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Background: Intrahepatic cholangiocarcinoma is the second most common primary liver cancer after hepatocellular carcinoma with an increasing incidence worldwide. Surgical resection is still the only potential cure, and survival rates are dismal due to disease relapse after resection and/or metastatic disease. Positive resection margins are associated with recurrence, with conflicting studies regarding the benefits of wide resection margins to reduce recurrence rates., Methods: 126 patients with an R0 resection treated with hepatic surgery for intrahepatic cholangiocarcinoma at the Surgical Department at the Medical University Centre Essen, Germany were identified in a database and retrospectively analysed. Patients were grouped into three groups according to margin width, <1 mm (very narrow margin width) 1-5 mm (narrow margin width) and >5 mm (wide margin width). Epidemiological as well as perioperative data was analysed, and a univariate analysis as well as Kaplan-Meier plots carried out to investigate recurrence-free and overall survival., Results: Wider resection margins did not lead to better recurrence-free survival. A wider resection margin >5 mm was not significantly associated with improved overall survival. Positive lymph nodes (HR 2.50, 95% CI 1.11-5.61, p=0.027) and non-anatomic resections (HR 2.06, 95% CI 1.13-3.75, p=0.019) are significantly associated with poorer overall survival. Regarding recurrence-free survival, V2 vascular invasion was the only risk factor statistically significantly associated with poorer recurrence-free survival (HR 8.83, 95% CI 0.85-2.83, p=0.005)., Conclusion: Resection margins did not have a significant impact on disease free survival or overall survival following hepatic resection for intrahepatic cholangiocarcinoma. Non-anatomical resections, lymph node and vascular invasion all significantly impacted oncological outcomes., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Esophagectomy carries a high risk of morbidity and mortality compared to other major surgeries. With the aim of creating an easy-to-use clinical preoperative risk assessment tool and to validate previously described risk factors for major complications following surgery, esophagectomies at two tertiary medical centers were analyzed., Methods: A total of 450 patients who underwent esophagectomy for esophageal carcinoma at the University Medical Centre, Hamburg, or at the Medical Center University Duisburg-Essen, Germany (January 2008 to January 2020) were retrospectively analyzed. Epidemiological and perioperative data were analyzed to identify the risk factors that impact major complication rates. The primary endpoint of this study was to determine the incidence of major complications., Results: The mean age of the patients was 63 years with a bimodal distribution. There was a male predominance across the cohort (81% vs. 19%, respectively). Alcohol abuse ( p = 0.0341), chronic obstructive pulmonary disease ( p = 0.0264), and cardiac comorbidity ( p = 0.0367) were associated with a significantly higher risk of major complications in the multivariate analysis. Neoadjuvant chemotherapy significantly reduced the risk of major postoperative complications ( p < 0.0001)., Conclusions: Various patient-related risk factors increased the rate of major complications following esophagectomy. Patient-tailored prehabilitation programs before esophagectomy that focus on minimizing these risk factors may lead to better surgical outcomes and should be analyzed in further studies.

Background: Gastric cancer is one of the most common cancers worldwide and is the third most common cause of cancer related death. Improving postoperative results by understanding risk factors which impact outcomes is important. The current study aimed to compare immediate perioperative outcomes following gastrectomy., Methods: 302 patients following gastric resections over a 10-year period (January 2009-January 2020) were identified in a database and retrospectively analysed. Epidemiological as well as perioperative data was analysed, and a univariate and multivariate analysis performed to identify risk factors for in-hospital mortality., Results: In general, gastrectomies were mainly performed electively (total vs. subtotal 95% vs. 85%, p  = 0.004). Patients having subtotal gastrectomy needed significantly more PRBC transfusions compared to total gastrectomy ( p  = 0.039). Most emergency surgeries were performed for benign diseases, such as ulcer perforations or bleeding and gastric ischaemia. Only emergency surgery was significantly associated with poorer overall survival (HR 2.68, 95% CI 1.32-5.05, p  = 0.003)., Conclusion: In-hospital mortality was comparable between total and subtotal gastrectomies. Only emergency interventions increased postoperative fatality risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Stüben, Plitzko, Stern, Li, Neuhaus, Treckmann, Schmeding, Saner and Hoyer.)

Klatskin tumors have a bad prognosis despite aggressive therapy. The role and extent of lymph node dissection during surgery is a matter of discussion. This retrospective study analyzes our current experience of surgical treatments in the last decade. Patients and Methods: A retrospective single-center analysis of patients ( n = 317) who underwent surgical treatment for Klatskin tumors. Univariable and multivariable logistic regression and Cox proportional analysis were performed. The primary endpoint was to investigate the role of lymph node metastasis for patient survival after complete tumor resection. The secondary endpoint was the prediction of lymph node status and long-term survival from preoperatively available parameters. Results: In patients with negative resection margins, a negative lymph node status was the prognosis-determining factor with a 1-, 3-, and 5-year survival rate of 87.7%, 37%, and 26.4% compared with 69.5%, 13.9%, and 9.3% for lymph-node-positive patients, respectively. Multivariable logistic regression for complete resection and negative lymph node status demonstrated only Bismuth type 4 ( p = 0.01) and tumor grading ( p = 0.002) as independent predictors. In multivariate Cox regression analysis, independent predictors of survival after surgery were the preoperative bilirubin level ( p = 0.03), intraoperative transfusion ( p = 0.002), and tumor grading (G) ( p = 0.001). Conclusion: Lymph node dissection is of utmost importance for adequate staging in patients undergoing surgery for perihilar cholangiocarcinoma. In spite of extensive surgery, long-term survival is clearly associated with the aggressiveness of the disease.

Primary sclerosing cholangitis (PSC) is characterized by inflammation of the whole bile duct system. Liver transplantation is only approved as a curative treatment when it comes to end-stage liver disease. The aim of our study was to assess morbidity, survival rates and PSC recurrence and the impact of donor characteristics in long-term follow-up. This was an IRB-approved retrospective study. A total of 82 patients were identified who were transplanted between January 2010 and December 2021 for PSC. Among these patients, 76 adult liver transplant PSC patients and their corresponding donors were analyzed. Three pediatric cases and three adult patients with a follow-up within <1 year were excluded from further analysis. Median (range) age was 47 years (18-70) with a median (range) lab-MELD of 16 (7-40). Median (range) ICU and hospital stays were 4.6 days (0-147) and 21 days (1-176), respectively. The majority of patients suffered from Crohn's disease or ulcerative colitis as a concomitant comorbidity (65.8%). The ten-year survival rate was 74.6%. A significantly lower lab-MELD score was identified in patients surviving for > 10 years (15 vs. 22, p = 0.004). Most patients (65%) passed in the first year following transplantation, with primary non-function (PNF), sepsis and arterial thrombosis being the most common causes of death. Donor characteristics did not affect patient survival. Patients with PSC show excellent 10-year survival rates. While the lab-MELD score significantly affected long term outcomes, donor characteristics did not affect survival rates.

Introduction: Systemic therapy is firmly established in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Clinical efficacy is still modest and options are limited. Combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel (Gem/NP) define standard-of-care. Patients may receive a sequence of both regimens as first- and second-line palliative treatment. However, there is no guidance regarding a preferred order., Methods: This is a retrospective analysis of clinical characteristics, treatment trajectories, and outcomes of patients with advanced PDAC treated at the West German Cancer Center Essen from 2014 to 2020 to inform treatment decisions with respect to predictive factors, impact of chemotherapy regimen sequence, and maintenance treatment., Results: We identified 170 patients with available follow-up. Of those, 160 (94.1%) patients received palliative CTX for primary metastatic, locally advanced, or recurrent PDAC. Median progression-free survival (PFS) upon first palliative chemotherapy was 4.1 (3.1-5.9) months. First-line FOLFIRINOX was associated with superior PFS (median 6.3 months) and OS (9.7 months, HR 0.7, p = 0.03) as compared to Gem/NP or other regimens (PFS 3.0, OS 6.9 months). However, OS benefit of first-line FOLFIRINOX was lost in patients who received at least two treatment lines (median OS 12.1 vs. 13.1 months, p = 0.43). A landmark analysis of patients with clinical benefit (defined as CR/PR/SD for at least 20 weeks) upon first-line therapy revealed improved OS (HR 0.53, p = 0.02) for patients receiving continued deescalated maintenance therapy. Second-line regimens resulted in similar PFS (overall log-rank p = 0.92, median PFS upon second-line therapy 2.3 [1.8-2.9], per-regimen median between 1.8 and 3.9 months). A previously established systemic inflammation score proved to be strongly prognostic and allowed identification of a patient subgroup with dismal prognosis (OS 2.9 vs. 11.4 months, HR 5.23, p < 0.001), independent of other prognostic factors and with no relevant interaction with the choice of first-line regimen., Conclusion: In this real-world population of PDAC patients treated with contemporary combination chemotherapies, a positive impact of first-line FOLFIRINOX was only observed when no second or further line treatment was administered. Intensity-reduced maintenance therapy may lead to superior survival., (© 2023 S. Karger AG, Basel.)

Introduction: Gemcitabine and cisplatin is the standard first-line systemic treatment in patients with advanced cholangiocarcinoma (CCA). However, a substantial number of patients do not qualify for cisplatin due to comorbidities or poor performance status. The phase II pilot study NACHO evaluated the efficacy of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) given on days 1, 8, and 15 every 4 weeks as first-line therapy in patients with advanced CCA ineligible for cisplatin-based chemotherapy., Methods: Patients with any comorbidity precluding cisplatin therapy, such as renal impairment, impaired hearing, increased risk or history for thromboembolic events, intolerance of extensive hydration, or significant cardiovascular disease were eligible. Primary endpoint was overall response rate (ORR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and patient reported outcome., Results: From December 2016 to July 2017, 10 patients were prospectively enrolled and treated. The ORR with nab-paclitaxel/gemcitabine was 50%, the disease control rate (DCR) was 90%. Median PFS was 5.7 months (95% CI: 5.3-6.1), and median OS was 7.8 months (95% CI: 5.4-10.2). In total, 13 SAEs were documented without any new safety signals. There were 14 grade 3-4 treatment-related adverse events (TRAEs) in 10 patients of the ITT population. Exploratory subgroup analyses including known prognostic markers were performed., Conclusions: The NACHO trial supports safety and efficacy of nab-paclitaxel and gemcitabine in patients with advanced CCA ineligible for cisplatin-based therapy and should be further evaluated in a larger prospective trial., (© 2023 S. Karger AG, Basel.)

Background: HTK-N was developed based on the traditional HTK preservation solution, resulting in stronger protection against reactive oxygen species as well as better tolerance to hypothermia and ischemia. Aim of the present study was to compare HTK-N to HTK in clinical kidney transplantation demonstrating safety and non-inferiority., Methods: We performed a randomized controlled single blinded clinical phase II trial in patients undergoing living donor kidney transplantation. After retroperitoneoscopic nephrectomy kidneys were either perfused and stored with classical HTK solution or the new HTK-N solution. Primary endpoint was the glomerular filtration rate (eGFR according to CKD EPI) 3 months after transplantation. Secondary endpoints included graft and patient survival beside others., Results: The study included 42 patients, of which 22 were randomized in the HTK-N group and 20 in the HTK group. The primary end point showed a mean eGFR of 55.4 ± 14.0 ml/min/1.73 m 2 in the HTK group compared to a GFR of 57.2 ± 16.7 ml/min/m 2 in the HTK-N group (P = .72). Regarding secondary endpoints, there were no apparent differences. Posttransplant graft and patient survival was 100%., Conclusion: This study is the first clinical application of HTK-N for kidney preservation and demonstrates non-inferiority compared to HTK in the setting of living donor kidney transplantation., (© 2021 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1-9 ligands for 6-24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.

Small-donor kidneys (≤20 kg donor weight, SDK) are preferably transplanted en bloc in adults. Concerns about thrombotic complications or hyperfiltration hinder their use in children, particularly as single grafts. Low centre experience and donor-to-recipient size are rated critical regarding outcomes. We evaluated SDK transplantation (SDTx) in paediatric recipients at a specialized transplant centre. Between 2008 and 2018, SDTx was performed in 40 children (mean age 5.4 ± 1.4 years, single grafts n = 38, donor weight ≤10 kg: n = 10). Perioperative complications were rare (n = 3), mainly thromboses despite immediate heparinization and resulted in graft loss in one patient. Overall, early and long-term GFR were excellent (76 ± 21 and 100 ± 11 ml/min/1.73 m 2 , first month and year 5, respectively). Three patients presented with delayed graft function. Graft volume increased significantly (69 ± 38 vs. 111 ± 33 ml within 5 years; P < 0.0001). Patients showed catch-up growth to normal range (SDS for height -2.06 ± 1.6 to -1.60 ± 1.5). Stratification by recipient age and donor weight revealed superior results in young recipients (≤3 years) and ≤10 kg donors, respectively. Outcome of single SDK grafts was excellent. Gain of GFR and graft volume was even higher in patients with very small donor or recipient size, regardless of a reduced donor-to-recipient weight ratio. Therefore, SDTx should be considered favouring small paediatric recipients., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann-Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly ( p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories 'regulome', 'inflammaging', 'regeneration', and 'pharmacogenes'. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed 'aging cascade', wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1 . This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.