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Background: This report aims to describe preliminary results concerning secondary resectability after bidirectional chemotherapy for initially unresectable malignant peritoneal mesothelioma (MPM)., Methods: Between January 2013 and January 2016, 20 consecutive patients treated for diffuse MPM not suitable for upfront surgery received bidirectional chemotherapy associating intraperitoneal and systemic chemotherapy. Evaluation of the response to chemotherapy was assessed clinically and by laparoscopy., Results: The median peritoneal cancer index (PCI) score at staging laparoscopy was 27 (range 15-39). Altogether, 118 intraperitoneal chemotherapy cycles were administered without any specific adverse catheter-related event. Concerning tolerance, 85% of the patients experienced no pain or mild pain during chemotherapy administration. The clinical response rate was 60% after a median of three chemotherapy cycles. At laparoscopic reevaluation, the median PCI was 18 (range 0-35), and a secondary resectability was considered for 55% of the patients. Complete cytoreduction surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) was finally achieved for 10 patients (50%), with a median intraoperative PCI score of 14 (range 6-30). After a median follow-up period of 18 months, the 2-year overall survival rate was 83.3% for the patients treated by CRS followed by HIPEC and 44% for the patients treated by bidirectional chemotherapy., Conclusion: Bidirectional chemotherapy is a promising, well-tolerated treatment capable of increasing the resection rate for selected patients with diffuse MPM initially considered as unresectable or borderline resectable. For patients with definitively unresectable disease, bidirectional chemotherapy achieves a higher clinical response rate.

Background: First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA)., Patients and Methods: From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center's multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery., Results: Seventy-seven patients were enrolled. They received a median number of five cycles (1-30). Grade 3-4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2-3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65-86) and 1-year progression-free survival rate was 59 % (95 % CI 46-70)., Conclusion: First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial.

Background: Sorafenib is the only systemic treatment that has shown a significant benefit in overall survival (OS) and in progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients. No standard of care currently exists for second-line treatment. The association of Gemcitabine-Oxaliplatine (GEMOX) has shown efficacy in the first-line setting. The aim of this study was to evaluate the efficacy of GEMOX after failure of at least one line of anti-angiogenic (AA) therapy., Patient and Methods: We performed a multicenter retrospective analysis of advanced HCC patients that received GEMOX chemotherapy after progression on at least one line of AA therapy., Results: We analyzed a total of 40 patients that received a median of 7 cycles of GEMOX over a 6-year period. Grade 3/4 toxicity was observed in 25 % of patients, mainly neurotoxicity, thrombocytopenia and neutropenia in 12.5 %, 5 % and 5 % of patients respectively. Grade <3 toxicity was mainly hematological and neurotoxicity. In the sub-cohort of 35 patients evaluable for response, partial response was observed in 20 % of patients, while 46 % had stable disease. Median OS was 8.3 months, with a 6-month OS rate of 59 %. Median PFS was 3.1 months. Prognostic factors for OS in univariable analysis were the performance status and AFP levels at GEMOX start, and the BCLC score at diagnosis. None of these factors were prognostic for PFS or tumor response., Conclusion: The GEMOX schedule seems to show clinical activity and an acceptable toxicity profile in advanced HCC patients who progressed after anti-angiogenic treatment. The observed median OS of over 8 months is encouraging in this population of heavily pretreated patients. These results would merit confirmation in a prospective randomized study.

Background: The decision to perform optimal surgery when peritoneal metastases (PM) are associated with liver metastases (LM) is extremely complex. No guidelines exist. The purpose of this study was to present a simple and useful statistical tool that generates a graphical calculator (nomogram) to help the clinician rapidly estimate individualized patient-specific survival before undergoing optimal surgery., Materials and Methods: An analysis of 287 patients with liver metastasis (LM), 119 patients with peritoneal metastasis (PM), and 37 patients with LM + PM, who underwent optimal surgery plus chemotherapy between 1995 and 2010 was performed. A minimal number of parameters were taken into account to obtain a nomogram that would be very simple to use. With the overall tumor load as the main prognostic factor, we included the number of lesions for LM and the peritoneal carcinomatosis score (PCI) for PM. The Cox model was used to generate the nomogram., Results: The 5-year overall survival was, respectively, 38.5, 36.5, and 26.4 % in the LM group, the PM group, and the LM + PM group. The summation of 3 parameters (the number of LM, the PCI, and the type of surgery [liver resection, HIPEC, or both]), makes it easy to calculate a score that graphically corresponds to an estimation of survival after optimal surgery (nomogram). It can be used for LM alone, PM alone, or both., Conclusions: A graphic nomogram that is simple to calculate and easy to use enables us to rapidly appreciate the prognosis of patients according to the number of LM, the PCI, or both. This nomogram must be validated in prospective studies in other tertiary centers.

Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.

Purpose: To analyze the patterns of recurrence and the prognostic impact of ovarian metastases (OM) in a population of women with colorectal peritoneal carcinomatosis (CRPC) treated with curative intent., Methods: Data from all consecutive women with CRPC who underwent curatively intended complete cytoreductive surgery (CRS) plus intraperitoneal chemotherapy at our institution were retrieved from a prospective database. A bilateral oophorectomy or a complementary unilateral oophorectomy was systematically performed during CRS., Results: From 1994 to 2009, among 105 women who underwent CRS plus intraperitoneal chemotherapy for CRPC, 62 (60 %) had OM. Women with and without OM had comparable peritoneal cancer index (PCI) scores (10 vs. 12, respectively, p = 0.09). After a median follow-up of 60 (range 5-145) months, median overall survival of women with OM did not differ statistically from that of women without OM (respectively, 36 and 40 months; p = 0.75). Relapses occurred in 82 % of the patients, distributed similarly between the two groups except for retroperitoneal lymph node recurrence, which occurred in 19 patients (18 %), including 18 with OM. The only predictive factor for a retroperitoneal relapse was a history of OM (p = 0.0012)., Conclusions: Retroperitoneal lymph node recurrence seems to be linked to OM originating from colorectal cancer and could worsen the prognosis. A systematic lymphadenectomy could be evaluated in women with isolated OM or very limited peritoneal carcinomatosis to analyze the incidence of invaded lymph nodes and study its potential benefit on survival.

Background: We have previously shown promising activity of hepatic arterial infusion (HAI) oxaliplatin combined with intravenous (IV) 5-fluorouracil (5-FU) and leucovorin (LV) as first-line chemotherapy in patients with colorectal liver metastases (CRLM) (intent-to-treat [ITT] objective response rate [ORR], 64%; secondary resection rate, 18%; overall survival [OS], 27 months). Whether this regimen could be beneficial after systemic chemotherapy failure is unknown., Methods: Patients with unresectable CRLM and history of systemic chemotherapy failure were treated bimonthly with HAI oxaliplatin (100 mg/m(2) 2 hours) combined with IV LV and IV bolus and infusional 5FU (modified LV5FU2 regimen)., Results: Forty-four consecutive patients (median age 56 years; median number of prior systemic chemotherapy regimens, 2 range 1-5) were included, of whom 43 (98%) had previously received oxaliplatin (n = 34), irinotecan (n = 37), or both (n = 28). Patients received a median of nine cycles of HAI oxaliplatin and IV modified LV5FU2 (range 0-25). Toxicity included grade 3-4 neutropenia (43%), grade 2-3 neuropathy (43%), and grade 3-4 abdominal pain (14%). We observed 24 partial ORs (62%) among the 39 assessable patients (ITT ORR, 55%; 95% CI, 40-69%), including 17, 12, and 12 patients who had failed to respond to prior systemic chemotherapy with FOLFIRI, FOLFOX, or both, respectively. Tumor response allowed further R0 surgical resection (n = 7) or radiofrequency ablation (n = 1) of initially unresectable CRLM in eight patients (18%). Median progression-free survival and OS were 7 and 16 months, respectively., Conclusions: HAI oxaliplatin and IV LV5FU2 is feasible, safe, and shows promising activity after systemic chemotherapy failure, allowing surgical resection of initially unresectable CRLM in 18% of patients.

Background: Dramatic responses to chemotherapy are occurring more and more frequently in patients with multiple colorectal liver metastases (LMs), leading to resection. In a few patients, some LMs vanish on imaging studies, remain undetected during hepatectomy, and are left in place, which defines the "missing LMs." The aim of our study was to assess the long-term outcome of such "missing LMs.", Patients: Between January 1999 and June 2004, among 228 patients treated for colorectal LMs, missing LMs were observed in 16 patients. All the patients were operated within 4 weeks of imaging. Hepatic arterial infusion (HAI) with oxaliplatin was administrated in 12 patients (75%): seven before hepatectomy and five after., Results: Overall, 69 missing LMs were diagnosed and left in place. Among the persistent LMs resected, a complete pathological response was significantly more often observed in the group with preoperative HAI (6 of 7), than in the group without (2 of 9, P < .02). With a mean follow-up of 51 months (24-90), missing LMs did not reappear in 10 patients (62%). Adjuvant HAI was significantly correlated with the definitive eradication of missing LMs (P < .01), as it was not a complete pathological response. The overall 3-year survival rate of these highly selected 16 patients was 94%., Conclusion: Colorectal LMs under chemotherapy that vanish on high-quality imaging studies, remain undetected during hepatectomy, and are left in place, are definitively cured in 62% of cases. This excellent result seems to be due to the administration of adjuvant hepatic arterial infusion of chemotherapy and should stimulate new investigations.

Background: Recently, the combination of complete cytoreductive surgery followed immediately by intraperitoneal chemotherapy achieved cure in some patients suffering from peritoneal carcinomatosis (PC). It is now well established that the prognostic impact of the completeness of cytoreduction is high. However, two different modes of intraperitoneal chemotherapy are proposed: early postoperative intraperitoneal chemotherapy (EPIC), which lasts for 5 days and is normothermic, and peroperative intraperitoneal chemohyperthermia (IPCH). To date, the results of these procedures have never been compared., Aim of the Study: To compare the complications and therapeutic results of EPIC and IPCH after complete cytoreductive surgery of colorectal PC., Materials and Methods: Twenty-three consecutive patients with colorectal PC were selected based on the completeness of cytoreductive surgery and sufficient follow-up. They received IPCH with oxaliplatin (460 mg/m(2)) in 2 l/m(2) of dextrose, for 30 min at an intraperitoneal temperature of 43 degrees C, using the coliseum technique. We retrospectively carefully selected another 23 patients, for comparison purposes, suffering from the same disease, with characteristics as similar as possible, but treated earlier with EPIC (mitomycin C 10 mg/m(2) at day 0 and 5-FU 650 mg/m(2) from days 1 to 4), in 1 l/m(2) of ringer lactate. Data concerning these two groups were verified prospectively, but this study was a comparative historical analysis., Results: The two groups were statistically comparable, except for the duration of surgery which was 68 min longer for the IPCH group. Mortality and morbidity were not significantly different, even if two deaths occurred in the EPIC group, and none in the IPCH group. However, the rate of digestive fistulas was higher (P = 0.02) in the EPIC group (26%) than in the IPCH group (0%). Overall survival (OS) was higher in the IPCH group, (54% at 5 years vs. 28% for EPIC), but not significantly (P = 0.22). Peritoneal carcinomatosis recurred much (P = 0.03) more frequently in the EPIC group (57%) than in the IPCH-group (26%)., Conclusion: This study provides strong arguments indicating that IPCH with oxaliplatin is better tolerated than EPIC with mitomycin C and 5-FU, and is twice as efficient in curing residual peritoneal carcinomatosis measuring less than 1 mm.

Background: The presence of extrahepatic disease (EHD) is considered a contraindication to hepatectomy in patients with colorectal liver metastases. After resection, the prognosis is based more on the total number of resected metastases (located inside and outside the liver) than on the site of these metastases (only inside the liver or not)., Methods: A total of 308 patients with colorectal cancer underwent hepatectomy, and 84 (27%) also underwent resection of miscellaneous EHD. The study was a prospective data registration and retrospective analysis. When considering the total number of resected metastases, each liver metastasis and each EHD location was counted as one lesion. Univariate and multivariate analyses were performed., Results: The median follow-up was 99 months. The overall 5-year survival rate was 32%. In the multivariate analysis, the total number of metastases (inside or outside the liver) had a greater prognostic value than the criterion "presence or absence of EHD." Considering the total number of resected metastases (whatever their site), 5-year survival rates were 38% (SD: 4%) in the group with one to three metastases, 29% (SD: 5%) in patients with four to six metastases, and 18% (SD: 5%) in patients with more than six metastases (P = .002). A very simple prognostic score based on sex and the total number of metastases is proposed., Conclusions: EHD, when resectable, is no longer a contraindication to hepatectomy. More importantly, the total number of the metastases, whatever their location, has a stronger prognostic effect than the site of these metastases.