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.

MicroRNA 211-5p inhibits cancer cell proliferation and migration in pancreatic cancer by targeting BMP2.

MicroRNAs (miRNAs) are essential to the tumour growth and metastasis of several cancers. However, the implied functions of miR-211-5p in pancreatic cancer (PC) remains poorly known. In the present study, we discovered that miR-211-5p was a significantly downregulated miRNA in PC tissues compared to adjacent non-tumour tissues. Moreover, we revealed that miR-211-5p overexpression suppressed the proliferation and metastasis of PC cells. Mechanistically, miR-211-5p directly bond to 3'UTR of bone morphogenetic protein-2 (BMP2) and negatively regulated its expression. Rescue experiments showed that the biological function of miR-211-5p was reversed by BMP-2 overexpression in PC cells. Clinical data indicated that BMP2 expression was negatively correlated with miR-211-5p levels in PC patients. Our study provided evidence that miR-211-5p served as a significant suppressor in PC, provided potential targets for prognosis and treatment of patients with PC.

Lenvatinib Plus PD-1 Inhibitors versus Regorafenib in Patients with Advanced Hepatocellular Carcinoma After the Failure of Sorafenib: A Retrospective Study.

Purpose: To evaluate the clinical outcomes of lenvatinib plus PD-1 inhibitors (LP) and regorafenib (R) in patients with advanced hepatocellular carcinoma (HCC) after sorafenib failure. Methods: From June 2018 to September 2021, 68 patients from a single center who received lenvatinib combined with PD-1 inhibitors or regorafenib after sorafenib treatment failure were analyzed. The tumor response and survival outcomes were compared between the LP group and R group. Prognostic factors for OS and PFS were determined using Cox proportional hazard regression models. Results: The ORR increased in the LP group (19.5% vs 7.4%, p =0.294), and the DCR was better in the R group (73.2% vs 44.4%, p =0.017). Additionally, median PFS and OS were not significantly different between the LP group and R two groups in survival analysis (PFS: 5.3 months vs 3.0 months, p =0.633; OS: 11.8 months vs 8.0 months, p =0.699). The common adverse events (≥grade 3) were hand-foot skin reactions (13.1%). In multivariate analyses, AFP≥400 ng/mL and ECOG PS 2 were independent risk factors for poor prognosis. Conclusion: The LP group appeared to have a trend of greater tumor response and a higher disease control rate than the R group among patients with sorafenib-resistant HCC, although PFS and OS did not differ significantly between the two groups.

CKLF as a Prognostic Biomarker and Its Association with Immune Infiltration in Hepatocellular Carcinoma.

The Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family, comprising nine members, is involved in the tumorigenesis and progression of various cancers. However, the expression profiles and clinical significance of CMTM family members in hepatocellular carcinoma (HCC) are not fully clarified. In this study, the RNA-sequencing and clinical data were downloaded from The Cancer Genome Atlas (TCGA) databases. The Kaplan-Meier method and the Cox proportional hazards regression analysis were used to evaluate the prognostic significance of CMTM family members. Single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithms were employed to explore the relationship between CMTM family genes and the tumor microenvironment in HCC. Finally, the prognostic CMTM family gene expression was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining in clinical HCC tissue specimens. The results indicated that, compared with normal tissues, the expression of CKLF, CMTM1, CMTM3, CMTM4, CMTM7, and CMTM8 were significantly upregulated in HCC, while the expression of CMTM2, CMTM5, and CMTM6 were significantly downregulated in HCC. Univariate and multivariate Cox regression analysis demonstrated that CKLF was an independent prognostic biomarker for the overall survival (OS) of HCC patients. In HCC, the expression of CKLF was found to be correlated with immune cell infiltration, immune-related functions, and immune checkpoint genes. The qRT-PCR and IHC confirmed that CKLF was highly expressed in HCC. Overall, this research suggested that CKLF is involved in immune cell infiltration and may serve as a critical prognostic biomarker, which provides new light on the therapeutics for 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.

PD-1 inhibitors plus lenvatinib versus PD-1 inhibitors plus regorafenib in patients with advanced hepatocellular carcinoma after failure of sorafenib.

Background: Lenvatinib, regorafenib and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising clinical outcomes in patients with advanced hepatocellular carcinoma (HCC) after sorafenib failure, respectively. However, the combination of the two treatments has not been reported. We compared the efficacy of PD-1 inhibitors with lenvatinib (PL) and PD-1 inhibitors plus regorafenib (PR) in patients with advanced HCC in this study. Methods: We conducted a retrospective study of advanced HCC patients who undergone PD-1 inhibitors combined with lenvatinib or regorafenib after failure of sorafenib at Second Affiliated Hospital of Nanchang University from July 2018 and December 2020. The overall survival (OS), progression-free survival (PFS), effective rates and treatment-related adverse events (TRAEs) were investigated. Results: In total, 61 patients met the criteria and were included in the present study, and they were divided into the PL group (n = 32) and PR group (n = 29). The overall response rate (ORR) (12.5%vs. 10.3%, respectively; p = 0.557) and disease control rate (DCR) (71.9%vs. 58.6%, respectively; p < 0.207) were higher in the PL group than in the PR group, but there was no statistical difference.Furthermore, median PFS and OS were not significantly different between the two groups in Kaplan-Meier survival analysis (PFS: 5.3 months vs 4.0 months, p = 0.512; OS: 14.1 months vs 13.7 months, p = 0.764 for the PL group vs PR group). The most common treatment-related adverse events (TRAEs) were hand -foot skin reaction (24/61,39.3%), hypertension (20/61,32.8%) and hypothyroidism (13/61,21.3%). The frequent TRAEs (≥Grade 3) during PD-1 inhibitors plus lenvatinib or regorafenib treatment were hand-foot skin reaction (5/29,12.4%), thrombocytopenia (2/29 6.90%) and proteinuria (n =2/32,6.25%). Conclusions: Combination of lenvatinib/regorafenib and PD-1 inhibitors is a promising therapy for HCC patients after sorafenib failure.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with programmed cell death protein-1 antibody and lenvatinib for advanced hepatocellular carcinoma.

Background: The purpose of the study was to assess the efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) who are undergoing hepatic arterial infusion chemotherapy (HAIC) combined with programmed cell death protein-1 (PD-1) antibody and lenvatinib. Methods: We retrospectively evaluated 61 patients treated with HAIC combined with PD-1 antibody and lenvatinib at the Second Affiliated Hospital of Nanchang University between September 2020 and January 2022 for advanced HCC. We analyzed tumor response, progression free survival (PFS), and treatment-related adverse events (TRAEs). Results: The objective response rate (ORR) was 36.1% (RECIST 1.1)/57.4% (mRECIST) and the disease control rate (DCR) was 82.0%. The overall median PFS was 6.0 months, 6.7 months for first-line treatment, and 4.3 months for second-line treatment. The most common TRAEs were neutropenia (50.8%), abdominal pain (45.9%), and aspartate aminotransferase increase (39.3%). Conclusion: Hepatic arterial infusion chemotherapy combined with PD-1 antibody and lenvatinib is effective in the treatment of advanced HCC, and the TRAEs are generally controllable.