Search

Thi Phuong Thao Hoang,1 Philipp Schindler,2 Nikolaus Börner,3 Max Masthoff,2 Mirjam Gerwing,2 Philippa von Beauvais,2 Enrico N De Toni,4 Christian M Lange,4 Jonel Trebicka,5 Haluk Morgül,6 Max Seidensticker,1 Jens Ricke,1 Andreas Pascher,6 Markus Guba,3 Michael Ingrisch,1 Moritz Wildgruber,1,* Osman Öcal1,* 1Department of Radiology, University Hospital, LMU Munich, Munich, Germany; 2Clinic for Radiology, University Hospital Muenster, Muenster, Germany; 3Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany; 4Department for Internal Medicine II, University Hospital, LMU Munich, Munich, Germany; 5Department for Internal Medicine B, Universitätsklinikum Münster, Münster, Germany; 6Department of General, Visceral and Transplant Surgery, Universitätsklinikum Münster, Münster, Germany*These authors contributed equally to this workCorrespondence: Osman Öcal, Department of Radiology, University Hospital – LMU Munich, Marchioninistrasse 15, D-81377, München, Germany, Email osman.oecal@med.uni-muenchen.dePurpose: To investigate the prognostic value of computed tomography (CT) derived imaging biomarkers in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and develop a predictive nomogram model.Patients and Methods: This retrospective study included 178 patients with histopathologically confirmed HCC who underwent liver transplantation between 2007 and 2021 at the two academic liver centers. We evaluated dedicated imaging features from baseline multiphase contrast-enhanced CT supplemented by several clinical findings and laboratory parameters. Time-to-recurrence was estimated by Kaplan–Meier analysis. Univariable Cox proportional hazard regression and multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to assess independent prognostic factors for recurrence. A nomogram model was then built based on the independent factors selected through LASSO regression, to predict the probabilities of HCC recurrence at one, three, and five years.Results: The rate of HCC recurrence after LT was 17.4% (31 of 178). The LASSO analysis revealed six independent predictors associated with an elevated risk of tumor recurrence. These predictors included the presence of peritumoral enhancement, the presence of over three tumor lesions, the largest tumor diameter greater than 3 cm, serum alpha-fetoprotein (AFP) levels exceeding 400 ng/mL, and the presence of a tumor capsule. Conversely, a history of bridging therapies was found to be correlated with a reduced risk of HCC recurrence. In addition, Kaplan-Meier curves showed patients with irregular margin, satellite nodules, or small lesions displayed shorter time-to-recurrence. Our nomogram demonstrated good performance, yielding a C-index of 0.835 and AUC values of 0.86, 0.88, and 0.85 for the predictions of 1-year, 3-year, and 5-year TTR, respectively.Conclusion: Imaging parameters derived from baseline contrast-enhanced CT showing malignant behavior and aggressive growth patterns, along with serum AFP and history of bridging therapies, show potential as biomarkers for predicting HCC recurrence after transplantation.Keywords: hepatocellular carcinoma, transplantation, imaging, recurrence

Here, we present a detailed computational study of the stability and the electronic structure of nitrogen-doped graphene (N 4 V 2 ) supported Cu n ( n = 1-5) clusters, which are promising carbon-dioxide electroreduction catalysts. The binding of the clusters to the nitrogen-doped graphene and the electronic structure of these systems were investigated under vacuum and electrochemical conditions. The stability analysis showed that among the systems, the nitrogen-doped graphene bound Cu 4 is the most stable in vacuum, while in an electrolyte, and at a negative potential, the N 4 V 2 -Cu 3 is energetically more favorable. The ground state electronic structure of the nitrogen-doped graphene substrate undergoes topological phase transition, from a semimetallic state, and we observed a metallic and topologically trivial state after the clusters are deposited. The electrode potential adjusts the type and density of the charge carriers in the semimetallic models, while the structures containing copper exhibit bands which are deformed and relaxed by the modified number of electrons., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: While 4 randomized controlled clinical trials confirmed the early benefits of hypothermic oxygenated machine perfusion (HOPE), high-level evidence regarding long-term clinical outcomes is lacking. The aim of this follow-up study from the HOPE-ECD-DBD trial was to compare long-term outcomes in patients who underwent liver transplantation using extended criteria donor allografts from donation after brain death (ECD-DBD), randomized to either HOPE or static cold storage (SCS)., Methods: Between September 2017 and September 2020, recipients of liver transplantation from 4 European centers receiving extended criteria donor-donation after brain death allografts were randomly assigned to HOPE or SCS (1:1). Follow-up data were available for all patients. Analyzed endpoints included the incidence of late-onset complications (occurring later than 6 months and graded according to the Clavien-Dindo Classification and the Comprehensive Complication Index) and long-term graft survival and patient survival., Results: A total of 46 patients were randomized, 23 in both arms. The median follow-up was 48 months (95% CI: 41-55). After excluding early perioperative morbidity, a significant reduction in late-onset morbidity was observed in the HOPE group (median reduction of 23 Comprehensive Complication Index-points [p=0.003] and lower incidence of major complications [Clavien-Dindo ≥3, 43% vs. 85%, p=0.009]). Primary graft loss occurred in 13 patients (HOPE n=3 vs. SCS n=10), resulting in a significantly lower overall graft survival (p=0.029) and adverse 1-, 3-, and 5-year survival probabilities in the SCS group, which did not reach the level of significance (HOPE 0.913, 0.869, 0.869 vs. SCS 0.783, 0.606, 0.519, respectively)., Conclusions: Our exploratory findings indicate that HOPE reduces late-onset morbidity and improves long-term graft survival providing clinical evidence to further support the broad implementation of HOPE in human liver transplantation., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Climate change may well be the "largest threat" to humankind. Changes to our climate system lead to a decrease in global health. The healthcare sector presents one of the largest carbon footprints across all industries. Since surgical departments have one of the largest carbon footprints within the healthcare sector, they represent an area with vast opportunities for improvement. To drive change, it is vital to create awareness of these issues and encourage engagement in changes among people working in the healthcare industry., Methods: We conducted an anonymous cross-sectional survey study to assess awareness among surgeons regarding the impact of healthcare systems on climate change. The questions were designed to investigate surgeons' willingness to accept and promote changes to reduce carbon footprints. Participants included surgical professionals of all ages and levels of expertise., Results: A total of 210 participants completed the survey in full and were included in the evaluation. Sixty percent emphasized a lack of information and the need for personal education. Over 90 % expressed concern for the environment and a strong desire to gain new insights. Provided that clinical performance remains the same, more than 70 % are willing to embrace carbon-friendly alternatives. In this context, all participants accepted the additional time required for training and initially increased personal efforts to achieve equal performance., Conclusion: Limited awareness and information about carbon footprints were observed in surgical departments in German hospitals. Nevertheless, the vast majority of surgeons across all age groups are more than willing to acquire new insights and adapt to changes in order to reduce energy consumption and carbon dioxide production., Competing Interests: This work has not been published or accepted for publication, nor is it under consideration at another journal. Moreover, I would like to declare on behalf of the authors that there are no ethical, financial nor other conflicts of interests and that all authors have seen and approved the manuscript., (© 2024 The Authors.)

The purpose of this study is to evaluate the technical and clinical outcome of percutaneous transhepatic biliary drainage (PTBD) in patients with biliary leakage. All patients who underwent ultrasound-assisted PTBD between January 2017 and December 2021 due to biliary leakage with nondilated biliary systems were retrospectively evaluated for periprocedural characteristics, medical indications, technical success (successful placement of drainage catheter), clinical success (resolved leak without additional procedures), fluoroscopy time, procedure duration, and clinical outcomes. 74 patients with a mean age of 64.1 ± 15.1 years were identified. Surgery was the most common etiology of biliary leak with 93.2% of the cases. PTBD had a 91.8% (68/74) technical success rate and an 80.8% clinical success rate. The mean procedure and fluoroscopy duration were 43.5 and 18.6 minutes. Age > 65 years (P = .027) and left-sided drainage (P = .034) were significant risk factors of clinical failure. Procedure-related major complications were 2 bleedings from the liver and 1 bleeding from an intercostal artery (major complication rate 4%). PTBD is a feasible, safe, and effective treatment option in patients with biliary leakage with low complication rates., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

This observational study focuses on the characteristics and survival of patients taken off of the liver transplant waiting list. Assessment of post-delisting survival and a frequent follow-up of patients after delisting are important keys to improve the survival rate of patients with liver failure after being delisted. Within this study, delisted liver transplant candidates were divided into the following groups: (1) "too good" (54%) or (2) "too sick" (22%) for transplantation, (3) adherence issues (12%) or (4) therapy goal changed (11%). The 5-year survival after delisting within these groups was 84%, 9%, 50%, and 68%, respectively. Less than 3% of the delisted patients had to be relisted again. The clinical expert decision of the multidisciplinary transplant team was sufficiently accurate to differentiate between patients requiring liver transplantation and those who were delisted after a stable recovery of liver function. The assessment of post-delisting survival may serve as a complementary metric to assess differences in center practices and to estimate cumulative post-delisting mortality risk.

Adipose-derived mesenchymal stem cells are increasingly being used in regenerative medicine as cell therapy targets, including in the treatment of burns and ulcers. The regenerative potential of AD-MSCs and some of their immunological properties are known from in vitro studies; however, in clinical applications, cells are used in non-ideal conditions and can behave differently in inflammatory environments, affecting the efficacy and outcome of therapy. Our aim was to investigate and map the pathways that the inflammatory microenvironment can induce in these cells. High-throughput gene expression assays were performed on AD-MSCs activated with LPS and TNFα. Analysis of RNA-Seq data showed that control, LPS-treated and TNFα-treated samples exhibited distinct gene expression patterns. LPS treatment increased the expression of 926 genes and decreased the expression of 770 genes involved in cell division, DNA repair, the cell cycle, and several metabolic processes. TNFα treatment increased the expression of 174 genes and decreased the expression of 383 genes, which are related to cell division, the immune response, cell proliferation, and differentiation. We also map the biological pathways by further investigating the most altered genes using the Gene Ontology and KEGG databases. Secreted cytokines, which are important in the immunological response, were also examined at the protein level, and a functional assay was performed to assess wound healing. Activated AD-MSC increased the secretion of IL-6, IL-8 and CXCL-10, and also the closure of wounds. AD-MSCs presented accelerated wound healing under inflammation conditions, suggesting that we could use this cell in clinical application.

The proper functioning of mesenchymal stem cells (MSCs) is of paramount importance for the homeostasis of the body. Inflammation and infection can alter the function of MSCs, which can also affect the regenerative potential and immunological status of tissues. It is not known whether human herpes simplex viruses 1 and 2 (HSV1 and HSV2), well-known human pathogens that can cause lifelong infections, can induce changes in MSCs. In non-healing ulcers, HSV infection is known to affect deeper tissue layers. In addition, HSV infection can recur after initially successful cell therapies. Our aim was to study the response of adipose-derived MSCs (ADMSCs) to HSV infection in vitro. After confirming the phenotype and differentiation capacity of the isolated cells, we infected the cells in vitro with HSV1-KOS, HSV1-532 and HSV2 virus strains. Twenty-four hours after infection, we examined the gene expression of the cells via RNA-seq and RT-PCR; detected secreted cytokines via protein array; and determined autophagy via Western blot, transmission electron microscopy (TEM) and fluorescence microscopy. Infection with different HSV strains resulted in different gene-expression patterns. In addition to the activation of pathways characteristic of viral infections, distinct non-immunological pathways (autophagy, tissue regeneration and differentiation) were also activated according to analyses with QIAGEN Ingenuity Pathway Analysis, Kyoto Encyclopedia of Genes and Genome and Genome Ontology Enrichment. Viral infections increased autophagy, as confirmed via TEM image analysis, and also increased levels of the microtubule-associated protein light chain 3 (LC3B) II protein. We identified significantly altered accumulation for 16 cytokines involved in tissue regeneration and inflammation. Our studies demonstrated that HSV infection can alter the viability and immunological status of ADMSCs, which may have implications for ADMSC-based cell therapies. Alterations in autophagy can affect numerous processes in MSCs, including the inhibition of tissue regeneration as well as pathological differentiation.

Purpose: The objective of this work was to uncover inequalities in access to liver transplantation in Bavaria, Germany., Methods: For this purpose, the annual transplantation rate per 1 million inhabitants for the respective districts was determined from the aggregated postal codes of the place of residence of transplanted patients. The variables examined were proximity and travel time to the nearest transplant center, as well as the care category of the regional hospital. In addition, we assessed whether the head of gastroenterology at the regional hospital through which liver transplant candidates are referred was trained at a liver transplant center., Results: We could not demonstrate a direct relationship between proximity or travel time to the nearest transplant center and access to liver transplantation. Multivariate regression analysis shows that liver transplant training (p < 0.0001) of the chief physician (gastroenterologist) of the regional hospital was the most decisive independent factor for access to liver transplantation within a district., Conclusion: We show that the transplant training experience of the head of gastroenterology at a regional hospital is an independent factor for the regional transplantation rate. Therefore, it appears important to maintain some liver transplant expertise outside the transplant centers in order to properly identify and assign potential transplant candidates for transplantation., (© 2023. The Author(s).)

Background: The formation of neutrophil extracellular traps (NETs) was initially discovered as a novel immune response against pathogens. Recent studies have also suggested that NETs play an important role in tumor progression. This review summarizes the cellular mechanisms by which NETs promote distant metastasis and discusses the possible clinical applications targeting NETs., Method: The relevant literature from PubMed and Google Scholar (2001-2021) have been reviewed for this article., Results: The presence of NETs has been detected in various primary tumors and metastatic sites. NET-associated interactions have been observed throughout the different stages of metastasis, including initial tumor cell detachment, intravasation and extravasation, the survival of circulating tumor cells, the settlement and the growth of metastatic tumor cells. Several in vitro and in vivo studies proved that inhibiting NET formation resulted in anti-cancer effects. The biosafety and efficacy of some NET inhibitors have also been demonstrated in early phase clinical trials., Conclusions: Considering the role of NETs in tumor progression, NETs could be a promising diagnostic and therapeutic target for cancer management. However, current evidence is mostly derived from experimental models and as such more clinical studies are still needed to verify the clinical significance of NETs in oncological settings., (© 2022. The Author(s).)

Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs.

Objective: To present technical details and short-term experiences of liver transplantation as a 2-stage procedure using small for size grafts in a multicenter cohort study., Background: Two-stage liver transplantation using small for size grafts should be a feasible procedure with lower morbidity and mortality rates. Retrospective cohort study between 2015 and 2022 with multicenter experience. Twenty-three resection and partial liver transplantation with delayed total hepatectomy procedures for noncirrhotic indications were performed in 6 European centers (20 with grafts from living donors and 3 after deceased donation). Procedure's feasibility, graft volumetric changes, morbidity, and mortality of donor and recipient were explored., Results: There was a low donor morbidity (4.3%) in our cohort. Hypertrophy of the graft was rapid (mean graft volume increases 107% between both stages) and offered the opportunity for remnant hepatectomy after a median of 14 days. In all cases, portomesenteric flow was routed to the graft by right remnant portal vein ligation. Portal vein inflow modulation to alleviate transient harmful portal hypertension was not needed in any case. Early postoperative mortality (4.3%) of the recipients were low. Ten patients suffered from complications ≥IIIb according to the Clavien-Dindo classification., Conclusions: Two-stage liver transplantation is a feasible option for noncirrhotic patients allowing the safe use of small for size grafts and could possibly be extended with caution to liver diseases with portal hypertension and cirrhosis. The resection and partial liver transplantation with delayed total hepatectomy technique might be a viable option for expanding the donor pool given the current organ shortage especially for low-model of end stage liver disease patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target.

The importance of three-dimensional (3D) models in pharmacological tests and personalized therapies is significant. These models allow us to gain insight into the cell response during drug absorption, distribution, metabolism, and elimination in an organ-like system and are suitable for toxicological testing. In personalized and regenerative medicine, the precise characterization of artificial tissues or drug metabolism processes is more than crucial to gain the safest and the most effective treatment for the patients. Using these 3D cell cultures derived directly from patient, such as spheroids, organoids, and bioprinted structures, allows for testing drugs before administration to the patient. These methods allow us to select the most appropriate drug for the patient. Moreover, they provide chance for better recovery of patients, since time is not wasted during therapy switching. These models could be used in applied and basic research as well, because their response to treatments is quite similar to that of the native tissue. Furthermore, they may replace animal models in the future because these methods are cheaper and can avoid interspecies differences. This review puts a spotlight on this dynamically evolving area and its application in toxicological testing., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Author(s).)