Hepatic arterial infusion chemotherapy, lenvatinib plus programmed cell death protein-1 inhibitors: A promising treatment approach for high-burden hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has demonstrated remarkable local therapeutic efficacy in treating patients with large unresectable hepatocellular carcinoma (HCC). Additionally, the combination of lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has demonstrated promising antitumor effects in unresectable HCC. Therefore, we conducted a retrospective analysis to evaluate the efficacy and safety of combining HAIC with lenvatinib and PD-1 inhibitors as a first-line therapeutic approach in high-burden HCC patients. METHODS: We conducted a retrospective analysis on patients diagnosed with high-burden HCC who had major portal vein tumor thrombosis (Vp3 and Vp4) or tumor occupancy exceeding 50% of the liver. These patients received a first-line treatment consisting of HAIC with a combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), along with lenvatinib and PD-1 inhibitors between November 2020 and June 2023. The primary endpoints of this study included progression-free survival (PFS) and overall survival (OS), while the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). RESULTS: Ninety-one patients were enrolled in this study, with a median PFS of 8.8 months (95% confidence interval [CI]: 5.75-11.78) and a median OS of 14.3 months (95% CI: 11.23-17.31). According to RECIST 1.1 criteria, the ORR was 52.7%, and DCR was 95.6%. According to the mRECIST criteria, the ORR was 72.5%, and the DCR was 96.5%. Among all patients, 86 (94.5%) experienced TRAEs, and there were no instances of treatment-related deaths. CONCLUSION: The combination of HAIC-FOLFOX with lenvatinib and PD-1 inhibitors as a first-line therapy has exhibited notable therapeutic efficacy and well-tolerated adverse events among patients with high-burden HCC.

A comprehensive prognostic and immunological analysis of ephrin family genes in hepatocellular carcinoma.

Background: Ephrins, a series of Eph-associated receptor tyrosine kinase ligands, play an important role in the tumorigenesis and progression of various cancers. However, their contributions to hepatocellular carcinoma (HCC) remain unclear. Thus, we aimed to explore their prognostic value and immune implications in HCC. Methods: Multiple public databases, such as TCGA, GTEx, and UCSC XENA, were used to analyze the expression of ephrin genes across cancers. Kaplan-Meier analysis and Cox regression were used to explore the prognostic role of ephrin genes in HCC. A logistic regression model was utilized to evaluate the association between ephrin gene expression and clinical characteristics. Gene set enrichment analysis (GSEA) was conducted to elucidate their potential biological mechanisms. Various immune algorithms were utilized to investigate the correlation between ephrin genes and tumor immunity. We also analyzed their association with drug sensitivity, and gene mutations. Finally, RT-qPCR was performed to validate the expression of ephrin family genes in HCC cells and clinical tissues. Results: The expression of EFNA1, EFNA2, EFNA3, EFNA4, EFNB1, and EFNB2 was upregulated in most cancer types, while EFNA5 and EFNB3 was downregulated in most cancers. In HCC, the expression levels of EFNA1, EFNA3, EFNA4, EFNB1, and EFNB2 were significantly higher in tumor tissues than in normal tissues. High expression of EFNA3, EFNA4, and EFNB1 was associated with tumor progression and worse prognosis in HCC patients. The expression of EFNA3 and EFNA4 was negatively associated with the stromal/ESTIMATE scores, while EFNB1 was positively correlated with the immune/stromal/ESTIMATE scores. Moreover, these ephrin genes were closely relevant to the infiltration of immune cells, such as B cells, CD4+ T cells, CD8+ T cells, neutrophil cells, macrophage cells, and dendritic cells. EFNB1 expression was positively associated with most immune-related genes, while EFNA3/EFNA4 was positively related to TMB and MSI. In addition, EFNA3, EFNA4, and EFNB1 were related to drug sensitivity and affected the mutation frequency of some genes in HCC. Conclusion: EFNA3, EFNA4, and EFNB1 are independent prognostic factors for HCC patients and are closely correlated with tumor immunity, which may provide a new direction for exploring novel therapeutic targets and biomarkers for immunotherapy.