Management and outcomes of hemorrhage after distal pancreatectomy: a multicenter study at high volume centers.

BACKGROUND: Data on clinically relevant post-pancreatectomy hemorrhage (CR-PPH) are derived from series mostly focused on pancreatoduodenectomy, and data after distal pancreatectomy (DP) are scarce. METHODS: All non-extended DP performed from 2014 to 2018 were included. CR-PPH encompassed grade B and C PPH. Risk factors, management, and outcomes of CR-PPH were evaluated. RESULTS: Overall, 1188 patients were included, of which 561 (47.2 %) were operated on minimally invasively. Spleen-preserving DP was performed in 574 patients (48.4 %). Ninety-day mortality, severe morbidity and CR-POPF rates were 1.1 % (n = 13), 17.4 % (n = 196) and 15.5 % (n = 115), respectively. After a median interval of 8 days (range, 0-37), 65 patients (5.5 %) developed CR-PPH, including 28 grade B and 37 grade C. Reintervention was required in 57 patients (87.7 %). CR-PPH was associated with a significant increase of 90-day mortality, morbidity and hospital stay (p < 0.001). Upon multivariable analysis, prolonged operative time and co-existing POPF were independently associated with CR-PPH (p < 0.005) while a chronic use of antithrombotic agent trended towards an increase of CR-PPH (p = 0.081). As compared to CR-POPF, the failure-to-rescue rate in patients who developed CR-PPH was significantly higher (13.8 % vs. 1.3 %, p < 0.001). CONCLUSION: CR-PPH after DP remains rare but significantly associated with an increased risk of 90-day mortality and failure-to-rescue.

European validation of the classification for the anticipated difficulty of liver transplantation.

BACKGROUND: Appropriate risk stratification for the difficulty of liver transplantation (LT) is essential to guide the selection and acceptance of grafts and avoid morbidity and mortality. METHODS: Based on 987 LTs collected from 5 centers, perioperative outcomes were analyzed across the 3 difficulty levels. Each LT was retrospectively scored from 0 to 10. Scores of 0-2, 3-5 and 6-10 were then translated into respective difficulty levels: low, moderate and high. Complications were reported according to the comprehensive complication index (CCI). RESULTS: The difficulty level of LT in 524 (53%), 323 (32%), and 140 (14%) patients was classified as low, moderate and high, respectively. The values of major intraoperative outcomes, such as cold ischemia time (p = 0.04) and operative time (p < 0.0001) increased gradually with statistically significant values among difficulty levels. There was a corresponding increase in CCI (p = 0.04), severe complication rates (p = 0.05) and length of ICU (p = 0.01) and hospital (p = 0.004) stays across the different difficulty levels. CONCLUSION: The LT difficulty classification has been validated.

Cytoreductive Surgery and Intraperitoneal Chemotherapy in Advanced Serous Epithelial Ovarian Cancer: A 14-Year French Retrospective Single-Center Study of 124 Patients.

INTRODUCTION: Ovarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases. METHODS: A prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed. RESULTS: From January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%. CONCLUSION: CRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates.

Preoperative prediction of inadvertent enterotomy during adhesive small bowel obstruction surgery using combination of CT features.

OBJECTIVES: The purpose of this study was to identify the preoperative CT features that are associated with inadvertent enterotomy (IE) during adhesive small bowel obstruction (ASBO) surgery. METHODS: From January 2015 to December 2019, all patients with ASBO who underwent an abdominal CT were reviewed. Abdominal CT were retrospectively reviewed by two radiologists with a consensus read in case of disagreement. IE during ASBO surgery was retrospectively recorded. Univariate and multivariate analyses of CT features associated with IE were performed and a simple CT score was built to stratify the risk of IE. This score was validated in an independent retrospective cohort. Abdominal CT of the validation cohort was reviewed by a third independent reader. RESULTS: Among the 368 patients with ASBO during the study period, 169 were surgically treated, including 129 ASBO for single adhesive band and 40 for matted adhesions. Among these, there were 47 IE. By multivariate analysis, angulation of the transitional zone (OR = 4.19, 95% CI [1.10-18.09]), diffuse intestinal adhesions (OR = 4.87, 95% CI [1.37-19.76]), a fat notch sign (OR = 0.32, 95% CI [0.12-0.85]), and mesenteric haziness (OR = 0.13, 95% CI [0.03-0.48]) were independently associated with inadvertent enterotomy occurrence. The simple CT score built to stratify risk of IE displayed an AUC of 0.85 (95% CI [0.80-0.90]) in the study sample and 0.88 (95% CI [0.80-0.96]) in the validation cohort. CONCLUSION: A simple preoperative CT score is able to inform the surgeon about a high risk of IE and therefore influence the surgical procedure. KEY POINTS: • In this retrospective study of 169 patients undergoing abdominal surgery for adhesive small bowel obstruction, 47 (28%) inadvertent enterotomy occurred. • A simple preoperative CT score enables accurate stratification of inadvertent enterotomy risk (area under the curve 0.85). • By multivariable analysis, diffuse intestinal adhesions and angulation of the transitional zone were predictive of inadvertent enterotomy occurrence.

Post-Transplantation Cytomegalovirus Infection Interplays With the Development of Anastomotic Biliary Strictures After Liver Transplantation.

Background: Anastomotic biliary stricture (ABS) remains the most frequent complication after liver transplantation (LT). This study aimed to identify new anastomotic biliary stricture risk factors, with a specific focus on postoperative events. Additionally, ABS management and impact on patient and graft survival were assessed. Methods: All consecutive patients who underwent LT with duct-to-duct anastomosis between 2010 and 2019 were included. All patients who died within 90 days after LT due to non-ABS-related causes were excluded. Results: Among 240 patients, 65 (27.1%) developed ABS after a median time of 142 days (range, 13-1265). Median follow-up was 49 months (7-126). Upon multivariable analysis, donor BMI (OR=0.509, p = 0.037), post-LT CMV primoinfection (OR = 5.244, p < 0.001) or reactivation (OR = 2.421, p = 0.015) and the occurrence of post-LT anastomotic biliary fistula (OR = 2.691, p = 0.021) were associated with ABS. Anastomotic technical difficulty did not independently impact the risk of ABS (OR = 1.923, p = 0.051). First-line ABS treatment was systematically endoscopic (100%), and required a median of 2 (range, 1-11) procedures per patient. Repeat LT was not required in patients developing ABS. The occurrence of ABS was not associated with overall patient survival (p = 0.912) nor graft survival (p = 0.521). Conclusion: The risk of developing ABS after LT seems driven by the occurrence of postoperative events such as CMV infection and anastomotic fistula. In this regard, the role of CMV prophylaxis warrants further investigations.

Is it safe to perform an anastomosis for rectal cancer after prostate cancer? A multicentre study of 126 patients from the GRECCAR group.

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.

Liver transplantation for iatrogenic bile duct injury during cholecystectomy: a French retrospective multicenter study.

BACKGROUND: Major bile duct injuries (BDI) following cholecystectomy require complex reconstructive surgery. The aim was to collect the liver transplantations (LT) performed in France for major BDI following cholecystectomy, to analyze the risk factors and to report the results. METHODS: National multicenter observational retrospective study. All the patients who underwent a LT in France between 1994 and 2017, for BDI following cholecystectomy, were included. RESULTS: 30 patients were included. 25 BDI occurred in non hepato-biliary expert centers, 20 were initially treated in these centers. Median time between injury and LT was 3 years in case of an associated vascular injury (11 injuries), versus 11.7 years without vascular injury (p = 0.006). Post-transplant morbidity rate was 86.7%, mortality 23.5% at 5 years. CONCLUSION: Iatrogenic BDI remains a real concern with severe cases, associated with vascular damages or leading to cirrhosis, with no solution but LT. It is associated with high morbidity and not optimal results. This enlights the necessity of early referral of all major BDI in expert centers to prevent dramatic outcome. Decision to perform transplantation should be taken before dismal infectious situations or biliary cirrhosis and access to graft should be facilitated by Organ Sharing Organizations.

Delayed return of gastrointestinal function after hepatectomy in an ERAS program: incidence and risk factors.

BACKGROUND: Delayed return of gastrointestinal function (DGIF) after hepatectomy can involve increased morbidity and prolonged hospital stay. Yet, data on incidence and risks factors are lacking. METHODS: All consecutive patients who underwent hepatectomy between June 2018 and December 2020 were included. All patients were included in an enhanced recovery after surgery (ERAS) program. DGIF was defined by the need for nasogastric tube (NGT) insertion after surgery. DGIF risk factors were identified. RESULTS: Overall, 206 patients underwent hepatectomy. DGIF occurred in 41 patients (19.9%) after a median time of 2 days (range, 1-14). Among them, 6 patients (14.6%) developed aspiration pneumonia, of which one required ICU for mechanical ventilation. DGIF developed along with an intraabdominal complication in 7 patients (biliary fistula, n = 5; anastomotic fistula, n = 1; adhesive small bowel obstruction, n = 1). DGIF was associated with significantly increased severe morbidity rate (p = 0.001), prolonged time to normal food intake (p < 0.001) and hospital stay (p < 0.001) and significantly decreased overall compliance rate (p = 0.001). Independent risk factors of DGIF were age (p < 0.001), vascular reconstruction (p = 0.007), anaesthetic induction using volatiles (p = 0.003) and epidural analgesia (p = 0.004). Using these 4 variables, a simple DGIF risk score has been developed allowing patient stratification in low-, intermediate- and high-risk groups. CONCLUSION: DGIF after hepatectomy was frequently observed and significantly impacted postoperative outcomes. Identifying risk factors remains critical for preventing its occurrence.

Simultaneous Versus Delayed Resection for Initially Resectable Synchronous Colorectal Cancer Liver Metastases: A Prospective, Open-label, Randomized, Controlled Trial.

OBJECTIVE: To answer whether synchronous colorectal cancer liver metastases (SLM) should be resected simultaneously with primary cancer or should be delayed. SUMMARY BACKGROUND DATA: Numerous studies have compared both strategies. All were retrospective and conclusions were contradictory. METHODS: Adults with colorectal cancer and resectable SLM were randomly assigned to either simultaneous or delayed resection of the metastases. The primary outcome was the rate of major complications within 60 days following surgery. Secondary outcomes included overall and disease-free survival. RESULTS: A total of 105 patients were recruited. Eighty-five patients (39 and 46 in the simultaneous- and delayed-resection groups, respectively) were analyzed. The percentage of major perioperative complications did not differ between groups (49% and 46% in the simultaneous- and delayed-resection groups, respectively, adjusted OR 0.84, 95% CI 0.35-2.01; P = 0.70, logistic regression). Complications rates were 28% and 13% (P = 0.08, χ2 test) at colorectal site and 15% and 17% (P = 0.80, χ2 test) at liver site, in simultaneous- and delayed-resection groups, respectively. In the delayed-resection group, 8 patients did not reach the liver resection stage, and this was due to disease progression in 6 cases. After 2 years, overall and disease-free survival tended to be improved in simultaneous as compared with delayed-resection groups (P = 0.05), a tendency which persisted for OS after a median follow-up of 47 months. CONCLUSIONS: Complication rates did not appear to differ when colorectal cancer and synchronous liver metastases are resected simultaneously. Delayed resection tended to impair overall survival.

Evaluating the Risk of Irreversible Intestinal Necrosis Among Critically Ill Patients With Nonocclusive Mesenteric Ischemia.

INTRODUCTION: To identify factors associated with irreversible transmural necrosis (ITN) among critically ill patients experiencing nonocclusive mesenteric ischemia (NOMI) and to compare the predictive value regarding ITN risk stratification with that of the previously described Clichy score. METHODS: All consecutive patients admitted to the intensive care unit between 2009 and 2019 who underwent exploratory laparotomy for NOMI and who had an available contrast-enhanced computed tomography with at least 1 portal venous phase were evaluated for inclusion. Clinical, laboratory, and radiological variables were collected. ITN was assessed on pathological reports of surgical specimens and/or on laparotomy findings in cases of open-close surgery. Factors associated with ITN were identified by univariate and multivariate analysis to derive a NOMI-ITN score. This score was further compared with the Clichy score. RESULTS: We identified 4 factors associated with ITN in the context of NOMI: absence of bowel enhancement, bowel thinning, plasma bicarbonate concentration ≤15 mmol/L, and prothrombin rate <40%. These factors were included in a new NOMI-ITN score, with 1 point attributed for each variable. ITN was observed in 6%, 38%, 65%, 88%, and 100% of patients with NOMI-ITN score ranging from 0 to 4, respectively. The NOMI-ITN score outperformed the Clichy score for the prediction of ITN (area under the receiver operating characteristics curve 0.882 [95% confidence interval 0.826-0.938] vs 0.674 [95% confidence interval 0.582-0.766], respectively, P < 0.001). DISCUSSION: We propose a new 4-point score aimed at stratifying risk of ITN in patients with NOMI. The Clichy score should be applied to patients with occlusive acute mesenteric ischemia only.

Fluorescence-based pancreas stump perfusion is associated with postoperative acute pancreatitis after pancreatoduodenectomy a prospective cohort study.

BACKGROUND: Postoperative acute pancreatitis (POAP) emerges as a distinct pancreas-specific complication increasing both the risk and the burden of POPF after pancreatoduodenectomy. Among various risk factors, pancreas stump (PS) hypoperfusion might play a role in POAP occurrence but has never been investigated. The current study aimed at evaluating the feasibility of intraoperative fluorescence angiography (IOFA) of the PS using ICG and its association with POAP. METHODS: Consecutive patients who underwent pancreatoduodenectomy for a periampullary tumor with pancreatojejunostomy and PS perfusion assessment using IOFA between January 2020 and November 2020 were prospectively included. Perioperative management and surgical strategy were standardized. IOFA of the pancreas stump was performed before fashioning pancreatojejunostomy. POAP was defined according to the Connor definition and was confirmed upon radiological blind review. Outcomes between patients with normally perfused and hypoperfused PS were compared. POAP was the primary endpoint. RESULTS: Among 30 patients, nine patients (30%) developed POAP according to the Connor definition, and six patients (20%) had CT-confirmed POAP. Upon IOFA, six patients (20%) presented PS hypoperfusion; of which one patient underwent extended pancreatectomy further to the left. PS hypoperfusion was statistically associated with the occurrence of POAP (80% vs. 16%; p = 0.011) and CT-confirmed POAP (60% vs. 12%; p = 0.041). Clinically relevant POPF rate was 40% in case of PS hypoperfusion and 4% in case of normal PS perfusion (p = 0.064). CONCLUSIONS: PS perfusion assessment using IOFA seems safe and reliable to anticipate POAP. PS IOFA could be considered as a potential tool for perioperative assessment of surgical risk after pancreatoduodenectomy.

Surgical Management and Outcomes of Rectal Cancer with Synchronous Prostate Cancer: A Multicenter Experience from the GRECCAR Group.

BACKGROUND: Synchronous prostate cancer (PC) and rectal cancer (RC) is a rare clinical situation. While combining curative-intent management for both cancers can be challenging, available data for guiding the multidisciplinary strategy are lacking. METHODS: Consecutive patients undergoing rectal resection for a mid-low RC with synchronous PC treated at 9 tertiary-care centers between 2008 and 2018 were included. Management strategy and data on postoperative and long-term outcomes were retrospectively analyzed. RESULTS: Overall, 25 patients underwent curative-intent RC resection combined with PC management. Nine (36%), 10 (40%) and 6 (24%) patients had low-, intermediate-, and high-risk PC, respectively. Management mostly consisted of chemoradiotherapy combined in 18 patients (72%) with either TME in 12 patients or pelvic exenteration for resection of both cancers in 6 patients. Most patients underwent RC resection using a laparoscopic approach (n = 16, 64%). Anastomosis was performed in 18 patients (72%) of whom 13 received diverting ileostomy. The complete R0 resection rate was 96% (n = 24). The overall morbidity rate was 64% (n = 16) and 5 patients (20%) experienced severe surgical morbidity of which two died within 90 days of surgery after pelvic exenteration. Among patients with anastomosis, 2 patients (11%) experienced anastomotic leak requiring surgical management. After a median follow-up of 31.2 months, 3-year OS and RFS were 80.2% (CI 95% 58.8-92.2) and 68.6% (CI 95% 42.3-84.8), respectively. CONCLUSIONS: This series is the largest to report that simultaneous curative-intent management of synchronous PC and RC is feasible and safe. Pelvic exenteration might be a better option when RC complete resection seems not achievable through TME.

Well-Differentiated Papillary Mesothelioma of the Peritoneum: A Retrospective Study from the RENAPE Observational Registry.

BACKGROUND: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature. OBJECTIVE: We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry. PATIENTS AND METHODS: All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed. RESULTS: We report on 56 patients with a mean age of 52 years (range 21-74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0-33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified. CONCLUSIONS: Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.

Peritoneal Carcinomatosis of Rare Ovarian Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-Institutional Cohort from PSOGI and BIG-RENAPE.

PURPOSE: Ovarian cancer is the most common deadly cancer of gynecologic origin. Patients often are diagnosed at advanced stage with peritoneal metastasis. There are many rare histologies of ovarian cancer; some have outcomes worse than serous ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be considered for patients with recurrence. This study was designed to assess the impact of CRS and HIPEC on survival of patient with peritoneal metastasis from rare ovarian malignancy. METHODS: A prospective, multicentric, international database was retrospectively searched to identify all patients with rare ovarian tumor (mucinous, clear cells, endometrioid, small cell hypercalcemic, and other) and peritoneal metastasis who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working group. The postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 210 patients with a median follow-up of 43.5 months. Median overall survival (OS) was 69.3 months, and the 5-year OS was 57.7%. For mucinous tumors, median OS and DFS were not reached at 5 years. For granulosa tumors, median overall survival was not reached at 5 years, and median DFS was 34.6 months. Teratoma or germinal tumor showed median overall survival and DFS that were not reached at 5 years. Differences in OS were not statistically significant between histologies (p = 0.383), whereas differences in DFS were (p < 0.001). CONCLUSIONS: CRS and HIPEC may increases long-term survival in selected patients with peritoneal metastasis from rare ovarian tumors especially in mucinous, granulosa, or teratoma histological subtypes.

Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant. METHODS: A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease. RESULTS: Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant. CONCLUSIONS: Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved.

Evaluation of transcriptomic signature as a valuable tool to study drug-induced cholestasis in primary human hepatocytes.

Primary human hepatocyte (PHH) sandwich cultures from five different donors were daily exposed to cyclosporine A (CsA), ibuprofen (IBU), chlorpromazine (CPZ), amiodarone (AMI) and paracetamol (APAP) at their respective Cmax (total) for short-term (1-3 days) and long-term treatment (14 days). Whole genome mRNA profiles (34,693 genes in total) were conducted using an Illumina microarray platform. The impact of compound treatments on gene signatures involved in liver differentiation, cholestasis and in bile acid homeostasis was evaluated. Notably, PHH from the five donors showed a highly comparable phenotype of terminally differentiated hepatocytes. As expected, PHH exposed to 100 µM APAP showed no signs of hepatotoxicity both after short- and long-term treatment. CsA at 0.7 µM, IBU at 100 µM, AMI at 2.5 µM and CPZ at 0.1-0.2 µM presented, in line with their cholestatic syndromes reported at therapeutic doses, transcriptomic signatures of cholestasis in PHH cultures; deregulation of genes involved in bile acid homeostasis further confirmed this finding. The strength of the cholestasis signature obtained after treatment with CsA, IBU and AMI could be directly related to the basal expression of the respective drug metabolizing enzymes in the various PHH cultures from different individuals. Our data show that the PHH model system combined with transcriptomics carries the future promise to identify individual gene expression profiles predictive of increased cholestasis risk. As the present work suggests possible correlation between mRNA levels of ADME relevant genes and a transcriptomic signature of cholestasis, particular focus on this research question could be the emphasis of additional data collection.

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) incidence is increasing worldwide. Several studies have shown that lymphopenia was correlated with a poor prognosis but the potential interest to measure lymphopenia in the pre and post-operative setting as well as its added value among conventional prognostic factors was never investigated. METHODS: Data from two independent cohorts in whom patients underwent resection for pancreatic carcinoma were retrospectively recorded. We examined the association between perioperative findings, pre and post-operative lymphocyte counts and overall survival (OS) in univariate and multivariate analyses. Performance assessment and internal validation of the final model were evaluated with Harrell's C-index, calibration plot and bootstrap sample procedures. RESULTS: Three hundred ninety patients were included in the analysis between 2000 and 2011. Pre and post-operative lymphocyte counts were independent prognostic factors associated with OS in multivariate analysis (p = 0.0128 and p = 0.0764, respectively). The addition of lymphocyte count variable to the conventional parameters identified in multivariate analysis (metastatic lymph node ratio, veinous emboli and adjuvant chemotherapy) significantly improved the model discrimination capacity (bootstrap mean difference = 0.04; 95 % CI, 0.01-0.06). The use of a threshold and combining the categorical (≥1000; <1000) information in pre and post lymphocyte counts permitted the identification of 4 subgroups of patients with different prognosis (p < 0.0001). Finally, the description of patients in long-term remission showed that only 3 of 65 (4.6 %) patients with post-operative lymphocyte count under 1000/mm3 were alive 4 years after surgery contrary to 54 of 236 (22.8 %) patients with a post-operative lymphocyte count above 1000/mm3. CONCLUSION: Pre and post-operative lymphopenia are independent prognostic factors for OS and they have an additive value regarding conventional prognostic factors for death-risk stratification and to predict long-term survival. Lymphopenia should be included as stratification factors in future clinical trial assessing overall survival in pancreatic cancer patients.

Fatal acute respiratory distress by Toxoplasma gondii in a toxoplasma seronegative liver transplant recipient.

The risk of Toxoplasma gondii infection in solid organ transplant recipients is well known but mainly after heart transplantation. We discuss a case of acute respiratory distress caused by Toxoplasma gondii on Day 32 after liver transplantation. The reported case, which is extremely rare, emphasizes how direct examination and Quantitative Polymerase Chain Reaction (QPCR) in broncholaveolar lavage help to diagnose the infection. Given Trimethoprim/Sulfamethoxazole toxicity, systematic prescription of Toxoplasma gondii chemoprophylaxis is not commonly approved in liver transplantation.