After first‑line atezolizumab plus bevacizumab (ATE + BEV) in hepatocellular carcinoma (HCC), optimal second‑line (2L) therapy remains unclear. This study compared the real‑world effectiveness and hepatotoxicity of lenvatinib versus sorafenib as 2L treatment after ATE + BEV. This retrospective, multicenter study used electronic medical record data from the Liver Cancer IN Korea (LINK) database. Patients who received 2L lenvatinib or sorafenib after ATE + BEV were included. The primary endpoint was overall survival (OS). Secondary endpoints included time to treatment discontinuation (TTD), time to next treatment (TTNT), hepatotoxicity, and tumor marker dynamics. Analyses were conducted in the overall cohort, with additional propensity score (PS)–matched analyses performed. A total of 295 patients were included in the analysis (2L lenvatinib, n = 132; 2L sorafenib, n = 163). Median OS was significantly longer with lenvatinib (not reached) than with sorafenib (6.67 months [95
Matrix stiffness increases during fibrosis and drives hepatic stellate cell (HSC) activation through YAP-dependent mechanotransduction. Although recent studies have revealed HSC heterogeneity beyond classical quiescent and fully activated states, how physiological-range stiffness influences activation trajectories underlying this heterogeneity remains unclear. This study aimed to determine how substrate stiffness shapes the transcriptomic profiles and biases activation trajectories. We performed time-resolved single-cell RNA sequencing of primary mouse HSCs cultured on stiffness-tunable polydimethylsiloxane (PDMS) substrates (Soft, 0.2 kPa; Hard, 32 kPa), using tissue culture polystyrene (TCPS) as a conventional baseline. In vitro findings were anchored to public in vivo datasets from mouse and human liver injury. Matrix stiffness altered HSC morphology and transcriptional state, with softer substrates promoting a rounder phenotype and reducing the expression of activation markers, particularly during early activation. Pseudotime and RNA velocity analyses also revealed different early trajectories associated with matrix stiffness. Under the soft condition, HSCs exhibited an expanded quiescent-to-initiatory transitional state characterized by Nrf2-related features and regeneration-associated factors, including Hgf and Rspo3. In contrast, the hard condition induced a gene signature, which was upregulated from early stages of HSC activation onward, localized to fibrotic septa in human liver and correlated with cirrhosis severity in an HCV patient cohort. Matrix stiffness shapes early HSC activation trajectories toward transcriptional programs associated with regeneration or fibrosis. These findings support stiffness-controlled culture systems as improved models of HSC activation and provide a framework for regenerative and antifibrotic strategies.
Hepatocellular carcinoma (HCC) is a rapidly increasing healthcare burden in Australia. We aimed to evaluate the contemporary epidemiology, clinical characteristics, and real-world patterns of care for HCC in Australia using a prospective multicentre clinical quality registry. This interim analysis utilised data from the Upper Gastrointestinal Cancer Registry (UGICR) HCC module, a multicentre clinical quality registry involving 17 major centres across all mainland Australian states. Patients with a new diagnosis of HCC from 1 January 2021 were included. Clinical characteristics and initial treatment modalities were compared between liver transplant centres (LTCs) and non-transplant centres (NTCs). A total of 489 patients were analysed (333 LTC, 156 NTC). The cohort was predominantly male (76.7
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) may influence pathways involved in hepatocarcinogenesis, but evidence regarding their association with hepatocellular carcinoma (HCC) and mortality risk remains heterogeneous. We evaluated the association between GLP-1 RA initiation and HCC incidence compared with commonly used glucose-lowering medications, with secondary exploratory analyses of all-cause mortality following HCC diagnosis. We emulated active-comparator, new-user target trials using Patient-Centered Clinical Research Network data from UT Southwestern Medical Center (PCORnet–UTSW; 2010–2025). Adults with T2D initiating GLP-1 RA were compared with initiators of metformin, insulin, sodium–glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas. The primary outcome was incident HCC; a secondary analysis evaluated all-cause mortality after HCC diagnosis. Five-year risks and risk differences under the intention-to-treat (ITT) approach were estimated using pooled logistic regression with inverse probability of treatment weighting. Per-protocol analyses accounted for treatment adherence using inverse probability of censoring weights. GLP-1 RA initiators had lower five-year HCC risk than comparator groups. Under ITT, risk differences were − 0.37
