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Background: Failure to rescue (FTR) is defined as the inability to prevent death after the development of a complication. FTR is a parameter in evaluating multidisciplinary postoperative complication management. The aim of this study was to evaluate FTR rates after major liver resection for perihilar cholangiocarcinoma (pCCA) and analyze factors associated with FTR., Patients and Method: Patients who underwent major liver resection for pCCA at 27 centers were included. FTR was defined as the presence of a Dindo grade III or higher complication followed by death within 90 days after surgery. Liver failure ISGLS grade B/C were scored. Multivariable logistic analysis was performed to identify predictors of FTR and reported using odds ratio and 95% confidence intervals., Results: In the 2186 included patients, major morbidity rate was 49%, 90-day mortality rate 13%, and FTR occurred in 24% of patients with a grade III or higher complication. Across centers, major complication rate varied from 19 to 87%, 90-day mortality rate from 5 to 33%, and FTR ranged from 11 to 50% across hospitals. Age [1.04 (1.02-1.05) years], ASA 3 or 4 [1.40 (1.01-1.95)], jaundice at presentation [1.79 (1.16-2.76)], right-sided resection [1.45 (1.06-1.98)], and annual hospital volume < 6 [1.44 (1.07-1.94)] were positively associated with FTR. When liver failure is included, the odds ratio for FTR is 9.58 (6.76-13.68)., Conclusion: FTR occurred in 24% of patients after resection for pCCA. Liver failure was associated with a nine-fold increase of FTR and hospital volume below six was also associated with an increased risk of FTR., Competing Interests: Disclosures: Ulf Neumann presented for Astra Zeneca, Roche AG, Merck AG, and Dr Falk GMBH, BMS. No other conflicts of interest are present. Data available upon reasonable request., (© 2024. The Author(s).)

Background: Major hepatectomy in perihilar cholangiocarcinoma (pCCA) patients with a small future liver remnant (FLR) risks posthepatectomy liver failure (PHLF). This study examines combined portal and hepatic vein embolisation (PVE/HVE) to increase preoperative FLR volume and potentially decrease PHLF rates., Methods: In this retrospective, multicentre, observational study, data was collected from centres affiliated with the DRAGON Trials Collaborative and the EuroLVD registry. The study included pCCA patients who underwent PVE/HVE between July 2016 and January 2023., Results: Following PVE/HVE, 28% of patients (9/32) experienced complications, with 22% (7/32) necessitating biliary interventions for cholangitis. The median degree of hypertrophy after a median of 16 days was 16% with a kinetic growth rate of 6.8% per week. 69% of patients (22/32) ultimately underwent surgical resection. Cholangitis after PVE/HVE was associated with unresectability. After resection, 55% of patients (12/22) experienced complications, of which 23% (5/22) were Clavien-Dindo grade III or higher. The 90-day mortality after resection was 0%., Conclusion: PVE/HVE quickly enhances the kinetic growth rate in pCCA patients. Cholangitis impairs chances on resection significantly. Resection after PVE/HVE is associated with low levels of 90-day mortality. The study highlights the potential of PVE/HVE in improving safety and outcomes in pCCA undergoing resection., Competing Interests: Conflicts of interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The treatment of perihilar Cholangiocarcinoma (pCCA) poses specific challenges not only due to its high perioperative complication rates but also due its dismal long-term prognosis with only a few long-term survivors (LTS) among the patients. Therefore, in this analysis characteristics and predictors of LTS in pCCA patients are investigated., Material and Methods: In this single center analysis, patients undergoing curative-intent liver resection for pCCA between 2010 and 2022 were categorized into long-term and short-term survivors (STS) excluding perioperative mortality. Binary logistic regression was used to determine key differences between the groups and to develop a prognostic composite variable. This composite variable was subsequently tested in the whole cohort of surgically treated pCCA patients using Cox Regression analysis for cancer-specific survival (CSS)., Results: Within a cohort of 209 individuals, 27 patients were identified as LTS (median CSS = 125 months) and 55 patients as STS (median CSS = 16 months). Multivariable analysis identified preoperative portal vein infiltration (OR = 5.85, p = 0.018) and intraoperative packed red blood cell (PRBC) transfusions (OR = 10.29, p = 0.002) as key differences between the groups. A prognostic composite variable based on these two features was created and transferred into a Cox regression model of the whole cohort. Here, the composite variable (HR = 0.35, p<0.001), lymph node metastases (HR = 2.15, p = 0.001) and postoperative complications (HR = 3.06, p<0.001) were identified as independent predictors of CSS., Conclusion: Long-term survival after surgery for pCCA is possible and is strongly negatively associated with preoperative portal vein infiltration and intraoperative PRBC transfusion. As these variables are part of preoperative staging or can be modulated by intraoperative technique, the proposed prognostic composite variable can easily be transferred into clinical management to predict the oncological outcome of patients undergoing surgery for pCCA., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mantas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR., Methods: Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies., Results: Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR., Conclusions: Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Introduction: Explorative laparotomy without subsequent curative-intent liver resection remains a major clinical problem in the treatment of perihilar cholangiocarcinoma (pCCA). Thus, we aimed to identify preoperative risk factors for non-resectability of pCCA patients., Material and Methods: Patients undergoing surgical exploration between 2010 and 2022 were eligible for the analysis. Separate binary logistic regressions analyses were used to determine risk factors for non-resectability after explorative laparotomy due to technical (tumor extent, vessel infiltration) and oncological (peritoneal carcinomatosis, distant nodal or liver metastases)/liver function reasons., Results: This monocentric cohort comprised 318 patients with 209 (65.7%) being surgically resected and 109 (34.3%) being surgically explored [explorative laparotomy: 87 (27.4%), laparoscopic exploration: 22 (6.9%)]. The median age in the cohort was 69 years (range 60-75) and a majority had significant comorbidities with ASA-Score ≥ 3 (202/318, 63.5%). Statistically significant (p < 0.05) risk factors for non-resectability were age above 70 years (HR = 3.76, p = 0.003), portal vein embolization (PVE, HR = 5.73, p = 0.007), and arterial infiltration > 180° (HR = 8.05 p < 0.001) for technical non-resectability and PVE (HR = 4.67, p = 0.018), arterial infiltration > 180° (HR = 3.24, p = 0.015), and elevated CA 19-9 (HR = 3.2, p = 0.009) for oncological/liver-functional non-resectability., Conclusion: Advanced age, PVE, arterial infiltration, and elevated CA19-9 are major risk factors for non-resectability in pCCA. Preoperative assessment of those factors is crucial for better therapeutical pathways. Diagnostic laparoscopy, especially in high-risk situations, should be used to reduce the amount of explorative laparotomies without subsequent liver resection., (© 2024. The Author(s).)

Surgical resection is the only option to achieve long-term survival in cholangiocellular carcinoma (CCA). Due to limitations of health care systems and unforeseeable events, e.g., the COVID pandemic, the time from diagnosis to surgery (time-to-surgery (TTS)) has gained great interest in malignancies. Thus, we investigated whether TTS is associated with the oncological outcome in patients who underwent surgery for CCA. A cohort of 276 patients undergoing curative-intent surgery for intrahepatic and perihilar CCA excluding individuals with neoadjuvant therapy and perioperative mortality between 2010 and 2021 were eligible for analysis. Patients were grouped according to TTS (≤ 30; 31-60; 61-90; > 90 days) and compared by Kruskal-Wallis-analysis. Survival was compared using Kaplan-Meier analysis and characteristics associated with cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS) using Cox regressions. The median CSS was 39 months (3-year-CSS = 52%, 5-year-CSS = 42%) and the median RFS 20 months (3-year-CSS = 38%, 5-year-CSS = 33%). In univariable Cox regressions, TTS was not associated with CSS (p = 0.971) or RFS (p = 0.855), respectively. A grouped analysis with respect to TTS (≤ 30 days, n = 106; 31-60 days, n = 134; 61-90 days, n = 44; > 90 days, n = 29) displayed a median CSS of 38, 33, 51 and 41 months and median RFS of 17, 22, 28 and 20 months (p = 0.971 log rank; p = 0.520 log rank). No statistical difference regarding oncological risk factors were observed between the groups. This study is the first comprehensive analysis of TTS in CCA patients. Within a representative European cohort, TTS was not associated with earlier tumor recurrence or reduced CCS., (© 2024. The Author(s).)

Background: Perihilar cholangiocarcinoma (pCCA) is a malignant tumor of the hepatobiliary system which is still associated with a challenging prognosis. Postoperative complications play a crucial role in determining the overall prognosis of patients with pCCA. Changes in body composition (BC) have been shown to impact the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC, postoperative complications and oncological outcome in patients with pCCA., Methods: All patients with pCCA who underwent curative-intent surgery for pCCA between 2010 and 2022 were included in this analysis. BC was assessed using preoperative computed tomography and analyzed with the assistance of a 3D Slicer software. Univariate and multivariate binary logistic regression analyses were conducted to examine the relationship between BC and clinical characteristics including various measurements of postoperative complications and Cox regressions and Kaplan-Meier analysis to evaluate oncological risk factors in the study cohort., Results: BC was frequently altered in patients undergoing curative-intent liver resection for pCCA (n = 204) with 52.5% of the patients showing obesity, 55.9% sarcopenia, 21.6% sarcopenic obesity, 48.5% myosteatosis, and 69.1% visceral obesity. In multivariate analysis, severe postoperative complications (Clavien-Dindo ≥3b) were associated with body mass index (BMI) (Odds ratio (OR) = 2.001, p = 0.024), sarcopenia (OR = 2.145, p = 0.034), and myosteatosis (OR = 2.097, p = 0.017) as independent predictors. Furthermore, sarcopenia was associated with reduced overall survival (OS) in pCCA patients (sarcopenia vs. no-sarcopenia, 21 months vs. 32 months, p = 0.048 log rank)., Conclusions: BC is highly associated with severe postoperative complications in patients with pCCA and shows tendency to be associated impaired overall survival. Preoperative assessment of BC and interventions to improve BC might therefore be key to improve outcome in pCCA patients undergoing surgical therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients., Methods: Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality., Results: Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69-2.68) or 90-day mortality (OR 1.22; 95% CI 0.62-2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41-1.41) or 90-day mortality (OR 0.60; 95% CI 0.33-1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36-4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31-4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36-4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30-3.87)., Conclusion: In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA., (© 2023. The Author(s).)

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor and usually associated with a poor oncological prognosis. The current gold standard is the surgical resection of the tumor with subsequent adjuvant therapy. However, in case of irresectability e.g. in case of liver cirrhosis, a palliative treatment regime is conducted.This report demonstrates the case of an irresectable iCCA in liver cirrhosis due to primary sclerosing cholangitis (PSC) treated by living-donor liver transplantation (LDLT) facilitated by minimal invasive donor hepatectomy. No postoperative complications were observed in the donor and the donor was released on the 6 th postoperative day. Further, after a follow-up of 1.5 years, no disease recurrence was detected in the recipient.According to the recent international literature, liver transplantation can be evaluated in case of small solitary iCCA (< 3 cm) in cirrhosis. Less evidence is provided for transplantation in advanced tumors which are surgically not resectable due to advanced liver disease or infiltration of major vessels, however some reports display adequate long-term survival after strict patient selection. The selection criteria comprise the absence of distant metastases and locoregional lymph node metastases as well as partial remission or stable disease after neoadjuvant chemotherapy. Due to no established graft allocation for iCCA in Germany, LDLT is currently the best option to realize transplantation in these patients. Developments in the last decade indicate that LDLT should preferentially be performed in minimal invasive manner (laparoscopic or robotic) as this approach is associated with less overall complications and a shorter hospitalization. The presented case illustrates the possibilities of modern surgery and the introduction of transplant oncology in the modern therapy of patients combining systemic therapy, surgical resection and transplantation to achieve optimal long-term results in patients which were initially indicated for palliative treatment., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA., (© 2023. The Author(s).)

Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs., Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling., Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies., Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy., Lay Summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer., Competing Interests: Conflict of interest JC consults for Crosscope, KB is Crosscope Chief Technology Officer, JS is Crosscope Chief Executive Officer. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Cholangiocarcinoma (CCA) is a rare but highly aggressive malignancy of the biliary system. Although it is amenable to surgical resection in early disease, outcomes are frequently dismal. Here, we investigated the prevalence of body composition (BC) alterations and their prognostic role for surgical patients with intrahepatic (iCCA) and perihilar (pCCA) disease. Patients undergoing curative-intent surgery for iCCA or pCCA between 2010 and 2019 at University Hospital Aachen were included. Axial computed tomography images were retrospectively assessed with a segmentation tool (3D Slicer) at the level of the third lumbar vertebra to determine lumbar skeletal muscle (SM) index, mean SM radiation attenuation, and visceral fat area. The related BC pathologies sarcopenia, myosteatosis, visceral obesity, and sarcopenic obesity were determined using previously described cutoffs. A total of 189 patients (86 with iCCA, 103 with pCCA) were included. Alterations of BC were highly prevalent in iCCA and pCCA, respectively: sarcopenia, 33% (28/86) and 39% (40/103); myosteatosis, 66% (57/86) and 66% (68/103); visceral obesity, 56% (48/86) and 67% (69/103); sarcopenic obesity, 11% (9/86) and 17% (17/103). Sarcopenia and myosteatosis did not have a significant prognostic role for disease-free survival (DFS) and overall survival (OS). Patients with iCCA with sarcopenic obesity (n = 9) had significantly shorter OS than patients without sarcopenic obesity (n = 7; log-rank p = 0.002; median OS, 11 months and 31 months; 1-year mortality, 55.6% [5/9] and 22% [17/77]; 5-year mortality, 88.9% [8/9] and 61% [47/77], respectively). In multivariable analysis, only tumor-related risk factors remained prognostic for DFS and OS. Sarcopenic obesity may affect clinical outcomes after curative-intent surgery for iCCA, indicating that imaging-based analysis of BC may hold prognostic value for long-term survival and could aid preoperative patient selection., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

The neutrophil-to-lymphocyte ratio (NLR) is used as biomarker in malignant diseases showing significant association with poor oncological outcomes. The main research question of the present study was whether NLR has also prognostic value in cholangiocarcinoma patients (CCA). A systematic review was carried out to identify studies related to NLR and clinical outcomes in CCA evaluating the literature from 01/2000 to 09/2021. A random-effects model, pooled hazard ratios (HR) and 95% confidence interval (CI) were used to investigate the statistical association between NLR and overall survival (OS) as well as disease-free survival (DFS). Subgroup analyses, evaluation of sensitivity and risk of bias were further carried out. 32 studies comprising 8572 patients were eligible for this systematic review and meta-analysis. The pooled outcomes revealed that high NLR prior to treatment is prognostic for poor OS (HR 1.28, 95% CI 1.18-1.38, p < 0.01) and DFS (HR 1.39, 95% CI 1.17-1.66, p < 0.01) with meaningful HR values. Subgroup analysis revealed that this association is not significantly affected by the treatment modality (surgical vs. non-surgical), NLR cut-off values, age and sample size of the included studies. Given the likelihood of NLR to be prognostic for reduced OS and DFS, pre-treatment NLR might serve as a useful biomarker for poor prognosis in patients with CCA and therefore facilitate clinical management., (© 2022. The Author(s).)

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients.In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA.In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translationaldata is needed to fully unravel the importance of TILs in the treatment of CCA., (© 2022. The Author(s).)

Introduction: Major hepatectomy for perihilar and intrahepatic cholangiocarcinoma (CCA) is often associated with a significant intraoperative blood loss and the requirement for perioperative transfusion of blood products. The aim of this study was to investigate the oncological impact of fresh frozen plasma (FFP) transfusion during hospitalization in patients undergoing hepatectomy for CCA as adverse effects have been described in other malignancies., Material and Methods: Patients undergoing hepatectomy for CCA from 2010 to 2019 at a single institution were eligible for this study. Survival analysis was carried out according to Kaplan-Meier and the associations of cancer-specific (CSS) and recurrence-free survival (RFS) with in-hospital application of FFP and other clinico-pathological characteristics were assessed using Cox regression models. Perioperatively deceased patients were excluded from the analysis., Results: A total of 219 CCA patients were included in this survival analysis of which 53.0% (116/219) received FFP during hospitalization. Patients receiving in-hospital FFP showed a median CCS of 33 months (3-year-CSS = 46%, 5-year-CSS = 29%) compared to 83 months (3-year-CSS = 55%, 5-year-CSS = 53%) in patients who did not receive in-hospital FFP (p = 0.006 log rank). Further, in-hospital FFP was identified as an independent predictor of oncological outcome in multivariable analysis (CSS: HR = 1.71, p = 0.016; RFS: HR = 1.89, p = 0.003)., Conclusion: In a large European cohort of patients, in-hospital transfusion of FFP was identified as a novel independent prognostic marker in CCA patients undergoing curative-intent liver surgery. A restrictive transfusion policy is therefore recommended to improve long-term outcome in these patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons., Background: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking., Methods: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers., Results: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes., Conclusion: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: While a certain degree of tumor infiltration of the portal vein is common in patients with perihilar cholangiocarcinoma (pCCA) scheduled for surgery, complete tumor-associated portal vein occlusion (PVO) is less frequently observed. Here, we analyzed the impact of PVO on perioperative and oncological outcomes in pCCA patients., Methods: Between 2010 and 2019, 127 patients with pCCA underwent surgery in curative intent at our department of which 17.3% (22/127) presented with PVO. Extensive group comparisons were conducted and the association of cancer-specific (CSS) and disease-free survival (DFS) with PVO and other clinico-pathological characteristics were assessed using Cox regression models., Results: Patients without PVO showed a median CSS of 65 months (3-year-CSS = 64%, 5-year-CSS = 53%) compared to 31 months (3-year-CSS = 43%, 5-year-CSS = 17%) in patients with PVO (p = 0.025 log rank). Patients with PVO did also display significant perioperative mortality (22.7%, 5/22) compared to patients without PVO (14.3%, 15/105, p = 0.323). Further, PVO (CSS: HR = 5.25, p = 0.001; DFS: HR = 5.53, p = 0.001) was identified as independent predictors of oncological outcome., Conclusions: PVO has been identified as an important prognostic marker playing a role in inferior oncological outcome in patients with pCCA. As PVO is also associated with notable perioperative mortality, surgical therapy should be considered carefully in pCCA patients., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction :Although advances in understanding the molecular basis of cholangiocarcinoma (CCA) have been made, surgery is the only curative therapy option and the overall prognosis of patients suffering from the disease remains poor. Therefore, estimation of prognosis based on known and novel biomarkers is essential for therapy guidance of CCA in both, curative and palliative settings. Areas covered :An extensive literature search on biomarkers for CCA with special emphasis on prognosis was performed. Based on this, prognostic biomarkers from serum, tumor tissue and other compartments that are currently in use or under evaluation for CCA were summarized in this review. Furthermore, an overview of new biomarkers was provided including those determined from extracellular vesicles (EVs), metabolites and nucleic acids. Finally, prognostic markers associated with potential new therapy options for the treatment of CCA were summed up. Expert opinion :So far, an optimal prognostic biomarker for CCA has not been described. However, based on the increasing knowledge about the molecular basis of CCA but also due to novel, innovative technologies, a plethora of novel prognostic biomarkers is currently under evaluation and will be available for CCA in future.

Abdominal infections including cholangitis represent a major problem in patients with perihilar cholangiocarcinoma (pCCA). Thus, we investigated bacterial colonization of the bile ducts and determined its impact on postoperative outcome focusing on abdominal infections. A cohort of 95 pCCA patients who underwent surgery between 2010 and 2019 with available intraoperative microbial bile cultures were analyzed regarding bile duct colonization and postoperative abdominal infection by group comparisons and logistic regressions. 84.2% (80/95) showed bacterial colonization of the bile ducts and 54.7% (52/95) developed postoperative abdominal infections. Enterococcus faecalis (38.8%, 31/80), Enterococcus faecium (32.5%, 26/80), Enterobacter cloacae (16.3%, 13/80) and Escherichia coli (11.3%, 9/80) were the most common bacteria colonizing the bile ducts and Enterococcus faecium (71.2%, 37/52), Enterococcus faecalis (30.8%, 16/52), Enterobacter cloacae (25.0%, 13/52) and Escherichia coli (19.2%, 10/52) the most common causes of postoperative abdominal infection. Further, reduced susceptibility to perioperative antibiotic prophylaxis (OR = 10.10, p = .007) was identified as independent predictor of postoperative abdominal infection. Bacterial colonization is common in pCCA patients and reduced susceptibility of the bacteria to the intraoperative antibiotic prophylaxis is an independent predictor of postoperative abdominal infections. Adapting antibiotic prophylaxis might therefore have the potential to improve surgical outcome pCCA patients.

Background: Major liver resection has evolved as the mainstay of treatment for patients with perihilar cholangiocarcinoma (pCCA). Here we assessed the suitability of preoperative future liver remnant (FLR) measurement to predict perioperative complications, since surgical morbidity and mortality are high compared to other malignancies., Methods: Between 2011 and 2016, 91 patients with pCCA underwent surgery in curative intent at our institution. The associations of surgical complications with FLR and clinico-pathological characteristics were assessed using logistic regression analyses. Different methods of FLR assessment, the calculated-FLR (cFLR; ratio of FLR to total liver volume), standardized FLR (sFLR; ratio of FLR to liver volume estimated by body surface area) and FLR to bodyweight ratio (FLR/BW) were tested for validity., Results: Multivariable analysis identified preoperative cholangitis (Exp(B) = 0.236; p = 0.030) as the single significant predictor of postoperative mortality and cFLR (Exp(B) = 0.009, p = 0.004) as the single significant predictor of major postoperative morbidity (Clavien-Dindo ≥ 3b). Based on these findings we designed a futility criterion (cFLR<40% OR preoperative cholangitis) predicting in-house mortality., Conclusions: In patients with pCCA, the preoperative FLR<40% as well as preoperative cholangitis are two risk factors to independently predict perioperative morbidity and mortality. The cFLR should be the preferred method of liver volumetry., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: ALPPS is found to increase the resectability of primary and secondary liver malignancy at the advanced stage. The aim of the study was to verify the surgical and oncological outcome of ALPPS for intrahepatic cholangiocarcinoma (ICC)., Methods: The study cohort was based on the ALPPS registry with patients from 31 international centers between August 2009 and January 2018. Propensity score matched patients receiving chemotherapy only were selected from the SEER database as controls for the survival analysis., Results: One hundred and two patients undergoing ALPPS were recruited, 99 completed the second stage with median inter-stage duration of 11 days. The median kinetic growth rate was 23 ml/day. R0 resection was achieved in 87 (85%). Initially high rates of morbidity and mortality decreased steadily to a 29% severe complication rate and 7% 90-day morbidity in the last 2 years. Post-hepatectomy liver failure remained the main cause of 90-day mortality. Multivariate analysis revealed insufficient future liver remnant at the stage-2 operation (FLR2) to be the only risk factor for severe complications (OR 2.91, p = 0.02). The propensity score matching analysis showed a superior overall survival in the ALPPS group compared to palliative chemotherapy (median overall survival: 26.4 months vs 14 months; 1-, 2-, and 3-year survival rates: 82.4%, 70.5% and 39.6% vs 51.2%, 21.4% and 11.3%, respectively, p < 0.01). The survival benefit, however, was not confirmed in the subgroup analysis for patients with insufficient FLR2 or multifocal ICC., Conclusion: ALPPS showed high efficacy in achieving R0 resections in locally advanced ICC. To get the most oncological benefit from this aggressive surgery, ALPPS would be restricted to patients with single lesions and sufficient FLR2.

Background: Major liver resections with portal vein resection (PVR) have emerged as the preferred treatment for patients with perihilar cholangiocarcinoma (pCCA). Whether the resection of the liver should be preferably performed as left- (LH) or right-sided hepatectomy (RH) with or without hilar en-bloc technique is still subject of ongoing debate., Methods: Between 2011 and 2016, 91 patients with pCCA underwent surgery in curative intent at our institution. Perioperative, pathological and survival data from all consecutive patients undergoing hilar en-bloc resection for pCCA were analyzed retrospectively. Patients undergoing hepatoduodenectomy (n = 8) or ALPPS (Associating liver partition and portal vein ligation for staged hepatectomy) (n = 2) were excluded from the analysis., Results: Tumor grading, microvascular invasion, lymphovascular invasion, N-category, T-category, R-status and UICC-tumor staging were similar in the RH (n = 45) and LH (n = 36) groups. Perioperative morbidity and mortality were higher after RH compared to LH (mortality: 15.6% (7/45) vs. 8.3% (3/36) p = 0.003). Three-year (62% vs. 51%) and the 5-year OS (30% vs. 46%) were comparable between LH and RH groups respectively (p = 0.519, log rank)., Conclusions: The present study supports the concept of surgically aggressive therapy in pCCA. LH and RH hilar en-bloc resection demonstrate a comparable long-term survival, suggesting that LH hilar en-bloc resections are feasible and safe in high-volume centers., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Cholangiocellular carcinoma (CCA) is an aggressive malignancy with a dismal prognosis. Among curative treatment options for CCA, radical surgical resection with extrahepatic bile duct resection, hepatectomy and en-bloc lymphadenectomy are considered the mainstay of curative therapy. Here, we aimed to identify prognostic markers of clinical outcome in CCA-patients who underwent surgical resection in curative intent., Material and Methods: Between 2011 and 2016, 162 patients with CCA (perihilar CCA (pCCA): n = 91, intrahepatic CCA (iCCA): n = 71) underwent surgery in curative intent at our institution. Preoperative characteristics, perioperative data and oncological follow-up were obtained from a prospectively managed institutional database. The associations of overall- (OS) and disease-free-survival (DFS) with clinico-pathological characteristics were assessed using univariate and multivariable cox regression analyses., Results: The median OS and DFS were 38 and 36 months for pCCA and 25 and 13 months for iCCA, respectively. Lymphovascular invasion (LVI) and lymph node metastasis as well as surgical complications as assessed by the comprehensive complication index (CCI) and tumor grading were independently associated with OS for the pCCA (LVI; RR = 2.36, p = 0.028; CCI; RR = 1.04, p < 0.001) and iCCA cohorts (N-category; RR = 3.21, p = 0.040; tumor grading; RR = 3.75, p = 0.013; CCI, RR = 4.49, p = 0.010), respectively. No other clinical variable including R0-status and Bismuth classification was associated with OS., Conclusion: Major liver resections for CCA are feasible and safe in experienced high-volume centers. Lymph node metastasis and LVI are associated with adverse clinical outcome, supporting the role of systematic lymphadenectomy. The assessment of LVI may be useful in identifying high-risk patients for adjuvant treatment strategies., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Cholangiocarcinoma (CCC) is the second most common primary malignancy of the liver and is typically diagnosed at advanced disease stages. Among curative treatment options for CCC, radical surgical resection with extrahepatic bile duct resection, hepatectomy, and en-bloc lymphadenectomy are considered the mainstay of curative therapy. The assessment of the functional liver reserve by dynamic liver function tests and the estimation of the remaining future liver volume (future liver remnant, FLR) are of paramount importance. The introduction of novel interventional and surgical techniques, such as portal vein embolization, associating liver partition, and portal vein ligation for staged hepatectomy (ALPPS), have enabled clinicians to achieve resectability even in patients previously deemed unresectable. Radiofrequency ablation (RFA) shows acceptable results in small intrahepatic cholangiocarcinoma (IHCC) in liver cirrhosis and should be evaluated if cirrhosis precludes surgical treatment. Transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) alone or in combination with systemic therapy may be applied in cases of surgical irresectability. According to recent results of the British BILCAP trial, adjuvant therapy may be considered after surgical resection in curative intent.