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Proceedings of the Annual Meeting of the Austrian Society of Haematology and Oncology ¨hjahrstagung 2008 der Fru ¨ ¨r Ha¨matologie und Onkologie Osterreichischen Gesellschaft fu und der Arbeitsgemeinschaft ha¨mato-onkologischer ¨ sterreich (AHOP) Pflegepersonen in O

Innsbruck, 10.–12. April 2008

President: Univ.-Prof. Dr. G. Gastl Secretaries: a. Univ.-Prof. Dr. W. Hilbe Univ.-Doz. Dr. E. Gunsilius

memo Suppl 1/08

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Editorial

memo – an international platform of communication for the Austrian Society of Haematology and Oncology ¨ GHO) In 2007, the executive board of the Austrian Society of Haematology and Oncology (O ¨ hjahrstagung) in decided to publish henceforth the abstracts of their Annual Meeting (Fru the Journal ,,Magazine of European Medical Oncology‘‘ (memo). ¨ GHO the following arguments were taken into consideration: For the board of the O – memo was developed by an Austrian initiative together with Springer-Verlag Wien and ¨ GHO. most of the members of the Austrian Editorial Board are also members of the O This journal is dedicated to haematologists, oncologists and other oncology professionals and provides news and information most relevant for their daily practice. As a peerreviewed international journal memo also aims at discussing the clinical relevance of basic research. – Many clinical study groups, originally established by an Austrian initiative, have already entered an international level. Examples are the Central European Cooperative Oncology Group (CECOG, chaired by Prof. Zielinski), which had already made memo its official journal, the Austrian Breast and Colorectal Cancer Study Group (ABCSG, chaired by Prof. Gnant), the Central European Society for Anticancer Drug Research (CESAR, founded by Prof. Dittrich), and many others. As a consequence, it is reasonable to present the Austrian scientific activity in English and to make the abstracts available for all the European countries. – Within the last few years the European Community has grown rapidly. Austria has now gained a geopolitically central position and consequently scientific cooperations between all the neighboring nations will be facilitated. To jump on that historic opportunity an international platform to present and to discuss ongoing scientific activities could be the first step. ¨ GHO Congress is held in Innsbruck. An exciting program with outstanding experts will be presented covering The 2008 O the major topics in haematology and oncology. Two new initiatives have been introduced: – Education lectures are combined with scientific presentation to underscore that daily clinical routine and clinical and basic science are closely connected with each other. – Scientifically, the organizers focused on individualized strategies for the management of cancer patients based on new insights of translational research. For this purpose the organizers present the TEXO meeting, which is held on Thursday morning. This Tyrolean academic research group, chaired by Prof. Zwierzina, aims to intensify the contact between basic researchers and physician scientists. ¨ GHO will gain a more international profile to make our Congress more For the future we are convinced that the O attractive for our neighboring friends. Gu¨nther Gastl President of the Congress Eberhard Gunsilius Secretary Wolfgang Hilbe Secretary

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Abstracts

A1 Progression-free survival in a phase II study of perioperative Bevacizumab plus XELOX in patients with potentially curable metastatic colorectal cancer B. Grünberger1, K. Kaczirek2 , J. Schüller1, M. Bergmann2 , C. Zielinski3 , K. Aigner1, T. Grünberger2 1

KA Rudolfstiftung, Onkologie, Wien, Austria Universitätsklinik für Chirurgie, Wien, Austria 3 Universitätsklinik für Innere Medizin I, Wien, Austria 2

A2 Longitudinal assessment of clinical changes in treatment and outcome of multiple myeloma (MM) in Austria. Developmental progress of the LACCITO survey in 2008 E. Willenbacher1, J. Drach2 , H. Ludwig3 , M. Aichinger-Verdino4 , E. Rauch4 , U. Siebert5 , G. Gastl1 , W. Willenbacher1 1

Innsbruck University Hospital, Innsbruck, Austria Vienna General Hospital (AKH), Vienna, Austria 3 Wilhelminenspital, Vienna, Austria 4 VERDINOcom, Vienna, Austria 5 UMIT – Private University for Health Sciences, Medical Informatics and Technology, Hall, Austria 2

Background. Patients (pts) with colorectal cancer (CRC) and liver metastases have a poor prognosis and may benefit from perioperative chemotherapy and disease resection. Bevacizumab (BEV) improves outcomes in patients with metastatic CRC; its impact on the prolongation of progression-free survival (PFS) in the perioperative setting has not been evaluated. Methods. Metastatic CRC patients with liver metastases potentially curable by resection were eligible for this single-centre, nonrandomised phase II trial. Eligibility criteria define pts at high risk of early recurrence: synchronous, multiple or large liver metastases. Pts received BEV 5 mg=kg q2 weeks plus XELOX (capecitabine 3500 mg= m2=day days 1–7 plus oxaliplatin 85 mg=m2 day 1 of a 2-week cycle) for 6 cycles prior to liver surgery and 6 cycles thereafter. Feasibility has already been shown by our group and the aim of this analysis is the long term benefit of the perioperative approach. Results. Fifty-six patients have been enrolled and 52 curative resected pts are evaluable for PFS having received a median of 6 cycles of BEV plus XELOX in the neoadjuvant setting. Overall response rate was 73% (CR 9%, PR 64%), SD was achieved in 21%. After a median follow-up of 20 months the actual mean PFS of all patients is 27 months (95% CI 23.6–30.5). A significant PFS difference was noticed dependent upon response to neoadjuvant treatment (CR 100% recurrence-free, PR 75%, SD 36%; P < 0.001). A Cox regression model revealed response to neoadjuvant chemotherapy significantly correlated to a prolonged progression-free survival (P < 0.001). Additionally completion of adjuvant chemotherapy had an independent influence on PFS (P ¼ 0.04). Synchronous disease, large metastases, multiple tumors and bilobar metastases were of no influence on PFS. Overall survival was also significantly influenced by response to treatment (P < 0.01), with no death in the CR group, 2 PR pts died, one without tumor recurrence and 4 tumor related deaths in the SD group. Conclusions. These data suggest that the perioperative combination of Bevacizumab with XELOX can sufficiently increase progression-free survival in resected mCRC patients. Our data highlight the importance to identify responding patients, who seem to benefit most from the combination of Bevacizumab, chemotherapy and surgery. memo Suppl 1/08

Background. Practice does not adhere to approved indications or clinical guidelines. Routine effectiveness of treatments in ‘‘real life’’ often differs from their reported efficacy based on best evidence derived from clinical trials. Due to the necessity of homogenisation of study populations, often excluding pts. with significant comorbidities or elderly patients, (which on the other hand are epidemiologically extremely important), significant bias may be introduced. Concerning drug safety, approval studies are notoriously underreporting rare toxicities and long-term sequelae. These problems can be addressed by representative population-based pharmaco-epidemiologic surveys. As of today there is an urgent need for such analysis in the rapidly changing world of MM treatment options. Methods. Under the patronage of the OEGHO and in close cooperation with a scientific advisory board (SAB) consisting of myeloma and health economic specialists, as well as IT professionals, an internet based remote data entry system and data base structure has been developed, integrating basic patient data, myeloma characteristics, prognostic and predictive factors, therapy and diagnostic related variables, comorbidities, AEs, use of supportive care, etc., as well as health-economic data in a user friendly, anonymized and absolutely secure mode. All legal requirements will be met and IRB approval is pending. The tool will be used to generate both a retrospective snapshot of MM treatment in Austria in a reference period (2007), as well as a prospective survey of its changes over time (starting active recruitment in Aprile 2008). LACCITO aims to acquire data of at least 70% of MM pts. treated in Austria to generate a representative data set. Monitoring will be offered. Data will be open to participants for scientific analysis, exempt from charges, after SAB approval of research proposals and a yearly report including an anonymized benchmark analysis will be published. Results. The structure of the LACCITO data bank and choice of its variables will be discussed in detail. In addition a practical demonstration of the online functionality of the

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remote data capture tool and the plasticity of the system will be given. This includes features for self-directed analysis of own data. A ranking of the first planed analysis lines will be offered to vote on priorities (e.g., MM treatment in elderly pts., dynamics of diffusion of new drugs, etc.). Conclusions. LACCITO offers a promising new tool to be used for quality control and assurance, real life validation of treatment algorithms and health technology assessment by generation of a nationwide data set on trends concerning changes in management and outcome of MM over time. The success of LACCITO will be highly dependent on the committed participation of academic, as well regional treatment centers, which are all invited to join this common effort to promote our understanding of MM in the upcoming age of personalized medicine and thus optimize care of our MM pts.

Results. We could demonstrate that our inducible cell lines show significant upregulation of EpCAM after induction with doxycycline. After 24 h, first cleavage of the full-length protein was detectable. In comparison to EpCAM negative cells, EpCAM positive cell lines showed enhanced proliferation and changed migration properties. Neither the therapeutic antibody MT201 nor other antibodies against different extracellular epitopes were able to inhibit this events. Conclusions. For the first time we established an in vitro cell model with tetracycline inducible EpCAM expression. We could demonstrate that EpCAM overexpression was associated with enhanced proliferation, changes in cell motility and adhesion behaviour. Further characterization will help in elucidating EpCAM downstream signaling events. Additionally, this model provides a tool for testing EpCAM specific targeting strategies in vitro.

A3 Characterization of a human breast cancer cell line model with tetracycline inducible EpCAM expression J. M. Gostner1, M. Zitt1 , D. Fong1;2 , O. A. Wrulich3 , G. Gastl1;2 , G. Spizzo1 1

Tyrolean Cancer Research Institute, Laboratory for Experimental Oncology, Austria 2 Division of Haematology and Oncology, Medical University Innsbruck, Innsbruck, Austria 3 Division of Medical Biochemistry, Biocenter Innsbruck, Innsbruck, Austria

Background. EpCAM is a type I transmembrane glycoprotein of approximately 40 kDa composed of two EGF-like extracellular domains and a short cytoplasmic tail. EpCAM is detected at the basolateral membrane of the majority of epithelial tissues (all simple, pseudo-stratified and transitional epithelia), with the exception of the adult squamous epithelium and some epithelium-derived cells. For these cell types, de novo expression of EpCAM can be observed during active normal or neoplastic cell proliferation. Interestingly, EpCAM appears to be overexpressed by a significant proportion of human epithelial carcinomas. Especially for breast cancer our group could demonstrate a prognostic value of EpCAM overexpression in primary tumor tissue in different studies. Gires and coworkers showed that EpCAM is cleaved and its intracellular domain shuttles into the nucleus. Our aim was to establish an in vitro model with inducible EpCAM expression to identify specific signaling events which are triggered upon EpCAM activation. Methods. We used the T-RexTM system to generate tetracycline inducible as well as stable EpCAM expressing clones originating from the human breast cancer lines MDAMB231 and Hs578t. These cell models have been characterized in respect to proliferation, migration, apoptosis and their response to anti-tumoral agents.

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A4 Effects of the Plk-1 inhibitor BI 2536 alone and in combination with imatinib and nilotinib (AMN107) on growth of CML cells K. V. Gleixner1, V. Ferenc1 , A. Gruze2 , M. Kneidinger1, C. Baumgartner1, M. Mayerhofer3, W. F. Pickl2 , C. Sillaber1, P. Valent1 1

Division of Haematology and Haemostaseology, Department of Internal Medicine I, Vienna, Austria 2 Institute of Immunology, Medical University of Vienna, Vienna, Austria 3 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria

Background. Chronic myeloid leukemia (CML) is a myeloid neoplasm in which BCR=ABL enhances growth and survival of leukemic cells. In most early-stage patients, the disease can be kept under control by the ABL kinase inhibitor imatinib (STI571). However, because resistance against imatinib may occur during therapy. Therefore, current research is focusing on novel targets and targeted drugs in CML. Polo-like kinase 1 (Plk-1) is a serine=threonine kinase that plays an essential role in mitosis and is expressed in activated=phosphorylated form in various neoplasms. BI 2536 (Boehringer Ingelheim GmbH, Germany) is a novel inhibitor of Plk-1. In the current study, we evaluated expression and the potential role of Plk-1 as a novel target in CML cells. Methods and results. As assessed by PCR, Plk-1 mRNA was found to be expressed abundantly both in primary CML cells and in the CML blast cell line K562, whereas normal peripheral blood cells expressed only low or undetectable levels of Plk-1 mRNA. The Plk-1 protein was detected in primary CML cells and K562 cells by immunocytochemistry. In replicated experiments, we were able to show that CML cells exhibit phosphorylated Plk-1. As assessed by 3H-thymidine-uptake experiments, memo Suppl 1/08

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BI 2536 was found to inhibit the proliferation of K562 cells in a dose-dependent manner (IC50 5–15 nM). Moreover, BI 2536 was found to inhibit the proliferation of both imatinib-naive (n ¼ 6) and imatinib-resistant (n ¼ 3) primary CML cells (IC50: 1–15 nM). The growth-inhibitory effect of BI 2536 on CML cells was found to be associated with mitotic arrest, a G2-M cell cycle arrest, and consecutive apoptosis. In normal bone marrow or peripheral blood mononuclear cells treated with BI 2536, neither mitotic cell arrest nor apoptosis were observed. Next we incubated primary CML cells with BI 2536 in combination with imatinib or nilotinib (AMN107; Novartis) at fixed ratio of drug concentrations. In these experiments, BI 2536 was found to synergize with both ABL kinase inhibitors in counteracting the proliferation of CML cells. Conclusions. In conclusion, Plk-1 is expressed in phosphorylated form in CML cells and plays a role in cell cycle progression and viability. Targeting Plk-1 with BI 2536 leads to mitotic arrest, growth inhibition, and apoptosis in imatinib-naive and imatinib-resistant leukemic cells. Moreover, BI 2536 synergizes with imatinib and nilotinib in counteracting the growth of neoplastic cells in CML. Targeting of Plk-1 may be an interesting pharmacologic approach to counteract growth of CML cells.

at the ward of the Department of Haematology and Oncology, Innsbruck Medical University. Results. GA resulted in: WHO: 0: 20.5%, 1: 41%, 2: 32.1%, 3: 5.1%, 4: 1.3%; KI:
40 (self supply not possible): 4%; 50–70 (unfit for work): 21.7%; 80 (normal): 74.3%; ADL Scale: 100–91 (non depending): 70.5%; 90–61 (moderate): 26.9%; 60–21 (severe): 1.3%; 20-0 (total): 1.3%; iADL Scale: 8 (non depending): 38.5%; 0–7 (dependencies): 61.5%; MMSE (30): 0–10 (severe dementia): 0%; 11–24 (moderate): 25.6%; 25–30 (normal): 74.4%; GDS: 0–5 (non depressive): 75.7; 6–10 (depression probable): 21.8; 11–15 (severe depression): 2.5; impairment): 19.3%; 20–11 (moderate health impairment) 55.1%; <11 (severe impairment): 7.7%; (not done): 17.8; ‘‘Timed Up & Go’’ Test: 14.4 sec (mean); CIRS-G: Total Score’’ 5.5; Grade 3 Comorbiditiy 48.7%; Grade 4 Comorbiditiy 25.7%. Conclusions. These analyses demonstrate the feasibility and relevance of GA in geriatric tumour patients and demonstrate deficiencies in different dimensions in a substantial proportion of patients. Assessment will form the basis of individualised therapies in elderly cancer patients.

A6 A5 Detection of resources and deficiencies in elderly cancer patients by geriatric assessment K. Moser, C. Valentiny, M. Scheibner, R. Stauder Department of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Background. In Western countries the older population is undergoing a progressive expansion. As 60% of malignancies occur in patients over the age of 65, cancer in geriatric patients is becoming a challenge of outstanding relevance. Chronological age by itself is not reliable in estimating life expectancy, functional, personal and social resources or the risk of treatment complications. Therefore, the Geriatric Assessment (GA) was established to assess the domains function, emotional situation, quality of life, co-morbidity, cognition, mobility and social support of elder people to identify resources and needs and to plan care and therapy. However, data on geriatric assessment in elderly tumour patients are rare so far. Methods. Scores applied were WHO Scale (WHO), Karnofsky Score (KI), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Timed Up&Go and Cumulative illness rating scale for geriatricians (CIRS-G). Geriatric assessment was applied in 78 tumour patients 60þ (median 72.9; range 60– 93 years; 41 males, 37 females). All patients were treated memo Suppl 1/08

Unerwünschte Nebenwirkungen bei Radiotherapie==Chemotherapie im Mundbereich. Präventive und supportive zahnärztliche Maßnahmen J. Beck-Mannagetta Universitätsklinik für Mund-, Kiefer- und Gesichtschirurgie= PMU Salzburg, Salzburg, Austria

Grundlagen. Die oralen Nebenwirkungen einer systemischen Chemotherapie und=oder regionalen Radiotherapie ko¨nnen sich massiv auf die Lebensqualita¨t eines Patienten auswirken. Za¨hne sind durch eingeschra¨nkte Mundhygiene gefa¨hrdet; auch mehrfaches Erbrechen kann zu Schmelzscha¨den fu¨hren. Eine schwere Mucositis kann bis zur Unmo¨glichkeit der Nahrungsaufnahme und des Tragens von Prothesen gehen. Nach Zahnextraktionen ko¨nnen schwere Blutungen, Infektionen oder eine Osteomyelitis des Kieferknochens auftreten. Eine Verringerung des Speichelflusses und des Geschmackssinns beeintra¨chtigt gleichfalls die Lebensqualita¨t. Methodik. Sobald die Indikation zu einer systemischen Chemotherapie gegeben ist, sollte der Patient einem Zahnarzt vorgestellt werden, damit die wichtigsten ¨llungen, prophylaktischen Maßnahmen (Extraktionen, Fu Wurzelbehandlungen, Kontrolle von Implantaten oder Prothesen, Fluoridierung, Unterweisung in exakter Mundhygiene) getroffen werden ko¨nnen. Ergebnisse. Bei zahna¨rztlichen Problemen wa¨hrend einer Chemotherapie sollen Eingriffe vermieden oder nur unter großer Vorsicht (stat. Aufnahme, Antibiotika) ¨hrt werden. durchgefu

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Schlussfolgerungen. Eine zahna¨rztliche Betreuung vor, wa¨hrend und nach der onkologischen Therapie ist daher von gro¨ßter Wichtigkeit. Interdisziplina¨re Zusammenarbeit kann die Nebenwirkungen im Mundbereich sowie die Behandlungsdauer und Kosten einer Krebstherapie deutlich verringern, die Lebensqualita¨t und die soziale Akzeptanz der Betroffenen aber deutlich verbessern.

A7 Fatal breakthrough pulmonary Aspergillus niveus infection following allogeneic hematopoietic stem cell transplantation J. Auberger1, C. Lass-Flörl2 , J. Clausen1 , R. Bellmann3 , G. Gastl1 , W. Buzina2;4 , D. Nachbaur1 1

Clinical Division of Haematology and Oncology, Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria 2 Department of Hygiene and Social Medicine, Innsbruck Medical University, Innsbruck, Austria 3 Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria 4 Institute of Hygiene, Microbiology and Environmental Medicine, Graz Medical University, Graz, Austria

Background. A twenty-one-year-old woman underwent allogeneic human leukocyte antigen (HLA) fullymatched-unrelated HSCT for secondary acute myeloid leukemia (AML) evolving from Fanconi anemia following reduced intensity conditioning with busulfan, fludarabine and thymoglobulin. Primary antifungal prophylaxis consisted of amphotericin B colloid dispersion (ABCD) (3 mg=kg=d). Methods. Routinely performed surveillance cultures during the transplant period repeatedly revealed colonization with multi-resistant staphylococcus aureus (MRSA). On day þ8 following HSCT, the patient developed fever up to 38.5  C, which was unresponsive to cefepime and linezolid. Concurrently, several nodules with halo-signs in the right upper lobe were detected in a computerized tomography scan, raising strong suspicion of invasive Aspergillosis. Antifungal salvage combination therapy was initiated consisting of caspofungin (50 mg=d) and posaconazole (400 mg bid). On day þ13 after the transplant the patient, still being neutropenic, developed septical multiorgan failure necessitating catecholamines and mechanical ventilation. Blood cultures drawn at this time were positive for multiresistant Enterobacter cloacae, showing in vitro susceptibility only to polymyxin B and amikacin. CT scan of the chest performed on day þ26 showed significant progression of the pulmonary lesions in count and size. An immediately bronchoalveolar lavage (BAL) revealed pulmonary IA caused by A. niveus being susceptible to all established mold-active azoles and echinocandins, but not to amphotericin B (AMB). Despite adequate antifungal treatment and antibiosis with amikacin the

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patient succumbed on day þ31 due to septical multiorgan failure. At postmortem examination the diagnosis of pulmonary IA caused by A. niveus was confirmed. Results. A. niveus is an unusual clinical species found to be present in the air and in the agricultural field. We here report the first case of an A. niveus infection in a severely immunocompromised recipient of an allogeneic HSCT. Basing on rDNA sequence data it was suggested previously, that A. niveus is closely related to the A. terreus section, being frequently resistant to AMB. Species of Aspergillus other than A. fumigatus have been increasingly isolated and important species include A. flavus, A. niger and A. terreus. It is known, that preexposure of immunosuppressed patients to AMB or triazoles causes an emergence of AMB-resistant non-fumigatus Aspergillus species and of zygomycetes. It is recognized that a prompt initiation of antifungal therapy is likely to improve patients’ outcome. Although standard definitions for optimal diagnostic criteria of IFI have been established in clinical practice it still remains very difficult to obtain definite diagnosis of IFI in particular applying invasive procedures such as BAL or CT-guided biopsies. These are – especially in recipients of HSCT-frequently hampered by presence of thrombocytopenia thereby increasing the risk for bleeding following those interventions. However, even in this vulnerable category of patients CT-guided biopsies are feasible with an acceptable risk. Conclusions. In times of increasing isolation of non–A. fumigatus species and rising implementation of azole-based antifungal prophylaxis (especially in high-risk patients), drug-resistant Aspergilli should be taken into account when pre-emptive antifungal treatment has been initiated. Species identification by CT-guided biopsies and in vitro susceptibility testing seem to be mandatory prerequisites for probably life saving therapeutic decision making.

A8 Colorectal cancer survival and its association to a hereditary polymorphism in the promoter-gene of FAS G. Hofmann1 , T. Langsenlehner2, F. Fuerst3 , A. Gerger1, U. Langsenlehner4, H. Samonigg1 , J. Szkandera1 , P. Krippl4 , W. Renner5 1

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Department of Therapeutic Radiology and Oncology, Medical University of Graz, Graz, Austria 3 Division of Rheumatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 4 Department of Internal Medicine, Regional Hospital of Fürstenfeld, Fürstenfeld, Austria 5 Clinical Institute of Medical and Chemical Laboratory Diagnosties, Medical University of Graz, Graz, Austria memo Suppl 1/08

Abstracts

Background. Apoptosis plays an important role in embryogenesis, autoimmunity and tumorigenesis. Cell surface death receptors such as FAS (TNFRSF6) confer a major apoptotic effect. A single nucleotide polymorphism in the FAS promoter-gene, 670 A> G, modulates apoptotic signalling and has been related to susceptibility and progression of a variety of cancers. Aim of the present study was to evaluate the role of this polymorphism for overall survival of patients with colorectal cancer. Methods. We performed a retrospective analysis including 433 patients with histologically confirmed colorectal cancer. A Cox regression model including FAS 670 genotypes, age at diagnosis, tumor grade, tumor stage, primary tumor size larger than 2 cm and number of pathologic lymph nodes evaluated was used to estimate the effect of the FAS genotype on overall survival. Results. FAS 670A> G genotype frequencies were 24.2% (AA), 46.3% (AG) and 29.5% (GG). Fifty-one patients were excluded from the Cox-regression analysis because of missing values. Of the remaining 382 patients, 68 (7.9%) died during a follow-up of maximum 10 years. Mean follow-up time was 58  34 months (median 55 months). Carriers of the homozygous FAS 670GG genotype had a significantly lower survival rate compared to AA=AG genotype carriers (relative risk 1.82, 95% confidence interval 1.10–3.00; p ¼ 0.020). Conclusions. The FAS 670A> G polymorphism could be associated with overall survival time of patients with colorectal cancer.

with different VEGF expression, production and plasma levels according to allele status and influence the risk of developing different types of cancer. Therefore, these variants might be risk factors for colorectal cancer (CRC). Methods. In the present case-control study, VEGF genotypes of the þ936 C> T, 2578 C > A and 634 G> C polymorphisms were determined in 427 patients with histologically verified CRC and 427 age and sex-matched healthy control subjects. Genotypes were analyzed by a fluorogenic exonculease assay (TaqManTM). p-value for age at diagnosis was analyzed by student’s t-test, p-values for tumor characteristics were determined by Pearson’s Chi-square-test. Threshold for significance was p < 0.05. Results. At the time of diagnoses, patients were between 29 and 83 years of age, with a mean age of 61  10.9 years. VEGF 2578 C > A and VEGF 634 G> C genotype frequencies were similar among patients and controls. Carriers of the 936T-allele were found slightly more frequent among controls (27.2%) than among patients (22.5%), but this difference did not reach statistical significance (p ¼ 0.07). Furthermore, no correlation was found between all these variants and tumor characteristics like size, histological grading, positive regional lymph node metastases or tumor stage. Conclusions. We conclude that the investigated polymorphisms are not associated with individual susceptibility to colorectal cancer.

A10 A9 Single nucleotide polymorphisms in the vascular endothelial growth factor gene and colorectal cancer risk 1

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G. Hofmann , T. Langsenlehner , F. Fuerst , A. Gerger1, U. Langsenlehner4, H. Samonigg1 , H. Clar5, P. Krippl4 , W. Renner6 1

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Department of Therapeutic Radiology and Oncology, Medical University of Graz, Graz, Austria 3 Division of Rheumatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 4 Department of Internal Medicine, Regional Hospital of Fürstenfeld, Fürstenfeld, Austria 5 Department of Orthopedic Surgery, Medical University of Graz, Graz, Austria 6 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

Background. Tumor growth requires the formation of new blood vessels, a phenomenon known as angiogenesis. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF). Several common polymorphisms in the VEGF-gene have been associated memo Suppl 1/08

Murine vasohibin reduces large blood vessel formation in tumors and supports microvessel growth G. Untergasser, J. Kern, M. Steurer, E. Gunsilius Tumor Biology and Angiogenesis Laboratory, Division Haematology and Oncology, TILAK University Hospital Innsbruck, Innsbruck, Austria

Background. The murine homolog of human vasohibin (VASH1) is a putative antiangiogenic protein. Methods. VASH1 was investigated for its inhibitory effects on tumor growth and angiogenesis. Results. Immortalized murine endothelial cells (bEND.3) treated with purified recombinant protein showed reduced cell migration in the scratch assay. VASH1 was released into the culture supernantant after proinflammatory stimulation with IL-l
and IL-6. More tubes were generated in the matrigel assay by exogenous stimulation with recombinant mVASH1 protein. Murine VASH1, displaying a very high amino acid sequence homology to the chicken homolog, also inhibited large vessel growth in the chorioallantois membrane (CAM) assay and supported the formation of a dense fine capillary network. VASH1 overexpressing B16F10 melanoma cells were generated by the sleeping beauty transposase system.

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Subcutaneous tumor growth and tumor size in C57BL=6 mice was not affected within the observed time frame, but there was a significant decrease of large blood vessels and an increase of microvessels in the tumor. VASH1 overexpressing B16F10 cells showed a strongly reduced TGF-
, but unaffected VEGF and Ang2 gene expression. Conclusions. Our data implicate that the murine VASH1 affects angiogenic remodelling by inhibition of large vessel formation in vivo and by supporting microvessel growth.

A11 Trastuzumab and gemcitabine in heavily pre-treated patients with metastatic breast cancer R. Bartsch1 , C. Wenzel1 , U. Pluschnig1 , G. Altorjai1 , P. Dubsky2, R. Scheurer1, A. Rottenfusser3, M. Gnant2 , C. C. Zielinski1 , G. G. Steger1 1

First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Vienna, Austria 2 Department of Surgery, Vienna, Austria 3 Department of Radiotherapy, Medical University of Vienna, Vienna, Austria

Background. Her2-positive breast cancer is known to be associated with high recurrence rate and poor outcome. Introduction of trastuzumab (T) (RhMab45D), a monoclonal humanized antibody targeting the extracellular domain of Her2, was a major advance in this disease. Combination of T with taxanes is the best established option as first-line therapy of Her2-positive metastatic breast cancer. Vinorelbine may constitute an alternative, but phase III data is not available. While not supported by randomized trial, the use of T in multiple lines is recognized as common clinical practice. In this case, no standard combination regimen exits. We initiated this study to evaluate the activity of T and gemcitabine (G) in patients (pts) pre-treated with trastuzumab, anthracyclines, taxanes and=or vinorelbine, and capecitabine. Patients and methods. Patients received G at a dose of 1250 mg=m2 on days 1 þ 8, every 21 days. T was administered at a dose of 6 mg=kg body-weight in three-week cycles, following a loading-dose of 8 mg=kg. Re-evaluation of tumour status was performed with CT-scans every three cycles. Clinical benefit rate (CBR; CR þ PR þ SD 6 months [m]) was defined as primary endpoint. As secondary endpoints, time-to-progression (TTP), overall survival (OS), and toxicity were chosen. Based on previous data, a 50% CBR was considered to indicate clinical activity, and a CBR <25% was considered unacceptable. The targeted accrual for this study was set at 26 evaluable pts. If 11 patients experienced clinical benefit, a sample size of 26 pts provides statistical power of 80% to reject the null hypothesis that the CBR is <25% with an a of 0.05.

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Results. Twenty-nine pts were included as eligible. All are currently evaluable for toxicity, and 26 for response. Earlier therapies consisted of T (100%), anthracyclines (100%), vinorelbine þ T (93%), docetaxel þ T (62%), and capecitabine þ T (69%). We observed a PR in 19%, and SD 6 months in further 27%, resulting in a CBR of 46%. TTP was median 3 m, range 1–10, 95%CI 1.89–4.11, and OS 17 m, 4–31þ, 95%CI 14.68–19.36. CBR and TTP were superior in the 2nd-line setting as compared to beyond 2nd-line. Neutropenia (21%), thrombocytoperia (14%), and nausea (3%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity. Four pts (14%) developed brain metastases while on therapy. Conclusions. While CBR in our trial was low when compared to trastuzumab-based 1st-line therapy, it is higher than what might be expected from gemcitabine monotherapy in a similar setting. In particular, a trial of G following anthracyclin and taxane failure observed SD 4 m in 26%, while no case of PR was reported. A recently published trial of capecitabine and lapatinib following trastuzumab failure has set a new standard in pts progressing on trastuzumab. However, as most of our pts had already progressed on capecitabine, this combination did not present a valid option. Therefore, considering the favourable toxicity profile, trastuzumab and gemcitabine appears to be a safe and potentially effective option in a heavily pre-treated population.

A12 Results from the Austrian Fulvestrant Registry G. G. Steger1, B. Mlineritsch2 , R. Bartsch1 , M. Gnant3 , T. Niernberger4, U. Pluschnig1 , R. Greil2 , M. Pober5, J. Thaler6, C. C. Zielinski1 , on behalf of the Austrian Fulvestrant Registry 1

First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria 2 Third Medical Department, Paracelsus Private Medical University, Salzburg, Austria 3 Department of Surgery, Medical University of Vienna, Vienna, Austria 4 Department of Surgery, LKH Leoben, Leoben, Austria 5 Department of Medicine, KH St. Poelten, St. Poelten, Austria 6 Department of Medicine, Klinikum Kreuzschwestern Wels, Wels, Austria

Background. Endocrine treatment is the single most widely applied option in oestrogen- and=or progesterone-receptor (ER=PgR) positive metastatic breast cancer. Fulvestrant is a pure ER antagonist with receptor affinity similar to 17-estradiol. In two randomized trials, fulvestrant was found non-inferior to aromatase inhibitors in pre-treated patients. memo Suppl 1/08

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We present results from 58 Austrian centres that contributed patients (pts) to the Austrian Fulvestrant Registry. Methods. F was administered at a dose of 250 mg every four weeks by intramuscular injection. For baseline staging, CT-scans of the chest and abdomen, mammography, gynaecologic examination, and bone scan were mandatory. Tumour re-assessment was performed every three months. Time-to-progression (TTP) was defined as primary endpoint; secondary endpoints were clinical benefit rate (CBR; CR þ PR þ SD 6 months), and toxicity. TTP was estimated with the Kaplan–Meier product limit method. To identify factors associated with TTP, a multivariate analysis (Cox regression model) was performed. Results. Three hundred and fifty consecutive patients, median age 66 years (y), range 35–92 y, were included, and followed prospectively. Adjuvant chemotherapy (CT) was used in 36%, and 64% had received adjuvant endocrine therapy; 42% had prior CT for metastatic breast cancer. 49% had visceral metastases; 13.4% Her2-positive disease, and 45% were > 65 y. F was administered as 1st-line treatment in 92 pts (26.3%), 2nd-line in 170 (48.6%), 3rd-line in 67 (19.1%), and 4th-line in 21 patients, respectively (6%). Median TTP was 7 months, range 2–34 (95% CI 6.09–7.9). 2.3% experienced CR, 12.3% PR, and 46% SD 6 months, resulting in a CBR of 60.6%. 6.9% had SD< 6, and 32.6% had PD. In the Cox regression model, 1st-line treatment and non-visceral metastases only were significantly associated with longer TTP; other variables (age, time to recurrence
1 y, prior CT, Her2-status, PgR-status) had no influence. 1.4% experienced grade 3 joint pain, and 0.3% grade 3 hot flashes. Other toxicities (grade 1 and 2 only) consisted of nausea, headache, fatigue, weight gain, and depression. Sixteen patients developed mild local reactions. Conclusions. Our results confirm previous data that fulvestrant is an effective and well tolerated treatment option, even in pre-treated patients. Of interest is the high effectiveness in the elderly. TTP and response rates reported here are superior to other studies. This is probably due to the large number of patients receiving fulvestrant as 1st- or 2nd-line treatment. In difference to other endocrine agents, fulvestrant is apparently active in Her2-positive disease. This merits further investigation.

Department of Obstetrics and Gynecology, Medical University of Graz, Departments of Internal Medicine, Medical University of Vienna and University of Salzburg, Departments of Internal Medicine, Hospitals Vienna Hanusch, St. Pölten, Kufstein, Vöcklabruck, Leoben, Oberwart, Hohenems and Steyr, Department of Pulmology, Hospital Gaisbühel=Feldkirch, Department of Obstetrics and Gynecology, Hospitals Bregenz and Vienna Hietzing, Department of Gynecology, Hospital Barmherzige Schwestern, Linz, Austria

Background. Palonosetron is a second-generation 5-HT3 receptor antagonist. It is markedly different compared to the conventional setrons with its extended halflife, high binding affinity for the 5-HT3 receptor and the need of only a single IV administration on day 1, 30 min before chemotherapy (CT). To evaluate the antiemetic efficacy of palonosetron in the daily hospital practice setting an observational study was carried out in Austria. Special focus was given to the control of delayed nausea as this still remains a significant clinical problem for most chemotherapy patients. Methods. Palonosetron 0.25 mg was administered IV on day 1 of each CT cycle to 135 cancer patients who received moderately or highly emetogenic chemotherapy. Two thirds of these patients were female patients (n ¼ 90), the majority had breast cancer (n ¼ 38) and most patients received cisplatin, carboplatin, anthracyclines, 5-fluorouracil or cyclophosphamide. Results. The overall complete antiemetic response rate (CR: no emesis and no use of rescue medication) was 68%, with respectively 87% efficacy (CR) on day 1 and 72% efficacy (CR) on days 2 to 5. The proportion of patients with no emesis was greater than 90% on each day. The no nausea rate ranged between 83% on day 1 and 61% on day 3. Conclusions. Palonosetron resulted in high control of nausea and antiemetic efficacy in this study. Especially nausea data indicate a favourable control of nausea on days 1–5 post-CT. This result should be particularly considered in the hospital practice since the control of nausea is still a major challenge particularly on days 2 and 3 after CT.

A14 A13 Early Austrian multicentre experience with palonosetron as antiemetic treatment for patients undergoing highly or moderately emetogenic chemotherapy E. Petru, J. Andel, L. Angleitner-Boubenizek, G. Steger, M. Bernhart, K. Busch, O. Gehmacher, T. Hernler, U. Kastner, A. Lanz-Veit, U. Pluschnigg, J. Polachova, M. Rohde, L. Schiller, R. Schramböck, W. Stangl, R. Thödtmann, A. Zabernigg memo Suppl 1/08

Diagnostics of multiple myeloma by molecular cytogenetics E. Krömer, M. König, T. Lion Labdia Labordiagnostik, St. Anna Kinderkrebsforschung, Vienna, Austria

Background. Multiple myeloma (MM) is the second most common hematologic malignancy in adults. Conventional cytogenetics in MM is hampered by the low proliferative activity of the malignant plasma cells (PCs). During the last decade, studies using conventional and

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molecular cytogenetics revealed a high incidence (almost 100%) of specific chromosomal anomalies in the clonal PCs. Several of these genetic changes have been demonstrated to be important independent prognostic parameters for disease course and survival. Cytogenetic and molecular cytogenetic analysis are therefore of great importance in the diagnosis and follow-up of MM. Methods. For FISH-analysis, mononuclear cells were isolated from bone marrow samples by density gradient centrifugation and subsequently immobilized on cytospin slides. Immunofluorescent staining of cytoplasmic light chains (clg-FISH) was used for plasma cell identification (Fonseca et al.: Blood 100(4) 2002). Probes for the detection of various aberrations including 13=del (13)(q14), del(17)(p13), t(1 I;14)(q13;q32) and t(4;14)(p16; q32) represent our standard set for initial analysis. Results. Molecular cytogenetics in MM by means of clg-FISH is one of the two internationally recommended methods (the other one beeing PC enrichment by magnetic beads). The technique permits clear identification of PCs by cytomorphology and immunofluorescent staining of cytoplasmatic light chains, thus facilitating specific recognition of the malignant cells, which can be further investigated for the presence of disease-related aberrations by employing specific probe combinations. Conclusions. The use of clg-FISH markedly improves the sensitivity of interphase FISH in MM and allows for specific analysis of plasma cells even in samples with very low PC count. Identification of clonal PCs by simultaneous use of cytoplasmic light chain immunostaining and cytomorphology provides an important prerequisite for the detection of prognostically relevant genetic aberrations in MM.

A15 KIT and PDGFRA mutations in gastrointestinal stromal tumors – spectrum and clinical correlations in 68 cases

cantly. Although most of the cases respond well, primary or secondary drug resistance is a clinical problem. In this study, 68 GISTs were analysed for KIT and PDGFRA mutations and correlated with clinical and pathological data. Methods. DNAs from 68 histologically and clinically diagnosed GIST paraffin sections were analysed for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12, 14 and 18 by direct sequencing. Results. In 64.7% of the tumors, a mutation could be detected. 52.9% showed a KIT mutation (39.7% exon 11, 13.2% exon 9, no exon 13 and 17 mutations). 11.8% showed a PDGFRA mutation (10.3% exon 18, 1.5% exon 12, no exon 14 mutation). KIT exon 11 mutations could be divided into deletions (44%), point mutations (30%), deletion-insertions (19%) and duplications (7%); KIT exon 9 showed duplications (78%) and point mutations (22%). PDGFRA mutations were mainly point mutations (86%), only 14% were deletions. Interestingly, 66% of all detected silent mutations (KIT and PDGFRA) were detected in PDGFRA exon 12. Updated results and clinical correlation will be available at the meeting. Conclusions. Specific mutations of the receptor tyrosine kinases KIT and PDGFRA are correlated with clinico-pathological parameters and response to kinase inhibitor therapies like imatinib. Screening for these mutations should therefore be an integral part of the diagnostic setting of GIST.

A16 Denaturing High Pressure Liquid Chromatography (DHPLC) – a fast and cheap method for the detection of TP53 mutations in formalin fixed tissues M. Bernkopf1 , S. Heuritsch1 , W. Kranewitter1, R. Marschon1 , H. C. Bösmüller1, A. Amberger2, G. Webersinke1 1

W. Kranewitter1, S. Kriegner1, H. C. Bösmüller1, R. Marschon1 , T. Kühr2, L. Schiller3, M. Girschikofsky4, F. Lang1 , G. Webersinke1 1

Krankenhaus der Barmherzigen Schwestern, Linz, Austria 2 Klinikum der Kreuzschwestern, Wels, Austria 3 Landeskrankenhaus, Vöcklabruck, Austria 4 Krankenhaus der Elisabethinen, Linz, Austria

Background. Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal tumors of the gastrointestinal tract showing diverse morphological features. The majority harbours activating mutations of two receptor tyrosine kinases, mainly KIT (stem cell factor receptor) or rarely PDGFRA (plateledderived growth factor receptor alpha). Both kinases are possible targets of the receptor tyrosine kinase inhibitor imatinib (Glivec), which has improved treatment signifi-

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2

Krankenhaus der Barmherzigen Schwestern, Linz, Austria Tiroler Krebsforschungsinstitut, Innsbruck, Austria

Background. The protein p53 is jointly responsible for the control of cell cycle and programmed cell death (apoptosis). The lack of these p53 functions caused by TP53 gene mutations can be a key event in the development of diverse solid tumors, like colorectal and lung carcinomas and skin tumors, but also in haematological neoplasias like CLL, AML, MDS and ALL. A hereditary disease showing TP53 mutations is Li Fraumeni, associated with high tumorigenic potential. TP53 mutations mainly occur as point mutations in the DNA-binding-region of the protein and are of high prognostic relevance, also influencing therapy strategy. As direct sequencing is expensive and time consuming, a fast and cheap screening method for fixed tissues would be very helpful. memo Suppl 1/08

Abstracts

Methods. Within this study, formalin-fixed and paraffin-embedded samples from 26 colorectal carcinomas were analyzed for TP53 mutations. After DNA isolation, DHPLC of TP53 exons 5–9 using a transgenomic WAVE system was performed. Results of DHPLC were compared with direct sequencing; sequencing was performed on samples with aberrant DHPLC patterns and on random samples with normal DHPLC chromatogram as well. Results. In 12 samples (totally 46%), 12 different mutations were found, among them 2 lbp-Deletions, 9 missense mutations and 1 known polymorphism. 6 mutations were found in exon 5 (all missense mutations), 2 in exon 6 (polymorphism und deletion), 1 in exon 7 (deletion) and 3 in exon 8 (3 missense mutations). No mutation was found in exon 9. No mutation could be detected in the four microsatellite instability positive samples. Results of DHPLC correlated well with sequencing. Conclusions. DHPLC proved to be a reliable, fast and cheap prescreening method for the detection of TP53 mutations even on samples with reduced DNA quality like formalin fixed tissues.

ally received dexamethasone, one of them combined with VP16, the other with infliximab. Results. Two of three patients did not recover blood counts and died 1 and 47 days after diagnosis of HS. The patient who received infliximab þ dexamethasone recovered and is in partial clinical remission, yet with still elevated HS parameters. Conclusions. HS is a potentially fatal complication during treatment of malignant diseases, especially in states of pronounced immunosuppression. As observed in 2 patients on AML-maintenance therapy, the manifestation of HS was heralded by multiple episodes of pancytopenia and sepsis. In patients on antileukemic maintenance therapy presenting with fever refractory to antimicrobials and progressive pancytopenia there should be a high degree of suspicion of HS with the aim to initiate therapy as early as possible. Treatment options may include infliximab and – in cases not controlled by conventional therapy – also stem cell transplantation.

A18 A17 Refractory fever and pancytopenia during antileukemic maintenance therapy caused by hemophagocytosis P. Sovinz, H. Lackner, W. Schwinger, M. Benesch, A. Moser, T. Freidl, C. Urban Division of Paediatric Haematology=Oncology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria

Background. Antileukemic maintenance therapy is frequently complicated by various infections. Prolonged myelosuppression and refractory septic fever, however, should alert for differential diagnoses. Patients. A 4-year-old boy with relapsed ALL and two 17-year-old girls with AML were on maintenance therapy for 9, 12 and 6 months, respectively, during which both AML patients went through repeated episodes of pancytopenia and sepsis. All 3 patients presented with fever refractory to multimodal antimicrobial therapy, hepatosplenomegaly and severe transfusion dependent pancytopenia. Diagnosis of hemophagocytic syndrome (HS) was suspected in 2 patients by marked elevation of serum ferritin (39618 and 35520 mg=l, NR: < 250), s-IL2-receptor (21840 and > 20 000 pg=ml; NR < 700), TNF
(285 and 116.9 pg=ml; NR < 15) and triglycerides (420 and 784 mg= dl) as well as absence of NK-cells on FACS-analysis and confirmed in all 3 patients by the finding of massive hemophagocytosis in bone marrow. Probable triggering infectious agents were influenza A, EBV þ aspergillus and parvovirus B 19 þ chlamydia pneumoniae, respectively. Methods. All 3 patients were treated with virostatic combination therapy as well as IVIG; 2 patients additionmemo Suppl 1/08

The TYROL small cell lung cancer study: a retrospective analysis of 129 patients between 2000 and 2006 S. Hoschek1 , M. Fiegl2 , A. Zabernigg3 , G. Pall4 , E. Gunsilius5 , T. Auberger6, U. Hoschek-Risslegger7, H. Jamnig8 , W. Hilbe4 for the Tyrolean Association of Oncology (TAKO) 1

Department of Internal Medicine, Province Hospital Hochzirl, Hochzirl, Austria 2 Academic Hospital Natters, Division of Oncology, Department of Internal Medicine, Natters, Austria 3 Department of Internal Medicine, District Hospital Kufstein, Kufstein, Austria 4 Clinical Division of Oncology, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria 5 Clinical Division of Haematology and Oncology, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria 6 Department of Radiotherapy, Medical University Innsbruck, Innsbruck, Austria 7 Clinical Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria 8 Academic Hospital Natters, Division of Pulmonology, Natters, Austria

Background. In this retrospective analysis, covering the period from 2000 to 2006, 129 patients with small cell lung cancer (SCLC) of the federal province of Tyrol, Austria, were analyzed, in order to compare data on patients treated in daily practise to those treated in published clinical trials. Results: SCLC represents 10–15% of all lung cancers in the region. 97.4% were active smokers, 62% are male. The predominant histologic types were poorly differentiated and anaplastic (oat cell carcinoma, 95%). 55% (n ¼ 72) of the patients received combination

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chemotherapy, e.g., the Evans protocol, cisplatinum= carboplatin and etoposide as initial treatment. 27% (n ¼ 35) received combined treatment with chemotherapy and radiation. 15% (n ¼ 20) of the patients achieved a complete remission after six cycles of first line chemotherapy. The most common toxicity of chemotherapy was anemia (WHO grade I ¼ 5%, n ¼ 5; WHO grade II ¼ 6%, n ¼ 6; WHO grade 3 ¼ 1%, n ¼ 1) in 12% of patients, who received either chemotherapy, radio chemotherapy or have been treated by surgery and adjuvant chemotherapy (n ¼ 108). 50% of the patients received second-line treatment (n ¼ 63), 28% a third-line (n ¼ 36), 12% a fourth-line (n ¼ 15) and 4% a fifth line of chemotherapy (n ¼ 5). The median survival was 63 months for stage I (n ¼ 6), 25 for stage II (n ¼ 6), 17 for stage IIIA (n ¼ 19), 13 for stage IIIB (n ¼ 25) and 10 for stage IV (n ¼ 70). In stage IIIA, the median survival was 15.5 months in patients receiving chemotherapy and 25.4 months in patients receiving combined treatment. Patients with stage IIIB seem not to benefit from a combined therapy as the median survival after chemotherapy was 9.9 months and with radio chemotherapy 9.7 months. Current international clinical studies show identical survival data for those stages and treatment options. Results. An interesting aspect of the present analysis is the very poor prognosis of the IIIB cohort which is comparable to that seen in stage IV patients supporting the systemic nature of the disease. Patients with tage IIIA seem to benefit from combined treatment. During the period of documentation a shift from the EVANS protocol to the Platinum=Etoposide combination was detected, reflecting the general change of the current state of the art recommendations. Conclusions. Median survival in this patient population is comparable to that observed in clinical trials, implicating that routine treatment of SCLC in Tyrol meets current international standards.

A19 Case Report: Longterm complete remission of a patient with bcr-abl positive ALL with a complete molecular response after intermittent Glivec treatment U. Benold1 , E. Ulsperger1;2, I. Zimmer-Roth1 , S. Thury3, R. Jilch3 , K. Geissler1;2 1

5th Medical Department of Oncology, KHR Hietzing, Vienna, Austria 2 Ludwig Boltzmann Institut für Klinische Onkologie Lainz, Vienna, Austria 3 Chemistry and Laboratory Diagnostics, KHR Hietzing, Vienna, Austria

Background. In general adult patients with bcr-abl positive acute lymphoblastic leukemia (ALL) achieve long term survival by allogenic transplantation only. Imatinib therapy in bcr-abl positive CML has become standard of care. In ALL patients with the cytogenetic abnormality of

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the Philadelphia chromosome Imatinib has shown increasing evidence for response. Methods. Case Report of a 63-year-old male patient. Bone marrow aspiration resulted in a pre B-ALL, bcr-abl positive, t (9=22), monosomia 7 and 95% blasts. We started with Oncovin and Prednisolone due to enlarged lymphocyte count (36.000) (prephase), continuing the induction therapy based on Daunoblastine and Asparaginase. This treatment resulted in a marginal response (60% blasts) in repuncture, whereas reinduction therapy based on the MIDAC protocol (Alexan, Novantrone) was given. As no sibling or family donor was availabel peripheral stem cell pheresis was done after first MIDAC Regimen. This therapy reduced the blast count only to 10% with remaining bcr-abl positivity. The search for an allogeneic donor kept being negative. Due to impressive results of Imatinib therapy in bcr-abl positive leucemias we started with 400 mg Imatinib for 4 months. Following the results of the Japanese Leukaemia Study Group consolidation therapy with high dose methotrexate and cytarabine including intrathecal therapy (MTX, Ara-C) was performed. After reconstitution of bone marrow a 28 day period of 400 mg Imatinib followed. In total 4 cycles of chemotherapy and Imatinib alternatively were performed. The period of intermittent Imatinib therapy without chemotherapy was continued up to now for 24 months. Results. The application of Imatinib as part of the treatment for bcr-abl positive ALL, without response after re-induction, resulted in a complete remission in bone marrow histology. Continuing the intermittent Imatinib therapy also molecular biology of the bone marrow resulted negative for bcr-abl but bcr-abl remained detectable at a low level in peripheral blood. During Imatinib therapy the patient suffered from edema of the eyelid which made a continuous application hard to stand. Another 8 months later even peripheral blood molecular biology could be proven negative. Conclusions. Long term intermittent application of 400 mg Imatinib in bcr-abl positive ALL is well tolerated and a chance for patients to achieve molecular CR even in poor response to induction therapy.

A20 Antiproliferative effects of KIT tyrosine kinase inhibitors on feline neoplastic mast cells E. Hadzijusufovic1;2 , B. Peter1;2, L. Rebuzzi1 , C. Baumgartner2, K.V. Gleixner2, A. Gruze3 , M. Kneidinger2, W. F. Pickl3 , M. Willmann1 , P. Valent2 1

Department of Small Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria 2 Division of Haematology and Haemostaseology, Department of Internal Medicine I, Vienna, Austria 3 Institute of Immunology, Medical University of Vienna, Vienna, Austria memo Suppl 1/08

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Background. Systemic mastocytosis (SM) is characterized by abnormal growth and accumulation of neoplastic mast cells (MC) in various organs. In almost all SM patients, the KIT tyrosine kinase receptor is mutated and expressed in an activated form in neoplastic MC. In aggressive SM (ASM) or mast cell leukemia (MCL), neoplastic cells often are resistant against conventional cytotoxic therapy, and the prognosis is grave. Because of the rarity of ASM and MCL in the human system, we have recently started to employ canine and feline mast cells tumor models, with the goal to screen for novel more potent drugs. In the present study, we have examined the effects of four tyrosine kinase inhibitors (TKI), imatinib (STI571), midostaurin (PKC412), nilotinib (AMN107), and dasatinib (BMS354825), on growth and survival of feline neoplastic MC. Methods. Neoplastic MC were isolated from the spleen of three feline patients suffering from ASM=MCL. The identity of MC was confirmed by demonstrating expression of KIT=CD117. Anti-proliferative drug effects were determined by 3H-thymidine uptake experiments. For examination of apoptosis, we performed light microscopy and flow cytometry (Annexin V=FITC). KIT activation was determined by Western blotting. Results. All four TKI were found to inhibit the proliferation of feline neoplastic MC in a dose-dependent manner, with the following IC50 values: dasatinib: 1– 10 nM, imatinib: 5–100 nM, midostaurin: 10–250 nM, and nilotinib: 50–100 nM. The effects of the TKI were also time-dependent (maximum effects seen after 48 hours), and were associated with signs of apoptosis. Moreover, we were able to show that the TKI counteract KIT activation in our Western blot experiments. Conclusions. Various KIT-targeting TKI inhibit the growth and survival of feline neoplastic MC. Whether these TKI can also counteract the growth of feline MC tumors in vivo remains to be determined.

A21 The prognostic indices IPI and FLIPI are not applicable in patients with MALT lymphoma M. Troch, S. Wöhrer, M. Raderer Division of Oncology, Medical University of Vienna, Vienna, Austria

Background. The prognostic value of the international prognostic index (IPI) and the follicular lymphoma international prognostic index (FLIPI) has widely been demonstrated in diffuse large B-cell lymphoma and follicular lymphoma, respectively. No attempts to assess their applicability in MALT lymphoma have been performed so far. Patients and methods. A total of 153 patients with histologically verified MALT-lymphoma were analysed. Parameters of both IPI [age >60 years, extranodal involvememo Suppl 1/08

ment 2, elevated lactat dehydrogenase (LDH), ECOG performance status 2, stage 3] and FLIPI [age >60 years, elevated LDH, stage 3, nodal involvement 5, hemoglobin level
12 g=dl] were assessed and correlated with relapse and time to relapse as markers of clinical course. Statistical analysis was done with SPSS 14.0. Partial correlation was assessed with the Pearson coefficient (CF) and reassessed with multiple regression analysis. Estimated time to relapse curves were calculated with the Kaplan–Meier method and tested for significant differences with the Log-Rank test. Results. According to the IPI 109 patients (71%) were classifed to the low risk group, 21 patients (14%) to the low-intermediate group, 16 patients (10%) to the high-intermediate group and 7 patients (5%) to the high risk group. FLIPI identified 100 patients (68%) at low risk, 33 patients (22%) at intermediate risk and 14 patients (10%) at high risk. After a median follow up time of 58 months, 132 patients are alive and 60 patients have relapsed with a median time to relapse of 35 months. Neither IPI nor FLIPI correlated with relapse (IPI: CF ¼ 0.06, p ¼ 0.395; FLIPI: CF ¼ 0.06, p ¼ 0.4) or time to relapse. Univariate analysis demonstrated stage, extragastric disease, autoimmune disease, trisomy 18 and multifocal disease to be significantly correlated with relapse, while trisomy 18, extragastric disease and multifocal disease were correlated with shorter time to relapse. Multiple regression analysis, however, identified only extragastric (found in 98 patients) as well as mutifocal disease (which were significantly correlated) as predictive factors of relapse (p ¼ 0.08 and 0.011). In addition, the time=duration of follow-up was also found to be significantly correlated relapse (p ¼ 0.001), suggesting MALT lymphoma as a disease with a high propensity for relapse provided that the follow-up time is long enough. Conclusions. Our data demonstrate that both IPI and FLIPI are not relevant indices for predicting the clinical course of MALT-lymphoma irrespective of origin. Multiple regression analysis has demonstrated a significant correlation between follow-up time and relapse as well as extragastric MALT lymphoma and relapse and time to relapse. In view of this, prolonged follow-up is warranted in patients with MALT lymphoma, especially of extragastric origin.

A22 Lenalidomid therapy in osteomyelofibrosis D. Voskova, G. Hochreiner, R. Greul, M. Fridrik Department of Oncology, General Hospital Linz, Linz, Austria

Background. We present our first experiences with lenalidomid in the treatment of patients with symptomatic osteomyelofibrosis. Methods. Since May 2007, 4 patients received lenalidomid for symptomatic osteomyelofibrosis (2 with idiopathic (agnogenic) osteomyelofibrosis, 1 with postpo-

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lycythemic osteomyelofibrosis and 1 with postthrombocythemic osteomyelofibrosis). Starting dose of lenalidomid was 10 mg daily (or 5 mg if baseline platelet count <100  l09=L). The evaluation of response followed after 3 months. If no response can be established, the treatment was discontinued Evaluation of response: in terms of anaemia, thrombocytopenia, splenomegaly and quality of life. Results. Patient Nr. 1 (postpolycythemic osteomyelofibrosis; Jak-2 positive) – after 3 months haemoglobin level and platelet count were normalized; quality of life much better, no response in term of splenomegaly; adverse events: rash grad I; myopathy grad I. Patient Nr. 2 (idiopathic osteomyelofibrosis; Jak-2 negative) – no response after 3 months – no reduction of transfusions frequency – the treatment was discontinued; no adverse events. Patient Nr. 3 (postthrombocythemic osteomyelofibrosis; Jak-2 negative). Treatment was started in January 2008; response after 4 weeks: the platelet count was normalized, no response in term of anaemia; no adverse events. Patient Nr. 4 (idiopathic osteomyelofibrosis; Jak-2 positive) – the treatment was discontinued after the first dose because of sever allergic reaction (Quincke oedema). Conclusions. Lenalidomid engenders a treatment activity in any patients with osteomyelofibrosis with acceptable adverse events.

Results. Four patients (13%) are heterozygot and 26 (87%) wildtype for the R61C SNP. From 15 patients follow up of more than 18 months was available. Four of them did not reach a 3log reduction of bcr=abl transcripts after 18 months of imatinib treatment, only one was R61C heterozygot. On the other hand, 3=4 R61C heterozygot patients had a major molecular response after 18 months of imatinib treatment. Three patients changed for clinical reasons from imatinib to dasatinib=nilotinib treatment, all were R61C wildtype. Conclusions. According to the results of this small group of patients, the R61C polymorphism in exon 1 of the OCT1 transporter protein seems not to affect imatinib response in CML patients. However, R61C and other functional polymorphisms of OCT1 should be evaluated in a larger cohort of CML patients treated with imatinib.

A24 Lenalidomide in the treatment of multiple myeloma – multi-center clinical experience in Austria R. Ruckser1, H. Kasparu2 , J. Thaler3, H. Erb4 , T. Stranzl5 , H. Gisslinger6 1

SMZ Ost, Vienna, Austria KH der Elisabethinen, Linz, Austria 3 Klinikum Wels-Grieskirchen, Wels, Austria 4 CTM G.m.b.H., Vienna, Austria 5 Celgene G.m.b.H., Vienna, Austria 6 Medizinische Universität, Vienna, Austria 1–3 and 6 for the Lenalidomide Compassionate Use investigators 2

A23 OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment in CML patients O. Zach, O. Krieger, M. Födermayr, B. Zellhofer, D. Lutz Krankenhaus der Elisabethinen, Linz, Austria

Background. The organic cation transporter 1 (OCT1, SLC22A1) has been shown to be responsible for the cellular uptake of imatinib. Differences in the activity of OCT1 are predictive for response of CML patients to imatinib treatment (White DL et al.: Blood 110: 4064– 4072, 2007). Polymorphisms of the OCT1 transporter are involved in differences of transport activities and consequently might be associated with imatinib response in CML patients. The R61C single nucleotide polymorphism (SNP) in exon 1 has been linked to a decreased transport activity of OCT1 (Shu Y et al.: PNAS 100: 5902–5907, 2003). Whether this polymorphism is involved in imatinib uptake into cells and imatinib response in CML patients is unknown. Methods. DNA from 30 CML patients treated with imatinib was prepared out of peripheral blood and used for genotyping. The R61C genotype was assessed with a TaqMan SNP genotyping assay (Applied Biosystems).

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Background. Lenalidomide is a new immunomodulatory drug acting both directly on malignant cells and surrounding microenvironment and has been shown to be a more potent immunomodulator than thalidomide with different side effect profile. Promising results in the treatment of relapsed=refractory multiple myeloma (MM) led to its approval by the FDA and the EMEA, Aim of this project was to evaluate feasibility, efficacy, and safety of lenalidomide in clinical routine setting. Methods. We present data from 17 Austrian centers of a retrospective analysis of MM patients treated with lenalidomide on compassionate use basis. Dosing, schedule and dose adjustments of lenalidomide were at the discretion of treating physicians guided by the US prescribing information. Kaplan–Meier method was used to analyze time to progression and overall survival. Analyses are presented for the safety analysis set (all patients receiving lenalidomide) and the efficacy analysis set (patients with relapsed or refractory MM). Results. Thirty-nine patients with MM have been documented. Thirty-six were treated in relapsed= refractory setting, 2 patients received lenalidomide as memo Suppl 1/08

Abstracts

maintenance therapy, 1 patient with MM and AL-amyloidosis as initial therapy. The mean study duration was 126 days. 51% of patients were male, median age was 63 years. MM was of IgG-type in 17, of IgA-type in 16 pts., of light-chain type in 5 pts and 1 pt had non-secretory MM. Mean time since diagnosis was 3.9 years with a median number of 3 prior therapies (range 1–10). In the relapsed or refractory MM group lenalidomide was combined with dexamethasone in 32 pts. and with prednisone in 1 pt; 3 pts received lenalidomidemonotherapy. The mean number of documented cycles was 4.1 (range 1–12). Starting dose of lenalidomide was 25 mg in 89% of the cases, 15 mg in 6% (2 pts) and lower dosages in further 2 pts. The mean cumulative dose=cycle was 405 mg for lenalidomide and 275 mg for dexamethasone (77% of ‘‘target’’ dose for lenalidomide and 59% for dexamethasone). Antithrombotic prophylaxis was given in 92% of pts, mostly ASA and=or LMWH. F=U information was available for 32 pts (Feb. 2008), whereas 20 pts were still alive (median F=U 280 days). Using Blade´ criteria, 44% had PR or better, with CR=nCR=VGPR in seven pts; 28% had MR and four pts were not assessed for response. Median overall survival was 500 days (95% CI: 315– n.r.). Median time to progression was 347 days (95% CI: 210–451). Most frequent haematological toxicities (Gr. III=IV) in the safety analysis set were anaemia (10%), leucopenia (20%) and thrombocytopenia (18%). Infections occurred in 56%, fatigue in 39%, rash in 13% and diarrhoea in 8% of pts. No thromboembolic events or peripheral neuropathies have been reported. Conclusions. Remission rate (44%) and time to progression (11.4 months) were comparable to published results from two international phase III-trials (RR  60%; TTP  11 months). Median overall survival was 16.5 months in our patient population but follow-up is still short. Therapy with lenalidomide was in general well tolerated and safety profile was similar to published data with myelosuppression and infections as most common toxicities. While we were able to maintain start dosis of lenalidomide in most cases, doses of dexamethasone had to be reduced frequently. Rajkumar et al. showed in a trial with lenalidomide=low-dose dexamethasone in newly diagnosed MM that reduction of dexamethasone dosage reduces toxicities and may even improve long-term outcomes. In our experience lenalidomide is effective and safe in MM and we conclude that published phase III-data can be reproduced in a clinical routine setting.

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A25 UDP-glucuronosyltransferase 2B17 gene expression is a novel marker for prognosis in chronic lymphocytic leukemia M. Gruber1, E. Porpaczy1, T. Le1 , M. Bilban1 , D. Heintel1 , H. Esterbauer1, C. Fonatsch1 , C. Mannhalter1, K. Eigenberger1, A. Gaiger1, C. Skrabs1 , A. Hauswirth1 , S. Stilgenbauer2, U. Kroemer2, U. Jaeger1, K. Vanura1 1 2

Medical University of Vienna, Vienna, Austria University of Ulm, Ulm, Germany

Background. UDP-glucuronosyltransferase (UGT) 2B17 glucuronidates androgens and their metabolites. UGT2B17 shows by far the most dramatic difference in gene expression between the Asian and Caucasian normal populations and is associated with an increased prostate cancer risk in Caucasians. Interestingly, Asians have a strikingly lower incidence of chronic lymphocytic leukemia (CLL). In previous microarray-analysis we found that UGT2B17 RNA is differentially expressed between high and low risk CLL. Aims. (i) To evaluate UGT2B17 gene-expression as prognostic marker for CLL; (ii) to determine the genetic background (UGT2B17 DNA polymorphisms) of Caucasian CLL patients. Methods. (i) Real-time PCR results of 94 PBMCsamples of Austrian B-CLL patients were compared with clinical data and CLL risk factors. In addition, we analyzed CD19-sorted cells from selected CLL patients and normal controls, (ii) Conventional hot start PCR with 214 DNA samples of Austrian CLL patients and 449 samples of Austrian age-matched healthy donors (307 men, 142 women) were compared regarding the distribution of polymorphisms. Polymorphisms consist of deletions encompassing the entire UGT2B17 coding region (genotype: ins=ins, ins=del, or double deletion (del=del)). Results. UGT2B17 gene-expression ranged from 0 to 264.12 (median: 2.026) compared to normal PBMC (set as 1). Expression correlated with LPL-expression (p < 0.0002), CD38-expression (p ¼ 0.012), LDH-elevation (p ¼ 0.017), 14q aberrations (p ¼ 0.033) and Binet-stage B and C (p ¼ 0.005). Time to first treatment was significantly shorter in patients with high UGT2B17 (p ¼ 0.0002). UGT2B17 levels were up to 3 logs higher in CD 19þ selected CLL cells compared to CD19 negative cells. RNA expression was higher in ins=ins compared to ins=del patients, but was absent in del=del patients. Genotype frequencies in 214 CLL-patients were 38.97% ins=ins (# 35.04%, $ 44.87%), 49.74% ins=del (# 51.28%, $ 47.44%) and 11.28% del=del (# 13.68%, $ 7.69%), respectively. Within healthy donors we found 42.98% ins=ins (# 43.32%, $ 42.25%), 46.33% ins=del (# 45.60%, $ 47.89%) and 10.69% del=del (# 11.07%, $ 9.86%). There were no significant differences in polymorphism-frequency between CLL-patients and healthy subjects=gender. Double deleted patients had significant-

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ly longer time-to-first-treatment (p ¼ 0.035) than patients with wildtype or homozygous UGT2B17. Conclusions. UGT2B17 gene-expression is a prognostic marker for CLL patients and correlates with genotype. No difference in genotype distribution between CLL patients and controls was found in a Central European population.

A26 Erfahrungen mit Amphotericin B Lipidkomplex in einer pädiatrischen Population G. Kropshofer, M. Freund, C. Lass-Flörl, G. Wehl, A. Klein-Franke, B. Meister Medizinische Universität Innsbruck, Innsbruck, Austria

Grundlagen. Invasive Pilzinfektionen stellen eine ¨r Morbidita¨t und Mortalita¨t bei bedeutende Ursache fu immunsupprimierten Patienten dar. Gerade in den letzten Jahren ist es zu einer deutlichen Zunahme von Infektionen durch Aspergillus spp., Fusarien und Zygomykosen gekommen, unter anderem auch durch aggressivere Therapien bedingt, die zu einem ¨ hren. langem Ungleichgewicht der B- und T-Zellen fu Dem Bereich der pa¨diatrischen antimykotischen Therapien wurde nur wenig Beachtung geschenkt, so stellt sich immer wieder die Frage nach einer optimalen Therapie. Methodik. Alle unsere ha¨matoonkologischen Patienten erhalten wa¨hrend der intensiven Chemotherapie eine prophylaktische Therapie mit Fluconazol 3– 4 mg=kg=d per os. Bei Fieber in Aplasie (FUO) erfolgt prima¨r eine zweifach antibiotische Therapie (Imipinem und Gentamycin), eine Spektrumserweiterung mit einem weiteren Antibiotikum (Vancomycin) erfolgt nach weiteren 24 h. Spa¨testens nach 72 h wird zusa¨tzlich ein Antimyko¨hrung eines Thorax tikum verabreicht, nach der Durchfu Ro¨ntgen sowie nach einer Bildgebung durch CT. Von Dezember 2006 – Oktober 2007 wurden 12 Patienten mit Amphotericin B Lipidkomplex behandelt. Amphotericin B Lipidkomplex (Abelcet+) ist fu¨r die Therapie bei Kindern ohne Alterslimit zugelassen. Das Alter betrug im Mittel 13.5 Jahre (3–17), drei Patienten waren weiblich, 9 ma¨nnlich. Die zugrunde liegende Erkrankungen waren im Folgenden: AML 5 Pat, ALL 2 Pat, MDS 1 Pat, Neuroblastom 1 Pat, Ewing Sarkom 1 Pat, Morbus Hodgkin 1 Pat, NHL 1 Pat.. Ein Patient war im Zustand nach allogener Knochenmarktransplantation, 2 nach autologer Stammzelltrans¨ r eine antimykotische plantation. Die Indikation fu Therapie war in allen Fa¨llen prima¨r mit Fieber in Aplasie gegeben. In insgesamt 4 Fa¨llen konnte eine Pilzinfektion gesichert werden (1  Mucormykose, 1  Mucor und Aspergillus, 1  Candidasepsis).

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¨ hrte die CT gezielte Biopsie zur Zweimal fu Diagnose. Ergebnisse. Die Dauer der Therapie betrug im Median 9 Tage (2–90). Den Endpunkt stellte in 8 Fa¨llen die ha¨matologische Rekonstitution dar, bei 2 Patienten kam es zu einer deutlichen Besserung bzw. zur Eradikation einer nachgewiesenen Pilzerkrankung. Bei 2 Patienten wurde die Therapie abgebrochen (1 Todesfall unter Therapie, nicht mit dem Antimykotikum in Zusammenhang stehend). Die Startdosis von Abelcet+ betrug 4,9 mg=kg KG (3,6–5,4 mg). Serumkreatinin lag im Median bei 0,4 mg=dl (0,2–1,2) bei Ende der Therapie. Nebenwirkungen traten v.a. in Form von Schu¨ttelfrost auf. Bei 8 Patienten manifestierte sich diese NW nur bei der Erstinfusion, 1 Patient tolerierte auch in Folge die Infusion ¨ gliche nicht, 3 Patienten waren ohne jegliche diesbezu Symptomatik. Schlussfolgerungen. Eine Therapie mit Amphotericin B Lipidkomplex bei Kindern ist sicher zu handhaben, effektiv und vertra¨glich. Eine CT gezielte Biopsie zur schnellen und sicheren Diagnosesicherung bzw. zum Erregernachweis sollte standardma¨ßig erfolgen.

A27 Genetic polymorphisms of the methylenetetrahydrofolate reductase gene and colorectal cancer susceptibility E. Feik1 , A. Baierl2 , P. Fichtinger1, B. Hieger1, G. Führlinger1, M. Pusman1 , A. Pentz1 , G. Kornek3 , W. Scheithauer3, S. Stättner4, T. Pulgram5 , W. Weiss5 , K. Mach6 , M. Micksche1 , A. Gsur1 1

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria 2 Department of Statistics and Decision Support Systems, University of Vienna, Vienna, Austria 3 Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria 4 Department of Surgery, SMZ Süd, Vienna, Austria 5 Department of Gastroenterology, KH Rudolfstiftung, Vienna, Austria 6 Hospital Oberpullendorf, Austria

Background. Methylentetrahydrofolate reductase (MTHFR) is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. It catalyses the irreversible conversion of 5,10-methylene THF to 5-methyl THF. Polymorphic variants in MTHFR may modulate risk of colorectal carcinoma through DNA methylation and altered nucleotide synthesis and repair. The purpose of this case-control study was to determine whether two polymorphisms of MTHFR (rsl801131 and rs3737966) are susceptibility factors for colorectal cancer. memo Suppl 1/08

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Methods. In this ongoing molecular epidemiology study of colorectal cancer 3.464 cases and controls were recruited since May 2002 within a large colorectal screening study in the province Burgenland, Austria. Cases were newly diagnosed, previously untreated, and histologically confirmed colorectal cancer patients (n ¼ 124), patients with polyps were divided in an adenomatous (n ¼ 869) and a hyperplastic polyp group (n ¼ 224) and controls (n ¼ 1819) were polyp free at colonoscopy (n ¼ 1819). DNA was extracted by standard protocols (Qiagen) from peripheral blood. Genotyping was performed with ABI Prism 7500 Sequence Detection System (Applied Biosystems) using the fluorogenic 50 nuclease assay with TaqMan Minor Groove Binder probes. Analysis of data was performed using the computer software SPSS for Windows (version 15.0). Multiple logistic regressions were performed to calculate odds ratios (OR) and confidence limits (CL) and to control for possible confounders. Results. Both polymorphisms were found to be in Hardy-Weinberg equilibrium. Carriers of the homozygous polymorphic genotype of the polymorphism rs1801131 showed a slightly higher risk in cases compared to the polyp free controls with an OR of 1.52 (95% CL 0.72–3.19). The same moderate effect was observed when comparing cases versus the polyp group with an OR of 1.53 (95% CL 0.69–3.40). In a subgroup analysis according to histological type of polyps, this effect was found to be stronger in adenomatous polyps (OR ¼ 1.56, 95% CL 0.69–3.51) than in hyperplastic polyps (OR ¼ 1.34 95% CL 0.51–3.49), compared to cases. However, these findings were not of statistical significance. The other investigated polymorphism rs3737966 was not associated with colorectal cancer risk. Conclusions. Our results suggest that individuals with the homozygous genotype of the polymorphism rsl801131 are more likely to develop colorectal cancer. However, due to the relatively low number of colorectal cancer patients in this screening program this finding must be confirmed in a study population containing more cases. The final aim of this project is creating a polygenic model for cancer susceptibility due to multiple risk alleles in the one-carbon metabolism pathway. This work was supported by the ‘‘Herzfelder’schen Familienstiftung’’.

A28

Background. Apoptosis is implemented in colorectal cancer (CRC) development and has emerged as a potential target to cancer treatment at various stages of tumor progression. Measurement of the apoptosis (M30)=necrosis (M65) ratio may have a role in therapy monitoring. To define the value of preoperative assessment of apoptosis and necrosis we measured these parameters in the sera of CRC patients and correlated these values with conventional clinical parameters. Methods. We used an enzyme liked immunosorbent assay (ELISA) to detect an apoptosis specific product and necrosis (M30- and M65-atigens respectively) in the sera of 84 patients total. Fiftyone patients had CRC; UICC I: n ¼ 17; UICC II: n ¼ 7; UICC III: n ¼ 12; UICC IV: n ¼ 10; Relapse: n ¼ 5 and 27 patients served as non cancer (NC) controls. In addition M30- and M65-antigens were measured in an independent group of six patients receiving palliative chemotherapy for CRC. Results. Patients with CRC showed significant higher M30-antigen levels (p ¼ 0.001). When stratified to tumor stages the different preoperative M30 antigen expressions between normal controls and tumor patients remained throughout all stages. Preoperative M65 antigen serum levels were also significantly (p ¼ 0.001) higher than in normal controls. No correlation was found between M30 and M65 serum antigen levels and tumor grading and preoperative CEA levels. The M30=M65 ratio was 0.117 (25% Percentile: 0.094; 75 Percentile 0.170) in the patient group versus 0.279 (25% Percentile: 0.208; 75 Percentile 0.279) in the normal control group. Conclusions. Differences in M30 and M65 antigen expression between normal and CRC patients occur already in early stages of the disease. Therefore measurement of M30 and M65 antigen serum levels might have the potential to be used as a biomarker in determing prognosis. Larger studies are needed to verify this hypothesis and to determine if the M30=M65 ratio might be useful in predicting adjuvant treatment response in colorectal cancer patients.

A29 Low dose bevacizumab plus irinotecan in recurrent glioblastoma multiforme

Measurement of apoptosis and necrosis in the sera of colorectal cancer patients

M. Moik, B. Mlineritsch, A. Berer, R. Greil

K. Strecker1, C. Ausch3 , E. Ogris2 , E. Kitzweger1, W. Hinterberger1, G. Hamilton2 , V. Buxhofer-Ausch1;2

Background. Glioblastoma multiforme is a disease with a remarkably high mortality and very few treatment options once the patients have relapsed after surgery and postoperative adjuvant irradiation and chemotherapy. Methods. From September 2006 to February 2008 we treated 14 patients with recurrent glioblastoma multiforme. All patients had progressed after standard therapy consisting of surgery, radiotherapy and adjuvant temozo-

1

2nd Department of Medicine Danube Hospital, SMZ Ost, Vienna, Austria 2 Ludwig Boltzmann Society, Cluster for Translational Oncology, Vienna, Austria 3 Department of Surgery Danube Hospital, SMZ Ost, Vienna, Austria memo Suppl 1/08

3rd Medical Department, Paracelsus Private Medical University Salzburg, Salzburg, Austria

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lomide therapy. 10=14 pts were symptomatic at the time of progression and required initial glucocorticoid medication. 12=14 patients had edema grade 2 with more than 2 cm edema on MRI imaging. Patients received 5 mg=kg bevacizumab and 180 mg=m2 irinotecan every two weeks till progression. Radiological evaluation was performed every 8 weeks. Results. 10=14 patients showed objective responses (RR ¼ 57.1%) according to the MacDonald criteria. 8 of the 10 responding patients showed clinical benefit and glucocorticoid could be reduced or abandonded in all symptomatic responders. The 6-month-PFS was 57.1%, 6-months overall survival was 85.7%. TTP has not been reached in 6=14 patients. There was one thromboembolic complication, no other grade 3 or 4 for toxicity were observed. Conclusions. Low-dose bevacizumab plus irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicities.

A30 The MDS-specific impact of comorbidities on survival: analysis of subcategories of comorbidity indices-correlation with age and IPSS A. Makrai1;2 , H. Tüchler2, T. Nösslinger1;2, E. Pittermann1;2 , M. Pfeilstöcker1;2 1 2

Hanusch-Hospital Vienna, Vienna, Austria LBI for Haematology and Leukemia Research, Vienna, Austria

Background. Consideration of comorbidity has increasing importance in MDS. The Austrian MDS study group is currently analysing comorbidity, measured by the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) and the Charlson Comorbidity Index (CCI) including patients treated at our center. This single center substudy is focused on score components to evaluate disease specific importance of comorbidities. Methods. 187 primary MDS patients treated with supportive care only (med. age 73 yrs) were analysed retrospectively. We organized comorbidity-items of the two scores into 11 groups: cardiac=vessel diseases (observed in 28% of pts), solid tumors (15%), lung diseases (8%), diabetes (7.4%), peptic ulcera (6.4%), mental disorders (3.2%), adipositas, infections and rheumatological diseases (each 3%), liver diseases (2.7%), nephropathy (1%). We correlated original scores and these groups with age, sex, IPSS, cytogenetic part of the IPSS (c-IPSS) and overall survival. Results. Comorbidity was found in 46% and 53% of patients (CCI and HCT-CI, respectively). Both quantify similar characteristics with high correlation ( ¼ 73, p < 0.001). Influences on survival are pronounced for both CCI (Dxy ¼ 0.10, p ¼ 0.006) and HCT-CI (Dxy ¼ 0.09, p ¼ 0.017). Pulmonary diseases have significant effect on

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survival (Dxy ¼ 0.09, p ¼ 0.005), while cardiac=vessel diseases (p ¼ 0.077), diabetes (p ¼ 0.093) and solid tumors (p ¼ 0.082) show insignificant tendencies. Cox-models of characteristics together with IPSS, c-IPSS, sex and age: in combination with IPSS CCI (b ¼ 17, p< 0.001), HCT-CI (b ¼ 0.18, p ¼ 0.01), lung diseases (b ¼ 0.85, p< 0.001), diabetes (b ¼ 0.34, p ¼ 0.01) and solid tumors (b ¼ 0.48, p < 0.001) show additional predictive value regarding survival. In combination with the c-IPSS CCI (b ¼ 0.12, p ¼ 0.03), HCT-CI (b ¼ 0.17, p ¼ 0.01) and pulmonary disease (b ¼ 0.62, p < 0.001) enhance prediction. In models combining gender or age CCI, HCT-CI and pulmonary diseases are included as significant predictors. Correlations of comorbidities and IPSS, c-IPSS, sex and age: neither an index nor any comorbidity group correlate significantly with IPSS, but there are substantial correlations of CCI ( ¼ 0.19, p ¼ 0.010), HCT-CI ( ¼ 0.17, p ¼ 0.019), cardiac=vessel diseases ( ¼ 0.20, p ¼ 0.011) and solid tumors ( ¼ 0.18, p ¼ 0.025) with c-IPSS, i.e. more comorbidities at higher c-IPSS risk groups. Age correlates significantly with cardiac=vessel diseases (p ¼ 0.001,  ¼ 0.19), but not with CCI or HCT-CI as a whole. Conclusions. Presence of lung diseases, diabetes, solid tumors and cardiac=vessel diseases exhibit negative influence on survival of MDS patients. Comorbidity scores and evidence for some specific comorbidities are independent prognostic factors in additon to age and IPSS. The surprising correlations between comorbidity and c-IPSS warrant further elucidation. Analysis of specific comorbidities and recalibration of their weighting in comorbidity scores, preferably validated on larger data sets will make the inclusion of comorbidity in prognostic systems more valuable of their weighting in comorbidity scores, preferably validated on larger data sets will make the inclusion of comorbidity in prognostic systems more valuable.

A31 TROP2 as prognostic marker in gastric cancer G. Muehlmann1 , G. Spizzo2 , J. Gostner2, M. Zitt1 , H. Maier3, P. Moser3, G. Gastl2;4 , R. Margreiter1;2, D. Oefner1, D. Fong2;4 1

Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria 2 Tyrolean Cancer Research Institute, Innsbruck, Austria 3 Department of Pathology, Innsbruck Medical University, Innsbruck, Austria 4 Division of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Background. Gastric carcinoma is one of the most common neoplasias and most frequent causes of cancer related deaths worldwide. Although surgical resection remains the only means of cure, the recurrence rate is memo Suppl 1/08

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unacceptably high even after R0 resection and (neo)adjuvant chemotherapy. Therefore, there is an urgent need for identification of predictive and=or prognostic biomarkers to select high-risk patients who might benefit from additional tailored therapies. Expression of TROP2 was demonstrated to be associated with tumor aggressiveness and poor prognosis in patients with various epithelial cancers. The aim of this study was to investigate TROP2 expression in gastric cancer and its correlation with clinicopathological features and disease outcome. Methods. Expression of TROP2 was investigated by immunohistochemistry of paraffin-embedded tumor specimens from 104 patients who underwent resection for gastric cancer at the Department of Surgery, Innsbruck Medical University. Overall survival (OS) and disease-free survival (DFS) was calculated using Kaplan–Meier estimates. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. Results. TROP2 was found to be overexpressed in 58 (56%) of the tumor samples. According to Lauren classification significantly higher expression of TROP2 could be detected in intestinal-type gastric cancer than in diffusetype carcinoma (p ¼ 0.03). In intestinal-type gastric cancer, TROP2 overexpression was significantly correlated with shorter DFS (p ¼ 0.03). Among the total patient group, TROP2 overexpression was a prognostic marker for poor disease-free (p < 0.01) and overall (p ¼ 0.03) survival in lymph node positive patients but not in those without locoregional lymph node metastasis. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent prognostic marker for poor DFS in the subgroup of patients with intestinal-type gastric cancer irrespective of lymph node involvement. Conclusions. Our results demonstrate that TROP2 is an independent prognostic marker for disease recurrence in intestinal type gastric cancer. Due to its wide distribution TROP2 may become an attractive therapeutic target in a subgroup of patients with gastric cancer at particularly high risk for relapse.

A32 Difference in the relative distribution of naïve and memory CD4þ T cell subsets in mutated and unmutated B-CLL: implication for disease outcome I. Tinhofer, L. Weiss, F. Gassner, G. Rubenzer, C. Holler, R. Greil Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department at the Salzburg General Hospital and the Paracelsus Private Medical University, Salzburg, Austria

Background. B-cell chronic lymphocyte leukemia (B-CLL) consists of two clinical subsets distinguished by the incidence of somatic hypermutation in genes of the memo Suppl 1/08

immunoglobulin (Ig) variable heavy (VH) chain region. The poor clinical outcome of the subgroup with unmutated Ig VH genes (UM-CLL) has been linked to the persistent ability of the B-cell receptor (BCR) in tumor cells from unmutated cases to respond to antigen wheres tumor cells from mutated B-CLL cases (M-CLL) seem to be anergized. Signaling of the B-cell receptor and clonal B-cell expansion generally rely on T cell help and these interactions differ depending on the activation= differentiation status of T cells. We hypothesized that the course of disease in B-CLL is not only influenced by the mutational status of the BCR per se but also by the composition of the T cell pool. We determined the relative numbers of naive and memory CD4þ and CD8þ T cell subsets in M-CLL (n ¼ 70) and UM-CLL cases (n ¼ 40) and correlated it with clinical stage and disease activity. We then assessed the potential of predicting disease progression on the basis of the relative distribution of T cell subsets in a prospective manner. Results. A significant decrease in relative numbers of naive T cells in favor of a concurrent increase in central (TCM) and effector memory (TEM) cells was observed in the CD4þ but not the CD8þ T cell pool in UM-CLL as compared to M-CLL cases. This skewing from naı¨ve to memory CD4þ T-cells was also associated with high Rai stage and progressive disease. With a cut-off of <40% Tnaı¨ve cells within the CD4þ T cell population, a patient subgroup could be identified with significantly shorter treatment-free survival. Multivariate analysis revealed that the relative number of naı¨ve T cells was an independent prognostic markers for shortened treatment-free survival. The exact molecular mechanisms of these interactions between CD4þ T cells and tumour cells and their therapeutic potential remains to be elucidated.

A33 Single center experience with Lenalidomide in the treatment of MDS with del5q G. Aschauer1, E. Rechberger1, G. Tschurtschenthaler1, F. Lang1 , G. Webersinke2 , A. L. Petzer1;2 1

Internal Medicine I, Haematology and Oncology, Barmherzige Schwestern Hospital Linz, Linz, Austria 2 Internal Medicine I, Laboratory for Molecular Biology und Cytogenetics, Barmherzige Schwestern Hospital Linz, Linz, Austria

Background. Recent data have shown that treatment of MDS patients with del5q with Lenalidomide results in very high rates of transfusion independency and is also capable to induce cytogenetic responses in these patients. Here we present our experience with the first 6 patients treated with Lenalidomide at our institution. Methods. This retrospective analysis was performed from October 2006 to February 2008. All examinations (including bone marrow cytology, cytogenetics and mo-

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lecular biology analyses) and all clinical parameters were performed at our institution. The median age was 83.8 years with a median time since diagnosis of 7.5 months. All patients were female and dependent on transfusions with packed red blood cells (median: 4 PRBC transfusions in the month before treatment). According to the WHOclassification 3 pts had a 5q-Syndrome, 1 pt had RAEB-2, one RARS and one pt had an AML with del 5q (50% blasts in the BM). The prognostic score according to IPSS was low in 3 pts, int-1 in 1, int-2 in 1 and high risk in 1 pt. All patients received an initial dose of Lenalidomide 10 mg orally for 21 days every 4 weeks. Results. At the time of evaluation (February 20th, 2008) the pts had received a median of 6 cycles Lenalidomide and 2 patients are still on treatment. 4 of 6 patients (67%) achieved transfusion independency after a median time of 5 weeks. 3 of the 4 responders are still transfusion independent, one patient relapsed after 8 cycles of Lenalidomide. This patient received 5 mg Lenalidomide after the first course due to prominent gastrointestinal side effects with a dose of 10 mg. 2 transfusion independent patients are currently off treatment, one due to excellent recovery of anaemia with Hb levels >4 g=dl after 4 cycles and one patient is currently under observation after a total of 15 cycles of treatment. She became transfusion independent after 4 cycles and still is. The most frequent hematological toxicities were thrombocytopenia and neutropenia, which occurred mainly in the initial phase of treatment and resolved after response. Dose interruptions were necessary in only one patient due to neutropenia WHO grade IV. Relevant non-hematological toxicities occurred in 2 cases (rash with subsequent dyspnoe, gastrointestinal toxicity). The rate of infections was low (1 pt with erysipelas). Conclusions. Lenalidomide confirms to be a promising treatment for patients with MDS with deletion 5q leading to transfusion independency in 67% of our patients. Responses occur quickly and seem to be durable. In some cases the effect of Lenalidomide on transfusion dependency was prolonged even if treatment was interrupted. Lenalidomide was well tolerated despite high age of the patients with manageable toxicities.

Background. The protein kinase B (Akt) is crucially involved in several signalling pathways mediating tumour development and progression in human malignancies. Deregulation of Akt has been reported to promote cell growth and survival of multiple myeloma, suggesting Akt to be an interesting target for tumour therapy. Although recent studies confirmed the central role for Akt in myeloma cells, it is currently unknown which isoform has the most crucial function. Recognition of Akt isoforms as a selective target in tumour progression is due to recent findings which confirmed distinct roles for Akt1 and Akt2 in controlling migration and invasion in, e.g., breast cancer cell lines and Akt3 to promote tumour development in melanoma cells. Results. First we confirmed the presence of phosphorylated Akt in four of five myeloma cell lines. Significant induction of activated Akt was observed in all cell lines in response to IGF-I and IL-6, essential players of the tumour microenvironment in multiple myeloma. We tested new Akt specific inhibitors (Aktil=2 and SH-5) which are able to reverse growth factor mediated Akt activation, with Akt1=2 being more effective. Both inhibitors potently induced apoptosis in myeloma cells while cells of the immune system were spared. Then we investigated the isoform status in five myeloma cell lines and identified Akt1 and Akt3 as the predominant active isoforms. Interestingly, activated Akt3 was induced by IGF-I or IL-6 in all tested myeloma cell lines. SiRNA experiments indicate a crucial role for Akt3 during myeloma cell adhesion to stroma cells. Further functional assays on cell lines and analysis utilizing immunohistochemistry on patient samples are currently performed to elucidate the significance of distinct Akt isoforms and their specific downstream targets for targeted therapeutic intervention.

A35 Effect of the natural compound Cnicin in multiple myeloma M. Obkircher1, K. Joehrer1, E. Maizner1, A. Olivier1, K. Janke1 , R. Greil2

A34 Growth factor induced upregulation of active Akt3 in multiple myeloma: implications for tumour progression E. Maizner1, T. Möst1 , K. Jöhrer1, A. Olivier1, M. Obkircher1, M. Egger2, R. Greil1 1 2

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Tyrolean Cancer Research Institute, Innsbruck, Austria Laboratory of Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Disease at the Private Medical University Hospital Salzburg, Salzburg, Austria

1 2

Tyrolean Cancer Research Institute, Innsbruck, Austria Laboratory of Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Disease at the Private Medical University Hospital Salzburg, Salzburg, Austria

Background. Multiple myeloma (MM) is a malignancy of terminal differentiated B-lymphocytes and the second most common blood cancer. MM is characterized by an excessive amount of monoclonal plasma cells in the bone marrow (BM), serum and urine monoclonal immunoglobulin, and osteolytic lesions. Another characteristic of MM is the slow proliferation of malignant plasma cells and accumulation of those in the BM. The annual incidence for MM (3–4 per 100,000) is linked to aging popumemo Suppl 1/08

Abstracts

lation, the median age of patients diagnosed with MM is 65, and the median survival rate after diagnosis is 3 years. Cnicin is a naturally occurring Sesquiterpene lactone and has been shown to induce apoptosis in both the A-549 (lung carcinoma) and HT-29 (colon carcinoma) lines. It has also been shown that Cnicin inhibits cell proliferation in several different cancer cell lines. Little is known however concerning the underlying molecular mechanism responsible for its activity. Objectives. Despite high dose treatment regimes multiple myeloma (MM) disease is still not curable. Patients become resistant to cytotoxic drugs and die of disease progression. Therefore, new cytotoxic compounds are urgently needed. Results. In our study we show that Cnicin induces apoptosis in a time and dose dependent manner in MM cell lines (U266, OPM-2, NCI-H929, RPMI-8226) and in CD 138þ myeloma cells from patients whereas peripheral blood mononuclear cells remain almost unaffected. The combination of Cnicin with common anti-myeloma drugs (e.g. Velcade+, Melphalan+) results in additive apoptosis induction in myeloma cell lines. Microarray data of U266 cells treated with Cnicin show a regulation of several genes, 40 genes were up-regulated and 56 were downregulated. Most interestingly, Cnicin down-regulates Pim-2, a serine=threonine kinase playing an important role in cell survival, similar to Akt. Conclusions. We conclude that the combination of conventional drugs and Cnicin might be very effective and might represent a new strategy in the treatment of MM.

to second generation compounds, such as dasatinib (Sprycel+) or nilotinib (Tasigna+). These TK inhibitors were shown to be effective in most instances, but a range of specific mutations may also occur before and during treatment with dasatinib or nilotinib. These observations underscore the importance of monitoring patients on treatment with all current TK inhibitors for the presence of mutations. Methods. A number of methods have been employed to detect mutant clones in the BCR-ABL TK domain. PCR amplification coupled with direct bidirectional sequencing is relatively rapid and allows detection of emerging mutations at a sensitivity of approximately 20%. We have established a technique based on ligationdependent competitive PCR (LD-PCR) which allows more sensitive detection of specific clones facilitating timely detection of clonally expanding mutant cells during treatment. Results. In CML patients with suspected resistance to imatinib, the spectrum of mutations detected in our laboratory included predominantly common aberrations within and outside the P-loop. Moreover, we and others have made the observation that mutational analysis may reveal clones carrying deletions in the TK domain, including the exons 4 or 7. The biological significance of these aberrant splice variants is currently under investigation. Conclusions. We present our experience in mutation screening in CML patients and discuss the possible implications.

A37 A36 Analysis of mutations in the BCR-ABL TK domain in CML patients

Distinct dimensions are defined by geriatric assessment in elderly tumor patients

D. Denk1;2 , S. Preunier1, M. Nesslböck2 , T. Lion1;2

R. Stauder1, M. Scheibner1, K. Moser1, B. Holzner2, B. Sperner-Unterweger2, G. Kemmler2

1

1

2

Children's Cancer Research Institute (CCRI), Vienna, Austria Labdia Labordiagnostik GmbH, St. Anna Kinderkrebsforschung, Vienna, Austria

Background. The tyrosine kinase (TK) inhibitor imatinib (Gleevec+) directed against the BCR-ABL TK domain has become the standard of treatment in patients with chronic myeloid leukemia (CML). Despite its effectiveness in CML treatment, primary refractory disease or secondary resistance remains a problem. The mechanisms underlying resistance are probably heterogeneous, but resistance is most commonly associated with point mutations within the ABL TK domain. The level of resistance may vary from slightly reduced sensitivity to total insensitivity. In patients receiving treatment with imatinib, mutations conferring only moderately impaired sensitivity may be approached by increasing the dose, while the presence of mutations associated with a high level of resistance provides an indication for switching treatment memo Suppl 1/08

2

Division of Haematology and Oncology, Innsbruck, Austria Department of Biological Psychiatry, Innsbruck Medical University, Innsbruck, Austria

Background. Due to demographic changes the number of elderly cancer patients is increasing continuously. Thus, oncologists have to integrate scores of the geriatric assessment (GA) into decision analyses and treatment concepts in elderly cancer patients. GA represents a structured approach to assess different domains like functional activities, comorbidity, emotional situation, cognition, quality of life, and social support of elderly to identify resources and needs to plan care. GA scores range from simple screening tools to highly complex instruments, which have to be applied by specialists. Overall the performance of GA instruments in elderly is time consuming and costly. Aim of this study was to analyze which of the standard instruments used in GA cover overlapping aspects

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Abstracts

and which of them address different dimensions to form the basis for a rational application. Methods. Assessment scores were applied in 78 tumor patients 60þ (m: 41, f: 37; mean age 72.9 a) treated at the ward of the of the Department of Haematology and Oncology of the University of Innsbruck, Austria, by applying the Karnofsky-Index, WHO-Index, GDS, ADL, iADL, VES-13, PPT, CIRS-G, FACT-G, MMSE, f-Sozu and Charlson-Index. To estimate the identification of different dimensions these GA data were evaluated by means of an explorative factor analysis and a correlation analysis. Results. Five different dimensions can be essentially defined by factor analysis: functional status, quality of life, comorbidity, social support and cognition. For substantiation of the factor analysis a correlation analysis was carried out which basically confirmed these findings. Karnofsky-Index, WHO-Index, VES-13, ADL, iADL and PPT predominantly load on the factor functional status. The remaining four dimensions can be separated from this factor; hence they clearly address independent aspects. Further results from the ongoing study will be presented. Conclusions. These analyses establish solid information on the evaluation of different dimensions by GA tools in a cross sectional examination. Thus the basis for an effective and efficient application of GA in elderly cancer patients is formed.

chemokine profile of myeloma cell lines and found CCL27=CTACK upregulated in all cell lines as well as in bone marrow supernatants of tumor patients. We discovered this chemokine to impair the function of monocytederived dendritic cells in vitro. In allogeneic mixed leukocyte reaction a reduced activation capacity of dendritic cells differentiated and matured in the presence of CCL27 could be detected. This decreased proliferation of T-cells was accompanied by a decrease of IFN-, IL-2 and IL-5 production, which are indicators for potent immune response. These results suggest a new mechanism of tumor cells to bypass immune cell function and we are currently elucidating the involved mechanisms.

A39 Treatment outcome in unselected patients with acute myeloid leukemia: the single center experience of the Wilhelminen Hospital M. Schreder1, N. Zojer1, B. Brixler1, J. G. Meran2 , H. Ludwig1 1

A38 Multiple myeloma-chemokine network: CCL27=CTACK – a new player in tumor immune escape A. Olivier1, K. Jöhrer1, E. Maizner1, C. Zelle-Rieser1, J. Krugmann2 , M. Obkircher1, R. Greil3 1

Tyrolean Cancer Research Institute, Innsbruck, Austria Institute of Pathology, University of Innsbruck, Innsbruck, Austria 3 3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Disease at the Private Medical University Hospital Salzburg, Salzburg, Austria 2

Background. Multiple myeloma is still incurable using conventional chemotherapy and considerable efforts are undertaken to establish new immunotherapeutic strategies to target this B-cell neoplasm. Myeloma patients exhibit a variety of numerical and functional changes in immune cell subsets. Besides the abnormal changes in the T cell compartment, dendritic cell (DC) – dysfunction has been well documented. Dendritic cells are highly specialized antigen-presenting cells that play a critical role in the activation and potentiation of immune responses. The downmodulation of DCs is caused by the specific tumor microenvironment. Results. In order to reveal important actors of the chemokine network in multiple myeloma we analyzed the

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First Department of Medicine, Center for Oncology and Haematology, Wilhelminenspital, Vienna, Austria 2 Krankenhaus der Barmherzigen Brüder, Vienna, Austria

Background. Acute myeloid leukemia (AML) occurs with an annual incidence of 100,000 population, its frequency rising with age. Treatment is based on combination chemotherapy with cytosine arabinoside and anthracyclines and has not changed during the last 30 years. Allografting is a valuable option in younger patients with high-risk features or those relapsing after standard chemotherapy. Here we report on treatment outcomes in an unselected patient population treated in our institution since April 1999. Methods. One hundred and thirty-two consecutive patients diagnosed with AML between April 1999 and December 2007 have been included in the study. Median age at presentation was 67.7 years (range, 19.2–92.8 years) with an even gender distribution of 67 male and 65 female patients. Patients were stratified based on age and performance status and treated according to the current protocols of the ‘‘Ostdeutsche Studiengruppe fuer Haemato-Onkologie (OSHO)’’. Briefly, younger patients were scheduled to receive 1 or 2 courses of standard induction chemotherapy with intermediate-dose Ara-C (1 g=m twice over 3 hours on days 1, 3, 5, 7) and mitoxantrone (10 mg= m2 on days 1–3) or idarubicine (12 mg=m2 on days 1–3). Patients achieving complete remission (CR) after induction therapy received 3 cycles of consolidation chemotherapy using a five-day course of the same drugs as during induction. Patients over 60 years of age considered fit for intensive therapy received induction chemotherapy as dememo Suppl 1/08

Abstracts

scribed above with two consolidation cycles, whereas for the remaining patients, oral palliative chemotherapy or supportive care only, was offered. Results. All of the 40 patients below 60 years of age were submitted to standard therapy with curative intent. CR was achieved in 80% of these patients after 1 or 2 courses of induction therapy. Median progression-free survival in this cohort was 38.1 months, with an overall survival of 55% at 5 years. However, 20% of patients did not reach CR after double induction and 7.5% of patients died during the first cycle, mainly due to infectious complications. Allogeneic bone marrow transplantation was performed in 5 patients, resulting in long-term survival in 4 of these patients. Of the elderly patients among the study population, only 41 (45%) presented in excellent clinical condition and were thus assigned to a curative treatment approach. CR was achieved in only 61% of patients, whereas early deaths occurred in 15% of patients. Progression-free survival (median, 14.0 months) was found to be significantly shorter compared to younger patients, with a 5-year overall survival of only 21%. 53 patients received palliative chemotherapy or best supportive care only. Median survival in these cohorts was 2.5 and 0.3 months, respectively, showing no significant impact of oral chemotherapy on treatment outcome. Conclusions. These data reflect the ‘real life’ spectrum of patients with AML, with the majority presenting at age above 60 years. Results compared favourably with treatment outcomes reported in large clinical trials.

A40 Successful RIC-allo PBPCT in a patient with dyskeratosis congenita and bone marrow failure M. Huber, M. Binder, H. Kasparu, J. König, O. Krieger, D. Lutz Krankenhaus der Elisabethinen, Linz, Austria

Background. Dyskeratosis congenita is characterized by the triad of reticular pigmentation of the skin, nail dystrophy and mucosal leukoplakia. In 40%, mutations in genes involved in the telomere maintenance pathway can be detected. Malignant transformation of mucosal leukoplakias may occur, particularly in head and neck and esophagus in 60% of the patients, and colon and anus in 15%. Median age at cancer is 28 years (1.5–68 years), the median survival age is 45 years. Evolution to bone marrow failure with transformation to myelodysplastic syndrome or acute myelogenous leukemia is part of the natural course of the disease. Methods. We present a case of a 40 year old man who first showed clinical features of dyskeratosis congememo Suppl 1/08

nita Zinsser-Engman-Cole at the age of 21 years including dystrophic nails of hands and feet and typical skin pigmentation. Mutation analysis confirmed X-linked mutation of the DKC1 gene. 5 years later, he first presented in our hospital with mild thrombocytopenia and anemia. At the age of 32 years, a gastrectomy was performed because of a signet ring cell carcinoma in the gastric antrum (pTlpN0R0). Two years later, he had to undergo a laserresection of a carcinoma of the orophaynx (T2-3, N0M0). Three lineage dysplasia of hematopoiesis deteriorated over the years. At the age of 35, a bone marrow biopsy confirmed a hypocellular myelodysplastic syndrome managed by supportive treatment and growth factors for further two years. When he suffered repeatedly from severe infectious complications (pneumonia, acute exazerbation of chronic cholecystitis), a peripheral stem cell transplantation from an unreleated HLA identical donor was undertaken. We used reduced dosis of cyclophosphamid (total dose 5400 mg), fludarabin (total dose 220 mg) and ATG (1200 mg) for conditioning. The mononuclear cell dose of marrow infused was 2.93  108 CD3þ cells=kg and 6.6 106 kg CD34þ cells=kg. Neutrophil recovery (PMN >1000=ml) was documented on day þ10. A transient rash on day þ17 – histologically confirmed graft versus host disease – was managed with topic corticosteroids. On day þ30, mild gvhd of the mucosa of the mouth occurred, but resolved on continuous GVHD prophylaxis (ciclosporin A and mycophenolat mofetile). Because of substantial weight loss, he needed parenteral nutrition for 23 days. He was discharged from hospital on day 50. The patient is now 2 years post RIC-allo SCT well with normal blood counts. Conclusions. We suggest that a reduced intensity conditioning regimen is acceptable for HLA identical SCT in patients with bone marrow failure in DC.

A41 Impact of natural killer cell dose and donor killer-cell Ig-like receptor (KIR) genotype on outcome following HLA-identical haematopoietic stem cell transplantation J. Clausen, B. Kircher, J. Auberger, P. Schumacher, G. Gastl, D. Nachbaur Division of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Background. The contribution of NK cells to graftversus-malignancy mechanisms following HLA-identical peripheral blood stem cell transplantation (PBSCT) remains unclear. To determine the role of the grafted NK cell dose and the donor’s repertoire of activating and inhibitory killer cell Ig-like receptors (KIRs) for relapse-free and overall survival following T-cell-replete

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PBSCT from HLA-identical siblings, 83 consecutive transplants for haematological malignancies were retrospectively evaluated. A score based on the presence of the inhibitory KIR3DL2 missing its ligand, HLA-A3=A11, the activating KIRs 2DS2, 2DS4, 2DS5, and a high NK cell dose was associated with reduced relapse incidence (23% versus 61%; p ¼ 0.0013), superior relapse free survival (56% versus 23%; p ¼ 0.0011) and overall survival (61% versus 26%; p ¼ 0.068 for all transplants; 55% versus 9%; p ¼ 0.027 for reduced intensity conditioning transplants). Results. These results support the importance of NK cells for graft-versus-malignancy alloreactivity in HLAidentical PBSCT. While HLA-C incompatibility likely dominates NK alloreactivity in HLA-mismatched PBSCT, KIR3DL2 missing HLA-A3=11 and specified activating KIRs may contribute to NK reactivity following HLA-identical PBSCT.

A42 Bevacizumab þ Docetaxel þ Capecitabine as neoadjuvant therapy for invasive breast cancer: Results of a phase II pilot study B. Mlineritsch, M. Moik, S. Ressler, M. Stoll, K. Namberger, Ch. Menzel, R. Greil 3rd Medical Department, Paracelsus Private Medical University Salzburg, Salzburg, Austria

Background. Docetaxel þ Capecitabine is a highly active regimen for early and metastatic breast cancer (BC), and the addition of bevacizumab to chemotherapy improves outcomes in the metastatic setting. More recently, the combined regimen of Capecitabine þ Docetaxel þ Bevacizumab has shown preclinical synergy and has demonstrated high activity as first-line therapy for metastatic breast cancer. We conducted a single-center, pilot-phase II study to determine the efficacvy of this regimen in patients scheduled to receive pre-operative chemotherapy. Methods. Eligible females were aged 18–70 years with invasive HER2 – BC T2-4 (exept T4d) >2 cm, any N stage, no evidence of distant metastases, and no prior systemic therapy. Patients received 21-day cycles of bevacizumab (15 mg=kg day 1 for 5 cycles) plus docetaxel (75 mg=m2 day 1 for 6 cycles) plus capecitabine (950 mg=m2 bid for 14 days followed by a 7-day res period for 6 cycles). Surgery was performed 2–4 weeks after completion of therapy. The primary endpoint is pathologic complete response (pCR) rate, defined as no evidence of invasive tumor in the final surgical sample (T0 or DCIS), secondary endpoints include clinical objective response rate, breast-conserving surgery (BCS) rate, and safety. Results. The planned 18 patients have been treated. Baseline characteristics were: median age 48 years (range

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35–70); mean tumor size 5.6 4.6 cm (palpatory), 3.4 3.1 cm (mammography), 4.5 4.0 cm (MRI), 4.1 3.3 cm (sonography). All 6 cycles were delivered in 72% of patients. BCS was performed in 15 patients (83%), pCR rate was 22%. Conclusions. Pre-operative therapy with bevacizumab þ docetaxel þ capecitabine produced apCR in 22% of patients and enabled BCS in 83%. Based on this high activity, further evaluation of this combination is recommended.

A43 Exemestane as primary systemic treatment for hormone receptor positive post-menopausal breast cancer patients: a phasell trial of the Austrian Breast and Colorectal cancer Study Group (ABCSG-17) B. Mlineritsch, Ch. Tausch, Ch. Singer, G. Luschin-Ehrengreuth, R. Jakesz, F. Ploner, M. Stierer, E. Melbinger, Ch. Menzel, R. Greil 3rd Medical Department, Paracelsus Medical University, Salzburg, Austria

Background. A multicenter phase II study was conducted to analyse the clinical activity of the steroidal aromatase inhibitor exemestane in the neoadjuvant treatment of post-menopausal women with strongly ERand=or PgR-positive operable breast cancer. Methods. From September 2000 to December 2003, 80 women were recruited for treatment with exemestane 25 mg daily for 4 months. The primary endpoint was the clinical response rate according the WHO criteria; secondary endpoints included toxicity and the number of patients who qualified for breast conserving surgery at the end of treatment, comparability of evaluation methods for response, potential alterations of hormone receptor and Her2=neu status during treatment. Results. On an intention to evaluate analysis, according to the prespecified criteria the overall clinical response rate was 34%, the pCR rate was 3% and the rate of breast conserving surgery was 76%. When sonographic and mammographic longitudinal measurements were included in patients with missing palpation data, response rates were 38% and 41%, respectively. The tumor response was independent of the Her2=neu status which remained unchanged during treatment. In contrast, while the ER remained unaltered. Downregulation of the PgR was observed.The treatment was well tolerated with nomgrade 3 and 4 toxicities exept gastrointestinal (one grade 3 case) and hot flushes (two grade 3 cases). Conclusions. This study shows that exemestane is effective and safe as preoperative therapy in postmenopausal patients with strongly hormone receptor-positive breast cancer. memo Suppl 1/08

Abstracts

A44 Bortezomib and its impact on proliferating endothelial cells J. Kern1 , A. Djanani2 , W. Schgoer2, M. Egger2, R. Kirchmair2, G. Gastl1 , E. Gunsilius1 , G. Untergasser1, M. Steurer1 1

Divison of Haematology and Oncology, Tumor Biology and Angiogenesis Laboratory, Innsbruck Medical University, Innsbruck, Austria 2 Department of General Internal Medicine, Innsbruck Medical University, Innsbruck, Austria

Background. Clinical observations and recent experimental data suggest an anti-angiogenic effect of the proteasome inhibitor bortezomib independent from its direct anti-tumor activity. Aim. To assess bortezomib’s anti-angiogenic effects in vitro and in vivo and to characterise the exact mechanism of angiogenesis inhibition. Methods. Human umbilical vein endothelial cells (HUVEC) and endothelial colony forming cells (ECFC) were isolated from umbilical cords and cord blood, respectively. All experiments were performed separately for both cell types, proliferating and non-proliferating (confluent cells. Cell viability was determined using WST-1 assays, proliferation capacity was investigated using BrDU-assays. Apoptosis was assessed using DAPI and phalloidin staining, flow cytometry and cell cycle analysis. Tube formation was examined in Matrigel, cell migration was investigated using the scratch-assay. For assessment of anti-angiogenic effects in vivo, the chorionic allantois membrane (CAM) assay was used. Results. In proliferating endothelial cells, preincubation with bortezomib over 24 hours significantly reduced cell viability and proliferation capacity, in a dose-dependent fashion (EC50: 5 ng=ml). Moreover, bortezomib (5–10 ng=ml) induced apoptosis in proliferating HUVEC and ECFC involving the activation of caspase-3 and accumulation of p53, Noxa and Bok. In sublethal doses (e.g. 4 ng=ml), bortezomib exerted a cell cycle arrest in phase G1. In contrast, no apoptosis induction was detectable in confluent endothelial cell cultures even with bortezomib concentrations up to 1 mg=ml. Tube formation in Matrigel and endothelial cell migration were also significantly inhibited in a dose-dependent fashion (1– 10 ng=ml). In vitro observations were confirmed in our in vivo model where bortezomib inhibited VEGF-induced blood vessel growth. Conclusions. Our data show that bortezomib displays profound anti-angiogenic properties in vitro and in vivo. This effect is most pronounced in proliferating endothelial cells and involves apoptosis induction via p53, Noxa and Bok.

memo Suppl 1/08

A45 How good is our guess? Contrasting views of influencing factors on cardiopulmonary resuscitation of palliative care patients and oncological staff members R. Simanek, V. Requat, B. Hammerl, C. Geissler, K. Geissler Department of Oncology, Hietzing Hospital, Vienna, Austria

Background and aim. Making informed decisions is a critical issue for clinicians to address when caring for patients nearing the end of life (Lorenz 2008). However, discussion about cardiopulmonary resuscitation (CPR) might be avoided by many physicians due to the reason to offer a positive outlook (Higgison 2003). Additionally physicians trend to underestimate patients’ quality of life but rely on their assumptions when deciding not to resuscitate (Perron 2002). We aimed to find out whether influencing factors on palliative care patients’ decision on CPR exist and whether there is accordance with the employees’ estimation. Methods. Patients from our Palliative Care Unit underwent a structured interview within the first 5 days during their hospital stay. Attitudes regarding decline of CPR (binary variable: true=false) were asked, as well as risk factors (RFs), which were assumed to influence this decision: age higher than 75 years (representing collective’s 50% percentile), living alone, medium or severe immobility, psychical and physical limitation, need for help at personal hygiene, pain, nausea, dyspnoe and weakness (binary variables: true=false). Secondly, employees from the 5th Medical Department, who were completely unaware of the results evaluated these RFs and estimated them regarding their impact on the patients’ decision (binary variable: influencing yes=no). Employees’ answers were reviewed with respect to the patients’ answers. For statistical analysis Chi-square tests was applied. Results. From 01=2002 until 01=2006 350 patients were included into our study; questionnaires from 288 patients (168 females=120 males, mean age=std.dev. 72=  13 yrs.) were eligible for analysis. 130 patients (45.1%) refused CPR, when the aforementioned RFs were compared, there were no statistically significant differences between patients who refused CPR and patients who did not. However, there was a trend towards dyspnoe [22% vs. 13.6%, odds ratio (OR): 1.79, 95% confidence interval (CI): 0.96–3.34] as influencing parameter. These results were not in line with the employees’ (including 14 physicians, 18 nurses and 8 volunteers) estimation, who overestimated the prevalence (prev.) of most of the RFs [(prev. (%) in employees vs. prev. (%) in patients who refused CPR, p-value (p)): age: 72.5 vs. 50.8, p: 0.02; pain: 77.1 vs. 40.9, p< 0.01; weakness 78.0 vs. 54.8, p < 0.01; nausea 46.7 vs. 18.8, p < 0.01; dyspnoe 63.6 vs. 22.0, p < 0.01; immobility 59.5 vs. 28.2, p < 0.01; physical limitation 78.7 vs. 68.4, p ¼ 0.25; psychical limitation 94.3 vs. 64.3, p < 0.01] and underestimated the impact of living

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Abstracts

alone and need for help at personal hygiene [39.4 vs. 73.9, p < 0.01 and 20.0 vs. 54.0, p < 0.01], respectively. Conclusions. We were not able to detect influencing factors on palliative care patients’ decision on CPR. There was no accordance with the employees’ estimation, who mostly overestimated the occurrence of these symptoms in patients who refuse CPR. Apart from appraisal of physical limitation, significant differences were found between patients’ and employees’ assessment.

response meeting the RECIST criteria until now. Nevertheless Temsirolimus is of valuable importance despite its only temporary effect due to its good tolerability in the treatment of metastatic RCC. Further studies are needed to find the ideal combination or sequence to increase the rate of complete responses and therefore to overcome the onset of refractory disease.

A47 A46 Compassionate use program of Temsirolimus after previous treatment with Sunitinib and Sorafenib in metastatic renal cell cancer M. Grundbichler, B. Mlineritsch, M. Erl, R. Greil 3rd Medical Department, Paracelsus Private Medical University Salzburg, Salzburg, Austria

Background. Renal cell cancer (RCC) accounts for 2–4% of all malignancies. They range at 3rd place among all urogenital carcinomas affecting men twice often as women. Metastatic disease at the time of diagnosis occurring in about one third of all patients or recurrence after surgery is refractory to conventional chemotherapy. The frequent loss of the Von Hippel-Lindau tumor suppressor gene leading to a net gain of hypoxia inducible factors (HIF) in this highly vascular cancer have made antiangiogenic approaches an attractive strategy. Consequently antiangiogenesis targeting agents like Sunitinib, Sorafenib and Temsirolimus showed promising effects offering new options besides the classic cytokines (Interferon-
and Interleukin-2). Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) kinase, which regulates intracellular signaling pathways involved in growth, proliferation and angiogenesis, e.g. as an upstream inhibitor of HIF
. None the less after a while all the patients develop resistance and finally progress during antiangiogenic therapy. The ideal combination or sequence of antiangiogenic substances is still a point of discussion. Aim. The aim of our compassionate use program is to further analyze the impact of Temsirolimus in a practical clinical setting after previous treatment with Sunitinib and Sorafenib. Methods. Analyzes were done using the clinical data gained by the treatment of 6 patients with metastatic RCC within our single center compassionate use program. Temsirolimus was intravenously applied with 25 mg=m2 in a weekly interval. Statistical analyzes were done using SPSS software. Results. Our data gained by the treatment of 6 patients within our compassionate use program showed that Temsirolimus even after previous therapy including Sunitinib and Sorafenib may induce stable disease for up to 35 weeks. We neither saw any complete nor partial

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Results of 4 years of pretreatment screening of IVS14 þ 1G ! A mutation DPD-deficiency in patients planned to receive 5-FU containing therapy M. Grundbichler, M. Stöcher, B. Mlineritsch, M. Moik, R. Greil 3rd Medical Department, Paracelsus Private Medical University Salzburg, Salzburg, Austria

Background. 5-FU induced toxicity is closely linked to the function of Dihydropyrimidine dehydrogenase (DPD). This catabolic rate limiting key enzyme is responsible for the elimination of more than 80% of clinically administered 5-FU. Therefore deficiency of DPD may lead to dramatically increased levels of 5-FU. DPD-deficiency is related with approximately 30–40% of grade 3–4 toxicity to 5-FU, typically severe diarrhea, mucositis and neutropenia. The most commonly observed functional alteration of the encoding DPYD gene is the IVS14 þ 1 G ! A mutation responsible for about 50% of all DPDdeficiencies. This mutation results in a complete loss of DPD activity in the affected allele, due to skipping of the whole exon 14. The relatively high prevalence of 0.6–1% in the general Caucasian population raises the question if routine screening of DPD status for patients planed to receive 5-FU containing treatment should be performed. Aim. The aim of our report is to analyze the prevalence of IVS14 þ 1G ! A mutation in cancer patients planned to be treated with 5-FU containing drugs. Methods. DPD-analyses of 684 cancer patients (mainly breast and colorectal cancer) planned to receive 5-FU containing drugs have been performed in our laboratory in the last 4 years using Real-time PCR-FRET technique. Statistical analyses were done by means of SPSS software. Results. We discovered the IVS14 þ 1G ! A mutation in 4 patients representing 0.58% of all tested patients. All 4 patients had a heterozygote mutation. Our findings are in agreement with previous studies reporting an allelic frequency of 0.6–1% in the general Caucasian population. The relatively high allelic frequency of IVS14 þ 1G ! A imposes that prescreening of DPD-deficiency should be taken into account for all patients planned to receive 5FU containing therapy in order to prevent severe FU-related toxicity. memo Suppl 1/08

Abstracts

A48 VTD (Velcade, Thalidomide, Dexamethason) represents an active induction regimen for patients with multiple myeloma J. Drach1 , V. Odelga1 , J. Ackermann1 , V. Sagaster1, H. Kaufmann1 , N. Worel2 , W. Rabitsch3 , P. Kalhs3 , C. Zielinski1

Toxicity of VTD was mild (Grade 1–2 gastrointestinal side effects and peripheral neuropathy; one episode of deep vein thrombosis). Updated results will be presented at the meeting. Conclusions. Induction treatment with VTD results in rapid tumor mass reduction and a high remission rate (83%) in MM pts even with poor prognostic features. Stem cell collection was not compromised after VTD suggesting that VTD is an effective and safe induction treatment prior to autologous transplantation in MM.

1

Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria 2 Department of Blood Group Serology and Transfusion Medicine, Vienna, Austria 3 Department of Medicine I, Bone Marrow Transplant Unit, Vienna, Austria

Background. VTD was reported to be an active salvage regimen in patients with relapsed=refractory multiple myeloma (MM). Since initial results with VTD as frontline therapy were also promising, we used VTD as induction treatment prior to autologous stem cell transplantation in MM patients (pts), particularly in patients with poor prognostic features and=or high tumor burden. Methods. Bortezomib (Velcade) was administered at 1.3 mg=m2 on days 1, 4, 8, and 11; thalidomide was given at a daily dose of 100 mg; dexamethasone (20 mg orally) was given on days 1, 2, 4, 5, 8, 9, 11, and 12. Four to six cycles were scheduled every 3 weeks. Concomitant treatment included prophylaxis against deep vein thrombosis (low dose aspirin, 100 mg daily) and herpes zoster reactivation. Results. We here report our experience with 12 pts (7 males, 5 females; median age 50 years, range, 36–67 years) with newly diagnosed MM (3 pts had failed prior VAD or thal=dex) treated with VTD. Patients had a high tumor mass at presentation (for example, pt 1: BenceJones kappa MM with 95% plasma cell infiltration, serum free-kappa light-chains 4000 mg=l; pt 2: IgG-kappa MM with serum IgG >9000 mg=dl, bulky plasmacytomas in the iliac bones; pt 3: IgA-lambda MM with 70% plasma cells in the bone marrow, IgA 4500 mg=dl, plasmacytoma in the os sacrum >10 cm in diameter) and=or cytogenetic abnormalities associated with high-risk disease (deletion of chromosome 13q in 5 pts; amplification of 1q21 (CKS1B) in 4 pts; translocation t(4;14) in 1 pt). VTD resulted in a rapid response already after 1 cycle in 10 of the 12 pts (83%), 7 pts (58%) achieved a complete response (CR)=near CR, and 3 pts had a partial response (including one very good partial response). Only one pt experienced disease progression. Rapid tumor mass reduction was not associated with signs of tumor lysis, and two pts had a significant improvement in renal function (reversal from dialysis in one pt; serum creatinine down from 2.4 to 1.3 mg=dl). 5 pts have already completed G-CSF primed peripheral stem cell collection (2.4–7.9 CD34þ cells=kg body weight) and high-dose melphalan (MEL200) plus autologous stem cell transplantation (all 4 evaluable pts achieved a CR after completion of high-dose therapy). memo Suppl 1/08

A49 A cellular proteome map of human multiple myeloma J. Drach1 , A. Slany2, V. Sagaster1, N. Gundacker2, V. Haudek2 , V. Odelga1 , H. Wimmer2, C. Zielinski1 , C. Gerner2 1

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria 2 Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

Background and aims. Molecular profiling identifies proteins characteristically deregulated in malignant diseases. Characteristic biomarkers may be useful to support diagnosis and patient stratification, while the recognition of aberrant cell activities and cell survival strategies may lead to the development of specifically designed pharmacologic strategies. We therefore performed proteomic profiling of primary human multiple myeloma (MM) cells in order to define the impact of protein expression abnormalities in MM. Methods. Plasma cells were isolated from bone marrow of patients with MM or MGUS and forwarded to proteome analysis based on 2D gel electrophoresis in addition to shotgun analysis by nano-LC-MS=MS. Erythrocytes, platelets and plasma as well as quiescent and activated lymphocytes, monocytes, endothelial and dendritic cells from healthy donors were processed in an identical manner for comparative analysis. The resulting data were interpreted with the aid of a home-made SQL database. Results. Among about thousand proteins identified in MM cells, we found aberrant expression of proteins involved in fatty acid beta-oxidation (VLCAD), unfolded protein response=ER-stress (ARMET protein, cytosol aminopeptidase), oxidative stress (ste20=oxidant stress responsive kinase 1), interferon response (MX1), iron uptake (transferrin receptor=CD71), DNA modification (transforming protein ERG, methyltransferase-like protein 7A), apoptosis and survival (apoptosis-inducing factor 1, hsp75), protein synthesis (ribosome-binding protein, Unc-13 D), cell adhesion (CD9=tetraspanin-29, LYRIC=metastatic adhesion protein), signaling (sts-1) and cell-cell interaction (Cystatin F, basigin=collagenase stim-

25

Abstracts

ulatory factor, stem cell growth factor, small inducible cytokine B7, PD-ECGF=Gliostatin). Conclusions. The presently applied proteome analysis strategy, based on the systematic investigation of purified primary human cells, allowed us to find characteristic alterations in MM cells. Several proteins directly relate to known aberrant cell activities such as elevated protein synthesis and secretion resulting in ER-stress, which makes the cells sensitive to proteasome inhibitor treatment. Work is in progress to use quantitative assessment of such proteins for patient stratification, identification of response predictors, and biomarkers for the distinction of MM and MGUS.

A50 How often should prognostic scores in MDS be dynamically re-evaluated? H. Tüchler2, A. Makrai1;2 , T. Nösslinger1;2, E. Pittermann1;2 , M. Pfeilstöcker1;2 1 2

Hanusch-Hospital Vienna, Vienna, Austria LBI for Haematology and Leukemia Research, Vienna, Austria

Background. Standard prognostic scoring systems in MDS are applied at diagnosis only. As Malcovati et al. showed in the development of the WPSS, patient’s characteristics constituting scores, change considerably over time. Their proposal, the WPSS, is intended to be dynamically re-evaluated. Since the WPSS is partly based on important but rather subjective aspects (transfusion dependency), the question, if already established scoring systems like e.g. the IPSS would equally qualify for dynamical re-evaluation is still of interest. As a first step we

26

examined several well known scores regarding their predictive value over time. Methods. The study is based on data of a series of 243 primary MDS patients treated with supportive care only. Median survival was 31 mo and the median follow up 34 mo. The median age was 72 years. One hundred and twenty-four patients (51% median survival 29.5 mo) were male and 119 (49%, survival 31 mo) female. According to the FAB classification the distribution and median survival were as follows RA 74 pts (30.5%), 68 mo; RARS 27 pts (11.1%), 65 mo; RAEB 55 pts (22.6%) 14 mo; CMML 62 pts (25.5%), 25 mo; RAEBT 25 pts (10.3%), 9 mo. For these patients the values of the following scores were available: IPSS, Pi-Score, Lille, Duesseldorf, Sanz, Bournemouth, Lausanne-Bournemouth, c-IPSS. Survival time was split in two periods with different cutpoints (6, 9, 12, 18, 24, 30, 36, 42 months) and effect parameters, based in Cox-proportional-hazards-models were estimated. Results. All scores showed the highest predictive value when prediction was limited to the first 9 months; only the Duesseldorf-score had a higher coefficient at 6 months (b ¼ 1.89). The nine-months-coefficients were as follows: IPSS (b ¼ 95), c-IPSS (b ¼ 0.73), Pi-Score (b ¼ 73), Lille-score (b ¼ 1.50), Duesseldorf-score (b ¼ 1.60), Sanzscore (b ¼ 1.22), Bournemouth-score (b ¼ 1.21), Lausanne-Bournemouth-score (b ¼ 1.65); all of them significant with p < 0.01. The estimates for the one year period were a little, but not substantially lower. The c-IPSS and the Pi-score exhibited little change in their estimates over time. For periods above three years the IPSS, the Lausanne-Bournemouth-score and the Bournemouth-score showed no correct risk group discrimination regarding overall survival. Conclusions. All examined scoring systems could gain predictive power if dynamically re-evaluated. As a starting point re-evaluation on a yearly basis should be considered. For cytogenetical characteristics there seems to be little loss, if evaluated less frequently.

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Author index

Author index Aschauer G. 17 Auberger J. 4 Bartsch R. 6 Beck-Mannagetta J. 3 Benold U. 10 Bernkopf M. 8 Clausen J. 21 Denk D. 19 Drach J. 25 Feik E. 14 Gleixner K. V. 2 Gostner J. M. 2 Gruber M. 13 Gru¨nberger B. 1 Grundbichler M. 24

Hadzijusufovic E. 10 Hofmann G. 4, 5 Hoschek S. 9 Huber M. 21 Kern J. 23 Kranewitter W. 8 Kro¨mer E. 7 Kropshofer G. 14 Maizner E. 18 Makrai A. 16 Mlineritsch B. 22 Moik M. 15 Moser K. 3 Muehlmann G. 16

Ruckser R. 12 Schreder M. 20 Simanek R. 23 Sovinz P. 9 Stauder R. 19 Steger G. G. 6 Strecker K. 15 Tinhofer I. 17 Troch M. 11 ¨ chler H. 26 Tu Untergasser G. 5 Voskova D. 11

Obkircher M. 18 Olivier A. 20

Willenbacher E. 1

Petru E. 7

Zach O. 12

FACHKURZINFORMATION BEZEICHNUNG DES ARZNEIMITTELS: Aromasin+ 25 mg – Tabletten. ZUSAMMENSETZUNG: 1 Tablette entha¨lt 25 mg Exemestan. LISTE DER SONSTIGEN BESTANDTEILE: Tablettenkern: Siliciumdioxid-Hydrat, Crospovidon, Hypromellose, Magnesiumstearat, Mannitol, mikrokristalline Cellulose, Natriumsta¨rkeglykolat (A), Polysorbat 80. Zuckeru¨berzug: Hypromellose, Polyvinylalkohol, Simethicon, Macrogol 6000, Saccharose, leichtes basisches Magnesiumcarbonat, Titandioxid (E 171), Methyl-p-hydroxybenzoat (E 218), Cetylesterwachs, Talkum, Carnaubawachs. Drucktinte: Ethylalkohol, Schellack, Eisenoxid schwarz ¨ strogenrezeptor-positivem invasivem Mammakarzinom im ¨ r die adjuvante Behandlung bei Frauen in der Postmenopause mit O (E 172) und Titandioxid (E 171). ANWENDUNGSGEBIETE: Aromasin ist angezeigt fu ¨ber 2–3 Jahre. Aromasin ist angezeigt fu ¨ r die Behandlung des fortgeschrittenen Mammakarzinoms bei Frauen in natu ¨ rlicher oder induzierter Anfangsstadium nach einer initialen adjuvanten Tamoxifen Behandlung u ¨ strogenrezeptorstatus ist die Wirksamkeit nicht belegt. GEGENANZEIGEN: Aromasin ist kontraindiziert Postmenopause mit einer Progression nach Antio¨strogenbehandlung. Bei Patientinnen mit einem negativen O ¨ berempfindlichkeit gegenu ¨ ber dem Wirkstoff oder einem der Hilfsstoffe, bei Frauen in der Pra¨menopause, bei schwangeren oder stillenden Frauen. PHARMAKOTHERbei Patientinnen mit einer bekannten U APEUTISCHE GRUPPE: Steroidaler Aromatasehemmer; Antineoplastischer Wirkstoff. ATC-Code: L02BG06. NAME DES PHARMAZEUTISCHEN UNTERNEHMERS: Pfizer Corporation Austria Ges.m.b.H., Wien. ¨r die Anwendung, STAND DER INFORMATION: September 2007. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: NR, apothekenpflichtig. Informationen zu Warnhinweisen und Vorsichtsmaßnahmen fu Wechselwirkungen mit anderen Mitteln, Schwangerschaft und Stillzeit und Nebenwirkungen sind der Austria-Codex-Fachinformation zu entnehmen. BEZEICHNUNG DES ARZNEIMITTELS: Avastin+ 25 mg=ml Konzentrat zur Herstellung einer Infusionslo¨sung. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG: Bevacizumab 25 mg=ml. Jede Durchstechflasche entha¨lt 100 mg Bevacizumab in 4 ml bzw. 400 mg in 16 ml. Bevacizumab ist ein rekombinanter humanisierter monoklonaler Antiko¨rper, der mittels DNA-Technologie aus Ovarialzellen des chinesischen Hamsters (CHO-Zellen) gewonnen wird. ANWENDUNGSGEBIETE: Avastin (Bevacizumab) wird in Kombination mit einer Chemotherapie auf Fluoropyrimidin-Basis zur Behandlung von Patienten mit metastasiertem Kolon- oder Rektumkarzinom angewendet. Avastin wird in Kombination mit Paclitaxel zur First-Line-Behandlung von Patienten mit metastasiertem Mammakarzinom angewendet. Avastin wird zusa¨tzlich zu einer Platin-haltigen Chemotherapie zur First-Line-Behandlung von Patienten mit inoperablem fortgeschrittenem, metastasiertem oder rezidivierendem nicht-kleinzelligem Bronchialkarzinom, außer bei vorwiegender Plattenepithel-Histologie, angewendet. Avastin wird in Kombination mit Interferon alfa-2a zur First-Line-Behandlung von Patienten mit fortgeschrittenem und=oder metastasiertem Nierenzellk¨ berempfindlichkeit gegen den arzneilich wirksamen Bestandteil oder einen der sonstigen Bestandteile. – U ¨ berempfindlichkeit gegen CHO-Zellprodukte oder andere arzinom angewendet. GEGENANZEIGEN: – U rekombinante humane oder humanisierte Antiko¨rper. – Schwangerschaft (siehe vero¨ffentlichte Fachinformation Abschnitt ,,Schwangerschaft und Stillzeit‘‘). – Avastin ist kontraindiziert bei Patienten mit ¨ ¨ unbehandelten ZNS-Metastasen (siehe veroffentlichte Fachinformation Abschnitte ,,Besondere Warnhinweise und Vorsichtsmaßnahmen fur die Anwendung‘‘ und ,,Nebenwirkungen‘‘). LISTE DER SONSTIGEN ¨ r Injektionszwecke. INHABER DER ZULASSUNG: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 BESTANDTEILE:
,
-Trehalose 2H2O, Natriumphosphat, Polysorbat 20, Wasser fu 1TW, Vereinigtes Ko¨nigreich. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: rezept- und apothekenpflichtig, wiederholte Abgabe verboten. PHARMAKOTHERAPEUTISCHE GRUPPE: Antineoplastische ¨r die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige WechselwirSubstanzen, monoklonale Antiko¨rper. ATC-Code: L01X C07. Besondere Warnhinweise und Vorsichtsmaßnahmen fu ¨ ffentlichten Fachinformation zu entnehmen. kungen sowie Nebenwirkungen sind der vero BEZEICHNUNG DES ARZNEIMITTELS: Erypo+ 40.000 I.E.=ml Fertigspritzen. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG: 40.000 Internationale Einheiten (I.E.) oder 336,0 mg Epoetin alfa pro ml. 1 Fertigspritze zu 1 ml entha¨lt 40.000 I.E. oder 336,0 mg Epoetin alfa. Epoetin alfa wird mittels rekombinanter DNA-Technologie aus Ovarzellen des chinesischen Hamsters hergestellt. WIRKSTOFFGRUPPE: B03XA01. ¨ r Injektionszwecke. ANWENDUNGSGEBIETE: Behandlung einer HILFSSTOFFE: Natriumdihydrogenphosphat-Dihydrat, Natriummonohydrogenphosphat-Dihydrat, Natriumchlorid, Polysorbat 80, Glycin, Wasser fu Ana¨mie und Reduktion des Transfusionsbedarfs bei Erwachsenen mit soliden Tumoren, malignen Lymphomen oder multiplem Myelom, die eine Chemotherapie erhalten und bei denen das Risiko, eine Transfusion zu beno¨tigen aufgrund des Allgemeinzustandes (beispielsweise kardiovaskula¨rer Status, vorbestehende Ana¨mie bei Beginn der Chemotherapie) besteht. ERYPO+ kann zur Steigerung der autologen Blutgewinnung bei ¨ ber dem Risiko thromboembolischer Patienten angewendet werden, die an einem Spendeprogramm zur Vermeidung von Fremdblutkonserven teilnehmen. Die Anwendung in dieser Indikation muss gegenu Ereignisse abgewogen werden. Die Behandlung sollte nur bei Patienten mit mittelschwerer Ana¨mie (Hb 10–13 g=dl [6,2–8,1 mmol=l], kein Eisenmangel) durchgefu¨hrt werden, falls blutsparende Maßnahmen nicht verfu¨gbar oder unzureichend sind, bei geplanten gro¨ßeren operativen Eingriffen, die einen großen Blutvolumenersatz fordern (4 oder mehr Einheiten Blut bei Frauen oder 5 oder mehr Einheiten bei Ma¨nnern). Zur Reduktion von Fremdblut kann ERYPO+ vor einem großen orthopa¨dischen Eingriff bei Erwachsenen ohne Eisenmangel angewendet werden, bei denen ein hohes Risiko von Transfusionskomplikationen zu erwarten ist. Es sollte nur bei Patienten mit mittelschwerer Ana¨mie (z.B. Hb 10–13 g=dl) und einem erwarteten Blutverlust von 900–1800 ml angewendet werden, die nicht an einem autologen Blutspendeprogramm teilnehmen ko¨nnen. Gutes Blutmanagement sollte immer im perichirurgischen Bereich zur Anwendung kommen. GEGENANZEIGEN: Patienten, die auf Grund einer Behandlung mit Erythropoietinen eine reine ¨rfen weder ERYPO+ noch andere Erythropoietine erhalten [siehe Abschnitt Warnhinweise – reine Erythrozytenaplasie Erythrozytenaplasie (Erythroblastopenie)=Pure Red Cell Aplasie (PRCA) entwickeln, du ¨ berempfindlichkeit ¨ ssen, sind ebenfalls zu beru ¨ cksichtigen. U (Erythroblastopenie)]. Unkontrollierter Bluthochdruck. Alle Gegenanzeigen, die bei einem autologen Blutspendeprogramm beachtet werden mu ¨ ber dem arzneilich wirksamen Bestandteil oder einem der Hilfsstoffe. Die Anwendung von Epoetin alfa ist bei Patienten, die fu ¨ r einen elektiven orthopa¨dischen Eingriff vorgesehen sind und die nicht an einem gegenu autologen Blutspendeprogramm teilnehmen ko¨nnen, kontraindiziert, wenn schwere koronare Herzkrankheit, periphere arterielle Erkrankung, vaskula¨re Erkrankung der Karotiden oder cerebrovaskula¨re Erkrankung ¨ hrt werden kann. vorliegen, einschließlich Patienten, die vor kurzem einen Herzinfarkt oder ein cerebrovaskula¨res Ereignis erlitten haben. Patienten, bei denen keine ada¨quate Thromboseprophylaxe durchgefu ¨r die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen, Nebenwirkungen entnehmen Sie bitte der Weitere Angaben zu Warnhinweisen und Vorsichtsmaßnahmen fu ¨ ffentlichten Fachinformation. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: NR, Rp, apothekenpflichtig. ZULASSUNGSINHABER: Janssen-Cilag Pharma, 1232 Wien. Stand: 11.05.2007. vero

memo Suppl 1/08

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BEZEICHNUNG DES ARZNEIMITTELS: Herceptin 150 mg Pulver zur Herstellung eines Infusionslo¨sungskonzentrats. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG: 1 Durchstechflasche entha¨lt 150 mg Trastuzumab, einen humanisierten IgG1 monoklonalen Antiko¨rper, der aus einer Sa¨ugetierzelllinie (Ovarialzellen des chinesischen Hamsters, CHO) im kontinuierlichen Durchflussverfahren gewonnen wird. Die rekonstituierte Lo¨sung mit Herceptin entha¨lt 21 mg=ml Trastuzumab. ANWENDUNGSGEBIETE: Metastasierter Brustkrebs (MBC): Herceptin ist zur Behandlung von Patienten mit metastasiertem Brustkrebs ¨berexprimieren: a) als Monotherapie zur Behandlung von Patienten, die mindestens zwei Chemotherapieregime gegen ihre metastasierte Erkrankung erhalten haben. Die indiziert, deren Tumoren HER2 u ¨ r die Patienten nicht geeignet. Bei Patienten mit positivem Hormonrezeptor-Status vorangegangene Chemotherapie muss mindestens ein Anthrazyklin und ein Taxan enthalten haben, außer diese Behandlung ist fu ¨ r die Patienten nicht geeignet. b) in Kombination mit Paclitaxel zur Behandlung von Patienten, die noch keine Chemotherapie muss eine Hormonbehandlung erfolglos gewesen sein, außer diese Behandlung ist fu ¨ r die ein Anthrazyklin ungeeignet ist. c) in Kombination mit Docetaxel zur Behandlung von Patienten, die noch keine Chemotherapie gegen ihre gegen ihre metastasierte Erkrankung erhalten haben und fu metastasierte Erkrankung erhalten haben. d) in Kombination mit einem Aromatasehemmer zur Behandlung von postmenopausalen Patienten mit Hormonrezeptor-positivem metastasiertem Brustkrebs, die noch ¨hstadium nach einer Operation, Chemotherapie nicht mit Trastuzumab behandelt wurden. Brustkrebs im Fru¨hstadium (EBC): Herceptin ist zur Behandlung von Patienten mit HER2-positivem Brustkrebs im Fru (neoadjuvant oder adjuvant) und Strahlentherapie (soweit zutreffend) indiziert (siehe vero¨ffentlichte Fachinformation Abschnitt ,,Pharmakodynamische Eigenschaften‘‘). Herceptin ist nur bei Patienten anzuwenden, ¨ berexpression oder eine HER2-Genamplifikation aufweisen, die durch eine genaue und validierte Untersuchung ermittelt wurde (siehe vero¨ffentlichte Fachinformation Abschnitt deren Tumore entweder eine HER2-U ¨ berempfindlichkeit gegen Trastuzumab, ,,Besondere Warnhinweise und Vorsichtsmaßnahmen fu¨r die Anwendung‘‘ und ,,Pharmakodynamische Eigenschaften‘‘). GEGENANZEIGEN: – Patienten mit bekannter U ¨tzende Sauerstofftherapie Mausproteine oder einen der sonstigen Bestandteile. – Patienten mit schwerer Ruhedyspnoe aufgrund der Komplikationen der fortgeschrittenen Krebserkrankung oder die eine unterstu ¨ R DIE ANWENDUNG: Vorsicht ist bei Patienten mit syptomatischer Herzinsuffizienz, Hypertonie in der Anamnese oder beno¨tigen. BESONDERE WARNHINWEISE UND VORSICHTSMAßNAHMEN FU ¨ hstadium bei Patienten mit einer linksventrikula¨ren Auswurffraktion (LVEF) von 55% oder weniger. LISTE DER SONSTIGEN nachgewiesener koronarer Herzkrankheit geboten, und bei Brustkrebs im Fru BESTANDTEILE: L-Histidinhydrochlorid, L-Histidin,
,
-Trehalosedihydrat, Polysorbat 20. INHABER DER ZULASSUNG: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Vereinigtes Ko¨nigreich. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: rezept- und apothekenpflichtig, wiederholte Abgabe verboten. PHARMAKOTHERAPEUTISCHE GRUPPE: Antineoplastische Sub¨r die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen sowie stanzen, ATC-Code L01XC03. Weitere besondere Warnhinweise und Vorsichtsmaßnahmen fu ¨ ffentlichten Fachinformation zu entnehmen. Nebenwirkungen sind der vero BEZEICHNUNG DES ARZNEIMITTELS: MabThera 100 mg Konzentrat zur Herstellung einer Infusionslo¨sung. MabThera 500 mg Konzentrat zur Herstellung einer Infusionslo¨sung. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG: Eine Durchstechflasche zum einmaligen Gebrauch entha¨lt 100 mg Rituximab in 10 ml. Eine Durchstechflasche zum einmaligen Gebrauch entha¨lt 500 mg Rituximab in 50 ml. Die Lo¨sung entha¨lt 10 mg=ml Rituximab. Rituximab ist ein gentechnisch hergestellter monoklonaler chima¨rer Antiko¨rper (Maus=Mensch), ein glykosyliertes Immunglobulin. Seine konstanten Bereiche bestehen aus humanem IgG1, die variablen Bereiche aus murinen leichten und schweren Kettensequenzen. Der Antiko¨rper wird in einer Zellkultur aus Sa¨ugetierzellen (Ovarialzellen des chinesischen Hamsters) hergestellt und durch Affinita¨ts- und Ionenaustauscher-Chromatographie gereinigt, einschließlich spezifischer Schritte zur Virusinaktivierung und -entfernung. ANWENDUNGSGEBIETE: Non-Hodgkin-Lymphom: MabThera ist in ¨ r die Erstbehandlung von Patienten mit follikula¨rem Lymphom im Stadium III–IV angezeigt. MabThera ist fu ¨ r die Erhaltungstherapie bei Patienten mit rezidivierKombination mit einer Chemotherapie fu ¨ r die endem=refrakta¨rem follikula¨rem Lymphom angezeigt, die auf eine Induktionstherapie, bestehend aus einer Chemotherapie mit oder ohne MabThera, angesprochen haben. MabThera ist als Monotherapie fu ¨ ckfall haben. MabThera ist Behandlung von Patienten mit follikula¨rem Lymphom im Stadium III–IV angezeigt, die gegen eine Chemotherapie resistent sind oder nach einer solchen einen zweiten oder neuerlichen Ru ¨ r die Behandlung von Patienten mit CD20-positivem, großzellig diffusem B-Zell-Non-Hodgkin-Lymphom in Kombination mit einer CHOP-Chemotherapie angezeigt. Fu ¨r weitere Informationen siehe vero¨ffentlichte fu ¨ r die Behandlung erwachsener Patienten mit schwerer aktiver Fachinformation Abschnitt ,,Pharmakodynamische Eigenschaften‘‘. Rheumatoide Arthritis: MabThera in Kombination mit Methotrexat ist fu ¨gend auf andere krankheitsmodifizierende Antirheumatika (,,disease modifying antirheumatic drugs‘‘ [DMARDs]) einschließlich einer oder mehrerer Therapien mit rheumatoider Arthritis angezeigt, die ungenu ¨ berempfindlichkeit gegen den Wirkstoff oder einen der Tumornekrosefaktor(TNF)-Hemmern angesprochen oder diese nicht vertragen haben. GEGENANZEIGEN: Gegenanzeigen beim Non-Hodgkin-Lymphom: U ¨ berempfindlichkeit gegen den Wirkstoff oder einen der sonstigen Bestandteile dieses Arzneimittels sonstigen Bestandteile dieses Arzneimittels oder gegen Maus-Proteine. Gegenanzeigen bei rheumatoider Arthritis: – U ¨r die Anwendung‘‘). – Schwere Herzinsuffizienz oder gegen Maus-Proteine. – Aktive, schwere Infektionen (siehe vero¨ffentlichte Fachinformation Abschnitt ,,Besondere Warnhinweise und Vorsichtsmaßnahmen fu ¨ r Injektionszwecke. (NYHA Klasse IV) oder schwere, unkontrollierte Herzerkrankungen. LISTE DER SONSTIGEN BESTANDTEILE: Natriumcitrat, Polysorbat 80, Natriumchlorid, Natriumhydroxid, Salzsa¨ure, Wasser fu ¨ INHABER DER ZULASSUNG: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Vereinigtes Konigreich. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: rezept- und ¨r die apothekenpflichtig, wiederholte Abgabe verboten. PHARMAKOTHERAPEUTISCHE GRUPPE: Antineoplastische Substanzen, ATC-Code: L01X C02. Besondere Warnhinweise und Vorsichtsmaßnahmen fu ¨ ffentlichten Fachinformation zu entnehmen. Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen sowie Nebenwirkungen sind der vero BEZEICHNUNG DES ARZNEIMITTELS: NeoRecormon 10 000 I.E. Injektionslo¨sung in Fertigspritze. Eine Fertigspritze mit 0,6 ml Injektionslo¨sung entha¨lt 10 000 Internationale Einheiten (I.E.) entsprechend 83 ¨ sung in Fertigspritze. Eine Fertigspritze mit Mikrogramm Epoetin beta (rekombinantes humanes Erythropoietin). Ein ml Injektionslo¨sung entha¨lt 16.667 I.E. Epoetin beta. NeoRecormon 20 000 I.E. Injektionslo 0,6 ml Injektionslo¨sung entha¨lt 20 000 Internationale Einheiten (I.E.) entsprechend 166 mg Epoetin beta (rekombinantes humanes Erythropoietin). Ein ml Injektionslo¨sung entha¨lt 33.333 I.E. Epoetin beta. ¨ sung in Fertigspritze. Eine Fertigspritze mit 0,6 ml Injektionslo¨sung entha¨lt 30.000 Internationale Einheiten (I.E.) entsprechend 250 mg Epoetin beta (rekombinantes humanes NeoRecormon 30 000 IE Injektionslo Erythropoietin). Ein ml Injektionslo¨sung entha¨lt 50.000 I.E. Epoetin beta.  hergestellt aus Ovarialzellen des Chinesischen Hamsters (CHO) durch rekombinante DNA-Technologie. SONSTIGE BESTANDTEILE: Phenylalanin (bis zu 0,3 mg pro Fertigspritze), Natrium (weniger als 1 mmol pro Fertigspritze). ANWENDUNGSGEBIETE: – Behandlung der Ana¨mie infolge chronischer Nierenerkrankung (renale Ana¨mie) bei Dialysepatienten. – Behandlung der symptomatischen renalen Ana¨mie bei noch nicht dialysierten Patienten. – Vorbeugung einer Fru¨hgeborenenana¨mie bei Kindern mit einem Geburtsgewicht zwischen 750 und 1500 g, die vor der 34. Schwangerschaftswoche geboren wurden. – Behandlung der symptomatischen Ana¨mie bei erwachsenen Patienten mit nicht-myeloischen malignen Erkrankungen, die eine Chemotherapie ¨ r thromboembolische erhalten. – Steigerung der Menge an Eigenblut bei Patienten in einem Eigenblutspendeprogramm. Die Anwendung in dieser Indikation muss gegenu¨ber dem berichteten erho¨hten Risiko fu ¨ gbar oder Ereignisse abgewogen werden. Es sollten nur Patienten mit ma¨ßiggradiger Ana¨mie (Hb 10–13 g=dl [6,21–8,07 mmol=l], kein Eisenmangel) behandelt werden, falls blutsparende Verfahren nicht verfu unzureichend sind, sofern der geplante gro¨ßere chirurgische Eingriff große Mengen an Blut erfordert (4 oder mehr Blutkonserven bei Frauen bzw. 5 oder mehr Blutkonserven bei Ma¨nnern). DOSIERUNG, ART UND DAUER DER ANWENDUNG: Behandlung der Ana¨mie bei Patienten mit chronischer Nierenerkrankung, Erhaltungsphase: Bei subkutaner Anwendung kann die Wochendosis als einmalige Injektion gegeben werden oder auf drei bis sieben Einzeldosen pro Woche verteilt werden. Patienten, die in der einmal wo¨chentlichen Anwendung stabil sind, ko¨nnen auf eine Anwendung alle zwei Wochen umgestellt werden. In diesem Fall ko¨nnen Dosiserho¨hungen no¨tig werden. Behandlung der symptomatischen Ana¨mie bei Krebspatienten: Die Lo¨sung wird subkutan angewendet; die Wochendosis kann als einmalige Injektion pro Woche gegeben werden oder in Teildosen drei- bis siebenmal pro Woche. Die empfohlene Initialdosis betra¨gt 30.000 I.E. pro Woche (entsprechend ca. 450 I.E.=kg KG=Woche, berechnet auf einen Patienten mit durchschnittlichem ¨ berempfindlichkeit gegen den Wirkstoff oder einen der Gewicht). Die Dosierungen in den hier nicht genannten Anwendungsgebieten sind der vero¨ffentlichten Fachinformation zu entnehmen. GEGENANZEIGEN: U sonstigen Bestandteile. Schlecht kontrollierte Hypertonie. Beim Anwendungsgebiet ,,Steigerung der Menge an Eigenblut‘‘: Herzinfarkt oder Schlaganfall innerhalb eines Monats vor der Behandlung, instabile Angina pectoris, erho¨htes Risiko tiefer Venenthrombosen, wie z.B. bekannte veno¨se Thromboembolien. LISTE DER SONSTIGEN BESTANDTEILE: Harnstoff, Natriumchlorid, Polysorbat 20, Natriumdihydrogenphosphat, ¨ r Injektionszwecke. INHABER DER ZULASSUNG: Roche Registration Limited, 6 Dinatriumhydrogenphosphat, Calciumchlorid, Glycin, L-Leucin, L-Isoleucin, L-Threonin, L-Glutaminsa¨ure, L-Phenylalanin, Wasser fu Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Vereinigtes Ko¨nigreich. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: rezept- und apothekenpflichtig, wiederholte Abgabe verboten. PHARMA¨r die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige KOTHERAPEUTISCHE GRUPPE: Antiana¨mika, ATC-Code: B03XA. Besondere Warnhinweise und Vorsichtsmaßnahmen fu Wechselwirkungen sowie Nebenwirkungen und weitere Dosierungshinweise sind der vero¨ffentlichten Fachinformation zu entnehmen. BEZEICHNUNG DES ARZNEIMITTELS: Tarceva+ 100 mg Filmtabletten=Tarceva+ 150 mg Filmtabletten. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG: Tarceva 100 mg: Eine Filmtablette entha¨lt 100 mg Erlotinib (als Erlotinibhydrochlorid). Tarceva 150 mg: Eine Filmtablette entha¨lt 150 mg Erlotinib (als Erlotinibhydrochlorid). ANWENDUNGSGEBIETE: Nicht-kleinzelliges Lungenkarzinom (NSCLC): Tarceva ist zur Behandlung von Patienten mit lokal fortgeschrittenem oder metastasiertem nicht-kleinzelligen Lungenkarzinom angezeigt, bei denen mindestens eine vorausgegangene Chemotherapie versagt hat. Beim Verschreiben ¨ berlebenszeit stehen, beru ¨ berlebensvorteil noch andere ¨cksichtigt werden. Bei Patienten mit EGFR-negativen Tumoren konnten weder ein U von Tarceva sollten Faktoren, die im Zusammenhang mit einer verla¨ngerten U klinisch relevante Wirkungen durch die Behandlung gezeigt werden (siehe vero¨ffentlichte Fachinformation Abschnitt ,,Pharmakodynamische Eigenschaften‘‘). Pankreaskarzinom: Tarceva in Kombination mit Gemcitabin ¨ berlebenszeit stehen, beru ¨cksichtigt ist zur Behandlung von Patienten mit metastasiertem Pankreaskarzinom angezeigt. Beim Verschreiben von Tarceva sollten Faktoren, die im Zusammenhang mit einer verla¨ngerten U werden (siehe vero¨ffentlichte Fachinformation Abschnitte ,,Dosierung, Art und Dauer der Anwendung‘‘ und ,,Pharmakodynamische Eigenschaften‘‘). Bei Patienten mit lokal fortgeschrittenem Pankreaskarzinom konnte ¨ berlebensvorteil nicht gezeigt werden. GEGENANZEIGEN: Schwere U ¨ berempfindlichkeit gegen Erlotinib oder einen der sonstigen Bestandteile. LISTE DER SONSTIGEN BESTANDTEILE: Tablettenkern: Lactoseein U Monohydrat, Mikrokristalline Cellulose (E 460), Carboxymethylsta¨rke-Natrium (Typ A) (Ph.Eur.), Natriumdodecylsulfat, Magnesiumstearat (Ph.Eur.) (E 470b). Filmu¨berzug: Hyprolose (E 463), Titandioxid (E 171), Macrogol (400), Hypromellose (E 464). Tarceva 100 mg – graue Drucktinte: Schellack (E 904), Eisenoxidhydrat (E 172), Eisen(II,III)-oxid (E 172), Titandioxid (E 171). Tarceva 150 mg – braune Drucktinte: Schellack (E 904), Eisen(III)oxid (E 172). INHABER DER ZULASSUNG: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Vereinigtes Ko¨nigreich. VERSCHREIBUNGSPFLICHT==APOTHEKENPFLICHT: rezept¨ r die und apothekenpflichtig, wiederholte Abgabe verboten. PHARMAKOTHERAPEUTISCHE GRUPPE: Antineoplastisches Mittel, ATC-Code: L01XE03. Besondere Warnhinweise und Vorsichtsmaßnahmen fu ¨ ffentlichten Fachinformation zu entnehmen. Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen sowie Nebenwirkungen sind der vero BEZEICHNUNG DES ARZNEIMITTELS: Velcade+ 3,5 mg Pulver zur Herstellung einer Injektionslo¨sung. ZUSAMMENSETZUNG (arzneilich wirksame Bestandteile nach Art und Menge): Jede Durchstechflasche entha¨lt 3,5 mg Bortezomib (als ein Mannitol-Borester). Nach Zubereitung entha¨lt 1 ml der Injektionslo¨sung 1 mg Bortezomib. SONSTIGE BESTANDTEILE: Mannitol (E 421), Stickstoff. ANWENDUNGSGEBIETE: VELCADE ist ¨ r die Behandlung von progressiven, muliplen Myelom bei Patienten, die mindestens eine vorangegangene Therapie durchlaufen haben und die sich bereits einer Knochenmarktransplantation indiziert als Monotherapie fu ¨ berempfindlich-keit gegen Bortezomib, Bor oder einen der sonstigen Bestandteile. Schwere Leberfunktions¨ r eine Knochenmarktransplantation nicht geeignet sind. GEGENANZEIGEN: U unterzogen haben oder die fu sto¨rung. ATC-CODE: L01XX32. Rezept- und apothekenpflichtig, wiederholte Abgabe verboten. PHARMAZEUTISCHER UNTERNEHMER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg, 30, 2340 Beerse, Belgien. ¨ ¨ ¨ r die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und FUR OSTERREICH: JANSSEN-CILAG Pharma, Pfarrgasse 75, 1232 Wien, Austria. Weitere Angaben zu Warnhinweisen und Vorsichtsmaßnahmen fu sonstige Wechselwirkungen und Nebenwirkungen entnehmen Sie bitte der vero¨ffentlichten Fachinformation. Stand: 5=2007. BEZEICHNUNG DES ARZNEIMITTELS: Xeloda+ 150 mg Filmtabletten=Xeloda+ 500 mg Filmtabletten. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG: 150 mg=500 mg Capecitabin. Sonstiger Bestandteil: 150 mg Filmtabletten: 15,6 mg wasserfreie Lactose. 500 mg Filmtabletten: 52 mg wasserfreie Lactose. ANWENDUNGSGEBIETE: Xeloda ist zur adjuvanten Behandlung von Patienten nach Operation eines Kolonkarzinoms im Stadium III (Dukes Stadium C) indiziert (siehe vero¨ffentlichte Fachinformation Abschnitt ,,Pharmakodynamische Eigenschaften‘‘). Xeloda ist zur Behandlung des metastasierten Kolorektalkarzinoms indiziert (siehe ¨ ffentlichte Fachinformation Abschnitt ,,Pharmakodynamische Eigenschaften‘‘). Xeloda ist in Kombination mit einem Platin-haltigen Anwendungsschema als first-line Therapie des fortgeschrittenen Magenkarzinoms vero ¨ ffentlichte Fachinformation Abschnitt ,,Pharmakodynamische Eigenschaften‘‘). Xeloda ist in Kombination mit Docetaxel (siehe vero¨ffentlichte Fachinformation Abschnitt ,,Pharmakodynamische indiziert (siehe vero ¨ here Behandlung sollte ein Eigenschaften‘‘) zur Behandlung von Patienten mit lokal fortgeschrittenem oder metastasiertem Mammakarzinom nach Versagen einer zytotoxischen Chemotherapie indiziert. Eine fru Anthracyclin enthalten haben. Xeloda ist außerdem als Monotherapie zur Behandlung von Patienten mit lokal fortgeschrittenem oder metastasiertem Mammakarzinom indiziert, bei denen eine Therapie mit Taxanen und  Anthracyclinen versagt hat oder eine weitere Anthracyclinbehandlung nicht angezeigt ist. GEGENANZEIGEN: Schwerwiegende und unerwartete Reaktionen bei Vorbehandlung mit Fluoropyrimidinen ¨ berempfindlichkeit gegen Capecitabin oder einen der sonstigen Bestandteile oder gegen Fluorouracil  bekannter Dihydropyrimidin-Dehydrogenase-Mangel (DPD)  Schwangerschaft und Stillzeit  schwere  U Leukopenie, Neutropenie oder Thrombozytopenie  schwere Beeintra¨chtigung der Leberfunktion  schwere Beeintra¨chtigung der Nierenfunktion (Kreatinin-Clearance > 30 ml=min  gleichzeitige Behandlung mit ¨ r eines der Arzneimittel der Kombinationstherapie Gegenanzeigen vorliegen, darf dieses Arzneimittel nicht angewendet werden. LISTE DER Sorivudin oder dessen chemischen Verwandten, wie z.B. Brivudin. Wenn fu SONSTIGEN BESTANDTEILE: Tablettenkern: wasserfreie Laktose, Croscarmellose-Natrium, Hypromellose, mikrokristalline Cellulose, Magnesiumstearat. Filmu¨berzug: Hypromellose, Titandioxid (E171), Eisenoxidhydrat und Eisen(III)-oxid (E172), Talkum. INHABER DER ZULASSUNG: Roche Registration Limited., 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Vereinigtes Ko¨nigreich. VERSCHREIBUNGSPFLICHT== APOTHEKENPFLICHT: rezept- und apothekenpflichtig, wiederholte Abgabe verboten. Pharmakotherapeutische Gruppe: Zytostatikum (Antimetabolit), ATC-Code: L01BC06. Besondere Warnhinweise und ¨ r die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen sowie Nebenwirkungen sind der vero ¨ ffentlichten Fachinformation zu entnehmen. Vorsichtsmaßnahmen fu

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