The value of BRCA-1-associated protein 1 expression and cyclin-dependent kinase inhibitor 2A deletion to distinguish peritoneal malignant mesothelioma from peritoneal location of carcinoma in effusion cytology specimens.

OBJECTIVE: Diffuse malignant peritoneal mesothelioma (DMPM), represents 30% of all malignant mesothelioma, and is characterised by a difficult diagnosis and different presentations. Immunohistochemistry has improved the diagnostic sensitivity and specificity in the differential diagnosis between metastatic adenocarcinoma and malignant mesothelioma, and loss of BRCA-1-associated protein 1 (BAP1) expression is correlated with BAP1 somatic or constitutional genetic defects. Furthermore, cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently lost in DMPM. In the present study, we assessed the value of integrating BAP1 in the panel of antibodies used for the diagnosis of DMPM in cytological samples. Since p16 fluorescent in situ hybridisation (FISH) assay could constitute an additional useful adjunct, results of BAP1 immunostaining and p16 FISH assays have been compared. METHODS: Forty-eight DMPM patients and 71 peritoneal carcinomatosis patients were included. BAP1 immunohistochemical and CDKN2A FISH techniques were performed on tissue specimens of DMPM (n = 48) and peritoneal carcinomatosis (n = 71) then on cell-block of DMPM (n = 16), peritoneal carcinomatosis (n = 25) and peritoneal benign effusion (n = 5). RESULTS: Loss of BAP1 expression was observed in 56.3% of DMPM while none of the peritoneal carcinoma specimens showed BAP1 loss of expression. CDKN2A loss was observed in 34.9% DMPM and 2.1% peritoneal carcinoma. Although BAP1 immunostaining was successful in 100% of cytological DMPM samples, CDKN2A deletion status could be obtained for 75% of DMPM cases. CONCLUSION: BAP1 immunostaining represents an objective and reproducible diagnostic biomarker for peritoneal mesothelioma in effusion cytology specimens and should be preferred to CDKN2A FISH analysis on these precious samples.

Ninety-day post-operative morbidity and mortality using the National Cancer Institute's common terminology criteria for adverse events better describe post-operative outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The post-operative morbidity and mortality after CRS-HIPEC has been widely evaluated. However, there is a major discrepancy between rates reported due to different metrics and time of analysis used. OBJECTIVE: To evaluate the legitimacy of 90-day morbidity and mortality based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 classification as criteria of quality for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: A prospective database of all patients undergoing CRS-HIPEC for peritoneal carcinomatosis between 2004 and 2015 was queried for 90-day morbidity and mortality and survival. RESULTS: Among 881 patients, the 90-day major complication rate based on NCI-CTCAE classification and Clavien-Dindo's classification were 51% (n = 447 patients) and 25% (n = 222 patients), respectively. Among patients who presented with a 90-day complication based on the NCI-CTCAE classification, 50% (n = 225 patients) presented a medical complication not reported by Clavien-Dindo's classification. After surgery, 24 patients (2.7%) died of post-operative complications, for only 10 (42%) of them the death occurred within 30-day after surgery. Occurrence of major complication based on either NCI-CTCAE classification, Clavien-Dindo's classification or the medical complication not reported by Clavien-Dindo's classification all negatively impacts the overall survival. CONCLUSION: Among commonly reported morbidity's classification, 90-day morbidity based on NCI-CTCAE classification represents a legitimate metric of CRS-HIPEC quality. Post-operative morbidity after CRS-HIPEC should be reported using 90-day NCI-CTCAE classification.

Registries on peritoneal surface malignancies throughout the world, their use and their options.

AIM: The treatment of peritoneal surface malignancies ranges from palliative care to full cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy, HIPEC. Ongoing monitoring of patient recruitment and volume is usually carried out through dedicated registries. With multiple registries available worldwide, we sought to investigate the nature, extent and value of existing worldwide CRS and HIPEC registries. METHODS: A questionnaire was sent out to all known major treatment centres. The questionnaire covers: general purpose of the registry; inclusion criteria in the registry; the date the registry was first established; volume of patients in the registry and description of the data fields in the registries. Finally, the population size of the catchment area of the registry was collected. RESULTS: Twenty-seven questionnaires where returned. National databases are established in northwest European countries. There are five international general databases. Most database collect data on patients who have undergone an attempt to CRS and HIPEC. Two registries collect data on all patients with peritoneal carcinomatosis regardless the treatment. Most registries are primarily used for tracking outcomes and complications. When correlating the number of cases of CRS and HIPEC that are performed to the catchment area of the various registry, a large variation in the number of performed procedures related to the overall population was noted, ranging from 1.3 to 57 patients/million year with an average of 15 patients/1 million year. CONCLUSIONS: CRS and HIPEC is a well-established treatment for peritoneal surface malignancies worldwide. However, the coverage as well as the registration of treatment procedures differs widely. The most striking difference is the proportion of HIPEC procedures per capita which ranges from 1.3 to 57 patients per million. This suggests either a difference in patient selection, lack of access to HIPEC centres or lack of appropriate data collection.

Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort).

PURPOSE: The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma. EXPERIMENTAL DESIGN: Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort. RESULTS: The median age was 61 years (range 16-92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers. CONCLUSIONS: This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort.

BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas.

INTRODUCTION: Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma. METHODS: Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples. RESULTS: We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex. CONCLUSIONS: As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array.

Malignant peritoneal mesotheliomas (MPM) are rare, accounting for approximately 8% of cases of mesothelioma in France. We performed comparative genomic hybridization (CGH) on frozen MPM samples using the Agilent Human Genome CGH 180 K array. Samples were taken from a total of 33 French patients, comprising 20 men and 13 women with a mean (range) age of 58.4 (17-76) years. Asbestos exposure was reported in 8 patients (24.2%). Median (range) overall survival (OS) was 39 (0-119) months. CGH analysis demonstrated the presence of chromosomal instability in patients with MPM, with a genomic pattern that was similar to that described for pleural mesothelioma, including the loss of chromosomal regions 3p21, 9p21, and 22q12. In addition, novel genomic copy number alterations were identified, including the 15q26.2 region and the 8p11.22 region. Median OS was associated with a low peritoneal cancer index (P=.011), epithelioid subtype (P=.038), and a low number of genomic aberrations (P=.015), all of which constitute good prognostic factors for MPM. Our results provide new insights into the genetic and genomic background of MPM. Although pleural and peritoneal mesotheliomas have different risk factors, different therapeutics, and different prognosis; these data provide support to combine pleural and peritoneal mesothelioma in same clinical assays.

What made hyperthermic intraperitoneal chemotherapy an effective curative treatment for peritoneal surface malignancy: A 25-year experience with 1,125 procedures.

OBJECTIVE: To review our 25-year experience with hyperthermic intra-peritoneal chemotherapy (HIPEC). BACKGROUND: Combining cytoreductive surgery (CRS) and HIPEC as local treatments for peritoneal carcinomatosis (PC) was proposed 25 years ago. METHODS: A prospective database of all patients undergoing HIPEC for PC since 1989 was searched for clinicopathological data, 90-day morbidity and mortality, and survival. RESULTS: Among 1,125 HIPEC procedures, PC origin was colorectal (342; 30%), ovarian (271; 24%), pseudomyxoma peritonei (189; 17%), gastric (127; 11%), malignant mesothelioma (84; 8%), or other (112; 10%). Between 2004-2009 (n = 321) and 2010-2015 (n = 560), the median peritoneal cancer index decreased (11 vs. 8; P < 0.001), fewer patients underwent incomplete cytoreduction (CC2-3: 4% vs. 0.5%; P < 0.001), and more were included in randomized trials (5% vs. 16%; P < 0.001). Postoperative morbidity (52% vs. 50%, P = 0.672) was not different, but mortality significantly decreased (5% vs. 2%; P = 0.030). Median overall-survival was 42 months, and improved significantly for each 5-year period except for 2006-2010 vs. 2011-2015 (P = 0.097). The 10-year survival without recurrence was 53%, 14%, 4%, 10%, and 9% for pseudomyxoma, mesothelioma, ovarian, colorectal, and gastric PC, respectively. CONCLUSION: This study demonstrated that CRS and HIPEC provide long-term survival irrespective of PC origin, and survival improves with experience. J. Surg. Oncol. 2016;113:796-803. © 2016 Wiley Periodicals, Inc.

Resectability of Peritoneal Carcinomatosis: Learnings from a Prospective Cohort of 533 Consecutive Patients Selected for Cytoreductive Surgery.

PURPOSE: The aim of this study was to identify the risk factors and causes of unresectability in a large cohort of patients with peritoneal carcinomatosis (PC) selected for cytoreductive surgery (CRS), and to assess the contribution of the different imaging modalities to the patient-selection process. METHODS: The pre- and intraoperative data of 533 consecutive patients with PC planned for CRS at a single institution were reviewed. All patients underwent computed tomography (CT) magnetic resonance imaging and/or positron emission tomography/CT within the 2 days prior to surgery. RESULTS: Among the 533 patients, 436 (82 %) underwent complete CRS, 86 (16 %) underwent exploratory laparotomy without CRS because of multiple small-bowel involvement (n = 31), invasion of different digestive segments (n = 15), an elevated PC index (n = 14), invasion of the mesenteric root (n = 12), or another cause (n = 14), and 11 (2 %) did not undergo laparotomy because of disease progression on preoperative imaging findings. On univariate analysis, elevated levels of tumor markers and a short delay between the last cycle of chemotherapy and the scheduled surgery were identified as predictors of unresectability for the colonic PC population, while a younger age was identified in patients with gastric PC. Multivariate analysis disclosed the use of neoadjuvant chemotherapy and a younger age as independent predictors of unresectability in the colonic PC population. CONCLUSIONS: The current modalities for the assessment of PC resectability, including functional imaging examinations, have a low impact on patient selection for CRS. New tools are needed to decrease the rate of open-close procedures.

Intraperitoneal Vascular Endothelial Growth Factor: A Prognostic Factor and the Potential for Intraperitoneal Bevacizumab Use in Peritoneal Surface Malignancies.

INTRODUCTION: Intraperitoneal (IP) vascular endothelial growth factor (VEGF) levels have been shown to vary in the peritoneal cavity of patients with peritoneal surface malignancies. Our purpose was to correlate levels of IP VEGF with overall and disease-free survival to identify whether IP VEGF can be used to prognosticate patients and the possible role of IP bevacizumab. METHODS: From February to October 2012, 97 consecutive patients with peritoneal carcinomatosis were treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Intravenous (IV) VEGF levels were taken before surgery, whereas IP VEGF levels were taken at various time points during and after surgery. RESULTS: Median follow-up was 19.48 months. On univariate analysis, a lower IP VEGF taken just after incision (T1) was associated with improved overall (P = 0.0004) and disease-free survival (P = 0.0006) at 2 years. A lower T1/IV VEGF ratio also was associated with improved overall (P = 0.004) and disease-free survival (P = 0.0051). On multivariate analysis, a lower T1 was associated with improved overall survival, whereas a lower T1/IV VEGF was associated with improved disease-free survival. On subset analysis, these two variables were associated with improved survival in colorectal cancers. CONCLUSIONS: A lower IP VEGF level prior to surgery is associated with improved survival. The use of preoperative intraperitoneal bevacizumab for patients with a heavy disease load should be considered, especially in colorectal cancers.

Transferability of health cost evaluation across locations in oncology: cluster and principal component analysis as an explorative tool.

BACKGROUND: The transferability of economic evaluation in health care is of increasing interest in today's globalized environment. Here, we propose a methodology for assessing the variability of data elements in cost evaluations in oncology. This method was tested in the context of the European Network of Excellence "Connective Tissues Cancers Network". METHODS: Using a database that was previously aimed at exploring sarcoma management practices in Rhône-Alpes (France) and Veneto (Italy), we developed a model to assess the transferability of health cost evaluation across different locations. A nested data structure with 60 final factors of variability (e.g., unit cost of chest radiograph) within 16 variability areas (e.g., unit cost of imaging) within 12 objects (e.g., diagnoses) was produced in Italy and France, separately. Distances between objects were measured by Euclidean distance, Mahalanobis distance, and city-block metric. A hierarchical structure using cluster analysis (CA) was constructed. The objects were also represented by their projections and area of variability through correlation studies using principal component analysis (PCA). Finally, a hierarchical clustering based on principal components was performed. RESULTS: CA suggested four clusters of objects: chemotherapy in France; follow-up with relapse in Italy; diagnosis, surgery, radiotherapy, chemotherapy, and follow-up without relapse in Italy; and diagnosis, surgery, and follow-up with or without relapse in France. The variability between clusters was high, suggesting a lower transferability of results. Also, PCA showed a high variability (i.e. lower transferability) for diagnosis between both countries with regard to the quantities and unit costs of biopsies. CONCLUSION: CA and PCA were found to be useful for assessing the variability of cost evaluations across countries. In future studies, regression methods could be applied after these methods to elucidate the determinants of the differences found in these analyses.

Pathological response to neoadjuvant chemotherapy: a new prognosis tool for the curative management of peritoneal colorectal carcinomatosis.

PURPOSE: The primary objective of this study was to determine the incidence rate of pathological complete responses (pCRs) following neoadjuvant systemic chemotherapy for the treatment of peritoneal carcinomatosis (PC) of colorectal origin. The secondary objective was to evaluate whether pathological response assessments predict survival of patients treated with curative intent by complete cytoreductive surgery (CRS). METHODS: A retrospective review was performed of 115 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by 124 procedures of complete CRS alone or combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The pathological response was defined as the mean percentage of cancer cells remaining within all specimens. Univariate and multivariate analyses were performed to identify predictors of survival and pathological response outcome. RESULTS: Twelve procedures (9.7 %) resulted in pCRs, defined as no residual cancer cells in all specimens, 25 (20.2 %) resulted in major responses (1 to 49 % residual cancer cells), and 87 (70.1 %) resulted in minor or no responses (>50 % residual cancer cells). The cumulative 5-year survival rates were 75 and 57 % for patients with pCR and major responses, respectively. Using multivariate analysis, pathological response was the only independent predictor of survival (P = 0.01; major response: hazard ratio [HR] = 4.91; minor response: HR = 13.46). No significant predictor of pathological response was identified. CONCLUSIONS: Pathological complete response can be achieved with preoperative systemic chemotherapy for patients with PC of colorectal origin. The degree of pathological response can be assessed and represented as a new outcome for prognosis following treatment with curative intent.

[The RENAPE network: towards a new healthcare organization for the treatment of rare tumors of the peritoneum. Description of the network and role of the pathologists]. / Réseau RENAPE : vers une nouvelle organisation des soins pour le traitement des tumeurs rares du péritoine. Description du réseau et rôle des pathologistes.

As part of the national 2009-2013 Cancer Plan, and with the support of the National cancer Institute and the French ministry of health, the National network for the treatment of rare peritoneal malignancies (RENAPE) has been organized. Its main objective is to optimize the framework for the healthcare management and treatment of rare peritoneal malignancies. This specific organization covers the whole national territory including clinical expert and specialized structures and should lead to an appropriate treatment based on expertise and proximity. Within the RENAPE network, the RENA-PATH group gathers the pathologists actively involved in the management of rare peritoneal malignancies. The actions of RENA-PATH are focused primarily on the harmonization of pathological diagnostic criteria, reporting of new cases in the RENAPE registry and histology reviewing.

[Peritoneal pseudomyxoma: an overview emphasizing pathological assessment and therapeutic strategies]. / Mise au point sur le pseudomyxome péritonéal. Aspects anatomo-pathologiques, et implications thérapeutiques.

Pseudomyxoma peritonei is a clinical entity characterized by a gelatinous ascite associated with mucinous tumor deposits spreading on peritoneal surface and potentially invading abdominal organs. It is considered as a tumor process linked, in most of cases, to a mucinous appendiceal neoplasm. Pseudomyxoma peritonei may benefit from a therapeutic strategy combining cytoreductive surgery and intra-peritoneal chemotherapy, which has led to a major prognosis improvement. Different classifications are available and the last one corresponds to the WHO 2010 version, which individualizes pseudomyxoma peritonei in two classes: low grade and high grade mucinous carcinoma. The very low frequency of this entity and its specific therapeutic strategy need specific health care centres, as well as physicians and pathologists collaborating through dedicated networks. The aim of this article is to summarize the pathology, causes, mechanisms and therapeutic approaches of pseudomyxoma peritonei, as well as their interfaces with dedicated networks.

Territorial inequalities in management and conformity to clinical guidelines for sarcoma patients: an exhaustive population-based cohort analysis in the Rhône-Alpes region.

BACKGROUND: Sarcomas are rare cancers with great variability in clinical and histopathological presentation. The main objective of clinical practice guidelines (CPGs) is to standardize diagnosis and treatment. METHODS: From March 2005 to February 2007, all patients diagnosed with localized sarcoma in the Rhône-Alpes region were included in a cohort-based study, to evaluate the compliance of sarcoma management with French guidelines in routine practice and to identify predictive factors for compliance with CGPs. RESULTS: 634 (71 %) patients with localized sarcoma satisfying the inclusion criteria were included out of 891 newly diagnosed sarcomas. Taking into account initial diagnosis until follow-up, overall conformity to CPGs was only 40 % [95 % confidence interval (CI) = 36-44], ranging from 54 % for gastrointestinal stromal tumor to 36 % for soft tissue sarcoma and 42 % for bone sarcoma. In multivariate analysis, primary tumor type [relative risk (RR) = 4.42, 95 % CI = 2.79-6.99, p < 0.001], dedicated multidisciplinary staff before surgery (RR = 4.19, 95 % CI = 2.39-7.35, p < 0.001) and management in specialized hospitals (RR = 3.71, 95 % CI = 2.43-5.66, p < 0.001) were identified as unique independent risk factors for conformity to CPGs for overall treatment sequence. CONCLUSIONS: With only 40 % of total conformity to CPGs, the conclusions support the improvement of initial sarcoma management and its performance in specialized centres or within specialized dedicated networks.

Intraperitoneal cytokine level in patients with peritoneal surface malignancies. A study of the RENAPE (French Network for Rare Peritoneal Malignancies).

BACKGROUND: Prognosis of peritoneal surface malignancies is influenced by the adequacy of surgical and chemotherapeutic treatment and by tumor spread at the time of diagnosis. By promoting morphological changes in the mesothelium, inflammatory cytokines reflect tumor biology and could be evaluated as biomarkers. Our objective was to evaluate intraperitoneal levels of IL-6, IL-8, IL-10, TNF-alpha, and sICAM in patients with pseudomyxoma peritonei and peritoneal mesothelioma. METHODS: Serum and peritoneal fluid samples were prospectively collected in patients managed for peritoneal surface malignancies including pseudomyxoma peritonei (PMP), mesotheliomas, and other rare primitive peritoneal cancers (cancer group) and patients who underwent intraperitoneal laparoscopic surgical procedures for benign diseases (noncancer group). Samples were analyzed for IL-6, IL-8, IL-10, TNF-alpha, and sICAM concentrations. Correlations were assessed with tumor spread related clinical scores. RESULTS: In both patient groups, intraperitoneal cytokine levels were higher than serum levels. Cancer patients had significantly higher intraperitoneal cytokine levels than noncancer patients. Peritoneal levels tended to increase in cancer patients with free tumor cells in peritoneal fluid. They were significantly higher in patients with tumor implants ≥2 cm and/or patients with peritoneal carcinomatosis index (PCI) >19. Furthermore, patients with malignant pseudomyxoma peritonei (grades II and III) had higher levels than patients with nonmalignant disease (grade I). CONCLUSIONS: Assessment of intraperitoneal IL-6, IL-8, IL-10, TNF-alpha, and sICAM levels can be performed in patients with peritoneal surface malignancies. They can be considered as both diagnostic and prognostic biomarkers that could be used as useful adjuncts for therapeutic decision making.

Impact of hyperthermic intraperitoneal chemotherapy on Hsp27 protein expression in serum of patients with peritoneal carcinomatosis.

Despite the strong rationale for combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis, thermotolerance and chemoresistance might result from heat shock protein overexpression. The aim of the present study was thus to determine whether the heat shock protein 27 (Hsp27), a potential factor in resistance to treatment, could have a higher level in serum from patients under this combined therapy. Patients receiving CRS plus HIPEC for peritoneal carcinomatosis (group 1), patients with cancer or a history of cancer undergoing abdominal surgery (group 2), and patients without malignancies undergoing abdominal surgery (group 3) were included. Hsp27 serum levels were determined before and at different times following CRS and HIPEC using enzyme-linked immunosorbent assay. In group 1 (n = 25), the high Hsp27 levels, observed at the end of surgery compared with before (p < 0.0001), decreased during HIPEC, but remained significantly higher than before surgery (p < 0.0005). In groups 2 (n = 11) and 3 (n = 15), surgery did not significantly increase Hsp27 levels. A targeted molecular strategy, inhibiting Hsp27 expression in tumor tissue, could significantly reduce resistance to the combined CRS plus HIPEC treatment. This approach should be further assessed in a clinical phase I trial.

Clinicians' adherence versus non adherence to practice guidelines in the management of patients with sarcoma: a cost-effectiveness assessment in two European regions.

BACKGROUND: Although the management of sarcoma is improving, non adherence to clinical practice guidelines (CPGs) remains high, mainly because of the low incidence of the disease and the variety of histological subtypes. Since little is known about the health economics of sarcoma, we undertook a cost-effectiveness analysis (within the CONnective TIssue CAncer NETwork, CONTICANET) comparing costs and outcomes when clinicians adhered to CPGs and when they did not. METHODS: Patients studied had a histological diagnosis of sarcoma, were older than 15 years, and had been treated in the Rhône-Alpes region of France (in 2005/2006) or in the Veneto region of Italy (in 2007). Data collected retrospectively for the three years after diagnosis were used to determine relapse free survival and health costs (adopting the hospital's perspective and a microcosting approach). All costs were expressed in euros (€) at their 2009 value. A 4% annual discount rate was applied to both costs and effects. The incremental cost-effectiveness ratio (ICER) was expressed as cost per relapse-free year gained when management was compliant with CPGs compared with when it was not. To capture uncertainty surrounding ICER, a probabilistic sensitivity analysis was performed based on a non-parametric bootstrap method. RESULTS: A total of 219 patients were included in the study. Compliance with CPGs was observed for 118 patients (54%). Average total costs reached 23,571 euros when treatment was in accordance with CPGs and 27,313 euros when it was not. In relation to relapse-free survival, compliance with CPGs strictly dominates non compliance, i.e. it is both less costly and more effective. Taking uncertainty into account, the probability that compliance with CPGs still strictly dominates was 75%. CONCLUSIONS: Our findings should encourage physicians to increase their compliance with CPGs and healthcare administrators to invest in the implementation of CPGs in the management of sarcoma.

Iterative procedures combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal recurrence: postoperative and long-term results.

OBJECTIVE: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the best treatment of several peritoneal surface malignancies. Isolated peritoneal recurrence may be treated by iterative procedures. The aim of this study was to evaluate immediate postoperative and long-term results after iterative CRS-HIPEC. METHODS: From 1990 to 2010, 30 patients with isolated peritoneal recurrence underwent iterative procedures combining CRS-HIPEC. RESULTS: Origins of peritoneal carcinomatosis were ovarian, colorectal, pseudomyxoma peritonei, peritoneal mesothelioma, gastric cancer, cholangiocarcinoma, leiomyosarcoma, and primary peritoneal serous carcinoma. Median recurrence-free survival (RFS) was 16.2 months from the first procedure. After the second procedure, one (3.3%) postoperative death occurred. Severe morbidity following the second procedure was 40% versus 30% after the first procedure (P = 0.37). At most recent follow up, 11 patients were disease-free, 10 were alive with recurrence, and 9 were dead with recurrence. Five-year overall survival after initial CRS with HIPEC was 65%, and overall median survival from diagnosis was 140 months. CONCLUSION: Iterative procedures combining CRS-HIPEC are feasible and allow long-term survival but may result in significant morbidity and mortality. Patients must be carefully selected, based on the following criteria: Origin of carcinomatosis, magnitude of first procedure, length of RFS, physiological age, co-morbidity, and possibility of complete cytoreduction.