Ann Surg Oncol (2010) 17:2370–2377 DOI 10.1245/s10434-010-1039-7
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Peritoneal Carcinomatosis from Gastric Cancer: A Multi-Institutional Study of 159 Patients Treated by Cytoreductive Surgery Combined with Perioperative Intraperitoneal Chemotherapy Olivier Glehen, MD, PhD1, Franc¸ois Noel Gilly, MD, PhD1, Catherine Arvieux, MD, PhD2, Eddy Cotte, MD1, Florent Boutitie3, Baudouin Mansvelt, MD, PhD4, Jean Marc Bereder, MD5, Ge´rard Lorimier, MD6, Franc¸ois Quenet, MD7, Dominique Elias, MD, PhD8 and Association Franc¸aise de Chirurgie 1
Departement de Chirurgie Generale, Thoracique et Endocrinienne, Centre Hospitalier Lyon-Sud, Pierre Be´nite Cedex, France; 2CHU Grenoble, Grenoble Cedex 9, France; 3Hospices Civils de Lyon, Service de Biostatistiques, Lyon, France; 4 Hopital Jolimont, Haine Saint-Paul, Belgium; 5CHU Nice, Nice Cedex 3, France; 6Centre Paul Papin, Angers, France; 7 Centre Val D’Aurelle, Montpellier, France; 8Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, France
ABSTRACT Background. Peritoneal carcinomatosis (PC) from gastric cancer has long been regarded a terminal disease with a short median survival. New locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved and suggest improved survival. Materials and Methods. A retrospective multicentric study was performed in French-speaking centers to evaluate the toxicity and the principal prognostic factors in order to identify the best indications. All patients had cytoreductive surgery and PIC: hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC). Results. The study included 159 patients from 15 institutions between February 1989 and August 2007. The median follow-up was 20.4 months. HIPEC was the PIC used for 150 procedures. Postoperative mortality and grade 3–4 morbidity rates were 6.5 and 27.8%, respectively. By multivariate analysis, the institution had a significant influence on toxicity. The overall median survival was 9.2 months and 1-, 3-, and 5-year survival rates were 43, 18, and 13%, respectively. The only independent prognostic indicator by multivariate
Ó Society of Surgical Oncology 2010 First Received: 27 November 2009; Published Online: 25 March 2010 O. Glehen, MD, PhD e-mail:
[email protected]
analysis was the completeness of cytoreductive surgery. For patients treated by complete cytoreductive surgery, the median survival was 15 months with a 1-, 3-, and 5-year survival rate of 61, 30, and 23%, respectively. Conclusions. The therapeutic approach combining cytoreductive surgery with PIC for patients with gastric carcinomatosis may achieve long-term survival in a selected group of patients (limited and resectable PC). The high mortality rate underlines this necessarily strict selection that should be reserved to experienced institutions involved in the management of PC and gastric surgery.
Peritoneal dissemination from gastric cancers is common and occurs in 5–20% of patients being explored for potentially curative resection.1,2 In the past, carcinomatosis has been regarded as a terminal disease, especially when the primary tumor was gastric, and most oncologists would regard it as a condition only to be palliated. However, recent reports suggest curative treatment options for selected patients with carcinomatosis from digestive cancer.3–7 Over the past 2 decades, novel therapeutic approaches to peritoneal carcinomatosis (PC) have emerged, combining cytoreductive surgery and peritonectomy procedures with perioperative intraperitoneal chemotherapy (PIC), including hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC).8–11 Theoretically, cytoreductive surgery is performed to treat macroscopic disease and PIC to treat
Peritoneal Carcinomatosis from Gastric Cancer
microscopic residual disease aiming to remove disease completely with a single procedure. Many consider it a standard of care for diseases such as pseudomyxoma peritonei, peritoneal mesothelioma, or localized and resectable colorectal carcinomatosis.4,5,7,12–15 A collaborative effort of 25 French-speaking institutions involved in the treatment of peritoneal surface malignancies was performed on a large number of patients with PC from nongynecologic carcinomatosis to evaluate the tolerance and the efficiency of this treatment. In this article, we present the results obtained with this combined approach on patients with gastric carcinomatosis to identify the main prognostic factors based on a population of 159 treated patients. PATIENTS AND METHODS Patient Population A total of 159 patients from 15 institutions were treated by procedures combining cytoreductive surgery and PIC for PC of gastric origin between February 1989 and August 2007, making up the study population. One institution included more than 50 patients, one more than 20, three others included 10, and 10 less than 2. The inclusion criteria were PC of gastric origin confirmed by pathologic examination; HIPEC, EPIC, or both were administered within 7 days of surgery. The exclusion criteria were PIC performed more than 7 days after the surgery and the presence of extra-abdominal metastases. Standardized clinical data on consecutive patients from each of the 15 institutions involved in the management of peritoneal surface malignancies were received and entered into a central database. The same author reviewed all data sheets before their entry into the database in an effort to make this a uniform interpretation of retrospective data. Data Forms A standard data form was created to retrieve information on the status of the patient before undergoing the combined procedure, including age, sex, extent of peritoneal carcinomatosis, and previous treatment with systemic chemotherapy. The extent of PC was assessed intraoperatively. Institutions used two different tools [Gilly’s classification and Sugarbaker’s Peritoneal Cancer Index (PCI)] to assess the extent of PC.16,17 For the descriptive analysis, 4 subgroups of PCI were created: 1–6, 7–12, 13–19, and [19. Information recorded about the combined procedure included the date, the completeness of the cytoreductive surgery, the simultaneous resection of primary tumor or of liver
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metastases, the presence or absence of lymph node metastases, the type of perioperative intraperitoneal chemotherapy (HIPEC or EPIC) and its modalities (drugs used, ‘‘closed’’ or ‘‘open’’ HIPEC, temperatures, duration), and treatment with adjuvant systemic chemotherapy. The assessment of the completeness of the cancer resection (CCR) by cytoreductive surgery was performed by the surgeon at the end of the procedure and classified in 3 categories: CCR-0 indicated no macroscopic residual cancer remained, CCR-1 indicated no residual nodule greater than 2.5 mm, and CCR-2 indicated that the diameter of residual nodules was greater than 2.5 mm. The institutions were classified regarding their length of experience in performing cytoreductive surgery at the time of the procedure (0–3 years, 3–7 years, 7–11 years, and more than 11 years). Another 4 groups were also analyzed regarding the period of the procedure (before 1997, between 1997 and 1999, between 2000 and 2002, between 2003 and 2004, and after 2005). Information was obtained regarding the postoperative course, including postoperative death (within 30 postoperative days) and its cause, major complications (grade 3 and 4 complications according to the National Cancer Institute’s Common Toxicity Criteria), and reoperations. Follow-up data recorded included the date of the most recent follow-up and the status of the patient. Statistical Analysis Influence of patient, disease, and treatment characteristics were related to the risk of postoperative morbidity or mortality events using univariate and multivariate logistic regression models, adjusted by institution. The analysis of long-term mortality censored information after the cutoff date of December 31, 2006, since an active inquiry was performed in all institutions to collect the status (dead/ alive) of the patients at that date. There were 7 patients included after the cutoff date. No patients were lost to follow-up. The analysis of total mortality considered the interval from the first procedure to the date of death, the date of last follow up, or the cut-off date, whichever came first. The analysis of recurrence or death was based on the interval from the first procedure to the date of first recurrence, the date of death, the date of last follow-up, or the cutoff date, whichever came first. When the date of recurrence was unknown in patients who died, the date of death was used instead. Kaplan–Meier survival estimates were calculated and compared between strata with the logrank test. Influence of baseline risk factors on the hazard of death was assessed using a multiple proportional hazard regression model stratified by institution. Stratification was justified by a large heterogeneity of hazards between institutions and by a strong potential confounding effect on other risk factors. In all multivariate analyses, age and PCI were entered as continuous variables. Completeness of
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cytoreduction (four categories) was also entered as continuous when justified by a linear trend across categories. An indicator variable for the HIPEC procedure (yes/no) was forced in the model when an associated covariate (i.e., temperature, heating duration, open/closed abdomen) was significant. Risk factors with a significance degree B 0.10 were retained in the final model. The SAS statistical software (Windows, V9.1; SAS Institute Inc., Cary, NC) was used for all analyses.
O. Glehen et al. TABLE 1 Type of drugs and regimens used for HIPEC and EPIC HIPEC Mitomycin C based Mitomycin 30–50 mg/m2 ± Cisplatin 50– 100 mg/m2 for 60–120 min at 41–42.5°C regimens Oxaliplatin based regimens
Oxaliplatin 360–460 mg/m2 ± irinotecan 100– 200 mg/m2 ± I.V. 5-FU and leucovorin for 30 min at 43°C
EPIC
Abdominal cavity filled at the end of surgery with 1L/m2 of Ringer’s lactate EPIC lasted 5 days (days 1–5)
RESULTS
Drains were clamped 23 h/24 h
Patients Characteristics
Day 1: Mitomycin C 10 mg/m2 and Days 2–5: 5-Fluorouracil 600 mg/m2
There were 76 female patients (48.1%). The mean age was 53.4 years (standard deviation [SD]: 12.8). In the majority of cases the diagnosis of carcinomatosis was an incidental finding at laparoscopy or laparotomy (35%). Primary lesions were well differentiated (20%), moderately differentiated (22.5%), or poorly differentiated (57.5%). Also, 59 patients (37.1%) were previously treated with neoadjuvant or palliative systemic chemotherapy. Treatment The assessment of carcinomatosis extent was performed using Gilly’s classification for 125 patients (79%) and PCI for 95 patients (60%). Gilly stage was 0, 1, or 2 in 75 patients, 3 or 4 in 67 patients. The mean PCI was 9.4 (SD: 7.7). Following best surgical effort at cytoreductive surgery, 89 patients were considered a CCR-0 resection (56.0%), 40 patients were considered a CCR-1 (25.2%), and 30 patients a CCR-2 (18.8%). The cytoreductive surgery was synchronous with the resection of primary in 60 patients (44.1%). A total of 150 (94.3%) were treated with HIPEC, and 12 (7.5%) with EPIC. The drugs and regimens used for this intraperitoneal chemotherapy are reported in Table 1. All HIPEC procedures were performed intraoperatively after cytoreductive surgery, but with variations in exposure techniques (open abdomen in 67 patients [46.5%] and closed abdomen in 77 patients [53.5%]), drugs, duration (30–120 min with a mean duration of 80.1, SD: 19.3 min), intraperitoneal temperatures (40–43°C with a mean intraperitoneal temperature of 42.6 [SD: 1.0°C]), type of perfusate, and flow rates. There were 2 patients who underwent a second combined procedure involving cytoreductive surgery and perioperative surgery. Also, 53 patients (37.6%) received postoperative adjuvant systemic chemotherapy and/or radiotherapy when they demonstrated an objective response to preoperative chemotherapy (if administered) or when they possessed bad prognostic features (CCR-1 or CCR-2, involved lymph nodes or liver metastases).
Postoperative Mortality and Morbidity A total of 10 patients (6.5%) died postoperatively. The causes of death were multiorgan failure (2 patients), septic shock (2 patients), respiratory complications (2 patients), digestive fistula and peritonitis (1 patient), cardiopulmonary embolism (1 patient), cardiac arrhythmia (1 patient), and hematologic toxicity (1 patient). Major complications (grade 3–4 complications) occurred in 38 patients (27.8%). A reoperation was necessary in 14.0% of patients. Digestive fistula occurred in 15.9% of patients. Mean duration of hospitalization was 24.2 (SD: 19) days. By univariate analysis, most factors had no significant influence on postoperative complications: sex, performance status, treatment, treatment with neoadjuvant systemic chemotherapy, and period of the procedure. The impact of the PIC techniques (drugs, drug concentration, temperature, duration) could not be analyzed because of significant variations across centers. The rate of postoperative complications was 44.7% for patients older than 61 years, whereas it was 23.4% for younger patients (P = .010). It was 60.0% when an EPIC was performed, compared with 28.8% when it was not (P = .051). The logistic multiple regression analysis of factors that significantly increased the risk of postoperative morbidity and mortality showed 1 important factor: the institution where the procedure was performed (P \ .0001). Survival The median follow-up was 20.4 months (1st–3rd quartiles: 9.1–46 months). The overall 1-year, 3-year, and 5year survival rates were 43, 18, and 13%, respectively. Disease-free survival rates at 1 and 3 years were 31 and 12%, respectively (Fig. 1). By univariate analysis, the factors that did not have prognostic impact were the tumor differentiation, presence
Peritoneal Carcinomatosis from Gastric Cancer
Survival Probability 1.0
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Overall survival Disease-free survival
0.8
0.6
0.4
0.2
0
1
2
3
4
5
Years FIG. 1 Overall and disease-free survival rates of the 152 patients with peritoneal carcinomatosis from gastric origin
of lymph node involvement, performance status, year’s experience of institution, type of HIPEC technique, and treatment with EPIC or with adjuvant systemic chemotherapy. All other clinical and therapeutic factors had a significant prognostic impact (Table 2). There was a strong prognostic influence of centers in which procedures were performed (P \ .001). There was significant improvement in survival from 1989 to 2004 (Fig. 2). The carcinomatosis extent assessed by Sugarbaker’s PCI and by Gilly classification had a prognostic impact. The neoadjuvant treatment by systemic chemotherapy also improved the survival results (P = .018). The impact of PIC techniques (drugs and concentrations used, temperature, duration) could not be analyzed because of marked variations between institutions. By multivariate analysis, the principal independent prognostic factor was in addition to the center’s effect, the completeness of cytoreduction (P \ .001, relative risk [RR] of 2.04; Fig. 3). We also showed a negative prognostic impact close to significance for female gender (P = .0573, RR of 1.45). We also specifically studied the prognostic factors in patients who had undergone complete cytoreductive surgery (CCR-0 resection). The multivariate analysis identified only one prognostic factor: the extent of carcinomatosis assessed by PCI (P = .047) (Fig. 4). Despite the complete cytoreductive surgery, no patient was alive at 6 months when they had a PCI more than 19 and none at 3 years when they had a PCI more than 12. DISCUSSION Peritoneal carcinomatosis of gastric origin has long been considered a fatal clinical entity to be treated palliatively. Since the 1980s, the development of new surgical
techniques (cytoreductive surgery and peritonectomy procedures) combined with PIC and preferentially HIPEC has given new hope of potential cure for patients with PC from primary origin or for colorectal or appendix cancers.3–5,12 Because of its worse prognosis, the question regarding the efficiency of this combined procedure still remains controversial for carcinomatosis from gastric origin. The experience of few single institutions, combined with phase II studies, have reported encouraging survival results following treatment of PC with this therapeutic strategy.13,18,19 This collaborative effort of 15 institutions collected data from 159 patients and represents the largest experience of the treatment of PC from gastric origin. With a median follow-up of 20.4 months, the overall median survival was only 9.2 months, but the 5-year survival rate was 13% with some long-term survivors. These survival results are less encouraging than those obtained for other peritoneal surface malignancies, reflecting either a more aggressive disease process less responsive to this combined treatment modality or the need for better patient selection. However, the combination of cytoreductive surgery with PIC was the only therapeutic strategy that reported longterm survivors at 5 years.13,19,20 One of the most important issues arising from our analysis is the strong influence of the institution not only on survival but also on morbidity and morbidity rates. The institution in which the procedure was performed was an independent prognostic indicator of postoperative complications. It is, however, reasonable to make the assumption that experience may provide better patient selection, surgical expertise with a higher rate of complete cytoreductive surgery, and postoperative management. A learning curve had been already reported by several authors and institutions performing the combination of cytoreductive surgery with PIC for the management of PC. Moran et al. reported a decreased mortality rate from 18 to 3%, the Netherlands Cancer Institute from 8 to 4%, and Yan et al. from 7 to 1%.21–23 All interventional complex procedures have an inherent risk and experience undoubtedly diminishes, but can never abolish this.24 If the morbidity rate of 27.8% appeared reasonable and was similar to those following other major surgical procedures such as esophagectomy or pancreaticoduodenectomy, the postoperative mortality rate was high and reached 6.5%. This high rate of mortality did not appear to be caused by a high rate of digestive fistula (15.9% that caused only 1 death). Piso et al. 25 reported recently that performing gastrectomy in combination with HIPEC was safe in experienced centers, with no leakages related to gastric resection among 37 procedures. Anyway, these high rates of postoperative complications emphasize the necessity for patient selection using strict criteria. Patients have to be young (morbidity rate reached 40% for patients older that 61 years), with good performance
2374 TABLE 2 Prognostic impact of clinical and therapeutic factors on overall survival by univariate analysis
O. Glehen et al.
Factors
Number Median 1-year 3-year 5-year Log-rank (collected) survival survival survival survival test (P) (months) (%) (%) (%)
Age
–
–
–
–
Sex
.363*
Male
73
8.5
42
24
20
Female
78
9.6
43
10
5
Performance status
.269
0–1
108
10
48
20
17
9
6
33
11
11
1–2
71
14
53
27
20
3–4
64
7
31
6
6
–
–
–
–
–
\.001
Synchronous carcinomatosis
56
8
44
23
17
.575
Metachronous carcinomatosis
75
9
43
15
10
Yes
89
10
47
17
10
No
30
11
48
29
23
64
10
43
16
12
2–3 Gilly stage
.004
Sugarbaker’s PCI
Lymph node involvement
.387
Tumor differentiation
.678
Poor Moderate
26
9
43
23
17
Well
24
8
39
15
15
Centers’ experience
.272
0–3 years 3–7 years
61 35
8 5
38 37
16 20
8 20
7–11 years
22
11
45
12
12
More than 11 years
34
16
56
16
16
Before 1997
18
7
36
17
11
1997–1999
34
6
28
11
11
2000–2002
17
10
44
9
9
2003–2004
59
10
41
20
20
After 2004
24
NA
Period of procedures
.021
Institution
82
73
73
–
–
–
–
Neoadjuvant systemic chemotherapy 55
13
52
25
18
No
97
8
38
14
10
CC-0
85
15
61
31
23
CC-1 CC-2 or CC-3
37 30
6 4
31 10
5 3
3 3
Yes
52
14
55
13
0
No
83
5
32
18
15
\.001*
Adjuvant systemic chemotherapy
status and acceptable renal, myocardial, and pulmonary functions. The carcinomatosis extent assessed by Sugarbaker’s PCI also demonstrated its significant influence on survival and was strongly correlated with the completeness of
.009 .039
Yes Completeness of cytoreductive surgery
* Independent prognostic factor by multivariate analysis
.006
.156
cytoreduction (size of residual tumor nodules). For intraperitoneal chemotherapy to be effective, residual disease following attempted cytoreductive surgery must be of low volume. Long-term survival, with a 5-year survival of 23% and a median survival of 15 months was obtained only in
Peritoneal Carcinomatosis from Gastric Cancer Survival Probability 1.0
2375
Procedure Date Before Jan. 1997 Jan. 1997–Dec. 1999 Jan. 2000–Dec. 2002 Jan. 2003–Dec. 2004 After Jan. 2005
0.8
0.6
0.4
0.2
0
1
2
3
4
5
Years FIG. 2 Overall survival according to time period of the procedure
Survival Probability 1.0 Completness of Cytoreduction 0mm <2.5mm ≥2.5mm
0.8
0.6
0.4
0.2
0
1
2
3
4
5
Years FIG. 3 Overall survival according to completeness of cytoreductive surgery
Survival Probability 1.0 Peritoneal Cancer Index 0–6 7–12 13–19 >19
0.8
0.6
0.4
0.2
0
1
2
3
4
5
Years FIG. 4 Overall survival of patients treated by complete cytoreductive surgery according to carcinomatosis extent assessed by Sugarbaker’s PCI
patients treated with complete macroscopic resection (CCR-0). Yonemura et al. 18 reported similar encouraging results with a 5-year survival rate of 27% and a median survival of 15.5 months for patients with gastric PC treated with complete cytoreduction and HIPEC. Hall et al. 26 observed a median survival of 11.2 months for CC-0 patients with gastric PC treated with HIPEC using mitomycin C, whereas no patient with residual disease was alive after 2 years. An aggressive attempt at complete resection, including surgical excision of all sites of macroscopic disease, may add to the efficacy of PIC. When cytoreductive surgery does not allow sufficient downstaging, the survival benefit of PIC and especially of HIPEC remains extremely low, and median survival did not exceed 6–8 months. In light of the risk of postoperative complications, PIC should not be indicated in patients with CCR-1 or CCR-2 resection. PC with localized or small tumor nodules seems to be the best indication for this combined procedure. In patients who had undergone complete cytoreductive surgery, the extent of carcinomatosis represented the only strong prognostic factor. When the PCI was more than 12, despite a complete cytoreductive surgery, no patient was alive at 3 years. Fujimoto et al. 19 reported also impressive survival results in patients with limited PC (5-year survival rates of 40–50%), whereas 1-year survival rate was only 18% for patients with more extensive PC. Regarding these results it may not be recommended to propose this combined treatment for patients with extensive PC, even if complete cytoreductive surgery appears to be possible. Patients with gastric PC and Sugarbaker’s PCI of more than 12 should be contraindicated for this kind of therapeutic strategy. Laparoscopy may play an important role in the selection of patients regarding the extent of carcinomatosis. It may exclude patients with micronodules or small bowel involvement, for example, and avoid unnecessary laparotomy. Many authors recently reported the use of this important tool for limited and unknown carcinomatosis (that represent the best indication of the combined procedure) and for the assessment of carcinomatosis extent (to contraindicate patients not amenable to complete cytoreductive surgery).27–29 Since recent randomized trials, the use of neoadjuvant chemotherapy is routinely used and recommended, especially in Europe for the management of gastric adenocarcinoma without PC.30 In our study, neoadjuvant systemic chemotherapy improved survival results, by univariate analysis only. It may help physicians to better select indications. Patients who progress or develop extraabdominal metastases during this preoperative treatment may be excluded for an aggressive and complex procedure that would probably not improve prognosis because of postoperative and systemic progression of disease.
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For many Korean and Japanese researchers, HIPEC has been performed prophylactically or in an adjuvant setting and was evaluated into phase III trials. Most of them demonstrated the benefit of HIPEC, especially for T3, T4, and N? gastric tumors.31–34 In Western countries, some small experiences suggested also the benefit of using HIPEC as adjuvant treatment for the prevention of PC recurrence in advanced gastric cancer.35,36 Prospective randomized studies are needed in Europe to demonstrate the benefit of HIPEC in earlier stages of PC disease. This large multicenter study demonstrates that long-term survival for patients with PC from gastric cancer is a realistic goal in selected patients and PC should not be considered a terminal event. The principal prognostic factors are carcinomatosis extent and the completeness of cytoreductive surgery. The high rate of mortality rate underlines the necessity of strict selection of patient (younger than 60 years and with good performance status). Patients who may benefit from cytoreductive surgery and HIPEC are those with PCI less than 12, following response to neoadjuvant chemotherapy, with no diffuse small bowel involvement demonstrated by CT-scan and laparoscopy, and with a high probability of complete macroscopic cytoreduction. HIPEC should also be evaluated and used as adjuvant treatment in Western countries in prevention of development of PC. ACKNOWLEDGMENT Acknowledgements to Faheez Mohamed for help with English editing and to other authors of Association Franc¸aise de Chirurgie: Jack Porcheron and Karine Abboud (CHU St Etienne), Lucas Sideris (Hopital Maisonneuve Rosemont, Montre´al),Turrini Olivier (Centre Paoli Calmette, Marseille), Arvieux Catherine (CHU Grenoble), Rat Patrick (CHU Dijon), Gertsch Philippe (Hopital San Giovanni, Bellinzona), Ferron Gwenael (Centre Claudius Regaud, Toulouse), Meeus Pierre (Centre Le´on Be´rard, Lyon), Brigand Ce´cile (CHU Strasbourg), Marchal Frederic (Centre Alexis Vautrin, Nancy), Tuech Jean Jacques (Centre Charles Nicolle, Rouen), Pocard Marc (Hopital Lariboisie`re, APHP), Loungnarath Rasmy (Hopital St Luc, Montre´al), Tasseti Vincent (Centre Emile Muller, Mulhouse), Lermite Emily (CHU Angers), Durand Sylvaine (Centre Dupuytren, Limoges), Van der Speeten Kurt (Zieken Oost Limburg, Genk).
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