Citations

Background and Aims: Liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype in metabolic dysfunction–associated steatohepatitis (MASH), characterized by enhanced expression of adhesion molecules and inflammatory mediators, a process termed lipotoxic endotheliopathy. However, the molecular drivers of this transformation remain incompletely defined. Approach and Results: We employed complementary models of lipotoxicity and MASH, including palmitate-treated primary human LSECs (in vitro), cultured precision-cut liver slices (PCLS) from MASH mice and normal human liver treated with MASH-inducing media (ex vivo), and diet-induced MASH models (in vivo). GeoMx digital spatial profiling of human MASH livers revealed enriched proinflammatory and fibrogenic signaling between LSECs and myeloid cells. Among the top upregulated genes and ligand–receptor pairs was ICAM1 , whose expression correlated with disease severity and was increased in human MASH by immunostaining. ATAC-seq on primary mouse LSECs showed enhanced chromatin accessibility at the Icam1 promoter in MASH. Chromatin immunoprecipitation confirmed enrichment of the active epigenetic mark H3K27ac and BRD4 binding at the ICAM1 promoter in human LSECs under lipotoxic stress. Mechanistically, we identified the GSK3β/c-Jun/BRD4 axis as a key regulator of ICAM1 induction in LSECs. In vivo, ICAM1-neutralizing antibody or endothelial-specific epigenetic suppression reduced hepatic inflammation, injury, and fibrosis in MASH mice. Conclusions: ICAM1 is epigenetically upregulated in LSECs during lipotoxic stress and promotes myeloid cell recruitment in MASH. Targeting the epigenetic regulation of ICAM1 may offer a novel therapeutic strategy for treating human MASH.

Background: Metastatic squamous cell carcinoma of the anus (SCCA) carries a poor prognosis, with systemic therapy remaining the standard of care. While metastasis-directed therapy improves outcomes in select gastrointestinal malignancies, the role of liver-directed intervention in metastatic SCCA remains undefined. We evaluated clinicopathologic features and oncologic outcomes of patients with liver-limited metastatic SCCA treated with curative-intent hepatic local therapy at a tertiary academic center. Methods: We conducted a retrospective cohort study of adults with histologically confirmed SCCA and liver-only metastatic disease who underwent curative-intent hepatic resection or ablation at Mayo Clinic between 1993 and 2023. Patients with extrahepatic disease or incomplete records were excluded. Demographic, tumor, treatment, and outcomes data were abstracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method. Prognostic factors were assessed using univariate Cox proportional hazards models. Results: Twenty-five patients met inclusion criteria. Median age was 56.7 years, and 92% were female. Most patients had metachronous metastases (76%), a single hepatic lesion (56%), and unilobar disease (76%). Pre-intervention systemic therapy was administered in 52% of patients, with radiographic complete or partial responses observed in all treated patients. Liver-directed therapy consisted of surgical resection in 80% and thermal ablation in 20%. Among surgical patients, 90% achieved microscopically negative margins. With a median follow-up of 22 months, disease recurrence occurred in 80% of patients, most commonly within the liver. Median DFS was 7.27 months. Median OS from the date of liver-directed therapy was 51.3 months. On univariate analysis, poorly differentiated tumor histology was associated with inferior OS (hazard ratio 4.67, p = 0.018). No other clinicopathologic variables were significantly associated with DFS or OS. Conclusions: In this single-institution experience, carefully selected patients with liver-limited metastatic SCCA undergoing curative-intent hepatic-directed therapy achieved prolonged overall survival, substantially exceeding historical outcomes with systemic therapy alone. Despite frequent recurrence, the observed median OS exceeding four years supports consideration of liver-directed therapy within a multidisciplinary framework for patients demonstrating favorable disease biology and response to systemic treatment. Prospective studies are needed to better define patient selection and optimal integration of local and systemic therapies in the modern treatment era.

Background: Upfront resectable pancreatic ductal adenocarcinoma (PDAC) is defined by the NCCN as disease with ≤180° portomesenteric vein (PMV) abutment. However, the clinical significance of PMV abutment in this cohort remains unexplored, and we sought to investigate its impact. Methods: This multi-institutional study included patients who underwent pancreatoduodenectomy (PD) for upfront resectable PDAC from 2002 to 2023. Patients with PDAC with ≤180° PMV abutment were compared with those without. Overall survival (OS) was compared and stratified based on whether patients underwent upfront surgery or neoadjuvant therapy (NAT). Results: Among 1,446 patients included, 521 (36.0%) had PMV abutment. Median OS for patients with PMV abutment was 28.8 months compared with 31.2 months for those without ( P =.17). In a stratified analysis of patients who underwent upfront surgery, patients with PMV abutment had worse OS (19.2 vs 27.6 months; P <.05) and lower R0 resection rates (63.1% vs 87.2%; P <.05) compared with those without. However, in patients who underwent NAT, this difference in R0 resection rate was not observed (91.4% vs 94.0%, respectively; P =.27). Furthermore, there was no significant difference in median OS with NAT (42.5 vs 51.6 months, respectively; P =.48). Conclusions: In this largest cohort to date of patients with upfront resectable PDAC, PMV abutment was associated with worse OS compared with no PMV abutment when an upfront resection strategy was used. The use of NAT in patients with PMV abutment mitigated this survival difference with increased R0 resection rates. These findings suggest that patients with upfront resectable PDAC with PMV abutment benefit from a NAT approach for optimal survival outcomes, and that the current criteria guidelines need to be redefined.

Cholangiocarcinoma (CCA) represents a biologically and clinically heterogeneous group of biliary tract malignancies. Growing evidence underscores that the 3 major anatomic subtypes—intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)—are distinct tumor entities rather than a single disease. Each subtype differs in embryologic origin, carcinogenesis mechanisms, molecular landscape, and immunogenic profile, all of which contribute to variability in diagnosis, treatment responsiveness, and prognosis. The importance of understanding these distinctions is reinforced by the rising global incidence of CCA, which highlights the need for precision medicine approaches based on these subtypes. Recent advances have deepened our insight into subtype-specific risk factors, including chronic biliary diseases and metabolic conditions, while artificial intelligence–driven tools are improving diagnostic accuracy and risk stratification. Surgical innovations now allow for more tailored resections and perioperative care, and therapeutic strategies are increasingly guided by molecular and immune profiling. Emerging strategies for early diagnosis and chemoprevention in high-risk populations further emphasize the significance of recognizing the unique biology of each subtype. In this review, we provide a comprehensive overview of the distinct anatomic subsets of CCA, integrating their molecular and biological foundations with clinical management to inform practice and guide future research.

Abstract Background Liver surgery carries a high risk of complications due to the complex interplay of patient-related factors, disease characteristics, and liver function. Expertise is essential for healthcare professionals managing hepatobiliary patients. This European consensus provides evidence-based guidance on selected aspects of peri- and postoperative care. Methods A modified Delphi process was used to achieve consensus, with a 70% agreement threshold. The expert panel comprised hepatobiliary surgeons, anaesthetists, hepatologists, a specialist nurse, and a physiotherapist. A systematic literature search was conducted in PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases. Six topics were addressed: thromboprophylaxis; perioperative antibiotics; prehabilitation/nutrition/mobilization; bile leak including bilioenteric anastomosis leaks; post-hepatectomy haemorrhage; and post-hepatectomy liver failure (PHLF). Evidence appraisal and statement development followed Scottish Intercollegiate Guidelines Network methodology. A patient representative reviewed the guideline. Results Searching the literature yielded 204 included publications from an initial 6514. Thirty-two statements were formulated with a median evidence level of 2. Evidence strength varied by topic with noticeably lower evidence levels in complex surgery settings and less prevalent conditions. In some topics, study heterogeneity and specific inclusion criteria resulted in conditional recommendations, despite high-level evidence. Notably, the weakest evidence was found for perioperative thromboprophylaxis and PHLF management. Strong recommendations were formulated for prehabilitation, early postoperative mobilization, and avoidance of routine drain use. Several evidence gaps warranting multicentre studies were identified. Conclusion Optimizing peri- and postoperative care after liver resection remains challenging. Standardizing key practices and addressing evidence gaps through collaborative research are vital to improve outcomes.

Background and Aims: Hypothermic oxygenated machine perfusion (HOPE) improves outcomes in orthotopic liver transplantation (OLT), but reliance on University of Wisconsin machine perfusion solution (UW-MPS) increases costs and logistical burden. Histidine-tryptophan-ketoglutarate (HTK) has potential as a single-solution alternative for HOPE. This study evaluated the safety and efficacy of HTK versus UW-MPS during HOPE. Methods: A retrospective, propensity score-matched cohort study including 46 patients who received donation after brain death (DBD) grafts that were preserved with HOPE at the Medical University of Vienna between May 2018 and October 2024 was conducted. A total of 23 patients received grafts perfused with HTK; another 23 patients transplanted with organs perfused with UW-MPS were matched based on recipient age and sodium model of end-stage liver disease score, donor age and sex, cold ischemia time, and perfusion time. Postoperative outcomes, perfusion parameters, and cost differences were assessed. Results: The HTK and UW-MPS cohorts demonstrated comparable perfusion dynamics and vascular resistance. While arterial pressure and flow were higher in the UW-MPS group, clinical outcomes—including early allograft dysfunction (47.8% each), ICU stay, and comprehensive complication index—were statistically similar. A trend toward fewer biliary complications (13.0% vs. 30.4%) and reduced hemodialysis requirement (17.4% vs. 30.4%) was observed in the HTK group. Use of HTK reduced perfusion-related costs by approximately EUR 560 per procedure. Conclusion: HTK is a viable alternative to UW-MPS during HOPE in OLT of DBD grafts, offering comparable short-term outcomes and relevant cost savings. Prospective studies are warranted to validate these findings and explore broader applications of single-solution perfusion strategies.

Importance Total pancreatectomy (TP) is indicated for advanced pancreatic cancer or multifocal tumors. Furthermore, TP may be performed to avoid the risk of pancreatic fistula in selected patients to improve the perioperative risk profile. Objective To define reference values for TP based on a low-risk cohort treated at expert centers. Design, Setting, and Participants This multicenter study analyzed outcomes from patients undergoing primary TP for malignant or benign lesions from 25 international expert centers from January 2017 to November 2023. Low-risk patients undergoing TP (LR-TP) were without vascular resections or significant comorbidities. Exposures TP. Main Outcomes and Measures Twenty reference values were derived from the 75th or the 25th percentile of the median values of all centers. Outcomes of LR-TP were compared with a cohort of TP with vascular resection, TP due to high-risk pancreatic anastomosis, and the benchmark values for low-risk pancreatoduodenectomy. Results Of 994 patients, 333 (33.5%; median [IQR] age, 66 [58-72] years; 171 male [51.4%]) qualified as the LR-TP cohort. Reference values included blood loss (≤1000 mL), major complications (≤37%), 3-month postoperative mortality (&amp;lt;6%), and retrieved lymph nodes (≥29). Compared with TP with vascular resections, reference cutoffs were not met for major complications (51% vs LR-TP ≤37%) and 90-day mortality (11% vs LR-TP ≤6%). For TP due to high-risk anastomosis, failure to rescue rate (38% vs ≤6%) and 90-day mortality (11% vs LR-TP ≤6%) were not met. Compared with pancreatoduodenectomy, reference values for postoperative mortality were 3 times higher for LR-TP (≤2% vs ≤6%) and less for resected lymph nodes (≥16 vs ≥29). Conclusions and Relevance This case-control study provided global reference values for TP, indicating significantly higher postoperative morbidity and mortality compared with pancreatoduodenectomy. Perioperative morbidity of TP was especially increased in patients with vascular resections. These reference values can serve for quality control of pancreatic surgery.

BACKGROUND: The first total pancreatectomy (TP) resulting in survival past the immediate postoperative period was performed at Mayo Clinic in 1944. Although still uncommonly performed, indications have recently fluctuated. We aimed to evaluate trends in TP use and outcomes over four decades. STUDY DESIGN: Patients who underwent single-stage TP at Mayo Clinic Rochester from 1988 to 2024 were analyzed in two cohorts: early era (EE, 1988 to 2009) and modern era (ME, 2010 to 2024). RESULTS: In total, 437 patients were identified: 118 during EE (mean 8 per year) and 319 during ME (mean 21 per year). Primary indications were adenocarcinoma (42% EE vs 60% ME), intraductal papillary mucinous neoplasm (31% EE vs 17% ME), and chronic pancreatitis (11% EE vs 13% ME; p < 0.001). Concurrent vascular resection was performed in 9.3% (EE; all venous only) vs 53% (ME; venous alone in 20% and arterial with or without venous in 33%; p < 0.001). Multivisceral resection was performed in <1% (EE) vs 24% (ME; p < 0.001). Major complications occurred in 13% (EE) vs 27% (ME; p = 0.018), and 90-day mortality was 3.4% (EE) vs 6.3% (ME; p = 0.35). For adenocarcinoma, 5-year median overall survival from both surgery and diagnosis was significantly improved in ME (p = 0.009 and p < 0.001, respectively). Median last HbA1c was 7.7 (EE) vs 7.3 (ME; p < 0.001). Among patients surviving more than 1 year, insulin pumps were used in 12% (EE) vs 49% (ME; p < 0.001). Conclusions: The use of TP has dramatically increased in recent years, primarily for adenocarcinoma alongside increased use of neoadjuvant therapy and ever-expanding criteria for anatomic resectability. Operative complexity has significantly increased with resultant increased perioperative morbidity. TP remains a higher-risk procedure, specifically with en bloc vascular resections, emphasizing the importance of appropriate patient selection, preoperative patient education, and thoughtful postoperative and long-term management.