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International audience; Aim Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3-year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial. Method PRODIGE 22 was a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild-type RAS patients, a third arm testing perioperative FOLFOX-cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and time to recurrence (TTR). Results Overall, 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients represented our intention-to-treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow-up was 54.3 months. Three-year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3-year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed. Conclusion Perioperative FOLFOX has no detrimental effect on long-term oncological outcomes and may be an option for some patients with locally advanced CC.

International audience; To evaluate whether systematic mesh implantation upon primary colostomy creation was effective to prevent PSH.Summary of background data: Previous randomized trials on prevention of PSH by mesh placement have shown contradictory results.Methods: This was a prospective, randomized controlled trial in 18 hospitals in France on patients aged ≥18 receiving a first colostomy for an indication other than infection. Participants were randomized by blocks of random size, stratified by center in a 1:1 ratio to colostomy with or without a synthetic, lightweight monofilament mesh. Patients and outcome assessors were blinded to patient group. The primary endpoint was clinically diagnosed PSH rate at 24 months of the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01380860.Results: From November 2012 to October 2016, 200 patients were enrolled. Finally, 65 patients remained in the no mesh group (Group A) and 70 in the mesh group (Group B) at 24 months with the most common reason for drop-out being death (n = 41). At 24 months, PSH was clinically detected in 28 patients (28%) in Group A and 30 (31%) in Group B [P = 0.77, odds ratio = 1.15 95% confidence interval = (0.62;2.13)]. Stoma-related complications were reported in 32 Group A patients and 37 Group B patients, but no mesh infections. There were no deaths related to mesh insertion.Conclusion: We failed to show efficiency of a prophylactic mesh on PSH rate. Placement of a mesh in a retro-muscular position with a central incision to allow colon passage cannot be recommended to prevent PSH. Optimization of mesh location and reinforcement material should be performed.

Summary 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.

Background and Aims Intestinal epithelial cells [IECs] from inflammatory bowel disease [IBD] patients exhibit an excessive induction of endoplasmic reticulum stress [ER stress] linked to altered intestinal barrier function and inflammation. Colonic tissues and the luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown. We aimed to study the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions Methods The impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cell lines or organoids. Moreover, treating human intestinal cells with protease-activated receptor antagonists allowed us to investigate ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology. Results Colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apical trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 [CXCL8]. The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of protease-activated receptors 2 and 4. Conclusions Excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, promoting the development of inflammatory process.

Background Spleen-preserving distal pancreatectomy with resection of the splenic vessels (VR-SPDP) is an effective procedure. However, hemodynamic changes in splenogastric circulation may lead to the development of gastric varices (GV) with a risk of gastrointestinal (GI) bleeding. This retrospective study aimed to assess the long-term postoperative clinical follow-up of patients and review the late postoperative abdominal computed tomography (CT) or endoscopic examination. Methods From 1988 to 2015, 48 consecutive VR-SPDP for benign or low-grade malignant disease were included. Late postoperative follow-up was undertaken with the use of a prospective database and assessment undertaken by CT and/or endoscopy. Results The median follow-up was 76 months (range: 12–334 months). Two patients were lost to follow-up. Gastrointestinal hemorrhage occurred in one patient. Endoscopy and abdominal CT showed submucosal GV in five patients. Ten patients had perigastric varices (27%), but none developed clinical complications from their varices. All varices occurred within one year after distal pancreatectomy and remained stable during follow-up. Discussion Asymptomatic varices frequently occurred in patients who underwent VR-SPDP, but bleeding risk seemed low. Abdominal CT could identify GV and distinguish submucosal varices with a higher risk of gastric bleeding.

Ventral mesh rectopexy (VMR) is a surgical option to treat rectal prolapse with pelvic floor dysfunction (PFD). Using synthetic surgical glue to fix the mesh to the anterior rectal wall after ventral dissection could be advantageous in comparison with sutured or stapled fixation. This study aimed to evaluate the safety and efficacy of synthetic surgical glue for mesh fixation compared with suture mesh fixation in VMR. This observational cohort study is a retrospective analysis conducted in a University Hospital Pelvic Surgery Center. All consecutive female patients (n = 176) who underwent laparoscopic or laparotomic VMR between January 2009 and December 2014 were included. Two groups were defined based on mesh fixation technique of the rectal wall: VMR with synthetic glue (n = 66) and VMR with suture (n = 110). The recurrence-free survival after VMR was determined by Kaplan–Meier method and multivariate analysis by Cox regression. Short-term postoperative complications, postoperative symptom improvement, the need for complementary treatment postoperatively, and procedure length were evaluated. A total of 176 females patients (mean age, 58.6 ± 13.7 years) underwent VMR with synthetic mesh. Mean recurrence-free survivals after VMR were 17.16 (CI 95% 16.54–17.80) and 17.33 (CI 95% 16.89–17.77) months in the glue group and the suture group, respectively (p > 0.05). Cox regression identified an independent effect on the recurrence risk of the external rectal prolapse, alone, or in combination with other anatomical abnormalities (HR = 0.37; CI 95% 0.14–0.93; p = 0.03). There was no significant difference of short-term postoperative morbidity, procedure length, postoperative symptom improvement, or need for complementary treatment postoperatively between suture versus glue groups (all p > 0.05). Use of glue to fix the mesh in VMR was safe and had no impact on outcomes. External prolapse was the unique significant predictive factor for recurrence.

4110 Background: Neoadjuvant chemotherapy in a perioperative setting has proven valuable in locally advanced resectable colon cancer (CC) in terms of toxicity, postoperative morbidity and downstaging, but its effect on oncological outcomes remains uncertain. Methods: Prodige 22 was a randomized multicenter phase II trial in patients with resectable high-risk T3, T4 and/or N2 CC on baseline CT-scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type (wt) patients a third arm testing perioperative FOLFOX-cetuximab was added. Primary endpoint was the Tumor Regression Grade. Secondary endpoints were 3-years overall (OS), disease-free survival (DFS) and time to recurrence (TTR). Results: 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients (control, n = 52; FOLFOX peri-op n = 52) represented our intention-to-treat population. In the FOLFOX peri-op group, 96% received the schedule 4 cycles prior to surgery and all but one underwent adjuvant FOLFOX for a total of 12 cycles. In the control arm, 38 patients received adjuvant FOLFOX (1 postoperative death and 13 low-risk stage II patients). Median follow-up was 54.3 months [48.5-57.2]. Nineteen deaths and 26 disease recurrences were observed leading to a 3 years-OS of 90.3% in both arms (p = 0.7) and to a 3-years DFS of 76.8% and 69.2% in the peri-op and control arm respectively (p = 0.6). A trend to a better TTR in the peri-op arm was observed with a 3-years TTR of 82% as compared to 72% in the control arm (p = 0.3). No benefit from adding Cetuximab was observed in the 16 RAS-wt treated patients. Conclusions: In this pilot randomized study, perioperative FOLFOX chemotherapy has no detrimental effect on long term oncological outcomes and may be an option for some patients with locally advanced CC. A pooled analysis of randomized trials testing peri-operative strategies in this setting is warranted. Clinical trial information: NCT01675999 .

IF 3.061; International audience; IntroductionThis document is a summary of the French Intergroup guidelines regarding the management of rectal adenocarcinoma published in February 2016.MethodThis collaborative work, under the auspices of most of the French medical societies involved in the management of rectal cancer, is based on the previous guidelines published in 2013. Recommendations are graded into 3 categories according to the level of evidence of data found in the literature.ResultsIn agreement with the ESMO guidelines (2013), non-metastatic rectal cancers have been stratified in 4 risk groups according to endoscopy, MRI or endorectal-ultrasonography. Locally-advanced tumors are limited to groups 3 and 4 (T3 ≥4 cm or T3c–d or N1-2 or T4). These tumors are usually treated using neoadjuvant treatment and total proctectomy (TME). Adjuvant treatment depends on the pathological findings. Very early (group 1) or early (group 2) tumors are managed mainly by surgery, and organ preservation may be an option in selected cases. For metastatic tumors, the recommendations are based on less robust evidence and chemotherapy plays a major role.ConclusionSuch recommendations are constantly being optimized and each individual case must be discussed within a Multi-Disciplinary Team.

Introduction Les protheses biologiques sont utilisees dans des indications limitees, notamment la reparation parietale en milieu contamine en raison de leur cout eleve. Leur efficacite est remise en question par plusieurs etudes recentes. Nous avons donc etudie les resultats, dont la recidive, de l’ensemble de nos patients ayant recu une prothese biologique. Materiel et methode Au total, 68 patients ayant eu une mise en place de prothese biologique de 2009 a 2015, dans un seul centre, ont ete revus retrospectivement. Resultats Le site de pose etait sur la paroi abdominale anterieure dans 72 % des cas, pelvien dans 28 %. La mediane de suivi etait de 19 mois. En postoperatoire precoce, 30 % des patients ont eu un abces de paroi ; 73 % ont presente une complication tardive dont 16 % d’infection de site operatoire. Au total, 56 % des patients ont presente une recidive d’eventration. En analyse multivariee, les facteurs de risque de recidive etaient une eventration peri-stomiale (p = 0,007) et la cure d’une recidive d’eventration (p = 0,002). Conclusion Une majorite de patients presente une recidive d’eventration a moyen terme ce qui remet en question l’utilisation des protheses biologiques. Leurs resultats devront etre confrontes a ceux des protheses semi-resorbables.

L’artere hepatique commune, issue du tronc cœliaque (TC), se divise en 2 branches : l’artere hepatique propre (AHP) se divisant elle-meme en 2 branches terminales, et l’artere gastroduodenale (AGD). Cette vascularisation modale n’est retrouvee que dans 76 % des cas. Dans 10 %, une artere hepatique droite (AHD) nait directement de l’artere mesenterique superieure (AMS). Elle peut vasculariser le foie droit, le lobe droit ou l’ensemble du foie (AHD foie total). Cette variante anatomique peut compliquer la duodenopancreatectomie cephalique (DPC), seul traitement curatif des tumeurs pancreatiques cephaliques (80 % des tumeurs pancreatiques totales). Si elle nait precocement sur l’AMS, alors son trajet passe au sein de la lame retro-portale, necessairement resequee lors de la DPC pour etre en resection microscopiquement complete (R0). Cependant la ligature de l’AHD risque d’entrainer une ischemie hepatique ainsi qu’un plus haut risque de fistule anastomotique (bilio-digestive). Nous avons observe, dans notre centre, notre pratique face a une AHD lors d’une DPC. Entre janvier 2012 et janvier 2015, 83 patients ont eu une DPC. Neuf d’entre eux presentaient une AHD (11 %). Leur prise en charge a consiste en peropertatoire a une section et reimplantation dans 1 cas (11 %), ligature-section simple dans 1 cas (11 %), et conservation dans 7 cas (77 %). Aucune ischemie hepatique n’etait notee. En presence d’une AHD, le pourcentage de resection microscopiquement incomplete passait de 22 % a 33 %, ce qui n’etait pas significatif. La presence d’une AHD complique nettement la DPC et a meme longtemps ete consideree comme une contre-indication a cette chirurgie. Cependant, dans notre etude, nous constatons qu’elle ne compromet pas le resultat oncologique. En 2014, une equipe lilloise proposait meme une embolisation de l’AHD 3 semaines avant la DPC pour permettre le developpement d’une collateralite et donc sa section en securite. Aujourd’hui une AHD ne doit plus contre indiquer une DPC.

Le traitement chirurgical par duodeno-pancreatectomie cephalique (DPC) est, ce jour, le seul traitement curatif des tumeurs pancreatiques cephaliques (80 % des tumeurs pancreatiques). Il permet une survie globale a 5 ans de 20 % (vs 3 %) si la resection chirurgicale est microscopiquement complete (R0). La situation anatomique de la tete du pancreas explique le faible pourcentage de resecabilite (environ 20 % d’emblee). En effet, elle est au contact de structures majeures : la veine mesenterique (VMS), l’artere mesenterique (AMS) (avec la lame retro portale s’y inserant) et la veine porte en posterieur, ainsi que le tronc cœliaque en superieur. L’engainement de ces vaisseaux par une tumeur la rend alors non resecable. Nous avons recueilli dans notre centre tous les patients ayant presente une tumeur pancreatique cephalique entre janvier 2012 et janvier 2015. Les limites vasculaires a la resecabilite etaient observees. Trois cent quarante et un patients etaient recenses, avec 80 (23 %) operes d’emblee d’une DPC. Cent quatre patients (30 %) presentaient des limites vasculaires a leur resecabilite (tumeur localement avancee) ; principalement par engainement de l’AMS dans 42 % des cas (n = 43), et de la VMS dans 35 % des cas (n = 36). Quatre-vingt trois patients (80 %) ont alors recu un traitement neo adjuvant au terme duquel 3 seulement (3,5 %) ont pu etre operes. Chez 9 patients (10,8 %), nous avons associe une resection segmentaire veineuse (mesenterico porte) pour autoriser la DPC. Au total, 83 patients etaient operes d’une DPC (24 %) : 18 (soit 22,5 %) etaient R1 (resection microscopiquement incomplete) : 8 sur la lame retro portale, 8 sur les vaisseaux mesenteriques et 3 sur la tranche pancreatique. Ce pourcentage etait statistiquement plus eleve en cas de resection veineuse associee a la DPC (77 % vs 16 %) (p = 0,001). Les tumeurs pancreatiques cephaliques voient leur incidence augmenter de facon considerable. Des propositions apparaissent pour ameliorer leur resecabilite, notamment en cas de contacts vasculaires, avec des resultats pour l’instant discordants.