ding on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for an ideal phase II and phase III study design, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism towards hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate prescription of compounds to people

esign: We collected cross-sectional clinical data for a Derivation Cohort (n=86) and a Validation Cohort (n=431), totaling 517 subjects with the liver biopsy. Advanced liver fibrosis was defined by the METAVIR pathological score (F≥3). Dual cut-off values for diagnosis were explored. Results: In the Derivation Cohort, plasma FSTL-1 levels were significantly elevated in patients with advanced liver fibrosis, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval [CI], 0.74-0.92). In the Validation Cohort, plasma FSTL-1 maintained good diagnostic performance, with an AUROC of 0.88 (95% CI, 0.83-0.92). Plasma FSTL-1 levels were significantly associated with individual histological features of METAVIR scoring system, including interface hepatitis, lobular necrosis, and hepatocellular ballooning (p<0.0001). A cut-off value≤0.43 ng/mL was the optimal rule-out threshold, with a sensitivity of 84.62% (95%CI 76.46%-90.30%) and a specificity of 79

based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based non-curative systemic therapies, 174 (4.4%) achieved CR according to mRECIST (CR-mRECIST) and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; BCLC-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95%CI, 29.9-34.4) months. One- and 3-year overall survival (OS) rates were 98% and 86%. One- and 3-year recurrence-free survival (RFS) rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after first mRECIST CR had a longer RFS than those who discontinued immunotherapy earlier (p=0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathologica

systematically evaluated. In this study, we analyzed a large data set comprising 317 drugs and their interactions in vitro with 42 non-CYP enzymes as substrates, inducers, and/or inhibitors retrieved from historical regulatory documents. We examined how these in vitro drug-enzyme interactions are correlated with the drugs’ potential for DILI concern, as classified in the Liver Toxicity Knowledge Base database. Our study revealed that drugs that inhibit non-CYP enzymes are significantly associated with high DILI concern. Particularly, interaction with UDP-glucuronosyltransferases (UGT) enzymes is an important predictor of DILI outcomes. Further analysis indicated that only pure UGT inhibitors and dual substrate inhibitors, but not pure UGT substrates, are significantly associated with high DILI concern. Notably, drug interactions with UGT enzymes may independently predict DILI, and their combined use with the rule-of-two model further improves overall predictive performance. These findi