Introduction: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. Methods: MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. Results: 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I²=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I²=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I²=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2–F4), while 14.95% (95% CI 11.03% to 19.95%, I²=99.00%) had advanced fibrosis (F3–F4). Conclusion: This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO registration number: CRD42022360251.

Liver cancer, primarily HCC, exhibits highly heterogeneous histological and molecular aberrations across tumors and within individual tumor nodules. Such intertumor and intratumor heterogeneities may lead to diversity in the natural history of disease progression and various clinical disparities across the patients. Recently developed multimodality, single-cell, and spatial omics profiling technologies have enabled interrogation of the intertumor/intratumor heterogeneity in the cancer cells and the tumor immune microenvironment. These features may influence the natural history and efficacy of emerging therapies targeting novel molecular and immune pathways, some of which had been deemed undruggable. Thus, comprehensive characterization of the heterogeneities at various levels may facilitate the discovery of biomarkers that enable personalized and rational treatment decisions, and optimize treatment efficacy while minimizing the risk of adverse effects. Such companion biomarkers will also refine HCC treatment algorithms across disease stages for cost-effective patient management by optimizing the allocation of limited medical resources. Despite this promise, the complexity of the intertumor/intratumor heterogeneity and ever-expanding inventory of therapeutic agents and regimens have made clinical evaluation and translation of biomarkers increasingly challenging. To address this issue, novel clinical trial designs have been proposed and incorporated into recent studies. In this review, we discuss the latest findings in the molecular and immune landscape of HCC for their potential and utility as biomarkers, the framework of evaluation and clinical application of predictive/prognostic biomarkers, and ongoing biomarker-guided therapeutic clinical trials. These new developments may revolutionize patient care and substantially impact the still dismal HCC mortality.

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression‑free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate‑stage HCC refractory to TACE using a data‑mining analysis. A total of 171 patients with intermediate‑stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan‑Meier method and analyzed using a log‑rank test. Factors associated with PFS time were evaluated using multivariate and decision‑tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up‑to‑seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up‑to‑seven, P=0.001). The decision‑tree analysis revealed that patients beyond the up‑to‑seven criteria, treated with lenvatinib and with albumin‑bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up‑to‑seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate‑stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate‑stage HCC refractory to TACE, ALBI grade 1 and who are within the up‑to‑seven criteria.

Background: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. Materials and Methods: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs). Results: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs. Conclusion: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1.

The cytokine transforming growth factor‑β (TGF‑β) serves a key role in hepatic fibrosis and has cytostatic effects on hepatocytes. The present study investigated the anti‑fibrogenic and regenerative effects of the TGF‑β receptor type I kinase inhibitor galunisertib (LY2157299) in mice with carbon tetrachloride (CCl4)‑induced liver cirrhosis and in vitro. Mice were intraperitoneally treated with CCl4 for 8 weeks. At week 5, the mice were divided randomly into four treatment groups: Vehicle‑treated; and treated with low‑; middle‑; and high‑dose galunisertib, which was administered from weeks 5‑8. The mice were sacrificed after 8 weeks of CCl4 treatment. Liver fibrosis, as evaluated by histology and determination of hydroxyproline content, progressed during week 4‑8 of CCl4 treatment in the vehicle‑treated mice. Galunisertib treatment dose‑dependently prevented liver fibrosis, as demonstrated by the direct inhibition of α‑smooth muscle actin‑positive activated hepatic stellate cells (HSCs) after 8 weeks of CCl4 treatment. The levels of active matrix metalloproteinase (MMP)‑9 in galunisertib‑treated livers were significantly increased compared with the vehicle‑treated livers. In the high‑dose group, the number of PCNA‑positive hepatocytes and endothelial cells markedly increased compared with the vehicle group. Reverse transcription‑quantitative PCR analysis verified that interleukin‑6 and epiregulin expression levels were significantly increased in livers from the group treated with high‑dose galunisertib compared with the vehicle‑treated group. Galunisertib inhibited the proliferation of activated HSCs and collagen synthesis in addition to restoring MMP activity. Moreover, galunisertib promoted liver remodeling by proliferating hepatocytes and vascular endothelial cells, while significantly increasing liver weight. These results are consistent with the cytostatic action of TGF‑β that negatively regulates liver regeneration, and demonstrated that galunisertib inhibited TGF‑β signaling, halted liver fibrosis progression and promoted hepatic regeneration. The results of the present study suggest that galunisertib may be an effective treatment for liver cirrhosis.