Individual learning curve of cytoreductive surgery for peritoneal metastasis from colorectal cancer: A process with an impact on survival.

BACKGROUND: This study aimed to assess the learning curve (LC) of cytoredutive surgery (CRS) of peritoneal metastasis (PM) from colorectal cancer (CRC). Information about learning curves is important for developing teaching tools and well-structured training programs for the implementation of this complex procedure in new healthcare centers. The aim of this study was to estimate how many procedures an inexperienced surgeon must perform (the length of the learning period) in order to demonstrate an acceptably low rate of locoregional recurrence. METHODS: All consecutive 74 patients with CRS for CRC performed by a novice surgeon between 2012 and 2017 in a tertiary cancer center were included. The learning curve was calculated by a cumulative sum control chart (CUSUM) graph. Two groups were formed based on the length of the learning period and were compared on overall and disease free survival. RESULTS: The risk of locoregional recurrence decreased after surgeons had performed 19 cases, suggesting a learning period of this length. Overall survival and postoperative morbidity were not significantly different between learning and proficiency periods. Multiple linear regression analysis showed that the learning period and peritoneal cancer index are the only factors affecting disease free survival. A second learning period was observed in cases where patient care became more complex. CONCLUSIONS: This study confirms that learning period has negative impacts on disease-free survival. An initial experience supervised in specialized centers allow to have a short learning curve for CRS for peritoneal metastases for CRC.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. METHODS: We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed. FINDINGS: Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). INTERPRETATION: Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. FUNDING: Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.

Primary versus delayed repair for bile duct injuries sustained during cholecystectomy: results of a survey of the Association Francaise de Chirurgie.

BACKGROUND: Bile duct injuries (BDIs) sustained during a cholecystectomy still remain a major surgical problem, and it is still not clear whether the injury should be repaired immediately or a delayed repair is preferred. METHODS: A retrospective national French survey was conducted to compare the results of immediate (at time of cholecystectomy), early (within 45 days after a cholecystectomy) and late (beyond 45 days after a cholecystectomy) surgical repair for BDI sustained during a cholecystectomy. RESULTS: Forty-seven surgical centres provided 640 cases of bile duct injury sustained during a cholecystectomy of which 543 were analysed for the purpose of the present study. The timing of repair was immediate in 194 cases (35.7%), early in 216 cases (39.8%) and late in 133 cases (24.5%). The type of repair was a suture repair in 157 cases (81%), and a bilio-digestive reconstruction in 37 cases (19%) for immediate repair; a suture repair in 119 cases (55.1%) and a bilio-digestive anastomosis in 96 cases (44.9%) for the early repair; and a bilio-digestive reconstruction in 129 cases (97%) and a suture repair in 4 cases (3%) for late repair. A second procedure was required in 110 cases (56.7%) for immediate repair, 80 cases (40.7%) for early repair (P < 0.05) and in 9 cases (6.8%) for late repair (P < 0.001). CONCLUSION: The timing of surgical repair for a bile duct injury sustained during a cholecystectomy influences significantly the rate of a second procedure and a late repair should be preferred option.

Prognostic factors of ischemic colitis after infrarenal aortic surgery.

BACKGROUND: Postoperative ischemic colitis (POIC) remains a frequent and extremely severe complication of infrarenal abdominal aorta surgery. However, its diagnosis and treatment are not always consensual because the incidence is very small. The aim of this retrospective study was to evaluate the prognostic factors of severe colitis after infrarenal aorta surgery. MATERIALS AND METHODS: We analyzed peroperative and perioperative data of the patients who, between 1998 and 2004, underwent infrarenal abdominal aorta surgery and were presented with confirmed POIC. We set two distinct groups: acute colitis group (operated POIC, perioperative deaths, or evolution toward a colic stenosis secondarily operated on) and a moderate colitis group (recovery without aftereffects and no surgery). The main goal was to individualize the prognostic factors of acute colitis. Using the Student's t-test or the Fisher's exact test, the potential prognostic factors were compared between these two groups. RESULTS: Between 1998 and 2004, 679 patients underwent infrarenal abdominal aorta surgery. Among these patients, 28 POIC cases were confirmed: 20 patients had acute POIC and eight had moderate POIC. Demographic and peroperative data were similar in the two groups. Among the 20 patients with acute POIC, 17 were operated on with a postoperative mortality rate of 58.8%. All the patients had at least a left colitis. In 59% of the cases, Hartmann's procedure was performed with a mortality rate of 50%. Early digestive symptoms (p = 0.05), use of vasopressors (p = 0.0377), diagnosis in intensive care unit (p = 0.0095), and a pH <7.35 at D1 (p = 0.0261) were independently associated with acute ischemic colitis. Moreover, we could observe the important role of endoscopy aiming at making diagnosis and prognosis. CONCLUSION: This study highlighted significant prognosis factors of severe colitis. These factors could help take the decision to operate POIC, especially to lower the effect of multiple organ failure syndrome (MOFS).

[Cholangiocarcinomas developing on multiple bile duct hamartomas syndrome]. / Cholangiocarcinomes sur syndrome des microhamartomes biliaires multiples.

Two cases of cholangiocarcinoma arising in a background of multiple bile duct hamartomas are reported. In each case, the clinical and radiological investigations showed a liver tumor with no other concomitant disease. Tumors were resected, and microscopic examination revealed in one case a hilar cholangiocarcinoma, in the other case a peripheric cholangiocarcinoma, both being well-differentiated. It revealed also numerous bile duct hamartomas scattered throughout the liver. In one case, some bile duct hamartomas showed a gradual morphologic transition from benign to dysplastic and neoplastic epithelium. Patients with multiple bile duct hamartomas may have an increased risk of developing cholangiocarcinomas.

OPG, RANK and RANK ligand expression in thyroid lesions.

Receptor activator of NF-kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) play essential roles in bone metabolism. RANKL binds to RANK, which is expressed by osteoclasts whereas OPG acts as its decoy receptor blocking the RANK-RANKL interaction. OPG/RANK/RANKL are produced by variety of tissues including epithelial and mesenchymal cells. However, the role of RANKL/OPG in thyroid pathophysiology remains unclear. The aim of this study was to determine the expression pattern of RANK/RANKL/OPG in primary neoplastic thyroid lesions and in lymph node metastases. 27 specimens from total thyroidectomy were studied by immunohistochemistry: 9 papillary carcinomas (PC), 9 medullary carcinomas (MC), 9 macrovesicular adenomas (MA). Immunohistochemical evidence of RANKL was found in 30 % of MC, 22% of PC while RANKL has never been detected in PC. The expression of RANK is closely related to RANKL. OPG was restricted to the cytoplasm of epithelial in 1 MA and 1 MC. In contrast to pathological tissues, any expression of OPG/RANK/RANKL was detected in healthy thyroid tissue. This work reveals for the first time that OPG/RANK/RANKL are expressed in the pathological thyroid gland by follicular cells, by malignant parafollicular cells as well as in metastatic lymph node microenvironment. Thus OPG/RANK/RANKL molecular triad might play a role during pathogenesis of follicular and parafollicular tumors.

Up-regulated expression of ADAM17 in human colon carcinoma: co-expression with EGFR in neoplastic and endothelial cells.

The ADAM17 metalloproteinase (a disintegrin and metalloprotease 17) controls epidermal growth factor receptor (EGFR) activation through regulated shedding of EGFR ligands. With the advent of new therapeutic options targeting EGFR signalling in colon carcinoma, it was decided to determine ADAM17 status in relation to clinico-pathological parameters and EGFR status. To this end, a series of 39 colon carcinomas were analysed. Immunohistochemistry and immunofluorescence were used to localize ADAM17, EGFR, and the activated forms of EGFR. The activated form of ADAM17 was assessed in primary cancers and colon cell lines by immunoblotting. ADAM17 and EGFR mRNA levels were assessed by quantitative RT-PCR. Chromogenic in situ hybridization (CISH) was used to quantify the HER1 gene. ADAM17 was strongly expressed in all tumours, by both neoplastic and endothelial cells. It was expressed both as a pro- and as an active form in tumours and colonic cancer cell lines. ADAM17 mRNA was up-regulated in 90% of colon carcinomas relative to the paired normal mucosa, whatever the tumour grade or stage. When present, activated EGFR was co-expressed with ADAM17 by colon carcinomas, although at a variable level among tumour cells, and by endothelial cells. EGFR mRNA was overexpressed in 77% of colon carcinomas compared with the paired normal mucosa. One case showed high-level amplification of HER1. In conclusion, this study is the first demonstration that ADAM17 is overexpressed in human primary colon carcinoma, whatever the tumour stage and differentiation and whatever the level of EGFR expression. Its co-expression with EGFR, in both neoplastic and endothelial cells, suggests a role for ADAM17 in tumour growth and angiogenesis.

Repeat hepatectomy for colorectal liver metastases.

This study includes 16 patients (9 men, 7 women; mean age 64 years) who underwent a total of 19 repeat hepatectomies for metastasis after colon (n=7) or rectal (n=9) carcinoma. All patients were reoperated for recurrent liver metastasis after the first resection (mean, 21 months; range, 7-40 months), and three had a third hepatectomy 13, 24, or 65 months after the second. Perioperative mortality was 0% and morbidity was 37%. The 3- and 5-year survival rates after the second resection were 56.8% and 28.4%, respectively, with a median survival of 42.3 months. Seven patients died (mean survival, 25.7 months; range, 9-58 months) before the end of the study. Six patients were alive with one or more recurrences, and three (24, 51, and 173 months of follow-up) were alive without known recurrence. Survival rates for repeat resections of colorectal liver metastases in selected patients were comparable with those obtained after resection of a first liver metastasis.