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Background: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis., Methods: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878., Findings: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase., Interpretation: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma., Funding: Bristol-Myers Squibb., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Comprehensive analysis of ferroptosis in Hepatocellular Carcinoma (HCC) and its relation to the tumor immune microenvironment are needed. Data included HCC in The Cancer Genome Atlas and International Cancer Genome Consortium. And two datasets from Gene Expression Omnibus (GEO) were used as the validation set. Based on the expression of ferroptosis-related genes, HCC patients were divided into two subtypes. Cluster 1 showed lower tumor grade, lower CTLA-4, and a more favorable prognosis than Cluster 2. Patients with higher SLC7A11 (50%) had a poorer prognosis in HCC. SLC7A11 is characterized by more NK CD56bright cells, less DC, and neuroactive ligand-receptor interaction and cytokine receptor interaction. Ferroptosis-related genes especially SLC7A11 might be a valuable prognostic factor in HCC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Chromosome 11q13.2, which contains genes cyclin D1 (CCND1), fibroblast growth factor 19 (FGF19), and Oral Cancer Overexpressed 1 (ORAOV1), is the most highly amplified peak in hepatocellular carcinoma (HCC). CCND1 and FGF19 have been already suggested as therapeutic targets of HCC, but the role of ORAOV1 in carcinogenesis of HCCs has not been reported., Methods: This retrospective study investigated ORAOV1 expression using immunohistochemistry performed on tissue microarray blocks obtained from 259 HCC patients with curative resection, between 2000 and 2006. We assessed the prognostic significance of ORAOV1 expression by Kaplan-Meier method with log-rank test and Cox proportional hazards model. Also, we performed invasion, migration, apoptosis, and cell cycle assays in HCC cell lines, and evaluated the tumorigenicity of HCC xenografts in nude mice, after knockdown of ORAOV1., Results: High expression of ORAOV1 protein was observed in 80% of HCC tissues. The ORAOV1 high expression group showed shorter recurrence free survival (RFS) (p < 0.001) and shorter disease-specific survival (DSS) than the low expression group. It was an independent prognostic factor for predicting early recurrence [Odds ratio 2.74 (95% confidence interval (CI) 1.27-5.93), p = 0.01] as well as short RFS [hazard ratio 2.23 (95% CI 1.40-3.54), p = 0.001] and DSS [hazard ratio 2.30 (95% CI 1.27-4.17), p = 0.006]. Knockdown of ORAOV1 induced significant decreases in migration, invasion, and tumorigenicity of HCC cells in in-vitro model, and inhibited the growth of HCC xenografts in nude mice., Conclusion: We demonstrated unfavorable prognostic effect of ORAOV1 expression with supporting experimental data in HCC. ORAOV1 may be used as a biomarker for predicting HCC prognosis and is a potential candidate for targeted therapy.

Oncogenic fusion of the tropomyosin receptor kinase (Trk) receptor family encoded by the NTRK gene has been found in several carcinomas. About ten targeted therapies have been developed and clinical trials are in progress. However, the results of studies on expression of the Trk receptor in HCC have not yet been published. Immunohistochemical staining was performed using anti-TrkA+B+C antibody (ab181560, Abcam) in 288 curatively resected primary HCC samples, and the correlation between Trk expression and NTRK copy number was assessed. Targeted next generation sequencing was performed in cases with Trk overexpression to detect NTRK fusion genes. Overexpression of Trk protein was observed in 21 (7.3%) of 288 cases. The Trk overexpression group showed a trend toward shorter recurrence-free survival (RFS) (p = 0.092) and overall survival (OS) (p = 0.079) than the low expression group, with frequent multicentric occurrence. Differences in RFS and OS were statistically significant in specific sub-populations including AJCC T1 stage HCCs, tumors less than 5 cm, patients without cirrhosis, tumors without vascular invasion, or Edmondson grades I and II. Trk expression was also an independent prognostic factor in both RFS and OS. Trk expression was not associated with copy number of each NTRK gene, and NTRK fusion was not detected in HCCs with Trk overexpression. Trk expression might play an important role in the development and progression of HCC, and emerging target therapy against the Trk protein could be applicable in patients with Trk-overexpressing HCC.

The second line treatment of hepatocellular carcinoma (HCC) has recently become an exciting area of interest since new emerging options have demonstrated survival benefits versus placebo. Unfortunately, predictive biomarkers are unavailable for these treatments. Ramucirumab, a monoclonal antibody against VEGFR-2, has demonstrated overall survival superiority against placebo as a second line therapy for patients with AFP > 400 ng/ml in the recent REACH-2 trial. This review will provide the current updated knowledge regarding the HCC cancerogenesis and angiogenic VEGF/VEGFR-2 pathways and the clinical development of ramucirumab in advanced HCC. This study will also critically assess the gaps in a previous negative phase III trial that tested other potentially useful treatments and suggest ways to modernise clinical trials and personalise therapy for advanced HCC.