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Background: Postoperative rectovaginal fistula leads to a loss of patients' quality of life and presents significant challenges to the surgeon. The literature focusing specifically on postoperative rectovaginal fistulas is limited. The objective of the present study is to identify factors that can enhance the success of the management of this postoperative rectovaginal fistula. Methods: This retrospective multicentric study included all patients undergoing surgery for rectovaginal fistulas, excluding those for whom the etiology of rectovaginal fistula was not postoperative. The major outcome measure was the success of the procedure. Results: A total of 82 patients with postsurgical fistulas were identified, of whom 70 were successfully treated, giving a success rate of 85.4%. On average, these patients required 3.04 ± 2.72 interventions. The creation of a diversion stoma did not increase the success rate of management [odds ratio (OR) = 0.488; 95% confidence interval (CI) 0.107–2.220]. Among the 217 procedures performed, 69 were successful, accounting for a 31.8% success rate. The number of interventions and the creation of a diversion stoma did not correlate with the success of management. However, direct coloanal anastomosis was significantly associated with success (OR = 35.06; 95% CI 1.271–997.603; p = 0.036) as compared with endorectal advancement flap (ERAF). Other procedures such as Martius flap did not show a significantly higher success rate. Conclusion: The creation of a diversion stoma is not necessary in closing a fistula. ERAF should be considered as a first-line treatment prior to proposing more invasive approach such as direct coloanal anastomosis. [ABSTRACT FROM AUTHOR]

The long-term tolerability of linezolid is low because of mitochondrial toxicity, whereas tedizolid may represent a better option for suppressive therapy. We report a first presumed case of tedizolid-associated optic neuropathy after a very prolonged (18-month) intake and believe that screening for optic neuropathy should be considered for patients undergoing tedizolid suppression. [ABSTRACT FROM AUTHOR]

Background: It is assumed that robotic-assisted surgery (RAS) may facilitate complex pelvic dissection for rectal cancer compared to the laparoscopic-assisted resection (LAR). The aim of this study was to compare perioperative morbidity, short- and long-term oncologic, and functional outcomes between the RAS and LAR approaches. Methods: Between 2015 and 2021, all rectal cancers operated on by (LAR) or (RAS) were retrospectively reviewed in two colorectal surgery centers. Results: A total of 197 patients were included in the study, with 70% in the LAR group and 30% in the RAS group. The tumor location and stage were identical in both groups (not significant = NS). The overall postoperative mortality rate was not significantly different between the two groups. (0% LAR; 0.5% RAS; NS). The postoperative morbidity was similar between the two groups (60% LAR vs 57% RAS; NS). The number of early surgical re-interventions within the first 30 days was similar (10% for the LAR group and 3% for the RAS group; NS). The rate of complete TME was similar (88% for the LAR group and 94% for the RAS group; NS). However, the rate of circumferential R1 was significantly higher in the LAR group (13%) compared to the RAS group (2%) (p = 0.009). The 3-year recurrence rate did not differ between the two groups (77% for both groups; NS). After a mean follow-up of three years, the incidence of anterior resection syndrome was significantly lower in the LAR group compared to the RAS group (54 vs 76%; p = 0.030). Conclusions: The use of a RAS was found to be reliable for oncologic outcomes and morbidity. However, the expected benefits for functional outcomes were not observed. Therefore, the added value of RAS for rectal cancer needs to be reassessed in light of new laparoscopic technologies and patient management options. [ABSTRACT FROM AUTHOR]

Objective: Technical ex-vivo comparison of commercial nebulizer nozzles used for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC). Methods: The performance of four different commercial nebulizer nozzles (Nebulizer; HurriChemTM; MCR-4 TOPOL®; QuattroJet) was analysed concerning: i) technical design and principle of operation, ii) operational pressure as function of the liquid flow rate, iii) droplet size distribution via laser diffraction spectrometry, iv) spray cone angle, spray cone form as well as horizontal drug deposition by image-metric analyses and v) chemical resistance via exposing to a cytostatic solution and chemical composition by means of spark optical emission spectral analysis. Results: The Nebulizer shows quasi an identical technical design and thus also a similar performance (e.g., mass median droplet size of 29 μm) as the original PIPAC nozzles (MIP/ CapnoPen). All other nozzles show more or less a performance deviation to the original PIPAC nozzles. The HurriChemTM has a similar design and principle of operation as the Nebulizer, but provides a finer aerosol (22 μm). The principle of operation of MCR-4 TOPOL® and QuattroJet differ significantly from that of the original PIPAC nozzle technology. The MCR-4 TOPOL® offers a hollow spray cone with significantly larger droplets (50 μm) than the original PIPAC nozzles. The QuattroJet generates an aerosol (22 μm) similar to that of the HurriChemTM but with improved spatial drug distribution. Conclusion: The availability of new PIPAC nozzles is encouraging but can also have a negative impact if their performance and efficacy is unknown. It is recommended that PIPAC nozzles that deviate from the current standard should be subject to bioequivalence testing and implementation in accordance with the IDEAL-D framework prior to routine clinical use. [ABSTRACT FROM AUTHOR]

Background: In the decision to perform elective surgery, it is of great interest to have data about the outcomes of surgery to individualize patients who could safely undergo sigmoid resection. The aim of this study was to provide information on the outcomes of elective sigmoid resection for sigmoid diverticular disease (SDD) at a national level. Methods: All consecutive patients who had elective surgery for SDD (2010–2021) were included in this retrospective, multicenter, cohort study. Patients were identified from institutional review board-approved databases in French member centers of the French Surgical Association. The endpoints of the study were the early and the long-term postoperative outcomes and an evaluation of the risk factors for 90-day severe postoperative morbidity and a definitive stoma after an elective sigmoidectomy for SDD. Results: In total, 4617 patients were included. The median [IQR] age was 61 [18.0;100] years, the mean ± SD body mass index (BMI) was 26.8 ± 4 kg/m2, and 2310 (50%) were men. The indications for surgery were complicated diverticulitis in 50% and smoldering diverticulitis in 47.4%. The procedures were performed laparoscopically for 88% and with an anastomosis for 83.8%. The severe complication rate on postoperative day 90 was 11.7%, with a risk of anastomotic leakage of 4.7%. The independent risk factors in multivariate analysis were an American Society of Anesthesiologists (ASA) score ≥ 3, an open approach, and perioperative blood transfusion. Age, perioperative blood transfusion, and Hartmann's procedure were the three independent risk factors for a permanent stoma. Conclusions: This series provides a real-life picture of elective sigmoidectomy for SDD at a national level. Trial registration: Comité National Information et Liberté (CNIL) (n°920361). [ABSTRACT FROM AUTHOR]

Background: In the decision to perform elective surgery, it is of great interest to have data about the outcomes of surgery to individualize patients who could safely undergo sigmoid resection. The aim of this study was to provide information on the outcomes of elective sigmoid resection for sigmoid diverticular disease (SDD) at a national level. Methods: All consecutive patients who had elective surgery for SDD (2010–2021) were included in this retrospective, multicenter, cohort study. Patients were identified from institutional review board-approved databases in French member centers of the French Surgical Association. The endpoints of the study were the early and the long-term postoperative outcomes and an evaluation of the risk factors for 90-day severe postoperative morbidity and a definitive stoma after an elective sigmoidectomy for SDD. Results: In total, 4617 patients were included. The median [IQR] age was 61 [18.0;100] years, the mean ± SD body mass index (BMI) was 26.8 ± 4 kg/m2, and 2310 (50%) were men. The indications for surgery were complicated diverticulitis in 50% and smoldering diverticulitis in 47.4%. The procedures were performed laparoscopically for 88% and with an anastomosis for 83.8%. The severe complication rate on postoperative day 90 was 11.7%, with a risk of anastomotic leakage of 4.7%. The independent risk factors in multivariate analysis were an American Society of Anesthesiologists (ASA) score ≥ 3, an open approach, and perioperative blood transfusion. Age, perioperative blood transfusion, and Hartmann’s procedure were the three independent risk factors for a permanent stoma. Conclusions: This series provides a real-life picture of elective sigmoidectomy for SDD at a national level. Trial registration: Comité National Information et Liberté (CNIL) (n°920361). [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the feasibility and perioperative safety of high-pressure/high-dose pressurized intraperitoneal aerosol chemotherapy (HP/HD-PIPAC) to manage peritoneal surface malignancies (PSM). Methods: Retrospective analysis of a prospective database of about 130 consecutive patients scheduled for HP/HD-PIPACs for PSM. Doxorubicin plus cisplatin (PIPAC-C/D) or oxaliplatin (PIPAC-Ox) were nebulized into a constant capnoperitoneum of 20 mmHg at doses of 6, 30, or 120 mg/m2 of body surface area (BSA). Outcome criteria were perioperative complications (Clavien–Dindo). Results: The median age of patients was 62 years (range 9–82), and the primary tumor site was of colorectal (CRC), upper gastrointestinal tract (UGI), unknown primary (CUP), malignant epithelioid mesothelioma of the peritoneum (MPM), hepato-pancreatic-biliary tract (HPB), and other origin in 30 (23.1%), 27 (20.8%), 16 (12.3%), 16 (12.3%), 6 (4.6%), and 35 (26.9%) patients, respectively. Abdominal access failed for a first, second, third, and fourth or more HP/HD-PIPAC in 12/130 (9.2%), 4/64 (6.3%), 6/40 (15.0%), and 2/33 (6.1%) patients. A total of 243 procedures were performed in 118 patients. No intraoperative complications related to increased capnoperitoneal pressure occurred, but an intraoperative bleeding complication was observed in 1/243 (0.4%) patients. The overall rate of postoperative procedure-related complications was 19.3% (47/243), while 15.3% (37/243), 1.6% (6/243), 1.6% (1/243), 0.4% (1/243), and 0.4% (1/243) were Grade I, II, III, IV, and V complications, respectively. Conclusions: Perioperative complications of HP/HD-PIPAC are comparable with standard pressure/dose PIPAC treatment protocols. Prospective studies are warranted to examine potential improvement in therapy outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is a major cause of morbidity and mortality that affects men and women equally. Here, we present the role of voltage-gated sodium channels (NaV) and Sodium/hydrogen exchanger type 1 (NHE-1) in conferring invasive capabilities to colorectal cancer cells. We also study how pharmacological inhibition or suppression of their expression by siRNA modifies the aggressive cancer cell phenotype. Our findings suggest that NaV channels and NHE-1 are pertinent molecular targets for cancer therapy. Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming α-subunits of NaV channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for NaV1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of NaV1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule NaV1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC. [ABSTRACT FROM AUTHOR]

Aim: A stoma exposes patients to several complications which could impair their quality of life (QoL). In the last decade, the market for stoma therapy in France has evolved, with a significant increase in the activities of home health providers, meeting a need for patient follow‐up and companionship. International studies have demonstrated the impact of the stoma therapist (ST) follow‐up on the improvement of an ostomy patient's QoL. However, the impact of home stoma nurse management has not been analysed. In this context we would like to assess the added value on health‐related QoL from the enhanced follow‐up of ostomy patients by STs. Methods: This is a randomized, controlled, open, national and multicentre trial (12 centres) which includes patients with an ostomy who benefit from either standard follow‐up or from an enhanced and personalized follow‐up with, in particular, regular consultations with an ST after discharge. The primary end‐point is the 3‐month QoL score obtained from the Stoma‐QoL questionnaire. The secondary end‐points are satisfaction of the care, comparison of QoL scores (Stoma‐QoL and EuroQuol EQ‐5D) and the economic gains by calculating the consumption of resources between the two arms. There will be a modified intention‐to‐treat analysis with 6‐month follow‐up in both study arms. Discussion: The StomaCare trial will be the first randomized controlled study in France to evaluate the impact on QoL of an enhanced follow‐up at home of ostomy patients by an ST. [ABSTRACT FROM AUTHOR]

Aim: Ano‐rectovaginal fistulas (ARVF) are challenging for the surgeon. Most of the series mix aetiologies, leading to confusion with respect to the conclusion. The aim of this study was to assess the factors associated with the success of ARVF management following obstetrical anal sphincter injury (OASIS). Methods: This retrospective multicentric study included all the patients undergoing surgery for ARVF identified by the hospital codes. Patients for whom the aetiology of ARVF was not OASIS were excluded. The major outcome measure was the success of the procedure. Results: Sixty patients with treated ARVF due to OASIS were identified. The success of overall management was 91.7%. Female patients underwent a mean of 2.5 (±1.7) procedures. A diverting stoma was formed in 29 patients (48.3%) of which 26 were closed at the end of the management period (89.7%). Of the 148 surgical procedures, only 55 were successful (37.2%). The order of the procedures (OR = 1.38; 95% CI: 0.75–2.51) or the diverting stoma (OR = 1.46; 95% CI: 0.31–6.91) were not significantly associated with the success of the surgery. However, Martius flap (OR = 4.13; 95% CI: 1.1–15.54) and Musset procedures (OR = 5.79; 95% CI: 1.77–18.87) produced better results than the endorectal advancement flap (ERAF). The other procedures did not show a significant correlation with management success. Conclusion: A diverting stoma is not mandatory in the management of ARVF due to OASIS to improve the success of the surgical procedure. While the Martius flap procedure offers better results, the ERAF procedure may be preferred as a primary intervention in the absence of sphincter injury as it is less invasive. In cases of residual sphincter injury, the Musset procedure is most likely to be the best option. [ABSTRACT FROM AUTHOR]

Background/aim: To develop and validate a nebulizer device for anti-cancer research on pressurized intraperitoneal aerosol supply in a preclinical peritoneal metastases (PM) rat model.Material and Methods: For aerosol generation, an ultrasonic nebulizer (USN) was modified. Aerosol analyses were performed ex-vivo by laser diffraction spectrometry (LDS). Intraperitoneal (IP) 99mtechnetium sodium pertechnetate (99mTc) aerosol distribution and deposition were quantified by in-vivo single photon emission computed tomography (SPECT/CT) and compared to liquid IP instillation of equivalent volume/doses of 99mTc with and without capnoperitoneum. PM was induced by IP injection of HCT116-Luc2 human colon cancer cells in immunosuppressed RNU rats. Tumor growth was monitored by bioluminescence imaging (BLI), 18F-FDG positron emission tomography (PET) and tissues examination at necropsy.Results: The USN was able to establish a stable and reproducible capnoperitoneum at a pressure of 8 to 10 mmHg. LDS showed that the USN provides a polydisperse and monomodal aerosol with a volume-weighted diameter of 2.6 μm. At a CO2 flow rate of 2 L/min with an IP residence time of 3.9 s, the highest drug deposition efficiency was found to be 15 wt.-%. In comparison to liquid instillation, nebulization showed the most homogeneous IP spatial drug deposition. Compared to BLI, 18F-FDG-PET was more sensitive to detect smaller PM nodules measuring only 1-2 mm in diameter. BLI, 18F-FDG PET and necropsy analyses showed relevant PM in all animals.Conclusions: The USN together with the PM rat model are suitable for robust and species-specific preclinical pharmacological studies regarding intraperitoneal delivery of pressurized aerosolized drugs and cancer research. [ABSTRACT FROM AUTHOR]

Background: Traditionally, patients with peritonitis Hinchey III and IV due to perforated diverticulitis were treated with Hartmann's procedure. In the past decade, resection and primary anastomosis have gained popularity over Hartmann's procedure and recent guidelines recommend Hartmann's procedure in two situations only: critically ill patients and in selected patients with multiple comorbidity (at high risk of complications). The protective stoma (PS) is recommended after resection with primary anastomosis, however its interest has never been studied. The aim of this trial is to define the role of systematic PS after resection and primary anastomosis for peritonitis Hinchey III and IV due to perforated diverticulitis.Methods/design: This DIVERTI 2 trial is a multicenter, randomized, controlled, superiority trial comparing resection and primary anastomosis with (control group) or without (experimental group) PS in patients with peritonitis Hinchey III and IV due to perforated diverticulitis. Primary endpoint is the overall 1 year morbidity according to the Clavien-Dindo classification of surgical complications. All complications occurring during hospitalization will be collected. Late complications occurring after hospitalization will be collected during follow-up. In order to obtain 80% power for a difference given by respective main probabilities of 67% and 47% in the protective stoma and no protective stoma groups respectively, with a two-sided type I error of 5%, 96 patients will have to be included in each group, hence 192 patients overall. Expecting a 5% rate of patients not assessable for the primary end point (lost to follow-up), 204 patients will be enrolled. Secondary endpoints are postoperative mortality, unplanned reinterventions, incisional surgical site infection (SSI), organ/space SSI, wound disruption, anastomotic leak, operating time, length of hospital stay, stoma at 1 year after initial surgery, quality of life, costs and quality-adjusted life years (QALYs).Discussion: The DIVERTI 2 trial is a prospective, multicenter, randomized, study to define the best strategy between PS and no PS in resection and primary anastomosis for patients presenting with peritonitis due to perforated diverticulitis.Trial Registration: ClinicalTrial.gov: NCT04604730 date of registration October 27, 2020. https://clinicaltrials.gov/ct2/show/NCT04604730?recrs=a&cond=Diverticulitis&draw=2&rank=12 . [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to externally evaluate the accuracy of four predictive scores for conversion to open surgery after rectal laparoscopic resection. None of the four scores achieved external validation previously.Methods: This was a retrospective analysis of two prospectively maintained databases from two academic centers in France and Morocco. All consecutive patients who underwent laparoscopic resection for rectal adenocarcinoma between 2005 and 2020 were included. Logistic regression was used to assess the association between the factors present in the four scores and conversion. The accuracy of each score was assessed using the area under the curve (AUC). Observed and predicted conversion rates were compared for each score using the Chi-square goodness-of-fit test.Results: Four hundred patients were included. There were 264 men (66%) with a mean age of 65.95 years (standard deviation 12.2). The median tumor height was 7 cm (quartiles 4-11) and 29% of patients had low rectal tumors. Conversion rate was 21.75%. The accuracy to predict conversion was low with an AUC lower than 0,62 for the four models. The observed conversion rates were significantly different from the predicted rates, except for one score.Conclusions: The four models had low accuracy in predicting the conversion to open surgery for laparoscopic rectal resection. There is a need for new well-designed studies, analyzing more specific variables, in a multicentric design to ensure generalizability of the results for daily surgical practice. [ABSTRACT FROM AUTHOR]

Aim: To determine the safety of performing an anastomosis after rectal cancer (RC) resection in patients with a previously treated prostate cancer (PC). Methods: Patients with a previously treated PC who underwent rectal resection from 2008 to 2018 were retrospectively included. Outcomes were compared between patients who underwent rectal resection with anastomosis (restorative surgery, RS+ group) and those with a definitive stoma (RS− group). In the RS+ group, anastomotic leak (AL) rates were assessed according to the type of reconstruction. Results: A total of 126 patients underwent rectal surgery for mid‐low RC after a previous PC treated by radiotherapy (RT) and/or radical prostatectomy. Overall, 80 patients (63%) underwent a RS and 46 patients (37%) underwent rectal surgery with a definitive stoma. There was no statistical difference between the two groups in terms of intraoperative data, except for the type of resection with more multivisceral resection in the RS‐ group (p < 0.01). In the RS+group, a diverting stoma was performed in 74% of cases. No difference between the two groups in terms of overall morbidity was found. In the RS+group (n = 80), 17 patients (21%) experienced AL. Of these, none was observed when delayed coloanal anastomosis was performed (p = 0.16). Long‐term permanent stoma in the RS+ group was 16% (n = 13). Conclusion: Restorative surgery after resection for RC in patients with a previous history of RT and/or radical prostatectomy for PC is safe without additional morbidity. In selected patients for restorative surgery, performing delayed coloanal anastomosis may represent a promising option. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is the third most common cancer in France and by the time of the diagnosis, 15-25% of patients will suffer from synchronous liver metastases. Surgery associated to neoadjuvant treatment can cure these patients, but few studies focus only on rectal cancer. This study was meant to compare the outcomes of patients who underwent a simultaneous resection to those who underwent a staged resection (rectum first or liver first) in the University Hospital of Tours, France.Methods: We assessed retrospectively a prospective maintained data base about the clinical, pathological and survival outcomes of patients who underwent a simultaneous or a staged resection in our center between 2010 and 2018. A propensity score matching was used, considering the initial characteristics of our groups.Results: There were 70 patients (55/15 males, female respectively) with median age 60 (54-68) years. After matching 48 (69%) of them underwent a staged approach and 22 (31%) a simultaneous approach were compared. After PSM, there were 22 patients in each group. No differences were found in terms of morbidity (p = 0.210), overall survival (p = 0.517) and disease-free survival (p = 0.691) at 3 years after matching. There were significantly less recurrences in the simultaneous group (50% vs 81.8%, p = 0.026).Conclusions: Simultaneous resection of the rectal primary cancer and synchronous liver metastases is safe and feasible with no difference in terms of survival. [ABSTRACT FROM AUTHOR]

Management of malignant left-sided colonic obstruction remains challenging and requires a stoma in 40–65% of patients. In those with obstructive splenic flexure colon cancer (OSFCC), a debate still exists regarding the most appropriate surgery. The aim of this muticenter study was to report and compare the different surgical procedures in OSFCC patients with a special focus on operative and histological characteristics and survival outcomes including 12-month stoma-free survival. Between 2000 and 2015, 2325 patients were treated for obstructive colon cancer in centers members of the French National Surgical Association (AFC). Among them, 198 underwent surgery for OSFCC and were retrospectively analyzed. Patients with OSFCC and proximal colonic ischemia or perforation were excluded. Four procedures were performed: decompressing stoma (DS, 39%), splenic flexure colectomy (SFC, 39%), subtotal colectomy (STC, 17%,) and left hemicolectomy (LHC, 5%). All patients treated with LHC underwent a Hartmann's procedure. There was no significant difference between groups for postoperative mortality and morbidity. Hospital stay was significantly longer after DS. The length of the specimen, longitudinal resection margins and number of harvested lymph nodes were significantly higher in the STC group. There was no difference for overall and disease-free survival. Stoma-free survival was significantly lower after LHC (62%) in comparison with the other groups (p < 0.0001). At the end of follow-up, 50% of patients who underwent LHC had a permanent stoma. In OSFCC patients without proximal colonic ischemia or peritonitis, LHC should no longer be recommended due to a high risk of permanent stoma. [ABSTRACT FROM AUTHOR]

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to manage gastric cancer peritoneal metastasis (GCPM). Methods: This study analyzed a prospective database of GCPM patients treated with cisplatin and doxorubicin PIPAC (PIPAC-C/D). The outcome criteria were adverse events, pathologic response [peritoneal regression grading score (PRGS)], and overall survival (OS). Results: The PIPAC-C/D procedure was scheduled for 144 patients with a median age of 57 years (range 22–88 years). Access to the abdominal cavity for the first PIPAC failed in 11 patients (7.7 %). A total of 296 procedures were performed for 131 patients. Of the 144 patients, 52 (36.1%) underwent one PIPAC, 32 (22.2%) underwent two PIPACs, 24 (16.7%) underwent three PIPACs, and 21 (14.6%) underwent four or more PIPACs. The overall morbidity/mortality was grade 1 for 22 patients (15.3%), grade 2 for 32 patients (22.2%), grade 3 for 7 patients (4.9%), grade 4 for no patients (0%), and grade 5 for 2 patients (1.4%). Of the 37 patients who had three or more PIPACs eligible for histopathologic response analysis, 27 (73%) had major or complete regression (PRGS 1/2). A median OS of 11 months (range 0–61 months) for the total study population and 16 months (range 2–61 months) for the patients with three or more PIPACs was observed. For 10 patients (7%) who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, the median OS was 15 months (minimum, 4 months; maximum, 27 months). Multivariate analysis showed three or more PIPACs to be an independent prognostic factor for improved OS (hazard ratio, 0.36; p < 0.0001). Conclusions: Repetitive PIPAC-C/D ± systemic chemotherapy is associated with low morbidity and mortality rates. Prospective randomized trials are needed to confirm whether three or more PIPAC-C/Ds improve clinical outcome. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is a major public concern, being the second deadliest cancer in the world. Whereas survival is high for localized forms, metastatic colorectal cancer has showed poor prognosis, with a 5-year survival barely surpassing 11%. Conventional chemotherapies against this disease proved their efficiency and remain essential in first-line treatment. However, the large number of authorized protocols complexifies treatment decision. In common practice, such decision is made on an empirical basis, by assessing benefits and risks for the patient. In other words, there is currently no efficient means of predicting the efficacy of any chemotherapy protocol for metastatic colorectal cancer. Methods/design: The use of a chemosensitivity assay, the Oncogramme®, should help clinicians administer the best chemotherapy regimen to their patients. We hypothesize it would ultimately improve their survival. In this multicentred, prospective trial (ONCOGRAM), eligible patients with metastatic colorectal cancer are randomized to determine whether they will receive an Oncogramme®. For clinicians whose patients benefited from the assay (arm A), results are used as a decision support tool. Patients not undergoing the Oncogramme® procedure are treated according to current practice, without the assistance of the assay (arm B). Primary outcome is 1-year progression-free survival. Secondary outcomes include response rates, as well as 6-month and 1-year survival rates. Discussion: This study aims at investigating the clinical utility of the Oncogramme® as a decision support tool for the treatment of patients with metastatic colorectal cancer. If the Oncogramme® positively influenced patient overall survival and/or progression-free survival, it would be of great value for clinicians to implement this assay within the current landscape of personalized medicine tools, which include genomics and biomarker assays. Trial registration: ClinicalTrials.gov identifier NCT03133273. Registered on April 28, 2017. [ABSTRACT FROM AUTHOR]

Background: The benefit of repetitive PIPAC specifically in CPM patients has yet to be demonstrated in terms of oncological and functional outcomes. Objective: The aim of this study was to evaluate the outcome of patients with non-resectable colorectal peritoneal metastases (CPM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Methods: We conducted an analysis of a prospective single-center database of all CPM patients who underwent PIPAC with oxaliplatin 92 mg/m2 body surface (PIPAC-Ox). The outcome criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.0), Peritoneal Regression Grading Score (PRGS), and survival. Results: Overall, 102 patients with a median age of 64 years (33–88) were scheduled for PIPAC-Ox. Access to the abdominal cavity for the first application failed in 22/102 (21.6%) patients. A total of 185 PIPACs were performed, with 26/102 (25.5%), 20/102 (19.6%), 17/102 (16.7%), and 17/102 (16.7%) patients undergoing one, two, three, and four or more PIPACs, respectively. Perioperative overall morbidity/mortality Grade I–V occurred in 14 (7.6%), 29 (15.8%), 6 (3.2%), 1 (0.5%), and 1 (0.5%) patient without significant differences between each cycle. Of 27 patients who underwent three or more PIPACs, 20/102 (19.6%) had major/complete CPM regression (PRGS 1–2). In a multivariate analysis, independent predictive factors for > 12 months' survival following the first PIPAC-Ox administration were three or more PIPACs (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.35–15.2; p = 0.014) and younger patient age (OR 1.058, 95% CI 1.00–1.12; p = 0.039). Conclusions: Repetitive PIPAC-Ox for CPM patients, alone or combined with perioperative systemic chemotherapy, is feasible. Our data suggest that three or more consecutive PIPAC-Ox cycles for advanced CPM can improve survival. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is a major public concern, being the second deadliest cancer in the world. Whereas survival is high for localized forms, metastatic colorectal cancer has showed poor prognosis, with a 5-year survival barely surpassing 11%. Conventional chemotherapies against this disease proved their efficiency and remain essential in first-line treatment. However, the large number of authorized protocols complexifies treatment decision. In common practice, such decision is made on an empirical basis, by assessing benefits and risks for the patient. In other words, there is currently no efficient means of predicting the efficacy of any chemotherapy protocol for metastatic colorectal cancer.Methods/design: The use of a chemosensitivity assay, the Oncogramme®, should help clinicians administer the best chemotherapy regimen to their patients. We hypothesize it would ultimately improve their survival. In this multicentred, prospective trial (ONCOGRAM), eligible patients with metastatic colorectal cancer are randomized to determine whether they will receive an Oncogramme®. For clinicians whose patients benefited from the assay (arm A), results are used as a decision support tool. Patients not undergoing the Oncogramme® procedure are treated according to current practice, without the assistance of the assay (arm B). Primary outcome is 1-year progression-free survival. Secondary outcomes include response rates, as well as 6-month and 1-year survival rates.Discussion: This study aims at investigating the clinical utility of the Oncogramme® as a decision support tool for the treatment of patients with metastatic colorectal cancer. If the Oncogramme® positively influenced patient overall survival and/or progression-free survival, it would be of great value for clinicians to implement this assay within the current landscape of personalized medicine tools, which include genomics and biomarker assays.Trial Registration: ClinicalTrials.gov identifier NCT03133273 . Registered on April 28, 2017. [ABSTRACT FROM AUTHOR]

Introduction: During the COVID-19 pandemic, cancer patients have been regarded as having a high risk of severe events if they are infected with SARS-CoV-2, particularly those under medical or surgical treatment. The aim of this study was to assess the posttreatment risk of infection by SARS-CoV-2 in a population of patients operated on for colorectal cancer 3 months before the COVID-19 outbreak and who after hospitalization returned to an environment where the virus was circulating. Materials and methods: This French, multicenter cohort study included consecutive patients undergoing elective surgery for colorectal cancer between January 1 and March 31, 2020, at 19 GRECCAR hospitals. The outcome was the rate of COVID-19 infection in this group of patients who were followed until June 15, 2020. Results: This study included 448 patients, 262 male (58.5%) and 186 female (41.5%), who underwent surgery for colon cancer (n = 290, 64.7%), rectal cancer (n = 155, 34.6%), or anal cancer (n = 3, 0.7%). The median age was 68 years (19–95). Comorbidities were present in nearly half of the patients, 52% were at least overweight, and the median BMI was 25 (12–42). At the end of the study, 448 were alive. Six patients (1.3%) developed COVID-19 infection; among them, 3 were hospitalized in the conventional ward, and none of them died. Conclusion: The results are reassuring, with only a 1.3% infection rate and no deaths related to COVID-19. We believe that we can operate on colorectal cancer patients without additional mortality from COVID-19, applying all measures aimed at reducing the risk of infection. [ABSTRACT FROM AUTHOR]

Résumé: Cinq à dix pour cent des chirurgies digestives se compliquent d'une fistule anastomotique responsable d'une morbi-mortalité élevée. La prise en charge endoscopique est devenue le traitement de premier choix, associé ou non à un drainage radiologique ou chirurgical. Parmi les techniques endoscopiques, on trouve les prothèses, les clips, les sutures endoscopiques, colles et endothérapies par pression négative. La stratégie thérapeutique est fonction de la taille, la localisation, la cause, la durée d'évolution de la fistule et l'expérience de l'opérateur. Nous proposons de détailler les différentes techniques et leurs résultats dans le traitement des fistules anastomotiques digestives. About 5 to 10% of gastro-intestinal surgeries are complicated by anastomotic leakage, responsive of a high morbidity and mortality. Endoscopic management of these complications has become the first-line of treatment whether or not combined with radiological or surgical drainage. Several technics are available: Stents, clips, endoscopic suturing, EndoVac™ therapy. The size, the localization, the experimentation of the endoscopist must be taken into account in the decision. We propose to detail the different techniques and their results in the treatment of digestive anastomotic fistulas. [ABSTRACT FROM AUTHOR]

The acquisition of invasive capacities by carcinoma cells, i.e. their ability to migrate through and to remodel extracellular matrices, is a determinant process leading to their dissemination and to the development of metastases. these cancer cell properties have often been associated with an increased Rho-ROCK signalling, and ROCK inhibitors have been proposed for anticancer therapies. In this study we used the selective ROCK inhibitor, Y-27632, to address the participation of the Rho-ROCK signalling pathway in the invasive properties of SW620 human colon cancer cells. Contrarily to initial assumptions, Y-27632 induced the acquisition of a pro-migratory cell phenotype and increased cancer cell invasiveness in both 3- and 2-dimensions assays. This effect was also obtained using the other ROCK inhibitor Fasudil as well as with knocking down the expression of ROCK-1 or ROCK-2, but was prevented by the inhibition of NaV1.5 voltage-gated sodium channel activity. Indeed, ROCK inhibition enhanced the activity of the pro-invasive NaV1.5 channel through a pathway that was independent of gene expression regulation. In conclusions, our evidence identifies voltage-gated sodium channels as new targets of the ROCK signalling pathway, as well as responsible for possible deleterious effects of the use of ROCK inhibitors in the treatment of cancers. [ABSTRACT FROM AUTHOR]

Background: Defining severe postoperative ileus in terms of consequences could help physicians standardize the management of this condition. The recently described classification based on consequences requires further investigation. The aim of this study was to obtain a snapshot of postoperative ileus in patients undergoing colorectal surgery within enhanced recovery programs and to identify factors associated with non-severe and severe postoperative ileus. Methods: This prospective registry data analysis was conducted in 40 centers in five different countries. A total of 786 patients scheduled for colorectal surgery within enhanced recovery programs were included. The primary endpoint was the incidence rate of postoperative ileus as defined by Vather et al. Results: A total of 121 patients experienced postoperative ileus (15.4%). Non-severe POI occurred in 48 patients (6.1%), and severe postoperative ileus occurred in 73 patients (9.3%). In multivariate analysis, the male gender and intra-abdominal complications were associated with severe postoperative ileus: odd ratio (OR) = 2.03 [95% confidence interval (CI) 1.14–3.59], p = 0.01 and OR = 3.60 [95% CI 1.75–7.40], p < 0.0001, respectively. Conversely, open laparotomy and urinary retention were associated with non-severe POI: OR = 3.03 [95% CI 1.37–6.72], p = 0.006 and OR = 2.70 [95% CI 0.89–8.23], p = 0.08, respectively. Conclusions: Postoperative ileus occurred in 15% of patients after colorectal surgery within enhanced recovery programs. For 60% of patients, this was considered severe. The physiopathology of these two entities could be different, severe POI being linked to intraabdominal complication, while non-severe POI being linked with risk factors for "primary" POI. The physician should pay attention to male patients having POI after colorectal surgery and look for features evocating intraabdominal complications. [ABSTRACT FROM AUTHOR]

Background: There is no quality evidence of the benefit of defunctioning ileostomy (DI) in ileal pouch-anal anastomoses (IPAAs) performed for inflammatory bowel disease (IBD), but most surgical teams currently resort to DI. In the case of a staged procedure with subtotal colectomy first, completion proctectomy with IPAA is performed for healthy patients, namely, after nutritional support, inflammation reduction and immunosuppressive agent weaning. Therefore, the aim of this trial is to assess the need for systematic DI after completion proctectomy and IPAA for IBD.Methods/design: This is a multicenter randomized open trial comparing completion proctectomy and IPAA without (experimental) or with (control) DI in patients presenting with ulcerative colitis or indeterminate colitis. Crohn's disease patients will not be included. The design is a superiority trial. The main objective is to compare the 6-month global postoperative morbidity, encompassing both surgical and medical complications, between the two groups. The morbidity of DI closure will be included, as appropriate. The sample size calculation is based on the hypothesis that the overall 6-month morbidity rate is 30% in the case of no stoma creation (i.e., experimental group) vs. 55% otherwise (control group). With the alpha risk and power are fixed to 0.05 and 0.80, respectively, and considering a dropout rate of 10%, the objective is set to 194 patients. The secondary objectives are to compare both strategies in terms of morbi-mortality at 6 months and functional results as well as quality of life at 12 months, namely, the 6-month major morbidity and unplanned reoperation rates, 6-month anastomotic leakage rate, 6-month mortality, length of hospital stay, 6-month unplanned readmission rate, quality of life assessed 3 and 12 months from continuity restoration (i.e., either IPAA or stoma closure), functional results assessed 3 and 12 months from continuity restoration, 12-month pouch results, 12-month cost-utility analysis, and 12-month global morbidity.Discussion: The IDEAL trial is a nationwide multicenter study that will help choose the optimal strategy between DI and no ileostomy in completion proctectomy with IPAA for IBD.Trial Registration: ClinicalTrial.gov: NCT03872271, date of registration March 13th, 2019. [ABSTRACT FROM AUTHOR]

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new technology for delivering intraperitoneal chemotherapy. It is generally assumed that with PIPAC, the ratio of peritoneal to systemic drug concentration is superior to liquid hyperthermic intraperitoneal chemotherapy (HIPEC). To date, no direct comparative data are available supporting such an assumption. Materials and Methods: Twelve 65-day-old pigs were randomly separated into three groups of four pigs each, all of which received intraperitoneal chemotherapy using the following administration methods: PIPAC with oxaliplatin 92 mg in 150 ml dextrose 5% (Group 1); PIPAC with electrostatic aerosol precipitation (ePIPAC; Group 2); or laparoscopic HIPEC (L-HIPEC) with oxaliplatin 400 mg in 4 L dextrose 5% at 42 °C (Group 3). Serial blood and peritoneal tissue concentrations of oxaliplatin were determined by spectrometry. Results: In all three groups, the maximum concentration of oxaliplatin in blood was detected 50–60 min after onset of the chemotherapy experiments, with no significant differences among the three groups (p = 0.7994). Blood oxaliplatin concentrations (0–30 min) were significantly higher in the L-HIPEC group compared with the ePIPAC group (p < 0.05). No difference was found for the overall systemic oxaliplatin absorption (area under the curve). Overall concentrations in the peritoneum were not different among the three groups (p = 0.4725), but were significantly higher in the visceral peritoneum in the PIPAC group (p = 0.0242). Conclusions: Blood and tissue concentrations were comparable between all groups; however, depending on the intraperitoneal area examined and the time points of drug delivery, the concentrations differed significantly between the three groups. [ABSTRACT FROM AUTHOR]

Aim: The aim was to define risk factors for postoperative mortality in patients undergoing emergency surgery for obstructing colon cancer (OCC) and to propose a dedicated score. Method: From 2000 to 2015, 2325 patients were treated for OCC in French surgical centres by members of the French National Surgical Association. A multivariate analysis was performed for variables with P value ≤ 0.20 in the univariate analysis for 30‐day mortality. Predictive performance was assessed by the area under the receiver operating characteristic curve. Results: A total of 1983 patients were included. Thirty‐day postoperative mortality was 7%. Multivariate analysis found five significant independent risk factors: age ≥ 75 (P = 0.013), American Society of Anesthesiologists (ASA) score ≥ III (P = 0.027), pulmonary comorbidity (P = 0.0002), right‐sided cancer (P = 0.047) and haemodynamic failure (P < 0.0001). The odds ratio for risk of postoperative death was 3.42 with one factor, 5.80 with two factors, 15.73 with three factors, 29.23 with four factors and 77.25 with five factors. The discriminating capacity in predicting 30‐day postoperative mortality was 0.80. Conclusion: Thirty‐day postoperative mortality after emergency surgery for OCC is correlated with age, ASA score, pulmonary comorbidity, site of tumour and haemodynamic failure, with a specific score ranging from 0 to 5. [ABSTRACT FROM AUTHOR]

Background: Patients with recurrent malignant epithelioid mesothelioma (MM) after surgery and standard chemotherapy with cisplatin and pemetrexed have limited treatment options.Methods: We performed a retrospective cohort study of patients with recurrent MM undergoing Pressurized IntraPeritoneal/Thoracal Aerosol Chemotherapy (PIPAC/PITAC) with doxorubicin 1.5 mg/m2 and cisplatin 7.5 mg/m2. Data were retrospectively collected in a prospective registry of patients undergoing PIPAC/PITAC. Study outcomes were microscopic tumor regression grade (TRG), survival and adverse events (v4.0 CTCAE).Results: A total of 29 patients (m/f = 17/12) with MM with a mean age of 62.4 (range: 42 to 84) years were analyzed. A total of 74 PIPAC and 5 PITAC procedures were performed. The mean number of PIPAC applications was 2.5 (range: 0 to 10) per patient. Twenty patients (69%) had > 2 PIPAC procedure and were eligible for TRG analysis. TRG 1 to 4 was observed in 75% (15/20) of patients. Major regression (TRG 3) or complete regression (TRG 4) was observed in 20% and 10%, respectively. PIPAC induced significant tumor regression in 51.7% (15/29) of patients with a cumulative effect after repetitive PIPACs (PIPAC #1 vs. PIPAC #2: p = 0.001; PIPAC #1 vs. PIPAC #3: p = 0.001; PIPAC #1 vs. PIPAC #4: p = 0.001). Postoperative CTCAE grade 4 complications were observed in two patients (6.9%) who had cytoreductive surgery (CC2) and intraoperative PIPAC. One patient (3.4%) died due to postoperative kidney insufficiency. After a follow up of 14.4 (95% CI: 8.1 to 20.7) months after the last PIPAC/PITAC application, median overall survival was 26.6 (95% CI: 9.5 to 43.7) months (from the first application).Conclusion: After prior abdominal surgery and systemic chemotherapy, repetitive PIPAC applications are feasible and safe for patients with end-stage MM. Furthermore, PIPAC induces significant histological regression of malignant mesothelioma in the majority of patients. PITAC is feasible, but its safety and efficacy to control malignant pleural effusion remain unclear. [ABSTRACT FROM AUTHOR]

Backgrounds: Central pancreatectomy (CP) is an alternative to pancreaticoduodenectomy and distal pancreatectomy in benign tumours of pancreatic isthmus management. It is known for a high post‐operative pancreatic fistula (POPF) rate. The purpose of this study was to compare POPF incidence between pancreatico‐jejunostomy (PJ) and pancreatico‐gastrostomy (PG). Methods: Fifty‐eight patients (mean age 53.9 ± 1.9 years) who underwent a CP in four French University Hospitals from 1988 to 2011 were analysed. The distal pancreatic remnant was either anastomosed to the stomach (44.8%, n = 25) or to a Roux‐en‐Y jejunal loop (55.2%, n = 35) with routine external drainage allowing a systematic search for POPF. POPF severity was classified according to the International Study Group on Pancreatic Fistula (ISGPF) and Clavien‐Dindo classifications. Results: The groups were similar on sex ratio, mean age, ASA score, pancreas texture, operative time and operative blood loss. Mean follow‐up was 36.2 ± 3.9 months. POPF were significantly more frequent after PG (76.9 versus 37.5%, P = 0.003). PG was associated with significantly higher grade of POPF both when graded with ISGPF classification (P = 0.012) and Clavien‐Dindo classification (P = 0.044). There was no significant difference in post‐operative bleeding (0.918) and delayed gastric emptying (0.877) between the two groups. Hospital length of stay was increased after PG (23.6 ± 3.5 days versus 16.5 ± 1.9 days, P = 0.071). There was no significant difference in incidence of long‐term exocrine (3.8 versus 19.2%, P = 0.134) and endocrine (7.7 versus 9.4%, P = 0.575) pancreatic insufficiencies. Conclusion: PG was associated with a significantly higher POPF incidence and severity in CP. We recommend performing PJ especially in older patients to improve CP outcomes. [ABSTRACT FROM AUTHOR]

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformedhuman tumor cells fromnon-transformed murine stromal cells computationally.We obtained 29 pancreatic ductal adenocarcinoma(PDAC) xenografts fromeither resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypeswith distinct clinical outcomes. These subtypes uncovered specific alterations inDNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC. [ABSTRACT FROM AUTHOR]

All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs) using TRF (Telomere Restriction Fragment) analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG) sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B), PIK3CA (phosphatidylinositol 3-kinase catalytic subunit), or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor. [ABSTRACT FROM AUTHOR]

c- MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets ( MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the in vitro and in vivo pancreatic anticancer activity of a nano-sized formulation based on novel polyallylamine grafted with 5% mole cholesteryl pendant groups (CH-PAA). Methods: Insoluble novel anticancer drug, Bisnaphthalimidopropyldiaaminooctane (BNIPDaoct), was loaded into CH-PAA polymeric self-assemblies by probe sonication. Hydrodynamic diameters and polydispersity index measurements were determined by photon correlation spectroscopy. The in vitro cytotoxicity evaluation of the formulation was carried out by the sulforhodamine B dye assay with human pancreatic adenocarcinoma BxPC-3 cells, while for the in vivo study, Xenograff mice were used . In vitro apoptotic cell death from the drug formulation was confirmed by flow cytometric analysis. Results: The aqueous polymer-drug formulation had a mean hydrodynamic size of 183 nm. The drug aqueous solubility was increased from negligible concentration to 0.3 mg mL. CH-PAA polymer alone did not exhibit cytotoxicity, but the new polymer-drug formulation showed potent in vitro and in vivo anticancer activity. The mode of cell death in the in vitro study was confirmed to be apoptotic. The in vivo results revealed that the CH-PAA alone did not have any anti-proliferative effect, but the CH-PAA-drug formulation exhibited similar tumour reduction efficacy as the commercial drug, gemcitabine. Conclusions: The proposed formulation shows potential as pancreatic cancer therapeutics. [ABSTRACT FROM AUTHOR]

The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide) NAD+-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes. [ABSTRACT FROM AUTHOR]

Microparticles are plasma membrane vesicles produced by apoptotic or activated cells and resting cancer cells. The concentration, origin and procoagulant properties of circulating microparticles are reported to differ according to pathological settings (inflammation, cancer and cardiovascular diseases). In case of cancer, different studies have reported a variation in the concentration of circulating microparticles, with an increase in procoagulant and tumor-associated antigen-bearing microparticles. However, the cancer specificity of these results remains unknown. The objective was to establish a specific signature of colorectal and pancreatic cancers (CRC, PC) by characterizing circulating microparticles. Patients presenting with CRC, PC, inflammatory bowel or pancreatic diseases, and healthy subjects, were prospectively included. Circulating microparticles were analyzed by flow cytometry, combining the analysis of Annexin V-positive with characterization of their origin and determination of their procoagulant activities. We included 85, 36, 15, 18 and 20 patients presenting with CRC, PC, inflammatory bowel or pancreatic diseases, and healthy subjects, respectively. Here, we depict a specific signature, which differed between CRC, PC, associated inflammatory bowel and pancreatic diseases and healthy subjects. Furthermore, in patients with remission, this signature returned to the levels observed in associated inflammatory or healthy patients. Our results indicate that circulating microparticles differ depending on the evolution of a cancer. The analysis of the circulating microparticles reveals the specificity of the signature and can be used as a new complex biomarker reflecting the evolution of the disease. [ABSTRACT FROM AUTHOR]

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse. [ABSTRACT FROM AUTHOR]

Background: Surgical resection of pancreatic metastasis (PM) is the only reported curative treatment for renal cell carcinoma. However, there is currently little information regarding very long-term survival. The primary objective of this study was to determine the 10-year survival of this condition using the largest surgical series reported to date. Methods: Between May 1987 and June 2003, we conducted a retrospective study of 62 patients surgically treated for PM from renal cell carcinoma at 12 Franco-Belgian surgical centers. Follow-up ended on May 31, 2012. Results: There were 27 male (44 %) and 35 female (56 %) patients with a median age of 54 years [31-75]. Mean disease-free interval from resection of primary tumor to reoperation for pancreatic recurrence was 9.8 years (median 10 years [0-25]). During a median follow-up of 91 months [12-250], 37 recurrences (60 %) were observed. After surgical resection of repeated recurrences, overall median survival time was 52.6 months versus 11.2 months after nonoperative management ( p = 0.019). Cumulative 3-, 5-, and 10-year overall survival (OS) rates were 72, 63, and 32 %, respectively. The corresponding disease-free survival rates were 54, 35, and 27 %, respectively. Lymph node involvement and existence of extrapancreatic metastases before PM were associated with poor overall survival. Conclusions: Aggressive surgical management of single or multiple PM, even in cases of extrapancreatic disease, should be considered in selected patients to allow a chance of long-term survival. [ABSTRACT FROM AUTHOR]

Ductal adenocarcinoma of the pancreas is ranking 4 for patient' death from malignant disease in Western countries, with no satisfactory treatment. We re-examined more precisely the histone deacetylases (HDAC) and Sirtuin (SIRT) gene expression patterns in pancreatic cancer with more pancreatic tumors and normal tissues. We also examinedthe possible relationship between HDAC gene expression levels and long term disease outcome. Moreover, we have evaluated by using an in vitro model system of human pancreatic tumor cell line whether HDAC7 knockdown may affect the cell behavior. We analyzed 29 pancreatic adenocarcinoma (PA), 9 chronic pancreatitis (CP), 8 benign pancreatic (BP) and 11 normal pancreatic tissues. Concerning pancreatic adenocarcinoma, we were able to collect biopsies at the tumor periphery. To assess the possible involvement of HDAC7 in cell proliferation capacity, we have generated recombinant human Panc-1 tumor which underexpressed or overexpressed HDAC7. The expression of HDAC1,2,3,4,7 and Nur77 increased in PA samples at levels significantly higher than those observed in the CP group (p = 0.0160; 0.0114; 0.0227; 0.0440; 0.0136; 0.0004, respectively). The expression of HDAC7, was significantly greater in the PA compared with BP tissue samples (p = 0.05). Mean mRNA transcription levels of PA for HDAC7 and HDAC2 were higher when compared to their counterpart biopsies taken at the tumor periphery (p = 0.0346, 0.0053, respectively). Moreover, the data obtained using confocal microscopy and a quantitative method of immunofluorescence staining strongly support the HDAC7 overexpression in PA surgical specimens. The number of deaths and recurrences at the end of follow up were significantly greater in patients with overexpression of HDAC7. Interestingly, the rate of growth was significantly reduced in the case of cell carrying shRNA construct targeting HDAC7 encoding gene when compared to the parental Panc-1 tumor cells (p = 0.0015) at 48 h and 96 h (p = 0.0021). This study strongly support the notion that HDAC7play a role in pancreatic adenocarcinoma progression. [ABSTRACT FROM AUTHOR]

Leishmania infantum causes a chronic infectious disease named visceral leishmaniasis (VL). We employed a non-human primate model to monitor immune parameters over time and gain new insights into the disease. Rhesus macaques were infected with L. infantum and the T helper and B cell immunological profiles characterized during acute and chronic phases of infection. Parasite detection in visceral compartments during the acute phase was associated with differentiation of effector memory CD4 T cells and increased levels of Th1 transcripts. At the chronic phase, parasites colonized novel lymphoid niches concomitant with increased expression of IL10. Despite the occurrence of hypergammaglobulinemia, the production of parasite-specific IgG was poor, being confined to the acute phase and positively correlated with the frequency of an activated memory splenic B cell population. We noticed the expansion of a splenic CD4 T cell population expressing CXCR5 and Bcl-6 during acute infection that was associated with the differentiation of the activated memory B cell population. Moreover, the number of splenic germinal centers peaked at one month after infection, hence paralleling the production of specific IgG. However, at chronic infection these populations contracted impacting the production of parasite-specific IgG. Our study provides new insights into the immune events taking place in a physiologically relevant host and a mechanistic basis for the inefficient humoral response during VL. [ABSTRACT FROM AUTHOR]

In mammals subverted as hosts by protozoan parasites, the latter and/or the agonists they release are detected and processed by sensors displayed by many distinct immune cell lineages, in a tissue(s)-dependent context. Focusing on the T lymphocyte lineage, we review our present understanding on its transient or durable functional impairment over the course of the developmental program of the intracellular parasites Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Trypanosoma cruzi in their mammalian hosts. Strategies employed by protozoa to down-regulate T lymphocyte function may act at the initial moment of naïve T cell priming, rendering T cells anergic or unresponsive throughout infection, or later, exhausting T cells due to antigen persistence. Furthermore, by exploiting host feedback mechanisms aimed at maintaining immune homeostasis, parasites can enhance T cell apoptosis. We will discuss how infections with prominent intracellular protozoan parasites lead to a general down-regulation of T cell function through T cell anergy and exhaustion, accompanied by apoptosis, and ultimately allowing pathogen persistence. [ABSTRACT FROM AUTHOR]

In mammals subverted as hosts by protozoan parasites, the latter and/or the agonists they release are detected and processed by sensors displayed by many distinct immune cell lineages, in a tissue(s)-dependent context. Focusing on the T lymphocyte lineage, we review our present understanding on its transient or durable functional impairment over the course of the developmental program of the intracellular parasites Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Trypanosoma cruzi in their mammalian hosts. Strategies employed by protozoa to down-regulate T lymphocyte function may act at the initial moment of naïve T cell priming, rendering T cells anergic or unresponsive throughout infection, or later, exhausting T cells due to antigen persistence. Furthermore, by exploiting host feedback mechanisms aimed at maintaining immune homeostasis, parasites can enhance T cell apoptosis. We will discuss how infections with prominent intracellular protozoan parasites lead to a general down-regulation of T cell function through T cell anergy and exhaustion, accompanied by apoptosis, and ultimately allowing pathogen persistence. [ABSTRACT FROM AUTHOR]