Starlinger, P

Objective: To evaluate the institutional learning curve of robotic liver resection (RLR), its association with surgical complexity and outcomes in an international multicenter cohort. Summary of Background Data: RLR is increasingly adopted worldwide, but the dynamics of the learning process and its impact on surgical outcomes remain poorly defined. Methods: This international, multicenter, retrospective cohort study included consecutive patients who underwent RLR between 06/2013 and 12/2024 across 22 expert centers. Based on the first 150 cases at each center, three phases were used to define the learning curve: operative time for competency, major complications for proficiency, and textbook outcome for mastery. Risk-adjusted generalized additive models were used to assess the learning process. Benchmark performance was compared to international reference values. Results: Among 2,331 patients, the most common indications were hepatocellular carcinoma (36%), benign lesions (23%) and colorectal liver metastases (21%). Operative time decreased after achieving competency (case #62), from 240 to 220 minutes ( P <0.001). Major morbidity reached a plateau during the proficiency phase (cases #63–138; 9% vs. 11%, P =0.144), while progression to mastery (cases #139–150) was associated with a higher rate of textbook outcome (76% vs. 87%, P =0.021). In contrast, conversion (5.1% vs. 4.9% vs. 2%), bile leak (4.0% vs. 5.3% vs. 3.8%), and 90-day mortality (0.7% vs. 0.9% vs. 0.9%) remained low and stable across all learning phases. Importantly, benchmark criteria for operative time, hospital stay, and textbook outcome were met across all complexity groups, including during the early learning phase. Conclusions: Robotic liver surgery shows progressive outcome improvement with early achievement of benchmark-level results and stable performance across increasing complexity. These findings indicate that, in experienced centers, RLR can be safely implemented and integrated into clinical practice, supporting its key role in modern hepatobiliary surgery.

Pharmacological plasminogen reduction enhanced liver regeneration experimentally and clinically. siRNA-induced plasminogen deficiency promoted hepatocyte proliferation after partial hepatectomy in mice, contrasting genetic deficiency models. In the HeLiX trial, tranexamic acid reduced post-hepatectomy liver failure odds, suggesting a novel therapeutic strategy.

Abstract Background Indocyanine green (ICG) fluorescence imaging is increasingly incorporated into robotic liver resections (RLR), yet clinical practice regarding timing, dosage, and staining techniques is divergent. Aims This international expert survey aimed to characterize current practices for ICG in RLR. Methods Experts in RLR were invited to participate based on surgical volume (experience of 50 RLR and 30 annual RLR). A 74-item questionnaire was developed following a literature search and reviewed by a steering committee. The survey addressed indications, timing, dosage, imaging technology, benefits, limitations, training, and future directions of ICG use. Responses collected between September and October 2025 were analyzed. Results Seventy experts from 19 countries completed the survey, corresponding to an 88% response rate. Centers performed a median of 180 annual liver resections, including 55 RLR. Most experts used ICG (96%) during RLR. Anatomical demarcation (91%), tumor localization (60%), and biliary anatomy assessment (60%) were the most frequent indications. 60% of experts use preoperative ICG, while intraoperative ICG is mainly administered for demarcation (67%) and biliary tract visualization (40%). Considerable heterogeneity exists in dosage, timing, and staining techniques, particularly in cirrhotic livers and for tumor localization. Only half of the experts had standard operating procedures, whereas 64% expressed the need for a higher degree of standardization. Reported benefits of ICG use included improved anatomical orientation, margin assessment, lesion detection, and support during complex resections. Perceived limitations included background fluorescence, tissue penetration and variable staining in diseased parenchyma. 80% anticipated improved outcomes with combined ICG and three-dimensional image-guidance. Conclusion ICG fluorescence is widely used in RLR and is an important cornerstone for precision-guided robotic liver surgery. Standardized clinical practice guidelines, structured training, and technological improvements in imaging and navigation systems are claimed to optimize its clinical use.

In metabolic dysfunction–associated steatohepatitis (MASH), liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype termed lipotoxic endotheliopathy. We previously identified glycogen synthase kinase 3β (GSK3β) as a central signaling hub in LSECs during MASH. To elucidate the molecular mechanisms and functional outcome of lipotoxicity-induced GSK3β activation in LSECs, we utilized endothelial cell–specific Gsk3 β -KO ( Gsk3 β ΔEnd ) mice fed MASH-inducing diets. Endothelial Gsk3 β deletion significantly reduced markers of lipotoxic endotheliopathy, including adhesion molecules and chemokines, alongside liver injury, inflammation, and fibrosis. Immune profiling via flow cytometry and mass cytometry by time of flight (CyTOF) identified decreased hepatic infiltration of proinflammatory myeloid populations, particularly mature DCs in Gsk3 β ΔEnd mice. In a coculture system, GSK3β in lipotoxic LSECs promoted DCs maturation. Mechanistically, GSK3 inhibition restored lipotoxicity-induced alterations in LSEC mitochondrial morphology and respiration by regulating AMP-activated protein kinase and dynamin-related protein 1. This rescue suppressed chemokine and adhesion molecule expression, thereby limiting immune cell recruitment. Collectively, under lipotoxic stress, GSK3β amplifies mitochondrial dysfunction and inflammatory signaling in LSECs, enhancing myeloid cell homing and DC maturation. Targeting LSEC GSK3β may, therefore, represent a promising therapeutic strategy to mitigate LSEC-driven fibroinflammatory response in human MASH.

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.