v o i d of major cress-reactivities. Such antibodies are more likely to be induced by substantial f r a g m e n t s of the n a t i v e p r o t e i n r a t h e r t h a n by short peptides. In o r d e r to o b t a i n s u c h m a j o r portions of oncoprotein molecules for immunizations we expressed various oncogenefragments with 80-40 kd coding capacity as fusion proteins w i t h the N - t e r m i n a l 37 kd of the E . c o l i trpE polypeptide under control of the trp p r o m o t e r in a pATH expression system. The specificity of t h e s e fusion proteins was verified by Western blotting with rabbit antisera obtained by immunization with synthetic peptides corresponding to certain oneoprotein sequences. The fusion proteins were further purified in the a b s e n c e of d e t e r g e n t s by C 8 reversed-phase HPLC. Currently, we are using purified o n e o p r o t e i n f r a g m e n t s abl, fms, moo, myb, myc, H - r a s , K - r a s , N - r a s , s i s a n d src for t h e g e n e r a t i o n of monoclonal antibodies. F i v e m o n o c l o n a l a n t i b o d i e s w i t h s p e c i f i c i t y for four different oncoproteins are at present further characterized, and p r e l i m i n a r y r e s u l t s will b e p r e s e n t e d . Institut fur Pathologie, Klinikum Steglitz, Freie Universit~t Berlin, Hindenburgdamm 30, D1OOO Berlin A5

2/P-GM057 STIMULATE Fi~big,

B.

THE Win-

In o r d e r to d e v ~ l o p a c l o n o g ~ n i c assay for hum a n t u m o r c ~ l l g r o w t h , t u m o r c ~ l l s w~r~ = c u l t u r e d in t h e p r e s e n c ~ a n d a b s m n c ~ o f h u m a n b o n ~ m a r r o w s t r o m a l c ~ l l s as f ~ d ~ r c~lls~ Using a b i l a y ~ r soft: a g a r a s s a y , h u m a n t u m o r c ~ l l s passag~d in nud~ m i c = w e r = p l a t e d in t h ~ a g a r overlayer on an u n d e r l a y = r containing detached s i n g l e b o n e m ~ r r o w s t r o m a ~ c e l l s at c o n c e n t r a t i o n s o f l x 1 0 ~ u p to l x l O - / m l . H u m a n s t r o m a l cells stimulated the g r o w t h o f t u m o r c e l l s in a dose-dependent f a s h i o n w i t h a g r o w t h p e a k at a stromal cell density of 0.5-1x10~/ml. The maximal stimulation of t u m o r c e l l g r o w t h w a s 13-fold. Further, the c o - c u l t u r e of t u m o r a n d s t [ o m a l c e l l s (both at a c o n c e n t r a t i o n o f lx l O - / m l ) w i t h i n t h e s a m e a g a r l a y e r l e d to a marked stimulation of tumor cell growth, suggesting a short range stimulatory action of the stromal cells on the tumor cells. Tumor cell colonies were picked and the cells characterized for morphology by Pappenheim and for surface antigens by peroxidase-antiperoxidase staining. Monoclonal a n t i b o d i e s C E A 5/1, E M A , H E A ~ S a m 2, S a m 10 d e t e c t e d t u m o r a s s o c i ated antigens. To rule out hemopoietic origin of the colonies, momoclonal antibodies against leucocyte antigens BA-I~ BA-2, Leu-MI~ MY4 and H l e - 1 w e r e u s e d . T h i s a s s a y is an i m p r o v e m e n t of the t u m o r s t e m c e l l a s s a y p ~ r m i t t i n g futur~ analysis of human tumor cell biology. Medizinische Univ~rsit~tsklinik, S t r a B e 55, D /~00 F r ~ i b u r g , W e s t

BACTERIAL EXPRESSION OF ONCOGENES AND POLYPEPTIDE PURIFICATION FOR IMMUNOLOGICAL APPLICATIONS H. H e r b s t , M. H u m m e l ~ B. E h l e r s , H. B e n t l a g e , H. S t e i n .................................................

Hugstett~r Germany.

GENE

J.

AMPLIFICATION OF THE erbB-20NCOGENE MAMMARY CARCINOMA Fontaine, V. Klein, G. Bastert, N.

IN

Blin

B r e a s t t u m o r s , one of the m o s t c o m m o n t y p e s of human cancer, form a heterogeneous group when judged by histopathological parameters. The e v i d e n c e that c h a n g e s in the s t r u c t u r e a n d e x pression of particular transforming cellular gene sequences, referred to as o n c o g e n e s cont r i b u t e to the g e n e s i s of t u m o r s is o f t e n b a s e d on the o b s e r v a t i o n that these genes are r e a r r a n g e d or a m p l i f i e d . Alterations in the s t r u c t u r e a n d e x p r e s s i o n of the e r b B - 2 o n c o g e n e were investigated in 23 human mammary tumors. This sequence was form e r l y s h o w n to be of p r o g n o s t i c v a l u e s i n c e its a m p l i f i c a t i o n w a s n e g a t i v e l y c o r r e l a t e d to s u r v i v a l time. In 7 of the s a m p l e s (3@%), a m p l i f i c a t i o n by the f a c t o r 5-28 w a s d e t e c t e d , some samples displaying an a d d i t i o n a l E c o R I r e s t r i c t i o n f r a g m e n t at 3.4 kb. In s o m e t u m o r t i s s u e w i t h a m p l i f i e d e r b B - 2 s e q u e n c e s f r o m w h i c h intact R N A was o b t a i n e d e n h a n c e d e x p r e s s i o n was noted. Correlation of the m o l e c u l a r data to clinical parameters indicated a correlation of the e r b B - 2 o n c o g e n e a m p l i f i c a t i o n to t u m o r g r a d i n g a n d thus, p o o r p r o g n o s i s .

I n s t i t u t f~r H u m a n g e n e t i k Frauenklinik, Universit~t Homburg/Soar

und Universit~tsdes S a a r l a n d e s , D - 6 6 5

S 62

2/P-GM058

2/P-GM 060

EXPRESSION OF CELLULAR ONCOGENES IN HUMAN T E R A T O C A R C I N O M A CELL LINES H. Tesch I, R. F~rbaB I, J. Casper 2 and H.J. Schmoll 2

C y t o g ~ e t i c a l t e r a t i o n s of human carcinoma cell lines and t h e i r evolution during longterm propagation and a f t e r oncogene transfection R.T. Petrusevska, P. Boukamp, and N.E. Fusenig A l t e r a t i o n s in growth behaviour, d i f f e r e n t i a t i o n and karyotype of human keratinocytes at d i f f e r e n t stages of transformation were studied in culture and in vivo models. Immortal human keratinocytes have been obtained spontaneously (HaCaT), by transfection with o r i g i n defective DNA of SV40 and DNA of HPVI6 (human papilloma virus 16). These were compared with two cell lines from human skin squamous cell carcinomas. The primary cultures and early passages were characterized by a heteroploid chromosome complement and d i s t i n c t marker chromosomes, i n d i c a t i n g a monoclonal o r i g i n . The major type of struct u r a l chromosomal aberrations were isochromosomes and der i v a t i v e chromosomes, both established through centromer i c breakages. The nonrandom involvement of chromosome Nos. 3, 4, 7, 8, and 9 in the i n i t i a l chromosomal rearrangements indicates the importance of these chromosomes f o r immortalization of human keratinocytes. During in v i t r o propagation chromosome No. 1 displayed frequently breakages in the v i c i n i t y of the c o n s t i t u t i v e f r a g i l e s i tes or near the locations of the known c e l l u l a r protooncogenes. Upon transfection of the HaCaT cell l i n e with the c e l l u l a r Ha-ras (EJ) oncogene, subclones with i n d i v i dual r a s - i n t e g r a t i o n pattern emerged and seven of them grew progressively to form carcinomas. These clones showed selection of preexisting markers and additional 2 to three new marker chromosomes, while the non-malignant clones contained only preexisting marker chromosomes. These data strongly support the idea that s p e c i f i c chromosome changes leading to gene imbalance are causally related to early steps of transformation.

Cellular oncogenes are frequently a c t i v a t e d or d e r e g u l a t e d in human tumor cells. We have analysed by northern blot experiments the expression of 14 cellular o n c o g e n e s in cell lines established from human teratocarcinomas. Our results indicate that some oncogenes (ie. p53, cKi-ras2, o-Ha-rasl and c-rafl) are e x p r e s s e d in c o m p a r a b l e a m o u n t s in all t e r a t o m a lines and in a variety of other human tumor cell lines tested. Low e x p r e s s i o n of c-myc was detected in some but not all teratoma lines. Expression of the N-myc and the c-fos gene were detected in s i g n i f i c a n t a m o u n t s in all t e r a t o m a lines analysed, whereas these genes could n o t be d e t e c t e d in a v a r i e t y of o t h e r human tumor cells. By s o u t h e r n blot experiments t h e r e is no i n d i c a t i o n of a m p l i f i c a t i o n or rearrangments of the Nmyc or c-fos genes in the teratoma lines. Thus our data indicate that human teratoma cell l i n e s s h o w a d i s t i n c t expression p a t t e r n of c e l l u l a r o n c o g e n e s , which is not detected in a variety of other human tumors. I I. M e d i z i n i s c h e Klinik, Universit~t KSln, J. Stelzmann Str. 9, 5000 K~in 41 2 Medizinische Hochschule Hannover, Abteilung H~matologie, KonstantyGutschowstr. 3000 Hannover

Div. of D i f f e r e n t i a t i o n and Carcinogenesis in v i t r o , I n s t i t u t e of Biochemistry, German Cancer Research Center, D-6900 Heidelberg

2/P-GM 059

2/P-GM 061

E X P R E S S I O N OF CELLULAR ONCOGENES IN CELL LINES DERIVED FROM HUMAN LYMPHOMAS AND LEUCEMIAE M. J ~ c k e r , V. Diehl, M. Schaadt and H. Tesch

RAS RFLP DO NOT INFLUENCE THE TRANSCRIPTION OF THE GENE IN MELANOMA DERIVED HUMAN CELL LINES F. Csaikl, L. M~llauer, M. Vetterlein and U. Csaikl

We have analysed the expression of c e l l u l a r o n c o g e n e s in h u m a n c e l l l i n e s derlved from Burkitt s lymphoma, Hodgkzn s d i s e a s e and T- and myeloid leucemiae. In northern blot experiments expression of cmyc, N-ras and c-rafl genes were detected in comparable amounts in all lines tested. p53 s p e c i f i c R N A s were seen in lines of the B and T b u t n o t of t h e m y e l o i d lineage. High amounts of c-myb specific mRNA were observed in lines of the T and the myeloid lineages, whereas low expression occured in B c e l l lines. E x p r e s s i o n of c-met was detected in Raji, a Burkitt lymphoma l i n e and in L 4 2 8 , L428KSA and L540, which were isolated from patients with Hodgkin's disease. T r a n s c r i p t i o n of the c-fes gene was found in t h e m y e l o i d l i n e H L 6 0 a n d in U 9 3 7 ; aberrant transcripts of I kb were detected in t h e H o d g k i n ' s d e r i v e d lines L428 and CO. Thus our data demonstrate differential e x p r e s s i o n of certain cellular oncogenes in human lymphoma and leucemia cell lines. I. M e d i z i n i s c h e Klinik, U n i v e r s i t ~ t J. Stelzmann Str. 9, 5000 l<~in 41

Both restriction fragment length polymorphisms (RFLPs) and enhanced or altered transcription of oncogenes have been described to correlate with tumor development or progression. In melanomas the existence of various BamHI RFLPs for Ha-ras-1 are a matter of controverse discussion because no clear correlation with prognosis and hereditary predisposition was found. So far, only few investigations on transcription and associated RFLPs have been published. Southern analysis of BamHI cleaved DNA of nine melanoma derived cell lines revealed four different types of RFLPs (type1: 6.4kb; type2: 8.5kb, 7.0kb, 4.3kb; type3: 8.5kb, 6.Skb, 4.3kb; type4: 8.Skb, 4.3kb). Interestingly, all types differed from both placenta-DNA and DNA from other human cell lines studied bY us. The BamHI RFLPs are due to variable VTR regions outside of the Ha-ras-1 reading frame. The influence of these mutations on transcription is not completely clear. Therefore, we investigated Ha-ras-1 transcription using total RNA. In contradiction to the findings on DNA level the Northern analysis experiment revealed an equal transcript of approximately 4.6kb in all cell lines. This leads us to the conclusion that the different RFLPs do not influence transcription.

K~in, Institut fur Tumorbiologie/Krebsforschung der Universit[t Wien, Borschkeg.8a, A-1090 Wien

S 63 2/P-GM 062

2/P-GM 064

MYC O N C O G E N E S IN H U M A N N E U R O B L A S T O M A C E L L L I N E S L. M u l l a u e r , M. V e t t e r l e i n , U. C s a i k l and F. C s a i k l

MELANOMA-SPECIFIC REGULATION OF PROTO-ONCOGENEEXPRESSION IN XIPHOP~ORUS. 1 M.Schartl I , W.M~ueler , F.Raulf I A.Barnekow2, S.M.

In h u m a n n e u r o b l a s t o m a s a m p l i f i c a t i o n of the c-myc or N - m y c o n c o g e n e is o f t e n found. U n f o r t u n a t e l y , it is not c l e a r w h e t h e r g e n e a m p l i f i c a t i o n m a y l e a d to an e n h a n c e d e x p r e s s i o n of a p a r t i c u l a r g e n e a n d / o r to an a l t e r e d g e n e p r o d u c t . A d d i t i o n a l l y , the b i o l o g i c a l c o n s e q u e n c e is not w e l l u n d e r s t o o d . G e n e r a l l y it has b e e n a c c e p t e d t h a t at least the i n c r e a s e of the N - m y c c o p y n u m b e r can serve as a r e l i a b l e p r o g n o s t i c factor. T h e r e f o r e , we e x a m i n e d the o n c o g e n e s c - m y c a n d N - m y c in two n e u r o b l a s t o m a d e r i v e d h u m a n cell lines (NDHCL) at b o t h D N A and R N A levels. N o r t h e r n b l o t a n a l y s i s u s i n g total R N A r e v e a l e d a 5.5kb and 1 . 9 k b t r a n s c r i p t for N-myc, w h i l e t r a n s c r i p t i o n of c - m y c was u n d e r the l e v e l of d e t e c t i o n . S o u t h e r n a n a l y s i s of E c o R I - d i g e s t e d D N A r e v e a l e d a 1 3 . 0 k b f r a g m e n t for c - m y c in b o t h cell l i n e s s t u d i e d . In c o m p a r i s o n to p l a c e n t a D N A a w e a k a m p l i f i c a t i o n of c - m y c in o n e N D H C L could be d e t e c t e d . In S o u t h e r n a n a l y s i s of the N - m y c locus no a m p l i f i c a t i o n w a s found. B e s i d e the 2 . 0 k b f r a g m e n t w h i c h a l s o o c c u r s in the p l a c e n t a D N A an a d d i t i o n a l 1.5kb f r a g m e n t was p r e s e n t in o n e N D H C L . T h e s e r e s u l t s are i n t e r e s t i n g in s e v e r a l r e s p e c t s : F i r s t l y , b e c a u s e a m p l i f i c a t i o n of c - m y c d o e s n o t l e a d to o v e r e x p r e s s i o n in NDHCL. Secondly, because the mutated N-myc gene does not lead to an a b b e r a n t t r a n s c r i p t .

In ~ h o r u s the causative, primary c e l l u l a r oncogene f o r melanoma formation has been assigned by c l a s s i c a l genetics to a chromosomal locus (designated Tu). A c t i vation of Tu was proposed to be the r e s u l t of t--F~e e l i m i nation o f T ~ - s p e c i f i c r e g u l a t o r y genes or anti-oncogenes which norma-l-ly suppress the transforming f u n c t i o n in the non-tumorous s t a t e . In order to understand the molecular basis of t h i s process, we have analyzed how proto-oncogenes (homologous to the transforming genes of c e r t a i n r e t r o - v i r u s e s ) might be f u n c t i o n a l l y involved in melanoma formation in Xiphophorus. We could show t h a t in the melanomas several proto-oncogenes are expressed to higher l e v e l s than in any normal t i s s u e . For c-src our data i n dicate t h a t t h i s gene in non-tumorous or----gans exerts a f u n c t i o n r e s t r i c t e d to the t e r m i n a l l y d i f f e r e n t i a t e d s t a t e of c e l l s , e.g. b i p o l a r neurons, while in melanoma c e l l s i t seems to play a r o l e during c e l l p r o l i f e r a t i o n . Studies on the c-src encoded p r o t e i n t y r o s i n e kinase were performed to invesTtTgate whether an a l t e r e d gene product i s expressed in the melanoma. Using a c e l l l i n e derived from normal embryos and a melanoma c e l l l i n e we found t h a t c e r t a i n proto-oncogenes are subjected to a d i f f e r e n t r e g u l a t i o n in normal and tumorous c e l l s . As none o f the h i g h l y expressed proto-oncogenes was found to be located at or in the v i c i n i t y of the Tu-locus, a coordinated der e g u l a t i o n of several oncogen~s is suggested to be i n volved in the m u l t i - s t e p process of melanoma formation. In our attempts to molecularly c h a r a c t e r i z e the Tu-locus and t o understand i t s i n f l u e n c e on p r o t o - o n c o ~ n e expression we have i d e n t i f i e d a RFLP located less than 0.5 centimorgan to __Tu, thus allowing the a p p l i c a t i o n o f reverse genetics s t r a t e g i e s f o r cloning of the gene. I : Gene Center, M a x - P l a n c k - l n s t i t u t e of Biochemistry, M a r t i n s r i e d b. MUnchen 2: Inst.Human.Virology, Univ. o f Giessen, Fed. Rep. Germany.

I n s t i t u t fur T u m o r b i o l o g i e / K r e b s f o r s c h u n g der Universit~t Wien, Borschkeg.8a, A-I090 Wien

2/P-GM 063

2/P-GM 065

E F F E C T S OF E G F O N THE G R O W T H P A T T E R N OF OVARIAN, ENDOMETRIAL AND CERVICAL CARCINOMAS T. Bauknecht, J. Janz, M.Runge, A. Pfleiderer

SRC-I, A FUNCTIONAL HUMAN MONOCLONAL ANTIBODY AGAINST AUTOLOGOUS STOMACH CARCINOMA CELLS R.O'Connor, J. Mfiller, T. Kirchner, H.K. Mfiller-Hermelink and H. P. Vollmers* Inst. f. Pathologie Universitgt WHrzburg Josef-Schneider Str.2 8700 Wfirzburg FRG

Studies on the expression of epidermal growth factor receptors (EGF-R) in cervical, endometrial and ovarian carcinomas have shown, that s q u a m o u s carcinomas are in 100% a n d adenocarcinomas are in 30-50% E G F - R positive. The discovery of EGF like factors (EGF-F) in these tumors contribute the E G F system as one important growth promoting p a t h w a y in epithelial tumors. In this study we analyzed the colony formation of permanent cell ~,ines a n d tissue specimens of cervical, endometrial and ovarian carcinomas under the influence of increasing concentrations of EGF (3-100 ng/ml). Furthermore, Furthermore, we estimated the n u m b e r of E G F - R by a two point receptor assay. With respect to the n u m b e r of E G F - R binding s i t e s we d e t e c t e d EGF i n d u c e d g r o w t h s t i m u l a t i o n and inhibiLion at these tumor types. Tumors with a h i g h n u m b e r of b i n d i n g s i t e s ( > 30 f m o l / m g ) w e r e inhibited in c o l o n y f o r m a t i o n , w h e r e a s a r e d u c e d n u m b e r of E G F - R c o i n c i d e w i t h g r o w t h s t i m u l a t i o n b y EGF. I n c o n t r a r y , EGF-R- ovarian and endometrial carcinomas d i d n o t r e s p o n d to t h e EGF s t i m u lus. These results chemonitrate, t h a t EGF s e n s i tive and unsensitive tumors can be discriminat e d , w h e r e a s EGF e x e r s t s d i v e r g e n t effects on t h e EGF s e n s i t i v e t u m o r s .

Tumor growth and metastasis involve a series of specific cellular processes such as independent proliferation, migration, adhesion and infiltration of tumor cells. In animal experimental systems using functionally active monoclonal antibodies a variety of surface receptors have been identified, which are involved in these processes We describe here that cancer patients with stomach carcinomas produce antibodies which block adhesion and movement of the autologous tumor cells. The human monoclonal antibody SRC-I, an IgM, was isolated by fusion of patient's spleen and lymph node cells with the heteromyeloma cell line SPMO-4 9 In functional assays on long-term cultures of tumor cells from patients, and in immunoperoxidase bindings on cryostat sections of frozen tissues, we found that SRC-I reacted with signet-ring cell carcinomas of the stomach and identified a protein with a molecular weight of 50.000 daltons. The antibody did not react with either normal tissue or with other tumors. These results provide the first evidence of tumor-specific structures in humans and suggest their possible involvement in the cellular mechanisms of cancer cells. They also demonstrate the existence of a humoral response resulting in functionally active antibodies against these structures.

$64 2/P.GM 066

2/P-GM 068

LECTINS ZN HUMAN HE~ATOPOIETZC CELL LINES H.-J. Gabius, K.P. Hellmann, C. Bokemeyer, M. Andreeff

EFFECTS OF HORMONES ON GROWTH OF RECTAL CARCINOMA CELLS IN MONOLAYER CELL CULTURE B. Mentges M. von BHlow,B. Dittgen

Human hematopoietic cell lines offer an excellent model of the sk~ldy of the expression of lectins with respect to cell lineage and modulation by differentiation. Quantitative flow cytofluorometry demonstrated differential expression of lectins for the B lyr~phoblast line Daudi, the T cell lymphoblastic leukemia line PI2, the erythroleukemic line K562 and the premyelocytic line EL60 with and without DMSO-induced differentiation. Profile differences were substantiated by biochemical analyses with affinity chromatography and underscored potential to contribute to understanding aspects of biological behavior of hematopoietic cells and related malignancies via participation of sugar-leetin interactions. Max-Planck-Institut for experimentelle Medizin, Abt. Chemic, Hermann-Rein-StraBe 3, D-3400 G~ttingen

Colorectal cancer in still on the increase and ranks second behind lung cancer in industrialized nations.The aim of this study was to observe growth of rectal carcinoma cell cultures under influence of several hormones to study tumor biology and possibly derive therapy modalities for incurable cases. Sterile tumor samples were mechanically and enzymatically disaggregsted and cell cultures established.After 18 passages six different hormones were added in five to eight concentrations each:epidermal growth factor (EGF),cholecystokinin (CCK),dihydrotestosteron (DHT),secretin, gastrin,estradiol.Four cultures with different medium additives without hormones acted as controls.Cultures were incubated at 37,5~ in 5% C02.Cell count was performed after seven days. Compared to the control with the same medium additives cell proliferation was stimulated by EGF,CCK,DHT and gastrin,whereas secretin had an inhibitory effect.The strongest cell proliferation was caused by DHT and gastrin. Estradiol seemed to have no effect. We concluded,that EGF,gastrointestinal and sexual hormones exert an influence on growth of rectal carcinoma cell lines.Further investigations with tumors of different grades,different hormones and their inhibitors seem indicated to study this phenomenon. Klinik fHr Allgemein- und Abdominalchirurgie der Universit~tsklinik Mainz,65 Mainz,Langenbeckstr.l

2/P-GM067

2/P-GM 069

P R E O P E R A T I V E IMMUNOTHERAPY USING SYSTEMIC CORYN E B A C T E R I U M PARVUM IN PATIENTS WITH COLORECTAL CANCER. A PROSPECTIVE RANDOMIZED TRIAL R__u.Grundmann , K. Peters , J. Kluger, G. pul~erer.

THE D I A G N O S T I C S I G N I F I C A N C E OF F R E Q U E N C Y AND LOC A L I S A T I O N OF NUCLEOLI IN CARCINOMAS AND A T Y P I C A L H Y P E R P L A S I A OF THE PROSTATE B. Helpap ~n h i s t o l o g i c a l l y and c y t o l o g i c a l l y a n a l y s e d tissue specimens of the prostate the frequency and localisation of nucleoli in carcinomas and typical as well as atypical hyperplasia of the prostate were studied. With increased degree of m a l i g n a n c y the number of solitar and multiple nucleoli per nucleus increase. The nucleoli change their localisation from the centre to the p e r i p h e r y of the nucleus. There are only few nucleoli in typical and m i l d atypical hyperplasia of the prostate. The nucleoli are exclusively c e n t r i c a l l y located. Intermediate localisation may be found in moderate atypical hyperplasia. The nucleoli significantly increase in m a r k e d atypical h y p e r p l a s i a and b o r d e r l i n e cases w i t h changing the localisation to the periphery. The analysis on frequency and localisation of nucleoli is a simple resource in histologically and c y t o l o g i c a l l y differential diagnosis of carcinomas and atypical hyperplasia of the prostate.

The effect of p r e o p e r a t i v e nonspecific immunetherapy using i.v. C o r y n e b a c t e r i u m p a r v u m (C.p.) on p o s t o p e r a t i v e c o m p l i c a t i o n and survival rates should be investigated in patients with oolorectal resection. Methods: 100 patients who underwent tumor resection for primary a d e n o c a r c i n o m a of the colon and rectum entered a p r o s p e c t i v e l y randomized study. ~h~K~Y_~Ke~_i~Z~!i: These patients r e c e i v e d i.v. 10mg C.p. in 100ml 0.9% NaC1 within 30 min., not later than 3 days before operation. Patients of the s /~Z!21 were not treated at all. Results: I. comPl!~9~!9~_Xg~2e: therapy group (control group): wound infection 0% (10%), p n e u m o n i a 2% (4%), reoperations 0% (8%), mortality rate 0% (6%). 2. ~2aHz!~[9_9~[Y!Y~!: The mean observation p e r i o d was 21 months. Patients of the therapy and control group did not differ significantly as regards the survival rates (72.5% and 71.7% resp.) and the local recurrences (15.7% and 15.2%). 3: ~_n~_un2!9~ic_~ea~ti2ns: The number of peripheral lymphocytes decreased significantly after C.p. infusion. Simultaneously a decline of the delayed type of h y p e r s e n s i t i v i t y reaction was observed, even 10 days after operation. Conclusions: Preoperative unspecific immunotherapy with C.p. reduces significantly the septic complication rates in patients with colorectal resections. The immunotherapy, however, did not influence the patients' survival and recurrence rates. C h i r u r g i s c h e U n i v e r s i t [ t s k l i n i k K@ln-Lindenthal, Joseph-Stelzmann-Str. 9, D-5000 K~in 41

Institute of Pathology, FRG

PO Box 720, 77o0 Singen

S 65

2/P-GM 070

2/P-GM072

RESULTS OF AN IMMUNOHISTOCHEMICAL STUDY INDICATE THAT THE PRESERVATION OF OVARIAN FUNCTION IS JUSTIFIED IN CERVICAL SQUAMOUSNEOPLASIA D. Mosny, J. Herholz, W. Degen, H. SchnOrch, H.G. Bender

INVESTIGATIONS ON THE EGF-STIMULATION OF HUMAN TUMOR CELL LINES J. Czech, G. D i c k n e i t e , K. B o s s l e t p H.P. K r a e m e r , H.H. S e d l a c e k

Squamous c e l l s of the vagina and cervix u t e r i are induced in growth by s t e r o i d hormones during the menstrual cycle. However, carcinoma of the cervix can not be influenced by any hormon therapy. So f a r , 28 d i f f e r e n t cervix specimens ( d i f f e r e n t days of the menstrual cycle in healthy women, dysplastic lesions and carcinomas of the cervix) were tested f o r estrogen (ER) and progesteron (PR) receptor protein content using the ER immunocytochemicat assay (ER-ICA, Abbott) and the PR - 1808 antibody (Dianova). The ER content of the squamous c e l l s depends to the menstrual cycle: i n the early proliferative phase all layers are negative. In the mid proliferative phase basal layers get positive and in the late proliferative and entire secretivy phase positive cells can be found in all layers. Dysplastic lesions of the uterine cervix show a week reaction of ER-staining only in mild forms, severe dysplastic forms and carcinomas were ell negative~ In no squamous cell tissue any positive PR reaction could be found, Stroma cells of the uterine cervix showed no consistent ER and PR contents in relation to the changes in the squamous epithelium. Conclusions: different ER can be found did not show staining,

In squamous epithelium of the cervix contents depending from the menstrual cycle , Severe dysplastic lesions and carcinomas any reaction in the ER immunocytochemical

C u r r e n t l y the p o s s i b l e a u t o c r i n e s t i m u l a t i o n of h u m a n t u m o r g r o w t h t h r o u g h the s e c r e t i o n of T G F ~ / E G F - l i k e growth factors is in d i s c u s s i o n . T h e r e f o r e we h a v e t e s t e d the influe n c e o s EGF on the g r o w t h of 35 e s t a b l i s h e d h u m a n t u m o r cell lines. T h e s e cell lines w e r e derived from multiple kinds of t u m o r s and i n v e s t i g a t e d in m o n o l a y e r in m e d i u m w i t h non or low s e r u m c o n t e n t . 24 cell lines s h o w e d a positive growth response, especially 5/5 pancreatic carcinomas, 4/5 breast carcinomas and 2/3 n o n - s m a l l c e l l lung c a r c i n o m a s . Some of t h e s e p o s i t i v e cell lines and in a d d i t i o n cells from human xenografted tumors from nude mice were f u r t h e r i n v e s t i g a t e d in the s o f t agar c l o n i n g assay In the presence o f 10% FCS and ~EGF. A s i m i l a r or even b e t t e r growth stimulation was s e e n . C o l o n y f o r m a t i o n o f t h e lung c a r c i n o m a c e l l l i n e A549 was s t i m u l a t e d 4 - f o l d by EGF, and for f u r t h e r e v a l u a t i o n of the autocrine mechanism the conditioned m e d i u m of A 5 4 9 w a s i n v e s t i g a t e d . It c o n t a i n e d an a c t i v i t y w h i c h c o m p e t e s w i t h EGF for the E G F - r e c e p t o r and is p o s s i b l y T G F ~ .

Dr. J. Czech, Research Laboratories B e h r i n g w e r k e AG, 3550 M a r b u r g , FRO.

Universit~tsfrauenklinik DOsseldorf, MeorenstraBe 5 D 4000 OOsseldorf 1

2/P-GM071 GENERATION OF I N T E R N A L IMAGE ANTI MABs K. B o s s l e t , J. F r i e s e n , H.P. H a r t h u s

2/P-GM 073 PARATOPE

TUMOR

GROWTH INHIBITING

ACTIVITY

FROM

HUMAN MALIGNANT MELANOMA

The m u r i n e m o n o c l o n a t a n t i b o d y (NAb) BW 494, b i n d i n g t o a c a r b o h y d r a t e e p l t o p e on a pancreatic c a r c i n o m a a s s o c i a t e d m u c i n , was used to generate syngeneic anti-idiotypic MAbs. C o u p l i n g of the M A b ' s F ( a b ) f r a g m e n t to KLH and immunization with this conjugate, resulted in h u n d r e d s of a n t f - i d l o t y p i c MAbs. Out os t h e s e NAbs, 6 a n t i - p a r a t o p e N A b s w h i c h are a b l e to r e p l a c e the a n t i g e n in i m m u n o b i n d i n g assays, were selected. Coupllng of F(ab) f r a g m e n t s d e r i v e d f r o m t h e a n t i - p a r a t o p e NAbs t o KLN, immunization of x e n o g e n e i c animals and s c r e e n i n g f o r a n t i b o d i e s having a specificity identical t o t h a t o f MAb BW 494, w i l l reveal internal image anti-paratope NAbs r e p l a c i n g t h e e p i t o p e d e t e c t e d by NAb BW 494 on t h e p a n c r e a t i c c a r c i n o m a a s s o c i a t e d m u c i n . F(ab) fragments of internal image a n t i - p a r e t o p e NAbs a r e b e i n g d i s c u s s e d as an a n t i paratopic v a c c i n e t o i n d u c e tumor s e l e c t i v e human a n t i p a n c r e a t i c c a r c i n o m a a n t i b o d i e s in the p a t i e n t . Dr. K. Bossier, Research Laboratories B e h r i n g w e r k e AG, D-3550 M a r b u r g , FRG.

AUTOCRINE

of

U.Bogdahn,M.Gerlach,M.Hahn,C.Behl,F.M~ller Departm. of Neurology, University of W6rzburg, FRO. Autocrine secreted tumor cell growth inhibiting activities were isolated from supernatants of a malignant melanoma cell line HTZ 19-dN, established from a CMS-melanoma-metastasis. NTZ 19-dM was characterized by tyro- and immunocytochemistry and karyotyping; cells could be propagated in defined serum-free tissue culture medium for up to 8 months. Supernatants were ultrafiltrated, dialysed, lyophilized, and purified 5y Bio Gel PIO gelpermeation chromatography, leading to 3 active fraction pools MIAI (Melanoma inhibiting activity (approx. 2 kDa), MIAII (approx. 11.5 to 17 kDa) and MIAI~I (proteins at the cut-off of Bio~Gel P i0) inhibiting growth of HTZ 19-dM cells with IC~ovalues of 0.79 pg/ml (MIAI), 0.13 pg/ml (MIAmi), and 16.7 pg/ml (MIAmi,). MIA,I could be further purified to homogeneity by reverse phase high pressure liquid chromatography; the main activity displayed an I C ~ of 0.33 ~g/ml. On NaDodSO4Polyacrylamide-gel-elecfrophoresis 1 major band (approx. 8 kDa) was identified. Macromolecular synthesis was inhibited in HTZ 19-dM cells by > 99.5%, tumor stem cell colony formation was reduced by 99.89 % (at 10.6 inhibitory units). The inhibitory effect of MIAII was irreversible and non-cytotexic. MIAmi was heat stabile (3 mln at IOOoC) and trypsin-labile. The effect of MIAmi on allogenic neuroectodermal tumors was also investigated: p~oliferation of 2/3 malignant melanomas and 2/4~gliohlastomas was inhibited up to 85.2 %; proliferation of a neuroblastoma cell line could be inhibited to 33.8%, ~hereas normal fibroblasts and low grade gliomas Were not influenced in their proliferation. Neurolog. Univ.-Ktinik u. Potiklinik im Kopfktinikum WQrzburg

of

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2/P-GM 074

2/P-GM 076

ADJUVANT IMMUNETHERAPY WITH BCG-VACCINE IN PATIENTS WITH COLORECTAL CARCINOMA--A CONTROLLED RANDOMIZED TRIAL-PRELIMINARY REPORT P. Prohm, V. Seewald, E. Hoffmann

IN VITRO INDUCPI(ZN OF T ~ R S P E C I F I C T-SUPPRESSOR(Ts) CELLS H.-D. Haubeck~ -!~ M i n k ~ and E. K~isch .......................

A prospective randomized trial was carried out to investigate the effectiveness of adjuvant immunostimulation in patients with colorectal carcinoma. 60 patients entered the study, 31 patients underwent adjuvant immunotherapy, 29 patients served as a c o n t r o l l g r o u p with surgical treatment only. All M-stages (UICC) were excluded. The Copenhagen stock 1331 was applied and the patients were, following operative procedure, to receive intradermal BCG using an increased dosage of 250 000 to 750 000 units for each application. This prodedure was repeated for 12 weeks, then it was changed to a 2-weekly application for 6 times. Cellular and humoral immune parameters of immune response were measured before and 2 months after surgery. All parameters within the BCG-group showed an increase postoperatively and the cell-mediated immune-response could be clearly stimulated. Survival dates were evaluated of 59 patients (98,3~) after a p o s t o p e r a t i v e period of at least 2 years. All results were interpolated according to the method of Kaplan and Meier and the resulting curves were analyzed for significance after Mantel and Haentzel. All results showed no significant difference after 2 years, final results will be expected at the end of the study.

We have shown previously that t~m~orspecific Ts cells were induced in vivo Ln BALB/c mice by the syngeneic pla~Tac?~<~a(PC) ADJ-PC-5 at very. early stages of tumorige.nesis(1). These Ts cells which s'appress a strong primary Ln vitro cytotoxic t ceil respor~e have been characterized in de#_ail. There is evidence that Ts cell inducing antigens(Ts-Ag) on ADJ-PC-5 PC cells are expressed to scme ext~t on normal BALB/c spleen cells and are therefore "self" antigens ratchet than tu~/orspecific neoa/ttiger~s.(2).To characterize Ts-Ag in more detail we have developed an in vitro system for the Jm~duction of t~z~orspecific Ts cells. Ts cell function would be masked in the in vitro Ts assay in the presence of activated cytotoxic :T cells(CTL) which are no= susceptible to suppression. Activation of CTL is prevented by fixation of ADJ-PC-5 stimulator cells with glutaraldehyd. In contrast s[~cific Ts cells were activated by this approach which suppress a primary mixed lymphccyte-t~m~3rcc&t'are(MLTC) of BALB/c spleen cells against ADJ-PC-5 but not agalnst the syngeneic control tumors DT~MC (lymphoma) and METH A(fibrosarccma). Even in lectin-kill-assays these Ts cells have no cytolytic or NK-like activity, excluding2+_ a veto-~ffect. +The ~h_enoty~ of these Ts cells was Thy I Lyt 2.2 , L3T4 ,I-A~-" I-E~'" as evidenced by treat~ne.nt with r mAb and ccalole/nent. I. Ln~unology (1982) 47, 503-509 2. Eur. J. Ifmm/nol. (~986), 16, 659-664 Department of ~ o l c g y , University of Miinster,Dcmagkstr.3 D-4400 Miinster (FRG) + present address: D e ~ n t of clinical chemisr_ry and pathobiochemist~r,University of Aaclne.n, Pauwelstr., D-5100 Aachen (FAG)

Chirurgische Klinik Krankenhaus St. Joseph, Bergstr. 6-12, 5600 Wuppertal I

2IP-GM 075

2/P-GM 077

DECREASE OF SUPPRESSOR-T-CELLS (Ts) IN A PATIENT WITH

REACTIVITY OF THE MONOCLONAL ANTIBODY DF 3 WITH CARCINOMATOUS AND BENIGN FEMALE BREAST LESIONS. G. Ronay, W. J~ger, A. Bieber, A.H. Tulusan

MALIGNANT

MELANOMA AFTER LOW DOSE CYCLOPHOSPHAMIDE

(LDCY). C.

Lersch,

Previous

Rewes, U. Fink, H.Dancygier, M. Classen

B.

studies

tumor-beeping

have

shown that

LDCY reduces Ts in

mice and thereby stops tumor progression.

Encouraging r e s u l t s on immunostimulating e f f e c t s of LDCY in men were recently reported (P.O. Livingston, Jr B i o l . Response

Modifiers

LDCY (300 mg/kg} from

a metastosizin9

old

man had

interferon patient a

6:392,

to a p a t i e n t s u f f e r i n g

malignant melanoma. The 43 years

already

therapy.

undergone

surgical,

BCG and

Since the tumor progressed and the

i n s i s t e d on f u r t h e r therapy LDCY was given once

week f o r

cells

1987). In the present study

was given i . v .

3 weeks. Subpopulations of immunocompetent

were consequently monitored. A f t e r LDCY CD8-posi-

rive

Ts c e l l s decreased from 364/p[ to 52/pl w i t h i n

day.

The

effect support

t

CD4/CD8-ratio increased from 0.6 to 2.1. This

was

repeatedly

the

observed.

experimental

data

Our that

results further LDCY therapy may

r e s u l t in immunostimulotion and be thereby of b e n e f i t to the p a t i e n t . II.

Medizinische

Klinikum

r.d.

K l i n i k und P o l i k l l n i k

deP TU MOnchen,

[saP, Ismoninger Str,22,

8000 MOnehen 80

The monoctonal antibody (mAB) DF 3 (donated by ID-CIS Dreietch, FRG) with antibody | 15 D8 part of the marker system CA 15-3 was used for the purpose of immunhistochemical dia,qnostic. The aim of the study was to investigate the reactivity of the mAB on carcinomatous tissue, corresponding metastases as welt as benign tumors. Avldin-Biotln detection revealed, that 86 % o f the invosive carcinomas (n=100) carried the specific antigen although there was a marked heterogenity among the carcinomatous cells in respect of the number of positive entities and intensity of starning. In most cases there was a diffuse cytoplasmic reaction except few examples of apical membrane staining. Lobular carcinomas didn't shaw any staining or were faintly dyed. No correlation was found pertaining to the following parameters: tumor size end localisation, degree of malignancy, lymph node metastased and receptors. CA 15-3 serum levels didn't show any significant relationship to the detected bound mAB. The metastases staining pattern resembled that of the primary tumors (n=13) in all cases. AI benign tumors (n=12) showed a homogeneous diffuse cytoplasmic staining of the epithelial glands. The obtained results suggest, that mAB OF 3 cannot be used for differentiation of benign and malignant breast lesions. Farthermore albeit the bulk of tumors possessed the ability of expression of the corresponding antigen only o small number secreted the antigen which was consecutively followed by increased CA 15-3 marker levels.

$67

2/P-GM 078

2/P-GM 080

EXPRESSION OF HLA CLASS I AND I I ANTIGENS IN COLORECTAL CARCINOMA - CORRELATION WITH SURVIVAL F. Momburg 1 , p. S c h l a q 2 . a n d P. M611er 1 Colorectal carcinoma primaries of an unselected group of 159 patients were examined immunohistologically for the expression of HHC class I antigens with monoclonal a n t i body WB/32 directed a g a i n s t a n o n - p o l y m o r p h i c d e t e r m i n a n t o f HLA-A,B,C heavy c h a i n . 69 Z o f t h e tumors were found to express HLA-A,B,C antigens in normal q u a n t i t i e s , 21 X showed a substantial reduction in expression, while 10 Z lacked these antigens e i t h e r completely or incompletely. The loss of HLA-A,B,C was inversely correlated with the degree of d i f f e r e n t i a t i o n . Tumors with d i s t a n t metastatic spread at the time of operation tended to be oormal with respect to HLA-A,B,C expression. Within the c u r a t i v e l y resected group (126 p a t i e n t s ) , p o o r d i f f e r e n t i a t i o n and mucus production were risk factors for survival as could be shown by life table analysis after a maximum f0110w-up of 39 months, In contrast, the mode of HLA-A,B,C expression of the primary tumor did not influence s u r v i v a l

C Y T O L O G Y OF H I V - P O S I T I V E P A T I E N T S AND GYNECOLOGY Th. Weyerstahl, A. Sch~ifer, Th. Genz

within this time of observation. The expression of MHC class I I antigens (HLA-OR, HLA-DP was and HLA-DQ) and the associated i n v a r i a n t chain (Ii)

studied in epithelial cells of normal c01orectal mucosae, c010rectal aden0mas and carcinomas. In contrast to class II antigens, l i was detected in some specimens of normal mucosa d i s t a n t from the tumor, In residual non-neoplastic mucosa adjacent to carcinomas, li and class I I antigens were induced i n the order l i ~ HLA-DR ~ HLA-DP Z HLA-DQ,

the reactions being most pronounced in cases with inflammatory alteration o f t h e c r y p t s . In 22/37 adenomas and 77/123 c a r c i n o m a s I i e x p r e s s i o n d i s t i n c t l y exceeded c l a s s I I antigen expression. Class I I antigens w e r e found in 20/37 adenomas and 62/123 c a r c i n o m a s , m o s t l y i n a nonc o o r d i n a t e manner f o l l o w i n g t h e above o r d e r . Expression

of li in all tumor cells, not. however, expression of HLA-0R, -DP, -DO, was inversely correlated with survival. Pathol0gisches Institut I und Chirurgische Universit~t Heidelberg, D-6900 Heidelberg

Klinik2 der

2/P-GM 079 HLA-RESTRIC~ED RECOGNITION OF MULTIPLE ANTIGENS OF AV MELANOMA BY CYTOLYTIC T LYMPHOCYTE (CTL) CLONES T.Wolfel,E.Klehmann,K.H.Meyer zum B'uschenfelde,A.Knuth Little is known about the mechanisms of antigen recognition by CTL clones on autologous tummr target cells. In continuation of earlier work (A.Knuth, PNAS 81:3511, 1984) we studied this question with autologous CTL clones directed against the malignant melanoma cell line SK-MEL-29 derived from a patient AV. Six CTL clones (T3+,T4-,T8+) recognizing autologous melanoma but not other autologous or allogeneic targets were selected for this study. Their cytolytic activity directed against three different determinants defined by im~/noselection experiments was blocked by antibodies against T8 and monomorphic HLA class I determinants. Lysis of autologous tumor cells expressing HLA-A2 was inhibited by HLA-A2 reactive serum from pregnant women. This blocking activity could be absorbed with meuse cells expressing HLA-A2 after gene transfer. Monoclonal antibodies directed against HIA-A2 (MA2.I,PA2.1) blocked the recognition of AV melanoma cells by all AV CTL clones studied. Further evidence that HIA-A2 might be the restriction element for the recognition of different T cell defined antigens came from the analysis of AV melanoma clones 22 and 29, derived by immunoselection. They had lost the expression of HIA-A2 while still expressing other HLA class I molecules as detected by FACS analysis. They Were not lysed by any AV CTL clones due to the loss of HLA-A2 expression on the cell surface. IFN-gamma and TNF-alpha could not reinduce the expression of HLA-A2. We conclude that AV CTL directed against SK-MEL-29 recognize different antigenic determinants in association with HLA class I molecules and that HLA-A2 is a dominant restriction element in the AV melanoma system. I. Medizinische Klinik und Poliklinik, Joh.GutenbergUniversit~t, LangenbeckstraSe i, D-6500 Mainz, FRG

IN O B S T E T R I C S

Since 1984 the Univ. Hosp. Berlin Dep. of Obstet. and Gynec. is involved in the medical care of HIV-pos. patients - often heroin addicts who take part in a withdrawal program during pregnancy. Cytological controls done as part of the clinical routine showed a growing percentage of pathol. cytology findings was noted in such patients. 106 Pap.-smears taken from 45 patients from Dec. 84 until July 87 were looked at, 60.4% of the patients were pregnant, 39.6% were not. 55.7% of the smears were classified in Pap.-Gr. I/II. 6.6% were unclassifable due to marked inflan~aations. The relative mznber of pathological ~nears was 37.8%: 26.4% were classified in Pap. III D, 5.7% in Pap. IV a, 3.8% in Pap. IV b and 1.9% in Pap. V. The occurence of pathol, cytology in all hospital patients examined during this period was only 3.6%. Regarding the cytol. picture several findings were noted: A large portion of the examined smears (38.3%) showed non-specific i n f l ~ tory signs, 23.6% showed atypical metaplasia, double nuclei were seen in 21.7%, koilozytosis in 14.2%, dyskeratosis in 11.3% and clue-cells in 10.4% of the ~nears. However, we didn't find cytol, changes specific for HIV in the Pap-smears. The proportion of patients with pathol, cytology in our study was ten times t/~mt of the general female patient population of our hospital (37.8% vs. 3.6%). Comparing our results with international publications on cytol, screening results in high-risk-group patients (frequent change of sexual partners) there was a two- to three-fold incidence of pathol, cytology. Our conclusion;therefore, is that frequent cytological controls are strongly indicated in HIV-infected female patients. I. Universit~ts-Frauenklinik M[tnchen, Mmistr. 11, D-8000 M'Onchen 2

2/P-GM 081 S T R E P T A V I D I N - B I O T I N AS T U M O R I M A G I N G A G E N T S P. O e h r r J. W e s t e r m a n n , U, G e r m e r , H . S c h o ! t e s t H.J. B i e r s a c k The purpose of our study was to use the strong affinity of streptavidin to biotin to improve imaging. Biotin was conjugated to anticytokeratin antibodies and injected into rats containing cytokeratin as a tumor-associated antigen. Three days later, radiolabeled streptavidin was injected i.v. The uptake of activity was detected by scintigraphy as well as by radioactivity determination in tumor and various organ tissues. Control experiments were performed with biotin conjugated nonspecific IgG or radiolabeled streptavidin. It turned out that the tumor could be localized within one hour after injection of radiolabeled streptavidin. Conventional methods for irsaunoscintigraphy need between four hours and six days. Furthermore, the tumor/blood ratio was higher compared to that after application of radiolabeled antibodies alone. Another advantage of our system is that the same radiolabeled tracer can be used for any biotin conjugated antibody. Our system allows application of a tracer with high energy and short half life. We assume that the biotin-avidin-system could give new perspectives for diagnosis and therapy. P. Oe/or, Institut fear klin. und exp. Nuklearmedizin, Universit~t Bonn, Sigmund-Freud-Str. 25, D-5300 Bonn I

S 68

2/P-GM 082

2/P-GM 084

T E C H N I Q U E S FOR T A R G E T I N G T U M O R S W I T H A N T I B O D I E S FOR T U M O R T H E R A P Y P. Oehr, B. Bj~rklund*, V. Bj~rklund*, F. Werner, U. Wuddel, U. Rumbach, U. Germer, H. Scholtes, H. Rink**, A. Bockisch,.K. T[lnsmeier t H.J. Biersack

PHASE-I-STUDY WITH NATURAL INTERLEUKIN 2 IN ADVANCED CANCER PATIENTS

The aim of this experimental study was to improve the binding of radioactive or drug conjugated antitumorantibodies to the tumor, to protect the organs frcm the antibodies, and to reduce the amount of antibodies in the circulating blood. Experiments were performed in rats bearing HeLa cell tumors. The binding of antibodies to the t ~ r was improved by irradiation of the tumor. The tumor/organ ratio of antibody binding was increased by blocking of epitopes at the organs with "cold" nonspecific and specific antibodies. Repeated injections of radiolabeled antibodies increased the turm~r/organ activity ratio. The radi~ctive blood pool background could be reduced tenfold by injection of a second non labeled anti-antibody against the radiolabeled antibody.

P.v.Wussow,F.Hartmann,R.Jacobs,M.Stahl,C.Sch~ber,H.Wilke, H.J.Schmoll,A.Thrun,R.E.Schmidt and H.Deicher In a phase l - t r i a l 11 patients with advanced mal~gnant d i sease,who had relapsed on a l l standard therapies were t r e a ted with an highly p u r i f i e d natural IL 2 preparation obtained from stimulated buffy coat leukocytes (Biotest Frankfurt).Each patient received d a i l y n i l 2 s . c . injections in increasing doses f o r up to 8 weeks.Starting from 10.000 U/d the dose was doubled twice per week.8/11 p a t i ents were consecutively treated with d a i l y i . v . bolus inj e c t i o n s of n i l 2 following the same dose regimen.The presently highest dose administered s.c. and i . v . is 6 Mio. U/d. Pharmakokinetics of n i l 2,NK-celIs,IL 2-receptor,and Gamma-IFN in serum as well as c l i n i c a l side effects and responses were recorded during treatment.

2) C ~ i n a t i o n of the other methods mentioned above can improve the tumor/organ ratio to an extent of > 20 which means that immunotherapy of tumors might becc~ne superior to conventional chemotherapy.

S.c. niL 2 i n j e c t i o n s led to measurable,dose dependent t i ters in serum f o r up to 12 hours with maximal t i t e r s a f t e r 2 hours.ln contrast,niL 2 given by i . v . bolus reached maximal concentrations within 30 minutes,but disappeared within 4 hours.Both s.c. and i . v . administered niL 2 induced fever,fatigue,and e o s i n o p h i l i a . S i g n i f i c a n t weight gain was observed only during i.v.-therapy.An increase in NK-cell numbers and a c t i v i t y was noted both during s.c. and i . v . niL 2-treatment.No CR or PR was observed.1 p a t i ent showed amixed response with a more than SO%shrinkage of l i v e r metastases,but a s l i g h t increase in lung metastases.We conclude,that natural IL 2 can be safely administered both s.c. and i . v . . I n a d d i t i o n , s . c , injections of niL2 lead to measurable systemic t i t e r s and to t y p i c a l IL 2 related side e f f e c t s .

Institut filr klin. und exp. Nuklearmedizin, Univ. Bonn * SBL Stockolm, Schweden ** Institut fur Strahlenbiologie, Univ. Bonn

Abt. K|inische Immunologie im Zentrum Innere Medizin der Medizinischen Hochschule Hannover, Konstanty-Gutschow -Strage 8, 3000 Hannover 61

2/P-GM 083

2/P-GM 085

MACGI, A MONOCLONAL ANTIBODY DETECTING A MONOSIALOGANGLIOSIDE P R E S E N T ON T U M O R INFILTRATING MACROPHAGES F. S c h r i e v e r , R. D. D e n n i s , G. R i e t h m H l l e r and J. P. J o h n s o n

TUMOR REGRESSION BY GANGLIOSIDE ANTIBODY IN MENINGEOSIS MELANOTICA W.G. Dippold, E. Boosfeld, U. Moebius, H. Bernhard, H.P. Dienes, K.-H. Meyer zum BHschenfelde

Our results lead to the following assumptions: I ) Reduction of blood background by injection of second anti-antibodies has the drawback of possible deterioration of liver, spleen and kidneys.

MacG1 is a mouse monoclonal antibody (mAb) directed against a ganglioside, which is differentially expressed by macrophages infiltrating malignant melanomas and benign m e l a n o c y t i c lesions. MAb MacG1 was o b t a i n e d by immunization with !iposomes c o n t a i n i n g a m i x t u r e of gangliosides e x t r a c t e d from m a l i g n a n t m e l a n o m a . The a n t i b o d y was selected for binding to melanoma gangliosides and for reactivity with frozen tissue s e c t i o n s of m a l i g n a n t m e l a n o m a . M A b MacG1 s h o w e d r e a c t i v i t y in 25 of 46 m e l a n o m a s e x a m i n e d but o n l y in I of 51 nevi tested. T h e m A b d i d not react w i t h m e l a n o m a c e l l s but w i t h cytoplasmic granules and deposits associated with large d i s p e r s e d cells, w h i c h w e r e a l s o f o u n d in some non-melanoma tumors and in some lymphoid tissues. Using mAbs directed against differentiation antigens these cells were identified as macrophages. In n e a r l y all reactive tissues MacG1-positive macrophages accounted for a minority of the total macrophages. It is s u g g e s t e d that m A b MacG1 m a y define a functionally distinct subpopulation of tumor infiltrating macrophages. Staining of cells other than m a c r o p h a g e s was observed in some n o r m a l and m a l i g n a n t n e u r a l tissues. MacG1 bound to a m o n o s i a l o g a n g l i o s i d e extracted from melanoma a n d r e a c t e d o n l y with GM3 w h e n tested w i t h a panel of g a n g l i o s i d e s t a n d a r d s . Institute of Immunology, Goethestrasse D - 8 0 0 D M u n i c h 2, West G e r m a n y

31,

Evidence for the importance of gangliosides as target molecules on melanoma cells for the human immune system is accumulating. Several investigators were able to demonstrate local inflammatory responses and tumor regressions after application of ganglioside antibodies (Ab) (Dippold et al., Eur. J. Cancer Clin. Oncol., 1985; Houghton et al. PNAS, 1985). Here we report on the therapeutic application of GD3-ganglioside Ab R-24 (Dippold st al., PNAS, 1980) in two patients with melanosis melanotica. The first patient received once 2 mg and then nine times I0 mg mAb R-24 intrathecally over a period bf five weeks. The second patient was treated with 5 doses of I mg mAb R-24 over a period of two weeks after incomplete removal of a malignant melanoma in the area of the brain stem. Tumor cells, inflmmr~tory cells in the cerebrospinal fluid (c.s.f.) were determined during and after treatment. GD3-ganglioslde negative tumor cells were found at high Ab levels in the c.s.f, of the first patient. Nevertheless regressive changes of tumor cells were observed six weeks after starting mAb-therapy. No GD3-negative tumor cells were observed in the c.s.f. of the second patient, who received the low Ab dosage. Meanwhile nine months have passed and no evidence for tumor has been obtained in c.s.f, cytology nor in CAT or NMR-images. He is working again full-time. Six weeks after the end of mAb-tratment c.s.f, lymphocytes were cultured and tested for tumor cell cytotoxicity. They showed a high degree of cytotoxicity for malignant melanoma cells, but not for the corresponding EBV-transformed B-cells. Therefore this treatment approach may induce a cellular response against the tumor. Supported by Di-245/33 of the DFG. Department of Internal Medicine, Johannes GutenbergUniversit~t, Langenbeckstrasse I, D-6500, West Germany

$69 2/P-GM 086

2/P-GM 088

M O N O C L O N A L A N T I B O D I E S AGAINST BLADDER TUMORS B.J. Schmitz-Dr~ger, D. Rohde, C. Peschkes, T. Ebert and R. Ackermann

The Use of a Modified 3H-Thymidine Release Assay to Assess Rapid Cell Mediated Cytotoxicity U. Keilholz, R. Dummer, H. Welters

The reliability of urinary cytology in the diagnosis of transitional cell carcinoma (TCC) is influenced by the degree of cellular anaplasia and concomitant infection. Therefore, the s e n s i t i v i t y of this m e t h o d is limited espe~ cially in low grade TOG. The d e v e l o p m e n t of the h y b r i d o m a technology by K 8 h l e r and M i l s t e i n provides the p o s s i b i l i t y of producing u n l i m i t e d amounts of m o n o s p e e i f i c antibodies against tumor associated antigens, The aim of this study was the p r o d u c t i o n of m o n o c l o n a l antibodies (mabs) against TCC. Using SW 1710 tumor cells, a permanent cell line derived from a papillary bladder tumor, for immuniza~ tion of Balb/c m i c e cell fusion was performed b e t w e e n a c t i v a t e d spleen cells and X63 Ag 8.653 m y e l o m a cells. Three mabs d e s i g n a t e d as Due ABC i, 3 and 4 were found to recognize antigens present on the cell membrane of most TCC but rarely on normal u r o t h e l i a l cells. While Due ABC 1 reacted with 67% of all TCC investigated, mabs Due ABC 3 and 4 were posi~ tive in 82% and 83%, respectively. Cross reactions were seen with proximal tubular epithelium of the kidney and renal cell carcinoma. Furthermore, the antigens were e x p r e s s e d by some g a s t r o i n t e s t i n a l epithelia, seminomatous testicular tumors and breast carcinoma. The clinical value of these m a b s in the diagnosis of TCC is currently being evaluated. U r o l o g i s c h e Klinik der Universit~t, Moorenstr. 5, D-4000 DGsseldorf, FRG

Since the adoptive immunotherapyusing LAK cells and IL2 has been introduced into clinical medicine, there is ~'owing interest in cytotoxicity assays. The standard ~chromium release assay has certain disadvantages, especially poor sensitivity becat~e of a high background release. Triated thymidine (H-TdR) has mainly been used to assess macroph~ge mediated cytolysis. We modified this assy, using OH-TdR labeled tumor cells as targets for rapidly cytolytic effector cells, especially LAK cell s. Unstimulated peripheral blood mononuclear cells and LAK cells stimulated with 1000 U IL-2/ml for 3 days are used as effector cells. Daudi, K562, ~ d two melanomacell lines are used as target cells. 10 ~arget cslls/ml are labeled for 24 hours with 10 /uCi/ml H-TdR, and coincubated with effector cells in'g6 well round bottom culture plates at effector: target ratios of 40:1, 10:1, and 2.5:1 for 24~to 72 hours. Cytotoxicity is assessed by the amount of ~H-TdR re~eased into the supernatant. The background release of H-TdR is in the rang~1of 3-8% per 24 hours, compared to 3-5% per hou~L using Cr. In the standard system, up to 22% of the H-TdR released by the target cells is incorporated by active LAK cells, resulting in false results. T h i s problem can be abolished by addition of cold TdR to the assay medium. The results of this cytotoxicity assay show clos#~correlation to results obtained with the standard ~Cr release assay, using LAK cells as effector cell3~ L for all target cells tested. The sensitivity of the H-TdR release assay, however, is increased. Reliable results can even be obtained at effector:target ratios of 2.5:1, using non-stimulated mononuclear cells as effector cells. Additionally the number of cells necessary to carry out the assay can be reduced five-fold. These data provide sufficient evidence th3at reliable results can be obtained using the modified H-TdR release assay for LAK cells and similar rapid cytotoxic effector cells, and that the s ~ s i t i w t y of this assay is superior to the standard Cr release assay. Medizinische Klinik u. Poliklinik V, Hospitalstr.3, 6900 Heidelberg, FRG

2/P-GM 087

2 / P - G M 089

HIGH RESOLUTION METABOLIC IMAGING IN TUMOR SPHEROIDS WITH BIOLUMINESCE~CE S. Walenta, -W. Paschen and W. M~ller-Klieser

EFFECTS OF EPIDERMAL GROWTH FACTOR, INSULIN AND INSULIN-LIKE GROWTH FACTOR-I ON THE PROLIFERATION OF HUMAN OVARIAN CARCINOMA CELLS T. Schmidt X, J. Hofmann X, A. Drescher ~, R. H a c k e n b e r g $, F. H61zel # and K.-D. Schulz * ..................... ~......................... For the purpose of investigating endocrine effects in human ovarian adenocarcinomas, 5 ovarian carcinoma cell lines were established and characterized by chromosome banding techniques and polymorphic enzyme analysis. 8day proliferation assays were performed p r e f e r a b l y in serum-free medium. 2 cell lines, however, needed charcoal-treated fetal calf serum (DC-FCS) for maintenance over the test periods. In these cases growth effects were assayed at various DC-FCS concentrations in the incubation mediums 0.1 - I nM epidermal growth factor (EGF) and a c h o r i o n g o n a d o t r o p i n preparation c o n t a i n i n g EGFlike peptldes were highly mitogenic for 3 of the 5 cell lines investigated. I0 - I00 nM insulin and l - I0 nM insulin-like growth factor-i (IGF-I) stimulated the growth of 2 cell lines, The cell lines sensitive to insulin and IGF-I were the ones that did not respond to EGF. No significant effects on the cell growth were observed with follitropin and lutropin. Since ovarian carcinomas may secrete peptides that hind to EGF receptors, the stimulation of ovarian carcinoma cell growth by the factors examined indicates possible mechanisms of autocrine growth regulation. Supported By Deutsche Forschungsgemeinschaft (SFB 215) and K e m p k e s - S t i f t u n g Marburg.

Multicellular tumor spheroids are characterized by pronounced gradients of oxygen tensions, as has been shown through microelentrode measurements (W. M~ller-Klieser, J. Cancer Res. Clin. Oncol. !13,101,1987). However, no obvious correlation was found among the distribution of oxygen tensions, of proliferating and non-proliferating cells, and of the emergence of necrosis. To identify further factors in the metabolic micromilieu of spheroids that may be interrelated with the biological phenomena described, a technique for metabolic imaging in brain slices (W. Paschen et el., J. Neurochem. 36, 513, 1981) was modified for measurements in cellular aggregates. The substance of interest is enzymatically linked to a bioluminescence reaction. The photon emission is registered by film exposure and microdensitometry or by an imaging photon counting system (ARGUS, Mamamatsu, Herrsching). The method allows for the determination of glucose-, lactate-, and ATP-distributions with a spatial resolution of around 50 ~m in serial cryostat sections. Thus, a comparison can be made among the different substances determined at similar locations. Also, the substance distributions can be related to'the histological structure of the tumor cell aggregates by sequential sections. A calibration procedure was developed for measuring the concentration of each individual substrate in absolute terms. - The data obtained in HT29 or in EMT6/Ro spheroids demonstrate the absence of ATP in the necrotic center and the presence of this phosphate in the viable nell rim. There was no indication of a lack in glucose in the spheroid center. Lactate seemed to be accumulated considerably in the inner regions of these cell aggregates. This accumulation may contribute significantly to the emergence of cellular quiescence and of cell death in this in vitro tumor model. - Supported by the DFG (Ms 576/2-3) ~Mpbtlg. Angew. Physiologie, Univ, Mainz, 6500 Mainz I ffir neurologische Forschung, 5000 KCln 91

Universit~ts-Frauenkllnlken, Pilgrimstein 3, D-3550 Marburg (*) and Martini-Sir. 52, D-2000 Hamburg 20 (#)

S 70

2/P-GM 090

2/P-GM092

COMPARATIVE FLOW CYTOMETRICAL ANALYSIS OF DNA AND CEA IN GASTRIC CARCINOMAS. W.Mellin, G.Heidl, F.P.Dirschauer, E.Grundmann

CD4 § HELPER CELLS ARE REQUIRED FOR RESISTANCE TO A HIBHLY METASTATIC HURINE TUMOR H - J ~hild, B Kyowski,P. vonHcogen,endY.,Schirrmecher

In 55 g a s t r i c carcinomas, c l a s s i f i e d h i s t o l o g i c a l l y according to Laur~n, Ming, and WHO, and tested immunohistol o g i c a l l y f o r CEA, flow cytometry assessed simultaneously DNA, CEA, and volume status whereby r e l a t i v e CEA concentration was established, a more relevant parameter than mere CEA l e v e l s . - 44 of these 55 gastric carcinomas (80%) were DNA aneuploid. Based on d i s t i n c t l y posit i v e CEA expression, an additional DNA d i p l o i d tumor cell population could be i d e n t i f i e d in 13 of these 44 cases. In each of 5 aneuploid tumors we found 2, in 2 others 3 aneuploid stemlines. No c o r r e l a t i o n could be established between DNA ploidy and the tumor's extension, h i s t o l o g i c c l a s s i f i c a t i o n , and grading. - The overall CEA expression of each tumor stemline was assessed representatively in the respective defined G~.~ cells, where i t depended not so much on the relativ~/~ean CEA concentration than on the percent proportion of CEApositive cells. The aneuploid tumor stemlines showed weakly significant differences in the percentage of CEA positive cells, between well and poorly differentiated carcinomas (WHO) or intestinal and diffuse lesions (Laur~n), whereas the histologic types of Ming revealed no differences. These results support the immunohistologic definition of CEA as a differentiation-dependent antigen. The so-called mean relative CEA concentration, however, revealed no significant differences.

The inductionof effectivetumor-spscific adjuvantimmunity is an obvious therapeutic Oral. in particular in postoperativetreatment of residual,

disseminated metastases. In defining the parameters for induction of anti-tumor immunity we analyzed a role of CD4+ T helper coils in induction of tumor transplant re]astlan leadingto completeregressionof a highly metastaticDBA/2 mouselymphema.Using an anti-CD4 monoclonal antibody(OK 1.5)which eliminates T helpercellsin viva and in vitro,we found that CD4+ cells are required for tumorrasistance in syngeneic DBA/2 mice or allogeneiobut major histocompatibilitycomplex-identical B IO.D2 mice. In contrast,in allogeneicC57BI/6 mice tumorrejectienwas independentof CD4 § cells.An analogousrequirement for immune CD4 + cells for in v/tpo induction of ODe+ turner-specific cytotoxic T cells was

found in theserespectivestrains. The requirementfor immuneCD4+ calls /n vLtr#could be replacedby recombinant interleukin-2. Theseresults demonstrateo roleof CD4+ regulatoryT cellsandT-T call cooperationin the induction d anti-tumor immunity and tumorrejection and point at possible therapeutic interventions in the afferent phase of anti-tumor immune responses Institut far Immuenlogieund8enatik, DoatschesKrabsforschungezentrum, Im NeuenheimerFold280, 69 Heidelberg.

Dr.Walter Mellin, Gerhard-Domagk-lnstitut fur Pathologie der Westf~lischen Wilhelms-Universit~t, Domagkstr. 17, D-4400 MUnster

2 ~ - G M 091

2/P-GM 093

TUMORIMMUNECELLS RECRUITEDAND ACTIVATEDIN$1TU BYA TUMOR VACCINE:FUNCTIONALSTUDIESUSINGA 5PONOE-MATRIXMODEL.

A NEW BETWEEN

U. Zangemeister,K+ Thiede,and V. 8chirrmacher

MELANOMAS Ute Rothb~cher, P.Johnson

tt is assumedthat spscific T call-mediated immune respen~ end local inflammatory reactions ere critical in elimination of tumor calls in viva The analysis of this Cellular micrconvironmant has been hampered by methodologicallimitations. Here, we use a subcutaneouslytransplantedcoil free spongematrix as an expeMmantal]yconfined /nsituenvironment to study the local interactionsbetweena highly metastaticmurine tymphoma, ESb, and host cells. This approachallows us to predeterminethe site of tumor Orowthand to recover both the tumor calls and the infiltrating host calls by excising the spongeand by releasing the cellular infiltrate by pressing the sponge.When ESb tumor immunemice were implantedwith a spongeand irradiated tumor Ceilsware reinJecteddirectly into the sponge, a local recruitment of lympbocytaswas observed. Four days later the sponge infiltratingcoils exhibitedhighlyspecificcytotoxicityagainstthe

injected tumor when anah,zed in vitro The tumor-specific cells were typed as Thy I+ , C'D8+ T cells. These isolated tumor-infiltrating lymphocytee conferred specificprotection,when adaptivelytransferred together with a lethaldose of tumor ceils in a Winn assay. Moreover, spange-infiltrating immune cells had the capacity to recruit other circulatinglymphoid host cellsinto the sponge.Thus, the sponge matrix

model will enableus to more precisety define tie contribution of distinct cell typesto tumor ~ i t t o n and rejection processes Institut fiJr Immunologieund Oenetik, DeutscheKrabaforschungszentrum, Im NeuanhelmerFold280, 69 Heidelberg

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.

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.

MONOCLONAL ANTIBODY DISCRIMINATING BENIGN NEVOCELLULAR NEVI AND MALIGNANT

.

.

.

.

.

.

.

.

Gert

.

.

.

.

.

.

.

Riethm~ller

.

.

.

.

.

.

.

.

.

.

.

.

and

.

.

.

.

.

.

Judith

.

.

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.

C L I P . M is a m u r i n e m o n o c l o n a l a n t i b o d y o b t a i n e d following immunization with melanoma cell lines. It is able to d i s c r i m i n a t e between benign and m a l i g n a n t melanocytic lesions in situ. F r o z e n t i s s u e s e c t i o n s of 33 nevi and 43 melanomas were examined using an immunoperoxidase staining technique. All nevi w e r e n e g a t i v e w i t h C L I P . M w h i l e 34 m e l a n o m a s were clearly stained. Weak reactivity with e p i d e r m i s , l y m p h o c y t e s and e n d o t h e l i u m was also seen. B i o c h e m i c a l studies showed that C L I P . M precipitates HLA class I antigens from melanoma and B l y m p h o b l a s t o i d cell lines. In c o n t r a s t to CLIP.M, o t h e r m o n o c l o n a l a n t i b o d i e s r e c o g n i z i n g m o n o m o r p h i c r e g i o n s on H L A - A , B , C m o l e c u l e (W6/32, PA2.6, BB7.5 or MB40.5) react with n e v u s c e l l s as w e l l as m e l a n o m a cells. A l t h o u g h it has previously been shown that m e l a n o m a cells express higher levels of H L A c l a s s I a n t i g e n s t h a n n e v u s cells, b i n d i n g of C L I P . M to n e v u s c o u l d not be d e m o n s t r a t e d e v e n w h e n h i g h concentrations of a n t i b o d y - c o n t a i n i n g ascites were used. However comparisons of the affinities of the v a r i o u s class I m o n o c l o n a l antibodies must still be done. These observations suggest that the epitope r e c o g n i z e d b y C L I P . M r e f l e c t s an a l t e r a t i o n of class I molecules associated w i t h the c h a n g e from b e n i g n to m a l i g n a n t p h e n o t y p e . I n s t i t u t e of I m m u n o l o g y , F.R.G., G o e t h e s t r a ~ e 31,

U n i v e r s i t y of Munich, 8000 M ~ n c h e n 2.

S 71

2/P-GM 094

2/P.GM 096

HUMAN MONOCLONALANTIBODIES AGAINST BREAST CARCINOMA ASSOCIATED ANTIGENS S. Kaul, Chen Xiaolong, R. A. Ott, A. Eichler and G. Bastert In contrast to monoclonal antibodies (MAbs) developed in mice and r a t s , the human MAb technology is hampered by severe d i f f i c u l t i e s , r e s u l t i n g from unfavourable charactar i s t i c s of the permanent human fusion partners and from inadequately stimulated human B-cells. At present, some of these problems can be circumvented by the construction of mouse-human interspecies hybridomas. To generate human MAbs against breast cancer antigens by interspecies hybridomas, we fused lymph node lymphocytes and intratumoral lymphocytes from twelve d i f f e r e n t patients with X 63-8.653 mouse myeloma c e l l s . Immunoglobu!in (Ig) secreting hybrids could be selected at a frequency of I to 2 clones per I0 ~ lymphocytes. The main disadvantage of mouse-human hybridomas, namely the unstable Ig production, could be overcome in more than 50 % of these clones by an early and repeated subcloning. The s p e c i f i c i t y of human MAbs was determined c y t o l o g i c a l l y using normal and tumor tissue from the lymphocyte donor and a panel of normal f i b r o b l a s t s and d i f f e r e n t tumor c e l l l i n e s . Generally, the immune response of breast cancer patients was dominated by MAbs against cytoskeletal proteins and nuclear antigens present in normal and tumorous c e l l s . Reactivity with cell surface a n t i gens was seldom (below 1%), weak and usually unspecific. However, from a t o t a l of 2000 hybridomas tested, we could select f i v e d i f f e r e n t human MAbs with s p e c i f i t y f o r cytoplasmic (4) and nuclear ( I ) antigens expressed by breast carcinoma c e l l s , which had l i t t l e or no r e a c t i v i t y with normal c e l l s from skin, breast, colon and l i v e r . These MAbs were p u r i f i e d by a combination of a f f i n i t y chromgtography and FPLC g e l f i l t r a t i o n . They were conjugated with radioactive isotopes for experimental immunological studies with human breast carcinomas in nu/nu mice and l a belled with b i o t i n for detailed immunohistochemical studies.

EPIDERMAL GROWTH FACTOR-LIKE ACTIVITY AND BINDING SITE IN GYNECOLOGICAL SQUAMOUS CELL CARCINOMAS D.G.Pfeiffer, P.Scheidel, W. Meier, R. Kimmig, A.Pfeiffer The Epidermal Growth Factor (EFG) and its receptor (EGF-Rc) are involved in the growth regulation of breast cancer. The role of EGF and its receptor in human vulval and cervical carcinomas is not known. We measured EGF-Rc binding capacity and affinity and the EGF-like activity in human cervical and vulval carcinomas and correlated the results to clinical staging, histological grading and age. Tissue was obtained on occasion of surgery or local radiotherapy. The membrane fractions were tested for displacement of 125-1 EGF by unlabetled EGF. EGF-like acitivity was extracted with 1 N acetic acid. EGF-like activity was quantified by displacement of 125-1 EGF from human placenta EGFRc. In 25 cervical and 4 vulval carcinomas the affinity was not significantly different from the affinity in normal tissue. The EGFRc binding capacity varied from 12-190 fmol/mg protein in 25 cervical carcinomas (mean: 45.4 fmol/mg) and was significantly higher than the capacity in normal tissue (7.3 _+ 2.7 fmol/mg protein) (t3 ~ 0.05). The 3 patients with the highest EGF-Rc capacity of 190, 149 and 119 fmol/mg had rapidly growing tumours as jugded clinically by tumour progression. In patients with cervical carcinoma and lymph node metastases the EGFlike activity extracted was significantly higher (85.0 + 12~6 ng/g wet weight) than in patients with negativ lymph nodes (21.0 + 8.5 ng/g wet weight) (p< 0.01). In summary, we find an increased expression of the EGF-Rc in cervical and vulval carcinomas and more EGF-like acitivity in tumours of patients with lymph node metastases. Frauenklinik im Klinikum GroBhadern, Ludwig.Maximilians-Unh versit&t, MarchioninistraBe 15, 8000 M(~nchen 70

Universit~ts-Frauenklinik, D-6650 Homburg/Saar

2/P-GM 095

2/P-GM 097

TH~ SIGNIFICANCE OF CIRCULATING ANTINEURONAL ANTIBODIES IN S M A L L C E L L LUNG CANCER

EPIDERMAL GROWTH FACTOR {EGF) RECEPTORS AND EGF-LIKE ACTIVITY IN GASTRIC MUCOSA AND GASTRIC CARCINOMASOF PATIENTS UNDERGOINGGASTRECTOMY A.PfeJffer, E.Rothbauer, B.Wiebecke, H.-J,Krdmling, E.Pratschke, K.Mann EGF is a mitogenic growth factor for normal and

D r l i c e k M, G r i s o l d W, J e l l i n g e r K, L i s z k a U, Popp W L.Boltzmann Inst.f.Klin. Neurobiologie, Wolkersbergenstr. I,A 1130 Wien C i r c u l a t i n g a n t i n e u r o n a l a n t i b o d i e s (CANA) a g a i n s t P u r k i n j e c e l l s are c o n s i d e r e d to o c c u r in p a r a n e o p l a s t i c n e u r o l o g i c a l s y n d r o mes (i.e: s e n s o r y n e u r o n o p a t h y , s u b a c u t e cerebellar degeneration). We e x a m i n e d 150 p a t i e n t s w i t h l u n g c a n c e r , i n c l u d i n g 52 p a t i e n t s of the s m a l l c e l l type, a n d c o m p a r e d r e s u l t s w i t h a c o n t r o l l group. CANA directed against Purkinje - and dorsal r o o t g a n g l i a c e l l s w e r e d e t e c t e d o n l y in p a t i e n t s w i t h s m a l l c e l l l u n g c a n c e r ( 40 %). H o w e v e r c l i n i c a l l y and e l e c t r o p h y s i o l o g i c a l l y in b o t h g r o u p s (CANA p o s i t i v e vs n e g a t i v e ) n o differences appeared. T h e p e n e t r a t i o n a n d the b i o l o g i c a l e f f e c t of C A N A in the c e n t r a l n e r v o u s s y s t e m and in the lung tumor cells have not been clarified up to now. O u r i n v e s t i g a t i o n s d o n o t c o n f i r m an a s s o c i a t i o n b e t w e e n the a p p e a r a n c e of C A N A and n e u r o l o g i c p a r a n e o p l a s t i c s y n d r o m e s .

transformed

epithelial ce~is. Malignant cells were shown

to frequently produce an EOF-like factor, transforming growth factor-alpha (TGF-a!pho), which may act on t h e i r own EGF-reaeptors (EGF-R) to stimulate growth by an autocrine mechanism. We measured EGF-R and EGF-like activity in histologically normal mucosa and in carcinoma tissue from patients undergoing gastrectomy to assess

their eventual role in the development and growth

of gastric carcinomas. Methods: EGF-R characteristics were determined by a ] 2 $ j _ ~ : radioligand binding assay and the data were evaluated by the curve f i t t i n g program "LIGAND'. EGF-like

activity

of

acid

extracts

was measured in a

placenta radioreceptor assay. EGF-R were present

in tissue from all 14 evaluated. 7/14 patients had increased and 5 / ] 4 hod decreased levels Of EGF-R compared to normal mucosa ~rom the same individuals. Binding as163 varied between 0.] and 10 nM Kd and significant differences between mueosa and carcinoma tissue were found in 5/14 patients. EGF-like activity was not elevated in most carcinomas compared to normal Results~ patients patients

mucoea. Conclusion: These data suggest that gastric carcinomas show heterogenous changes in EGF-R binding capacity and generally no increase in extractab]e EGF-li~e activity. These resuJts should stimulate further studies regarding eventual asssociations between tumor progression and EGF-R characteristics. Med. K1inik I I , Pathol. Inst. und Chir. Elinik, Klinikum Gro~hadern, Universit~t M0nchen, 8000 M0nchen 70.

$72 2/P-GM 100

2/P-GM 098 LYMPHOKINE-MED!ATED SUPRESSION IN NORMAL ERYTHROPOIES~S AND IN RETROViRUS-ASSOCIATEDLYMPHOPROUFERATIVEDISEASE

Lee Levit and Stefan Burdach Activation of genes for interleukin 2 (Ik2) end its receptor by the tat gene product of the human rmrovirus HTLVq has been linked to the pathogenesis of adult T cell leukemia. In earlier studies we have demonstrated that tL2 -induced inNbition of erythropNesis is mediated by interferon-{ (Wy) [Burdach et aL Btood 68, 16l@ We have new examined the role of activated T ceils and IF't in inhibition of normal erythropoiesis and in HTLV I associated lymphoproliferative disease. T cells were activated by triggering of the antigen receptor complex with CD3 monoclonal antibody. T cell act[vation was monitored by assessment of IL2 receptor (p55) expression (Burdach et aL J. ImmunoL t39:452), Incubation with CD5 antibody recognizing a T cell epitope distinct from the antigen receptor served as a control Erythropoietic progenitors were cultured in the absence and presence of CD3 or contret CD5 triggered T ceils [n the absence and presence of various concentrations of purified, synthetic gone-derived [Fy. IF7 caused a dose-dependent inhibition of erythroid but not myeloid progenitors in the presence of CD3 triggered T eelIs 9(>75% inhibition of erythropoiesis at 102 U/ml IFy). In contrast, only 25% inhibiton of erythropoiesis was observed in the presence of non-activated T cells or in the absence of T ceils. Next we investigated the mechanisms for acquired pure red ceil aplasia in a patient with TT-lymphopro[iferative disease (TT-LPD). Patient marrow erythroid progenitors were 17• of control end Increased to 88-t02% of control following marrow T cell depletion. Myetoid progenitors were normat. Patient suppressor T cef{e inhibited growth of autologous and al]ogeneic marrow erythreid but not myeloid progenitors and produced high titers of IF-/. The inhibitory factor in patient T cell supernatant was acid labile and sensitive to trypsin, consistent with properties of IF'/, Prior depletion of activated T cells abrogated the suppressive effect of patient T cell-derived supemstant Patient T cells showed an f6-21 fold increased proliferative response to exogenous IL2. Antibodies to HTLVq c'bre proteins pt9 and p24 were detected in patient serum by Western blotting. Patient cultured peripheral blood monuclear ceils demonstrated integrated HTLV-I genomic sequences by Southern technique end expressed specific HTLV I genomic sequences as assessed by RNA dot Not and reverse transsedptase activity. Patient ceils also stained positive with p19 and p24 antibodies, Demonstration of T cell receptor [3 chain rearrangement provided evidence for clonality of the lymphoptoliferative process. We conclude: (1) IF,,, inhibits erythropoiesfs in the presence of activated T eetls (2) activated suppressor T cells in association with endogenous IF-/release can mediate inhibition of er/thropoiesis in certain instances of T"/-LPD. Data indicating Infection with HTLV I suggest the pcesibiIity of an etiologic link between human retrovirus infection and some instances of large granutar tymphocytie leukemia (TT-LPD).

MEXADECYLPHOSPNOCMOLINE: ANTINEOPLASTIC ACTIVITY-METABOLISM-ORGAN DISTRIBUTION

A. Brelser, E.A.H. Fleer, M. Berger, D.-J. Klm, P. Hilgard, G.A~ Hegel, H. Eibland C. Unger Alkylphosphochollnes are a new class os antitumor drugs. In this study with hexadecyl~hospho~hollne (MePC) we report cytotoxlc effects on leukemia cell lines. In addition, organ distribution was studied in mice and the metabolic fate of He-PC was followed in different organs. The cell studies revealed ID 50 and LD (48 h) of 5 . 0 1 7 . 7 u g / m l

50 values

(U 9 3 7 ) , I0,0126.0 uglm! (RaJ!) and 15,5 I>40 uglml (K 562}. The (HL 6 0 ) ;

3.0/16,0ug/ml

in vlvo studies showed that He-PC is well absorbed the intestinal tract;

from

Iv and oral administration led to

similar organ distributions with highest accumulation of Me-PC in liver, are choline,

This

lung and kidney. The metabolites formed

phosphocholine and

indlcates

that

1,2-(diacyl)-lecithin.

the important

enzymes

for

the

bloconverslon of He-PC are phospholipases C and D.

Zentrum Inhere Medlzln, Abt. H~matologie/Onkologle Robert-Xoch-Str. 40, D-3400 G~ttlngen

Abt, P~.d. Onko/ogie, Untversit~t D0sselderf; Hematology DIv., Stanford University

2/P-GM 099

2/P-GM 101

PHOSPHOLIPIDS: SELECTIVE DRUGS IN CANCER THERAPY ? ...........

H. Eibl and C. Unger

The chemical treatment of malignant alterations in human

tissue by irradiation or surgery

curative.

Even

macroscopic

more

methods

complex is

and

not

the problem

is often

not

controlled

by

of

metastasis.

Theoretically, thls can be solved only by chemotheraphy which acts on a cellular level and may include the advantage of a selective therapy. In practice,

the clinically applied antlneoplastlc

agents are strong toxins and their

administration

is

llmlted in concentration and time. Especially the strong supresslun of immune response will restrict

continuous

application over extended time periods, The malngoal of our work, therefore, antltu~or

drugs,

methods.

For

is to improve the s e l e c t i v i t y

This

instance,

can be the

achieved

of

by d i f f e r e n t

drug can be

directed

selectively to organs by altering the surface charge of carrier

molecules,

for

instance

of

llposomes.

experiments with N-methylnitrosourea-induced carcinomas i n r a t s we have demonstrated a

antltumor

effect

with

lysoleclthln

In

mammary specific

analogs

at

concentrations that were not toxic for the animals.

The

new compounds are alkylphosphochollnes.

M.P.I. far Biopbyslkallscbe Chemle, D-3400 GBttlngen

ACYLATION OF ALKYLGLYCEROPHOSPHOCHOLINES BY RAT LIVER HICROSOHES W, Neum~ller, E.A.H. Fleer, C. Unger and H, Eibl ~uikyls (A1-GPC) have antineoplastic activity. The toxic effects of these compounds

are less pronounced than for the corresponding (AI-Me-GPC), most

alkyl-methyl-Rlycero[zhosphoc2nolines

probably due to the slower metabolic conversion of AIMe-GPC's. Different metabolic mechanisms have been described for the detoxlflcatlon of AI-GPC, In the present report the

acylatlon

of AI-GPC by acyl-CoA

dependent

transferases and by acyl-CoA independent

acyl-

transacylases

is studied. Using acylatlon conditions that are optimal for the acylation of l-~almltoyl-sn-c~lycero-3-~hespho~hollne (P-GPC), product formation with l-9~tadecyl-sn~lycero-3-1~hospho~hollne (Oc-GPC) as substrate was not observed, indicating that AI-GPC are no substrates for acyl-CoA dependent acyltransferases. In addition, OcGPC does not inhibit the acyltransferase reaction with P-GPC, However, Oc-GPC was acylated by transacylases,

which

transfer the arachldonoyl residue from phosphattdyllnositol to AI-GPC. These results demonstrate that

dlfferent pathways are used for the acylatton of esterand ether-lysophosphollplds. M.P.I. f~r Biophystkallsche Chemle, D-3400 GOttlngen,

S 73

2/P-GM104

2/P-GM 102

TREATMENT OF DIFFERENT HUMAN 6LIOMA CELL LINES WITH BLEOMYCIN-CONTAINING LIPOSOMES E. Mentrup, H, F i s c h e r and H. S t r i c k e n

HEXADECYLPHOSPHONOCHOLINES AS NEW ANTITUHOR DRUGS

Ries,

U.

E.A,H,

Fleer,

A.

Brelser,

J,

Stekar,

H.Berger, C. Unger and H. Eibl ~ikyl~3~ospho~hollnes

(&I-PC) have

strong

anti-

neoplastic activity. AI-PC are substrates for phosphollpases

C and D,

an important requirement

for

cell

toxicity. To get more information about the importance phospholipases

C and D for tumor

toxicity,

we

of have

prepared compounds with only one enzymatic breakpoint, either for phospholipase C or for phospholipase D. For

hexadecanol-{2-trlmethylammoniumethyl)phos-

instance, phonate is has

a substrate only

almost

for phosphollpase C.

the same toxiclty for

hexadecylphosphochollne

cell

It

cultures

as

and thus is highly active

in

the treatment of rat mammary carcinomas.

In contrast,

2-trimethylammoniumothanol-hexadecylphosphonate,

is

only a substrate for phosphollpase D and is less toxic than

hexadecylphosphochollne.

These results

clearly

indicate that substrate properties for phosphollpase C are

more

important

for

toxicity

than

those

L i p o s o m e s can be useful as depot s y s t e m s for e n c a p s u l a t e d drugs. For s u c c e s s f u l local t r e a t m e n t of t u m o r s it is n e c e s s a r y to develop liposomes with acceptable stability at s t o r a g e and with c o n t r o l l e d r e l e a s e of the e n c a p s u l a t e d drug or c o n t r o l l e d cell i n t e r a c t i o n . The r e l e a s e of e n c a p s u l a t e d b l e o m y c i n in cell c u l t u r e (37 ~ was f o u n d to be b e l o w 5~ a f t e r 120h For v e s i c l e s c o m p o s e d of an e q u i m o l a r m i x t u r e os h y d r o g e n a t e d plant l e c i t h i n e and c h o l e s t e r o l

(PPC/CH). Free Bleomycin shows a dosedependent d e s t r u c t i o n of human glioma c e l l s (HeRo-SV>HeRo)t508>t406). The rank o r d e r f o r the c y t o t o x i c i t y os the d i f f e r e n t lipids (empty l i p o s o m e s ) was as f o l l o w s : p o s i t i v e l y charged - n e g a t i v e l y charged - n e u t r a l . The entrappment o f b l e o m y c i n i n t o uncharged l i p o s o m e s composed o f PPC/CH l e d to significant r e t a r d a t i o n o f the t o x i c e f f e c t . The c e l l l i n e s showed an i n d i v i d u a l response t o the b l e o m y c i n - l i p o s o m e s r a n g i n g from 80% ( t 4 0 6 ) t o 5g (HeRo-SV) v i a b i l i t y , The r e s u l t s i n d i c a t e t h a t the t o x i c i t y o f b l e o m y c i n - c o n t a i n i n g liposomes i s mediated p n i m a r e l y by the uptake o f liposomes i n t o cells.

for Institut

phospholipase D.

for P h a r m a z e u t i s c h e

Technologie

und

B i o p h a r m a z i e , Im Neuenheimer Feld 366, U n i v e r s i t ~ t H e i d e l b e r g , 0-6900 H e i d e l b e r g

H.P.I. Biophyslkalische Chemic, D-3400 Gdttlngen

2/P-GM 103

2/P-GM 105

DETERMINATION OF HEX&DECYLPHOSPHOCHOLINE IH BLOOD

STRUCTURE-ACTIVITY ~ L A T I o N S H Z P S OF ALKYLPHOSPHOCHOLINES IN METHYLNITROSOUREA (MNU)-INDUCED RAT MAMMARY CARCINOMA. ~ M.R. Berg e [, D . $ c h m ~ h l , H.J. Eibl, C: U n d e r Alkylphosphocholines are a new class of membrane-directed antineoplastic agents with an unusual spectrum of antineop!astic activity. For determination of structure-activity relationships, the alkyl chain was varied in its length from either 14 carbon atoms (tetradecylphosphocholine; TPC) to 16 (hexadecylphosphocholine; HPC) and to 18 carbon atoms (octadecylphosphocholine; O P C ) ; the longest alkyl chain was used as a basis for introducing a double bond between carbon atoms 9 and i0 to yield oleylphosphocholine (OIPC), and the distance between the phosphate- and the trimethylammonium-group within the polar moiety of the molecule was extended to six carbon atoms, which generated oleylphospho-(N.N.N.-trimethyl)hexanolamin (OIPC). THese agents were examined in MNU-induced, a ~ t ~ h s rat mammary carcinoma, which has been found to be a suited model for ranking the anticancer a c t i v i t y o f this class of agents (Bergen et al, J. Cancer Res. Clin. Oncol. iii, $24, 1986). The following results in terms o f T / C % and % mortality were obtained after five weeks of peroral treatment at optimal dosages: TPC 42-13; HPC 13.2-0; OPC 6.0O; OIPC 3~ OIPC~ 114-20. Clearly, the prolongation of t_he al~yl chain led to compounds with increased antineoplastic activity. The introduction of a double bond into the alkyl chain increased the therapeutic ratio, whereas the extension of the phosphate-trimethylammonium distance to six carbon atoms abolished the anticancer activity. !nstitut f~r Toxikologie und Chemotherapie, DKFZ, Im Neuenhe~mer Fold 280, 6900 Heidelberg

W. Oamenz, E.A.M. Fleer, J. K~tting, G.A. Nagel, H. Elbl and C. Unger

.

.

.

.

.

&ikylphosphochollnes are a new class of antltumor agents.

Clinical phase I studies with Hexadecyl~hospho-

~hollne {He-PC) are in progress. this

study

Therefore,

the aim of

was to develop a sensitive method

for

the

determination of He-PC in blood of treated patients. Blood

allquots from patients were taken

EDTA containing centrifugatlon. potassium

tent.

extracted

and

monovette and serum After

was

separated

the by

remaining high

limit

were liquid

acetonitrll/

The amount os He-PC

phosphate determination with

of I0 nmoles.

with

lipids

performance

chromatography using sillcagel columns and

by

an by

hydrolysis of ester lipids

butylate

methanol/water as mobil phase. measured

using

obtained

a

was

detection

The elution time of He-PC and

the

recovery rate were evaluated using radiolabeled He-PC as internal standard. of

This method allows the determination

alkylphosphocholines

cholines such as phospho-chollne Zentrum [nnere Robert-Koch-Str.

and

of

alkylglycerophospho-

l-O-octadecyl-2-O-methyl-rac-glycero-3in serum of patients. Medizin,

Abt.

H&matologielOnkologle,

40, D-3400 Gdttingen

$74

2/P-GM 1.06

2/P-GM 108

INTERSTITIAL RADIOTHERAPY AND CONSERVATIVE TREATMENT OF PROSTATIC CARCINOMA. H. Sommarkamp

A M P U T A T I O N VERSUS LIMB SALVAGE IN M A L I G N A N T BONE TUMORS OF THE INNOMINATE BONE W. Mutschler, .C. Burri, ' P. H~ussler ........

Surgical e x c i s i o n o f the tumor bearing organ i s the p r i n c i p l e o f most cancer treatment p r o t o c o l s . In e a r l y pros t a t i c carcinoma r a d i c a l surgery i s advocated to achieve curs, t a k i n g i n t o account r i s k s l i k e u r i n a r y incontinence and loss o f sexual potency. Radiotherapy, by e x t e r n a l or interstitial sources, can c o n t r o l l o c a l tumor growth w i t ~ out removal o f the gland. Treatment p r o t o c o l s ere: p e l v i c lymphsdenectomy f o r diagnosis o f lymphatic spread, permanent (1-125, Au-198) or temporary ( I r - 1 9 2 ) i n t e r s t i t i a l implantation of radioactive sources, with or without external beam combination therapy. Higher local tumor dose and a lower incidence of side reactions ere thus achieved High precision of seed placement is necessary for optimum local control in 1-125 protocols. This is feasible by ultrasound-monitored transperineal implantation. Loss of potency is particularly low (8 %) in brachytherapy with 1-125. Patients with lymph node involvement require adjuvant hormonal treatment. Systemic therapy alone is indicated in old patients with localized cancer unsuited for more aggressive forms of therapy. A wait- and watch-policy is acceptable in patients over 70 yrs. with 10w-v01ume tumors (Tla) of high diffsrentiati0n.

In primary m a l i g n a n t bone tumors of the pelvic bone wide local excision with limb salvage has become an alternative to hemipelvectomy. A rev i e w of 50 p a t i e n t s o p e r a t e d on b e t w e e n 1978 and 1987 was u n d e r t a k e n to evaluate the functional and oncological results after different types of resection. 18 pat. u n d e r w e n t a type I, II or III resection (Enneking, JBJS 60 A, 731, 1978), 18 a partial or total internal h e m i p e l v e c t o m y followed by r e p l a c e m e n t with a polyacetal hemipelvis, 10 a c l a s s i c a l or anterior flap hemipelvectomy. In 4 pat. extended b i o p s i e s were performed. The following conclusions were b a s e d on our data: I. In low grade m a l i g n a n c y bone tumors (n=15) all patients survived. The number of local rec u r r e n c i e s was low (n=3), the functional results were e x c e l l e n t or good, the c o m p l i c a t i o n rate low (n=4). 2. In high grade m a l i g n a n c y tumors the 5-yearssurvival rate was about 30%. Local recurrencies and lung m e t a s t a s e s often occured (n=8;I0). 3. Internal h e m i p e l v e c t o m i e s a n d h e m i p e l v e c tomies c a u s e d a high rate of c o m p l i c a t i o n s (n=18) m a i n l y due to the tumor's extent. 9 comp l i c a t i o n s remained. 4. The functional results after internal hemip e l v e c t o m i e s were much b e t t e r than after hemipelvechomies. 5. A d d i t i o n a l c h e m o t h e r a p y and irradiation h a d little effect on the oncological outcome. A b t e i l u n g f. U n f a l l c h i r u r g i e der U n i v e r s i t ~ t Ulm Steinh6velstr. 9, D-7900 Ulm

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IS A M P U T A T I O N N E C E S S A R Y IN SOFT TISSUE SARCOMAS OF THE EXTREMITIES ? H. U. Steinau, E. Biemer, V. Gerein~ B. Kornhuber*

PATHOPHYSIOLOGY, DIAGNOSIS AND THERAPY OF DRUG-INDUCED GONADAL TOXICITY IN PATIENTS TREATED FOR MALIGNANT

Limb sparing resection and r a d i o / c h e m o t h e r a p y has become the treatment of choice in STS of the extremities. However, w i t h local recurrencies, infiltration of blood vessls, nerves and joints it is very likely, that the patient will loose his limb. Since 1978 61 patients have been treated according to the following rationale: C o m p a r t m e n t ectomy or radical resection in combination w i t h pre- or p o s t o p e r a t i v e chemo- radiotherapy. The o n c o l o g i c a l l y required large soft tissue defects could be covered by m i c r o s u r g i c a l free tissue transfer in 26 cases. In addition functional r e h a b i l i t a t i o n could be established by tendon transfers (29), muscle t r a n s p o s i t i o n (6) nerve grafts (6), v a s c u l a r i z e d bone transfer(3) and V S M - g r a f t s (3). 8 patients received stump d i s t a l i s a t i o n procedures using plastic surgical techniques. During an average follow up of 37 months, 6 patients succumbed due to d i s t a n t metastasis. Only 2 developed local recurrenoies which could be treated in one case with repeated large resection and in the other case with amputation. All others gained functional results superior to comparable prosthetic devices, though 2/3 were addmitted with the first or multiple local recurrencies. D e p a r t m e n t for Plastic Surgery, Tec~inical University Munich, F. R. G. D e p a r t m e n t for Pediatric Oncology, U n i v e r s i t y Hospital Frankfurt, F. R. G.*

DISEASES.

E.D. Kreuser Considerable progress has been made in the treatment of certain types of neoplastic diseases. This prolonged survival has focused attention on chronic or late side effects of chemo- and radiotherapy. Particularly young adults are concerned about their subsequent endocrine and reproductive dysfunctions. Only limited data is available about gonadal toxicity after aggressive chemotherapy. Therefore, this investigation was conducted to evaluate the impact of therapy on reproductive and endocrine gonadal functions in female and male patients. 33 patients successfully treated for Hodgkins's disease, 20 with ALL/AUL, 40 after bone marrow transplantation, and 40 patients treated for germ cell tumors were studied. Diagnostic proeeduces to establish acute and chronic gonadal toxicity included i) hormone analyses using ILIA for FSH, LH, testosterone, progesterone, estradiol, prolactin, 2) interviews with a standardized questionnaire, and 3) sperm analyses. All men treated for Hodgkin's disease showed irreversible infertility after COPE-chemotherapy. Ovarian failure occurred in 57% of women suffering from premature menopausal symptoms influencing significant the quality of life. In men and women treated for AL~/AUL, there was no evidence of chronic endocrine or reproductive dysfunction. Irreversible reproductive impairment occurred in all men and women after bone marrow transplantation and estrogen deficiency only in women, All men treated for germ cell tumors showed reversible reproductive impairment. Recovery of spermatogenesis occurred in 80% of the patients 2-4 years after chemotherapy. Abt. Innere Medizin III (H~matologie/Onkologie) Univ. Ulm, Steinhavelstr. 9, 7900 Ulm, F.R.G. Supported in part by a grant from Deutsche Krebshilfe (M16/86, He3).

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'I~E RADIOTHERAPEUTIC CONSERVATIVE MANAGEMENT OF RECTAL TUMORS: RESULTS ACCORDING TO THE DIJON STAGING SYSTEM. S.L. Roth(2),J.C~ Horiot{i) At the C.G.F~ Leclerc, DIJON, 91 patients with early rectal tumors received intracavitary 50 kV contact radiotherapy alone or associated with interstitial brachytherapy according to the guidelines of J. Papillon. 72 patients presented with a rectal cancer. 19 had a villous adenoma~ The majority of the patients had contra-indications for major surgical procedures. - According to the clinical and endoscopic staging system (HORIOT 1986), 30 of the 72 rectal cancer patients presented with a clinical stage CS A1 (i.e.purely exophytie tumors of less than 3 cm). The 5 year local relapse free actuarial survival rate was 98 %. - This was significantly different (p: 0,01) in 42 of the 72 rectal cancer patients with borderline indications for intracavitary treatment: 9 patients in CS A2 (with larger exophytic tumors), 14 patients with CS BI (infiltrative component but diameter ~ 3 cm) and 19 patients with CS B2 (larger infiltrative but not fixed tumors). Their local relapse free rate was 67 %. The local relapse free rate including treatment of relapse by a second intracavitary treatment or surgery was 93 % at 5 years. - 19 patients with benign villous tumors had a five year local relapse free rate of 60 % and including treatment of relapse 82 % were NED at 5 years. Other prognostic factors will be presented.

ORGAN PRESERVATION FOR ANAL CARCINOMA BY SIMULTANEOUS RADIOCHEMOTHERAPY

In conclusion, CS Ai can be safely treated with intracavitary contact therapy alone. CS A2, B1 will more often require the co~ination of intracavitary and interstitial therapy, whereas CS B2 should be delivered external irradiation first and in case of good response receive intracavitary and/ or interstitial to resume the conservative treatment. From Service de radiotherapie Centre Lutte centre le Cancer G.F.Leclerc, DIJON~ France (i), Strah]entlnerapeutische Universit~tsklinik G0%~fINGEN, West-Germany (2).

G. Grabenbauer, J. Ounst, M. Herbst, N. Wolf, P. Hermanek, R. Sauer Since January 1985 20 patients with anal carcinoma were treated by simultaneous irradiation and chemotherapy as primary treatment modality. The primary tumor and regional lymph nodes received a total dose of 50 Gy for five weeks. During the first and fourth week of the combined treatment regimen 5-FU (i000 mg/sqm daily for 96 hours by continous infusion) and Mitomycin C (lO mg/sqm on day 1) were administered parallel to conventionally fractionated radiotherapy. Treatment was well tolerated by all patients without severe hematological or gastrointestinal complications. 19/20 patients achieved clinically complete response at the end of the treatment (no tumor palpable). In 16/20patientsmultiple biopsies were obtained from the primary tumor region four weeks after treatment. In 15/20 patients no further operative treatment was necessary since the biopsies showed no evidence of disease. Median follo~-up is 12 months. Simultaneous radiation and chemotherapy is considered as the treatment of the choice for anal carcinoma.

Strahlentherapeutische Klinik und Poliklinik, Chirurgische Klinik der Universit~t Erlangen-NOrnberg.

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CARCINOMATA OF FISTULAS IN CHRONIC OSTEITIS. AMPUTATION

THE PRETHERAPEUTIC INVESTIGATIONS FOR DIAGNOSIS AND STAGING OF MUSCULOSCELTAL TUMORS A. H ~ r l e , M. R e i s e r L R. E r l e m a n n , P. W u i s m a n

OR LIMB-CONSERVING RESECTION? R. Ketterl, A.M. Fel]er, H.U. Steinau, T. Beckurts In case of chronic o s t e i t i s with reoccuring f i s t u l a s and a duration of decades, the p o s s i b i l i t y of carcinomatous degeneration has to be kept in mind. Until recently, the therapy of choice in patients with fistula-carcinomata in the lower leg or knee region was either an amputation at thigh leweI or even an exarticulation in the hip j o i n t . Since the introduction of techniques for free tissue transfers capable of covering large soft tissue defects, we have performed limb-conserving resection of f i s t u l a carcinomata in four patients aged 43 to 68 years. In a f i r s t operative session, the tumors were resected radic a l l y inclusive of a l l neighbouring soft tissue and bone structures. Then, after histological examination and proof of tumor-free resection borders, the defects were covered by microvascular free tissue transfer. Within the follow-up periods of 2 to 5 years, we have not observed a local tumor reoccurrence. All patients could be reintegrated into t h e i r professional and family lives within 4 to 6 weeks. According to our results, the e f f o r t of limb-conserving resection techniques seems f u l l y j u s t i f i e d , provided cert a i n t y in radical tumor removal. In our opinion, a l l f i s t u l a s in patients with chronic o s t e i t i s should be treated operatively for reasons of prevention; especially since modern techniques of microvascular free tissue transfer allow for satisfactory functional and cosmetic results. Departement of Surgery and Departement for Plastic Surgery of the Technical University MUnchen, Ismaninger Strasse 22, O-8000 M~nchen 80

As a consequence of refined methods in b o n e t u m o r s u r g e r y , m e t i c u l o u s d i a g n o s t i c w o r k - u p is m a n d a t o r y . N e w m o d a l i t i e s of r a d i o l o g i c i m a g i n g , e.g. C T a n d M a g n e t i c R e s o n a n c e T o m o g r a p h y (MRT) brought about dramatic improvement. At our ins t i t u t i o n c l o s e c o o p e r a t i o n of s u r g e o n s , p a t h o logists, oncologists and radiologists has b e e n e s t a b l i s h e d for t h i s p u r p o s e . B e f o r e b i o p s y is p e r f o r m e d , relevant imaging modalities h a v e to b e u t i l i z e d , thus allowing for selection of adequate biopsy approach as w e l l as a v o i d i n g a r t e f a c t s r e s u l t i n g f r o m b i o p sy. In a d d i t i o n to c o n v e n t i o n a l radiograms and b o n e s c a n n i n g , C T a n d M R T is u s e d on a r e g u l a r basis. W h i l e CT is s u p e r i o r in d e t e c t i o n of b o n e destruction and calcifications, MRT proved highly reliable in t h e a s s e s s m e n t of soft tissue expansion and bone marrow infiltration. By virtue of m u l t i p l a n a r a n a t o m i c r e p r e s e n t a t i o n , M R T e n a b l e s a c c u r a t e d e t e r m i n a t i o n of c o m p a r t i m e n t a l t u m o r spread. Following cytostatic chemotherapy, r e s p o n s e of t u m o r c o u l d be p r e d i c t e d q u i t e r e l i a b l e by u s i n g bone scanning and MRT. Gadolinium-DTPA, a paramagnetic contrast material was administered in 5 4 p a t i e n t s . T h e t i m e d e p e n d e n t increase in s i g n a l i n t e n s i t y a s m e a s u r e d by g r a d i e n t e c h o sequences exhibited clearcut differences in r e s p o n d e r s a n d n o n - r e s p o n d e r s . The p r e o p e r a t i v e s e l e c t i o n of the a d e q u a t e s u r g i c a l p r o c e d u r e a n d the c o n s i d e r a t i o n of l i m b s a l v a g e a r e t h u s b a s e d on relevant findings and can be reevaluated objectively. Orthop~dische Universitits-Klinik, Klinische Radiologie, M~nster

Institut

f~r

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TREAT~ENT OF ADVANCED BLADDER CARCINOMA WITH VP 16 AND CISPLATINUM SPLIT DOSE

M-VEC POLYCHEMOTHERAPY OF ADVANCED TUMORS OF THE BLADDER AND UPPER URINARY TRACT

J. Wiedeck, K.F. Klippel, B. H'dbner, Depart.of Urology, General Hospital, 3100 Celle , West Germany

U.RBthar, K.B~uerle, H.Konyar, P.3ipp, 3.Rassweiler , F.Eisenberger, C.G.Schmidt

A prospectiv phase II-study of the known ccmbinaticn of VP 16 and Cisplatinum split dose was carried out cn 14 pts. All pts. entered on study had advanced, measurable TCC cancer and hat not received previous chem~otherapy. Cis-platin (40 mg/m 2 ) was given on day I + 8, Etoposid on day 3, 4 and 5 (150 mg/m 2) with repetition every 4 %~e_ks. The median age of the pts. was 59 years (R: 37-73 y). CR was seen in 3 pts. = 21%, PR in 5 pts. = 36 % ~4~.ich means a total response rate of 57 % with a median dictation of 21 ~ e k s (CR) or 15 weeks (PR). NC was seen in 3 pts. = 21%,median dur. of 11 weeks. Progress had 3 ptso = 2 1 % . ~ne combination had better results in the primary tumor than in its metastasis. 8 pts. ~ r e treated with ~_his c~bination pT 3 b, G 3 (6 x) and pT 4a, G 3 (2 x), TCC (Nx, Nb). CT was performed before beginning of the inductive chemotherapy amd after second course. Total response rate was 87 % with CR in 5 pts. = 62 % and PR in 2 pts. = 25 %. NC was seen in I pts. Median age ~as 62 years (R: 41 - 83 y.). Side effects: ~ i t e count nadir: ndn 800/~i, median 5.300/~i, nadir t h r ~ i a rain 79.000/~i , median 253.000/~i. Nausea und vomiting was tolerable in both groups. Alopecia quite conmDn. No drug related death. Although response rate of the second group seems cor~parativly high (s~all number), the cor~b~nation of VP 16 and Cis-Platin~n seems to have less toxicity t~kln other coml~inations and shews better effect on primary tumor than on metastasis.

Polychemotherapy with methotrexate, vinblastine, doxorubiein and cisplatin (M-VAC) has proved most effective in the management of advanced tumors of the bladder and upper urinary tract, response rate reaching 75~ with complete remissions in 36%. Since average patient age and frequency of cardiovascular disorders are high, however, we have investigated the use of less cardiotoxic epirubicin at equal dose within the above regimen, replacing highly cardiotoxic doxorubicin (M-VED). From 10/85 to 5/87 45 patients at an average age of 66 years completed M-VEC therapy, initial staging showing locally advanced disease in 38%, nodal metastases in 29% and distant visceral metastases in 25%. Response rate reached 73% with complete remissions in 51% at a median follow-up of 18 months. Epirubicin doses ranging from 200 to 300 mg, no clinical evidence of cardiatoxicity was found, neither of the acute nor of the chronic type. Significant decrease of left ventricular ejection fraction was shown in 13% of patients by radionuclide ventriculography. Thus M-VEC can be looked at as a highly effective regimen in the:management of advanced urothelial tumors, comparable to M-VAC, yet applicable to patients with pre-existent cardiovascular disease, too. Zentrum fBr Innere Medizin, Katharinenhospital, Kriegsbergstr.60, D-7000 Stuttgart I

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D E T E C T I O N OF L Y M P H N o D E M E T A S T A S E S IN B L A D D E R C A R C I N O M A P A T I E N T S BY C O M P U T E R T O M O G R A P H Y H. Buszello, V. M O l l e r - M a t t h e i s , R. A c k e r m a n n

Radio:-Chemotherapy of bladder2 cancer

For the m a n a g e m e n t of b l a d d e r c a c i n o m a n e w reg i m e n h a v e b e e n e s t a b l i s h e d d u r i n g the last f e w years, p a r t i c u l a r l y those, e m p l o y i n g polyc h e m o t h e r a p y . T r e a t m e n t of b l a d d e r c a n c e r dep e n d s on the p r e c i s e s t a g i n g of the tumour. Computertomography (CT) seems to be the m o s t s e n s i t i v e m e t h o d for d e t e c t i o n of m e t a s t a t i c d i s e a s e in r e g i o n a l l y m p h nodes.

Strahienklinik und Urologische Klinik der Universit~t Erlangen-NOrnberg, Strahlenklinik des St~dt.Kliniku~s NOrnberg

In o r d e r to d e t e r m i n e the v a l u e of CT in det e c t i o n of l y m p h n o d e m e t a s t a s e s , a r e t r o s p e c tive s t u d y of 37 p a t i e n t s w i t h b l a d d e r carcinoma was c a r r i e d out. P r e - o p e r a t i v e CT w a s comp a r e d w i t h the r e s u l t s of h i s t o p a t h o l o g i c a l e x a m i n a t i o n of d i s s e c t e d p e l v i c l y m p h nodes, which had been removed either during radical c y s t e c t o m y or s t a g i n g laparotomy. In 31 patients CT scan did not d e m o n s t r a t e l y m p h node e n l a r g e m e n t ; in 22 of t h e s e patients, CT findings w e r e c o n f i r m e d by h i s t o l o g i c a l e x a m i n a tion. A single l y m p h node m e t a s t a s i s w a s f o u n d in 4 patients, w h e r e a s two or m o r e l y m p h nodes w e r e f o u n d p o s i t i v e in 5 p a t i e n t s . All p a t i e n t s w i t h l y m p h n o d e e n l a r g e m e n t in CT h a d m e t a s t a tic disease, as w a s c o n f i r m e d by h i s t o D a t h o l o g y . In our study, s p e c i f i c i t y of CT scan in detecting lymph node m e t a s t a s i s was 100%, w h e r e a s s e n s i t i v i t y was 40% only. Thus we conclude, that a p e l v i c l y m p h node d i s s e c t i o n should be c a r r i e d out b e f o r e r a d i c a l c y s t e c t o m y , even if CT did not show l y m p h node e n l a r g e m e n t . Urologische Moorenstra~e

Klinik

der U n i v e r s i t ~ t

5, D - 4 0 0 0

DNsseldorf

DOsseldorf

J.Dunst, H.J.Thiel, K.Ziegler, K.M.Schrott, R.Sauer

Since 1985, 44 patients with invasive bladder cancer have been treated by a simultaneous radio-chemotherapy. Treatment aims were local tumor control and preservation of bladder function. 35 male and nine female (age 44-77 years) with a median follow-up of 12 months were evaluated. Tstage was : Tl:lO, T2:2, T5:22, T4:5. All patients had initial TUR and a bladder mapping prior to radio-chemotherapy, 18 patients with TS- and all patients with T4-tumors had macroscopic residual tumor after TUR. Radiotherapy was performed with daily fractions of 1.8Gy up to 41.4Gy to the pelvis (box-technique) and 50.4Gy to the bladder (boost by rotation-technique). Cisplatin was administered on five consecutive days in the first and fifth treatment week in a dosage of 25mg/qm/d. Six ~,eeks after radio-chemotherapy, control cystoseopy with biopsies from the primary tumor region was performed. 40/44 patients achieved complete remission after TUR and radio-chemotherapy. 17/21 patients with T3-4 cancers and macroscopic residual tumor after TUR had a histologically CR after radio-chemotherapy. Three local recurrences have occurred in complete responders, one with distant metastases also. Four cystectomies have been performed. All patients with preserved bladders had a normal bladder function. Severe complications did not occur, even in older patients. Primary radio-chemotherapy with curative intent yields a high local response rate and can preserve bladder function in most patients. We consider primary radio-chemotherapy with cystectomy restricted to non-responders or recurrences as locoregional treatment of choice in musele-invasive bladder cancers.

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SOCIAL W O R K AS A P A R T OF AN A C T I V A T I N G I N T E G R A T I V E C O N C E P T IN THE A F T E R C A R E OF TUMOR PATIENTS G.Felder end H.Delbrueek

LIMITS OF SURGICAL TUMOR THERAPY: PELVIC EVISCERATION WITH VAGINAL AND UR]NARY BLADDER RECONSTRUCTION A.H. Tulusan, M. DiPaoio, D. May

Tumor p a t i e n t s are eonfrontated w i t h a n u m b e r of fundamental problems by the o c e u r e n o e of their d i s e a s e ~ B e s i d e s medical d e c i s i o n s t h e s e p r o b l e m s include important p s y c h i c and emotional aspects as well as social and p r o f e s s i o n a l ones. Leaving the responsibility of his medical problems to the doctors, the p a t i e n t s often represses the other ones or only realizes t h e m w h e n being at home. R e h a b i l i t a t i o n in an a c t i v a t i n g way of a f t e r c a r e of t u m o r p a t i e n t s d o e s n o t only mean to offer somat~ help to the p a t i e n t but to h e l p him t o r e s o l v e his social and p s y c h o l o g i c a l p r o b l e m s as well. This includes the f o l l o w i n g m a i n tasks: l . d i s e u s s i o n of simple questions of social law 2. i n t e r d i s c i p l i n a r y c o n c o m i t a n t advice 3.psychological and pastoral s u p p o r t of t h e patient Psychological and SOcial problems seem to be e s p e c i a l l y hard for the p a t i e n t s when they just finish therapy.83~ of our patients p r o f i t e d of our h e l p in the social and p s y c h o l o g i c a l domain during the aftercare, compared to 2 5 ~ of the patients during t h e i r Ist stay in e sanatory and 5~ of %.he p a t i e n t s d u r i n g their 2nd stay in a sa~uatory. 53~ of the consultations lasted for about 1 hour, 3 9 ~ for 4hours and 8~ t o o k m o r e then iOheurs time.

Treatment of advanced pelvlne malignancies by extensive procedures reflecting the possible limits of surgery are considered to be an inexpendlble part of modern gynecologic oncology. 63 patients were operated on from 1977 till t987 at the University clinic of Ertangen. Pelvic exenteration was done for the reduction of extensive and advanced recldlves of pelvine malignant tumor end subsequently patients morbidity, mortality as well as life quality were analyzed. The 5 year survival rate reached desplte the advanced stage of disease 40 %. Patients who underwent preoperative radiation course suffered significantly more of intra - as well as postoperative complications due to wound healing disturbances. Mortality reached 5 %. Some patients proved to be carrier of small tumor rest despite the exhaustive surgical effort. In such cases the value of adjuvant radiation therapy was reexamined. A second group was treated by extensive surgery for the rodiological approach feiled due to tumor necrosis and fistulizatlon o r cloak-formatlon on the urogenital tract. Those patients were treated by a second palliative surgery of course accounting for the limits set by their general health. This particular group had the worst survival prognosis although life quality seemed to improve as compared to the preoperative situation. Modern advances in surgery, onaesthesiology and intensive care creates the foundation for treatment o~ conditions, which only few years ago gave rise to situations where patients had to undergo terrible Hfe ordeals due to medical incapability. After oH the investigation shows, that combination of extensive surgery with reconstructive manipulations conserving certain organ functions will improve dearly patients life quality.

K l i n i k 'Bergiseh-Land" d e r LVA R h e i n p r o v i n ~ Im S a a l s e h e i d 5, 5600 W u p p e r t a l - 2 1 (Ronsdorf)

UnNersltets~Frauenklinlk Edangen (Direktor: Prof.Dr.N.Lang), Universltetsstral3e 2]/23, D-8520 Erlangen

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3/18-G 001

CHANCES F O R F U N C T I O N P R E S E R V A T I O N E X T E N D E D S U R G E R Y IN G Y N E C O L O G I C M A L I G N A N C I E S H.-G. Schn~rch, H. G. Bender, L. Beck

LARYNX CANCER: PRESERVATION OF LARYNGEAL FUNCTIONS BY PRINARY RADIOTHERAPY E. Richter

One of the m a j o r o b j e c t i o n s a g a i n s t e x t e n d e d radical surgery for a d v a n c e d g y n e c o l o g i c m a l i g nancies has b e e n that these p r o c e d u r e s w o u l d be to mutilating. W i t h the d e v e l o p m e n t of newer surgical techniques q u a l i t y of life maybe even improved w i t h these procedures. We have e v a l u a t e d the data of 53 e x e n t e r a t i o n s for g y n e c o l o g i c m a l i g n a n c i e s p e r f o r m e d at the D e p a r t m e n t of G y n e c o l o g y and Obstetrics, D~sseldorf U n i v e r s i t y M e d i c a l Center. The e v a l u a t i o n focussed on the m a n a g e m e n t of u r i n a r y tract and bowel. In 42 p a t i e n t s c y s t e c t o m y was performed. In 26 patients a c o n d u i t was c r e a t e d for u r i n a r y d i v e r s i o n (18 ileum conduits, 8 colon conduits). In 7 p a t i e n t s an u r e t e r o s t o m y and in 8 nephrostomy was used. It is our e x p e r i e n c e that urinary d i v e r s i o n s w i t h their b a g - c o n t i n e n c e are much b e t t e r a c c e p t a b l e than complete incontinence due to fistula formation. In 25 patients a bowel resection was p e r f o r m e d in the course of exenteration. In 12 patients primary anal c o n t i n e n c e could be g u a r a n t e e d by colonic anastomoses. In 4 patients a temporary loop c o l o s t o m y offers the chance of s e c o n d a r y c o n t i n e n c e re-establishment. C o n t i n e n t pouches offer the chance of an even b e t t e r functional result for urinary diversions. So far 2 of our patients enjoy the advantages of a Kock-pouch. U n i v e r s i t ~ t s - F r a u e n k l i n i k DHsseldorf, M o o r e n s t r a B e 5, D - 4 0 O O D ~ s s e l d o r f

In order t o accomplish successful management o f l a r y n x cancer i t i s necessary beth to know the best cure r a t e and t o keep the p r e s e r v a t i o n o f l a r y n g e a l f u n c t i o n s in mind. For the p a t i e n t loss o f the voice leads t o s o c i a l and psychologic problems. Radiotherapy i s so f a r the only form of treatment which allows to r e t a i n the anatomic s t r u c t u r e s and t h e i r f u n c t i o n s , t h e r e f o r e i t i s treatment o f choice f o r T1 l e s i o n s , As f o r the r a d i a t i o n technique a 60-Co. u n i t or a l i n e a r a c c e l a r a t o r must be employed nowadays, usually a tumor dose of al least 60 Gy (5 x 2 Gy weekly) will be sufficient. Preliminary to application of the prescribed dose in the target volume and greatest possible sparing of the surrounding tissue is an individual and computer assisted planning of radiation therapy. The recently published results suggest radiotherapy cure rates for Tla and Tlb lesions of 80 95%. For T2 glottic lesions a survival-rate of 60 - 70% can be expected. For persistant or recurrent tumors surgical salvage after radiation has the same success rate as primary operation. With the introduction of megavoltage irradiation the side affects are less common, erythems and edema appear regularly end are susceptible to conservative treatment. Severe radiation sequela like chondritis and cartilage necrosis are rare provided the suggested tumor doses are applied. Klinik und Poliklinik for Strahlentherapie der Universit~t UOrzburg dosef-Schneider-StraBe 11 D-8700 WOrzburg

$78

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CHANGE OF MARKER CONCENTRATIONS IN S~3RT TIME FOLI/]W-UP STUDIES K. Kohlhas~ P. Oehr~ U. Loos

CA 125 - PROBLEMS WITH THE ANTIBODY 5. M Q l l e r - H a ~ e n ~ , L . H o f f m a n n ~, J , N e p p e r t 2

Determimmtion of tumor marker concentration changes during follow-up studies of tumor patients after therapy might lead to false interpretations due to variable factors influencing the blood marker concentrations. In a prospective study over a period of 6 weeks, serial determinations of TPA, CEA-19-9, CF9%-15-3, CA-50, NSE, SCC, and Thymidine Kinase were made in short time intervals. The investigation was related to patients (n=80) with radio- or chemotherapy suffering from either breast, bronchial or gastrointestinal cancer. Each marker sh~wed an individual sensitivity and specificity for each tumor localization. There were different typical effects of each marker during treatment. NSE for example had a biphasic curve for marker elevation in patients with bronchial carcinoma. SCC could hardly be interpreted. All the other markers showed similar trends during radiotherapy in bronchial and breast cancer. Our study s~Dws the characteristic properties of each marker and gives proof of the fact that the date of determination of marker elevation plays an important part within the first 6 weeks during therapy. Assessment of tumor growth or tumor damage on the basis of marker concentration changes within the first 6 weeks during therapy will lead to false interpretations when the characteristic of each marker is uz2~nown. Dr.P.Oehr, Institut f.klin, und exp. Nuklearmedizin der Universit~t Bonn, Sigmund-Freud-Str. 25, D-5300 Bonn I

ANTIGEN (C/A)

DIF~RENT fTXl"RFS5ION IN

DIF'FTTRITNrTCANCFR.~ ?

P. Rahn, W. Jigger. I . WIIdt Utlllz-lng mon(x=lonal antibodies ( m a b ) it could be dernonstratod that t h e C E A molecule Is defined by a t teast slx d i f f e r e n t arttig~nlc deter'mlnants. The e x p r e s s i o n o f t h e s e d e t e r m i n a n t s , h o w e v e r , m a y d i f f e r b e t w e e n various c a r c i n o m a s . Polyclonal antibodies for s e r u m m e a s u r e m e a t s w e r e not able to distinguish b e t w e e n d i f f e r e n t CFA~ VVith newly

available r a d i o { m r n u n o a a s a y s using m a b d i r e c t e d a g a i n s t single ~ p l t o p a s the differentiation b e t w e e n various C E A should be possible. We

In 7 / 9 1 ( 7 ~ 8 % ) of sere ~ i t h p l a s m a levels b e t m e e n 200 and 500 U/ml J.n u n d i l u t e d " r o u t i n e ' - a n a l y s J s PPH was d i s c o v e r e d too. We c o m p a r e d 3 a v a i l a b l e RIAs and one EIA. All 3 RIAs t e s t e d ( C I 5 - 1 s o t o p e n D i a g n o s t i c s , Abbott~ SorJn) d e m o n s t r a t e d the p r o b l e m in the same m a n n e r . The EIA (Abbott) did not. C o n c l u s i o n : CA 125 tests are s u s c e p t i b l e to PHH b e c a u s e a n t l b o d y b i n d i n g can be i n t e r f e r e d . The p h e n o m e n o n can even occur in sera ~ith r e l a t i v e ly low a n t i g e n c o n c e n t r a t i o n s , lhJa p r o b l e m ~s often found in a n a l y s i s of e f f u s i o n s . To avoid misinterpretation of m a r k e r levels, e s p e c i a l l y for a s s e s s m e n t of c l i n i c a l course, a n a l y s i s s h o u l d be p e r f o r m e d m i t h d i l u t e d sera as a standard p r o c e d u r e . 1 O n k o l o g J s c h e Abt., A l l g e m e i n e s Krhs. B s r m b e k , R O b e n k a m p 148, D 2000 H a m b u r g 60 2 1 n s t i t u t f. T r s n s f u s i o n s m e d i z J n , GieBen

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3/19-0 002 CARCINOFMi3RYONIC

A lot of i m m u n o l o g i c a l tests deal ~ith the prozone p h e n o m e n o n (PPH)or " H i g h - d o s e - h o o k - e f f e c t " (HDHE) m h j c h leads to falsely Io~ results. In g e n e r a l the p r o b l e m o c c u r s only ~hen a large a n t i g e n amount, and thus a large tumor mass Js present. We e x a m i n e d the f r e q u e n c y of PPH Jn CA 125 tests J.n serum (S) and a s c i t e s (A) s a m p l e s of p a t i e n t s (pat.) ~J.th o v a r i a n c a r c i n o m a . R e s u l t s : A PPH ~as o b s e r v e d Jn 6/8 pat. ~ J % h large t u m o r mass, 4 of them ~ith r e s u l t s far b e l o w 500 U/ml in u n d i l u t e d sets. seradlluW.F. P.H. H.R. A,G. G.H, G.M. tion "Ji',l 392""~ " ' 3 9 2 423 472 > 500 > 500' U / m l 1:128 1 6 9 8 3 i l i 1 9 4 15570 19520 7488 14820

therefore (~mpared

t h e CTTA c o R ~ n t r a t l o n s

treasured with a

m i x t u r e o f polyclonal antlbodk~s ( C F A K PR, ID. CL~, Dr~telch, F R G ) w l t h the concentrations obtained by the combination o f t h r e e mab (F[ 5 A -

CEA, I['~-CL%).

THE PROGNOSTIC VALUE OF NEOPTERIN DETERMINATIONS IN PATIENTS WITH GYNECOLOGIC MALIGNA~;CIES L. C. Faith+. D. Fuchs*, A. Hausen m, H. Hetzel+, G. Reibne~er*, E. R. Werner*, and H. Wachter ~ Neopterin is a pyrazinopyrimidine compound originating from guanosine trJphosphate. In vitro, neopterln is excreted by human macrophages after stimulation with supernatants from activated T-lymphocytes or with gamma-interferon. Pretherapeutic and serial urinary neopterin levels during follow-up were measured in 186 women with cervical carcinoma, and in 174 patients with ovarian carcinoma. Neopterin levels prior to therapy showed a prognostic significance for the survival expectation in both types of cancer. Furthermore, in ovarian carcinoma neopterin determination at the time of second-look laparatomy reflected significantly the presence or absence of tumor.

S e r u m levels w e r e determ|rmd In 4 . 0 0 0 p a t i e n t s with d{fforant g y r a t e logical c a n c e r s . F o r statistical analysis w e d~velopod a p r o g r a m which rens on every p e r s o n a l computer.

In s o m e patients suffering f r o m p r o g r e s s i v e cervical c a n c e r elevated C E A concentrations w e r e only observed with the PolycIonal antlbodles, while t h e C E A level w e r e below detection r a n g e In t h e monoclonal

a s s a y s y s t e m . T h e f u r t h e r anatysls o f o u r d a t a d e r r ~ n s t r a t e d COr~parable p h e n o m e n a in patients with m e t a s t a t i c b r e a s t c a n c e r during t h e C O u r s e o f t h e i r d i s e a s e . So f a r t h e r e s u l t s o f this s t ~

streng-

t h e n the a s s u m p t i o n t hat different c a n c e r s m a y produce different CF'A molecules and that during m e t a s t a t i c disease the e x p r e s s i o n o f epltopea m a y change. t~partment

of Obstetrics

and Gyrmcology, University o f F~rlang~n.

L~lverslt~t~sstr.21. D - - 8 5 ~ 0 Erlangen.

In cervical carcinoma a highly significant correlation of serial neopterin measurements with the risk of relapse, metastasis and death was found. Neopterin is not a tumor-specific marker. However, elevated neopterin levels reflect the degree of macrophage activation and therefore indicate the permanent presence of antigen. Thus, the recognition of antigenic structures seems to be intact while the effector functions appear to be suppressed. +) Universit~ts-Klinik fur Frauenheilkunde Innsbruck, Anichstrage 35, A-6o2o Innsbruck *) Institut f~r Medizinische Chemic sad Biochemie der Universit~t Innsbruck, AnichstraBe 35, A-6o2o Innshruck

S 79

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EVALUATION OF SQUAMOUS CELL CARCINOMA ANTIGEN (SCC) IN PATIENTS WITH ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCH&N) AND SQUAMOUS CELL CARCINOMAS OF OTHER LOCATIONS H~A~ Vaupe!~.M. Echroedey and M. Westerhausen In order to examine the clinical value of the recently available marker SCC (Abbott Diagnostic Products GmbH) for staging and follow up in patients (pts) with SCCH&N we monitored SCC in 27 pts suffering from SCCH&N between ianuary and november 1987. 15 male pts with locally advanced SCCH&N (stages PT2_ 4 with or without cervical node involvement) with a median age of 52 years (range 34-75) entered the study. The control group was formed of 12 pts (4females aged 44-62, mean 49 years, and 8 males aged 46-77, mean 60 years) with _n~ clinical e_vidence of disease (NED). These pts were in biopsy-proven continuous complete remission after prior surgery and/or chemo-/radiationtherapy. SCC levels were elevated (}2,0 ng/ml) in ].i/15 pts (73 %) with clinical evidence of disease and in 1/12 pts (8,3 %) in the control group (NED). There was a statistically significant difference between both groups. All II pts with elevated SCC levels at the onset of treatment are eligible for response and outcome of treatment with 3 or more serial specimens obtained during therapy. SCC levels were strongly correlated with clinical status and outcome of therapy, 8 pts showed decreasing SCC levels while responding to therapy, 7 pts had increasing SCC levels with progressiv disease (4/7 after initial response). To verify these observations we tested a group of 15 pts with other squamous cell carcinomas (6 esophagus, 1 vulva, 1 anus, 3 cervix, 4 lung) and found the same correlation between SCC levels and clinical course in 12/15 pts presenting elevated SCC levels prior to therapy. Only 1/20 pts in a control group of non squamous celI solid tumors (15 lung, 2 urinary bladder, 1 ovary, 1 prostate, 1 mesothelioma) showed a slightly elevated SCC level. Mad. Klinik II, St. Johannes-Hospital, An der Abtei 7-11, D 4100 Duisburg Ii

I M M U N O L O C A L I Z A T I O N OF M A L I G N A N T T U M O U R S W I T H 99m-Tc-LABELED MONOCLONAL ANTIBODIES AGAINST C A R C I N O E M B R Y O N I C A N T I G E N (CEA).

OF

A. B r u c h h a u s e n S. F i s c h e r K-H@hn We e x a m i n e d 8 p a t i e n t s w i t h m a l i g n a n t in m o s t cases colorectal carcinomas, c r e a s e d p l a s m a CEA levels, w i t h a n e w hal m o u s e IgG I a n t i b o d y a g a i n s t CEA, with 9 9 m - T e (BW 431/26o Fa. B e h r i n g ) .

%umoursl and inmonoololabeled

The p u r p o s e of oUr s t u d y was to e v a l u a t e the use of a n t i - C E A - a n t i b o d i e s in d e t e c t i o n and specific i m a g i n g of c o l o r e c % a l and o t h e r t u m o u r s exp r e s s i n g CEA and to e s t i m a t e the i m p o r t a n c e of immunoscintigraphy in the f o l l o w up of p a t i e n t s with p r i m a r y and m e t a s t a t i c d i s e a s e . An a c t i v i t y b e t w e e n 740 a n d 1110 MBq ( 2 0 - 3 0 m C i ) was a p p l i e d to each patient. Planar and S P E C T s c i n t i g r a p h y were p e r f o r m e d w i t h a d o u b l e h e a d g a m m a c a m e r a two or t h r e e times b e t w e e n 6 a n d 30 h o u r s post i n j e c t i o n . The r e s u l t s of p l a n a r and t o m o g r a p h i c i m a g i n g were c o m p a r e d to e a c h o t h e r a n d both j u d g e d r e l a t i v e to u l t r a s o u n d , CT and s u r g e r y f i n d i n g s . F u r t h e r m o r e ~ c o r r e l a tion with plasma CEA levels was e s t i m a t e d . Abt. f~r N u k l e a r m e d i z i n , K l i n i k u m der Gutenberg-Universit~t~ Langenbeekstr. Mainz

Johannes I, 6 ~ O O

3/19-0 008

3/19-0 006 RESULTS

FIRST RESULTS.

TUMORM/uRKER

-

INITIATED

HEOPERATIONS

FOR

COLORECTAL CANCER A.Ouentmeier, P.Schlag, Ch.Herfarth ......................................................... Disparate claims have been published recently concerning as well the reliability of serial CEA measurements in the diagnosis of recurrent colorectal cancer as the benefit of early reoperations essentially initiated by increasing CEA values. Therefore we studied the diagnostic and therapeutic gains obtained by closely monitoring serial plasma levels after curative resection of eoloreetal cancer. Between 1978 and 1986, 179 patients with colorectal cancer have been treated. Of the 17S patients 147 (82.2%) had elevated CEA levels (>_ 5 ng/ml) at the time of diagnosis. In 104 of 179 patients (58.1 ~) the CEA increase preceded the reco&~aition of recurrence and influenced essentially the diagnostic procedures. In 24 patients (13.4~) the diagnosis could be confirmed not before a second look operation, which was indicated exclusively by the development of the CEA curves. Patients with metastases (88.9%) showed CEA elevation more often than those with locoregional recurrence

(Ti.z~). 137 patients have been operated upon, 64 (46.7~) potentially for cure. This resectability rate is considerably higher than that of historical control groups (20-25~). The improvement in the reseetability of recurrent colorectal cancer is significantly influenced by an early diagnosis at an asymptomatic stage of disease. In our observation the resectability rate amounted to 34.5% in patients with CEA negative but symptomatic recurrence, to 52.7~ in patients with CEA positive tumors and CEA guided diagnosis, and to 82.5~ in patients with CEA initiated second look surgery, respect ively Chirurgische Universitfitsklinik, Abteilung 2. i. I., Im Neuenheimer Feld 110, 8900 Heidelberg, FRG

THE SYNTHESIS OF THREE DIFFERENT TUMOR MARKER S U B S T A N C E S AS A N I N D I C A T O R F O R C H A N G E S O C C U R R I N G IN S E R I A L L Y X E N O T R A N S P L A N T E D H U M A N T U M O R S AS C O M P A R E D TO THE P R I M A R Y T U M O R S. y o n K l e i s t , J. W e i B i n g e r and H.H. F i e b i ~ It is o f g r e a t i m p o r t a n c e for t h e r a p y s t u d i e s t o knowwhether a p r i m a r y t u m o r t r a n s p l a n t e d into n u d e m i c e k e e p s its o r i g i n a l c h a r a c t e r i s t i c s t h r o u g h o u t n u m e r o u s p a s s a g e s . We, t h e r e f o r e , e x a m i n e d 111 v a r i o u s h u m a n c a r c i n o m a s , m e l a n o m a s and s a r c o m a s for the s y n t h e s i s of 3 t u m o r m a r k e ~ (HCG, CEA, SPI) u s i n g the P O - t e c h n i q u e . T h e i r d i s c o n t i n u o u s p r o d u c t i o n w a s t a k e n as a n i n d i c a t o r for c h a n g e s in the p r o p e r t i e s o c c u r r i n g in the p a s s a g e d t u m o r t r a n s p l a n t as c o m p a r e d to t h e p r i m a r y tumor. It w a s s h o w n t h a t in all bronchial a n d I b l a d d e r c a r c i n o m a H C G s e i z e d to be p r o d u c e d a f t e r the 3rd p a s s a g e , w h i l e the 3 p o s ~ i v e primary gastric carcinomas continued their HCGp r o d u c t i o n t h r o u g h the p a s s a g e s . T h e 75 t u m o r s s t u d i e d for C E A w e r e p o s i t i v e in 33%, i n c l u d i n g all t u m o r s of t h e g a s t r o - i n t e s t i n a l tract. T h e renal carcinomas, melanomas, and sarcomas were n e g a t i v e . In c o n t r a s t to H C G C E A w a s continuously p r o d u c e d in all p a s s a g e s . O n l y 3/5 of the c o l o r e c t a l c a r c i n o m a s e x a m i n e d for SPI w e r e p o s i t i v ~ After the xenotransplantation of H C G - p o s i t i v e t u m o r s to n u d e m i c e it has b e e n s h o w n t h a t n o t all t u m o r s k e e p the a b i l i t y to p r o d u c e this h o r m o n e . W e t a k e this as an i n d i c a t i o n t h a t t h e t r a n s p l a n t e d t u m o r s m i g h t not all r~nainconstant in t h e i r p r o p e r t i e s and this i m p l i c a t e s t h a t x e n o t r a n s p l a n t s , if t a k e n as a m o d e l system, for i n s t a n c e for t e s t i n g n e w c h e m o t h e r a p e u t i c s u b s t a n c e s s h o u l d b e r e g u l a r l y t e s t e d if t h e y still express their original characteristics. Inst. o f I m m u n o b i o l o g y , M e d i c a l F a c u l t y , Univ. Stefan-Meier-Str. 8, D-78 F r e i b u r g

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NOVEL ANTIGEN MARKERS ON STOMACH CANCER AND GASTRO-INTESTINAL TUMNORS G. Kron, R. Klingel, H. Bernhard, K.-H. Meyer zum B ~ s c h e n f e l d e and ....................

VALIDITAT EINES NEUEN NEUROPEPTIDS (HEAD AKTIVATOR ALS TUMORMARKER BEI HIRNTUMOREN W. Sachsenheimer, W. Piotrowski und C.H. Schaller

Although s t o m a c h c a n c e r has n o t o n l y a h i g h incidene in J a p a n b u t is a l s o prevalent in Europe, its a n t i g e n i c p r o f i l e has not been s t u d i e d v e r y extensively. T h e r e f o r e we u s e d a recently established signet ring carcinoma cell line (Dippold et el. Ear. J. C a n c e r Clin. Oncol. 23: 697-706, 1987) to g e n e r a t e m o n o c l o nal a n t i b o d i e s (mAb) and to d e f i n e n o v e l tumor a s s o c i a t e d structures. From 1700 tested hybridoma supernatants we received three ntAb: M-44, I-2 and P-9 w i t h high a s s o c i a t i o n to g a s t r o i n t e s t i n a l tumors, in p a r t i c u l a r to s t o m a c h and colon c a n c e r as s h o w n b y i m m u n p e r o x i d a s e s t a i n i n g of cultured cell lines and f r e s h f r o z e n normal and m a l i g nant h u m a n tissues. N o cross r e a c t i o n of these a n t i b o d i e s to b l o o d g r o u p substances, i n c l u ding Le ~ and Le b , m o n o n u c l e a r cells and the C E A - a n t i g e n was detectable. B i o c h e m i c a l chara c t e r i z a t i o n of the antigen, r e c o g n i z e d b y m A b M-44, y i e l d e d a p r o t e i n m o l e c u l e of 180 to 250 kD, as s h o w n b y S D S - p o l y a e r y l a m i d e g e l e l e c t r o phoresis a n d by W e s t e r n - b l o t - i m m u n o s t a i n i n g . In c o n t r a s t the m A b I-2 and P-9 d e f i n e n e u t r a l glycosphingolipids, extracted from cultured stomach cancer cells and d e t e c t e d by T L C i m m u n o s t a i n i n g . A c c o r d i n g to these p r e l i m i n a r y d a t a on tissue typing, the a n t i g e n s r e p r e s e n t new t u m o r r e s t r i c t e d m a r k e r s for s t o m a c h and c o l o n cancer.

In einem hochsensitiven und hochspezifisehen Radioimmunotest wurden Konzentrationen des Neuropeptids Head Aktivator im Tumorgewebe und im Serum yon Hirntumorpatienten bestimmt. Nach Festlegung der Normalkonzentration wurden deutlich erhShte Tumorgewebskonzentrationen und Blutkonzentrati0nen des Head Aktivator bei Hirntumorpatienten gefunden. Ein Unterschied zwischen malignen und benignen Tumoren oder eine Korrelation zum Malignititsgrad der Tum0ren konnte bislang nicht bewiesen warden. Deutliche Konzentrationsabf~].le des Head Aktivator warden nach Entfernung des Tumors beobachtet. Seine potentielle Bedeutang als mbglicher Hirntumormarker wird diskutiert.

Department of I n t e r n a l Medicine, Johannes G u t e n b e r g - U n i v e r s i t ~ t , L a n g e n b e c k s t r a s s e I, D6500, W e s t G e r m a n y

3/19-0 010

3/19-0 012

LIPID-BOUND SIALIC ACID: WHAT DOES IT MEAN IN SERA OF PATIENTS WITH MALIGNANCY R. Voigtmann, J. Pokorny and A. Meinshausen

TUMOR MARKERS I N hUNG LAVAGE F L U I D FOR D I A G N O S I S OF BRONCRIAL CARCINOMA

Previous and our own studies have reported about raised. levels of lipid-bound sialic acid (LSA) in sera of patients with various neoplasms. This phenomenon has drawn considerable interest because of carbohydrate aberrations in malignant cells and reports of increased glyeolipid levels in cancer cell me~0rane shedding glycosides into the blood stream. Most authors have used the method of Katapodis et al. (Res. Commum.Chem.Pathol.Pharmacol. 30: 171,1980) for isolation serum-LSA. Because of the discrepancy of the amount of extracted LSA with t/he content of pure gangliosides in sara by other groups (Kundu et al.t Arch.Biochem.Biophys.: 238,388,1985) we analyzed the composition of the extracted LSA by immunochemieal approaches. We are able to isolate considerable amounts of glyeoproteins containing sialic-acid as acid OLl-glycoprotein, antitrypsin, haptoglobin, antichyn~otrypsinand immuneglobulins from the so celled "LSA"-fraetion. There is a very strong correlation (r=0.958} between the raised LSA level and the content of acid ~l-glycoprotein in the sera of patients with malignancy. Therefore the term lipid bound sialic acid applied to this test is misleading, since glycoproteins containing sialic acid are mostly responsible for the high "LSA"levels, and gangliosides are probably only minor components of this isolated fraction. These studies support the hypothesis that acute phase reactant proteins associated with the inflammation in malignant disease are responsible for raised "LSA"-levels in human neoplasm sere. Medizinische Klinik der Ruhr-Universitat Bochum, Marienhospital, H~ikeskampring 40, D-4690 Herne i-

Material from the lung can be obtained by broncho-alveolar lavage (BALF, 100 ml 0.9 % NaCt into a b r o n c h u s a n d r e a s p i r a t i o n of the fluid). The m e a s u r e m e n t of the t u m o r m a r k e r s (TM) CEA~ T P A a n d SCC in p l a s m a and B A L F a l l o w s to d i f f e rentiate between benign and malign pulmonary diseases. The q u o t i e n t T M / h u m o r a l p a r a m e t e r (= TM/protein, TM/albumin, T M / p h o s p h o l i p i d s ) in the B A L F o f f e r s a "normed" tumor m a r k e r w h i c h m a k e s the d i a g n o s i s e a s i e r a n d m o r e reliable, We i n v e s t i g a t e d T M in p l a s m a and B A L F of 142 p a t i e n t s w h o were d i v i d e d into the f o l l o w i n g three subgroups: 16 v o l u n t e e r s (I0 smokers), 78 p a t i e n t s w i t h b e n i g n lung d e s e a s e s (29 smokers), 48 p a t i e n t s w i t h b r o n c h i a l c a r c i n o m a (25 smokers). We found that f o r b r o n c h i a l c a r c i n o m a I) in the m a j o r i t y all T M in p l a s m a a n d B A L F w e r e s i g n i f i c a n t l y i n c r e a s e d c o m p a r e d to b e n i g n l u n g deseases. 2) T P A a n d SCC w e r e m o r e s e n s i t i v e in BALF t h a n in plasma. 3) the T M values in the B A L F i n c r e a s e d w h e n the Iavage was p e r f o r m e d c l o s e l y to tumor. 4) the q u o t i e n t s s h o w e d the s a m e p a t t e r n as the TM themselves. T h e c o m b i n a t i o n of the T M d e t e r m i n a t i o n s as d e s c r i b e d a b o v e is i m p o r t a n t for the d i a g n o s i s of b r o n c h i a l carcinoma, e s p e c i a l l y w h e n b i o p s i e s c a n n o t be o b t a i n e d easily. M e d i z i n i s e h e K l i n i k a n d i n s t i t u t f~r und P a t h o l o g i c der Universit~t~ S i g m u n d - F r e u d - S t r a B e 25, D - 5 3 0 0 B o n n I

Nuklearmedisin

$81 3/21-G 001

3/21.G 003

MODIFIED RADICAL MASTECTOMIE WITH LIMITED SKIN RESECTION

COSMETIC RESULTS AFTER QUADRANTECTOMY OR SEGMENTECTOMY DEPEND ON SURGICAL TECHNIQUE AND POSTOPERATIVE IRRADIATION THERAPY M. Reitzenstein, A.H. Tulusan

AND IMMEDIATE BREAST RECONSTRUCTION K, Exner, G, Lemperle The standar~ r a d i c a l mastectamie(HALSTED)is no longer the operation of choice f o r breast cancers. Selective surgery as f i r s t described by PATEY can o f f e r comparable surv ival and recurrence r a t e s . The m u l t i c e n t r i e i t y of breast cancer es a proven f a c t makes obvious t h a t l o c a l excision ss tumorectomy or tylectomy is an inadequate therapie. The primary radiotherapie following local tumorectomy has early and late complications. Unpredictable tissue reactions as fibrosis,ulcerations or radiation induced tumors jeopardize this treatment. Complete removal of the mammary gland and dissection of the axillary nodes improves diagnosis end therapy. In consideration of the reconstructive surgery one can limit skin resection. The choice of which pattern should be resected is based on a number of criteria: 1. the anatomical extent of the cancer,its stage,size and iocalisation 2. the histological type,growth pattern,lymphatic permeation and blood vessel invasion 3, the patient's age and constitutional status. In some cases the nipple-areola-complex may be preserved. Our series of 270 patients with primary breast cancer show the modification of mastectcmy with limited skin resection and different methods of reconstructive surgery using skin flaps,silicone implants or subpectoral skinexpanders. The immediate breast reconstruction after modified mastectomy is now the operation of choice in our Dept.of Plastic Surgery in the St.Markus-Hospital

The main problem of breast-conserving surgery in breast cancer is the possibility of a local recurrence in the remaining breast. Extended excisions fearing a too close distance to the tumor result a large tissue deficiency might lead to an unfavourable cosmetic outcome. Furthermore the cosmetic results might be influenced by the postoperative irradiation of the remaining breast. Since 1985 we have carried out more than 200 segmentectomies. Different risk groups were distincted following the complete histologically working up of the recovered quadrants in large surface preparation. Only one third of our patients having a higher risk of local relapse received a postoperative irradiation. Cosmetic results after irradiation were opposed to the not irradiated breasts. Further we compared several possibilities of procedures of breast incision. About three months after surgery the judgement of surgeon and patient were asked after healing of the wounds. According to our findings the safest procedure for the patient seems to be the conventlonol e l l i p t i c a l incision with the ma)or axis radial from the nipple, which still can obtain satisfactory cosmetic results. In our hands most favourable cosmetic results are gathered with the incision in the perimamillar line, However, under these circumstances after a preceding biopsy the danger of a spreading of tumor cells can not be excluded. Unlversit~ts-Frauenklinlk Erlangen, Universitatsstraf3e

21-23,

D-8520 Erlangen

Frankfurt 1982-84, The psychological advantage of an immediate breast reconstruction will be compared with a higher incidence of postoperatve complications. The survival and recurrence rates will be demonstrated, #linik for Plastische-und Wiederherstellungschirurgie St,Markus-Krankenhaus 6 Frankfurt 50, W.Epsteinstr~2

3/21-G 004

3/21-G 002 COSMETIC RESULTS AND COMPLICATIONS FOLLOWING BREAST CONSERVING TREATMENT ~.Enqel,M,~fmann.W,Schmidt.D.v. Vn~1~n~r

Fort- und Weiterbildung: "Brusterhaltende Therapie bei Mamma-Carcinomen" __

D u r i n g a one y e a r f o l l o w - u p p e r i o d ( 6 / 8 6 - 6 / 8 7 ) 203 u n s e l e c t e d p a t i e n t s ( p t s . ) t r e a t e d conservatively (quadrantectomy/segmentectomy,radiotherapy) for i n v a s i v e c a r c i n o m a of t h e b r e a s t (TI 6 9 ~ %, T2 27,2%, T 3 / 4 2 , 5 % - N . p o s 26,2%) w e r e s e e n at o u r c l i n i c . D i s t r i b u t i o n of p t s . w a s r e p r e s e n t a t i v e f o r a t o t a l of 665 pts. t r e a t e d f r o m 1 9 7 4 - 6 / 1 9 8 7 . C o s m e t i c r e s u l t s ( s i z e / s h a p e of b r e a s t , s c a r , s k i n c h a n g e s ) w e r e g e n e r a l l y good. P t s . w e r e m o r e o f t e n satisfied than the investigators (pts:/investigatore' p o i n t of v i e w - v e r y good: 3 7 , 3 % / 3 4 , 9 % , g o o d : 4 7 , 4 % / 3 4 , 9 % , fair: 1 2 , 5 % / 2 1 , 5 % , poor: 3 , 2 % / 8 , 7 % ) . Best results were associated with tumor localizat i o n in the u p p e r o u t e r q u a d r a n t a n d i r r a d i a t i o n (CO-60) not e x c e e d i n g a t o t a l d o s e of 5 0 G y d e l i v e r e d to the w h o l e b r e a s t . O t h e r f a c t o r s ( t w o - s t e p p r o c e d u r e s w i t h p r e v i o u s b i o p s y , s i z e of the breast t y p e of i n c i s i o n a n d / o r a d j u v a n t c h e m o t h e r a p y ) h a d n o s i g n i f i c a n t e f f e c t on t h e c o s m e t i c o u t c o m e . Long-term results (~3years) showed a higher i n c i d e n c e of f a i r a n d p o o r r a t i n g s as c o m p a r e d to s h o r t - t e r m a n a l y s i s w h i c h c o n f i r m s r e p o r t s of a somewhat progressive deterioration of c o s m e s i s after breast conserving therapy. The most serious complication was lymphedema(cuto f f 3 c m ) o f t h e a r m (6,4%). O t h e r s i d e e f f e c t s ( m a r k e d f i b r o s i s of t h e b r e a s t 9,7%, i m p a i r e d f u n c t i o n of t h e a r m 65,6%) w e r e g e n e r a l l y less d i s a b e l l i n g to the p a t i e n t . E f f o r t s s h o u l d he d i r e c t e d t o w a r d s c o m b i n i n g m a x i m u m l o c a l t u m o r c o n t r o l l , r e d u c t i o n of c o m p l i cations and good cosmetic outcome.

Universit~tsfrauenklinik, D-69oo Heidelberg

VoSstrasse

9

A NEW METHOD FOR PKAEPECTORAL PRIMARY BREAST RECONSTRUCTION AFTER RADICAL MASTECTOMY WITH A TEMPORARY SPACE-GIVING PROSTHESIS OF METACRYLATE Gertfried Schweikhart The problems of primary breast reconstruction after radical mastectomy with usual siliconegel-filled prostheses are well known. The up-todate methods reducing capsule fibrosis by implanting an inflatable water-filled prosthesis are not satisfying totally. Mostly, the prosthesis must be placed subpectoral, an unphysiological placing. In 1982, the author found in cooperation with RHOM GmbH., Factory for Chemistry, an unflexible, rigid space~giving prosthesis made with methacrylate for medical use, frequently taken for eye-lens-implantations since many years.Till now, more than 50 women with primary breast cancer have been operated radically unilateral or bilateral. Immediately after removing the breast tissue totally a special fo~med, air-filled spacer prosthesis of methacrylate sterilized by x-rays was placed praepectoral filling and splinting the skin. With the inert~ noa-wettable, pore-free material methacryldte~ the over-reacting healing reaction of the wound tissue is reduced to a minimum. The weight of the prosthesis is about 20 grams sothat the skin is not loaded. Seromes can be punctured easily. After total healing, the spacer-prosthesis will be removed - mostly after 12 months - and replaced by a remaining siliconsgel prosthesis. In about l0 % of all cases, the prosthesis had to be removed because of trophic problems of the skin. After changing the prosthesis nearly no complications have been seen further on. The psychological acceptance of the hard prosthesis and the compliance of the patients is excellent. German Clinic for Diagnostic, Department of Gynaecology and Senology, Aukammallee 33~ D-S2SO Wiesbaden, F~R.G.

S 82 3/P-GM 0Ol

3/P-GM 003

MORPHOLOGIC AND CYTOKINETIC PHENOMENA AFTER HETEROTRANSPLANTATION OF VARIOUS HUMAN TUMORS P. K ~ p f - M a i e r , U. K e s t e n b a c h a n d M. J ~ c k e l

DIMINISHED CORTICOSTERONE LEVELS IN ATHYMIC MICE IMPLaNTED WITH MCF-7 OR ZR-75-1 BREAST Tb}~OR CELLS S. Lehrer, E. Diamond, R. Blumenthal, H.K, Song, S. Kalni_cki, J. Dalto_~n~R. Lipsztein, A. S i n ~ W . D . Bloomer

Following heterotransplantation of various human tumors of different histologic type into athymic mice, the same cascade of analogous morphologic a n d c y t o k i n e t i c p h e n o m e n a r u n s o f f in all t u m o r s i n v e s t i g a t e d (tumors o f t h e c o l o n , s t o m a c h , p a n c r e a s , lung, h e a d a n d neck). A m o n g t h e s e p h e n o mena, the penetration of host connective tissue a n d t h e i n v a s i o n o f c a p i l l a r i e s i n t o the c o r d s of c o n n e c t i v e t i s s u e o b v i o u s l y p l a y a c r u c i a l r o l e f o r the s u c c e s s o f h e t e r o t r a n s p l a n t a t i o n , whereby both factors apparently influence the v e l o c i t y of g r o w t h o f h u m a n t u m o r s in n u d e m i c e . In c o n s e q u e n c e , w h e n t h e f o r m a t i o n o f c a p i l l a ries and their invasion into the strands of connective tissue are stimulated by experimental manipulations, the velocity of growth of human xenografts can be markedly accelerated. Further experimental studies are necessary to evaluate if t h e s e m a n i p u l a t i o n s a r e a l s o a b l e t o e n h a n c e the r a t e of s u c c e s s f u l s e r i a l t r a n s p l a n t a t i o n o f h u m a n t u m o r s to a t h y m i c n u d e m i c e .

There have been multiplestudies of cortisol levels in women with breast cancer. Both significant and non-significant increases have been reported. The cause of the fluctuation might be the tumor itself, or the anxiety of pre-operative patients. We studied corticosterone in athymic mice bearing human breast tumors derived from MCF7 or ZR-75, two well established human breast cancer cell lines. Female nu/nu athymic mice 3-4 months of age were used. Cell suspensions of the breast cancer cells were injected subcutaneously into the mammary pad region. Age matched controls were injected with iO0 ul of Tyrode's solution. One to two days prior to cell injections, a 21 day estradiol (E2) pellet with 0.5mg E2 was inserted into the scapular region of each animal with a 13 gauge trocar, Five to six weeks after injection, when the tumors measured 5-iOm~ in diameter, each mouse was bled from the retro-orbital plexus at 1700 hrs., when corticosterone levels peak in mice. Corticosterone was assayed with a commercially available RIA kit developed for rodent blood. ZR-75-1 Controls No. mice 7 iO t=3.1, p < 0 . 0 ] Corticosterone (ng/ml) 89• 363• MCF-7 Controls No. Mice iO i0 t=4.26, p <0.01 Corticosterone (ng/ml) 39.5• 241.5• The diminished corticosterone levels in athymic mice implanted with tumors derived from human breast cancer cells may be due to the production of an agent by the cells which specifically lowers corticosterone, either by a direct action on the adrenal cortex, or by inhibiting the release of ACTH from the anterior pituitary~ or the tumors may cause conversion of eorticosterone to a non-cross reacting metabolite. Depts. Radiotherapy & Medicine (Endocrinology), Mount Sinai School of Medicine, New York 10029

I n s t i t u t f~r A n a t o m i e , F r e i e U n i v e r s i t ~ t B e r l i n , K ~ n i g i n - L u i s e - S t r a B e 15, D - 1 0 0 0 B e r l i n 33

3/P-GM 002

3/P-GM 004

THE PROLIFERATION OF CERTAIN HUMAN TUMORS IN DISTINCT DEPENDENCE OF THE AVAILABLE VITAMINB6, H.P. Fortmeyer

EXPRESSION OF EPITHELIAL ANTIGENS EXO-I AND EPM-I DEFINES SUBPOPULATIONS IN HUMANEPIDERMAL KERATINOCYTES R.Klingel,W. Dippold,P. Boukamp,G, Kron,W.Tilgen, N.Fusenig, K.,N.Meyer zum BUschenfelde ~eoplastic'ce'~] populations are' heterogeneous for a Va~ r i e t y of characteristics bat the cell surface phenotype often reflects deregulated but s t i l l tissue-associated gene expression programs. Recently we defined by monoclonal antibodies two new antigens of the cell surface of normal and neoplastic epithelia: Exo-1, a polar neut r a l g l y c o l i p i d (Dippold et a l . , Can~ Res. 47, 2092, 1987), and EPM-I, a high-molecular weight glycoprotein (Dippold et e l . , Can. R e s , 47, 3873, 1987). Here we describe the immueohistochemical analysis of Exo-I and EPM-I expression in normal and neoplastic human epidermal tissue, ln v i t r o we investigated human epidermal keratinocytes either spontaneously immortalized or transformed with ST40 or rendered tumorigenic by the Na-ras oncogene grown in organotypical culture and transplanted in nude mice (Boukamp et e l . , J, Cell.Biol, in press, 1988). In normal regularly s t r a t i f i e d epidermis only EPM-I is present in the basal cell layer and the benign basal cell papilloma also contains upto 100% positive cells, In contrast basal cell epithelioma does not express EPM-I or Exo-l, An increasing amount of cells undergoing squamoas cell d i f f e r e n t i a t i o n (acanthosis, psoriatic lesion, wart) is accompaniedwith a rapid decrease of EPM-I antigen in the basal cells and an appearance of Exo-I in spinocellular layers, Precancerous lesions and squamous cell carcinomas (SCC) express both antigens with a predominance of EPM-I r e a c t i v i t y but vary in the percentage of positive cells, In nude mouse transplants both antigens are detectable and the expression correlates with the tumorigenity of the cells. The Exo-I/EPM-I antigenic system can be used to monitor and define subpopulations of neoplastic epidermal keratinocytes, (Supported by a grant of the DFG). I, Med, Klinik der Universit~t Mainz, Deutsches Krebsforschungszentrum and Universit~ts-Hautklinik Heidelberg

The experimental model

of human malignant tumors, xenotransplanted and pessaged into athymic nude mice, showed to be a valuable new tool for research in the field of nutritive ontology. It became obvious that not so few human tumors proliferate in distinct dependence on the available amount of vitamin B6. A surplus of the vitamin leads to an enhancement of tumor growth. Proliferation is retarded in cases of reduced availability.

The t o t a l amount of available vitamin B6 not only depends on the supply by the uptake of food. The contribution of the intestinal flora may be a considerable one. Therefore the tumor growth reducing effect of e diet, free or poor of vitamin BB, is distinctly intensified by additional application of a vitamin antagonist. It has to be emphasized that this even happens in situations, in which no symptoms of vitamin deficiency could be observed at all, Our experimental findings in athymic nude mice may have consequences for the care of certain human cancer patients, A dietary guidance seems to be advisable, at least. partially supported by Tumorzentrum Rhein-Main TVA des Klinikum der d.W.Goethe-Universit~t, Theodor~Stern-Kai 7, D ~ 6000 Frankfurt/M 70

$83

3/P-GM 005

3/P-GM 007

TERMINALLY DIFFERENTIATED POSTMITOTIC TUMORCELLS IN A RHABDOMYOSARCOMACELL LINE. R. Engers, C.-D. Gerharz, R. Moil, W. MUller-Klieser, H. Gabbert

HISTOLOGICAL CHANGES, PROLIFERATION KINETICS AND GROWTH PATTERNS OF SQUAMOUS CARCINOMAS AND BONE TUMORS TRANSPLANTED TO NUDE MICE

A permanent r a t rhabdomyosarcoma c e l l l i n e was established, which is phenotypically characterized by the coexistence of myoblast-like mononuclear cells and multinuclear myotube-like giant c e l l s . The f a i l i n g attempts to further separate these two cell types by repeated cloning procedures indicate t h e i r close ontogenetic r e l a t i o n s h i p and suggest that d i f f e r e n t i a t i o n in t h i s tumor proceeds in a similar manner as in normal s t r i a t e d muscle, where postmitotic myotubes arise from mononuclear myoblasts by fusion. The morphologically rather undifferentiated mononuclear tumor cells were shown to be a c t i v e l y p r o l i f e r a t i n g incorporating 3Hthymidine. The myotube-like giant c e l l s neither incorporated 3H-thymidine nor showed any mitosis and exhibited no clonogenic p o t e n t i a l . After retransplantation i n t o syngenic rats, tumor growth proved to be markedly retarded, i f the tumor c e l l inoculum contained a high percentage of myotube-like giant c e l l s . These data show, that the p r o l i f e r a t i o n a c t i v i t y in t h i s rhabdomyosarcoma cell l i n e is confined to the mononuclear tumor c e l l s , whereas the multinuclear myotube-like giant cells have withdrawn from the c e l l cycle i . e . represent t e r m i n a l l y d i f f e r e n t i a t e d postmitotic c e l l s . This c e l l l i n e w i l l provide a valuable tool f o r further investigations on coherent aspects of p r o l i f e r a t i o n and d i f f e r e n t i a t i o n using various d i f f e r e n t i a t i o n inducers.

W. G6hde, ~. Wagner, A. R~ssner~ A. H~rle, H.D.B~ttcher

Since 1984, cell lines of 9 squamous carcinomas from the ENT region, 4 osteosarcomaa and 4 semimelignant bone tumors have been established in nude mice and studied on a systematic schedule during the consecutive passages. Tissue specimens from the tumors were excised before, during and after each passage, and processed for pulse eytometry and histological studies. Results: Solid tumors are able to spontaneously develop hem stemlines. Solid tumors may contain divergent DNA histograms within the same lesion. There is no fixed correlation between S-phase, ploidy~ rate of "taking"~ and tumor doubling time. Histologically, in all bone tumors and in 7 squamous carcinomas, signs of changing differentiation towards a lomer or higher grade were found. The change in grading doesn't correlate with changes of FCM. All results demonstrate a considerable heterogeneity of human tumors. Representative biologic informations about a given tumor cannot be obtained from single studies in order to determine radiotherapeutic schedules (hyperfractionation).

Pathologisches I n s t i t u t der Johannes GutenbergUniversit~t, Langenbeckstr, I, D-6500 Mainz, FRG Department of Radiology~ University Clinics MUnster, Albert-Sch~eitzer-Stra~e 35~ ~400 M~nster, FRG

3/P-GM006

3/P-GM 008

CHARACTERIZATION OF A NEWLY ESTABLISHED HUMANGASTRIC CA~ CINOMA CELL LINE - HM-51. D.Schnalke, F.Friedrich, C.Wittekind, G.Kovacs, T.Benther, D.Reile, H.-U.Hemelt, H.-J.Meyer, H.Poliwoda, ~-J.Schmoll and H.Wilke

CLINICAL EVALUATION OF A P R E T H E R A P E U T I C C Y T O STATIC DRUG ASSAY USING P R O L I F E R A T I N G MONOLAYER CELL CULTURES H. Arps, A. Niendorf, U. Bals and M. Dietel

Only very few gastric carcinoma cell lines are established in v i t r o , mostly derived from malignant ascites. HM-51 was established in v i t r o from fresh tumor specimen of a predominantly u n d i f f e r e n t i a t e d adenocarcinoma of the stomach. Tumor material was minced mechanically and a f t e r two enzymatic steps with a short culture for 24 hours be~ ween each enzymatic step, a single cell suspension was o~ tained. Cellswere then seeded in tissue culture flasks. HM-51 has been in continous culture for over 50 passages with a population doubling time of 44 +/- 4 hours (exponential growth phase).Chromosomal analysis ( 3. and 38. passage) revealed a hyperdiploid chromosome number and numerous chromosomal aberrations without obvious chromosomal changes between passage 3 and passage 38. Microscopically HM-51 cells have typical c e l l u l a r features of malignancy and growth and stain p o s i t i v e l y f o r CEA and e p i t h e l i a l markers ( Keratin, EBM ( e p i t h e l i a l membrane marker )). HM-51 growths rapidly in nude mice with a take rate over 90% (appoximately I00%), forming tumors consisting of poorly d i f f e r e n t i a t e d adenocarcinoma with p a r t l y solid and p a r t l y glandular structures. Oncogene expression, electronmicroscopical features, end~ crine properties, p r o l i f e r a t i o n markers, l e c t i n s and CEA and CA 19-9 production in culture and in nude mice are currently investigated. Abt. H~matologie/Onkologie, Medizinische Hochschule Hanrover, Konstanty-Gutschow-StraSe 8, 3000 Hannover 61

Based on t h e U n c e r t a i n p r e d i c t a b i l i t y of the individual clinical response in patients treated with c y t o s t a t i c drugs for systemic spread of cancer we d e v e l o p e d a p r e t h e r a p e u t i c assay using p r o l i f e r a t i n g m o n o l a y e r cell cultures (H. Arps et al., Int. J. Immunother. 3,229, 1987). Tumor tissue of the individual-- patient is deslntegrated, the r e s u l t i n g cell cultures are c h a r a c t e r i z e d as to c o n t a i n malignant cells and afterwards treated with clinically relevant concentrations of d i f f e r e n t cytostatics for three days and the growth inhibitlng potency of a drug is e v a l u a t e d by c o m p a r i s o n to u n t r e a t e d controls. The clinical outcome of 63 patients has been m o n i t o r e d a c c o r d i n g to the g u i d e l i n e s of the W H O for at least 4 month (median 8 month) and compared to the in vitro results. A correct p r e d i c t i o n of either response or resistance was possible in 81% of the cases: in vivo progress/no in vitro resistant 41 in vitro sensitive 5

ch~nqe

partial

remission 4 13

The test r e v e a l e d a c o n s i d e r a b l e variance in the r e a c t i o n of d i f f e r e n t tumors to c y t o s t a t i c drug treatment not correlated to the tumor type. The results of the clinical follow up d e monstrate a high c o r r e l a t i o n of in vitro results to in vivo behaviour of the individual tumor. The clinical a p p l i c a b i l i t y of the prot h e r a p e u t i c assay for the i n d i v i d u a l i z a t i o n of cancer treatment with c y t o s t a t i c drugs should be e l u c i d a t e d in further studies. Supported by H a m b u r g e r L a n d e s v e r b a n d zur K r e b s bek&mpfung und Krebsforschung and Hamburger Stiftung zur F 6 r d e r u n g d e r Krebsbek&mpfung. Instltut of Pathology. U n i v e r s i t y of Hamburg. M a r t i n i s t r a s s e 52. D-2000 Hamburg 20

$84

3/P-GM 009

3/P-GM 011

DIFFERENTIATION OF CLONED HUMAN EMBRYONAL CARCINOMA CELL LINE~ J. Casper~, D.L. Bronson2, . .K.D.. Reed . . 3 . and . H.-J. . . Schmoll . 1

Variations of Biominerals during Various Types of AntiTumor Chemotherapy

D i f f e r e n t i a t i o n potential and pathways of human germ cell tumors are s t i l l controversial points in current concepts of histogenesis. We have investigated the d i f f e r e n t i a t i o n potential of two cloned human embryonal carcinoma (EC) cell lines {1777N-RP CL-I and CL-IN). Cells were cultured in suspension for I~ days in ~he presence or absence (controls) of IxlO" or 5xI0 "~ M a l l - t r a n s r e t i n o i c acid (RA) and further cultured without RA f o r up to 50 days. At lO-day i n t e r v a l s culture specimens were taken for paraffin sections and growth on coverslips. Also, culture supernatants were assayed for AFP and B-HCG. The presence of collagen type IV, fibronectin, laminin and neurofilament proteins was evaluated with indirect immunofluorescense (IIF) assays using cells growing on coverslips. Cells in suspension formed solid or cystic aggregates. High levels of AFP and B-HCG were secreted into the supernatant of CL-I RA treated suspension cultures, whereas only high AFP levels were detected in reattached CL-I RA cultures. The outgrowth of CL-IN aggregates (with or without RA treatment) seeded on coverslips consisted primarily of cells with EC morphology and clusters of neural cells i d e n t i f i e d by IIF assays using monoclonal neurofilament protein antibodies. CL-I cells treated with RA formed a v a r i e t y of d i f f e r e n t cell types other then EC. Collagen type IV, fibronectin and laminin could be demonstrated almost exclusively in these cultures. These results indicate that ectodermal (neuronal) d i f f e r e n t i a t i o n occurs in suspension cultures of CL-IN c e l l s , and yolk sac endoderm and trophoblastic cell types are formed by CL-1 cells especially a f t e r RA treatment. i . Abt. H~matologie/On~ologie, Med. Hochschule Hannover, 3000 Hannover 61, FRG, 2. Southwest Foundation for Biomedical Research and 3. Wilford Hall USAF Medical Center, San Antonio, Texas 78284, USA

WISCHNIK, A.*, W. ZIEGER*, H. WESCH ~ , H.-G. SCHLEICH*, F. MELCHERT* *Frauenklinik, Faku!t6t f@r Klinische Medizin ManlJ]eim der Universit6t Heidelberg,Th.-Kutzer-Ufer, 6800 Mannheim ~ f~r Nuklearmedizin am DKEZ, Heidelberg It is known, that anti-tumor chemQther~py especially when includin[ cis-Platinum-causes disturbances in biomineral regulation. Biomineral deficiencies commonly are associated with disturbances which also are very well known as side effects in anti-tumor chemotherapy such as: - cardiac necrosis/cardiomyopathy (Mg/Se-deficiency) - bad immunologic state (Zn/Mg-deficiency) - alopecia (Zn-deficiency) - nausea, vomiting, poor general state, psychic affections (Mg-defieiency) As possibly biomineral substitution could contribute to the reduction of these side-effects, we took interest in the variations of the serum levels of various biominerals. Determinations have been carried out by means of atomic absorption spectrophotometry and neutron activation analysis respectively. The following table s~ows the variations of different biominerals during the first analyzed course (percent of control) Cu Fe Ca Mg Se Zn CP(n=8) + 5,2 +54,4 -6,8 -17,7 -14,5 -18,8 CMF(n=6) +12,1 +53,3 -4,6 - 3,8 -33,2 -47,1 Mitoxantrone(n=6) +12,8 -16,6 -7,7 -18,3 -13,4 -34,5 As these biominerals are mainly concentrated in the cell, serum variations may reflect intracellular changes only partially, as it has been s h o ~ for magnesium. Thus, these preliminary results indicate, that more scientific, diagnostic and therapeutic attention will have to be payed to biominerals during anti-tumor drug treatment.

3fP-GM 010

3/P-GM012

HYPEREOSINOPHILIC SYNDROME(HES) AND BENIGN VARIANTS d.AnaBnou ...........

T H E R E S P O N S E OF T W O R O D E N T T U M O R S TO H I G H E N E R G Y P U L S E D U L T R A S O U N D (HEPUS) W A V E S E . ~ . H a h n I, R . R i e d l i n g e r 2, J . M a t t e r n I, ~ . U b e r l e 2, M. Bak I, L . G e r l a c h I, A . L o r e n z I, M. Volmlt G . v a n K a i c k I a n d W . J . L o r e n z 1

Cases of HES with prolonged course have been r a r e l y described so that some authors have suggested that a benign variant of the HES does e x i s t . I present a unique case of HES with prolonged mild course evolving into a frank leukaemic condition. The patient was f i r s t admitted at age of 20 on June, 197/ because of a car accident. At this time the WBC and eosinophil counts were 22000 and 13860/ mm3 respectively (63% eos.). Since then leukocytesis and eosinophilia persisted showing fluctuations and going up as high as 65000 and 40000/~ ~ (58%-87% eos.). The i n i t i a l Hb(15.5 g%) and p l a t e l e t count (300000/ mm3) remained stable. Repeated bone marrow aspirations and biopsies showed a heavy i n f i l t r a t i o n by mature eosinophils without blastic cells at any time. Explorative laparotomy with splenectomy was performed on June, 1978.The suspected lymphoma could not be confirmed. Histology of the enlarged l i v e r and spleen showed massive tissue eosinophilia. Haematological and c l i n i c a l scores according to recommended grading systems were low and thus compatible with a good prognosis. Indeed, through the 6 years tha patient had only s l i g h t recurrent abdominal pains, arthralgias and pruritus. On March, 1984 blasts up to 60% appeared in blood with a drop in Hb and p l a t e l e t count. The new bone marrow aspiration and biopsy showed heavy blastic i n f i l t r a t i o n . He did not respond to chemotherapy and died on May, 1984, i . e . , 7 years a f t e r the f i r s t documentation of blood and tissue eosinophilia. The case c l e a r l y underlines that close monitoring ( i n t e r v a l l s of 6 to 8 weeks seem me to be more appropriate than the recommendedones of 3 to 6 months) even of these occasional patients with prolonged benign course is imperative for early i d e n t i f i c a t i o n of sudden transformation of this protean, s t i l l aenigmatic disease. Abteilung H~matologie/Onkologie, Department Innere Medizin, Medizinische Hochschule Hannover, Konstanty-Gutschow-StraBe 8, 3000 Hannover 61

A prototype apparatus was designed and built by R . R i e d l i n g e r , A c o u s t i c s L a b o r a t o r y 2, w h i c h produces HEPUS waves. The current studies were c a r r i e d out to d e t e r m i n e w h e t h e r this n e w w a v e f o r m c o u l d p r o d u c e a c y t o t o x i c r e s p o n s e at depth within a tumor. U s i n g a n e s t h e t i z e d a n i m a l s , we e x p o s e d D u n n i n g p r o s t a t e t u m o r s ( E 3 3 2 7 - A T , C o p e n h a g e n rats) a n d h u m a n lung t u m o r x e n o g r a f t s (L3, n u d e mice) g r o w i n g on the t h i g h a n d i m m e r s e d in w a t e r , to H E P U S t r e a t m e n t s of v a r y i n g i n t e n s ity and duration., T h e r e s u l t s s h o w t h a t H E P U S c a n be f o c u s e d at d e p t h a n d is c y t o t o x i c . A t 24hrs, a l a r g e a r e a of t r e a t m e n t i n d u c e d d e v e l o p i n g n e c r o s i s w a s p r e s e n t in the H E P U S a n i m a l s w h i c h w a s n o t p r e s e n t in the c o n t r o l s . By 48 and 72 h o u r s t h e s e c h a n g e s b e c a m e m o r e e x t e n s i v e l e a d i n g to a l a r g e c e n t r a l n e c r o s i s and a s u b s t a n t i a l r e d u c t i o n in the s i z e of the L3 t u m o r s r e a c h e d a n a d i r of 35 % of c o n t r o l s by d a y 5, w i t h a r e s u l t a n t g r o w t h d e l a y of 6 d a y s . T h e c a u s e of c e l l d e a t h is n o t k n o w n . T h e o b s e r v a t i o n at 2 4 h r s of h e m o s t a s i s and n e c r o s i s l e a d s us to b e l i e v e t h a t it is p r o b a b l y a d i r e c t c e l l d e a t h , c a u s e d by t h e h i g h p o s i t i v e a n d n e g a t i v e r e s u l t i n g in u l t r a s o u n d i n d u c e d cavitation. G e r m a n C a n c e r R e s e a r c h C e n t e r I, D - 6 9 0 0 H e i d e l b e r g , a n d Univ. of K a r l s r u h e 2, D-7500 Karlsruhe

S 85

3/P-GM013 P A L L I A T I V E T R E A T M E N T OF M A L I G N A N T O S T E O L Y S E S OF THE C E R V I C A L SPINE ~ Ch. J~rgens, Ch. E g g e r s and D. W o l t e r

3/P-GM 015 EFFECTS OF SPLEE~I PEPTIDES ON CELL GRO~H M. Hartleb, W. D i t t r i c h , H. Lamberti, A. W i l l i g , R. Groscurth, P.P. Jaros

P o l y s e g m e n t a l m a l i g n a n t osteolyses of the c e r v i cal spine often lead to instability by destruction of the v e r t e b r a l bodies or d e s i n t e g r a t i o n of j o i n t f o r m i n g s t r u c t u r e s . I n s t a b i l i t y a n d growth of tumor increase the risk of n e u r o l o g i c d i s t u r b a n c e s up to transverse lesion. S t a b i l i z a t i o n by u s e of m e t a l l i c i m p l a n t s is often not possible.In these cases a new a p p r o a c h for s t a b i l i z a t i o n had to be made c o n s i d e r i n g the reduced g e n e r a l condition and the shortened exp e c t a t i o n of life of the patients. C o m b i n e d use of the h a l o a p p a r a t u s and radiotherapy (40 G r a y / 28 d a y s ) s h o w e d s o m e h o p e f u l r e s u l t s b e t w e e n 1 9 8 3 a n d 1985. We t r e a t e d 5 p a t i e n t s t h i s way. 2 p a t i e n t s died in consequence of m u l t i p l e metastases. In 3 p a t i e n t s ~t~e halo was r e m o v e d a f t e r 8 to 18 weeks. T h e x-rays showed c o m p l e t e s c l e r o s i s of t h e s e g m e n t s c o n c e r n e d a n d n e u r o l o g i c disturbances were regressive or unchanged. The s u r v i v a l t i m e a f t e r t h e r a p y w a s 5 to 25 m o n t h . Since 1985 we made some new experience w i d e n i n g the range of treatment by surgical r e s e c t i o n of the involved vertebral bodies. The resulting defect was filled with a composite bone graft from the os ilium. S t a b i l i z a t i o n was a c h i e v e d by the h a l o apparatus. A l l 3 patients treated this w a y so f a r h a d s e v e r e n e u r o l o g i c d i s t u r b a n c e s b e f o r e therapy. 6 to 8 weeks after operation the bone grafts became incorporated and the h a l o was r e m o v e d . In a l l c a s e s n e u r o l o g i c d i s t u r b a n c e s w e r e r e g r e s s i v e . U p to n o w the s u r v i v a l t i m e a f t e r therapy is 6 to 15 month.

Investigating p r o l i f e r a t i o n i n h i b i t i n g properties of spleen peptides, trypsin cleaved and chromatographically isolated fractions of polypeptides below I0.000 Dalton were used for in v i t r o studies of Walker 256 cells added to 103 c e l l s / w e l l . After 5 day incubation remaining cells were counted in a Coulter Counter against nontreated controls. Depending on the spleen peptide fraction used, growth i n h i b i t i o n between 64 and 90 % was observed. To exclude non-specific effects, i d e n t i c a l l y processed BSA fragments were used as an additional control. No i n h i b i t i o n of cell growth has been recorded. To evaluate the findings, SV 40 transformed 3T3 and non-transformed L 929 cells were used in colony forming assay. Application of identical concentration of the peptide fractions abolished colony forming a b i l i t y of both c e l l lines completely. A d d i t i o n a l l y lactate production was studied under the influence of the spleen peptides. SV 40 transformed 3T3 showed a low decrease, whereas nontransformed L 929 secreted a d i s t i n c t increase of l a c t a t e , indicating cell type specific metabolic differences. Biochemical characterization of the active substance(s) w i l l be continued.

II.Chirurgische Abteilung, AK St.Georg, L o h m ~ h l e n s t r . 5 , D-2000H~mburg 1

Univ. Oldenburg, Abt, Zoophysiologie, 2900 Oldenburg, FRG

3/P-GM014

3/P-GM 016

I~CTINS IN HUMAN HEM~TOPOIETIC CELL LINES H.-J, Gabius, K.P. Hellmann, C. Bokemeyer~ M. Andreeff

U P T A K E OF P L A S M A P R O T E I N S IN T U M O R S U. Schilling~ H.J. Sinn~ H~A. Dresel, M a i e r - B o r s t and E.A. F r i e d r i c h

Human hematopoietic cell lines offer an excellent model of the study of the expression of lectins with respect to cell lineage and modulation by differentiation. Quantitative flow cytofluorometry demonstrated differential expression of lectins for the B lymphoblast line Daudi~ the T cell lymphoblastic leuke/~ia line PI2~ the erythroleukemic line K562 and the promyelocytio line HL60 with and without DMSO-induced differentiation. Profile differences were substantiated by biochemical analyses with affinity chromatography and underscored potential to contribute to understanding aspects of biological behavior of hem~topoietic cells and related malignancies via participation of sugar-leetin interactions. Max-Planek-Institut for experimentelle Medizin, Abt. Chemie, Hermann-Rein-Stra~e 3, D-3400 G6ttingen

W.

To study the uptake of p l a s m a p r o t e i n s (albumin, transferrin, low d e n s i t y l i p o p r o t e i n ) i n tumors we used e x p e r i m e n t a l rats w i t h v a r i o u s transplantation tumors (Walker carcinosarcoma~ Y o s h i d a h e p a t o m a and o v a r i a n c a r c i n o m a (0-342, ZELLER)). Plasma proteins labelled with 131-Iodine with a specific a c t i v i t y of 5 m C i / m g p r o t e i n were i n j e c t e d via a tail vein. W i t h the g a m m a camera (Phogamma !II, N u c l e a r chicago} d i s t r i b u t i o n of r a d i o a c t i v i t y was m o n i t o r e d after I0 min, 2,4,6, and 24 hours. in the three tumors i n v e s t i g a t e d p l a s m a p r o rain uptake was 10% to 20% after 5 hours. Relative a c c u m u l a t i o n r e a c h e d 20% to 30% after 24 hours. This p h e n o m e n o n was only seen if plasma proteins >50 000 D were injected. Smaller m o l e c u l e s like 1 3 1 - l - c y t o c h r o m e C, 131-I-tyrosine and 1 3 1 - I o d i d e were r a p i d l y w a s h e d out from the tumor r e g i o n (>95% after 2 hours). We conclude from these data that certain plasma proteins a c c u m m u l a t e in tumors. The i m p o r t a n c e of this p h e n o m e n o n for the tumor g r o w t h and the p r o c e s s e s i n v o l v e d are discussed. German Cancer Research Center, Dept. of N u c l e a r Medicine; Dept. of M e d i c i n e of the U n i v e r s i t y of Heidelberg; D-6900 Heidelberg, F.R.G.

S 86

3/P-GM 017

3/P-GM 019

MOLECULAR CLONING AND CHARACTERIZATION OF A NEW FELINE SARCOMA VIRUS ISOLATE; THEILEN-PEDERSON FeSV (TPI-FeSV) Barbara Kappes*, Andrew Ziemiecki ~ , Gordon Theilen**, Heinz Bauer* and Angelika Barnekow*

EVALUATION OF CLINICAL IHPORTANCE OR HPV 16/18 INFECTIONS ASSOCIATED WITH NORMAL EPITHELIUM, CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) AND SQUAMUS CELL CARCINOMA OF THE CERVIX UTERI USING IMMUNOHISTOCHEMICAL METHODS AND IN SITU HYBRIDISATION

We have isolated a new feline sarcoma virus, designated Theilen-Pederson (TPI-FeSV), from a spontaneous fibresarcoma of a domestic cat. The virus encodes a 83 ~KD ga~-onc fusion protein with an associated tyrosyl kinase activity (Ziemiecki et el: Virology 138, 324 (1984)). For further characterization of the virus we established CCL64 nonproducer cell lines, lacking the TPI-FeSV associated helper virus (FeLV). Southern Blot analysis of the genomic DNA from these cell lines reveals, that the oncogone of the TPI-FeSV isolate is related to the the fgr oncogene of the Gardner-Rasheed FeSV, GR-FeSV, but does not show any hybridization to the Wactin homologous sequences of the GR-FeSV. For the construction of a genomic library we used Embl3 as vector and ~ O I partials of genomic DNA from a TPI-FeSV transfected NIH cell line, containing the TPI-FeSV proviral genome in ~n amplified manner~ Several clones were obtained by double hybridization with a f q r and a FeLV specific probe. One of these clones was further characterized by hybridization to fj_rr, FeLV, gag, pol, env and U3 specific probes. The data enable us to predict a restriction map of the TPI-FeSV proviral genome, which has in the meantime been proved by sequencing parts of the isolated viral clone. Sequence data of t~e TPI-FeSV fg___~rrelated oncogene and its viral junction sequences will be discussed.

K.Goerke, H.H,Zippel, A.R~ck, K,D,Schulz, R,Neumann, H.J~Eggers

*Inatitut for Mad. Virologie der Justus-Liebig-UniversitQt Gie~en, Frankfurter Str. I07, D-6300 Gie~en, FRG; ~ Institut f~r F/'ebsforschung, Inselspital, CH-3010 Bern, Switzerland; **Clinical Oncology Section, University of California, Davis, CA 9561, U.S.A.

The role of human papilloma virus (HPV) infections, in particular of types 16 and 18, in the aetiology of cervical intraepithellal neoplasla, carcinoma in sltu and cervical cancer has been discussed for many years. Almost 500 swab samples obtained from the uterine cervix of patients attending our clinic were screened for HPV 16/18 DNA using in situ hybrldisatlon methods. Cells were fixated on nitrocellulose filters and denatured and neutralized in sltu, They were then hybridized with ~'~P-labelled viral DNA, using a compound of HPV types 16 and 18. No statistically significant relation between patient age or menopausal statue and }{PV 16/18 infection could be seen, Cytological features of viral infections, as koilooytosis or dyskeratosls, were present in high prevalence in cases positive for HPV 16/18 DNA. In samples taken from patients with suspect cytological smears (Pap Ill D to V) viral DNA could also be detected more frequently~ About 80% of our patients showed normal cytological features (Pap I and If). Still 15% of these patients were positive for HPV 16/18 DNA. After a mean interval of 14 months no viral DNA could be detected in 80% of the cases; the patients with persistent HPV 16/18 infections showed no evidence for the develepement of squamus cell carcinoma or its precursors. Tissue sections of squamus cell carcinoma frozen in liquid nitrogen were also investigated for HPV antigen using the indirect Immuno-persxidase method with primary antisera raised in rabbit against specific papilloma-vlrus antigen. According to the results obtained through cytological investigation HFV antigen could be detected in several cases. Medizinisches Zentrum fur Frauenheilkunde und Geburtshilfe der Universit~t Marburg, Pilgrimstein 3, D-3550 Marburg

3/P-GM018

3/P-GM 020

BIOTIN-LABELED DNA PROBESTO DETECT HUMAN CYTOMEGALOVIRUS (HCMV)-DNA IN LUNG TISSUES FROMPATIENTS WITH INTERSTITIAL PNEUMONITIS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION G. D61ken, A.D. Riggs, J.A. Zaia and K.G. Blume

HPV DNA IN CARCINOMASOF IHE VULVA

Cloned DNA fragments of human cytomegalovirus (HCMV)-DNA were used to examine lung tissues obtained from patients, who died with i n t e r s t i t i a l pneumonitis a f t e r allogeneic bone marrow t r a n s p l a n t a t i o n , f o r the presence of HCMV-DNA. Cellular DNA was prepared from frozen tissue by standard techniques, digested with EcoRl, separated by agarose mini gel electrophoresis and transferred to n i t r o c e l l u l o s e by Southern Blotting. Biotinylated DNA bound to the immob i l i z e d DNA was detected by a s t r e p t a v i d i n - a l k a l i n e phosphatase conjugate. The s e n s i t i v i t y of this technique is at least I-2 copies of a 3-5kb fragment of v i r a l DNA per c e i l . Under the conditions of hybridization we did not observe any r e a c t i v i t y of the two d i f f e r e n t HCMV-DNA probes with normal c e l l u l a r DNA. In a retrospective c H n i c a l study the HCMV-specific DNA probes detected v i r a l DNA in 14 out of 16 lung tissue samples obtained from patients who died a f t e r allogeneic bone marrow transplantation: 10 of these patients had suffered from HCMV-associated i n t e r s t i t i a l oneumonitis based on c l i n i c a l findings, virus cultured from lung t i s sue and the presence of inclusion bodies upon histopathological examination. HCMV-DNAcould also be demonstrated in lung tissues of 4 out of 6 patients who died from idiopathic pneumonitis ( I / 2 ) or other transplantation related complications (3/4), i . e . severe acute GVHD, brain abscess and septicemia. Because of the s e n s i t i v i t y of the assay, the s t a b i l i t y of b i o t i n y l a t e d probes and the methodological safety, the techniques described are very suitable f o r rapid diagnostic procedures to detect HCMVDNA in c | i n i c a ] samples. Abt. f o r H~mato]ogie und Onkologie der Medizin. Universit ~ t s k l i n i k Freiburg, Hugstetter Str. 55, 78 Freiburg

H.Ikenberg,

D.SchwSrer,

A,G~ppin~er and A.Pfleiderer

]here is strong evidence for a causal relationship between human papillomaviruses (HPV) and cervical neoplasia. An etiological role for HPV in carcinoma of the vulva is discussed. Due to the relative rareness of this disease only a very limited number of tumours could be tested until now. We investigated the prevalence of HPV DNA in 18 invasive tumours of the vulva in 17 patients b~ Southern blot hybridization of total cellular DNA with ~ P labelled HPV DNA under nonstringent and stringent conditions. 6/11 primary squamous carcinomas of the vulva contained UPV 16 (one to 30 copies HPV DNA/celI). One of these HPV positive cases represented a carcinoma of the Bartholinic gland. In 5/11 primary tumours and in all 7 recurrent malignant tumcurs of the vulva (5 squamous cell carcinomas, 1 fibrasarcoma and 1 zylindroma) no HPV DNA could be detected at a sensitivity of 0.2 copies/cell. 11 inguinal lymph nodes of 7 patients were tested for HPV DNA. One metastatic lymph node of a HPV 16 positive primary tumeur contained HPV 16 at a slightly elevated copy number~ Two nodes corresponding to HPV negative tumours and 8 tumour free nodes were HPV negative. In tumour free abdominal skin of 12 patients no HPV DNA was detected, lhsre was no correlation between the prevalence or copy number of HPV DNA and the grade of differentiation or keratinization or with the clinical stage and lymph node status of the tumour. ]he clinical course of the disease could be followed for more than six month in 9/17 patients. No correlation between HPV status and disease free interval or time of survival was found. The mean age of HPV positive and HPV megative patients did no% differ significantly. Universit~ts-Frauenklinik Freiburg, Hugstetterstr, 55, D 7800 Freiburg

$87 3/P-GM 021

3/P-GM 023

ISOLATION AND CHARACTERIZATION OF TRANSFOR~,LAT!ONDEFEKTIVE MUTaNtS OF THE MCDONOUGH STRAIN OF FELINE SARC~4A VIRUS Dagmar Hennig, Bruce Boschek, Heiner Niemann and Teruko Tamura

TUMOUR KARYOTYPE AS THE MOST iMPORTANT PROGNOST}C FACTOR IN 28 CHILDREN WITH NEUROBLASTOMA

Using 5"-azaeytidine to mutagenize nonproducer SM-FeSV transformed NRK-eells we have isolated various cell lines expressing a nontransformed phenotype. Superinfection of such cloned cell lines with Simian Sarcoma Associated Virus lead to the rescue of mutant virus particles carrying the transformation-defective (td) phenotype. In addition, transfection of RatI cells with recombinant mutant fms-EMBL4-DNA harboring the mutated v-fms gene resulted in the formation of cell lines expressing the td-phenotype. Two classes of mutants were obtained: The first class was temperature-sensitive and failed to express the mature form, gp~40 v-fms, at the plasma m e m brane at the nonpermissive ten~erature. As a consequence, no in vivo kinase activity was observed under such conditions. The second type of mutant seemed to lack one glycosy~ation site within the N-terminal domain of gpl40 ~ - ~ . This mutant exhibited again tyrosine kinase activity in vitro but not in vivo. Our data suggest that t-~e td-effects do not involve the tyrosine kinase domain but rather alter a domain which plays a role in the in vivo activation of the kinase. Institut f~r Med, Virologic der Justus-Liebig-Universit6t Gie~en, Frankfurter Str. 107, D-6300 GieBen, FRG

H. Christiansen and F. Lampert* In 28 patients with neurobtastoma of different EVANS' stages the karyotype was determined in the primary turnout and/or in the metastases by direct chromosome preparation or short term ceil culture. In addition, DNA analysis (SOUTHERN) for the proto--oncogene N-myc was performed for comparison in 10 cases. Abnormalities (deletions, translocetions, derivations) of the short arm of chromosome 1 (besides rarer aberrations in other chromosomes) were found in the turnout karyotype of 15 of 18 (= 83 %) patients with metastatic disease (stage IV) and in 1 of 3 patients with stage Iit, but in none of the 7 patients with stages I, It, IV-S who are all alive with no evidence of disease. These 7 surviving patients with good prognosis had a hyperdiploid tumour karyotype, mainly in the triploid range. 11 of the 18 (= 6t %) patients with stage tV and 1 of 3 patients with stage I[[ also contained double minutes (DMs) and/or homogenously staining regions (HSRs) in their tumour karyotypes. N-myc amplification (30 to 60 copies) in the tumeur DNA was detected in 2 of 6 (= 33 %) examined cases with stage IV, in 1 out of 2 examined cases with stage HI, and correlated with the presence of DMs/HSRs. Life table analysis showed a probability of surviving of 90 % in patients lacking the lp abnormality as compared to less than 10 % in patients with an aberrant lp chromosome in the tumour cells. We conclude that tumour karyotype, in particular the structure of the short arm of chromosome 1, is the most important factor in determining the different outcome in children with neuroblastoma. Children's University Hospital, Feulgenstr. 12, D-6300 Giessen *Supported by the Deutsche Forschungsgemeinschaft (SFB 215-A7)

3/P-GM022 GENERATION OF MONOCLONALANTIBODIES AGAINST E6 PROTEINS OF HUMAN PAPILLOMAVIRUSES G. B a s t e r t , S. Kaul (a. G.) and A. Schneider-G~dicke A d i s t i n c t subset o f human P a p i l l o ~ v i r u s (HPV) types can be i d e n t i f i e d in a l l human c e r v i c a l carcinomas, HPV 16 and 18 being the most p r e v a l e n t types. The e a r l y p r o t e i n E6 seems to be p r e f e r e n t i a l l y expressed in the m a j o r i t y o f v i r a l l y transformed c e l l s . To analyse the expression and f u n c t i o n o f these markers in more d e t a i l , murine monoclohal a n t i b o d i e s (MAbs) were developed using b a c t e r i a l f u sion p r o t e i n s MS2-E6 (HPV 16) and MS2-E6* (HPV 18) expressed in E. c o l i as im~unogen. Furthermore, the terminal 23 amino acids o f HPV 16 and 18 E6 p r o t e i n s were chemic a l l y synthesized, conjugated with keyhole limpet hemocyanine and used f o r the immunization o f a second set o f BAL8/c mice. Hybridoma supernatants from 6 fusions were screened by an ELISA with b a c t e r i a l MS2 p r o t e i n , MS2-E6 f u s i o n proteins and the s y n t h e t i c peptides as s o l i d phase antigens. The s p e c i f i t y o f hybridomas with r e a c t i v i t y towards E6 prot e i n s was v e r i f i e d a f t e r cloning by Western immunoblotting with MS2 p r o t e i n , MS2-E6 p r o t e i n s and 300 mM s a l t nuclear e x t r a c t s from HPV 16 and 18 p o s i t i v e c e l l l i n e s . We have selected a panel o f ~ b s r e a c t i n g with the C - t e r minal p a r t o f E6* o f HPV 18, with E6* plus E6 o f HPV 18 and two MAbs r e a c t i n g with HPV 16-E6. With these a n t i b o dies we could c h a r a c t e r i z e the p u t a t i v e E6 p r o t e i n s in human c e r v i c a l c e l l l i n e by immunoprecipitation and in primary c e r v i c a l carcinomas by immunohistology. Experiments are now in progress to analyse the expression of E6 p r o t e i n s in c e r v i c a l smears and primary tumors. U n i v e r s i t ~ t s - F r a u e n k l i n i k , D-6650 Homburg/Saar

3/P-GM 024 A R E C E S S I V E C A N C E R G E N E IN M E N I N G I O M A S ? ~. H e r z o g , E. M e e s e , K.D. Zang, N. B l i n

In s o m e h u m a n t u m o r s , l o s s of g e n e s m a n i f e s t e d by loss of heterozygosity seems to uncover e i t h e r n u l l m u t a t i o n s at c o r r e s p o n d i n g l o c i of homologous chromosomes or h e m i z y g o s i t y leading to a g e n e d o s i s e f f e c t . M e n i n g i o m a , a benign h u m a n t u m o r d e r i v e d f r o m the c o v e r i n g s of b r a i n and spinal cord is a s s o c i a t e d with complete loss, r a r e l y d e l e t i o n s , of c h r o m o s o m e #22. 5 @ ~ 69% of m e n i n g i o m a s e x i b i t m o n o s o m y 22 in all o r part of cells, however, about 4@% d i s p l a y a n o r m a l k a r y o t y p e . C o m p a r i s o n of c o n s t i t u t i o n a l a n d t u m o r g e n o m e s u s i n g a s e r i e s of p a t i e n t s ' DNA and several chromosome 22 s p e c i f i c RFLP p r o b e s s h o w e d in s o m e c a s e s loss of h e t e r o z y g o s i t y s u g g e s t i n g the i n v o l v e m e n t of on the D N A l e v e l i.e. r e g u l a t o r y s e q u e n c e s ( a n t i o n c o g e n e s , suppressor genes). Additional data from Karolinska Institute, Stockholm and Harvard Medical School, Boston confirm our findings; all in all, the r e s u l t s l e d to d e s i g n a t i o n of a m e n i n g i o m a c h r o m o s o m e r e g i o n (MGCR) at 2 2 q ! 2 - q t e r at the H u m a n G e n e M a p p i n g C o n f e r e n c e 1987. M a p p i n g of p r o g r e s s i v e l y smaller deletions on c h r o m o s o m e 22 s h o u l d f i n a l l y l e a d to p r e c i s e d e s c r i p t i o n of a r e c e s s i v e t u m o r l o c u s in m e n i n g i o m a in a m a n n e r s i m i l a r to the RB l o c u s in r e t i n o blastoma.

I n s t i t u t f~r H u m a n g e n e t i k d e r U n i v e r s i t ~ t des Saarlandes, Universit~tsklinik, Geb. 68, D-665 Homburg/Saar

$88 3/P-GM 025

3/P-GM 027

ABNORMALITIES OF CHROMOSOME 16 IN PATIENTS WITH ACUTE NON-LYMPHOCYTIC LEUKEMIA U.Graeven, R.Becher, D.KUhn, and C.G.Schmidt

KARYOTYPIC ABERRATION PATTERNS IN GYNECOLOGICAL CARCINOMA CELLS

Chromosomal abnormalities can be identified in most patients with acute non-lymphocytic leukemia (ANLL). Moreover specific chromosomal abnormalities correlate with particular subtypes of ANLL, with characteristic morphological and clinical features. Herein we report on 8 patients with acute myelomonocytic leukemia (FAB M4) and structural abnormalities of chromosome 16. The mean age of the patients (6 female and 2 male) was 43 years (17-72 years). Chromosome analysis was performed on bone marrow cells prior to specific treatment in 6 patients and at the time of first relapse in 2 patients. Six patients showed an inversion 16, inv(16) (p13;q22),one patient a deletion 16, del(16)(q22), and one patient showed a translocation t(16;16)(p13;q22). Only one patient had additional clonal chromosomal abnormalities, a t(l;l) and a t(4;12). Residual normal metaphases were detested in five cases. All patients presented with acute myelomonocytic leukemia (FAB M4). The bone marrow of 6 patients showed abnormal eosinophils as characterized by a mixture of eosinophilic and large basophilic granules. Four patients had marked eosinophilia of the bone marrow with more than four percent eosinophils. Seven of the 8 patients entered complete remission following intensive chemotherapy. Our findings confirm the observation that structural abnormalities of chromosome 16 like inv(16), t(16;16), and del(16) are associated with acute myelomonocytic leukemia with atypical eosinophils (FAB M4 E0). Innere Klinik und Poliklinik (Tumorforschung) Universit~tskliniknm Essen,Hufelandstr.55,D-4300 Essen 1

R. Kunzmann, F. H61zel Multiple abnormalities of the chromosome structure are common in human carcinoma cells, Presently, specific chromosomal aberrations are not known for tumor cells of mammary, ovarian or endometrial origin. We have established a number of cell lines which show unique aberration patterns specific of the tumor cell populations of individual patients. In general, the number of structural aberrations was greater in cells stermming from patients with preceding chemotherapy. This agrees with the idea that the genomie instability of tumor cells is increased by chemotherapy. As an example, in 3 cell strains obtained by repeated explants from the same patient with metastatic breast cancer after chemotherapy the alterations of the chromosomal aberration pattern were analyzed during long-term in vitro cultivation and after in vivo growth~ All cells derived from the ist explant contained persistently 8 marker chromosomes, marl to marS. Fragmentation of mar3, terminal deletion of mar4 and an additional mar9 were observed after in vitro cultivation. The karyotype of cells derived from the 2nd and 3rd explant expressed multiple alterations which had occurred in vivo. In cells of explant iI and III, marl to mar4 were present only as derivated markers. Derivated markers and newly acquired markers had evolved only in cells of strains II and III. Mar 5, 6 and 8 had remained unchanged in all cell strains and passages Of cultivation; thus these aberrations were stable markers apparently indicating very early chromosomal rearrangements in the evolution of the tumor cell population of this individual patient. Frauenklinik der Universit&t Hamburg, Martinistrasse 52, 2000 Hamburg 20, FRG

3/P-GM 026 INCREASED

UV

3/P-GM 028 -

SENSITIVITY

IN

HETEROZYGOTE

FOR XERODERMA'PIGMENTOSUM V . B i e l f e l d * , M . R o s e r * , U.ReimersJ , E . S e e m a n o v a 2 , E.Breitbart 3 , H.Berger 4 , H.W.R~diger I ......................... _ ...................... CARRIERS

CHROMOSOMAL CHANGES AND THE INITIATION OF PLEOMORPHIC ADENOMAS J. B u l l e r d i e k , S. B a r t n i t z k e , G. B r a n d t , R. C h i l l s , J. H a u b r i c h

X e r o d e r m a p i g m e n t o s u m (XP) is an a u t o s o m a l rec e s s i v e l y i n h e r i t e d d i s o r d e r w h i c h is c h a r a c t e r i z e d b y c h r o m o s o m e i n s t a b i l i t y , i n c r e a s e d uv s e n s i t i v i t y , and a s t r o n g l y e n h a n c e d r i s k for cutaneous cancer. Family studies have revealed t h a t v a r i o u s c a n c e r s d o o c c u r at h i g h e r f r e q u e n c i e s a l s o in a s y m p t o m a t i c h e t e r o z y g o t e c a r r i e r s for XP. S i n c e this c o u l d a l s o be a c o n s e q u e n c e of a n i n c r e a s e d s e n s i t i v i t y to g e n o t o x i c d a m a g e we studied uv-induced sisterchromatide exchange (SCE) and m i c r o n u c l e i (MN) in t h e s e o t h e r w i s e healthy individuals. Fibroblast cultures were i n i t i a t e d f r o m s k i n b i o p s i e s of 18 o b l i g a t e X F h e t e r o z y g o t e s , 6 X P h o m o z y g o t e s and 18 n o r m s l h e a l t h y c o n t r o l s . T h e c e l l s w e r e uv e x p o s e d to 500 J o u l e / c m z for 20 - 40 s e c o n d s , SCE and M N w e r e d e t e r m i n e d b y s t a n d a r d t e c h n i q u e s . As a result cells from obligate heterozygetes exhib i t e d a s i g n i f i c a n t l y h i g h e r a m o u n t of SCE (p<0.002) a n d of M N (p<0.001) t h a n n o r m a l c o n trols. W h e n d a t a of b o t h t e s t s w e r e c o m b i n e d b y stepwise discriminant analysis uv sensitivity c o u l d b e s u c c e s s f u l l y u s e d to d e t e r m i n e h e t e r o z y g o t e s for XP in f a m i l i e s at risk. W e c o n c l u d e that c h r o m o s o m e i n s t a b i l i t y can be d e t e c t e d in o t h e r w i s e h e a l t h y h e t e r o z y g o t e s fo XP and m a y e x p l a i n the c a n c e r r i s k in t h e s e i n d i v i d u a l s .

The results of chromosome studies on pleomorphic a d e n o m a s of t h e h u m a n p a r o t i d g l a n d show, t h a t t h i s t u m o r is o f t e n c h a r a c t e r i z e d b y c l o n a l a b n o r m a l i t i e s . T w o g r o u p s of t u m o r s c h a r a c t e r i z e d b y 8 q 1 2 or 1 2 q 1 4 - 1 5 r e a r r a n g e m e n t s , r e s p e c t i v e ly, a r e o f p a r t i c u l a r i n t e r e s t . In o u r s e r i e s (60 a d e n o m a s ) , t h e s e b o t h g r o u p s c o m p r i s e m e r e t h a n 50% o f the t u m o r s . B a s e d o n t h e s e r e s u l t s as w e l l as o n c h r o m o s o m a l r e a r r a n g e m e n t s of o t h e r t u m o r s w e h a v e p r o p o s e d the h y p o t h e s i s , that - in t u m o r s w i t h 8q12 o r 1 2 q 1 4 - 1 5 r e a r r a n g e m e n t s these chromosomal changes are primary steps n e c e s s a r y for t h e i n i t i a t i o n o f the t u m o r - t h e m e c h a n i s m , b y w h i c h the c h r o m o s o m a l r e arrangement contributes to tumor initiation is t h e r e a c t i v a t i o n of " g r o w t h " g e n e s (protoo n c o g e n e s ?) b y t h e i r j u x t a - p o s i t i o n t o c e l l s p e c i f i c a n d h i g h l y e x p r e s s e d g e n e s of the salivary gland. - these growth-related genes may be "early" g e n e s , b e c a u s e t h e y c a n s w i t c h b a c k the c e l l to a n e a r l y s t a g e of d i f f e r e n t i a t i o n a l l o w i n g s t i l l m o r e t h a n one d i f f e r e n t i a t i o n p a t h w a y . Thus, the a c t i v a t i o n of o n l y one g e n e (at 8q12 or 1 2 q 1 4 - 1 5 , r e s p e c t i v e l y ) c a n w e l l a c c o u n t for the h i s t o m o r p h o l o g i c a l h e t e r o g e n e i t y f o u n d e v e n w i t h i n o n e t u m o r (pleiotropic effect).

A r b e i t s g r u p p e T o x i k o g e n e t l k , O r d i n a r i a t f~r A r b e i t s m e d i z i n I , H a u t k l i n i k ~ ~ A b t e i l u n g f~r Medizinische Dokumentation und Statistik 4 , U n i v e r s i t ~ t H a m b u r g , u n d A b t e i l u n g ffir M e d i z i nische Genetik der Karls Universit~t, Prag 2

Z e n t r u m fHr H u m a n g e n e t i k u n d G e n e t i s c h e B e r a t u n g d e r U n i v e r s i t ~ t B r e m e n , L e o b e n e r S t r a B e N W 2, D - 2 8 0 0 B r e m e n 33, Fed. Rep. of G e r m a n y

$89

3/P-GM 0 2 9

3/P-GM 0 3 1

TRISOMY 4 IN ACUTE MYELOID LEUKEMIA

THYRIDINE KINABE (TK) AS A TUHflR HARKER IN ACUTE LEUKEHIAS (AL): COHPARISON OF ACTIVITIES IN CYTDSOL AND PLASHA H, Bauer, W. R~hrl a,nd W. Wileanns TK catalyses an essential enzymatic stop in DNA-synthesis, TK i s a log-phase-mnzyoe which i s highly active in p r o l i f e r a t i n g cells~ especially during B-phase. I t is high in AL c e l l populations as nell as in the plasma or serum of AL-pationts. In t h i s work TK in AL-cells is compared with normal hone marrow c e l l s and with TK in the plasma aT AL-patients. Bone aarrnx specimens were assayed Tree 28 noroal controls~ 85 patients at f i r s t diagnosis o~ AL, 164 patients with AL in cooplote remission and 34 patients with AL in relapse. In comparison to controls ( l ( . 6 1 7 . & nmolestein x 10 T M cells) TK was s i g n i f i c a n t l y increased in AL at f i r s t diagnosis or in relapse (64.?~5g.4 reap. [email protected]). During complete remission TK was i n s i g n i f i c a n t l y d i f f e r e n t from normal bone marrow specimens r TK does not correlate with the blast count or the amount o~ prol i f e r a t i n g c e i l s tn the bone marrow, But~ i t correlates wtth thyeidine- or deoxyuridino-incorporation or aS-phase c e l l s . AL c e l l populations are characterized by a high specific T K - a c t i v i t y in r o l a t i e n to XS-phase cells~ thyoidine- or deoxyuridtne-incorporation (factors around 5) choreas in normal bone marrow c e i l s these factors are about 2, This means~ that TK-activtty is not only an I n dicator for cell p r o l i f e r a t i o n , but also a characteristic feature of AL c e l l s . Thus~ TK can be used as a tumor marker for the characterisation of AL. There is a positive correlation between high TK in AL bone warrow and plassa ( r = | . 4 7 4 ; p ( g . e e 1 ) . The s e n s i t i v i t y to find an increased TK in patients math AL is 7@Z for plasma and 64% for hone sarroo tests. Both assays give a cumulative s e n s i t i v i t y o+ 85:(, The d e f i n i t e value oT the tumor marker TK for prognosis and follow-up of patients with AL s t i l l has to be established, Aed. Klinik I I I ~ Klinikum 6roBhadern~ Ludotg-HaximiliansUnivorsit~t, flarchioninistraBe 15, D-EDgE HQnchen 7E.

D.K. Hossfeld, R. Kuse, C. B. Meier, S. Suciu, H.J. Weh Recently it was suggested that trisomy 4 identifies a new subset of acute myeloid leukemias. So far only 11 cases have been described. Nine of these 11 cases had FAB-type M4-AML, 2 had M2. Trisomy 4 as the sole anomaly was detected in g cases, whereas additional abnormalities were seen in 2 cases. An intruiging question why such an obvious anomaly has not been found previously led to the speculation that such leukemias might reflect a new environmental or other exposure or effect operative within the last 1 to 2 decades. This prompted us to review our material. During the last G years we analysed 200 cases of AML and 120 cases of myelodysplastic syndrome (MDS). Two cases with trisomy 4 were found, beth with M4-AML. One case demonstrated a deleted chromosome No. 3 in addition to trisomy 4. In both patient a therapeutic or professional or other exposure to leukemogenic agents was not apparent. Abteilung Onkologie und H~matologie, Universit@tskrankenhaus Eppendorf, Martinistr. 52, D-2000 Hamburg 20

3/P-GM 030

3/P-GM 032

IMMUNOCYTOCHEMICAL LABELLING OF HUMAN LEUKEMIC METAPHASE CELLS S. Suciu, H.J, Weh, W. Z e l l e r , S. Gohla, D.K. Hossfeld

CLINICAL RELEVANCEOF THE TUMORMARKER CA 15-3 IN BREAST CANCER

A method f o r the simultaneous i d e n t i f i c a t i o n of immunoeytochemically labeled metaphase c e l l s and t h e i r chromosome c o n s t i t u t i o n is described. Cultured leukemic c e l l s are treated with a mild hypotonic s o l u t i o n and cytocentrifuged onto glass s l i d e s , Preparations are then f i x e d in a v a r i e t y f i x a t i v e s and incubated with a p r i mary mouse monoclonal antibody against a c e l l antigen, followed by r a b b i t anti-mouse immunoglobulin and the a l k a l i n e phosphatase monoclonal a n t i - a l k a l i n e phosphetase (APAAP) complex. A red color product i s developed

The value of tumor markers b a s i c a l l y depends on t h e i r use~ fulness in diagnosing early tumor stages or metastases Which can be treated successfully. The monoclonal a n t i bodies CA 15-3 were developed against the two antigen 115D8 of the human milk f a t - g l o b u l e membrane and DF3 of breast cancer. In a prospective study the new radioimmunoassay was determined pre- and postoperatively. Patients: G I: breast cancer n=63; G I I : benign disease of the breast n=52; G 111: malignom~ outside the breast n=114; G IV: benign surgical disease and healthy blood donors n=288. Results: GI G II G III G IV CA 15-3 (U/ml) Minimum 12,0 5,4 4,6 5,4 Maximum 357,0 75,3 58,8 75,3 Median 21,5 15,1 15,3 15,1

with Fast Red TRnaphtol AS-MX phosphate. Following cell identification, the preparations are destained, treated with acide fixative and counterstained with Giemsa or "Stains all". Weak G-bands can be induced by trypsinization, incubation in S~rensen buffer or 2 x SSC. This technique was tested with primary monoelonel antibodies against various membrane surface antigens from human leukemic cells. It is fast, reproducible, allows intensity adjustment of staining and enables light microscopic analysis. Abteilung Onkologie und H~matologie, Universit~tskrankenhaus Eppendorf, Martinistr. 52, D-2000 Hamburg 20

F. Sofa, M. Kreibich, H.O. Klein e, H.,G..Beger . . . . .

The normal value of the CA 15-3 being f i x e d below 25 U/ml~ we ascertained in this study a s e n s i t i v i t y of 37% f o r mamma carcinoma, a s p e c i f i c i t y of 85% and a t o t a l accuracy of 80%. In the course of the follow-up treatment CA 15-3 and CEA were determined simultaneously in 392 patients who had been treated s u r g i c a l l y because of breast cancer. The s e n s i t i v i t y rate in detecting metastases or r e c i d i vation was 72% in CA 15-3 and 40% in CEA. The CA 15-3 RIA turned out to be not mammaspecific for ~screening, but i t is d e f i n i t e l y superior to CEA for the detection of metastases from breast cancer in the tumor follow-up treatment. Department of General Surgery, University of Ulm, Steinfl~velstra~e 9, D-7900 Ulm.

S 90

3/P.GM 033

3/P-GM 035

DIAGNOSTIC PROCEDURE BEFORE REOPERATION IN PATIENTS WITH MEDULLARY THYROID CARCINOMA (MTC) F. Raue, K. Frank, D. Lorenz, Ch. Herfarth, R. Ziegler

THE DISTRIBUTION OF "EARLY" AND "LATE" DIFFERENTIATION MARKERS DISTINGUISHES NORMAL AND LEUKEMIC CLONES IN VITRO H.H.Gerhartz, H.Schmetzer

Elevated calcitonin (CT) levels after primary operation are e reliable marker for persistence, recurrence or metastases of MTC. The main sites for relaps of MTC are the neck and mediastinel region. The value of different localisatien methods in comparison before reoperation and the outcome of these patients has been proven. Patients and methods: 45 of our 61 patients with MTC had

elevated CT l e v e l s in the f o l l o w up. They were examined every 6 months by ultrasonographie (US) of the neck (~3 exam.), every year by CAT scan of neck and mediastinum (142 exam.). Some had a selective venous catheterisation (SVC) with CT determination (47 exam.) and a fine needle biopsy(32 exam.). 28 patients were than reoperated 48 times. Results: Table - Histological conformation of suspected relapses localized by different methods.

Method No.exam. % of pus

PALP 48 60

US 33 79

CAT 32 72

SVC 29 62

FNB 20" 85

findings The f i v e year s u r v i v a l rate in patients with elevated CT levels improved in reopersted pat, (86%) compared to pat, (n= 19) without rein~ervention (89%). Conclusion: For precise preoperative staging ultrasonography i s the most predictable and r e l i a b l e method, The prognosis of MTG patients with elevated CT l e v e l s in the follow up could be improved by reoperation. Msdizinische Universit~tsklinik, Bergheimerstr. 58, 8900 Heidelberg

Culture techniques o f f e r the opportunity to study the acute myeloid leukemia (AML) c e l l s which are responsible for p r o l i f e r a t i o n . The d i s t i n c t i o n of leukemic clones from normal colonies, however, is a problem because both cell types respond to the same growth factors (colony stimulating factors, CSFs). Cytogenetic techniques are sensitive but d i f f i c u l t to perform on single clones a n d too inconvenient to be done on a larger scale. We studied the expression of " e a r l y " and " l a t e " myeloid d i f f e r e n t i a t i o n markers on single c e l l s and complete agar clones in situ from AML patients at presentation (n=13) and normal controls (n=8) by an i n d i r e c t enzymimmunoassay to determine possible c h a r a c t e r i s t i c d i f f e r ences. AML c e l l s showed a r e l a t i v e l y low expression of " l a t e " ~veloid d i f f e r e n t i a t i o n markers l i k e VIM-D5 (COl5) but increased r e a c t i v i t y to nearly normal levels during culture with CSF. In contrast to normal bone marrow (BM) c e l l s they were characterized by a high proportion of "early" or "blast c e l l " markers (MylO, J5 (CDIO), B-I (CO20)) which was maintained during culture in agar. The best s p e c i f i t y was achieved by B-I which was p o s i t i v e in the majority of a l l tested AML clones but v i r t u a l l y absent on normal colonies. Double marker experiments with B-I/VIM-D5 and with J5/VIM-5 showed that these antigens were present on the same c e l l s in AML but on d i f f e r e n t cell populations in normal BM. Our results demonstrate that AML clones are able to part i a l l y d i f f e r e n t i a t e in v i t r o but can be distinguished from normal clones by t h e i r r e a c t i v i t y with blast markers which is maintained even under the d i f f e r e n t i a t ing stimulus of CSF. Med.Klinik I I I , Klinikum GroChadern, Marchioninistr. 15, D 8000 Munich 70.

3/P-GM 034

3/P-GM 036

PROTEIN S IN MALIGNANT DISEASES B. Kemkes-Matthes, K.J. Matthes and B. Pralle

THE GRADIENT OF CEA,CA 125 AND PLAP BETWEEN SERUM,ASCITES AND TUMOR CYTOSOL IN PATIENTS WITH OVARIAN TUMORS M.ALBRECHT, J.S.E.DERICKS-TAN,M.STEGMOLLER

INTRODUCTION: Protein S is a vitamin K-dependent protein of liver origin which functions in its free form as cofactar of the anticoagulatory and profibrinolytie active protein C. Bound to C4 binding protein, protein S loses its protein C cofactor function but is now able to influence local activation of the complement system on phosphoiipid bilayers. The aim of our study was to find out I. whether there are differences in protein S concentrations in patients suffering from malignant lymphomas or carcinomas in comparison to normals and 2. whether thrombotic incidences in such patients could be correlated to protein S diminutions. EXPERIMENTAL: Protein S, protein C, coagulation factors IX and X and antithrombin III were determined in 9 healthy persons, i0 patients with malignant lymphomas and 12 patients suffering from carcinomas. RESULTS: I. There were no significant differences in protein C, factor IX, factor X and antithrombin III levels between the three groups. 2. Concentrations of free protein S were significantly diminished in patients suffering from carcinomas (25• 7% of total protein g) in comparison to healthy persons ( 43 • Patients with malignant lymphomas presented free protein S levels of 33• 13%. CONCLUSIONS: I. Differences in protein S concentrations in patients suffering from malignant diseases in comparison to healthy persons could be demonstrated, while there were no differences concerning the other coagulation factors tested. 2. The diminution of free protein S in patients suffering from carcinomas could be one reason for thrombotic incidences in these patients. In one of them presenting with thromboembolism free protein S was reduced to 16% of total protein S concentration. Zentrum fur InnereMedizin der Universit~t Giegen, KlinikstraBe 36, D-6300 GieBen

Most of the available tumor m a r k e r s d e t e r m i n e d in s e r u m are of l i m i t e d value for the monitoring of c a n c e r pts. I n c r e a s e d s e r u m l e v e l s are found in h e a l t h y pts., w h e r e a s in pts. w i t h advanced ovarian cancers m a r k e r levels are o f t e n in the n o r m a l r a n g e . T o i m p r o v e the c l i n i c a l s i g n i f i cance s i m u l t a n e o u s d e t e r m i n a t i o n s of the tumorassociated antigen CA 125,the c a r c i n o e m b r y o n i c antigen CEA a n d the p l a c e n t a l a l k a l i n e phosphatase P L A P w e r e p e r f o r m e d in the tumor cytosol the peritoneal fluid(ascites) and in s e r u m of were 49 p t s ( b e n i g n : 2 6 , m a l i g n a n t : 2 3 ) . R I A - k i t s used for the determination of CEA(BEHRING) a n d PLAP(MALLINCKRODT).CA 125 was t e s t e d w i t h the e n z y m e i m m u n o a s s a y (ABBOTT-ELISA)o cancer: RESULTS: I. In pts. w i t h o v a r i a n

CA 125: in all pts. marker concentrations were elevated in tumor c y t o s o l and in a s c i t e s ; i n s e r u m 18%(4/22) were false n e g a t i v e . CEA: Positive results were found in 72% in c y t o s o l ( 8 / l l ) and o n l y in 9 % ( 2 / 2 2 ) in a s c i t e s . All serum concentrations were b e l o w the cutoff level. PLAP: Elevated concentrations w e r e d e t e r m i n e d in 8 1 % ( t u m o r c y t o s o l : 9 / l l ; a s c i t e s : | 8 / Z 2 ) a n d in 69% in s e r u m ( 9 / 1 3 ) . Z. In pts. w i t h b e n i g n ovarian tumors: F a l s e p o s i t i v e r e s u l t s in this g r o u p were in the range of 1 3 - 3 6 % ( s e r u m ) and I S - 6 9 % ( c y s t fluids). Universit~tsklinikum

Frankfurt/Main,

Zentrum ffir Gyn~kologie,Theodor-Stern Kai 7 D-6ooo

Frankfurt

7o

S 91

3/P-GM 037

3/P.GM 039

ESTROGEN - AND ~TIESTROGEN RELATED SHORT TERM RECEPTOR MODULATION IN XENOTR~NSPLANTED HUMAN BR[~ST - AND ENDOMETRIAL CANCER A.Vering R.Th. Michel H.Kuhl M.Stegm~ller

ASSOCIATION B E ~ ~A 15-3 S ~ U M ~ AND THE HOIKMONE RECEPTOR STATUS IN BREAST CANCER PATIENTS. A.Bieber, E.Merkle, W.Sauerbrei,W.JZger

The actual measureahle capacity of hormone receptors of endocrine related tumors depends on the hormonal environment, especially during hormonal treatment. We treated 2 carcinomas, {ER +/ PR +) serially passaged into nude mice with single doses of Estradiol, Depot Esbradiol or Tamoxifen, I-3 mg/kg B.W.i.m. In the breast cancer BO we observed a rapid decrease of ER to values near O within the first 3 hours after therapy with E 2 and Depot E 2. Tam treatment induced as well a decrease of ER, but only from control levels around ~oo fmol/mg to 2o fmol/mg., negative values did not occur. Furthermore the maximal decrease could be observed later, after 24 hours. In a period of I week after Depot E 2 therapy, no recovery of ER took place, in spite of the fact, that serum levels of E 2 were near O after 48 hours. In case of E 2 treatment ER recovered 24 hours after injection, in case of Tam this happened Ioo hours after therapy. Control levels were never reached again within i week. In all treatment groups a priming of the PR to 5 fold higher levels compared to controls could be found. But in the case of E 2 and Depot E 2 treatment this oocured within 48 hours, while this needed more time in the case of Tam namely iio hours. This effect was reversible within 7 days only with E 2 treatment. Studies with the endometrial carcinoma LA, which has very high receptor capacities showed comparable results Universit~tsfrauenklinik Theodor Stern Xai 7 600o Frankfurt/Main

3/P-GM 038

~M,A.l.brecht

Department of Obstetrics and Gg~lecology, University of Erlangen, 8520 Erlange~, FRG

3/P-GM 040

COI~iPARISON O F T H E T0~iOR M A ~ E R S CEA, CA A N D C A 50 IN SEPt& A N D T U M O R T I S S U E F R O M PATIENTS IWITH B~ASTIC~NCER S,Re~ter

The two routine monoclonal antibodies DF 3 and 115D8 define an antigen, coded CA 15-3, which can he detected immur~histochemically in the cytoplasm of breast c~ncer cells. In previous studies it was suggested that CA 15-3 serum levels may he dependent on the amount of estrogen (ER) or progesteron receptors (PR) in the tumor. In our study serum samples from 403 patients with primary breast cancer were obtained before surgery. Sera were assayed using an i~unradiometric assay (ELSA-CA 15-3, ID-CIS, DREIEICH, FRG) and ER and PR concentrations of the tumors were measured with the dextran-coated charcoal procedure. No correlation could be exhibited between CA 15-3 serum levels end the PR concentrations. From 222 ER positive ()15 fmol/mg c%,tosol protein) patients 16.6% had elevated CA 15-3 levels ()30 U/ml), while 7.2% frcm !81 ER negative patients bed levels exceding 30 U/ml. Frown 107 promenopausal patients 8.4% had elevated levels and from 296 postmenopausal patients 13.6%. 37 (74%) frown 50 patients with elevated CA 15-3 levels had ER positive tt~nors. Five of these patients weme premenopausal whereas 32 patients were postmenopausal. 78% of all postmenopausal patients with elevated CA 15-3 levels exhibited l~ positive tumors. Frcm these data the proposed correlation between receptor concentrations and CA 15-3 serum le%~is can not he rejected.

~M.

Dietel.

15-3

~.....................

F o r the m o n i t o r i n g of p a t i e n t s w i t h b r e a s t c a n c e r the 3 t u m o r m a r k e r s C E A , C A 15-3 a n d C A 50 are w i d e l y u s e d . P r e v i o u s s t u d i e s h o w e v e r , h a v e shown,that even with simultaneous determinations the v a r i o u s m a r k e r s a r e o f l i m i t e d v a l u e f o r the discrimination of normal and elevated serum l e v e l s . The a i m of o u r s t u d y w a s , t o c o m p a r e the a n t i g e n e x p r e s s i o n i n the t u m o r t i s s u e (by i~unohistochemical s t a i n i n g ) w i t h the c o r r e s p o n d i n g s e r u m l e v e l s o f the 3 m a r k e r s . The s e r u ~ l e v e l s w e r e m e a s u r e d b y r a d i o i m m u n o a s s a y (CA 50: B E H R I N G ) o r e n z y m e i m m v m o a s s a y (CEA: A B B O T T ; C A 1 5 - 3 : C I S ) . The a n t i g e n s t a i n i n g p r o c e d u r e f o r the p a r a f f i n e m b e d d e d t u m o r t i s s u e w a s b a s e d on the p e r o x i d a s e - a n t i p e r o x i d a s e - s y s t e m ( S T E ~ N B E R G E R 1 9 7 0 ) r e s p e c t i v e l y the a v i d i n - b i o t i n s y s t e m ( H S U , 1981)~ C o m m e r c i a l l y a v a i l a b l e k i t s w e r e u s e d ( k i n d l y p r o v i d e d b y B E H R I N G : C A 50 a n d C I S : C A 1 5 - 3 C E A ) . The r e s u l t s o f o u r s t u d y s h o w e d , that i n m a n y c a s e s e l e v a t e d s e r u m l e v e l s o f the t u m o r m a r k e r s i n v e s t i g a t e d c o u l d o n l y be d e m o n s t r a t e d in patients with positive staining results in the t i s s u e o f the p r i m a r y tumor. C O N C L U S I O N : W i t h r e g a r d to the p r e l i m i n a r y results we suggest, that improvement in monitoring of breast cancer patients, marker determin a t i o n i n the s e r u m s h o u l d f o l l o w the r e s u l t of the i m m u n o h i s t o c h e m i c a l s t a i n i n g i n the t i s s u e . Iuniversit~tsklinikt~ Frank~drt~ain, der Gyn~kologie, Theodor- Stern- Kai 6 0 0 0 F r a n k f u r t 70

Zentrum 7

2Universit~tsklinikum Eppendorf, Institut f~r P a t h o l o g i c , M a r t i n i s t r . 52, 2 0 0 0 H a m b u r g 20

EVALUATION OF SERb~v~DEOXYTH~Imn~E KI~ASE ($-TK) I:N MYELODYSPLASTIC SYNDROMES (MDS} AND ACUTE MYELOID LEUKEMIA

(AML)

H. G. Derigs, C. Aul~ A. Heyll, W. Sehneider

DeoxytbRmindinekinaserepresentsan important'salvagepathway'enzymeinthe synthesisofDNA. Elevateds-TK levelsarefoundinseveralhematologicalmalignancies,Ithasbeensuggestedthattheenzymeaetlvltycorrelateswithtumorcell mas% gradeofmalignancy ~and prognosisofthedisease,The aim ofourstud)'was toevaluatethebehaviorofs-TE activityinPatientswithMDS or AML. Using a commercial radloenzyme assay (SanStec Medical, Bromma, Sweden) sTK was mea.vared in 72 patients with MDS (FAB subgroups: RA 8, RARS 12~ RAEB 20~ RAEB-T 12,CMML 20) and 45 patients with AML at the time of diagnosis. In comparison to 69 healthy probands (Mean =hSDM: 3.1 • L2U/#t) 70% of MDS patients presented with pathotosicat s-TK levels. In most cases coneentratinns were only moderately increased (5-15U/#1). in a smaller s u b , nap of 12 patients with RABB~T and CMML~ markedly elevated activities up to 300U/vI

were measured.S-TK levelsweresignificantly correlatedwithLDH (r = 0-~9~ p < 0.001) and white blood cell count (~- = 0.43, p < 0.G2)~whereas other parameters (ESR, hemoglobin, marrow blast cell carrot) had no influence on the s-TK expression. Using life table analysis no significant difference was observed in the

eur~va/ofpatientspresentingwiths-TK levelsbelowor above10U//d(Breslow test: p < 0.9). Patie:ats with AML ah~ays prese~ted with increased s-TK values rangin~ from

5.1to IIMIU/,ul(Mean• SEM: 58.5~ 10.6U/#l)In contrastto the MDS group a significantcnrrelationwas foundbetweens-TK and bone man~w blastcount (r = 0.60, p < 0.01fi). Successful chemotherapy was followed by a decrease and

normafisntionofs=TK levels. Our datasugsestthat pathological s~TK waluesoccur

not

onlyin acutelenke-

mine, but also in the majority of MDS patients. Although the eu~'me expression was found to increase in the more advanced FAB subgroup% there was no significant correlation with the meduUa.,T blast count. The close relationship between s-TK levels and conventional laboratory parameters saggests that the measurement of s-TK wilt not provide additional ilfformation for the MDS ~zoup. Med. Klin~kA Universit~t Dfisseldorf, Moorenstr. 5, ]9-4000 Dfisseldoff

S 92

3/P-GM 041

3/P-GM 043

LIPID-BOUND SIALIC ACID AS A MARKER IN BREAST CANCER A. Meinshausen, J. Pokorny and R. Voi~tmann

TISSUE POLYPEPTIDE ANTIGEN (TPA) IN THERAPY MONITORING AND SURVEILLANCE OF PATIENTS WITH UPPER URINARY TRACT CANCER M.L(~thgens I , U.R~ther I , K.B~uerle I , P.Jipp I , G.Schlegel I J.Rassweiler I , F.Eisenberger I , and C.G.Schmidt 2

Previous studies have shown an increased amount of lipidbound sialic acid (LSA) in sera of patients with different malignant diseases using the method of Katapodis et al. (Res.Commun.Chem.Pathol.Pharmacol.30:i71-180~1980). In mind the criticism of some authors that gangliosides are probably minor components of the discovered amount of "LSA", we investigated 677 sera of i08 patients with breast cancer only in view of the clinical significance of LSA as a tumor marker. Contrary to previous studies we did not only compare individual healthy and pathological values but we observed the change of LSA during malignant disease. Data analysis indicated significant increase (p < 0,001) in mean LSA-serum level of patients with progression of their tumor burden (34.5 mg/dl) compared with those in complete remission (20.4 mg/dl). Specificity was 86.4% and sensitivity was 98.4%, respectively. With regard to the clinical significance of LSA in monitoring breast cancer we collected from everyone of our 108 patients 3-17 sera (E=6.3) during an observation time between 6 and 24 months (E=I4.0). 36 of 45 courses from patients with no evidence of malignant disease were reflected correctly by the corresponding LSA-values (80%). 59 of 63 courses of patients with a progression during observation period were correct described by LSA (94%), altogether 95 of 108 courses (88%). In some patients we could see a pathological increase of LSA I-7 months before clinical observation of tumor progression. LSA seems to be a value aid in monitoring breast cancer.

37 primarily inoperable patients with locally invasive (pT2-4b, n = 13), local regional (NI-4, n = 16) or distant metastasizing cancer (MI, n = 8) of the upper urinary tract were followed up by TPA and CEA during and after chemotherapy applying MVEC. The age of the patients varied between 42 - 79 (~ = 67) years. TPA and CEA were determined at diagnosis and transurethral resection, nephrectomy and/or urethrectomy, prior to each MVEC-cyoIe or in 3 monthly periods following treatment. Using the Prolifigen IRMA kit by Sangtec Medical for TPA and the RIA Monoclonal kit by Abbott for CEA analysis the low detection limits amounted to 5 /i and 0.2 ng/ml, respectively. In healthy blood donors the 95 percentiles (specificity) were found to be 50 U/I or 3.0 ng/ml, resp. In the patient group prior to therapy 35/37 cases (95 %) had elevated values in TPA comparing to 16/37 cases (43 % sensitivity) in CEA analysis. The results of both markers are distinctly independent of the stage. In therapy monitoring TPA demonstrated highly significant concordances to the clinical status in CR 16/21 (76%), PR 7/7 ( 100 %), and PD 6/9 ( 67 %), whereas CEA signalized significant concordance in PD only ( 56 %). Thus, the overall concordance was 78 % in TPA and 27 % in CEA. From oDr data it is concluded that TPA is the sole marker available for therapy monitoring and surveillance of patients with cancer of the upper urinary tract. The study is being continued.

Medizinische Klinik der Ruhr-Universit~t Bochum, Marienhospital, H61keskampring 40, D-4690 Herne I

IKatharinenhospital, D-7000 Stuttgart 2Westdeutsehes Tumorzentrum, Innere Universit~tsklinik, D-4300 Essen

3/P-GM 042

3/P-GM044

T U M O R M A R K E R P R O F I L E S IN G A S T R I C C A N C E R T I S S U E S C O R R E L A T I O N T O T H E H I S T O L O G I C A L T Y P E AN[) CLASSIFICATION OF T H E C A R C I N O M A S K o c h O.M.. H e i d l G., Zumdick-Neumann N.. W d s t

-

G.

M e d i c a l C l i n i c s , U n i v e r s i t y of M u n s t e r (Dir.: P r o f . D r ~ m e d J . v a n d e Loo) * I n s t i t u t e of P a t h o l o g y . U n i v e r s i t y of M d n s t e r (Dir.: P r o f . D r med. Ekk~ G r u n d m a n n ) D-4400 M~nster. FRG @Iycoprotein and carbohydrate tumormarkers (CEA, CA 1 9 - 9 , C A 50. CA 125) w e r e d e t e r m l n e d in c y t o s o l i c e x t r a c t s of g a s t r i c c a n c e r t i s s u e s (n=54) T h e c a r c i n o m a s w e r e cut off macroscopically f r o m the s u r r o u n d i n g c o n n e c t i v e tissue, peritoneal serosa and were frozen rapidly after surgery. The histological classification was d o n e a c c o r d i n g to the WHO. M I N G a n d L A U R E N . N o c o r r e l a t i o n w a s f o u n d f o r CA 1 9 - 9 / C E A . f o r C E A / C A 50 a n d f o r CA 125 w i t h a n y of t h e o t h e r m a r k e r s T h e c l o s e in~nunochemica[ r e i a t i o n s h l p b e t w e e n t h e g l y c o s i d i c s t r u c t u r e of C A 19-9 a n d C A 50 m a y e x p l a i n t h e the h ~ g h g r a d e of c o r r e l a t i o n (r=0 8)~ Significant differences in the t i t e r s of the tumormarkers were found for CEA/protein. CEA/carbohydrate between differentiated vs undifferntiated + u n c l a s s i f i e d c a n c e r s {WHO). f o r CEA/protein. CA 19-9/protein or carbohydrate and CA 50/protein between expanding vs ~nfiltrative + m i x e d (MING), f o r CA ! 9 - 9 / c a r b o h y d r a t e and CA 5 0 / p r o t e i n b e t w e e n i n t e s t i n a l vs d l f f u s e (LAUREN) t y p e s of g a s t r i c c a n c e r s ( p < 0 , 0 2 ~ - 0 . 0 5 ) ~

COMPARATIVE H I S T O P A T H O L O G Y AND CEA BEHAVIOR HUMAN LUNG CANCER XENOGRAFTS. J. T o u s s a i n t , H.H. F i e b i g , Ch. W i t t e k i n d , G . W . L ~ h r

OF

S. v o n K l e i s t ,

55 h u m a n l u n g c a n c e r s w h i c h c o u l d s u c c e s s f u l l y b e g r o w n in n u d e m i c e in s e r i a l p a s s a g e s w e r e analyzed for histological changes and express i o n of C E A in c o m p a r i s o n to t h e d o n o r t u m o r , The histological s u b t y p e s i n c l u d e d 27 s q u a m o u s cell, 13 a d e n o , 5 s m a l l cell, 4 l a r g e c e l l a n d 1 adenosquamous cell carcinoma. Overall the mouse grown tumors showed a similar histological and cytological picture as the donor tumor. However, minor changes in t h e d e g r e e of d i f f e r e n t i a t i o n were observed in 27% (12/45). 7 tumors showed a dedifferentiation which was correlated with an increase in doubling time, 5 tumors showed a higher differentiation. Using the indirect immunperoxidase technique CEA was positive in the t u m o r t i s s u e of 92% o f t h e d o n o r t u m o r s . A l l adenocarcinomas were positive and demonstrated the h i g h e s t d e g r e e of p o s i t i v i t y . Small cell carcinomas were positive i n 2/5 c a s e s only. After growth in nude mice slowly growing tumors revealed a tendency of higher CEA positivity. R a p i d l y g r o w i n g t u m o r s s h o w e d in 2 0 % a d e c r e a s e of CEA. Overall human tumor xenografts remain quite stable even in long term passage, however, a c h a n g e in t h e d e g r e e of d i f f e r e n t i a t i o n w a s o b s e r v e d i n 2 7 % a n d a d e c r e a s e in C E A e x p r e s s i o n i n 21%. In o r d e r t o h a v e s t a b l e tumor models xenografts should be frozen in early passages. Med.Univ.Klinik, Abt.H~matologie und Onkologie, Hugstetter Str.55, D-7800 Freiburg im Breisgau.

S 93

3/P-GM 045 PARALLEL MEASUREMENTS OF CA 125, ~Nase ACTIVITY AND FIBRIN DEGRADATIONPRODUCTS IN OVARIAN CYSTS OF VARIABLE HISTOLOGY M. Neises~ C.E. Dempfle, F. Melchert We investigated 30 ovarian cysts (23 benign, 3 borderline, 4 malignant). In the cyst fluids CA 125 (ELSA-CA 125 RIA, CIS), total ribonuelease activity (enz~nneactivity by substrate depolymerization)~ D-dimer (ELISA), fibrinogen-related material (electroirnmunodiffusion),and thrombinantithrombin III complex (TAT) were determined. Fibrinogen/fibrin derivatives were fractionated according to molecular weight and identified by immunoblotting wif~ monoclonal and polyclonal antibodies. CA 125 and total ~Naee activity were also determined in the corresponding blood sere. Results: Corresponding with the histologic f~idings a slight increase in RNase activity was detected in the fluids of corpus luteum and follicle cysts (n=15, Median (M): 270 ngeqvs/ml}.The corresponding serum values were found in the normal range (cut off values: CA 125:65 U/ ml, RNase: 250 ngeqvs/ml>.A considerable, yet not significant, increase was measured in the group of cystadenomas (n=ll, M: 325 U/ml; 307 ngeqvs/ml), coupled with ~Nase increase in the corresponding sere (M: 8,3 U/ml; 291 ngeqvs /ml). The highest activities in this group were expressed in borderline tumors (max 2074 U/ml, 2450 ngeqvs/ml).Significant elevations in cyst fluids as well as sera were measured in ovarian carcinomas (M: 578 U/ml; 391 ngeqvs/ n~). Concerning the fibrin degradation products the group of corpus luteum and follicle cysts showed high thrombinantithrombin III complex (TAT) levels and high portions of high molechlar degradation products. This supports a prevailing thron~in activity. The group of cystadenomas showed small portions of fibrinogen and high molecular degradation products but rather high portions of low mole-" cular degradation products. This pattern shows a higher fibrinolytic than coagulating activity. Frauenklinik~ Fakult~t f~r Klinische Medizin Mannheim der Universit~t Heidelberg, Th.-Kutzer-Ufer, 6800 Mannheim

3/P-GM 047 N O N I N V A S I V E D I S C R I M I N A T I O N B E T W E E N B E N I G N AND M A L I G N A N T O V A R I A N T U M O R S BY S I M U L T A N E O U S D E T E R M I N A T I O N OF SRA A N D CA125 B.Ebert,I.Hofmann,H.Schleich,R.Schmidt,W.Wiest, J . I n t h r a p h u v a s a k , and F . M e l c h e r t An at p r e s e n t u n s o l v e d p r o b l e m in g y n e c o l o g y is the n o n i n v a s i v e d i s c r i m i n a t i o n b e t w e e n b e n i g n and m a l i g n a n t o v a r i a n tumors. S i n c e we could i m p r o v e t h e n u m b e r o f c o r r e c t l y i d e n t i f i e d ca. hosts (sensitivity) to m o r e t h a n 90% by simultaneous m e a s u r e m e n t of two r e c o m m e n d e d o v a r i a n ca. markers, S R A (serum r i b o n u c l e a s e activity) and C A 125, w i t h o u t i n c r e a s e of the n u m b e r of f a l s e p o s i t i v e s (specificity), we i n v e s t i g a t e d the c l i n i c a l v a l i d i t y of this m a r k e r c o m b i n a t i o n in d i s c r i m i n a t i n g b e t w e e n b e n i g n and m a l i g n a n t o v a r i a n tumors. We i n v e s t i g a t e d a total of 145 p a t i e n t s (78 w i t h histologically confirmed benign ovarian tumors a n d 67 s u f f e r i n g from h i s t o l o g i c a l l y c o n f i r m e d o v a r i a n carcinomas). The d e c i s i o n m a l i g n a n c y y e s / n o was m a d e u s i n g the b o r d e r l i n e c a l c u l a t e d by l o g i s t i c r e g r e s s i o n analysis. Comb.SRA&CA125: CA 125 SRA

Spec. Sens. Spec. Sens. Spec. Sens.

91% 83.6% 91% 74.6% 85.9% 76.1%

71/78 56/67 71/78 50/67 67/78 51/67

W e find an i n c r e a s e An s e n s i t i v i t y by about 10% in favor of the combination. We are of the opinion that further i n v e s t i g a t i o n s of g r e a t e r n u m b e r s of b e n i g n t u m o r s w i l l i n c r e a s e this imp r o v e m e n t by t a k i n g into a c c o u n t the i n f l u e n c e of the v a r y i n g h i s t o l o g y of t h o s e b e n i g n tumors. U n i v . - F r a u e n k l i n i k am K l i n i k u m der S t a d t M a n n helm, T h e o d o ~ - K u t z e r - U f e r , D-6800 M a n n h e i m

3/P-GM 046

3/P-GM 048

SNORT TIME OSCILLATIONS OF CARCINOEMBRYONICANTIGEN (CEA) SERUM LEVELS A. B i t t l , W. J~ger, L. Wildt

P A R A L L E L M E A S U R E M E N T S OF S R A A N D C A 125 IN P A T I E N T S W I T H O V A R I A N CARCINOMA. A COMPARISON. I.Hofmann,H.Ebert,R.Schmidt,H.Schleich,W.Wiest, H . A l t e n b u r @ v J . I n t h r a p h u v a s a k , and F . M e l c h e r t

In previous studies we demonstrated that serum levels of CEA in breast cancer patients fluctuate during a 24 hour period. In order to characterize the secretory pattern more precisely, we developed an automated method to obtain blood samples, using a system that can be assembled from general hospital equfpment. Blood is continuously withdrawn by a p e r i s t a l t i c pump via an intravenous cannula placed in a forearm vein (sampling catheter). To prevent coagulation within the system, heparine solution is added at a fixed rate to the withdrawn blood over a thin tubing inserted into the intravenous cannula. This prevents heparine solution from entering into the systemic c i r c u l a t i o n . Dilution of blood is held constant at about I%. In patients with primary breast cancer CEA serum levels were examined for periods ranging from 1.5 to 6 hours at a sampling interval of 5 minutes. CEA serum concentrations were measured with an immunoradiometric assay using monoclonal antibodies (CEA-ELSA, ID-CIS, Dreieieh FRG). The intraassay coefficient of variation for duplicate determinations was less than 5%. CEA serum levels revealed frequent o s c i l l a t i o n s that were not always explained by the inherent assay v a r i a b i l i t y . The withdrawal system developed for t h i s study should enable us to examine further, i f the pattern of CEA in serum of breast cancer patients follows some endogenous or exogenous rhythm. Universit~ts-Frauenklinik, Universit~tsstraBe 21-23, D-8520 Erlangen FRG.

M o r e t h a n 80% of o v a r i a n c a r c i n o m a s have r e a c h e d or e x c e e d e d FIGO III w h e n d i a g n o s i s is made. So, the a v a i l a b i l i t y of a r e l i a b l e n o n i n v a s i v e test is of p a r t i c u l a r c l i n i c a l interest. W e c o m b i n e d two m u t u a l l y i n d e p e n d e n t t u m o r m a r k e r s , S R A (serum r i b o n u c l e a s e activity) and C A 125 (cancer a n t i g e n 125), b o t h w i t h reports of high specificity and s e n s i t i v i t y in o v a r i a n carcinomas. F o r the e v a l u a t i o n w e used l o g i s t i c r e g r e s s i o n a n a l y s i s (LRA). We also took into a c c o u n t the age of the b l o o d s a ~ p l e donors. Results: In 193 females (67 w i t h h i s t o l o g i c a l l y c o n f i r m e d o v a r i a n c a r c i n o m a and 126 h e a l t h y volunteers) S R A was d e t e r m i n e d by our s t a n d a r d assay (Schleich&Wiest, E u r . J . G y n a e c o l . O n c o l . 5 , 1984, 186-194). C A 125 was d e t e r m i n e d by an E L S A from CIS. By e v a l u a t i o n u s i n g L R A w e c a l c u l a t e d a b o r d e r l i n e for the d e c i s i o n ca y e s / c a no. W i t h this b o r d e r l i n e w e found the f o l l o w i n g r e s u l t s for s p e c i f i c i t y and sensitivity: Comb. S R A & C A 125: Spec. Sens. CA 125 Spec. Sens. SRA Spec. Sens.

95.2% 92.5% 93.7% 73.1% 90.5% 76~1%

120/126 62/ 67 118/126 49/ 67 114/126 51/ 67

T a k i n g into a c c o u n t that the m e a s u r e m e n t of these two m a r k e r s does not e x p o s e the p a t i e n t s to i n c r e a s e d stress we can r e c o m m e n d the routine p a r a l l e l m e a s u r e m e n t of SRA and CA 125 for d i a g n o s i s and m o n i t o r i n g of o v a r i a n carcinoma. Universit~ts-Frauenklinik, Theodor-Kutzer-Ufer, D-6800 Mannheim I

$94

3/P.GM 049

3/P-GM 051

DETERMINATION OF ESTROGENERECEPTORIN MALIGNANTEFFUSIONS IN PATIENTSWITH ADVANCEDBREASTCANCER. Lorenz,L, Langecker,P., Doischer,E., Schenk~U., Possinger,K., Wilmanes,W.; GSF , MUnchen-Neuherberg; Med. K]inik 111, Klinikum Gro~hadern, Universit~t M~nch~n, Inst. f~Zytolo.9_q~e=TU MUnchen. One t h i r d of a l l breast cancers have a positive estrogens receptor (ER) status. In the case of (ER) positive breast cancer there is a response to hormonal treatment in 50% of the p t s . , whereas 90% w i l l f a i l to respond in case of neg, ER-status, Since ER-status of the primary tumor is often unknown and since i t can change during the course of disease, i t is necessary for treatment decisions to reevaluate the ZR-status in the metastasized state. More than 50% of pts. with metastatic breast cancer w i l l devellop malignant pleural effusions, from which malignant c e l l s can easily be seperated. Due to the small tumor mass of effusion cells in most cases the determination of ER by labeled estrogens (DCC) is impossible, Therefore immunecytochemic detection of ER by a monoclonal antibody (ERICA) is a good alternative. We performed ERICA on f i x i a t e d albumin covered cytospin samples. The results of ERICA were correlated to a cytomorphological evaluation of ER-status considering cytoplasms/nucleus r e l a t i o n , number of nucleoli, vacuolisation and nuclear polymorphism, Results: 21 pts. with malignant effusions of breast cancer were examined, I0 pts, showed ER positive c e l l s , 8 pts. were ER negative and 3 pts. could not be evaluated. 8 of the ]0 ERICA positive pts. were also cytomorphologically classified ER positive, whereas only 2 pts of the 8 ERICA neg. were classified ER pos. Prior to our investigation 12 pts. had an unknown ER-status. 3 of 4 pts., who where ER pos. at primary diagnosis, remained ER pos. by ERICA and l pt, became neg. All primary ER neg. pts, (2) had ER neg, e f f u s i { # cells by ERICA. These data show a good correlation between ER-status as determined by ERICA, to the cytomorphological grading and to the ER status of the primary tumor as determined by DCC. We conclude that ER!CA Is a safe method to determine ER status in effusions even with a low cell numbers, Lorenz,T.,Langecker,P.,Doischer,E,~Schenk~U.,Possinger,K~, Wilmanns,W.; GSF, MUnchen-Neuherberg; Med.Klinik l l I , Klinikum Gro~hadern, Universit~t MUnchen; I n s t i t u t fur Zytologie, TU MUnchen.

GONADOTROPIN-RELEASING BREAST CANCER

3/P-GM 050 PROBNOBTICAL516NIFIC~NCs OF THE PROBESTERONERECEPTOR@ITH BREASTCANCER I. Ederer, E. Merkle, C, Seidl, M, Rsitzenstein

660 patients suffering from breast cancer were registered in a retrospective study betwen Juty t975 and October 1984 in which an analysis of the progesterone receptors of the prisary tumor was carried out, @omenwith positive progesterone receptors (n=253) sho~e4 a surviral time of more than 5 years (78%) in contrast to those petient~ ~ith negative progesterone receptors (n=406; 55%). Categorization according to affected lymph nodes showed that patiente with a• lymph node metastase~and positive progesterone receptors (n=128) had a similar survival time (75%after 5 years) as those without axillary Iysph node metastases and negatire progesterone receptors (n=176; 74~). The progesterone receptor is therfore, as pregnostical factor, comparable to the lymph node status, Among a second group of 75 patients with a localised relapse, whose progesterone receptors were determined, there were 23 uoeen with positive progesterone receptors mho also had s lon~r survival time (49% after 4 years) than 52 patients ~ith negative progesterone receptors (27% after 4 years). 6ynaecologicai Hospital of the Erlangen University, Head: Prof.Or, N. Lang, Universit~tsstr. 2!/23, D-8520 Erlangen

HORMONE

RECEPTORS

IN

t . Kiesel, M. Kaufmann, H. Schmid, T. Rabe, K. Klinga and B. Runnebaum Gonadotrepin-releasing hormone (GnRH) apologues are presently under Lnvestigation f o r the treatment o f metastatic breast cancer. Their maim effects seem to be mediated via the suppression of gonsdotrepins and gormdai steroids, although there are various reports that they could also act directly on the turnout.

In 97 p r i m e r / human breast carcinoma tissues, the binding of a GnRH-agomist was measured in membrane fractions. In 43 samples (44 %), the presence of specific GnRH receptor binding sites (above 3 f o o l / r a g membrane protein) was demonstrated. The mean GnRH accepter content was 6.4 f o o l / r a g membrane protein in estradiol receptor (ER) positive tissues and 3.5 f o o l / r a g membrane protein in ER negative samples (p .<: 0o05). Progesterone receptor (PR) positive tiss~Je contained 4.8 f o o l i n g membrane protein and PR negative carcinoma contained 3.6 fmoi/mg membrane protein. In postmenopausal women, the mean GnRH ~ e p t e r concentration was 5.4 and 2.9 f o o l / r a g membrane protein (p ~?~ 0.05), respectively, in ER positive and negative tissues, compared to 4.4 and 5.2 fool/rag

membrane protein, respectively, in PR positive and negative samples. Using Mann-Whitney-U-Test, a significant difference was observed f o r GnRH receptor content between ER positive and negative tissues in pro- and postmenopauseI patients. In a clinical trial, the GnRH agenist Zoladex R, applied as monthly depot preparation, produced effective response rates in 10 out of 22 premenopsusal patients.

Universit~ts-Frauenklinik,Voss-Str. 9, [~6900 Heidelberg.

3/P-GM052 THE IMPORTANCE OF T U M O R M A R K E R S IN THE D I A G N O S I S AND FOLLOW-UP OF C O L O R E C T A L HEPATIC ONLY METASTASES C. HOTTENROTT, Mo LORENZ, R.P, B A U M Due to the d e v e l o p m e n t of hybridoma technique it was p o s s i b l e to identify several new tumor antigens. Although they were o r i g i n a l l y thought to be more tumor specific, none of these markers w e r e found e x c l u s i v e l y in tumors or in serum of tumor patients. Compared with CEA (carcinoembryonic antigen) and clinical laboratory test the role of these markers (CA 19-9, CA 125, CA 15-3) was prospectively evaluated in 95 patients with colorectal livermetastases. Patients were c l a s s i f i e d a c c o r d i n g to tumor volume (TI < 25%, T2 25-75%, T3 > 75%). Patients with benign liver or biliary disease served as a control group (n=60). An overall sensitivity of 85% for GGPT and 80% for AP was recorded with an s i g n i f i c a n t correlation to the tumorvolume, LDH showed a high specificity and a sensitivity of 34%, Elevated CEA serumlevels were found in 84% of all patients, w h e r e a s CA 19-9 was positive in 52%, CA 125 in 34% and CA 15-3 in 30%. Because of complementary elevations, the c o m b i n e d use of CEA, CA 19-9 and CA 125 increased sensitivity up to 94%. Correlation with tumor volume exists, however, only for CEA. CONCLUSION: CEA and GGPT showed highest sensitivity for liver metastases during follow-up of colorectal tumors. CA 19-9 and LDH could be useful for confirmation because of their higher specificity. It is proved to be d i f f i c u l t to make the differential diagnosis between benign and m a l i g n a n t liver diseases by laboratory tests. DEP. SURGERY AND NUCL. M E D . - U N I V E R S I T Y OF FRANKFURT, WEST GERMANY

S 95

3/P-GM053

3/P-GM 055

SERUM LEVELS OF SCC ANTIGEN AND CEA IN PATIENTS WITH CERVICAL CANCER - A COOPERATIVE STUDY OF THE GTMG G. CROMBACH I H. WORZ I, R. KREIENBERG 2 V. NOBUS 2, P. SCHMIDT-RHODE 3, G. STURM 3, H. CAFFIER 4, H. KAESEMANN ~

S Q U A M O U S C E L L C A R C I N O M A (SCC) A N T I G E N IN M O N I T O R I N G C E R V I C A L C A N C E R - A C O M P A R I S O N TO CEA, TPA,CA 125,CA 50 AND CA 15.3. H.H~fnerIP.Schmidt-Rhode~K.D.Schulz,H.J.KGnzig

(Squamous Cell Carcinoma) antigen is a subfraction of tumor antigen TA-4, isolated from a cervical squamous cell carcinoma. In a retrospective study the Gynecological Tumor Marker Group (GTMG) evaluated SCC antigen (RIA-kit, Abbott) and CEA {kits of different manufacturers) as serum tumor markers in cervical cancer. The cut-off values for SCC antigen (2.5 ng/ml) and CEA corresponded to the 95% specificity in healthy controls. The incidence of elevated serum marker concentrations is shown in the Table below. SCC antigen values in women with cervical squamous cell carcinoma were significantly higher than those in normal controls, in women with CIN l-III and in patients with NED (p<0.O001). The incidence of elevated SCC antigen and CEA levels increased with local tumor extent and metastatic involvement of iliacal lymph nodes. SCC antigen was more sensitive for squamous cell carcinomas, while CEA proved to be superior for adenocarcinomas. By simultaneous determination of both markers the sensitivity increased to 79% for recurrent cervical cancer. During long-term follow-up (6-24 months) progression of a cervical squamous cell carcinoma was accompanied by an increase of marker levels in 95% of cases (n=42). Total SCC+ CEA+ SCC/CEA+ .......................................................... Female controls 280 4 5 7 CIN I -III 41 10 2 10 Primary cervical cancer 294 53 39 68 Squamous cell carcinoma 273 55 38 69 Adenocarcinoma 21 24 48 62 Recurrent cervical cancer 96 67 46 79 Remission Iii 3 9 12 .......................................................... Universit~ts-Frauenkliniken K61n I , Mainz 2 , Marburg 3 , WGrzburg 4, Kerpener Str. 34, D-5000 K61n 41

The squamous cell c a r c i n o m a a s s o c i a t e d a n t i g e n (SCC) was g e n e r a t e d from a l i v e r m e t a s t a s i s of c e r v i c a l squamous cell c a r c i n o m a . i d e n t i f i e d as a s u b f r a c t i o n of the TA-4 a n t i g e n , t h e SCC is d e t e c t a b l e in the plasma of p a t i e n t s w i t h invasive cervical c a r c i n o m a by radioimmunoassay. U s i n g a limit value of 2,5 n g / m l , e l e v a t e d SCC levels w e r e o b s e r v e d in 5,8 % of h e a l t h y cont r o i s , i n 7 % of p a t i e n t s w i t h CIN III and in 64,4 % of patients w i t h invasive cervical squamous cell c a r c i n o m a . I n c r e a s e d SCC titers also were d e t e c t a b l e in 15 % in e n d o m e t r i a l and ovar i a n c a r c i n o m a s with squamous cell a r e a s , a n d in 37 % in p a t i e n t s w i t h v u l v a r c a n c e r . T h e incidence of abnormal SCC titers in cervical can cer d e p e n d s u p o n the t u m o u r load, i n c r e a s i n g s i g n i f i c a n t l y w i t h a d v a n c e d stage d i s e a s e . I n o p e r a b l e cervical c a r c i n o m a s elevated SCC values r a p i d l y d e c l i n e d after radical surgery. In cases of r a d i o t h e r a p y n o r m a l a n t i g e n levels were m e a s u r e d n o t before 4-6 weeks after start of t r e a t m e n t . T h e success of both t r e a t m e n t mod a l i t i e s was a n n o u n c e d by an early rise of the SCC c o n c e n t r a t i o n in the initial phase of the t h e r a p y . P a t i e n t s w i t h complete r e m i s s i o n only d e m o n s t r a t e d a b n o r m a l titers in 3,8 % . R e t r o spective evaluations in ten p a t i e n t s w i t h progressive disease showed the r e a p p e a r a n c e and further increase of abnormal titers p r e c e e d i n g the c l i n i c a l l y d e t e c t a b l e r e l a p s e w i t h a median interval of 8 w e e k s . S C C d e t e r m i n a t i o n is n n o t u s e f u l for s c r e e n i n g i n v e s t i g a t i o n s , h o w ever for the s u r v e i l l a n c e of c e r v i c a l cancer. D e p a r t m e n t of Obstetrics and Gynecology, Philipps U n i v e r s i t y , M a r b u r g (Lahn),Germany FR

3/P-GM 054

3/P-GM 056

SCC AND CEA SERUM LEVELS IN PATIENTS WITH CERVICAL CARCINOMA P. Stieber*, W. Meier, D. Pfeiffer, A. Fateh-Moghadam*, W. Eiermann

P l a s m a C o n c e n t r a t i o n s Of CA 50,CA 125,CA And CA 19.9 In E n d o m e t r i a l C a n c e r S.HubgrrP.Schmidt-RhodeIK.D.Schulz~G.Sturm

SCC

N

%

%

%

Squamous cell carcinoma (SCC) antigen was first described by Kato et al. in patients with carcinoma of the cervix uteri. SCC serum levels can be measured with a radioimmunassay, in our investigation 2,0 ng/ml were taken as the upper limit of the standard range. In 35 healthy women there were no elevated SCC levels, 8 of 40 patients with breast, endometrial and ovarian cancer showed elevated levels; SCC was also elevated in some patients with benign gynecological diseases. 64 % of the 80 patients with primary and 73 % of the 37 patients with recurrent cervical cancer showed pathological values, CEA was elevated in 31% and 5t % respectively. The percentage of positive levels and the absolute values increased with the stage of the disease. 69 % of the patients with squamous cell carcinoma had elevated levels. Pathological values could also be found in adenosquamous and adenocarcinomas. SCC shows a low specificity but a high sensitivity for squamous cell carcinomas of the cervix uteri. The tumor marker might be helpful in the control of primary therapy and follow-up of cervical cancer patients. Institut for Klinische Chemie* und Frauenklinik im Klinikum GroBhadern, Ludwig-MaximiIians-Universit&t, MarchioninistraSe 15, 8000 MQnchen 70

15.3

The p r e s e n t study investigates the m e n t i o n e d a n t i g e n in the p l a s m a of e n d o m e t r i a l c a n c e r p a t i e n t s . T h e data show the i n c i d e n c e of a b n o r mal values of all antigens r e l a t e d to the stage of the d i s e a s e , T h e CA 50 seems to be the most sensitive m a r k e r w i t h a p o s i t i v i t y rate of 34 % in stage l , i n c r e a s i n g to 7 1 % in stage I I I / I V and r e c u r r e n t e n d o m e t r i a l c a n c e r . l n com p a r i s o n elevated CA 125 levels were a s s o c i a t e d in 10,5 % w i t h stage I and in 57 % w i t h stage I I I / I V and r e c u r r e n t d i s e a s e . P a t h o l o g i c a l plas ma titers of CA 15.3 and CA 19.9 were only ana lyzed in special cases of a d v a n c e d disease m o s t l y . F o l l o w i n g total tumour r e s e c t i o n in sta ge I and II of endometrial c a n c e r , i n c r e a s e d a n t i g e n plasma values r e t u r n e d to n o r m a l w i t h in a short t i m e . T h e o b s e r v a t i o n of only a small n u m b e r of p a t i e n t s w i t h d i s s e m i n a t e d disease f u r t h e r m o r e shows CA 50 and CA 125 ref l e c t i n g the tumour response and p r o g r e s s i o n under systemic c a n c e r o s t a t i c treatment. The p r e s e n t study d e m o n s t r a t e s , t h a t none of the i n v e s t i g a t e d antigens is useful for the early d i a g n o s i s of e n d o m e t r i a l c a n c e r . B u t the the m e a s u r e m e n t of the CA 50 and CA 125 provides a p o t e n t i a l means for m o n i t o r i n g the efficacy of individual a n t i c a n c e r therapy and for d e t e c t i n g a r e c u r r e n t disease. D e p a r t m e n t of Obstetrics and Gynecology, Philipps University,Marburg (Lahn)

Germany

FR

S 96 3/P-GM057

3/P-GM059

Effect of various culture conditions to the immunocytochemical steroid r e c e p t o r by mammary carcinoma cell lines. A. ROck, H.H. Z i p p e l , R. H a c k e n b e r g , F. H ~ l z e l , K . - D . Schulz

CA 125 IN PATIENTS WITH OVARIALCARCINOMA: PROGNOSIS, COURSE, EXAMINATION OF EFFUSIONS L. H o f f m a n n , S. M U l l e r - H a g e n , E. 5 c h ~ f e r

The i n vitro growth o f MCF-7 c e l l s can be stimulated by e s t r a d i o l - 1 7 6 (E 2) and i n h i b i t e d by antiestrogenic tamoxifen (TAM). In the present investigation we e x p l o r e d t h e a l t e r a tions o f ER and PgR i n g r o w i n g mammary c e l l cultures under various culture conditions by i m m u n o c y t o c h e m i c a l (ER-ICA , m PR I ) and b i o c h e m i c a l (DCC) methods. Under s t e r o i d - f r e e conditions ER, d e t e r m i n e d by DCC, was h i g h e r t h a n i n t h e p r e s e n c e o f 10 -9 M Ep whereas PgR was i n d u c e d more t h a n t e n f o l d b~ lO - ~ M E2. With i n c r e a s i n g doses o f E2 t h e i m m u n o c y t o c h e mical presence of intranuclear ER d e c r e a s e d whereas PgR i n c r e a s e d . After t h e s w i t c h from s t e r o i d - f r e e conditions t o t h e p r e s e n c e o f 10 -9 M E2 t h e ER c o n t e n t dramatically droped w i t h i n 1 h. A f t e r s u p p r e s sion of ER by 7 days i n c u b a t i o n i n medium with 10-9 M E2 c o m p l e t e r e c o v e r y o f t h e ER c o n t e n t was n o t e d w i t h i n 6 d a y s . I n t h e p r e s e n ce o f TAM t h e i m m u n o c y t o c h e m i c a l ER c o n t e n t was j u s t as h i g h as under s t e r o i d - f r e e conditions, w h i l e t h e PgR c o n t e n t d e c r e a s e d . Our r e s u l t s are a c o n t r i b u t i o n in the discuss i o n o f t h e de novo s y n t h e s i s o f t h e r e c e p t o r p r o t e i n by e s t r o g e n . Universit~ts-Frauenklinik Pilgrimstein 3 D 3550 Marburg

Marburg

The aim of a c o o p e r a t i v e s t u d y was to a n s w e r the f o l l o w i n g q u e s t i o n s : l) do preoperative m a r k e r l e v e l s p r e d i c t c l i n i c a l o u t c o m e ? 2) Do d y n a m i c s of m a r k e r d e c r e a s e p r e d i c t e f f e c t of t h e r a p y ? 3) Is m a r k e r n o r m a l i s a t i o n (MN) ident i c a l w i t h CR? 4) Are m a r k e r l e v e l s in a s c J t e s / p l e u r a l e f f u s i o n s of d i a g n o s t i c v a l u e ? R e s u l t s : l) We a n a l y s e d 119 p r e o p e r a t i v e sara (n = 69 > 500 U/ml, n = 50 < 500 U/ml). A c c o r ding to the life t a b l e s t a n d a r d test the g r o u p w i t h p r e o p e r a t i v e l o w e r l e v e l s had a s i g n i f i c a n t l y l o n g e r s u r v i v a l time. 2) If m a r k e r n o r m a l i s a t i o n did not o c c u r a f t e r the 3rd c h e m o t h e r a p y course, CR was not a c h i e v e d . 3) 32 p a t i e n t s (pat.) w i t h c l i n i c a l CR and MN had a second-look-laparotomy, 12/32 (37,5%) d e m o n s t r a t e d r e s i d u a l t u m o r (6 w i t h m i c r o s c o p i c tumor). In c o n t r a s t , e v e r y m a r k e r i n c r e a s e was a l w a y s f o l l o w e d by d i s c o v e r y of r e s i d u a l tumor, t u m o r p r o g r e s s i o n or r e l a p s e . 4) In 36 s a m p l e s of a s c i t e s (A) CA 125 was m e a s u r e d and c o m p a r e d w i t h s e r u m (5) levels.

I

I

I

A 11352 5546 83742 U/ml S 2230 736 30052 In a d d i t i o n 9/9 e f f u s i o n s of ~at. w i t h c a r c i n o ma of the b r e a s t (x = 2473, x = 1449 U/m1) end 5/5 b e n i g n e s c i t e s (x : 790, ~" = 840 U/ml) showed high p a t h o l o g i c a l levels. C o n c l u s i o n s : Preop. l e v e l s of CA 125 and d y n a m i c s of MN are r e l i a b l e p r o g n o s t i c p a r a m e t e r s . MN is no p r o o f of CR. CA 125 is not u s e f u l in the d i f f e r e n t i a l d i a g n o s i s of e f f u s i o n s . Onkologische Abteilung, B a r m b e k , R ~ b e n k a m p 148,

Allgemeines Krankenhaus D 2000 H a m b u r g 60

3/P-GM058

3/P-GM 060

F L U O R I N A T E D P O L Y A M I N E S AS T U M O R M A R K E R S : D E T E R M I N A T I O N IN N O R M A L T I S S U E S A N D A N I M A L T U M O R S BY 1 9 F - N M R S P E C T R O S C O P Y .

CAN STANDARD CHEMOTHERAPY SHORTEN SURVIVAL IN METASTATIC BREAST CANCER?

T r e a t m e n t of laboratory a n i m a l s b e a r i n q t r a n s Dlantable tumors with a-difluoro-methylo r n i t h i n e , an i n h i b i t o r of o r n i t h i n e d e c a r b o x ylase, f o l l o w e d bv 2 , 2 - d i f l u o r o - D u t r e s c i n e a l l o w s the p a r t i a l r e p l a c e m e n t of the e n d o g e nous Dolyamines spermidine and spermine by their fluorine-containing analogs 6,6-difluorospermidine and 6,6-difluoro-spermine. Quantit a t i v e d e t e r m i n a t i o n of the f l u o r i n a t e d p o l y a m i n e s in e x c i s e d tumor t i s s u e by in vitro 1 9 F - N M R at 11.7 T e s l a ( d e t e c t i o n t h r e s h h o l d ca. 1 n m o l e / g ) q a v e r e s u l t s s i m i l a r to HPLC. In a d d i t i o n , 1 9 F - N M R a l l o w e d the d e t e c t i o n of s e v e r a l as yet u n i d e n t i f i e d d i f l u o r o o o l y a m i n e m e t a b o l i t e s . One of t h e s e was f o u n d o n l y in M 5 0 7 6 a n d L e w i s L u n g t u m o r s and not in n o r m a l tissue, w h i l e o t h e r s w e r e c h a r a c t e r i s t i c for liver. W i t h a s u r f a c e coil at 2,4 Tesla, f l u o r i n a t e d p o l y a m i n e s c o u l d be d e t e c t e d in tumor, l i v e r and b l a d d e r (urine) of m i c e in vivo at ca. 5 0 - 1 0 0 n m o l e / g in 1 0 - 2 0 min. ie. w h e n 2-5% of the n a t u r a l D o l v a m i n e s h a v e b e e n r e p l a c e d bv t h e i r ( l u s t s a n a l o g s . S i n c e the f l u o r i n a t e d D o l y a m i n e s D r e f e r e n t i a l l y a c c u m u l a t e in tumors, these c o m p o u n d s m a y a l l o w the a p p l i c a t i o n of I g F - N M R for t u m o r d i a g n o s i s a n d t h e r a p v c o n t r o l . The d e t e c t i o n of t u m o r - s p e c i f i c D o l y a m i n e m e t a b o l i t e s d e m o n s t r a t e s that 1 9 F - N M R will contribute to our k n o w l e d g e of p o l y a m i n e I n s t i t u t for B i o c h e m i e . D e u t s c h e s K r e b s f o r s c h u n g s z e n t r u m , N e u e n h e l m e r F e l d 280, D - 6 9 0 0 H e i d e l b e r g and * M e r r e l l D o w R e s e a r c h I n s t i t u t e , Strasbourq.

F. Porzsolt, E. D. Kreuser, S. Mende, G. Meuret, L. Buchelt, P. Strigl, M. Redenbaeher, F. Klumpp, M. Schmelz, R. KnSchelmann, V. Hiemeyer, K. Fleiseher, W. Gaus, R. Leichtle, C. Popp, R. Kloiber, W. Schreml Recently, we have shown that a complex strategy for treatment of metastatie breast cancer can be used in non-research hospitals. This strategy considers four Low Risk and four High Risk subgroups of MBC patients, recommends eight different first llne therapies and up to nine consecutive lines of therapy. 335 evaluable patients from 27 participating hospitals in the service area of the Tumorcenter Ulm were included in this phase IV study. 50% of these patients were treated according to the proposed strategy. In the remaining patients deviations from the strategy were recorded. These patients received either more aggressive", "less aggressive" or "similar" therapies. The results demonstrate that survival of Low Risk patients is significantly (p=0.009) longer without deviations from protocol than in those who received either more aggressive, or less aggressive, or similar therapies. In High Risk patients survival is significantly (p=0.016) longer in patients who received less aggressive therapies than in those who received the proposed therapies. The reasons for deviations from the proposed strategy are described. It is concluded that some but not all subgroups of MBC patients with different prognoses can be identified prospectively. The restricted use of chemotherapy in the treatment of MBC will not shorten survival of these patients. Survival of some patients may be longer if aggressive therapies are avoided. Regionale Studiengruppe, Tumorzentrum der Universit~t Ulm, SteinhSvelstr. 9, D~7900 Ulm

S 97

3/P-GM061

3/P-GM 063

DEPOT FORMULATION OF B U S E R E L I N (D-BUS) IN T R E A T M E N T OF PREMENOPAUSAL ADVANCED BREAST C A N C E R (BC) R. Callies, K. H~ffken, E. Kurschel, M.E. Scheulen, O. Weinhardt, R. Becher, J ~ , Sandow~ C.G. Sc~midt . . . . . . . . . .

THE ANALGESIC EFFECT OF SALMON-CALCITONIN IN CANCER PATIENTS WITH OSTEOLYTIC BONE DISEASE I. Vainas, N. Kaklas, I. Stergiu and K. Dimitriadis

Continuous application of LH-RH agonists like BUS results in hypogonadotropic ovarian insufficiency. Since subcutaneous or intranasal application is annoying and m a y lead to compliance problems, depot formulations are being developed. In a phase I-II study, 6 patients (pts) with premenopausal advanced BC received 6,6 mg D-BUS as a subcutaneous implant every 4 weeks. In this depot formulation, BUS is released from a c o m p l e t e l y resorbable polylactide/glycolide copolymer. In 4 pts, D-BUS was the first hormonal treatment, in 2 pts D-BUS was replaced for intranasal application. Hypogonadotropic ovarian insufficiency was induced in all 4 untreated pts, 3 weeks after treatment initiation, and was m a i n t a i n e d in the 2 pretreated pts. Pharmacokinetic studies revealed sufficient serum BUS levels and BUS urine excretion at the end of each treatment period. With the 4 untreated pts, there were 2 partial remissions and 2 disease stabilisations. Remissions in the 2 pretreated pts were maintained. We conclude that D-BUS is a reliable replacement for the treatment w i t h BUS in premenopausal BC. Universit~ts-Frauenklinik und Innere Universit~tsklinik und Poliklinik (Tumorforschung) , Westdeutsches Tumorzentrum, Hufelandstr. 55, D-4300 Essen 1

The main symptom of osteolytic bone involvement in malignancy is bone pain. Radiotherapy and cheme-hormonal treatment both provide a moderate analgesic effect~but in most cases analgesic and /or anti-inflammatory drugs have to be co-admi~ nestered.lt is known in the last years, that o s t ~ otropie salmon-ealeitonin(sCT),whieh inhibits osteoclastic bone resorption(L.A. Austin, N e w Engl. J.Med.,304,269,1981)and has a marked central effect o n-'~e pain threshold(A.Pecile,Experimentia 3__!1,332,197~),possesses special analgesic qualities on patients with osteolytic metastases(A.C. Hindley~Cancer Chore.and Pharm.,~, 71,1982). In this prospectiv study we treated 15 patients, s u ~ feting from chronic severe pain due to esteolytic bone involvement caused by lung and breast neoplasias, with sCT adminestered for 7 consecutive days at a dose of 200 l.U,/die in 500 ml 0,9% NaCl-solution(infusion time 2 hours).The intensity of pain was daily simultaneously evaluated by doctor and patient, starting ~ days bsvore treatment and continued up to 8 days after sCT administration, and it was based on a visuoanalogie scale. We observed a marked reduction of the bone pain and of analgesics consumption in 12 of the 15 patients. This kind of sCT-treatment, haring only moderate side effects, did net affect any biochemical parameters except for urinary excretion of h y d r o x ~ r o l i n e . l n conclusion, this stud y shows the very good analgetic effect of sCT in an optimal therapeutic regimen(i.v, and short duration treatment, moderate doses)in patients with painful osteolytic metastases. Medical Oncology Department il, Theagenion Cancer Center, 2 A. Symeonidistr.,GR-54007 Thessaloniki

3/P-GM 062

3/P-GM064

AROMATASE INHIBITION WITH 4-HYDROXYANDROS T E N E D i O N E (4-OHA) IN T R E A T M E N T OF P O S T M E N O P A U S A L ADVANCED B R E A S T CANCER (BC) K. H6ffken, W. Jonat, K. Possinger, M. K61bel, M. Kloke~ R. Becher~ R. Callies, C.G. Schmidt

VARIABILITY OF ANTIGENICITY AS A PROGNOSTIC PARAMETER IN PATIENTS WITH BREAST CANCER D. Seitzer, B. Brandt und W. Niedner To improve the prognostic criteria in patients with breast cancer, we studied biochemical and i~unohistochemical Ca 15-3 variability and Ki67expression in 88 tumor tissues. Ca 15-3 con~ centr, were measured in serum and cytosol, immunohistochemical examinations were made on fixed tissue sections. Upper limit values were determined 0.3 U/mg protein for serum and 40 U/mg protein in cytosol. Staging of patients results in 54 T 1-2, 34 T 3-4, 42 were nodal positiv. 22 patients have recurrent disease within the follow up of maximal 2 1/4 years. In case of cytosol levels above the cut-off we found good prognosis (i). In the opposite, bad prognosis was found in tumors with cytosol levels below the cut-off (2). (i) n = 41 recurrence 2 (5%); grad II 29 % (2) n = 47 recurrence 19 (40%); grad III 96 % Variability of antigenic property in tumor cells may explain these results. Tumor grading(= II, as demonstrated in our results, assume a relative constant antigenicity, therefore cytosol concentration should be high. On the other hand, in grad III tumors translatory as well as post-translatory modification indicate more and more different protein sequences and therefore a different antigenicity. This results in low cytosol concentrations. The data were confirmed in im~unohistochemical fixed tissue sections. Correlation was found with the results measured by the expression of Ki-67. Klinik und Poliklinik fur Geburtshilfe und Frauenheilkunde A, Albert-Schweitzer-Str. 33, D-4400 M~nster

Estrogen deprivation b y aromatase inhibition is an effective treatment in BC. Since October 1986, 65 postmenopausal patients (pts) with BC entered a phase II-study p e r f o r m e d jointly in 3 centers to investigate the new aromatase inhibitor 4-OHA. Pts received every 2 weeks intramuscularly 500 mg 4-OHA for 6 weeks and 250 rag, thereafter. W i t h 45 evaluable pts, there were l complete (CR) and Ii partial remissions (PR) (response rate, 27%). In 17 pts disease stabilisation (NC), in 16 pts (36%) disease progression occurred. Duration of the CR is 8+ months, m e d i a n durations of PR and NC are 9 and 6 months, respectively. So far, receptor status did not influence treatment results. Pts w i t h bone metastases or those with relapse-free intervals of >2 years responded better than the respective counterparts. Serum estradiol levels decreased significantly after i week on treatment. High performance liquid chromatography revealed serum 4-OHA levels up to 70 hrs after injection. Long-term follow-up could not d e t e c t measurable serum levels with the dosage of 4-OH chosen. Side effects were m o s t l y unspecific and of low degree. We conclude that aromatase inhibition with 4-OH is efficacious in treatment of postmenopausal BC. Inhere Universit~tsklinik und Poliklinik (Tumorforschung) , Westdeutsches Tumorzentrum, Hufelandstr. 55, D-4300 Essen 1

S 98

3/P-GM 065

3/P-GM 067

EFFECTIVENESS AND PROGNOSTIC VALUE OF ULTRASOUND IN SCREENING FOR LIVER METASTASES IN RECURRENTBREAST CANCER H. Nandt

EPIRUBIClN, COMBINEDWITH CISPLATIN AND CYCLOPHOSPNAMID IN THE TREATMENT OF ADVENCEDOVARIAN CANCER D. Christmann

Between Jan. 84 and Dec. 86, all patients with breast cancer admitted to our clinic or outpatient clinic were routinely screened by means of ultrasound at 3 to 6 months intervals for liver metastases. The purpose of this retrospective study was to determine the diagnostic value of ultrasound compared to history/clinical examination and routine laboratory parameters. Among 495 pts. with breast cancer examined during this period, 82 were detected to have liver metastases. In 62 out of these 82 pts. this diagnosis was confirmed either by histological/cytological examination of the lesion or by followup evaluation. Only these patients were found eligible for the present study. The diagnosis of liver metastases was established by history and/or clinical examination in 9/62 cases, laboratory parameters in 50/62 cases, ultrasound examination in 60/62 cases. In our series, liver metastases were detected in 12/62 patients (19%) o-~6yultraso'und, On the other hand, 10 out of these 12 pts. showed symptoms of recurrent disease at other sites (lung, bone, brain or skin). Thus, the number of cases of recurrent disease detected by

ultrasound alone was 2/~2 (3%). I t is well know today that early detection and treatment of liver metastases does not influence overall survival of breast cancer pts. Periodic screening for liver metastases by means o f ultrasound examination has no proven value in the follow-up of these pts. Instead of screening all pts., it is sufficient to perform ultrasound examination in pts. with elevated serum transaminases or y-GT and in pts. with signs of recurrent disease at other sites.

In 25 patients, avarage age 59,16 years (46-74 years) with ovarian cancer, stage I I I and IV, according to FIGO, Epirubicin in combination with Cisplatin and Cyclophoshamid (PEC~ was administered. Every 4 weeks the Ratients ot 50 mg/m bodysurfa~e (BS) Epirubicin, 50 mg/m~ BS Cisp]atfn and 500 mg/m BS Cyclophesphamid. The dosage of Epirubicin was increased in 19 of 252Patients in the 2 second cycle of treatment to 75 mg/m BS and to 90 mg/m BS in the t h i r d cycle of treatment. This t r i a l should answer t h e q u e s t i o n wether the increased dosage of Epirubicin would lead to a higher rate of response, depending on cardial and myeloic t o x i c i t y . Bloodpictures and cardial functiontests (echocardiografie and ECG) were done immediate befere a new cycle of therapy. We achieved with PEC in 18/25 (72%) patients response (15 CR/ 3 PR), in 4/25 (16%) N.C. and only in 3/25 (12%) there was a primary progression of the tumor. The effect of PEC t r e a ~ ment was higher than treatment with PAC (Cisplatin,Cycle T phosphamid, Doxorubicin) which we used e a r l i e r in 18 patients with advanced ovarian cancer; with PAC we achieved 50% response, 38% N,C. and 12% progression. The evaluation of myelotoxicity in 13 patients showed Hbdecrease grade I (WHO), in 2 patients Hb-decrease grade I I , in seven patients leucopenia grade I and in one patient leucopenia grade I I . Only in one patient l i g h t cardial disturbances made the interruption of Epirubicin treatment necessary; the combination with Doxorubicin (PAC) made in 2 of 18 patients the interruption of t r e a t ment with Doxorubicin necessary due to cardial sideffects, The overall rate of responders was higher in the combination with Epirubicin whereas the myoloic and cardial t o x i c i t y was lower.

~

5. Med. Klinik und Inst. f. Mad. H~matologie und Onkologie, Flurstr. 17, D-8500 NOrnberg

Frauenklinik, St~dtisches Krankenhaus, Lamprechtstra6e 2, 8750Aschaffenburg Germany

3/P-GM 066

3/P-GM 068

LUMPECTOMY, AXILLARYDISSECTION, AND TELE-TNERAPY (LAITT)

THERAPIE RESULTS OF BREAST CANCER TREATED WITH OR WITHOUT LIMITED SURGERY IN COMPARISON TO RADICAL MASTECTOMY H, yon Essen, G. Blum, J. Lenz, W. Schaeben

OF MAMMARIAN CANCERS D. Berg~ J. Heckrodt~ R. Bahr and M. Gampe

The increasing move a~ay from radical operating techniques of MC is based on the fact that the fate of the patient does not depend on the location of the primary tumor, but t h r ~ the presence or absence of metastases. Treatments which can guarantee a breast saving procedure justify themselves not only for psychological but also for medical reasons. Since November, 1985 ~e have r u n a breast saving therapy for TI cancers independent of N and M cancer status. In this study of operative treatment, interstitial boost radiotherapy and teleradiation, are combined. A special advantage of our methods, compared to others, can be seen by: I. Needle application for the boostering is carried out under visual control. 2. Operation and interstitial boostering are carried out simultaneously, by one person. Having removed the lump, the surgeon places the applicators into the tumor bed under visual and touch control ~hile the wound ist still open. A boostering mith 20 Gy high dose Iridium 192 follows. Ue shall discuss the selection, treatment details and results of our first 50 patients. Curative and cosmetic results are quite encouraging. Frauenklinik und Radiologisches Institut des St~dt. Marienkrankenhauses D-8450 Amberg

Report on more than 200 patients with breast cancer in the categories TI-4, N0-1 treated with or without limited surgery (breast preserving method) during the years from 1980-1987, and additional observation on a significant number of patients with radical mastectomie. The breast saving technic showed remarkably better results according to local recurrence as well as to rate and delayed date of occurence of distant metastases. Special indications for primary radiation therapy without surgery will be stated, Long term results are expected to be published within a reasonable period. Onkologische Arbeitsgemeinschaft Radiologisches Institut , Dr. A. yon Essen, Emil-SchC~ller-StralSe 29, D-5400 Kob~ Ienz

$99

3/P.GM 069

3/P-GM 071

N O V A N T R O N / STERECYT IN THE T R E A T M E N T OF METASTATIC BREAST CANCER E. Schwarzenau, J, Hilfrich, J. PreiS, H, Boden~e~ J. S!omska~ H. Corterier~

SELECTIVE EMBOL!ZATION OF HEPATIC METASTASES IN PATIENTS WITH CARCINOMA OF THE BREAST J. P e t e r s , D. L i e r m a n n and M. A l b r e c h t In the treatment of hepatic metastases in patients with carcinoma oF the breast general chemotherapy is the mostly used therapeutic c o n c e p ~ Ne should like to introduce a different concept namely that of selective embolization of l.iver metastases via angiography catheters. Prereqisite for this method is e selective anglo graphy ofthe celiac trunk and the mesenteric artery including the venous phase to study vascular anatomy and to assure that the portal vein is patent. If vascular anatomy is regular, that is if the right liver lobe receives its blood supply from the celiac trunk end net from the mesenteric artery,embolization is relatively simple. An angiogrsphy catheter is placed into the hepatic artery preferably distal to the gastroduodehal artery. Then epinephrine is injected intraarterially in order to close intact vessels and thus selectively leave tumor vessels patent. Then a mixture of lipiodol and dura is injected and washed into the vessels with contrast media. An alternative method is total closure of arterial hepatic vessels with coils, but this method is only applicable if liver function is very good and thus oxygen supply via portal vein is sufficient. For patients with carcinoma of the breast we would recommend embolization with lipidol - dura because it is more selective and can be repeated in case new metastases occur or the kown ones become revasculerized, which sometimes happens. ZRed und ZFG; d.-W.-Goethe-Universit~t, Theodor-Stern-KaJ 7, ~000 Frankfurt 70

This study was undertaken to examine remission and q u a l i t y of life in p a t i e n t s with m e t a s t a t i c b r e a s t cancer under the t r e a t m e n t of combination chemot h e r a p y w i t h N o v a n t r o n a n d S t e r e c y t (NOSTE). From J a n u a r y 1986 to A u g u s t 1987 93 p a t i e n t s h a d been t r e a t e d with at least 3 cycles of c h e m o t h e r a p y a c c o r d i n g to t h e following protocol,. N o v a n t r o n 12 rag/m2 i v d a y 1 a n d S t e r e c y t 120 rag/m2 po clay 1 - 5, n e x t c o u r s e on d a y 29. There was a uniform distribution af m e t a s t a s e s in l i v e r , l u n g , bone a n d s k i n in o u r g r o u p of p a t i e n t s , 45 of t h e m h a v i n g more t h a n 1 o r g a n involved. Complete (CR) and partial remission (PR) in all patients was 42%. Primary progress of disease (PD) w a s s e e n in 26 % of o u r p a t i e n t s . 50 % a f t h e p a t i e n t s w i t h o u t p r i e r c h e m o t h e r a p y r e s p o n d e d to o u r t r e a t m e n t s c h e d u l e ~ w h e r e a s o n l y 27 % of t h e c h e m o t h e r a p e u t l c a l l y p r e t r e a t e d women achieved remission. A similar difference was seen in patients with only i organ involved vs patients with more than 8 organs involved ( 50% vs 25% remissions ), Comparison of pre/pastmenopausal women and receptorpositive/negative patients did not show a n y significant differences so far. The median overall survival cannot y e t be assesd, since more than 50 % of our patients are still alive, with a median observation period of 15 month. Treatment related subjective toxicity is very mild. Especially alopecia and nausea/emesis a r e s e e n to a f a r l e s s e r e x t e n t t h a n in conventional chemotherapy schedules. F r a u e n k l i n i k tier M e d i z l n i s c h e n H o c h s c h u t e H a n n o v e r P o d b i e t s k f s t r a S e 880, 3000 H a n n o v e r 51

3/P-GM 072

3/P-GM070 I F O S F A M I D E / E T O P O S I D E AND MESNA U R O P R O T E C T I O N ADVANCED BREAST CANCER C. Manegold_~u P~Worst J.Bickel H.Schmid

IN

The purpose of our study was to evaluate the effect of i f o s f a m i d e / e t o p o s i d e in metastatic breast cancer. 38 patients (pts) were included in the trial, Eligible pts had measurable, refractory disease, prior a n t h r a c y c l i n e therapy (or c o n t r a i n d i c a t i o n to it), a life expectancy of at least 3 months (mts), adequate hepatic, renal, CNS and bone marrow function. All pts were less than 70 years old. The median age was 50 years and the ZPS { 50%. There were 31 evaluable pts. The ER status was positive in 3, negative in 15, and unknown in 13 cases. Sites of metastatic disease included bone (17), skin (17), liver (8), lung (ll), lymph node(18)~ and miscellaneous (7). Treatment consisted of ifosfamide 1500mg/m ~ day 1-5, etoposide 12Omg /m 1.v.eay i-3, mesas 4OOmg qgh i.v.day 1-5. Cycles were repeated every 28 days. Initial doses were reduced by 25 % in pts with both prior chemo - and radiotherapy. A median of 4 cycles (range 2-8) were given. The myelotoxicity was marked: leucopenia < 3 0 0 0 (19), ~ 2 0 0 0 (17), < I O O O (3), thrombocytopenia < 5 0 0 0 0 (7), ~ 3 0 0 0 0 (3), hemoglobin < l O m g % (15). Because of myelotoxicity dose reduction or prolongation of treatment free interval was necessary in 25 pts. Alopecia was found in 29 pts, CNS toxicity in 8. Gastrointestinal toxicity was mild. Partial response was obtained in 3 and complete response in 3 pts. Sites of response were lueg(2),skin (2), lymph node (4), Ascites (I). Duration of response was 2+,4 and 5 mts for CR and 2 mrs(2) and IO mts for PR. We conclude that I-VPI6 is effective. M y e l o t o x i c i t y is treatment limiting. KKH Bgblingen, B u n s e n s t r a s s e 120,7030 BSblingen

DETECTION OF LOCOREGIQNARY RECURRENCE OF BREAST CANCER 8Y ULTRASOUND P.Herzog, K.Exner, J.Hecker, W.Nollbrink, l.Sch~fer, G.Lemperle, K.H.HoltermOller The early detection of the locoregionary cancer recurrence (LRCR,thoracic region and lymphnode metastasis) after ablative surgery of the breast in pts. with breast cancer needs much clinical experience. Scars and percutaneous radiation renders the examinations extremly. Therefore, we proved the detection rate of LRCR by ultrasound. In 12 of 16 pts. with 19 LRCR we investigated by ultrasound (5MHz transducer Picker LS 3000, LS 7000) the thoracic region and the regionsry lymphnodes a f t e r a b l a t i v e surgery o f the breast, We found i n 12 pts. 13 tumors with mostly echopoor structure without dorsal sound enhancement, but one time it had an echodense structure pattern, The smallest tumor size was 6 mm in diameter. The palpation of LRCR was in 9 of 12 pts. solid, but in 3 pts. the LRCR couldn't be palpated, only demonstrated by ultrasound, 6 LRCR (in 4 pts,) were detected during reconstructive plastic surgery procedures (3x) or were recognized accidently because of the positive palpation result (3x).The sonographic differentiation between LRCR and lymphnode metastasis independing of the tumor localisation is difficult.

We summarize that ultrasonography is well qualified to detect LRCR even in pts, with negative palpation findings. I.Med.Klinik, St.Markus-Krsnkenhsus, Wilhelm-EpsteinStr. 2, D-6000 F r a n k f u r t a.M. 50

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3/P-GM 073

3/P-GM 0 7 5

POSSIBILITY OF IMPROVING THE QUALITY OF LIFE FOR BREASTCANCER PATIENTS FROM A PLASTIC SURGEON'S VIEWPOINT L. D o e b l e r , C. T i z i a n

RANDOMIZED STUDY OF EPIRUSICIN AND CYCLOPHOSPHAMIDE IN ADVANCEDBREASTCANCER R. Becher, E. Kurschel, O. Kloke, H. HSfeler, Ch. Reiners, H. Hirche, C. Massion, G. Hartwich (1), Olbrich (1), K. Stahl (2), A. lHiger (3) and C.G. Schmidt

I t i s n o t seldom t h a t a b r e a s t c a n c e r p a t i e n t comes t o a p l a s t i c s u r g e o n i n an u t m o s t r e g r e t t a b l e p s y c h i c s t a t e , a f t e r h e r p r i m a r y more o r less mutilating operation. A l t h o u g h she may be c o n v i n c e d o f t h e n e c e s s i t y of the amputation with its radiation and chemot r e a t m e n t s and o f t h e p o s t o p e r a t i v e examinations c a u s i n g h e r e v e r y t i m e renewed u n c e r t a i n t y , she has l o s t h e r c o n f i d e n c e in u s , t h e p h y s i c i a n s , because our whole attention in the medical care in g e n e r a l seems t o aim o n l y a t t h e " s i c k n e s s " itself and n o t a t t h e p a t i e n t as a human b e i n g . Her f e a r o f l o s i n g t h e f e m i n i n e a t t r a c t i v e n e s s , w h i c h does n o t n e c e s s a r i l y correspond to the a c t u a l c i r c u m s t a n c e s i s even more s t r e s s e d in t h e s o c i e t y we l i v e , striving for physical perfections and i d e a l s . At t h e t i m e o f h e r p r i m a r y o p e r a t i o n she i s seldom a d v i c e d , i f n o t a t a l l r e j e c t e d o f t h e possibility o f an i m m e d i a t e or l a t e r r e c o n struction. This manifests the psychical trauma, depriving h e r o f h e r r i g h t t o an e a r l y r e i n t e gration, both socially and p s y c h i a l l y as w e l l as s e x u a l l y . I consider the preoperative information about possible plastic reconstruction for the breastcancer patients - also at the advanced stage under certain c i r c u m s t a n c e s - t o be i n e v i t a b l e , as means o f p s y c h o - o n c o l g y and as means o f improving the quality of life for the concerned. L. Doebler, K l i n i k f o r Plastische, Hand- und Wiederhers t e l l u n g s c h i r u r g i e , K l i n i k e n des Main-Taunus-Kreises, D 6238 Hofheim a. Ts., West-Germany

3/P.GM

In pts. with advanced breast cancer after failure of first and second-line chemotherapy (CT), response rates with further CT a r e o f t e n v e r y p o o r . Due t o t h e w e l l known s i d e e f f e c t s most pts. refuse further treatment with cytotoxic drugs.Therefore most attention has to be

given t o w e l l t o l e r a t e d and e f f e c t i v e drug combinations. In our study p t s . were t r e a t e d with the FUMI-combination o v e r S days, initially every 4 weeks.After clinical response treatment courses were extented to 6 or 8 weeks.On d a y I S, S-FU(9oo mg/m~q) was infused over 8 hours On day S Mitomycin C (6 mg/m 2 q) was given as bolus injection.The FUMI-regimen was well tolerated.After 24 cycles so far in no case treatment had to be discontinued.The main sideeffect we observed was thrombocytopenia, but no secondary effect of clinical significance was noticed.Clinical response was usually observed after 1-Z courses and was predominant in pts. with soft-tissue and osseous lesions. From our preliminary results we conclude, that the FUMI-regimen as third-line chemotherapy in refractory breast cancer is well tolerated even in elder pts. It has no severe side effects (exept mild thrombocytopenia) and shows immediate clinical response.

6ooo Frankfurt 70

Innere UniversitAtsklinik (Tumorforschung), Nuklearmedizin, Institut f{k ned. Informatik und Biomathemafik, West German Tumor Center, Hufelandstr. 55, D-4300 Essen, lnternistische Gemeinschaftspraxis N~rnberg (1), St. Barbara Klinik Heesen (2), St~.dtische Klinik OIdenburg

(a)

3/P-GM 076

074

S-FLUOROHRACIL AND MITOMYCIN C (FUMI) IN PATIENTS Eil il ADVANCED BREAST CANCER AS THIRDLINE CHEMOTHERAPY A.Nesterburg , M.Albrecht,J.P. Pfuhl

Universit~tsklinikum Frankfurt/Main Zentrum f~r Gyn~kologie,Theodor-Stern

A prospektive multicenter study of epirubicin (Epi) and cyclophosphamide (CTX) in advanced breast cancer was designed to analyse the efficacy and the toxicity of two different dose intensities and the weekly application of Epi. Treatment schedules: Group A: CTX, 600 mg/)n2 iv, Epi 60 mg/rn2 iv every 3 weeks Group B: CTX, 600 mg/m2 iv, Epi 40 mg/m2 iv every 3 weeks Group C: CTX, 600 rag~m2 iv, every 3 weeks, Kpi 20 rag~m2 weekly. Pts were stratified according to the duration of the relapse free survival, menopausal age, pretreatment and metastatic site. Response was evaluated according to the UlCC criteria and the toxicity also by self assessment of the patients. At the time of this report 154 pts were randomized and 124 pts evaluable for response. Objective remissions (CR and PR) were achieved in 18/42 pts in arm A, 18/45 pts in arm B and 10/37 pts in arm C. respectively, Disease stabilization (NC) was observed in 17/42 pts in arm A, 16/45 pts in arm B and 20/37 pts in arm C. At present there are no significant differences in response rates or survival between the different treatment modalitiss although the frequency of objective remissions tends to be higher in arm A and B, Toxicity was generally wsIt tolerable and less severe in arm C; e.g. as reveated by the occurrence of complete alopecia, which was uncommon in arm C. Cardiac toxicity was monitored by measuring the ]eft ventricuJar ejection fraction in arms A and 8. Results indicate /ess cardiotoxicity for the weekly application of EpI.

Kai 7

FIRST EXPERIENCE WITH THE IMMEDIATE START OF BREASTRECONSTRUCTION FOLLOWING MASTECTOMY N. Golz, H. Mast St. Bernward-hospital , Hildesheim FRG Since 1983 the aesthetic and reconstructive breast surgery is offered to patients of the St. Bernward hospital Hildesheim. First we started with the delayed breast reconstruction following mastectomy. In 1984 the f i r s t breast was reconstructed by a submusculofascial implant immediat e l y a f t e r mastectomy. By an increased frequency o f mastectomies the demand o f d i r e c t b r e a s t r e c o n s t r u c t i o n f o l l o w i n g mastectomy r i s e d . So, in 1984 one p a t i e n t (2,5%), 1985 t h r e e p a t i e n t s (6,4%) and in 1986 f i f t e e n (28,9%) women were t r e a t e d immediately by breast r e c o n s t r u c t i o n . In summary, two women got a s u b c u s c u l o f a s c i a ] p r o s t h e s i s

but the method of choice is the submusculo-fasciale implantation of a tissue-expander following by an implantation of a d e f i n i t i v e prosthese and correction o f the opposite breast in a second operation. By this way good skincondition was achieved. Except malposition of tissue-expander following complications appeared: ]st infection of tissue-expander 2nd prolapse of tissue-expander 3rd prolapse of valve

2 (11,1%) 2 (11,1%) i (5,5%)

In summary, the immediate start of breast reconstruction with a submusculofascial tissue expander achieve optimal conditions for a d e f i n i t i v e aesthetic and recontructive treatment. The apparent high complication rate is of course to decrease by more experience with the implantation of tissue expander and course of antibiotics.

$101

3/P-GM077

3/P-GM 079

ESTROGEN-INDUCIBLE G-G-PDH AS A MARMERFOR MORMONRESPONSiVNESS OF BREAST ~ANCER H.rJ. LDck, E. 5q.hwgr.z~neu an,d 3., Hi,,l,,friq,h

THE EFFEC9 OF CLINICAL HISTOLOGICAL AND ~h~P~PEUTICAL FACTORS ON ~}~ ~Ir~ OF OCCURRENCE OF LOCOREGiONAL IKECURP~NCE IN BREAS~ CANCER R,W,M. Sc.hulte~ I, Adamiet z. . . . . . . . . . . . . . . . . . . . .

The enzyme glucose-G-phoepha% dehydrogenese (G-G-PDH) is - like ~he preges~eron receptor (PR) a final product of estrogenic action in breas~ sance~ tissue. Preliminary e~udiea have shown that in breast cancer tissue wi~h PR concentrations of mare than 2o fmolee/mg protein there is also in 9o % of all samples a G-6-PDH ao~ivi%~ of mare than Io nmeles/min/mg protein. Therefore the change of the enzvme activity was s~udied after incubation of tumor tissue with estradiol. B~eaat cancer tissue was incubated with end without I • lo-8 mol/1 eetradiol far one hour at 37o C. Subsequently ~he enzyme ectivit V was measured photometrically in the tumor cy~osal. Eatragen receptor (ER) and PR were measured by dex%ran charcoal assay. In cancer ~ieeue with receptor constellations JR+ PR+ and ER- PR+ there was an obvious increase of G-6-PDM sctlvi~ y up to 25 nmoles/min/mg protein or morm. In tumor ~iesue with receptor constellations ER+ PR- end ER- PR- the G-6-PDH did not change after incubation wi%h eatradiol. The enzyme values did not exceed 5 nmoles/min/mg protein. The measurement of G-6-PDH activity in breast cancer tissue and its inducibility bV eatradlol seems ~o be an indies%or for ~he function of the estrogen receptor mechanism. Therefore %he additional measure of G-6-PDM might improve the selection of harmon responsive end umreaponaive tumors.

The prognosis of early recurrance in primary operable breast cancer is bad compared to late recurrances. A retrospective study was performed for 9~ patients with locoregional recurranoe of breast carcinoma after modified radical masteetomy in combination or without adjuvant radiotherapy (RT), chemotherapy (C~) or hormonethe~apy (HT). ~he impact of c l ~ i c a l ~ histological and therapeutical factors on the time of relapse was determined b y calculating the mean recurrance-free -interval (RFI) and the proportion of early and late failures in different subgroups. The results can be summarized as follows: (1)the proportion of late recurrences was significantly higher in patients treated with RT and those with negative axillary nodes. (2) ~hose groups with undifferentiated tumors (G3) and negative hormone receptors were characterized by significantly higher percentage of early recurrences. (3) Patient age, tumor diameter as well as adjuvant CT and HT Imd no influence on the ~ I . According to these outcomes a numerical prognostic factor was defined, which may be helpful in identification of patients with a high risk of early locoregional relapse. Institut fir Strahlentherapie u. spezielle O~eologie der Medizinischen Hochsehule Harmover Podbielski-Str. 980, D-~OO0 Har~over 5Q

Frauenklinlk der Medizinischen Heohschule Hannover im Os%s~adtkrankenhsus (Direktor: Prof. Dr. 3. Schneider), Podbielskis%r. 3Be, D-3ooo Mannover 51

3/P-GM 078

3/P-GM 080

BREAST-PRESERVING THERAPY FOR STAGE I I BREAST CANCER ? R. Margreiter, J. Wiegele, M. D~nser

CLINCAL VALUE OF A PLASMA LEVEL ADAPTED ORAL MEDROXYPRDGESTERONE ACETATE TREATMENT IN METASTAS~ZED BREAST CANCER.

Until now, breast-preserving therapy in most centres was r e s t r i c t e d to T~ Nn cases. We have always f e l t t h a t t h i s kind of treatmellt ~ould also be applied to patients suffering from more advanced tumors, since p o t e n t i a l systemic tumor spread represents the l i m i t i n g f a c t o r f o r these patients. From 1976 u n t i l 1986 a t o t a l of 112 patients with stage I and I I breast cancer underwent p a r t i a l mastectomy or lumpectomy plus radical a x i l l a r y lymph node dissection. Patients were followed f o r a mean of 37.4 months. Of the tumors 63.4 % were less then 2 cm in diameter (T~), 32 % between 2 and 4 cm and 4.5 % were in s i t u carcin6mas (TIS). Surgery was supplemented by i r r a d i a t i o n of the e n t i r e breast with a t o t a l dose of 5000 reds plus a limited boost of 1000 reds. Of the 60 premenopausal and 52 postmenopausal women, 57 were c l a s s i f i e d as stage I and 55 as stage I f . All patients with p o s i t i v e lymph nodes received adjuvant chemotherapy (CMF) f o r s i x months. Local recurrence which seems to be the on!y important f a c t o r in evaluating the accuracy of p r i mary treatment f o r breast cancer, was found in 'three (5.3 %) of the stage I and f i v e (8,7 %) of the stage I I patients. Two patients having been operated f o r stage I and s i x with stage I I breast cancer developed d i s t a n t metastases, s i x of whom died meanwhile. Two f u r t h e r patients developed cancer in the c o n t r a l a t e r a l breast, The a c t u a r i a l patient survival at ten years was calculated at 92 % f o r stage I and 75 % f o r stage I f , whereas the d i sease-free s u r v i v a l was 70 % and 45 % r e s p e c t i v e l y . These results compare favourably with radical surgical methods in our own i n s t i t u t i o n as well as in other centers. From these data i t is concluded t h a t breast-preserving therapy is appropriate not only f o r stage I but also f o r selected cases of stage I I breast cancer. Department of I . Surgery, University Hospital, A-6020 Innsbruck-Austria

MUller,A.,Possinger,K,,Langecker,P.,Doischer,E.,W~Lmanns,W. Med. Klinik [II~Universit~tsklinikum Gro~hadern, MUnehen In patients (pts) ~ ~ -b~e'ast C a b c e r ~ favourable prognostic factors hormonal treatment combines high therapeutic efficacy with moderate systemic t o x i c i t y To detect whether a MPA plasma level adapted oral therapy with MPA offers better therapeutic results and less t o x i c i t y than a fixed high dose therapy we performed a prospective randomized study with two treatment modalities: Group I was treated continously with 1500 mg MPA p,o./day; dose reduction only after t o x i c i t y +=grade 3 (WHO) occurred. Group 2 was given 1500 mg MPA p.o./day for 6 weeks, after that MPA-dosage for pts with MPA-plasma levels above 150 ng/ml was reduced to 1000 mg/day, for pts with MPA-plasma levels below IO0 ng/ml MPA dosage was increased to 2000 mg/day. MPA plasma levels were measured every 4 weeks by modified RIA technique, 70 pts with hormonal and/or cytostatic pretreatmenC were enrolled and evaluable for t o x i c i t y ; 63 pts were evaluable for response (group 1 : 3 0 pts; group 2:33 pts). Toxic side effects +:grade 3 in 5 pts of group I made a dose reduction to I000 mg/day necessary. In group 2 we reduced MPA dose to I000 mg/day according to MPA plasma levels in I I pts and because of toxicity in 4 pts. A dose escalation to 2000 mg/ day because of low MPA plasma levels was necessary in 5 pts. There was no significant difference in response between the two treatment modalities: Group l : CR: n=2 (6.7%), PR: n=7 (23,3%)~ NC: n=8 (26.7%), PD: n=13 (43.3%). Group 2: CR: n=l (3.0%), PR: n=3 (9.1%), NC: n=17 (51.5%), PD: .n=]2 (36.4%}. Toxic side effects differed only i%=lackof weight increase: lO of 36 pts (32.3%) of group l;" but 18 of "34 pts (64.3%) of group 2 had no increase in weight. There was no difference in frequency

and intensity of edema, cushingoid, cramps and tremor between the two treatment modalities. MPA plasma levels differed significantly between pts with CR, PR or NC {med. 200 ng/m]) and pts with PD (med. 87 ng/ml), p = 0.027. MUller,A~,Possinger,K.,Langecker,P.,Doischer,E.~Wilmanns,W. Med. Klinik I l l , Universit~tskiinikum GroBhadern, MUnchen.

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3/P-GM 081 FNC-THERAPYOF METASTATICBREASTCANCER E. Merkle, U, Fuchs, R. Adam ................................................................. 69 patients suffering from metastatic breast cancer were treated according to the FNC-sche~e during a prospective study at the By~aecologicel Hospital of the Erlangen University, 500 ~gl~2 Fluoro-urscil, lO mg/e2 Novantron, and SO0 eg/m= Endo• were administered at 4-week intervals. 426 theme-therapeutic cycles have been administered up to now (l2l cycles), 6G patients are evsluable, SO patients underwent adjuvant treatment because of axillary lymph node metastases, 42 of them underwent adjuvant theme-therapeutic treatment, 50 patients were recurrence-free for more than 2 years. 36 patients had already undergone a systematic treatment due to formation of metastases~ 16 of them underwent theme-therapy. The response ratio to FNC (CR+PR+NC)was 65%, Remissions (CR+PR)were observed among40%, The therapy was subjectively well-tolerated, and the alope~ia rate ~ae low, Bone-marrow depression was observed in individual cases; cardiotoxity was not observed, Therapy of lS patients has not been concluded yet. The average remission period is, at the moment, B months, This can, however, not uliestely be evaluated until our observations are concluded, I t seems to us that, with regard to response ratio and good subjective toleration, FNC-therapy is a suitable scheme of treatment in cases of metastatic breast cancer.

3/P-GM 083 AD3UVANTCMFV-THERAPYOF BREASTCANCER U, Fuchs, E. Merkle, C, Seidl, I, Ederer In erda,' to investigate the effectiveness of an adjuvant therapy the data of 124l patients who had undergonebreast cancer surgery , in the 6ynaecologi(al Hospital of the Erlangen University between ]975 and 1984 ~ere retrospectively evaluated, 95% of all patients with axillary lymph node metastases were ad~uvantly treated~ 244 patients were uniformly treated with 6 CMFVcycles, Analysis of the patient population shows that per-menopausal patients (n=60) with I-3 affected axillary lymph nodes had the same survival Lime as per-menopausalwomenwith no axillary ~etaetases and without adjuvant therapy (88% with a survival time of S yeses). 6B% of all poet-menopausal patients with l-3 affected axillary lymph nodes and CMFVtherapy (n=70) had a survival time of five years whereas the rate among the post-menopausal control group with no affected lymph nodes and without adSuvent therapy (n=340) was B3%, Our investigations show that pre-menopausal patients obvioouly benefit more from adjuvant chemotherapy than post-menopausal women, 6ynaecological Hospital of the Erlangen University, Head: Prof,Or, N, Lang, Univereit~tsetP, 21/23, 0-8520 Ertangen

8ynaecological Hospital of the Erlangsn University, Headl Prof.Or. N, Lang, Universit4tsstr. 21/23, D-8520 Erlangen

3/P-GM 082 THERHO-SENSZBILITYOF HORHONERECEPTORS WITH BREASTCANCERCASES I, BAhr, E, Merkle In }987~ the thermo-sensibility of progesterone and eetradiol her=one receptors Iocalised in the cytostol was investigated among 100 patients who had undergone breast cancer / breast cancer relapse surgery in the @ynaecologicsl Hospital of the Erlangen University, Hoe=one receptors were determined by means of a double ligend kit, In order to investigate the thermo-ssnsibility the available tumor tissue of the patient was divided in half. One half was preserved in liquid nitrogen immediately after surgery, The other half was stored at room temperature for I hour and then deep-frozen at -38.7 ~ We found that I, the receptors of primary breast cancers and breast cancer relapses did not show any differences with regard to thermosensibility 2. the progesterone receptors localised in the cytostol showed a decrease in receptor density of 30-60% after I hour at room temperature and s decrease of 5-30% of the estradiol receptors localissd in the cytoetol. This leads to the conclusion that progesterone receptors ate thereo-nenaible to a higher degree. It can be taken from this investigation that deep-freezing hormone receptors immediately after surgery is of utmost importance because otherwise grave mistakes in determining the receptor assay could result which would lead to a false estimation of the patient with regard to prognosis and adequate therapy. Bynaecological Hospital of the Erlangen University, Head: Prof.I)r, N. Lang, Universit4tsstr. 2~/23, 0-8S20 Erlangen

3/P-GM 084 E F F E C T S OF M E D R O X Y P R O G E S T E R O N E - A C E T A T E ON P R O L I F E R A T I O N A N D R E C E P T O R C O N T E N T OF H U M A N B R E A S T C A N C E R CELLS A N D ITS I N T E R A C T I O N W I T H G R O W T H P R O M O T I N G S T E R O I D S IN V I T R O R. H a c k e n b e r g , A. RHck, J. Hofmann, F. H S l z e l x a n d K.D. S c h u l z Progestagenic m e d r o x y p r o g e s t e r o n e - a c e t a t e (MPA) is w i d e l y used in the e n d o c r i n e t r e a t m e n t of b r e a s t cancer. In this study the e s t r o g e n sens i t i v e b r e a s t c a n c e r cell line M C F - 7 w a s u s e d to i n v e s t i g a t e the influence of M ~ A on cell proliferation and steroid hormone receptor c o n t e n t and its i n t e r a c t i o n w i t h 1 7 B - e s t r a d i o l (E2) a n d d i h y d r o t e s t o s t e r o n e (DHT). P r o l i f e r a t i o n a s s a y s w e r e done in a m e d i u m w i t h 10% d e x t r a n - c h a r c o a l - t r e a t e d FCS over a p e r i o d o f 7 days. If cell g r o w t h w a s s t i m u l a t e d b y 10 n M E2 o r I D M DHT p r o l i f e r a t i o n w a s inh i b i t e d d o w n to c o n t r o l levels by I n M to I p M MPA. Y e t M P A had no e f f e c t on the p r o l i f e r a t i o n of u n s t i m u l a t e d cells. R e c e p t o r a n a l y s e s of E R and P R w e r e d o n e bioc h e m i c a l l y a n d immunoeytoche/Bically. P R w a s m a r k e d l y s t i m u l a t e d b y 10 n M E2 or I p34 DHT. A f t e r i n c u b a t i o n w i t h M P A the P R w a s d e t e c t a b l e only by the immunocytochemical method. E R w a s m a r k e d l y d e c r e a s e d a f t e r M P A treatment. T h i s m a y e x p l a i n the r e d u c t i o n of E 2 - s t i m u l a tion b y MPA. Yet the i n h i b i t i o n of g r o w t h r e s p o n s e to DHT by M P A indicate, that a d d i t i o n a l m e c h a n i s m s are i n v o l v e d in M P A action. S u p p o r t e d b y D F G (SFB 215) and Kempkes-Stiftung, Marburg Universit~ts-Frauenkliniken, Pilgrimstein D - 3 5 5 0 M a r b u r g and M a r t i n i - S t r . 52, D - 2 0 0 0 H a m b u r g (x)

3,

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3/P-GM 085

3/P-GM087

OSTEOCALCtN (OC), a New Marker for Patients with Breast Carcinoma and Bone Metastases? H.U, Ulmer, E. Goepei

SEQUENTIAL THERAPY OF ADVANCED BREAST CANCER WITH TAMOXIFEN FOLLOWED BY MEDROXYPROGESTERONEACETATE: A PROSPECTIVE MULTICENTER STUDY H.v. Matthiessen I, J.Ddllmann, H.Wagner, e t a l . ...............................................

In 1975, Hauschke et al. and Price et al, reported the discovery of OC, In 1980 Price and Nashimoto had developed a radioimmunoassay, which allowed to determine OC in human blood serum. Since that time a number of papers reported increased OC levels in P a g e t ' s disease, hyperparathyroidiem, osteoporosis and bone fractures. We investigated the r a i s e of OC in the follow up of 62 patients with breast carcinoma and bone metastases and compared the results with those of 59 women with breast carcinoma without evidence of local recurrence or distant metastases. In the patients with bone metastases we distinguished between "small, solitary lesions" and "large or multiple areas". In 36 women with follow up of at 1east 15 months we have 76 controls and distinguished between "progressive" and "non-progressive" forms. In patients without locat recurrence and distant metastases the OCvalue was 4.55 • 2.2 ng/mL For the 62 pat. with bone m e t a s t a s e s the mean value was 5,39 +_ 3,45 ng/ml. Distinguishing between small and large areas, the values are significantly different. Evaluation of the follow-up shows that OC-levels rose in 42 of 48 controls, fell in 5 and remained constant in 1 case. In the 28 controls with unchanged osseous finding the OC-value remained unchanged too in 22 cases, in 6 the value rose. In conclusion wecan s t a t e that OC gives a good reflection of the clinical course of the disease in pat. with breast carcinoma and osseous metastases.

Previuos studies have proved that tamoxifen (TAM) treatment of advanced breast cancer patients leads to a response rate of approximately 30%. Little information is available about the response rate of medroxyprogesteroneacetate (MPA) therapy following tamoxifen treatment. Therefore patients with advanced breast cancer were treated in a multicenter study with tamoxifen (30mg/day). in case of progression and no contraindication to further endocrine therapy NPA was applied (6 weeks 1500mg followed by 1000mg orally/day). At present 66 tamoxifen treatments and 31 consesecutive MPA treatments are eligible. The preliminary results of this ongoing study are reported: The response rates t o TAM are CR:I2%, PR:21%, NC:33%, PD:33%. Related to site of metastases (CR+P~): soft tissue: 57%, visceral: 28%, osseus: 32%, multiple sites: 14%. Disease free interval (DFI) less than 2 years~ 17%, exceeding 2 years: 46%. The median estrogen receptor levels according to response to TAM: CR: 621fmol, PR:367fmol, NC:252fmol, PD: 199 fmol. The preliminary results of MPA-therapy are: 16% CR+PR, 48% NC, 36% PD. There was no significant correlation between response to TAM and the results of MPA-therapy, Due to the fact that PD is earlier stated and reported to study center than CR or PR higher response rates are expected at the end of this ongoing trial.

Universitats-Krankenhaus Eppendorf - Frauenklinik Martinistr, 52, 2000 Hamburg 20

i: Universit~tsfrauenklinik, D-4000 D~sseldorf 1

Moorenstra~e

5~

3/P-GM 086

3/P-GM 088

MORPHOMETRY,IMMUNOHISTOCHEMISTRY AND ULTRASTRUCTURAL INVESTIGATIONS IN PRIMARY BREAST CARCINOMAS WITH "ENDOCRINE" DIFFERENTIATION , . . . . D.Klndermann_~.Voqel,D.Hultenschmldt,VTotov/~q

CHANGE IN AROMATASEACTIVITY IN HUMAN BREAST CANCER CELt LINES UNDERTHE INFLUENCE OF DRUGS. Classen:S., Langecker,P., Sgouropoulou, S., Staebler, A, Possinger,K., Wilmanns~W.; GSF, MUnchen-Neuherberg; Bed, .Kli.n.ik l ~ I I Klinikum GroShadern: Univ_ersitgt MUnch~n. . .... The determination ef autocrine or paracrine estrogene production via aromatase a c t i v i t y in tumor cells becomes increasingly important in the treatment of advanced breast cancer. We examined the influence of d i f f e r e n t drugs on c e l l u l a r estrogene praduotion in three human hormone receptor positive and negative breast cancer cell lines, We determined the influence of unspecific and specific aromatase inhibitors {aminoglutethimide, CGS-16949A), antiestrogenes (tamoxifen), gestagenes (MPA) and glucocorticoides on the aromatase a c t i v i t y . To determine aromatase a c t i v i t y we used a modification of the t r i t i u m release assay (steroid biochemistry, vol 28, D-122, 1987,) measuring the t r i t i a t e d water set free during the conversion of IB3H-androstendione to estrone. By isolating the t r i t a t e d water via lyophilisation and liquid s c i n t i l l a t i o n counting we6are able to measure a turnover as low as 5 fmol El / I0 c e l l s . AG and CGS-1694gA were added to the cells 12 h, hydrocortisone and dexamethasone 24 h before measurement of aromatase a c t i v i t y . Tamoxifen and MPA were added every 24 h troughout the experiment. AG induced an inhibiti~q to 40% of control a c t i v i t y at a con#entration of I0- M and to 10% at a concentration of lO- M. CGS-16949A induced a suppression to about 15%8of control a c t i v i t y even at a concentation .of I0" M. Tamoxifen increased the aromatase a c t i v i t y by 10%-30% as compared to the control experiment at a concentration of 5xlO ~M. This may be due to a weak estrogene a c t i v i t y of tamoxifen. MPA , dexamethasone and hydrocortisone at concentration's of I00 ng/ml and 1,5 ug/ml enhanced aromatase a c t i v i t y and estrogene production up to 300-600% as compared to the control experiment. This effect was suppressed by the addition of CGS-16949A or AG.

p

28 breast carcinomas of "endocrine differentiation, showing well demarked tumor borders and solid/trabecular or adenoid/cribriform architecture, were investigated by morphometric and i~a~unohistochemical methods. 13 carcinomas (I) showed a mean cell profile density of more than 4500/mm 2 and at the same time a mean nuclear profile area of less than 70 ~m - criteria valid for intestinal carcinoids (n=10) which were evaluated for comparison . The remaining 15 carcinomas (II) showed parameters outside these limits. All tumors were Vimentin-negative and Pancytokeratine-positiv. 13/13 and 14/15 showed a sometimes strong reactivity to NSE, 4/13 and 4/15 were positive for Chromogranine, 3/13 and 8/15 were positive for PHE5 in i and ii, respectively. Preliminary EM-investigations showed dense-cored membrane-limited granules in 2/3 (I) and 3/5 ( I I ) tumors. A surprisingly high proportion of tumors (10/13 in I and 12/15 in II)) had a strong reactivity to Sl00-protein. These data suggest a potential endocrine activity in mammary carcinomas of "endocrine" differentiation, irrespective whether or not they fulfill morphometric criteria valid for typical (intestinal) carcinoids. Whether S100 immunoreactivity may be related to any endocrine activity needs to a point of further investigation.

Pathologisches Institut der Universit~t Sigmund-Freud-Str.25 D-5300 BONN i

Bonn

Classen,S., Langecker,P., Sgouropoulou,S., Staebler~A., Possinger,K,, Wilmanns,W.; GSF, MUnchen-Neuherberg; Med. K l i n i k I l l , Klinikum Gro~hadern, Universit~t MUnchen.

S 104

3/P-GM 089

3/P-GM 091

HIGH VERSUS REDUCED MEDROXYPROGESTERONE ACETATE IN PATIENTS WITH METASTATICBREASTCANCERAND VERYFAVOURABLE PROGNOSTIC FACTORS: Langecker,P,,Possinger,K.,M~ller A.~Wagner,H.,Wi]manns~W. Med. Kljnik I I I , K~inikum GroBhadern~ UniveTsit~t ~nchen In a prospective randomized c l i n i c a l study in ~atients with metastasized breast cancer we t r i e d l ) to define the subgroup of pts benefitting most from hormonal treatment and 2) determine the adequate individual hormonal dose. Realizing that some patients achieve objective tumour remissions with MPA plasma levels less than I00 ng/ml we analized the characteristics of these patients. We found that' this subgroup of pts had either presented with a positive hormonal receptor (ER) status or limited stage of the d~sease (only one or two tumour infiltrated organs), with bone, skin, soft tissue or nodular pulmonary metastases, disease free interval (DFI) of 2+ years or with a response to previous hormonal treatment. In this subgroup of patients we compared A): the conventional high dose MPA treatment with 1400 mg p.o./day for the f i r s t six weeks followed by dose reduction to lO00 mg/day to B):reduced dosage of lO00 mg MPA p.o./day for six weeks followed by a further dose reduction to 600 mg/day. So far 59 pts have been enrolled in this study. In A) 27/27 pts and in B) 30/32 pts are evaluable for response and toxicity. There were no significant differences in response between the two treatment modalities: A): PR: n=9 (33%), NC: n=9 (33%), PD: n=9 (33%). B): PR: n=7 (21,9%), NC: n=14 (43.8%), PD: n=9 (28.1%),not evaluable n=2 (6.3%). Toxicity did not differ significantly between the two forms of therapy but weight gain occurred less frequent under reduced dosage (B), With respect to tumour remission or disease stabilization we found no sigificant difference in MPA plasma levels between the responders and non-responders under both treatment modalities: (140 vs 98 ng/ml, p=0.49). Conclusion: In pts with very fevourable prognosis (DFI of 2+ years, one or two infiltrated organ sites, positive ER-status, response to previous hormonal treatment) doses of less than I000 mg MPA p.o./day do not reduce treatment efficacy. Langecker,P.,Possinger,K.,MUller,A.,Wagner,H.,Wilmanns,W.; Med.Klinik I11, Klinikum GroShadern, Universit~t MUnchen.

REMISSION OF D I S S E M I N A T E D B R E A S T CANCER ~NDER COMBINED THERAPY W I T H T A M O X I F E N AND D I A Z O X I D E A F T E R P R O G R E S S I O N UNDER TAMOXIFEN-MONOTHERAPY. M, Fink (i), Ch. Clemm (I), B. O s t e r m a y r (2) Insulin is a growth s t i m u l a t i n g h o r m o n e for experimental and human breast cancer (review: Fink, Berger: Kktuelle Onkologie 27 (1986), Zuckschwerdt, MUnchen, S.162), In rat m a m m a r y carcinomas remissions after induction of a reversible, Diazoxide-induced diabetes have been demonstrated (Berger, Fink et al,: Int. J, Cancer 35 (1985), 395). Breast cancer of a now 61-year-old woman had been operated in 1980 without subsequent r a d i o or chemotherapy. Supraclavicular metastases were removed surgically, but incompletely in VII/1985~ receptors were positive with ER Ii and PR 31 fmol/mg protein, Antihormonal treatment with 30 mg Tamoxifen daily was started in XII/1985. U n d e r this therapy local metastases around the s u p r a c l a v i c u l a r soar developed in XI/86; treatment w i t h 50 Gy Co-60 from XII/1986 to 1/1987 was almost ineffective. 5 weeks after the end of radiotherapy continuous treatment with 30 mg T a m o x i f e n w a s s u p p l e m e n t e d by 2x100 mg Diazoxide/day p,o.~ fasting blood "glucose levels under this therapy did not exceed I00 m ~ . Continuous r e g r e s s i o n of skin metastases by>50% was d o c u m e n t e d until X/!987 when liver metastases were detected by sonography. These data indicate, that the insulin-estrogenaxis which is w e l l - k n o w n in experimental systems m a y be of clinical value by using the combined antlhormonal therapy w i t h T a m o x i f e n and Diazoxlde. 1) Ill Mad K l i n i k Sro~hadern, D-8000 MGnchen 70 2) Waldhaus-Klinik, D-890! S t a d t b e r g e n 3

3/P-GM 090

3/P-GM 092

ADJUVANT THERAPY IN OPERATED BREAST CANCER - RESULTS OF i0 YEARS FOLLOW-UP OF RANDOMIZED TRIALS P. Faber und H.J. Tram~isch This report refers to two randomized controlled multicenter trials in adjuvant therapy of breast cancer run by a cooperative group in the DGsseldorf region. ~nis first trial compared a monochemotherapy (L-P~M) with a polychemotherapy (Chlorambucil, Mtx, 5-FU) six courses each, in women with 1 to 3 positive l[~mph nodes, the second trial compared this polychemotherapy (12 courses) with a combinded irradiation (2x40 Gy) and a polychemotherapy (3 courses before, 9 courses after radiotherapy) in women presenting with more than 3 positive l ~ p h nodes (P. Faber, W.D. Schoppe, H.J. Jesdinsky, Verh.Dtsch. KrebsGes. 3,181 (1982). The trial was startet in May 1977, admission to trial stopped 1981, when 132 patients had entered the first, and 88 the second trial. By Oktober 1986, the two regimens in study I, and in study II, respectively, did not substantially differ in disease free survival (median about 5 years in both arms of study I, and around 2,5 years in both arms of study II). However, there were more protocol violations in the combined radiochemotherapy group, especially more dropouts due to side effects. ER and PgR were studied in about 50 per cent of the patients. Neither lymphangiomatosis carcinomatosa nor ER and PgR gave a uniform impression as predicting factors according to study and target parameters (disease free survival or overall survival). A multivariate analysis (cox-regression) showed that not either by combining these three variables an essential improvement of the prognosis was possible. In patients with 1 to 3 positive lymph nodes no preference can be seen for either L-PAM alone Or a combination of chlorambucil, Mtx and 5-FU. In Patients with more than 3 positive lymph nodes radiotherapy switched-in between two periods of polychemotherapy did not lead to better results than polychemotherapy alone. Frauenklinik Prosper-Hospital, D-4350 Recklinghausen Medical Statistics/Universit~t, D-4000 DGsseldorf~ Moorenstr. 5

THE D I A G N O S T I C V A L U E OF T H E CA 15.3 D E T E R M I N A TION IN THE S U R V E I L L A N C E OF B R E A S T C A N C E R PATI E N T S : F I R S T R E S U L T S OF A P R O S P E C T I V E STUDY P.Schmidt-Rhode~K.D.Schulz~S.Stracke:G.Sturm R e t r o s p e c t i v e studies o f CA 15.3 d e t e r m i n a t i o n s in b r e a s t c a n c e r p a t i e n t s , r e v e a l e d this a n t i g e n to be h e l p f u l for the e a r l y d i a g n o s i s of r e c u r r e n t d i s e a s e . T h e p r e s e n t p r o s p e c t i v e s t u d y attemps to i n v e s t i g a t e , i f the CA 15.3 m e a s u r e m e n t can r e a l l y give e a r l i e r i n f o r m a t i o n of a recurrentdisease,than the c o n v e n t i o n a l c l i n i c a l a n d l a b o r a t o r y p a r a m e t e r ( l e a d - t i m e ) . N e a r l y 200 p a t i e n t s w i t h no e v i d e n c e of the d i s e a s e h a v e b e e n i n c l u d e d in the m o m e n t . F o r d e t e r m i n a t i o n we are u s i n g the i m m u n o r a d i o m e t r i c assay of C a n t c c o r . U p to n o w 16 p a t i e n t s d e v e l o p e d a d i s s e m i n a t i o n . O n l y 8 of t h e m (50 %) w e r e a c c o m p a n i ed by r i s i n g a n t i g e n t i t e r s . F u r t h e r 6 p a t i e n t s r e v e a l e d p a t h o l o g i c a l CA 15.3 l e v e l s w i t h o u t c l i n i c a l l y d e t e c t a b l e p r o g r e s s i o n in the mom e n t . C o n c e r n i n g the 16 cases w i t h e s t a b l i s h e d p r o g r e s s i v e d i s e a s e , 4 / 1 6 (25 %) w e r e f o u n d to h a v e i n c r e a s e d levels p r i o r to c l i n i c a l d e t e c t l o n . I n the o t h e r 4 cases the a n t i g e n e l e v a t i on was s i m u l t a n e o u s l y m e a s u r e d w i t h the clin i c a l d i a g n o s i s . I n spite of the a c t u a l l y small n u m b e r of c a s e s , e s p e c i a l l y l i v e r and b r a i n m e tastases r e f l e c t the t e n d e n c y of early r i s i n g CA 15.3 t l t e r s . D a t a a b o u t a d d i t i o n a l d e t e r m i n a t i o n of CEA and TPA w i l l be r e p o r t e d . T h e pre l i m i n a r y r e s u l t s indicate the CA 15.3 d e t e r m i n a t i o n to be h e l p f u l for the e a r l y d e t e c t i o n o f p r o g r e s s i v e b r e a s t c a n c e r in special c a s e s . B u t a c t u a l l y we are n o t able to e s t i m a t e , i n w h i c h p e r c e n t a g e of b r e a s t c a n c e r p a t i e n t s a leadtime c a n be expected. D e p a r t m e n t of O b s t e t r i c s and Gynecology, Philipps University,Marburg(Lahn),Germany

FR

S 105

3/P-GMO93

3/P-GM 095

Thermography of the femal breast r e f e r e n c e to m a m m a r y c a r c i n o m a s . R. E u l e n b u r g , G. Lauth

with

special

Since 1870 we have e x a m i n e d 60.000 patients, a t o t a l of 1350 c a r c i n o m a s were found. The value of thermography for detection of mammary carcinomas and the combination of different diagnostic methods for breast e x a m i n a t i o n are discussed,

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H. Schmid,M. Kauf-maml, E.M. Grischke and G. Slavetinsky In 118 pts with ABC (104 pts with distant metastases and 14 pts with primary" inflamnatory breast cancer)different subclasses of leucocytes were determined with commercially available monoclonal antibodies (NAB) using flowcytometr/ instrumentation.~(-cclls were measured with t ~ different MAB (anti-leu 7+I ]), T-helper-lymphocytes (TH) with the anti-leu 5, T-suppressor-cells (TS) with the anti-leu 2. The applied chemotherapy regimens were VAC/ ~C/FAC/FEC (n=59) ,OdF(n=]7), and NOSTE (n=42) .The iammnological data were determined at the beginning of CHT, during CHT,and at the time of remission or progression of

disease.

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PROGNOSTIC VALUE OF N A ~ - K I L L E R [NK)-CELLS ~TD TL~HO~S IN PATIENTS (PTS) WITH ADVANCED BREAST CANLT~ (ABC) TREATED BY COMBINATION CHh-WOTHERAPY(CHT)

@5,7%

Our data show that the absolute number of NK-andT-cells are without prognostic relevance, whereas the ratios of NX 7 /NK 11, of lid-cells / TS-cells , end changes of these both ratios correlate with the clinical outcome. In the case of complete remission ( continuing > 6 months ) the ratios measured were 1,6- > 1,8 , and in the case of nonresponder ~0,7. The Nq< 7/N!< 11- and the TH-/Tg-cells - ratio are early (within 2 cycles of CHT)prognostic factors to predict response of cytotoxic CHY in ABC.

{1980 - 198~)

Universit~ts-FrauenklinikHeidelberg D-6900Heidelberg Universit~ts-Frauenklinik Pi!grimstein 3 D 3550 M a r b u r g

, Voss-Str. 9

Marburg

3/P-GM094

3/P-GM 096

PERIOPlI~ATIXTE THERAPY IN BREAST CANCER WITH 4-EPIRUBICIN ~.PreiB, C.T. Beck, J. Huter

LONG-TERl{ OBSERVATIO~ OF BREAST CANCER PATIENTS AFTER DETECTION OF TUMOR CELLS IN-BONE l{ARROW AT TIME OF PRIl{ARY THERAPY; FREQUENCY OF METASTASIS AFTER THREE YEARS M. Untch, N. Harbeok, W. Eiermann ..........................................................

Proven benfit from early beginning of adjuvant chemotherapy (aC) in breast cancer led us to start a cooperative trial of perioperative treatment (PT). All patients (p) (age 65 y) with primary- breast cancer, considered for modified mastectcmy entered the study. If malignancy is proved by frozen biopsy, P T w i t h Epirubicin (E) 30 mg/m = day 0+I startet within 6 hours. Postoperativ p were divided into 3 group according to the pathological stage and hormonreceptor. Group I with good prognosis got no further aC. Group Ill with worse prognosis ( 10 12{pus) or postmenopausal status aC would be of no benefit. In group II (premenc>pausal, LN I-9, I~R/PR +/- or LN -, ER/PR - or postmenopausal LN I-9, ER/PR -) aC with 4 x C M F a n d 2 x E (40 + 50 mg/m 2 day I+2) started on day 22. Further radiotherapy and/or hormonal treatment was given if neccecary. Till now 308 p entered the study, which is still going on. This evaluation (7/84 7/87) consists of 258 p (Group I 73, Group II 134, Group IIl 51). Mean observation time is ]9.5 months (I - 36) amd only toxicity and complications of PT is evaluable in group II on day 22. Wo~]d healing conplication are in the normal range like in series without any periopC. 8% minor disorders are probably without relationship t o t h e P T . All p got supportive therapy. Nausea/emesis WHO grade 2 was seen in 15 p (17%) WHO grad 3 in 3 p (2 %). Alopecia grade I is not visible and was not recorded, but when questioned nearly all p agreed to have some hairs on the sheet. Visible hairloss had 9 p and only 3 needed a wig. Myelosuppression were not seen, 3/134 p had fever up to 38.0 C, possible not related to the PT. As a positive side effect all p aggreed with the further aC (if necessary) in order to the good ~xperi~]ce of the perioperative PT. KlinJ~ fgr Strahlentherapie und Onkologie, St~dt. Krankenhaus, Weinberg I, D-3200 Hildesheim

Long-term monitoring of breast cancer patients was carried out in order to test the effectiveness of immunocytochemical detection of tumor cells in bone marrow at the time of primary therapy as a predictor of bone metastasis. Bone marrow aspirates of 67 patients (TI-3,N0-2, l{0-1) were taken from six sites at the time of primary therapy~ All patients were screened for distant metastasis (X-ray, bonescan). Tumor cells in the bone marrow aspirates were detected by an immunocytochemical method using monoclonal antibodies against EMA and Cytokeratin. In 25/67 patients, bone marrow aspirate staining of tumor cells was demonstrated (5/17 patients at stage I, 18/S2 at stage If, 5/18 at stage III, 2/5 at stage IV of the disease). The median follow-up time was 16 months (min. 3 months, max. 85). Notably, 12/25 EMA-positive patients have already developed distant metastases, compared to only 8/42 El{A-negative patients~ Of the 25 El{A-positive patients, 7 developed bone metastases, 2 soft tissue metastases, I visceral metastases and 2 multiple metastases. However in three years of observation, not a single one of the 45 El{A-negative patients developed bone metastases, only 1 soft tissue metastases, and 2 visceral metastases. The median time from bone marrow sampling to metastasis in EMA-positive patients was 7 months. Bone marrow sampling (in conjunction with Immunocytochemistry) allowed us to detect bone micrometastasis in 37% of our patients. Together With our follow-up, these results support the use of bone marrow sampling in primary breast cancer patients as a predictive criterion for the development of bone metastasis. Department of Gynecology and Obstetrics, Klinlkum $rosshadern, LMU l{~nehen.

S 106

3/P-GM 097

31P-GM 099

Breast Conserving Therapy of Mammary Carcinoma: Result% Sequelae, Side Effects of the Treatment D. v. Fournier, K. Engel, A. MQller, M. Kaufmann

Induction OF MITOXANTRONE and DOXORUBICIN resistance in s e n s i t i v e h u m a n b r e a s t c a n c e r cells.

From 1985 - Sept. 1987 breast conserving therapy has been carried out in 650 patients. The criteria for admission were the following."Tumor size 2 em max. (until 1984); 3 em max. (after 1984); patient'sdesire to undergo this treatment. The therapy consists preferably im a• iymphadeneotomy, segmental resection, irradiation with 50 Gy, boost dose of iO Qy, depending on histeleglc findings. In case of positiv nodes (27 %) administration of CMF (premenopausat) or TAM (postmenopeusal~ receptor positiv). With the exilic net being irradiated, eccuring arm edema have been sequelae

3.Ahrens a n d W.E.Simon ~ The p r o l i f e r a t i o n rates of the h u m a n breast cancer cell line E F M - 1 9 is i n h i b i t e d by low c o n c e n t r a t i o n s of D O X O R U B I C I N , #-EPIDOXORUBICIN, and MITOXANTRONE that correspond t o t h e r a p e u t i c s e r u m levels. S t o c k c u l t u r e s o l t h e s e n s i t i v e cell line were exposed to increasing concentrations M I T O X A N T R O N E in e a r l y p a s s a g e s of in v i t r o c u l t i v a t i o n . A f t e r 5 m o n t h s of in v i t r o t r e a t m e n t t h e s e n s i t i v i t y o f t h e tumor ceils to MITOXANTRONE, #-EPIDOXORUBICIN, and D O X O R U B I C I N w a s e v a l u a t e d in e x p e r i m e n t a l i n c u b a t i o n s . T h e M I T O X A N T R O N E t r e a t e d c e i l s p r o l i f e r a t e d e v e n in t h e p r e s e n c e o f 60 n g / m l M I T O X A N T R O N E , a c o n c e n t r a t i o n w h i c h w a s t o x i c f o r t h e u n t r e a t e d EFM~I9 c e l l c u l t u r e s . In c o m p a r i son to t h e u n t r e a t e d c e l l s t h e r e s i s t a n c e to M I T O X A N T R O N E i n c r e a s e d by a ~ a c t o r o f 700, In p a r a l t e l i n t u b a t i o n s t h e r e s i s t a n c e to D O X O R U B I C I N a n d g - E P I D O X O R U B I C I N inc r e a s e d by a f a c t o r of I00. The c h r o m o s o m e a n a l y s i s of t h e EFM-19 s e n s i t i v e a n d r e s i s t a n t c e i l s did n o t show s i g n i f i c a n t differences.

to surgery and occured as follows: above 3 c a : 6 %; 2 - 3 c a : 23 %. In case of tess than 25 dissected lymph nodes tha rate of arm edema is nat related to the number of dissected lymph nodes, in case of more than 25 dissected lymph nodes the number of eecuring ere edema is directly releted to the increase in lymph node dissection.

Because of favorable selection recurrences did only occur in 4.6 % of cases during e 5-years period, 2/3 of all recurrences oceured in the quadrant of the primary tumor. These recuerenees correlate with the supposed volume of tumor dissemination in the same quadrant. The role of multteentrietty is less important, in this ease present recarrences were inflammatory in all quadrante in 1/5 % of the cases (supposingly net curable primarily). The 5-years overall survival (OAS) was 91%. From a total of 8 % of the patients who died because of the tumor, only 2 % were suffering from simultaneous local reeurreneea~ the other 6 % of the patients were suffering from distant metastases without local recurrences in the retained breast. During the first 10 postoperative years local reetlrrenees seem to develop with a frequency of 1% per year. The treatment acceptance amounts to 95 % as against 55 % after ablatio plus reconstruction. University Hospital for Women~ 6900 Heidelberg, VoBstr.

Since M I T O X A N T R O N E t r e a t m e n t of t h e h u m a n b r e a s t c a n c e r cell line EFM-19 induced increased resistance to M I T O X A N T R O N E and o t h e r c y t o s t a t i c d r u g s , t h e in v i t r o t r e a t m e n t is s u g g e s t e d t o s e l e c t f o r m u l t i d r u g r e s i s t a n t t u m o r cells. Diakonissen-Krankenhaus, 2800 Bremen *Universit~ts-Frauenklinik, SchleichstraBe #, D-7#00 T{ibingen

3/P-GM 098

3/P-GM 100

PATHOPHYSIOLOGY OF HYPERPROLACTINENIIA IN BREAST CANCER Holtkamp,W., Wuttke,W., Nagel,G.A.

FIRST Vtgc

To characterize the prolactin secretion in human breast cancer, 7074 basaI plasma prolactin levels were measured in 1130 patients with breast cancer and controls in long term follow up studies. In subgroups of patients suppression and stimulation tests were performed and the 24h secretion profile was recorded. Tissue extracts and sara of hyperprolactinemic (HYPRL) breast cancer patients were incubated with cultured pituitary cells in vitro to detect a Prolaetin releasing activity (PRF) in these specimens.

14ith VNC. (V = Vincristin .=~iO Im~lm , N = NOVAt~tTROI~tEt Mi'~oxaqt~one .. = 12 mg!mZ~ C = Uvr :a bOO lIX.~/ll~-) ~1s adalirii~lte~,'eo Oa Df~Y [ arid }"epea{:~_*d q weeks,, toxicity permitting> all 25 a r e evaiuMalo for toxicity a n d 20 f o r ' re~pon.~e. ~t t o ~ l of' 122, ~ r o admin~hered. Pal;lent c h a t ' a c - t~'eatment r

25

Results and conclusions: 40% of breast cancer patients develop HYPRL i n the course of the disease. PRL levels undergo great fluctuations, b u t HYPRL over 1000 mU/l is only found in patients with progressive metastatic disease. HYPRL i n b r e a s t cancer patients is caused in 35% of measurements by non tumor related factors, e.g. surgery, prolactin releasing drugs, uremia. Excluding such eunspecific" influences on the prolactin level, patients w i t h HYPRL h a v e a s h o r t e r survival time and are more frequently therapy resistant. HYPRL is associated with tumor load, but not correlated to BSG, CEA or prognostic factors,e.g. lymphnode-, receptoror menopausal status. HYPRL i n b r e a s t cancer is not of paraneoplastic origin. HYPRL i n b r e a s t cancer is not caused by PRF's secreted by tumor tissue. Tumor related HYPRL i s a new prognostic factor in breast cancer. Medizinische Universit~tsklinik, Sir, 34 GOttingen

Robert

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B, Such.v~,

Koch

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~.

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advar~r

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teri'Jtics: 17 p a t i e n t s ware rated a.~ h i g h r'i.~k, aui:or'di.l'ltj LO 'the P o ' . l s i n g e r ,~core (A'.liO...Stu'Oien z u r IBlhltldltJrl~ des ttlet t a |:a I [ el"el+lden P~lmlla-.Ka r'z ~rloms",

Possit~]er,

Wibn~nn~,

V e r ' l a g 1 9 8 6 ) ; 66 % ) pausi.~:[, 7 1 % Previmf~

in Mamma..-K~irzinullle Springer-bO )tear~ oF age, 67 % p o s t e n o r~dlotherapy.

~"

Metastatic

sltef~ ~, lur~ = 5 pa~;~ent~ li~er = 6, se~;t t i c , L i e , lyi~}ph n ~ ' e a , et'fu.~ion~ = 14, other = 6, 16 of the 2.0 dvaluable patients had more th,;m one me~aat~d:ic site:- 46 % ha~ a disease free i n t e r w ~ l of: ( 19 months. b o n e .= ItS,

.~kin.

R e = l u l L s : The o v e r c a l l r e s p o n s e was s CRs. 5 PRs 7 SD~, v ~ i t h an overall mean re.~ponse d u r a t i o n

and of'

7 month.~. ]'he l#OSh frequent[~t cheer'rod ~oxieities ~er'e : leucoperlia, ~lopeci[~, "r and vomiting, ~ h e r e thu entries in the cells represent the % of total c vclea administered, WHO Grade 2 ~ 4 mi~siu~ 0 I h~ucop~.mi a

aloper nmuao~ arid

~UE""<"I'~ %"-" -2~J[ "-- -2"8~C-- - ~ ' t ~ " "'~"7;..... 50'& 11% 7% B't& 2% 22% 69% 21% 6% ~% 0 0

ficants chan~ea ~ere s e e n . Q detailed analysis will be presented o f responee ve, the v a r i o u s p a r a m e t e r s o f t h e risk f a c L o r s~:orir~.] SVS~:~a~: metastatic sitos~ DFi af}d tel:ephor" s{:ati;s~ a. Rudoif-Virchow-..Hospital, B e r l i n GmbH. Wolf'rat:~hau~en

9)e)l. Ledr

S 107 3/P-GM 101

3/P-GM 103

OVERADDITIVE EFFECTS OF A COMBINATION THERAPY WITH THE BISPHOSPHONIC ACID APD AND THE

F I ~ T CL~!CAL EX~ERI~WCES W I ~ A ~ 4 A~ZflESTROGEN (D~O~OXL~S~ ) R. Kl~eienberg, V. ~[~bws, G,P. Breitbach, G. Bastert, H.J. Staab

PHENYLALANIN- MUSTARD

MELPHALAN

(MEL)

IN

MNU-INDUCED RAT MAMMARY CARCINOMA. F. Wingenl), T. Klenner2), D. Schm~ihl2) Previous studies have shown strong inhibiting effects of 1-hydroxy-3-aminopropylidene-l,l-bisphosphonic acid (APD) on the osteoclastic activity in bone metastasis in prophylactic and therapeutic treatment. No antitumor activity, however, was observed in rat osteosarcoma or Walkercarcinosarcoma. Since bone metastasis occur frequently in mammary carcinoma, we investigated the antineoplastic activity of APD in MNU-indueed, autochthonous rat mammary carcinoma. Tumor induction was performed according to previously published methods. Evaluation was based on tumor volume, tumor number, bodyweight, mortality, and survival time. Treatment of the animals was conducted through 6 weeks 5x/week by i.v. (APD) and i.p. (Mel) injections (doses see table). The results are listed below: Treatment singte median tumor p-value median % Mortality doses volume (cm3) =0.05 survival at week 7 mg/kg at week 7 time Control 43.2 67 5 APD 23.50 2.7 0.0352 34 60 APD 11.75 5.2 0.0121 65 10 APD 3.88 30.7 n.s.a) 70 10 MEL 0.60 11.4 0.0011 77 O MEL 0.30 18.2 n.s.a) 56 40 APD+MEL 11.75+0.6 0.2 0.0000 78 10 APD + MEL 11.75+ 0.3 2.0 0.0011 63 20 APD+MEL 5.88+0.3 21.8 n.s.a) 62 0 a) n.s. = not significant APD monotherapy resulted in significant reduction of tumor growth, Combination therapy of APD + mdphalan showed overadditive effects on tumor growth as well as number of complete remissions. These findings may be of importance in adjuvant treatment of bone metastasing mammary carcinoma in patients. 1) Dept. Clinical Research, Rhone-Poutem Sante/Nattermann, 5000 K~51n30, FKG 2) Institute of Toxicolo'~yand Chemotherapy,German Cancer Research Center

I~ a phase I/II trial, efficacy and tolermnce of the new antiestrogen d~oloxifene (3-OH-tamoxifen) were assessed in 17 post~nopausal women with evaluable metastatic breast cs~ncer u s ~ g oral doses of 20 or 40 mg tablets daily. Pr~clinical investigations gave evidence that drolo~ifene in comparison to tamoxifen has a superior binding affinity to the estrogen receptor, a superior antiestrogenic effect, a lower ~qtrinsic estrogenicity and a lower accmmulation in the system. Clinical respons% tolerability and the ~fluence on co~r mort labo~mto
Langenbeckstr. 1, D-6500 Ybs

3/P-GM 102

3/P-GM 104

DEVELOPMENT OF NEW PLATINUM COMPLEXES FOR THE THERAPY OF HORMONE DEPENDENT BREAST CANCER AND OTHER ESTROGEN RECEPTOR POSITIVE TUMORS H. Sch~nenberger, R. Gust, 7. SpruB, J. E n g e l *

BREAST CANCER AND EARLY CONTACT TO BOVINE M I L K E-J-Rie~i99 . . . . . . . .

Diastereoisomeric platinum complexes with e s t r o g e n r e c e p t o r b i n d i n g l i g a n d s were s y n t h e s i z e d and t e s t e d f o r s p e c i f i c a c t i v i t y against hormone-dependent mammary carcinomas. They l e a d to a marked i n h i b i t i o n of s e v e r a l hormonedependent b r e a s t cancer models l i k e the MXTmammary carcinoma of the mouse and the DMBAinduced mammary carcinoma of the S D - r a t . The new compounds a l s o show c y t o s t a t i c e f f e c t s on hormone-independent tumor models, which are caused by the P t C l ~ - g r o u p . This can be demons t r a t e d by the in v i v o - t e s t on the l y m p h o c y t i c leukemia P 388 of the mouse and on the e s t r o g e n r e c e p t o r n e g a t i v e MXT-mammary carcinoma of the mouse. S o n d e r f o r s c h u n g s b e r e i c h 234, I n s t i t ~ t fur Pharmazie, Pharmaz. Chemie I I , U n i v e r s i t ~ t Regensburg, D-8400. Regensburg, FRG *Degussa-Pharma-Gruppe, D-6000 F r a n k f u r t ,

FRG

Breast cancer is uncommon in peoples without dairy producte.These are Japanese and other East Asian ones~ Eskimos and African Bantu. in East African regions inhabited by tribes using bovine milk and blood as food for infants breast cancer is abundant.Immigrants keep the incidence of their place of birth. Their daugthers~ born in the new country acquire the new country's incidence rate. Cohort analyses, too, show the importance of the time of birth. Rising incidence started with cohorts born after introduction of formulas for bottle feeding. Obesity, early menarche, and tallness, typical for patients are typical for bottle-fed children, too. Tallness and early menarche are not explicable by influences exerted during adult life. The expensiveness of artificial feeding explains the tendency of the disease to occur in the wealthy, well educated women who get their first child late. After matching for education(Herity BA,Br J Prev Soc Hed 29:178~1975.Gjorgov AN, Contr Gyn Obst 8:8o-84,198o)or use of neighborhood controls(Choi NW,Am J Epid lo7:51o,1978) risk associated with late first birth vanishes. Infant food is prone to transmit infections giving rise to later occurring tumors, since viral oncogenesis is much more successful in newborn animals. The bovine leukemia virus BLV is transmitted by milk. It integrates into the DNA of B-lymphocytes which are secreted with the milk.The DNA copy is not destroyed by pasteurization. The tumor induced in the cow likes to settle in lymph nodes, mammary glands~ spine, and lungs~ places preferred by breast cancer, too. Hagazussa eV~ZHlpicherstr.177,FRG-SK~in 41

S108

3/P-GM 105 "CANCER IS A PROBLEMOF CO~gRdNICATION" G. Schweikhart and M.C. 8ettex Regarding the fact that in up-to-date cancer diagnostics, treatment and research the contact and the con~unication of all experts with each other and with the cancer patients and their families themselves frequently is not sufficient - similar as it happens in the disease itself which is characterized as a chaotic proliferation of cells - the German Task Group for Psychoonkofogy devotes itself to that social scientific phenomenon, the "problem of communication". Beginning 1978 as a small communicative group of psychologists and social workers professionally attended with the contact to cancer patients in all stages of disease, in 1983 the German Task

Group for Psychoonkology was established. Now, more than 100 active members, physicians, surgeons, psychologists, social workers~ physictherapists, nurses, pastors, scientists and other professionals looking for cancer patients are in close contact to interchange actual experiences and to come along to new steps of improving treatment possiblilities, care and quality of life involving psychosomatic and psychosocial aspects. To that end ~rkshops are organized, individual initiatives are co-0rdinated, advice regarding individual therapy and contact to special institutiones are given as well as expert statements. Special meetings for attendant research take place. Showing the work which is done till now and looking forward to further initiatives is the aim of that paper. DAPO e.V., Stiftung Linerhaus, Alte BDrfstr. 1 D-3100 Celle, F.R.G.

3/P-GM 107 P S Y C H O L O G I C A L SUPPORT FOR CANCER PATIENTS SUFFERING FROM PAIN H.M.Seemann One third of all cancer patients have pain in the course of their illness, but during the last weeks of their lives 60-87% suffer from severe p a i n . ' E f f e c t i v e cancer pain relief'is a progran~e now p r o m o t e d by the WHO. It consists of guidelines for an adaequate p h a r m a c o l o g i c a l treatment of cancer pain and points out the need for additional p s y c h o l o g i c a l care for those suffering from pain. There are three crucial phases during the course of the illness where the doctor should focus p a i n problems. First, when the patient is told about the diagnosis he/she will perhaps experience massive anxieties about painful treatments and about dying painfully. These fears will influence lateron the way pain is actually experienced. Second, w h e n painful therapies or therapy consequences must be accepted, it is necessary to teach the patients s e l f - h e l p - t e c h n i q u e s which allow them to develop feelings of control and self-efficacy in order to improve treatment compliance. Third, in the terminal stage, when the patient needs symptom control it may happen, that severe pain cannot be relieved sufficiently. Then the p a t i e n t ( or a family member ) c a d be taught pain coping techniques like self-hypnosis to overcome anxiety and pain. The author provides explicit guidelines how to talk w i t h patients and how to help them develop strategies for effective pain management. Ii. Pllysiologisches Institut der Universit~t Heidelberg, Im N e u e n h e i m e r Feld 326 6900 H e i d e l b e r g

3/P-GM 106

3/P-GM 108

Q U A L I T Y OF LIFE OF PATIENTS WITH T H Y R O I D CARCINOMA H. Steinert and D. Eissner

PSYCHOLOGICAL AND NEUROPSYCHOLOGICALINVESTIGATIONS TO ASSESS LIFE QUALITY IN PATIENTS WITH GLIOMA OF THE BRAIN E.Birk, W. Traber~, K.Schnabel~ K.Schimrig~, P.Jacobi

In a prospective comparative study the psychosocial situation of patients with thyroid carcinoma and benign thyroid lesions is examined covering the first year after operation. The purpose of the study is to describe the effects of I. the carcinoma itself and II. the different treatment modalities on the patient's quality of life. Parameters investigated are: coping strategies, social support, personality structure, defense mechanisms, anxiety, perception of the disease. The study is being done i n t e r d i s c i p l i n a r y and in c o o p e r a t i o n with the Mainz Tumor Centre. The concept of the study and p r e l i m i n a r y resuts are presented by case reports. Abteilung Nuklearmedizin, U n i v e r s i t ~ t s k l i n i k e n Mainz, Langenbeckstr. I, 6500 Mainz.

New developments in the treatment of human cancer lead to a growing interest in measuring l i f e q u a l i t y during and a f t e r therapy, The assessment of l i f e q u a l i t y is well established i . e . in internal or gynecological oncology but not in neurooncology. We present a psychological and neuropsychological test battery f o r the assessment of l i f e q u a l i t y parameters in patients with glioma of the brain using the l i f e quality-index (LQI) of Spitzer and a s e l f - r a t i n g - s c a l e concerning l i f e contentment. Anxiety was judged by STAl-questionnaire (Spielberger). A finger-tapping-test (Halstead-Reitan) and the Purdue-pegboard-test ( T i f f i n ) were applied to estimate the general psychomotor tempo of the patients. A verbal-fluency-test (Horn) and the t r a i l - m a k i n g - t e s t (Reitan) served f o r grading the int e l l e c t u a l impairment. We report the p r a c t i c a b i l i t y and f i r s t results of this test battery in 20 patients with glioma of the brain at the beginning, during and three months a f t e r a radiation therapy. Fachrichtung Medizinische und Klinische Psychologie, Universit~t des Saarlandes, 6650 Homburg/Saar Universit~ts-Nervenklinik - Neurologie, 6650 Homburg/ Saar ZRadiologische U n i v e r s i t ~ t s k l i n i k , Abteilung fur Strahlentherapie, 6650 Homburg/Saar West Germany

SlOP

3/P-GM 109

3/P-GM111

REPRODUCTIVE AND ENDOCRINE GONADAL CAPACITY IN PATIENTS TREATED FOR OSTEOSARCOMA E. Kreuser, K. Winkler, W.D. Hetzel, B. Hertenstein, H. H e i m p e l In recent years it h a s become apparent that 50-70% of patients with localiced ostsosarcoma achieve long-term survival using new chemotherapeutic regimen (Winkler e t a l . J. Clln. Oncol. 2: 617-624, 1984). Particularly in case of young patients, this prolonged survival has focused attention on chronic or late side effects of chemotherapy. This study was conducted to evaluate the impact of chemotherapy on endocrine and reproductive gonadal toxicity in both, female and male patients. 5 women and 9 men treated successfully for osteo ~ sarcoma according the COSS-protocol were studied 4-35 months after therapy. Diagnostic procedures to establish gonadal functions included serum hormone analyses using RIA for FSH, LH, estradiol, progesterone, testosterone, and prolactln, interviews with a standardized questionnaire, and sperm evaluation (Kreuser e t a l . J. Cancer Res. Clio. Oneol. 113. 260-266, 1987). In 9/9 men LH, FSH, testosterone, and 176-estradlol were within normal limits. In 5/5 women progesterone, 178-estradiol, FSH, and LH were normal. No pregnancy occurred after cessation of chemotherapy. Standardized questionnaire revealed normal sexual function in both, male and female patients. These preliminary data suggest i) normal gonadal steroid synthesis in male and female patients 2) no evidence of chronic impairment of reproductive capacity in men and women after treatment according the COSS- protocol. Abteilung fHr Innere Medizln III (H~matologle/Onkologie) und I (Endokrinologie) der Unlversit~t Ulm, StelnhSvelstr. 9, 7900 Ulm. Supported in part by a grant from Deutsche Krebshilfe (M16/86, He3).

DEVELOPMENT OF CARDIOSELECTIVE PROTECTION IN THE CYTOSTATI~ TREATMENT WITH ANTHRACYCLINES

The c l i n i c a l use of the h i g h l y e f f e c t i v e anticancer antibiotics daunomycin (DNH) and a d r i a m y cin (AO~) is l i m i t e d by t h e i r c u m u l a t i v e c a r d i o toxicity (CCT), There is s t r o n g e v i d e n c e t h a t CCT as well as the a n t i n e o p l a s t i c a c t i o n are c l o s e l y r e l a t e d to t h e i r e n z y m a t i c r e d o x - c y c l i n g which m a y c a u s e " o x i d a t i v e s t r e s s " by f o r m a t i o n of t o x i c o x y g e n r a d i c a l s in c o m b i n a t i o n w i t h an insufficiency Of cellular detoxifioation mechanisms due to a c r i t i c a l e x h a u s t i o n of N A D P H and reduced s u l f b y d r y l s (XSH). The concomitant' application of XSH per se is c a r d i o p r o t e c t i v e ~ but interferes with the antitumor activity of ADM as demonstrated for N-acetyl-cysteine in: Ehrlich ascites tumor(EAT)-bearin0 mice. Thus. cardioprotection based on r e a c t i o n s e l e c t i v i t y may not be feasible. In contrast to tumor tissue. NADPH, a e o e n z y m e for the r e g e n e r a t i o n Of r e d u c e d 9 1 u t a t h i o e e , is i n t r a c a r d i a l l y formed via the isocitrate-dehydrogenase r e a c t i o n . Acc o r d i n g l y , the c a r d i o p r o t e c t i v e e g g e c t of i a o c i trate, the s u b s t r a t e for this r e a c t i o n , as w e l l as for niacin, a p r e c u r s o r Of NADPH, could be demonstrated in A D H - t r e a t e d mice. w h i l e a n t i t u mor efficacy was not i n h i b i t e d in EAT in r i v e and in h u m a n l e u k a e m i c b l a s t s in v i t r o respectively. A c l i n i c a l s t u d y w a s d e s i g n e d to d e t e r mine the value Of n i a c i n as a c a r d i o s e l e c t i v e protector in patients with acute myel0genous leukaemia with DNM-containing combination chemot h e r a p y a c c o r d i n g to the T A D - r e g i m e n .

3/P-GM110

3/P-GM 112

QUALITY OF LIFE ASSESSMENT TRIALS: AN OVERVIEW A. N e i 8 , M, B u l l i n g e r

IN CANCER

....

T h e s e p r o b l e m s as w e l l as a p p r o a c h e s t o t h e i r solution will be presented. Special attention w i l l b e g i v e n to a v a i l a b l e Q L - i n s t r u m e n t s with regard to principles in scale construction and criteria for evaluating these instrument{ psychometric properties and clinical acceptability. In a d d i t i o n , s t r a t e g i e s f o r t h e i m p l e m e n t a t i o n o f Q L - a s s e s s m e n t in c l i n i c a l t r i a l s as w e l l as c o n c e p t s f o r a n a l y s i s of Q L d a t a r e l a t i o n t o clinical data will be presented. It is h o p e d t h a t a d i s c u s s i o n of p o s s i b i l i t i e s a n d l i m i t a t i o n s of Q L a s s e s s m e n t in c l i n i c a l t r i a l s w i l l c o n t r i b u t e to t h e d e v e l o p m e n t of this new research field.

fur Therapiestudien

(Supported by PEG: SFB I 0 2 . } Inhere Universit~tsklinik und P o l i k l i n i k (Tumorforschung), Westdeutsches Tumarzentrum, Hufelandstr. 55. 0 - & 3 0 0 E s s e n I

~rgit

CLINICAL

In s p i t e of t h e i n c r e a s i n g a c k n o w l e d g e m e n t of q u a l i t y of l i f e (QL) as a n i m p o r t a n t o u t c o m e v a r i a b l e in o n c o l o g i c a l r e s e a r c h , i n c l u s i o n o f QL assessment in cancer clinical trials has been hampered by conceptual, methodological and practical problems.

Biometrisches Zentrum Pettenkoferstr. 35 8000 MUnchen 2

M. E. S c h e u l e n

GmbH

von Kerekjarto

Quality of Life in Cancerpatients I t is attempted to define the term 'Oualitv of L i f e ' The necessary conditions of l i f e . which make up aaood q u a l i t y of l i f e f o r each human being, are discussed, and the subjective importance of this q u a l i t y of l i f e is t r i e d to describe. Quality of l i f e is not a s t a t i c but a dynamic one, i . e . i t is changing during the course of l i f e in one and the same person. There are s p e c i f i c differences between chronically i l l patients and healthy people. The most important dimensions were discussed, which make out a considerable improvement of q u a l i t y of l i f e of cancerpatients, in d i f f e r e n t stages of i l l n e s s . Approaches to measure q u a l i t y of l i f e were pointed out. The p r a c t i c a b i l i t y and usefulness of functional status, e.g. Karnofsky-lndex and global psychological measures as standard dimensions of q u a l i t y of l i f e , are shown on some examples of patients.

SllO

4/22-G 001

4/22-G 003

ACTIVITY OF NEW HUMAN a-INTERFERON (B/D) HYBP,.IDS ON NORMAL ~ NEOPLASTIC HUMAN CELLS R.Heicappell, I.Salkl, M.Gr0tter, R.Ackermann, and l.J.Fidler

THE EFFECT OF TWO SCHEDULES OF LOW DOSE INTERFERON ALFA ON REMISSION MAINTENANCE IN HAIRY CELL LEUKAEMIA O.Kloke, N . M e d e r l e , D.May, H.Kruse, H.Bartsch~ U.Wand~,

R.Osieka and C.G.Schmidt Sixteen hybrid molecules between h u m a n recombinant lymphoblastoid interferon B (~* 8) and h u m a n recombinant lymphoblastold Interferon D (c~ 1) have been constructed by

recombinant D N A techniques. Fragements werde generated comprising of genes coding for amino acids 1-60, 61-92, 9 8 - 1 5 0 , and 151-166. The purpose of this study was to determine the antiproUferative activity of sixteen ~-IFN(B/D) hybrids on h u m a n non-transformed and neoplastic cells. H u m a n tumor cell llnes used were of melanoma, glioblastoma, prostate carcinoma, renal cell carcinoma, and colon carcinoma origin, There was a strong direct antiprollferative activity on all neoplastic cells tested of those ~-IFN(B/D) hybrids, that were of type "B" in their N-terminus, whereas nontransformed cells (flbroblasts, normal h u m a n kidney cells) remained unaffected. In contrast, hybrids, whose N-terminal 92 amino acids were coded for by genes derived from LyIFN D dld virtually not inhibit tumor cell proliferation. A n exchange of amino acids in the carboxy-termlnal 78 amino

acids dld not markedly influence the antiproliferative activity of a given molecule, e.g. a molecule of type "BBBB" had the same actlvly as a molecule of type "BBDD", on the other hand, a molecule of type "DDDD" did not gain antiproliferative activity by exchange of the two carxoxyterminal domains CDDBB"). Thus w e conclude that h u m a n :-IFN (B/D) hybrids are molecules with a strong antiproliferative activity on a variety of h u m a n tumor cell lines. Our data suggest that the activity m a y be determined by the configuration of the molecule In amino acids 1-92.

Over the past three years, numerous c l i n i c a l t r i a l s have established the e f f i c a c y of I n t e r f e r o n (IFN) a l f a f o r induction of remission in hairy c e l l leukaemia patients (pts). A f t e r discontinuation of the drug, a progressive recurrence of the disease has recently been reported. In most of the relapsing pts, however, IFN a]fa was shown to remain an a c t i v e agent. Twenty-seven pts with progressive h a i r y c e l l leukaemia were treated with recombinant IFN alfa-2b (Intron A ~ administered subcutaneously every second day at an i n i tial6dos ~ of 4x1ObU/m~ (n=7pts), 2x?O6U/me (n=12pts) and Ix10 U/m (n=8pts). In a l l pts treated, a haematological improvement could be induced which appeared to be independent of the i n i t i a l dose IFN. A f t e r induction of stable remission - on the average ~2 months a f t e r beginning of treatment - 20 of these pts were randomized into two d i f f e r e n t schedules of maintenance therapy~ II pts received IFN alfa-2b at a t o t a l dose of Ix10~ twice a week f o r one year (regimen A), the other 9 pts were a l l o cated to treatment with 2x10~ once weekly (regimen B). Five out of 6 pts in regimen A showed stable haematological remission, whereas I pt developed a decrease of p e r i pheral blood granulocytes. In contrast, treatment had to be discontinued in 2 of 4 pts randomized to regimen B : I pt experienced' f l u - l i k e symptoms f o l l o w i n g the weekly IFN a p p l i c a t i o n , the second developed' progressive pancytopenia. These preliminary data suggest that the weekly administration of low dose IFN a l f a seems to be i n s u f f i c i e n t to maintain haematologica] remission in hairy c e l l leukaemia.

Urologlsche Universit~tsklinik, Moorenstr.5, 4 0 0 0 DOsseldorf

Innere K l i n i k und' P o l i k l i n i k (Tumorforschung), Universi~ t ~ t s k l i n i k u m , Hufelandstr.55, D-4300 Essen l *Med. K l i n i k u. Polikl.,Robert-Koch-Str.,D-3400 G~ttingen

4/22-G 002

4/22-G 004

CYTOCONVERSIO~ OF PLURIPOTENT STE~ ELLS OF PATENTS WITH CHRONIC ~YELOGE~OUSLEUKEMIATREATEDWtT~RECO~INA~!TINTERFERON. A.A. Faumer~ K,

N A T U R A L INTERFERON ~ {nIFN ~) IN A P A T I E N T WITH CML AND ANTIBODIES TO rIFN a 2b. g. Exeriede, M. Freund, R. Eisert, P. van Wussow U. Pohl and H. Poliwoda.

H~amn~awl L. Kanz and G.W, LeAr. The antimroiiferetive actims demons~r~teJ

mf human alpha interferm~

has

bee~

in a ~m~or of hm~mR b ~ r m as sell ae i~ smrsmi mnd mye!mid

io~b~im progenitor ce!tm. ~s stadied the effect of recombinant haman interferen alphm (r-IFN w., } on bone marrow 6erivmd hemmtupoietia stem cells of narmai individuals add mf patimetm with Ph' poeitbe chronic myelmgmomum ieu~esi~ (C~Lh and evaluated the :ybc~nversiam af s~em cells grmwn in the proeence mf hu~aR recombinant lntorferun, We found that the inhibitory effect of i~terferei~was mmTeprmemumcediR mu!tiliRemge colony fmrmi~g cells CCFU-GE~MT) mf sarroH cells ~f matie~tm ~ith c~rmnic myelogm~o~m leukemia (CML; compared with stem cells of normal m~rrem, T-cell melody fmrmabio~ CF~-TL; of Fh' positive (Ph') T-cells obtained from primary mdti!ineage hemo:.opoietic colonies ~am i~hibiBed by rlFN ~ , Inhibition of l ceil colony formation of Ph' T-ceils was mmre profound by i#terfernn camoared nith ~mcondary T-coils mf healthy individuals. Southern bimt analysis of secondaryT-ceils from nmr~al individual revealed a ~erm line pattern ~he~ examir,ed f~r T-celi receptor ~TcR) gs~e rearrangements ~mi~g ~he cBNA for the ~mhoin, Siibc!o~ed Ph' T ceils of m Tom patients with CML deeoRmtrated 9one rearran~emeots of the TcR, We mlsm demanstratm~ the disappearance of ?h: positive multilimeage heaatmpoietic colonies when metros ceils mere preiocubated with interferoR and mubmeoumntlycultured in the presence ~f ieterfero~, The cytoconvermlon of the Ph~ chrommmase ie metaphasee obtained from imdividmally m~alyzmd multilioeage hematopoietic eob~lem suggests that iwterfermo might al!m~ the restmration of i~onclm~al hematopoi~s!s in patie~tm ~ith CML, DWioion of Hematology, Royal Victoria Hes@ital, ~cGiii University~ Mc,ntieal~ Cana~a~ and Med, Klieih Albert Ladmigm-Universitat, Freiburg, Wemt Germa~,

A n t i b o d y formation is a major p r o b l e m in long lasting application of r e c o m b i n a n t interferons in CML. A change in the type of i n t e r f e r o n may o v e r c o m e this problem. On this b a c k g r o u n d we describe the follwing case. In a 49 year old man, CML was diagnosed. After induction with busulfan, a m a i n t e n a n c e t h e r a p y with rIFN 2b I0 M i o U thrice w e e k l y was initiated. Leuk o c y t e count rose however and h i g h titer antib o d i e s w e r e found after 2 months. W e s t e r n blotting showed no cross r e a c t i v i t y of antibodies w i t h n I F N ~, to which the t r e a t m e n t was s w i t c h e d over therefore. With the i n i t i a t i o n of nIFN the typical interferon side effects reappeared. Side effects were tolerable however. The effect of the t s on the l e u k o c y t e count is demons t r a t e d below: ,~ After initiation of t h e r a p y w i t h nIFN a 9 Mio U thrice weekly, the leukocyte count fell from 89 600 to 58 600 /pl within 40 days.

,0 , , ,~

/

\

,0!

We conclude that nIFN ~ may be an for patients with antibodies to interferons. Further investigation way.

alternative recombinant is on its

Dept. Hematology/Oncology, Medical School, stanty Gutschowstr. 8, D-3000 H a n n o v e r 61

Kon-

S Ill

4/23-M001

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THE MALIGNANT TUMOURS OF THE NASAL CAVITY AND PARANASAL SINUSES - PATHOLOGICAL CONSIDERATIONS H.-J. Pesch

P R O L I F E R A T I V E A C T I V I T Y IN SQUAMOUS CELL CARCINOMA OF HU~LAN HEAD AND NECK TUMORS M.L6rz, C.Metz, E.Wendler and E.Meyer-Breitung.

Today, malignant tumours are d e f i n e d according to the criteria: typing, grading and staging. The h i s t o l o g i c a l typing of the tumours of the nasal cavity and the paranasal sinuses is based on the 1978 c l a s s i f i c a t i o n by the WHO (vol. 19), and is i n t e r n a t i o n a l l y binding.The m a l i g n a n t epithelial tumours include various forms of squamous cell carcinoma (keratinizing, n o n - k e r a t i n i zing, verrucous, spindle-cell, l y m p h o - e p i t h e l i al) and of a d e n o c a r c i n o m a (tubular, tubulopapillary or tubuio-villous, acinar, cystic, mucinous, signet-ring cell), but also transitional/ adenoid cystic and m u c o e p i d e r m o i d carcinoma. These tumours are rare; even rarer are m a l i g n a n t lymphomas and sarcomas. H i s t o p a t h o l o g i c a l grad i n g is based on the updated TNM g r a d i n g (UICC, 1987) which, in turn, is a m o d i f i c a t i o n of the WHO version. Here, four d i f f e r e n t i a t i o n grades ranging from well d i f f e r e n t i a t e d to u n d i f f e r e n tiated (GI-4) are distinguished. Staging, the clinical and h i s t o p a t h o l o g i c a l c l a s s i f i c a t i o n of stages, is also carried out in accordance with the TNM or pTNM system (UICC, 1987). As a result, the m a l i g n a n t tumours, with respect to their size, lymph node and distant metastases, are not only correctly d e f i n e d as to stage, but are also i n t e r n a t i o n a l l y comparable. This means that large-scale therapeutic studies are now possible. Although the a e t i o p a t h o g e n e s i s of most of the malignant tumours m e n t i o n e d here is largely unclear, in the adenocarcinomas, an o c c u p a t i o n a l exposure to oak and beech sawdust is assumed to be a c a r c i n o g e n i c factor. This is discussed.

Growth pattern and histological differntiation of squamous cell carcinoma of human head and neck tumors were studied with two different m o n o c l o n a l antibodies by immunhistochemical techniques.The p r o l i f e r a t i o n rate was investigated using the m o n o c l o n a l antibody Ki 67 (Gerdes et ai.,1983) which is suitable to be used as a marker for proliferative activity in squamous cell carcinoma of head and neck (LSrz and M e y e r - B r e i t u n g 1987). These carcinomas show a correlation between Ki 67 labelling index and histological differ e n t a t i o n : a c c o r d i n g to the loss of differentation the Ki 67 l ~ e l l i n g increased up to 50 % in u n d i f f e r e n t i a t e d carcinomas. The m a p p i n g of tumors showed a distinct proliferative heterogenity. P r e ~ e a t m e n t of tumors (e.g.radiation) resulted in a remarkable loss of Ki 67 labelling index. The second m o n o c l o n a l antibody was directed against transferrin receptors which are related to the growth rate of human tumors (Trowbridge and Omery, 1981). The t r a n s f e r r i n receptor was w i d e l y d i s t r i b u t e d in squamous cell carcinoma, all tumors showed a high (~70%) labelling index. In contrast to Ki 67 labelling we couldn't detect a significant correlation between transferrin receptor expression and histological d i f f e r e n t i a t i o n . T h e decline of labelling after p r e t r e a t m e n t was less pronounced. ZHNO,Universit~tsklinikum,Theodor Kai 7, D 6000 F r a n k f u r t / M a i n 70

Stern

Pathological Institute; U n i v e r s i t y of ErlangenNuremberg, Krankenhausstr. ~-I0, D-8520 Erlangen

4/23-M 002

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RADIOTHERApy OF MALIGNANT TUMOORS OF THE NASAL CAVITY AND PARANASAL SINUSES H.-J.Thiel Prognosis and therapy of malignant tumours of the nasal cavity and paranasal sinuses depend on the histologial type, site of origin and extent of the tumour, The variety of possible treatment modalities demands individual treatment planning .A single modality approach is only feasible in very early tumour stages .Generally a cow,bined modality, surgical and radiotherapeutic approach, possibly supplemented by small volume intracavitary br aehytherapy or polychemotherapy in some defined histological tumour types, has been accepted as treatment of choice. The radiotherapeutic treatment modalities are teletherapy (external beam megavoltage irradiation with photons and electrons) as well as brachytherapy (interstitial implantation of Ra-needles, Au-grains or It-seed ribbons and intracavitary surface therapy with Co-6o pearls or Ra-226 tubes) . Irradiation can be given preoperatively (young age, posltive nitrogen balance, good general health,radiosensitive tumours) or op~stoperatively (age over 70 years, negative nitrogen balance, reduced performance and nutrition status e radioresistent tumours) . Tumour dose is 50 Gy in 5 weeks preoperatively and 60 Gy in 6 weeks postoperatively with a boost to the tumour region to 70-80 Gy in 7-8 weeks if necessary. In accordance with major treatment centers we recommend the following treatment strategy : comJoination of surgery and irradiation for all squamous cell carcinomas (sequence of modalities depending On age, general health and nutrition of the patient, extent of tumour and infiltration of skin and bone) - radiotherapy only for malignant Non Hedgkin-Lymphomas - surgery only (in selected cases with small volume irradiation postoperatively} for adenocarcinomas, malignant melanomas, bone and soft tissue sarcomas - adjuvant chemotherapy for rhabdomyosarcomas, Ewing's sarcomas, Non Hodgkin-L>~phomas (depending on histological subtype and clinical stage). In the literature a five year survival rnte of 35-45% is reported for squamous cell carcinomas. The causes for failure are firstly local persistence of tumour (18%) or local recurrence (37%) . The cumulative recurrence rate after one and two years is 76% and 95% respectively. Late recurrences occur in 2.5% of cases. The complication rate with combined modality therapy reaches 27% with minor complications occuring in 12% and major complications in 15% especially affecting the irradiated homolateral eye. Klinik und Poliklinik fHr Strahlentherapie der Universit~t Erlangen-NHrnberg, Universit~tsstraBe 27, D-8520 Erlangen

Tumors of the n o s e a n d p a r a n a s a i sinuses i n d u c e d by asbestos? Deitmer, Thomas

-

Radiotherapie

von

Nasen-

und

Nasennebenh~hlentumoren,

T u m o r s o f t h e n o s e a n d t h e p a r a n a s a l sinuses a r e n o t y e t a p p r o v e d as a n o c c u p a t i o n a l d i s e a s e . A s b e s t o s is k n o w n as a c a r c i n o g e n f o r p l e u r a l m e s o t h e l i o m a a n d b r o n c h i a l c a r c i n o m a in r e l a t i o n w i t h an a s b e s t o s i s of t h e lung. C o n c e r n i n g t h e a e r o d y n a m i c s a n d the m o d e of d e p o s i t i o n t h e nose m u s t be looked upon as p r o n e for an a s b e s t o s d i s e a s e , as t h e r e is a w i d e r a n g e o f p a r t i c l e size for asbestos. T h e s e m o d e s of d e p o s i t i o n a n d t h e e x p e r i m e n t s for e a r e i n o g e n i c i t y of a s b e s t o s on r e s p i r a t o r y e p i t h e l i u m a r e r e v i e w e d . T h r e e e a s e s o f t u m o r s of t h e p a r a n a s a l sinuses in r e l a t i o n w i t h a s b e s t o s a r e r e p o r t e d , f o r w h i c h w e h a d to give a m e d i c a l opinion in our d e p a r t m e n t . We w a n t to d r a w a t t e n t i o n to the possible c o n n e c t i o n b e t w e e n a s b e s t o s e x p o s u r e and m a l i g n a n t t u m o r s of t h e u p p e r r e s p i r a t o r y t r a c t . To be able to s e e t h e e x p o s u r e s o m e p r o f e s s i o n s a r e listed, f o r w h i c h t h i s is known, s u c h as a s b e s t o s m i n e r s , ship y a r d w o r k e r s , building c r a f t s m e n and brake repair workers.

U n i v e r s i t f i t M a n s t e r , Klinik und Potiklinik f a r H a l s - , N a s e n - und O h r e n h e i l k u n d e - K a r d i n a l - v o n - G a l e n - R i n g 10, D-4400 Mtlnster

Sl12

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STEREOTACTIC INTERVENTIONAL CURIE-THERAPY FOR R E O C C U R R I N G N A S O P H A R Y N G E A L T U M O R S I N V A D I N G THE S K U L L - B A S E M. MOHADJER, A. ETOU, F. M U N D I N G E R

Alpha~-Interferon in Renal Cell Carcinoma: A_~s~istic Report on 3 Responders

The primary therapy of malignant nasopharyngeal tumors provided that the d i a g n o s i s is v e r i f i e d , is the p e r c u t a n e o u s irradiation. If the t u m o r is e x t e n d i n g to the c r a n i a l and cervical region p r i m a r y s u r g e r y and additional irradiation may improve the results. Commonly neurosurgical treatment is n o t r e a s o n a b l e in c a s e of tumor extent to the m i d d l e c r a n i a l f o s s a or p a r a s e l l a r region. Complicated is the therapeutic regimen when a t u m o r r e l a p s e o c c u r s in the s k u l l b a s e d e s p i t e a p p l i c a t i o n of r a d i o t h e r a p y . B y C T - or MRI-guided stereotactic biopsy to discriminate radionecrosis and tumor recurrence in the case of tumors interstitial Curie-Therapy with Iodine-125 or Iridium-192 can be applied. The operative technique is well established and was published before. Including one case presentation, e f f i c a c y of t h i s m e t h o d is d i s c u s s e d .

(B. W e i d m a n n , F .

Migeod,W.

Hoffmann,S.

Seeber)

Metastatic renal cell carcinoma is characterized by a high resistance to b o t h single drug and combination chemotherapy, but it seems to be particularly dependant on hormonal and immunological factors. Different i n t e r f e r o n s h a v e b e e n s t u d i e d in this d i s e a s e . We report on our results in 6 patients without prior chemotherapy with metastases of various s~tes. Recombinant alphas-interferon (Intron A ~') w a s administered suDcutaneously three times weekly. ~he maximum tolerated single dose was 20x10 units. Dose limiting side effects were fever, nausea, fatigue, and thrombocytopenia. 3 p a t i e n t s h a d p r o g r e s s i v e d i s e a s e (PD) a n d 3 h a d p a r t i a l r e m i s s i o n (PR) of l u n g m e t a s t a s e s . T h e l o n g e s t d u r a t i o n of r e s p o n s e so f a r is 11 months. X-rays of the three responders are presented.

the

Abt. S t e r e o t a x i e und N w e u r o n u k l e a r m e d i z i n Neurochirurgische Universit~tskiklinik H u g s t e t t e r Str. 55, D - 7 8 0 0 F r e i b u r g i.Br.

Medizinische Klinik III, Stadtisches Krankenhaus, D-5090 Leverkusen

4/24-0 001

4/24-0 003

R E S U L T S OF A M U L T I C E N T ~ R T R I A L IN T H E T R E A T M E N T OF A D V A N C E D R E N A L C E L L C A R C I N O M A W I T H A C O M B I N A T I O N OF R E C O M B I N A N T A L P H A - 2 A - I N T E R F E R O N (IFN) AND V I N B L A S ~ I N E (VB) ~ D. Schuster-,- G. S c h n e i d e r ~ , N. Ade , M.E. H e i m I

PHASE I/II STUDY OF INTERFERON-GAMMA AND #C-DIFLUOROMETHYLORNITHINE (DFMO) FOR THE TREATMENT OF METASTATIC MALIGNANT MELANOMA,GASTROINTESTINAL CARCINOMAS AND HYPERNEPHROMA IN CONVENTIONALLY PRETREATEO PATIENTS. W. Zeller, M. Garbrecht and O,K. Hossfeld

E x p e r i m e n t a l r e s u l t s s u g g e s t synergistic activity of IFN w i t h d i f f e r e n t c y t o t o x i c a g e n t s i n c l u d i n g v i n b l a s t i n e . B o t h IFN and VB h a v e s h o w n s y n e r g i s t i c a c t i v i t y a g a i n s t renal cell c a r c i n o m a in the h u m a n s t e m cell assay. In t h i s m u l t i c e n t e r p h a s e II s t u d y p a t i e n t s (pts) w i t h h i s t o p a t h o l o g i c a l l y ' d o c u m e n t e d advanced r e n a l c e l l c a r c i n o m a w e r e ~ r e a t e d w i t h IFN ( R o f e r o n A) at a d o s e of 1 8 x i 0 - I U i.m. 3 days per w e e k and V B 0,1 m g / k g b o d y w e i g h t i.v. q 3 weeks. C o m b i n a t i o n t h e r a p y was g i v e n for 6 m o n t h s e x c e p t for pts w i t h p r o g r e s s i v e d i s e a s e . So far 3[ p t s are e v a l u a b l e for r e s p o n s e a f t e r a t r e a t m e n t p e r i o d of at last 3 m o n t h s . We obs e r v e d 6 p a r t i a l r e m i s s i o n s and 14 s t a b l e d i s e a ses. All r e s p o n s e s w e r e seen in p u l m o n a r y m e t a s t a s e s w i t h a m e d i a n r e s p o n s e d u r a t i o n of 6 m o n t h s . A d o s e r e ~ u c t i o n 4 b e c a u s e of IFN t o x i c • was n e c e s s a r y in 14 pts. M a i n side e f f e c t s w e r e f e v e r and f l u - l i k e s y m p t o m s of d i f f e r e n t i n t e n sity in 70 % d e c r e a s i n g d u r i n g the t r e a t m e n t periods. O t h e r s y m p t o m s w e r e f a t i g u e and d e c r e a s e d :mental s t a t u s in 20 %, l e u c o p e n i a and t h r o m b o c y t o p e n i a in 20 %, w e i g h t r e d u c t i o n in 30 %. One p a t i e n t had a c o m p l e t e h a i r loss. We c o n c l u d e t h a t IFN plus VB is an a c t i v e r e g i men in a d v a n c e d r e n a l cell c a r c i n o m a w i t h a 19 % r e m i s s i o n r a t e s e e n m a i n l y in p u l m o n a r y m e t a s t a ses. U p d a t e d r e s u l t s w i l l be p r e s e n t e d . I O n e o l o g y C e n t e r M a n n h e i m , Univ. of H e i d e l b e r g , D-6800 Mannheim 2 City Hospital Augsburg, D-8900 Augsburg 3 Chest Hospital Rohrbach, D-6900 Heidelberg

I t i s w e l l known from previous studies t h a t g a s t r o i n t e s t i n a l carcinomas, malignant melanoma and hypernephroma are tumors which poorly respond to conventional chemotherapy. In a Phase I / I I study in c o n v e n t i o n a l l y pret r e a t e d p a t i e n t s with these malignomas a combination o f ~ - d i f l u o r o m e t h y l o r n i t h i n e , an i r r e . v e r s i b l e enzymea c t i v a t e d i n h i b i t o r o f o r n i t h i n e deoarbo• and Interferon-gamma was given over a period o f three months. DFMO was taken p e r o r a l l y in a constant dose, the dose o f IFN-y, which was i n j e c t e d subcutaneously, was duplicated every f o u r weeks. Of s i x p a t i e n t s with hypernephroma, one presented with p a r t i a l response, i n three p a t i e n t s the disease could be s t a b i l i z e d , two p a t i e n t s showed progressive disease. Of s i x p a t i e n t s with malignant melanoma in only one case s t a b l e disease could be achieved, a l l other p a t i e n t s did not respond. In a l l f o u r p a t i e n t s with g a s t r o i n t e s t i n a l carcinoma the growth o f tumor could not be a l t e r e d by therapy. During the t r e a t ment period o f three months, n a t u r a l - k i l l e r - c e l l assays, I n t e r l e u k i n 2 assays and the determination o f IFN-y serum l e v e l s were performed every two weeks. NK-cell a c t i v i t y raised to high values in the first weeks of treatment, falling to nearly pretreatment levels in the following weeks. Significant relations between NK-cell values and tumor response could not be observed.

Abteilung Onkelogie und H~matologie, Universit~tskrankenhaus Eppendorf, M a r t i n i s t r . 52, D-2OO0 Hamburg 20

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ADOPTIVE IN~UNOTHERAPY IN P A T I E N T S W I T H G A S T R I C C A N C E R A N D R E N A L C E L L C A R C I N O M A - IN V I T R O A N D IN V I V O I N D U C T I O N OF L A K - C E L L S L. B e r g m a n n , P.S. M i t r o u , E. W e i d m a n n , A. Schmidt-Matthiesen, P. H a n k e , D. H o e l z e r

ENDOTHELIAL CELL PROLIFERATION IN HUMAN KIDNEY CARCINOMAS AND SEMINOMAS M. L6rz, G. Moog and H.M. Rabes

The adoptive immunotherapy (AI] w i t h l y m p h o k i n e a c t i v a t e d k i l l e r c e l l s (LAK) a n d i n t e r l e u k i n - 2 (Ii-2) is a n e w a p p r o a c h for c a n c e r p a t i e n t s , in w i c h a u t o l o g o u s c y t o t o x i c cells w e r e i n d u c e d by i[i-2 i n c u b a t i o n . In p a t i e n t s w i t h g a s t r i c c a n c e r a n d r e n a l c e l l c a r c i n o m a we i n v e s t i g a t e d the in v i t r o i n d u c t i o n of L A K - a c t i v i t y a n d p o s s i b l e e f f e c t s of Ii-2 on N K - a c t i v i t y of p e r i p h e r a l MNC. P a t i e n t s with gastric cabcer had a significant reduced N K - a c t i v i t y c o m p a r e d to h e a l t h y c o n t r o l s . A f t e r Ii-2 i n c u b a t i o n for 3 days the N K - a c t i v i t y to K 5 6 2 was h i g h l y r e s t o r e d . The L A K - a c t i v i t y in g a s t r i c c a n c e r p a t i e n t s w a s s i m i l a r to t h a t of c o n t r o l s . T h e m a x i m u m a c t i v i t y of L A K - a c t i v i t y c o u l d be a c h i e v e d b e t w e e n 3 - 6 d a y s of Ii-2 incub a t i o n , the o p t i m a l c o n c e n t r a t i o n of Ii-2 was b e t w e e n 250 U / m l a n d 1,000 U/ml. In 4 p t s . a n i n c r e a s e of c i r c u l a t i n g L A K - c e l l s occurred after CIVI-application of Ii-2 ( B i o g e n / B i o f e r o n , L a u p h e i m , FRG). T h e lytic a c t i v i t y w a s less t h a n t h a t of in v i t r o i n d u c e d L A K - c e I ~ obtained by leukaphereses, which were retransf u s e d f o r LAK t h e r a p y . S u r f a c e m a r k e r s t u d i e s s u g g e+s t m+a t u r e + L A K - c e l l s to be of T - c e l l o r i g i n (CD2 CD$ NKH-] ). O u r r e s u l t s p o l n t to a p o s s i b le b e n e f i t of L A K - c e l I s and Ii-2 for the t h e r a py in g a s t r i c c a n c e r p a t i e n t s .

An essential prerequisite for tumor progression is an adequate vascular supply. A potential of tumors to induce neoangiogenesis has been described, but the actual mode of endothelial cell proliferation in human tumors is largely unknown. In order to investigate endothelial proliferation we used the method of vascular perfusion of human tumors with tritiated thymidine (3H-TdR) immediately after surgical resection under simulated physiological conditions (Rabes et al., Cancer 44, 799-813, 1979; Cancer 55, 1758-1769, 1985). It was possible to determine the proliferation of endothelial cells in human kidney carcinomas and seminomas by combining the methods of 3HTdR autoradiography to evaluate DNA synthesising cells and of factor VIII-i~unocytochemistry to identify endothelial cells. In the normal parenchyma of perfused human kidneys with an adenocarcinoma endothelial cell proliferation is very low. In kidney tumors a high labeling index is found in endothelial cells of small vessels. It decreases with increasing vessel size. High labeling indices were observed in capillaries at the tumor periphery. This indicates a strong angiogenic stimulus on vessels at the border between tumor and normal parenchyma. Human seminomas show a lower rate of neovascularization. In capillaries the labeling index is small, but in venules und small venes an increased endothelial cell proliferation is observed which is higher by a factor of about 20 as compared with vessels in normal testis tissue, Each tumor has apparently a different angiogenie potential. Such differences may have important implications for the actual growth rate of a tumor and its cell loss and might be a critical determinant for tumor structure, clinical doubling time and even for therapeutic Considerations.

D i v i s i o n of H a e m a t o l o g y , D e p a r t m e n t of I n t e r n a l M e d i c i n e , J.W. G o e t h e U n i v e r s i t y , F r a n k f u r t , FRG

Pathologisches Institut der Universit~t MOnchen, Germany

4/24-0 005

4/25-0 001

Oncodevelopmental aspects of renal c e l l sarcinmma J-E.Scherberich,J,Karich,C.Albers,G.Wolf,P.Fischer, W.Schoeppe

PROTEIN

In order to elucidate oncodevelopmental aspects of renal adenocarcinoma (CA), expression of CA epitopes in common with those in nSrmal kidney (K) and fetal tissue were studied. BALB/c mice were challenged with crude membrane fractions isolated from CA ( clear cell type), K or placenta trophoblast and hybridoma secreting monoclonal antibodies (MAB] were obtained according to standard Procedures. A panel of MAB- secreting clonotypes were established and selected M A ~ w e r e used in the present study. Three major types of MIB were found capable of recognizing : I. antigens of CA membranes, 2. antigens localized in the cytoplasma, and 3.,interstitial epitopes including those of capillary endothelia. Part of MAB reacting with CA-membrane antigens also did with those of proximal tubule origin. However, tumor reacting MAB which were positive on placenta trophoblast membranes gave strong reactions w i t h epitopes of the distal tubule only. The distal tubule epitope IHI2 w a s restricted to very few segments ( also found in fetal kidney), and was not expressed by the liver, stomach, ileum, colon,pancreas,smooth muscle,lymphnodes. Binding of MAB ( I H 12) to CA depended on the grading of t h e tumor ( 1-3 according to WHO classification). A progressive loss in the synthesis of the IHI2 epitope was found between grading 2-3, whilst grading 1 parallel expression of IHI2 in all cases (n = 15) including metastases eatched in local lYmphodes. These and additional data evidenced that CA exhibits a distinct pattern of antigenic microheterogeneity, shares epitopes in common with K, fetal kidney and htunan placenta, looses antigenic determinants according to CA differentiation and, finally, may also develop from transformed cell clusters of K distal tubule origin, ZIM, Univ.Hosp., Theod.Stern Kai 7, D-6 Frankfurt/M.

Supported by grants from Wilhelm Sander-Stiftung.

ISOLATION AND PURIFICATION OF HUMANPROLACTIN RECEPTOR G. P. Breitbach, S. Kaul (a. G.), J. Knodel (a. G.), G. Bastert Estrogen- and progesterone receptors are now detectable by monoclonal antibodies (MAbs) in immunohisto- or -cytochemical procedures. In analogy, our aim has been to isolate and purify prolactin receptor protein (hPRLR) from human tissues for future immunisation experiments with Balb/cmice in order to produce corresponding MAbs against the prolactin receptor antigen. Our sources have been T47D cells, a permanent human breast cancer cell l i n e , and human placental tissue, respectively. Original tissues have been homogenizedby pottering, dissolved in CHAPSand a crude membranefraction was received by ultracentrifugation. As growth hormone (hGH) is well known to show the same lactogenic potency as prolactin (PRL), hPRLR is not able to discriminate these hormones. Therefore hGH was coupled to agarose (Affi-Gel 10, Bio Rad Laboratories), and soluble hPRLR was purified by a f f i n i t y chromotography technique. The receptor protein was eluted by use of 5M MgCl2. For analytical proof, crude membranefractions and purified hPRLR were both incubated with 125J-hGH. The labelled hPRLR was analyzed by FPLC g e l f i l t r a t i o n at room temperature. Two hormone binding fractions were separated in each experiment at approximately 1000 kD and the other one at 60 kD. Similarly, polyacrylamide gel electrophoresis of both, the crude membranefraction and the purified hPRLR, produced bands in the high molecular range (app. 180kD), and several ones in the range of 50-70 and 40-45 kD, the last ones representing probably the smalles subunits of the receptor complex. In summary, prolactin receptor protein can be pur i f i e d by hGH-affinity-chromotography from T47D cells and human placental tissue. The purified receptor w i l l be used for the creation of monoclonal antibodies. Universit~ts-Frauenklinik, D-6650 Homburg-Saar

Sl14 4/25-0 002

4/25-0 004

EGF-RECEPTORS AND STEROIDRECEPTORS IN ENDOMETRIAL CANCER W. K l e i n e , Th. Rauknecht, K. Kaufmehl, H, Geyer, A. P f l e i d e r e r Estrogen (ER)- and Progesterone Receptors (PR)

BIOCHEMICAL AND SEMIQUANTITATIVE IMMUNOHISTOCHEMICAL MEASUREMENTOF HORMONERECEPTORSCONTENT IN BREASTCANCERS: THE CORRELATIONWITH TUMORSTAGE AND TUMORGRADE, PROLIFERATION RATE AND DNA-CONTENT: K.Neumann, J.RUschoff, A.Horstmann, L.Zwiorek, H.Kalbfleisch In our study we examined the well known connections between the content of hormone receptors, tumor stage, tumor grade and p r o l i f e r a t i o n rate. Additionally we correlated these findings with the DNA content of the tumor ce]Is.We analysed 95 breast cancer specimens (78 invasive ductal,4 predominant intraductal,6 invasive lobar,4 medullary,2 tubu1~r,1 mucinous) by biochemical an immunohistochemical methods,using the ER-ICA (Abott),the ERD5 (Amersham) antibodies and an antiprogesterone receptor antibody (Dianova).Furthermore,we determined the prol i f e r a t i o n rate (KI 67) and tumor stage and tumor grade. With the aid of single ceil cytophotometry the grade of malignancy (B~cking),the DNA index (Barlogie) and the d i ploid deviation index (Fossa)were a d d i t i o n a l l y measured. Our study confirmed the widely accepted correlations between the biochemical measu:'ed and the immunohistochemic a l l y assessed content of estrogen receptors.The correspondence of 90% for the ER-ICA antibody was considerably higher than 65% for the ER-D5 antibody. Further s i g n i f i cant correlations were also found between the estrogen receptors content of invasiv ductal carcinomas and the tumor stage,the tumor grade, the p r o l i f e r a t i o n rate and the diploid deviation index.Moreover a striking dependence was observed between the biochemically measured estrogen receptors content and the size and transport time of the specimens.Tumor tissues from frozen sections were more often receptor positive than those from mastectomy specimens,which,in our opinion i s t probably due to a slow and insufficient cooling of the large mastectomy specimens.These differences were not observed when using immunohistochemical methods. Zentrum fur Pathologie der Philipps Universit~t KlinLkum Lahnberge, D-3550 Marburg

were determined in endometrial cancer tissue of 240 patients by dsxtran coated charcoal method (DCC). Tissue was receptor positive at 50 fml/mg protein or more, In addition in 60 cases EGF-receptor s (EGF-R) were determined by biochemical method. These results were correlated to anamnestical and clinical data and clinical course as: age, stage, histological type and differentiati0R as well as survival time according to f0110w up up to eight years. 68 percent of endometrial cancer were ER and/or PR positive. Related to anamnestical data (age, menarchs, menopause) no difference was seen between receptorpositive and -negative patients. There was a positive correlation to other prognostic factors in endometrial cancer as stage, grade of histological differentiation and myometrial invasion, Multivariance analysis demonstrated the PR as most important prognostic factor in endometrial cancer. 80 cases with EGF-R analysis in addition showed an inverse correlation: most of the steroidreceptor positive cases were EGF-R-negative and vice versa,.According to this first results endometrial cancer with high EGF-R-concentration seems to be correlated with poor prognosis.

Universitw D 7800 Freiburg

Hugstetterstr.55

4/25-0 003 VISUAL AND CYTOMETRIC RESULTS CONCERNING THE HORMONERECEPTOR STATUS AS DETERMINED BY THE DEXTRANE COATED CHARCOAL METHODAND BY MONOCLONALANTIBODIES U.Schenck, G.Burger, U.JUtting, U.B.Schenck, W.Eiermann High resolution image analysis (HRIA) was applied to 69 Feulgen stained biopsy smears of primary breast carcinomas. The Estrogen receptor (ER) was determined by the Dextran Coated Charcoal (DCC) method and with mABs by ER Enzyme Immuno Assay (ER-EIA) and by the ER Immuno Cytochemical Assay (ER-ICA). The progesteron receptor (PR) content was measured by the DCC method. We were able to show that by means of NRIA of I00 randomly selected cell nuclei per case a c l a s s i f i c a t i o n of the cases with respect to their HRS and to their visual grade from May-GrUnwald-Giemsa (Pappenheim) stained smears was possible. Best classification results were obtained for the cases with concordant cytosolic receptor determination by DCC and ER-EIA. Our data show clearly a closer relationship of cytomorphology with ER evaluated by EIA than with ER(DCC) and PR(DCC). The ER-EIA status alone correlated better with morphology than the HRS evaluated by DCC method (receptor positive = ER-DCC and/or PR-DCC pos.). Classification rates concerning ER-DCC and PR-DCC were similar. In cases with disaggreeing results from ER-DCC and ER-[IA the morphological classifications were predominantly in correspondence with the ER-EIA results indicating that the DCC method for ER evaluation is l i k e l y to be the less accurate one. HRIA resolution image analysis provides a tool for the intercomparison of hormone receptor assays and for the prediction of a functional cellular state closely correlated with the HRS. * Supported by the DFG (SFB 324) Inst.fUr Klinische Zytologie der Techn. Uni.MUnchen, Prinzregentenplatz 14, D-8000 MUnchen 80 Inst. fur Strahlenschutz der GSF, MUnchen-Neuherberg Uni.Frauenklinik im Klinikum Groghadern, MUnchen

4/25-0 005 EPIDERMAL G R O W T H F A C T O R R E C E P T O R S T A T U S AND P ~ S I S IN BREAST CANCER

E. Giese, W, Kleine, T. Bauknecht, A. Pfleiderer The prognosis of patients with primary breast carcinomas is influenced by different prognostic factors which include lymph node status, tumor size, steroid hormone receptor status and the amplification of the Her-2/neu oncogene. Recently, Sainsbury et al reported about expression of EGF-R as a predictor of poor prognosis in breast carcinomas. 19/59 (33%) b r e a s t c a r c i n o m a s w e r e E G F - R + w i t h binding capacities ~ o m 1-30fmol/mg by the two point assay with 0,4ng 1 J-EGF. Breast c a r c i n o m a s w i t h the tumor stage II (tumor diameter 2-5cm) were used to correlate the EGF-R expression w i t h different prognostic criterias such as lymph node status, steroid hormone receptor status and differentiation. There is a higher proportion of poorly differentiated tumors, with positive lymph nodes and capsula involvement in the EGF-R + group compared to the EGFR- group or to all patients respectivly~ The reported inverse rel~tion w i t h E R status but also with PR status could again be demonstrated. If one analyses the e x p r e s s i o n of EGF-R, steroid h o r m o n e receptor and lymph node status we d i s c o v e r e d lymph node capsula i n v o l v e m e n t in: 1/14 ER + EGF-R-, 0/2 EREGF-R- and 3/7 ER+ EGF-R +, 5/9 ER- EGF-R +. These results d e m o n s t r a t e a s i m i l a r correlation between the EGF-R expression and the p a r a m e t e r of poor prognosis as have been reported by the study of Sainsbury group. We hope to define the EGF-R status as an important prognostic factor in breast carcinomas by an increased case n u m b e r resulting in a treatment study of breast c a r c i n o m a s which include the EGF-R status. Universit~tsfrauenklinik 7800 Freiburg, Hugstetterstrasse 55

$115 4/25-0 006

4/26-G 002

THE I M M U N O H I S T O C H E M I C A L EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF)-RECEPTORS IN VARIOUS G Y N E C O L O G I C A L TUMORS F.M. Wittmsack~ D. SchwSrer~ O. Wintzer, T. Bsuknecht~ and A. Pfleiderer

L I F E - S I T U A T i O N OF ADULT BONE HARROW T R A N S P L A N T RECIPIENTS WtH6rner~? B-Seen ~ , G. Ehninger ~ a n d K. Foerster ~

Monoclenal antibodies to the extracellular domain of the EGF-receptor were used for immunohistoehemiesl staining. Cryoseetions of various g y n e c o l o g i c a l tumors were stained using immunoperoxidaae and the avidin-biotin method. All 15 squamous cell carcinomas of the cervix, vagina, and vulva showed strong staining for EGf-receptors. On the other hand~ we ~ere not able to identify E G F - r e c e p t o r s in the lO breast tumors analyzed so far. Of 15 endometrial carcinemas and lO ovarian tumors approximately 50% revealed moderate staining. As anticipated from the polyclonsl nature of tumors, ceils with im -~ m u n o h i s t o c h e m i c a l l y identifiable EGF-receptors and those without coexist in EGF-receptor positive tumors. On the average, squamous ceil carcinomas composed of large cells stained he s higher percentage (appr. 90~) than these of small cells (appr. 10%). The percentage of positive cells in endometrisl carcinomas was higher than in ovarian earcinomas~ 80% and 25%, respectively. There was good correlation between the immuoohistochen~al detection of EGF-receptors and the amount of E G F - r e c e p t o r s quantitated by biochemical methods (see T. Baukneeht et al.~ Cancer Res. ~6, 2614, 1986)~ although immunohistochemistry appeared to be somewhat leas sensitive
25 (=96%) out of 26 patients s u r v i v i n g in complete remission (all t r a n s p l a n t e d before 10/85) s r t i c i p a t e d in a r e t r o s p e c t i v e analysis more had 18 months a f t e r BMT. The aim of the study was to e v a l u a t e psychosocial consequences, coping strategies, a n d personal e x p e r i e n c e s with the disease and the therapeutic interventions. Our analysis included s e m i s t r u c t u r e d interviews, p s y c h o m e t r i c and p r o j e c t i v e tests (such as the Freiburg P e r s o n a l i t y Inventory or FPI-R, WAIS, Rorschach test) as well as physical findings. The 25 patients (7women, 18men) p a r t i c i p a t i n g in the study l8 to S9 months after BMT (median, 33months) were 18 to 48 years old (mean, 25yrs) at the time of examination. All donors were H L A - i d e n t i c a l siblings (aged iS-5Oyrs; mean, 25yrs), 12 d o n c r - r e c x p i e n t pairs were of same sex (men only). The underlying diseases the p a t i e n t s were t r a n s p l a n t e d for were: 8 SAAs (severe aplastic anemia) and 17 leukemias. 2 out of the 3 women t r a n s p l a n t e d for SAA became pregnant and d e l i v e r e d healthy babies.

F r a u e n k l i n i k and Immunologisehes (O.W.) der Universit~t Freiburg, Str. 55, D-7800 Freiburg

P s y c h o s o s i a l c o n s e q u e n c e s of adult bone marrow transplant recipient long-term survivors have not been e x t e n s i v e l y s t u d i e d up to now.

~

Our findings indicate that from a medical point of view about 75% of the long-term s u r v i v o r s are doing well (Karnofsky-Index more than 9St), p s y c h o s o c i a l also most of the patients are content with their life after BMT, but reported different changes in their p s y c h o l o g i c a l state. ~Universit~ts-Nervenklinik 74-T~bingen, FaG

and SHed.

Klinik

Instihut Hugstetter

4/26.G 001

4/26-G 003

PSYCrKILOGICAL STRESS ~ BONE MAP~R
RECOMBINANT H U M A N G R A N U L O C Y T E - M A C R O P H A G E COLONY STIMULATING FACTOR (rh-GM-CSF) FOR HEMATOLOGICAL RECONSTITUTION AFTER BONE M A R R O W TRANSPLANTATION: FIRST CLINICAL RESULTS H. Link, H. Kirchner, M. Freund, M. 8toll, J. 8eldel, H, Sehmid, R.E. Schmidt, P. Bucsky, G. Schulz', H. Riehm, H_~ Poliwoda, K. Welts .....

Severe stress may result in breakdown of psychological functioning being classified as Adjustment Disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III). Such stress reactions are accompanied by disorders of affect and so the prevalence of mood disturbance under I94T is an indicator of the stress impact of the procedure. Moreover, it is a matter of high clinical relevance. In t_he present study 30 consecutive ~MT-patients with Acute Leukemia or CML were followed up during the transtransplantation period. Patients' self-ratings of mood were taken every fifth day by means of an adjective check list and the ntmlber of patients with high scores of the depression or anxiety scales was recorded. Furthermore prescriptions of psychotropic drugs were determined from the hospital records. Neither patients nor physicians were aware of the purpose of the study. Five of the 30 patients had elevated scores on the depression or/and anxiety scales at least at one measure. Four of these received antidepressant or antipsychotic medication and one further patient received antip~izchotic drugs after the sudden onset of a agitated psychosis, bet then was unable to give a mood rating, qhus, considering both criteria, the relative frequency of patients with mood disturbance of clinical relevance was 20% (95%-confidence limits: 7.7 and 38.6%). ( ~ i s o n s of patients with and without mood disturbance with regard to personality traits and treatment related variables revealed mood disturbance being closely related to medical complications. I~nstitut f{Jr Medizinische Psychologie, Universit~[tsklinikum Essen, Hufe!andstr. 55, D-4300 Essen I

The issue of this ongoing study is to assess the effects of rh-GM-CSF on hematological r e g e n e r a t i o n a f t e r a u t o l o gous and a l l oge ne i c BMT. Rh-GM-CSF was a d m i n i s t e r e d d a i l y by c ont i nuous 24 hrs i nfus i on from day 0 - 2 8 p o s t BMT a t a dose of 500 pg/m' u n t i l n e u t r o p h i l c o u n t s r e a c h e d 1000/pl, t h e n reduced by ~ a t 3 da y i n t e r v a l s to a f i n a l dose of 80 pg/m~, provided n e u t r o p h i l s remained >1000/pl. To d a t e s i x p t s a re enrolled i n t h i s s t u d y . 8 p t s w i t h neurobtastoma, 1 with Hodgkin's d i s e a s e , I w ith ALL r e c e i v e d autologous and 1 w i t h ALL a l l oge ne i c bone marrow a f t e r c o n v e n t i o n a l conditioning. As of 11/11/87 d a t a of t h e f i r s t 4 p a t i e n t s a re e v a l u a b l e . G ra nul ocy te c o u n t s re a c he d >500/pl a t da y 7, 10, 11, 12 and >lO00/pl a t da y 8, 12, 18, 16 r e s p e c t i v e l y . The p e r c e n t a g e of bands, immature myeloid cells, monocytes an d e o s l n o p h i l s was i n c r e a s e d i n t h e p e r i p h e r a l blood. In one p a t i e n t t e s t e d so far, chemotaxis of g r a n u l o c y t e s as a s s e s s e d by l e u k o t r i e n e B4 and FMLP c o n t i n u o u s l y i m proved, w he re a s b a c t e r i c i d a l a c t i v i t y and p h a g o c y t o s i s re ma i ne d u n a f f e c t e d . There was no t o x i c i t y c l e a r l y due to t he t r e a t m e n t with rh-GM-CSF. Our f i r s t r e s u l t s show, t h a t rh-GM-CSF e n h a n c e s r e g e n e r a t i o n of m y e l s p o i e s i s a f t e r bone marrow t r a n s p l a n t a t i o m I n t e r d i s c i p l i n a r y Unit fSr Bone Marrow T r a n s p l a n t a t i o n , Medizinische Hochschule, K ons t a nt y Gutschowstr. 8, D-8000 Hannover 61; "Behringwerke AG, D-8550 Marburg; F e de ra l Republic of Germany

$116 4/27-M 003

4/27-M001 DIFFERENT TYPES OF MANDIBULAR BONE INVASION BY TUMORS OF THE ORAL CAVITY, DO THE RESULTS OFFER A NEW CONCEPT OF THERAPY? F. Hoppe and K. Donath 30 tumors o f the o r a l c a v i t y w i t h tumorous i n filtration o f t h e mandibula were i n v e s t i g a t e d on u n d e c a l c i f i e d t i s s u e h ~ s t o l o g i c a l l y , We found t h r e e types o f tumor i n v a s i o n : I. M o s t l y (16 ou~ o f 30 cases) s u p e r f i c i a l l y eroded a l v e o l a r p r o cem w i t h s o l i d tumor masses in the s o f t t i s s u e . 2. Bone marrow i n f i l t r a t i o n by small tumor s t r a n d s or i s l a n d s w i t h less bone d e s t r u c t i o n o f the a l v e o l a r p r o c e s s . 3. Basal o r l a t e r a l tumor i n f i l t r a t i o n o f the mandibula w i t h e a r l y bone marrow i n f i l t r a t i o n . Our r e s u l t s i n d i c a t e t h a t the t h e r a p y o f tumor invaded mandibulas should be t r e a t e d in d i f f e r e n t ways.

I n s t i t u t f u r Pathologie der U n i v e r s i t ~ t WUrzburg, Josef- Schneider - s t r . 2 8700 WUrzburg und I n s t i t u f Hamburg

f u r Pathologie der U n i v e r s i t ~ t

4/27-IVl 002 ESTHESIONEUROEPZTHELIOMA: H I - - S I S CLUES M. Vollrath, M. Altmannsberger

ADVANCESOF DIAGNOSTICULTRASOUNDIN PREOPERATIVE CHEMOTHERAPYAND RADIOTHERAPYCONTROL P.Reimer, H.Milbradt, M.Prokop, Ph.Hendrickx

Real-time ultrasonography with high frequency transducers (7.5 MHz) is a technological advance in diagnostic imaging,. Preoperative staging of patients with tumours of the o r a l c a v i t y , especially tongue tumours, can be performed by ultrasonography. Tumour size, relation to midline and degree of tumourous lymph node i n f i l tration are basic informations for treatment planning. In our c l i n i c preoperative chemotherapy(cisplatin, 5 d, 12h pre XRT, 20mg i . v . ) and radiotherapy (32 GY, a 2 Gy in 4 weeks) is normally performed before operation. We used ultrasound as a method of preoperative assessment and investigated 20 patients with head and neck ttmmurs before preoperative therapy and after 5,10 and 15 radiotherapies. Our g~al was to detect and eliminate non-responders. We utilized a special examination sheet controlling size and structure of marked lymph nodes. An adaequate response occures with a significant decrease in size of the defined lymph nodes. In 6 patients they showedno change in size and structure. The necessary consequence for all non-respondersshould be immediatetumour resection in combinationwith netk-dissection. The advantage of diagnostic ultrasound comparedwith palpation is ~ the v i s i b i l i t y of non-palpable lymph nodes. Lymph nodes of the neck can beexamined with a time saving method in relation to CT whereas exact cFiterias of benign and malign lymph nodes do not exist in both methods. Diagnostische Radiologie I Medizinische Hochschule Hannover Konstanty-Gutschow-Str. 8 D-3000 Hannover 61

4/27-M 004 AND DIAGNOSTIC

The correct histological diagnosis of esthesioneuroepi~helioma (ENE) - a rare neoplasmaof the nasal cavity - alnDst always causes extreme difficulties and seems to be narly s on the ligth microscopical level alone. In addition, its histogenetic origin is still a matter of controversy. Recently we were able to induce ENE in rats experimentelly, showing anundifferentiated sa~all round cell tumor with scattered rosethe formations. Ultrastructurally tumor cells contained dense cored vesicles and centrioles. Irsmanohistological investigations revealed thah these tumor c e l l s ~ r e negative when tested with antibodies against all types of intermediate filarcerfc proteins (Keratin, Vimentin, Desmin, Neurofilaments and C#AP). Five human ~ showed an identical ligth- and elektronmicroscopical picture up to the cytoskeletae level, likewise lacking any kind of intermediate filaments. S ~ i l a r investigations of olfactory epi~helium showed that its l i ~ b a s a l cell w~re negative against interffediate filaments, indicating - beside other ultrastructural findings - that these cells are very likely r o b e the stem cell of ~ E . Thus the negative ~ o h i s t o l e g i c a l staining with intemmediate filar~=ntantibidies seems to be t_he only diagnostic clue for establishing a correct histopat/lological diagnosis on the ligth microscopical level. M. Vollrath, HNO-KlinikderMedizinischen Hochschule Hannover, Konstanty-Gutschow-Str. 8, D 3000 Hannover 61 M. Alt/na~/~sberg~r, Pathol. Ir~tihut Universit~t GieBen

TUMOURSURGERYIN THE OCCIPITOCERVICALPASSAGE 3. Harms, R. Schmelzle affaiR'; Baum Rather frequently the occipitoeervical passage ist the seat of tumours which often cannot be proved for a long time. Mostly first complaints are neck-oeciput pains which are interpreted as vertebrally caused or as an occipital neuralgia. In addition to an exhaustive conventional radiological examination and the CT, an early diagnosis is possible by the computerbased myelographyr and~ recently~ the NMR. Neurological dysfunctions often occur relatively late. The operative access is difficult. The transoral access mentioned by Fang and 0ng 1956 only allows a limited survey. The access suggested by Harms and Schmelzle 198% with resection of the bony palate for processes in the base of the skull - CI/C2 area, offers a more comprehensive survey. By this means extensive tumour resection and stabilization is possible. Difficulties often arise from dorsal and lateral parts of the tumours, which may require to lay open the vertebral artery and involve the danger of instability. This procedure allows both an extensively radical operation and a good stabilization. Hence there is no reason for therapeutic (surgical) ~ihilism concerning tumours in the occipitocervical

passage. Examples for diagnostic and surgical proceedings are given. Rehabilitationskrankenhaus 0-7516 Karlsbad-LangensteLnbach

Sll7

4/27-M005

4/27-M 008

RESULTS IN TREATMENT OF CARCINOMAS OF THE E X TERNAL A U D I T O R Y CANAL. H,3. Feldmann, N. S a u e r w e i n , M, M o l l s , H. S a c k

Effects of combination chemotherapy with cisp l a t i n u m and b l e o m y c i n o n a d v a n c e d s q u a m o u s cell carcinoma of the oral cavity and orop h a r y n x : an p a t h o h i s t o l o g i c e x a m i n a t i o n o n serial sections R. B e t t i n g e r , A, K l i m a

Between 1973 and 1 9 8 6 12 p a t i e n t s w i t h c a r c i nomas of the external auditory canal were t r e a t e d w i t h c o m b i n e d t r e a t m e n t of s u r g e r y add radiotherapy as well as r a d i o t h e r a p y alone. The o v e r a l l 5 - y e a r a c t u a r i a l s u r v i v a l r a t e w a s &gz. Two patients with facial nerve involvem e n t s u r v i v e d o n l y one y e a r a f t e r i n i t i a l treatment. Irrespective of the f i n a l o u t c o m e 5 patients o b t a i n e d pain r e l i e f a f t e r r a d i o t h e rapy alone. A n a l y z i n g our r e s u l t s in d e t a i l the f o l l o w i n g c o n c l u s i o n s can be drawn: In e a r l y t u m o r s w i t h o u t involv'ement of b o n e or cartilage surgery is an e f f e c t i v e t r e a t m e n t ~, H o w e v e r , in t h e s e c a s e s r a d i o t h e r a p y a l o n e can be performed successfully. In m o r e a d v a n c e d tumors the c o m b i n a t i o n of s u r g e r y and r a d i o therapy is the b e s t t r e a t m e n t m o d a l i t y . P o s t operative irradiation improves local contro~ in patients with r e s e c t a b l e d i s e a s e a n d and can be a c c o m p l i s h e d by m e a n s of a pair of &5 wedged portals. A t u m o r d o s e of 50 Gy has to be delivered homogenously tO e x t e r n a l ear, temporal bone and adjacent structures. In case of m a c r o s c o p i c r e s i d u a l tumor, a f t e r surgery the tumor dose must beincreased to 70 Gy, S i n g l e d o s e s of ~.8 to 2 . 0 Gy are f a v o u r able to a v o i d o s t e o r a d i o n e c r o s i s or n e c r o s i s of c a r t i l a g e , Radiologisches Zentrum, UDiversitw D-4300 Essen I

45 p a t i e n t s w i t h a d v a n c e d s q u a m o u s c e l l c a r c i n o m a of the o r o p h a r y n x a n d o r a l c a v i t y w e r e treated with a combination of bleomycin and cis-platinum. A f t e r s u r g e r y h i s t o l o g i c a l s e r i a l s e c t i o n s of r e s e c t i o n s p e c i m e n s w e r e e x a m i n e d . In n o c a s e the tumor tissues showed a complete response. A f t e r i n d u c t i o n c h e m o t h e r a p y 36 p a t i e n t s h a d histologically a partial response-shrinkage m o r e t h a n 50%. In t h e s e c a s e s h i s t o l o g i c a l e v a l u a t i o n r e v e a l e d tumorareas with pseudocysts containing on one s i d e n e c r o t i c m a t e r i a l a n d o n the o t h e r s h o w e d keratinization. A l t h o u g h in 9 o a s e s t h e r e w a s a c o m p l e t e clin. t u m o r r e m i s s i o n p o s t u l a t e d , in the h i s t o l o g i c a l s e r i a l s e c t i o n s of t h e r e s e c t i o n s p e c i m e n s in all cases tumor was found under regrown epithelium. 9 patients had histologically a minor r e s p o n s e - s h r i n k a g e u n d e r 50% w i t h o n l y v e r y little necrotic areas. ZHNO, U n i v e r s i t ~ t s k l i n i k u m , D - 6 0 0 0 F r a n k f u r t / M a i n 70

Theodor

Stern Kai 7

4/27-M 006

4/27-M 009

COMBINED MODALITYTHERAPYFOR ADVANCEDSTAGE I I - I V HEAD AND NECKCANCEREMPLOYINGSIMULTANEOUSCHEMOTHERAPYWITH VINDESINE (CT), RADIOTHERAPY(RT) ANDs,SURGERY(S) J. W~hrisch, P. Stern, N. Niederle, W. Alberti, J. Heer-

ANTIONCOGRAM-0RIENTED CHEMOTHERAPY CAN MARKEDLY PROLONG THE SURVIVAL OF PATIENTS WITH ORAL CAVITY CARCINOMAS H.-R.Me~lmann t E.Schlenk and H.Kindermann ....

mann

The aim of this study was to determine the value of adjuvant chemotherapy given simultaneously to radical RT. Combined m~dality therapy employing CT, RT and S was used in patients (pts) with locally advanced previous untreated head and neck cancer (stage IT-IV). Between July 1986 and August 1987 32 pts (27 males, 5 females), median age 58 yrs (range 32-70), have been entered onto study. These pts were classified according to stage: IT - 4, I l l - 17 and IV - 11 pts and according to site: nasopharynx - 3, oropharynx - 16, hypopharynx - 5, larynx - 5 and oral cavity - 3 pts. CT consisted of Vindesine 1,5 mg iv, day 1-5 (n = 18) or day I-5 and 29-33.(n = 14). RT was performed with Co60 using parallel opposing fields and with electrons to treat neck disease. The total dose was 70 Gy in 18 pts with CT + RT alone and in 6 pts with RT + CT + S. Forty Gy + CT was delivered in 8 pts followed by complete resection. Response were the following: complete - 24 (75 %), partial 7 (22 %) and progresive disease in I pL The main side effects were~ WB~ < 1000 - I , resulting in septicaemia, and < 2000/mm pt, severe mucositis - 7 (22 %) and polyneuropathy - 3 (g %). Five pts died due to local recurrence 3 to 10 mos after treatment. Twenty-seven pts are alive with NED (24) or with disease (3). In conclusion, the favorable response rates at low side effects should be confirmed in a prospective randomized study in pts with locally advanced head an neck cancer.

Klinik fur Strahlentherapie Alfried Krupp Krankenhaus Alfried-Krupp-Str. 21 D-4300 Essen 1

Squamous cell carcinomas of the oral cavity can be grown to form tumor clones in a double layer soft agar system. The resulting individual in vitro tumor model is suitable for rout i n e e x a m i n a t i o n o f the d i f f e r e n t i a t e d effect i v e n e s s o f e y t o s t a t i c s , w h i c h is c a l l e d a n t i o n c o g r a m (AOG). I n a r e t r o s p e c t i v e m a t c h e d p a i r s a n a l y s i s w e i n v e s t i g a t e d the i n f l u e n c e of an AOG-based selection of cytostatics on the s u r v i v a l t i m e o f p a t i e n t s w i t h o r a l c a v i ty c a r c i n o m a s t r e a t e d b y c h e m o t h e r a p y . T h e 22 p a t i e n t s o f t h i s s t u d y h a d , i n p a i r s ~ an identical distribution of risk factors acc o r d i n g to the t h e r a p y d e p e n d e n t p r o g n o s i s i n d e x (TPI) o f t h e D O S A K ( P l a t z et a l . , J . M a x . F c , Surg. 11,3,1983) and moreover showed concurrence i n t u m o r l o c a l i z a t i o n ~ h i s t o l o g i c a l d i f f e rentiation, general condition and pretreatment. The difference in each of the pairs was that one patient had received a drug combination that did not contain any substance effective i n v i t r o , w h e r e a s the o t h e r one h a d h a d a r e g i m e n i n c l u d i n g at l e a s t o n e d r u g a c t i v e i n the AOG. The retrospective course control s h o w e d t h a t 5 o f 1~ p a t i e n t s w i t h A O G - c o n f o r m i n g c h e m o t h e r a p y w e r e s t i l l a l i v e a f t e r 36 m o n t h . O n the o t h e r h a n d a l l b u t I p a t i e n t w i t h AOG-contrary treatment, in spite of the identical risk factor co~tellation, had died within 12 m o n t h . Klinik fGr Kieferchirurgie und Plastische Gesichtschirurgie, Klinikum Steglitz, FU Berlin, Hindenburgdamm 30, D - I O 0 0 B e r l i n 45

S118 4/27-M 010

4/27-M012

Clinical Experience With Pirarubicin In The Treatment Of Patients With Pretreated Head And Neck Cancer M. Schroeder, H. Purea and M. Westerhausen

NEW PROCEDURESIN PAIN THERAPYFOR INOPERABLE CARCINOMAS OF THE HEAD AND NECK AREA A. Bremerich, W. W i e g e l V. Tronnier and Th. Thein

Pirarubicin (4-O-Tetrahydropyranyl Ooxorubicin) is a new anthracycline analog with a s i m i ] i a r antitumor a c t i v i t y as Adriamycin showing less c a r d i o t o x i c i t y and alopecia. From Jan. 85 to Oct. 87 a c l i n i c a l p i l o t stuiy was done. 23 pts with advanced head and neck cancer were p a l l i a t i v e l y treated with Pirarubicin. There were 19 males and 4 females aged 34-78 years. Performance status 30-90 %. For a l l pts previous treatment included surgery, local i r r a d i a t i o n and a Cis-platinum containing chemotherapy regimen without anthracyclines. At the beginning of t h i s t r i a l a l l pts had progressive disease. The dosage of Pirarubicin was 70 mg/m i . v . as bolus every three weeks up to a further tumor progress. The t o x i c i t y of this schedule was evaluable for a l l 23 pts who underwent a total of 58 cycles. Anemia WBC Platelets Nausea/Vomiting Alopecia Cardiotoxicity

WHO Grade I 14/58 10/58 1/58 6/58 3/58 0/58

II ]3/58 18/58 2/58 17/58 1/58 0/58

III 6/58 17/58 1/58 2/58 2/58 0/58

IV 2/58 2/58 0/58 0/58 0/58 0/58

Remissionrate (evaiuable 16/23, who received two or more cycles) CR 2 (13 %);

PR 5 (31%);

NC 6 (37 %);

PD 3 (19 %)

Duration of CR: 5 mos+, 6 mos+ As conclusion: Pirarubicin was well tolerated, showed minimal side effects and could be given to outpatients. Further studies should be done to evaluate this new promising substance. l l . M e d . K l i n i k , St. Johannes-Hospital, An der Abtei 7 - ] I , D-4100 Duisburg 11

It was the aim of this study to develop simple, effective end secure methods in the treatment of chronic pain due to carcinomas or to conditions after tumor resections of the msxillo-fscial end neck ares, Since ~985 20 patients were treated by the following 2 methods in an interdisciplinary oral and maxillo-facial ardneurosurgical pain ambulance: i. The chemoneurolysis with pure glycerol nearby the foramina ovale and rotundum for the second and the third branch of the trigenimal nerve~ 2~ The extraforminel chemorhizolysis with 6 % phenol in glycerin for the second up to the forth cervical root~ A cessation of pazn was achieved in 3g of 20 patients. Analgetics could be abandoned or reduced drastically. Freedom of pain could be achieved up to the patients' s• - s time intervall reachin 9 from several days up to twelve months. Severe complications have not been recogoised. Therefore, effective, of chronic especially and with a

we recommend the CNL and CRL as a simple, secure and riskless method in the treatment malignant pain of the head and neck area for patients in a reduced general contition short life expectancy.

Universit~tsklinik for Zahn-, Mund- und Kieferheilkunde Abteilung for Mund-, Kiefer- und Gesichtschirurgie im Bundeswehrkrankenhaos Ulm Oberer Eselsberg 40 D-7900 Ulm

4/27-M Oll

4/27.M 013

PHASE I I TRIAL WITH CARBOPLATIN/SFU IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCEDSQUAMOUSCELL CARCINOMA OF THE HEAD AND NECK M. Schr~der, P. Volling, W. Achterrath, W. Rauschning, E. Stennert, G. Nagel

I ~ P R O V ~ f OF ~OPHAGEAL SPEECH ~ LARYNGECIDMIZEDFAT~TS ~SDIAN MfOIDMf OF ~ E M. C~N~TRICTORPR~RYNG~ INFF/~ZOR F. ~ e , G. Bullinger,, L.E. Cste~ald~, U. Plener, E.J. B < a ~ d t

39 previously untreated patients (pts) with advanced squamous c e l l carcinoma of the head and neck were admitted into a disease oriented phase I I study with Carbop l a t i n 300 mg/m~ i v day I and 5Fu I g/m~ iv over 24 hours daily on days I-5 every 3-4 weeks (CT), All pts received at least one course of CT and are evaluable for response and t o x i c i t y ~ f/m r a t i o 5/34, mean age 54 (39-74) yrs, mean performance status 0,6 (0-2). 37 pts received a mean of 2,7 (I-3) courses, 2 pts had the f i r s t course of CT. 31 of 33 pts responded a f t e r the f i r s t course. Response and t o x i c i t y were assessed acc. to WHO-classification. Results a f t e r I-3 courses of CT: 11(28%) CR, 33(85%) CR+PR, 4 NC, 2 PD (95% confidence l i m i t s : CR 14-42%, CR+PR 74-96%). Results by stage of disease: pts no CR CR+PR T4 NO-3 MO 21 3 (14%) 17 ( 8 1 % ) T3 NO-3 MO 10 3 (30%) 8 (80%) T2 NO-2 MO 8 5 (63%) 8 (100%) Worst non-hematologic t o x i c i t i e s a f t e r administration of CT per patient: SGOT, SGPT grade I : 18% + 19%, S,Creatinine grade I : 3%, nausea, vomiting grade I+2: 28%, grade 3: 5%, alopecia grade 2: 3%. Hematologic t o x i c i t i e s grade 3: WBC 3%, p l a t e l e t s 10%. No t o x i c i t i e s of grade 4 were observed. Pts with CR and PR a f t e r completion of CT (mostly 3 courses) underwent surgery and/or radiation. Updated results w i l l b e presented. Hals-Nasen-Ohren-Klinik der Universit~t G~ttingen, GeiststraBe 5, D-3400 GSttingen

_

Cancer of the larynx representsabout ~ of total cancer risk and recent studies of trends in ear~er i.~cidenoeah(~,an s tendency. ~ r gies~l treatment is the method of choice but while the use of cordectomy or he/~ilaryngesta~,with the o p p e r ~ t y of voice preser~ticn is
Sl19 4/28-0 001

4/28-0 003

PATHOLOGY OF CENTRAL NERVOUS SYSTEM METASTASES

AN APPROACH TO LOCAL TUMOUR CONTROL USING POLYLACTIDE RODS AND LIPOSOMES AS CARRIERS FOR CHEMOTHERAPEUTICS,

K. JELLINGER L.B.Insfitute of Clin.Neurob~oL, Lainz-Hospltal, Vienna, Austria Metastases involving the CNS and its coverings occur in 12 to 30 % of all patients with solid rr)al[gnencies, and account for 15 to 30 % of all intracraniai neoplasms. The most frequent prima ry neoplasms metastasizing into the braln are lung, beast, urogenital, GI tract cancer, and meIanomas, with increasing percen rage of lung cancer. The highest tendency to metasteslze into the CNS have melanoma% germ cell tumars~ |ung cancer, particuIarly of small cell type (76 % in recent autopsy serles),end breast cancer, less frequently urinary tract, head and neck, liver/biUary tract~ GI tract, end thyroid cancer.Brain metastases are either solitary (15 to 30 %), but more often multiple (50 to 70 %), while diffuse involvement of the brain and/or meninges (brain and meningeal careinomatosis) are rather rare.About 75 % of cerebral metastases are located in the supratentorial, 25 % in the infratentorial space. There is rather uniform invol vement of the cerebral hemispheres related to their actual volume. Mid]ire structures end cerebellum are affected in about 30 % each; isolated involvement of the bralnstem is seen in 510 %. The pituitary gland is a frequent target organ of metast atic tumors, and can be the only involved intracranial structure particularly in breast and lung cancer. Compared to frequent in volvement of the spine and extradural space~ intromedullary me tastases are rare. They are to be expected in 0,3 % of cancer patients and account for about 2 % of el| CNS metastases. Me ningeal involvement can be localized or dlffuse,and in about 60 percent is associated with solid metastases, while one to 5% of all cancer patlents show pure meningeal carclnematosis, most frequently in lung, breast, gastric cancer and meIanomas. Diffuse cerebral carcinomatosls showing perivascular cuffing with or without involvement of the inner and outer C S F spaces is rare The pathagenes~s of CNS metastases of soiid tumors is most oft en due to hematogeneus dissemination, and less frequently due to continuous invasion of the CNS or via the C S F spaces.

4/28-0 002 SIGNIFICANCE O F TUMOR BIOPSIES METASTASES B. Volk and K. Schwechheimer

B. W o w ~ T. Remmele~ E. Mentrup~ W.J. Zeller~ H. Stricker~ K. S#hwechhelnaer and V. Sturm In an e x p e r i m e n t a l animal model (neurogenic s.c. t r a n s p l a n t e d tumours of BD IX r a t s ) t h e c a r r i e r p r o p e r t i e s for t h e chemotherapeutic compound m e t h o t r e x a t e (MTX) of p o l y l a c t i d e rods (PL) and liposomes (LP) were studied. In PL rods (1.6 nag MTX) an i n i t i a l peak r e l e a s e was followed by a continous r e l e a s e of the drug with a r a t e of 3 ~g/day for 4 naonths. Multilamellar LP sized 600 nm in d i a m e t e r showed a zero order k i n e t i c s of drug r e l e a s e (60 pg/day) a f t e r l n t r a n e o p l a s t i c a p p l i c a t i o n . Because of t h e i r f a v o u r a b l e p h a r m a c o k i n e t i c s MTX-PL and MTX-LP were s t u d i e d for t h e i r chemotherapeutic efficacy a f t e r local i n t r a n e o p l a s t i c a p p l i c a t i o n in t h e same e x p e r i m e n t a l turnout model. When compared to r e p e t i t i v e systemic MTX-chemotherapy t h e c a r r i e r m e d i a t e d local chemotherapy was found to be s i g n i f i c a n t l y (p
4/28-0 004 IN

BRAIN

RESULTS OF RADZOTHERAPY IN CEREBRAL METASTASES ASSESSED BY COMPUTED TOMOGRAPHY M.Flentje i , B.Kober ~ , J.G~rich i , B.Kimmig i

In a n e u r o s u r g i c a l serie the f r e q u e n c y o f i n t r a c e r e bral metastases is about 5 %. The site o f p r i m a r y t u m o r is u n k n o w n in 15 % of all b r a i n metastases. Those cases r e p r e s e n t a challenge to the n e u r o p a t h o logist, In

a

general,

a reliable differentiation between brain tumors a n d metastases can be d o n e b y light microscopic examination of paraffin sections. Problematic cases, h o w e v e r , require immunocytochemical m e t h o d s using a panel of cellular markers, especially c o m p o n e n t s of the cytoskeleton. It is easily possible to differentiate a glial filament

autochthonous

e x p r e s s i n g glioma from a c y t o k e r a t i n - d e s m o p l a k l n p o s i t i v e carcinoma metastasis. C y t o k e r a t i n s form a multigene family o f d i f f e r e n t p o l y p e p t i d e s which are expressed in a d i f f e r e n t i a t i o n - d e p e n d e n t manner. Using monoclonal antibodies against i n d i v i d u a l c y t o k e r a t i n p o l y p e p t i d e s e p i d e r mold and g l a n d u l a r carcinomas can be d i f f e r e n t i a t e d . In metastases o f p a p i l l a r y adenocarcinomas, the lack o f c y t o k e r a t i n p o l y p e p t i d e No. 7 is i n d i c a t i v e f o r a coto-rectal carcinoma. Up to d a t e , those r e s u l t s , h o w e v e r , are p r e l i m i n a r y and should t h e r e f o r e be interpreted with caution. The site o f p r i m a r y tumor can be specifically localized b y p o s i t i v e immunocytochemical d e m o n s t r a t i o n of t h y r o g l o b u t i n ( t h y r o i d cancer) as well as p r o s t a t i c acidic phosphatase and p r o s t a t e - s p e c i f i c antigen [ p r o s t a t i c n e o p l a s m s ) . In conclusion, immunomorphob g y is a v a l u a b l e method to d i f f e r e n t i a t e b r a i n metastases.

A b t e i l u n g Neuropathologie, Pathologisches I n s t i t u t d e r U n i v e r s i t ~ t , A l b e r t s t r a B e 19, D-7800 F r e i b u r g i. B r .

B e t w e e n 1979 and 1985, 195 p a t i e n t s w e r e s u b m i t t e d to r a d i o t h e r a p y o f the b r a i n f o r b r a i n metastasis. Primary irradiation was Performed in 159 p a t i e n t s , 3& p a t i e n t s h a d b e e n t r e a t e d by s u r g e r y before. The m e d i a n s u r v i v a l a f t e r d i a g n o s i s of all i r r a d i a t e d P a t i e n t s [&O to 60 Gy in i to 6 w e e k s ) w a s & . 9 m o n t h s , 22~ of t h e p a t i e n t s s u r v i v e d l year. P a t i e n t s with b r e a s t a n d lung o m n c e r s h o w e d m a r k e d differences in median survival [6.9 and K.2 months, respec-tively) a n d one y e a r s u r v i v a l r a t e (32~ and $1%). W i t h i n t h e h i s t o l o g i c a l g r o u p s , e x t e n t of e x t r a c e r e b r a l disease was the decisive pa-rmmeter f o r s u r v i v a l . At the e n d o f r a d l o t h e - r a p y ~ &7~ of P a t i e m t s s h o w e d m a r k e d improve-merit o f n e u r o l o g i c d e f i c i e n c y , 16~ deteriore-ted. Follow uD by computed tomograDhu with observation periods between i a n d 5E m o n t h s was D o a s i b l e in i03 P a t i e n t s . Most of these patients ahowed improvement oonoernimg size Of the lesions ~nd edema d u r i n g a p e r i o d of & to 2O w e e k s a f t e r start

Of

radiotherapy.

Later

on,

about

2/5

Of

the

patients controlled had a g a i n d e t e r i o r a t i o n with local progression or f o r m a t i o n of n e w Of t o t a l brain brain metastases in s p i t e irradiation. i R a d i o l o g i a c h e K l ~ n i k , Abt. a l l g e m e i n e R a d i o logie mit eoliklinlk der Univ.-Heidelberg, VoBstr. 3 Zlnstitut f~r Nukleermadizin, DKFZ, H e i d e l berg ~Abt. Rediologie If, St~dt. Kliniken Darmstadt

S 120

4/P-GM 002

4/28-O 005

Zentrum der Kinderheilkunde, Abtlg.fHr P~diatrische Neurologie und Abtlg.fHr P~diatrische H~matologie und Onkologie, D-45000 Frankfurt/MainFRG

TESTIOJLAR GERM-CELL TUMORS: HLA ASSOCIATIONSHITH PURE SEMINOMAAND METASTATICSPREAD H.v. Keyserlingk, U. Angelldes, U. Geidner, B. Kirsch~N. HBllert and K~P. D)eckmann Clinical and epidemiologlcal studies suggest that genetic factors may be involved in the etiology and pathogenesls of testlcular germ~cell tumors (GCT). Previous HLA-studles have so far yielded inconsistent results, mainly due to small and inhomogenousstudy populations. Recently, an association of increased DR7 frequency with hematogenous dissemination for the entire group of GCT was described (Oliver e t a l . , Lancet i:1506,1986). As seminoma and nonseminoma are quite different neoplasms concerning their clinical behaviour, we have in the present study separately H~-typed 52 patients with histologically pure semlnomaby standard two-stage mlcrolympbocytotoxicity method for 13 HLA-A, 23 HLA-B, 7 HLA-C and lO HLA-DR antigens. 310 healthy blood-donors from the same geographical area served as controls. Statistical comparison was carried out using the Chi-square test with Yates' correction. There was no difference in the frequencies of HLA-A antigens between the patient groups and controls. For the HLA-B locus antigens the frequency of BW41 was significantly increased (XZ=12.73; p=O.O005). Of the HLA-DR locus antigens, DR] was decreased (x2=5.63; p=O.O17) and DR7 increased (x2=3.403; p=O.061). Selective evaluation of 14 patients with lymphogenic metastases showed a trend towards an increase of A29 (4/14), BH4I (3/14) and DR7 (5/10), although this group was too small for sta~istlcal evaluation. Our results provide some evidence for the Involvement of HLA-associated factors in the pathogenesis of semlnoma, but more prospective studies of larger patient populations, including especially patients with metastatic disease, are needed to confirm these findings. Abt. fur H~matologle und Onkologie, Klinlkum Steglitz, FU Berlin, Hindenburgdamm30, D-lO00 Berlin 45

4/P-GM 001

4/P-GM 003

PROSTATE SPECIFIC ANTIGEN - PROGRESS IN DIAGNOSIS AND FOLLOW-UP OF PROSTATE CANOER E~ Allhoff, R. Engelkiog , ~. Oette and U. Jonas

NEO-ADJUVANT CHEMOTHERAPY OF N O N - T E S T I C U L A R MALIGNANT NON-SEMINOMATOUS GERM CELL TUMORS (NSGCTs) IN C H I L D R E N A N D A D O L E S C E N T S U G~bel*, G Calaminus*, RJ Haas, J Engert, JPM B~kkexink, H Gadnerz_H J[tr~ens* , D Harms B--~ween J~un i, 1983 and Sept i, 1987, 51 protocol-~ / tients (pts) with extracranial N S G C T s were entered into the germ ce/l tumor trisl of the German Society of Pediatric Oncology (GPO) (MAKEI 83/86). According to the therapy regimen these pts are c/assif/ed into 3 groups. Group A: Pts with comple~y resected ov~isn N S G C T s received 4 course R of vinblastine 3 mg/m days i+2~ bleomycin 15 mg/m days I-3 and cisplatinum 20 mg/m days 4-8 (VBC). In cases with FIGO stages ib+Ic, where residual disease was suspected, 2nd-look surgery was performed. Group B: Pts with incompletely resected N S G C T s received after primary surgery 4 courses of V B C followed by 2ndlook surgery. Thereafter chemotherapy was continued with 4 e~urses of VP 16 I00 mg/m daysgl-3, ifosfamide 1,5 g/m days 1-5 and cisplatinum 20 rag/~ days I-5 (VPIC). Group C: Pts with extended N S G C T s diagnosed by biopsy or elevated tumor markers received neo-adjuvant chemotherapy consisting of 4 courses V B C prior to definite surgery followed by 4 courses of VPIC. Results: Group A: 6/14 pts underwent 2nd-look surgery and showed no residual tumor. 13/14 pts remained disease-free (92 %). Group B: 13/20 pts underwent 2ndlook surgery. 5/20 pts showed residual disease. 12/20 pts remained disease-free (60 %). Group C: After neo-adjuvant chemotherapy 17/17 pts underwent 2nd-look surgery. 14/17 pts showed no residual disease. All pts remained tumor-free. 1 pt died of septicemia without evidence of disease (Survival rate 94 %). Neo-adjuvant chemotherapy is a safe and effective treatment for advanced N S G C T s and results in an improved disease-free survival.

BRAIN METASTASES IN CHILDREN G.Weiermann,G.Jacobi,D.Schwabe

and B.Kornhuber

Amongst 286 children with intracranial tumors 15(=5,2%)had primary extracranial tumor location Two groups are distinctive: a.continous tumor spread (Spatients) through t ~ sku~ or paranasal cavities. Primary diagnose was: ret~noblastoma(2), neuroblastoma(NBL) IV, chemodect~na, rhabdomyosarcoma, osteosarcoma, juvenile nasopharyngeal fibroma and aneurys~atic bone cyst. b.hematogeneous seedl in~ (7patients) was seen in various malignant sarcomas : Letterer Sie~t~pe of reticulosis, Hodgkin' s disease, myxoid fibrosarcor~a, synovial- osteogenic and EwLng sarc
Prostate specific antigen (PSA) was first characterized in 1979 as tissue-specific glycoprorein, synthezised in the epithelial cells of ductus and acini of the gland. In a prospective study over three years PSA- and prostate specific acid phosphstase (PSAP) were evaluated as tumor markers by simultaneous determination of their serum levels in 597 patients with adenoms of the prostate and in 186 patients with prostate cancer of all stages and grades before onset of therapy as well as in 386 patients already treated. ELISA technique employing monoclonal antibodies was used. Follow-up samples were taken 3.monthly and the obtained titers correlated with conventional monitoring modalities and course of the disease. Using s cut-off value of 10 ng/ml only 10 % "false"-pasitive" results with respect to malignant transformation were received whereas nsoplsstic disease was reflected by pathological levels in 68 %. Due to specific gens suppression PSA clearly proved superior to PSAP which only in 55 % showed pathological titers. Correlation with the course of the disease could be observed in 73 % For PSA whereas for PSAP in only 45 %. Complementary to rectal examination and ultrasound PSA especially with serial determinations improves diagnosis of prostate cancer, in monitoring PSA proved to be the most valuable parameter compared to conventional modalities. Orologisuhe Ml.inik der Medizinischen Hochsshule Konstanty-Gutschow-Str. 8, 5000 Hannover 61 * with kindly support by the Secretary for Science end Researoh~ N o r t h - R h i n e - W e s t f a l i s ~ F ~

Supported by B M F T No 01 ZP 850 12 *Universit~'ts-Kinder~, Moorenstr. 5, 4000 D doff

S12I

4/P-GM 004

4/P-GM006

ADJUVANT CHEMOTHERAPY IN NONSEMINOMATOUS TESTICULAR TUMOR STAGE lIB J.H. Hartlapp, L. Wei6bach*, B. Horstmann-Dubral f o r T e s t i c u l a r Tumor Study Group

PHASE-If STUDY OF THP-DOXORUBICIN (THP) IN ADVANCED NONSMALL CELL LUNG CANCER (NSCLC). H.W~ U.Gatzemeier, W.E.Berdel, M.Stahl, L.Edler, P.Drings - AIO-Phase-II Study Group

With the advent of polychemotherapy, v i r t u a l l y a l l pat i e n t s (pts) with early stage t e s t i c u ] a r tumor can expect to be cured. The main goal of current treatment regimens is to obtain the same e x c e l l e n t r e s u l t s with less t o x i c i ty. Results of a random prospective m u l t i c e n t e r t r i a l a c t i v a Led since IV/82 to investigate the necessary extent of adjuvant chemotherapy in stage lIB patients ( r e t r o p e r i t o neal lymph node metastases~ 5 cm) are presented. PostRLND pts were a11ocated randomly to 2 vs 4 courses of adjuvant therapy with PVB. Results: 225 pts entered the protocol, of whom 218 have been followed f o r 3-24 months (mean 21 months). Seven pts have relapsed; 5 (4 %) were on the adjuvant arm with 2 courses PVB, 2 (2 %) were t r e a t e d with 4 courses PVB. A l l relapses occurred within I year a f t e r chemotherapy. To date, 5 of the relapsed pts are in complete remission one p a t i e n t is s t i l l undergoing treatment and the l a s t p a t i e n t , o r i g i n a l l y randomized to receive 4 courses, died. Two f u r t h e r pts died before having received t h e i r assigned adjuvant treatment. T o x i c i t y was t o l e r a b l e in both therapeutic arms and consisted mainly of nausea, vomiting and loss of h a i r . 85 % of the pts randomized to be treated with 2 courses completed t h e i r treatment without deviation from protocol, whereas only 49 % of the pts scheduled to receive 4 courses finished the programme. Conclusion: For stage lIB pts, a therapy with only 2 courses of adjuvant chemotherapy is s u f f i c i e n t . The follow-up is being continued and the results w i l l be updated. StudienzentraIe d. Med. U n i v . - K l i n i k , Sigmund-Freud-Str. 25, 5300 Bonn I *Krankenhaus Am Urban, Uroiog. Abteilung, Dieffenbachs t r . I , 1000 Berlin 61 -

4/P-GM 005 PRIMARY CHEMOTHERAPY AND FACULTATIVE SURGERY IN PATIENTS W I T H NONSEMINOMATOUS TUMORS OF THE TESTIS J. Mack, K.-H. Pfl0ger,*B. UlshSfer, *A. v. Keitz, and K. Havemann The goal of treatment programs desighed for control ot nonseminomatous testicular cancer is eridication of all disease. The sequence currently used is orchiectomy followed by retroperitoneal lymph node dissection (RPLND) and polychemotherapy (PC). Often a second look RPLND is necessary in cases with residual disease. Lymph node dissection in these cases is often accompanied by side effects such as ejaculatory dysfunction. The present study therefore evaluated the following concept: All patients including those with resectable retroperitoneal lymph nodes after orchiectomy received PC and only patients with operable residual masses after a total of 4 courses underwent surgery. Up to now 37 patients have been included. Median age was 28 years (range 17-41 y). Fifteen presented with stage II and 22 with stage III (Lugano 79). PC consisted of cisplatin, vinblastine~ and bleomycin (PVB). Since 1985 vinblastine was replaced by etoposide (PEB). 32/37 patients (86%) entered CRo One further patient having unresectable residual masses is in the follow up since 5 months without evidence of disease. Seven patients died: 4 with progressive disease after PR~ 2 after relapse and 1 patient from liver cirrhosis being in CR for >2 years. All other patients live in CR (5-114 mo). 16/37 patients underwent surgery of residual masses after PC (13 x mature teratoma and/or necrosis, 3 x residual tumor). This study shows that primary PC with facultative surgery is equally effective in terms of CR (86%) and long term survival as compared to routinely performed primary RPLND. Zentrum f(Jr Innere Medizin, Abteilung H~matologie/Onkologie/Immunologie, BaidingerstraSe, D-3550 Marburg Zentrum for Operative Medizin II, Abteilung Urologie, Baldinger StraSe, D-3550 Marburg*

50 patients (pts) entered this multicenter phase-II trial between June 1986 and June 1987. Treatment: 4-0-tetrahydropyranol-adriamycin (THP) 70 mq/sqm as a 30 min. infusion day 1 every 3 weeks. Pts with an early progress (EP) or an early death in due of tumorprogression before the 2. treatment cycle were not excluded from the evaluation. Characteristics: 47 pts eligible; all had no prior chemotherapy; 26 adeno-ca, 19 squamous-cell-ca, 2 mixed-cell-ca; 39 males, 8 females; median age 59 yrs (45-70); P8 2,1% WHO-grade 0, 48,9% I, 48,9 II; all pts had extensive disease, bone metastases 44,7%~ Results: 2 pts refused treatment after the i. cycle, so 45 pts are evaluable for response: 0 CR, 5 (ii.1%) PR, 17 (37,8%) NC, 9 (20%) had an EP before the 2. treatment -cycle, 14 (31.1%) PD~ 3 out of the 17 pts with NC had a minor response. 6 out of the 9 pts with an EP died within 1 mth after the i. treatment. Overall mean survival time was 4,6 months. Untill now no patient with a PR died (4,7+, 5,5+, 7,0+ 10,5+, and 13,9+ mths), with only 1 in progression. Toxicity: leucopenia 29% WHO-grade I, 34% II, 6,4% III, 4.3% IV; thrombocytopenia 5,2% I., 1,54 II, 2,2% III and 0,7% grade IV; anaemia 26,1% I, ~'i~;8% II, 1,4% III. Nausea and vomiting 19% I, 23% II, 4% III; alopecia 35% I, 2% If, 2% III. There were no cardiotoxicity or other significant side effects. Conclusion: THP is effective in advanced NSCLC, comparable to other anthracycline-derivates like doxorubicin. Side effects are usually mild. Thoraxklinik Heidelberg - Rohrbach, Medizin / Onkologie, Amalienstr. 5,

Abteilung Innere D-6900 Heidelberg

4/P-GM 007 SECONDARY L Y M P ~ A D E N E C T O M Y AND/OR T H O R A C O T O M Y AFTER C H E M O T H E R A P Y IN N O N S E M I N O M A T O U S G E R M - C E L L TUMOR (NSGCT). W.Mair,Ch. C l e m m , G . S t ~ h l e r , W . W i l m a n n s . In a large percentage of N o n s e m i n o m a t o u s Germ Cell Tumor (NSGCT) after c h e m o t h e r a p y secondary surgery was n e c e s s a r y , b e c a u s e of remaining tumor m a n i f e s t a t i o n s . F r o m 1979 until now 61 patients had such a t r e a t m e n t . 2 0 patients had a thoacotomy,29 a retroperitoneal lymphadenectomy and 12 patients had both of them.These 12 and 6 other patients had primary Bulky tumor m a n i f e s t a t i o n s (lymphnodes larger than i0 cm, organ metastases larger than 5 cm). Secondary surgery revealed three types of histology:MTU was found in six patients (group I), MTD in 26 patients (group II),fibrotic and necrotic tissue was found in 29 patients (group III). Of the 32 p a t i e n t s , w h o had a t h o r a c o t o m y , 1 3 patients had a group II h i s t o l o g y , 1 9 patients group III.Of the 41 p a t i e n t s , w h o had a retroperitoneal l y m p h a d e n e c t o m y , 6 pts. had group I, 18 pts. group II,17 pts. group III. Of all 61 pts.,54 pts. remained tumor free after secondary surgery from 8 to 108 months (median 46 m o n t h s ) . T h o u g h the relaps free survival rate was 88,5%.7 pts. reached only partial remission and relapsed after 2 to I0 m o n t h s . 6 of them died,l pt. was lost follow up.These 7 pts. had preference for the first two h i s t o l o g i c a l groups:4 pts. group 1,3 pts. group II. The fact,that no patient of group III histology r e l a p s e d , d o c u m e n t s poor prognosis for patients with active tumor in secondary surgery. M e d i z i n i s c h e Klinik I I I , K l i n i k u m GroBhadern, M a r c h i o n i n i s t r . 1 5 , D - 8 0 0 0 M U n c h e n 70.

S122

4/P-GM 008 THYMUS HYPERPLASIA FOLLOWING RETROPERITONEAL LYMPHADENEGTOMY AND/OR CHEMOTHERAPY OR RADIOTHERAPY OF PATIENTS WITH TESTICULAR TUMORS. U.ROther, H.A.G.MOller, K.B~uerle, L.Fausar, P.Jipp, F.Eisenbe~ger, C.G.Schmidt 105 patients with malignant testicular tumors (44 seminoma, 61 non-seminomatous tumors) were treated between 1984 and 1987. 6-20 months after therapy, CAT-scan revealed occurencs of a tumor of the upper ventral mediastinum in 25 patients (7x after radiation of pure seminoma, 8x following retroperitoneal lymphadenectomy of non-seminomatous tumors, 10x after additional chemotherapy). Surgery performed in 7 of these showed thymus hyperplasia histologically in all cases, undifferenciated teratomous calls within thymus tissue in one case. Flew cytemetry of peripheral lymphocytes, determination of lymphocyte markers and T4/T ~ ratio did not show any specific pattern correIated to the presence of thymus hyperplasia. No differenciation was achieved by CAT-scan criteria between benign and malignant thymus hyperplasiao Conclusions: Thymus hyperplasia seems to be more frequent after lymphadenectomy and/or polychemotherapy of non-seminomatous testicular tumors than after radiation of pure seminoma. Since malignant variants cannot be distinguished by non-invasive methods yet, CAT-scan of the madiastinum at short intervals must be recommended following to treatment of testieular tumors as well as surgical/pathological imvestigation of progressive mediastinal tumors that occur after such treatment.

4/P-GM010 TREAT~:;~T OF POOR RISK ~ON-SE~INO~IATOUS T~ 500) ifosfamide 5gr/qm 24h cont.inf.d15,bleomycin 15mg/qm d!,8,vincristin 1,4mg/qm d 1 , 8 ~ q d 2 8 . E ] i ~ l i t v ?riter~m: AbS.mass>lOcm,mediast.mass)Scm,11ung m e t ~ ~51ung met.with at least one~2cm or)20]un~ met: Pts.charaet.:34 pts.,age 27(17-~8),PS 70%~40-9o). Mean prop ability of CR/NED 28%(calc.by multivariate analysis,Bos11983).Results:7pts too early to evaluate,CR 1 2 / 2 7 ( ~ D 4/27(15%), 2R-(neg,markers) 5/27(19%)~PR+ 2/27,NC/P 2/27, 1/27 early death(lung emb.),1/27 death after sec.surgery(bleeding).2pts relapsed from N E D . After median follow up of 9 mos(2-23)24/27 P%~, are alive,19/24 have no sign of progrs ~/o~ r~o~ ~ont- ~ree o~ oisease.Toxicm~z: (WHO) leucopenia(b%oel)3 51%,4 a~%~(bl~ 4"11% thrombopenia(blocl)3 11%,& 4%,(blocz)D ~,'~,

Zentrum for Innere Medizin, Katharinenhospital, Kriegsbergstr. 60, D-7000 Stuttgart I

43%,2"5%,neurotox.1"48%,2 ?4%,3 5%,~nfect:2 29%, 3"24%,diarrhea 2"!9%.Conclusions:This regimen sems %o be superior t ~ s % a n d a r d regimens in ooor risk pts.Neverthelese high toxicity and still suboptimal results warrant the development of new protocols for this subset of patiens. Abt.H~ma%ol./Onkol. ~ed.Hochschule Hannover

4/P-GM009

4/P-GMOll

PENILE CANCER: THERAPEUTIC APPROACHES IN DIFFERENT T/N - CATEGORIES V. MUller-Mattheis, St. Peter, H. Buszello, R. Ackermann

LATE RELAPSE IN SEMINOMA OF THE TESTES C. N J e d e r h o l d and L. H o f f m a n n

The low incidence o f penile cancer is the main problem f o r a 8 e n e r a l l y accepted approach in t h i s hish malisnant tumour. The prosnosis o f squamous c e l l carcinoma depends upon the stase o f disease as determined by local invasion and involvement of insuinal nodes, A v a i l a b l e data are based on r e t r o s p e c t i v e analyses, but formerly tumour s t a Bin8 was performed by usin8 Jackson's c l a s s i f i c a t i o n ( B r i t . J. Sur8,,53: 33, 1966), In these r e t r o s p e c t i v e studies a r e - c l a s s i f i c a t i o n was performed accordin8 to TNM-system. Nevertheless, cross comparison of r e s u l t s amon8 d i f f e r e n t s e r i e s , s p e c i f i c a l l y with resard to the c h a r a c t e r i s t i c o f the i n i t i a l primary lesion and with r e ~ard to nodal metastases ( s o l i t a r y , m u l t i p l e , p e l v i c , deep insuinal e t c . ) is often quite impossible. Therapeutic r e s u l t s o f chemotherapy and radiotherapy were not convineins, Sur8ery is the primary mode o f treatment with chemotherapy and radiotherapy bein8 of only adjunct i v e or p a l l i a t i v e b e n e f i t , Small s u p e r f i c i a l lesions i n volvin8 only the prepuce can be treated by circumcision, p a r t i a l or t o t a l penectomy is necessary in cases with more advanced tumours i n v o l v i n 8 81ans penis or proximal penile s h a f t . The prosnosis is markedly worsened by the presence o f insuina! metastases, and t h i s f a c t o r a f f e c t s the prosnosis much more than tumour 8rade and microscopic tumour patterns, In the presence o f p o s i t i v e in8uinal nodes 20% - 50% o f patients can be cured by primary i n s u inal node d i s s e c t i o n . The modified s u r s i c a l concept w i l l be presented and discussed, Dr. Volker MUller-Mattheis, Urolosische K l i n i k und P o l i k l i n i k der U n i v e r s i t ~ t DUsseldorf, MoorenstraBe 5, D-4000 DUsseldorf

A house c a s e end a r e p o r t (M, W a r h o l e t e l , , CANCER 52: 1 9 5 7 - 1 9 5 8 ~ 1983) i n d u c e d t h e s e a r c h For p a t i e n t s #ho had a r e l a p s e w i t h i n a minimum o f 3 y e a r s a f t e r d i a g n o s i s and p r i m a r y t h e r a p y , Questionaires a n s w e r e d by more t h a n 500 U r a l s gists, O n c e t o g i s t s and R a d i o - T h e r a p i s t s yielded 12 c a s e r e p o r t s ~ w h i c h a r e p r e s e n t e d i n d i v i d u ally. The c a s e s d i f f e r considerably. The p e r i o d b e tween p r i m a r y t h e r a p y and r e l a p s e v a r i e s From 4 t o I 6 y e a r s ( m e d i a n 5 , 8 y e a r s ) . The m e t a s t a ses were located retroperitoneally (8)~ in the thigh soft tissue ( t ) and i n t h e s u p r a c ] a v i c u l a r and c e r v i c a l nodes (5). After relapse 3 patients died of progressive d i s e a s e , 1 d i e d o f m e t a s t a s i s o f a semJnoma Jn the contralaterat testis, five ~ere still living 3 years later, and t h r o e o t h e r s s u r v i v e d p e r i o d s b e t w e e n 9+ and 18+ m o n t h s . This

small

number o f c a s e s c a n n o t

change f o l l o ~

up regime. On the other hand, the frequency of ]ate metastases in seminoma seems to be higher than previously reported. This can be of importance in differentia3 diagnosis. Onkologische AbteJlung~ Allgemeinas Krankenhaus Barmbek, RObenkamp 148~ D 2000 Hamburg 60

S 123

4/P-GM 012

4/P-GM014

IMMUNCYTOCHEMICAL ER AND PR RECEPTOR DETERMINATION IN FINE NEEDLE ASPIRATES OF PRIMARY BREAST TUMORS, METASTASES AND LOCAL RECURRENCES K. J. Neis, P. Christmann, G. Bastert

I M M U N O H I S T O C H E M I C A L R E C E P T O R STATUS IN C A R O I N O M A S 0F THE E N D O M E T R I U M A N D IN M A L I G N A N T TUM O U R S OF THE OVARY. C O M P A R I S O N W I T H C L I N I C A L DATA D. Schw~rer~ W. K l e i n e and A. P f l e i d e r e r

When planning the therapy of metastatic breast cancer,the receptor content of the tumor represents an important factor, emphasized by the fact that in todays therapy endocrinological methods are used rather than chemotherapy under the special regard of q u a l i t i y of l i f e . In most cases the therapeutic management is to be planned according to the receptor content of the primary tumor, also i t is a known fact that receptor changing is observed in about 30 % of a l l metastases. In most cases a pretherapeutic testing of the tumor is not possible because metastases are not good accessable or the amount of tumor is not s u f f i c i e n t f o r a biochemical assay. Since the development of mABs against ER and PR i t seems to be possible to determinate the receptors by fine needle aspiration followed by immuncytochemical staining. In order to judge the val i d i t y of immuncytochemical receptor assays, 56 primary breast cancers were punctured. The aspirates were examined concerning the receptor content of ER and PR by immuncytochemistry. The results were compared to those of DCC analyses. A high agreement was found in this study. Only in 4 cases a DCC positive finding was classified false negative in immuncytochemistry. However 2 of these cases had a rather low receptor content of 10 respectively 16 fmol/ mg. Meanwhile 32 metastases and 14 local recurrences of breast cancer were analysed by fine needle puncture receptor assay. In I/3 of these cases a receptor changing compared to the primary tumor was observed. Immuncytochemical determination of ER and PR in metastases in our experience seems to be the most e f f i c i e n t pr~herapeutic tumor testing, over a l l in breast cancer. Another advantage of this method are the only minimal pains f o r the patient.

I m m u n o h i s t o c h e m i c a l i n v e s t i g a t i o n s on e s t r o g e n r e c e p t o r s were p e r f o r m e d on f r o z e n s e c t i o n s of 65 e n d o m e t r i u m carcinomas and of 70 m a l i g n a n t t u m o u r s of the ovary. The i m m u n o h i s t o e h e m i c a l d e t e e t i o n was p e r f o r m e d w i t h m o n o e l o n a l antib o d i e s a g a i n s t n u c l e a r r e c e p t o r p r o t e i n (~RICA, A b b o t t Lab.). The s e m i q u a n t i t a t i v e evalua t i o n is b a s e d on a h i s t o l o g i c a l score accord i n g to the r e c o m m e n d a t i o n of the 2. E R - I C A C o n s e n s u s M e e t i n g (Mainz, O c t o b e r 1986). R e s u l t s in E R - I C A were c o m p a r e d w i t h b i o c h e m i cal E R m e a s u r e d by DeC. I m m u n o h i s t o c h e m i c a l e s t r o g e n r e c e p t o r status was c o r r e l a t e d to c l i n i c a l d a t a and survival. U n i v e r s i t i t s f r a u e n k l i n i k , H u g s t e t t e r s t r a B e 55, D - 7 8 0 0 F r e i b u r g i.Br.

Universit~ts-Frauenklinik und P o l i k l i n i k , D-6650 Homburg/ Saar

4/P-GM 013

4/P-GM 015

ESTRADIOL AND TAMOXIF~N MEDIATED LONG TERM H O R M O N E blb]GE~s M O D U L A T I O N IN X E N O T R A N S P L A N T ED POSTMENOPAUSAL HUMAN BREAST AND ENDOMETRIAL GANGER R.-Th. M i c h e l , A . V s r i n g , H . K u h l and M . S t e g m ~ l ] e r

LOCALISATION OF FUNCTIONAL H U M A N O V A R I A N CANCER. PJ Albert, A Hohenhaus, S S Wacker

The n u d e m o u s e x e n o t r a n s p l a n g a t i o n m o d e l was u s e d for t e s t i n g h o r m o n e r e c e p t o r m o d u l a t i o n in h u m a n b r e a s t and e n d o m e t r i a l c a n c e r u n d e r h o r m o n a l t r e a t m e n t . T h e c a p a c i t i e s of e s t r o g e n (ER) and p r o g e s t e r o n e r e c e p t o r s ( P g R ) w e r e m e a sured by the D G G m e t h o d u n d e r l o n g t e r m e s t r a d i o l and t a m o x i f e n treatment. E s t r a d i o l ( P r o g y n o n D e p . R , l m g / k g 3x the week) and t a m o x i f e n ( 3 and 15 m g / k g , 3 x the week) w e r e g i v e n i.m. in castrated male nude mice with xenotransplanted h o r m o n e r e s p o n s i v e b r e a s t and e n d o m e t r i a l canc e r . T r e a t m e n t time was 4-6 weeks. Xn h u m a n b r e a s t c a n c e r E R d e c r e a s e s to l e v e l s a r o u n d zero a f t e r some h o u r s , w h e r e a s P g R capac i t y b e g i n s to g r o w s t e a d i l y to 10 f o l d l e v e l s o v e r the 4 w e e k t r @ a t m e n t p e r i o d . U n d e r t a m o x i fen t r e a t m e n t the E R l e v e l s d e c r e a s e to 1/10 w i t h i n the f i r s t d a y r e m a i n i n g at that l e v e l d u r i n g the w h o l e t r e a t m e n t p e r i o d of 5 weeks, w h e r e a s P g R v a l u e s g r o w s t e a d i l y w i t h i n the f i r s t days r e m a i n i n g at a 20 f o l d l e v e l o v e r the w h o l e t r e a t m e n t per~od. In h u m a n e n d o m e t r i a l c a n c e r c o m p a r a b l e r e s u l t s w e r e observed. The n u d e m o u s e x e n o t r a n s p l a n t a t i o n m o d e l seems to be a u s e f u l tool f o r t e s t i n g v a r i a t i o n s in the h o r m o n e r e c e p t o r c o n c e n t r a t i o n under hormonal m a n i p u l a t i o n . A b t e i l u n g f ~ r G y n ~ k o l o g i e u n d O n k o l o g i e dsr U n l v e r s i t ~ t s - F r a u e n k l i n i k F r a n k f u r t am Main, T h e o d o r S t e r n Kai 7 , 6 0 0 0 F r a n k f u r t ~ m M a i n

LH-RECEPTORS Jurchen,

R

IN

Port,

A d i r e c t e f f e c t of g o n a d o t r o p i n s in m o d u l a t i o n of h u m a n o v a r i a n c a n c e r was shown by an increased sensitivity of adenylate cyclase to gonadotropins and an increased tumor growth f o l l o w i n g g o n a d o t r o p i n a d m i n i s t r a t i o n in vitro. We n o w report the p r e s e n c e of f u n c t i o n a l (agonistic) L H - r e c e p t o r s in tissue samples of h u m a n ovarian cancer using a specific monoclonal a n t i b o d y p r e p a r a t i o n and a s u b s e q u e n t v i s u a l i sation by i m m u n o p e r o x i d a s e staining. The antibody was p r o d u c e d and t e s t e t w i t h L H - r i c h luteal plasma m e m b r a n e s of rats. B i n d i n g studies with a s e l e c t e d n u m b e r (n=26) of clones (IgM) resulted in a c o m p e t e t i v e h C G - r e p l a c e m e n t w i t h o u t i n t e r f e r e n c e to o t h e r peptides. I m m u n o p e r o x i d a s e s t a i n i n g of d i f f e r e n t tissues showed a s p e c i f i c s t a i n i n g of rat and human luteal tissue and a lack of b i n d i n g in muscle, liver, kidney and i n t e s t i n a l organs. F o l l o w i n g in r i v e a p p l i c a t i o n in p s e u d o p r e g n a n t rats one clone (B-30) was able to stimulate p r o g e s t e r o n secretion (P4) in a time and dose dependent manner. Progesteron secretion was s t i m u l a t e d 3-fold w i t h i n 60 m i n u t e s and 10fold in 120 minutes. In all o v a r i a n c a n c e r tissues so far i n v e s t i g a t e d (n=20) functional LH-receptors could be visualized with this clone. T h e r e was a h e t e r o g e n e o u s r e c e p t o r distribution and c o n c e n t r a t i o n in the c a n c e r tissue samples. This data suggest that h u m a n o v a r i a n cancer may be d i r e c t l y m o d u l a t e d by functional receptors for g o n a d o t r o p i n s . Universit~ts-Frauenklinik, Str. 4, D-8700 Wuerzburg, FRG

Josef-Schneider-

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IMMUNHISTOCHEMICAL ASSAY OF ESTROGENRECEPTORSIN COMPARISON WITH A BIOCHEMICAL ASSAY IN HUMANBREAST AND ENDOMETRIAL CARCINOMATISSUE.

EGF RECEPTORS AND SYNTHESIS OF EGF-LIKE ACTIVITY (TGF~) IN LUNG CANCER CELL LINES M. Hider, M. Rotseh, C. Hermit, G. Hartogh, G. Jaques, M. Maasberg, and K. Havemenn

J.-P.Pfuhl, M.Albrecht, M.StegmSller The detection of estrogen receptors(ER) in human breast and endometrial carcinoma tissue became an unrenouncable tool in therapy planing and determination of prognostic aspects.Until recently the"in v i t r o " q u a n t i t a t i v e measurement of ER was performed exclusively in human tissue cytosoIs.The c l i n i c a l u t i l i t y of biochemical assays f o r theese receptors had been proved within the l a s t years. Nevertheless up to 50% of the patients with ER+ breast cancer -depending on the employed c u t - o f f values- are non responders to an endocrine therapy.One reason may be found in a part of the tumor consisting of ER- tumor c e l l sub-population giving rise to hormon unresponsive metastases.ln theese cases a more p r i c i c e h~stopathologicaI method permits a better characterisation of ER+ and ERc e l l s . l t concerns a d i r e c t antigenic recognition of ER+ c e l l s . A l s o the potential interference in ER detection caused by other steroid binding proteins seems to be eliminated. In 32 cases we compared a q u a n t i t a t i v e method in human tissue cytosoI (dextran-coated-chareoal) with the immuncytochemical assay ER-ICA by ABOTT Diagnostics to detect differences in the results of both methods. In 24 patients the results of the biochemical and immunhistochemical assay were in accordance (ER+ :14 p a t . , ER- :10 p a t . ) . 7 cases were biochemicaly p o s i t i v e and immuncytologicaly negative.ln one patient we found a vice versa r e s u l t .

Zentrum f o r Frauenheilkunde und Geburtshilfe der Univers i t a r Frankfurt,Theodor-Stern-Kai 7,6000 Frankfurt/M.70

The hypothesis of an autocrine mechanism in cancer cells implicating combined synthesis of growth factors and their receptors led to a connection between oncogene and growth research. The E~F-reeeptor may play a central role in cancer growth control as evidenced by the sequence homology between the v-erb-B oncogene product and the eytoplasmatic and membrane part of the EGF-receptor or the production of TGF~ in tumor cells. TGFw belongs to the EGF-gene family and binds to the EGF-receptor with affinity similar to EGF (Goustln et al., 1986). We studied EGF-receptor expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines. All NSCLC cell lines analyzed (9/9) had specific high affinity binding sites for EGF, whereas only 5/11 SCLC cell lines bound EGF. Binding parameters obtained by Scatchard plots revealed K values of 0.5-4.5 nM and as maximum D amount of binding sites (B ) 71-1000 fmol/mg protein in NSCLC cells and 26-143 fmo~a~GF/mg protein in SCLC cells. In order to analyze the autocrine hypothesis in-lung cancer cell lines we studied the production of EGF-like activity (TGF~) and could detect EGF-like activity in NSCLC and SCLC cell lines by radioreceptor assays with cell line A431. EGF-like activity was identified to be TGF when cell extracts were subjected to gelfiltration (Superose 12) and the fractions analyzed in a RIA (Biotope) by an antibody which recognizes HMW and LMW forms of bioactlve TGF~ specifically. Preliminary growth data showed an approximately 2-3 fold growth stimulation in the cloning assay of 3 NSCLC cell lines with EGF/TGF~ whereas the growth of two SCLC cell lines remained uneffeeted. Zentru~ f~r Inhere Medizin, Abteilung H~matologie/Onkologie/Immunologie, BaldingerstraBe, D-3550 Marburg

4/P-GM017

4/P-GM019

E F F E C T S OF H O R M O N E S A N D G R O W T H F A C T O R S ~ O N H U M A N E N D O M E T R I A L CARCI;NOMA CELLS: PROLIFERATION AND RECEPTOR STUDIES h~ J. H o f m a n n m, A. D r e s c h e r *, R. K u n z m a n n ~,_ R. H a c k e n b e r g ~, F. H d l z e l # a n d K.-D. S c h u l z .................................. _ ........... The cell llne EFE-184, established from a patient suffering from r e c u r r e n t endometrial adenocarcinoma, was characterized By Giemsa b a n d i n g of c h r o m o s o m e s and i s o e n z y m e analysis. In S-day proliferation assays ~ith 10% charcoal-treated fetal calf serum in the i n c u b a t i o n medium, 1 nM e p i d e r m a l g r o w t h factor (EGF), i00 nM insulin, i0 nM insulin-like growth factor-I (IGF-I) a n d I00 nM cortisol each w e r e a b l e to s t i m u l a t e the g r o w t h of E F E 184 cells. No s i g n i f i c a n t e f f e c t s of e s z r a d i o l , dihydrotestosterone or progesterone on the proliferation were o b s e r v e d u n d e r she chosen conditions. For EGF, insulin and IGF-I h i g h numbers of membrane r e c e p t o r s were d e t e r m i n e d on EFE-184 cells; dissociation constants were in the concentration range required for growth promotion. High affinity glucocortlcoid receptors were also detected. The m l t o g e n i c IGF-I a n d c o r t i s o l c o n c e n t r a t i o n s are in the r a n g e of the corresponding plasma levels, suggesting their possible importance for endometrial carcinoma growth. Though the stimulatory EGF c o n c e n t r a t i o n s a r e well above b l o o d levels, EGE-like factors may have a role in a possible autocrine growth stimulation. Supported by Deutsche Forschungsgemeinschaft (SEB 215) a n d K e m p k e s - S t i f t u n g M a r b u r g .

CARRIER MEDIATED ACTION OF PLATINUM COMPLEXES ON ESTROGEN RECEPTOR POSITIVE TUMORS

Universit&ts-Frauenkliniken, P i l g r i m s t e i n 3, D - 8 5 5 0 M a r b u r g (~) a n d M a r t i n i s t r . 52~ D-2000 H a m b u r g 2 0 (@)

E. von Angerer, N. Knebel, J. Karl, M. R. Schneider, H. Sch~nenberger

R. Gust,

The aim of these i n v e s t i g a t i o n s is the development of platinum complexes t h a t e x e r t a spec i f i c action on mammary and p r o s t a t i c carcinomas. To reach t ~ i s goal, complexes with high binding a f f i n i t y f o r estrogen receptor and c y t o s t a t i c a c t i v i t y were synthesized. Two d i f f e r e n t types of ligands w e r e used f o r comp l e x a t i o n . Platinum complexes with substituted diphenylethylenediamines p o s s e s s moderate binding a f f i n i t y f o r the estrogen receptor, but strong endocrine a c t i v i t y . The growth of hormone-dependent experimental mammary and p r o s t a t i c tumors was s t r o n g l y i n h i b i t e d . In the second class of compounds the cis-diaminod i c h l o r o - p l a t i n u m group is linked by a spacer group to a substituted 2-phenylindole as homing device f o r the estrogen receptor, These structures e x h i b i t high binding a f f i n i t i e s f o r the estrogen receptor and a s e l e c t i v e cytostatic action on tumors containing estrogen receptors l i k e transplanted MXT mammary tumors of the mouse. I n s t i t u t f u r Pharmazie, Univ. Regensburg, U n i v e r s i t ~ t s s t r . 3], D-8400 Regensburg

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4/P-GM022

The e f f e c t of steroid hormones on pancreatic carcinoma, grown in nude mice and tissue culture, M. v. B~low 1, G. Kl~ppel 2, H.d. G r i l l 3, K, Pel low 3 , W. Wahl~, M. Moesta ~

TWO MONOCLONAL ANTIBODIES REVEALING STRONG REACTIVITY WITH RENAL CELL CARCINOMA (RCC) P.FJsche____r,__J~E,Scherberich~ @__=Wo_[f__~_W,Schoep~e

P a n c r e a t i c d u c t a t adenocarcinoma occurs more f r e q u e n t l y

in men than in women. I t has also been reported that pancreatic carcinoma contains high estregene binding protein concentration. To obtain more infOrrr,~tion regarding the possible involvement of sex s t e r o i d hormones in growth of pancreatic carcinoma we examined the e f f e c t of testosteron, cyproteronacetat, estradiol and tamoxifen on growth rate of four ductular carcinomas of the pancreas grown in nude mice. Hormone treatment was started when the implanted tumors has reached a diameter of 0.6 cm. Tumor size was measured weekly. In three of the four tumors cyproteronacetat administration induced a s i g n i f i c a n t growth r e t a r d a t i o n . No e f f e c t on the growth rates of tumors were observed under treatment of testosterone, e s t r a d i o l and tamoxifen, Cell culture studies of two of the transplanted tumors revealed an increase c e l l growth rate a f t e r the addition of testosterone to the medium, Our results ~uaaest that some pancreatic ductal carcinoma may be influenced in the growth by sex s t e r o i d hormones.

~I

Dept.of General Surgery, University of Mainz 3~Pathol. Ontleedkunde, University of Br[issel ' I n s t . of Experimental Endocrinology, University of Mainz

Netastase~ are found in 90% of the patients when the diagnosis of RCC is made; generation and dissimination of filiae will develop in additional 30% of the cases after t u m o r nephrectomy. One hope for earlier diagnosis and treatment of RCC and its metastases is the production of monoclonal antibodies (NAb), Our group proceeded i n developing a panel of MAbs against specific antigens from human RCC, Membrane components solubilized from human renal cleaY cell carcinoma by bromelain and enriched by ConA-affinity c h r o m a t o g r a p h y and gelfiltration on Sephacry! S-200 were used for inm~unizing female BALB/c m i c e Sensitized spleen lym~hocytes were fused with X63.Ag8 myeloma cells using PEG 4000 (P.Fischer, Imm~unobio[ 175. 287, 1987). Two of the selected NAbs, eal!ed IIC2 and SOB5. in normal kidney were able to recognize in glomeruli: IIC2 restricted epitopes only bound to very few nuclei and small fibrous strucures, 30B9 to mesangial ep~topee, In contrast. I[C2 was capable of reaetin~ with a highly increased quantity of nuclei, intracellular globuli~ and stroma constituents on tissue sections of RCC~ whilst NAB 30B5 recognized epitopes which were distributed ~n a more inho~ mogenous pattern on the tumor parenchyrna. Immunobiotting of kidney and RCC extracts after to bands of SDS-PAGE revealed binding of I [ C 2 31 + 25 kDal and, 30B5 to a single band of 29 kDa]. Further studies are in work to investigate the clinical aspects of these promising MAbs Universitits-Klinik. Stern-Kai 7, D-6000

Theodor-

4/P-GM 023

4/P-GM 021 A D J U V A N T CHENOTHEPAPY (CCNU-VINBLAST!NE) RENAL CELL C A N C E R (2 YEARS REPORT) J. K~hb~ck, T. Madaras and P. P~tzi

ZIg. Nephroiogie. F r a n k f u r t 70

IN

STUDIES ON THE PERIOPERATIVE IMMUNE STATUS IN PATIENTS WITH RENAL CELL CARCINOMA S. Pomer, V. Daniel, T. Kfilble, K. M6hring, G. Riedasch

An adjuvant chemotherapy program was initiated at patients with renal cell cancer following I) tumornephrectomy and/or radical exstirpation of metastases c o n j o i n t l y with 2) "high risk" constellation on the basis of histological tumor invasion as well as G3-grading and/or bilateral tumors or suprarenal metastases resp. Material: 14 nephrectomized patients (11 males, 3 females) aged 47-72 (mean 48,1)years. Preceding 6 patients had undergone resection of mostly extensive metastatic bone lesions. Treatment consisted of a combination of vinblastine (Velbe R) 5 mg/m 2 i.v. on Day I, followed 6 hours later by p.o. administration of CCNU 130 m g / m 2 under strict antiemetic prophylaxis. Side effects {mainly hematological depression, gastrointestinal disturbances, neuropathias) were observed relatively rare. V i n b l a s t i n e was repeated 5 x {= one cycle) with W B C - d e p e n d e n t intervals of 1-2-3 weeks up to a total of 6 cycles (20-22 months duration). Results and conclusions: 10/14 patients are ~ f l l remaining without any tumor manifestations, 2/14 patients developed new osseous metastases and died with general progression; 2 further patients showed local recurrence and/or d i s t a n t metastases w • generalization. These results demonstrate effectivity of C C N U - V i n b l a s t i n e c o m bination in renal cell cancer w h i c h may prolong the tumor free interval but can n o t prevent further metastases in approximately 30 % of patients after nephrectomy.

Tumor patients are discussed to have an impaired cellular immunity. We report about perioperative immune profiles using T-lymphocyte subsets and skin test reactivity as parameters of cellular immunity.T-lymphocyte subsets and skin test reactivity were studied in 95 patients with renal cell carcinoma. T-lymphocyte subsets were determined by flow-cytometry with the monoclonal antibodies 0KT 4 and 0KT 8. Skin test reactivity was measured by multitest MERIEUX. 16/95 (17 %) of tumor patients had decreased T4/T8 ratios < I , 0 in contrast to 5/175 (3 %) of normal controls (p < 0 , 0 0 0 5 ) . Tg/T8 ratios after tumor resection increased from i~6 + 0,i to 1,8 + 0,2 and 2,0 + 0,2 when controlled three times-postoperatively. T-lymphocyte subsets were not correlated with tumor size, lymph node involvement and metastases, although percentages of patients with T4/T8 ratios < 1,0 increased slightly with T-stage. Scores of skin test reactivity w e r e 15,3 + 0,7 preoperatively and increased to 14,2 + I,~, 18,0 + 2, 21,5 + 2 w h e n controlled 4 Times postoperatively? They also showed no correlation with TNM stages and T-lymphocyte subsets. CONCLUSION: Tumor patients had abnormal cellular immunity and it seems that cellular immunity improves after surgery.

II. Medical Department, University of Vienna, Garnisongasse 13, A-I090 Vienna, Austria

Urologisehe Unlversit~tsklinik Heidelberg, Im Neuenheimer Fold ii0, D-6900 Heidelberg

i

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4/P-GM 024

4/P-GM 026

COUMARIN AND CIMETIDINE IN THE TREATMENT OF METASTATIC RENAL CELL CARCINOMA R~ Herrmann, T. E ~ i , C. Mzane~old and W. Matthiessen

INTRAORAL SOFT TISSUE METASTASIS IN RENAL CELL CARCINOMA M. Hagen, V. MUller-Mattheis, J. Lentrodt, R, Ackermann

In v i t r o and in animal experiments coumarin and c i m e t i dine have been shown to be immune modulators. C l i n i c a l l y the combination o f both has shown a c t i v i t y in malignant melanoma and renal c e l l cancer. Marshall et a l . (J. Clin. Oncol. 5, 862, 1987) reported a 33% o b j e c t i v e response rate in renal c e l l cancer. In order to confirm t h i s rep o r t we i n i t i a t e d a phase I I t r i a l in metastatic renal c e l l cancer s t a r t i n g 7/86. E l i g i b i l i t y included h i s t o l o g i c a l l y confirmed, metastatic, measurable disease, performance status_<3, no previous medical treatment. The p a t i e n t s received coumarin 100 mg/d p.o. and cimetidine 400 mg p.o. every 8 hours, the l a t t e r s t a r t i n g on day 15. The treatment was continued u n t i l disease progression. So f a r , 15 p a t i e n t s have been admitted to the study. Of the 13 evaluable p a t i e n t s , 10 had had a nephrectomy. The median age was 63 years (44 - 80), median performance status 1 (0 - 3). Metastatic s i t e s were predominantly lung and bone. Median time from f i r s t diagnosis was 1.5 years (0 - 10). None o f the p a t i e n t s had an o b j e c t i v e response. So f a r , 5 p a t i e n t s have died, the median s u r v i val being 6+ months. 3 patients complained o f g a s t r o i n t e s t i n a l side e f f e c t , I o f them discontinued treatment a f t e r 1 week only. Conclusion: So f a r our r e s u l t s do not confirm the favourable e f f e c t o f coumarin and cimetidine in renal c e l l carcinoma. Medizinische K l i n i k , Klinikum Rudolf Virchow, Standort Charlottenburg, Spandauer Damm 130, D - 1000 B e r l i n 19,

Renal c e l l carcinomas are notorious f o r t h e i r a b i l i t y to metastasize e a r l y in t h e i r course. At the point o f time o f making diagnosis 30% - 40% o f p a t i e n t s present d i s t a n t metastatic lesions. I% - 3% o f a l l tumours found in o r a l c a v i t y are metastases o f malignant tumours from d i s t a n t primary s i t e s . In renal c e l l carcinoma hematoge~ neous metastasizing p o s s i b l y is o f g r e a t e r importance than in other carcinomas, The most r e a d i l y apparent route f o r hematogeneous spread is via the caval venous system, then through the pulmonary c i r c u l a t i o n , thence from the heart to the a r t e r i e s o f the head and neck. In a d d i t i o n , A.M. Nahum and B.J. Bailey emphasize the r o l e o f epidural and p r e v e r t e b r a l veins (Batson's plexus), t h a t communicate with e i t h e r the i n t e r c o s t a l veins, the venae cavae, the azygous system or the p e l v i c veins (Laryngoscope, 73: 942, 1963), During periods of g r e a t l y increased i n t r a t h o racic or intraabdominal pressure a retrograde flow occurs from the usual venous channels back i n t o the v e r t e b r a l venous plexus, inasmuch they are without valves. Tumour c e l l emboli reach the great venous sinuses o f the head in t h i s way. Carcinoma o f the breast and renal c e l l c a r cinoma were noted to be the most common primary tumours t h a t predominate in metastatic lesions of oral c a v i t y . An own c l i n i c a l case o f i n t r a o r a l s o f t t i s s u e metastasis o r i g i n a t e d from renal c e l l carcinoma w i l l be presented and discussed based on c l i n i c a l data and h i s t o l o g i c a l findings. K l i n i k f u r Kiefer~ und Plastische Gesichtschirurgie der U n i v e r s i t ~ t DUsseldorf, MoorenstraBe 5, D-4000 DUsseldorf

4/P-GM025

4/P-GM 027

ESTIMATION OF MALIGNANT POTENTIAL IN RENAL CELL CARCINOMA BY MONOCLONAL ANTIBODIES, R. Ackermann, D. Rohde , B.J. S q h m l t z - D r ~ e r

LOW DOSES OF 4-HYDROXY-CYCLOPHSOPHAMIDE (MAFOSFAMIDE) MODULATE IMMUNE REACTION IN VIVO IN TUMOR-BEARINGMICE AND IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA H.O. Klein, H.-G. Kreysch, C. Coerper, P. Voigt

Todays prognosis of a patient with renal cell carcinoma (RCC) is mainly based on tumor stage and grade. However, additional information concerning the malignant potential of a given tumor is requied in order to select for patients who could benefit from radical surgical treatment. Monoclonal antibodies (mab) Due ABC 3 and 4, directed against transitional cell carcinoma, were found to react with proximal tubular epithelium and renal cell carcinoma specimens. The aim of~tbls study was to investigate whether tke p~esence of the corresponding antlgens ABC 3 and 4 on the tumor cell membrane can be correlated with the prognosis of renal cell carclnema. Using the immunoperoxidase t e c h n i q u ~ I n formalin fixed and deparaffined sections ~f RCC specimens, the percentage of antigen positive cells was calculated. A negative correlation between the presence of the corresponding antigens ABC 3 and 4 and tumor grade and stage was observed. While approx:Imately 80 % of the low grade tumors were found to consist of antigen positive cells (~ 60 %), 75 % of the dedifferentiated tumors w~re found to be negative (< 30 % positive cells). Similar observations were made conc@rnlng the tumor stage. In a retrospective investigation the correlation between the expression of antigens ABC 3 and 4 and the long term survival of patients with RCC are analysed. Urologische Klinlk der Universit~t, Moorenstr. 5, D~4000 DGsseldorf, FRG

Low doses o f cyclophosphamide (CPA) modulate immune r e s ponses and induce complete tumor regression and cures in mice. The mechanism of action is r e l a t e d to the development o f a T-cell-dependent immune r e a c t i o n . We s t a r t e d a t r i a l with mafosfamide (MAF), the a c t i v e metabolite o f CPA and found t h a t the response of Ehrlich ascites tumor (EAT) c e l l s in vivo to t h i s compound is biphasic. The highest cure r a t e (70 %) is obtained with a low i . p , dose o f 7 mg/kg/d. Hematologic side e f f e c t s were not observed, Arguments f o r an immune mechanism involved are t h a t ( I ) mice t r e a t e d with MAF showed a s t a t i s t i c a l l y s i g n i f i c a n t increase in spleen weight compared with untreated cont r o l s , (2) a f t e r treatment large numbers of mononuclear c e l l s appeared in the a s c i t e s , and (3) long-term s u r v i v ing mice were r e s i s t a n t to f u r t h e r challenge with large inocula of EAT. We s t a r t e d a p i l o t t r i a l in p a t i e n t s with metastasizing and advanced renal c e l l carcinoma - a d i sease which can be considered to be influenced by the immunologic response of the tumor host. The s t a r t i n g dose of MAF was 24 mg/m~/d administered i . v . Therapy was r e peated at 14 days i n t e r v a l on an o u t - p a t i e n t basis. Monit o r i n g o f mononuclear c e l l s in the p e r i p h e r a l blood with monoclonal antibodies using a FACS IV were performed two times a week. No t o x i c side e f f e c t s were observed. Median weight increased by 3 kg, median Karnofsky-lndex improved from 70 to 80 %. A l l p a t i e n t s showed an increase in monocytes/macrophages, NK- c e l l s and in DHT response - c l e a r l y r e l a t e d to therapy. Although t h i s i s a phase l - t r i a l , we observed in 1/18 a PR, in 1/18 a mixed response, in 1/18 a MR, in 11/18 a no change and in 4/18 a PD of t u mor, Medizinische U n i v e r s i t ~ t s k l i n i k I, Joseph-Stelzmann-Str. 9, D-5000 K~In 41

S 127

4/P-GM028

4/P-GM 030

T R E A T M E N T AND FOLLOW-UP IN PEDIATRIC BP~IN TUMORS G.Jacobi,B.Kornhuber,G.Weiermann,D.Schwabe

A RAT TUMOR MODEL WITH INTACT IMMUNE SYSTEM AND DISTUR= BED CENTRAL NERVOUS FUNCTIONS Alexandra v , M e t z l e r and Cordula Nitsch

If signs and symptoms in a child favor the diag= nosis of brain tumor this today is e s t a b l i s h e d by CT-scan, MRI and cerebral a n g i o g r a p h y . A f t e r surgery and n e u r o p a t h o l o g i c a l evaluation two co= horts emerge: a) those with benign lesions who do not need chemotherapy(CHT) or radiotherapy(RT) either. A n t i c o n v u l s a n t t h e r a p y is m a i n t a i n e d fol= lowing surgery in s u p r a t e n t o r i a l lesions for 2 years and might d i s c o n t i n u e d then if there were no more seizures, no tumor recurrence, and no seizure d i s c h a r g e s in the EEG. Clinical followup is done 4/8/12/18/24 months after o p e r a t i o n EEG included, and C T / H R I - c o n t r o l s every 6 months in the 2 and once w i t h i n the next years. - b ) i n children with m a l i g n a n t lesions (grade III/IV) CHT is done b e f o r e RT in the sandwich principle: in p a t i e n t s who have germ cell tumors according to the "EINHORN" regime (Neuwelt, 1979) and in all o t h e r s 2 a c c o r d i n g to a mixed protocoll of HDMTX{12 g/m ) and the "7 in I day"(Bleyer, 1983). RT then might be started 10-12 weeks after the surgery. CT-controls here are 5 days after opera= tion, in the middle and end of CHT and RT.There= after 6/12/18/24/36/48/60 months. C T - s c a n might be replaced by MRI if distant m e t a s t a s e s in the neuraxis are considered. M y e l o g r a p h y should be done after ependymoma and m e d u l l o b l a s t o m a remo= val 6/J8 and 36 months l a t e r . C . S . F . e x a m i n a t i o n should include c y t o l o g y , B - H G , A F P , C E A , P R L in the g e r m cell group and the polyamines in M B L . - E n d o = crine tests (TSH/STH) should be done every 2 years and p s y c h o l o g i c a l evaluation 1,2 and 4 years af= ter RT.

Rats injected subcutaneous]y with 3-methylcholantrene (3MC) developed tumors in a dose-dependent manner after 4-6 months.ln an attempt to test the involvement of the im = mune system,we destroyed the reticule-endothelial system of tumor-bearing rats by X-ray irradiation of 780 r,a do= sage wh• they tolerated much batter than tumor-free controls.Yet,the following heterologous transplanation of bone marrow or spleen cells from healthy rats lead to the death of tumor bearing animals.When,however,the dose of irradiation was reduced to 140 r,the infusion of bone marrow or spleen cells was tolerated,the survival time doubled and some tumor remissions occured.Thus,it seemed unpropable that the immune system played a major role in the control of 3-MC induced tumors. On the other hand,in 3-MC treated rats neuropathological changes comparable to the paraneoplastic syndrom were ob= served.In addition,EEB-recordings 24 h after administre = tion of 3-MC revealed an increased occurance of rapid frequencies.Rats with Walker carcinoma or Jansen sarcoma also showed a substantial increase in rapid frequencies. These EEG-change are accompanied by increases in GABAcon= tent in hypothalamus and hippocampus and reduced concen= trations of monoamines or their metabolites in hypothala= mus and hippecempus and reduced concentrations of mono = amines or their metabslites in hypothalamus and caudate nucleus.Daily treatment with psychoactive substances such as imipramin or piracetam,normalized the EEG-changes,re = versed the disturbances in transmitter metabolism end prevented tumor developement and growth. Based on these observations a direct communication betwe= en the central nervous system and the tumor cells with = out interrelation of the immune system is postulated.

Zentrum der K i n d e r h e i l k u n d e , A b t l g . f ~ r P~diatri= sche N e u r o l o g i e und A b t l g . f ~ r P ~ d i a t r i s c h e H~ma= tologie und Onkologie, Thecdor Stern-Kai 7 D-6000 F r a n k f u r t / M a i n - 7 0 , F R G

MPI f.Hirnfarsehun~, 6 Ffm l,Deutschordenstr. 48, BRD Patholog.Institut, Uni Basel, Pestalozzistr.20, CH

4/P-GM029

4/P-GM 031

T o x i c i t y of a new intensive c h e m o t h e r a p y protocol for m a l i g n a n t brain tumors in children. D. Schwabe, G. Jacobi, V. Gerein, B. K o r n h u b e r

SIGNIFICANCE OF T U M O R BIOPSIES METASTASES B. Volk and K. Schwechheimer

A protocol which constists of alternating high dose m e t h o t r e x a t e and an "8 drugs in 1 day" regimen (Bleyer,1983) is e v a l u a t e d for bone m a r r o w and n e u r o l o g i c a l toxicity. MTX was given at 12g/m2/4 h w i t h c i t r o v o r u m factor rescue 6 h after the end of the MTX infusion. The "8 in i" cycle c o n s i s t e d of methylprednisone, vincristine, hydroxy-urea, procarbacine, CCNU, cisplatinum, c y t o s i n e - a r a b i n o s i d e and cyclophosphamide. Each cycle was scheduled to be given up to six times if tolerated. The c h e m o t h e r a p y was followed by radiation. Seven patients suffering from medulloblastoma, astrocytoma grade III and e p e n d y m o m a were treated with this protocol. A total of 38 courses of H D - M T X and 30 courses of "8 in I" were given. Bone m a r r o w d e p r e s s i o n was more p r o - n o u n c e d after "8 in l" than after HD" MTX. With H D - M T X the average d r o p of the leukocytes was 20% of the p r e t h e r a p e u t i c value after 5.3 +/~ 2.6 days. In contrast to that with "8 in i" the leukocytes dropped to an average of 40 % of the p r e t h e r a p e u t i c value w i t h i n I0 +/- 3.7 days. The next cycle of c h e m o t h e r a p y could be given I0 +/- 4 days following H D - M T X and 19.5 +/- 8.3 days f o l l o w i n g "8 in I" respectively. Major n e u r o l o g i g c a l c o m p l i c a t i o n s were not seen after cytostasis. We conclude that a our combin a t i o n of "8 in I" and H D - M T X offers a possib i l i t y to further increase intensity of chemotherapy for m a l i g n a n t brain tumors. H e m a t o l o g i cal and n e u r o - l o g i c a l toxicity are tolerable. Dept. of Pediatric H a e m a t o l o g y and Oncology, Johann W o l f g a n g Goethe Universit~t, Theodor Stern Kai 7, D 6000 Frankfurt 71, G e r m a n y

In a neurosurgical eerie the frequency of intracerebral metastases is about 5 %. The site of primary tumor is unknown in 15 % of aH brain metastases. Those cases represent a challenge to the neuropatholegist. In a general, a reliable d i f f e r e n t i a t i o n between autochthonous brain tumors and metastases can be done by light microscopic examination of p a r a f f i n sections. Problematic cases, however, r e q u i r e immunocytochemical methods using a panel of cellular markers, especially components of the cytoskeleton. It is easily possible to d i f f e r e n t i a t e a gila1 filament e x p r e s s i n g glloma from a c y t o k e r a t i n - d e s m o p l a k i n positive carcinoma metastasis. Cytokeratins form a muttigene family of d i f f e r e n t polypeptides which are expressed in a d i f f e r e n t i a t i o n - d e p e n d e n t manner. Using monoclonal antibodies against individual c y t o k e r a t i n polypeptides e p i d e r moid and glandular carcinomas can be d i f f e r e n t i a t e d . In metastases of papillary adenocarcinomas, the lack o f c y t o k e r a t i n polypeptide No. 7 is indicative f o r a cole-rectal carcinoma. Up to date, those results, however, are preliminary and should t h e r e f o r e be interpreted with caution. The site of primary tumor can be specifically localized by positive immunocytochemieal demonstration o f t h y r o g l o b u l i n ( t h y r o i d cancer) as well as prostatic acidic phosphatase and prostate-specific antigen (prostatic neoplasms}. In conclusion, immunomorphofogy is a valuable method to differentiate brain metastases.

IN

BRAIN

Abteilung Neuropathologie, Pathologisches Institut der Universit~it, Albertstra6e 19, D-7800 Freiburg i.Br.

S128

4/P-GM 032

4/P-GM 034

RESULTS OF SURGICAL TREATMENT OF 215 PATIENTSWITH METASTATIC BRAINTUMOURS R. ScbGnmayr, J.C. Tonn and C. Keller

CENTRAL NERVOUS INVOLVEMENT IN BREAST CANCER H.J. Lenz, B. Steinke, U.M. Roos, M. Biedritzky, H.D. Waller .....

215 Patients with metastatic brain tumours who were treated at the Neurosurgical University Clinic Giessen between 1977 and 1986, have been analyzed. 180 patients underwent surgery, 38 out of them more than once. Alltogether 239 operations have been performed. In 84 patients the site of the primary tumour was unknown at the time of diagnosis of the metastasis. The most frequent location of primary tumours Were the lung followed by the kidney. After that malignant melanomas, then carcinomas of the breast and of the gastrointestinal tract. Solitary metastases were found in 69%, two in 9% and three or more in 22% of the patients. The accuracy of radiological diagnosis was 100%with MRT, 99% with CT, and 86% with angiography. Patients who were not operated survived 5 weeks (median). Postoperative median survival ranged from 17 (pulmonary tumours) up to 37 weeks (malignant melanomas). The median survival from the operation of the primary tumour was between 50 (pulmonary tumours) and 190 weeks (malignant melanomas). 25 patients are s t i l l alive, 10% of patients at working age went back to work. The rate of postoperative neurological complications was 10%, of non-neurological complications 14%. The 30-day postoperative mortality rate was 6,9%. Age and sex distribution, neurological symptomatology and general condition of patients with different primary tumours have been studied. The outcome is dependent on site and grade of malignancy of the primary tumour, age and clinical condition of the patient.

Out of 281 patients with breast cancer treated in our i n s t i t u t i o n between 1980 and 1986, 43 (16%) had central nervous involvement: 8 patients developed meningeosis carcinomatosa, 27 cerebral metastases and 8 both forms of manifestations. Leading symptoms of central nervous involvement were: cranial nerve pulsies in 54 %, headache (42 %), psychic alterations (30 %) and nausea and vomiting (30 %). 27 % of patients had signs of meningeal i r r i t a t i o n independent of the form of the manifestation. In 3 patients, cerebral symptoms were the f i r s t signs of breast cancer and led to the diagnosis of the disease. In 15 patients ( 35 %), the cerebral manifestations were diagnosed at the time of f i r s t relapse after primary treatment. All other patients (59 %) developed central nervous involvement during the further course of t h e i r disease. The mean time from diagnosis oF bl-~asL ca(ic~F to Lhs di~,,u~i~ oF cerebF~] involvement was 64 months in patients with meningeosis carci nomatosa and 41 months in patients with cerebral metastases. Central nervous system was the only site of :disease only in 4 patients, all others had further metastases in bones (60 %), lungs (58 %) or l i v e r (35 %). Patients with meningeosis carcinomatosa were treated with methotrexate i t h . , in 5 patients combined with i r r a d i a t i o n of cerebrum and neuroaxis, patients with brain metastases recieved cerebral i r r a d i a t i o n , both modalities combined with systemic treatment. Average survival after the diagnosis of central nervous involvement was 8 months. Medizinische Universit~tskl inik, Medizin IT, D-7400 TQbingen

Abteilung

Inhere

Zentrum fur Neurochirurgie der Justus-Liebig-Univers i t a r Giessen, Klinikstr. 29, D-6300 GIESSEN, FRG

4/P-GMO33

4/P-GM 035

THERAPY OF A RAT BRAIN GLIOMA WITH A METHOTREXATE (MTX)-PUMP APPLIED INTRANEOPLASTICALLY B.Rama,J.Bircher,T.Schott,A.Langer,H.D.Mennel and E.Markakis

HYPERFRACTIONATED IRRADIATION OF MALIGNANT GLIOMAS: FIRST RESULTS OF A PILOT STUDY K.Schnabel, W.Berberich, B.Seharding, H.J.Tkocz, M.Niewald, Ch.B,Osterteg, W.Trebert

The b l o o d - b r a i n - b a r r i e r is responsible for poor results in systemic chemotherapy of human prima ry brain tumors.By applying the drug directly to the tumor,the intraneoplastic concentration of the drug was higher than by i.v. application (CH.Tator et al.J Neurosurg 46,165,1977).Transplanted mammary carcinoma in mice (HU.Langendorf et al.Langenbecks Arch Chir 371,123,1987) as well as a rat brain glioma (B.Rama et al. Acta N e u r o c h i r (Wien) 87,70,1987) showed a decrease of tumor growth when MTX-Palacos (P~LMA) was inserted into the tumor.Because of the very quick release of MTX from P M ~ in the rat brain tumor model the median survival time of animals treated with MTX as opposed to untreated animals was was increased by only 69 %. To maintain a higher MTX concentration for a lon get period of time within the tumor a mini-osmo tic pump was used.Therapy started on day 14 post tumor transplantation by stereotactic implantation of the tube of the pump into the brain tumor (n=8;0,2 m g MTX/kg daily for 14 days).Untrea ted rats (n=10) or rats with placebo-pump (n=9) served as controlsoMTX treatment via pump increa sed median survival time by 168 % = 37 days.

Recent results of fundamental research in radiation biolegy suggest that the healthy brain suffers less damage if irradiation is hyperfractioneted, i.e. a reduced dose applied several times a day without shortening the overall treatment time, Over e period of about 3 years 37 patients considered suitable for a phase I study (sstrocytomas grades III und IV, including glioblastomas) were hyperfractionally irradiated. A total dose of 70 Gy was applied to 29 patients in 70 fractions of 2 a day for 7 weeks~ The ether 8 patients received e total dose of 77 Gy in that the evening dose was increased from 1.0 to 1.2 Gy. During the same period 11 patients were treated conventionally, either because they had refused hyparfrectionation or because the patient frequency was too high. The hyperfractionally treated patients, including those who were applied the 77 Gy, tolerated the treatment well in general. The Keplan-Meier estimate of survival showed no difference between the hyperfractionated and the conventionally treated groups. After one year 35 % of the patients were alive. Unexpectedly the average course o f the Karnofsky indices also did not differ significantly.

Clinical trials with this method with glioma appear justified.

in patients

Neurochirurgische Klinik und Abt. Klinische Phar makologie der Universit~t G~ttingen,Rob.-KochStr. 40, D-3400 G~ttingen und Neuropathologische Abt. der Universit~t Marburg, Baldinger Str., D-3550 Marburg

Abteilung for Strahlentherapie, Radiologieche Universit~tsklinik D-6650 Homburg/Saar

S 129

4/P-GM 036 COMPUTERIZED

4/P-GM 038 CRANIAL

TOMOGRAPHY

IN

2A2

PATIENTS WITH BRAIN METASTASES OF LUNG AND BREAST CARCINOMAS J.G~rich, F.G~cKel~

M.Fientje ~ , S.A.Beyer-Enke, G.Probst2~ 1,7una, G.van Kaiok

2C2 brain or Lung cancer patieots with pathological computed tomography (CT) of t h e b r a i n were reviewed. More than 580 metastases were detected. Incidence is h i g h e s t between the a g e s of 4 0 a n d 70 y e a r s f o p l u n g c a n c e r patients, under 40 years for breast cancer patients (p < O ~ O l ) ~ CNS (Central nervous system) metastasis and increased edema occurred more frequent[y in y o u n g e r patients than older patients (D < 0,03). Analysis of the amount of edema on CT s h o w e d that usually ademocarcinoma has more often e big surrounding edema compared with other oarainomas ( p
R e p o r t on the r e s u l t s o b t a i n e d when o p e r a t i n g oll 29 c a s e s of b r a i n m e t a s t a s i s due to lung c a n c e r F r a n z X. Weinzierl, A. E. T r a p p e , J.D. R o d e r , W.E. G0bel, Summery: We a r e r e p o r t i n g on 29 p a t i e n t s , who w e r e o p e r a t e d on for b r a i n m e t a s t a s i s d u e to lung c a n c e r . O u r p r o g nosis is d i f f e r e n t i a t e d a c c o r d i n g to d i f f e r e n t w a y s of t r e a t m e n t of t h e lung c a n c e r involved, t h e l o c a l i z a t i o n and f r e q u e n c y of r e c u r r e n c e o f the b r a i n m e t a s t a s e s . N e u r o c h i r u r g i s e h e A b t e i l u n g der C h i r u r g . K!inik und Potiklinik des K l i n i k u m s r e c h t s der Isar der T e c b n i s e h e n Universit~tMQnchen

Heidelberg

4/P.GM 037

4/P-GM 039

STEREOTACTIC R A D I O T H E R A P Y OF S O L I T A R Y BRAIN METASTASES WITH A LINqEAR ACCELERATOR

COHBINED CHEMOTHERAPYWITH ACNU/IFOSFAMIDE AND SIMULTAN~ EOUS RADIOTHERAPY IN PATIENTS WITH BRAIN METASTASES OF LUNG CANCER H. Purea, M. Schroeder, R. Donhuijsen-Ant, H.A. Vaupel and M. Westerhausen

R. Eugerdmrt, V, Sturm, B. Kimmlg, M,Marln-Grez, W. Wowra, B. Rhein, K.H, t-t6ver For radiosurgery, at the German Cancer Research Center in Heidelberg, a linear accelerator was first adapted and has been in clinical use since 1984 for stereotactic irradiation. The most important component of the planning system is the compatibility with the accelerator and CT. Speed and precision are also important as the patient is under anesthesia during this time. Therapy is carried out with an arc technique through eleven Nanes giving an extremely steep dose fall off on the field tam'gin. The tumor dose is applied in either one or two fractions. The procedure has been proven on intracranlal lesions. In the follow'g, experience in the treatment of secondary brain tumors is reported. 27 patients with solitary, inoperable metastatic brain lesions from radioresist~t primary Oamors were treated. 12 patients with a follow up of more than three months were evaluated. In 8 of 12 cases the results were good with complete or nearly complete reduction of the metastasis and edema as shown on CT exanfmatioa, Con'esponding neurological symptoms were also substantially reduce&Only one patient showed tumor progression. One patient with an extensive infratentorium edema suffered complications following therapy and died, No further severe side effects were seen, Palliative effect of the described method is excellent. Another consideration is that compared to com,entional radiafiort therapy, the time involved per treatment is three days. Further improvements are expected, for example, the use of head masks with the stereotaetle cordinate system. Any experience acquired in this direction MII also be reported. Tumorzentrum Heldelberg-Mannheim Im Neuenheimer Fold 105; 6900 Heidelberg

ACNU is a nitroseurea compound with proven a c t i v i t y in brain tumours and lung cancer. An additive e f f e c t can be achieved by combination of ACNU with simultaneous i r r a d i a t i o n or with other cytostatic drugs especially Ifosfamide. Since May 1986 we started the combined treatment in 24 brain metastasized patients with small cell (SCLC) and non-small cell lung cancer (NSCLC). All patients had primarily an advanced disease and all but two were heavily pretreated with different cytostatic combinations. At time of relapse with cerebral metastases the following schedule was ~iven: ACNU 80 mg/m d I , Ifosfamide 1.2-1.5 g/m2 d I-5. A simultaneous i r r a d i a t i o n was started with a t o t a l dose of 30-40 gy. Up to now we achieved f o r SCLC (n=16) CR 2 (12.5 %), PR 6 (37.5 %), NC 6 (37.5 %), PD 2 (12.5 %). For NSCLC we found respectively (n=8) PR 2 (25 %), NC 5 (62.5 %}, PD l (12.5 %). Four grade IV haematological t o x i c i t i e s h a v e been registrated during 49 ACNU/Ifosfamide courses combined with simultaneous radiotherapy. Two drug related deaths by septicemia were noticed. In our experience the simultaneous application of chemotherapy with ACNU/Ifosfamide and irradiation of the skull was well tolerated. Due to these early encouraging results we started a clinical trial with ACNU/Ifosfamide combined with simultaneous i r r a d i a t i o n of the brain as f i r s t line therapy f o r patients with cerebral metastases caused by lung cancer. I I . Med.K1inik, St.Johannes-Hospital, An der Abtei 7-II~ D-4100 Duisburg I I

$130

4/P-GM 040

4/P-GMO42

ASPECTS OF N E U R O S U R G I C A ~ INTERVENTION FOR SPINAL M A N I F E S T A T I O N S OF M A L I G N A N T LYMPHOMAS D. Gruia, M. Brandt, J. ~ m a g n o s t o p o u l u s - S c h l e e p , E. Cloke

SURGICAL TREATMENTIN CERVICAL SPINE METASTASES R. Kalff, K. Roosen, W. Kocks, W. Grote, K.P. Schmit-Neuerbur~

Spinal m a n i f e s t a t i o n of m a l i g n a n t lymphomas are rare. Most times we are dealing w i t h ~ e x t r a l dural tnmor infiltrate o r i g i n a t i n g from osseous metastases or paravertebral lymphomas. Primal extra - or intradural o r spinal m e t a s t a s e s are a rarity. Treatment of choice is chemo- or radiotherapy. Neurosurgical intervention is only necessary in case of m a n i f e s t or imminent n e u r o l o g i c a l complication. During the last ten years eleven patients with spinal c o m p l i c a t i o n s 6f m a l i g n a n t lymphomas have under~one surgical teatment.Our intervesti% gations included type and location of tumor manifestations, the state of primary disease at the time of manifestation, indication for surgery, therapeutical results and longterm prognosis. The correct therapeutic decision depends on an exact d i f f e r e n t i a t i o n between a genuine tumor m a n i f e s t a t i o n and complication r e s u l t i n g from farmer clinical procedures. Results will be competed w i t h scientific literature. N e u r o c h i r u r g i s c h e Klinik der W e s t f ~ l i s c h e n Wilhelms-Universit~t, Albert-Schweitzer-Str. D-44OO M[~ster

33,

In about 5 % of malignant tumours there is an involvement of the spine. Because of destruction of anterior or posterior structures c l i n i c a l i n s t a b i l i t y of the spine may occur combined with unavoidable progressive neurological d e f i c i t s . To prevent this, early operation with decompression of the spinal cord and nerve roots as well as following s t a b i l i z a t i o n of the spine should be done. By this more quality of l i f e can be achieved for the remaining time. We report on 18 patients operated because of cervical spine metastases during the last 6 years with an average age of 56 years. Sex r a t i o was 1,5 : 1 with female preponderance. At time of operation the average history of cancer disease was 4 years, related to neurological symptoms 5 months. Preoperative neurological deficits consisted in radicular lesions in 14 cases. Four patients had incomplete tetraparesis. Ventral spondylectomyand fusion was done in 10 patients, dorsal spondylodesis in 4 cases and combined ventral and dorsal s t a b i l i z a t i o n was necessary in another 4 cases. There was a neurological improvement of two patients with i~ncomplete tetraparesils. They were able to walk again, whereas in one patient the neurological status worsened because of luxation of the dowel. In the remainilng patients the neurological status was unchanged. Average survival time was 11,5 months. Neuroc~irurgische und Unfallchirurgische" Klinik der Unive~sit~tsklinik Essen, Hufelandstra6e 55, D-4300 Essen 1

4/P-GM041

4/P-GM 043

DIAGNOSIS, THERAPY AND SPAN OF SURVIVAL OF 180 PATIENTS WITH HIGH-GRADE GLIOMAS B. Salzberger.~ .j. Jeske

SURGICAL TREATMENTOF CEREBRALMETASTASES W. Kocks, R. Kalff, K. Roosen, W. Grote

A l l p a t i e n t s (n = 180) a d m i t t e d t o the U n i v e r sit~ts-Nervenklinik KBln between 1972 and 1984 because o f h i g h - g r a d e g l i o m a s ( W H O - c l a s s i f i c a t i o n grade I I I or IV) were e v a l u a t e d r e t r o s p e c t i v e l y concerning r e l e v a n t c l i n i c a l , d i a g n o s t i c and t h e r a p e u t i c a l i t e m s . The median s u r v i a l t i m e o f 30 weeks f o r pat i e n t s i n the period from 1979 to 1984 (n = 87) was significantly longer than the 8 weeks for patients in the period from 1972 to 1978

(p

0,05).

I t can be shown t h a t t h i s d i f f e r e n c e i s a r e s u l t o f changes in s t r a t e g i e s o f d i a g n o s i s and t h e r a p y , such as m i c r o s u r g e r y , a d i f f e r e n t r a d i o - t h e r a p y and f i n a l l y t h e s y s t e m a t i c a p p l i c a t i o n of dexamethasone. P a t i e n t s i n t h e p e r i o d from 1979 t o 1984 were at an average of 2,3 years younger when diagnosed for the first time, This remarkable observation can only partly be due to the introduction and availability of CT in the diagnosis of brain tumors. Universit~ts-Nervenklinik doseph-Stelzmann-Str. 9 D - 5000 K6in 41

K61n

We report on 204 patients, operatedbetween 1976 and 1985 because of brain metastases of various origin. The age ranged from 19 to 79 years, with an average of 53,5 years. There was a high male preponderancewith a ratio of nearly 2:1. Bronchial carcinoma represented the most frequent primary tumor, followed by melanoma,breast carcinoma, hypernephroma, various types of gastrointestinal tumors, carcinomas of the genitourinary tract and sarcomas. In 40 % cerebral symptomswere the f i r s t manifestation of cancerous disease. In case of well knownprimary tumor (60 %) the average time betweendiagnosis of cancer and the beginning of cerebral symptomswas 32 months. The average duration between the beginning of cerebral signs and diagnosis of brain metastasis was function of the kind of those symptoms. Indications for surgical treatment, results and complications are presented. I t is important to discuss the influence of survival time and quality of daily living upon the indication for operative therapy in function of the different kinds of tumors; e.g. we see nobenefit in surgical treatment of sarcomametastases. Neurochirurgische Klinik der Universit~tsklinik Essen, Hufelandstra6e 55, D-4300 Essen i

S 131

4/P-GM044 RADIOTHERAPY AND ACNU METASTATIC BRAIN LESIONS. D. Katsohi, J.H. Karstens,

4/P-GM 046 IN

PATIENTS

WITH

J. A m m o n

R a d i o t h e r a p y is the t r e a t m e n t of c h o i c e in patients (pts) with brain metastases (BM) . To improve local control we added ACNU, an injectable nitrosourea compound, to external beam i r r a d i a t i o n . W e t r e a t e d 48 pts w i t h BM f r o m solid t u m o r s w i t h this c o m b i n e d regimen, Pts were included if performance status was > 50and immediate t r e a t m e n t of the p r i m a r y t u m o r or f u r t h e r d i s t a n t m e t a s t a s e s w a s not necessary. Whole brain irradiation was perform e d w i t h a t o t a l m i d l i n e dose of 30 Gy (single dose: 1,8-2,0 Gy) and concomitant administrat i o n of steroids. In pts t r e a t e d i n i t i a l l y with this regimen, ACNU was given at a m a x i m u m single dose of 75 mg/qm. Because the duration of response is limited in pts with brain metastases, a 4 w e e k i n t e r v a l s e e m e d m o r e a p p r o priate than the recommended 6 week intervals, E r o m this p r a c t i c a l p o i n t of view, a s i n g l e dose of 55 m g / q m (range 50-75 m g / q m ) q 4 w e e k s w a s used. 45 pts (~3 cycles ACNU) are evaluable for t o x i c i t y and response, N a u s e a and v o m i t i n g o c c u r r e d rarely. T h r o m b o c y t o p e n i a with this schedule was registered as follows: W H O I 14 pts; W H O II 3 pts; W H O III 1 pt w i t h no bleeding complications. Complete remission w a s o b s e r v e d in 15 pts, p a r t i a l r e m i s s i o n in 17 pts. Observations: irradiation and ACNU in pts with brain metastases is feasible with the proposed dose schedule of 55 m g / q m q 4 weeks. F u r t h e r e v a l u a t i o n of this r e g i m e n w i l l be necessary,

Rapid hi#h-dose radiation schedules for the treatment of Brain metastases N, u T. G. Fendt, R. Rohloff

From 1981 to 1986 300 patients (pts.) (male:female=l:l, median age: 55 yrs., range: 18-83) with intracranial metastases from peripheral solid tumours (breast carcinoma: 32%, small cell lung cancer [SCLC]: 11%, non small cell lung cancer [NSCLC]: 17%, malignant melanoma: 8%, renal cell carcinoma: 7%, unknown primary: 8%, other tumours: 17%) received brain irradiation. 36% of pts. revealed solitary intracranial lesions, 64% multiple metastases. Only six pts. were seen postoperatively. All pts. were treated by lO X 3 Gymidline dose/ 2 weeks whole brain irradiation, those with slowly progressive disease or who were supposed to have a fairly good prognosis with regard to their peripheral disease were given an additional dose of 14 to 20 Gy/l.5 to 2 weeks either confined te the lesion(s) or to the whole brain. The most striking prognostic factor turned out to be the event of complete response in CT followed by the activity of peripheral disease (in breast cancer) and to a lesser extent the number of intracranial lesions. Overall survival at 6, 12 and 24 months was 35%, 20% and 15% (Kaplan-Meier) irrespective of the primary. One ysar survival rate amounted to 15% in breast carcinoma with unfavourable prognosis, 35% in those with a fair prognosis, 0% in SCLC and NSCLC, 30% in melanoma, 25% in renal cell carcinoma, 30% in unknown primary and 17% in other tumours. Following conclusions can be derived: i. In contrast to other studies it appears justified to apply a higher than standard dose to the brain in pts. with a supposed more favourable prognosis esp. in breast carcinoma. 2. Pts. with SCLC or MSCLC have such a short live span to experience that rapid treatment is advisable. Dr. T. G. Wendt, Dep. Radiology, University of Munich, Klinikum Grosshadern, Marchioninistr.15, 8000 Munich 70.

Abt, Strahlentherapie, Med. Fakult~t, Klinikum R W T H Aachen, D-51 Aachen, Pauwelsstr.

4/P-GM 045

4/P-GM 047

BREAST CANCER AND METASTATIC BRAIN LESIONS: RAPID REGRESSION OF SYMPTOMS WITH IRRADIATION. T.A.M,Verschueren, J.H. Karstens,D. Katsohi, J.J. Jager, F.M. Gescher, J. A m m o n

MONONUCLEARINFILTRATES IN CARCINOMAMETASTASES OF THE HUMAN BRAIN l.Becker, W.Roggendorf, W.Paulus, J . P e i f f e r

In ~---~nts ipts) with breas't cancer and m e t a Cs t a t i c b r a i n lesions, radiotherapy is the established form of treatment. Rapid improvem e n t of s y m p t o m s is the m a j o r a i m in t h e s e pts. In close cooperation of two institutions, 45 c o n s e c u t i v e pts w i t h b r e a s t c a n c e r and brain metastases were treated with whole brain irradiation during the period 1982 - 1986 with a t o t a l d o s e of 30 Gy. The m a j o r i t y of pts received additional steroids. Using RTOG c l a s s i f i c a t i o n of n e u r o l o g i c f u n c t i o n 42 pts are evaluable. The d e g r e e of r e s p o n s e w a s documented with computed tomography in 20 pts, Improvement of neurologic function by at least one c l a s s w a s r e g i s t e r e d in 21/42 pts by the end of the first week and i n 75/~? pt~ by the end of the s e c o n d week. W h e n u s i n g r e s p o n s e c r i t e r i a p u b l i s h e d by R o s n e r (Cancer 58, pp 832, 1986) the following remission rates were observed: CR 4/20, PR 9/20, s t a b l e d i s e a s e 6/20, progressive disease 1/20. Medium survival t i m e in 42 pts is 6,5 (3-36+)months. C o n c l u s i o n : p r o m p t n e s s of c l i n i c a l r e s p o n s e and t h e l o w rate of p r o g r e s s i v e d i s e a s e are the main arguments in favour of irradiation. R a d i o t h e r a p e u t i c I n s t i t u u t Limburg, Heerlen, T h e N e t h e r l a n d s u n d Abt. S t r a h l e n t h e r a p i e , Med. Eakult~t, K l i n i k u m R W T H Aachen, D-51 Aachen, Pauwelsstr.

Analysis of subpopulations of inflammatory cells in 20 metastases of carcinomas was done using monoclenal antibodies to mononuclear inflammatory c e l l s . On paraffin embedded or cryostat sections the inflammat o r y cells were i d e n t i f i e d by the following antibodies: LC, OKT4, keu3a, OKT8, Leu2a, OKM5, Leu7, Leullb, Leu12. Visualisation was achieved with PAP or APAAP staining. The percentage of positive cells was determined at a magnification of x160 counting four microscopic f i e l d s of each biopsy. I n f i l t r a t i n g mononuclear c e l l population represents averagely 16,5% (range 9,9-21,4%) of t o t a l c e l l s . ~eavy lymphocytic i n f i l t r a t s were f~und in perivascular spaces and along connective tissue. The density of i n f i l t r a t i o n varied in d i f f e r e n t areas of the tumors without conceivable c o r r e l a t i o n to local tumor morphology. Most of the i n f i l t r a t e c e l l s were T-lymphocytes with a M i g h t preponderance of OKT8+Leu2a+ c y t o t o x i c / suppressor T-cells. Monocytic cells (OKM5+) were present in the boundary area between i n f i l t r a t e and tumor parenchyma. The i n f i l t r a t e s also contain considerable numbers of B-cells (Leu12+). NK-cells account only f o r a minor percentage of inflammatory cells never exceeding 10%. NK-cells were closely associated with mononuclear i n f i l t r a t e s , No c o r r e l a t i o n of i n f i l t r a t e composition and degree of d e d i f f e r e n t i a t i o n or primary tumor s i t e ( g a s t r o - i n t e s t i n a l , lung, urogenital, mama) was evident. Our results indicate, that antigen mediated immunereactions, especially by cytotoxic cells as well as natural immunity are engaged in defense of intracerebral cancer metastases. I n s t i t u t f~r Hirnforschung der Universit~t T~bingen, Calwer Str.3, D-7400 T~bingen

S 132

4/P-GM 048

4/P-GM 050

DETERMINATION OF PROLIFERATIVE POTENTIAL IN RECURRENT BRAIN TUMORS W. Roggendorf, K. Elmer, T. Schuster

ASPECTS OF N E U R O S U R G I C A L INTERVENTION FOR SPINAL MANIFESTATIONS OF MALIGNANT LYMPHOMAS D. Gruia, M. Brandt, J. A n a g n o s t o p o u l u s - S c h l e e ~

Immunohistological characterization of c e l l p r o l i f e r a t i o n using Ki-67 and anti-bromodeoxyuridine monoclonal a n t i bodies was applied recently to various brain tumors e.g. human gliomas (Burger et a l . , Am J Surg Pathol 10, 611, 1986) and meningiomas (Roggendorf et a l . , A c t a ~ u r o p a t h 73, 361, 1987). In order to establish the p r o l i f e r a t i o n Y-~te in recurrent brain tumors we investigated 9 meningiomas, 8 g l i a l tumors (4 of them with frozen material from both f i r s t and second operation), 3 metastases of c a r c i nomas and 7 other tumors (chordoma, p i t u i t a r y adenoma, neurinomas e t c . ) . Frozen sections were investigated with Ki-67 antibody (Dianova GmbH, Hamburg) using a modified APAAP-technique. Evaluation of p r o l i f e r a t i o n rate was done by counting K i - p o s i t i v e c e l l s in respresentative areas of the biopsy. The p r o l i f e r a t i o n rate of recurrent meningiomas was between 6.6 and 32.4 % which corresponds to the range of the prol i f e r a t i o n rate seen in t r a n s i t i o n a l and anaplastic meningiomas. P r o l i f e r a t i o n rate in normal meningotheliomatous, fibrous and angiomatous meningiomas ranges from 1.0 to 5 %. There was no treatment by e i t h e r chemotherapy or r a d i a t i o in these recurrences. In the g l i a l tumor group (mostly gliomas WHO grade 4) the p r o l i f e r a t i o n rate of recurrences was unchanged i f compared to 40 cases of glioblastomas investigated previously (Elmer et a t . , unpublished). Moreover, in these 4 cases in which we could compare the tissue from the f i r s t and second surgical treatment the p r o l i f e r a t i o n rate gives no clear hints f o r a reduction or increased p r o l i f e r a t i o n p o t e n t i a l of the tumor. Most of the 8 gliomas were postoperatively treated with chemotherapy or/and r a d i a t i o . These preliminary data suggest that there is an increase in the p r o l i f e r a t i o n p o t e n t i a l of recurrences only in meningiomas whereas g l i a l tumors are nearly unchanged. I n s t i t u t f u r Hirnforschung der Universit~t TObingen Calwerstrasse 3, D-7400 Tfibingen

Spinal m a n i f e s t a t i o n of malignant lymphoma are rare. Most times we are dealing with extradural tumor infiltrate originating from osseous m e t a s t a s e s or paravertebral lymphomas. Primal extra- or intradural or spinal metastases are a rarity. Treatment of choice is chemo- or radiotherapy. N e u r o s u r g i c a l intervention is only necessary in case of manifest or imminent n e u r o l o g i c a l complication. During the last ten years eleven patients w i t h spinal complications of m a l i g n a n t lymphomas have undergone surgical treatment. Our investigations included type and location of tumor manifestation, the state of primary disease at the time of manifestation, indication for surgery, therapeutical results and longterm prognosis. The correct therapeutic decision depends on an exact d i f f e r e n t i a t i o n between a genuine tumor m a n i f e s t a t i o n and complication resulting from former clinical procedures. Results will be competed with scientific literature. N e u r o c h i r u r g i s c h e Klinik der W e s t f ~ l i s c h e n Wilhelms-Universit~t, Albert-Schweitzer-Str. D-4400 MHnster

4/P-GM 049

4/P-GM051

IN-VIVO HALF LIFE AND TOLERANCEOF INTRATHECALLuADMINISTERED HUMAN INTERLEUKIN 2 IN CATS R. Martin, U. SchwOlera, G. Menke, W. Rudolph, K. Buch, U. Bogdahn, N. Rietbrock und P. Krauseneck

POSSIBILITIES OF TUMOUR SURGERY OF THE SPINE R, Baum, J. Harms and D, S t o l z e

Following activation of T cells, interleukin 2 (IL2) provides the second signal for T cell proliferation. Apart from its growth-promoting activity, I[2 has been shownto activate lymph(kineactivated killer (LAKe) cells and natural killer (NK-) eells which are bo~ effective in the lysis of various tuners. For these reasons IL2 seem~to be a good candidate for therapeutic approachesin cancer immunotherapyand is now'being tested in clinical trials. To assess the potential use of IL2 in brain tmmr therasy, we initially investigated t ~ in-vivo half life and tolerance of intrathecally administered humannatural IL2 (n-IL2; U. Sci~16ra, Biotest P~rma and H. Mohr, ~RK Spring~) in cats. After suboccipital p ~ r e , repeated doses (10~ - 1,5xI0~ units) of either unlabeledor 14C-labeledn-IL2 were instilled. Sequential cerebrospinal fluid (CSF) sappleswere then taken to documentthe in-vivo half life within the CSF. The IL2 activity was assayedby either 3H-th~wdine incorporation of PHA-blastswhich were cultivated in the presenceof serial dilutions of CSFor by liquid scintillation counting to detect 14C-IL2. Wecould showthat the in-vivo half life after intrathecal administration of n-IL2 ranges between 7 and 80 hours dependingon the dose of n-IL2 injected. Moreover i t could be sho~, that n-IL2 crosses ~ blood-brain-barrier in both directions. It is therefore suggestedthat a transport ~ n i s m with a constant turn-over is mediatingthe transition Of ~ material. Apart from that, n-IL2 even in e x t r ~ l y high doseswas wall tolerated beth after i.v. and intrathecal ~hninistration. Neither bodytemperature, nor bodyweight or differential blood count were significantly influenced. Fnlm these results we conclude, that intrathecally administerednatural IL2 is well tolerated and that the long in-vivo half life within the CSFfavours this route of administration for its potential use in neureencolngical t~erapy strategies. NeurologischeL~iversit~ts-Klinik, Josef-Schneider-Str. 11, 8700 WOrzburg

33,

Tumours of the spine are malnly a matter of metastases. D i f f i c u l t i e s in surgery concern the s t a b i l i t y of the supporting organ~ because of the neighbourhood of nerval structures ( e s p e c i a l l y spinal cord) and large vessels, which c a l l In question the r a d s of the operation, In the l a s t years operative considerably by the further procedures, included tumour to replace vertebral bodies an improvement of s t a b i l i t y , zatlon of the patients.

methods have been improved development of r a d i o l o g i c a l embolization. The p o s s i b i l i t y contributes significantly to and allows an early mobili-

Exampies f o r diagnostic and surgical proceedings are given. Odeborn-Klinik, Hinterm Sehlo6park, D-5920 Bad Berleburg

S 133

4/P-GM 052

4/P-GM 054

ARE REOPERATIONS OF VALUE IN CHILDREN

Unusual ~m~nifestations of cerebral metastases malignant Tumors.~

WITH RECURRENT BRAIN TUMORS?

S. Sielecki, H.-P. Backer, J. P. Haas

B~ K~hler I, T. Tzonos 2, and D. Class 3 In 16 children with recurrent ependymona, astrocytoma and sarcoma a study was designed to find out whether reoperations were of benefit for these patients, particularly in regard to the quality of life i. e. the duration of asymptomatic intervals and the development of children's functional and social status~ Using a 5 grads quality of survivals scale (SPUNBERG) and a composite Quality of Survival Index (QQS-Index),

the

values of rsoperation were retrospectively confirmed, mainly for patients with ependymooa and astrocytoma~ The results were

not satisfying in childre~ ~ith sarcomas~

In total the rate of complications diminished with the number of reoperations. 1

Kinderklinik des P~diatrischen Zentrums, Bismarckstr. 8, D 7000 Stuttgart i

Olgahospital,

2

Abteilung for Unfa31- und Kinderneurochirurgie, Katharinsnhospital, B 7000 Stuttgart 1

3

Nsurochirurgische Klinik, Universit~tsklinikum~ D 6000 Frankfurt 70

Incidence of inetastatic brain t ~ r is high in adults after middle age and is said to account for 3,3 - 15,3% (Cushing H. 1935, Olivecrona H. 1967, Zdlch KJ. 1956). In order of frequenc99 of the primary lesions, metastases originate frc~ tl%e lungs, breast, skL~, digestive syst~nl and kidhleys~ Frequently there may be no sign of prLmary lesions. Diagnosis of intracer~bral metastases is relatively simple in cases of multiple, diffuse and irregular low-density areas containing nodular or ring-like lesions on plain CT and nodular or ring-iLke em_hancecents after administration of contrast ~editl~. Differential diagnosis from malignant qlic~na or i~alignant lymp_hc~a is difficult when the lesion is solitary and shows an i r r e c n l ~ , not-ring-like enhancement or a r~d~xed (solid and cystic-necrotic) structure. He~rmrrhage into cerebral n~atastases are knc%~ in melmnoma and chorionepit~helioma (Gildersleeve et al. 1977). Calcifications in metastases are often r e c c ~ i z e d in osteosarcc~a. We demonstrate sc~e e x i l e s of unusual morphologic Manifestations of cerebral _metastases e,g. I .a huge solitary glioma-like lesion by adenocexcinoma of the lungs; 2.multiple ~ r ~ r r h a g i c ~_~etastases of adeno~arcinc~a of stomach; 3. prim~__~y calcifications in metastases of adenocarcincs~% of the It~ng. We point to the great ~Drp_~ologic variety of c~rebral metastases and ~ p h a s i z e , that morpholoqic signs alone (also o n ~:~-Imaging) are not sufficient for a correct diagnosis in a lot a cases. Pr~maz~_ brain timbers, inflammatory processes and malignant 1 3 ~ h o m a s are the most important lesions to be differentiated. R'dntgeninstitut, St~dtische Kliniken, D-6400 Fulda

4/P-GM 055

4/P-GM 053 ~SULTS

O F RADIOTHER/APY

I~ ~ A T I E ~ S

WI~H

BRAIN

METASTASES

M. Schmidt, W. Hinkelbein, N. eodapp~ M. Wannen~acher Abteilung fdr Strahlentherapie, Universit~tsklinik Freiburg, Nugstetter sir. 55, 7800 Freiburg

From 1971 until 1986 we treated 450 patients with train metastases originating from different primary tlumors (with th~ exception of meningeosis carcinomatosa or malignant lymphoma) with a megavoltage radiotherapy. 400 patients gst a total dose exceeding 30 Gy. Their one-year-survival rate was 26 %. Favourable prognostic factors were operation (in case of solitary metastases), a good Karnofsky-Index at the beginning of the therapy end regression of the neurologic symptoms under therapy~ Extremely unfavourable prognostic factors were an extracerebral metastastatic spread that could mot be influenced or bronchial carcinomas ~s primary tumors. In all other cases the histology of the primary tumor ~ade not significant differences. Accurate diagnosis is a must to improve the therapy results andin some cases - to avoid an uneffective treatment.

SPINAL INTRADURAL SEEDING OF NEOPLASTIC DISEASE B. Schuknecht, B~ MUller, P. Krauseneck

Of 86 patients with neuroradiologically diagnosed spinal neoplastic manifestation, 71 showed a pure extradural location (12 breast ca., i0 prostata ea~, 8 lung ca., 8 malignant melanomas, 8 leukemias and lymphomas. 4 hypernephromas~ 3 GI ca., I0 misceli., 8 unknown primary tumors). Intramedullary metastases in 2 cases originated from a lung c a . and a malignant melanoma respectively. In 13 cases an intradural seeding was proven by myelography and spinal CT (5 brain tumors, 3 lung ca., 3 leukemias and lymph0mas, i testicular teratoca, and 1 epipharynx ca. Preferential tumor sites were the conus and cauda equina and the dorsal region of the subarachnoid space. Three times the thecal sac was considerably obstructed. Disseminated nodules were demonstrated in ll cases, CSF investigation revealed malignant cells (1-96% of leukocytes) in all patients. Highest pleocytoses were found in hematological fflalignancies due to a high number of malignant cells. In all 13 cases of intradural neoplastic spread specific therapy by irradiation Or intrathecal cytostatic treatment was untertaken. Two of three patients reexamined by myelography showed morphological regression. Two deaths occurred within one month, ii patients were still alive three months after diagnosis of the intradural spread. The neuroradiological findings and treatment outcome will be described in detail. Kopfklinik der Universit~t, Abteilung f~r Neuroradiologie Josef-Schneider-Str. Ii, D-8700 W~rzburg

S 134

4/P-GM 058

4/P-GM 056 INTRAMEDULLARY SOLID TUMORS

SPINAL CORD METASTASIS

Prognosis and Treatment Cord Compression

IN

Kilian, M., Dittman, Krauseneck, P.

F~ .... ~ ~ Driieek M, Grlsold W Je!iinger K~ Weiss R 9 .Bcltzmann . . . . . In~t . . . .~ . K.~:~ Neurobioiogie, Wc!kersbergenstr~ 1,1130 Wien intramedullary spinal cord metastasis is a rere complication in patients with solid tumors. Differential diagnosis comprises cDmvressive mye!opathy, meningeal carcinomatests, radiation m y e i o p e t h y and paraneep!astic necrotic myelcpathy. Pain and a unchar a c t e r i s t i c pattern ef motor deficit are the leading symptoms. We report 12 patients with intrameduilary secondary growths form lung-, breast carcinoma and me!ancma. The site of the metastatic lesion was most commonly cervical and thoracic spinal cord. Multiple spinal cord metastasis was only seen in one patient. Clinica!~ neureradio!egic and auteptic findings are demonstrated~

INTRATHECAL TREATMENT OF LEPTOMENINGEAL OF M A L I G N A N T M E L A N O M A BY DTIC

SPREAD

C., Krauseneck, P., Pflughaupt, E., Mertens, H.-G.

K.-W.,

Treatment of l e p t o m e n i n g e a l spread of malignant m e l a n o m a by whole brain irradiation or intrathecal application of m e t h o t r e x a t e or c y t o s i n e - a r a b i n o s i d e often is unsatisfactory. Since 1979 we therefore used DTIC for intrathecal treatment in a small series of melanoma patients. Dosages up to 80 mg were a d m i n i s t e r e d in artificial CSF, u s u a l l y given intraventricularly. DTIC has to be mixed with buffered solution and be applicated by slow continous infusion. Side effects may be headache, nausea, emesis, or reversible disturbance of consciouscess if bolus application is done. Because of frequent side effects following lumbar a d m i n i s t r a t i o n (heavy local pain) we prefer v e n t r i c u l a r administration. In one case, whose previous metastases had shown an excellent response to DTIC, we have observed long term survival (7 years until now), and partial remissions were seen. M i c r o s o m a l activation of DTIC within the CSF may be achieved by macrophages. Since intrathecal DTIC treatment has considerable more toxicity than administration of m e t h o t r e x a t e or c y t o s i n e - a r a b i n o s i d e it should be restricted to non-responders or to patients with known high DTIC sensitivity of the primary melanoma. Neurologische

Richter,

Spinal

E.,

Clinical course and therapeutic medalities of 143 pts. treated at the department of neurology of the Univ. W O r z b u r g between 1973 and 1983 for m e t a s t a t i c spinal cord compression were analysed in a retrospective study. The most frequent primary tumors were ca. of the breast, lung, kidney, prostate and lymphoma ranging from 18% to 10%. 17% of p r i m a r y tumors remained unknown. Pain was the first symptom in 87% of the patients. Nevertheless a mean time of 5 months elapsed from the first n e u r o l o g i c a l symptom to the diagnosis of spinal cord compression and thus 90% of the patients already suffered from a neurological deficit and 26% were paraplegic when the diagnosis was made. Negative plain X-ray examinations were seen in 25% of all cases while 89% of these had positive m y e l o g r a p h i c findings. Analyses of possible p r o g n o s t i c factors in relation to treatment m o d a l i t y revealed type of p r i m a r y tumor and age as most important p r o g n o s t i c factors: Unfavorable are ca. of lungs, prostate and m y e l o m a whereas lymphoma and carcinoma of the breast have a more favorable outcome. Besides older age a progressive paresis or a severely impaired motor function were of unfavorable prognostic significance. Because of small subgroups a s i g n i f i c a n t l y different therapeutic outcome could not be demonstrated, but there is a clear tendency for better results with combined therapies than with s u r g e r y or r a d i o t h e r a p y alone. Neurologische Univ.-Klinik, D-8700 W ~ r z b u r g

4/P-GM 059

4/P-GM057

Meesmann, Rohrbach,

W.,

of M e t a s t a t i c

Univ.-Klinik,

D-8700 W~rzburg

Treatment of Leptomeningeal Solid Tumors

Carcinomatosis

of

Scheiber, S., Krauseneck, P., Rohrbach E., Kappos, L., Pflughaupt, K.-W., Seybold, J.-D,, Mertens, H.-G. We report on until now 52 cases of leptomeningeal spread (carcinoma of the breast (N=I4), of the lungs (N=I0), melanomas (N=II), m i s c e l l a n e o u s / u n k n o w n (N=9), intrinsic brain tumors (N=8)) diagnosed c y t o l o g i c a l l y (Sayk sedimentation chamber or cytospin). Intrathecal cytostatic treatment - u s u a l l y alternating methotrexate and c y t o s i n e - a r a b i n o s i d e applications in doses up to 50 mg (MTX) or 120 mg (Are-C) - was given in 46 cases with no serious side effects. Median survival times were in the range of 3 months with poorest prognosis for patients with unknown primaries or bronchial carcinoma (~I month). Single long term survivors (more than 12 months) were seen in all subgroups but bronchial ca.. The group of patients a d d i t i o n a l l y receiving intravenous c h e m o t h e r a p y showed a better outcome. Neurologische

Univ.-Klinik,

D-8700 W ~ r z b u r g

S135 4/P-GM060

4/P-GM 062

F r e q u e n c y of different types metastases in the s p i n a l cord A. Perez-Cant6 (I), Cerv~s-Navarro (i)

W.

of

hematogenous

JSnisch

(2),

J.

(i) Institut fgr N e u r o p a t h o l o g i e der Freien UniversitSt Berlin, Hindenhurgda~n 30, !000 B e r l i n 45 (2) Pathelogisches Institut, 8 e r e i c h 5Jedizin (Charit&) der Hmmboldt-UniversitSt zu Berlin, SchumannstraSe 20/21, D D R - I O 4 0 B e r l i n The origin of the most reported c a s e s of intradural spinal metastases are bronchial carcinomas. As bronchial carcinomas are the m o s t f r e q u e n t type of m a l i g n a n c y we u n d e r t o o k a study of 1.479 spinal cords of p a t i e n t s h a v i n g d i e d of a m a l i g n a n t t ~ m o r in an a t t e m p t to a s s e s s a r e l a t i v e f r e q u e n c y of the v a r i o u s kinds of spinal metastases. Leukoses and malignant lymphomas were excluded. We found intradural spinal metastases in ii cases, 4 of them bronchial carcinomas, 4 breast carcinomas, 2 m a l i g n a n t m e l a n o m a s and 1 carcinoma of the prostate. The relative f r e q u e n c y of intradural spinal m e t a s t a s e s in our series amounts to 4.9% for malignant melanoma, 4.4% for b r e a s t cancer, 1.9% for prostate c a n c e r and o n l y 1.4% for b r o n c h i a l carcinoma. Therefore in a large randomized g r o u p m a l i g n a n t m e l a n o m a and b r e a s t c a n c e r are the tuK,~ors with highest probability of metastases in the s p i n a l cord.

4/P-GM061

Grisold W L . B o l t z m a n n Inst. Wolkerebergenstr.

f. K!in. I,A ~!3o

~eurobio!~ie Wien

Meningeal carcinomatosis (MC) o c c u r s in 9-!9 % of s o l i d t u m o r s e i t h e r as p u r e ]eptomeD'_~ goal carcinomatosis or in c o m b i n a t i o n w ~ t h C?[S - s o l i d m e t a s t a s i s . L u n g - , b r e g s t c s r c ~ n o m a and m e l a n o m a are the p r i z e r y t u m o r ~ in m o s t cases 9 C l i n i c a l l y ce~-abra!, spine] or c r a n i a l n e r v e d ~ . ~ _ h ~ t ~ , or m e r e cc
4/P-GM 063

CEREBROSPINAL FLUID PHARMACOKINETICS OF METHOTREXATE AND CYTOSINE-ARABINOSIDE AFTER CONTINUOUS INTRATHECAL ADMINISTRATION Krauseneck, R., R ~ d e r * ,

C L I N I C A L F I N D I N G S IN M E N I N G E A L C A R C I N O M A T O S I S

P., K.,

P a h l k e G., B i t t k a u R ~ t t g e r I, E.

S.,

Martin,

In t h e r a p y r e f r a c t o r y c a s e s of l e p t o m e n i n g e a l s p r e a d of s o l i d t u m o r s ( m e l a n o m a , ca. of the b r e a s t , p l e x u s c a r c i n o m a , PNET, n a s o p h a r y n x c a r c i n o m a ) we u s e d d i f f e r e n t s c h e d u l e s of continous intrathecal cytostatic treatment i n s t e a d of b o l u s i n j e c t i o n t w i c e to t h r e e t i m e s a week. Intraventricular a p p l i c a t i o n of s m a l l d o s e s of m e t h o t r e x a t e e v e r y 12 h o u r s as p r o p o s e d by B l e y e r et al. 1978 in o u r h a n d s l e a d to i n c o n s i s t e n t a n d u n p r e d i c t a b l e MTX l e v e l s in the CSF. T h e r e f o r e we u s e d c o n t i n o u s i n f u s i o n s of M T X o r A r a - C at d o s e s of 1 m g / h o u r via ventricular ( R i c k h a m c a p s u l e ) or l u m b a r r o u t e ( i n t r a d u r a l c a t h e t e r or s u b c u t a n e o u s p o r t ) . I n f u s i o n t i m e s w e r e up to 72 hours. C S F and serum levels were monitored. Constant " t h e r a p e u t i c " C S F l e v e l s of 1 umol MTX were a c h i e v a b l e a f t e r i n i t i a l b o l u s i n j e c t i o n s of 5 a n d / o r I0 m g MTX. L u m b a r i n f u s i o n s w e r e tolerated well whereas with ventricular infusions technical problems arose and toxic r e a c t i o n s w e r e seen. C S F i n f e c t i o n s o c c u r r e d b u t c o u l d be c o n t r o l l e d . Impressive remissions in f a r p r o g r e s s e d d i s e a s e c o u l d be a c h i e v e d . Neurologische + Neurochirurgische D-8700 WOrzburg *Fa. Mack, I l l e r t i s s e n

I Univ.-Klinik,

DIACETYLDIANHYDROGALACTITOL (DADAG) IN GLIOMA-TIIER~PY: AN IN VITRO COMPARATIVE STUDY A. Beck, U. Bogdahn, B. Pfeuffer, P. Kra useneck, M. Lu tz Department of Neurology, University of ~rzburg, FRG The activity of DADAG against 13 different malignant brain tumors was assayed and compared to BCNU (carmustine). Tumor cell lines were established from biopsy specimen and characterized by cytochemistry, immunocytochemistry and partially by cytogenetic analysis. 4 gr. IV-gliomas, 4 gr. II gliomas, 1 ganglioglioma, 1 hemangiosarcoma, 1 malignant melanoma, 1 meningeoma and 1 bronchial carcinoma cell line were analysed. In vivo pharmacokinetic data for BCNU (AUC: 4.77 ~Mhr) and DADAG (AUC: lll3HMhr) were obtained from previous studies. From in vitro pharmacokinetic studies "cutoff"-concentrations for evaluating in vitro results were calculated as 9 pM (BCMU) and 1.82 NM (DADZG) ; the drug effect was determin_ed by a longterm 3H-uridine incorporation assay, employing a liquid scintillation counting protocol. Drug effects were expressed in terms of a sensitivity index SI, which is the ratio of the area under the survival curve to the area under the 100~ to the "cutoff"survival curve (both determined concentration). Mean sensitivity indices were 0.961 +_ 0.17 (BCHU) and 0.521 _+ 0.06 {DADAG) for gr. IV gliomas, 1.002 +_ 0.26 (BCNU) and 0.4835 _+ 0.23 (DADAG) for gr.II gliomas; both types of gliomas were significantly more sensitive to DADAG (p
S 136

4/P-GM 064

4/P-GM 066

INDIVID~LIZED BRAI~ TUMOR CHEMOTHERAPY - ~ NE~ APPROACH U.Bogdahn, P.Kranseneck, Deptm.Neurology, Univ.~rzburg, FRG Tumour cells of 22 patients with malignant brain tumours (glioblastoma,astrocytoma,ependymoma) were examined for their sensitivity to 1,3-bis-{2-chloroethyl)-l-nitrosourea (BCNU) employing an in vitro microassay~ In rive and in vitro pharmacokinetic data for BCNU were obtained; in vitro drug exposures were identical to in rive achievable concentration time products. Cells were exposed to BCNU; after 5 to 8 population doubling times of untreated controls, (5,6ZH)-uridine incorporation into cellular RN~ was determined by a liquid scintillation counting protocol. The cytotoxic effect of BCNU on each cell population was expressed in terms of a sensitivity index SI (ranging from 0,063 to i,i16; SI=I indicating complete drug resistance). Patients originally harbouring these 22 tumours were treated by surgery (partial~complete macroscopic resection), radiotherapy (usually 60Gy) and chemotherapy with nitroseureas ~ n some cases additional chemotherapy with V~[ 26, procarbazinc, vincristine was applied).Censored relapse free intervals (2patients are still without relapse) of these patients were directly correlated to corresponding sensitivity indices determined by in vitro drug testing. A high degree of correlation was found, employing a linear analysis of regression (Rz=0.520~ or following non-linear regression models (exponential regression model: ~ =0. 743 7,0=-0. 746; 1 ogari thmi c regression model: R ~ =0.7176); for non-linear regression models a minimal prognosis of relapse free intervals may be predicted for all SI-values on a 95% probability level. There were no complete predictive failures (high SI/long relapse free interval or low SI/short relapse free interval). Median relapse free intervals were 19 months for in vitro sensitive, 7 months for in vitro resistent tumours (p<0.0005). Effects of radiotherapy were not calculated. The system is able to discriminate between patients, who might benefit from BCNU-chemotherapy and those, who should be spared fro~ the toxicity of the drug because of anticipated lacking efficacy.

NEUROSURGICAL MANAGEMENT OF M E T A S T A S E S IN M A L I G N A N T M E L A N O M A K.H.Kr~hling, J~Anagnostopeuios-Schleep, D.Gruta

CEREBRAL H.-J.KSnig,

T h i r t y - t w o c a s e s with h i s t o l o g i c a l l y proven m a l i g n a n t melanoma a f f e c t i n g t h e c e n t r a l n e r v o u s s y s t e m (CNS) have been a n a l y s e d r e t r o s p e c t i v e l y . All patients u n d e r w e n t s u r g i c a l r e s e c t i o n and t w e n t y - o n e received postoperative radiation therapy. Patients with primary lesions of the head, neck or trunk and those with invasive primary tumors as evaluated by Clark's staging had higher incidences of CNS metastasis. In 28% of the patients there was CNS metastasis alone, without involvementof other organs. Single CNS metastases were s e e n in 75% of t h e cases. Headache, mental impairment, motor d y s f u n c t i o n and c r a n i a l n e r v e d i s t u r b a n c e were t h e most common m a n i f e s t a t i o n s , I n t r a c r a n i a l hemorrhage was not an i n f r e q u e n t mode of p r e s e n t a t i o n . Local recurrence was observed in two and meningeal melanosis in t h r e e case. There was no e v i d e n c e t h a t p a l l i a t i v e radiotherapy had any effect on the survival rate. The median survival after craniotomy was 10 months. Favorable prognostic factors included solitary CNS manifestation, absence of local or systemic disease at time of cranietomy and long latent interval between the primary tumor diagnosis and CNS metastasis. Concomitant liver metastases carried the worst prognosis. There was no significant difference in survival between patients with right- or left-slded cerebral lesions but those with right hemispheric involvement had a better quality of survival 84% of the patients were self-dependent at the time of discharge from the hospital. Neurochirurgische Kllnik der Universit~t Albert-Schweitzer-Strasse 33, D-4400 Mfinster

Mfinster,

4/P-GM 065

4/P-GM 067

T E S T A S T C L A S S 2 6 8 - A C L A S S I F I E R O F M A L I G N A N C Y IN ASTROCYTOMAS H.P.Schmitt, Ch.Oberwittler ................................................ C l a s s i f i c a t i o n of b r a i n t u m o r s in t e r m s o f t h e i r malignant expression ("grading") has become a standard requirement in c l i n i c a l n e u r o - o n c o l o g y as a g n e r a l b a s i s f o r prognostic assessment and t h e r a p y p l a n n i n g . In m u l t i c e n t e r t h e r a p y s t u d i e s malignancy grading is t h e c o m m o n b a s i s on w h i c h r e s u l t s of t r e a t m e n t are c o m p a r e d . H o w e v e r , the v a l u e of t h i s b a s i s is q u e s t i o n a b l e , s i n c e it is t h e r e s u l t of a s u b j e c t i v e e v a l u a t i o n o f histologic f e a t u r e s w i t h an i m p r e c i s e d e f i n i t i o n of the classification criteria. Too much diagnostic l a t i t u d e is l e f t t o t h e i n d i v i d u a l e x a m i n e r impairing the reproducibility of g r a d i n g r e s u l t s . In a d d i t i o n , g r a d i n g s o l e l y b a s e d o n m i c r o s c o p i c f e a t u r e s of t h e t u m o r h a s b e e n shown to be prognostically inadequate since the clinical course also largely depends on non-morphologic factors, s u c h as age, t u m o r l o c a t i o n a n d size, etc. The clinical s i g n i f i c a n c e c a l l s for i m p r o v e m e n t of malignancy grading by t h e i n t r o d u c t i o n o f n u m e rical m e t h o d s and the inclusion of non-morphologic f a c t o r s i n t h e f e a t u r e s p e c t r u m . Development and v a l i d a t i o n of a n u m e r i c a l malignancy classifier for a s t r o c y t o m a s will be d e m o n s t r a ted, w h i c h m a y b e implemented on a common small pocket computer for practical application.

PROSTAGLANDIN F~a AND E~ IN CEREBRAL AND SPINAL CORD NEOPLASIA: PATHOPHYSIOLOGICAL CONSIDERATIONS J.Anagnostopoulos-Schleep i, K.H.Kr~hling i, H.-J.Kfnig ~, C.V~danos 2

Institut far Neuropathologie der Universit~t H e i d e l b e r g , I m N e u e n h e i m e r Feld 220, D - 6 9 0 0 H e i d e l b e r g i.

High Prostaglandin F ~ (PGF~) and Ez (PGE~) synthesis is known to be a feature of the neoplastic cell growth. In the present report, tumor, adjacent brain tissue and Cerebrospinal Fluid (CSF) from thirty-five patients with cerebral and spinal cord neoplasia were examined for the presence of both prostaglandins by radioimmunoassay. Control CSF samples were o b t a i n e d from ten normal persons. Tumor and edematous tissue removed during surgery demonstrated significantly higher concentrations of PGF~, and PGE~ as compared to normal cerebral samples. The dura mater seems to be a natural barrier for the diffusion of prostaglandins. Both substances appeared in considerable amounts in the cerebrospinal fluid by pituitary adenomas and intradural spinal cord tumors, whereas extradural lesions exhibited no such effect. Prostaglandins synthesized and released by neoplastic cells m a y alter the local environment of a brain tumor, Extent of perifocal e d e m a ' w a s closely associated with increased PGF2a and PGF~ concentrations in neoplastic and edematous tissue and not with anatomical characteristics of the primary brain lesion, such as lobar location or size. These findings support evidence from experimental studies and emphasize the possibility of cerebral prostaglandins in mediating the secondary alterations of perltumoral environment. *Neurochirurgische Klinik der UniversitSt Mfinster, Albert-Schweitzer-Strasse 33, 4400 Mfinster, W.Germany SDepartment of Surgery, University Hospital, 22185 Lund, Sweden

S137 4/P-GM070

4/P-GM 068 CT- / MRI-GUIDED STEREOTACTIC OF CEREBELLAR METASTASES F. M U N D I N G E R , M, M O ~ A D J E R , A.

BIOPSY

INTRAORAL MALIGNANT MELANOTIC SCHWANNOMA K.W.Gr~tz, M,Makek

ETOU

Neuroimaging methods like CT and MRX, according to our experience in 3.500 cases of p e r f o r m e d stereotactic biopsy, do not permit histological diagnosis, even it has been stated repeatedly. Multiple intracranial tumors having some certain appearence in the CT or MRI may resemble metastases of a carcinoma, but the histological examination may reveal e,g. Non-Modgkin-lymphomas, germinomas, multifocal gliomas or inflammatory disease (like multiple sclerosis). To avoid misdiagnosis and inadequate treatment, or even to omit possible therapy it is therefore necessary to confirm the diagnosis histologically by CT- or MRiguided stereotactic biopsy, a method of low risk. Technical standard and results are reported.

The i n t r a o r a l m a l i g n a n t m e l a n o t i c Schwannoma i s r a r e . We p r e s e n t t h e c l i n i c a l and p a t h o l o g i c data including ultrastructural s t u d i e s in t h r e e cases.

K i e f e r c h i r u r g i s c h e K l i n i k und I n s t i t u t f o r Pathologie U n i v e r s i t ~ t s s p i t a l Z~rich, Frauenklinikstrasse 10, CH-8091 ZUrich

Abt. Stereotaxie und N e u r o n u k l e a r m e d i z i n Neurochirurgische Universit~tsklinik Hugstetter Strafe 55, D-7800 Freiburg

4/P-GM 069 ANTIGENIC HETEROGENEIT~ OF HUb~N BRAIN TUMORS U.Stocker, J.Groeneveld, B.Martin, D. Stavrou and E.Keiditsch The antigenic profile of human gliomas and in vitro established cell lines was investigated by using the selected monoclonal antibodies (HcAbs) MUC 8-22 and MUC 2-63 (Stavrou et al.: J. Neurol. Sci. 80, 205, 1987). The reactivity with tissue samples and cytospin preparations obtained from 45 neurogenic tumors was estimated by the indirect immunoperoxidase technique. In addition, according to hhe degree of antibody binding the immunocytochemical analysis of cell-surface antigens by indirect immunofluorescence resulted in a fluorescent reaction product which intensity and distribution was m e a s u r e d by c o m p u t e r - a s s i s t e d cytofluorometry. Zn most cases it could be demonstrated that the heterogeneity in antigen expression decreases during successive in vitro propagation of glioma cells. The data suggests that a variable percentage of cells was not recognized by the employed McAbs. Moreover~ the reactivity spectrum of the selected antibodies was independent of the histological grading of gliomas and showed significant difference in various stages of subcultivation of glioma lines. A various degree of antibody-binding among and within gliomas and glioma-derived cell lines could be observed. The extent of variance in stain intensity values was different within cell populations and reflected the antigenic heterogeneity of tumor cells.

4/P-GM 071 Cis-plati,m (ci~-DllP), 5 - F 1 ~ a ~ i l {5-FJ) wit~folimcacid (FM ~ t a~ ~ a~erated ra~ot~ezapy (a~) in T.G.Mm~t, R. C. ]E~rtenstein,T.P.U. ~strow, K. R. Trott In a ~mse II study previomly tmtreated patlents(pts,) sufferin~ from an mresectable s~.mmam cell carclnam of the head an6 reck ~mre treated by three cycle~ of simltamo~ radio-cb~otheraI~ consisting of cis-RP, 60 ~ I s ~ i.v., 5-FJ 350 ~ I s ~ i.v. and FA 50 ~ I s ~ i.v. day 2 and ~ 350 ~Is:jml~ hrs. ~ ~ 100 ~Ism/24 hrs. i~X~ed cc~tinuously fraa day 2 to 5, Concc~tant aRT was ;erformed on ~ys 3-5 and 8-11, Two fractla0sper ~ay of 1.8 Gy each ~are adminxs"feted with a of 4 hrs. iutervall, This combined mcdality regimen was repeated ca da~s 22 and 44. RacRation dose amotmted to 70.2 Gy/7weeks. Until now 80 ;~s.were treated. ~ rate was 100% (eCR: 75% cPR: 25%). Oral mucoea an~ bone marrow were the main sites of acute

~dty. ~ ~ ~ split immrte~ triI~sic orat and mcositis healed ralxidlya~l was not a llmitin~ factor. In 6~. pts. (stage I~: 53, stageIV: 9) (followup 18+ to 36+ months) followir@ remJlts are achieved: n 12 months 24 mmths mmvival 62 73 +-4 % 52 +-8 % local c~tr01 59 81 +-5 % 76 +-6 % disease free survival 59 68 +-5 % 60 +-7 % Three pts. e~iZed due to fatal hemorrhage duri~ thera~/. Five pts. ex~r/eaeed distant metastases 4urir@ follow up. In conclusion this

I~toeol showsmoderateacutetoxicity ~ yields~ ( m t

pa]]/atic~.

Compared to raO/ation alone or sequential chemo~ad/otheraI~ I~ormed at the same institutica a surplus of 30 % in Io~ term survival is i/t~y to be achieved. Ref.: Pror. Am. S0c. Cl~n. 0ncol. 1987

Institut f~r Pathologie, Klinikum Bogenhausen, Englschalkingerstr. 77, D-B000 M~nchen 81

~.

~iol0gy,

Kli~k~

Gro~hadem, ~iw~i~y

Marchioninistr. 15, D 8000 Munich 70, F.R.Germany.

of

M~mich,

S138 4/P-GM072

4/P-GM074

SURGERY OF MALIGNANT TUMORS OF THE PARANASAL SINUSES INVOLVING THE SKULL BASE. W.Draf ( I ) , M.Samii (2)

PREOPERATIVE CHEMOTHERAPY DISADVANTAGES A.Klima, R.Bettin~er

In tumors of the paranasal sinuses w i t h signs of s k u l l base i n f i l t r a t i o n s e v e r a l approaches come i n t o c o n s i d e r a t i o n : 1. E x t r a c r a n i a l p a r t i a l r e s e c t i o n of the a n t e r i o r s k u l l base w i t h p a r t i a l or t o t a l removal o f the paranasal sinuses and p r e s e r v a t i o n of orbital contents. 2. E x t r a c r a n i a l r a d i c a l r e s e c t i o n of the m a x i l l a , ethmoid and a n t e r i o r s k u l l base w i t h orbital exenteration. 3. Combined i n t r a - e x t r a c r a n i a l approach, This s t r a t e g y has proved to us s u f f i c i e n t and needs r h i n o - n e u r o s u r g i c a l c o o p e r a t i o n . S u r g i c a l d e t a i l s w i l l be demonstrated in a few examples.

(1) K l i n i k f u r HNO-Krankheiten und p l a s t i s c h e G e s i c h t s c h i r u r g i e der S t ~ d t i s c h e n K l i n i k e n , P a c e l l i a l l e e 4, 6430 Fulda (2) N e u r o c h i r u r g i s c h e K l i n i k des N o r d s t a d t krankenhauses, H a l t e n h o f f s t r . 41, 3000 Hannover

AMELOBLASTOMA

I. C. Kiricuta,

Ameloblastomas

of the jaw are rare epithelial

H, K. Beyer

They must be differentiated

cysts or other malignant surgery

tumors.

from the beginning

of choice.

must be the therapy

If Ameloblastomas

an exact preoperative

from simple

The radical

are incompletely

excised they have a high recurrence diagnosis

rate,

into the surrounding

(infratemporal

fossa,

pterygopalatine

parapharyngeal

space,

orbit intracranial

are necessary.

In this presentation

picture

is presented.

of a recurrent

Different

graphic procedures

So

of the tumor

and its spread

genologic

I t i s o f t e n suggested t h a t tumors w i l l respond t o i n d u c t i o n chemotherapy and r e s u l t i n improved s u r v i v a l f o r p a t i e n t s w i t h squamous c e l l carcinoma o f the head and neck r e g i o n . The c o m b i n a t i o n of c i s p l a t i n and bleomycin has been r e p o r t e d t o produce a high response r a t e f o r stage III/IV tumors, 8ecause of the promising results reported in pilot studies there has been widespread usage of various combinations of chemotherapeutic drugs as induction agents, There are surgical oncologists who question the proposed benefits of chemotherapy and consequently refrain from use of such agents in their patients. Another large group of encologists has used these drugs extensively, We initiated this trial to review the results of a modified drug regimen and to asses the role of preoperative chemotherapy with special emphasis on the analysis of survival. In s non-randomized pilot study two cycles of chemotherapy were followed by definitive surgery. 45 patients were entered in this pilot-study. Chemotherapy consisted of cis-platin 60mg/m 2 and bleemycin lOmg/m ~ on days I and 8. The response rate was complete in 12/45 and partial in 28/45 patients for an over all response rate of 88%, Toxic side effects were maild and reversible, Due to the application of chemotherapeutic drugs in g patients serious wound healing problems occured. Survival was analysed statistically by the Gehan-Test. The survival duration indicates no clear advantage for patients receiving a preoperative chemotherapy compared to those with no delay of the radical tumor resection. ZHN0 U n ~ r e r ~ i + q + ~ ! ~ Ff~

BKACHYCURIETHERAPY IN ~EAa AND NECK CANCERS. S.-J.Thiel, R.Fietkau, M.Weidenbecher,W.apitzer

OF THE JAW

H. Hoetzinger,

tumors,

ADVANTAGES AND

4/P-GM 075

4/P-GM 073 RECURRENT

-

tissue fosse, space)

the roent-

Ameloblastoma

conventional

radio-

are shown in comparison

CT. The value of different

diagnostic

to

procedures

is discussed. Marienhospital Hoelkeskampring

Herne,

Ruhruniversit~t

40, D-4690 Herne 1

Bochum

The control of primary tumours and metastatic neck nodes by any means of treatment remains a major problem in the management of head and neck cancer. Principially there is a relationship between tomcat control, volume of tumour as indicated by T-stage and the dose Of radiation. Interstitial irradiation, the use of sealed radioactive materials, which are inserted directly within and around the tumosr, has the unique advantage of continuously delivering a high dose within a short time to a well-circumscribed area without excessive irradiation to the surrounding normal healthy tissues providing a better likelihood of local tumour control and reduced likelihood of normal tissue complications. Therefore we observe a renaissance ~f brachycurietherapy in the last decade due to the perfection of afteriQad!n9 ' techniques increasing the flexibilit#""""o{ implant design, minimizing radiation exposure levels and resulting in more accurate placement of needles and go&des, the availability of new artificial radionuc!ides (192-Ir, 125-I) and the i n t ~ d u c t i o n of c ~ p u terlzed dosimetry providing a comprehensive description of the distribution of radiation dose around implanted sources. According to the experience of major treatment centers interstitial implantation of head and neck tnmours can produce excellent local tumour control in up to 85-90% of patients with minimal functional and cosmetic impairment and acceptable treatment related complications such as soft tissue necrosis or osteoradionecresis in the order of 6-io~. None Of the patients is subjected to mutilating surgery and functional and esthetic integrity is well preserved in most cases. Therefore these treatment modality should be considered in all accessible localized t~mo~rs and as part Of the possible ways of managing advanced tumours. In addition 35-45% of patients with recurrent and/or persistent tumours can be salvaged by interstitial irradiation with acceptable morbidity of 20-30%. In this situation interstitial irradiation can also be combined with low concomitant Systemic chemotherapy dose, continuous, using CDDP and 5FU as well a~ interstitial hyperthermia as radlosensitizing agents. In conclusion brachycurletherapy is a promising therapeutic tool being aware of the need to consider our treatment results not only in terms of local tumour control, but also in terms of the quality of life of the patient who has been cured of a malignancy. Klinik und Poliklinik fur Strahlentherapie der versit~t Erlangen-N~rnberg, Unlversit~tsstr. D-8520 Erlamgen Brachycurietherapie

yon KNO-Tumcren.

Unl27~

$139 4/P-GM 076

4/P-GM 078

RADIOTHERAPY FOR PARANASAL SINUS CANCER - TREATMENT RESULTS AND OPTIMIZATION -

POSSIBILITIES AND LIMITATIONS OF DIAGNOSTIC IMAGING PROCEDURES WITH REGARD TO THE THERAPEUTIC OPERATIVE TREATMENT OF PRIMARY AND SECUNDARY MALIGNANT TUMOURS OF THE MAXILLARY CAVIT Y . A FOLLOW-UP CHECK CONSISTING OF OUR OWN PATIENTS OBSERVED DURING THE LAST 15YEARS. St.W, Bonorden and E.Mmchtens

A. Nasz~ly~ G. Nemeth 301 patients ~ere treated in this institute . 157 patients ~ere treated with combined radiotherapy and surgery~ 153 patients under~ent solely radiotherapy, ll patients were treated ~ith local recurrence many years after primary treatment. Intraeavitary braehytherapy ~as applied in 82 patients alone or in combination with external beam as a postoperative treatment. Survival data are presented ~ith special regard to the prognostic factors (stage~ hystology, metastatic growth etc.)~ and to treatment modality. Five-year survival for all stages is 54 % in the combined treatment group and 15 % for radiotherapy alone. The best result of 42 % ~as found ~ith preop, irrad. + op. + postop, irrad, treatment group, the data suggest that preoperative radiotherapy + surgery + postoperative radiotherapy seems to be the optimum treatment modality and underlines the reasons for the application of intracavatary brachytherapy after no radical surgery. By the systemic changing of the irradiation parameters it was attempted to develop field arrangements and brachytherapy source arrangements ~ith optimal dose distribution and easy reproducibility and ~e tried to find quantitative optimization criteria. Computerized treatment planning ~as performed simultaneously in t~o or more parallel CT scans. Optimization parameters oriented to the type of tumor spread are discussed here. Department of Radiology~ University Clinics MOnster~ Albert-Schweitzer-StraBe 33, 4400 M~nster, FRG

Primary malignant turnouts of the maxillary cavity and such not metastatic regional neoplasms,which secundary invade this region from the peripherial oral mucosa.often show less clinical symptoms than other malignant manifestations of the oral c a v i t y . l n case of sudden diplopia.growing protrusio bulbi,tumor-invasion in the nose cavity or disabled language and swalling the malignoms almost have reached a level of inoperability. Therefore we report about a great number of patients,we<,e observed during the last 15 years [ t972 - 1987 J and point out to the importance of modern diagnostic imaging procedures.to investigate this kind of tumor as early as possible. The limitations of these methods with regard to the pre- and intraoperative orientation will be discussed, Especially f i r s t results of patho-morphological pattern of mid-face bone and tumor-tlssue will be demonstrated by comparison of known light - microscopic findings with new aspects,recelved from Scanning acoustic microscopy ( SAM . ELSAM ). The prospective value of this method for intraoperative bone - examination will be dicussed. Klinik f . M u n d - , Kiefer-und Gesichtschlrurgie -p!ast. Operationen- der Ruhr-Unlversit~t Bochum, Knappschaftskrankenhaua. In der Schornau 23/25; D- 4630 Bochum - 7

*Centre of Radiation Oncology~ Budapest Uzsoki u. 29, I145 Budapest, Hungary

4/P-GM 077

4/P-GM 079

CLINICAL RESULTS IN TREATMENT OF ADVANCED CARCINOMAS OF THE HYPOPHARYNX

A COMPLEX CHEMOTHERAPEUTIC CONCEPT TO TREAT ORAL CARCINOMAS WITH CISPLATIN AND 5-FLUOROURACIL H.P.Howaldt and K.Bitter

S. Dinges, M. Balla, H.J. Feldmann, V. Budach .................................................... Twenty-three patients ( 1 female, 22 male ) with a diagnosis of squamous cell carcinoma of the hypopharynx were treated with a combination of surgery and radiotherapy or radiotherapy alone between 1978 and 1986 at the West German Tumor Center in Essen. The mean age was 55 years. All patients received external beam radiation either with 60-Co, 5.7 MeV or 15 MeV photons of linear accelerators to a total dose of 50 to 70 Gy. The primary site and both sides of the neck were treated with bilateral opposed fields. From 1984 to 1986 an anterior split field covering the lymph nodes of the lower neck was added to the above portal arrangements. All patients were in stages Ill or IV ( TNM criteria of the American Joint Committee on Cancer ). In TI/T2 tumors the actuarial two years survival rate ( Kaplan and Meier ) was 50 %, in Ti/T4 tumors 30 %. The disease -free interval ranged from 15 months in TI/T2 tumors to 11 months in T3/T4 tumors. These differences were statistically not significant. The results in detail and treatment failures of the technique of the irradiation will be reported.

Dept. for Radiation Oncolo6~y, University of Essen Hufelandstr. 55, D-4300 Essen 1

This drug combination~ which was inaugurated at the Wayne State University (USA) proved to be very effective aganist squamons cell carcinomas~ developed to the most often use one in the U.S.. Various modifications concerning dosis and pre- or postoperative treatment are performed. This is briefly discussed in order to present our concept which since 1985 has been applied to ca. llO patients suffering from carcinomas of the oral cavity. After a radical intended operation patients receive three courses of this chemotherapy. Tumors of inoperable seize are irradiated after three cycles of chemotherapy containing the same dosis. There are pointed out contraindications such as very small tumors and indications for this chemotherapy. Furthermore the complications while treating are discr~bed. The results referring to the TNM System and the therapeutic prognostic index TPI are presented. The survival time of the patients are compared to the estimated survival rate of the TPI in order to show sucees or failure of this adjuvant oncologic treatment. Uniklinik Frankfurt/Main~ Abt. fQr Mund-~ Kiefer- und Gesichtschirurgie~ Theodor-Stern-Kai 7, D-6000 Frankfurt

S 140

4/P-GM 082

4/P-GM080 MALIGNANT

TUMORS OF THE N O S E AND PARANASAL

SINUSES:ARE

INVERTED

PAPILLOMAS

PRECANCEROUS

LESIONS? J.-P,Luhn,K.H~rmann

Related

to clinical

logical

appearance

findings

types of inverted papilloma paranasal

sinuses.

Follow-up

(i970-i987)

papillomas

and pathomorpho-

we could define

these carcinomas

one subtype

papilloma.Apparently

consequence

an adequate

of this sub

criterion.As

radical

treatment

to be done if there is evidence type characterising

in only

inverting

the morphology prognostic

sinuses

of malignan-

originated

the socalled m y x o i d

type iS a decisive

sub-

of 39 cases of inverted

of the nose and paranasal

showed in four cases developement cies.All

three

of the nose and

a has

for the sub-

the inverting m y x o i d

papilloma. HN0.1bt.Marienkrankenhaus,Alfredstr.9, 2000 Hamburg

76,und Univ.HN0-Klinik

Eppendorf,Martinistr~

Hamburg-

Hamburg

20

Universit~ts-Kinderk iinik, D-4400 M'dnster

Albert-Schweitzer-Str.

33,

4/P-GM083

4/P-GM 081 LEUCOVORIN

THE SIGINIFICANCE OF THERAPY REALIZATION IN THE PEDIATRIC AML-STUDY BFM-83 U. Creutzig, J. Ritter, J. Hofmann, U. Bertram and G. Schellong for the AML STUDY GROUP Data on the therapy realization and complications occurring are available for 159 children (92%) out of 173 protocol patients entered into study A~-BFM-83. During the 8day ADE induction (cytosine arabinoside, daunorubicin, etoposide) 16 % of the children received less than 80 % of the required doses (SD) of one or more of these drugs. The proportion of patients who subsequently became non-responders (NR) was particulary high ~n~ng the patients with < 80 % SD of etoposide and daunorubicin.Considerable deviations from the protocol with respect to dosage and time frame during t/]e 8-week consolidation period with 7 drugs are also found in the group of NR. Considerable bleeding complications occurred during the initial phase in 38 % of patients. This was the case more often in children experiencing an unfavourable course (NR, relapse) later on, than in children who had been in continuous first remission (CCR) for 1-4 years at the date of evaluation (1.09.87). Infections in the initial phase are without prognostic significance, while severe infections (sepsis, pneumonia, abscess) ~ during the consolidation phase were more frequent (X- test, p = 0.02) in NR and early relapse. In 3 children who died during remission, death was causally related to severe infections during the consolidation phase. Maintenance therapy generally presented no problems.- It is ass%m%ed that the induction therapy according to protocol with the required doses of daunorubicin and etopeside will improve the remission rate, although it cannot be excluded that the leukemic disease itself was responsible for the cc~orcsdsed realization of therapy.

IN, C H E M O T H E R A P Y

WITH M E T H O T R E X A T E

K 9H~rmann, W. Kehrl

in a randomised

prospective

trial patients

suffering

from primarily

carcinoma

of the o r o p h a r y n x a n d

the oral cavity

underwent

two different

sohemes.ln[both

groups radical

curable therapy

surgery was followed

tion.Additionally

intraarterial

with methotrexate

and leueovorin

ded surgery and irradiation value,schedule,dosage application of malignant

squamous

by irradia~

chemotherapy rescue prece-

in one group~The

and the technique

of l e u c o v o r i n i n

cell

of

the chemotherapy

tumors of h e a d and neck is discus-

sed on the background

of the results

of this

study. Univ.HNO-Klinlk D-2000 Hamburg

Hamburg-Eppendorf,Martinistr.52 20

PHASE I CLINICAL TRIAL OF CARBETIMER. Hanauske A, M e l i n k T, Harman G, Clark G, Craig J Koeller J, Boldt D, Kantor B, Kisner D, Orczyk G Anderson D, Paqet E, Sarosy G, V o n Hoff D D Carbetimer (Carbethimer, N-137,Carboxyimamidate) is a low m o l e c u l a r weight polyelectrolyte with antitumor activity in a v a r i e t y of tumor models. This phase I trial evaluated a single dose of Carbetimer infused over 1-2 hours ever 28 days. Forty-three patients received 71 courses2of the drug at doses ranging from 180-8500 mg/m . The dose-limiting toxicity was hypercalcemia (serum Ca > 12,52mg/dl ) noted in 2/3 pats at a dose of 8500 mg/m . Serum calcium levels between 10.512.5 mg/dl were noted in an ~dditional 3 pats treated at doses > 1600 mg/m . Calcium balance studies in 3 pats treated at 6500 mg/m 2 showed an increase in urinary cAMP and p h o s p h a t e excretion after treatment accompanied by a m i l d elevation of serum PTH. Immunologic studies in these pats showed a statistically significant increase in the percentage of peripheral Thelper cells. An increase in T - h e l p e r / s u p p r e s s o r cell ratio was observed in 2/3 pats. Interleukin-2 production by phythemagglutininstimulated peripheral mononuclear cells was increased in 2/3 pats. One pat with renal cell carcinoma had a mixed response. The recommended dose for phase II ~rials as assessed from this study is 6500 m g / m . U n i v of Texas Health Sci Centr at San Antonio, Dep. M e d i c i n e / O n c o l o g y and Medicine/Hematology; Department of Research and Development G.D. Searle Company; Mad. Hochschule Hannover, Dep. Innere Medizin und Dermatologie, Abt. Haematologie. Supported by a grant from the Monsanto Company, NIH grant RR-O1346, DFG grant Ha 1347/1-1, and a grant from the Freundesges. der Medizinischen Hochschule Hannover.

S 141

4/P-GM084

4/P-GM086

F A I L U R E OF S E Q U E N T I A L HIGH-DOSE METHOTREXATE ( MTX )5-FLUOROURACIL 6FU) A N D F O L I N I C A C I D (FA) T O I N C R E A S E R E S P O N S E R A T E S IN A D V A N C E D C O L O R E C TAL CARCINOMA M.E. H e i m , D. S c h u s t e r , H. F l e c h t n e r , W. Q u e i ~ e r

DEVELOPMENT OF CARDIOSELECTIVE PROTECTION IN CYTOSTATIC TREATMENT WITH ANTHRACYCLINES

The combination of s e q u e n t i a l l y delivered NTX a n d PU, as w e l l as h i g h d o s e FA a n d FU h a v e shown synergistic e f f i c a c y in e x p e r i m e n t a l tumor s y s t e m s a n d in c l i n i c a l s t u d i e s w i t h c o l o r e c t a l tumorpatients. Our own experience with high-dose MTX/FU and the excellent results (50 % r e s p o n s e ) in a p i l o t s t u d y u s i n g the s e q u e n t i a l combinat i o n of M T X / F U / F A ( G l i m e l i u s et al 1986) e n c o u r a g e d us to s t a r t a s t u d y w i t h the g e q u e n t i a l combination of t h e t h r e e d r u g s in h i g h d o s a g e . Patients with histologically confirmed advanced colorectal cancer and measurable disease were t r e a t e d w i t h 8 0 0 m y / m ~ M T X as a 4 - h o u r i n f u s i o n . 1 5 0 0 m g / m ~ FU w a s g i v e n 4 h o u r s l a t e r as a 24hour continuous i n f u s i o n . FA {200 m g / m ~ ) w a s s t a r t e d 24 h o u r s a f t e r M T X as a 2 4 - h o u r c o n t i o r a l l y 48 a n d 72 h o u r s a f t e r NTX. T r e a t m e n t w a s accompanied by hyperhydration, alkalinization and m o n i t o r i n g of M T X s e r u m l e v e l s to p r e v e n t toxicity. Of 27 p a t i e n t s (pts) w i t h a d v a n c e d c o l o r e c t a l c a n c e r e n t e r i n g the s t u d y 12 p t s w e r e pretreated with fluoropyrimidines. 23 p t s w h o r e c e i v e d 2 or m o r e c y c l e s w e r e e v a l u a b l e f o r response. 0 n l y o n e p a r t i a l r e m i s s i o n of 6 m o n t h s duration was observed~ stable disease was noted in 9. M y e l o s u p p r e s s i o n was not observed, main toxicity was gastrointestina}, (26 %), s t o m a t i t i s (20 %), h a i r l e s s (18 %) a n d d e c r e a s e of r e n a l f u n c t i o n in o n e c a s e . We c o n c l u d e t h a t the sequential combination of h i g h - d o s e MTX/FU/FA c o u l d n o t i m p r o v e the r e s p o n s e r a t e s in t h i s protocol. Onkologisches Zentrum, D-6800 Mannheim

H.

E.

THE

Scheuten

The clinical use of the highly effective anticancer antibiotics daunomycin (DNM) and adriamyc i n ( A O M ) is l i m i t e d by their cumulative cardiotoxicity (CCT). There is s t r o n g e v i d e n c e that CCT as well as the antineoplastic action are closely related to their enzymatic redox-cycling which may cause "oxidative stress" by f o r m a t i o n Of toxic oxygen radicals in combination w i t h an insufficiency of cellular detoxification mechanisms due to a c r i t i c a l exhaustion of NADPH snd reduced sulfhydryls (XSH). The concomitant application of XSH p e r s e is c a r d i o p r o t e c t i v e but interferes with the antitumor activity o~ AOM as demonstrated fo~ N-mcetyl-cysteine in Ehrlich ascites tumor(EAT)-bearing mice. Thus, cardioprotection based on r e a c t i o n selectivity may not be feasible. In contrast to tumor tissue, NAOPH, a coenzyme for the regeneration o f reduced glutathione, is i n t r a c a r d i a l ! y formed via the isocitrate-dehydrogenase reaction, Accordingly, the cardioprotectiwe effect o{ i s o c i ~ trste, the substrata {or this reaction~ as w e l l as for niacin, a precursor o~ N A D P H , c o u l d be demonstrated is A O M - t r e a t e d mice~ while antitumor efficacy was not inhibited in E A T in ~ v q and in h u m a n l e u k a e m i c b l a s t s i_nvitr__qo, r e s p e c tively. A clinical study Was designed to d e t e r mine the value of n i a c i n as a c a r d i o s e l e c t i v e protector in patients with acute myelogenous leukaemia with DNM-containing combination chemotherapy according to t h e T A D - r e g i m e n .

(Supported

by DFG:

SFB 1 0 2 . )

Innere

Universitatsklinik und Poliklinik (Tumorforschung)~ W e s t d e u t s c h e s Tumorzentrum, Hufelandstr, 55, O - & 3 O e Essen t

4/P-GM 085

4/P-GM 087

PHASE1tSTUDYWITH LEUCOVORINAND 5-FLUOROURAC1L E. Kurschel, R. Becher, O. Kioke, M. Scheulen, H. Hbfeler, O. Weinhardt, St. Bergner, H. Khan, N. Niaderle, K. H6ffken and C.G. Sehmidt

PHASE II-STUDY WITH CARBOPLATIN/VINCRISTINE/ETOPOSIDE AS FIRST LINE THERAPY IN SMALL CELL LUNG CANCER (SCLC). U. K a c h e l - F i s c h e r , N. N i e d e r l e , R. Michels-Giermanns, D. May, W. A c h t e r r a t h , G. Schumacher and C.G. Schmidt.

Based on reports of synergistic effects of leucoverin and 5-FU we performed a phase 11 study to evaluate the efficacy and toxicity of this combination in advanced and progressive gastrointestinal tumors. In addition we started to study its value in various chemotherapy resistant malignancies and others for which 5-FU has been known as active single agent Two treatment schedules were used. Schedule I: Continuous infusion of 5*FU (600rag/m2) and leucovorin (200 mglm2), push on days 1-5, every 4 weeks. Schedule I!: 2 hour infusion of leucovorin (200mg/m2) days 1-5 and thereafter 5-FU (400 rag/m2) as push, iv., days 1-5, every 3 weeks. A total number of 70 pts are evaluable at this time. 20 pts with cslorectal cancer were treated according to schedule I and the others according to schedule IL (Colorectal 33, gastric 9, pancreatic 3, gallbladder 2, prostatic 8, breast 6. renal 2, adenoca, of the lung and of unknown origin 2 each, carcinoid 1, adrenal 1, bladder 1). Treatment results were: A CR could not be achieved. Cslorectal cancer (schedule I and II): PR 4 pts, MR 4 pts, NC 12 pts, PD 13 pts. Gastric cancer: PR 1 pt, MR 1 pt, NC 3 pts and PD 4 pts. Breast cancer: PR 2 pts, NO 2 pts, PD 2 pts. Adenocarcinoma of unknown origin: PR 1 pt, PD "i pt No objective response could be achieved in: pancreatic, prostatic, renal and adrenal carcinoma, bladder and gallbladder cancer, adenocarcinoma of the lung and carcinoid. Toxicity of both schedules was tolerable. Dose limiting side effects were stomatitis and diarrhea, which were more pronounced by the combination of 5-FU with leucovorin than observed with cemparabIe doses of 5.FU alone. So far it can be concluded that 5-FU and leucovorin are active in advanced progressive colorectal cancer and breast cancer. The results in heavily pretreated breast cancer are promising and recommend further evaluation. Innere Universitg.ts- und Poliklinik (Tumorforschung) and Urotog{sche UniversitAtsItinik, West German Tumor Center, Hufelandstr. 55, 4300 Essen, FRG.

In the t r e a t m e n t o f SCLC, c a r b e p l a t i n seems t o be s i m i l a r t o c i s p l a t i n in i t s e f f e c t i v e n e s s . In January 1987, an e a r l y phase I I t r i a l was i n i t i a t e d t o evaluate the e f f i ciency and t o x i c i t y o f the c y t o s t a t i c combination carbop l a t i n (300 mg/m2 i v day I ) , v i n c r i s t i n e (I~5 mg i v days 1 , 8 , 1 5 , 2 1 ) , and etoposide ( I h - i n f u s i o n days I - 3 , escal a t i n g doses: 180 mg/m~ - 11 p a t i e n t s ( p t s ) , 120 mg/m2 8 p t s , 140 mg/m~ - 5 p t s , 160 mg/m2 - I p t ) , every 4 weeks. So f a r , 25 pts - 3 women, 22 men; l i m i t e d disease (LD) 5 p t s , extensive disease (ED) 20 pts (14 ED I I , 6 ED I ) ; median age 58 years (range, 36-75); median performance s t a t u s (WHO) I (range, 0-2) - were t r e a t e d . They are a l l evaluable f o r t o x i c i t y . Side e f f e c t s (WHO) i n c l u ded myelosuppression - leukocyte n a d i r 0-4 (median, 2) days 13-22; p l a t e l e t n a d i r 0-3 (median, 2) days 13-19; henmglobin n a d i r 0-2 (median, I ) - , nausea and vomiting 0-2 (median, I ) , polyneuropathy 0-2 (median, I - median v i n c r i s t i n e dose/pt 10 my), and a l o p e c i a w i t h o u t s i g n i f i cant nephro- o r o t e t o x i c i t y . There was, however, one poss i b l y drug r e l a t e d death from i n f e c t i o n s during l e u k o c y t o penia. A f t e r 3 courses o f therapy 14 pts (6 ED I I , 5 ED I , 3 LD) are evaluable f o r response: 11 p a r t i a l remissions (PR - 6 ED I I , 2 ED I , 3 LD p t s ) , 2 no changes (NC - 2 ED I p t s ) , and I progressive disease (PD - ED I p t ) . A f t e r a t o t a l o f 6 courses o f therapy 2 o f the ED I I pts have achieved CR and I ED I pt PR. In c o n c l u s i o n , the a n t i tumor a c t i v i t y o f the combination c a r b o p l a t i n / v i n c r i s t i n e / etoposide is promising and produces only mild side e f f e c t s . Innere U n i v e r s i t ~ t s k l i n i k und P o l i k l i n i k Westdeutsches Tumorzentrum, H u f e l a n d s t r .

(Tumorforschung), 55, 4300 Essen I .

S 142

4/P-GM 088 ETOPOSIDE/LEUKOVORIN/5-FLUOROURACIL(ELF) IN ELDERLY PTS. OR PTS. WITH CARDIAC RISKS-A PHASE-II-STUDY IN ADVANCED GASTRIC CANCER. H.Wilke,P.Preusser,U.Fink,N.Achterrath,Ch.Sch~ber,M.Stahl, H.Link,H.-J.Meyer,H.Poli~da and H.-J.Schmoll Pts. older than 55 years often suffer from tumor unrelated diseases ( h e a r t , l u n g , l i v e r , k i d n e y ) which might be contraindications for intensive c y t o s t a t i c treatment. Therefore e f f e c t i v e and t o l e r a b l e chemotherapy regimens without cu~ J l a t i v e organ t o x i c i t i e s are needed, From 2/86 to 10/87 a phase-ll-study with Etoposide/Leukovor i n / 5 - F l u o r o u r a c i l was conducted in pts, with advanced g a s t r i c cancer. Dosage and schedule: Leukovorin 300mg/m2 (10 min.inZ) f o l ~ 1 2 0 mg/m2 (40 m i n . i n f . ) followed by 5Fluorouracil 500~/m 2 (15 m i n . i n f . ) , d I-3, q d 22-28. E l i g i b i l i t y c r i t e r i a : H i s t o l o g i c a l l y proven advanced gasT r i c cancer; ~ b l e disease; age=,65 y r s . ; a g e ~ 6 5 y r s plus cardiac r i s k s ; Karnofsky performance s t a t u s ~ 6 0 % , Patient c h a r a c t e r i s t i c s : Male 22; female 12; age 66 years ~48-75); K a r n o ~ s ~ ' S ~ 0 % (60-100); l o c a l l y advanced d i sease 6; disseminated disease 28, Results: 30 pts, are evaluable f o r response and t o x i c i t y , ~ e a r l y ): CR 4(13%); CR+PR 13(43%)(95%confidence l i m i t 25%-61%); MR/NC 9(30%); P 8(27%); mod. remiss, durat i o n 8,5 mos.; mod, survival time 10 mos,. Toxicity(WHO grade):Leukocytes 2~ 3~ thromboc y - ~ 2 ~ ~ ) ; nausea/vomiting 2~ mucositiS/ stomatitis 2~ diarrhea 2~ 3~(7%); alopezia 3~ (50%). No t o x i c i t y of WHO grade 4 eccured. Conclusions: Etoposide/Leukovorin/5-Fluorouracil is t o l e ~a~derly patients and f o r patients with cardiac risks. Objective response rates, remission duration and survival time compare favourably with FAM or FAM-modifications. Abt. H~m~tologie/Onkologie, Medizinische Hochschule Hamlover, Konstanty-Gutschow-StraBe 8, 3000 Hannover 61

4/P-GM 090 INTRAOAVITARY MITOXANTRONE FOR TREATMENT OF MALIGNANT EFFUSIONS. E.:.Musch.. , D.Seitzer A.Chemaissani, U.Bode, A.Werner, J.Peiss. Recurrent malignant effusions present a difficult management prob!em in anticancer therapy. Locoregional treatments are suitable for patients failing to respond to systemic therapy : 44 patients with recurrent pleural effusion in metastatic breast cancer (n=27), bronchial carcinoma (n=10), pleural mesothelioma (n=4), ovarian cancer (n=2) and Hodgkin~s tymphoma (n=l) were treated with intrapleureJ Mitoxantrone (M). Chest tube drainage (with aspiration of pleural fluid as complete as possible) was followed by intrapleural M-instillation at a dose of 30 mg M diluted in 50 ml sodium chloride. After a 48 hrs interval with the chest tube blocked pleural drainage was repeated , in case of relevant reaccumutation of fluid within this 24 hrs period of re-drainage intrapteural instillation of M in an identical dose of 30 mg was repeated. Based on the actual data of our follow up ( until now 2.5 months (mean) +/- 2.3 months (SD) , range 0.25 - 9 months) remission rate (CR + PR) is 82 % in the patients with breast cancer, 80 % in the patients with bronchial carcinoma, 75 % in the patients with pteural mesothelioma. In one patient with ovarian cancer follow up of CR was possible for t month , in the other progression (P) occured one week after intrapleura! M. M-instillation in a patient with bilateral pteural effusions "associated with Hodgkin's lymphoma resulted in CR of 10 months duration in the left pleural cavity and 3.5. months in the right pleurat space, where intrapleural M-application had to be repeated. This patient exhibited chemotherapeutic resistance to the combination DX,BLM~VLB,DIC prior to intrapteural M. Intrapleural M was tolerated without local toxicity. Pharmacokinetic analysis demonstrates low pteurat clearnace of M, which represents one of the major prerequisites of M being used in selective tocoregional treatment. Apart from the current study with intrapleural M-therapy we performed intracavitary application of M in 5 patients with malignant asc[tes (n=4) and maligant perlcar'Jial effusibn.(n=l) Medizinische Universit~tsktinik D 53 Bonn-Venusberg

4/P-GM 089

4/P-GM 091

PILOT STUDY OF CONTINUOUS DOXORUBICIN INFUSIONS IN YOUNG PATIENTS WITH THERAPY-RESISTENTTUMORS, U, Bode and W. K~hler

PRIMARY

Eleven children and adolescents had been treated with surgery, radiotherapy, and chemotherapy for solid tumors (rhabdomyosarcomas 4, hemangiopericytomas 2, osteosarcoma, liposarcoma, neuroblastoma, Ewings sarcoma and neuroectodermal tumor). Though they had received 4-11 c y t o t o x i c drugs before, including doxorubicin in a l l but one, the disease was progressive, 32 w infusions of doxorubicin at doses of 5-i0 mg/m /day were given by central venous route via a subcutaneous reservoir on ambulatory basis, One p a t i e n t received the infusion i n t r a a r t e r i a l l y for f i v e days, one p a t i e n t by peripheral venous access f o r eight days, The duration of infusions was l i m i t e d by the appearance of mucositis, which occurred afte~ 7-20 days and 12-35 days at a dose of lOmg/m~ and 5mg/m , respectively. The q u a l i t y of l i f e was e x c e l l e n t , as t o x i c i t y was low. In 3/32 infusions a n t i b i o t i c treatment was necessary f o r fever and neutropenia, but bone marrow depression was only mild to moderate. Neither nausea and vomiting nor hepatic t o x i c i t y were ~ncountered. Though patients had received up to 1700mg/m doxorubicin t o t a l dose, no cardiac t o x i c i t y was seen. 8/11 patients showed non-dose related therapeutic improvement, of which four were mild, two moderate and two dramatic (PR) responses, As this therapy can be applied on ambulatory basis, is r e l a t i v e l y non-toxic and gives satisfying r e s u l t s , a larger phase ll-trial of continuous doxorubicin infusions f o r chemoresistent tumors is i n i t i a t e d and f i r s t results w i l l be presented. U n i v . - K i n d e r k l i n i k , Adenauera]]ee 119, 53 Bonn 1, FRG

EWING~S SARCOMA OF BONE: UPDATED RESULTS OF THE GPO COOPERATIVE EW1NG'S SARCOMA STUDIES (CESS) 81/86 H. JQrgens*+. UB. Graubner. St. MQller-Weihrlch, J. Ritter, M. Pfreundschuh, R. Sauer. H J. Schmoll. Ch. Urban, PA. Voete, P. Weinel. H. Winkler. and U. GSbel* The GPO CESS 83 trial with 4 nine-week cycles of 4d r u g chemotherapy (vincr~istine, actinomycin D, cyctophosphamlde, adrlamycln = VACA) and local control following two cycles of chemotherapy with s u r g e r y and/ or radiation has resulted in a Kaplan~Meier estimated disease-free survival rate of 5 1 % (_+ 6 %) after 6 years (51193 patients ( p t s . } disease-free). Tumor volume and histologic response to primary chemotherapy were identified as most significant factors influencing prognosis, As a consequence the treatment regimen of the follow-up trial CESS 86 was stratified according to Hsk of relapse. Standard risk pts, (extremity tumors <.100 ml tumor volume) continued to receive VACA chemotherapy. In high risk pts, (extremity tumors >100 ml. central t u mor~) conventional dose cyclophosphamlde was replaced by high dose ifosfamide (3 glm2td, days 1+2) with mesna uroprotection ( V A I A ) , Local therapy was now administered following week 9, Pts, w~th radiation were randomlsed for either conventional fractionation or accelerated split-course hyperfractionation. The s t u d y was piloted from Feb. to Dec. 85. 27/37 pts. were disease-free on Nov. t . 87. The ongoing trial was started on Jan. 86. On Nov. 1. 87. 63/66 pts. were disease-free. According to Kaplan-Meier life-table analysis pts, with large tumors who received VAIA instead of VACA chemotherapy had a significantly improved disease-free s u r v i v a l . The t o x i c i t y of both regimens was comparable. +Supported b y BMFT grant no. 01 ZP 063 5 and Deutsche Krebshilfe *Univers~t~tskinderklinlk, Abt. f. H~matolocj{e und Onkologie. Moorenstr, 5. D-~O00 D•sseldorf

S 143

4/P-GMO92

4/P-GM094

MITOXANTRONE, CYCLOPHOSPHAMIDE; AND VINCRISTINE (NCO) IN SMALL-CELL LUNG CANCER - A PROMISING NEW INDICATION FOR MITOXANTRONE P.A. Maubach, S. Seeber, A. Hollunder, C. Dibelius, A. Zeidler, E. En~hofer

CLINICAL STUDIES WITH CISPLATIN DERIVATIVES IN GYNECOLOGICAL TUMORS W. Achterrath,

Thirty-three patients with histologically proven small-cell lung cancer (SCLC) w e r e treated with a chemotherapy regimen combining mitoxantrone, cyclophosphamide, and vincristine (MCV). Twentynine patients had extensive disease; four had limited disease. Age distribution ranged from 44 to 79 years (mean, 59.3 years). Twenty-five patients were male, eight female. The regimen combined mitoxantrone 6 mg/m2 on days I and 2; cyclophosphamide 500 mg/m2 on days I and 2, with dose escalation of cyclophosphamide to 600 mg/m2, depending on myelosuppression; and vincristine 2 mg (total dose) on days I and 8, w i t h dose reduction to I mg for patients over 60 years old. In 23 patients (70 %), treatment response was achieved; complete response (CR) in 6 (18 %) and partial response (PR) in 17 (52 %). NO change was observed in 2 patients (6 %) and progressive disease in 6 (18 %). Ten (30 %) of the patients died: 3 due to progressive disease; I due to septic complications of therapy-related myelosuppression; I due to hemorrhagic complications, also as a consequence of myelosuppression; and 5 developed progressive disease (PD) and died after an initial PR. Survival time ranged from ~ to 8.5 months.

Carboplatin (JMS) and I p r o p l a t i n (JMg) were the f i r s t Cisplatin derivatives to become widely a v a i l a b l e f o r c l i n i c a l t r i a l s . In phase I I studies, both analogues were tested in m u l t i p l e dose schedules and pharmacokinet i c data were obtained. Myelosuppression was i d e n t i f i e d as dose l i m i t i n g t o x i c i t y . I t consisted of profound thrombocytopenia and less severe leucocytopenia. Nephro-, neuro-, and o t o t o • were extremely rare. JM8 and JMg appeared to be less emetic than C i s p l a t i n . The recommended dose f o r phase I I studies in previously untreated and in heavily pretreated patients of JM8 is 400 mg/m2 and 300 mg/m2 i v , r e s p e c t i v e l y , of JMg 300 mg/m2 and 270 mg/m~ i v , respectively. Results of disease oriented phase I I studies suggest that JM8 and JM9 have comparable a c t i v i t y to C i s p l a t i n in ovarian, c e r v i c a l , and pretreated breast cancer. In c i s p l a t i n - r e f r a c t o r y ovarian cancer appr. 25% responses were achieved with JM8 and JM9 (30-50% overall responses in patients relapsing a f t e r Cisplatin and appr. 10% responses at resistance to C i s p l a t i n ) . In advanced ovarian cancer, JM8 was tested versus C i s p l a t i n in two prospective randomized t r i a l s . Comparable results (CR, overall responses, median remission duration, survival time) were achieved. In both studies, JM8 induced s i g n i f i c a n t l y less non-hematologic t o x i c i t i e s (nephro-, ore-, n e u r o t o x i c i t y , nausea/ vomiting) than C i s p l a t i n . JM8 and JM9 were tested in combination with a l k y l a t o r s and other active agents in p i l o t and in randomized t r i a l s in ovarian cancer. Updated results of phase I I and I I I studies in gynecological tumors w i l l be presented.

Treatment results w i t h NCO are comparable w i t h standard regimes (response rate 70 %) whereas side effects are markedly lower. Definite results and survival time of the ongoing study will be available at the time of presentation. Med. Klin. Ingolstadt, St~dt. Klin. Leverkusen, Klin. KSln-Merheim, Augusta-Kr. Boch~mm, Lederle

Bristol-Myers Company, C l i n i c a l Research Anticancer, HermannstaBe 54, D-6078 Neu-lsenburg

4/P-GM 093

4/P-GM 095

PILOT STUDY W I T H CARBOPLATIN/ETOPOSIDE AS FIRST LINE CHEMOTHERAPY IN ADVANCED OVARIAN CARCINOMA (STAGE III, IV) W. Eiermann,

50 MONTHS TOTAL-BODY-IRRADIATION PRIOR TO BONE MARROW TRANSPLANTATION USING A WHOLE-BODY-COMPENSATOR

A pilot study with Carboplatin/Etoposide was carried out for determination of the recommended dose for phase II studies. In addition, first data on antineoplastic activity in ovarian cancer were ascertained. Carboplatin/Etoposide were applied in the following starting dose schedule: Carboplatin 350mg/m ~ i.v. day i, Etopoeide 70mg/m 2 i.v. days 1-3. Carboplatin was given in a fixed dose. The dose of Etoposide was escalated step by appr. 20% until intolerable toxicity cccured in 3 out of 5 patients. 13 pts., mean age 56 (42-75 yrs) received a total of 58 courses (mean 5,3). Intolerable toxicity was defined as hematologic toxicity ~ III WHO, renal toxicity > II WHO. 5 pts each received 210mg/m 2, 2 7 0 m g / m 2 and 3 patients received 330mg/m ~ Etoposide i.v. per course. I0 patients are available for toxicity and response. Dose limiting toxicity is not reached yet. Up until now (270mg/m 2 Etoposide per course) no m y e l o t o x i c i t y > grade 3 ace. WHO were observed. Other toxieiti~s acc. to WHO: Vomoting/nausea grad III, hair loss grade III, were observed in all patients. Diarrhoe grade I and !I were observed in 6/10 patients. No other toxicities oecured. 3 path. CR and 4 NC were achieved, 3 pts. had progressive disease, Updated results will be presented. Dept. of Obstetrics and Gynecology, Klinikum Grosshadern, L u d w i g - M a x i m i l i a n s - U n i v e r a i t y Munich, West Germany

F. Brix, A. Quirin

From March 1983 to August 1987 allogeneic (n = 72) or autologous (n = g) bone marrow transplantation was performed in 81 patients between 4 and 45 years of age at the Kiei Transplantation Center. Predominantly they suffered from acute or chronic leukemia (n = 64). A l l o f the l a s t received a conditioning regimen consisting of high-dose chemotherapy either with cyclophosphamide (n = 31) or VP 16-213 (n = 33) and fractionated t o t a l body i r r a d i a t i o n using i n d i v i d u a l t o t a l body compensators at a l i n e a r accelerator. The i r r a d i a t i o n was performed on three consecutive days with two fractions per day up to the t o t a l dose of 12 Gy. The compensators were used to homogenize the d o s e - d i s t r i b u t i o n on the midplane of the patient who l i e d in supine p o s i t i o n , For the l a s t 24 patients an additional lung-block was integrated into the compensator by this reducing the lung-dose to 11 Gy. Both conditioning-regimens provide an antileukemic effect comparable to similar techniques without using a compensator. Acute toxicity mainly depends on the chemo-therapeutic regimen. The side-effects in the VP 16-213 group are pronounced whereas the incidence of interstitial pneumonitis is obviously influenced by multiple factors as for example the pretherapeutic CMV-status.

Radiologische Klinik der Christien-Albrechts-Universit~t Kiel, Arnold-Heller-Stre6e 9, 2300 Kiel 1

S 144

4/P-GM 096

4/P-GM 098

CARDIOTOXICITY OF MYELOABLATIVE THERAPY: ENHANCEMENT BY PRETREATMENT WITH ANTHRACYCLINES ? - AN AUTOPSY STUDY IN AUTOLOGOUS BONE MARROW TRANSPLANTATION PATIENTS

BONE MARROW TRANSPLANTATION (BMI) FROM RELATED DONORS OTHER THAN HLA-IDENIICAL SIBLINGS K.Quabeck, D.W.8eelen, U.Graeven, H.G.Sayer, U.W.Schaefer, C.G.Schmidt

A. van Herbay I

B. D6rken 2

G. Mall I , M, K0~bl!nq

Cardiotoxicity of myeloablative therapy in the preparation for autologous bone marrow transplantation (BMT) has been considered as a major complication following BMT. We investigated histological lesions of the myocardium in 7 patients who died between 9 and 85 days (median 22 days) after autologous bone marrow (n = 5) o r blood stem-cell (n = 2) transplantation. Myeloablation was performed with total body irradiation (12,0-15~6 Gy) and high-dose cyclophosphamide (200 mg/kg)~ Morphological findings were graded semiquantitatively and correlated to previous and current therapy. Myocardial alterations with contraction band necrosis; probably related to high-dose cyclophosphamide but not to total body irradiation, were present in 5/7 patients; four of them died suddenly from cardiac cause. However, irregular shapes and chromatin clumping of myocardial cell nuclei (4/4 pts.) as well as pronounced interstitial fibrosis (2/4 pts.) could not be explained by the acute cardiotoxicity of cyclophosphamide. Retrospective analysis of leukemia therapy prior to BMT revealed that high cumulative doses of cardiotoxic anthracyclines and mitoxantrone had been applicated in those 4 patients. In 3 patients who died from noncardiac causes, the myocardial alterations described above were not detected, and cumulative anthracycline doses were considerably lower. On the basis of our observations we suggest that pretreatment with high doses of anthracyclines enhances the cardiotoxicity of the myeloablative regimen. Pathologisches Institut und 2 Medizinische Poliklinik der Universit~t Heidelberg. D - 6900 Heidelberg, Im Neuenheimer Feld 220/221, West Germany

As of November 1987~ eighteen patients (pts) received allogeneic marro~ grafts from haploidentJeal related donors at the West German Tumor Center Essen. The median age of the 9 males and 9 females #as 31 yrs (6-49 yrs). The underlying disease ~as acute leukemia (AL) in ist (n=5) or 2nd remission (n=3) or in relapse (n=3); chronic myeloid leukemia (CML) in ist chronic phase (n=5), accelerated phase (n=2) or 2nd chronic phase after lymphoid transformation (n=l)~ severe aplastic anemia (SAA) (n=l), Eight donors ~ere parents, 6 ~ere siblings, 3 mere children, and one was a grand uncle. All patient-donor pairs ~ere genotypically identical for one haplotype. Four pts ~ere phenotypieally identical for the unshared chromosome. The other fourteen pts received grafts from donors incompatible for one (n=12), 2 (n=l) or 5 (n=l) class I - antigens. The protreatment consisted of total body irradiation follo~ed by cyclophosphamide (n=15) or etoposide (n=2) in pts mith leukemia. As prophylaxis of graft-vs-host disease (GvHD) methotrexate (MTX) alone (n=lO), short-course MTX and eyclosporine A (n=6) or prednisolone and cyelosporine A (n--2) ~as given. Six of nine pts fulfilling standard risk criteria (i.e. AL in remission~CML in 1st chronic phase,SAA) are alive and disease-free at a median observation time of 28 months~ resulting in a cumulative probability of disease-free survival of 44% at 6 yrs. Of the pts in morm advanced stages of their disease 2/9 (22%1 are alive and disease-free at 3 and 60 months, respectively. Graft failure oceured in 1 patient. Eight pts developed GvHD. T#o pts relapsed ~ith their respective leukemia. - Though our patientgroup is heterogenous in various aspects, the results suggest that BMT from related donors other than HLA-identieal siblings may beafeasibieapproach in selected pts~ith leukemia andSAA. Inhere Klinik und Poliklinik (Tumorforschung) Universit~tsklinikum Essen,Hufelandstr.55,D-4300 Essen i

4/P-GM 097

4/P-GM099

INFLUENCE OF TREATMENT-RELATED FACTORS ON THE RESULTS OF ALLOGENEIC MARROW TRANSPLANTATION FOR LEUKEMIA D.W. Beelen, K. Quabeck~ U. Graeven, H.G. Sayer, U.W. Schaefer, C.G. Schmidt.

T-CELL SUBSETS IN ACUTE GP~FT-VERSUS-HOST DISEASE (GVHD) IN BONE MARROW TRANSPLANT (BMT) RECIPIENTS AFTER IN VITRO-T-CELL DEPLETION H.P. Sinn, P.J. Eenslee, M. Cibull, J.S. Thompson

We retrospectively analyzed the influence of different preparative regimens and post-transplant treatment protocols on the results of allogeneic bone marrow transplantation (BMT) in 149 consecutive patients (pts) ~ith acute leukemia (AL) (n=96) or chronic myeloJd leukemia (CML) (n=53), who received transplants from HLA-identical siblings. At the time of BMI lO0 pts ~ere in 1st remission of AL (n=53) or 1st chronic phase of CML (n=47) (group l) and 49 pts ~ere in advanced stages of their disease (group 2). T~o treatment-associated factors predictive of survival ~ere identified: fractionated (4x2.5 Gy) vs single dose total body irradiation (TBI) (p
While T-cell depletion has reduced the severit Z of acute GV}{D greatly, we have not observes a significant decrease in its incidence. This study was designed to o/~alyze the jymphog~te sub@ets in skin from haplo- and nistocompa~ioLe patients after monoclonal an~Inooy me@tared (CD3 and CD6) T-cell depleted BMT. ~ , in a consecutive series of 37 patients who unaerwen~ BMT for hematologic malignancies, 24 patients de. veloped acute GVHD and were biopsies aerate ~ne onse~ of therapy. A panel of monaclonal antibodies (MoAb), including pan-leucoc3Hce, Leu4, Leubb, Leu3a+3b, OKTB, OKTI0, Leul4, LeuT, Leullb, L234(la), LeuMl, and OKT6 was employed on frozen tissue sections. ResulTs were compared with 8 normal control skin biopsies which were processed identically. . The de~ree of mononuelear infiltrate af the onset or acute GVHD (pre-therapy), was more marked than in the normal control in only 5 cases, helper/insurer tcells (Leu3+) always outnumbered c>%oto~ic/suppressor T-cells (OKT8+), the latter represented greater than i0~ of cells in only 32% of cases. An increases proportion of helper cells was found comparedwiththe normal controls (71~ vs. 37~ >50% Leu3+ cells), ann NE-cells were also increased (71% vs. 12~ scattered LeuT+ cells). Epidermal Langerhans cells were reduced (50%) or absent (50~) in BMT biopsies regardless of GV}ID status; no si~n~Ificant differences were observed in the immunohistoehemieal markers Dy comparing tne haploidentical (n=13) with the histoeompatible (n=ll) group or patients with highly reactlve (>20%) mixed lymphocyte culture (MLC) assay in=6) with low or moderately reactive MLC (!20~) (n=18). We eoneIude %ha% T-cell depletion effeetiyel~ reduces the nw~ber of effeetor cells in aeuxe GV}{D of skin. Most notably, OKTB+ suppressor/eytotoxie cells appear less prom~ngnt in the skin infiltrate 9 of p~tien~s ~nannas oeen reported in non-T-eel eepleated. BMT recipients where this population pre-ll dominates. An increase in inril~rating natural K i er cells was also observed, providin~ further suppo[t for an effector role in the GVHD reaction by this suoset of lymphocytes. Dept. of PatholoRT~ and Medicine, University of Kentucky Medical-Uenter, 800 Rose St., Lexington KY 40536, USA. Patholo~isehes Institut der Universit~t, Im meuenneimer ~eld 220, I)-6900 Heidelberg

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SERUM CSA CONCENTRATION AND SEVERITY OF ACUTE GVHD AFTER BONEMARROWTRANSPLANTATION H. Schmidt*, G. Ehninger*, R. Dopfer&, R. Naumann*, H. Einsele*, M. Haen~, K. Sch~ch~, D. Niethammer~, H.D. Waller ~

ALLOGENEIC BONE MARROW TRANSPLANTATION (BMT) IN THE ABSENCE OF AN HLA -IDENTICAL SIBLING

During the last 5 years 51 patients were treated with ciclosporin (CSA) to prevent graft versus host disease (GvHD) after bone marrow transplantation. 12 patients were suffering from acute lymphocytic leukemia, 15 from acute non lymphocytic leukemia, 14 from chronic myeloic leukemia and 12 f r o m severe aplastic anemia. As described before major side effects of CSA were tremor, hypertension, hepatotoxicity and nephrotoxicity. As soon as the patients were treated with cotrimoxazol nephrotoxicity was even enhanced. Despite the use of CSA acute GvHD 0~ to IT ~ occurred in 80 % of the patients, GvHD I I I ~ and IV~ in 20 % starting 8 to 20 days after BMT. Two to 4 days before the onset of GvHD CSA serum levels were on average significantly (p-value < 0.05) lower in patients who got GvHD l i t ~ and IV ~ (130 - 190 ng/ml) compared to the others (350 to 450 ng/ml). Our data indicate that h i g h enough serum concentrations of CSA (200 to 400 ng/ml) during the f i r s t months after BMT may be important to reduce the severity of acute GvHD. Department of Internal Medicine I I , Department of Haematology and Oncology, D7400 TUbingen, FRG Children Hospital, Department of Haematology and Oncology, D7400 TQbingen, FRG

G. E h n i n g e r , R. Dopfer, C.A. M d l l e r , G. Pawelec, H. E i n s e l e , H. Schmidt, M. Haen, K. SchQch, D. Niethammer, and H.D. W a l l e r Fourteen p a t i e n t s (age range 7-34 y e a r s , median 19 y e a r s ) were t r a n s p l a n t e d drum donors o t h e r than HLA i d e n t i c a l a n d / o r MLC n e g a t i v e s i b l i n g s . Ten p a t i e n t s had p a r t i a l l y matched r e l a t e d donors, and 3 were t r a n s p l a n t e d from u n r e l a t e d donors. The diagnoses were: AML 2nd CR (N=2), ALL/AUL 2rid and 3rd CR (N=4), SAA ( N = I ) , and CML a c c e l e r a t e d phase or b l a s t c r i s i s (N=7). C i c l o s p o r i n plus m e t h o t r e x a t e was u s u a l l y given as GvHD p r o p h y l a x i s . Engraftment was documented in 12 p a t i e n t s . 9 out of 11 e v a l u a b l e p a t i e n t s d e v e l o p e d aGvHD (grade IT, N=4; grade I l l and IV, N=5). Four p a t i e n t s died from i n f e c t i o n s and p n e u m o n i t i s , two p a t i e n t s r e l a p s e d . Six p a t i e n t s are a l i v e w i t h a median f o l l o w up of 4 months (range 1-12 months). The group of p a t i e n t s t r a n s p l a n t e d is small and the f o l l o w up is s h o r t . N o n e t h e l e s s , the f r e q u e n c y of aGvHD in such p a t i e n t s was h i g h e r than in HLA/MLC-matched p a t i e n t s and, moreover, appears to be h i g h e r than r e p o r t e d by o t h e r s f o r s i m i l i a r s e r i e s . M e d i z i n i s c h e K l i n i k und K i n d e r k l i n i k U n i v e r s i t ~ t , 7400 TObingen

der

4/P-GM 101

4/P-GM 103

First results of fractionated versus single dDse TBI in conditioning allogeneic bone marrow transplantations VOSS,A.-C., HEIT, W., MULLER,F., SCHLIMOK,G., WANNENMACHER, M., W I E S N E T H , M.

COLONY-STIMULATING FACTOR AS ~K]LTI-DO~IN PROTEIN? K. Vehmeyer, W. Brandt, G.A. Nagel, H.-J. Gabius

Since June 1985 46 adults and children were conditioned by fractionated TBI before ~MT with 6 fractions of 2 Gy within 3 days with HEK-compensators. A group of 32 allogeneic transplantated adults is compared with 48 adults who received 10 Gy single dose TBI in Freiburg. All patients were treated by the same chemotherapeutic regimen in the department of Bone Marrow Transplantation of the University of Ulm. Since introducing the T-cell-depletion as a GvHD-prophylaxis 26 patients radiated in Freiburg are comparable with 20 patients radiated in Augsburg. So far the results for the fractionatedgroup with c a . 7 ~ versus ca. 38% for the single dose group seem to be better, however the observation time in the first group is shorter. In patients with standard risk the results were ca. 80% versus 50%. The rate of acute and chronic GvHD reactions and rejections in both groups is approximately the same. But the relapse rate seems r o b e higher in the single dose group. In this group 9 of 26 patients suffered from a relapse, while in the fractionated group none of 20 patients had a recurrence. The radiation caused side effects were lower in the fractionated group, especially regarding interstitial pneumonitis. From these first results we could be able to conclude that fractionated TBI appears to have less relapses and side effects and is able-to improve the survival rates better than single dose TBI. It seems to have no influence on the rate of GvHD reactions and rejections. The effectiveness of compensators, in use for only 2 and a half years, cannot jet be judged.

Hematopoietic progenitor cells proliferate and mature in semisolid media in response to exogenously added hematopoietic cell growth factors such as the multipotential colony-stimulating factor (multi-CSF). This CSF-mediated proliferation can be reduced in vitro by several saccharides, prominently including lactose, mannose and phosphorylated fructose and mannose, to a lesser extent phosphorylated galactose or the charge-bearing sialic acid. From the sulfated polysaccharides tested, only dextransulfate proved inhibitory. Computer analysis of sequence similarities using a mutation distance matrix indicates homologies between multi-CSF and various lectin sequences, extending the hypothesis of potential capability of multi-CSF to interact with carbohydrates besides the receptor. Homologies were also detected between lectin sequences and other biological response modifiers such as interleukin 1 and tumor necrosis factor. These results serve to propose that CSF may belong to the family of multi domain-proteins such as interleukin i (Muchmore and Decker, J. Immunol. 138: 2541-2546, 1987), the chondroitin sulfate proteoglycan core protein (~Lrusius et al., JBC 262: 13120-13125, 1987) and the lectin discoidin 1 (Gabius et al., Cell 42: 449-456, 1985). Abt. H~matologie-Onkologie der Medizinischen Universit~tsklinik, Robert-Koch-StraBe 40, D-3400 GSttingen

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TUMOR NECROSIS FACTOR REGULATES ANTIBODY D E P E N D E N T C E L L U L A R C Y T O T O X I C I T Y (ADCC) O F HUMAN POLYMORPH NUCLEAR CELLS S.Oz, M . H a d a m , C.B~hrer, E.Platzer, J.Atzpodien, and K.Welte .......................................... H u m a n p o l y m o r p h n,~clear cells (PMN) h a v e b e e n s h o w n in a n t i b o d y d e p e n d e n t cellular cytotoxicity (ADCC) a s s a y s to be cytotoxic t o w a r d a n t i b o d y coated p a t h o g e n s or t u m o r cells. While the specificity of this killing p r o c e s s largely d e p e n d s on t h e antibodies employed, the efficiency is also influenced b y t h e f u n c tional activation of t h e P M N as effector cells. W e f o u n d T u m o r Necrosis Factor a l p h a (TNF) a n d G r a n u l o c y t e - M a c r o p h a g e Colony S t i m u lating Factor ( G M - C S F ) to be potent regulators of P M N m e d i a t e d A D C C against the h u m a n p r o m y e locytic l e u k e m i a line HL-60, as m e a s u r e d in a s t a n d a r d 4 h 5 1 - C r release assay. W h e n a d d e d simultaneously with targets, T N F at I'000 U/ml i n d u c e d an up to sevenfold increase in specific lysis of H L - 6 0 cells. In contrast, cytotoxicity was only twofold e n h a n c e d w h e n effector cells w e r e p r e i n c u b a t e d for I h with T N F (I'000 U/ml). Following incubation of P M N with G M - C S F , an up to fivefold A D C C a u g m e n t a tion was observed, r e g a r d l e s s of the timepoint of c y t o k i n e addition. P r e i n c u b a t i o n with TNF, but not with G M - C S F , for I h r e d u c e d the expression of g r a n u l o c y t e F c - r e c e p t o r s (CD 16) by PMN. O u r results s u g g e s t s that A D C C - t y p e P M N m e d i a t e d cytotoxicity can be differentially potentiated by v a r i o u s h u m a n biological resp o n s e modifiers.

PHASE-II TRIAL OF RECOMBINANT INTERFERON-ALPHA2C IN PATIENTS WITH METASTATICCARCINOIDTUMORS F. StSckmann, H.H. Bartsch, R. Arnold and W. Creutzfeldt The c l i n i c a l symptoms of patients with metastatic ~ a r c i noid tumors are dependent from local tumor masses, metastatic spread and the secretion of gastrointestinal hormones from the tumor cells. Flushs, diarrhea and hypoglycemia are the most frequent symptoms in these patients. The median survival of pts with metastatic carcinoid tumors is about three years. The response rate to combination chemotherapy with 5-FU and Streptocytocin as well as for somatostatin analoga is about 30%. Recent reports described c l i n i c a l improvement and objective responses following IFN-alpha therapy in these pts. For this reason we started a phase-II t r i a l with recombinant IFN-alpha 2c in pts =with metastatic carcinoid tumors. The pts receive 2xlOEu U/mE2 recombinant IFN-alpha daily s.c. for at least 3 months. I f pts show clinical or objective improvement as measured by hormone secretion and x-ray/cat-scan the duration of treatment w i l l be prolonged until there is evidence for progression. Up to now we included 7 pts into this protocol, 4 pts with metastatic carcinoid and 3 pts with metastatic gastrinoma. In 2 pts c l i n i c a l and objective response was noted after 3 months of therapy. There were no major side effects due to IFN-alpha application in any of the pts. We present c l i n i c a l data and hormone levels of our patients. Zentrum Innere Medizin der Str. 40, D-3400 GSttingen

Universit~t,

Robert-Koch-

S.Oz, Kinderklinik M H H , D - 3 0 0 0 H a n n o v e r 61

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4/P.GM107

LOW D O S E R E C O M B I N A N T I N T E R F E R O N ~ 2b IN C H R O N I C M Y E L O G E N O U S LEUKEMIA: R E S U L T S AND QUESTIONS. H. Diedrich, M. Freund, P. von Wussow, R. Eisert, B. M e t z n e r and H. Po!iwoda.

INDUCTION OF HLA-DR ANTIGENSON HUMANCOLONCA CELLS AS SPECIFIC AND SENSITIVE BIO-ASSAY FOR HUMAN INTERFERONGAMMA H. Feuerhahn, H.H. Bartsch, P. Scheurich. G.A. Nagel and K~ Pfizenmaier

For the v a s t m a j o r i t y of p a t i e n t s w i t h CML no c u r a t i v e treatment s t r a t e g y could be d e v e l o p e d up to now. So the d e m o n s t r a t i o n of cytogenetic r e m i s s i o n s in p a t i e n t s w i t h CML treated with r e c o m b i n a n t i n t e r f e r o n s rouse broad interest. We have treated 28 p a t i e n t s w i t h CML in a phase II study w i t h IFN ~ 2b. 26 p a t i e n t s r e c e i v e d 5 Mio U s.c. thrice weekly, one IO Mio U, another 2,5 M i o U. M e d i a n age was 46.9 yrs. (18.4 67.8 yrs.). 17 p a t i e n t s were p r e t r e a t e d w i t h busulfan, two of them w i t h h y d r o x y u r e a or IFN g a m m a aditionally, II p a t i e n t s h a d no pretreatment. Low dose IFN ~ 2b r e s u l t e d in p r o m p t cytoreduction in the m a j o r i t y of patients, I0 of them a c h i e v i n g a c o m p l e t e h e m a t o l o g i c r e m i s s i o n (CHR; WBC <9000/DI, normal differential blood count, no splenomegaly) w i t h a median projected duration of 5.8 mo. 6 m o r e h a d a partial h e m a t o l o g i c r e m i s s i o n (PHR; WBC 50% of initial value and 20 000/DI). All C H R o c c u r r e d w i t h i n 7 months, all P H R w i t h i n 12 months. There was one minor c y t o g e n e t i c r e s p o n s e in a p a t i e n t w i t h C H R but no c o m p l e t e cytogenetic remission. Toxicities c o n s i s t e d in fever, "flu-like" symptoms, fatigue, w e i g h t loss, and h e m a t o t o x i c i t y . Formation of a n t i b o d i e s is a serious l i m i t a t i o n for low dose IFN ~ 2 b in CML. 8 p a t i e n t s d e v e l o p e d antibodies up to now. A n t i b o d i e s occurred late b e t w e e n 4 and 21 months. In life table analysis therefore 50~ of p a t i e n t s are p r o j e c t e d to have a n t i b o d i e s after 20.4 months. F u r t h e r e x p e r i e n c e is n e c e s s a r y to d e f i n e late p r o b l e m s w i t h rIFN. Dept. H e m a t o l o g y / O n c o l o g y , M e d i c a l School, s t a n t y Gutschowstr. 8, D-3000 H a n n o v e r 61

Kon-

Human Interferon-gamma (IFN-g) is a lymphokine produced from T-lymphocytes upon stimulation with mitogen or spec i f i c antigen. Besides antiviral and antiproliferative effects, IFN-g has pleiotropic biological a c t i v i t i e s in immuneregulation. Since IFN-g is already introduced into clinical t r i a l s , i t is necessary to detect biological active IFN-g in human blood or body fluids. The disadvantage of the most commonly used bioassay for interferons (antiviral assay) is that this test does not a l low a discrimination between the different IFN-types. The assay described here is based on the selective a c t i v i t y of IFN-g namely induction of MHC class I I antigens. Using the human colon ca cell line Colo 205 we found a dose and time dependent induction of HLA-DR by natural and recombinant IFN-g as measured by cytofluometry using conjugated monoclonal ABs. In contrast, human IFN-alpha or beta did not induce class I I antigens on the respective cells. Although TNF-alpha alone has no effect on HLA-DR expression i t showed a clear synerg i s t i c a c t i v i t y in combination with IFN-g. Under these conditions antigen expression was maximal after 32 hours stimulation. In contrast to monocytic cells the HLA-DR induction on Colo 205 was not influenced by corticosteroids or prostaglandin E. This assay is sensitive to detect 0.2 U/ml IFN-g in serum as well as cell culture supernatants. We present data from serum of pts with leukemias during therapy with IFN-g and bone marrow serum levels from pts with different hematologic diseases. Abt. H~matologie/Onkologie, Zentrum Innere Hedizin der Universit~t, Robert-Koch-Str. 40, D-3400 GSttingen

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I M M U N O M O N I T O R I N G DURING TREATMENT WITH INTERFERON ALFA IN HAIRY CELL LEUKEMIA (HCL) AND CHRONIC M Y E L O I D L E U K E M I A (CML). E. Salewski, I. Doxiadis, D. May, N. Niederle, H. G r o s s e - W i l d e

RECURRENT VULVAR BUSCHKE-LOWENSTE!N'S TUMOR-LIKE CONDYLORATA ACUNINATA AND HODGKIN'S DISEASE EFgECTIVELY TREATED WITH r!FN ALPHA 2cGEL AS ADJUVANT TO ELECTROSURGERY G. Gross and H, Pfister

Interferons (IFN) are a group of proteins with pleiotropic biologic effects on target cells. TO determine the i m ~ u n o m o d u l a t i n g efficacy of IFN alfa-2b in patients (pts) with HCL (n=17) and CM~ (n=21), various h e m a t o l o g i c and immunologic p a r a m e t e r s (T- and B-lymphocytes, T - s u p p r e s s o r and T-helper cells) were analyzed before and during treatment. In addition, the p r o l i f e r a t i v e in vitro response to mitogens (PHA, Con A, PWM) and a series of antigens (PPD, TET, DIP, CAN, TRI, CMV, HSV, RUV, VZV) was tested. Three pts with HCL a c h i e v e d a complete r e m i s s i o n and 11 a partial remission. Granulocytes, lymphocytes, platelets, and h e m o g l o b i n values were n o r m a l i z e d w i t h i n 5 months of b e g i n n i n g treatment (p <0.05). In this period, T - l y m p h o c y t e s increased from 30% to 80% and T-helper cells from 8% to 20%. T-supp r e s s o r cells increased from 15%-23%. During IFN therapy there was a major increase in response of lymphoid cells to mitogens ( > 2 0 % ) but not to antigens. In C ~ pts, h e m a t o l o g i c r e m i s s i o n was induced in 14 pts, partial h e m a t o l o g i c r e m i s s i o n in a further 4 pts. T- and B - l y m p h o c y t e s were n o r m a l i z e d within 7 months of treatment. An increase of T - h e l p e r and T - s u p p r e s s o r cells (> 15%) was noted. There was, however, no s i g n i f i c a n t change in the TH/T S ratio. M i t o g e n r e s p o n s i v e n e s s increased by mole than 50% during IFN treatment c o m p a r e d to p r e t r e a t m e n t values. In conclusion, the h e m a t o l o g i c improvement during therapy with IFN alfa-2b in pts with HCL and CML was accompanied by a r e s t o r a t i o n of d i s t i n c t l y m p h o c y t e subpopulations and functions. Institut f~r Immungenetik, U n i v e r s i t ~ t s k l i n i k u m , Hufelandstr. 55, 4300 Essen I

Aeter e l e c t r o c a u t e r i z a t i o n recombinant i n t e r f e r o n (rlFN) alpha 2c (Thomae/Bo~hringer, Ingelheim, FRG) as hydrogel (concentration lxlO I . U . / g ) was l o c a l l y applied 5 times per day t o a woman s u f f e r i n g from re cu rre n t Bueehke-L6wens t e i n ' s t u m o r-like condylomata acuminata (Papillomavirus type 6, analysed by Southern b l o t technique) o f the genitoanal region. Using t h i s therapeutic procedure during 8 weeks after surgery no relapse has been seen since 5months. The condylomata had arisen two years prior to therapy and 26 months after polychemetherapy and radiotherapy because of Hodgkin's disease stage II/III. The male partner presented with the same disease and was treated effectively by electrocauterization. In:the case of our Hodgkin's patient the genital warts recurred immediately after CO~laser surgery and increased rapidly in volume. The gian~ condylomata did not respond to the systemic (subcutaneous) low dose rIPN alpha 2c treatment, a very potent therapeutic approach given at intervals during 4 months, This case is of special interest because: (1)the systemic rIFN alpha treatment was ineffective, but (2) the local rIFN alphatherapy given as adjuvant to electrocauterization lead to a complete cure of the lesions. It is suggested that individuals suffering from both genital papillomavirus infections and defects of the cell-mediated immunity as seen in Hodgkin's disease, in HIV infection and during drug addiction (personal observation) cannot respond to the low-dose systemic rlFN alpha 2c therapy, probably because of functional defects of the macrophages. The local application given as an adjuvant may have direct antiproliferative and possibly direct antiviral activities, Univ.-Hautklinik Eppendorf, Nartinistr, 52 2000 Hamburg 20, West-Germany

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I~N VITRO INDUCTICN OF T~ORSPECIFIC T-SU~PRESSOR(Ts) CELLS H.-D. Haubeck,< I ~ [email protected] E. K~lsch

SYNTHESIS OF PEPTIDE HORMONES AND AUTOCRINE GROWTH FACTORS IN PERMANENT CULTURES OF LEUKEMIC CELLS K.-H. Pfl0ger, A, GrLiber, P. Kiefer, H. KGppler, and K. Havemann

We have shown previously that tt~norspecific Ts cells were induced in vivo in BALB/c mice by the syng~neic plas,q~cytd~(PC) ADJ-PC-5 at very early stages of t~morigenesis(!). These Ts cells which suppress a strong primary in vitro c2~otoxic t cell response have been characterized in detail. There is evidence t/~t TS cell Lnducing antigens (Ts-Ag) on ADJ-PC-5 PC cells are expressed to scme extent on nozlrel BALB/c spleen cells and are therefore "self" antigens rather than t~orspecific neoantige~ns~ (2).To cb~aracterize Ts-Ag Ln more detail we have developed an in vitro system for the induction of ttlm~rcspecific Ts cells. Te cell function would be masked in the in vitro Ts assay in the presence of activated cytotoxic T cells (CTL) which are not susceptible to suppression. Activation of CIL is prevented by fixation of ADJ-PC-5 stimulator cells with glutarald~hyd. In contrast specific Ts cells were activated by this approac.h which suppress a prLmary mixed lymphocyte-tumorculture (~LTC) of BALB/c spl~n cells against ADJ-PC-S but not against the syngeneic control tumors UI~MC (12m&3h~a) and ~%~4 A(fibrosarccma). Even in lectin-kill-assays these Ts cells b,ave no cytolytic or ~-~<-li/
Permanent leukemic ceil lines for in vitro proliferation need supplements such as serum or special growth factors. The 3 ceil lines, established in our laboratory, EW2, LG3, and MS6 were adapted to serum free culture conditions in media supplemented with transferrin, selenium, and insulin. These ceU lines show myelomonocytic characteristics and are able to synthesize human calcitonin (h-CT) and calcitonin gone related Peptide (CGRP). Conditioned medium (CM) of one of these lines exhibits proliferation inducing activity when tested with HL60 or other lines as target cells. Proliferation was determined using 3H-thymidine incorporation. Soft agar cloning assay or cell counting. Addition of h-OT, of CGRP, and of salmon CT (s-CT) in various concentrations resulted in no or only slight induction of proliferation. However, the addition of antibodies to h-OT completely inhibited 3H-thymidine incorporation. The calcitonins produced by these cells were found to be high molecular weight prohormones. Using northern blot analysis in HL60 cells after induction of differentiation a marked increase of specific mRNA for h-OT was found. The proliferation inducing activity in CM's was further characterized by chromatography. The most potent growth factor so far identified is transferrin produced by the celf lines. This was shown by quantitation of transferrin in CM's and by specific methods including a radioimmuno~preeipitation assay. These results demonstrate that in vitro growth of human leukemic cells is regulated in an autocrine or paracrine manner. Zentrum fiJr Innere Medizin, AbteHung H~matologie/OnkologJe/tmmunologie, BaldingerstraGe, D-3550 Marburg

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H L A C L A S S II A N T I G E N E X P R E S S I O N IN H U M A N B R E A S T CARCINOMA: COMPARISON OF PROTEIN AND MESSENGER R N A L E V E L B Y IN S I T U H Y B R I D I Z A T I O N Christine Sers, Christine Brunner, Gert R i e t h m ~ l l e r a n d Judith P. J o h n s o n

Malignant tumors of the inner nose and the paranasab sinuses

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HLA class II molecules control antigen recognition by regulatory T cells. Although they are mainly expressed on cells known to be involved in antigen presentation, class II antigens have also been found on certain tumors. Investigations on breast carcinoma using MoAbs against class I! molecules reveals a heterogeneity among the tumors. 35 of 60 tumors reacted with MoAb against eptiopes on DR ~I and ~III chains. Some reacted also with Moabs against DQ and DP products.Among the 25 negative tumors, 17 reacted with MoAb 3E6, directed to a broadly polymorphie epitope of an HLA D product.As the available Moabs recognize only a minor fraction of the D region chains, probes for various chains were tested with in situ hybridization to investigate which subloci are expressed in these tumors. Preliminary results indicate that at least some tumors which showed no reactivity with MoAbs against DR ~ chains express mRNA for DR ~ chains, suggesting that the regulation of class II expression in these tumors may be very complex. In malignant melanoma the appearance of DR ~ has already been correlated with a poor prognosis. Further characterization of class II and ~ chain expression in breast carcinoma may reveal patterns of antigen expression that can also been correlated with prognosis. Institute of Immunology, University of Munich, F.R.G., Goethestra~e 31, 8000 M~nchen 2.

4/P-GM 11.3 ANALYSIS OF THE C-ERBB-2 PROTO-ONCOGENE IN HUMAN BREAST CARCINOMAS: CORRELATION OF GENE AMPLIFICATION, PROTEIN "EXPRESSION AND CLINICAL PARAMETERS, N.E. Hynes*, H.-G. Locher', H. Gerbersw M. Berber**, J. Richner*, A. Goldhirsch*, W. Gullick+ and B. Groner We have analyzed a series of primary human breast tumors for amplification of the c-erbB-2 p r o t o oncogene. Twenty-five percent (13/5I) of the DNA samples contained multiple gene copies. Paraffin-embedded tumor material was available from 47 of the cases, We used a c-erbB~2 specific antiserum (Guliick et al., 1987, Int. J. Cancer 400:246-254) to immunohistochemieally stain the tumor sections. There was a correlation (p=0.03 between tumors containing amplified c-erbB-2 gene copies and positive staining with the c-erbB-2 specific serum. We also observed that some tumors containing single copy c-erbB-2 sequences were strongly stained with the antiserum. This suggests that mechanisms other than gene ampIification may lead to elevated levels of c-erbB-2 protein. Finally, we observed a statistically significant correlation between c-erbB-2 protein expression and parameters used in breast cancer prognosis. Positive staining was associated wit.h the positive nodal status of the patient (p=0.02) and with tumors showing a poor nuclear grade (p=0.02). These results suggest that the determination of the level of c-erbB-2 protein may be o f prognostic value for the course of human breast cancer, We are currently carrying out a retrospective study to see if c-erbB-2 wotein staining has prognostic value in the course bf the disease in nodenegative patientns. Paraffin-embedded tumor sections from 80 node-negative breast cancer patients, half of whom have relapsed, are being stained with two c-erbB-2 specific antisera. The results of the analysis will be discussed. Ludwig Institute for Cancer Research (LICR), Bern Branch, lnselhospitaI,30~0 Bern, Switzerland*; Wo~en% Hospital, Berne; LICR, University College Branch, London**; and Chester Beatty Laboratory, London+.

J.Wustrow,

H.Rudert,

M.Diercks,

A.Beigel

In the years between 1949-1982 a total of 275 patients with malignant tumor of the inner nose and the paranasal sinuses were treated. 53% of the tumors were squamous cell carcinomas, 19% malignant tumors of the small salivary glands and 6% were malignant melanomas. Mesenchymal and neurogenic tumors made up the remainder of cases. The maxillary sinus is with 50% of cases the most frequent localisation of squamous cell and adenoid-cystic carcinomas. Adenocarcinomas, however are mostly found at the nasal roof (56%). By far the most malignant melanomas were detected at the nasal septum and on the nasal floor (88%). All tumors presented with an unspecific clinical picture corresponding to chronic sinusitis. The most important prognostic factors for squamous cell carcinomas were size of tumor. In squamous cell carcinomas age and degree of differentiation had no influence on the rate of survival. Therapy was mostly surgical and combined surgical and radiologieal approach~ A more detailed analysis of therapeutic regimens depending on tumor stage will be given. The 5 year survival rate in squamous cell carcinomas was 38%, in adenoid-cystic carcinomas 21%, in adeno-carcinomas 59% and in malignant melanomas 52%. The fate of a particular patient with a squamous cell carcinoma was clear during the first 5 years after diagnosis. A significant decrease in the probability of survival was seen with adenoid-cystic carcinomas and melanomas after 10 years.

4/P.GMll5 The value of MRI when applied to malignancies of the nose and of the paranasal sinuses In connection with the value of MRI 70 tests on patients suffering from benign and maliqnant diseases of the nose and the paranasal sinuses were analyzed.The maliqnancies were established h i s t o l o q i c a l l y . Method: superconductinq magnet ( i Tesla ) , surface c o i l , Tl-weighted, balanced and T2-weiqhted imaqes, f a s t seouences ( FISP, FLASH ) In most cases of MRI i t is not necessaru to i n j e c t contrast medium. The tissue of soft harts which, in a computed tomonraph>~ ( CT ) cannot be distinnuished c l e a r l y , can be made out d i s t i n c t l y by evaluating the T1- and T2-weighted MR-images. The magnetic resonance does not contain any signal of compact bone. Compared to CT this is a certain disadvantaoe when paranasal sinuses are bein~ examined. However, MRI makes i t possible to distinquish c l e a r l y more extended bone lesions. By means of MRI vessels can be i d e n t i f i e d d e f e n i t e l y and hemorrhages can be visualized in a l l modes as well. With regard to the diaqnostics of malinnant tumors e s p e c i a l l y the assessment of the tumor extension is of nreat importance. A ~reat part of the tumors in this area only accept a r e l a t i v e l y small amount of contrast medium during the CT-test. In T2-weiqhted images the tumors" signal i n t e n s i t y is mostly increased; i t is however not so pronounced and homoqeneous as is the case in infla.qr~atory processes. One advantage of ~IR1 is that i t makes a multiplanar imaqing o~ the complex structure of the viscerocranium possible and that i t establishes the evidence of affected lymph nodes. Thus valuable information is supplied by ~RI concerninn diseases affecting the nose and the paranasal sinuses. P. Held, N. Obletter, S, B r a i t i n g e r Radiolonische Abteilun?, St~dt. Krankenhaus Passau

S 149

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5/30-M 002

THE E F F E C T I V E N E S S OF R A D I O T H E R A P Y A F T E R

PROGNOSTIC PARAMETERS IN HODGKIN'S LYMPHOMAS (NHL)

C O N S E R V A T I O N S U R G E R Y IN THE T R E A T M E N T OF EARLY B R E S T CANCER. M, Heckmann, U, Mlynek, W. Hoeffken .............................................. F r o m 1983 to 1987, 196 w o m e n w i t h i n v a s i v e b r e a s t c a n c e r u n d e r w e n t e x c i s i o n a l b i o p s y or q u a d r a n t - r e s e c t i o n and a x i l l a r y node diss e c t i o n f o l l o w e d by d e f i n i t i v e r a d i o t h e r a p y . R a d i a t i o n t h e r a p y c o n s i s t e d of 5000 c e n t i g r a y (cGy) to the w h o l e breast using o p p o s e d t a n g e n t i a l fields. A boost to the p r i m a r y t u m o r bed was d e l i v e r e d w i t h e l e c t r o n s to a total d o s e of 7000 cGy. P a t i e n t s with positive axillary lymphnodes were additinally g i v e n r e g i o n a l irradiation~ S y s t e m i c c h e m o t h e r a p y was a d m i n i s t e r e d to n o d e p o s i t i v e prem e n o p a u s a l women, A m o n g 196 patients, 4 p a t i e n t s f a i l e d 1 0 t a l l y (2 %), but not in t h e boost area, In a f u r t h e r case, the r e g i o n a l r e c u r r e n c e was l o c a l i z e d at the m a r g i n of the p r i m a r y tumor bed, In 4 of these 5 patients microscopically pathology m a r g i n s from the e x c i s i o n a l b i o p s y or a m u l t i focal c a r c i n o m a w e r e found at the p r i m a r y surgery~ T h e s e r e s u l t s c o m p a r e f a v o r a b l y w i t h t h e r e s u l t s of m a s t e c t o m i e . S t r a h l e n i n s t i t u t f~r D i a g n o s t i k u n d T h e r a p i e Prof, Dr. med. W. Noeffken, M a c h a b a e r s t r . 19-27~ D - 5 0 0 0 K ~ i n i

LOW GRADE MALIGNANT NON-

B~ Stei~e J . Mau H.D. Waller______ The course of low glade malignant NHL may vary greatly between individual patients, some showing a rather benign, indolent disease, some others having rapid progression. In order to select the best treatment strategies for these patients, i t is essential to know prognostic parameters, which allow to estimate the probable course of disease. We therefore analysed retrospectively prognostic factors in 200 patients with low grade malignant NHL according to the Kielclassification (lymphocytic 61, immunocytic 61, centrocytic 10, centroblastic-centrocytic 68), treated in our institution between 1974 and 1983. Out of 10 clinical and 9 biochemical parameters, increasing age, a poor performance status, presence of B-symptoms, elevation of serum-LDH activity and ESR as well as thrombocytopenia were significantly correlated to a poor overal survival. Histology and stage did not a t t r i b u t e to the overa] prognosis, In a regression model, serum-LDH a c t i v i t y proved t o be the most important prognostic parameter. Presence o f B-symptoms, thrombocytopenia and increasing age were f u r t h e r relevant factors, Regarding therapy, outcome of treatment s i g n i f i c a n t l y influenced s u r v i v a l . However, t her e was no d i f f e r e n c e between p a t i e n t s achieving a

complete or a partial remission respectively. Achievement of a remission was strongly correlated to stage. There was no influence of any of the clinical or biochemical parameters investigated on remission duration. Medizinische Universit~tsklinik, D-74 T~bingen

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LONG TERM RESULTS IN 184 PATIENTS WiTH NONHODGKIN{S LYMPHOMAS (NHL) - PROGNOSTIC FACTORS AND ROLE OF RADIOTHERAPY E. D0hmke, H. Gremmel and U. Huber

PREDNIMUSTINE VERSUSCHLORAMBUCIL (CLB) + PREDNISOLONEIN LOW GRADELYMPHOMA E. H i l l e r , R. Schlag, E. Musch, T. Lipp, B. Emmerich, R. Herrmann, W. Wellens, A.D. Ho, B. Termander, B. Nilsson, E. Thiel

Between 1970 and t980, 184 patients with NHL were referred to the Department of Radiotherapy of the Univer .... sity of Kiel. According to the Ann Arbor classification~ patients with stages I and II and also patients with centroblastic-centrocytic NHL of stage Ilia mainly received radiotherapy alone~ whereas more advanced stages underwent combined modality treatment. 89 % complete remissions (CR) were achieved in the localized stages I and Itl, whereas a proportion of only 74 to 48 % resulted in stages II 9 to IV. 61% of patients with CR survived 10 years, all of "those without CR died within 5 years from NHL. Furthermore, prognosis was significantly influenced by age (above or below 60 years), histology (Kiel classification) and stage (Ann Arbor classification). A special difference existed in patients with high grade malignant NHL between stage II 1 and 1!2, according to the description of Musshcff~ which c6uld not be found in patients with low grade malignant NHL. An anatysis of in field-relapses of 76 patients with Ioealized stages I and ll~ revealed that tumor control could be provided beyond 45 Gy in immunocytic, 25 Gy in centroblasticcentrocytic~ 45 Gy in centrobtastic, 50 Gy in immunoblastic and 45 Gy in ~ymphobiastic malignant NHL. These findings may be important for combined modality treatmen% too~ regarding involved field radiotherapy.

In a multicenter study prednimustine -a prednisolone ester of CLB- and CLB + prednisolone were compared in low grade lymphoma in a randomized fashion. Patients with histologically verified lymphocytic leukemia (CLL) in RAI stages 3 and 4 or immunocytic lymphoma (IC) in clinical stages I l l and IV as patients with B-symptoms qualified for the study, 151 patients were registered, 98 with CLL and 53 with IC as of September 1987. 97 of the patients were untreated, 54 patients had previous treatment. 112 patients were evaluable for response. The patient characteristics and the clinical stages in both treatment groups were evenly matched. Prednimustine was given in a dosage of 200 mg daily for 3 consecutive days, CLB in a dosage of 0.2 mg/Rg daily and prednisolone 50 mg daily for 3 consecutive days. Cy61~s were repeated every 2 weeks with 10% increments of daily prednimustine and CLB, respectively,each following cycle until effect or t o x i c i t y was noted. Of the 112 patients evaluable for response I CR and 43 PR in the prednimustine arm and 37 PR in the CLB + prednisolone arm were noted. Toxicity was mild tomoderate and there was no difference in the two treatment groups. We conclude prednimustine is at least as effective as CLB + prednisolone in inducing PR in low grade lymphoma. Of major future interest is the question whether prednimustine w i l l allow a longer duration of remission.

Radio[ogische K[inik der Univereit~t G6ttingen, Robert-KechStrage 40, D-3400 G6ttingen

Med. Klinik I I I , Klinikum GroBhadern der Univ. MUnchen, Marchioninistr. 15, D 8000 MUnchen 70.

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FIVE YEARS EXPERIENCE IN THE TREATMENTOF NON-HODGKIN'S LYMPHOMAS OF LOW GRADEMALIGNANCY STAGE I l l AND IV WITH COMBINED FRACTIONATED WHOLE BODY IRRADIATION AND CHEMOTHERAPY l G. Huhndorf , ~R. Donhuijsen-Ant], M. WesterhausenI and H.-Br. Makoski~

RADIOTHERAPY IN LOCALIZED ORBITAL NHL R. P Q t t e r , R.P. M~11er, H. Busse

While the spontaneous course and the response to therapy is usually quite satisfactory in Non-Hodgkin's lymphomas {NHL) of low grade malignancy stage I I I and IV, cure is extremely rare. We have attempted to improve the results by combining chemotherapy and irradiation. 20 untreated pts received the following drug treatments: LOP, COP, BACOP. When reaching complete remission (CR) we followed the fractionated whole body irradiation (upper and lower hemibody irradiation with 3 Gy each, using a Siemens-MeV Mevatron 12 linear accelerator}. Complete clinical remissions have been obtained in 85 % of pts with 5 (20 %) remissions s t i l l lasting. Analysis of the pts CR followed by Remissions t i l l s t i l l living (n=9) recurrency lasting Age and Sex 34-62 years l~,3~22-54 years 5'~ Histology and stage 1 pt LP-immuno- 4 pts cb/cc I l l cytoma IV 1 pt cb/cc I I I 1 pt cb/cc IV 1 pt cb/cc IV l pt cc I l l Duration (months) Median14 (5-22} Median 60+ (21+-65+) Until now, II pts died from tumourprogression and infection. Three of these patients developped secondary malignancies (2 solid tumours, one AML). The bone marrow t o x i c i t y was mild and reversible (WHOgrade 0-2). l Med.Klinik I f , St.Johannes-Hospital, An der Abtei 7-11, D-4100 Duisburg 11 2 Institut fur R~ntgentherapie und Nuklearmedizin der St~dt. Kliniken Duisburg

The r e c o r d s of 41 pts i r r a d i a t e d f o r o r b i t a l NHL from 1958 t o 1986 were r e v i e w e d . A l l were histologically v e r i f i e d . According t o the K i e l classification t h e r e were 15 low m a l i g n a n t and 9 high m a l i g n a n t lymphomas. The 17 pts r e s t i n g had been c l a s s i f i e d a c c o r d i n g t o the old German c l a s sification as r e t i c u l u m c e l l sarcoma (15 p t s ) and lymphosarcomas (2 p t s ) . Stage d i s t r i b u t i o n showed 14 pts in stage I , 19 in stage I f , 8 in stage Ill/IV, a l l E. Megavoltage i r r a d i a t i o n was given in c o n v e n t i o n a l f r a c t i o n a t i o n from a t o t a l dose of 26 Gy up t o 46 Gy using d i f f e r e n t t e c h n i q u e s . Since 1978 t r e a t m e n t has been based upon CT scans and c o r r e s p o n d i n g computed t r e a t m e n t p l a n n i n g (8 p t s ) . Whenever p o s s i b l e , the lens was s h i e l d e d . Clinically complete r e m i s s i o n was achieved f o r stage I in 13/14 pts (93%), f o r stage I I in 17/19 pts (90%) and f o r stage I l l / I V in 5/8 pts (63%). There were 9 pts w i t h l o c a l r e c u r r e n c e : w i t h i n the r a d i a t i o n f i e l d 3 p t s , on the f i e l d edge 6 p t s . D i s s e m i n a t i o n was seen in 6 cases. Recurrence r e s p . d i s s e m i n a t i o n occured o n l y t w i c e beyond two y e a r s . Only 2 pts out of t h i s group s u r v i v e d more than 3 y e a r s . The freedom from r e lapse r a t e i s t 65% (10/14) f o r stage I , 75% (13/ 17) f o r stage I I a f t e r a median f o l l o w - u p of 36 months. As t o l o w / h i g h m a l i g n a n t lymphomas the freedom from r e l a p s e r a t e is 89% and 43% r e s p . The r a t e of s i d e e f f e c t s was low. 2 pts showed a s l i g h t l y d r y eye; t w i c e the lens had t o be r e moved because of p r o g r e s s i v e c a t a r a c t . We c o n c l u d e , r a d i o t h e r a p y is the t r e a t m e n t of c h o i c e f o r l o c a l i z e d o r b i t a l NHL. Freedom from r e l a p s e r a t e is h i g h , m o r b i d i t y low. R a d i o l o g i s c h e K l i n i k und A u g e n k l i n i k der U n i v e r sit,t, A l b e r t - S c h w e i t z e r - S t r . 3 3 , D-4400 Mfinster

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LOW-GRADE NON-HODGKIN LYMPHOMAS OF THE ORBIT

CLINICAL RELET~ANCE OF DE~)XYTHYMIDINE KINASE (DTK) AS SERUM MARKER IN NON-HODGKIN-LYMPHOM~S (NHL) K. Bremer and A. Eberhard

N. H(~wel. K. Sch(~rmann, R, Hohle. H,H. Goebel

Previo~as studies in patients (pts) with NHL and Hodgkin's disease revealed that dtk has a higher clinical significance than ~2microglobulin or neopterin as serum marker in malignant lymphom~s (reed. welt 38, 683~ 1987). Looking for additional aids in the clinical--management and treatment monitoring of malignant lymphomas we have determined the serum concentration of dtk by means of a radioenzyme assay (Prolifigen , AB Sangtec Medical,Bromma, Sweden) in 111 pts with NHL: 5o pts with untreated or progressive disease (group 1 ), 45 pts in partial remission (PR) (group 2) and 16 pts in complete remission (CR) (group 3). The hrHL-pts of group I showed a mean 5.5 fold increase of dtk, but on the average normal values after induction of PR or CR. Comparing dtk serum levels within the advanced disease stages III-IV of group I, the pts with low grade malignant NHL revealed significantly lower values than those of high grade malignancy. Furthermore, within the group of high grade NHL, pts with stages l-II showed significantly lower dtk levels than the advanced disease stages Ill-IV. Concerning the histologic subtypes (Kiel classification) of stages Ill-IV low grade malignant NHL, similar average serum concentrations of dtk have been observed in chronic l~phocytic leukemia and i~munocytic, centrocytic or centroblastic-eentrocytic N2dL respectively. Additional analyses revealed lower dtk values in those pts, in which a "watchful waiting" treatment policy could be performed because of stable or only slowly progressive disease. Because serum dtk dete~nations have been found to be of clinical relevance in the diagnosis, treatment and follow up of NHL, its regular control seems to represent a helpful parameter in the management particularly of low grade malignant NHL.

During the years 1979 to 1986 nine cases of primary non-Hodgkin-lymphomas were operated on, Modern immunohistologlc investigations allow an essentially better classification of ~hese lymphomas. Clinically in all cases a systemic manifestation was not observed, In five cases we found a lymphocytic B-cell-lymphoma. in two cases a lympho-plasmo-cytoid immunocytoma. and in one case each a centrocytic B-cell-lymphoma resp. centrocytic-centroplastic B-cell-lymphoma. Immunog!obulins were identifiable in the cytoplasm of a lymphocytic lymphoma of both lympho-plasmocytoid immunocytoma and the centrocytic lymphoma. A relapse was observed partially but only locally. A systemic spread, however, was not seen. Compared to previous studies we noticed that in contrast to the manifestation of lymphomas in the brain, in lymphocytic nodes or in the gastro-lntestinal tract, lymphocytic lymphomas of the orbit predominate. Clinical. neuroradiologic and immunohistologic data are demonstrated,

Neurosurgical Department of the Johannes GutenbergUniversity Mainz, W,-Germany

Abteilung f ~ H~matclogie und Onkologie, Augusta-Krm~kenAnstalt, Bergstra~ 26, D-463o Bochum I

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I n f i l t r a t i o n of b o n e - m a r r o w by N o n - H o d g k i n L y m p h o m a s - a r e t r o s p e c t i v e study in 93 p a t i e n t s w i t h NHL. A. D 6 r i n g ~ H. H e n n e m a n n , P, P f i e s t e r In 40 % of p a t i e n t s w i t h NHL ( e x c e p t CLL) b o n e m a r r o w was i n f i l t r a t e d . N H L s of low m a l i g n a n c y w e r e r e p r e s e n t e d by 54 %, and t h o s e of h i g h m a l i g n a n c y by 15 %. In 29 p a t i e n t s with NHL the e x a m i n a t i o n of the b o n e - m a r r o w was p e r formed by c y t o l o g i c a l and by h i s t o l o g i c a l e v a l u a t i o n as well. In 21 (=72 %) the r e s u l t of t h e s e two m e t h o d s was i d e n t i c a l . In 8 p a t i e n t s (=28 %) it was d i f f e r e n t : In 5 p a t i e n ~ it was p o s i t i v e only :in h i s t o l o g i c a l and in 2 p a t i e n t s o n l y in c y t o l o g i c a l e x a m i n a t i o n . In 1 p a t i e n t no r e s u l t was o b t a i n a b l e . - A m o n g the NHLs of low m a l i g n a n c y the i m m u n o c y t i c l y m p h o m a s p r e v a i l e d , f o l l o w e d by c e n t r o c y t i c and by l y m p h o c y t i c l y m p h o m a s . A m o n g the h i g h m a l i g n a n t N H L s p r e v a i l e d the l y m p h o b ] a s t i c f o l l o w e d by the c e n t r o b l a s t i c l y m p h o m a s . The i n f i l t r a t i o n of the b o n e - m a r r o w is of no n e g a t i v e p r o g n o s t i c v a l u e in low m a l i g n a n t NHLs, w h e r e a s it has a bad p r o g n o s t i c s i g n i f i c a n c e as s y m p t o m of g e n e r a ] i s a t i o n in h i g h m a l i g n a n t N H L s . T h e r e w e r e o t h e r f a c t o r s of n e g a t i v e p r o g n o s t i c s i g n i f i c a n c e s u c h as m y e l o p o e t i c i n s u f f i c i e n c y in N H L s of low m a l i g n a n c y and t h r o m b o p e n i a s in h i g h - m a l i g n a n t NHLs, and a n e m i a s in c b - c c - l y m p h o m a s . i I I . M e d . K l i n i k ( L e h r s t u h l f. I n n e r e M e d i z i n II~ Dir.: Porf. Dr. H.H. H e n n e m a n n ) und P a t h o l o g i s c h e s I n s t i t u t (Prof. Dr. U. Bleyl) der F a k u l t ~ t fHr K l i n i s c h e M e d i z i n M a n n h e i m K n o c h e n m a r k b e f a l l bei N o n - H o d g k i n - L y m p h o m e n als p r o g n o s t i s c h e r F a k t o r - eine r e t r o s p e k t i v e S t u d i e an 93 L y m p h o m - P a t i e n t e n .

PHARMACOKINETIC EVALUATION OF HIGH DOSE ANAXIRONE (TGU; NSC 332r

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~ICALCHARAcrh%~IZATIONOF~FOSFAMIDE U, Niemeyer, J, Engel, M, Meyer zu~ Heyde, K. Molge and E. Wolf-Heuss ............................-.......................... Mafosfamide (eis-4-sulfoethylthio-cyelophosphamide) Llysine salt is evaluated in clinical studies as a stable analogue of 4-hydroxycyclophospha~dde. The pharmaceutical characterization is based on 31 PNMR-speetroscopy (C.-H. Kwon, R.F~ Borch, J. Engel and U. Niemeyer, J, Med. Chem. 3_O0,395,1987) and o n h i g h l y efficient HPLC (nucleosil RP-CI8-5 ~m with a mobile phase of aqdeous tetrabutylammonit~n hydrogenesulfonate: methanol, 50:50). Mafosfantlde, its trans-isomer, Llysine, 2-mercaptoethanesulfonate, and its disulfide are separated and quantified by one single chrc~atogram. In aqueous solution, mafosfamide hydrolyses reversibly to 4-hydroxyc~-clopho~hamide and 2-mercaptoethanesulfonate and degrades irreversibly at a slower rate to the alkylatingphosphoramideim/stard. T ~ coimplex reaction kinetics are characterized by the different rate constants for reversible dissociation, for isomerisation to trans-mafosfamide and for irreversible degradation. Stability of mafosfamide in so]uti(m is greatest at pH 4. Both, at lower a n d h i g h e r p B , stability decreases exponentially. For clinical studies, mafosf_amide is lyophilised from a solution adjusted to pH 4. Reconstituted solutions are sufficiently stable for use over several hours. T~ne storability of the lyophilisate has been investigated at different temperatures and stability is proven for more than three years at 4~ Therefore, mafosfamide can be considered as a stable analoc~ae of 4~hydroxycyclophosp~mide, ~tablefor clinical use. ASTA-PHARMAAG, P.O.Box 140129, D-4800 Bielefeld 14

R.B, Schilcher, D.W~ Beelen, A,C, Schmidt-Weimar, U,W, Schaefer. M~R~Nowrousian. B, Nengst~ and C,G, Schmidt TGU, a new triepoxide, h~s shown dose-limiting bone marrow suppression during Phase I/ll studies~ A sensitive NPLC essay was developed to determine elimination behaviour o9 the agent. Using solid extraction CIB columns (Baker-10 SPE 0ctadecyl; I ml sample) conditioned with CHCI_ and H20~ plasma standards were linear ~rom 10 ng/m~ to 20 mg/ml with an 81~ recovery. The organic phase was evaporated and redissolved in !00 pl MoON and 20 pl were injected into a HPLC system, consisting of a M&S pump (Waters Assoc ) with mobile phase CH CN/H 0 " 9 3 2 (15]85 V/V) I ml flow rate. CIR p-Bondapak IOp column, UV detector set at 2IS rim, and ~ s t r i p chart recorder. In

FI

heart,

mice sustained drug concentrations were found i n

liver,

lung and kidneys (905,8!5,r162

ng/ml)

a f t e r a sisgle dose of ~08 mS TGU/kg body weight ip. Weekly times r doses Of 36 ms/ks given ip~ or i v , were tolerated by all animals; however, a single dose of 1&4

ms/ks was lethal to must animals~ Beagle dogs received escalating doses from 28 to 60 mg TGU/kg daily (total dose &D to 15D ms/ks) iv. bolus with or without total body irradiation (9 Gy) followed by marrow trsnsplantation. Peak plasma levels increased from 5.5 to 15.5 pg/ml. A rapid initial distribution phase (tll 2 ~ 2~5 min) was followed by prolonged decay. P~rent ~6mp0und was found in bowel tissue (8.4Z) associated with dose-limiting hemorrhagic colitis~ In conclusion, TGU is rapidly distributed into the body followed by a prolonged excretion phase suggesting drug recycling ~rom deep compartements. Animal studies underscore extensive drug binding to tissues. Pronounced bone marrow suppression warrant ~urther studies in con ~ ditioning therapy Dept.

of

Internal

Hufelandstr. 55, 0-r

Medicine

( T u m o r Research)~

Essen

5/32-0 003 PILOT STUDY WITH CARBOPLATiN (C) / ETOPOSIDE (E) IN EXTENSIVE STAGE OF SMALL CELL LUNG CANCER H. W. Tessen, M. Wolf, K, Hans, W, Achterrath, K. Havemann, P. Drings In a p i l o t study, the reco~ended dose f o r phase I I studies of C/E was determined and f i r s t data on antineoplastic a c t i v i t y were ascertained, Starting dose schedule: C 300 mg/ms i v day I , E 80 mg/ma iv days I-3. C was given in a fixed dose, E was escalated step by step by appr. 20% u n t i l i n t o l e r a b l e t o x i c i t y (tox) (hematologic and/or renal m-WHO I I ) occurred in 2 out of 5 patients (pts) per dose l e v e l . 20 pts with distant metastases ( f / m r a t i o 1/19, mean Karnofsky PS 90 (70-100), mean age 56 (33-74) were admitted into the study. 20 pts received a t o t a l of 66 courses (mean 3,3}. 2 pts received one course and were evaluable for tox and response in case of PD. 18 pts had at least 2 courses and were evaluable f o r response and tox, 5 pts each received 240/300/360/420 mg/ m2 E iv per course, Dose l i m i t i n g tox was myelosuppress~ ion at an E level of 420 mg/m~ per course. Other tox: anemia WHO I : 15%, WHO I I : 10%, WHO I I I : 5%, Nausea, vomiting WHO 1:25%, WHO I I : 15%, WHO I I I : 15%, WHO IV:5%. Alopecia WHO I: 15%, WHO I I : 30%, WHO 111: 15%. C l i n i c a l l y relevant hearing loss occurred in I pt. 10 pts received C 300 mg/ms and E 240 mg/m2 and 300 mg/m2 iv per course. I CR and 2 PR were observed. At the higher dose levels (E 360-420 mg/m2) 6 overall responses i n c l . I CR were gained in 10 pts. Median PFI is 4,5 months, Conclusion: the recon~ended dose of C/E appears to be 300 mg/ms C and 420 mg/m~ s per course. C/E seem to be of comparable antineoplastic a c t i v i t y to DDP/E in pts with distant metastases but i t induces less non-hematologic tox, A randomized study investigates presently a c t i v i t y of an a l t e r n a t i n g chemotherapy with AIO+DDP/E vs AIO+C/E, Thoraxklinik Heidelberg-Rohrbach, Amalienstra5e 5, D-6900 Heidelberg

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RODORUBICIN: A NEW ANTHRACYCLINE WITH UNTYPICAL SPECTRUM OF ACTIVITY AND TOXICITY H.P. Kraemer, H.H. Sedlacek

ACTIVITY OF THEPRUBICIN - A NEW ANTHRACYCLININ VITRO A N D IN VIVO. G,~@dgr~ H.H. Fiebig, H. HenB t G.W. L~hr ......

Rodorubicin (HLB 8 1 7 ) i s a new t e t r a g l y c o s i dic anthracycline w h i c h was d e t e c t e d because of its remarkable activity in a human tumor based screening system. The d r u g is highly cytotoxic to animal and human t u m o r cell ilnes i n v i t r o and i s n o t cross-reslstant to the standard anthracycline Doxorubicln. R o d o rublcin is not active i n conventional animal tumor test systems, but shows high degree of activity against human tumors ~n the human tumor clonogenic assay (HTCA). In this predlctive in vitro system a remarkable number (I9/35) os human t u m o r s , espectal;y gastrointestinal tumors were sensitive to Rodorubicin at a drug concentration which could be r e a c h e d in human t u m o r t i s s u e in nude m i c e after injection of the maximum tolerated dose. In a d d i t i o n Rodorubicin was able t o produce a significant tumor growth delay in human tumors t r a n s p l a n t e d subcutaneously into nude mice, in comtrast to its inactivity against murine transplantation tumors. Toxico]oglca] evaluation in anlmals has demonstrated that at the maximum tolerated dose ]eve| there is only a slight bone marrow toxicity whereas a delayed nephrotoxicity resulting in proteinuria and clearance reduction seems t o be dose l i m i t i n g .

Theprubicin (THP) was screened for cytotoxicity in a modified Hamburger and Salmon colony assay. Human tumor xenografts and bone marrow were rated as sensitive if the colony number was <30% of the control. THP revealed effectivity in 4/4 bone marrows at the lowest concentration of 0.01Mg/ml. At this concentration 5/7 xenografts were sensitive with efficacy in a large and a small cell cancer of the lung and a m a m m a r y cancer. Overall, activity of THP (1015 m g / k g / d a y , i v , d a y 1 , 1 5 ) and Adriamycin (ADR,8 mg/kg/day,iv, day 1,15) were compared in 6 tumors growing in nude mice to untreated controls and evaluated at the time of maximal tumor regression or after 3-4 weeks. Both drugs showed regression (51-75% of initial tumor size) of a small cell lung cancer, whereas in the in vitro sensitive mammary cancer THP a n d ADR showed a regression and a no change (76-124%), respectively. Similar effects of both drugs were observed with progression (7125%) in 2 colon, I stomach and I testicular cancer. Mortality at the maximal tolerable dose of THP (12 mg/kg/day, day 1,15) and ADR was identical after 4 (21%) and lower for THP after 2 weeks (5 vs.14%). In conclusion THP and ADR demonstrated similar activity. The pharmacokinetics of anthracyclines differ in mice and man, as the maximal tolerable dose with respect to body surface is higher in man. Therefore, the superiority of T H P to ADR must be evaluated by clinical trial, being presently conducted.

Dr. H.P, Kraemer, Research Laboratories Behringwerke AG, 3550 Marburg, FRG

of

Med.Univ.Klinik, Abt. H~motologie und Onkologie, Hugstetter Str.55, D-7800 Freiburg im Breisgau.

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COMPLEX PATTERNS OF PLASMtNOGEN ACTiVATiON IN NON SMALL CELL LUNG CANCER CELL LINES H. H. Heidtmana and K. Havemann Seven celi lines of non small ceil lung cancer were investigated for plasminogen-activators (PA). They comprised one adenocarcinoma, three squamous ceil carcinomas, two large cell carcinomas, and one mesothelioma. In fibrin autography~ extracts of all cell lines except for the mesethelioma shewed comptex patterns of plasminogen dependent fibrinolysis. Lysis bands appeared at molecular weights of approx. 62 kD, 55 kD and 52 kD. in addition, bands of high molecular weight around 100 kD could be detected in four instancee. Further, one large ceil carcinoma gave a band of low molecular weight in the range of 32 kD. In the corresponding serum free eupernatants, one or two additional high molecular weight bands around 100 kD appeared in al! cell lines except one. To quantitate PA-activity, we used a parabolic assay with p{asminogen and H-D-VaI-Leu-Lys-pNA as substrates. All cell lines were positive. Both large cell carcinomas produced extremely high levels of activity, which could be further enhanced by addition of fibrin split products. In several cases, pronounced stimulation of PA-activity in serum free eupernatants could be elicited with epidermal growth factor and transforming growth factor alpha. We conctude~ that different types of plasminogen activators are being produced by our cell lines. The low molecular weight forms probably correspond to Urokinase-like PA, whereas the 62 kD form resembles tlssue-type PA. Stimulation of activity by fibrin split products also indicates the presence of tissue-type PA. The appearance of high molecular weight bands in the supernatants can be interpreted as complexes of PA with endogenous inhibitors. PA stimulation by EGF and TGF~ may be linked to tumor invasion and metastasis.

DEGRADABLE STARCH MICROSPHERES (DSM) IN LOCOREGIONAL CHEMOTHERPY OF EXPERIMENTAL LIVERTUMORS Th.Riemenschneider, C~Ruf, G.Sp~th,G.Stuhldreier ................................................ Injection of DSM in the hepatic artery causes a decrease of blood flow and a redistribution to hypovascular areas. Transient hypoxemia and prolonged exposition to bolus-injected drugs are the consequences. DSM with Mitomycin C (Mito) or Floxuridine (FUdR) may improve tumor response in man, compared to Mito or FUdR alone (Fujimoto S et al., Cancer 56:2404, 1985). The aim of the paper was to study the effect of DSM with drugs in a controlled standardisized animal model. In Sprague-Dawley rats 4xlO ~ cells of from Novikoff-hepatoma (DKFZ,Heidelberg) are injected in the central lobe of the liver to produce solid hepatoma. At day 5 p.op. an intraarterial (i.a.) catheter connected with a micro-port was implanted. At day 5 and 8 p.op. an 0.5 ml i.a. bolus with DSM (gxl06/ml) (Pharmacia) or 210 mg/kg FUdR or 2 mg/kg Mite alone or in the combination DSM+FUdR or DSM+Mito was applicated. Tumorvolumes at day 5 and 12 were recorded and an tumor-multiplication-factor (TMF) was calculated. The following results were obtained (*significant, p<0.05, Wilcoxon-test): GroupIcontrol D S M FUdR Mito DSM+FUdR DSM+Mito TMF I 9.4 9.6 5.6 8.2 4.2 1.2" N= I 52 12 28 12 12 12 After bolus injection only Mito+DSM causes a significant tumor response. Mito+DSM may be an effective therapeutic alternative to the eontinous infusion of fluorinated pyrimidines.

Zentrum fiJr Innate Medizin, Abteiluog H~matologie/Onkologie D-3550 Marburg

Chirurgische Universit~tsklinik, Abt. Ailgemeine Chirurgie, Calwerstrasse 7, D-7400 T~blngen

/Immunoiogie~ BaldlngerstraBe,

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A Portable Infusion Pump for Administration of Cytestatiea in Liver Metastases ~ n z ~ { h r , R., Wilhelra, 5 .

DOES INCREASED TUMOR PERFUSION AND VASCULARISATION LEAD TO IMPROVED SURVIVAL IN K&I CHEMOT}[ERAPY ? B.Lehner, B.Bubeck, V.Kretsehmar~ P. Schlag

For administration of c y t o s t a t i e a in the a. hepatica fior non resectabte l i v e r metastases o f c o l o r e c t a l carcinomas subcutaneous ports are very useful (Port-A-gath~ I n f u s a i d ) . In order to supply the port with the infusion there i s developed a portable~ computer-aided pump, so that there i s no need for the patient for hospitalisation: a ne~ psychological very helpful device for meliorisation of the life of a palliative treated patient. The pump is delivered by Pharmacia Deltee CADD I (computerized ambulatory drug delivery). The weight is 459gr, the measures 16~0 x 8,9 x 2,8 cm. The flo~ rates are from 0 up to 299 mi/24 hours. The paper presents the case of a successful treated schoolteacher, ~ho ~as able to attend allhis school-hours ~ith this pump ~ithout missing any time. Chirurgische Klinik and If. Medizinische Klinik, St~dt. Klinikum Karlsruhe, Meltkestr. 18, D-7500 Karlsruhe

In patients with colorectal cancer metastatic to the liver hepatic artery infusion chemotherapy has become popular. It is thought that increased vascularisation and perfusion of the tumors would lead to an increased dru~ concentration at the tumor site and hereby to an increased response rate. We therefore performed liver angiography and liver perfusion scintigraphy with Tc-99m labeled macroagg~egated albumin (M/A) in 36 patients with liver metastases from colorectal cancer prior to continuous 5-Fluorouraell hepatic artery infusion chemotherapy. Of the 26 patients showing metastases on arteriogram 5 revealed increased tumor vascularisation, 5 normal and 16 decreased vascularisation of the metastases relative to liver. In liver perfasion seintigraphy 15 of the 36 patients showed increased perfusion of the metastases, 4 had normal and 17 patients decreased tumor per fusion. The observed differences in survival in the different groups were statistically not significant - 15 months in the group of increased, 8 months in the group for normal and 14 months for decreased tumor vascularisation and 28 months for the group of increased, 13 and 14 months for the group of normal and decreased tumor peri~asion. Also response rates with 80%, 40~ and 75~ responders in the group of increased, normal and decreased tumor vaseulsrisation, respectively, and 80~, 50~ and 59~ responders in the group of increased, normal and decreased perfusion, respectively, were not statistically significantly different. These results indicate that increased tumor vaseularisation or perfusion as demonstrated by asgiography and perfusion scintigraphy does not lead to an increased survival or response rate in patients with colorectal hepatic metastases receiving ~J~I. Chirurgische Universit&tskliniR. Ahteilung 2, I. I., Im Neuenhelmer ~elff [~0, 6900 Heidelberg,

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SHORT-TERM INTRAHEPATLC INFUSION OF FOLINIC ACID (FA)/5-FLUOROURACIL (FU) IN PATIENTS WITH UNPJ~SECTABLE LIVER METASTASES FROM COLORECTAL CARCINOMA - A PILOT STUDY E.Schmoll I, R.Raab 2, H-J.Schmoll I, C.Sch6ber I, M.Stahl I , H.Wilke I, R.Ringe 2 , H.Poliwoda I, R.iPichlmtyr2

C O M P L I C A T I O N S O F I N T R A A R T E R I A L CIIEMOTHERAPY U. K a n i a , J . B o e s e - L a n d g r a f , C. G e r m e r , K.-J. Bauknecht

A prospective study to evaluate the effectiveness and toxicity of a short-term arterial hepatic infusion of FU in combination with FA in pts. with stage II liver metastases was initiated in July 1985. All pts. underwent resection of the primary tum6r and explorative laparatomy to determine the extend of extrahepatic disease and to insert the port (Implantofix R, Braun,FRG) into the hepatic artery. Pts. with abdominal distant metastases or larger regional lymphnodes metastases were excluded. 20 pts.were treated with different FA-dosages. Dose and schedule: FA 170 mg/m 2 (medium-dose -~ MDFA;10 p t s . ~ or 300 mg/m 2 (high-dose = EDFA; i0 pts.) as 20 min. i.a.hep.inf., 20 min. later followed by FU 350 mg/m 2 20 min~ i.a.hep.inf., d 1-5, q d 22(29); FU-dose was escalated intraindividually to a maximum-dose of V50 mg/m2/d 1-5. Results: n CR PR MR REM.DUR SURV MDFA/FU I0 1 8 1 10+(3-19) 18+(3-26) HDFA/FU i0 0 4 6 6+(3-14) 8+(3-17) Toxlcit~: Leuko 1 (2), 2 (I); Thrombo 1 (I); Stomatitis 1 (4), 2 (2), 3 (3); Nausea 1 (6); Diarrhea I (8), 2 (3), 3 (I); Alopecia 1 (7). No chemical hepatitis or biliary sclerosis was seen. A prospective, randomized study i.a.hep. vs.systemic HDFA/FU is currently under way. Abtg. f~r H~matologie/Onkologie I and Klinik f~r Abdominalund Transplantationschirurgie 2 Med.Hochschule Hannover, 3000 Hannover 61.

I n t r a a r t e r i a l C h e m o t h e r a p y is p r e d o m i n a n t l y u s e d to t r e a t s e c o n d a r y m a l i g n a n c i e s of the liver. As c o m p a r e d w i t h s y s t e m i c c h e m o t h e r a p y less side e f f e c t s w e r e o b s e r v e d . S o m e c o m p l i c a tions that m a y o c c u r c a n w e l l b e m a n a g e d by an experienced physician. D u r i n g the p a s t 3 y e a r s 35 P o r t - A - C a t h s y s t e m s w e r e i m p l a n t e d into the h e p a t i c a r t e r y . 30 p a t i e n t s s u f f e r e d from u n r e s e c t a b l e m e t a s t a sis of the l i v e r c u e to c o l o r e c t a l cancer. 4 patients died perioperatively, 2 of them d u e to s p e c i f i c t r e a t m e n t . 4 p a t i e n t s p r e s e n t e d w i t h l e u c o c y t e d e p r e s s i o n . 12 t h r o m b o s i s of the P o r t o c c u r e d d u r i n g d i f f e r e n t t r e a t m e n t periods, 5 were successfully lysed with urokinase. No i n f e c t i o n s w e r e o b s e r v e d . An involuntary performed subcutaneous injection of 5-FU c a u s e d no n e g a t i v e c o n s e q u e n c e s .

A b t e i l u n g fNr A l l g e m e i n - , G e f ~ B - und T h o r a x c h i r u r g i e der C h i r u r g i s c h e n K l i n i k und P o l i k l i n i k im K l i n i k u m S t e g l i t z der F r e i e n U n i v e r s i t a r B e r l i n (Leiter: Prof. Dr. R. H~ring) H i n d e n b u r g d a m m 30, D - I O O 0 B e r l i n 45

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DNA CONTENT AND DISTRIBUTION OF CELL CYCLES PHASES AND INCIDENCE OF METASTASIS IN HUMAN PRIMARY LUNG CARCINOMA M. Bak, M. Volm, E.W. Hahn, J. Mattern and E. Weber. The aim of the study was to investigate the relationship between DNA and S-phase distribution in primary non-small cell lung carcinomas with the incidence of metastasis. Patients with non-small cell lung carcinomas were divided into two groups depending on whether at time of surgery there were metastases or not and these groups were correlated with the data obtained by flow cytometry or autoradiography. As expected from other studies, survival times was significantly longer for those patients without metastases at time of surgery (p= 0.0002) and the incidence of metastasis was significantly~ higher when the primary tumor was ~ 70 cm ~ (p= 0.026). In this study, a total of 185 fresh specimens of lung carcinomas were investigated by flow cytometry. Patients with aneuploid tumors had a higher tendency to have metastases (p= 0.016). Patients with tumors with a higher proportion of S phase cells measured by either flow cytometry or autoradiography demonstrated significant increase in the formation of metastases (p=O.02 and p= 0 ~ German Cancer Research Center, Dept. Exp. Pathol., Im Neuenheimer Feld 280, 6900 Heidelberg 1

TETANUS TOXIN AS A MARKER FOR HUMAN SMALL CELL LUNG CANCER J~ Heymanns, K. Neumann, K. Havemann,and E. Habermann* Small ceil lung cancer (SOLO) together with other neuroendocrine tumors, such as neuroblastoma, pheochromocytoma etc. express numerous markers of the amine precursor uptake and decarboxylation system (neurosecretory granules, dopa-decarboxylase, neuron specific enolase, creatine kinase isoenzyme BB). Since tetanus toxin (TT) which is an established marker for neuronal and neuroendocrine cells has been used in human neuroblastoma differential diagnosis (Berliner and Unsicker, Cancer 56: 419, 1985) we investigated TT-tabeling of human SOLO and non-small cell lung cancer (NSCLC) cell lines by means of flow cytometry and peroxydase antiperoxydase (PAP) labeling. Cells of characterized permanent celt lines (8 SCLC classic type, 6 SOLO variant type, and 6 NSCLC) were incubated with saturating concentrations of TT and subsequently with FiTO-labeled human anti TT antibodies and showed an intense fluorescence restricted to the cell membrane. The percentage of positive ceils was between 50% and 95%. There was no obvious difference in TT labeling between the classic and variant type of SOLO. TT binding could be increased using tris-aoetate buffer pH 6.0 instead of phosphate buffered saline pH 7.4 thus demonstrating a pH dependency of TT binding also in SOLO. In all NSCLO cell lines examined percentage of positive cells was lower than 10%. Using the formalin denatured toxold no immunofluoreseence could be detected in any cetl line. TT binding to SCLC cell lines could also be found using a mouse monoclonat anti-fragment O (a portion of the heavy chain of the tetanus toxin molecule) antibody and a subsequent labeling with PAP or a FtTC conjugated antimouse antibody. These results indicate that TT labeling may become a useful diagnostic marker for SCLC cells in histopathology. Zentrum f~ir lnnere Medizin, Abteilung H~matoIogie/Onkotegie/Immunologie, BaldingerstraBe, D-3550 Marburg *Buchheim tnstitut f~ir Pharmakologie, D-6300 GieSen

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LONG-TERM SURVIVAL AND PRETREATMENT PROGNOSTIC FACTORS IN SMALL CELL LUNG CANCER (SOLO). N. N i e d e r l e , W. Eberhardt, J. SchUtte, V. Budach, H. Hirche and C.G. Schmidt.

PRODUCTION AND SECRETION OF IMMUNREACTIVE INSULIN LIKE GROWTH FACTOR I IN SMALL CELL rUNG CANCER CELL LINES G. Jaques, C. Wegmann, M. Rotsch, M. Maasberg, and K. Havemann

Two hundred t h i r t y patients (pts) - l i m i t e d disease (LD) 133, extensive disease (ED) 97 - with h i s t o l o g i c a l l y proven SCLC were t r e a t e d in three consecutive studies (ACO = Adriamycin/Cyclophosphamide/Vincristine; CEM = CCNU/Etoposide/Methotrexate; and s e q u e n t i a l l y ACO+EP = E t o p o s i d e / C i s p l a t i n ) . In both stages (LD+ED), pts with complete remission (CR) had a s i g n i f i c a n t s u r v i v a l advantage (median, 17 months (mo)/15 mo) over pts with part i a l remission (median, 12 mo/9 mo), no change (median, 8 mo/6 mo), and progressive disease (median, 8 mo/5 mo). Long-term s u r v i v a l (> 24 mo; LD 23%, ED 3%) was mostly confined to CR pts. Time between s t a r t o f therapy and i n duction o f OR, however, did not s i g n i f i c a n t l y influence s u r v i v a l . Several pretreatment f a c t o r s were examined to determine t h e i r relevance in the prognosis o f OR, s u r v i v a l and long-term s u r v i v a l . In the t o t a l group o f p t s , disease extent (LD vs ED p=0.0001) and serum l a c t a t e dehydrogenase l e v e l s (LDH<207 vs ~ 207 p=O.O001) had a s i g n i f i c a n t impact on the induction o f OR. In LD pts, serum LDH and urea were found to be independent prognostic f a c t o r s pred i c t i n g s u r v i v a l . In ED p t s , however, serum LDH turned out to be the only s i g n i f i c a n t parameter a f t e r e l i m i n a t i n g the influence o f c y t o s t a t i c chemotherapy - the CEM-protocol being less e f f e c t i v e than the other two c o ~ i n a t i o n s . Stage o f disease was the most important f a c t o r in d e t e r mining the p r o b a b i l i t y o f s u r v i v a l beyond 18 mo. In LD, a d d i t i o n a l s i g n i f i c a n t f a c t o r s were serum LDH and urea. These data demonstrate t h a t the induction o f CR is the p r i n c i p a l therapeutic aim in SCLC. A f u r t h e r f a c t o r i n fluencing the therapeutic outcome is the stage of disease. Moreover, serum LDH and urea in LD pts and LDH in ED pts are independent pretherapeutic prognostic f a c t o r s .

The insulin-like growth factors (IGF) are polypeptides, which are structurally similar to insulin but which do not crossreact with antiinsutin antibodies. They are produced by a variety of normal and malignant cells. In the latter, it has been suggested that IGF~s are part of the autocrine system in which they interact with specific receptors to stimulate growth of the cells, which secreted them. Recently it has been reported that human neoplastic lung tissue obtained at surgery contained more tGF-! than the corresponding lung tissue (F. Minute, Cancer Res.46:985, 1986). We now demonstrate that permanent celt lines established from small cell lung carcinoma (SCLC) express and secrete immunoreactive IGF-h IGF-I immunreactivity was detected in 11/14 pellets of SOLO cell lines determined by RIA. The levet ranged from 12-76 mlU/mg protein. ~ndividual IGF-t levels in the ceil pellets showed a correlation to the corresponding serumfree culture media. To further show that SOLO cell lines synthesize and secrete IGF-I a time dependent enrichment of conditioned media with IGF-! could be shown which was blocked by the protein synthesis inhibitor cyclohex{rnide (10-5M). Two major molecular weight forms of immunoreactive IGF-I were observed after gel exclusion chromatography under neutral conditions (MW 60,000 and 7,000). In addition binding sites for IGF-I were present on all celt lines investigated. We further examined the effect of added recombinant IGF-I on 3H -thymidine uptake and on cell growth in semisolid cultures. Maximum stimu{ation was found at 1-100 nM (7.5-750 ng/mI) depending on the individual cell line. The addition of a monoclonal antibody against IGF-I inhibited the growth stimulatory effect of tGF-t. Further studies should address the role of 1GF-I in lung tumor biology. Zentrum f~r Innere Medizin~ Abteilung Hgmatologie/Onkologie/immunologie, BaldingerstraBe, D-3550 Marburg

Innere U n i v e r s i t ~ t s k l i n i k und P o l i k l i n i k HufelandstraBe 55, 4300 Essen I.

(Tumorforschung),

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DECREASED REPAIR OF GUANIN-O6-METHYL DNA ADDUCTS IN P A T I E N T S WITH LUNG CANCER H.W.R~diger t , T.Krause~ , M.Stief ~ , U.Schwarz ~ , E.Serrant t , G.Lehnert z ................................................

CYCLIC ALTERNATING VS. RESPONSE~ORIENTATED ALTERNATING 'CHEMOTHERAPY IN SMALL CELL LUNG CANCER (SCLC). K. Havemann, M. Wolf, R. Holle, P. Drings, K. Hans, M. Schroeder, H. Flechtner, H. Becker~ and E. Hruska

DNA methylation at O 4 - T o r O e - G b e a r a h i g h mutagenic/cancerogenic r i s k d u e to m i s p a i r i n g during DNA replication. These adducts can be removed from DNA by Guanin-Oe-methyltransferase (MT),a specific enzyme which simultaneously captures the cleaved methyl residue and thereby becomes inactivated. Thus the cellular concent r a t i o n of M T is a c r i t i c a l parameter for this t y p e of D N A r e p a i r a n d m i g h t b e r e s p o n s i b l e in p a r t f o r an e n h a n c e d genetic susceptibility to cancer. We have tested this hypothesis using cultured fibroblasts f r o m 48 p a t i e n t s with lung c a n c e r a n d 30 h e a l t h y controls. MT was determined by HPLC + fluorescence detection of u n r e acted O6-methylguanin after incubation of t h e homogenate f r o m i0 ~ c e l l s w i t h a k n o w n a m o u n t of methylated DNA eligonucleotide. We found a significantly reduced repair capacity in l u n g c a n cer patients (6.4 p m o l e s vs l l . l i n n o r m a l c o n trols,p<0.005), and 7 patients without a detectable MT activity. We conclude that a reduced capacity to r e m o v e O S - m e t h y l g u a n i n DNA adducts may represent a biochemical basis for a genetically enhanced cancer lung cancer risk. Arbeitsgruppe Toxikogenetik I , am Ordinariat f~r Arbeitsmedizin 2 , Universit~t Hamburg, Adolph Sch6nfelderstra#e 5, 2 0 0 0 H a m b u r g 76

From May, 1985, to January, 1987, 334 patients with SCLC were randomized to receive either a cyclic alternating regimen consisting of IE (ifosfamide 1500 mg/m2d I-5, etoposide 120 mg/m 2 d I-3; cycles I~3,5) and CAV (cyclophosphamide 600 mg/n~ d I+2, adriamycin 50 mg/m a d I, vineristine 2 mg d I; cycles 2,4~6) in 3-week intervals (IE/CAV) or a response orientated alternating regimen consisting of IE therapy up to maximum response and subsequently an im~nediate switch to CAV (IE..CAV). After chemotherapy patients with limited disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation was applied to all patients with CR. 326 pts. were evaluable, 161 receiving IE/CAV and 165 receiving IE..CAV. Known prognostic factors were well balanced. Overall response was (CR+PR) was 75% for IE/CAV and 78% for IE..CAV for all patients, 85% vs. 92~ for pts. without distant metastases (M-)~ and 59% vs. 57% for pts. with distant metastases (M+). CR rate was 28% vs. 29% for all patients, 40% in both groups for M- and 8~ vs. 12~ for M+. Analysis of survival also showed no remarkable difference between both treatment modalities. Median surviyal was 9.6 mo vs. I0.2 mo for all patients, 11.2 mo vs. 12.8 mo for M-, and 6.5 mo vs. 8.1 mo for M+~ all slightly in favor of IE..CAV. The 18-months survival rate was 13% vs. 16% for all pts. 247~ vs. 21% for M-~ and 2% vs. 2% for M+. Toxicity of both regimens was moderate. Thus~ alternating chemotherapy with IE and CAV is an effective regimen in SCLC, and none of both modalities of alternating treatment is superior to the other. Zentrum for InnaTe Medizin, Abteilung Himatologie/Onkologie/Immunolegie, BaldingerstraSe, D-3550 Marburg

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NSCLC - PROSPECTIVE RANDOMIZED STUDY COMPARING IMMEDIATE RADIOTHERAPY (RT), COMBINED CHEMO AND R A DIOTHERAPY (CT + RT), AND DELAYED RADIOTHERAPY W.. A l b e r t i , N. Niederle, M. S t u s c h k e , N. Konietzko, H. Sack

CARBOPLATINUM/VINCRISTINE AND ETOPOSIOEAS FIRST LINE THERAPY IN SMALL-CELL-LUNG-CANCER (SCLC) R. Neuhauss (1), N. Achterrath (2), U, gatzemeier (1), M. Heckma~ (1), D.K. Hossfeld (3), R. Zschaber (3)

The optimal management of patients with inoperable nonsmall cell lung cancer (NSCLC) having a few or absent respiratory symptoms at diagnosis remains under debate, This ongoing study was designed to investigate whether inuuedlate treat4ment (RT or C T + RT) results in a better survival than delayed palliative treatment in patients with inoperable NSCLC. From January '83 to October '87, 48 patients with limited disease TI-8, N2 or N3, median age: 88 yrs (44-70) were treated according to the following regimen: 1. Immediate RT: 2 x 4 Gy weekly up to 62-56 Gy. 2. CT + RT: VDS 3mg/m s, day 1 + 3, D D P 80 m g / m z, day #., 2-3 courses, followed by irradiation as under 1. 8. Delayed RT: Monthly control and start of treatment at onset of s y m ptoms. Forty-five patients are evaluable. Response rates: A r m I: 7 6 ~ (13/17pts) (CR:7, PR:6, NC+PD:4pts), a m If: 71% (10/14pts) CR:4, PR:6, NC+PD:4pts), arm IH: Median interval to the start of treatment: 9 mos (range 2-16). Median survival: A r m I: 15 mos. (2.5-87+), arm If; 19 mos. (5.5-44)), arm III: II rues. (8.5-30) (p~O.06). Early side effects including esophaglts (15), cough (5), and nausea (4) were common but mild. Late complications such as pneumonltis (15) and pulmonary fibrosis (15) commonly were clinically insignificant and seldomly required treatment (8), The main cause of death was metastatic disease. Distant metastases occurred in 24/45 (58%) patients after a latency of 2-88 mos. (median 9). Brain was the most frequent slte (12/24 pts). So far survival related to the 8 treatment modallties demonstrates borderline slgnlfieance in favor of immediate treatment. This data seems to demonstrate that in asymptomatic NSCLC confined to the hemitherax (T1-3; N2-8) immediate treatment is superior to the delayed treatment. Alfried Krupp Krankenhaus, Strahlentherapie, Alfried Krupp Str. 9.1, D - 4800 Essen 1

INTRODUCTION: In the p i l o t dose-finding study with f i x e d doses CarbopIatimum/Vincristin and escalating doses of Etoposide we looked f o r the t o x i c i t y and the e f f e c t i v e ness of t h i s combination in extended SCLC. In the ongoing p h a s e - I I - t r i a l with the recommended dose and schedule also remission-rate und s u r v i v a l is observed. PATIENTS AND METHODS: In the p i l o t study 25 patients were trested, f/m r a t i o 8/17, mean age 59 (37 - 69). ED I/EO I I 11/14. Dose l ~ l i t i n g t o x i c i t y was myelosuppression when Etoposide exceeded 420 mg/qm per course. As r e s u l t the recommended d o s e and schedule f o r the following p h a s e - I I - t r i a l was as fallows: Carboplatinum 300 mg/qm i . v . day 1, VCR 1,4 mg/qm (max. 2 mg i . v . ) day 1 + 8 + 15, Etoposide 140 mg/qm i . v . day 1 - 3. Since 2/87 54 patients were entered into the ongoing protoooll, f/m r a t i o 12/42, meanage 57,8 (23 - 76). Lim,/Ext. 26/24. RESULTS: In the pilot study 48 % CR and an overall response rate of 88 % were achieved, In the following phese-II-trial up to now 48 patients are evaluable for response and survival. An overall objective response-rate o f 9i,7 % has been observed.{CR 29~2 %, PR 62,5 %). Overall the toxicity was very moderate. Nausea end vomiting WHO 3 + 4 occured in 28,6 % of the patients. Other toxicity according to WHO: Pslyneuropathy 1:61,5 % and 6 % rasp. grade 2 and 6 % resp. grade 3. CONCLUSION: The combination Carboplatinum, Vincristin and Etoposide is highly effective in the treatment of SCLC. The response rate and also the early survival data are encouraging, especially in combination with the very moderate toxicity, Compared with historical data achieved by DDP/Vp-16 or DDP/VDS or CAV this combination seems to be superior. Dep.of Thoracic Oncology, Gro6hansdorf Hospital (1) Bristol-Myers Company (2) Dep.of Hematology and Oncelogy, Univ,of Hamburg (3)

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PHASE-II-STUDY WITH TAUROMUSTINE (TCNU) IN ADVANCED NONSMALL-CELL LUNG-CANCER (NSCLC) U. Gatzemeier (1), P. Drings (2), H.H. Fiebig (3), A. Hinke (4), K. Rieche (5), H.W. Tessen (2), f o r the PhaseII-Study Group, Association of Medical Oncotogy, German Cancer Society

MITOXANTRONE IN THE TREATMENT OF MALIGNANT PLEURAL EFFUSION M. Heckmayr (1), U. Gatzemeier (1), R. Neuhauss (1), d_=von Pawel (2), K. H~uBinger (2)

INTRODUCTION: TCNU i s a newly developed nitrosourea compound. Because of molecular m o d i f i c a t i o n TCNU i s more h y d r o p h i l i c than 8CNU + CCNU, In experimental data there was a high therapeutic index, esp. in WALXER 256 carcinosarcoma in rats~ In phase-I-trials (SMITH and HANSEN) antitemor-activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleuramesotheliomas and ovarian cancer. To look for the effectiveness, duration of response and toxicity the following Phase-II-trial was performed. PATIENTS AND METHODS: Patients received 130 mg/qm TCNU every 35 days orally. 25 patients were treated, 19 are evaluable for response, f/m ratio 19/4, stage IIl 1 pt, s t . I V 21 pts. resp., mean age 59,3 (range 34 - 70). 1 t o 4 courses (mean 1,9) were administered. Histology: 7 squamous cell, 10 adeno, 2 large cell carcinoma. RESULTS: No objective response (OR + PR) have been observed. 6/19 patients had stable disease, 8/19 progress. The median survival time is 4,8 months. The most severe side effects were myelosuppression with thrombocytopenia (WHO 3 + 4 8/25). CONCLUSION: TCNU administered at t h i s dose and schedule does not show s u b s t a n t i a l antitumor a c t i v i t y in p a t i e n t s with NSCLC. The f a c t t h a t no o b j e c t i v e tumor remission was observed suggests t h a t the t r u e response r a t e is ~20 % (p ~ 0 , 0 5 ) . I t i s inprobabla t h a t TCNU has a r e l e v a n t impact on the course o f inoperable NSCLC Dep. of Thoracic Oncotogy, Groehansdorf Hospital (1) Dep, o f Oncology, Chest-Hospital Heidelberg-Rohrbach (2) Dep. o f Hematology, U n i v e r s i t y Ereiburg (3) Mad. Dep. Pharmacia A r z n e i m i t t e l GmbH, Ratingen (4) St. J o s e f - H o s p i t a l , Galsenkirchen (5)

INTRODUCTION. To achieve e f f e c t i v e pteurodesis in malignant p l e u r a l e f f u s i o n s many d i f f e r e n t substances, such as tetracyctines, 5- f l u o r o u r a c i l etc. are u s e f u l . Mitoxantrone, an anthracenediona, which i s a new important drug in the therapy o f breast carcinomas, not c r o s s - r e s i s t e n t t o adr• seems t o have a p o s i t i v e i n f l u e n c e on malignant pleural effusions stemming from metastasising carcinomas of different histology and from masetheliomas. PATIENTS AND METHODS.Since 1/87 24 patients were treated with malignant pleural effusion stemming from mesothelioma (n=4), SCLC (n=2), NSCLC (n=l), breast carcinoma (n=3), and other different adenocareinomas (n=6). There were 18 men and 7 women with a mean age of 61.9 years (35 - 81 yrs). The mean Karnovsky-index was 70%. After drainage of the pleural fluid 30 mg mitoxantron8 were administered with a pleural tube. No concomitant chemotherapy ware given at least 4 weeks before and during the local therapy. RESULTS. The overall effectiveness was 22/24 pts (91,6 %). CR 15/24 (62,5 %), PR 7/24 ( 2 9 , 1 % ) , only 2/24 pts had no b e n e f i t o f the t h e r a p e u t i c procedure. D e f i n i t i o n of the results: CR= complete disappearing of pleural fluid. PR= halving of the fluid or doubling of time interval if more punctions were necessary. The patients" tolerance of the treatment was good with only minor sideeffects such as pain and occasional fever, 1 fistula. CONCLUSION. With a remission rate of 91,6 %, mitoxantrone is a very effective drug in achieving pleurodesis in malignant pleural effusions from tumors of different histologies. In an ongoing randomized study we are going to compare the described therapy with mitoxantrone with pleural tube alone. Dep, of Thoracic Oncology, Hospital Grosshansdorf (1), Dep. of Pneumology, Hospital Gauting (2),

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5/P-GMOOl

C H E M O T H E R A P Y OF ADVANCED NON SMALL CELL LUNG CANCER (NSCLC) W I T H IFOSF~[IDE (IFO) AND VINDESINE (VDS) P. Drings, N. Djawid, H. BOlzebruck, A. Schm~hl, H.W. Tessen

THE TREATNE[IT OF DYING CANCERPATIENTS HOHEOPATHIC DRUGS

41 u n t r e a t e d pat. w i t h h i s t o l o g i c a l l y proven NSCLC within an age range between 35 and 75 years (mean 57 years) were entered into a phase II study. The regimen consisted of IFO 2000mg/m 2 on days I-5 and VDS 3mg/m 2 on day I and 8 every 4 weeks. A c c o r d i n g to the severe hematologic toxicity the IFo dose had to be reduced to 1500mg /m 2 and the VDS dose to 2,3mg/m ~ . Supportive treatment with mesna (20% of the IFO dose at 0, and 4, and 8 hours) was performed. Patients were given a m i n i m u m of 2 courses of treatment for evaluation. 27 pat. are evaluable. For 3 pat.the cut off was to early, I pat. refused further treatment, in 2 pat. treatment was stopped because of toxicit Z in 8 pat. because of early p r o g r e s s i o n during the first cycle (including 4 early tumor death's 8 out of 27 p a t . a c c h i e v e d a partial response, in 10 pat. the result was no change. 17 pat. are still alive. Median survival time of all 41 pat.: 7 months, of the 27 evaluable pat.: 8,5 months. The toxicity of the t h e r a p y was quite high: leucocytopenia grade IV : 21 (infections grade III : 16), t h r o m b o c y t o p e n i a gradeIV:1 (without severe bleeding), nausea gradeIII:5, n e u r o t o x i c i t y grade III:3. Urotoxicity has never been observed In summary the results show that the combination IFO/VDS is effective in the treatment of NSCLC but as a palliative t h e r a p y tco toxic. Abt. Innere M e d i z i n - O n k o l o g i e der Thoraxklinik Heidelberg-Rohrbach,Amalienstr.5pD-69 Heidelberg

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$157 5/P-GM002

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THE TREATMENT OF GIANT CELL TUMOR OF BONE AND ANEURYSMAL BONE CYST PRESERVING THE JOINT AND JOINT FUNCTION. P. Wuisman, A, H~rle, R, Erlemann, M. Reiser, A. Roessner

PSYCHOONCOLOGY IN A HOSPITAL SETTING - AN INTEGRATIVE APPROACH H. Kappeuf (1), R. Dietz (2), W. Pontzen (2),

Giant cell tumor of bone has been one of the most misunderstood and controversial bone diseases. In the past many authors have subdivided the tumor histologically and roentgenologically into several grades as a means of predicting the behavior of these tumors. The practical value of these staging procedures is controversial in literature leading to increased confusion. As in aneurysmal bone cysts, the factor that definitely seems to influence prognosis is the surgical procedure. Low recurrence rates are reported after wide excision including the joint and after intralesional excision and adjunctive poly methylmetacrylate therapy. Temporary polymethylmetacrylate packing of intralesionally excised giant cell tumors and aneurysmal bone cysts has been performed in our clinic for more than ten years. We thus perform a very careful intralesional excision followed by temporary Pallacos implantation, using optical devices. After three months we remove the bone plug, followed by bone grafting and anatomical reconstruction of the cortex. Further therapy includes intensive physiotherapy training in order to maximise the joint function. We have treated more than 30 patients (15 giant cell tumors) according to this scheme, until now no local recurrences have been reported.

W.M. Gallmeier (1) With quality of life issues becoming more predominant in oncology, cancer centers are confronted by the difficulty to reconcile the psychosocial needs of their patients with the medical treatment modalities according to the state o f the art. Since 1980 an integrative model o f psychooncology has been developed at the 5. Medizinische Klinik Cancer Center NOrnberg in close cooperation with the psychosomatic department. Psychosocial aspects of oncological diseases and coping beheviour are to be considered from the time of diagnosis, during treatment to discharge end follow-up or death. As the main principle of our approach psychosocisl needs of the cancer patients are to be met by the oncologists and the nursing staff end not by referral to psychiatrists or psychotherapists. A psychooncological working group comprising a psychotherapist (2), an oncologist/psychotherapist (1) a social worker (2) and an art therapist (1) has been established to offer supervision of staff-patient interaction, training of the medical and nursing staff, and psychotherapeutic interventions in special cases. The structure and experiences of this integrative approach ere reported and evalued as an important and efficient step towards comprehensive cancer care.

(1) 5. Medizinische K l i n i k , I n s t i t u t f~r H~matologie und Onkelogie Klinikum N~rnberg, F l u r s t r . 17, D-8500 NOrnbsrg (2) Psychosomatische Abteilung, Klinikum NOrnberg

Orthop~dische Universit~ts-Klinik, Institut f~r Klinische Radiologie und Institut f~r Pathologie der Westf~lischen Vilhelms-Universit~t, M~nster

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COMPERATIVE TRIALS OF FOUR SEROLOGICAL ME~fHODS FOR CMV-INFECT1ON DIAGNOSTIC BY CANCER PATIENTS J. Ci_natl, V. Gerein, B. Kornhuber Cytomegalovirus (CMV) infection is a potientally hazard for individuals with immundeficiency (immunmocomproraised) as a result of t r e a t m e n t or disease, There are many sorts of commercial diagnostic kits for CMV-antibody tests in serum but using them causes interpretation problems. Moreover, the comparative trials of specificity and sensitivity of these kits fail to be made by patients suffering from cancer. In consideration of the above constraints, a comparative trial of four methods was undertaken to determine the most suitable system. Method~ selected were: CFT {Complemen,~ Fixation Test), IFA* {Immunoflot~rscence Assay), ELA (Enzyme Labelled Assay) and ELISA (Enzyme Linked Immunosorbent Assay}. The tests were carried out with cancer patients daring their chemotherapie and 161 serum samples were tested. CFT negative sera were found IFA-IgG, ELA-IgG and ELISA[gG positive in 14,4%, 17,1% 22,3% as well. IFA-IgG and ELA-IgG dissented in I5% and IFA-IgG and ELISA-tgG in 10%, IFA-IgM and ELA-IgM testa were discordant in 4% and IFA-IgM and ELISA-IgM in 5%. The comparative trials between ELA-IgG and EMSA-IgG were discordant in 8,4% end between ELA-IgM and EL1SA-tgM in 5%. The relative high discordance between CFT and other methods has led to the suggestion of its nonavailability for the CMV-antibody diagnostic of cancer patients. IFA, ELA and ELISA give almost identical outcomes. However, tFA can supply more of false positive and ELISA more of false negative results. The CMV-antibody diagnostic of complicated patients shouid be made simultaneously by aid of two methods. Klinikum der J.W.Goethe-Universit~it, Zentrum der Kinderheilkunde, Theodor-Stern-Kai 7, 6000 Frankfurt am Main 70 West-Germany i. Fa. CAS, 2. Fa. Medac, 3. Fa. Behring

ANTIEMETIC TREATMENT OF CANCER PATIENTS UNDER CHEMOTHERAPY K.Dimitriadis, I~Vainas, Ch. Kousis a n d l. Ster~iu Nausea and vomiting are the most frequent and d $ sturbing side effects of the chemotherapeutic treatment of neoplastic diseases(L.J.Seigel,Ann. Inter. Med.,95,352,1981).The aim of this prospective trial has been to determine the efficiency of some combinations of well known antiemetic drugs(R.J.Bertino,ln Lederle Cancer Monographs, 1,1986)in comparison to the menotherany with the ~ame drugs.146 cancer patients, who were under systemic chemotherapy for various histological types of p r i m a r y cancer, received either one of the three antiemetics(Metoclepramide, Alizapride or Domperidone)alone or in combinations with: a) Triphthorioperazine plus Glovazame or Lorazepame (3 drug-combination)for Metoclopramide and b)Dexamethasone for the other two drugs. The evaluation of the antismetic result was based on a quastiennaire seale(R.G.Morrow, Cancer, 5~3,2267,1984). It has been graded with O(fer excellent results) to 4(for no result)according to the number of vomiting fits and the duration os vomiting and/ or nausea. The combinations and especially the ones with Metoclopramide or Alizapride showed a distinktly better antiemetic activity with excellent plus good results up to 81% and 79% respectively.Parameters such as age, sex and extent of disease seem to have no effect on the anticmetie result. Medical Oneology Department II, Theagenion Cancer Center, 2 A.Symeonidistr.,GR-54007 Thessaloniki

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A R A N D O M I Z E D TRIAL WITH A L I Z A P R I D ALONE VERSUS ALIZAPRID AND D E X A M E T H A S O N E FOR P R E V E N T I O N OF CYCLOPHOSPHAMIDE I N D U C E D V O M I T I N G IN P A T I E N T S U N D E R G O I N G BMT Hermann Einsele, Helmuth Schmidt, Roland Depfer, Karl Jaschonek, Michael Hash, Hans D i e r k Waller, G e r h a r d E h n i n g e r ............................................... 29 patients who underwent bone marrow transplantation for acute l e u k e m i a or c h r o n i c m y e l o g e n o u s l e u k e m i a were r a n d o m i z e d to r e c e i v e either high-dose a l i z e p r i d ( 30 mg/kg body weight ) alone or in combination with dexamethasone ( 4x4 mg ). Alizaprid was a d m i n i s t e r e d as a 15 min i n f u s i o n 30 min b e f o r e and at the end of the c h e m o t h e r a p y and as a 24 hour-hour i n f u s i Q n with 20 mg/kg body weight. A n t i e m e t i c t h e r a p y wag s t a r t e d a f t e r the total body irradiation and p e r f o r m e d during the chemoconditioning regimen on two successive days. All the p a t i e n t s in the s t u d y received cyclophosphamide in a d o s a g e of 2x60 mg/kg b o d y weight. 4 p a t i e n t s were a d d i t i o n e l l y g i v e n V P - 1 6 30 mg/kg b o d y weight for a d v a n c e d d i s e e s e prior to BMT. A d d i t i o n of d e x a m e t h a s o n e to the antiemetic r e g i m e n r e s u l t e d in a significant reduction in the n u m b e r and s e v e r i t y ( v o l u m e of emesis, hematin in t h e emesis) of emetic e p i s o d e s (p
RESULTS AFTER POSTOPERATIVE IRRADIATION OF 36 PATIENTS WITH MALIGNANT FIBROUS HISTIOCYTOMA

5/P-GM 007 HAEMOSTASEOLOGICALDISORDERSIN CHILDRENW l ~ THROMBOTICEVENTSDUE TO MALIGNANTTUMORS

(MFH) J. Langrock, v. Budach, W. Alberti, M, Bamberg, C. Donhulisen This retrospective study analyses the r e s u l t s in p a t i ents with MFH after combined treatment (surgery and radiation therapy), Between 1976 and 1987, 86 patients (pts) with MFH (19 mate, 17 female), median age 58 yrs (range 28-78) were irradiated postoperatively, TNM staging revealed for T2 No Me - 21 pts and T8 No Me - 17 pts. All but two pts (subtotal resection) were completely resected and irradiated p o s t - o p e r a t i v e l y with photons _+ electrons (n=lO) • f a s t neutrons (n = 20L or fast neutrons alone (n = 6). Total dose was 50 to 70 Gy in the photon group including a boost therapy (electrons or neutrons), or 50 Gy photon equivalent dose (fast neutrons alone), Sixteen pts died due to metastatic disease + local r e currence after 2-58 me (median 17). Four pts are p r e sently alive after surgical salvage of recurrence by amputation (1), by wide resection (I) and chemotherapy for metastatic dtesease (1). 18/21 pts with T2 No Me stage are alive NED, 8 were salvaged after local r e c u r rence by surgery. Five died due to local and d i s t a n t progressive disease, Only 4/17 TS No Me stage pts are alive (NED), whereas the others died due to local relapse (9) and distant metastases (4). The median s u r v i v a l was 36 me in T2 and 12 me in T8 lesions, Late side effects of irradiation were of different degrees of subcutaneous fibrosis, in two cases even chronic ulceration requiring surgical treatment occurred. D e p t of Radiation Oncology, University of Essen, Hufelandstr. 55, D-4SO0 Essen-1

5/P-GM009 AMPHOTERICIN B-INDUCED NEPH~OTOXIC~TY BY S O D I U M L O A D I N G M. Arning, R.E. Scharf, W. S c h n e i d e r

DECREASED

U. Nowak-GSttl, W.D. Kreuz, V. Hach-Wunderle*, B. Krackhardt, H. Freund, D. Schwabe, B. Komhuber Thrombotic events in association with malignant tumors are well known in adults in opposit to childhood where dangerous bleedings are described but only few cases of manifest thrombosis due to tumor or cytostatic therapy, especially methotrexate, bleomycin or 1asparaginase. From 1982 to 1987 out of 335 children with new diagnosed malignancies t2 patients (3.6%) developed manifest thrombotic events. In these 12 children suffering from ALL, a s t r o c y t o m a , medulloblastoma, liver cell carcinoma, synovialis sarcoma and tesficular tumor platelet count, spontaneous platelet aggregation, von Willebrand factor, fibrinogen, plasminogen, antithrombin III, Protein C, C - l - e s t e r a s e inhibitor, a l p h a - l - a n t i t r y p s i n , alpha-1anfichymotrypsin, alpha-2-antiplasmin and alpha-2-macroglobulin have been investigated immediately after the onset of clinically manifest thrombosis, Compared to an age matched control group (n=32) accquired deficiency of protein C, AT III and plasminogen have been found as well as increased levels of von Willebrand factor and fibrinogen. Alpha- 1antitrypsin and alpha-l-antichymotrypsin were enhanced whereas alpha-2-antiplasmin and alpha-2-macroglobulin, both inhibitors of the fibrinolytic system were decreased in some patients. In our patients these changes have been found duNlg induction therapy as well as during maintenance therapy and ifi patients without therapy. Zentrum der Kinderheilkunde and *Inneren Medizin, Universit~tt Frankfurt, Theodor Stern Kai 7, 6 Frankfurt/Main

N e p h r o t o x i c i t y is the m a j o r l i m i t a t i o n in the use of amphoteriein B (ampho B). We o b s e r v e d a m p h o B , i n d u e e d Penal failure in 25~ of our patients evaluated r e t r o s p e c t i v e l v . Several intrarenal mechanisms are involved in the n e p h r o t o x i c response to ampho B, among them s o d i u m depletion. On the basAs of experimental and clinical findings we performed sodium loading in 31 patients (17 male, I~ female, median age 49 years, range 20-74 years) treated with a m p h o B in a dosage of 0,5-I m g / k g body weight b e c a u s e of suspected (n:21) or d o c u m e n t e d (n=10) s y s t e m i c fungal infeetions. All p a t i e n t s suffered from hematologlo malignancies: AML = 24, A L L / A U L : ~, NHL high grade = I, CML blast crisis = I, m y e l o d y s p l a s i a RAEB = I. A m p h o B was a d m i n i s t e r e d for ~ to 136 days (median 21 days), S o d i u m loading was performed as follows: up to an ampho B dosage of 0,5 m g / k g body w e i g h t 50 m] MaC1 10 % w e r e infused over ~ to 6 hours. Whe~ u s i n g h i g h e r doses of a m p h o B, 100 m] NaC] 10 were given. U s i n g sodium l o a d i n g no n e p h r o t o x l c i t y occured in 30/31 p a t i e n t s d u r i n g 9!0 days of t r e a t m e n t with ampho B despite the c o - a d m i n i s t r a t i o n of other p o t e n t i a l l y n e p h r 0 t o x i c drugs such as vanc o m y c i n or a m i n o g l y c o s l d e s in 25/31 patients. These results demonstrate that sodium loading decreases ampho B - i n d u c e d n e p h r o t o x i e ~ t y providing that there is no c o n t r a i n d i e a t i o n for sodium loading. N e d . U n i v . - K l i n i k , M o o r e n s t r . 5 , D - 4 0 0 0 D~}sseldorf

$159 5/P-GM 010 Nutritional support via a percutanous gastrostomy (PEG) i n p a t i e n t s with diseases. H.J.K6nig, S.Kolb, H.Iro, H.J.Thiel

5/P-GM 012 endoscopic malignant

TREATFEh~OF CANCER ASSOCIATEDHEMOLYTICUREMICSYNDROMEWITH PROTEIN k ~ORPTION E.J. Borghardt,J. inagnou, E.~L Wirche~z

Medizinische Univ.-Klinik, HNO-Klinik und Strahlenklinik der Universit~t ERLANGEN-NORNBERG, K r a n k e n h a u s s t r . 12, 8 5 2 0 E r l a n g e n

Plasma-perfusionover sepD~se - boLr~ Sta~hylocoocalprotein A (SPA) was used to treat 7 patientswith adenocarcino~m~!o dew,eloped a Qmncer associatedhemolytic%tremics~.~ome (c-HUS). Micrc~ngiopathich~olytic anemia (FHA) is a well describedcomplication of neoplasticdiseeseparticularlyad~nocareinaraof t/hestomach, pancreas and .lung.~is h~l}%ic proc~ is not a s~gle entity, but rather occursas a featureof one of severalpossibleunderlyingproceases that includered cell f ~ n t a t i o n in tt~or-obstructedmicrovasculature, disseminatedintravascularccagu]ationand thrombotic thrombocytoper/cpurpura (TIP). In the past several ye,re, a new form of TIP has been describedin cancer ~tiente called c-HL~. ]be c-HUB consists of thrombesytopania,M ~ and progressivere~el failure, ~rith a mortalityrate of 80% within 12 m~nths from establishmentof the diagnosis. 7n general, this entity develo~ in patient~r tu~norsare either in a completeor partial _~avissionafter mit~Din-C ch~mo?/qerepy. High levsls of circulatingimmune cxx~plexes(clC)with susbt~ntia! p]atelet aggregateryactivityare present in the sere. In patientsv~_th a d e n a s a r c ~ who developa C~@JS IC may play a role in the so far unkn.J~aetiology. - ProteinA (SPA)is a cell wall c ~ n t of patho~e~ic Stephyloeses~.[t binds nonspecificallyto the Fc portionof the IgG moleculeand has a preferentialbindingof YgC-~rmunecomplexes. A Clinical study was started to prove the therapeuticalbenefitsof SPAimmmadsorption and to investigatethe possiblemecDanismsof imnunmodulationafter protein A tzeatmont.Plas~ was separatedby blood filtratinnusirg a capillaryp l ~ i l t e r (P]aarafluxP~, FreseniusAG). ~he treatmentp r 0 c ~ e consistsof 2-3 wt~kly SpA-i~mu~adsorptionsof 30% - 404 of the p ~ a vo!:are.Adsorptioncapacityfor ~ G of the 200 ml-colu~r~used was 25 ~/ml gel. ~ p e r f u s i o n resultedin clearance of D~etrea%~entelevatedlevels of circulatingL~m~ne o~plexes; with nor~slizationof complementvaluesw~eh were ~tially depressedat the start of the therapy~ A significantrise in b~ptoglobL% platelets~nd e~ythrocytecou~ntswas achievedin 5 patients,with stabilizatic~of progressiverenal impairment.~he responsewe~ incompleteand shortlived in two patientswith clinicallyevidenttt~or recurrence.THe median symptc~free survivaltime in four patientsis 16 months. Cn average, respor~ewas achieved after 5 trest/nenteover a period of 10-14 days. AbteiluTIgP~telcgie/Oi
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MANAGEMENT OF MALIGNANT P L E U R A L EFFUSIONS H.G. Bischoff, D. Branscheid, G. Probst, I. Vogt-Moykopf

HEPATOLIENAL FUNGAL INFECTIONS IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES. M. E s s i n k , M. Y o n Eiff, W. H i d d e m a n n , T. B ~ c h n e r , J. v a n d e L o p I n a r e t r o s p e c t i v e e v a l u a t i o n of p a t i e n t s W i t h hematological malignancies admitted to our d e p a r t m e n t b e t w e e n 1 9 8 0 a n d 1986 a s y s t e m i c f u n g a l i n f e c t i o n c o u l d b e d o c u m e n t e d i n 32 cases. 30 of 32 p t s (94%) w i t h t h i s c o m p l i c a tion had a period of profound neutropenia foll o w i n g i n t e n s i v e c h e m o t h e r a p y . 21 (66%) p t s developed hepatomegaly and/or splenomega!y. In 12 of t h e s e p t s multiple lesions 0.5 -2 c m 2 i n d i a m e t e r c o u l d be d e t e c t e d b y s o n o g r a p h y o r CT scan. In 5 p t s l a p a r o s c o p y r e v e a l e d mult i p l e round, y e l l o w l e s i o n s o n t h e s u r f a c e of t h e e n l a r g e d liver. I n 2 of t h e 5 c a s e s typical fungal myce!ia were found in biopsy material. The remaining 3 cases revealed multiple small granulomas besides necrotic a r e a s o n h i s t o l o g i c e x a m i n a t i o n . A m o n g t h e 12 p t s w i t h h e p a t o l i e n a l l e s i o n s I0 d e v e l o p e d organ involvement after recovery from critical n e u t r o p e n i a , only. All pts recovered completely after systemic antimycotic chemotherapy (9 pts) or e v e n s p o n t a n e o u s l y (i pt). H e n c e , h e p a t o l i e n a l f u n g a l i n f e c t i o n s e e m s to rep r e s e n t a s p e c i a l v a r i a n t of the p o s t c y t o s t a tic s y s t e m i c f u n g a l i n f e c t i o n o c c u r r i n g in p t s with comparatively well maintained or restored infection defense mechanisms.

In many cancer-patients the tumour leads to a severe malnutrition. Nutritional support therefore is indicated if the oral intake of food is insufficient. Total parenteral nutrition and n a s o g a s t r i c t u b e - f e e d i n g a r e c o m m o n l y used. T h e latter has limited acceptance because the patient can be identified. This disadvantage can be avoided by use of a PEG. The aim of this prospective study was to investigate the practicability of this technique. 185 patients (mean age 54+/-12 years) were nourished via a PEG-tube so far. 162 patients suffered from malignant diseases of the oro/hypopharynx. 23 p a t i e n t s had cancer of the oesophagus. The total observation period was 19421 days with mean of 105+/-79 days. Serious complications were not seen d~ring the implantation. The acceptance of the nutrition-system by the outpatients was generally g o o d . 12 l o c a l i n f e c t i o n s are seen so far, only one PEG tube had to be removed two month after implantation. In all patients, a significant increase of body weight o f 3,4 + / - 2 . 8 k g c o u l d b e o b s e r v e d . Enteral nutrition via PEG is a safe and effective method. It offers cosmetic advantage with better acceptance compared with nasoenteral tube-feeding. Home parenteral nutrition can be avoided in most patients who have to undergo artificial nutrition by feeding them with elem e n t a l d i e t s v i a P E G o n a n o u t p a t i e n t s basis.

Malignant p[eural effusions are a common complication of malignant disease. Effective palliation is therefore an important aspect in management of patients with disseminated canceF.

136 patients {$ 43/~ 93. X / 59 years) with malignant pleural effusions were analysed retrospective|ywith following primary tumors: 35% bronchogenic, 25% malignant pleuralmesothelioma, 13% brest, 6% adeno~ 4% uterus. 3% gastrointestinal, 14% others. Thoracoscopy takes a central role in our diagnostic procedu ~ res, with the success rate of 98%. Cytology were positiv in 76%; CEA showed in bronchogenic carcinomas a sensitivity of 68, 7%, a specifity of 95, 3%. Local treatment consisted of tube thoracostomy (-20 cm H20) with or without tetracyclin-hydrochloride/procain ins~|ilation or surgery. All patients were followed for recurrency for an average of 4 112 months. Our scheme of diclsion and treatment give following s u c c e s s r a t e : no r e l a p s e o f e f f u s i o n 74%, i n t e r v a l o f relapse 4 weeks 9%, 4 weeks 17%; - excluding patients after surgical management. We saw no relapse of effusion after partial pleurectomy Sl5; decorticatlon 24128 (86%), pleuropneumonectomy 11 l I 2 (92%). It is obvious that malignant pleural effusions need early diagnosis, rapid alleviation of symptoms and treatment for a particular paHent determind by the exigencies of the situation. Chest Hospital Heidelberg-Rohrbach, Department for Thoracic S u r g e r y , Amalienstr. 5, D-6900 Heidelberg, FRG.

Med. U n i v . - K l i n i k Abt. A, A l b e r t - S c h w e i t z e r S t r a s s e 33, D - 4 4 0 0 M ~ n s t e r W e s t G e r m a n y

$160 5/P-GM014

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RISK FACTORS FOR SYSTEMIC FUNGAL INFECTIONS IN HEMATOLOGICAL MALIGNANCIES M. von Eiff, M. Essink, W. Hiddemann, T. Bfichner, J. van de Loo A retrospective inalySis of patients"with hematological malignancies admitted to our department between 1980 and 1986 revealed systemic fungal infections in 32 cases. 14 of 15 pts in whom a fungal infection could not be verified clinically and who did not receive antifungal therapy succumbed to this post m o r t e m diagnosed complication while only 5 of 17 cases receiving systemic antimycotic treatment died. In an attempt to improve on these results and to identify risk factors for systemic fungal infections the following parameters w e r e determined based on a retrospective analysis: I. malignant diseases especially acute leukemias (27 of 32); 2. myelosuppressive cytostatic treatment (n=32); 3. profound aplasia < 500 granulocytes/cmm (n=30) - average duration 38 days (range i0 - 90 days); 4. systemic multidrug antibiotic therapy (6.7 different antibiotics on average); 5. oorticosteroid m e d i c a t i o n (n=16), diabetes mellitus (n=2); 6. Inadequate oral antifungal prophylaxis (n=12); 7. Second fever episode after prior clinically effective antibiotic treatment within a preceding 8 week period. Hence, systemic antimycotic combination chemotherapy should be included very early in the design of empirical anti-infectious regimens for pts receiving myelosuppressive and repeated chemotherapy for hematological malignancies.

PALLIATIVE TREATMENT OF MALIGNANT OSTEOLYSES THE CERVICAL SPINS Ch. Jfirgens, Ch. Eggers and D. Wolter

Med. Univ.-Kinik Abt. A., Albert-Schweitzerstrasse 33, D-4400 M~nster, West Germany

II.Chirurgische Abteilung, AK St.Georg, Lohmfihlenstr.5, D-2OOOHamburg 1

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THE SURGICAL ATTENTION OF PATHOLOGICAL FRACTURES CONDITIONED BY A MALIGNOMA J. Rosenberger, H.U. Z i e r e n , K.E. Rehm

EXPERIENCES IN HOMETREATMENT OF CANCER-PATIENTS S.Frohmiiller, R.Leucht, J . Ophof, G.Ruoff, P.Schlag

P a t h o l o g i c a l f r a c t u r e s c o n d i t i o n e d by a m a l i g noma are m a i n l y caused by bone m e t a s t a s i s and more r a r e l y by p r i m a r y bone t u m o r s . The f r a c t u r e is q u i t e o f t e n the f i r s t symptom o f an a l r e a d y advanced tumor d i s e a s e . Three q u a r t e r s of our p a t i e n t s who had been o p e r a t e d on, showed m u l t i p l e bone m e t a s t a s i s at the time of o p e r a t i o n . The aim of a s u r g i c a l t r e a t m e n t is the q u i c k r e c o v e r y o f t h e f u n c t i o n and p a i n e l e m i n a t i o n along w i t h a low s t r e s s of o p e r a t i o n . Several methods o f o p e r a t i o n are a v a i l a b l e h e r e t o . A c o m b i n a t i o n of ray t h e r a py, chemotherapy or hormontherapy i s i n g e n i o u s depending on t h e i n d i v i d u a l case. We a c h i e v e d a good or s a t i s f y i n g p a l l i a t i o n in 56 p a t i e n t s w i t h p a t h o l o g i c a l f r a c t u r e s by t h i s t r e a t m e n t . Problems a r i s e in p l a n i n g a t h e r a p y i f the p a t i e n t is in a bad g e n e r a l c o n d i t i o n o r in case of a s h o r t l i f e e x p e c t a n c y . Second o p e r a t i o n s may become necessary and i n g e n i o u s in case of a r e - f r a c t u r e caused by p r o g r e s s i v e tumors.

Oncological t h e r a p y today i s c h a r a c t e r i z e d by h i g h l y s p e c i a l i z e d and multimodal forms o f treatment. The tumor p a t i e n t has to face f r e q u e n t v i s i t s t o the tumorcenter and is often hospitalized. To shorten the clinical stay and t o improve the q u a l i t y o f l i f e o f t h o s e c h r o n i c a l l y i l l p a t i e n t s an i n v e s t i g a t i o n a l p r o j e c t was s t a r t e d w i t h the i n t e n t i o n t o t r a n s f e r s p e c i a l oncological treatment to the homes of the patients. In November 1986 a team consisting of 2 physicians, 2 n u r s e s and 1 p s y c h o l o g i s t was s e t up a t the s u r g i c a l oncology unit of the University of Heidelberg. This team regards i t s e l f as a l i n k between tumor c e n t e r , general practioner, community nursing services, patient and their relatives. From November 1986 to August 1987 72 cancer patients were treated at home. The modalities of therapy were continuous chemotherapy (36 patients), emteral / parenteral nutrition (13 patients), care after mutilating surgical procedures (15 patients) and terminal care including pain control (8 patients). The experience of I0 months demonstrates the possibility to transfer these forms of oncologieal treatment to the ambulatory area. Complications were rare. Psychological examinations found that treatment in the home o f the patient improves the quality of life.

Abteilung fur Unfailchirurgie (Leiter: P r o f . Dr. K. E. Rehm) der C h i r u r g i s c h e n Universit~tsklinik (Direktor:Prof.Dr.Dr.H. P i c h l m a i e r ) , J o s e p h - S t e l z m a n n - S t r . 9, 5000 KEin 41 - L i n d e n t h a l

OF

Polysegmental malignant osteolyses of the cervical spine often lead to instability by destruction of the vertebral bodies or desintegration of j o i n t f o r m i n g s t r u c t u r e s . Instability and growth of tumor increase the risk of neurologic disturbances up to transverse lesion. Stabilization by u s e of m e t a l l i c i m p l a n t s is often not possible.ln these cases a new approach for stabilization had to be made considering the reduced general condition and the shortened expectation of life of the patients. Combined use of the halo apparatus and radiotherapy (40 Gray/ 28 days) s h o w e d s o m e h o p e f u l r e s u l t s b e t w e e n 1983 a n d 1985. We t r e a t e d 5 p a t i e n t s this way. 2 patients died in consequence of m u l t i p l e metastases. In 3 patients the halo was removed after 8 to 18 weeks. The x-rays showed complete scler o s i s of the s e g m e n t s c o n c e r n e d and n e u r o l o g i c d i s t u r b a n c e s w e r e r e g r e s s i v e or u n c h a n g e d . T h e survival time a f t e r t h e r a p y w a s 5 to 25 month. Since 1985 we made some new experience widening the range of treatment by surgical resection of the i n v o l v e d v e r t e b r a l bodies. T h e r e s u l t i n g defect was filled with a composite bone graft from the os ilium. Stabilization was achieved by the halo apparatus. A l l 3 patients treated this way so far h a d s e v e r e n e u r o l o g i c d i s t u r b a n c e s before therapy. 6 to 8 weeks after operation the bone grafts became incorporated and the halo was r e m o v e d . In a l l c a s e s n e u r o l o g i c d i s t u r b a n c e s w e r e r e g r e s s i v e . Up to n o w the s u r v i v a l time after therapy is 6 to 15 month.

Chirurgische 5h~iversitfitsklinik, Abteilung Neuenheimer Feld II0, 6900 Heidelberg, FRG

2. I. i.,

Im

S 161

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Tumorreduktion und interstitielle Strahlentherapie mit Jod-125-Seeds als Therapiekonzept ~ i m anaplastischen SchilddrOsenkar zinom W.-D.Hamperl I ,W ~Kanitz 2 ,J. Kopp 2 ,Ch.Wilmanns ]

PROTECTION OF B O N E M A R R O W - C P ~ L S T H E R A P I E IN V I T R O BY I L O P R O S T ~"

C~r a period of 5 jesurs at the ZK of Augsburg a total thyroid carcinoma. The mean survival time of 14 patients, all with a tumor stage pT4, was only three month. One patient (pT2 NO ~ ) is alive since 4 jeers without recurrence of disease. The case of one further patient is presehnted below. Considering the poor results of st~rgery and consecutive percutaneous radiation we changed our therapeutic procedure into surgical reduction of the tumor and interstitial radiation therapy using 1-125-seeds_ The case of a 67 year-old female patient with an anaplastic thyroid carcinoma (DT4 NO M0) is reported~ who underwent as basis therapy thy~oidectomy and a modified leftside neck-dissectic~. %be patient refused percutaneoua radiation. 2 month later a large recurrence of tumor was diagnosed infiltrating the left carotie artery. Distant metastases were not present. Parts of the tumour have been surgically removed and 67 1-125-seeds (981 MBq) were implanted into the remaining tumour tissue. The radiation dose delivered to the turnout should exceed 160 Gy. The tumor continuously reduced in size and showed no local recurrence during a follow-up ;~riod of 18 month up to sow. Encouraged by this success t ~ more patients underwent interstitial radiation therapy[ 'the cases of these ~atients will also be demonstrated~

W. W a l d m a n n ~

W, Zant,

UNDER

CHEMO-

J. B i e r

Chemotherapie of m a l i g n a n t tumours is l i m i t e d by the s i d e - e f f e c t s of the treatment, e s p e c i a l l y on the h a e m o p o e t i c system. Therefore attempts have b e e n m ~ e to p r o t e c t the b o n e m a r r o w - o e l l s by lloprost under chemotherap.ie in vitro, In the stammeell-assay line i0 tumoureell.s and bonemarrow-cells of s t r a i n 2 guinea-pigs have been treate~ with differend eytotoxic d r u g s and I l o p r o s t . So far the e f f e c t of the eytotoxie drugs on Rthe tumourscells war increased by l l o p r o s t wereas the d r u g t o x i c i t y o n the b o n e m a r r o w - e e l l s war r e d u c e d . A b t e i l u n g Zahn-~ M u n d - , K i e f e r - u n d P l a s t i s c h e Gesichtsehirurgie der Medizinischen Fakult[t der Rheinisch-Westf[lischen Technischen Hochschule A a c h e n Vorstand: o. Prof. Dr. med, Dr. med. dent, Wolfgang Koberg~ Pauwelsstr, o.Nr.~ D 5100 Aachen

I ) IZ~Chirurgisehe Klinik ,Krankenhauszweckverband Augsburg, StenglinstraBe, 8900 Augsburg. 2) Institut fiir Nuklearmedizin, Krankenhauszweckverband Augsburg, StenglinstraBe, 8900 Augsburg.

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DIAGNOSTIC PROCEDURE BEFOR~ REOPERATION IN PATIENTS WITH MEDULLARY THYROID CARCINOMA (MTC) F. Raue z K. Frank, D. Lorenz~ Ch. Herfarth, R. Zieoler

Tumor patients and hemodialysis

Elevated csloitonin (CT) levels ~f~ar primary operation are a reliable marker for persistence, recurrence or metastases of MTC~ The main sites for relaps of MTC are the neck and mediastine! region. The value of different lees ~ lisation methods in compacison before reoperstion and the outcome of these patients has been proven. Patients and methods: 45 of our 6~ patients with MTC had elevated CT levels in the fellow up. They were examined every 6 months by ultresonegraphie (US) of ~he neck (2!3 exam,)~ every year by CAT scan of neck and mediastinum (!42 exam.). Some had a selective venous cazheterisa%ion (SVC) wi~h CT determination (47 exam.) and a fine needle biopsy(32 exam,). 28 patients ware than reopereted 4S times. Results: Table - Histological conformation of suspected relapses localized by diffsk'en% methods. Method No.exam. % of pos findings

PALP 48 60

US 33 7S

CAT 32-72

SVC 29 62

FN8 20 85

The five year survival rate in patients with elevated CT levels improved in reopsrstsd pa~, (86Z) compared to pat. (n= $s without rsin~ervention (68%). Conclusion: For precise preoperative staging ultrasonooraphy is the most predictable and reliable method. The prognosis of MTC patients with elevated CT levels in the follow up could be improved by reoperatiom. Medizinische Universit~tsklinik, Bergheimerstr. 58, 6900 Heidelberg

H.-P. Brodersen, F,W. Korsten, Dr, Larbig, H.E. Reis The indication of cytatoxic therapy for patients on chronic hemodialysis or dialysis treatment for oncological patients is a matter of debate. There is a urgent demand for data concerning pharmacokinetics of cytotoxie compounds and/or experience with tumor patients on chronic hemodialysis. O~4r experience with i0 patients - 3 women and 5 men with a median age of 65 years at the time of tumor diagnosis is reported. The patients suffered from the following malignanaiea: plasmocytoma (5)~ breast cancer (2), carcinoma of the lung (2) and hypernephroma (i). Tumordiagnosis was achieved before onset of renal failure in 3 cases, at the same time as the development of renal failure in 5 patlents~ following the start of dialysis therapy in 2 cases. 1 tumor patient had no cytotoxic or radiation therapy~ 2 reeieved palliative radiation, 7 were treated with cytotoxic agents, 2 of these recieved additional s~rgical and 4 radiation therapy. 1 patient with a plasmecytoma had reversible acute renal failure. 9 patients died with a median of 8 (1-57) months after the day of tumor diagnosis. 1 patient Iives 9 months after the diagnosis of plasmocytoma~ Conclusions: In patients on chronic intermittent hemodialysis a newly diagnosed tumor has to be treated according to the guidelines of oncological therapy~ When there ist preexisting malignancy acute or chronic renal failure has to be treated adequately - even by hemodialysis - if tumor therapy can be expected to be sucessfull. There is a lack of data on pharmaookinetics of cytotoxie compounds in different stages of renal failure and hemodialysis~ Therefore at the present time dusts reduction of the cytotoxic agents and/or prolongation of application intervals have to be recommended in the first weeks of therapy, Under observation the therapy has to be adjusted. Dr. med. Hans-Peter Brodersen, Medizinische Klinik, Krhs. Maria Hill GmbH, D-4050 M~ncheng]adbach, BRD

S 162

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PRENEOPLASIA OF MESOTHELIUM,INDUCED BY MINERAL FIBRES EXPERIMENTAL RESULTS IN ANIMALS O. Friemann, F. Port, B. Voss, S. Gonzsl~s, K,-M.-M~Iler

E F F I C A C Y OF NEW C I S P L A [ I N - L I N K E D 8 1 S P H O S P H O N A T E S IN I R A N S P L A N T A B L E RAT O S T E O S A R C O M A . T. Klennerl, H. M~neh2~ F. W i n g e n l , D. S c h m ~ h l I, B. Ke_e_Bpler2 .

The intraperitoneal test has proven to be an appropriate method controllinq fibrogenicity and canceroqenicity of asbestos fibres and fibrous asbestos substihutes. I.p. injection of for instance 2 mq of crocidolite asbestos into rats abdominal cavity results in development of malignant tumors in 87,5%.According to recant results the malignant transformstion of connective tissue and mesothelial ceils are likely to be taken as a basis for these tumors. Therefore our experiments aimed for the presen= ration of changes in extrscellular matrix molecules in foreign body granulomas of rat omentum after i.p. injection of UICC-chrysotile and crocidolite asbestos.Moreover we analyzed the early reaction types of mesothelial cover Isyer to asbestos fibres and fibrous asbestos substitutes For our immunofluorescence microscopical investigations ~e used antibodies against collagen type I/III,laminin and fibronectin.ln grenulomas induced by l, 5 and 15 mg of chrysotile end crocidolite the extraeellulsr matrix molecules sho~ed distinct reaction patterns within a period clown to 6 months.Moreover ell asbestos dusts(crocidolite, chrysotile,setinolite) and asbestos substitutes(glass fibres,aremid) at different concentrations led to a multiserial ,papillomatous end partly atypical proliferation of rat omentum mesothelium accompanied by submesothelial fibrosis.Proliferation end submesothelial fibrosis,both are not observed after application of particle-shaped dusts as mine dust and quartz. The results document the complex pattern of fiber induced injuries concerning the interaction of subserous mesenchyme and mesothelial cells before formation of malignant mesotheliomas.

A new class of a n t i n e o p l a s t i c agents with carc i n o s t a t i c and o s t s o t r o p i c p r o p e r t i e s has been s y n t h e s i z e d . The a n t i t u m o r p o t e n t i a l was i n v e s t i gated in the t r a n s p l a n t a b l e o s t e o s a r c o m a of the rat. This tumor model is c h a r a c t e r i z e d by osteoid f o r m a t i o n and s p o n t a n e o u s m e t a s t a s i s to lungs, kidneys, and l y m p h n o d e s . To 1 5 - d a y - o l d SD rats the o s t e o s a r c o m a was transp l a n t e d i n t r a t i b i a l l y . S t a r t i n g from day 21 after t r a n s p l a n t a t i o n t h e r a p y of t u m o r - b e a r i n g a n i m a l s mas started. The c o m p o u n d s were d i s s o l v e d in 0.9 ~ saline and i n j e c t e d i n t r a v e n o u s l y t~ice a ~eek over 5 ~eeks. Tumor volume and b o d y ~ e i g h t ~ere recorded. T h e r a p e u t i c efficancy was e v a l u a t ed in terms of i n h i b i t i o n of tumor volume in c o m p a r i s o n to c o n t r o l s (T/C Z). On day 52 after t r a n s p l a n t a t i o n the f o l l o w i n g T/C values ~ere c a l c u l a t e d : 2.9 mg/kg of DMP, c i s - [ D i a m m i n o (methyleminomethandiphosphonato)platinum(II~ , 54 ~; 5.8 m g / k g of DCP, e i s - [ D i a m m i n o ( d i c h l o r methandiphosphonato)platinum(II~ , 52 ~; 2.6 mg/ kg of ADP, c i s - [ ( A m i n o t r i s ( m e t h y l e n p h o s p h o n a t o ) ) diamminoplatinum(II~ , 50 %; 2.6 mg/kg of DBP, cis_[Diammino(bis(methylenephosphonato))diemminop l s t i n u m ( I I ) ] , 56 %. C o n c l u s i o n : This new class of c o m p o u n d s gives the chance of a more s e l e c t ive t r e a t m e n t of o s t e o g e n i c m a l i g n a n c i e s .

Institut f~r Pathologic der Berufsgenossenschaftlichen Krankenanstalten"Bergmannsheil"-Universit~tsklinikGilsingstr. 14,D-4630 B0chum i

l) Institut for T o x i k o l o g i e und C h e m o t h e r a p i e am D e u t s c h e n K r e b s f o r s c h u n g s z e n t r u m ~ Im Nauenheimer Feld 280, D - 6 9 0 0 H e i d e l b e r g . 2) A n o r g a n i s c h - C h e m i s c h e s Institut der U n i v e r sit~t H e i d e l b e r g , Im N e u e n h e i m e r Feld 270, D6900 H e i d e l b e r g .

5/P-GM 023

5/P-GM025

USE OF CLODRONATE (CI ~MDP) FOR TREATMENT OF HYPERCALCEMIA IN MALIGNANT DISEASE S.H~ Scharla, H.w. Minne~ H. S c h m i d t - G ~ ~ Zieqler

Introduction: Hypercalcemi a caused by malignant diseases is relatively common. The therapy of this ectopic hormonal syndrome caused by cancer is not satisfactory. Diphosphonates such as clodronate inhibit osteoclast activity and seem to be effective in hypercalcemia of malignancy. Patients: We studied consecutively 34 patients with hypercalcemia caused by d i f f e r e n t tumours (in most cases breast or lung cancer). At first the patients received clodronate (300 mg/day, intravenously) as single therapy. After normalization of serum calcium concentration, clodronate was administered o r a l l y (0.4-3.2 g/day), the dose being adjusted according t o serum calcium levels. In addition, in 21 patients the effect of clodronate on serum concentrations of 1-84 PTH and I,~(OH)~D~ was evaluated, Results: Inltravenoua clOdfonate decrea~ea serum calcium concentration from 3.30+0.41 mmol/l to 2.44+-0.33 mmol/! within one week. In 8 patients a s l i g h t asymptomatic hypocalcemia occurred. D u r i n g oral therapy there was a renewed slight rise oT calcium concentration (2.72_+0.45mmol/l). In most patients, clodronate therapy caused an increase of 1-84 PTH and 1,25(OH)2D~ serum levels. Severe side effects did not Occur. Conclusion.'_ Intravenous clodronate is very effective in hypercalcemia of cancer, O r a l administration of clodronate is able to keep the majority of patients normocalcemi c. Department of Internal Medicine I (Endocrinology and Metabol iam), Uni versi ty of Hei del berg, Bergheimerstrs[~e 58~ 6900 Heidelberg~ West Germany

E F F E C T S OF T E T R A C H L O R O D E C A O X I D E IN A M E T A S T A S I Z I N G L Y M P H O S A R C O M A OF T H E S Y R I A N G O L D E N H A M S T E R

R.Bartkowski, B.Osterloh, a n d A. Schafmayer

E.Schwahn,

H.L~hrke

We have e s t a b l i s h e d a m e t a s t a s i z i n g l y m p h o s a r c o m a model, w h i c h d l s p l a y s a h i g h and constant i n c i d e n c e of m e t a s t a s e s in the liveD, lungs, k i d n e y s , s p l e e n and lymph nodes. The e f f e c t s of Tetrachlorodecaoslde (TCDO) a f t e r s u b c u t a n e o u s and i n t r a v e n o u s t u m o r cell t r a n s p l a n t a t i o n were s t u d i e d . 92 a n i m a l s were g i v e n daily i n t r a p e r i toneal i n j e c t i o n s of TCDO (10 ~g/kg bwt) or NaCI 0,9 % only. After subcutaneous tumor transplantation and t r e a t m e n t with T C D O we o b s e r v e d a p r o l o n g a t i o n of the m e d i a n s u r v i v a l t i m e to 122 days as opp o s e d to 65 days in the c o n t r o l group. A rare m e t a s t a t i c i n v o l v e m e n t of the liver, the kidneys a n d the p e r i t o n e a l lymph n o d e s was s h o w n w h e r e a s the i p e i l a t e r a l a x i l l a r y lymph node s i t e s w e r e m o r e f r e q u e n t l y involved. After intravenous tumor transplantation we f o u n d no d i f f e r e n c e in s u r v i v a l time and metastatic i n v o l v e m e n t of liver, lungs, k i d n e y s and lymph nodes. An a s c i t e s was more f r e q u e n t in the c o n t r o l group. F r o m o u r f i n d i n g s we c o n c l u d e , t h a t the dis t i n c t p r o l o n g a t i o n of s u r v i v a l time a f t e r t r e a t m e n t w i t h TCDO is p r o b a b l y due to d i s t a n t m e t a s t a s i s w h i c h is d e l a y e d and has a c h a n g e d s p e c t r u m . The m e c h a n i s m of a c t i o n of TCDO is still u n c l e a r . A s t i m u l a t i o n of m a c r o p h e g e s by TCDO l e a d i n g to i n c r e a s e d p h a g o c y t o s i s a c t i v i t y was shown by P o l n d r o n (1986). A c o r r e s p o n d i n g m e c h a n i s m w o u l d be a s u i t a b l e e x p l a n a t i o n for the f i n d i n g s p r e s e n t e d . Chlrurgische Unlversit~tskllnlk GOttingen Robert-Koch-Strafe 40, D-3400 G~ttingen

S 163 5/P-GM 026

5/P-GM 028

Toxicity of Azidothymidine and Two Additional 2"-3"-Dideoxynucleoside Analogues on the in vitro Colony formation of Hemopoietic Progenitor Cells

AN ANTITUMORACTIVE, IMMUNOMODULATING 8-I.3/I.6-GLUCAN FROM PHYTOPHTHORAPARASlTICA J. Kraus, W. Blaschek and G. Franz

JOrgen Greher, Arnold Ganser, Bernd V61kers, Schlomo Staszewski and Dieter Hoelzer Department of Hematology, University of Frankfurt, Frankfurt/M, Federal Republik of Germany Therapy of patients with the aquired immunodeficiency syndrome (AIDS) or AIDS related complex (ARC) with azidothymidine (AZT) is complicated by severe anemia and neutropenia. We therefore tested the effect of AZT and two additional 2"-3"-dideoxynucleoside analogues, 2"-3"-dideoxycytidine (DDC) and 2"-3"-dideoxyadenosine (DDA), on the in vitro colony formation of hemopoietic progenitor cells derived from the bone marrow of normal persons and patients with AIDS/ARC. All three substances exerted a dose-dependent inhibition of the in vitro colony formation of the pluripotent progenitor cells (CFU-GEM), as well as the erythroid (BFU-E) and the granulocyte-macrophage progenitor cells (CFU-GM). With AZT the 50% inhibition for normal progenitors was reached for CFU-GEM at 0.1 pM, for BFU-E at 0.2 pM and for CFU-GM at 13 pM, while with DDA the respective values were 14 pM for CFU-GEM, 46 pM for BFU-E and 170 pM for CFU-GM. DDC was the most toxic agent tested. Comparing in vitro hematotoxicity to the concentrations necessary to inhibit the cytopathic effect of the human immunodefficiency virus (HIV) DDA was the agent with the least hematotoxicity as compared to AZT and DDC. This data suggest that DDA may have less hematologic side effects than both AZT and DDC. Supported by grant FKZ II-009-86 from the Bundesgesundheitsamt (AIDS Research)

Various polysaccharides are known to e x h i b i t an antitumor a c t i v i t y , which is thought to be mediated by the host's immune system (G. Chihara, EOS Riv. Immunol. Immunofarmacol. 2, 1984, 85). From the fungus Phytophthora p a r a s i t i c a a watersoluble glucan with a pronounced a c t i v i t y against experimental tumors could be i s o l a t e d . According to structural analysis the 200 000 d - f r a c t i o n of the glucan is composed of a 8-1.3-1inked glucose backbone. Every t h i r d glucose residue is branched via C-6. The side chains mainly consist of 8-I .3-1inked diand trisaccharides (M. Bruneteau et a l . : Carbohydr. Res., in press). The antitumor activity of this glucan against Sarcoma-180 in CD-I mice is dose dependent with an optimum a c t i v i t y at I0 x 1 mg/kg. A pretreatment is as well e f f e c t i v e as treatment a f t e r tumor inoculation. The glucan showed no d i r e c t c y t o t o x i c effects against Sarcoma-180 c e l l s in v i t r o i n d i c a t i n g an i n d i r e c t mode of action. A simultaneous treatment with ciclosporin-A i n h i b i t e d the antitumor effect completely due to a suppression of T-cell a c t i v a t i o n . The immunmodulating properties of the glucan were investigated in v i t r o . In the MLR- and mitogenicity test the glucan markedly augmented the p r o l i f e r a t i o n of lymphocytes. I t also induced TNF-production in cultured macrophages and enhanced macrophage c y t o t o x i c i t y against P 815 tumor c e l l s . These results c l e a r l y show, that the Phytophthora glucan may be a usefull immunomodulating and antitumoractive agent for an adjuvant cancer therapy. Department of Pharmacy, D-8400 Regensburg, F.R.G.

University

of

Regensburg,

5/P-GM 027

5/P-GM 029

ANDROGEN-LINKED NITROSOUREAS: DIFFERENCE BETWEEN IN VIVO AND IN VITRO ANTINEOPLASTIC ACTIVITY. M. Beth, M. R. Berber, ]. Floride, M. Kaufmann and E. Petru The antineoplastic activity of 1-(2-chloroethyl)-l-nitroso- car~ bamoyl-L-alanine-dihydrotestosterone- 17-ester ( C N C - a l a DHT; I) was compared in vitro to its unlinked single agents CNC-ala + DHT (II) and CNC-ala (III) in methylnitrosourea-induced rat mammary carcinoma and - in vitro only - in human mammary carcinomas. In vivo treatment of mammary carcinoma bearing rats with four i.p. injections of 75 #mol/kg administered within five weeks revealed the following results in terms of T/C % and % mortality: h 33, 0; Ih 69, 40; HI: 39, 30. In vitro investigation with the bilayer soft agar clonogenic assay (1 h drug exposure, 7 days of incubation, dose range of 1-100 ~mol/L) gave the following inhibition of colony formation (less than 70% of control) in rat (a) and human (b) mammary carcinoma cells: Ia: 54%, Ib: 71%. Ha: 56%, IIb: 67%. IIIa: 60%, IIIb: 100%. These data show, that the superiority of I in vivo was not reflected by in vitro results. Future experiments will concentrate on the in vitro assay's ability to evaluate the activity of receptor affine agents and the cause of the low toxicity of I in vivo. Institute of Toxicology and Chemotherapy, German Cancer Research Center, Im Neuenheimer Feld 280, D-6900 Heidelberg.

ANDROGEN-LINKED NITROSOUREAS: ANTICANCER EFFICACY IN METHYLNITROSOUREA (MNU)-INDUCED RAT MAMMARY CARCINOMA H.P. Brix, M.R. Berger, J. Fischer, G. Eisenbrand, D. Schm~hl The therapeutic efficacy of linking 2-chloroethylnitrosocarbamoyl (CNC) to three androgens (testosterone (T), nortestosterone (NT), dihydrotestosterone (DHT)) via three amino acid spacers (glycine (gly), methionine (meth), sareosine (sare)) was investigated in hormone-dependent MNU-induced autoehthonous rat mammary carcinoma. The agents displaying relative binding affinities (RBA) of 0.2-1.8% and 1-4.5% to the progesterone and androgen receptor, respectively, were administered i.p. each to groups of ten rats at log-spaced dosages at weeks i, 2, 4 and 5 after a tumor volume of 0.8 em 3 per animal had been reached. The following treatment results of optimal dosages were observed in terms of T/C%, tumor number and mortality at week 6: CNC-gly-T (54 pmol/kg): 15-5-0; CNCgly-NT (54 ~mol/kg): 50-7-0; CNC-gly-DH~ (105 Nmol/kg): 17-2-0; CNCmeth-DHT (54 pmol/kg): 19-5-0; CNC-sarc-DHT (38 pmol/kg): 42-5-80; control: 100-10-60. With respect to the hormonal carrier, the NT derivative of CNC-gly was distinctly less active than its T and DHT congeners. The latter two agents showed equivalent anticaneer activity, but CNC-gly-DHT displayed a higher therapeutic ratio. The importance of the amino acid spacer becomes obvious when comparing the sarc derivative which was the most toxic and least active agent with its gly and meth congeners which were equally active. Future studies will concentrate on the improvement of therapeutic activity by varying the spacer in its molecular form to obtain higher RBA. Institute of Toxicology and Chemotherapy, German Cancer Research Center, D-6900 Heidelberg

S 164

5/P-GM030

5/P-GM032

THE IN-VITRO CYTOTOXICITY OF PANCRATISTATIN AND MERBARONE ON HUMAN TUMOR XENOGRAFTS. B . W i n t e r h a l t e r r H.H.Fiebiqt C.Scholz t G.W. L~hr

APPLICATION OF THE CLONOGENIC ASSAY AS BIOASSAY FOR PHARMACOKINETIC STUDIES. B. Hennemann, H.H. Fiebig, B. Winterhalter, G. W. Lahr

Pancratistatin (NSC 349174, PAN) and Merbarone (NSC 336628, MB) are two novel compounds which have emerged from the NCI screening-programm. We studied the in-vitro cytotoxicity of PAN and MB on human bone-marrows (HBM, CFU-C), P 388 murine leukemia and on human tumors propagated as xenografts in nude mice. The evaluation was performed by the clonogenic assay using a modification of the method described by Hamburger and Salmon. Effectivity was defined as a >70 % reduction of colonies as compared to controls. PAN was effective at 0.01 ~g/ml in 2/2 HBM (T/C 6 and 20 %) and in 18/24 xenografts, namely in carcinomas of the breast 2/3, colon I/3, lung 7/8, pancreas 2/2, stomach 3/4 and in melanomas 2/2. However, at the dose of 0.003 Ng/ml activity was only observed in 3/20 human tumors; carcinomas of the lung 2/5 and pancreas I/2 without an effect on HBM. MH was active at 3 ~g/ml in 2/2 HBM (T/C 2 and 20 %) and in 5/22 tumors, namely in carcinomas of the lung 3/7, pancreas I/2 and stomach I/4. At the dosage of I Ng/ml it was only active in 2/24 tumors; in 1/3 small cell cancer of the lung and I/2 pancreas carcinomas w i t h o u t any effects on 3/3 HBM and P 388. In conclusion, PAN and MB demonstrated a steep dose-response effect and a tumorspecific cytotoxicity compared to HBM on some tumortypes. To confirm these in-vitro results, we propose to test PAN and MB in-vivo in s.c. growing tumors using those tumors most sensitive in-vitro.

Physical or chemical methods are suitable for examining the pharmacokinetics of anticancer drugs. However, they do not reveal information about the biological activity of metabolites. Using the colony-assay in a m o d i f i c a t i o n of Hamburger and Salmon we were able to measure biologically active serum concentrations performing the assay with a well established human large cell carcinoma of the lung propagated in nude mice. The serum of 6 white New Zealand rabbits was tested after a single i.v. b o l u s - i n j e c t i o n of 12.5 mg/m 2 cisplatinum. We compared the inhibition of colony formation after continuous incubation using serum of the same animal taken before drug administration containing standardized drug concentrations with sera samples taken after drug application. The mean serum levels measured were 0.096 pg/ml after 5 minutes, 0.045 ~g/ml after 15 minutes, 0.019 ~g/ml after 30 minutes and 0.0075 ~g/ml 60 minutes after drug injection. After 120 minutes no more inhibition by the serum could be seen. This corresponded to a mean d i s t r i b u t i o n halflife period of 25.07 minutes, which is comparable to data obtained by chemical methods. Therefore, the colony-assay represents a valuable bioassay to estimate the decrease of the biological activity after drug administration as well as a method to obtain first pharmacological data about new anticancer drugs, when physical or biochemical tests are not available.

Med.Univ.Klinik, Abt. H~matologie und Onkologie, Hugstetterstr.55, D-7800 Freiburg im Breisgau.

Med.Univ.Klinik,

5/P-GM031

5/P-GM033

IN VITRO AND IN VIVO DIAMIDINES. D.P. Berger, H.H. Fiebig, O. Dann I G.W. L~hr

STUDIES

WITH

TWELVE

B.a. Winterhalter,

Synthetic diamidines (DMD) show marked affinity to nucleic acids and demonstrated antitumor activity against P388 in vivo. We have conducted in vitro and in vivo studies w i t h twelve derivatives of 4 ' - 6 - D i a m i d i n o - 2 - p h e n y l i n d o l to determine potential tumorspecific activity. Employing a modified Hamburger & Salmon clonogenic assay, the in vitro cytotoxicity of twelve DMD on two human bone marrows (HBM,CFU-C), P388 and on 8 human tumor xenografts was studied. Efficacy was defined as a > 70% reduction of colonies as compared to controls. In the investigated range of 0.1 to 100 pg/ml (continuous exposure) a clear dose-response relationship was found. Overall, five DMD showed tumorspecific colony inhibition at dose levels non-toxic to HBM (310 pg/ml). P388, carcinomas of the breast I/I, lung 1/2, pancreas 1/I and I/2 renal tumors were sensitive to DMD. We tested the active compounds, NSC240892, NCS240898, NSC341082, NSC313689 and NSC377363 in vivo in athymic nude mice using the two in vitro most sensitive tumors. At toxic dosages around the LD50, no drug achieved tumor inhibition compared to the untreated control group. In conclusion, despite the promising in vitro cytotoxicity, there was no in vivo activity of the investigated DMD against the tumors studied, suggesting that the HBM is not the d o s e - l i m i t i n g organ in vivo. However, the approach of combined in vitro and in vivo testing comprises a valuable tool in the development of new a n t i c a n c e r drugs. Med.Univ.Klinik,

Hugstetterstr.

55,D-78 Freiburg

A

Hugstetterstr.55,

D-78 Freiburg

D E T E R M I N A T I O N OF CELLULAR DAUNOMYCIN-UPTAKE BY HUMAN LEUKAEMIC BLASTS I N V I T R O AND IN V I V O W. K. R e i c h a n d M. E . S c h e u l e n The d e t e r m i n a t i o n O~ c e l l u l a r tumor pharmacokinetics mnd m e t a b o l i s m (CTPKM) o f c y t o s t a t i c s may be o s g r e a t value for the determination of individual drug sensitivity and f o r the optimization of the treatment schedule. In the clinic, CTPKM can only be measured in peripheral leukaemic blasts (PL8) without major discomfort for the patients. We have developed a method for the iso].atJ.on of PLB w i t h subsequent extraction Of daunomycin (DNM) and quantitative analysis by HPLC with fluorescence detection (Scheulen et al., 1987). Up t o n o w , CTPKM w a s s t u d i e d i n 30 patients with acute myelogenous leukaemia (AML), either after exposure to 0.02-8.0 pg/ml DNM

in vitro or after induction therapy with S-thioguanine. cytosine arabinoside and DNM (TAD) (86cheer e t a ] , I g 8 5 ) A great interindividual variation Of the maximal DNM-concentrations in PLB b e t w e e n 4 . 0 a n d 2 3 . 1 N g / m l and i n the areas under the curve during the first two hours between 6.8 a n d 3 0 . 7 Ng h / m l w a s f o u n d .

There was no statistically sJgnigicant correlation between in vit~o- and in vivo-pharmacokinetic parameters, nor did they predictively correspond with t h e o u t c o m e O f TAD t h e r a p y . Thus, CTPKN of DNM in PLB may only be exploitable for the intraindividual comparison os different treatment schedules. Differences in DNM-sensitivity in various AMLs may be mere critically influenced by other factors than CTPKM of DNM in the

clinic.

(Supported

by

DFG:

SFB

102.)

Innere Universit~tsklinik und PoliklinJk (Tumorforschung), Westdeutsches Tumorzentrum. Hufelandstr. 55. D-&300 Essen I

S 165

5/P-GM034

5/P-GM 036

P R O P H Y L A C T I C T R E A T M E N T OF SKELETAL METASTASES TUMOR INDUCED OSTEOLYSIS AND H Y P E R C A L C E M I A IN RATS W I T H THE B I S P H O S P H O N A T E CI2MDP . B.Kremp~is~n~J.Schloen,L_.~9~.i ~ and C . M a n e q g , l d

SYNTHESIS AND THERAPEUTIC EFFECT OF NEW CISPLATINUM COMPLEXES ON EXPERIMENTAL TUMORS R.Voegeli, 3.Pohl~ P.Hilgard, 3.Engel, W.Schumacher H.Brunner~ M.Schmidt , U.Holzinger, H.SchSnenberger

The effect of a p r o p h y l a c t i c treatment with the b i s p h o s p h o n a t e CI2MDP (Clodronat) on bone metas t a s e s , o s t e o l y s i s and h y p e r c a l c e m i a was studied in an animal model (Krempien et al.,Dtsch,Ges. Path. 68,211,1984). 2oo g m a l e W i s t a r rats were treated w i t h CI2MDP for 5 days (3omg/kg bw/d). 7, 3 and I w e e k later IO I~ cells of the hypercalcemic Walker CS 256 w e r e transplanted (i.a.,s.e., i n t r a o s s e o u s ) . A n i m a l s were sacrificed after io days, serum Ca ++ was measured, the skeleton radiographed and studied histologically. Results: P r e t r e a t m e n t with CI2MDP, even w h e n given 7 weeks prior to tumor transplantation, was followed by a significant decrease of skeletal m e t a s t a s e s (Co 44,CI2MDP 2 0 % ) , o s t e o l y t i c bone destruction (severe lesions Co 33,CI2MDP O Z) and h y p e r c a l c e m i a (Co 18.5,CI2MDP 12.1 mg%). Tumor growth was not affected excluding a cytostatic effect of CI2MDP. However, formation and function of osteoclasts was impaired leading to skeletal r e s i s t a n c e against formation and p r o g r e s s i o n of skeletal m e t a s t a s e s , t u m o r o s t e o p a t h y and severe hypercalcemia. Our experimental studies dem o n s t r a t e that p r o p h y l a c t i c t r e a t m e n t is effective in the p r e v e n t i o n of skeletal metastases, tumor induced o s t e o l y t i c bone d e s t r u c t i o n and severe hypercalcemia. P a t h o l c g i s c h e s Institut der U n i v e r s i t [ t H e i d e l berg, Im Neuenheimer Feld 220,D-69OO Heidelberg.

__

Substituted benzylethylenediamines were synthesized from phenylalanine derivatives by known methods. After conversion of the amino acids to their methylesters the amides were prepared by reaction with ammonia. Reduction of the carbonyl group with LiAIH4 gave the diamines which were used as ligands for the eis-dichloro-(benzylethylenediamine)platinum(II)complexes. These complexes were found to be effective against a number of experimental tumors of rats and miee~ without being nephrotoxic as determined by measurement of blood urea nitrogen (BUN). The maximum increase in life span (1LS) of mice inoculated with the leukemia P388 a f t e r treatment i . p . with

D 17 872 (R= 4-CI, 152% at 215 mg/kg) ahd D 17 871 (R= H, 156% at 32 ms/ks) exceeded that o b t a i n i b l e with eDDP (55~ at 5.2 mg/kg). Response to treatment i.p. with D 17.872 of the LI210 leukemia (45Z ILS at:147 mg/kg) was d6mparsble to that to eDDP (58Z IL5 at ~.2 mg/kg) whereas D 17 871 was oat effective in this model.

Treatment of the BI6 melanoma with repeated doses of D 17 872 (6*6.8 mg/kg i.p.) resulted in a decrease of tumor mass of 49% (cDDP 9"1 ms/ks: 64Z). LDSO of D 17 872 was 460Vmg/kg and of D 17 871 70 mg/kg (cDDP 10 mg/kg). Further study of compounds of this class will hopefully lead to substances with good efficacy and low toxicity for the use in the treatment of humsn malignant disorders. ASTA Phsrma AG, WeismOllerstr.45, D-6000 Frankfurt 1 Fakult~t IV -Chemic u. Pharmazie- der Universit~t Regensburg: Universit~tsstr. 51~ D-8400 Regensburg

5/P-GM 035

5/P-GM 037

A N E W IN V I T R O

TERMINALDIFFERENTIATIONANDGROWTHINHIBITIONIN A RATF ~ , f f O SARCg4ACELLLINE AFTEREXPOSURETOALL-TR~S RETINOICACID IN VITRO. H.Gabbert, C.D.Gerharz, R.Engers, K.Biesalsk!, C.Luley

S C R E E N I N G S Y S T E M FOR A N T I C A N C E R DRUGS FOR THE T R E A T M E N T OF N O N - S M A L L C E L L LUNG CANCER. H a n a u s k e U, H a n a u s k e A-R, Clark G M, Tsen D, B u c h o k J, Von Hoff D D ....

We h a v e e v a l u a t e d a s e m i a u t o m a t e d r a d i o m e t r i c assay (BACTEC 460 system) for s c r e e n i n g of a c t i v i t y of a n t i c a n c e r drugs against h u m a n nonsmall cell lung c a n c e r cell lines. Cells from seven cell lines w e r e e x p o s e d to s t a n d a r d antin e o p l a s t i c agents at 4 d i f f e r e n t c o n c e n t r a t i o n s u s i n g a o n e - h o u r i n c u b a t i o n schedule. A l p h a ~ i n t e r f e r o n was tested u s i n g a c o n t i n u o u s inCub a t i o n since e a r l i e r experiments had indicated g r e a t e r a c t i v i t y under these conditions. M a x i m a l daily increases in m e t a b o l i c a c t i v i t y as determ i n e d by [ C]O_ r e l e a s e w e r e o b s e r v e d after 9 days of incubation. In v i t r o drug activity was a n a l y z e d in relation to c l i n i c a l l y a c h i e v a b l e serum concentrations. U n l i k e e a r l i e r observations w i t h colon cancer cell lines, the ratio of IC90 over 0.I x peak plasma drug c o n c e n t r a t i o n was not useful for c o r r e l a t i n g in v i t r o and in v i v o results. A c c e p t a b l e c o r r e l a t i o n s w e r e found u s i n g the p e a k plasma c o n c e n t r a t i o n alone. Our results indicate that 3 cell lines (CALU-3, SK -MES-I, SE-LU-I) exhibit in v i t r o drug s e n s i t i v ity p a t t e r n s closest to those o b s e r v e d in clinical studies. These 3 cell lines m i g h t be u s e f u l for s c r e e n i n g new a n t i c a n c e r compounds for act i v i t y in non-small cell lung cancer. The radiom e t r i c assay as a s e m i a u t o m a t e d s y s t e m has adv a n t a g e s o v e r other, m o r e t i m e - c o n s u m i n g s c r e e n i n g systems. U n i v Texas H e a l t h Sci Centr at San Antonio, Dep. M e d i c i n e / O n c o l o g y ; Med. H o c h s c h u l e Hannover, Dep. Innere Med. u. Dermatologie, Abt. H a e m a t o l o g i e u. H a u t k l i n i k Linden. S u p p o r t e d by a grant from J o h n s t o n L a b o r a t o r i e s and DFG grant 1347/1-1.

Malignant tmDrs are consideredto possess intrinsic defects in triggering terminal differentiation. However,successful attempts to induce differentiation in vitro have shownthat these defects are not irreversible in all tw~or cells. A very potent substanceto irr du~-edifferentiation is retinoic acid (RA), which has been especially tested in leuce~as, teratoearcinoamsand melanomas. In contrast, investigations on s ~ are very sparse. W~report here on the effects of RAon a clonal rat rhabdcmyosancomacell lira which closely imitates the normal embryogenesisof striated muscle and which is characterized by the coexistenceof proliferating mononuclear cells and terminally differentiated postmitotic myotube-like giant cells. It could be shown, that RAwas able to induce differentiation in about 30%of all tumor cells and to inhibit growth in a time am/ dose dependentmanner. The t~nor cells weremoreregularly arranged than undernomTBlconditions, exhibiting signs of contact inhibitia~. The mononuclearcells revealedbundlesof ne~ly formedthick and thin myofilaments, neverobservedin untreated cultures. In addition, there was a statistically significant increase (p=O.GCOl)of the ntmberof postmitotic myotube-likegiant cells and of the creatinkinase activity (p < 0.05) as a bioe~ical differentiation marker. At the sametime tumor growthwas significantly inhibited (p <0.001) and a decreasein the plating ~iciency ~ observed. Saturati~ density was reducedfrom 6.4 x lO cells/o~ (controls) to 2 x 10 cells/cm~. Our results showthat RAmaybe a potent differentiation inducer in mesench~al tumors, too. However,despite the clonal nature of our cell line, manytumor cells failed to respondto RA. The causes are wlknownat the present time and v~ll be s~ject of further studies. Pathologisches Institut der JohannesGute~g-L~iversit~t, Langenbeckstr. l, D-6500Mainz, FRG

$166 5/P-GMO38

5/P-GM04O

GROWTH INHIBITION OF XENOGRAFTED HUMAN COLON A D E N O C A R C I N O M A S BY TITANOCENE DICHLORIDE P. KOpf-Maier

POTENT CYTOSTATIC EFFECT OF THE MARINE SPONGE PRODUCT AEROPLYSININ-1 ON MOUSE LYMPHOMA CELLS (L5178Y) AND HUMAN COLON CARCINOMA CELLS M.H. Kreuter*, A. Bernd+, B. Diehl-Seifert*, W. MOller-Klieserw A. Maidhof*, N. WeiBmann*, R. B a t e l # , H.C. S c h r ~ d e r * and W.E.Go M O i l e r *

The organometallic titanocene dihalides and related compounds are characterized by antiproliferative properties against numerous experimental tumors. Moreover, they are able to inhibit the growth of some human tumors heterotransplanted to athy~nic mice. In the present study, the antiproliferative properties of titanocene dichloride were investigated against eleven xenografted human adenocarcinomas of the colon. Significant growth inhibition was observed in nine out of the eleven carcinomas, the T/C ratios ranging between 50 and 90 %. Histologic and electron-microscopic studies revealed severe structural lesions within the tumor cells of responding tumors after application of titanocene dichloride. Generally, nuclear changes, especially chromatin condensation and nuclear segmentation, preceded occurring cytoplasmic alterations such as the appearance of bundles of microfilaments and virus particles and the increase in number of lipid droplets, inclusion bodies and lysosomes. Giant cells were formed and numerous necrotic tumor cells were present some days after substance application. These merphologic results confirm the tumor-inhibiting potency of titanocene dichloride against human colon adenocarcinoma and underline the discriminatory power of morphologic studies in the preclinical evaluation of cytostatic drugs against xenografted human tumors.

Aeroplysinin-I <1-(3',5'-dibromo-i',2'-dihydroxy-4'-methoxycyclohexa-3',5'-dien-$'-yl)methylcyanide> is a natural compound isolated from the marine sponges Verongia aerophoba and Verongia cavernicole,--~-~-6~ compound shows pronounced an~umor activity in vitro especially against L5378y mouse lymphome cells (EDSO: 0.47 pM) and human colon carcinoma cells (ED50: 2.96 pM), and a moderate cytostatic activity against normal murine spleen lymphomalign cytes (ED5O: 4.36 - 6.32 pM) and human melanoma cells ( E O 5 0 : 9 . 4 7 pM). Moreover, Aeroplysinin-1 displays also a strong antileukemic activity in vivo using the L5178y cell/NMRI mice system; a - ~ n i s t e r e d at a dose of 50 mg/kg for five days, the T/C (%) value was determined to be 291. The compound is less toxic (LDSO, acute: 249 m9/kg; LDSO, subacute: 177 mg/k9) and is neither a direct mutsgen nor a premutagen in the umu/Salmonella typhimurium test system. *Institut for Physiologische Chemie der Universit~t Mainz, Duesberweg 6, D-6500 Mainz; +Zentrum der Dermatologie der Universit~t 7, D-600O Frankfurt, Theodor-Stern-Kai Frankfurt; w Institut der Universit~t Mainz, Duesbergweg 6, 0-6500 Mainz; #Institut Ruder Boscovic, Center for Marine Research, 52210 Rovinj, Yugoslavia

Institut fHr Anatomie, Freie Universit~t Berlin, K~nigin-Luise-StraBe 15, D-I000 Berlin 33

5/P-GMO39

5/P-GMO41

TUO NOVEL EFFECTS OF THE CYTOSTATIC COMPOUND APURINIC ACID: INDUCTION OF INTERFERON-GAMMA IN HUMAN LYMPHOCYTES IN VITRO AND INHIBITION OF REPLICATION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV-1) H.C. S c h r 6 d e r * , P.S. S a r i n + , D. Sun+, R. V o t h w S. Rossolw G. Hessw K . H . M e y e r zum BOschenf e l d e w and W.E.G, M O i l e r *

ANTILEUKEMIC AND ANTI-HUMAN IMMUNODEFICIENCY VIRUS ACTIVITY OF AVAROL AND AVARONE W.E.G. MOiler*, P.S. Sarin+ and H.C. SchrBder*

Apurinic acid (APA) has been shown to inhibit growth of tumor cells both in vitro and in vivo, How it was found t h a t ~ A ~ - : ~ a potent inducer of interferon-gamma in. human lymphecytes in vitro. This effect is caused at APA concentr~'~'(O.05 - 1 pg/ml) which are at least 300-fold lower than those required for inhibition of cell growth. The maximal titer of 50 units/ml was reached at 0.2 pg/ml of APA. Given in combination with phytohemagglutinin A, APA displays a significant synergistic induction ability. APA was also determined to be an effective inhibitor of human immunodeficiency virus (HIV-1) replication in H9 cells. At a concentration of 10 pg/ml, APA causes a 49% inhibition of virus growth; at 20 pg/ml of APA the expression of HIV-1 p17 and p24 gag proteins is inhibited by 60%. The inhibition of HIV gone expression was also demonstrated at the level of mRNA by Northern blot hybridization experiments using HIV-DNA from the 3'orf/LTR region, including the polyadenylation s~e, as a probe. The mechanism of anti-HiV activity of APA is likely on the level of viral reverse transcriptase. *Institut for Physielogische Chemie der Universit~t Mainz, Duesbergweg 6, D-S500 Mainz; +Laboratory of Tumor Cell ~iology, National Cancer Institute, Bethesda, MD 20892, USA; w Medi~ zinische Klinik und Poliklinik der Universit~t Mainz, Naunynweg 1, D-6500 Mainz

.

Avarol and a v a r o n e a r e secondary metabolites from the marine sponge O y s i d e a avara, Both compounds were d e t e r m i n e d (e) ~ moderate antibacterial and a n t i f u n g a l activity, (b) to show s t r o n g a n t i l e u k e m i c activity both in vivo and i n v i t r o (M~ller, N.E.G. e t a1.(198~) Cancer Res. 4 5 , ~ 8 2 2 - 4 8 2 6 ) , (c) t o cause b i p h a sic and d i f f e - r e n t i a l effects on DNA m e t a b o l i s m of human T and B l y m p h o c y t e s ( " T - l y m p h o t r o p i c " effect; HOller, W.E.G. et a1.(1986) Eur. J. Cancer Clin, Oncol. 2 2 , 4 7 3 - 4 7 6 ) , (d) to be neither direct mutagens nor premutagens, (e) to display antimutagenic activity, (f) to show a low toxicity in mice, (g) to cause no impairment of immune responses, (h) to be able to penetrate the blood-brain barrier, (i) to induce interferon-gamma production in vitro and (j) to inhibit replication of h u m a n ~ e f i ciency virus (HIV-1) in H9 cells in vitro, resulting in a cytoprotective e f f e c t , P . S . e t a 1 ~ ( 1 9 8 7 ) J. N a t l . C a n c e r I n s t . 78, 8 6 3 666). On t h e s u b c e l l u l a r level, avarol/avarone interferes with the formation of microtubules and causes an inhibition of superoxide dismutase. In addition, avarol was found to be a compound which modulates posttranscriptionsl processing events of mRNA, resulting in an increase of the degree of complexity of mRNA species in the non-abundant mRNA class. *Institut for Physiologische Chemie der Universit~t Mainz, Duesbergweg 6, D-6500 Mainz, FRG; +Laboratory of Tumor Ceil Biology, National Cancer Institute, Bethesde, MD 20892, USA

S167

5/P-GM 044

5/P-GM 042

ENHANCEMENT OF THE ANTIPROLIFERATIVE EFFECT OF CIS-DIAMMINEDICHLOROPLATINUM(II) AND NITROGEN ~JSTARD BY INHIBITION OF PROTEIN KINASE C 7. Hofmann, W. Doppler, A. Jakob, K. Maly, F. Oberall~ L. Posch, H. Fiebig ~ and H. Grunicke

METABOLISM OF ETHER LIPIDS IN RAJI CELLS

E.A.H. Fleer, C. Dnger and H. Eibl

The ether lysophospholipid l-O-9_qtadecyl-2-O-methylrac-Rlycero-3-~hospho~hollne

(OcMe-GPC)

is known

to

inhibit tumor growth. It Is generally accepted that its slow

metabolism

can

be

neclected

stodles whlch last three days,

in cell

Recently,

culture

however,

we

were able to demonstrate a correlation between the slow metabolism of the compound and its cytotoxlc effect

on

Rail cells. From the results obtained with OcMe-GPC labeled in the polar region of the molecule, we proposed that this metabolism was an important event in the cytotoxic effects of OcMe-GPC on Rail cells. One of the suggested

metabolic products Is l-O-octadecyl-2-O-

methyl-rac-glycerol.

In the present study,

we

report

about the fate of this metabollte.

Alkylating and platinating agents have been shown to cause a series of membrane effects at therapeutic concentrations. It has been investigated whether these membrane lesions can be exploited for chemotherapy by combining alkylating or platinating drugs with inhibitors of membrane bound enzymes of growth factor signal transduction. It is demonstrated that quercetin (3,3' ,4',5,7-pentahydroxyflavone), an inhibitor of protein kinase C, enhances the antiproliferetive activity of cis-damminediehloroplatin(II) and nitrogen-mustard in cell culture. A synergism is also observed if other protein kinase C inhibitors (tamoxifen, staurosporin) are combined with cis-diamminedichloroplatin(II). In all cases the inhibition of protein kinase C correlated with the depression of cellular proliferation by these compounds. First results with nude mice transplanted with large cell lung carcinoma LXFG 529 indicate that the potentiation of cis-diamminedichloroplatinum(II) by nontoxic concentrations of quercetin can also be obtained in vivo. The results suggest that the potentiation of alkylating or platinsting drugs by inhibitors of protein kinase C may be useful in tumor chemotherapy.

Robert-Zoch-StraBe, D-3400 GSttlngen.

Institute for Medical Chemistry and B~ochemistry, University of Innsbruck, Austria and "Department of Internal Medicine, University of Freiburg/Br., West Germany

5/P-GM 043

5/P-GM 045

LASER ACTIVATION OF A PHO]7)Rs VINBLASTINE DERIVATIVE RESTORES SENSITIVI~ IN CHEMORESISTANT ASCITES CEL~ STRAINS G. Nasiulas., K. GrammbitterI, C. Granzow2, M. St6hr3, H. Ponstingl I

C Y T O S T A T I C T R E A T M E N T OF G Y N A E C O L O G I C A L T U M O R S W I T H I L M O F O S I N E IN N U D E M I C E H.A. N e u m a n n I H. T h o r a n d 2, M. R u n g e 2, D. .. J. ..B... . .H.e.r.r.m.a.~.n.3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

M.P.I,

s

Blophysikallsche Chemle, Am Fassberg, D-

3(00 G6ttlngen and Kllniken der Unlverslt~t G6ttingen,

Resistance to drugs o f t e n develops in tumors the% relapse after i n i t i a l regression in response to chemotherapy. The underlying mechanisms are not well understood. We reasoned that covalent bonds betweendrug and cellular target proteins w o u l d overcome chemoresistance i f i t was due to altered a f f i n i t y to the targets or to an increase in active outward transport. We have synthesized a new photoreactive vinblastine derivative absorbing light around 450 nm (Grammbitter, K., Gerzon, K. & Ponstingl, H., Eur.J.Cell Biol. 33, Suppl. 5, 14, 1984) and show that intracellular activation of the compound by an argon laser at 457 nm restores chemosensitivity. We used two mutant,vinca- and colchicine resistant Ehrlich ascites cell strains (Granzow, C., J. Cancer Res.Clin.Onco]. 102, 57, 1981; HD33, ~C50 5.5 x IO-~ vinblastine, and"-HD33C, IC50 4 x IO'DM vinblastine), and a sensitive wild type strain for comparison (HD34K, ICSO 1.8 x IO"M vinblastine),Aliquots of cell suspensions were incubated for lh with the photoreactive or_ underivatized drug, irradiated for 15 min with 83 mW/cmz with an argon laser at 457 nm, and grown in fresh mediumfor 30 hrs before counting cell numbers. In the resistant cell lines activation of the photoreactive compound by laser restored the chemosensitivity to approximately the level of the vinblastine sensitive wild type strain. Irradiation in the presence of underivatized vinblastine had no effect. (Supported by the Wilhelm and Maria ~eyenburg Foundation). ~Project Molecular Biology ~of Mitosis, 2Institute of Cell and Tumor Biology, JProject Cytometry, German Cancer Research Center, D-6900 Heidelberg/Federal Republic of Germany.

I l m o f o s i n e is a n e w t h i o e t h e r p h o s p h o l i p i d d e r i v a t e w h i c h i n t e r f e r e s w i t h the m e m b r a n e m e t a b o l i s m . By in v i t r o e x p e r i m e n t s and in exp e r i m e n t a l a n i m a l t u m o r s its c y t o t o x i c e f f e c t h a s b e e n s h o w n , In this s t u d y w e h a v e t e s t e d the e f f e c t s of I l m o f o s i n e o n t h r e e h u m a n o v a r i a n c a r c i n o m a s and on one a d e n o c a r c i n o m a of the c e r v i x i m p l a n t e d i n t o n u d e m i c e . A n i m a l s w e r e t r e a t e d w i t h 0,25 m g / k g I l m o f o s i n e and 2.5 m g / k g I l m o f o s i n e p.o. for ten d a y s . The t h e r a p e u t i c e f f e c t w a s a s s e s s e d by m e a s u r e m e n t of two p e r p e n d i c u l a r d i a m e t e r s of the tumor. T h e t u m o r s i z e w a s m e a s u r e d in 5 d a y s i n t e r v a l l s u p to 40 d a y s a f t e r t r e a t m e n t . In one o v a r i a n c a r c i n o m a t r e a t e d w i t h 0.25 m g / k g I l m o f o s i n e 2 / 1 8 s h o w e d c o m p l e t e r e m i s s i o n , 6/18 s h o w e d p a r t i a l r e m i s s i o n w h e r e a s in the g r o u p t r e a t e d w i t h 2.5 m g / k g 25 % had c o m p l e t e rem i s s i o n and 40 % h a d p a r t i a l r e m i s s i o n (n=20), In t h e s e c o n d o v a r i a n c a r c i n o m a no r e m i s s i o n was seen. In the t h i r d o v a r i a n c a r c i n o m a at a c o n c e n t r a t i o n of 0.25 m g / k g no r e s p o n s e was o b s e r v e d . In the g r o u p t r e a t e d w i t h 2.5 m g / k g 8 % c o m p l e t e and 8 % p a r t i a l r e m i s s i o n s w e r e s e e n (n=24). In the c e r v i x c a r c i n o m a no c o m p l e t e and no p a r t i a l r e m i s s i o n w e r e seen. T h e s e o b s e r v a t i o n s c o n f i r m the c y t o s t a t i c p o t e n t i a l of i l m o f o s i n e but the i n d i v i d u a l d r u g s e n s i t i v i t y of h u m a n t u m o r s m u s t b e c o n s i d e r e d . 1 Medizinische Klinik der Ruhr Universit~t Bochum, 2 Univ. F r a u e n k l i n i k F r e i b u r g , 3 Boehringer Mannheim

S 168 5/P-GM 046

5/P-GM 048

I M M U N O H I S T O C H E M I S T R Y IN BRAIN TUMOUR DIAGNOSIS. WHICH ARE THE FACTS? F. Gullotta

IN SITU INMUNOHISTOCHEMtCAL STUDIES OF SPLENIC LYMPHOCYTE AND NACROPHAGE SUBPOPULATIONS IN PATIENTS WITH NALIGNANT TUMORS

The introduction of i m m u n o h i s t o c h e m i s t r y in brain tumour diagnosis has raised the hope that this m e t h o d would allow to answer some important questions concerning a) the nosological identification of "embryonic" tumour cells, and b) the correlations b e t w e e n presence of a given cell m a r k e r and biological behaviour of the tumour. In the past years many c o n t r a d i c t o r y results concerning the specificity of neuronal or glial cell markers have been reported. ~his point has been confirmed by our personal ~ v e s t i gations on a large group of more than 500 brain tumours (among them 60 medulloblastomas). These contradictions can be easily explained by considering two basic facts: I) Every neoplastic cell population, e s p e c i a l l y of e m b r y o n ~ t u m o u r s , infiltrates diffusely the brain tissue: Nonneonlastic cells, intermingled with t~n~our celis, can therefore give rise to il~munohistochemical and histogenetic misinterpretations. 2) D i f f e r e n t cell m a r k e r s can be e x p r e s s e d by one and the same cell (f.i., GFAP, NSE, Vimentin); the nosological interpretation of the tumour will be therefore difficult or impossible - or at best rather subjective. A clear-cut m a r k e r s - p o s i t i v i t v is mostly seen in those differentiated tumours the nosological classification of which is already evident by the usual histological methods. In embryonic brain tumours (so-called PNET) no correlations between the presence of a given cell marker and the b i o l o g i c a l behaviour of the tumour has been detected so far.

S.

Falk,

H. M O i l e r ,

G, S e i p e l t ,

H,J.

Stutte

25 s p l e e n s f r o m p a t i e n t s w i t h g a s t r i c c a r c i n o m a (GC) and 16 s p l e e n s f r o m p a t i e n t s w i t h H o d g k i n ' s d i s e a s e (HD) were s t u d i e d by i n s i t u i m m u n e h i s t o c h e m i c a l methods w i t h m o n o c l o n e l a n t i b o d i e s r e c o g n i z i n g l y m p h o c y t e ( L e u - s e r i e s ) and macrophage subpopulations (KiM-series). In both groups the topographic distribution o f t h e s e immunocompet e n t c e l l s i n t h e s p l e e n was p r e s e r v e d ; s e m i q u a n titative a n a l y s i s r e v e a l e d t h a t t h e number o f K i M - 2 , -3 and -5 p o s i t i v e c e l l s was r e d u c e d . I n HD CD4+ c e l l s and t h e CD4/CD8 r a t i o were i n c r e a sed, w h i l e i n GC t h e r e v e r s e was t r u e . Th~se phenomena were n o t r e l a t e d t o t h e e x t e n t or t h e h i s tologic s u b t y p e o f t h e d i s e a s e . I n HD t h e r e d u c t i o n o f macrophagas was a l s o e v i d e n t i n n o n i n v o l red s p l e e n s . P r o l i f e r a t i o n activity of lymphatic c e l l s as a s s e s s e d by t h e a n t i b o d y Ki67 was r e d u ced i n GC o n l y and r e l a t e d t o t u m o r b u r d e n . Thus b o t h GC and HD e x e r t i n f l u e n c e s on l y m p h o c y t e and macrophage s u b p o p u l a t i o n s i n t h e s p l e e n t h a t r e s e m b l e phenomena d e t e c t a b l e i n t h e s t r o m a o f e p i thelial t u m o r s ( H . M O l t e r a t e l , Cancer D e t e c . P r e y . 1 1 , 124, 1 9 8 7 ) . The changes i n t h e n u m e r i c a l c o m p o s i t i o n o f immunocompetent c e l l s i n t h e s p l e e n may r e p r e s e n t m o r p h o l o g i c e v i d e n c e f o r t h e i m m u n e s u p p r e s s i o n d e t e c t a b l e by f u n c t i o n a l stud i e s o f p e r i p h e r a l b l o o d i n b o t h HD and GC. S e n c k e n b e r g i s c h e s Zentrum der P a t h o l o g i e Universit~t Frankfurt, Theodor-Stern-Kai D - S 0 0 0 F r a n k f u r t 70

der 7,

Institut f. N e u r o p a t h o l o g i e d. Universit~t, Domagkstr. 17, D-4400 M~nster

5/P-GM047

5/P-GM 049

HETEROGENEOUS EXPRESSION OF CYTOKERATINS IN EPITHELIAL CELL PROLIFERATIONSAND CARCINOHASOF THE HAHHARYGLAND

IMMUNOREACTIVITY OF TUMOUR-REGIONAL AXILLARY LYMPH NODES

E.-D. Jarasch, M. Kaufmann, C. Maurer, and W. BOcker

H.-P. Horny and H.-A. Horst

By immunohistochemistry and biochemistry we have shown that, in the mammarygland, luminal cells of ducts and acini express cytokeratins (CK) typical of simple epithelia (nos. 7,8,18,19) whereas the basal or myoepithelia] cells contain CK characteristic of stratified epithelia (nos. 5,14, possibly 17). More than 90% of 200 primary breast carcinomas as well as their lymph node metastases exhibit only simple epithelia-type CK. Using diverse specific antibodies, we demonstrate that CK 8 and 18 apparently are homogeneouslyexpressed in the carcinoma cells, whereas CK 7 and 19 often exhibit a heterogeneous distribution; some carcinomas are negative with antibodies to these proteins. In adenosis, scleradenosis and epitheliosis, proliferating cell populations expressing CK patterns of either the luminal epithelium, the basal epithelium, or of both types simultaneously, are detected. Cells revealing the combined CK pattern of basal and luminal cel]s form the luminal lining of tumor cells in "pagetoid" spreading of in situ carcinomas. Some invasive carcanomas also are positive with antibodies to CK of both the luminal and basal epithelium; none of the carcinomas expressed CK 5 and 14 without the presence of CK 8 and 18. A squamous epithelial cell carcinoma of the breast exhibited a very complex pattern of cytoskeletal components: In addition to the CK present in normal mammarygland epithelial cells, i t was strongly positive with antibodies to vimentin and partly with those to CK 4 and 13. The data are discussed with respect to the pathologic classification as well as the development and proliferation patterns of benign and malignant mammary lesions.

The immunohistology of B regions and T regions in 577 axillary lymph nodes (ALN) draining invasive breast carcinomas (104 cases) and of 34 control nodes (CLN) exhibiting histological signs of chronic non-specific lymphadenitis was investigated with the monoclonal antibodies TO15 (pan-B-lymphocyte marker), Leu-I (pan-T-lymphocyte marker) and Ki67 (a monoclonal antibody to a proliferation-associated antigen). The functional status of the B regions was determined by calculation of the germinal centre index (GCI, number of germinal centres divided by the total number of primary lymphatic follicles) and that of the T regions by the number of proliferating lymphoid cells in the parecortex. In addition, the extent of B regions and T regions in each lymph node was determined semiquantitatively (B>T, B=T, B
Inst.f. Zell- und Tumorbiologie, Deutsches Krebsforschungszentrum, Im HeuenheimerFeld 280, D-6go0 Heidelberg.

Pathologisehes Insdtat der Universitfit s t r a ~ 8, D-7400 Tiibingen, FRG

Ti~bingen,

Liebermeister-

S 169

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5/P-GM052

SELECTIVE MARKING OF COLOREKTAL CANCER TISSUE WITH MONOCLONAL ANTIBODIES IN A HUMAN EX VIVO PERFUSION MODEL E.Lahde, O.Abri~ H.Schlicker, S. Matzku, H.Kalthoff, E.Kraas

DIFFERENTIAL DIAGNOSIS OF EWING'S SARCOMA: AN IMMUNOHISTOCHEMICALANALYSIS.

The successful use of radioactively marked monoclonal antibodies (RMA) in tumor diagnosis and treatment is strongly dependant upon their specifity to their corresponding tumor associated antigen. The situation of binding kinetics and distributional patterns of RMA in solid human tumor tissue is still unclear. Method: After operative removal of the tumor pulsative perfusion via the supplying artery was performed, with continuous measurement of pressure, flow velocity, temperature, pH, an control of various metabolic parameters, including lactate, CK-mb, electrolytes, glucose, and CEA. The distributional pattern of RMA (CI P83 anti CEA coupled w/J 131) was determined to immunoscintigraphy, autoradiography, and immunohistologieal examination of perfused tumorous tissue. Results: After initial perfusion of tumorous tissue one observes a diffuse binding pattern which becomes increasingly specific: Thereafter the selective marking of tumorous tissue remains approximately from lines higher than that of neighbouring tissue. RMA binding appears unrelated to the serum CEA concentration. Autoradiographie examination of perfused tissue shows an itregular RMA binding pattern. One finds strongly binding areas in a tumor beside weakly binding tumor areas. In human tissue this heterogeneous distributional tendency of tumor antigens has also been documented. Conclusion: The present technique of ex vivo perfusion of human colorectal tumors is well suited toward characterizing the binding affinities of RMA to tumor associated antigens. The employed RMA C1 P83 shows a high affinity even to serum-CEA-negative tumors.

A.Roessner, H.Garcia, E.Vollmer, E.Grundmann The unequivocal i d e n t i f i c a t i o n of primary round c e l l tumors of childhood occurring in bone has always been difficult. U l t r a s t r u c t u r a l and immunohistochemical in vestigastions attempted to improve the d i f f e r e n t i a l diagnosis of neuroblastomas, lymphomas, small c e l l osteosarcomas, and Ewing's sarcomas. More recently the description of primary peripheral neuroectodermal neoplasms of bone has added more problems to the d i s t i n c t i o n of these neoplasms from Ewing's sarcoma and neuroblastoma. The d i f f e r e n t i a l diagnosis is considered important in view of chemotherapy planning. Our immunohistological results show that lymphomes can be a p t l y d i f f e r e n t i a t e d by staining with leucocyte common antigen. C l a s s i f i c a t i o n in Band T-cell lymphomas is f a c i l i t a t e d by certain markers such as KB 3 and Pan-T. Neuroblastomas w i l l stain posit i v e f o r neuron-specific enolase (NSE), chromogranin, and synaptophysin, whereas malignant peripheral neuroectodermal tumors w i l l show a p o s i t i v e reaction with NSE, too, while chromogranin and synaptophysin are negat i v e . The small cell osteosarcoma shows at least some foci with p o s i t i v e reaction f o r osteocalcin. H i s t o l o g i c a l l y and c l i n i c a l l y t y p i c a l cases of Ewing's sarcoma w i l l show p o s i t i v e reactions f o r vimentin, k e r a t i n , and in some instances, a f a i n t reaction of NSE. Thus, immunehistological results may f a c i l i t a t e the diagnosis of small round and blue c e l l tumors in bone. Problems are l i k e l y to arise in d i f f e r e n t i n g between peripheral neuroectodermal tumors and Ewing's sarcomas, because an increasing body of evidence points to neural features appearing also in Ewing's sarcoma c e l l s .

I.Chir.Abtlg.,Krankenhaus Moabit,Turmstr.21,I000 Berlin 21, Deutsches Krebsforschungsinstitut Heidelberg, Abt.f.klinische Immunologic, Universit/it Hamburg

Prof.Dr.A.Roessner, Gerhard-Domagklnstitut fur Pathol o g i e der WestfNlischen Wilhelms-Universit~t, Domagkstr. 17, D-4400 MUnster.

5/P-GM 051

5/P-GM053

VIMENTIN: AN IMPORTANT PROGNOSTIC MARKER IN RENAL CELL CARCINOMA? K. Donhuijsen and St. Schulz

NEW MEMBER OF THE PROTEIN-TYROSINE KINASE FAMILY : THE SRC- AND LCK-RELATED PROTOONCOGENE C-TKL H.R~bsamen-Waigmann,K.Strebhardt,J.Mul]ins,C.Bru

Histological c r i t e r i a s of prognosis are concerned with immunohistochemical methods. Until now the prognostic relevance of vimentin expression in renal c e l l carcinoma is unknown. Material and Methods: Deparaffinized sections of 94 ~ ] l carcinomas were submit to the reaction with Antivimentin by PAP-technique. Vimentin expression was determined s e m i q u a n t i t a t i v e l y . The results were compared with TNM-stage, survival data and f u r t h e r h i s t o l o g i c features e.g. nuclear morphology. All patients were observed f o r at least 4 yrs. Results: In 28 carcinomas we found a p o s i t i v e vimentin expression (30 %). In these cases the 4 y r s . - s u r v i v a l time was 36 %. Metastases could be detected in 54 %. On the contrary in the 66 vimentin negative cases (70 %) a 4 y r s . - s u r v i v a l was reached by 53 %, metastases were found in 12 %. These differences were s t a t i s t i c a l l y significant. However, II of the cases with vimentin expression were of high grade malignancy based on usual h i s t o l o g i c parameters as pleomorphic/spindle-shaped c e l l s or nuclear atypias. I f a l l cases with such c r i t e r i a s are eliminated the prognostic significance of the vimentin reaction is markedly diminished {4 y r s . - s u r v i v a l : 55 % vs. 47 %). Conclusion: In renal c e l l carcinoma the vimentin expression-correlates s i g n i f i c a n t l y with an infavourable prognosis. However, t h i s correlation i s n ' t independent of other h i s t o l o g i c c r i t e r i a s . U n i v e r s i t ~ t s i n s t i t u t fur Pathologie (Dir.: Prof. Dr. L.-D. Leder) , HufelandstraBe 55, D-4300 Essen [

We report the isolation and nucleotide sequence of a 3.7-kilobase (kb) cDNA clone from chicken sp]een corresponding to a peviously undescribed member of the src family of protooncogenes. It encodes a protein with a C-terminal domain related to the src family of protein-tyrosine kinases and, among these, has most significant homology to the Ick gene isolated from a murine leukemia virus-induced thymoma cell line. The gene is therefore referred to as c-tkl for cellular tyrosine kinase related to Ick. Analysis ~f genomi~ DNA reveals that-c-tkl is a chromosomal locus distinct from c-src and c-lek, Furthermore, the size of c-tkl mRNA as well as its pattern of expression indicates that it is not the chicken homologue of Ick but a different gene. A 3.8-kb transcript of the c-tkl gene, identical to the size determined for c-src mRNA, was observed in cultered chicken embryo fibroblasts and in chicken spleen and brain. In contrast, detection of a definite c-src mRNA signal with mRNA from spleen was not possible under the hybridization conditions employed when the 5"end of v-src was used as the probe, and none of the Ii clones obtained from the cDNA library corresponded to a c-src transcript. Thus previous studies of c-src mRNA expression may have actually detected c-tkl transkripts. Chemotherapeutisches Forschungsinstitut, Georg-Speyer-llaus, Paul-Ehrlich-Str. 42-44, D-6000 Frankfurt 70 and D e p a r t m e n t of Cancer B i o l o g y , H a r v a r d School Public Health,665 Huntington Avenue,Boston

of

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5/P-GM 056

EF~EC~ OF Ha-ras ON PHOSPHATIDYLINOSITOL METABOLISM, Na~/H~-ANTIPORTER AND MOBILIZATION OF INTRACELLULAR CALCIUM K. Maly W~ Doppler, J. Hoflacher, R. + ' H. Oberhuber, + Jaggi , B. Groner and H. Grunicke

PARAN~EOPLASTIC AurOIM~fl0NE DISEASE: CELL D ~ i A T I O N AND AUTOANTIG~N EXPRESSION IN THYMOFIAS ASSOCIATED WITH MYASTHENIA GRA%rfS, ~ . Kirchner, F. Hoppe, A. ~k~x, B. Schalke, H.K. M~lierHermelink

Several oncogenes have been shown to code for growth factors, growth factor receptors or elements of the growth factor signal transduction pathway. For the ras-gene family in particular, there is increasing evidence that their products are intimately involved in the control of ceilular growth, differentiation and carcinogenesis. We describe data obtained with NIH3T3 cells transfected with the activated, transforming Ha-ras and the corresponding Ha-ras proto-oncogene, both subjected to transcriptional control of glucocorticoids by in vitro recombination with the MMTV-LTR. Induction of p21 ras expression in quiescent cells by dexamethasone causes an increased turnover of phosphatidylinositol 4,5-bisphosphate with a concomitant rise in Sno$itol phosphates, and an activation of the Na /H -antiporter. Addition of serum growth factors to dexamethasone treated cells does not .result in of . . an. additional stimulation ++ phosphat~dyl~nos~tol metabol~sm or Na /H -exchange. There is also a desensitization ~ exogenous growth factors of the intracellular Ca---mobilizing system, leading to a depression of the transitory increase in cytosoiic Ca ' after addition of serum growth factors. None of these effects are seen after expression of the Ha-ras proto-oncogene. Results are discussed as indicating a constitutive growth factor independent activation of growth factor signal transduction by the activated Ha-ras.

Myasthenia gravis (~) is found in 30-40 percent of all th~ patients, and can be considered as a classical example of paraneoplastic autoirmmane disease. Using histological and immunohistochemical methods we co~pared the differentiation of neoplastic epithelial cells and associated lymphoid cells in ~ s of myasthenic (15 cases) and non-myasthenic (8 cases) patients to the cortical and medullary epithelial cell (EC) phe~notype in normal thymus. Particularily we looked also for an expression of acetylcholine receptor (AChR) epitopes as possible clues for a specific intrathymr~retous autc~ensitization in MG. All myasthenic t/lymomas showed a distinct cortical differentiation that was predcrainant in 11 cases and mixed with a medullary EC phenotype in 4 cases. A predcminant medullary EC phenotype was only seen in non-myasthenic thyn-~m~s (2 cases). A special feature of thymorm~s with predominant cortical and mixed EC phenotype was the expression of AChR epitopes in 15 out of 21 cases, where~ medullary t h ~ were AChR epitope negative. AChR epitope expression was seen in almost all myasthenic th~omas (13 our of 15 cases), but rarely obsezved in nonmyasthenic neoplasras (2 out of 8 cases). We conclude that the unique exvpression of AC/IR epitopes by neoplastic EC and the association of cortical EC differentiation with ialq%~tureCD1-positive T-lyr~ohocytes could be the prerequisites for a specific intratumorous automation in MG-associated th~Taomas.

Institut fHr Medizinische Chemie und Biochemie, Universit~t Innsbruck, A-6020 Innsbruck, Fritz Pregl Str.3 und +Ludwig Institut fHr Krebsforschung, Inselspital, Bern, Schweiz.

Pathologisches Institut und Neurologische Klinik der Universit~t W(irzburg, J~sef-Scb~eider-StraBe 2, 0-8700 Wttrzburg

5/P-GM 055

5/P-GM057

ESTABLISH~E~Ff AND CHARACI~RIZATION OF 15 P~RMANF~NT Hi,dAN OVARI~N T~V~DR CELL I ~ E S V. M~bl~, R. Moll, H./J. Grill, R. Kreier~erg In the field of gynecological oncology ther~ has been an increase in efforts to provide a basis for fundamental oncologieal research tklroug,h the establishment of perm~nent tumor cell lines. In the last two years we succeeded to establish 15 new p e r ~ e n t ovarim~ tumor cell lines. The lines were taken partially from ascites, partially from solid tu~iors. At present the lines are between the 15. and 75. culture transfer, the ce]l doubling time oscillates between 28 and 62 ho~s. qhe lines are characterized by their cyt~eratin and vimentin pattern, the secretion of tmnor associated s~ntigens and their aromata~e activity. Up to date we know of 20 different cytekeratins which are in various combinations in the cKfferent epithelia. For nearly all lines the cytokeratins 8, i8 mud 19 have been found, in some, cases also the cytoke~atins 7 and 17. Im~ addition all the lines showed an expression of vimentin. This distribution pattern gives evidence that the origin of the tumor cell lines is the ovary. Nearly all the lines secrete the t~nor associated antigen CA 125 ~n ~ar~ing amounts. The antigen is secreted Fainly by proliferating cells not by resting cells. In contrast CFA is not secreted by any of the iknes. There is clear evidence that the tumor cell has the potential to s2~thesize estrogen from androgen p ~ c u r s o r s . For this reason the cells were incubated with -~ C !abelee androstenedione. Androstenediene was con~rted to oestrone depending on the incubation period. 3 of the 12 lines tested were positive for the aromatising enzymes. These results show that ovarian cancer cell lines are a useful model of peripheral systems against which to test putative arorr~tase i~hibitors.

ANALYSIS OF GENE REARRANGEmeNTS IN ACUTE LYMPHOBLASTIC L E U K E M I A (ALL) OF ADULTS W.Knauf, A.D.Ho, E.Thiel, D.Hoelzer, G.Heger and W. Hunstein D e t e c t i o n of gene rearrangements of immunoglobulin genes or T-cell receptor genes is b e l i e v e d to be an evidence for m o n o c l o n a l i t y of lymphoid neoplastic cells. We have investigated gene rearrangements in ALL of adults and have correlated them to immunological f i n d i n g s . S o u t h e r n - b l o t analysis was performed in DNA samples from leukemic cells of 30 patients. Gene probes for the joining regions of the i m m u n o g l o b u l i n heavy chain gene (JH) and for tJ%e constant region of the beta chain of the T-cell receptor g e n e ( T ~ ) were used.All the ten patients w i t h pre-T or Tcell p h e n o t y p e showed rearrangements of T ~ , whereas in the 19 cases with cALL, one p a t i e n t with B-ALL and one w i t h null-ALL rearrangements Of JH w e r e found.One patient with an acute unclassified leukemia w i t h both lymphoid and myeloic surface antigens had a r e a r r a n g e m e n t of JH, which suggests that this leukemia was of B-cell origin. In ten of the 22 non-T-ALL and in four of the eight T-ALL a b i a l l e l i c gene r e a r r a n g e m e n t was found. There was no d i f f e r e n c e in the incidence of biallelic rearrangements between patients at first diagnosis and those with relapses. There has been so far no discrepancy b e t w e e n im~unotyping and analysis of gene rearrangements However, the study of gene rearrangements may be helpful in cases where the results of imm~notyping are inconclusive, The finding of a high percentage of leukemic samples with biallelie rearrangements is surprising and its clinical significance still ~nknown.

Univerait[tsfrauerakl~mik, Langenbeckstr. I, F~-6500 Y~kinz

M e d . K l i n i k und P o l i k l i n i k der Universit~t~ Hospitalstr.3, D-6900 H e i d e l b e r g

S 171

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5/P-GM 060

AMPLIFICATION AND ENHANCED F_XPR[~SION 0? THE c-erb____B2PR@I~OONCOGENE &ND PROGNOSTIC FACIOR$ IN HhVAN PRDflARY BREAST CANC[~. M. Kauf~Ea~_~_~I. bister, E.D. garaseh, M. Schwab Cellular oneogenes play" an JsnDorte~nt role in gro~-th and progression of huma~ timbers. ~lification of cellul&<~ oneogenes~ i~e. the selective i~nc~ease of the copy n ~ b e r of DNA-sequenees, has been found ~hq several hb~en ca~c~n
P H E N O T Y P I C C H A N G E D U R I N G T U M O R P R O G R E S S I O N IN MELANOMA: FOUR A N T I G E N S AND T H E I R P R O P O S E D BIOLOGICAL FUNCTIONS J~rgen M. Lehmann, B e r n h a r d Holzmann, Gert Riethm~l!er and Judith P.Johnson .

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The tumor model human malignant melanoma offers numerous advantages for studying stepwise changes during the course of tumor progression. Using the monocional antibodies 15.75, p3.58, MucIe, MUC54 and PALMI (1,2) which discriminate b e t w e e n nevi and malignant melanoma we found that histopathologically and clinically observed alterations are accompanied by changes in the antigenic phenotype of melanocytes (3). between the A striking similarity exists biochemical and functional characteristics of the p3.58 antigen and the intercellular adhesion molecule (ICAM-!)(4).Both molecules are expressed on activated lymphoid cells and endothelia~ can be induced by various lymphokines and appear to play a role in colony formation in vitro by activated PBL. These observations suggest that one of the changes occurring during the tumor progression in melanoma is the acquisition of functional capabilities involved in normal lymphoid cell interaction~ References: I. Nolzmann et el. J.Exp.Med.161:366 (1985) 2. Lehmann et el. Cancer Res. 47:841 (1987) 3. Holzmann et el. Int.J.Cancer 39:466(1987) 4. Dustin et el. J.Immunol. 137:245 (1986) Institute of Immunology, University of Munich, F.R.G., Goethestra~e 31, 8000 M~nchen 2.

5/P-GM 059 ANTIGENIC H E T E R O G E N E I T Y OF HUMAN BRAIN TUMORS U.Stocker, J.Groeneveld, B.Martin, D. Stavrou and E.Keiditsch The antigenic profile of human gliomas and in vitro established cell lines was investigated by using the selected m o n o c l o n a l antibodies (McAbs) MUC 8-22 and MUC 2-63 (Stavrou et al.: J. Neurol. Sci. 80, 205~ 1987). The reactivity with tissue samples and cytospin preparations obtained from 45 neurogenic tumors was estimated by the indirect immunoperoxidase technique. In addition, according to the degree of antibody binding the immunocytochemical analysis of cell-surface antigens by indirect immunofluorescence resulted in a fluorescent reaction product which intensity and distribution was measured by computer-assisted cytofluometry. In most cases it could be demonstrated that the heterogeneity in antigen expression decreases during successive in vitro propagation of glioma cells. The data suggests that a variable percentage of cells was not recognized by the employed McAbs. Moreover, the reactivity spectrum of the selected antibodies was independent of the histological grading of gliomas and showed significant difference in various stages of subeultivation of glioma lines. A various degree of antibody-binding among and within gliomas and glioma-derived cell lines could be observed. The extent of variance in stain intensity values was different within cell populations and reflected the antigenic h e t e r o g e n e i t y of tumor cells. Institut f~r Pathologie, Klinikum Bogenhausen, Englschalkingerstr. 77, D-8000 Mfinchen 81

5/P-GM 061 VIRAL INTEGRATION SITES IN THE G E N O M E O F WITH FRIEND MURINE LEUKEMIA VIRUS-INDUCED THROLEUKEMIA

MICE ERY-

Ansgar Schulz and Roland Friedrich

Induction of disease by routine leukemia viruses is assumed to involve l~ser~ional activation of cellular genes. Localization of newly integrated viruses is hampered by the presence of a large number of endogenous viruses in the cellular genome~ As a tool to stud}" the localization of possible integration sites of Friend routine leukemia virus in mice developing erythroleukemia we have constructed a virus containing a bacterial supressor tRNA (supF) gene as a selectable marker,

Virus was s u b s e q u e n t l y injected into s u s c e p t i b l e newborn mice. The animals developed e r y t h r e i e u k e m i a a f t e r a l a t e n t period of 3 to 5 months. D N A prepared from spleens of these mice ~.;as analyzed by Southern blot hybridization with the supF gene as a probe~ Each of several spleens examined so far showed integrated proviral D N A containing the supF gene. The DNA from spleens of diseased animals gave rise to 3 to 10 supF containing restriction fragments showing that each spleen consisted of only a few clonal tumors. Genomic l i b r a r i e s from spleen tumors were prepared in amber m u t a t e d phage Lambda and selected for the supF gene in supF n e g a t i v e b a c t e r i a . To determine common i n t e g r a t i o n regions, phages c o n t a i n i n g v i r u s - c e i l j u n c t i o n s e q u e n c e s are c u r r e n t l y f u r t h e r c h a r a c t e r i z e d . Data o b t a i n e d frem t h e s e phage clones will be discussed. Institut ffir medizinische Virologie der Universit~It Gief~en, Frankfurter Str. i07, 6300 GieBen

S172 5/P-GM 062

5/P-GM 064

THE HUMANLYMPHOKINE-ACTIVATEDKILLER PHENOMENON: REGULATION OF PROGENITORAND EFFECTORFUNCTIONS J. Atzpodien, S. Gulati, D. Wisniewski, C. Shimazaki, C. B~hrer, S. Oz, K. Welte, H. Link, H. Poliwoda, and B. Clarkson

STRUCTURE-ACTIVITY-STUDIES AND EVALUATION OF MAMMARY TUMOR INHIBITINGACTIVITY OF NEW AROMATASE INHIBITORS OF THE AMINGGLUTETUIMIDE(AG)-TYPE R. Hartmann, C. Batzl, H. Sch~nenberger

Recently, a new approach to cancer immunotherapyhas been described employing the adoptive transfer of autologous patient-derived lymphokine-activated k i l l e r (LAK) cells. LAK cells for c l i n i c a l use are commonly generated via incubation with interleukin-2 (IL-2) of unseparated peripheral blood mononuclear cells (PBMC). In our laboratory, substantial LAK-like i . e . , MHC-unrestricted, k i l l i n g acti v i t y against various human tumors could be induced in highly purified PBMC-derived cell subpopulations. When compared to unseparated PBMC, purified natural k i l l e r (NK) cells were more than ten-fo]d enriched for non-speci f i c cytotoxicity against NK-sensitive targets on day O, and acquired optimal LAK cytotoxicity after 5-day stimulation with IL-2. However, no significant difference in per cell cytolytic a c t i v i t y against LAK-sensitive targets was noted when purified NK cells were stimulated with IL-2 in the absence or presence of T cells and/or monocytes. In contrast, the t o t a l LAK cytotoxicity ( i . e . , percent cytotoxicity x percent cell recovery) generated in IL-2-NK cell cultures was substantially (two-fold, four-fold~ and eleven-fold) enhanced when NK cells were co-incubated with equal numbers of monocytes, T cells, and T cells plus monocytes, respectively. While no significant LAK t o x i c i t y could be induced in IL-2 cultures that were depleted of NK cells on day O, removal of this cell subset after 5-day stimulation with IL-2 resulted in an up to 60% abrogation of LAK a c t i v i t y . In summary, our results suggest that T ceils and monocytes regulate the generation and contribute to the functional a c t i v i t y of human lymphokine-activated k i l l e r cells.

The aromatase inhibitor AG has shown benefit in the treatment of disseminated, hormone-dependent breast cancer. But AG is not an optimal drug, for i t also inhibits the enzyme desmolase and shows strong CNSdepressive a c t i v i t y . This is why stronger inhibitors of aromatase exhibiting less i n h i b i t i o n of desmolase and a weaker CNS-depressive a c t i v i t y than AG are required. For that purpose s t r u c t u r a l l y modified derivatives of AG and cyclohexylaniline were synthesized and tested for their i n h i b i t o r y potency towards human placental aromatase and bovine adrenal desmolase. Only in the case of an elongation of the 3-ethyl group of AG more active compounds were found. The most active derivative - the cyclohexyl compound showed a 123-fold stronger inhibition of aromatase and a markedly decreased i n h i b i t i o n of desmolase compared to AG. The new compound showed also a stronger i n h i b i tion of the plasma E2 concentration of PMSG-primed SDrats (0,3 mg/kg: 52 % inhibn; AG, l mg/kg: 28 %) and the testosterone stimulated tumor growth of ovariectomized rats bearing DMBA-induced mammary tumors. Tested for i t s CNS-depressive a c t i v i t y this compound showed no a c t i v i t y in the rotarod test and the m o t i l i t y test - even in very high doses. Being a stronger and more selective i n h i b i t o r of the estrogen biosynthesis than AG, the new cyclohexyl compound might be a better candidate for the treatment of hormone-dependent breast cancer.

Memorial S1oan-Kettering Cancer Center, New York, NY I0021, and Medizinische Hochschule, D-3000 Hannover 61

I n s t i t u t fur Pharmazie, Universit~t Regensburg, Universit~tsstr. 31, D-8400 Regensburg

5/P-GM 063

5/P-GM 065

THERAPEUTIC ACTIVITY OF CONJUGATES OF LIPIDS AND 1-B-DARABINOFURANOSYL-CYTOSINE (ARA-C) IN MURINE TUMOR (3-LL) AND LEUKEMIA (WEHI-3B) MODELSIN VIVO. W. E. Berdel, S. Danhauser, C. I . Hong, J. Rastetter, W. R. y og_ler. Five d ~ e ~ n t l i p i d conjugates of ara-C were tested in comparison to either ara-C, or the ether lipids ET-18-OCH~ and BM 41.440, or t h e i r equimolar mixtures for therapeutlc a c t i v i t y in Lewis lung carcinoma (3-LL) of BL6 mice and in acute myelomonocytic leukemia WEHI-3B) of Balb/c mice in vivo. Among the conjugates tested in 3-LL were the -d-iacyl analog ara-CDP-L-dipalmitin ( 1 ) , ~ 1-S-alkyl l i p i d analog ara-CDP-D,L-PTBA ( I I ) and the 1-O-alkyl l i p i d analogs ara-CDP-D,L-PBA ( I I I ) , ara-CDP-D,L-PCA (IV) and ara-CDP-D,L-MBA (V). I , I f , and I l l had the most significant therapeutic effects on the growth of i.p. implanted primary tumor and when given in an adjuvant situation on the lung metastasis of 3-LL . Treatment led to a significant increase of both median survival times and numbers of long term survivors. Optimal therapeutic schedules consisted of 80 ( I I ) - I 0 0 ( l , I I I ) mg/kg q dX5 given shortly after implantation or surgical removal of the 3-LL respectively. The conjugates proved to be superior to ara-C, the ether lipids or t h e i r equimolar mixtures. Conjugates I and I] were tested in WEHI-3B leukemia. Administration of optimal doses ( 3 0 0 - ~ - 4 0 0 [ I ] mg/kg once or 60 mg/kg q dX5 [ I l l ) led to a significant increase of median survival times and numbers of long term survivors in mice injected i . p . with I04 and 105 cells. C57BL6 mice tolerated I] at 80 mg/kg q dX5 i . p . well, but t o x i c i t y of I ] at this dose or at 400 mg/kg once i . p . exceeded the LDIO in Balb/c mice in some experiments. Although the mode of action of these conjugates remains speculative, in vivo experiments with L1210 leukemia could show a 16n-g~elevation of i n t r a c e l l u l a r ara-CTP levels after application of II over ara-C. DFG Be 822/2-4, Be 822/3-1 and NIH CA 29850-04A1. Emory University, Atlanta, GA: Roswe]l Park Memorial I n s t i t u t e , Buffalo, N.Y., USA; Technische Universit~t, Munich, FRG.

RESULTS OF S U R G I C A L OR M U L T I M O D A L T H E R A P Y IN 65 P R I M A R Y N O N - H O D G K I N ' S LYMPHOMAS OF THE S T O M A C H H.-J. Meyer, J. J~hne, H. W i l k e and R. P i c h l m a y r

~57

The p r i m a r y i n v o l v e m e n t of the stomach by nonHodgkin's lymphomas (NHL) yet is a r e l a t i v e rare d i s e a s e and d i f f e r e n t c l a s s i f i c a t i o n s are still available. B e c a u s e of these facts c o n c r e t e rules of optimal t h e r a p y are lacking. To p r o v i d e more a c c u r a t e data, even in regard to the e f f i c a c y of m u l t i m o d a l therapy, the own patient material has been reviewed. B e t w e e n 1968 and 1987 a total of 65 pts. with p r i m a r y NHL of the stomach was operated. T h e r e were 35 w o m e n and 30 men, aged 29 to 87 years. The overall rate of r e s e c t a b i l i t y was 95,4 (62 of 65 pts.); 20 subtotal - and 42 total g a s t r e c t o m i e s were performed w i t h a o p e r a t i v e m o r t a l i t y of 9,7 ~. High g r a d e lymphomas w e r e p r e d o m i n a n t in 64,6 % as well as stage I E in 47,7 ~ of cases (KIEL and M U S S H O F F c l a s s i f i c a t i o n ) . Surgical treatment alone has b e e n c a r r i e d out in 39 pts.; radio- and/or c h e m o t h e r a p y as an adjuvant or in a d v a n c e d d i s e a s e s was performed in 26 pts.. The o v e r a l l 5-years survival rate was 64,9 % and r a n g e d for the stage IE, IIE and IV E from 83,8 to 53,2 and 25 %. The best r e s u l t s (90,5 %) c o u l d be achieved in the g r o u p of surgical r e s e c t i o n alone, but w i t h a m a j o r i t y of stage IE-disease. A l t h o u g h the a d e q u a t e treatment for p r i m a r y g a s t r i c l y m p h o m a is disputed, surgical r e s e c t i o n seems to be t h e r a p y of choice, suggested by the own r e t r o s p e c t i v e results. But f u r t h e r m o r e the effect of additional radio- and/or chemotherapy, even in high risk cases or advanced diseases, has to be e v a l u a t e d in c l i n i c a l trials. Klinik f. Abdominal- u. T r a n s p l a n t a t i o n s c h i r u r g i e , M e d i z i n i s c h e H o c h s c h u l e Hannover, D-3000 H a n n o v e r

S173 5/P-GM068

5/P-GM 066 CLINICAL RESULTS OF TOTAL SKIN ELECTRON T H E R A P Y IN M Y C O S I S F U N G O I D E S LYMPHOMA

RADIO-

D.Annweiler, M.Damberg, U.Quast, H.J.Feldmann, H.Sack Between January 1983 and June ~987, 23 patients with biopsy proven Mycosis Fungoides lymphoma were treated with total skin electron radiotherapy (TSER). 17 patients (7 female, 10 male; age: 31 to 72 years) received rotational TSER and 5 patients (2 female, 4 male; age: 65 to 78 years) were irradiated in a lying position by using a multifields technique. A dose of 4 to 6 Gy per week (4 x ~ 0 - 1 . 5 Gy) was given until a total dose of 30 to 36 Gy. The irradiation was carried out at a linear accelerator using an energy of 5 or 7 MeV electrons according to the infiltration in the depth of the skin. All patients were staged at the date of TSEB by using the classification of the Mycosis Fu~goides Co-operative Group: IB 6 pts,~ IIB 12 pts., IVA 2 pts~ and IVB 3 pts.. Of the 6 patients in stage IB w,bo entered complete remission, 5 continued to he free Of disease until now and 18to 48 months (medium 34 months) after completion of therapy. One patient relapsed after 6 months. All patients in stage IIB died 3 to 30 months (medium I ! months) after therapy. 2 patients in stage IV died 2 and 12 months after TSER and 3 patients are alive with disease (survival 5, 6 and 17 months). With respect to the date of diagnosis the survival times are in general much longer. Before TSER most of the patients had a specific tumortherapy (chemotherapy,PUVA). Methods of irradiation, results of TSER and the possibility of curing patients with Mycosis Fungoides will be discussed. Universit~tsstrahlenklinik, Hufelandstr. 55, D-4300 Essen

P R O B L E M S OF E V A L U A T I O N IN C L I N I C A L T R I A L S W I T H E X T E N D E D T H E R A P Y DURATION, M E D I U M C R - R A T E A N D L O N G S U R V I V A L I L L U S T R A T E D BY H O D G E I N ' S D I S E A S E STAGE IIIB/IV D. H a s e n c l e v e r a n d M. L 6 f f l e r In clinical trials with a medium expected C o m p l e t e R e m i s s i o n Rate (CRR) of 20-80% and a m e d i a n survival of more than 5 years the wellknown endpoints, Survival (SV) and R e l a p s e Free Survival (RFS), are not fully adequate: SV demands a p r o l o n g e d f o l l o w - u p to detect a difference, is influenced by rescue therapies and is a n i n p l a u s i b l e endpoint for a c u r a t i v e therap e u t i c approach, RFS excludes patients who do not a c h i e v e CR; thus CRR and RFS p o s s i b l y lead to conflicting results. These problems are a v o i d e d by using F r e e d o m From T r e a t m e n t Failure. FFTF measures the time from diagnosis to the first of the following events: progression, nonCR at the end of treatment, relapse or death. This d e f i n i t i o n has to be refined if there are irregularities during treatment (e.g, excessive toxicity, protocol violations, treatment refusal). There are several p l a u s i b l e ways to account for these irregularities in FFTF. We d i s t i n g u i s h a) a p a t i e n t - c e n t e r e d pragmatic, b) a biological efficiency-oriented, and c) a p e r f o r m a n c e des c r i p t i v e approach. FFTF versions based on these a p p r o a c h e s differ s i g n i f i c a n t l y w h e n a p p l i e d to t h e d a t a f r o m t h e p r o s p e c t i v e trial of stage I I I B / I V H o d g k i n ' s d i s e a s e of the G e r m a n Hodgkin Study Group, We conclude that the approach c h o s e n to e v a l u a t e irregularities s h o u l d be specified in any publication. (supported by BMFT 01ZP550A)

U n i k l i n i k K61n, Hodgkin-Studie, Innate M e d i z i n I Josef-Ste~zmann-Str.9, D 5000 K61n 41

5/P-GM 067

5/P-GM 069

Primary gastric lymphoma: A r e t r o s p e c t i v e analysis of 24 cases K.R.Brandstetter,U.Keilholz,B.D~rken,W.Hunstein Medizinische Universit~ts-Peliklinik Heidelberg

COMBINED MODAL~TY TR~TMENT WITH CHOP-VP16 AND INVOLVED FIELD IRRATIATION FOR HIGH MALIGNANT NON-HODGKIN-LYMPHOMA: A PROSPECTIVE MULTICENTER PHASE II TRIAL H. K6ppler*, K.H. Pfldger*, K. Havemann*, I. Esehenbach*, R. Pfab, K. Lennert, W. Wellens, M. Schmidt, W.D.Gassel, T.Kolb, R. H~61er, K. Schumaeher,G.v. Speth~ C.Gropp, W.D. Hirschmann, H.H.GoSmann, S. 0hl, ~. Drings, D.K. Hossfeld U. Bruntsch

T h e r a p y of p r i m a r y gastric lymphoma is controv e r s e l y discussed. We have studied 24 patients treated b e t w e e n 1 9 7 5 - 8 7 : 5 patients w i t h stage I lJ p a t i e n t s w i t h stage II, 3 patients with stage ~I! and 5 patients w i t h stage IV. M o s t frequent were c e n t r o b l a s t i c iymphomas(9 pts). Either p a r t i a l or total g a s t r e c t o m y was p e r f o r m e d in 16 of 17 patients in stages I and II. 2 of 5 patients in stage I got local radiotherapy. All patients with s~age II received 6 cycles of poly c h e m o t h e r a p y ( C O P , C H O P or C O P B L A M ) . P a t i e n t s with stages III and IV w e r e p r i m a r i l y treated w i t h chemotherapy. RESULTS: Stage I: 3 of 5 patients survive d i s e a s e free. 2 patients died of other diseases than lymphoma. Stage I f : D i s e a s e free survival is 10/11 patients (follow up: 42(13-80) months). I p a t i e n t d e v e l o p e d bone m a r r o w relapse. Stages III and IV: 6/8 patients died 1-24(median IO)months after diagnosis. 2/8 patients are alive in relapse. CONCLUSION: In v i e w of the good results we recommend additional c h e m o t h e r a p y after o p e r a t i o n for patients in stage II of primary gastric lymphoma.

Sixty patients with high malignant Non-Hodgkin-Lymphome (NHL) stage If-IV were treated with 6 courses CHOP-VP16: cyelophosphamide 750 mg/m2 iv, adriamycin 50 mg/m= iv and vincristine 2 mg iv day I and etoposide 100 mg/m~ iv days 3-5. Between courses 4 and 5 an involved field irradiation with 25 Gy was employed. The overall response rate was 93% with a 82% complete remission rate (CR). During the median follow up of 40 months 22 of the 49 patients~ which had initially achieved CR relapsed. A maintained CR up to 60 months was seen in 65% of the patients in CR with a plateau of the disease free survival curve from 36 months on. Mean side effects of the drug regimen were alopecia (89%), nausea and vomiting (76%) and leukopenia (61%). No therapy related death were reported. In 15% of patients dose adjustments or omission of courses 5 and 6 occurred due to persistent leukopenia. This group of pts~ showed no difference to fully treated patients in terms of response or survival. As some of the relapses occurred in irradiated fields the chosen dosis of 25 Gy seems not adequat. Based On these data a randomized multicenter phase III trial was initiated comparing 4 courses of CHOP-VP16 + involved field irradiation with 35 Gy with 4 courses of an alternating chemotherapy (high dose CHOP alternating with IVEP (ifosfamide, vindesine, etoposide, prednisolone) + involved field irradiation (35 Gy). First analysis of 40 so far randomized patients show a complete remission rate in both arms in the same range as in the phase II trial. *Zentrum fHr Innate Medizin, Abteilung H~matologie/Onkologie/Immun01ogie, Baldingerstra6e, D-3550 Marburg

S 174

5/P-GM 070

5/P-GM 072

LONG-TERM OBSERVATION OF CENTROBLASTIC-CENTROCYTIC NON-HODGKIN~S LYMPHOMAS WITH E• MANIFESTATION IN STAGE IVA Annemarie K l 0 v e r , A . C a l a v r e z o s , R.Kuse

COP-BLAM/IMVP-16 SEQUENTIAL CHEMOTHERAPY FOR ADVANCED STAGE AGGRESSIVE NON-HODGKIN'5 LYMPHOMAS. H.H.Gerhartz, E.Thiel, G.Brittinger, B.D~rken, M.Engelhard, A.Engert, W:Enne, R.Fuchs, D.Huhn, E.Kayser, G.Kuse, E.Lengfelder, M.Sch~fers, H. Seibt, W.Siegert, W.Wilmanns, T.Zwingers, K.Lennert for the NHL-Study Group (Coordination Committee: G.Brittinger, R.Heinz, D.Huhn, P.Meusers, W.Siegert, A.Stacher, E.Thiel, W.Wilmanns)*

In 31 o u t o f 41 p a t i e n t s o v e r t h e p e r i o d 1976 1986 (median age 48, range 30-72 y e a r s ) t h e bone marrow was i n v o l v e d . The o t h e r s had p r e d o m i n a n t l y an i n v o l v e m e n t of l i v e r , p l e u r a a n d / o r i n t e s t i n e . P o l y c h e m o t h e r a p y (68%: CHOP, 17%: COP) achievedacomplete r e m i s s i o n (CR) in o n l y 10/41 p a t i e n t s . Most o f them r e c e i v e d c o n s o l i d a t i o n by l a r g e - f i e l d r a d i o t h e r a p y ; w i t h one e x c e p t i o n a l l remained r e l a p s e - f r e e . A second chemotherapy ( u s u a l l y HOAP-Bleo) o r a r a d i o t h e r a p y a t t a i n e d a CR in a n o t h e r 14 p a t i e n t s , a l t h o u g h o n l y 45% o f them remained r e l a p s e - f r e e . In a l l , 60% CR were a c h i e v e d and d i m i n i s h e d t o 36% w i t h i n 5 years. 5-year-survival probability for patients who n e v e r reached CR was 31%. However, t h e 10year-survival probability f o r a l l p a t i e n t s was 71% w i t h a c o n t i n u o u s p l a t e a u from t h e f o u r t h y e a r on. This was p o s s i b l e because even in p r i m a r i l y l e s s f a v o u r a b l e cases a s t a b l e d i s e a s e c o u l d be m a i n t a i n e d by f u r t h e r t h e r a p e u t i c efforts, like long-term chlorambucil treatment. The 31 p a t i e n t s w i t h bone marrow i n v o l v e m e n t had a s u r v i v a l r a t e o f 59% a f t e r 10 y e a r s , w h e r ~ as none of t h o s e w i t h o u t marrow i n f i l t r a t i o n d i e d . At t h e end of o b s e r v a t i o n 21 o u t of 32 l i v i n g p a t i e n t s had a CR. These r e s u l t s j u s t i f y p r i m a r y c u r a t i v e g o a l s u s i n g combined t r e a t m e n t m o d a l i t i e s in advanced CB-CC lymphomas o f stage IVA. H f i m a t o l o g i s c h e A b t e i l u n g des A l l g e m e i n e n Krankenhauses S t . Georg, LohmOhlenstraBe 5, D-2000 Hamburg I

We report on the German-Austrian multicenter chemotherapy t r i a l for aggressive non-Hodgkin's lymphomas of stages I I - I V which employs sequentially COPBLAM (5 cycles) plus IMVP-16 (2 cycles) followed by the randomized use of involved f i e l d radiotherapy. Response was determined after 3 courses and patients not achieving a complete remission (CR) were switched early to IMVP-16 ( f l e x i b l e strategy). Between 05/86 and 10/87 191 previously untreated patients entered the study (I01 male, 90 female, median age 55 years). 72 cases (38%) were in stage I I , 50 in stage I I I (26%) and 69 in stage IV (36%). Cons t i t u t i o n a l symptoms were present in 45%, bulky disease was found in 66%. Presently 145 cases are evaluable at I s t restaging ( a f t e r 3 cycles): 73 (50%) achieved CR, 56 (39%) were in p a r t i a l remission (PR) and 16 cases (11%) were unchanged or progressive. Second restaging or f i n a l outcome was evaluable for 85 patients: 52 (61%) achieved CR, 9 (11%) were in PR and 24 (28%) have not responded. Side effects of COPBLAMwere hematotoxicity (77%), nausea or diarrhoea (40%), infections (26%) and septic episodes (7%). Four patients died from infection in CR. Probability of survival reached a plateau at 60% by 1 year, relapse free survival of complete resonders was 65%, These data show that the majority of patients with aggressive non-Hodgkin" s lymphomas of advanced stages, though representing a group of r e l a t i v e l y high age, can be successfully treated by the sequential use of COPBLAM/IMVP-16 with an acceptable rate of side effects. *Supported by BMFT No. OIZP024. Med. K l i n i k I I I , Klinikum GroBhadern, D 8 Munich 70.

5/P-GM 071

5/P-GM073

HODGKIN" 8 DISEASE WITH PRIMARY BONE MARROW (BM) INVOLVEMENT: AN ANALYSIS OF 55 CASES. E . H i l l e r , H.H.Gerhartz, K.Smith, H.RUhl, H.FUIIe, M. L ~ f f l e r , M.Pfreundschuh, W.Wilmanns, V.Diehl for the German Hodgkin Study Group.

TREATMENT OF RELAPSING ~CUTE LYMPHOCYTIC LEUKEMIA IN ADULTS. M. Freund , A. C a l a v r ~ o s , M.~De Boben, H. Diedrich, A. Gans~r, G. Heil~ A. Heyll, M ~ H e n k e , W. Hiddemann, D. Hoelzer, P. Koch, H. Link, M. Planker, D. Renner and N. Schmitz (Relapsing ALL Study Group).

Primary bone marrow (BM) involvement by Hodgkin" s disease (HD) is r e l a t i v e l y rare but deserves special considerations for therapeutic strategies. During a 5 year period 55 cases of HD with primary BM involvement were reported to the German Hodgkin study group (6.7% of a l l documented cases) 43 of whom q u a l i f i e d for the study protocol (HD-3, stages IIIB and IV), The majority of these patients had B symptoms {80%) and an extension of the disease over 3 or more lymphatic regions (78%). Additional extralymphatic sites or the spleen were involved in 27 and 29%, respectively. The d i s t r i b u t i o n of histological subtypes was somewhat d i f f e r e n t to the whole population with a predominance of mixed c e l l u l a rity {42%) and nodular sclerosis (21%). A large mediastinal mass was s i g n i f i c a n t l y less frequent (5%) than in the whole study group. Patients qualifying f o r HD-3 had a similar mean age as all patients in that protocol (36 vs. 34 years) and a similar response rate (70 vs. 75%), So f a r , 3 relapses have occured. Therefore, patients with primary BM involvement, despite thought to be a poor prognostic group, have a very good chance of obtaining complete remission when treated by combination chemotherapy. Supported by BMFT No. OIZP5OOA. Med. K l i n i k I I I , Klinikum GroBhadern, Marchioninistr. 15, D 8000 Munich 70.

Only few systematic experience has been reported in the treatment of relapsing ALL in adults. Results with different treatment modalitiee in the ALL/AUL BMFT study group have been poor, Therefore a new treatment protocol has been established to test an intensive induction and consolidation therapy in relapsing adult ALL/ AUL. Induction consists in a first phase of VCR, DNR, Pred, Asp and a second phase of Hd (Id) AraC and VPI6. Patients achieving CR are randomized for two consolidation regimens. The first consists in Hd Ifosfamide end Vindesine, the other in Id MTX, AraC, VM26, Dexamethasone, 23 patients are evaluable for preliminary results. 19 patients had let relapse, 4 had 2nd relapse. 15/22 patients achieved CR (65%), I0 of them after induction phase I, 5 after phase If. Median remission duration was 2.8 mo. Side effects of induction consisted predominantly in hematotoxicity: Cytopenia grade IV occurred for mean 17 days in phase I, for mean 14 days in phase Ii. Infections, hepatotoxicity, mucositis, nausea/vomiting, diarrhea, alopecia were also observed. We conclude that the treatment regimen has high power for remission induction in relapsing ALL/AUL with tolerable toxicity. Whether the remission duration can be improved has to be determined in a greater number of patients.

Dept. Hematology/Oncology, Medical School, Konstanty Gutschowstr. 8, D-3000 Hannover 61

$175 5/P.GM074

5/P-GM076

ADDITION OF INTERFERON ALPHA 2 B IN PATIENTS WITH ADVANCED STAGES OF MULTIPLE MYELOMA (MM) OR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) REFRACTORY TO CHEMOTHERAPY (CT).

FREQUENT LACK OF MHC CLASS I AND CLASS II ANTIGENS IN B CELL LYMP~OMAS OF HIGH-GRADE MALIGNANCY 2 I P. MGllor-, G M01d~nhauer and F. Homburg An unsolectod series of 66 immunohistologically proven 8 cell lymphomas was examined for the expression of HHC class I antigens with monoclonal antibodies directed against non-polymorphic determinants of HLA-A,B,C, 8~microgl0bulin, HLA-OR, HLA-DP, HLA-DQ, and the class ~[ antigen-associated invariant chain (Ill by means of immunohistology using monoclonal antibodies against nonpolymorphic determinants. The tumors wore classified according to the Kiel classification, 30 being of highgrade and 36 being of low-grade malignancy, In 37 cases

J. Selbach, G. Huhndorf, H. Purea, H.-A. Vaupel, M. Westerhausen

Primary treatment generally can induce partial remission and prolong survival in MM as well as in CLL patients (pts). No optimal salvage therapy has been established for MM after M2 and VAn protocols and for CLL after LOP/COP treatment. Interferon alpha 2 b was added to cytostatics in six MM pts and in three CLL pts r e f r a c t o r y to CT. A slightly modified M2 protocol was used for MM pts. CLL pts had a combination of Mitoxantrone, Chlorambucil and Prednisone. In two out of six MM pts and in two out of pts good responses could be registered. In response to these regimens pts died within Partial remissions are lasting now for 4+ to

three CLL case of no three months, 6+ months.

In responding pts we could notice a measurable increase of performance status, weight gain,less frequent periods of hospitalisation, and fewer severe infections. Although the number of patients in those phase-ll studies is still small, we consider Interferon alpha 2 b a valuable adjunct to the management o f end stage MM and CLL pts. Med, Klinik I I , St. Johannes-Hospital, An der Abtei 7-11, D 4100 Duisburg 11'

(56 Z), a l l tumor c e l l s exhibited a strong staining f o r class I antigens as observed i n normal B c e l l s . The

remaining 2g cases (44 ~) showed an abnormally low or undetectable class I expression in varying tumor cell subsets~ 13 cases wore completely devoid of HLA-A,B,C. 22/30 lymphomas of high-grade malignancy but only T/36 lymphomas of low-grade malignancy presented defective class I expression. This d i f f e r e n c e i n proportion i s highly s i g n i f i c a n t (p=O.gOgO2). 1~/13 of the class I negative lympbomas belonged to the group o f high-grade

malignancy. Only 6 high-grade lymphomas and 16 low-grade lymphomas showed the coordinate strong expression of a l l HLA

class

I I antigens and i n v a r i a n t chain as observed in the normal peripheral B c e l l , 18 high-grade lymphomas and 12 lowgrade lymphomas contained varying tumor cell subsets t h a t were negative f o r NLA-OR, -DP, -DQ and l i in a selective

or

combined

of

class

II

manner. Three high-grade tumors were devoid antigens

and

Ii,

,expressed i n v a r i a n t chain only. grade malignancy was significantly

2

high-grade

tumors

The presence of high-

correlated with the occurrence of tumor c e l l s lacking HLA-DR (p=O.Og4), HLA-DP (p=0.013), HLA-DQ (p=O.O0?) or l i (p=0.024).

IPathologisches I n s t i t u t U n i v e r s i t ~ t Heidelberg. I n s t l t u t f u r Immunologie und Genetik am Oeutschen

und

Krebsforschungszentrum, O-BgOO Heidelberg

5/P-GM 075 DIAG~LST1CPROgbS~BIN PRItv~RYiqALIQ~tT LY~,PPGv~SOF T ~ STGv~OH R. Zankovich, R. Lorenz, V. Diehl A retrospective analysis is presentod of 24 cases of malignant l~ehcmas of the stc~ach classified according to the Kiel-Classification: 7 centroblastic/centroc~,$ic, 5 centroblastic, 3 !~!phopl~s~ocytoid, 3 l~i~obl~stic, 3 unclassifiable, I centroc/cic, I i1~munoblastic, ! peripheral T-cell l~phoma and I Hodgkin's l>~,~PhO~% mixed cellularity type. The Primary slte was the corpus (13 cases) and antrL~ (12 cases); in some patients multiple lesions were encountered. The sy~Dtc~,atology seemed to be like that of peptic ulcer or carcinoma of tlqe stomach: postprandial Pain 14 anorexia 14 vc~dting 14, weight loss 14, gastrointestinal bleeding ~ (heT~temesis and melaena), perforation 4 patients. The histological diagnosis of malignant l~,~homa of t~he stcmach is usually unexpected. Because of their uncharacteristic aPPearance ti~ese extranodal non-Hodgkin-h~Dhomas are d i f f i c u l t to ider~tify by endoscopic and radiologic procedures, Th~ features of ultra-sonography, bari~-meal and computed to~)graphy were anal~ed retrospectively, Only b a r i ~ meal could reveal suspicious features in 16 Patients, whereas ultra-sonography and CT sho~.~ in most cases a non-specific thickening of the wall. The most important diagnostic method has proved to be endoscopic ex~nination, which revealed solitary or multiple exulcerations in 14, erosions in 3, clubbing of the [~acosal folds in 9 and a diffuse ~ r a l infiltration in 6 cases, ~ire-loop biopsy serw~ to obtain sufficient ~L~ri~l ~uF t~~ histulogica~ ex~!1i~mtion.

~L~dizinische Universit~tsklinik I, Joseph-StelziT~nn-str, 9, D-5000 i<~In 41

5/P-GM 077 MACOP-B WITH RADIOTHERAPY IN ADVANCED HIGHG R A D E N O N - H O D G K I N ' S L Y M P H O M A (NHL) G. Krieger, M. Kneba, K. Wellenhofer, D. Meyer, G.A. N a g e l ............................................. MACOP-B has been reported to be a highly effective chemotherapeutic regimen for diffuse large cell lymphoma with acceptable toxicity (P. K l i m o et al., Ann. I n t e r n . Med. 102, 596, 1985). S i n c e O c t o b e r 1985, 28 p a t i e n t s (pts) w i t h a d v a n c e d N H L (stage II w i t h e x t r a n o d a l o r bulky disease: 9, III: 7, IV: 12) h a v e b e e n treated with MACOP-B and involved field irradiation. T h e N H L s w e r e c l a s s i f i e d a c c o r d i n g to the K i e l c l a s s i f i c a t i o n as f o l l o w s : CB : 10, C B / C C - - > C B : 4, IB : 4, K i - I - L . : 5, o t h e r s : 5. T h e m e d i a n a g e w a s 43 (22-75) yrs. O u t of 21 p r e v i o u s l y u n t r e a t e d pts, 19 a r e s t i l l in complete remission (CR). T h e m e d i a n f o l l o w - u p w a s 18 (2-24) m o n t h s . O n e p t r e l a p s e d a n d 1 p t died after partial remission. All pts received > 90% of the s c h e d u l e d d o s a g e . T h e m o s t f r e q u e n t t o x i c i t y w a s m u c o s i t i s w i t h g r a d e 1-3 i n all pts. T h e r e w e r e n o e p i s o d e s of s e v e r e s e p sis. 5 of 7 pts w h o r e c e i v e d M A C O P - B as s e c o n d a r y t h e r a p y for r e l a p s e a f t e r r a d i o t h e r a p y a n d / o r c h e m o t h e r a p y a c h i e v e d CR. In 6 p t s the d o s e h a d to b e r e d u c e d b e c a u s e of m y e l o s u p pression. MACOP-B combined with involved field r a d i o t h e r a p y is h i g h l y e f f e c t i v e w i t h t o l e r a b l e t o x i c i t y in p r e v i o u s l y u n t r e a t e d p t s w i t h a d v a n c e d h i g h - g r a d e NHL. It is e f f e c t i v e b u t too m y e l o t o x i c for p r e t r e a t e d pts. Abteilung H~matologie/Onkologie, M e d i z i n i s c h e Universit~tsklinik, Robert-Koch-err. 40, D4300 G G t t i n g e n

S176 5/P-GM 078

5/P-GM 080

EX~P~/~gDAL NON HCOGE/~'S LY~HOMA (h~L) OF THE HEAD ~ND NECK REGION A CURABLE DISEASE OF THE ELDERLY. C.R. Meier., B. Schrader 2, R. Chilla2, H.J. Habern~Iz 3, -

In 1986, 25 of 105 NHL patients (pts) seen here had extranodal NHL of ~he head and neck region, diagnosed during that year (n=5) or earlier, mostly in early stages (6 in stage I, 12 in stage If). Median age was 68 (range 16 - 91) years. 8 had sinuses or nose involved, 4 epipharynx, 5 t o n s i l / o r o / h y ~ , 3 salivary glare, 3 thyroid, and 2 orbital invasion. 11 have died, 10 of which with ~4L, one in cc~lete remission (CR). 11 pts are presently in CR, 13 to 50 (median 28) months post diagnosis. Median sn_rvival of pts who died was only 11 mmuths. 6/11 who died had high grade (Kiel) malignant 5~L, and 5 of these died within 9 m~n~hs. One with low grade NHL died after a 15 year course. All 4 with epipharyngeal NHL died (2/4 with high grade ~,~L). Presently in CR are 4/6 after surgery, 0/6 after radiation, and 7/13 after chemotherapy as first trea~nent. 5 of these latter 7 had received intensive (but age-adjusted) ccrabination (CABOPP) chemotherapy (M.R. Nowrousian, C.R. Meier et al, Blur 55, 246, 1987). CABOPP was used as 2~nd or 3rd m~dal i t y ~ another 3 pts now in CR. In 6/8 pts now in C R who received CABOPP, moder~ate to severe but slowly reversible neurotoxicity was the gravest side effect. Pts with low grade NHL did not receive J_ntensive chemothexapy. 18/25 pts had two, and 10/25 three m0da!ity therapy. However, 5 of 11 now in CR had only One, 5 had two (cY~motherapy and radiation), and only I had all three modalities. Pts now in CR are of similar age as the entire group, i.e. 3 are age 60 or younger, 5 are61 - 75, and 3 axe older than 75 years. We conclude that intensive, even mLlltimodality therapy may benefit s~lec~.ed pts with high grade NHL of the head and neck r e g ~ despite their o ~ ~ age. Medizinische , HNO-% Radiologlscbe Klinik ~ St. J ~ r g ~ a S e , Bremen

5/P-GM079

Between 1978 and 1985 140 adult patients with f i r s t diagnosis of high-grade NHL were seen in our oncological out-patient-department. I19 were evaluabel for fellow-up. Most of them received combination-chemotherapy (specially CHOP or a similar adriamycin-containing protocol). The majority was treated additionally with radiotherapy (mostly involved f i e l d ) , 31 pts. had a primary extranodal manifestation. 8 pts. died before beginning of therapy. The median follow-up was 31 months (1-I01), 93 pts. (78%) achieved a complete remission. 56 (47%) are alive and disease-free. 29/119 pts. are disease-free m o r e than 36 months following combination-chemotherapy and/or radiotherapy and have been examined with regard to late t o x i c i t y (16 male, 13 female; median age at diagnosis 39 years (19-70); histology: 8 cb, 6 ib, 8 Ib, 4 Burkitt-type, I anaplastic cc, 2 unclassified; stage (Ann Arbor): I 11, I I 7, I I I 5, IV 7; 12 pts. with B-symptoms; 7 pts. with primary extranodal manifestation; treatment: 20 pts. combined chemo-radiotherapy (mostly CHOP), 3 chemotherapy alone, 6 RT alone). A detailed analysis of this investigation w i l l be presented. Serious late t o x i c i t i e s were not seen. 2/29 pts. (6,9%) developed secondary cancer (1 breast, 1 uterus). Abteilung H~matologie Hochschule Hannover, D-3000 Hannover 61

und Onkologie, Medizinische Konstanty-Gutschow-StraBe 8,

5/P-GM 081

SURGICAL TREATMENT OF MALIGNANT LYMPHOMAS PRIMARY GASTRIC MANIFESTATION RELATED TO TUMOR-STAGING M.Pliesss K.-H.Schultheis, Ch.Gebhardt

WITH

The following retrospective study investigates 29 cases of malignant lymphomas with primary gastric manifestation,which were surgical treated in the Centre of Surgery,Clinic N~rnberg within a period of the last I0 years. The ocurrence was 2,6% of the overall gastric neoplasms,which were surgically treated.All cases were diagnosed by a preoperatively endoscopic biopsy. In relation to the staging specific surgical methods were used,lik e gastrectomy (n=ll) with the sametime splenectomy (n=7), B-II-resection (n=10), B-I-resection (n=4), local tumor-excision (n=3) and cardia-fundectomy (n=l). The prognosis was dependent on the staging following Ann-Arbor-classification,size of the tumor and infiltration of the gastric wall,but not of sex,age or histological classification. The letality was 10,3%(n=2),both not related to the neoplasm-de~ease(pneumonia,acute liverfailure). An adjuvant chemotherapy followed in II and radiation followed in 2 cases. Therefore chemotherapy and radiation is a therapy with acceptable results in the treatment of generalised malignant lymphomas,the surgical procedure should be elected as the primary ther apy of malignant lymphomas with primary gastric manifestation,following the principles of surgery in gastric cancer,depending o5 exact staging. Zentrum fur Chirurgie,Klinikum Flurstr.17 8500 N~rnberg

LATE TOXICITY IN PATIENTS WITH HIGH-GRADE NON-HODGKINLYMPHOMA. B. Metzner, M. M~llers, I. Schildmann, M. Freund, H.H. Kirchner, H . - j . Schmoll, H. Poliwoda

N~rnberg.

TREATMENT RESULTS OF ADVANCED HODGKIN'S LYMPHOMA V.Diehl, M.Pfreundsehuh, M.L~ffler, U.R~hl, H.Gerhartz, E.Hiller, D, Schoppe, H,Bartels and R.Fuchs, German Hodgkin Study Group 143 untreated patients with Hodgin's lymphoma in stages I - I l I A with r i s k factors received a combined chemo-radiotherapy (2 x COPP+ABVD + 40 Gy EF vs. 2 x COPP+ABVD + 20 Gy EF), HDi-Trial.230 Patients in stages IIIB/IV received induction chemotherapy (3 x COPP+ABVD) and w e r e randomized into consolidation by radiotherapy (20 Gy IF) vs. chemotherapy (1 x COPP+ABVD), HD-3 T r i a l . In HDI 73 of 89 evaluable patients (82%) achieved a complete remission. In HD3 86 of 137 patients (63%) achieved complete remission a f t e r induction chemotherapy with COPP+ABVD, This is s i g n i f i c a n t l y better than the 31% complete remission rate observed (p < 0.01), in a p i l o t study with COPP alone Including salvage therapy (radiotherapy in case of p e r s i s t i n g nodal disease; chemotherapy with 4x CEVD in ease of p e r s i s t i n g disseminated disease) a total of 76% complete remissions in stages IIIB/IVABwere achieved. Recruitment continues and updated r e s u l t s will be presented. Supported by BMFT 01ZP550A

S177

5/P-GM 082

5/P-GM 084

FAST ALTERNATING CHEMOTHERAPY WITH COP-ABV-IMEP IN PATIENT'S WITH ADVANCED HODGKIN'S DISEASE. C.Tirier, M.Pfreundsehuh, R.Fuehs, F.Wendt, M.Lbffler, H. Gerhartz, V. Diehl. German Hodgkin Study Group Med. Univ.Klinik D-500O Kbln

Lymphotoxin Expression end Secretion by Human B celt-

The German Hodgkin Study Group s t a r t e d a p i l o t study of a f a s t a l t e r n a t i n g chemotherapy cons i s t i n g of 3 non - cross - r e s i s t a n t combinat i o n s : COP (Cyelop~osphamide 800mg/m d l , Vinc~ ristin 1.4 mg/m d l , Predni~one 40 mg/m~ d l - 1 5 ) , ABV ~Doxorubicin 40 mg/m dl~, Bleomycin I0 mg/m d15, Vinblast~n 6 mg/m~ d15), and II~P (Ifo~famide 1000 m g / m d 2 9 - 3 3 , Et~posld 100 mg/m" d29-31~ Methotrexate 30 mg/m~ d31, Prednisone 40 mg/m d29-35) in order to improve r e s u l t s and p a t i e n t s ' compliance. Each part of the therapy was given two w e e k s a f t e r the preceding part ~r as ~oon as leucocytes recovered to ~.5 x 10 /n~a~ and p l a t e l e t s to 80 x 10~ / mm . Dose was not reduced u n l e s s therapy had to be delayed more than 2 weeks. 50 patients with Hodgkin's disease stages li - I I I A with r i s k f a c t o r s (large med i a s t i n a l mass, 3 or more involved lymph node a r e a s , extranodal d i s e a s e , and / or high ESR) and IIIB/IV have so f a r s t a r t e d COP/ABV/IMEP therapy. To date, 43 are evaluable for response. 32 p t s . had no prior therapy, 11 p t s . had been previously t r e a t e d . 3 0 / 4 3 (70%) p t s . achieved complete remission (CR) a f t e r 2-4 cycles of chemotherapy. With a d d i t i o n a l r a d i o t herapy, 38/43 (88%) of p t s . are in CR, COP/ABV/IEM~ was well t o l e r a t e d . Main t o x i c i t i e s w e r e leukopenia, s l i g h t nausea/vomiting and alopecia. COP/ABV/IMEP should be t e s t e d a g a i n s t standard protocols in a prospective randomized t r i a l . Supported by BMFT 01ZP550A

Lines

Lvmphotoz,in (LT) is sm~'reted b,,~T-;vmohocyte$ a~'teran{i.oen~cor m}togsmc st;mulation and snares most of its Notogicat activities with TNF alpha, a parUal homo;cgou~macroonegeproduct. We s:umiedLT mRNAexoressmn and LT sscret;on m vamous human B ceil tines.Three EBV transform~ B-ivrnphoNastoid ce!l lmes( BLCL), LICR.LON.HMy2(B lymphob~astic)and Raii (Burkitt ~ympnoma)were ShOWnto express an~ secrF,e LT, Se3re[]oa could be enhancedby phorbol myristate acetate(PMA), EBY n~3ativeBurkitt lymphemas Ramos and BJAB do not s~re{e LT but express LT mRNA. In contrast, BCABtB95.8t6,an EBV infected subclone,seeretesLT

constitutively. We conc!u~: LT mRNAexoress;en and secrstmn of the mature protein are independentlyr~uiated in trans~orm~ B ce!Is.

~.W.Hei!ig,M.Mapara,&$chuhm~cher,M.Hdner,W.Huns!ein an~ B,Dorken

Pied. Universit~ts-PolikHnik Heidelberg, HosDitatstr, 3 ,69 Heidelberg

5/P-GM 083

5/P-GM 085

CHEMOTHERAPY OF REFRACTORY HODGKIN'S DISEASE WITH CCNU, VINDESINE, ETOPOSIDE AND DEXAMETHASONE (CEVD). D. Schoppe, M. Pfreundschuh, K.-H. PfIUger, R. Fuehs, M. L6ff l e r and V. Diehl. German Hodgkin Study Group

MALIGNANT LYMPHOMAS OF THE HEAD AND NECK - AN INTERDISCIPLINARY CONCEPT D, Kn6bber~ H,-J, Wilhelm,V, Barth

The management of p a t i e n t s with advanced Hodgkin's d i s e a s e who f a i l to respond to primary treatment or r e l a p s e e a r l y a f t e r achieving complete remission (CR) remains a problem. To improve the prognosis of these p a t i e n t s , the German Hodgkin Study Group i n i t i a t e d a prospect i v e t r i a l with CEVD in p a t i e n t s r e s i s t a n t to both COPP and ABVD therapy. The CEVD protocol c o n s i s t s o~ CCNU (80 mg/m" p.o, dl) , Etoposid (1202 mg/m~ p.o. d l - 5 , d22-26), Vindesine (3 mg/m2 i , v . dl, d22), a~d Dexamethasone (3 mg/m p.o. d i - 8 ; 1.5 mg/m d9-26). To date, 32 p t s . are evaluable for response. 1 3 / 3 2 (41%) achieved CR, 5/32 (16%) achieved PR with an overall response r a t e of 56%. 3 p t s . showed s t a b l e d i s e a s e and 11 progressed. The median d u r a t i o n of CR was 8 months (range 2 to 34+). The main side e f f e c t s were leukopenia, thrombocytopenia, Cushing's syndrome including the man i f e s t a t i o n of l a t e n t d i a b e t e s m e l l i t u s and alopecia. The regimen was well t o l e r a t e d with only minimal nausea and vomiting. The observed response r a t e as well as the fact that long-term responses could be achieved is very encouraging. The e f f i c a c y of the CEVD regimen s u g g e s t s that the incorparation of t h i s r e g i mens or p a r t s of i t into primary chemotherapy of Hodgkin's d i s e a s e might be advantageous. Supported by BMFT 01ZP550A.

During the p e r i o d 1982 - 1987, 55 p a t i e n t s s u f f e r i n g from malignant Non-Hodgkin-lymphomaa

in the otolaryngo-

logical area have been diagnosed at the ENT-clinic of the University of Homburg/Saar.

There were 30 women and

25 men, their age ranged from 23 to 84 years. Different local sites have been found= tonsils, epipharyn• throat, paranasal sinuses, salivary glands and lymph nodes of the neck. The diagnostic pathway will bee demonstrated and it is pointed out, that the patients will be treated by an interdisciplinary concept. The results of this therapy are discussed concerning recurrences and survival rates. An unnsual case of Non-Hodgkin-Lymphoma

of the epiglottis developing

under intact mueosa ~ill he demonstrated by video (3 Min.) before and after therapy. Hals-Nasen-Ohren-UniversitQtsklinik D-6650 H o m b u r g / S a a r

S178 5/P-GM 086

5/P-GM 088

A ~eevalua~ion of Richter "s Ss~drome: De~elopmen~ of Cenfroblas~ic ~ of #he Thyroid in a Case of B ~ i . Tr~per, U. ~ a e ~ , W~ KT~Ui~, P. ~511er

COMBINED CH~STHEP4~Y(CT) WITH ADRIAMYCIN,BLEONYCIN,VINCRISTIN,ETOPOSIDE AND PREDNISONE(ABOEP) DOES ~ r INI)UCE GONADAL DYSPdNCTION IN MALE PATIENTS WITH HODGKIN'S DIS. G, Lautenschl~ger~ P.S. Mitrou, Th. Klippstein~ F. Walther

S i n c e M. R i c h % o r i n 1928 f i r s t d e s c r i b e d a reticular c e l l s a r c o m a i n a lm%ien% a l r e a d y ~ r ~ f f e r i r ~ f r o m c h r o n i c lymphocytic leukemia f o r several years, t h i s coincidence of %~o lymphore%ieulsr neoplasms is a well recognized

clinical and patholoa/cal entity. The term "Richter' s S~drcm~e" refers %0 a diffuse ~ds%ioc~ic l~nphom~ developing as %he %ermi~l mlignancu in a patient wi%h lon~s%andln~ CLL. We present a case of m cen%roblas%ic lymphoma, confined %0 %he %hyrold gland ~tnd %he adSolnin~ %iss~/es in an elderly woman with a five-year his%ox%~ of B-CLL (Stage I acc. %0 ]~ai). q~%e clinical picture ~r characteristic of a "prlmary" %h~vroid l~mphoma rather than a R/ch%er's s~ndrome. Bis%olo~icall~, the %hyroid %uz~or showed a mixture of sm~ll 15m~phoc~%ic cells and prolifert~%ing blastic tumor cells. Immumohistochemis%~ showed %ha% %he two B-cell populations expressed different la~G light chains on %heir surface. The bielonnlit~ of the two populations was proven hy ~ demons%ration of differen• rear~mx~-ed bands for the kappa ,rid lambda light ehe/n and %he heavy chain genes (~ene probes for the ~oinlnE regions of %he immunoglobulin hea~y chain and the constant r e g i o n o f %he kappaand lambda l i g h • chain genes were used, provided by P. Leder, Boston, [ ~ ) . We regard the cen%roblas%ic lym~hoa~a as a %rue s e c o ~ maliE~ancy supervening CLL in the case of our p~%ien%. The %era "Richter's S~ndrome" is i~z~pp~opria~e for this fsq~e of double l~amphoma. We suggest %o critieall~ evaluate %his term ar~ possibly restrict i% %o cases where a progressive ~%Ii8~n% %ransfoxTaa%ion of a single B cell clone occurs. Medizinische Kllnik und Poliklin/k V und Pa%hologisches L~isti%u% der Universi~%, Hospitals%r.3, 69 Heidelberg.

Gonadal dysfunction and increased risk of developing second malignancies are frequent late complications in HI) patients treated with CT or C~+RT. Their frequency is significantly lower with ABVI) than with MOPP. ABVD treatment is complicated by severe GI-toxicity. We present preliminary results with a regimen which do not contain either alkylating agents or DTIC. Patients: 13 pts. with stage IIA to IIIA and adverse progno~c--factors were entered in the study. Tile median age of the 8 mm.les and 5 females was 35 yrs.. Histology was nodular sclerosis(7/13) or mixed cellularity(5/13). 12 pts. were previously untreated and 1 in first relapse. Treatment: ABOEP: AI~! 25 mg/m = i.v., Bh%~ I0 mg/m ~ i.v., TR~R 2 mg i.v. days I+8, E I00 mg/m ~ i.v. days I-4, PDN 40 rag/m2 p.o. days I-8. All pts. received at least 4 cycles of CT followed by EF-radiation with 30-36 Gy. Results: 12 pts. entered CR and 1 PR after 4 cycles of ~E~, All pts. were in CR after CT+RT. The median follow up is 13 mo. with all pts. remaining in CR. ~dO-grade 3 or 4 toxicity was observed in 2% for Hb, 18% for WBC, 2~ for platelets, 16% for GI, and 25 of mucositis of the ABOEP-courses. Pneumonia oc~ared in I pt.. Gonadal function: In a control group of pts. treated with ~ P P / A B ~ ) alls pts. had azoospermia with high FSH and IH levels I to I0 yrs. after discontinuation of treatment. 2 pts. treated with ABOEP and pelvic irradiation had also azoospermia. 3 pts. treated with 4-6 cycles of ABOEP without pelvic irradiation had a normal spermi0gram~ or asthen0spermia with normal FSH- and LHlevels 3 to 6 months after discontinuation of treatment. In conclusion~ from the preliminary results it appears that A]3OEP is an effective c0mbination with 10w toxicity, which d0es not cause infertility in young men. Division of Haema~,10gy/0ncol0gy, Dept. of Internal Med., J.W. Goethe University, Frankfurt/M.

5/P-GM 087

5/P-GM 089

COMBINATION CHEMOTHERAPY (CABOPP/VIM) FOR THE TREATMENT OF HIGH-GRADEYu~]IGNANT NON-HODGKIN'S LYMPHOMAS (NNL) M.R. Nowrousian, C.R. Meier, C. Anders, B. Schoetensack, K. H~ffken, R. Osieka and C.G. Schmidt

HODGKIN'S DISEASE AFTER THERAPY: AUTOPSYRESULTS. B. GUnther and K. Donhuijsen

A new treatment program was used in an attempt to improve the results in patients (pts) with aggressive NHL. Therapy was started with a combination of Cyclophosphamide (500 mg/m2, day I), Adriamycin (50 mg/m 2, day I), Bleomytin (i mg q 8h x 15), Vincristin (I mg/m2/day, days 1,8), Prednisone (50 mg/m2/day, days i-i0) and Proearbazine (i00 mg/m2/day, days 1-10)(CABOPP). Treatment was repeated every 3 wks. In pts with complete response (CR) after a maximum of 4 cycles of CABOPP, this regimen was given for a further 2 cycles. In pts with progressive disease or with only a partial remission, therapy was switched to a combination of VP-16 (90 mg/m2/day, days 1,3,5), Ifosfamide (1200 mg/m~/day + Mesna, days I-5) and Methotrexate (30 mg/m2/day, days 1,5)(VIM). In pts with bulky disease, additional radiotherapy was given to the involved area following chemotherapy. Between June 1983 and August 1986, a total of 42 pts with high-grade malignant NHL (Kiel classification) entered the study. Of these pts, 6 had stage I, 9 stage II, ii stage III and 16 stage IV of the disease. 36 out of 42 pts (86%) achieved CR. Of these 36 pts, 29 obtained CR with CABOPP regimen alone and 7 after additional chemotherapy with VIM. The rate of CR was 100% in pts with stage I or II, 91% in those with stage III and 69% in those with stage IV of the disease. The projected survival for the whole group of pts is 66% at 2 years. 56% of pts with CR are predicted to have continued CR at 2 years. On the basis of these results, CABOPP/VIM protocol appears to be an effeetJxe therapeutic program in pts with aggressive NHL. Effectiveness of this program as compared to the other newly developed protocols, however, can only be established by prospective randomized studies. Westdeutsches Tumorzentrum, Innere Universit~tsklinik und Poliklinik (Tumorforschung), Hufelandstr. 55~ 4300 Essen

Autopsy findings of 84 pts. with Hodgkin's disease (HD) out of the period 1975 - 1987 were reviewed. The o v e r a l l median age was 44 years (range 15 - 84). 79 pts. received r a d i a t i o n therapy and/or chemotherapy, 58 of them in combined form.

21 of 79 pts. (27 %) had no postmortem evidence of HD. 34 pts. (43 %) had widespread HD with pronounced manifestation. Histologically the LD subtype was the most frequent at autopsy whereas NS and MC subtypes predominated on diagnostic biopsies. Discreete histological rest i n f i l t r a t e s of HD could be detected in 15 pts. 45 pts. (57 %) showed serious side effects of therapy: pulmonary fibrosis (20 pts.), bone marrow depletion followed by bleedings or sepsis (12 pts.), second malignancies (7 pts.), pericarditis constrictiva (3 pts.), and in one case a necrotic c o l i t i s , an Opsi syndrome and a radiation induced myocardial infarction, The cause of death was independent of HD in two pts. only (bronchiogenic Ca; myocardial infarction). Our results exhibit that nearly the half of the pts. died in relationship to side effects of therapy. Even i f the series may be a negative selection the question w i l l arise wether the intensity of therapy is reducible or more individual therapeutic modalities are possible without diminishing the remission rates markedly. Universit~tsinstitut fur Pathologie (Dir. Prof. Dr. L.-D. Leder), HufelandstraBe 55, D-4300 Essen l

S179 5/P-GM 090

5/P-GM 092

RESPONSE AND T O X I C I T Y OF D I F F E R E N T DOSES IN HEPATIC ARTERIAL INFUSION U. Krause,

E. Gross,

M. Schax,

FUDRtHAI.)

M. Be?er

ANALYSIS OF TECHNICAL PROBLEMS RESULTING IN DISCONTINUATION OF LOCO REGIONAL CHEMOTHERAPY M. Burk, W.D. Sehoppe~ R.M. Jungblut, B. Ulrich, M. Sehmolke~ M. Planker~ F.W. Sehttter, W. Sqhneider -

Since 9/1984 - 10/1987 we treated 16 patients w i t h colorectal metastases of the liver by continuous arterial infusion of FUDR. From 1984 - 1986 we used an implantable infusion pump (Infusaid) and acimini~tered a dose of 0,3 m g / k g / d a y of FUDR for 14 days (i0 pts.). In 10/86 we changed the protocol and adrninistered 1.0 m g / k g / d a y FUDR for 5 days (6 pts.), using external pumps. Results: In the first group (long term infusion) we observed 1 complete response (duration: 6 months) and 4 partial responses. 4 patients were c l a s s i f i e d as minor response or no change. 2 patients were progressive under therapy. Hepatic toxicity occured in 5/10 patients. One patient developped b i l i a r y sclerosis. One patient had severe chemical hepatitis. Another 3 patients had significant rise of liver enzlnnes. In the second group (short term infusion) we administered 23 cycles of treatment. We observed no partial response. One patient had a minor response, one patient showed no change. 4 patients have p r o g r e s s i v e disease. Hepatic toxicity occured in 3 patients (i x chemical hepatitis, 2 x rise of enzymes). No biliary sclerosis was observed. Conclusion: We conclude from our experience with HAI, that short term F U D R - i n f u s i o n is less toxic to the liver than long term infusion, but response rates are poor. As a consequence, different drug regimens or combinations have to be studied.

Locore~ional chemotherapy is an attractive alternative to conventionally intravenous application of cytoreductive drugs. We studied technical complications of 30 consecutive patients with intra-arterial chemotherapy: 23 pat. with liver metastases of colorectal cancer, 4 pat. with hepatocellular carcinoma, i pat. with malignant sarcoma (all hepatic artery), and 2 with malignoma in the maxillar region (maxillary artery). 133 courses of regional chemotherapy have been applied (0 to 12 cycles per pat.). We observed the following local problems: easily manageable local infections {2 pats.); thrombosis of the catheter (5 pats.), of whom 3 could he readily lysed with l o c a l urokinase; progressive thrombosis of the hepatic artery (7 pats.); paravasal perforation (3 pats.) and breakage or leakage (2 pats.) of the catheter. A complication not described before was well documented radiographieally: therapy induced necrosis of tumor masses of the liver an4 consecutively formation of artery-biliary fistulas (3 pats.) leading to stop of the local treatment. Handling of subcutaneously implanted catheter systems is complex and must he carefully trained by all physicians involved. The most important problem is the thrombosis of the regional artery~ caused by as inappropriate surgical technique. Interruption of regional chemotherapy is often caused by local problems. We could not observe systemic adverse effects or dru~ induced regional toxicity leading to discontinuation of this therapeutic approach.

University

Abtlg. fdr H~matologie, Onkologie und kllnlsche Immunologic der Medizlnischen Klinik dam Universitfit~ Moorenstr. 5, D-400O Dfisseldorf

of Essen

5/P-GM 091

5/P-GM093

PROGRESSIVE LIVER METASTASES OF COLORECTAL CANCER AFTER SYSTEMIC CREMOTRERAPY RESULTS OF INTRAHEPATIC RETREAT~NT USING FLUOROPYRIMIDINES P.Hohenberger, P.Schlag, U.Raeth, R. Herrmann .........................................................

I n d i v i d u a l Drug S e l e c t i o n for R e g i o n a l C h e m o t h e r a p y by In Vitro Testing.

16 patients with liver metastases of eolorectal cancer being progressive under systemic chemotherapy underwent implantation of a port-system for regional intrahepatic chemotherapy. All patients had undergone at least two different systemic treatment schedules, mainly 8-FU and as a second-line drug methotrexate, mitomycin C or BCNU, All patients showed no evidence of extrshepatic metastases and the liver was the isolated site of ttD~or progression. At laparotomy two patients had positive lymph nodes at the hepatoduodenal ligament and were treated by external radiation therapy of the liver hilus, additionally to regional chemotherapy. Regional chemotherapy consisted of 8-FU (800 - I000 ~/m2/d) continuously given for 8 - i0 days in threeweeks intervals or FU-DR 0,3 mg/m~/d for 14 days. Reexamination by CT-scan was perfo~ed after each 3 cycles of therapy. Treatment results: At reexamination 3 patients had a partial response (PR), 1 had a minor response (MR), 3 patients had stable disease (SD), while 8 patients showed tumor progression (PD). 1 patient is too early to evaluate. Of the 8 patients with PD four had developed extrahepatic metastases additionally. Response rate including PR + ~ + SD was 7/18 = 48,~. Medis~u survival time was 12 months, median survival of respenders 14 months. Conclusion: In nearly the half of our patients regional chemotherapy was able to control progressive liver disease after previous systemic treatment. Department of Surgery and Internal Medicine, University of Heidelberg, Im Neuenheimer Feld ii0, 8900 Heidelberg, ~RG

K.H.Link Chir.l,

and H.G.Beger. University

Ulm

(Head:Prof. H.G.Beger)~

H i g h dose i n t r a a r t e r i a l c h e m o t h e r a p y (HD!AC) produces h i g h e r r e s p o n s e rates in the i n f u s e d tumor target than c o n v e n t i o n a l systemic chemot h e r a p y due to dose r e s p o n s e h e h a v i o u r of drugs s e l e c t e d for HDIAC. - To optimize r e s p o n s e r a t e s to H D I A C we i n v e s t i g a t e d the use of in v i t r o drug t e s t i n g of i n d i v i d u a l tumors a p p l y i n g the soft agar c o l o n y forming assay a c c o r d i n g to Hamburger/Salmon. We performed a p r o s p e c t i v e correlative ('test drugs' but 'treat to standard protocol') a n d a decision a i d i n g ('test drugs' a n d ' t r e a t w i t h drugs active in v i t r o or treat to s t a n d a r d protocol if no drug is active in vitro') trial. The c o m p a r i s o n of in vitro r e s p o n s e s w i t h in rive r e s p o n s e s y i e l d e d the f o l l o w i n g results (S= sensitive, R= resistant): in v i t r o / i n

rive

P r o s p e c t i v e correlative Decision aiding

S/S 21 6

S/R

R/S

O 1

3 I

-R/R

These r e s u l t s s u p p o r t our decision to use drug testing for i n d i v i d u a l drug s e l e c t i o n as part of a n e w protocol for H D I A C of hepatic colorectal=metastases.

Supported

by DFG grant Li 316/3-2.

S 180 5/P-GM 096

5/P-GM 094 ~XPERIMENTAL STUDIES ON ADJUVANT CHEMOTHERAPY IN COLORECTAL CANCER J.LANGE; J.SCHAFF, J.R,SIEWERT,G,BLUMEL Introduction: The issue of prevention

INTRAPERITONEAL

adjuvant chemotherapy in the

and systemic failure in patients with still debated. Systemic chemotherapy p e r i o p e r a t i v e l y d i d not i m p r o v e the r e s u l t s , Local r e g i o n a l t h e r a p y v i a the p o r t a l v e i n d e c r e a s e d the incidence of l i v e r m e t a s t a s i s , however the number of local f a i l u r e s and the number of p e r i t o n i t i s c a r c i n o m a t o s i s could not be i n f l u e n c e d . Objects: An e x p e r i m e n t a l s t u d y in r a t s w a s developed to i n v e s t i g a t e whether p e r i o p e r a t i v e i n t r a c a v t t a r y chemotherapy h a s a n e g a t i v e impact on wound h e a l i n g of colon a n a s t o m o s e s . Major objective of t h e s t u d y w a s the i d e n t i f i c a t i o n of the optimal t i m i n g for i n t r o d u c i n g the a d j u v a n t i n t r a p e r i t o n e a l chemotherapy perioperatively without causing major complications,

DRUG LEVELS IN ISOLATED EXTREMITY PERFUSION H. Walther, K.R. Aigner, H. Mueiler, H. Voigt Dept. of Surgery, KKH Trostberg , Siegerthoehe D-8223 Trostberg

I

of local

colorectal cancer is

Method: The colon of rats was cut at two points and the reanastomosation was done with 8xO Vicryl. 3 groups were formed: I. intraperitoneal c h e m o t h e r a p y with 8 FU (25 mg/kg body weight) 2. intraperitoneai chemotherapy with mitoxantrone (20 mg/mz body surface} 3, control: i n t r a p e r i t o n e a l R i n g e r solution Chemotherapy was i n j e c t e d i n t r a p e r i t o n e a l on d a y 0,2~4 and 8 p o s t o p e r a t i v e l y . Controls of the a n a s t o m o s e s were performed on d a y 2,4,8 a n d 14 p o s t o p e r a t i v e l y . Each s u b g r o u p c o n t a i n e d 10 a n i m a l s . The i n f l u e n c e of i . p . c h e m o t h e r a p y on the p r e s s u r e of the bursting point, the content of collagen, the angiogramm, the microscopic and the raster electron microscopic e f f e c t s was e v a l u a t e d . Results: The i n t r a o p e r a t i v e a p p l i c a t i o n of c y t o s t a t i e s led to a s i g n i f i c a n t d e c r e a s e Of the p r e s s u r e of the b u r s t i n g p o i n t : n a d i r for fi FU on d a y 4 (67% of controls}, f o r m i t o x a n t r o n e day 8 (50,7% of controls}, Application of c y t o s t a t i c s on d a y 2 p o s t o p e r a t i v e l y did not s i g n i f i c a n t l y d e c r e a s e the p r e s s u r e of the b u r s t i n g - p o i n t ( ~ 80% of control v a l u e ) The fact t h a t no i n s u f f i c i e n c y of a n a s t o m o s i s w a s o b s e r v e d m i g h t r e l a t i v a t e the c l i n i c a l importance of the p r e s s u r e of the b u r s t i n g point. Conclusion: According to our r e s u l t s a d j u v a n t i n t r a p e r i t o n e a l chemotherapy could be i n i t i a t e d e a r l y in the p o s t o p e r a t i v e period,

Tissue uptake of cytostatic drugs is directly related to serum concentrations in the perfused area. Increase of response can be achieved by increase of the AUC (Area Under the Curve) product at the tumor site. For iliac perfusien the extremity is isolated in a standarized technique according to Krementz In order to achieve permanently high arterial drug levels for enlargement of AUC, the drug is infused directly into the arterial line over a 15 - 30 min. period, while at high oxygen tension the roller pump flow rate is decreased to 80 - 120 ml/min.. By means of flow reduction and drug infusion into the arterial line max. arterial drug levels (CDDP, L-PAM, MMC) are increased significantly as compared with historical techniques: drug injected directly in oxygenater. Medium increase of serum levels was 2-fold in CDDP, 4-fo!d in MNC and 6-fold in L-PAN.

C h i r u r g i s c h e Ktinik und P o l i k l i n i k , Klinikum r e c h t s d e r I s a r l s m a n i n g e r Str. 22, D-8000 M~nehen 80

5/P.GM095

5/P-GM 097

TISSUE LEVELS OF MITOMYCIN C, M I T O X A N T R O N AND CIS-PLATINUM DURING I.A. VERSUS I.V. CHEMOTHEBAPY K.R. Aigner, H. Walther, H. Mueller, G. de Toma Dept. of Surgery, KKH Trostberg, SiegerthOhe i, 8223 Trostberg

Carboplatin and Etopoeide Combination Chemotherapy in Small Cell Lung Carcinoma (SOLO) W. Hoffmann, F.Lohove, B.Weidmann, F.Migeod, S.Seeber

The correlation between MNC serum levels and first pass extraction was investigated in isolated liver perfusion (ILP) (a). Tissue uptake of MMC and Mitoxantron was measured during intraoperative systemic as well as intraarterial c h e m o t h e r a p y (b). CDDP tissue levels were determined in liver tissue, center and periphery of metastases. Results: a) During 30 min. infusion into the arterial line in ILP M N C - l e v e l s range between 20 - 50 ug/ml, e x t r a c t i o n rate is 95 - 98 %, The foliowing 30 min. arterial MMC conc. decreases to 1 - 3 ug/ml and extraction to

7O %. b) During hepatic arterial versus i.v. bolus infusion max. tissue level ratios (i.a.:i.v.) in parenehyma, metastases and muscle are ~0 : i, 4 ~ i, I : 2. c) CDDP tissue levels are s i g n i f i c a n t l y higher in periphery than center of metastases (7 - 9) : i.

Garboplatin is a leas toxic second-generation platinum analog and is currently used in anticancer regimes. The combination of Carboplatin 2~0-300 mg/m2i.v. day I and Etoposide 100-120 mg/m days 1,2,3 was given every 21 to 28 days to 14 patients suffering from SOLO (all extensive disease). In 3 patients with pratreeted SGLC (ext.dis) a partial response was noted (30 %) 2 showed no change (20 %) and in 5 (50 %) progressive disease was observed. 4/14 patients had no prior chemotherapy. 5/4 patients showed a clinical response (I OR; 3 P.R.). In 1 patient a no change status was documented. Duration of remission in the group with pretrested SOLO ranged between 2 and 5 months and 4 end 6 months for untreated patients. Drug toxicity was moderate. WHO Grade I neutropanie occurred in 62 % of 73 courses eveluable for toxicity. Nausea and vomiting (Grade I or 2) were registered in 70 % of all courses. We conclude that Oarboplstin is s well tolerated and effective agent in the treatment of SOLO. I% offers useful palliation and shows even activity in pretreated patients with extensive stage of SOLO; the data will be extended in order to define the position of Gsrboplstin relative to Ois-platin in this disease.

S 181

5/P-GM 098

5/P-GM1O0

THE HYPERREACTIVITY OF THE BRONCHIAL AIRWAYS OF PATIENTS WITH BRONCHIAL CARCINOMASIS NOT INFLUENCED BY CHEMOTHERAPY. H. Magnussen, M~ Heckmayr, U. Gatzemeier, 6~ Reuss, R. Jerres.

MITONYCIN-C/IFOSFANID VERSUS MITOMYCIN-C/VINDESINE VERSUS BISPLATINUM/ETOPOSIDE IN ADVANCEO NON-SMALL-CELL LUNG CANCER (NSCLC) - A PROSPECTIVE RANDOMIZED TRIAL U. Gatzemeier (1), N. Heckmayr (1), D.K~ Hossfeld 2 (2)~ E. Kaukel (3), G~ Koschel (3), R. Neuhauss (1), R. Zsehaber (2)

INTRODUCTION. The hyperreactivity of the bronchial airways is effected by inflammatory cellular reactions within the bronchial epithelium. In animal experiments, inhalation of ozone leads to increased hyperreactivity of the bronchial airways, which increased proportionally with the number of neutrophil granulocytes in the bronchial epithelium, Due to cytotoxic drug like nitrosurea this reaction can be stopped in the animal model. PATIENTS AND METHODS. We investigated the effect of chemotherapy on the hyperreactivitiy of the bronchial airways and the number of leucocytes in the peripheral blood of ten patients with inoperable bronchial carcinomas. At the beginning of the investigation, all of the patients were extremely responsive to methacholin . All of the patients had clinical and endoscopic chronic bronchitis, which was not combined with increased airway resistance. The inhalative methacholin provokation and determination of differential blood pictures was done before, and 8 and 16 days after chemotherapy with eisplatin/etoposide or cytoxan /etoposide. RESULTS, The mean numbar of leucocytes was 9.4 cells/nl at the beginning of the chemotherapy, 4,1 cells/nl 8 days afterwards, and 5.2 calls/nl 16 days afterwards. The mean PD100 sRaw was 3.5 mg/ml at the beginning, 4.2 mg/ml 8 days afterwards and 5.2 mg/ ml 16 days afterwards, CONCLUSION. The chemotherapy lead t o a s i g n i f i c a n t decrease in the number of leucocytes in the peripheral blood, as expected, which had no relationship to the hyperreactivity of the bronchial airways. There is no influence of hyperreactivity by chemotherapeutic drugs like in the animal model. Krenkenhaus Grosshansdorf, Zentrum f~r Pneumologie und Thoraxchirurgie~ NShrendamm 80~ D-2070 Grosshansdorf.

INTRODUCTION: Despite of remission rates of 30 - 40 % in inoperable NSCLC the prolongation of survival due to chemotherapy is still questionable, PATIENTS AND METHODS: In a prosepctive randomized fashion patients received a chemotherapy consisting of: A: Nito-C 10 mg/qm day 1 i,v./Ifo. 1,8 g/qm day 1 - 5 inf. + uroprotection, B: Nity-C 10 mg/qm day I i,v./VDS 3 mg/qm day $ + 8 i.v. C: DDP 40 mg/qm day I § 4 i n f . / V p - 1 6 125 mg/qm day 1 - 4 inf. From July 1985 u n t i l 7/87 213 p a t i e n t s were entered into the protocoll. 192 were evaluable for response. All patients had extensive disease, Age, sex, performance status and histology were equally distributed over the treatment groups. RESULTS: Objective response (CR + PR) has been observed A: 30,3 %, B: 22,7 %, C: 25 % (p D,4, n,s.). Median survival time for all patients was A: 6,5 months, B: 5,5 months, C: 6,0 months (p 0,7). A significant difference between the different groups we had in gastrointestinal t o x i c i t y (WHO 3 + 4 ) . Nausea: A: 43,9 %, 8 : 6 , 1 % , C: 36,7 % (p 0,0001) and vomiting A: 28,8 %, 8: 1,5 %, C: 23,3 % (p 0,0001). No hematological problems occured in all groups. CONCLUSION: There is no significant difference in remission and survival between the different treatment groups. Mito-C/VDS is superior to the other groups because of the minima], toxicity esp. gastrointest, toxicity and alopecia, Furthermore patients with NSCLC shouldn't treated with DDP because of the toxicity, So there is a need for a prosp, randomized trial with the comparison between supp. care alone and a combination ehemotherapy. Dep. of Thoracic Oncology, Gre6hansdorf Hospital (1) Dep. of Hematology and Oncology, Univ. Hamburg (2) Dep. of Pneumoloey, Municipal Hospital HbB.-Harburo (3)

5/P-GM 099

5/P-GM 101

CARBOPLATIN IN THE TREATMENTOF NON SMALL CELL LUNG CANCER. A PHASE I I TRIAL. Th. Munski (1), M. Heckmayr (1) , U. Gatzameier (1), K.D. Hossfeld 2 ~ _ R , Zschaber ~ ) .

ORAL ETOPOSIDE ( VP 16.213 ) FOR ELDER PATIENTS WITH SMALL CELL LUNG CANCER, ,N, Dunkbase~ M. Heck q k ~ y r , U. Gatzemeier R, Neuhauss . . . . .

INTRODUCTION. Carboplatin is a cisplatin analogue without significant nephroto• or neurotoxicity and with less emetic potential than the parent compound. It has clinical activity against several tumor types and is especial~ ly effective in the treatment of small cell lung cancer. PATIENTS AND METHODS. In a phase II study of 29 patients ~ we tested the activity of carboplatin in inoperable advanced NSCLC~ The patients characteristics were as follows: 23 men and 6 women with the mean age of 58.4 years (47-70 yrs) and with a mean Karnovsky-index of 85%. 26/29 patients had an extensive metastasising tumor, and 3 had a limited, inoperable disease.The histology was adeno (n=5), epidermaid (n=15), undifferentiated (n=2), and large cell carcinoma (n=7). Schedule: 130 mg/qm day 1/3/5, every four weeks. RESULTS. Up to now 23 pts. ere evaluable for response, 4/23 (17,4 %) partial remissions have been observed. 11/23 (47,8 %) had no change~ 8/23 (34,8 %) had p r o gressive disease. The patients were better able to tolerate carbaplatin than cisplatin, although the myelotoxicity was more intense. CONCLUSION, Carboplatin is only moderately effective in the treatment of NSCLC with a remission rate of approximately 15 %, but without severe side effects~ Thereby this analogue is little less active than cisplatin in NSCLC. But because of the very less toxicity we have to look also for the effectiveness in combination with other active drugs like VP 16, ifosfamide, vinca- alkaloide etc. Department o f Thoracic Oncology, H o s p i t a l Grosshaosdorf, WShrendamm 80~ D-2070 Grosshansdorf (1) Department o f Hematology and Oncology, U n i v e r s i t y Hospit a l , N a r t i n i s t r . 20, D-20OO Hamburg (2)

INTRODUCTION. Etoposide, a podophyl l ot oxi n d e r i v a t e , i s one o f the most e f f e c t i v e agents i n the treatment o f small c e l l lung cancer. The drug i s t h e r e f o r e incorporated i n t o many combination chemotherapy regimens, and i s also used as a s i n g l e agent. Through s p e c i a l preparations i t i s possible t o give eteposide o r a l l y with a b i a a v a i b i Iity o f nearly 50% and with b e t t e r c o m p a t i b i l i t y . It is t h e r e f o r e e s p e c i a l l y u s e f u l in the therapy o f a g e - r i s k patients. PATIENTS AND METHODS. Since 2/87 we treated 24 patients more than 70 years or poor performance status with SCLC with oral etoposide 500 mg/qm weekly over 3 consecutive days.This schedule was repeated up to six times (mean 3 cycles). The patients" characteristics were as fellows: m/f r a t i o 17/7, mean age 74,5 (65 - 83), stage 14 LD, 10 EB. The mean Karnovsky-index was 80%~ Fourteen patients did net receive any other chemotherapy regimen previously~ RESULTS, There were 2/24 CR (8,3 %), 6/24 PR (25 %), 1/24 minimal response (4 %)~ 7/24 NC (29 %)3 6/24 progress (25 %). Overall response rate 33,3 %. The side-effects seen were alopecia, mild gastrointestinal disturbances, and myelosuprression. Severe myelosuppression was however observed in six patients. One patients died with signs of sepsis due to agranulocytoais: CONCLUSION. Oral etopeside which has a remission rate of 33,3 % is an effective drug in the treatment of SCLC for elder patients. By means of prominent myelotoxicity~ especially in previously treated patients, regular cantrols of blood pictures are necessary and the therapyfree intervals have to be prolonged or the dosage has to be reduced. Department of Thoracic Oncology, Hospital Groashansdorf, N6hrendamm 80, D-2070, Grosshansdorf,

S 182 5/P-GM 102

5/P-GM 104

CHEMOTHERAPY OF SCLC WITH 4-EPIRUBICIN/IFOSFAMIDE AND VINDESINE T. Stahlknecht, U. Gatzemeier, M. Heckmayr, R. Neuhauss

PILOT STUDY WITH CARBOPLATIN (C) / ETOPOSIDE (E) IN EXTENSIVE STAGE OF SMALL CELL LUNG CANCER H. W. Tessen, M. Wolf, K. Hans, W. Achterrath, K. Havemann, P. Drings

INTRODUCTION: Combination chemotherapy with CAV is one of the most common treatment in SCLC. 4-Epirubicin and Vindesine are newer drugs with also high activity but less toxicity in small-call lung-cancer. In addition, Ifosfamide containing regimen had also good effectiveness and seemed to be superior to Cytoxan containing regimen. That were the objectives to look for the effectiveness and toxicity of the combination 4-Epirubicin/Ifosfamide and Vindesine in SCLC. PATIENTS AND METHODS: From 10/88 - 2/87 23 patients were entered into the protocoll, f/m ratio 12/11, meanage 59,1 (39 - 69). All patients had limited disease, Schedule: 4Epirubicin 75 mg/qm day 1 i.v., Ifosfamide 1,8 g/qm day 1 - 5 i.v. + uroprotection with mesna, Vindesine 3 mg/qm (max. 5 mg) day 1 i . v . RESULTS: An o v e r a l l remission rate of 82,6 % has been achieved (CR 47,8 %, PR 34,8 %). Median s u r v i v a l time i s 12 (+) months in the moment for all patients. Severe hematological toxicity (WHO 3 + 4) with leucocytopenia and thrombocytopenia occured in 2/23 patients, Gastrointestinal toxicity was acceptable (nausea and vomiting WHO 3 + 4 38,8 %). No other severe toxicity occured. CONCLUSION: Remission rate and survival data of the combination 4-Epirubicin, Ifosfamide, Vindesine is good as expected. Toxicity is moderate. But aver-all in comparison to historical data, asp. by CAV-regimen there is no superiority. More randomized trials to compare the effectiveness and toxicity are necessary. Dep. of Thoracic Dncology, Groahansdorf Hospital WGhrendamm 80, D-2070 GroGhansdorf

In a p i l o t study, the recommended dose f o r phase I I studies of C/E was determined and f i r s t data on antineop l a s t i c a c t i v i t y were ascertained. Starting dose schedule: C 300 mg/m2 iv day I , E 80 mg/m2 iv days I-3, C was given in a f i x e d dose. E was escalated step by step by appr. 20% u n t i l i n t o l e r a b l e t o x i c i t y (tax) (hematologic and/or renal=-WHO I I ) occurred in 2 out of 5 p~tients (pts) per dose l e v e l . 20 pts with d i s t a n t metastases ( f / m r a t i o 1/19,~mean Karnofsky PS 90 (70-I00), mean age 56 (33-74) were admitted into the study. 20 pts received a t o t a l of 66 courses (mean 3,3). 2 pts received one course and were evaluable f o r tax and response in case of PD. 18 pts had at least 2 courses and were evaluable f o r response and tax. 5 pts each received 240/300/360/420 mg/ m~ E iv per course. Dose l i m i t i n g tax was myelosuppression at an E level of 420 mg/m~ per course. Other tax: anemia WHO I : 15%, WHO I I : 10%, WHO I I I : 5%. Nausea, vomiting WHO 1:25%, WHO I I : 15%, WHO l l I : 15%, WHO IV:5%, Alopecia WHO I : 15%, WHO I I : 30%, WHO I I I : 15%. C l i n i c a l l y relevant hearing loss occurred in I pt. 10 pts received C 300 mg/m2 and E 240 mg/m2 and 300 mg/mz i v per course. I CR and 2 PR were observed. At the higher dose levels (E 360-420 mg/m~) 6 overall responses i n c l . I CR were gained in 10 pts. Median PFI is 4,5 months. Conclusion: the recommended dose of C/E appears to be 300 mg/m2 C and 420 mg/m2 E per course. C/E seem to be of comparable antineoplastic a c t i v i t y to DDP/E in pts with d i s t a n t metastases but i t induces less non-hematologic t a x . A randomized study investigates presently a c t i v i t y of an a l t e r n a t i n g chemotherapy with AIO+DDP/E vs AIO+C/E. Thoraxklinik Heidelberg-Rohrbach, AmalienstraBe 5, D-6900 Heidelberg

5/P.GM 103

5/P-GM 105

HYPERFRACTIONATED RADIOTHERAPY OF NON SMALL CELL LUNG CANCER (NSCLC) W , B e r b e r i c h ( 1 ) , C,Beck ( 1 ) , K . S c h n a b e l ( 1 ) , P . S c h l i m m e r (2)

TWO MULTICENTER RANDOMIZED TRIALS FOR TREATMENTOF NONRESECTABLE NON-SMALL CELL LUNG CANCER (NSCLC) M. Wolf*,K. Havemann*, K. Hans, H. Becker, F.v.B~ItzingstSwen, R. Goerg, H. Klasen, R. H~Bler, and J. Dannh~userL

I n a p i l o t s t u d y we have i r r a d i a t e d 60 p a t i e n t s w i t h NSCLC. 30 p a t i e n t s were t r e a t e d t w i c e daily. They received 65 Gy in 50 fractions over five weeks. To perform a matched pairs analysi% further 30 patients were selected who had been irradiated in a conventional manner with 60 Gy in 30 fractions over 6 weeks. Due to matching age und sex d i s t r i b u t i o n , tumor stage, Karnofsky index and previous treatment shewed no differences between the therapy groups. Life table (Kaplan-Meier estimate) showed no difference between the therapy schedules. Mean survival was approximately 324 days. The treatment groups were not different with respect to progression-free interval and occurence of distant metastases~ Radiation pneumonitis occured in both groups but significant differences could not be seen. The comparison of the post-treatment quality of life (Karnofsky index) showed a slightly better course after the hyperfractionated regimen than after conventional irradiation, especially during the first year after treatment. Because tolerance of the hyperfractionatsd scheme s e e m ~ t o be better - without diminuishing the effectiveness of radiation therapy - we have the impression that hyperfractionatian could be of some value in the treatment of rapidly proliferating tumors.

In non-resectable limited stage NSCLC radiotherapy (R) + Cisplatinum (P) as a radiosensitiser was compared to chemotherapy (CT) followed by R+P. CT consisted of ifosfamide 1.5 g/m2, days I-5, 29-33 and vindesine 3 mg/m2~ days 1+5, 29+33. R was given in single dosis of 2 Gy per day, 5 days a week for 3 weeks and after a 2-week interval for an additional 2 weeks up to a total dose of 50 Gy. P (20 mg/m~) was given weekly concurrent to R. 54 patients were randomized, 42 are now evaluable. Response rate after CT were: CR 0%, PR 33%, NC 44%, PD 22%. Response rates after R+P were CR 12%, PR 62%, NC 21%, PD 6% with no difference between both groups. R+P is an active regimen in NSCLC, additional CT did not improve response rates, but its influence on survival is still undefined. In extensive stage NSCLC pts. were followed for 4 weeks and tumor growth was observed. Subsequently, all pts. were randomized to receive 1 cycle of IFO+VIN or IFO+VP16 (120 mg/m 2, days 1-3). CT was stopped immediately if no response was seen. Responders received a maximum of 4 cycles. Until now 85 pts. were randomized, 72 are now evaluable. Response rates and survival did not differ between both groups (CR 2% PR 21%, NC 54%, PD 23%, med. survival 6 months). Tumor growth was observed in 53 pts. Of 20 pts. with no change within 4 weeks, 2 (10%) achieved PR, 16 (80%) NC, and 2 (10%) PD. Of 33 pts. with progression, 1 (3%) achieved CR, 7 (21%) PR, 15 (45%) NC, and 10 (30%) PD. Thus, susceptibility to CT seemed to be higher in pts. with rapid tumor growth and observation of tumor growth may be helpful in order to select patients with extensive stage NSCLC for CT.

(1) Abteilung for Strahlentherapie (2) Abteilung for Pneumonologie Universit~tskliniken D-G650 Homburg/Saar

Zentrum fQr Innere Medizin, Abteitung H~matologie/Onko{ogie/Immunologie, BaldingerstraBe, D-3550 Marburg

S 183 5/P-GM106

5/P-GM 108

IFOSFAMIDE (IFO), MITO~IYCIN C (MMC) AND VINDESINE (VDS) ADAPTED TO THE PERFORMANCE. STATUS IN DISSEMINATED NON-SMALL CELL LUNG CANCER (NSCLC) I_.. R~ger, M. Schroeder, H. Purea and M. Westerhausen

INDUCTION OF REMISSION IN SMALL CELL LUNG CANCER (SCLC) WITH COMBINED ADRIAMYCIN/IFOSFAMIDE CHEMO~IERAPY F. Burghardt, P. Na~en, B. Sorge__and R. Voigtmann

Ifosfamide, Mitomycin C and Vindesine are three of the most active single agents in the chemotherapy of non-small cell lung cancer. Between Dec. ]984 and June 1987 53 pts with h i s t o l o g i c a l ly proven advanced NSCLC entered into a phase II study. We treated 47 men aged 38-75 years with a Karnofsky index between 50-100 % and 6 women aged 46-57 years with a Karnofsky index between 60-90 %. The dosage of VDS and Ifo was adapted to the individual performance status: Karnofsky 90-100 %: Ifosfamide ].8 9/m~ d I-5 Vindesine 2 m9 d 3-5 Mitomycin C lO mg/m~ d ] Karnofsky 60- 80 %: Ifosfamide 1.5 g/ma d 1-5 Vindesine 1.5 mg d 3-5 Mitomycin C lO mg/m~ d ] Histological subtypes: Squamous c e l l - c a 24, Adeno-ca 16, Large cell ~a 13. All pts had'extensive disease with distant metastases. Results: Up~ to now 41 pts were evaluable. 12 pts were lne-i~le ~7 pts received p r i o r chemotherapy or i r r a d i a t i o n , 3 early death within 4 weeks, 2 lost to follow up). We achieved: CR 2/41 (4.9 %); PR 15/41 (36.6 %); MR 8/41 (19.5 %); NC 10/41 (24.4 %); PD 6/41 (14.6 Z). Median survival time 8.5 months. The t o x i c i t y of our regimen was tolerable, l pt with Ifosfamide related encephalopathy, 1 pt with pulmonary t o x i c i t y of c l i n i c a l evidence, 1 pt with cardiac decompensation due to hyperhydration. Twelve grade 111 and IV hematological t o x i c i t i e s have been registrated. Although remission rates of this three drug combination are encouraging i s t seems that there w i l l be no s i g n i f i cant prolongation of survival time in our advanced pts. ll.Med. K1inik, St. Johannes-Hospital, An der Abtei 7-11, D-4100 Duisburg II

The efficacy of remission induction of combined ADM(50mg/ m 2 i.v.) and Ifosfamide($g/m 2 as 24h infusion] administered on day I and repeated on day 21 for median 3.23 cycles was proven in 21 patients(pat) (median age 58years) with histologically verified lung cancer(20 SCLC,I anaplastic). At time of diagnosis 15 pat had already metastatic disease, 5 pat who showed no evidence for metastasis were N2 positive. None of the pat was pretreated before chemotherapy, I pat received prior radiotherapy due to CNS metastasis. 15 pat received a combination of DDP and Etoposid following ADM/Ifosfamide to continue remission, 6 pat with nearly CR got radiotherapy of the prior tummrlocalisation and the mediastinum. After 3 cycles of ADM/Ifosfamide objective response was seen in 18 pat (85%) distributed to CR 2(9.5%),PR 13(62%), MR 3(14%), 2 pat (9.5%) showed NC, I pat (4.7%) PD. Remission induction started always after ~he ist cycle. Relapse free intervall was 4.28 month ~ 1.65 SD, median survival was 7.87 months 3.39 SD with so long 3 pat surviving more than 12months. 9 pat are still alive with a range from 5 to 16.5 months since diagnosis so that median values of relapse free intervall and survival may rise. Toxicity was mild to moderate with haematologic toxicity worse than stage 2 according to WHO classification for Hgb 12%, leucocytes 14%~ platelets 4% of 68 cycles. Gastrointestinal toxicity worse than stage 2 was observed in 3%, cystitis worse than stage 2 in 5%. There was no death due to therapy. We conclude, that the combination of ADM/Ifosfamide is active in advaneed SCLC with the possibility of remission induction in short time intervall with tolerable toxicity in previously untreated patients. According to the demonstrated results this concept should be proven in pat with limited disease. A successful therapy concept for prolonging relapse free survival remains an open problem. Medizinische Klinik der Ruhr-Universit~t Bochum, Marienhospital, ~ i k e s k a m p r i n g 40, D-4690 Herne i

5/P-GM 107

5/P-GM 109

TOXICITY OF ADR~MYC]/N ( A D M ~ I ~ O S ~ M I D E IN S~[ALL CELL LUNG CANCER (SCLC) P. Nauen, F. Burghardt, B. S o r ~ and R. Voigtmann

Efficacy of Epirubicin, cyclophosp~de, and vincristine alte~rmr with cispl~in and etoposide in the treatment of patients with small cell cancer of the lung F. Eich, G.W. Sybrecht

From 1/86 to 10/87 20 patients (pat) with histologically proven SCLC and i pat with anaplastic lung cancer (median age 58 years, range 42 to 71, Karnowsky above 70%) received 68 cycles of ADM/Ifosfamide alltogether. Drugs were administered on day 1 with ADM 50mg/m 2 i.v. followed by Ifosfamide at a dose of 5g/m 2 as 24h infusion, each cycle repeated after 3 weeks for a median of 3.23 cycles. Routineously Metoclopramide (3mg/kg/24h i.v.) and mesna (2.Sg/m2/36h) were given to each patient. Toxicity was evaluated according to WHO classification, calculation based on the total number of applicated cycles, We observed haematologic toxicity grade 0-I as follows: Hgb 78%, leucocytes 64%, platelets 93%. Analysis for grade 3-4 showed: Hgb 12%, leucocytes 14%, platelets 4%. There was i septic event due to E. coli septicaemia during leucocyte depression. Gastrointestinal toxicity was moderate with grade 0-I in 77% and severe with grade 3-4 in 3% of cycles. One patient suffered from a period of diar~)oea. Nairloss was almost complete in all pat after 2 to 3 cycles. Cystitis appeared during 9 cycles, 4 of these grade 3. Mucositis was seen for 3 times grade 3. Neurologic toxicity due to restlessness or confusion was seen during 4 cycles in 2 elder pat resolving spontaneously within 24 h. Persistent arrhythmia absoluta developed in I pat after 3 cycles. There was no death due to chemotherapy. In conclusion this highly effective chemotherapy in SCLC as shown by Santoro et al. (Ifosfamide plus anthraeycline in SCLC, in: Abstracts of Int. Conf. on SCLC, Ravenna 1987) and by our group is accompanied by only mild to moderate toxicity that never demanded delay of therapy. Medizinische Klinik der Ruhr-Universit~t Bochum, Marienhospital, H~ikeskampring 40, D-4690 Herne I

Doxorubicin, c y c l o p h o ~ d e ,

vincrist~, cisplatZn, and etoposide are

effectAve single agents in the ~ of ~nall cell lung cancer. We have the~oce c o r ~ a~ t r i a l on the e~icacy of I~o conf.nations of the drugs, where only doxor~bicinwas replaced by ep~-ubicin because of the lower cardiotoxicity. An altemat&ng r e 9 ~ with ~#o p u ~ v e l y non-c~oss r e ~

ccmbi-

l ~ following ~gimen w~s chosen. Epirubicin (70 mg/m ~1 ~.v.), cyclc~ d e (1.000 mg/m dl i.v.), and v ~ i s ~ r e (2 mg/m~ dl i.v.) were give~ as carbirmt~on A, cisplat3n (80 mg/m dl i~v.) and etoposide

(100 mg/m~ dl i,v. and 300 mg d 2-5 orally) as c o m b ~ o n B. Although the single desis for v i r ~ is very high, the cunulat.ivedosis, responsable for neurotoxicity, does not exceedthe ctm~ative dosis compared t o rr~y other schedules. Patients were rBmt~dzed to receive

6 alterrmCi~ cycles coosistiqg of AA BB AA (&"oup1) orB8 A&BB (Group.2). Each cycle was given at 21-28 days intervals. 20 pat3ents (ages42-74 years with a meanof 59,5 years, 1 female) entered our r e t z o s ~ v e study. Pm~mmmce status was 75 % r~xj~rg fm~ 30-i00 %. ~2 patients had L.D., 8 patients E.D. Pesponserate: CR70 %, F~ 15 %, no change15 %. One patient with Cq revealed an a s t h m a t i c brain metastasis, d i ~ c ~ y after having firished ~ p y ; he had z~fused proposedprophylactic ~ radiation. Significant diffe~nces concerning responserate bet~m the groups 1 and 2 w~re not seen. Tox/clty: Alopecia grade 1-3 100 %. Nauseaand vaulting, grade 0-4, mostly grade 1-2. C1/n/cal neu~otoxlclty grade 1-2 35 Z, conf~q~edby nerve ~ o n velocity/5 %. Q-e patient deve3opeda reversible paralytic subileus after combination A. Bonemarrowtoxicity did not liBtit the t~q~stment.Therewere no thecapy-relat~ddeaths. lhe data ~d&~te that the reojimenchosens h ~ h~gh z ~ rates with tolerable adverse effects even in E.D. cases. Dr.med.F. Eich and Prof.Dr.med. G.W. S y b ~ ,

Mectiz~sche K l ~ k und

Poliklinik, Abt. Pneumnologie,6650Fk~/Sear, kest-Deutschland

S184 5/P-GM 110

5/P-GM112

TREATMENT OF RECURRENTBRONCHIAL SMALL CELL CARCINOMA WITH VlNDESINE, IFOSFAMIDE AND ETOPOSlDE J. von Pawel, K..ObermUller, K. HBuIBing_e_r

SIMULTANEOUS RADIO- AND CHEMOTHERAPY (CISPLATIN/VINDESINE) IN NON-SMALL CELL LUNG CANCER: A C R I T I C A L A N A L Y S I S O F 35 P A T I E N T S . J . A m m o n , J.H. K a r s t e n s , D. ~ n d r e o p o u l o s

The proportion of long-term survivors a f t e r chemotherapy f o r small cell carcinoma of the lung is low, despite of improved chemotherapy protocols (some including radiation). The majority of patients s t i l l dies eventually from recurrent tumour. We report the results of 14 Patients who had been in remission for various length of time after receiving chemotherapy according to the CAV-protocol. After the diagnosis of recurrent small cell carcinoma they were treated with a combination of ifosfamide (15oo mg/m2/day I-5), etoposide (12o mg/m2/day I-3) and vindesine (3 mg/mZ/day I ) . In 12 cases remissions (at least 8 p a r t i a l , 4 complete) were obtained, and two progressive diseases have been seen. One patient was lost after achieving complete remission due to a drug-related-death showing the possibly greater myelotoxicity of the second chemotherapy treatment. These (encouraging) preliminary results should bei reconfirmed in controlled phase-llstudies, especially including patients who have been previously treated with different chemotherapy protocols. Pneumologisch-Onkologische Station im Zentralkrankenhaus Gauting/MLinchen Unterbrunner StraF~e 85, D-8o35 Gauting

P a t i e n t s (pts) w i t h s t a g e III a n d I V n o n - s m a l l cell lung cancer have a poor prognosis. Simult a n e o u s r a d i o - and c h e m o t h e r a p y a c h i e v e s p r o m i s i n g r e s p o n s e r a t e s and m a y p r o l o n g r e l a p s e f r e e i n t e r v a l s . W e c o m b i n e d r a d i o t h e r a p y (cont i n u o u s c o u r s e , t o t a l d o s e : 55 Gy) w i t h c o n current chemotherapy ( c i s p l a t i n w e e k 1,4,7; vindesine w e e k 2 , 3 , 5 , 6 , ; P r e c . A S C O 6: p 1 8 3 , 1987). Pts were evaluated for toxicity,response and site of first failure, Toxicity: one pt died during 2nd cisplatin cycle from c e r e b r o v a s c u ! a r insult. N o W H O g r a d e I ! I o r I V toxicity was registered; using prophylactic a n t i e m e t i c s , g r a d e I V n a u s e a and v o m i t i n g w a s n o t seen. A c u t e and s u b a c u t e r a d i a t i o n t o x i c i t y is n o t i n c r e a s e d . Response rates: in pts w i t h l o c o r e g , d i s e a s e (+ n e c k n o d e s ) o v e r a l l r e s p o n s e ( C R / P R ) w a s o b s e r v e d i n 2 4 / 3 0 (CR i n 6 pts). In pts with initially distant disease overall response w a s 2/5. I n 24 p t s ( m e d i a n follow-up: Ii m o n t h s ) s i t e s o f f i r s t f a i l u r e w e r e a n a l y s e d . I n 14 p t s w i t h a p r i m a r y t u m o r < 5 cm, first failure occurred distant in 8 pts, local/distant in 4 and local only in 2 pts; i n i0 p t s w i t h a p r i m a r y tumor >5 c m first failure was observed local in 8 pts, local/distant in 1 and distant o n l y i n 1 pt. Observations: concurrent radio- and chemot h e r a p y w i t h t h i s r e g i m e n is f e a s i b l e w i t h o u t major toxicities; whereas distant failures remain the predominant problem, local control in t u m o r s >5 c m is a p p a r e n t l y n o t s u f f i c i e n t . Abt. S t r a h l e n t h e r a p i e , Mad. F a k u l t ~ t , K l i n i k u m RWTH Aachen, D-5100 Aachen, Pauwelsstr.

5/P-GM 111

5/P-GM 113

COMBINATION CHEMOTHERAPY WITH CIS-PLATINUM AND ETOPOSIDE IN ADVANCED NON-SMALL CELL CANCER OF THE L[~G M. Hagmann, M. Winkelmann, W.-D. Schoppe und W. Schneider ....................................................... 28 Patients (2a male - ~ female, a~e ~ n g e d from 26 to 73 years, mean 53) with inoperable non-small ceil lung cancer, NSCLC, (stage III, M 0 or M I) were treated with Cis-Platinum and Etoposlde. Bisto]oglca] type of the tumors were squamous cell carcinoma (n:~), sdeno (n=16), large cell (n=8). Q patients recelved a high dose regimen (HD) with 100mg/m2 Cis-P]atinum on dav I end 100mg/m~ Etoposide on day 2, a and 6. IR patients received a fractionated dose regimen (FD) w~th 40mg/m2 Cis-Plat inum on day I and ? a~d 100mg/mL Etoposide on 0ay I, 2 end ~. 6 patients ,~ceived the high dose regimen plus Vindeslne ~m~/m2 and Ifosfamide 2g/mz (CD), Response rates were: a partial response was obtalne4 in 12 patients (a9%)~ 5 pts after HD, 5 pts after FD she 2 pts after CD-therapy. 7 patients (25%) shewed no change and a patients (~P%) had progressive disease. No complete remissions were observed. In 2 of the patients with partial response however, lobectomy could be carried out, thus achieving compJete remission. Both patients are free of disease since more than 12 months. Neither of the three regimen seems to be superior ~n treatment of advanced NSCLC, favourin~ frectlonate0 Cis-Platlnum regimen with reduced (nepbro-) toxicity. Some patients may benefit from treatment with Cie-Platinum/Etoposide as neoadjuvant chemotherapy.

Combined interdisciplinary aggressive therapy after radical surgery for small cell bronchial carcinomas (SCLC) at early stages (TNM I}

Abt. f0r N~matologie, 0nkologle und Irgm/nologie Medizinisehe Universit~tsklinik, Moorenstr. D~sseldorf, 0211-311/7714

kllniscbe 5,

4000

K.Karrer, H.Denck~ P.Drings, H.KarnickaMlodkowska, J.Erzen, G.M.Salzer, M.Thermann, A.Lattuneddu, Y.Sun, B.Berkarda, M.L.Lieo, M.Brunor J.Rotb~und, H.Osada, EoHata for the ISC-Lung Cancer Study Group As SCLC is a highly malignant and fast growing tumor for which effective treatment methods have been already approved, the chance for real cure by complete elimination of the vital tumor cells is given. Therefore "radical" resection of the primary tumor (T) and the tumor-positive regional lymph nodes (N) should be performed, as this procedure causes only few side effects while its efficacy is high and enables a precise definition of the extension of the tblmor (pTNM). As such early tumor stages with realistic chances for cure are very f e w , the cooperation of experienced thoracic-surgical centers as many as possible is necessary to gain reliable results within a reasonable space of time. The treatment used in our multicenter study considers for early stages after "radical" surgery an intermittent aggressive chemotherapy during the first 6 postoperative months and is finalized by a prophylactic cranial irradiation. The life-table survivalrates of 106 patients in ISC-studies I and !I projected for 3 years are: 44 patients at stages pTI-3 NO M0 62% 34 " pTi-3 N1 M0 61% 28 " pTI-3 N2 M0 32% It can be seen as an important result that the feasibility of this aggressive type of therapy could be shown. We therefore feel not only justified, but also obliged to invite further groups for participation in our cooperation.

$185 5/P-GM114

5/P-GM 116

PRE-THERAPBUTIC ASSESSMENT OF LUNG FUNCTION WITH CT AND SCINTIGRAPHY IN PATIENTS WITH 8RONCHQGBNIC CARCINOMA

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONEEXCESS (SIADH) IN SMALL CELL LUNG CANCER (SCLC). M.M.Klink, A.J.G. Riegger, M.van Aerrsen,H.Klinker, U. Gunzer, K.Kochsiek ~ ~ - o ~ t h e patients with SCL-C--h-av"e-lmpalre~wat e r excretion and elevated plasma arginine vasopressin values (P-AVP), even though many do not have evident hyponatremia. Methods: P-AVP-Ievels (RIA), plasma- and urine osmolalit~s,---Ffu point method) and e l e c t r o l y t e s (flame photometry) were measured. Case report: A 54 year old white male suffering from S C L C ~ L C - t r e a t ment (Cis-Platinum/Etoposide). BeTore s t a r t i n g prehydration for~the f i r s t cycle of chemotherapy (CT~ 134 mmol/l serum-Na" were determined. At day 7 serum-Na- decreased to 125 mmol/l. 3 days l a t e r , during the 2nd hydration period the patient developed mental $onfusion, dysphasia and dyspraxia. At that time serum-Na was dramatically reduced to 116 ~mol/l. This complication was combined with a low plasma-osmolality of 231 mosmol/kg HoO and a high urine-osmolality of 830 mosmol/kg H20 whil~ the plasma-AVP-level was i n a p p r o p r i a t e l y increased up to 24 pg/ml. SIADH was then treated by water r e s t r i c t i o n and intravenous infusions of high concentrated saline (3%). During the 2nd cycle of CT hyponatremia of 130 mmol/l w~ seen without c l i n i c a l signs of water i n t o x i c a t i o n . P-AVP returned to nearly normal levels (3-6 pg/ml). During the whole period increased a n t i d i u r e s i s was documented by a p o s i t i v e free water clearance. Water r e s t r i c t i o n and oral NaCl-administration (4-6 g per day) were necessary to avoid the development of water i n t o x i c a t i o n f o r months u n t i l complete remission of SCLC could be obrained. 10 months a f t e r onse~ of therapy, inappropriate secretion of AVP with serum-Na of 120 mmol/l, was associated with relapse of the disease. Conclusion: SIADH was unmasked by waterloading p r i o r to Cis-Platinum-therapy in a patient with SCLC. Once hyponatremia has developed, a rapid correction must be avoided because of possible pontine myel~ nosis. Treatment of f i r s t choice in paraneoplastic SIADH is the reduction of tumor masses, as i t could be documented in t h i s case. Medizinische U n i v . - K l i n i k WUrzburg, FRG

S.A.Beyer-Enke~M.Miebe!~J.Ciorius,J.G~ricb, H.Becker,G.van

Kaick

B6 p a t i e n t s

~ith histologically proven b r o n c h o g a n i o c a r o i n o m B were studied. C o m p u t e d tomography(CT], lung s c i n t i o r a p h y (perfusion, ventilation)~ s p i r o m e t ~ y (VC~ FEVI] end bronc h o s c o p y were used to assess the i n f l u e n c e which b r o m c h i a l o b s t r u c t i o n and p e r e n c h y m a l imfiltration have on lumg-function. CT Was used to e v m l u a t e p a r e n o h Y m a l infiltration. The C T - r e s u l t s were c l a s s i f i e d w~th respect to the area of lung involvement on a 5 step scale. S o i n t i g r ~ p h i c data were e x p r e s s e d as a r~tio: tumor-involved vs. unaffected lung~ S p i r o m e t r i c data were n o r m a l i z e d for ege~ sex end b o d y h e i g h t . Based on b r c n c h o s o o p y ~ 5 s t e m o s i s c l a s s e s were formed, A s i g n i f i c a n t r e d u c t i o n Of lung function was o b s e r v e d in proximal bronchial obstruction, while lobar stenosls failed to be a s s o c i a t e d with fumotion~l impairment. A linear reduction of function, as a s s e s s e d by scintigPaphy and s D i r o m e t r y was noted with i n c m e a a i n g pareD-ohymal infiltration, as d i a g n o s e d by CT. Lung perfusion and FEVI appeared to be mope sensitive then v e n t i l a t i o n end VC. A high m e r f u s i o n ratio end l o b a r i n f i l t r a t i o n in CT s t a n d s f o r iOW functional r e s e r v e s i n the lung w i t h o u t tumor. A io~ p a r f w s i o n ratio c o m b i n e d w i t h segmental i n f i l t r a t i o n i ~ i c a ~ ted high p r o b a b i l i t y of central tumor e• sign. Both,the CT-classifioation end the s c i n t i g r a p h i c p e r f u s i o n d~ts should be combined f o r pretherepeutio assessment of lung function.

5/P-GM 115

5/P-GM117

VALUE OF NSE AND CEA ASSAYS IN MONITORING OF" PATIENTS WITH SMALL CELL LUNG CANCER

EPIDEMIOLOGY G. S e i t z , M. a n d G. D h o m

W . E b e r t , G.Hug, P . D r i n g s . Thoraxklinik b e r g - R o h r b a c h ~ 6900 H e i d e l b e r g

Heidel-

Tumor m a r k e r a s s a y s are p l a y i n g an i n c r e a s i n g l y i m p o r t a n t r o l e in c l i n i c a l o n c o l o g y . We h a v e investigated the u s e f u l n e s s of s e r i a l d e t e r m i n a t i o n s of N S E and CEA d u r i n g t r e a t m e n t and f o l l o w - u p of 90 p a t i e n t s ~ i t h s m a l l cell l u n g c a n c e r (SCLC). The s e r u m c o n c e n t r a t i o n s of the m a r k e r s w e r e a s s e s s e d by use of N S E - R I A ( P h a r m a cia, F r e i b u r g ) and C E A - E I A (Roche, B a s e l ) . T r e a t m e n t of S C L C by c h e m o t h e r a p y was f o l l o w e d by a d e c r e a s e of NSE w h e n it had been r a i s e d at pres e n t a t i o n to r e a c h n o r m a l l e v e l s (<12.5 n g / m l ) ~ h e n there ~as c l i n i c a l e v i d e n c e of c o m p l e t e or p a r t i a l r e m i s s i o n in 2 7 / 3 1 (90%) p a t i e n t s a f t e r the 1st c y c l e and in 3 1 / 3 1 (IOOZ) a f t e r the 2nd cycle. By c o n t r a s t CEA r e a c h e d n o r m a l v a l u e s (<5 n g / m l ) in 6/31 (19.4Z) p a t i e n t s a f t e r the ist c y c l e and in 1 5 / 3 1 (48.~Z) after the 6th cycle. In l l / l l (100%) p a t i e n t s w i t h s t a b l e d i s e a s e NSE l e v e l s did not n o r m a l i z e and C E A v a l u e s r e m a i n e d a b o v e n o r m a l in 7/8 (87.5%). P r o g r e s s i v e d i s e a s e (PD) was a c c o m p a n i e d by r i s i n g NSE l e v e l s in A 0 / 4 2 (95.2%) p a t i e n t s and by r i s i n g CEA l e v e l s in 2 8 / 4 2 (66.7%). The rose of NSE p r e c e d e d c l i n i c a l e v i d e n c e of PD by 4 3 . 7 t 7.8 d a y s (n=16) w h e r e a s i n c r e a s i n g CEA v a l u e s w e r e o b s e r v e d 3 6 . 6 Z 15.4 d a y s p r i o r to X - r a y f i n d i n g s (n=5) and 54.2 Z 6.9 d a y s after the r a d i o l o g i c a l s i g n s (n=6). Survival of p a t i e n t s from the s t a r t of r i s i n g NSE v a l u e s at PD c o r r e l a t e d s i g n i f i c a n t l y w i t h the d o u b ling time of NSE c o n c e n t r a t i o n s ( y = l . 6 6 x + 42.2; r=O.82).Contrary, CEA d o u b l i n g - t i m e did not c o r r e l a t e w i t h s u r v i v a l of p a t i e n t s .

OF G A S T R I C C A N C E R IN S A A R L A N D S t r a u B , G. S c h ~ d e r , N. W e r n e r t

3193 c a s e s of g a s t r i c c a n c e r w e r e r e p o r t e d to t h e S a a r l a n d C a n c e r R e g i s t r y f r o m 1974 to 1983. T h e r e w e r e a b o u t 300 n e w c a s e s / y e a r d u r i n g t h e o b s e r v a t i o n p e r i o d . In 1974 t h e s e x r a t i o w a s 1.8 : I. D u e to a d e c r e a s e o f n e w c a s e s in m a l e s a n d a n i n c r e a s e in f e m a l e s , an a s s i m i l a t i o n to I : I c o u l d b e o b s e r v e d t i l l 1983. T h e " c r u d e " i n c i d e n c e s in m a l e s s h o w e d a s l i g h t d e c r e a s e in the observation period, whereas those of females r e m a i n e d c o n s t a n t . In 1984, t h e " c r u d e " i n c i d e n c e or m o r t a l i t y in m e n w a s 32.5 o r 24.6, in w o m e n 27.3 or 19.2. In a g e - s p e c i f i c incidences, t h e r e w a s an e v i d e n t c u r v e i n c r e a s e in m e n a f t e r t h e a g e of 50 a n d in w o m e n a f t e r 60 y e a r s of age. A s l i g h t d e c r e a s e in m e n o f the o l d e r a g e g r o u p s c o u l d be s e e n a l s o here, w h e r e a s t h e c u r ve f o r w o m e n n e a r l y r e m a i n e d i d e n t i c a l . In i n t e r n a t i o n a l c o m p a r i s o n t h e i n c i d e n c e of ffastric c a n c e r in m e n a n d in w o m e n in S a a r l a n d w a s in the upper third of the known cancer registries. 1597 of t h e p a t i e n t s (50%) u n d e r w e n t s u r g e r y , t h e t u m o r s t a g e w a s k n o w n in j u s t h a l f o f t h e c a s e s : 15.7% of t h e o p e r a t e d c a r c i n o m a s w e r e e a r l y c a n cers. A c l a s s i f i c a t i o n a c c o r d i n g to L A U R E N w a s s u b s e q u e n t l y p e r f o r m e d in 271 c a s e s (17% of t h e operated gastric carcinomas). I n t e s t i n a l type: 5 3 . 9 % , d i f f u s e type: 3 0 . 6 % a n d m i x e d type: 15.5%. The survival rates showed a pronounced decrease particularly in t h e f i r s t 2 y e a r s f o l l o w i n g d i a g n o s i s . A f t e r o n e y e a r 33% of t h e p a t i e n t s w e r e s t i l l a l i v e , a f t e r t w o y e a r s o n l y 24% h a d s u r vived. The 5-year-survival r a t e w a s 17%. Pathologisches Institut der Universit~t Saarlandes, D-6650 Homburg/Saar

des

S 186

5/P-GM 118

5/P-GM120

UPDATE OF THE CANCER REGISTRY REPORT OF THE WEST GERMAN TUMOR CENTER, ESSEN R. R i c h t e r , M. E, Scheulen, R. P f e i f f e r and C. G. Schmidt

CELL K I N E T I C S OF P R E N E O P L A S T I C H E P A T G C Y T E S A F T E R INITIAT I O N BY A S I N G L E DOSE OF N - M E T H Y L - N - N I T R O S O U R E A F. W i l l e m s e n and H.M. Rabes

The cancer registry of the West German Tumor Center now looks back to eight years of recording. The forms for collecting the items have been earlier defined (Verh. Dtsch. Krebsges. 5:4G, 1984). The programme system was improved and 1~as been transferred to the Tumor Centers of Bonn, Karlsruhe and TQbingen. The data are p e r i o d i c a l l y sent to the International Cancer Patient Data Exchange System (ICPDES) of the UICC at Houston, Texas. U n t i l November 1987 the number of base records (8R) increased up to 3T.191 and the number of f o l l o w up records up to 98.8?3, The f o l l o w i n g t a b l e shows the d i s t r i b u t i o n o f BR to p r i mary cancer s i t e s according to groups of the ICD-O.

SITE/HISTOLOGY

PREVIOUS TREATMENT

Breast (174) 4.424 (150-159) 1.980 Lung (162) 979 Non-Hodgkin lymphoma 1.255 Eye (190) 324 M. Hodgkin 720 Head & neck (140-149) 821 Leukaemia 578 Testis (186) 1.334 Brain (191-192} 442 Skin (173) 740 Soft t i s s u e (171) 533 Others 4.807 Total 1B.93B

GI-tract

NO P R E V I O U S TREATMENT

1.484 1.747 2.230 1.475 1.016 924 817 982 214 62? 232 129 3.292 15.769

Innere U n i v e r s i t ~ t s k l i n i k und Poliklinik W e s t d e u t s c h e s Tumorzentrum, Hufelandstr.

UNKNOWN

17 7 32 53 154 11 5 35 I 7 12 3 2.139 2.486

TOTAL

5.925 3.734 3.241 2.784 2.104 1.655 1.643 1.593 1.549 1.075 984 805 10.238 37.191

(Tumorforschung), 55, D-4900 Essen

Cell k i n e t i c s of h e p a t o c y t e s d u r i n g the p r e n e o p l a s t i c p e r i o d d e p e n d s on the mode of i n i t i a t i o n and p r o m o t i o n . We s t u d i e d the d e v e l o p m e n t and cell k i n e t i c s of A T P a s e d e f i c i e n t (ATPase-) p r e n e o p l a s t i c foci 3, 12 and 18 m o n t h s (m) after p a r t i a l h e p a t e c t o m y (PH) f o l l o w e d by a single i n j e c t i o n of N - m e t h y l - N - n i t r o s o u r e a (MNU) and prom o t e d by p h e n o b a r b i t a l (PB). Male W i s t a r rats (15o-2oo g) r e c i e v e d a single dose of MNU (25 mg/kg i.p.) in early S phase one hour after r e l e a s e from a h y d r o x y u r e a block from 14 to 24 hr after PH. T h e y were fed a standard diet (Altromin) or the same diet c o n t a i n i n g o.o5 % PB. A third group w i t h o u t MNU i n j e c t i o n was fed w i t h PB d i e t after PH and h y d r o x y u r e a . The a n i m a l s were i m p l a n t e d i.p. an o s m o t i c m i n i p u m p d e l i v e r i n g 3 H - T d R at a rate of 15bCi/ h (spec. act. 2 Ci/mmole) for 4 to 72 hr. By c o m b i n e d e v a l u a t i o n of a u t o r a d i o g r a p h i c and enzyme h i s t o c h e m i c a l p r e p a r a t i o n s in a mask c o m p a r a t o r m i c r o s c o p e it was p o s s i ble to d e t e r m i n e the n u m b e r and size of A T P a s e - foci and their l a b e l i n g index (LI). F r o m 3 to 18 m after MNU injection the n u m b e r of A T P a s e - foci i n c r e a s e d by 38o % and the size by 19oo %. A d d i t i o n of PB led to a f u r t h e r increase of 63 % in n u m b e r and 288 % in size. A few foci were also o b s e r v e d after PB only. The LI showed a h e t e r o geneous p a t t e r n in A T P a s e - foci with a m e a n h i g h e r than in n o r m a l h e p a t o c y t e s and i n c r e a s i n g v a l u e s at later stages, but with a wide range. PB alone led to a lower LI w h i c h also i n c r e a s e d from 3 to 18 m of PB feeding. W i t h i n several foci, m a i n l y in the liver of rats t r e a t e d with MNU and PB, s u b p o p u l a t i o n s with a s i g n i f i c a n t l y h i g h e r LI than in the rest of the focus were found. These data s u g g e s t that a single dose of MNU is capable of i n d u c i n g p r o g r e s s i v e l y g r o w i n g p r e n e o p l a s t i c foci, but these foci form a h e t e r o g e n e o u s p o p u l a t i o n with only a few of them d e v e l o p i n g into cancer. S u p p o r t e d by g r a n t s from D e u t s c h e F o r s c h u n g s g e m e i n s c h a f t . P a t h o l o g i s c h e s Institut der U n i v e r s i t 6 t M~nchen, G e r m a n y

5/P-GM 119

5/P-GM 121

EPIDI~IOLOG~ OF ORAL CARCINZ~A IN T}~ FEDERAL RFEUBLIC OF (~R~g~f. R.Coebbels*, E.Bader, N.Wernert, G.Seitz, G.Dhcm

EVALUATION OF THE "FOSSEL-TEST" AS SCREENING TEST FOR M A L I G N A N T TUMORS S. Berger s, K . - H . PfHJger, J. Fischer, Th. K~mpchen 3, and K. Havemann

During the period 1967-196/3 833 oral malignancies had been recorded by the regicnal Cencer Registry of the Baarland. 717 carcinomas had been proven by histology (690 s ~ u s cell careincmas= 96,~/~,ii tmdifferentiated c a r c ~ = 1,30/0, 6 muscepidermdid tunora : 0,~/0, i0 adenoid cystic carcincmas: 1,4%). 80,3% of carcin~as were diagnosed during first 6 monti~s after onset of symptoms. They were preferably iccated at the tc~oue (45,30/o),followed by floor of mouth (17,9%) and lip (17,6%]. Average age at the time of diagnosis was 59,0 years (males 58,4 years, f(~Telas 62,0 years), lincorrected incidence rates, according to a standard world population, averaged 6,i for n~les (0,4-25 worldwide) and 0,7 for f~m~Lles (0,0-i0,3 worldwide). Overall incidence rates were increasing during the time of investigation according to figures obtained in 5-ycara-intervals (males 3,4-6,6, females 0,7-1,2, whole s ~ l e 1,83,6). Age distribution shoved 2 peaks, for all cases recorded as well as for age specific incidanes rates and age st~g~tized incidence rates resp., with a first peak for the group A5-50 years old and a se(x~d for the g r o ~ ?0-75 years old. Investigation of the develo>ment of incidence r a ~ in 5-years-haterv~.ls showe,~ that the ~i.ret peak developed in recent years, exclesively affected the male group and solely was respcesible for the rise in incidences recorded. For the whole ssmple the population a5-50 years old is almost at highest risk now. Prognosis depended on location, being werat for carcinomes of the floor of the mouth (survival rates at 5 years 31%, i0 years 11%) and most favourable for these of the lip (survival rates at 5 years 6~/o, i0 years 5~/~). In floor of mouth and tongue prognosis ~as better for females than for males. Oral carcicem~ preferably metastesized into cervical ly~ohnodas (67,~% of metasi~ses). Distant metastases, preferably into the iLr~3, made up less than iC7/0.Recurrences were recorded in 22% of cases. Among occupational groups tmskilled Isbourere were at hi~est risk. 362 of 717 patients with oral c a r ~ died during the time of investigation. In FDst cases malignant disease had been documented as cause of death (81,7%). Pathologisehes Institut d.Univeesit&'t d.Saarlandes, D 6650 Hasbur~Saar ~erichtlich-~neOizinieches Institut d. Universit&~, CH 3012 Bern

The recent report of Fossel et al. (N. Engl. J. Med. 315: 1369-1376, 1986) outlines a procedure for suppression of water in plasma and measurement of line withs of plasma lipoprotein proton signals by proton nuclear magnetic resonance (NMR). The authors claimed that this test may be useful for the detection of malignant tumors. The present study is performed t o evaluate the general applicability of this method. Citrated blood samples from tumor patients (A), patients with non-malignant diseases (B) and helthy control persons were collected and plasma was stored at -20~ for later analysis. All proton NMR spectra w e r e obtained without knowledge of the patients clinical status in two different laboratories using different spectrometers (AC-300 MHz NMR Spectrometer, Bruker, and GX-400 MHz NMR Spectrometer, Jeol). A special spectroscopid procedure resulted in suppression of disturbing lactate peaks. The full width at half the height of the methylenpeak alone as well as the everage of the values of the methylene plus the methyl peak were measured. Up to now plasma specimen of; 107 patients (group A), 21 patients (group B), and 22 healthy' controls have been measured. A F t e r suppression of the lactate peaks both spectrometer yielded fairly comparable= results. The results of all 3 groups overlapped in a differen~ range: Group A 22-42 Hz, group B 22-34 Hz, controls 26-38 Hz. A f t e r suppression of lactate proton resonances the mean value from tumor patients was higher than those of the other groups. These first results indicate that a skeptical attitude toward this test as a general tool is in order. The study is still in progress. ZIM, Abt. H~matol./Onkol., Baldingerstr., D-3550 Marburg 2Fachbereich Chemie der Universit~t, D-3550 Marburg Slnst. f. Pharmazeut. Chemie, D-3550 Marburg

S187 5/P-GM122

5/P-GM 124

WATER~SUPPRESSED PROTON NUCLEAR MAGNETIC RESONANCE (NMR) SPECTROSCOPY OF PLASMA IN PATIENTS (pts) WITH NONSEMINOMATOUS T E S T I C U L A R CANCER (NSTC) H. H d f e l e r , M. E. S c h e u l e n , C, G. S c h m i d t and

DOES SYSTEMIC DETOXIFICATION REDUCE THE EFFICIENCY OF LOCO-HEGIONAL CHEMTOHERAPY ? P. Friedl ( I ) , M.R.Berger ( 2 ) , W.Rozycki-Gerlach (2), P.Schlag (i), D.Schmghl (2)

E. T. F o s s e l

To examine the efficiency o f a loco-regional therapy mode with alkylating agents against an implanted liver tumor (Novikoff hepatoma) was the aim of this experimental study. To further improve the therapeutic ratio of this method a concomitant systemic detoxification was applied, when administering intraarterially loco-regional infusion. All together female an-rats (180-3004,n=78) were used. Under ether anasthesia 10s Novikoff hepatoma cells were implanted under the capsule of the left liver lobe. Relaparotomy 6 days after was carried out and a double catheter system was implanted into the ~astroduodenal artery and veda cava. The alkylating agents infused were 1,2,4-triglycidylurazole (TGU) and mafosfamide (MF). Sarcosindithiocartamude (SDC) was administered i.v. to protect against bone marrow toxicity. Tumorgrowth inhibition and growth of bone marrow deviced stem cell colonies was recorded to evaluate therapeutic efficiency. Both, TGU and ME effectively inhibited tumor growth with superiority of i.a. administation (FGU x=84%, MF x=94%). Reduced bone marrow toxicity due to systemic application of SDC was observed after i.a. infusion of TGU. No reduction of systemic toxicity was observed after administration of MF together with SDC. The observed 21 day mortality was lower in groups following i.a. administration and in groups following systemic detoxification. In conclusion in this model investigated a high anti tumor activity accompaning i.a. infusion of both drugs were, observed. A distinct protection of bone marrow toxicity following i.a. infusion of TGU could be found. Systemic detoxification with SDC did not reduce the antineoplasticI activity of both drugs.

plasma from t42 pts w i t h NSTC a n d from 57 agematched healthy m a l e s w e r e c o d e d and sent f r o m tile N e s t G e r m a n T u m o r C e n t e r to Boston. T h e m e a n l i n e w i d t h o f m e t h y l and m e t h y l e n e r e s o n a n c e s of plasma lipoprotein lipids was m e a s u r e d by NMR without knowledge of the respective clinical data. Collection of plasma, s t o r a g e a n d NMRmeasurements were done a c c o r d i n g to F o s s e l et al. (N. gngl. 3. Ned. ! ! 5 : 1 3 6 B , 1986). F r o m c l i n i c a l r e c o r d s pts w e r e p r o s p e c t i v e l y a s s i g n e d to three groups: 54 w i t h a c t i v e tumor, 88 w i t h no e v i d e n c e o~ d i s e a s e (NED), and 57 c o n t ~ e l s ~ The line widths of the groups were (x-SD): 29.222.8 Mr, 3 5 . 8 t 4 . 5 Nz, and 3 9 . 1 ~ 3 . 4 Mr, respectively. Defining v a l u e s ~ 30.5 HZ as diagnostic for the presence of tumor, 69/54 pts w i t h a c t i v e t u m o r (91Z) w e r e c o r r e c t l y d e t e c t e d . In 11/88 pts with NED ( 1 3 Z ) v a l u e s ~ 30.5 Hz were measured. Up to now, a r e l a p s e c o u l d be clinically proven in two of them. The l o w e s t v a l u e in the c o n t r o l g r o u p was 3 3 . 5 HZ. In conclusion, water-suppressed p r o t o n NMR o f plasma is a potentially v a l u a b l e a p p r o a c h to monitoring o~ pts w i t h NSTC~ F o l l o w up o~ succesfully treated pts is n e e d e d to e x a m i n e the value of the test for early detection o~ relapse. I n n e r e U n i v e r s i t ~ t s k l i ~ i k und P o l i k l i n i k (Tumorforschung), Nestdeutsches Tumorzentrum, H u f e l a n d s t r . 55, D - 4 3 0 0 E s s e n I, and Department

Beth 330

of

Radiology,

Israel

Hospital

Brookline

Ave,,

Dana

Research

and H a r v a r d Boston,

Institute

Medical

HA 0 2 2 1 5 ,

School,

USA

(I) Dept. of Surgery University, Im Neuenheimer Feld llO, (2) Institut of Toxicology and Chemotherapy, DKFZ, Im Neuenheimer Fold 280, 6900 Heidelberg, FRG

5/P-GM 123

5/P-GM 125

UNEXPECTED DECREASE IN ANTINEOPLASTIC ACTIVITY AGAINST A H O R M O N E - D E P E N D E N T TUMOR AFTER LINKING C N C - ALANINE TO 3- HYDROXYDESMETHYL - TAMOXIFEN O R TO DESMETHYLTAMOXIFEN - HYDROCHLORIDE. T. Wetzel, M. Beth, M. Palm and M. R. Berger The aim of this study was to elucidate the effects of new antiestrosen-linked cytotoxic drugs on the colony growth of MNU-inducad rat mammary carcinomas, using the modified bilayer soft agar assay according to Hamburger/Salmon (Science, I97, 461, 1977). Isolated mammary carcinoma cells were exposed (1 hour) to CNC-alanine, either linked to the antiestrogen desmethyhamoxifen-hydrochloride (CNC-alanyl-desmethyl-tamoxifen; I) or to 3 - hydroxy- desmethyl - tamoxifen (CNC - alanyl - 3 - hydroxydesmethyl-tamoxifen; II) at concentrations ranging from 1 to I00 /~mol, and treatment results were compared to those following the single agents desmethyltamoxifen-hydrochloride plus CNC-alanine (tlI) and 3-hydroxy-desmethyl-tamoxifen plus CNC-alanine (IV). The following results in terms of T / C % were obtained after 7 days of incubation: I: 105; II: 105; III: 55; IV: 43. Unexpectedly, the unlinked single agents showed a significantly higher inhibition of colony growth in comparison to the linked compounds, which were inactive. The colony inhibiting efficiency of 3 - h y d r o x y desmethyl-tamoxifen, which has a higher receptor affinity (0.9) than desmethyl-tamoxifen-hydrochloride (< 0.5), was more pronounced in combination with CNC-alanine than the latter compound. These in vitro-results are in agreement with in vivo investigations on the hormone-dependent MNU-induced rat mammary carcinoma, which also was not influenced by I and II; they contrast with previous findings using CNC-alanine- estradiol-17-ester (Petru et al., Prec. AACR, 28, 257, 1987), which displayed a superior activity. Further investigations are planned to evaluate different hormonal carriers.

PROGNOSTIC FACTORS IN MEDULLARY CARCINOMA OF THE BREAST

Institute of Toxicology and Chemotherapy, German Cancer Research Center, Im Neuenheimer Feld 280, D - 6 9 0 0 Heidelberg.

M. Mitze, E. Goepel and H.-E. Stegner Department of Gynecology and Obstetrics, University of Hamburg Methods: In the files of the histological laboratory of the Department of Gynecology and Obstetrics, University of H a m b u r g between 1975 and 1984 55 medullary carcinomas were registered. The hlstoIogical sections of the tumors were reexamined a n d olassified by one experienced pathologist. The histologcial and clinical data were correlated with the data of the follow-up of the patients. Results: 23 (41,8%) of the women were p r e - , 32 (58,2%) postmenopausal. The size of the tumors was in 13 (25,5%) cases less than 2 cm in diameter, 27 (49%) measured between 2-5 cm and 6 (10,9%) had a size of more than 5 cm. In 8 (t4,6%) cases the t u m o r size was not clearly defined. 36 (67,9%) showed histologically no axillary node metastases. Only in 17 (32,1%) cases axillary node metastases were detectable. The histological grading o f the tumors showed in 52 carcinomas grade III carcinoma. In 3 cases the histological sections were not available. In 37 tumors the estrogen receptors were examined. 26 (70,3%) of these tumors showed no estrogen receptors. Only 11 (29,7%) tumors were positive for estrogen. Within a follow-up time of 68,1 + 35,1 month 15 (27,20/0) women had a recurrence of the disease. 7 patients showed a local recurrence, 8 had metastases. 39 (70,9%) women stayed free of disease, t2 patients (2t,8%) died. _Summary: The medullary carcinoma ist a histologically well defined entity of m a m m a r y carcinoma. Despite of the bad histological g r a ding and the high percentage of estrogen receptor negative tumors the medullary carcinoma shows a quite good prognosis. Within a median foltow up time o f more than 5 years 70 % of the patients showed a relapse free s u r v i v a l Only the axitlary node metastases proved to be a factor of a bad prognosis.

S 188

SAT 1/001

SAT 1/003

DOSE FINDING STUDIES WITH CARBOPLATIN (JM8), IFOSFAMIDE (IFO), ETOPOSIDE (VP16) AND MESNA IN NON SMALL CELL LUNG CANCER (NSCLC). N. van Zandwljk, W.W. ten Bokkel Hulnink, J. Wanders, G, Simonetti, R. Dubbelman, H. Franklin, M. Brouwer and J.G. MoVie. The Netherlands Cancer Institute, Amsterdam, The Netherlands. Carboplatin, a clinically active analogue of Cisplatin, was added to IFO and VP16 two agents with response rates of 28% and 15% respectively in NSCLC. 34 consecutive patients (pts.) (22 males,12 females), mean age 56 (range 30-73) yrs, p.s. & 3, with symptomatic inoperable NSCLC were accrued and recleved JM8 100 mg/m 2 day 1,3 and 5, 300 mg/m ~ day I or 350 mg/m 2 day I, IFO 1500 mg/m 2 day 1,3 and 5, combined with Mesna 2000 mg/m 2 and VP16 60 or 100 mg/m 2 day I, 3 and 5, q 4 wks. Twenty five pts. were previously untreated. Sofm~ 130 courses have been administered and 19 pts. reeleved 4 or more courses. With 350 mg/m 2 JM8 and 100 mg/m 2 VP16 in the combination myelosuppresslon was dose-llmltlng in 8 pts. and WHO III (or IV) toxicity was encountered in 49% (9%) for WBC's, and in 12% (13%) for platelets. Myelosuppression no. no. WHO grade WBC's pts. courses 0 I II III IV JM8 100 mg/m 2 x 3 6 20 3 2 4 10 I JM8 300 mg/m ~ x I 7 22 5 3 9 5 JM8 350 mg/m 2 x I 27 88 5 9 31 36 7 (+ 100 mg Etoposide x 3) One septic/toxlc death and one minor bleeding disorder were seen. Nausea and vomiting (WHO III) occurred in the majority of ptso and alopecia (WHO III) was universal after 3 courses. All pts. were effectively protected by Mesna and neurotoxicity did not occur. Evaluation of response after 2 and/or 4 courses in 29 pts. showed and objective response (CR=PR) in 15, 6 pts. progressed. Conclusions: For the combination JM8, IFO and VP16 with a promising actlvlty in NSCLC hematological toxlclty was dose-limiting, only rarely accompanied by sepsis or haemorrhage.

Standard combination chemotherapy versus two carboplatin containing regimens in SCLC. A randomized phase II study. EORTC protocol 08882. The EORTC lung cancer cooperative group. In April 1986 a randomized 3 arm phase II study was started. Arm i consists of cyclophcsphsmide i g/m2 i.v. d l, doxorubicin 45 mg/m~ i.v. d I, and etoposide i00 mg/m~i.v. d 1,3,5 (CDE) q 3 wks. Arm 2: Ifosfamide 5 g/m2i.v, in 24 hrs d 1 + mesna, carboplatin 400 mg/m2 i.v. d 1 (IMP) q 4 wks. Arm 3: vincristine 2 mg i.v. d 1+8, carboplatin 400 mg/m~ i.v. d I (VP) q 4 wks. A total of 5 cycles was given ~ud response evaluated after 2 and 5 cycles. Between April 1986 and June 1987 186 patients have been entered, LD 53%, ED 4?%, ECOG 0-i 80%, ECOG 2-8 20%. 139 patients have been evaluated. Best response to i st line chemotherapy: Therapy CDE IMP n 54 38

14

PR

o

WP 47

2 }62

SD 9 2 7 PD 3 6 IO NE 2 1 1 Toxicity: nausea/vomiting: CDE 75%, IMP 84?4, 9~ 81% of the courses. Alopecia: in almost all patients treated with CDE or IMP and in 53% of the VP patients. Neuropathy was seen in 41% of the VP patients. Median nadirs of CDE IMP VP

WBC 1.2 1.3 3.7

(range! ........ platelets (range) (0,1-10.9) 120 (12-311~ (0.2- 6.5) 59 (6-214) (0.6- 9.3) 120 (3-408)

Conclusions: i. ODE and I~[P give comparable response rates; 2. VP is less toxic and less effective. The evaluation of non-cross-resistance of IMP and CDE is currently evaluated,

SAT 1/002

SAT 1/004

COMBINATION CHEMOTHERAPYWITH MITOMYCINE-C, IFOSFAMIDE AND VINDESINE IN THE TREATM'ENT OF N O n ' L U N G CANCER. J.v.Pawel(1),K.H~uBinger(1),R.Laumen(2),W.Jungbluth(2).

THE TREATMENT OF SMALL CELL LUNG CANCER.

Since January 1987 47 patients with non-small-cell lung cancer t h a t were inoperable have received a combined treatment with mitomycine-C, vindesine and ifosfamide. Dosage and schedule were as f o l l o w s : mitomycine-C 10m~/m2 day 1. vindesine 3mg/m day 1 and ifosfamide 1500mg/m day 1-5. every 4th week, with a maximum of 6 cycles. E l i g i b i l i t y c r i t . e r i a : H i s t o l o g i c a l l y proven non-smallc e l l lung cancer, evaluable tumor parameter, age~70, no cerebral metastases Karnofsky performance status over 60%; no p r i o r chemo- or radiotherapy; no severe morbidity due to other reasons. 41 male and 6 female patients with an average age o f 56,5 years (40-69) and an average Karnofsky performance status of 85% (60-100) have been accepted f o r our study. Results: U n t i l now (November 87) 30 patients have r e ceived more than 2 cycles and t h e r e f o r e can be evaluated f o r response. The t o t a l response f o r l i m i t e d and extensive disease was 43,3%. A CR has not been seen yet. The response f o r l i m i t e d disease was 63,6% (7/11 p a t i e n t s ) , f o r extensive disease 31,6% (6/19 p a t i e n t s ) . The chemotherapy scheme described above was t o l e r a t e d by most pat i e n t s . G a s t r o i n t e s t i n a l symptoms occur in less than 50% of our patients; the haematological and renal t o x i c i t y was acceptable. The pulmonal t o x i c i t y did not cause problems Conclusions: With a t o t a l response of 43,4% the combinat i o n o f mitomycine-C, ifosfamide and vindesine can be applied in the treatment of non~small-cell lung cancer without causing major complications. The influence of t h i s therapy regarding the remission period and the surv i v a l time is not known yet, (1) Zentralkrankenhaus Gauting der LVA Obb,, Pneumolog. Abt., 8035 Gauting/M~nchen. (2) K l i n i k Seltersberg der LVA Hessen, 6300 Gie6en.

IFOSFAMIDE~ETOPOSIDE AND ADRIAMYCIN IN THE

M.LINDI.,H.ANDERSONI~M.BRONCHUD.,R.STOUT2., N.THATHCHERIo 1CRC

DEPARTMENT OF MEDICAL ONCOLOGY CHRISTIE

HOSPITAL AND HOLT RADIUM INSTITUTE MANCHESTER. 2 DEPARTMENT OF RADIOTHERAPY CHRISTIE HOSPITAL AND HOLT RADIUM INSTITUTE MANCHESTER. 23 Patients w ~ h

intermediate prognosis(Cerny et el)

1986) small cell lung cancer were treated with Ifosfamide 5G/M 2 IV day l with Mesna 8 G/M 2, Adriamycin 50 mg/M 2 day ItEtoposide 120 mg/M 2 IV days I&2 and 240 mg/M 2 orally on Day 3.A total of 6 courses were given to each patient.In addition 8 patients with limited stage disease(LD) received mediastinal radiotherapy following chemotherapy. The median age was 59 years(10 LD 13 ED).So far 120 courses have been administered .Non Haematological toxicity has been mild consisting mainly of nausea and Vomiting.However non hae~atological toxicity redulted in 14 courses being delayed because of myelosuppression;lO patients experiencing ~ W H O Grade 4 Leucopenia. To date there haoe been 8 CRs and 11 PRo giving an objective response rate of 83%.There have been 3 deaths from progressive disease and 1 toxic death.

S 189 SAT II/001

SAT 1/005 A PHASE

I/PHARMACOKINETIC

STUDY

COMPARING

ADMINISTERED

I~SFAMIDE

WITH

ADMINISTERED

IFOSFAMIDE

IN P A T I E N T S

CELL LUNG

ORALLY

CHEMOTHERAPY OF SCLC IN ELDERLY PATIENTS RUBICIN WEEKLY AS SINGLE AGENT U. Gatzemeier, M. Heckmayr

INTRAVENOUSLY

P . M . W I L K I N S O N 2. CRC D E P A R T M E N T

2 DEPARTMENT HOSPITAL

lung

OF C L I N I C A L

were

with

1-5 w i t h e q u i d o s e were

treated

and mesna The

PHARMACOLOGY

with

IV Mesna.A

but

1)Haematological

were

toxicity

non small

1 . 5 G / M 2 IV d a y s

furteh doses

the i f o s f a m i d e results

CHRISTIE

M~NCHESTER.

advanced

ifosfamide

with identicai

following

CHRISTIE

MANCHESTER.

INSTITUTE

treated

cancer

ONCOLOGY

INSTITUTE

AND HOLT RADIUM

10 P a t i e n t s cell

OF MEDICAL

AND HOLT RADIUM

10 p a t i e n t s

of ifosfamide

was a d m i n i s t e r e d

orally

obtained:was m i l d

and

similar

in

both arms. 2)Neurotoxicity

was

arm necessitating in 4 / 1 0 3)The

patients

terminal

half

on d a y

asociated

with

oral

life

in

the o r a l

o f the c o u r s e s

arm.

of ifosfamide

1 to 3 h o u r s o n

an i n c r e a s e

and increased

This is t h o u g h t P45Oo

severe

termination

in the

6.5 h o u r s

of the d r u g

far more

early

to be due

declined

day 5.This

alkylating

to i n d u c t i o n

from

was

in the n o n r e n a l peak

clearance

levels.

of c y ~ o e h r o m e

CARBOPLATIN,IFOSFAMIDE,ETOPOSIDE VINCRISTINE

AND THORACIC

sTAGE SMALL

CELL

LUNG

WITH MID

RADIOTI~ZRAPY

FOR L I M I T ~ D

CANCER.

1 CRC D E P A R T M E N T

2 DEPARTMENT

42 P a t i e n t s

limited

with

5G/M 2

day q,VP16-213

either

cell

Mesna

thoracic

as a s i n g l e

over

1&2 and

to a t o t a l

lung

cancer

2 IV d a y

240 m g / M 2

0.5 m g d a y cf ~ i x

14.

courses.

radiotherapy rotation

1

24 hours

was

or an 8 F

pair.

far 222 c o u r s e s

patients

small

Vincristine

4 weeks

HOSPITAL

300 mg/M

with equidose

chemotherapy

adminstered

stage

have

have been

received

administered,72%

6 courses.The

CR r a t e

of is 5 0 %

PR 3 1 ~ OR 8 1 % ~ % of p a t i e n t s r e s p o n d e d by 2 c o u r s e s . T h e M e d i a n s u r v i v a l ~s 13 m o n t h s r a n g e 1-18. 2 year survival

will

a s the s o l i t a r y

site occured

toxicity Despite

was severe this

performance.

there

be in e x c e s s

was

of 3 0 % . B r a i n

relapse

in 1 9 % . H a e m a t o l o g i c a l

w i t h 3 toxic a rapid

BREAST C~{CE~

SaP + RT (E~irubisiq~_~Mgthotrexate ~ Prednlsone + Radiotherapy), weekly fracti0nated imul__taneous R a d i o - P & ~ a o t h e r a p ~ .

IOI patients were inclu_ded from 1 2 . ! 3 1 : ~ 8 ~ t o ~ , 59 were prEtreated with sequential hormonal therapy and 44 with chemothe~ rapy ( 15 with adjuvant and 29 palliative chemotherapy ).

CHRISTIE

120 m g / m 2 I V d a y s

every

CHRISTIE

MANCHESTER~

Carboplatin

on day ~ with

Following

So

INSTITUTE

with

treated

Ifosfamide

ONCOLOGY

INSTITUTE.

OF RADIOTHERAPY

AND HOLT RADIUM

parallel

OF M ~ I C A L

AND HOLT RADIUM

repeated

more than WHO Grad II. About 45 % had mild to moderate alopecia. Furthermore we didn't have any other toxicity. Conclusion The mono-chemotherapy with 4-Epirubicin leads to a good remission in I/3 patients with SCLC aged more than 70 years without respectable toxicity. These patients do have a benefit in prolonged survival without alternatives in standard chemotherapeutic regimen, because of the toxicity and contraindications of many drugs, Dep. of Thoracic Oncology, Gre6hansdorf Hospital

M.Brandtner (I), R.Balas (2), F.HeS (3), E,a.Meumann (4), G.Seiler (2}, N.Janssen (2}, H.J6rg (4}. Radioonkolcgische Klinik Kreiskrankenhaus getzlar (i), Redioonkologische Abtl~. St~ Marienkrankenhaus Si~gen (2), Medizinisches Zentrum f~r Radiologie, Abtlg. Strahlentherapie, Universit~t Marburg/ Lahn (3), Radiolog. K!inik, Abteilung Radioonkologle, St. Vincenz - Krankenhaus Limburg [4)~

A N D N.THAT}~CHER 1 .

orally

of the p a t ie n t s had a OR (2/30 = 6 , 7 - ~ - ~ PR (7/30 = 23,3 %). The median s u r v i v a l in responding patients was 15 (+) months r e s p e c t i v l y in non-responders 4 month (p = O,O7), We d i d n ' t see any severe hematological side e f f e c t . Also the g a s t r o i n t e s t i n a l t o x i c i t y wasn't a problem. Only 1/30 of p a t i e n t s had nausea and vomiting

METASTATIC

CONRSE

~'~.J . L I N D . 1 ., H . A N D E R S O N I .~ D.B.:~M.l TH 1 . ~ R . S T O U T 2. ,

were

Introduction In the last decades we had a postponement in the peak of age distribution in lung cancer with a higher ratio of patients more than 70 years old. Because of performance status, side effects of cytostatic drug and other diseases these patients couldn't often receive a polychemotherapy or couldn't treated at all until now. With new eytostatie drugs with lower ratio of side effects there can be an approach to treat also these patients with a benefit, acceptable toxicity and without decreasing the quality of life. Patients and methods Since 01.01~86 30 patients with histolocically proven SCLC and age more than 70 years and Karnofsky-Status lower than 70 % were entered into the protoeoll. In all patients there were exclusion criteria for trials with polychemotherapy regimen. The median age was 74,5 years. 23 male, 7 female. 15 had limited disease, 15 extensive disease. More than 50 % of the extensive disease patients had distant metastases. Treatment schedule: 25 mg/qm 4-Epirubicin i.v. every week. Results 30 % (9/30)

SAT II/002

SAT 1/006

HOSPITAL

4-EPI-

WITH NON SMALL

CANCER.

M.J.LIND.I.,JoM.MARGiSON2.~N.THATHCHERI.~

HOSPITAL

WITH

deaths

from l e u e o p e n i a .

improvement

in K a r n o f s k y

Schedule E = epirubicln 30 mg i.v. M = Methotrexate 25 mg i.v, P = Prednisone 20 mg p.o. lO mg p.o, + RT = ~adlotherapy 1,5 Gy HD. day

+ + + + ~ + +++e++++++++++ § ++ ++ +e ++ +++++++++++++++++++++++++++§ 1 8 15 22 28

The cycles were given every 29 days without P, in case of complete remission ( CR ) 3 r with partial remission 3 more cycles with reduced dosages: E 30 mg + M 25 mg i.v. only day I + 8, RT ( -36 Gy ) possibly day 1 + 2, 8 + 9. Therapy - free days IO - 28. Definition of the remissions after All patients: CR 24 %, PR horm. pretreated: 2~ %, horm. not pretreated: 2& %~ chem. , pretreated:. 25 %; chem. not pretreated: 23 %. Complete remission of liver met.=

3 cycles 50 ~ MR 46 %, 57 ~, 45~ u 54 %, 37 ~ and

by WHO - criteria: 4 %, NC 13 %, PD 9 5 %, 17 ~, iO 2 %~ 7 ~, 7 O %, 16 %~ 14 7 %, Ii %, 5 bone met. = 32 %.

Side effects according to WHO grade: Alepecia X III= I0%, IV = 1% (RT); only II % needed a wig. I = 17%, II = 8%, ss / mucositis I = 3%, cardiec toxicity I = 1%. Other side effects not to IO % had a lengthenedtherapy free interval~ not observed,

%~ ~ %, %, %.

= 32%, II = 16%, Nausea / vomiting I I i i%, clinical Observed. Only up Leukopenia ( 2000

The median d~ratlo~of remission : median s~rvivslwas calculated On 12/1/87 with the Kaplan - Meier method as follows: All patients : 8,1 : 14,7, CR + PK : ~o.oz~_2~21 +~ non resp.(a~, NC, PD) 3,3 : 5,8, horm. pretreat: 7,7 : 13~2, hormon, n~t pretre~t: 9,1 : i~ +~ chemoth, pretteat:7~7: 15~2, chemoth.not pretreat: 8,~ : 14,7~ In conclusion~ the schedule EMP + KT is reco~endable because of its good results and minimal side effects as first line chemotherapy, especially in older patients. There i~ a quick T~sponse of liver metastases and painful bone metastases. Patients pretreated by chemotherapy had a response rate of 70 % ( CR 25 %, P~ 45 ~ ).

S 190

SAT I1/003

SAT II/005

BEHANDLUNG DES METASTASIERTEN ~A-KAR/INOMS MIT WOCHENTLICHER APPLIKATION VON EPIRUBICIN, METHOTREXATUND PREDNISON ( ~ ) . W.-D. Hirschmann,B. EggeHng,E.-U.Steinhauer,U.Zeymer Mit%eilungen ~ber die Effektivit~t der w6chentHchen AppHkation von Epirubicin bei metastasiertemMamma-Karzinom waren ~11a6, dieses Therapieprinzip im Rahmeneiner Kombinationsbehandlung zusammenmit Methotrexa%und Prednison einzusetzen. Es sollte OberprOft werden, ob sich mit w6chentlich fraktionierter Gabedieser Substanzen eine ahnHch hohe Remissionsquotewie bei konvent|oneller Chemotherapie erzielen und die Nebenwirkungsra%egleichzeitig verringern i~6t. FolgendesTherapieschemawurde verwendet: Epirubic~n 20 mg/m" i . v . und Methotrexat I0 mg/m~ i . v . a11e 8 Tage insgesamt ~2x, danach a11e 14 Tage insgesamt6x. Tag I bfs Tag 28 t~glich 25 mg Prednison per os. Zum Stichtag ~.I}.1987 waren 44 Pat. auswertbar. 5 Pat. waren vor EMP-Therapiezytostatisch vorbehandelt. Nach 12 EMP-Zyklen ergaben sich folgende Resultate: I CR (2%), 20 PR (45%), ~6 NC (34%), 8 PD (|8%). Nach Spreizung der Therapieintervalle auf 14 Tage gingen ~0 Pat. mit PR bzw. NC in eine PD ~ber. Die medianeOberlebenszeit ab Therapiebeginn betr~gt nach Kaplan-Meierfor alle Pat. 15 Mohate. Bei den Pat. mit CR+PRliegt die OberlebenswahrscheinHchkeit nach ~6 Monaten bei 77%. Die NebenwirkEngsrate des Therapieprotokolles ist gering: B1uZbildver~nderungen WHOGrad 0 = 67%, Grad I = 28%; Nausea und Erbrechen WHOGrad 0 = 48%, Grad I = 41%; A1opezieWHO Grad 0 = 31%, Grad I = 31%, Grad II = 36%. Resume: Die w6cbentlich fraktionierte Gabevon Eplrubicin und Methotrexat ergibt bei geringen Nebenwirkungen ahnHche Remissionsratenwie die konventionelle hochdosierte Chemotherapie.Bei ~4-t~giger Applikationsweise t r i t t ein Verlust an therapeutischer Efffzienz ein. Abteilung f~r ~atologie/Onkologie der Stadtischen KHniken, M6nchebergstr. 41, 3500 Kassel

EPIRUBICIN (E) WEEKLY, CYCLOPHOSPHAMIDE (C) AND VINCRISTINE (O) IN SMALL-CELL CARCINOMA OF THE LUNG (SCCL). H.W. Tessen, A. Kretzschmar, M.Eberlein-Gonska, P,Dr!ngs

SAT 11/004

SAT 11/006

EPIRUBICIM (E) w6chentlich, CYCLOPHOSPHAMID (C) und VINCRISTIN (O) in der Behandlung des Kleinzelligen Bronchialcarcinoms (KIBC). H.W. Tessen~ A. Kretzschmarr M.EberleinTGonska, P.Drings

CARBOPLATINUM/VINCRISTINE AND ETOPOSIDE AS FIRST LINE THERAPY IN SMALL-CELL-LUNG-CANCER (SCLC) R. Neuhauss (1), N. Achterrath (2), U. Gatzemeier (1), M, Heckmayr (1), D,K, Hossfeld (3), R, Zschaber (3)

32 Patienten (Pt) wurden behandelt mit E 30 mg/sq-~ i.v. Tag (T) I, 8 and 15, C i000 mg/sqm i.v. T I and 0 2 mg i~ T I, Therapieintervali 21 T. Pt mit einer kompletten (CR) und partiellen Remission (PR) im Stadium Limited disease (LD) erhielten eins Thoraxbsstrahlung. Bei CR wurds zus~tzlich eine Schidel-Hirnbestrahlung dnrchgef~hrt.Ein Pt verwaigerte die Behandlung nach dam i. Zyklus, sein Responseverhalten ist somit nicht beurteilbar. Patienteneharakterlstika: Keine Vorbehandlung, medianes Alter 59 J. (39-73), m 29, w 3, Karnofsky-Stadium 90 (80-100), LD 14 Pt, ED 18 Pt. Ergebnisse: 5 Pt (16,1%) erreichten eine CR, (LD 30,8% (4/14); ED 5,5% (1/18); 14 Pt (46,6%) elne PR (LD 38,5% (5/14); ED 50% (9/18). 7 yon 14 Pt mit einer PR warden zur Zeit noch behandelt, so da~ noah einige yon ihnen sine CR erreichen khnnen. Bei einer mittleren Beobachtungsdauer yon 189 T ist die mittlere 0berlebenszeit noah nicht erreicht. Haematologische ToxicitAt: Leucopenie WHO-grade I 32,5%, II 21,0%, Ill 15,0%, Anaemie WHO-grade I 24,1% and II 1,7% ; Keine Thrombozytopenie. Andere Nebenwirkungen: ~belkeit und Erhrechen 64,5% grade I, 6,5% II, 6,5% III; Alopecie 6,5% I, 16% II, 77% III. Kardiotoxicit~t wurde nicht beobachtet. Zusammenfassend ist das Therapieergebnis vergleichhar mit anderen bekannten Doxorubicin oder Epi-Doxorubicin enthaltenen Komhinationen bei weniger Nebenwirkungen. ECO-w6chentlich hat eine Indikation in F~llen, bei denen aus medizinischen Gr~nden sine aggressivere (und m6glicherweise effektivere) Behandlung nicht durehgef~hrt warden kann.

INTRODUCTION: In the p i l o t d o s e - f i n d i n g study with f i x e d doses C a r b o p l a t i n u m / V i n c r i s t i n and e s c a l a t i n g doses o f Etoposide we looked f o r the t o x i c i t y and the e f f e c t i v e ness o f t h i s combination in extended SCLC. In the ongoing phase-II-trial with the recommended dose and schedule also r e m i s s i o n - r a t e und s u r v i v a l i s observed. PATIENTS AND METHODS: In the p i l o t study 25 p a t i e n t s were t r e a t e d , f/m r a t i o 8/17, mean age 59 (37 - 69), ED I/ED I I 11/14. Dose l i m i t i n g t o x i c i t y was myelosuppression when Etoposide exceeded 420 mg/qm per course. As r e s u l t the recommended dose and schedule for the following phase-II-trial was as follows: Carboplatinum 300 mg/qm i.v. day 1, VCR 1,4 mg/qm (max. 2 mg i . v . ) day 1 + 8 + 15, Eteposide 140 mg/qm i . v . day 1 - 3. Since 2/87 54 patients were entered into the ongoing protocoll, f/m r a t i o 12/42, meanage 57,8 (23 - 78). Lim./Ext. 28/24. RESULTS: In the p i l o t study 48 % CR and an o v e r a l l r e sponse r a t e of 88 % were achieved. In the f o l l o w i n g phase-II-trial up to now 48 p a t i e n t s are evaluable f o r response and s u r v i v a l , An overall objective response-rate o f 91,7 % has been observed.(OR 29,2 %, PR 62,5 %)~ Overall the toxicity was very moderate. Nausea and vomiting WHO 3 + 4 occured in 28,8 % of the patients. Other toxicity according to WHO: Polyneeropathy 1:81,5 % and 11,5 % resp, grade 2 and 11,5 % rasp, grade 3. CONCLUSION: The combination Carboptatinum, V i n c r i s t i n and Etoposide is highly effective in the treatment of SCLC~ The response rate and also the early survival data are encouraging, especially in combination with the very moderate toxicity, Compared with historical data achieved by DDP/Vp-16 or DDP/VDS or CAV this combination seems to be superior. Dep.of Thoracic Oncology, GroBhansdorf Hospital (1) Bristol-Myers Company (2) Dep,of Hematology and Oncology, Univ.of Hamburg (3)

Thoraxklinik Heidelberg-Rohrbach, Medizin / Onkologie, Amalienstr.5,

Ahteilung Innere D-6900 Heidelberg.

32 patients (pts) entered this study. Treatment: E 40 mg/sqm i.v. day (d) i, 8 and 15, C I000 mg/sqm i.v. d 1 and O 2 mg i.v. d I, given every 3 weeks for 6 treatment cycles. Pts with a complete (CR) and partial remission (PR) in stage limited disease (LD) received chest irradiation. In all CR a whole brain irradiation was added. One pt refused further treatment after the I. cycle and was not evaluable for response. Characteristics: no prior treatment, mean age 59 yrs. (39-73), 29 males, 3 females, Karnofsky PS 90 (80-i00), LD 14 pts, ED 18 pts. Results: 5 pts (16,1%) achieved a CR, (LD 30,8% (4/14); ED 5,5% (1/18); 14 pts (46,6%) a PR (LD 38,5% (5/14); ED 50% (9/18). 7 out of the 14 pts with a PR are still under treatment, some of them might develop a CR. Median observation-time 189 days, median survival-time not reached. Haematologic toxicity: leucopenia WHO-grade I 32,5%, II 21,0%, III 15,0%, anaemia WHO-grade I 24,1% and II 1,7% ; there was no thrombocytopenia. Other side effects: nausea and vomiting 64,5% grade I, 6,5% If, 6,5% III; alopeeia 6,5% I, 16% If, 77% Ill, There was no cardiotoxieity. In summary, treatment of SCCL with ECO-weekly is well tolerated and accepted. The antineoplastic effect is comparable to other ECO or ACO regimens with less side effects. ECO-weekly should be recommended for indications where aggressive (and probably more effective) regimens cannot be carried out for medical reasons. Thor~xklinik Heidelberg-Rohrhaeh, Medizin / Onkologie, Amalienstr.5,

Abteilung Innere D-6900 Heidelberg.

S 191 SAT V/O01

SAT 11/007 D~Z BE~ANDL~NG DES

~OKMONKESIST~NTEN FKOS~ATAKARZINOMS

MIT EPIRUBICIN 25 mg/m ~ W6CHENTL~g~ Autoren: K.Burk. W.Schultze-Seemann. D Jona~. G.Rodeck

ANTITUMORAL EFFECT OF INTRALESIONAL (I.L.) APPLICATION OF B-INTERFERON (IFN) V E R S U S SYSTEMIC APPLICATION OF 5-IFN I.L. AND ~-IFN IN PATIENTS WITH OSTEOGENIC METASTASIS OF BREAST CANCER. Szepsi

In der Zelt van Oktober 19Ss bls Dezember 1986 wurden 60 Pe~ienre~ mit h@~monrefrak~aren "unter Estr~cyt progredlenten Pro~takarzi~ome~ mit Eplrubicln 25 mg/m w6chentlich behandelt. 55 Patienten sind ausw~rtbar. Des medians Alter betr~gt 65 Oahre , die mittlere Anamnesezeit 2 Jahre. BZs auf 5 % hatten alle Pat~enten Knochenschmerzen, 91% der Patienten hatten elne erh6hte alkalische Phosphatase, je 73 % elne erh6hte saute bzw. Prostataphosphatase. Die mediane Eeobachtungszeit f~r di9 55 auswertbaren Patienten betr~ jetZt i0 Monate (3-33). Die Evaluation land n~eh Kriterien der EORTC 3eweils~tach 3 Monarch sta~. Rime komplette Remission %~rde nlch~ erzlelt. Fartlelle Remis~ionen konnten in 36.% % nachgewlesen werden~ 14 ~er 20 Patlenten mit partieller Remission sind derzelt noah unter Beohaahtup~. Zu elnem minimalen Ansprechen Ram es in 16.3 % der Falls, 4 der 9 Patlenten leben noah. Nicht auf die Therapie angesproehen haben 16 Pstlens mi~ stabiler Rrkrankungsphase und iO Patlenten waren trotz ~nerapSe welter progredlent. 87 % der Patienten klagten ~ber kelnerlei Nehenwirkungen. In 4 % Ram es zu geringgradlgsm Haarausfall, 5 % der Patlenten gaben vor~bergehands leichte ~belkelt an und in 4 % kam es zur Myelosuppresslon, webel in elnem Fall dutch Sternslpunkt~on Knochenmarkmetastasen nachgewi@se~ werden konnten. Die medians heobachtungszeit f6r Patlenten mlt partieller und minimalet Remission ist mlt 18 respektive 15 Monaten si~nifikant la~zer ale f~r d~e Patlenten, ~ie auf die Behandlung nlcht ansprachen. PatienEen m~t NO Chan~e lebten median 7 Monate. Pa~lenten mit weiterer Progression nut 4.5 Monate. Zusammenfassend ksnn fe~tge~tellt warden, da~ die ~ch~ntliche There* p~e mlt Epirubicin ~5 mg/m die Bedim~u~en f~r ein~ pa!i~ative Thera~ pie yell erf01~t. Es k0mxc unter dieser Therapie in 80 ~ ru elmer Verbesserung der Lebensquali~t und zu e&ner ~leichzeitigen Lebensver]&n~ gerung for die 50 % der Patienten, die auf 4is Behand!ung objehtiv ansprachen.

S1,

Baew-Christow

T 1, Maul FD2, HSr G2

i Devision of radiotherapy and oncological nuclear medicine 2 Devision of nuclear medicine J.W. Goethe-Univ. Frankfurt am Main After local application of ~-Interferon in osteolytic metastasis of breast cancer we conclude a prolongued pain reduction and tendency of recalcification. An even better antitumoral e f f e c t is:_ s u s p e c t e d by intralesienal treatment w i t h B - I F N in c o m b i n a t i o n with a sequentiell/systemic ~-IFN treatment. If other usual oncological arrangements refuse or are rejected end symptoms and localisation of single metastasis stand to be fore it seems that this will be a new, significant method for p a l l i a t i o n . We intend a prospective/randomized study to prove the antitumoral effect of IFN alone in contrast to a combination with systemic ~-IFN. The efficacy of treatment was related to modification of pain, bone X-ray and bone scan final to treatment and 3-4 months after treatm e n t in c o m p a r i s o n to t h e m e d i c a l status before. Aim of study, randomisation, pre- and posttherapeutic diagnostic procedures, method and analysis of results will be demonstrate in d e t a i l .

SAT I7V7001

SAT WOO2

T R E O S U L F A N E IN C O M B I N A T I O N W I T H C I S P L A T I N U M FOR T R E A T M E N T OF A D V A N C E D O V A R I A N C A N C E R - A PHASE II TRIAL E. S c h w a r z e n s u and O. H i l f r i s h

H U M A N FIBROBLAST INTERFERON (INF-8) tN A D D I T I V E LOCOREGIONAL AND SYSTEMIC ANTtCANCER THERAPY : CASE STUDY IN DIFFERENT MALIGNANCIES, E.Musch, M.Darwish, D.Niese, H.Messler, A.Werneq U.Kgster. Department of Internal Medicine, Orthopedics, Gynecology and Radiology, University of Bonn, W.-Germany.

Even though t h e r e are high r e m i s s i o n rates in p a t i e n t s with ovarian c a n c e r under chemotherapv, p r o g n o s i s of t h e s e p s t i e n t s is bad espacisll V if it was not p o s s i b l e to r e m o v e most af the tumor surgically. C o m b i n a t i o n t h e r a p y s c h e d u l e s like for example e i s p l a t i n u m plus c v e l a p h a s p h s m i d e with or without a d r l a m y s i n (PAC, PC) show s high texicitv. To l o w e r the s u b j e c t i v e texieltv, t r a o s u l f s n e was selected as c o m b i n a t i o n p a r t n e r for c i s p l a t i n u m which is known to be the substance with the highest potency against ovarian cancer. T r e s s u l f a n e has been d e s c r i b e d as s s u b s t a n c e with few s u b j e c t i v e side effects and r e m i s s i o n r a t e s up to 5o % u s e d as m o n o t h e r a p v in ovarian cancer patients~ Up to F e b r u a r y 1987 we have t r e a t e d 25 p a t i e n t s with e p i t h e l i a l o v a r i a n cancer F I G O stages III or IV. All p a t i e n t s had r e s i d u a l t u m o r m a s s e s of m o r e than 2 cm in d i a m e t e r and were t r e a t e d with c i s p l e t i n u m (80 m g / m 2) and t r e a s u l f a n e (5 m g / m 2) i.v. on day I. We r e p e a t e d this s c h e d u l e avery 3 weeks, the number of courses given was 5. R e m i s s i o n rate (complete and partial) was 7 1 % and is thus c o m p a r a b l e to our r e s u l t s with PAC end PC~ After a m e d i a n o b s e r v a t i o n Lime of 13 m o n t h s 5 p a t i e n t s had died in p r o g r e s s i v e disease, on average 8.8 m o n t h s after b e g i n n i n g of treatment. Half of the p a t i e n t s w e r e still in rem i s s i o n at that point of time. The r e s u l t s of two years o b s e r v a t i o n will be reported. A d v a n t a g e s of t r a o s u l f s n e in c o m b i n a t i o n with c i s p l e t i n u m ware the greatly r e d u c e d a l o p e c i a and the m i l d e r nausea and v o m i t t i n g periods. F r a u e n k l i n i k der M e d i z i n i s c h e n H a c h s a h u l s H a n n o v e r im O s t s t a d t k r a n k e n h e u s (Diraktar: Prof. Dr. J. Schneider), P o d b i e l s k i s t r . 38o, D - 3 o o o H a n n o v e r 51

We report on Iocoregionat + systemic INF-8 therapy in patients with thyroid carcinoma (1), metastases of melanoma in nasal cavity with compression of the eye bulb (1) and brain metastasis ( t ) , metastatic breast carcinoma (5) and AIDS-associated Kaposi's sarcoma (4). A t the site of intratumoral {NF-8 injection necrosis of t h y roid tumor, tumor regression of the melanoma metastases with clinical decompression of the nasal tumor and of the orbita and reconstitution of normal visus has been documen. ted. A good remission of tumor symptoms could be maintained during the foHwing maintenance ~herapy with i n t e r m i t t e n t {.v. INF-13 application ( 1-2 x ( 4x10 i.U.)/ week. Complete remission of non-operable exutceretive breast cancer (2), immediate relief of severe pain with prompt recalcification on X - r a y control resulted from direct injection of INF-8 into the breast tumors and the osteolytic metastases (3). l a tra~esional tNF-8 injection in exulcerative breast tumor / osteotytic metastases of mammary carcinoma was performed because of non-operability, insensitivity to radiotherapy or cri,tical,:s[ze.or Iocalisation of the tumorous manifestations. In these patients with metastatic breast carcinomas intratumoral INF-8 injections were accompanied by systemic combination therapy ( chlorambucit or prednimustin + methotrexate + 5FU ( + antioestrogen) with only minor response / no change of metastases which were not directly injected by INF-8. tntralesional + low dose systemic }NF-8 resulted in comptete response of histologically proven manifestations of AIDS-associated Kaposi's sarcoma in a hemephifiac (hemophilia B) drug abuser. In 3 homosexual patients with AIDS-related Kaposi's sarcoma partiai response of Kaposi's sarcoma with multiple skin and oropharyngeal tumors could be documented.

S 192 SAT V/005

SAT V/003 Intraarterial Interferon-therapy

in Oral Cancer-

A Phase I Study

T. Thein, M. Beyer, J. Kreidler Dept.

of Maxillo-Facial Surgery, Universit~t Ulm

Patients with cancer of the oral cavity were treated with an intraarterial infusion of natural interferon-~. In order to get a high concentration in the tumor 4-5 Mio. I.U. interferon-~ were applicated by a carotis-catheter using a continous infusion for 12 hours daily. The follow up was repeated up to i0 times with a total amount of 30 to 50 Mio. I.U. interferon-~. The therapeutic efficacy was monitored by clinical control, flowcytophotometry, sonography and laboratory parameters. The clinical and sonographical examinations neither showed progression nor remission of the tumor during the treatment. In the eytophotometrical examination there were some indication for reduction of malignant cells in the tumor. Severe side effects or irritation of laboratory parameters could not be noticed. Further studies should examine antiproliferative and immunmedulative activity of interferon even by systemical and regional postoperative long time application.

Interferons in Disseminated Malignant Melanoma R.Stadler, C.Garbe, B.Bratzke, C.E.Orfanos, Dept. of Dermatology, University Medical Center Steglitz~ The Free University of Berlin, West Germany The rational for application of interferons in the treatment of melanoma is based(a) on their potent antitumor effects in vitro and (b) their immunomodulative properties possibly enhancing the host immune response. Three protocols were used to study the efficacy of interferons in advanced malignant melanoma: I. In stage IV malignant melanoma 10 patients were treated with 18 million IU rIFN-~2a s.c./ daily for 3 months and then every other day for another period of ]2 weeks. 2. In stage IV malignant melanoma 7 patients were treated with I million IU IFN-beta intralesional once a week combined with rIFN-gamma 50~g s.c. for 5 days every fourth week. 3. In stage II malignant melanoma after radical surgery 9 patients received as adjuvant therapy 9 million IU r I F N ~ 2 a s.c. every other day for 6 months~ and 9 patients received 5 millinon IU IFN-beta 3 x weekly for 6 months. According to these protocols we saw in d i s s e m i n a t e d malignant melanoma only partial regression of cutaneous metastases in one patient and hardly any responds to systemic application ofl- and B-interferons. In stage II malignant melanoma 70% of all patients showed progressive disease. The response to systemic interferon therapy according to these protocols were rather disappointing, however, new trials are in progress to determine the efficacy of interferon b e t a i n combination with gamma interferon in patients with high risk malignant melanoma.

SAT V/004

SAT V/006

%]{ERAPY OF M A L I ( ~ ~ WITH !NTERFEB:~qS M. Landthaler, O. BraL~l-Fa]co Department of Dermatology, University of Munich, F ~

C o m b i n a t i o n of p o l y c h e m o t h e r a p y w i t h interferon therapy in b r o n c h i a l carcinoma; p r e l i m i n a r y results.

Since l J ~ doses of interferons may have immunosuppressive effects, 20 patients w~th advanced malignant me/ancma were treated with low dose of recombinant alpha-2-interferon, i.e. 2.5 x 106 I.E.J.m. daily. 9 patients were aff]ictad with distant skin metastases, Ii patients with internal metastases (l~ng, liver, kidney, bone). In only one patient with a solitary skin metastasis complete remission for more than 2 years could be obtained by surgery and IF-therapy. In 19 patients fetal tumor progression occured. Mean survlva/ for a/] patients was 24 • 15 weeks. Patients w/th skin metastases survived 37 9 16 weeks, patients with internal i n v o l ~ t 16 98 weeks. Comparlson with advanced melancma patients without interferon therapy did not reveal a beneficial effect of low ~ e alpha2-inter feron therapy. In a pilot study, 25 patiants w/th hi~-rJsk malignant melancmas (a tumor thickness of more than 3 ~m and/or a prognostic index of more than 13) underwent standard surgical procedures. Afterwards, they were treated w/th gamma interferon in an adjuvant setting. Gamma interferon (200 Ng) was ~ v a n subcutaneously three times a week for 6 mcnths. For 25 patients, the follcw-up has been 9 to 21 mc~ths (m 16 • 4). q~ relapse occured in lO of 25 patients (40 %) with h~gh-risk primary t ~ o r s and 6 patients died t~T~or related. The survival was 9 to 21 months (in 14 9 5). Since these tumor-progression rates are in the same range as those in comparable patients, who did not ~dergo adjuvant therapy, one can conclude that the adjuvant galmna interferon regimen used is not effective in patients w/th high-risk r e a l i s t melanomas.

P. Zabel,

C. Kreiker,

Med. Klinik,

M. Schlaak

Forschungsinstitut

Borstel,

FRG

We investigate a c o m b i n a t i o n of p o l y c h e m o t h e r a p y w i t h beta- and g a m m a - i n t e r f e r o n in patients w i t h small cell and squamcus cell carcinoma. An imm u n o l o g i c a l m o n i t o r i n g was designed to detect the systemic and local i m m u n o m o d u l a t o r y effects of interferon therapy. Small cell carcinoma is t r e a t e d every 3 weeks w i t h adriamycin, cyclop h o s p h a m i d e and vincristin. Squamous cell carcinoma is treated every 3 weeks w i t h mitomycin, vindesine and iphosphamide. In one group of patients p o l y c h e m o t h e r a p y is c o m b i n e d w i t h betaand gamma-interferon. R e s t a g i n g is f o l l o w i n g 2 cycles of therapy. In case of PR and CR the initial schedule is continued, in case of no change or tumour progress c i s p l a t i n and etoposide are administered. T r e a t m e n t is stopped achieving CR after 6 cycles or in case of no response. Up to now 24 patients could be evaluated. P r e l i m i n a r y results indicate an increased response rate in patients w i t h small cell c a r c i n o m a in the interferon group and an u n c h a n g e d response rate in patients w i t h squamous cell carcinoma. Beside to the c o m m o n 'flu-like' symptoms in the i n t e r f e r o n group there is a c o n s i d e r a b l e m y e l o s u p p r e s s i o n in patients under i n t e r f e r o n therapy. In the interferon group we found m e a s u r a b l e gamma-interferon serum levels, an increase of the spontaneous IL-2 p r o d u c t i o n of lymphocytes, an increase of the spontaneous IL-I p r o d u c t i o n and p h a g o c y t o t i c c a p a c i t y of monocytes. In contrast, alveolare m a e r o p h a g e s as a part of the local immunity show a decrease of the spontaneous and L P S - i n d u e e d IL-1 production.

S 193 SAT V/007

SAT V/009

TREATMENT OF HAIRY CELL LEUKEMIAWITH NATURALBETAINTERFERON

Therapy of Interferon

W.-D. Hirschmann, 8. Eggeling Alpha interferon ( I F N - ~ ) is a very effective substance in the treatment of hairy-cell leukemia. Numerous clinical investigations have shown a response rate of 70-80%. Comparatively less experience howeverhas been made in the use of beta interferon (IFN-6). We can report about three patients with hairy-cell leukemia who were treated over a period of four to six month with natural IFN-6. All patients showed an improvementof hematologic parameters. The side effects were minlma1. In the case of two patients who suffered a relapse after discontinuing IFN-6, a marked improvementwas shown, when treatment was changed to I F N - ~ . The investigation demonstrate that IFN-B obviously has some efficacy in hairy-cell leukemia. In how far the clinical efficacy of IFN-6 against hairy-cell leukemia can be compared to that of IFN-~c can only be answered with larger numbers of similar cases. As f a r as we know we are describing for the f i r s t time that IFN-6 as well as IFN-o~have clinical efficacy in hairy-cell leukemia with the same patient.

Department of Hematologyand Oncology, St~dtische Kliniken Kassel, MOnchebergstr. 4~, 3500 Kassel

SAT V/008 K.von Wild, Clemenshospital~ 4400 M~nster, FRG Tretment of Malignant Gliomas With IFN-g Various preparations interferon (IFN) have been in clinical use demonstrating therapeutical responses to some extent in patients with malignant brain tumors.Especially with regard to iFN-S the Japanese IFN research group has reported beneficical effects of single use of IFN as well as of combined use of IFN with radiotherapy and/or chemotherapy. NAGAI end ARAI(1984)obtained the highest effectiveness rate (40 %} with IFN-~. IFN exerts its antiproliferative effects by direct inhibition of tumor growth snd,.indiractly, via the immune system. In order to prove these promising therapeutical prospects of additional iFN-~ treatment we performed a phase 2 trial in 13 patients who had proviously undergone surgery for a histologically confirmed primary (!0) and recurrent(3)malignant glioma (8 glioblastoma,5 astrocytoma III).IFN-5 was generally administered intravenously 5x10 IU/day up to ~ weeks continued by 3 times a week and 2.5xi0 iU/day IFN-~ respectively in case of additional local administration of 2.5xi0 IU/day into the brain tumor up to 2 weeks,depending upon circumstances of well-being, toxicity,and tumor progression.Treatment response was determined by serial neurological examinations, CCT scans, and time of survival. However complete response could not be obtained in both tumor groups, therefore 9 patients were treated with radiotherapy 40-60 Gy. No significant hematological,liver, or renal toxicities were observed.The most toxic response identified was neuro-toxicity in 4 patients with EEG changes, which cleared completely after temporary interruption of treatment. Results will be discussed in respect to those reported in the literature with conclusion to designe a following phase 3 trial on single use of IFN-g versus IFN-S and radiotherapy after tumor removal in 40 supratentorial malignant gliomas.

Malignant

Lechner Walter Department of W ~ r z b u r g , FRG

Melanoma

Dermatology,

with

University

beta-

of

Since J u n e 1 9 8 5 ~ e e v a l u a t e d t h e r e s u l t s of 18 patients ~ith high risk melanoma. Using betainterferon i0 p a t i e n t s received infusions, 8 patients got subcutaneous injections i n t o the regionary lymphatic nodules.ln addition to the Interferon-treatment ~e e x c i s e d the m e l a n o m a in a distance of 5 to 5 cm, p e r f o r m e d an e x s t i r p a tion of a f f e c t e d lymphatic nodules and excised potentially curable distant metastases. In s o m e p a t i e n t s of t h e F i b l a f e r o n - i . v . treated group es n o t i c e d an o b v i o u s l y p r o l o n g e d t i m e of s u r v i val, h o w e v e r in t ~ o c a s e s ~ h e r e ~e o n l y found a 5 month-survival, a n e g a t i v e e f f e c t of F i b l a f e ten c a n n o t be e x c l u d e d . A final evaluation of the r e s u l t s of the s.c. t r e a t e d g r o u p is n o t yet possible, nontheless the w e l l - b e i n g of the patients is r e m a r k a b l e .