Genomic profiling of small bowel adenocarcinoma: a pooled analysis from 3 databases.

BACKGROUND: Small bowel adenocarcinoma is a rare disease. The genomic profiling tumours according to clinical characteristics and its impact on the prognosis remains unclear. METHODS: A pooled analysis of clinical data, genomic profiling and MisMatch Repair (MMR) status from three databases was performed. RESULTS: A total of 188 tumour samples were analysed. A predisposing disease was reported in 22.3%, mainly Lynch syndrome and Crohn's disease. The tumours were localized in 80.2% and metastatic in 18.8%. The most frequent mutations were KRAS (42.0%) among them 7/79 are G12C, TP53 (40.4%), APC (19.1%), PIK3CA (18.6%), SMAD4 (12.8%) and ERBB2 (9.6%). Mutation distribution differed according to predisposing disease for TP53, ERBB2, IDH1, FGFR3, FGFR1 and KDR. KRAS and SMAD4 mutations were more frequent in metastatic tumour, whereas ERBB2 mutations were absent in metastatic tumour. For localized tumour, APC mutation was independently associated with a poor overall survival (OS) (p = 0.0254). 31.8% of localized tumours and 11.3% of metastatic tumours were dMMR (29.8% of the entire cohort). A dMMR status was associated with a better OS (HR = 0.61 [0.39-0.96], p = 0.0316). CONCLUSIONS: There is a different genomic profile according to the stage and predisposing disease. dMMR and APC mutation in localized tumour predict a better prognosis.

Is Delaying a Coloanal Anastomosis the Ideal Solution for Rectal Surgery?: Analysis of a Multicentric Cohort of 564 Patients From the GRECCAR.

OBJECTIVES: To assess the specific results of delayed coloanal anastomosis (DCAA) in light of its 2 main indications. BACKGROUND: DCAA can be proposed either immediately after a low anterior resection (primary DCAA) or after the failure of a primary pelvic surgery as a salvage procedure (salvage DCAA). METHODS: All patients who underwent DCAA intervention at 30 GRECCAR-affiliated hospitals between 2010 and 2021 were retrospectively included. RESULTS: Five hundred sixty-four patients (male: 63%; median age: 62 years; interquartile range: 53-69) underwent a DCAA: 66% for primary DCAA and 34% for salvage DCAA. Overall morbidity, major morbidity, and mortality were 57%, 30%, and 1.1%, respectively, without any significant differences between primary DCAA and salvage DCAA ( P = 0.933; P = 0.238, and P = 0.410, respectively). Anastomotic leakage was more frequent after salvage DCAA (23%) than after primary DCAA (15%), ( P = 0.016).Fifty-five patients (10%) developed necrosis of the intra-abdominal colon. In multivariate analysis, intra-abdominal colon necrosis was significantly associated with male sex [odds ratio (OR) = 2.67 95% CI: 1.22-6.49; P = 0.020], body mass index >25 (OR = 2.78 95% CI: 1.37-6.00; P = 0.006), and peripheral artery disease (OR = 4.68 95% CI: 1.12-19.1; P = 0.030). The occurrence of this complication was similar between primary DCAA (11%) and salvage DCAA (8%), ( P = 0.289).Preservation of bowel continuity was reached 3 years after DCAA in 74% of the cohort (primary DCAA: 77% vs salvage DCAA: 68%, P = 0.031). Among patients with a DCAA mannered without diverting stoma, 75% (301/403) have never required a stoma at the last follow-up. CONCLUSIONS: DCAA makes it possible to definitively avoid a stoma in 75% of patients when mannered initially without a stoma and to save bowel continuity in 68% of the patients in the setting of failure of primary pelvic surgery.

A prediction model to refine the timing of an early second-look laparoscopic exploration in patients with colon cancer at high risk of early peritoneal metastasis recurrence.

BACKGROUND: In patients at high risk of peritoneal metastasis (PM) recurrence following surgical treatment of colon cancer (CC), second-look laparoscopic exploration (SLLE) is mandatory; however, the best timing is unknown. We created a tool to refine the timing of early SLLE in patients at high risk of PM recurrence. METHODS: This international cohort study included patients who underwent CC surgery between 2009 and 2020. All patients had PM recurrence. Factors associated with PM-free survival (PMFS) were assessed using Cox regression. The primary endpoint was early PM recurrence defined as a PMFS of <6 months. A model (logistic regression) was fitted and corrected using bootstrap. RESULTS: In total, 235 patients were included. The median PMFS was 13 (IQR, 8-22) months, and 15.7% of the patients experienced an early PM recurrence. Synchronous limited PM and/or ovarian metastasis (hazard ratio [HR]: 2.50; 95% confidence interval [CI]: [1.66-3.78]; p < 0.001) were associated with a very high-risk status requiring SLLE. T4 (HR: 1.47; 95% CI: [1.03-2.11]; p = 0.036), transverse tumor localization (HR: 0.35; 95% CI: [0.17-0.69]; p = 0.002), emergency surgery (HR: 2.06; 95% CI: [1.36-3.13]; p < 0.001), mucinous subtype (HR: 0.50; 95% CI [0.30, 0.82]; p = 0.006), microsatellite instability (HR: 2.29; 95% CI [1.06, 4.93]; p = 0.036), KRAS mutation (HR: 1.78; 95% CI: [1.24-2.55]; p = 0.002), and complete protocol of adjuvant chemotherapy (HR: 0.93; 95% CI: [0.89-0.96]; p < 0.001) were also prognostic factors for PMFS. Thus, a model was fitted (area under the curve: 0.87; 95% CI: [0.82-0.92]) for prediction, and a cutoff of 150 points was identified to classify patients at high risk of early PM recurrence. CONCLUSION: Using a nomogram, eight prognostic factors were identified to select patients at high risk for early PM recurrence objectively. Patients reaching 150 points could benefit from an early SLLE.

Iatrogenic ureteral injury during colorectal surgery has a significant impact on patient outcomes: a French multicentric retrospective cohort study.

AIM: The long-term urological sequelae after iatrogenic ureteral injury (IUI) during colorectal surgery are not clearly known. The aims of this work were to report the incidence of IUI and to analyse the long-term consequences of urological late complications and their impact on oncological results of IUI occurring during colorectal surgery through a French multicentric experience (GRECCAR group). METHOD: All the patients who presented with IUI during colorectal surgery between 2010 and 2019 were retrospectively included. Patients with ureteral involvement needing en bloc resection, delayed ureteral stricture or noncolorectal surgery were not considered. RESULTS: A total of 202 patients (93 men, mean age 63 ± 14 years) were identified in 29 centres, corresponding to 0.32% of colorectal surgeries (n = 63 562). Index colorectal surgery was mainly oncological (n = 130, 64%). IUI was diagnosed postoperatively in 112 patients (55%) after a mean delay of 11 ± 9 days. Intraoperative diagnosis of IUI was significantly associated with shorter length of stay (21 ± 22 days vs. 34 ± 22 days, p < 0.0001), lower rates of postoperative hydronephrosis (2% vs. 10%, p = 0.04), anastomotic complication (7% vs. 22.5%, p = 0.002) and thromboembolic event (0% vs. 6%, p = 0.02) than postoperative diagnosis of IUI. Delayed chemotherapy because of IUI was reported in 27% of patients. At the end of the follow-up [3 ± 2.6 years (1 month-13 years)], 72 patients presented with urological sequalae (36%). Six patients (3%) required a nephrectomy. CONCLUSION: IUI during colorectal surgery has few consequences for the patients if recognized early. Long-term urological sequelae can occur in a third of patients. IUI may affect oncological outcomes in colorectal surgery by delaying adjuvant chemotherapy, especially when the ureteral injury is not diagnosed peroperatively.

Feasibility and Safety of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy With or Without Intraoperative Intravenous 5-Fluorouracil and Leucovorin for Colorectal Peritoneal Metastases: A Multicenter Comparative Cohort Study.

BACKGROUND: This retrospective multicenter cohort study compared the feasibility and safety of oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-Ox) with or without intraoperative intravenous 5-fluorouracil (5-FU) and leucovorin (L). METHODS: Our study included consecutive patients with histologically proven unresectable and isolated colorectal peritoneal metastases (cPM) treated with PIPAC-Ox in seven tertiary referral centers between January 2015 and April 2020. Toxicity events and oncological outcomes (histological response, progression-free survival, and overall survival) were compared between patients who received intraoperative intravenous 5-FU/L (PIPAC-Ox + 5-FU/L group) and patients who did not (PIPAC-Ox group). RESULTS: In total, 101 patients (263 procedures) were included in the PIPAC-Ox group and 30 patients (80 procedures) were included in the PIPAC-Ox + 5-FU/L group. Common Terminology Criteria for Adverse Events v4.0 grade 2 or higher adverse events occurred in 48 of 101 (47.5%) patients in the PIPAC-Ox group and in 13 of 30 (43.3%) patients in the PIPAC-Ox + 5-FU/L group (p = 0.73). The complete histological response rates according to the peritoneal regression grading score were 27% for the PIPAC-Ox + 5-FU/L group and 18% for the PIPAC-Ox group (p = 0.74). No statistically significant differences were observed in overall or progression-free survival between the two groups. CONCLUSIONS: The safety and feasibility of PIPAC-Ox + 5-FU/L appears to be similar to the safety and feasibility of PIPAC-Ox alone in patients with unresectable cPM. Oncological outcomes must be evaluated in larger studies.

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.

Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort.

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.

Half of Postoperative Deaths After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Could be Preventable: A French Root Cause Analysis on 5562 Patients.

OBJECTIVE: To perform a retrospective root-cause analysis of postoperative death after CRS and HIPEC procedures. BACKGROUND: The combination of CRS and HIPEC is an effective therapeutic strategy to treat peritoneal surface malignancies, however it is associated with significant postoperative mortality. METHODS: All patients treated with a combination of CRS and HIPEC between January 2009 and December 2018 in 22 French centers and died in the hospital, were retrospectively analyzed. Perioperative data of the 101 patients were collected by a local senior surgeon with a sole junior surgeon. Three independent experts investigated the typical root cause of death and provided conclusions on whether postoperative death was preventable (PREV group) or not (NON-PREV group). A typical root cause of preventable postoperative death was classified on a cause-and-effect diagram. RESULTS: Of the 5562 CRS+HIPEC procedures performed, 101 in-hospital deaths (1.8%) were identified, of which a total of 18 patients of 70 years old and above and 20 patients with ASA score of 3. Etiology of peritoneal disease was mainly colorectal. A total of 54 patients (53%) were classified in the PREV group and 47 patients (47%) in the NON-PREV group. The results of the study show that in the PREV group, WHO performance status 1-2 was more frequent and the Median Peritoneal Cancer Index was higher compared with those of the NON-PREV group. The cause of death in the PREV group was classified as: (i) preoperatively for debatable indication (59%), (ii) intraoperatively (30%) and (iii) postoperatively in 17 patients (31%). A multifactorial cause of death was found in 11 patients (20%). CONCLUSION: More than half of the postoperative deaths after combined CRS and HIPEC may be preventable, mainly by following guidelines regarding preoperative selection of the patients and adequate intraoperative decisions.

Sphincter-saving surgery for ultra-low rectal carcinoma initially indicated for abdominoperineal resection: Is it safe on a long-term follow-up?

BACKGROUND: Rate of abdominoperineal resection (APR) varies from countries and surgeons. Surgical impact of preoperative treatment for ultra-low rectal carcinoma (ULRC) initially indicated for APR is debated. We report the 10-year oncological results from a prospective controlled trial (GRECCAR 1) which evaluate the sphincter saving surgery (SSR). METHODS: ULRC indicated for APR were included (n = 207). Randomization was between high-dose radiation (HDR, 45 + 18 Gy) and radiochemotherapy (RCT, 45 Gy + 5FU infusion). Surgical decision was based on tumour volume regression at surgery. SSR technique was standardized as mucosectomy (M) or partial (PISR)/complete (CISR) intersphincteric resection. RESULTS: Overall SSR rate was 85% (72% ISR), postoperative morbidity 27%, with no mortality. There were no significant differences between the HDR and RCT groups: 10-year overall survival (OS10) 70.1% versus 69.4%, respectively, 10.2% local recurrence (9.2%/14.5%) and 27.6% metastases (32.4%/27.7%). OS and disease-free survival were significantly longer for SSR (72.2% and 60.1%, respectively) versus APR (54.7% and 38.3%). No difference in OS10 between surgical approaches (M 78.9%, PISR 75.5%, CISR 65.5%) or tumour location (low 64.8%, ultralow 76.7%). CONCLUSION: GRECCAR 1 demonstrates the feasibility of safely changing an initial APR indication into an SSR procedure according to the preoperative treatment tumour response. Long-term oncologic follow-up validates this attitude.

Multicystic peritoneal mesothelioma treated with cytoreductive surgery followed or not by hyperthermic intraperitoneal chemotherapy: results from a large multicentric cohort.

BACKGROUND: Multicystic peritoneal mesothelioma (MCPM) is a rare, slowly growing, condition prone to recur after surgery. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) added to complete cytoreductive surgery (CRS) remains controversial and difficult to assess. As patients are mostly reproductive age women, surgical approach, and fertility considerations are important aspects of the management. This observational retrospective review aimed to accurate treatment strategy reflections. METHODS: The RENAPE database (French expert centers network) was analyzed over a 1999-2019 period. MCPM patients treated with CRS were included. A special focus on HIPEC, mini-invasive approach, and fertility considerations was performed. RESULTS: Overall 60 patients (50 women) were included with a median PCI of 10 (4-14) allowing 97% of complete surgery, followed by HIPEC in 82% of patients. A quarter of patients had a laparoscopic approach. Twelve patients (20%) recurred with a 3-year recurrence free survival of 84.2% (95% confidence interval 74.7-95.0). The hazard of recurrence was numerically reduced among patients receiving HIPEC, however, not statistically significant (hazard ratio 0.41, 0.12-1.42, p = 0.200). A severe post-operative adverse event occurred in 22% of patients with five patients submitted to a subsequent reoperation. Among four patients with a childbearing desire, three were successful (two had a laparoscopic-CRS-HIPEC and one a conventional CRS without HIPEC). CONCLUSION: MCPM patients treatment should aim at a complete CRS. The intraoperative treatment options as laparoscopic approach, fertility function sparing and HIPEC should be discussed in expert centers to propose the most appropriate strategy.

Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients.

Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range 23-90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%) and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7% and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease and Peutz-Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5% and 35.6% of patients had localised and resectable, locally advanced unresectable and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage and duodenum location. Adjuvant chemotherapy (oxaliplatin-based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54-months median follow-up, the 5-year overall survival (OS) was 87.9%, 78.2% and 55.5% in Stages I, II and III, respectively. The median OS of patients with Stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p = 0.047) and T4 stage (p = 0.001) were associated with a higher risk of death. In conclusion, our study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA-resected tumours, the prognostic factors for OS were grade and T stage.

Multi-nanolayer drug delivery using radiofrequency plasma technology.

BACKGROUND: It may be impossible to perform cancer surgery with free margins in the presence of an unresectable structure. Local drug treatment after surgery has been proposed to increase the rate of tumor control. METHODS: Multi-nanolayers (10-330 nm) were generated by a low-pressure (375mTorr) inductively coupled plasma (13.56 MHz) reactor for anticancer drug delivery by the deposition of polycaprolactone-polyethylene glycol multistack barrier on the collagen membrane (100 µm thickness). Carboplatin (300 µg/cm2) was used for the in vitro and in vivo investigations. Energy-dispersive X-ray spectroscopy (15 keV), scanning electron microscopy and inductively coupled plasma mass spectrometry were used to detect the presence of carboplatin in the nanolayer, the tumor sample and the culture medium. Preclinical studies were performed on ovarian (OVCAR-3NIH) and colon (CT26) cancer cell lines as xenografts (45 days) and allografts (23 days) in Swiss-nude (n = 6) and immunocompetent BALB/cByJ mice (n = 24), respectively. RESULTS: The loading of carboplatin or other drugs between the nanofilm on the collagen membrane did not modify the mesh complex architecture or the drug properties. Drugs were detectable on the membrane for more than 2 weeks in the in vitro analysis and more than 10 days in the in vivo analysis. Cytotoxic mesh decreased cell adherence (down 5.42-fold) and induced cancer cell destruction (up to 7.87-fold). Implantation of the mesh on the mouse tumor nodule modified the cell architecture and decreased the tumor size (50.26%) compared to the control by inducing cell apoptosis. CONCLUSION: Plasma technology allows a mesh to be built with multi-nanolayer anticancer drug delivery on collagen membranes.

The role of single-incision laparoscopic peritoneal exploration in the management of patients with peritoneal metastases.

BACKGROUND: The outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) depends on the extent of peritoneal metastases (PM) and the completeness of cytoreduction (CCR). The role of preoperative assessment of PM is to identify potential candidates for CRS/HIPEC and to prevent unwarranted laparotomy for those who are not. Laparoscopy has been utilized for that purpose but with concerns related to technical difficulties and risk of trocar site metastases. Single-incision laparoscopic peritoneal exploration (SILPE) has not yet been evaluated in this setting. METHODS: This single-center retrospective study examined patients from January 2011 to December 2015 who underwent SILPE for diagnosis and staging of PM. Preoperative, intraoperative, and postoperative data were collected. For the patients who underwent subsequent laparotomy, a comparison between SILPE and laparotomy findings was made. RESULTS: A total of 183 SILPE were performed. Primary sites were mostly colorectal in 72 cases (39.3%) and gastric in 47 (25.7%). Overall, 157 patients (85.8%) had at least one prior abdominal surgery and 48 (26.2%) had 3 or more. SILPE was successfully achieved in 90.2% of the cases. Two (1.2%) intraoperative complications and five (3%) postoperative complications were observed. Eighty-one patients had laparotomy, with a median of 27 days between SILPE and laparotomy (4-162 days). The peritoneal carcinomatosis index PCI was 9.7 ± 7.5 at SILPE, and 13.5 ± 9.6 at laparotomy. The positive predictive value of SILPE to predict CCR was 79.5%. SILPE sensitivity was 75% and specificity 97%. The lowest sensitivity was in regions 9-12 ranging from 44 to 53%. CONCLUSION: SILPE can be safely incorporated in the management of patients with PM. It is a safe and feasible staging tool, allowing for preventing unwarranted laparotomy for patients not deemed candidate for CRS/HIPEC. Even though it may underestimate PCI, SILPE accurately predicts the possibility of CCR.

Are the recommendations for post-operative antibiotics in patients with grade I or II acute calculous cholecystitis being applied in clinical practice?

BACKGROUND: There is a level-1 evidence indicating that postoperative antibiotics are unnecessary following cholecystectomy for grade I or II acute calculous cholecystitis (ACC). We wanted to evaluate the applications of this recommendation in clinical practice four years after the original publication in ABCAL-participating centers. METHODS: A retrospective analysis of patients operated for grade I or II ACC from January to December 2016 in ABCAL-participating centers was performed. Inclusion criteria were the same as for the ABCAL-study. The primary endpoint was the postoperative antibiotic administration rate. The secondary endpoints were postoperative outcomes. RESULTS: Of the 283 patients included, 64% received postoperative antibiotics. Only 19% received antibiotics after POD1. The perioperative outcomes were similar between those that did or did not receive antibiotics after POD1. The median [range] length of stay was significantly shorter in patients who did not receive postoperative antibiotics (4 days [1-20]) compared to the others (6 days [1-50], p > 0.001). CONCLUSION: Despite strong recommendations included in the Tokyo 2018 guidelines, the results of the ABCAL-study are poorly applied even if the absence of postoperative antibiotics has no impact on morbidity. It is important to stress that postoperative antibiotics are not necessary after cholecystectomy for grade I or II ACC.

CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer.

BACKGROUND: Minimal residual disease is the main issue of advanced ovarian cancer treatment. According to the literature and previous results, we hypothesized that Mesenchymal Stromal Cells (MSC) could support this minimal residual disease by protecting ovarian cancer cells (OCC) from chemotherapy. In vitro study confirmed that MSC could induce OCC chemoresistance without contact using transwell setting. Further experiments showed that this induced chemoresistance was dependent on IL-6 OCC stimulation. METHODS: We combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions. RESULTS: We demonstrated that Tocilizumab® (anti-IL-6R therapy) in association with chemotherapy significantly reduced the peritoneal carcinosis index (PCI) than chemotherapy alone in mice xenografted with OCCs+MSCs. Further experiments showed that CCL2 and CCL5 are released by MSC in transwell co-culture and induce OCCs IL-6 secretion and chemoresistance. Finally, we found that IL-6 induced chemoresistance was dependent on PYK2 phosphorylation. CONCLUSIONS: These findings highlight the potential key role of the stroma in protecting minimal residual disease from chemotherapy, thus favoring recurrences. Future clinical trials targeting stroma could use anti-IL-6 therapy in association with chemotherapy.

Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Organ preservation is a concept proposed for patients with rectal cancer after a good clinical response to neoadjuvant chemotherapy, to potentially avoid morbidity and side-effects of rectal excision. The objective of this study was to compare local excision and total mesorectal excision in patients with a good response after chemoradiotherapy for lower rectal cancer. METHODS: We did a prospective, randomised, open-label, multicentre, phase 3 trial at 15 tertiary centres in France that were experts in the treatment of rectal cancer. Patients aged 18 years and older with stage T2T3 lower rectal carcinoma, of maximum size 4 cm, who had a good clinical response to neoadjuvant chemoradiotherapy (residual tumour ≤2 cm) were centrally randomly assigned by the surgeon before surgery to either local excision or total mesorectal excision surgery. Randomisation, which was done via the internet, was not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was required if tumour stage was ypT2-3. The primary endpoint was a composite outcome of death, recurrence, morbidity, and side-effects at 2 years after surgery, to show superiority of local excision over total mesorectal excision in the modified intention-to-treat (ITT) population (expected proportions of patients having at least one event were 25% vs 60% for superiority). This trial was registered with ClinicalTrials.gov, number NCT00427375. FINDINGS: From March 1, 2007, to Sept 24, 2012, 186 patients received chemoradiotherapy and were enrolled in the study. 148 good clinical responders were randomly assigned to treatment, three were excluded (because they had metastatic disease, tumour >8 cm from anal verge, and withdrew consent), and 145 were analysed: 74 in the local excision group and 71 in the total mesorectal excision group. In the local excision group, 26 patients had a completion total mesorectal excision. At 2 years in the modified ITT population, one or more events from the composite primary outcome occurred in 41 (56%) of 73 patients in the local excision group and 33 (48%) of 69 in the total mesorectal excision group (odds ratio 1·33, 95% CI 0·62-2·86; p=0·43). In the modified ITT analysis, there was no difference between the groups in all components of the composite outcome, and superiority was not shown for local excision over total mesorectal excision. INTERPRETATION: We failed to show superiority of local excision over total mesorectal excision, because many patients in the local excision group received a completion total mesorectal excision that probably increased morbidity and side-effects, and compromised the potential advantages of local excision. Better patient selection to avoid unnecessary completion total mesorectal excision could improve the strategy. FUNDING: National Cancer Institute of France, Sanofi, Roche Pharma.

Prediction of Resectability in Pseudomyxoma Peritonei with a New CT Score.

BACKGROUND: Curative treatment of pseudomyxoma peritonei (PMP) is complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). OBJECTIVE: The aim of this study was to build and evaluate a preoperative imaging score to predict resectability. PATIENTS AND METHODS: Between 2007 and 2014, all PMP patients in two tertiary reference centers who underwent laparotomy with intent to undergo CRS and HIPEC were included in this study retrospectively. Thickness of tumor burden was measured on preoperative multidetector-row computed tomography (MDCT) by two radiologists blinded to surgical results in five predetermined areas. Patients were divided into two cohorts with the same resectability rate (building and validation). The performances of the scores were assessed using receiver operating characteristic (ROC) curve analyses. RESULTS: Overall, 126 patients were included, with compete CRS being achieved in 91/126 patients (72.2%). Two cohorts of 63 patients matched by age, sex, burden of disease, resectability rate, and pathological grade were constituted. The MDCT score was the sum of the five measures, and was higher in unresectable disease [median 46.2 mm (range 27.9-74.6) vs. 0.0 mm (range 0.0-14.0), p < 0.001]. Area under the ROC curve was 0.863 (range 0.727-0.968) and 0.801 (range 0.676-0.914) in the building and validation cohorts, respectively. A threshold of 28 mm yielded a sensitivity, specificity, positive predictive and negative predictive value of 94, 81, 81 and 94% in the building cohort, and 80, 68, 59 and 85% in the validation cohort, respectively. Using our score, overall and disease-free survival were increased in the group classified as resectable. CONCLUSION: A simple preoperative MDCT score measuring tumor burden in the perihepatic region is able to predict resectability and survival of PMP patients.

Impact of RAS Mutations in Metastatic Colorectal Cancer After Potentially Curative Resection: Does Site of Metastases Matter?

BACKGROUND: RAS mutation status is an important prognostic factor after resection of liver metastases (LiM) from colorectal cancer (CRC). The prognostic significance of RAS after resection of lung (LuM) and peritoneal (PM) metastases from CRC is unknown. METHODS: Between 2005 and 2014, all consecutive patients with known RAS status who underwent potentially curative resection for LiM, LuM, or PM were evaluated. RESULTS: A total of 720 patients with known RAS status underwent resection of LiM (n = 468), LuM (n = 102), and PM (n = 150). RAS mutations were identified in 63 and 58% of patients with LuM and PM, respectively, compared with 41% of patients with LiM (p < 0.001). Five-year overall survival (OS) after resection of PM was 45%, compared with 52% after resection of LiM (p = 0.018) and 64% after resection of LuM (p = 0.005). RAS mutations were associated with significantly worse OS after resection of LiM (p < 0.001), but did not affect OS among patients undergoing resection of LuM (p = 0.41) and PM (p = 0.65). CONCLUSIONS: RAS mutations are more prevalent among patients undergoing resection of LuM and PM than LiM but do not affect survival after lung and peritoneal metastasectomy, as they do after hepatectomy. These results suggest that the prognostic significance of RAS mutations after resection of metastatic CRC depends on the specific site of metastases.

Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study.

BACKGROUND: The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM). OBJECTIVE: The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM. METHODS: From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age ≤ 80 years, performance status ≤ 2, and no extraperitoneal metastases. RESULTS: Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group 1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype. CONCLUSIONS: This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial.