Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.

Fibroblast growth factor receptor (FGFR)−2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited by a characteristic pattern of adverse events or evocation of kinase domain mutations. A comprehensive characterization of a patient cohort treated with the non-selective TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In a bed-to-bench approach, we investigate FGFR2 fusion proteins bearing critical tumor-relevant point mutations. These mutations confer growth advantage of tumor cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvatinib. In line with clinical observations, in-silico analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy, compared to FGFR-selective TKIs. Finally, the treatment of a patient with progressive disease and a newly developed kinase mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clinical data suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmountable adverse reactions of selective TKIs or acquired kinase mutations occur.

Herpes simplex virus 1 (HSV-1) is a frequently unrecognized, yet deadly cause of acute liver failure (ALF). We, therefore, analysed three cases of fatal HSV-1-induced ALF. All patients shared clinical (extremely elevated transaminases, LDH and AST/LDH ratio < 1) and virological characteristics (ratio of viral load in plasma versus throat swabs: 60-700-fold, lack of anti-HSV-1-IgG antibodies or low IgG-avidity during primary infection), which may help to identify patients at risk. Additionally, in vitro chemosusceptibility assays revealed high efficacy of the helicase-primase inhibitors (HPI), pritelivir and drug-candidate IM-250 compared to acyclovir (ACV) using HSV-1-isolates from two patients; hence, ACV/HPI-combinations might offer new therapeutic options for HSV-induced ALF.

Solute carrier family 26, member 9 (SLC26A9) is an epithelial chloride channel that was identified as a genetic modifier of disease severity of cystic fibrosis (CF) and other chronic muco-obstructive lung diseases. However, data on the in vivo role of SLC26A9 function in lung health and disease remain limited. Here, we investigated the effect of genetic deletion of Slc26a9 ( Slc26a9 ^–/– ) on the pulmonary phenotype of neonatal mice. We found that lack of Slc26a9 causes severe neonatal respiratory distress with high mortality. Histology, immunohistochemistry, and micro-computed tomography imaging studies identified airway obstruction with MUC5B-positive mucus plugs in neonatal Slc26a9 ^–/– mice. Bioelectric measurements demonstrated a reduced transepithelial potential difference indicative of reduced chloride secretion across tracheal explants of neonatal Slc26a9 ^–/– compared with WT mice. In addition, neonatal Slc26a9 ^–/– mice displayed hypoxic degeneration of airway epithelial cells associated with sterile neutrophilic airway inflammation. Collectively, our data show that SLC26A9-mediated chloride secretion is critical for proper mucociliary clearance, respiratory function, and survival after birth, and identify a role for SLC26A9 in neonatal adaptation during the transition from fetal to neonatal life.