Wnt1 gene expression in the heart left ventricle as a response to the various durations of the intensive exercise: An experimental study.

Objective. Myocardial fibrosis is a devastating condition causing millions of deaths yearly. Several factors, such as aging, cause myocardial fibrosis. The Wnt/ß-catenin pathway is one of the critical intracellular signaling for the development of cardiac fibrosis. Molecular and cellular mechanism of myocardial fibrosis induced by intensive exercise is not well-understood. The current study evaluates the effects of short- and long-term intensive exercise on the Wnt1 gene expression in a heart left ventricle in an animal model. Methods. Twenty-one male Wistar rats (mean weight 250±50 g) were divided into three groups (n=7): 1) control group (C); 2) short-term regular intensive exercise group (S-RIE, high-intensity exercise for one month six days weekly for 60 min with speed of 35 m/min), and 3) long-term regular intensive exercise group (L-RIE, high-intensity exercise for six months six days daily for 60 min with speed of 35 m/min). The heart left ventricle was isolated at the end of the experiment, and the relative gene expression of the Wnt1 gene was measured by the Real-Time PCR. Results. The L-RIE group showed a significant increase in the Wnt1 expression compared to the S-RIE and the control group. Although no difference was observed in the Wnt1 mRNA level in the S-RIE group compared to the control group, Wnt1 mRNA level increased in the L-RIE group compared to the S-RIE group. Conclusion. The exercise duration was of a great importance in the Wnt1 gene expression. Regular intensive exercise may be involved in the formation of the myocardial fibrosis by increasing the expression of the Wnt1 gene.

Methods to prevent lymphocele after kidney transplantation: Seeking the optimal technique for avoiding a preventable complication.

BACKGROUND: There are multiple methods for preventing lymphocele formation after kidney transplantation (KTx). However, lymphoceles still develop in up to one third of patients and the effectiveness of these different methods in preventing lymphocele is not well described. Here, we summarize the current strategies for preventing lymphocele after KTx. METHODS: We conducted searches across several literature databases, including Medline (via PubMed), Web of Science, EMBASE, and Cochrane Central. Lymphocele formation after KTx was the outcome of interest. A random-effects model was applied to evaluate pooled estimates, which were presented as hazard ratios (HRs) and odds ratios (ORs), along with the random pooled estimate (ES), 95% confidence interval (95% CI), and P value. We calculated the pooled rate of lymphocele formation after KTx with the following preventive methods: LigaSure, haemostatic materials, prophylactic drainage, ligation, peritoneal fenestration, and bipolar cautery techniques. RESULTS: The literature search retrieved 87 unique studies after excluding duplicates. Twenty papers reporting on 5445 patients were incorporated in the qualitative analysis. The pooled lymphocele rate was 3.0% (95% CI = 0.6-13.7) for the LigaSure method, 8.3% (95% CI = 6.4-10.7) for drainage, 9.2% (95% CI = 5.9-14.1) for haemostatic materials, 12.2% (95% CI = 9.2-16.1) for ligation, 14.4% (95% CI = 12.0-17.3) for peritoneal fenestration, and 20.5% (95% CI = 10.2-36.8) for bipolar sealing. CONCLUSION: Despite preventive methods, the incidence of lymphocele following KTx remains high. The use of LigaSure appears to be the most effective method for preventing lymphocele. However, given the broad range of reported lymphocele rates and lack of control groups, further validation of these findings is necessary.

Postoperative Management of Portal Vein Arterialization: An Interdisciplinary Institutional Approach.

Portal vein arterialization (PVA) is a surgical procedure that plays a crucial role in hepatic vascular salvage when hepatic artery flow restoration remains elusive. Dedicated diagnostic vascular imaging and the timely management of PVA shunts are paramount to preventing complications, such as portal hypertension and thrombosis. Regrettably, a lack of standardized postoperative management protocols for PVA has increased morbidity and mortality rates post-procedure. In response to this challenge, we developed a PVA standard operating procedure (SOP) tailored to the needs of interventional radiologists. This SOP is designed to harmonize postoperative care, fostering scientific comparability across cases. This concise brief report aims to offer radiologists valuable insights into the PVA technique and considerations for post-PVA care and foster effective interdisciplinary collaboration.

Evaluation of quality and quantity of randomized controlled trials in hepatobiliary surgery: A scoping/mapping review.

AIM: To evaluate the quantity and quality of randomized controlled trials (RCTs) in hepatobiliary surgery and for identifying gaps in current evidences. METHODS: A systematic search was conducted in MEDLINE (via PubMed), Web of Science, and Cochrane Controlled Register of Trials (CENTRAL) for RCTs of hepatobiliary surgery published from inception until the end of 2023. The quality of each study was assessed using the Cochrane risk-of-bias (RoB) tool. The associations between risk of bias and the region and publication date were also assessed. Evidence mapping was performed to identify research gaps in the field. RESULTS: The study included 1187 records. The number and proportion of published randomized controlled trials (RCTs) in hepatobiliary surgery increased over time, from 13 RCTs (.0005% of publications) in 1970-1979 to 201 RCTs (.003% of publications) in 2020-2023. There was a significant increase in the number of studies with a low risk of bias in RoB domains (p < .01). The proportion of RCTs with low risk of bias improved significantly after the introduction of CONSORT guidelines (p < .001). The evidence mapping revealed a significant research focus on major and minor hepatectomy and cholecystectomy. However, gaps were identified in liver cyst surgery and hepatobiliary vascular surgery. Additionally, there are gaps in the field of perioperative management and nutrition intervention. CONCLUSION: The quantity and quality of RCTs in hepatobiliary surgery have increased over time, but there is still room for improvement. We have identified gaps in current research that can be addressed in future studies.

Promising Results of Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy for Perihilar Cholangiocarcinoma in a Systematic Review and Single-Arm Meta-Analysis.

BACKGROUND: ALPPS popularity is increasing among surgeons worldwide and its indications are expanding to cure patients with primarily unresectable liver tumors. Few reports recommended limitations or even contraindications of ALPPS in perihilar cholangiocarcinoma (phCC). Here, we discuss the results of ALPPS in patients with phCC in a systematic review as well as a pooled data analysis. METHODS: MEDLINE and Web of Science databases were systematically searched for relevant literature up to December 2023. All studies reporting ALPPS in the management of phCC were included. A single-arm meta-analysis of proportions was carried out to estimate the overall rate of outcomes. RESULTS: After obtaining 207 articles from the primary search, data of 18 studies containing 112 phCC patients were included in our systematic review. Rates of major morbidity and mortality were calculated to be 43% and 22%, respectively. The meta-analysis revealed a PHLF rate of 23%. One-year disease-free survival was 65% and one-year overall survival was 69%. CONCLUSIONS: ALPPS provides a good chance of cure for patients with phCC in comparison to alternative treatment options, but at the expense of debatable morbidity and mortality. With refinement of the surgical technique and better perioperative patient management, the results of ALPPS in patients with phCC were improved.

Liver Histology Predicts Liver Regeneration and Outcome in ALPPS: Novel Findings From A Multicenter Study.

BACKGROUND AND AIMS: Alterations in liver histology influence the liver's capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. METHODS: This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. RESULTS: In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =-0.1 and r =-0.08, respectively), and future liver remnant ( r =-0.15 and r =-0.06, respectively). CONCLUSIONS: ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.

Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated. The ALPPS procedure in our center was modified in 2016 by minimizing the first stage of the surgical procedure through biliary externalization after the first stage, antibiotic administration during the interstage phase, and performing biliary reconstructions during the second stage. The rate of postoperative major morbidity and 90-day mortality, as well as the one- and three-year disease-free and overall survival rates were calculated and compared between patients operated before and after 2016. The ALPPS risk score before the second stage of the procedure was lower in patients who were operated on after 2016 (before 2016: median 6.4; after 2016: median 4.4; p = 0.010). Major morbidity decreased from 42.9% before 2016 to 31.3% after 2016, and the 90-day mortality rate decreased from 35.7% before 2016 to 12.5% after 2016. The three-year survival rate increased from 40.8% before 2016 to 73.4% after 2016. Our modified ALPPS procedure improved perioperative and postoperative outcomes in patients with extrahepatic and intrahepatic cholangiocarcinoma. Minimizing the first step of the ALPPS procedure was key to these improvements.

Risk factors and management of biliary leakage after Endocystectomy for hepatic cystic echinococcosis.

BACKGROUND: Endocystectomy is a conservative surgical approach to managing cystic echinococcosis. Bile leakage is the main complication of this technique. The aim of this study was to evaluate the factors associated with bile leakage and to assess the outcomes and cost efficiency of strategies used to treat bile leakage. METHODOLOGY/PRINCIPAL FINDINGS: Patients who underwent endocystectomy between 2005 and 2020 were included. The preoperative characteristics, intra- and postoperative outcomes, hospital costs, and cost efficiency (the Diagnosis-Related Group reimbursement minus the overall cost) were evaluated prospectively. A total of eighty patients with 142 cysts were included. Postoperative complications occurred in 17 patients (21%), including 11 patients with bile leakage (type A: 1, type B: 6 and type C: 4 patients, total 13%). Bile leakage was more frequent in patients with preoperative MRI signs of cysto-biliary fistulas or intraoperative visible cysto-biliary fistulas (p = 0.03 and p = 0.04, respectively) and in patients with cysts larger than 8 cm (p = 0.03). Patients with bile leakage who underwent reoperation (type C) had significantly shorter hospital stays (9 vs. 16 days, p<0.01) and better cost efficiency than those who received radiologic or endocscopic interventions (€2,072 vs. -€2,097 p = 0.01). No mortality was observed, and recurrence was seen in two patients. CONCLUSIONS/SIGNIFICANCE: Endocystectomy is a safe and efficient technique. Preoperative and intraoperative cysto-biliary fistulas and a cyst diameter larger than 8 cm are correlated to postoperative bile leakage. Early operative management of bile leakage reduces hospital stay and improves cost efficiency compared with radiologic or endoscopic treatments.

Association of perioperative use of statins, metformin, and aspirin with recurrence after curative liver resection in patients with hepatocellular carcinoma: A propensity score matching analysis.

BACKGROUND: Statins, metformin, and aspirin have been reported to reduce the incidence of hepatocellular carcinoma (HCC). However, the effect of their perioperative use on survival outcomes of HCC patients following curative liver resection still remains unclear. METHOD: Three hundred and fifty three patients with a first diagnosis of HCC who underwent curative liver resection were included. Propensity score matching analysis with a users: nonusers ratio of 1:2 were performed for each of the medications (statins, metformin, and aspirin). Overall survival (OS) and recurrence-free survival (RFS) were evaluated and multivariable Cox proportional hazard analysis was performed. RESULTS: Sixty two patients received statins, 48 patients used metformin, and 53 patients received aspirin for ≥90 days before surgery. None of the medications improved OS. RFS of statin users was significantly longer than that of nonusers (p = 0.021) in the matched cohort. Users of hydrophilic statins, but not lipophilic ones had a significantly longer RFS than nonusers. Multivariable analysis showed that statin use significantly improved RFS (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.17-0.97, p = 0.044). No difference was seen in RFS between metformin users and nonusers. Among patients with diabetes, RFS was nonsignificantly longer in metformin users than in non-metformin users (84.1% vs. 60.85%, p = 0.069) in the matched cohort. No difference in postoperative RFS was seen between aspirin users and nonusers. CONCLUSION: Preoperative use of statins in patients with HCC can increase RFS after curative liver resection, but metformin and aspirin were not associated with improved survival. Randomized controlled trials are needed to confirm the findings of the present study.

Assessing textbook outcomes following major liver surgery in association with obesity at a referral academic center.

INTRODUCTION: Outcomes of major surgeries in tertiary educational hospitals have been complicated by the referral of high-risk patients and the participation of trainees in surgical procedures. We analyzed outcomes of major hepatectomies in a tertiary academic setting emphasizing the role of training and obesity on textbook outcomes (TO). MATERIALS AND METHODS: 971 adult patients who underwent open major hepatectomy (Mesohepatectomy [n = 111], hemihepatectomy [n = 610], and extended hepatectomy [n = 250]) were evaluated. A TO was defined as: a negative resection margin, no grade B/C bile leak, no major complications, no in-hospital mortality, and no 30-day readmission. TOs were compared following operations performed by senior surgeons and those performed by junior surgeons under the supervision of senior surgeons and between patients with and without obesity. RESULTS: TO was achieved in 70.1% of patients overall (78.4% in mesohepatectomy, 73.1% in hemihepatectomy, and 59.2% in extended hepatectomy). The rate of TO was similar following operations performed by and supervised by a senior surgeon (69.3% vs 71.0%, p = 0.570). The rate of TO was significantly lower in patients with obesity (41.5% vs 74.6%, p < 0.001). Factors including increased age (odds ratio [OR] for 10-year increase = 0.83, 95% confidence interval [CI]: 0.73-0.96, p = 0.009), obesity (OR = 0.25, 95%CI: 0.16-0.37, p < 0.001), biliodigestive anastomosis (OR = 0.27, 95%CI: 0.19-0.40, p < 0.001), and portal vein resection (OR = 0.49, 95%CI: 0.28-0.87, p = 0.014) lower the rate of TO. CONCLUSION: Promising outcomes are possible after major hepatectomy in an academic setting. Obese patients and those undergoing more complex surgeries had a higher risk of poor postoperative outcomes.

Robot-assisted versus laparoscopic living donor nephrectomy: superior outcomes after completion of the learning curve.

The use of robots in donor nephrectomy has increased in recent years. However, whether robot-assisted methods have better outcomes than traditional laparoscopic methods and how surgical experience influences these outcomes remains unclear. This meta-analysis compares the outcomes of robot-assisted donor nephrectomy (RADN) with those of laparoscopic donor nephrectomy (LDN) and to investigate the effects of surgical experience on these outcomes. A systematic literature search was conducted in Medline (through PubMed) and Web of Science databases. Perioperative data were extracted for meta-analysis. To assess the impact of the learning curve, a subgroup analysis was performed to compare outcomes between inexperienced and experienced surgeons. Seventeen studies with 6970 donors were included. Blood loss was lower (mean difference [MD] = - 13.28, p < 0.01) and the warm ischemia time was shorter (MD = - 0.13, p < 0.05) in the LDN group than the RADN group. There were no significant differences in terms of conversion to open surgery, operation time, surgical complications, hospital stay, costs, and delayed graft function between the groups. Subgroup analysis revealed that operation time (MD = - 1.09, p < 0.01) and length of hospital stay (MD = - 1.54, p < 0.05) were shorter and the rate of conversion to open surgery (odds ratios [OR] = 0.14, p < 0.0001) and overall surgical complications (OR = 0.23, p < 0.05) were lower in experienced RADN surgeons than in experienced LDN surgeons. Surgical experience enhances the perioperative outcomes following RADN more than it does following LDN. This suggests that RADN could be the method of choice for living donor nephrectomy as soon as surgeons gain sufficient experience in robotic surgery.

Surgical management of primary liver cancers during the COVID-19 pandemic: overcoming the dilemma with standardization.

BACKGROUND: The present study evaluates the impact of the pandemic on outcomes after surgical treatment for primary liver cancer in a high-volume hepatopancreatobiliary surgery center. METHODS: Patients, who underwent liver resection for primary liver resection between January 2019 and February 2020, comprised pre-pandemic control group. The pandemic period was divided into two timeframes: early pandemic (March 2020-January 2021) and late pandemic (February 2021-December 2021). Liver resections during 2022 were considered as the post-pandemic period. Peri-, and postoperative patient data were gathered from a prospectively maintained database. RESULTS: Two-hundred-eighty-one patients underwent liver resection for primary liver cancer. The number of procedures decreased by 37.1% during early phase of pandemic, but then increased by 66.7% during late phase, which was comparable to post-pandemic phase. Postoperative outcomes were similar between four phases. The duration of hospital stay was longer during the late phase, but not significantly different compared to other groups. CONCLUSION: Despite an initial reduction in number of surgeries, COVID-19 pandemic had no negative effect on outcomes of surgical treatment for primary liver cancer. The structured standard operating protocol in a high-volume and highly specialized surgical center can withstand negative effects, a pandemic may have on treatment of patients.

Correction: Oweira et al. Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells. J. Clin. Med. 2022, 11, 4794.

There was an error in the original publication [...].

Comparison of the modified piggyback with standard piggyback and conventional orthotopic liver transplantation techniques: a network meta-analysis.

BACKGROUND: In conventional orthotopic liver transplantation (OLT), the recipient's retrohepatic inferior vena cava (IVC) is completely clamped and replaced with the donor IVC. The piggyback technique has been used to preserve venous return, either via an end-to-side or standard piggyback (SPB), or via a side-to-side or modified piggyback (MPB) anastomosis, using a venous cuff from the recipient hepatic veins with partially clamping and preserves the recipient's inferior vena cava. However, whether these piggyback techniques improve the efficacy of OLT is unclear. To address the low quality of the available evidence, we performed a meta-analysis to compare the efficacy of conventional, MPB, and SPB techniques. METHODS: Literature was searched in Medline and Web of Science databases for relevant articles published until 2021 without any time restriction. A Bayesian network meta-analysis was performed to compare the intra- and postoperative outcomes of conventional OLT, MPB, and SPB techniques. RESULTS: Forty studies were included, comprising 10,238 patients. MPB and SPB had significantly shorter operation times and fewer transfusions of red blood cell and fresh frozen plasma than conventional techniques. However, there were no differences between MPB and SPB in operation time and blood product transfusion. There were also no differences in primary non-function, retransplantation, portal vein thrombosis, acute kidney injury, renal dysfunction, venous outflow complications, length of hospital and intensive care unit stay, 90-day mortality rate, and graft survival between the three techniques. CONCLUSION: MBP and SBP techniques reduce the operation time and need for blood transfusion compared with conventional OLT, but postoperative outcomes are similar. This indicates that all techniques can be implemented based on the experience and policy of the transplant center.

Celiac Axis Stenosis is an Underestimated Risk Factor for Increased Morbidity After Pancreatoduodenectomy.

OBJECTIVE: To assesses the prevalence and severity of CAS in patients undergoing PD/total pancreatectomy and its association with major postoperative complications after PD. SUMMARY OF BACKGROUND DATA: CAS may increase the risk of ischemic complications after PD. However, the prevalence of CAS and its relevance to major morbidity remain unknown. METHODS: All patients with a preoperative computed tomography with arterial phase undergoing partial PD or TP between 2014 and 2017 were identified from a prospective database. CAS was assessed based on computed tomography and graded according to its severity: no stenosis (<30%), grade A (30%-<50%), grade B (50%-≤80%), and grade C (>80%). Postoperative complications were assessed and uni- and multivariable risk analyses were performed. RESULTS: Of 989 patients, 273 (27.5%) had CAS: 177 (17.9%) with grade A, 83 (8.4%) with grade B, and 13 (1.3%) with grade C. Postoperative morbidity and 90-day mortality occurred in 278 (28.1%) patients and 41 (4.1%) patients, respectively. CAS was associated with clinically relevant pancreatic fistula ( P =0.019), liver perfusion failure ( P =0.003), gastric ischemia ( P =0.001), clinically relevant biliary leakage ( P =0.006), and intensive care unit ( P =0.016) and hospital stay ( P =0.001). Multivariable analyses confirmed grade B and C CAS as independent risk factors for liver perfusion failure; in addition, grade C CAS was an independent risk factor for clinically relevant pancreatic fistula and gastric complications. CONCLUSIONS: CAS is common in patients undergoing PD. Higher grade of CAS is associated with an increased risk for clinically relevant complications, including liver perfusion failure and postoperative pancreatic fistula. Precise radiological assessment may help to identify CAS. Future studies should investigate measures to mitigate CAS-associated risks.

Prognostic Value of Red Blood Cell Distribution Width (RDW) in the Recurrence of Hepatocellular Carcinoma Following Curative Resection.

Purpose: Although surgery is associated with an acceptable cure rate, tumor recurrence is still a challenging issue in hepatocellular carcinoma (HCC) patients. Red blood cell distribution width (RDW) is considered an inflammatory marker for predicting overall mortality in a wide spectrum of malignancies. In the current study, the prognostic role of pre- and postoperative RDW in HCC recurrence after liver resection (LRx) is investigated. Patients and Methods: In 395 patients, RDW levels were evaluated preoperatively as well as six and twelve months after curative LRx. The RDW cutoff values were determined using receiver operating characteristic curves (ROCs) according to the recurrence-free survival (RFS). Survival analyses were performed using the Kaplan-Meier, and differences were compared using the Log rank test. Results: The RFS was significantly higher among patients with low RDW at the 6th month and 12th month, postoperatively (P < 0.001 and P = 0.028). RDW levels of higher than 16.15% at the 6th (HR: 2.047, P <0.001) and higher than 15.85% at 12th (HR: 3.105, P < 0.002) months after liver resection were independent predictors of RFS. Conclusion: Postoperative RDW values seem to be predictive of tumor recurrence in HCC patients. RDW levels at the 6th and 12th months postoperatively were independent predictors of recurrence after LRx.

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepG2 Tumor Cells.

There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.

Validation of the ISGLS classification of bile leakage after pancreatic surgery: A rare but severe complication.

INTRODUCTION: Hepaticoenterostomy is an important step of reconstruction during hepatopancreatobiliary (HPB) surgery with a subsequent bile leakage rate of up to 5%. The International Study Group of Liver Surgery (ISGLS) proposed a severity grading system for defining bile leakage after HPB surgery, which has not been validated after pancreatic surgery in a large patient cohort. The present study aimed to validate the ISGLS definition for bile leakage in pancreatic surgery and to investigate the postoperative outcomes of bile leakage after pancreatic resections. MATERIALS AND METHODS: Data from the prospectively maintained database for pancreas surgery were extracted for any type of pancreatectomy with hepaticoenterostomy between 2006 and 2019. The severity of bile leakage was graded according to the ISGLS definition. The influence of our standardized hepaticoenterostomy technique and of the complexity of the surgical procedure on the rate of clinically relevant bile leakages (B and C) were assessed in three different timeframes. RESULTS: Bile leakage was detected in 152 of 5,300 patients (2.9%). Clinically relevant bile leakages included seventy patients with grade B and eighty-two patients with grade C bile leakages (46.1% and 53.9%, respectively). During the study period, the overall rate of bile leakage showed to be stable (from 3.5% to 2.4%). Patients with grade C bile leakage had a higher rate of postoperative wound infection (P < 0.001) and longer ICU stays and hospital stays compared to patients with grade B bile leakage (P = 0.03 and P < 0.001 respectively). These parameters were significantly higher in patients with late grade C bile leakage but were similar between patients with grade B bile leakage and early grade C bile leakage (<5th day POD). In the whole patients' cohort, the 90-day mortality rate was 3.2% (174/5,300), with a rate of 25% in patients with bile leakage (38/152). CONCLUSION: The ISGLS classification is a valid method for classifying postoperative bile leak after pancreas surgery. Standardization of our hepaticoenterostomy technique resulted in a stable rate of bile leakage. Although rare, bile leakage following pancreas surgery is a severe complication that has a major impact on patient outcomes and contributes significantly to morbidity and mortality, even in the absence of POPF.