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Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC. The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c‐Met inhibitor tivantinib as second‐line treatment significantly prolonged progression‐free survival in a subpopulation whose tumor samples highly expressed c‐Met (MET‐high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. This randomized, double‐blind, placebo‐controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET‐high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice‐a‐day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression‐free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression‐free survival was 2.8 (95% confidence interval: 2.7‐2.9) and 2.3 (1.5‐2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52‐1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1‐11.6) and 8.5 (6.2‐11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58‐1.15). The most common tivantinib‐related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. (NCT02029157). Results of JET‐HCC.

Background/Aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab.Results: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response.Conclusions: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). Results In Phase 1b ( n  = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 ( n  = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P  = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. Trial registration ClinicalTrials.gov NCT01988493.

Hepatitis B Virus (HBV) is one of the most common human infectious agents, and the mutations in its genome may cause chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study was designed to characterize the enhancer-II (Enh-II) region of X gene in HBV positive patients to assess the association of such mutations with CH, LC, and HCC. HBV positive samples (N = 200) with patients' demographic and clinical data were collected from different regions of Khyber Pakhtunkhwa (KP), Pakistan. The Enh-II region of the HBx gene was sequenced and zanalyzed for polymorphism associated with advanced liver disease. Univariate and logistic regression analyses were performed to evaluate potent mutations associated with a risk for LC and HCC. HBV Enh-II region sequences analysis revealed 25 different mutations. The highest frequency of mutations S101F (62.2%), A102V/R/G/I (56.25%), M103L/A (68.75%)were found in HCC, followed in LC and CH patients as 57.1%, 42.8%, 28.52% 16%, 15.2% and 18.4% respectively. H94 deletion in the α-box of the Enh-II region, associated with a high risk of HCC was found in half of the HCC patients. This deletion was present in 28.5% of LC and 6.5% of CH patients. Importantly, the high frequency of some notable mutations such as E109A/Y, A110S/K, Y111D/E, and F112L was first time reported in the entire study population. The frequencies of these mutations were high in HCC (43.75%, 37.5%, 50% and 43.75% respectively) as compared to LC (14.28%, 14.28%, 28.2% and 42.8%) and CH patients (12.8%, 15.2%, 16.8% and 16% respectively). Mutations associated with LC and HCC are prevalent in the Enh-II region in Pakistani HBV isolates. The mutations found are alarming in CH patients as these may progress to LC and HCC in a large number of patients.

Sox2 is a major transcription factor essential to the stemness characteristics and is associated with various types of cancers. In this study, we investigated the expressions and functional roles of Sox2 in hepatocellular carcinoma (HCC). Our data show that high level of Sox2 expression correlates with metastasis and low survival rate in HCC. HCC cells overexpressing Sox2 are characterized by active epithelial-mesenchymal transition and exhibit increased ability of transwell invasion, soft agar colonization, and sphere formation. We also found Sox2 expression was correlated with the transcription activity of SLUG promoter region. These results present novel mechanistic insight into an important role of Sox2 in HCC and suggest a potential application of Sox2 in HCC prognosis and treatment.

To observe the curative effect of surgery combined with gene therapy on small hepatocellular carcinoma. Seventy-seven patients with small hepatocellular carcinoma (diameter < 5 cm) underwent surgical resection. The tumor located at the edge of the liver was treated by local excision or irregular hepatectomy. The tumor in the center of the liver was resected by hepatic lobectomy in order to ensure at least a 2-cm safety margin. Fifty-four patients underwent gene therapy (gene group) one or two times before operation, whereas 23 patients underwent surgery alone (control group) selected by themselves. The injectable gene was made of ADV-TK (adenovirus containing thymidine kinase suicide gene, with a concentration of 5 × 1012/ml). The prognosis of patients was analyzed by imaging twice a year. In the gene group, the 1-, 3-, and 5-year survival rates were 91.4, 63.6, and 52.1%. In the control group, the survival rates were 84.3, 54.4, and 32.6%, respectively. There was a significant difference in the overall survival rates between two groups. Factors associated with overall survival in univariate analysis included bilirubin, prothrombin activity, cirrhosis, and gene therapy (P < 0.05). In the multivariate analysis, it included cirrhosis, gene therapy, and bilirubin. The gene therapy hepatocellular carcinoma patients with a diameter < 5 cm could significantly reduce recurrence after operation. It was worthy of being popularized.

Purpose Although transcatheter arterial chemoembolization (TACE) is the most common treatment option in patients with hepatocellular carcinoma (HCC), its clinical benefits remain still controversial. Since TACE induces hypoxic necrosis in tumors, hypoxia-inducible factor 1α (HIF-1α) could critically affect biology in residual tumors after TACE treatment and subsequent prognosis. However, HIF-1α and its prognostic relevance in TACE have rarely been examined in human specimens. In the current study, we investigated the prognosis and expression of genes regulated by HIF-1α in HCC patients receiving preoperative TACE for the first time. Methods In total, 35 patients with HCC (10 patients undergoing preoperative TACE) were retrospectively studied. The prognostic significance of TACE was analyzed using Kaplan–Meier and Cox regression models. Protein levels of HIF-1α and mRNA levels of HIF-1α-associated genes were examined using immunohistochemistry (IHC) and real-time RT-PCR, respectively. Results Preoperative TACE was significantly associated with increased 2-year recurrence rate (80 vs. 36 %, P  = 0.00402) and shorter disease-free survival (DFS) time (11.9 vs. 35.7 months, P  = 0.0182). TACE was an independent prognostic factor for recurrence ( P  = 0.007) and poor DFS ( P  = 0.010) in a multivariate analysis. Immunohistochemical staining revealed in vivo activation of HIF-1α in human specimens treated with TACE. Notably, protein levels of HIF-1α were significantly increased in TACE tissues demonstrated by IHC. Transcriptional targets of HIF-1α showed mRNA expression patterns consistent with activation of HIF-1α in TACE tissues. Conclusions Our findings collectively demonstrate that preoperative TACE confers poor prognosis in HCC patients through activation of HIF-1α.

Background The acyclic retinoid, peretinoin, has been shown to be effective for suppressing hepatocellular carcinoma (HCC) recurrence after definitive treatment in a small-scale randomized clinical trial. However, little has been documented about the mechanism by which peretinoin exerts its inhibitory effects against recurrent HCC in humans in vivo . Methods Twelve hepatitis C virus-positive patients whose HCC had been eradicated through curative resection or ablation underwent liver biopsy at baseline and week 8 of treatment with either a daily dose of 300 or 600 mg peretinoin. RNA isolated from biopsy samples was subjected to gene expression profile analysis. Results Peretinoin treatment elevated the expression levels of IGFBP6 , RBP1 , PRB4 , CEBPA , G0S2 , TGM2 , GPRC5A, CYP26B1 , and many other retinoid target genes. Elevated expression was also observed for interferon-, Wnt-, and tumor suppressor-related genes. By contrast, decreased expression levels were found for mTOR- and tumor progression-related genes. Interestingly, gene expression profiles for week 8 of peretinoin treatment could be classified into two groups of recurrence and non-recurrence with a prediction accuracy rate of 79.6% ( P <0.05). In the liver of patients with non-recurrence, expression of PDGFC and other angiogenesis genes, cancer stem cell marker genes, and genes related to tumor progression was down-regulated, while expression of genes related to hepatocyte differentiation , tumor suppression genes, and other genes related to apoptosis induction was up-regulated. Conclusions Gene expression profiling at week 8 of peretinoin treatment could successfully predict HCC recurrence within 2 years. This study is the first to show the effect of peretinoin in suppressing HCC recurrence in vivo based on gene expression profiles and provides a molecular basis for understanding the efficacy of peretinoin.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone–releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.