Abstract Background Distal pancreatectomy with celiac axis resection (DP-CAR) is an established procedure for the resection of celiac-trunk-infiltrating carcinomas of the pancreatic corpus or cauda. In contrast, total pancreatectomy with celiac axis resection (TP-CAR) remains a controversial procedure, which is sporadically mentioned in the literature. This study aimed to compare perioperative and survival outcomes following TP-CAR with those of the established DP-CAR operation. Methods Between January 2010 and December 2023, 17 patients underwent DP-CAR and 8 patients TP-CAR in our institution. Pre-, intra-, postoperative, histopathological and survival data were compared between the two groups. Results The TP-CAR cohort was associated with higher rates of major complications (DP-CAR: 2[12%] vs. TP-CAR: 4[50%], p = 0.037) and stomach ischemia (DP-CAR: 1[5.9%] vs. TP-CAR: 3[37.5%], p = 0.044). Length of stay in the intensive care unit was longer for the TP-CAR group (DP-CAR:1[1–1] vs. TP-CAR:18[8–27] days, p < 0.001). One patient in our study died postoperatively, belonging to the DP-CAR group. Median overall survival (DP-CAR:21[95% CI:16–26] vs. TP-CAR 14[95% CI:11.4–16.6] months, p = 0.355) and disease-free survival (DP-CAR: 12[95% CI:9.2–14.8] vs. TP-CAR: 10.5[5.4–15.6] months, p = 0.659) were higher in the DP-CAR group, without statistically significant difference in the log-rank test. Conclusions Compared to DP-CAR, TP-CAR was associated with higher morbidity and longer stay in the intensive care unit, while mortality remained low in this cohort. Given the limited sample size and the absence of significant survival differences, TP-CAR may be considered in highly selected patients with good performance status and adequate tumour regression after neoadjuvant chemotherapy.

Introduction: Multidisciplinary tumor boards (MTBs) are the standard for oncologic decision-making but require substantial time and personnel resources. Large language models (LLMs) may support MTBs by generating structured, guideline-based recommendations. We evaluated concordance between MTB decisions and LLM recommendations in newly diagnosed cholangiocellular adenocarcinoma (CCA) and hepatocellular carcinoma (HCC). Method: In this retrospective single-center study, MTB protocols from 2022-2023 were screened. After exclusions, 50 CCA and 50 HCC cases were analyzed. Institutional MTB recommendations were compared with outputs from ChatGPT and Claude using identical structured clinical summaries available at the time of MTB presentation. Agreement was assessed using Cohen's kappa, and correlation using Spearman's rank coefficient. Results: For CCA, exact concordance between MTB and ChatGPT was 80%, with substantial agreement (k = 0.688) and strong correlation (r = 0.725; both p < 0.001). Concordance with Claude was at 56%. For HCC, concordance between MTB and ChatGPT was 66%, with substantial agreement (k = 0.604) and moderate correlation (r = 0.484; both p < 0.001). Concordance with Claude was only 38%, with fair agreement (k = 0.314, p < 0.001) and weak correlation (r = 0.086, p = 0.551). Conclusions: LLM-derived recommendations varied markedly by model. ChatGPT demonstrated substantial concordance, whereas Claude showed limited agreement. MTBs appeared more individualized, while LLM outputs were more guideline-oriented. These findings highlight the potential role of LLMs as supportive tools for structured clinical reasoning and guideline adherence. Prospective multicenter studies should evaluate real-time LLM integration into MTB workflows, efficiency, decision quality, and patient outcomes safely.

AIM:To report on initial experiences with cholangioscopies via an antegrade transhepatic approach by prior percutaneous insertion of a biliary drainage (PTBD) and tract dilation, describing indications, procedural characteristics, complication rates and peri-interventional laboratory changes. MATERIALS AND METHODS:This retrospective, single-arm study reviewed patients undergoing cholangioscopy via a PTBD access route in a tertiary hepatobiliary center from September 2020 to June 2023. Data on demographics and prior surgeries as well as clinical indications, pathology, lab values and medical reports were collected for PTBD insertion, drainage upsizing and cholangioscopy procedures. Complications were classified using the CIRSE classification (grade ≥ 3a defined as major). Follow-up time was defined as the interval between cholangioscopy and the last clinical contact. RESULTS:Thirteen patients (61.5 % female, mean age 58.3 years) underwent 41 interventions, including 13 PTBD insertions, 15 upsizings, and 13 cholangioscopies. The most common indication was cholestasis for PTBD placement and suspected biliary malignancy for cholangioscopy. Technical success was achieved in all procedures. PTBD insertion was associated with decreased bilirubin levels and an increase in CRP, whereas after cholangioscopy CRP remained stable. Overall complication rates were 2.4 % (n=1, relevant cholangitis) for major complications and 17.1 % (n=7, clinically silent infections) for minor complications. Mean follow-up time was 537.5 ± 400.6 days. CONCLUSION:Percutaneous antegrade cholangioscopy using PTBD as an access route appears to be a viable and safe alternative in patients in whom the usual endoscopic retrograde approach failed or is anatomically not accessible. Larger, preferably multicenter studies are required to validate these preliminary single-center findings.

Background: Hepatocellular carcinoma (HCC) is a leading indication for liver transplantation (LT), representing a curative treatment option for selected patients. A remaining clinical challenge is the recurrence of HCC after transplantation, impacting long-term graft and patient survival. The impact of different bridging therapies (BTs) such as transarterial chemoembolization (TACE), local ablation or liver resection on recurrence rates remains unclear. We assessed post-transplant HCC recurrence and survival focusing on the role of pre-transplant bridging therapies. Methods: Adult recipients undergoing LT for HCC at Hannover Medical School from January 2007 to September 2022 were retrospectively analyzed (n = 185). Recurrence was defined as confirmed intra or extrahepatic HCC after LT. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using Kaplan-Meier estimation and log-rank testing; multivariable Cox proportional hazards regression was used to identify independent factors influencing OS. Results: Pre-transplant BT was administered in 85.4% of patients, consisting of only TACE, (n = 20; 10.8%), local ablation, (n = 32; 17.3%), liver resection (n = 27; 14.6%) or a multimodal approach (n = 50; 27%). Post-transplant HCC recurrence rate was 9.2% with a median time to recurrence of 845 days (range 126-3978 days). Patients with post-transplant HCC recurrence had a significantly higher prevalence of viral hepatitis (70.6% vs. 57.1%; p = 0.01), higher pre-transplant AFP peak levels (37.5 vs. 10 ng/mL; p = 0.03), larger tumor sizes (median 3.95 cm vs. 2.6 cm; p = 0.03) and more poorly differentiated tumors (G3; 25.0% vs. 5.3%, p = 0.04). Kaplan-Meier analysis showed significant overall differences in OS and RFS among bridging therapy groups (p = 0.03). In the subgroup of early HCC < 3 cm, local ablation was associated with significantly improved OS compared to TACE (p = 0.035). Last measured pre-transplant AFP < 15 ng/mL was a significant predictor of both improved OS (p = 0.006) and RFS (p = 0.008), whereas peak AFP did not reach significance after correction. Multivariable Cox regression revealed HCC recurrence, high recipient BMI and low LabMELD as independently associated with reduced OS after LT. Median OS after HCC recurrence was 13 months. Conclusions: Our monocentric retrospective data indicate that post-transplant HCC recurrence is uncommon but remains a challenge regarding life expectancy and is influenced by pre-transplant bridging therapy. In the subgroup of early HCC < 3 cm, local ablation was associated with significantly improved OS compared to TACE. Last measured pre-transplant AFP < 15 ng/mL was associated with both improved OS and RFS, suggesting that treatment response may also represent a prognostically relevant factor. Further prospective validation of contemporary locoregional and systemic bridging approaches, especially in the context of tumor biology and treatment response, is warranted.

Background:The indication and timing of native nephrectomy in autosomal dominant polycystic kidney disease (ADPKD) kidney transplant recipients are a matter of ongoing debate. Data on bilateral nephrectomy in such patients is scarce. This study therefore compares the clinical outcome of ADPKD patients undergoing bilateral nephrectomy before or after transplantation. Methods:This retrospective single-center study analyzed all ADPKD patients undergoing kidney transplantation at our department between January 2007 and December 2017. Surgical complications, according to the Clavien-Dindo classification, and long-term graft outcomes were compared between ADPKD kidney transplant recipients undergoing bilateral nephrectomy pre- vs posttransplant. Results:A total of 273 kidney transplants were performed in ADPKD patients. Of these, 107 (39.2%) patients required native nephrectomy. Unilateral and bilateral nephrectomy was performed in 36 (33.6%) and 71 (66.4%) patients, respectively. We compared seven patients with bilateral nephrectomy before vs 20 patients after kidney transplantation. Pain and cyst infections were the most common indications in both groups. Operation time (P = .001) and perioperative transfusion requirements (P < .001) were significantly increased in the pretransplant nephrectomy group. The total number of Clavien-Dindo complications grade III (P = .054) and IV (P = .015) was greater in patients with nephrectomy preceding transplantation. However, 1-, 3- and 5-year graft and patient survival (P = .347 and P = .596) were not different between the pre- and posttransplant nephrectomy approaches. Conclusions:A posttransplant nephrectomy appears to be a relatively safe procedure. However, bilateral nephrectomies are highly invasive and should be avoided unless absolutely necessary. The timing and surgical outcome after nephrectomy do not significantly affect long-term graft or patient survival.

This report details the reactivation of immune checkpoint inhibitor (ICI)-related autoimmune hepatitis triggered by stereotactic body radiation therapy (SBRT) in a 55-year-old male with hilar cholangiocellular carcinoma. Initially diagnosed in December 2021, the patient underwent successful resection and subsequent adjuvant therapy. Despite stable disease following chemotherapy augmented with durvalumab, he developed grade 3 acute hepatitis after seven cycles of durvalumab. Following a brief prednisolone regimen and normalization of liver tests, SBRT targeting para-aortic lymph nodes was initiated. Remarkably, severe hepatitis reoccurred 7 days after starting SBRT, 88 days following the last durvalumab infusion, necessitating resumed and escalated prednisolone treatment. Another course of SBRT for a newly diagnosed metastatic liver lesion was administered in September 2023, with ongoing prednisolone adjustment. By February 2024, liver tests normalized, but subsequent radiological assessments indicated tumor progression, leading to the reintroduction of chemotherapy. This case underscores the potential of SBRT for activating severe immune-mediated hepatotoxicity in patients treated with ICIs, highlighting the need for careful monitoring and management of such patients. Further, this report highlights the possible survival benefit of the strategic application of SBRT in addition to systematic treatment in recurrent and metastatic cholangiocellular carcinoma.

SARS-CoV-2 infection is accompanied by elevated liver enzymes, and patients with pre-existing liver conditions experience more severe disease. While it was known that SARS-CoV-2 infects human hepatocytes, our study determines the mechanism of infection, demonstrates viral replication and spread, and highlights direct hepatocyte damage. Viral replication was readily detectable upon infection of primary human hepatocytes and hepatoma cells with the ancestral SARS-CoV-2, Delta, and Omicron variants. Hepatocytes express the SARS-CoV-2 receptor ACE2 and the host cell protease TMPRSS2, and knocking down ACE2 and TMPRSS2 impaired SARS-CoV-2 infection. Progeny viruses released from infected hepatocytes showed the typical coronavirus morphology by electron microscopy and proved infectious when transferred to fresh cells, indicating that hepatocytes can contribute to virus spread. Importantly, SARS-CoV-2 infection rapidly induced hepatocyte death in a replication-dependent fashion, with the Omicron variant showing faster onset but less extensive cell death. C57BL/6 wild-type mice infected with a mouse-adapted SARS-CoV-2 strain showed high levels of viral RNA in liver and lung tissues. ALT peaked when viral RNA was cleared from the liver. Liver histology revealed profound tissue damage and immune cell infiltration, indicating that direct cytopathic effects of SARS-CoV-2 and immune-mediated killing of infected hepatocytes contribute to liver pathology.

ABSTRACT Abundance of essential components of double-stranded RNA (dsRNA) recognition and the subsequent interferon (IFN) response vary widely between primary human hepatocytes (PHHs) and commonly used cell culture models based on derivatives of Huh7 cells, supporting replication of all hepatitis viruses. We used RNA sequencing to compare the innate immune response in hepatoma cells with primary cells and non-neoplastic immortalized hepatocytes (PH5CH). Stimulation with the dsRNA analog poly(I:C) in Huh7 and Huh7.5, either by supernatant feeding or by transfection, resulted in an induction of interferon-stimulated genes widely comparable to that of PHH and PH5CH, but Huh7 and Huh7.5 lacked efficient production of IFN-β. We identified interferon regulatory factor 7 (IRF7) as a critical component missing in Huh7-derived cells. Upon reconstitution of IRF7 expression, IFNB induction was restored to the levels observed in PHH upon stimulation with poly(I:C). In contrast to PH5CH cells, for which IRF3 was sufficient for full IFN induction, the lack of IRF7 could not be compensated by increased IRF3 expression in Huh7-derived cells. We further found significant IFNB induction upon Sendai virus and hepatitis delta virus infections in Huh7.5 cells reconstituted with IRF7, but not in hepatitis A or hepatitis C virus-infected cells, widely representing the characteristics of the IFN response observed in other models and in vivo . Our data suggest that the reconstitution of IRF7 expression in Huh7 cells can aid a more physiological analysis of cell intrinsic immune responses to hepatotropic viruses in future studies. IMPORTANCE Current in vitro studies often rely on Huh7-based hepatoma cells, which, although permissive for hepatitis viruses, lack critical components for double-stranded RNA recognition. We used RNA sequencing to compare the cell intrinsic innate immune responses of hepatoma cells with more authentic cellular models. We discovered that Huh7-derived cells, which are known to show very limited induction of IFNB upon pathogen recognition receptor stimulation, lack expression of interferon regulatory factor 7 (IRF7), an essential component for robust type I interferon induction. By reconstituting IRF7, we were able to restore the interferon response to levels observed in primary human hepatocytes. Our study not only identifies a key missing link in the Huh7/Huh7.5 innate immune response but also offers a way to enhance the physiological relevance of these cells in future studies. Our findings pave the way for more accurate modeling of the human hepatic response to viral infections, potentially improving the understanding and management of hepatitis.

Background & Aims: Hepatitis C virus (HCV) has a narrow species tropism and cannot infect mice. To understand HCV species tropism and to develop better animal models, we adapted HCV to infect mouse cells deficient in innate immunity and with minimal human HCV host factors. Methods: HCV was adapted via passaging an HCV infectious virus clone several times in human hepatoma cells, mouse liver cells, and eventually primary mouse hepatocytes deficient in innate immunity and ectopically expressing human occludin and human CD81. Using RNAseq the sequence of the adapted virus was analyzed, and several clones were generated to study replication and infection kinetics as well as neutralization assays in several human/mouse cell lines and primary hepatocytes from human, mouse, and macaques. Results: Accumulation of 35 non-synonymous and 66 synonymous mutations correlated with >1,000-fold enhanced production of infectious progeny from primary mouse hepatocytes. These mutations did not confer drug resistance or evasion from innate immunity. They did not enhance fitness in human or macaque hepatocytes. We show that non-synonymous mutations are necessary and sufficient for adaptation, and that changes to the glycoproteins are not essential. Mutations outside of viral envelope proteins enhanced specific infectivity and facilitated viral spread in murine cells. Conclusions: This study reveals key viral factors governing HCV species tropism. The mouse-adapted HCV opens up possibilities for the development of animal models to analyze HCV pathogenesis, immune control, and vaccine development. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: Cholangiocarcinoma (CCA) of the liver is a highly aggressive cancer that arises from malignant cells in the bile ducts. Radical surgery remains the only curative option, but major liver resection carries high perioperative risks. This study investigates the predictive value of preoperative bone mineral density (BMD), measured via CT, for perioperative complications, mortality, and long-term outcomes. Methods: The analysis included 202 patients who underwent curative-intent surgery for intrahepatic cholangiocarcinoma (iCCA; n = 97) or perihilar cholangiocarcinoma (pCCA; n = 105) between 2010 and 2019. Preoperative bone mineral density (BMD) was assessed using computed tomography segmentation at the level of the 12th thoracic vertebra. Osteopenia was defined according to established cutoffs. Results: Osteopenia was highly prevalent in both iCCA (53/97, 54%) and pCCA (54/105, 51%) subcohorts. Patients suffering from osteopenia were significantly older than those without (71.1 [62-76.6] years vs. 61.3 [52.9-69.2] years; p < 0.001). Alteration in BMD did not demonstrate a significant prognostic effect in terms of perioperative morbidity (Mann-Whitney U; comprehensive complication index-CCI: 34 [9-56] vs. 40 [21-72] p = 0.185; iCCA: p = 0.803; pCCA: p = 0.165). The median overall survival in our cohort was 19 [14-25] months. Patients with osteopenia did not exhibit a significantly different overall survival compared to those with normal bone mineral density (log-rank p = 0.234). Conclusions: In contrast to our previous observations in other oncological patient cohorts, osteopenia alone had no significant negative impact on clinical outcomes in our large European cohort of patients undergoing curative-intent surgery for CCA. To validate these findings, further prospective studies are warranted.

Hepatitis E virus genotype 3 (HEV-3) is a zoonotic pathogen with pigs representing the natural host. Although HEV-3 infections in humans are often self-limiting, severe or chronic cases can occur. In contrast, HEV-3 infections in pigs, the primary reservoir, remain asymptomatic. To assess the initial transcriptional response in porcine cells during HEV-3 infection and pave the way for mechanistic studies of species-specific virus-host interactions, we aimed to establish porcine cell culture models, including primary porcine hepatocytes (PPHs) and porcine cell lines. PPHs supported the full HEV-3 replication cycle while intrinsic immunity, driven by the interferon-stimulated gene (ISG) system, played a central role in restricting viral replication. JAK inhibition enhanced viral replication and suppressed ISG expression, highlighting the importance of IFN signalling in antiviral defense. Transcriptional profiling revealed a global modulation of host responses upon HEV infection, including pathways linked to immunity, inflammation, and metabolism. Porcine cell lines were permissive to HEV infection and treatment with recombinant porcine IFN-α subtypes induced a robust ISG response and effectively inhibited HEV replication in a dose-dependent manner. These findings establish porcine hepatocytes and cell lines as valuable tools to study HEV-host interactions, demonstrating the critical role of IFN-mediated intrinsic immunity in HEV restriction and highlighting subtype-specific antiviral effects of porcine IFN-α.

Purpose:Cholestatic complications remain a primary cause of post-liver transplantation (LTX) morbidity in pediatric patients. Standard biliary access by endoscopic retrograde cholangioscopy may not be feasible due to modified biliary drainage. Percutaneous transhepatic biliary drainage (PTCD) may be performed alternatively. However, systematic data concerning safety and efficacy of PTCD in these patients are scarce. Methods:In this retrospective study, procedural and safety characteristics of PTCD in pediatric patients following LTX were analyzed. We compared laboratory indicators of inflammation, cholestasis, and graft function before and at 6 and 12 months after the first PTCD insertion. Efficacy was analyzed by percentage of patients without cholangitis, need for surgical biliary re-intervention and re-transplantation during a follow-up period of 60 months. Results:Over a decade, PTCD was attempted in a total of 15 patients, with technical success (93.3%) in 14 patients. Periprocedural complications, including bleeding (7.1%) and cholangitis (21.4%) were observed in patients. During follow-up, both MELD-score (baseline: 13 [8-15] vs. 12 months: 8 [7-8], p<0.001) and parameters of cholestasis (GGT: baseline: 286 [47-458] U/L vs. 12 months: 105 [26-147] U/L, p=0.024) decreased. Prior to PTCD, cholangitis (64.3%) and cholangiosepsis (21.4%) were common complications. In contrast, following PTCD, cholangitis occurred in only one patient (7.1%). Five patients (35.7%) needed surgical biliary re-intervention and two (14.3%) required re-transplantation. Conclusion:PTCD in pediatric patients following LTX had an acceptable safety profile, demonstrating a biochemical improvement of both cholestasis and graft function and may prevent cholestatic complications, thus reducing the need for surgical re-intervention and re-transplantation.

BACKGROUND AND AIMS:Cholangiocarcinoma (CCA) is one of the most prevalent primary liver malignancies with increasing incidence and mortality rates, particularly in Southeast Asia. Surgical resection is a primary therapeutic option offered to patients with localised disease. Unfortunately, early disease recurrence is common and robust tools for tailored patient-centric post-operative management and follow-up schemes are highly desired but currently lacking. To address this unmet clinical need, this study investigated the clinical utility of the single nucleotide polymorphisms (SNPs) in DNA repair genes (ERCC5 rs1047768, APEX1 rs1130409, PARP1 rs1805414, XPC rs2228001 and ERCC5 rs873601) and patient prognosis after curative intent surgery. METHODS:A cohort of 229 patients who underwent surgical treatment for intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma was examined. Kaplan-Meier and multivariable Cox regression analyses were used to assess the impact of these SNPs on recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS:Within comprehensive multivariable analyses, the TT genotype of XPC rs2228001 was significantly associated with prolonged RFS (GG/GT = 1, HR = 0.50, p = 0.027), CSS (HR = 0.42, p = 0.018) and OS (HR = 0.31; p = 0.031) in iCCA. Similarly, in pCCA, the TT genotype of XPC rs2228001 was an independent prognostic factor for prolonged CSS (GG/GT = 1, HR = 0.48, p = 0.041). CONCLUSIONS:These findings suggest that SNPs in DNA repair genes, particularly XPC rs2228001, play a crucial role in modulating the prognosis of CCA.

Early Allograft Dysfunction (EAD) is a serious complication following liver transplantation. With more marginal donors and critical recipients, identifying EAD risk factors and their impact on long-term outcomes is crucial. We reviewed all liver transplants performed between 2007 and 2017 at our institution, excluding pediatric recipients, combined thoracic transplants, and retransplants in the same hospital stay. EAD was defined as either: (i) AST/ALT > 2000 IU/l in first 7 postoperative days (POD), (ii) Bilirubin ≥ 10 mg/dl on POD 7, (iii) INR ≥ 1.6 on POD 7. Of the 621 cases analyzed, the EAD rate was 53.6

Background & Aims: Liver fibrosis and its end-stage form cirrhosis contribute to millions of deaths annually. The lack of robust antifibrotic molecules is in part attributed to the absence of any functional screens to identify molecular regulators using patient- derived primary human hepatic myofibroblasts, which are key drivers of fibrosis. Methods: Here, to identify robust regulators of fibrosis, we performed functional microRNA screenings in primary human hepatic myofibroblasts followed by in vivo validation in three independent mouse models of fibrosis (toxin, cholestasis and MASH). Results: We identified miR-190b-5p and miR-296-3p as robust antifibrotic miRNAs that suppress liver fibrosis. Notably, the expression of miR-190b-5p and miR-296-3p was found to be significantly reduced in human livers with fibrosis. Mechanistically, we discovered hyaluronan synthase 2 ( HAS2 ) and integrin alpha-6 ( ITGA6 ) as novel targets of miR-190b-5p and miR-296-3p, respectively. Furthermore, we demonstrated that the antifibrotic properties of miR-190b-5p and miR-296-3p are, at least in part, dependent on HAS2 and ITGA6. Finally, we showed the antifibrotic function of both miRNAs in a human liver bud model, which mimics multiple features of the human liver. Conclusions: Collectively, in our study we discovered miR-190b-5p and miR-296-3p as two novel antifibrotic miRNAs, and that HAS2 and ITGA6 contribute to miR-190b-5p- and miR-296-3p-mediated inhibition of liver fibrosis. These results provide a foundation for future research to explore the clinical utility of miR-190b-5p and miR-296-3p in fibrosis. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).