An Oxidative Stress-Related Prognostic Signature Predicts Treatment Response and Outcomes for Hepatocellular Carcinoma After Transarterial Chemoembolization.

Purpose: Oxidative stress plays a critical role in promoting tumor resistance to hypoxia and chemotherapeutic drugs. However, the prognostic role of oxidative stress-related genes (OSRGs) in hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) has not been fully explored. Methods: We used transcriptome data from the GSE104580 cohort containing patients marked as responders or nonresponders to TACE therapy to identify differentially expressed OSRGs associated with TACE response (TR-OSRGs). We created a TR-OSRG prognostic signature based on TR-OSRGs using least absolute shrinkage and selection operator Cox and stepwise Cox regression analyses in a training cohort of patients with HCC (TCGA-LIHC). We verified this prognostic signature in two external cohorts of patients who received TACE for HCC (GSE14520-TACE and ZS-TACE-37). Finally, we constructed a prognostic nomogram model for predicting survival probability of patients with HCC based on Cox regression analysis. Results: The TR-OSRG prognostic signature was created and shown to be a robust independent prognostic factor for treatment response and outcomes for HCC after TACE therapy. Risk scores based on this signature correlated with tumor stage and grade. Tumor samples from patients with higher risk scores exhibited more infiltration of immune cells and significantly increased expression of immune checkpoint genes. We also developed a nomogram for patients with HCC based on the TR-OSRG prognostic signature and clinical parameters; this nomogram was a useful quantitative analysis tool for predicting patient survival. Conclusion: The TR-OSRGs signature exhibited good performance in predicting treatment response and outcomes in patients with HCC treated with TACE.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.

Immunotherapy for hepatocellular carcinoma / 临床肝胆病杂志

@#In the past 10 years, the progress in systemic therapy for hepatocellular carcinoma (HCC) is attributed to the application of molecular target therapy and the improvement in immunotherapy. The immunosuppressive microenvironment of HCC enables HCC cells to avoid attack by the immune system, which is also an important reason for the progression of HCC. Improving immune killing of HCC and correcting immunosuppressive conditions are important strategies for immunotherapy for HCC. Tumor vaccine therapy based on HCC specific antigen, genetically engineered T lymphocytes, and basic research and bench-to-bedside translation of immune checkpoint inhibitors have significantly improved the outcome of immunotherapy. Further studies should be performed for immunotherapy combined with other antitumor therapies such as local ablation, molecular targeted therapy, and tumor vaccine therapy.