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Background: Circular (circ)RNAs have emerged as crucial contributors to cancer progression. Nonetheless, the expression regulation, biological functions, and underlying mechanisms of circRNAs in mediating hepatocellular carcinoma (HCC) progression remain insufficiently elucidated. Methods: We identified circUCK2(2,3) through circRNA sequencing, RT–PCR, and Sanger sequencing. CircUCK2(2,3) levels were measured in two independent HCC cohorts using quantitative real-time PCR (qRT–PCR). We explored the functions of circUCK2(2,3) using gain- and loss-of-function assays. Techniques such as RNA-sequencing, RNA immunoprecipitation (RIP), polysome fractionation, RNA pulldown, dual luciferase reporter assay, inhibitors of EGFR downstream signaling, CRISPR–Cas9, and medium transfer assays were employed to investigate the regulatory mechanisms and the protumoral activities of circUCK2(2,3). Additionally, in vitro cytotoxic assays and patient-derived xenograft (PDX) models assessed the effects of circUCK2(2,3) on the cytotoxic synergy of lenvatinib and EGFR inhibitors. Results: CircUCK2(2,3) is upregulated in HCC tissues and serves as an independent risk factor for poor recurrence-free survival. The expression of circUCK2(2,3) is independent on its host gene, UCK2, but is regulated by its upstream promoter and flanking inverted complementary sequences. Functionally, circUCK2(2,3) enhances HCC proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, by sponging miR-149-5p, circUCK2(2,3) increases CNIH4 levels, which in turn amplifies TGFα secretion, resulting in the activation of EGFR and downstream pAKT and pERK signaling pathways. Moreover, circUCK2(2,3) overexpression sensitizes HCC cells to EGFR inhibitors, and increases the synergistic cytotoxicity of combined lenvatinib and EGFR inhibitor treatment. Conclusions: CircUCK2(2,3) regulates a novel oncogenic pathway, miR-149-5p–CNIH4–TGFα–EGFR, in HCC, presenting a viable therapeutic target and biomarker for the precision treatment of HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinomas (HCCs) are characterized by a vast spectrum of somatic copy number alterations (CNAs); however, their functional relevance is largely unknown. By performing a genome‐wide survey on prognosis‐associated focal CNAs in 814 HCC patients by an integrative computational framework based on transcriptomic data, genomic amplification is identified at 8q24.13 as a promising candidate. Further evidence is provided that the 8q24.13 amplification‐driven overexpression of Rab GTPase activating protein TBC1D31 exacerbates HCC growth and metastasis both in vitro and in vivo through activating Epidermal growth factor receptor (EGFR) signaling. Mechanistically, TBC1D31 acts as a Rab GTPase activating protein to catalyze GTP hydrolysis for Rab22A and then reduces the Rab22A‐mediated endolysosomal trafficking and degradation of EGFR. Notably, overexpression of TBC1D31 markedly increases the resistance of HCC cells to lenvatinib, whereas inhibition of the TBC1D31‐EGFR axis can reverse this resistance phenotype. This study highlights that TBC1D31 at 8q24.13 is a new critical oncogene, uncovers a novel mechanism of EGFR activation in HCC, and proposes the potential strategies for treating HCC patients with TBC1D31 amplification or overexpression. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of postoperative transarterial chemoembolization (TACE) for huge intrahepatic cholangiocarcinoma (ICC). Methods Data of 125 huge ICC (diameter ≥10 cm) patients with surgical treatment treated with or without TACE (TACE group 35 cases, and non-TACE group 90 cases) between January 2009 and December 2013 were analyzed retrospectively. Both recurrence rate and overall survival (OS) rate were analyzed using the Kaplan-Meier method and the difference using Log-Rank test. Cox regression analysis was used to explore the independent risk factors of postoperative recurrence and OS. Propensity score matching was used to reduce the difference between groups. Subgroup analysis was done for benefited patients from TACE based on the 8th TNM staging of ICC. Results TACE group had similar recurrence and OS with non-TACE group. 5-year recurrence rate and OS rate were 85.7% vs. 84.4%, P=0.487; 22.9% vs. 20.0%, P=0.426, respectively. After 1∶1 propensity score matching with 33 cases each group, there was no significant difference between two groups (P=0.114 for recurrence, P=0.197 for OS). According to TNM sta-ging, there were 61 cases in stage Ⅰ and 64 cases in stage Ⅱ. Staging analysis showed that TACE group and non-TACE groups yielded similar recurrence and OS in patients with stage Ⅰ. However, for patients in stage Ⅱ, TACE group had lower recurrence rate (91.7% vs. 97.5%, P=0.022) and higher OS rate (12.5% vs. 2.5%, P=0.002). After adjustment for multiple tumors, vascular invasion, and CEA ≥5 μg/L, TACE was independent risk factor of recurrence (hazard ratio: 0.564, 95%CI: 0.327-0.974) and OS (hazard ratio: 0.449, 95%CI: 0.259-0.777) in patients with stage Ⅱ. Conclusions For patients with huge ICC, postoperative TACE may improve the prognosis of patients with TNM stage Ⅱ.

Summary: Background: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). Aim: To compare the effect of different anti‐PD‐1 combination therapies as the first‐line treatments for uICC. Methods: This study included 318 patients who received chemotherapy alone (Chemo), anti‐PD‐1 plus chemotherapy (ICI‐chemo), anti‐PD‐1 plus targeted therapy (ICI‐target) or anti‐PD‐1 plus targeted therapy and chemotherapy (ICI‐target‐chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results: Patients with ICI‐chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42–0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39–0.94; p = 0.026), ICI‐target (7.2 months; HR: 0.54, 95% CI: 0.36–0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35–0.84; p = 0.006) or ICI‐target‐chemo (6.9 months; HR: 0.65, 95% CI: 0.47–0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31–0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI‐target was not inferior to ICI‐chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55–1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51–1.55; p = 0.680). ICI‐target‐chemo yielded similar prognoses as ICI‐chemo (HR for PFS: 1.07, 95% CI: 0.70–1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45–1.31; p = 0.328) and ICI‐target (HR for PFS: 1.20, 95% CI: 0.77–1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51–1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. Conclusions: Among patients with uICC, ICI‐chemo or ICI‐target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI‐target‐chemo. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) persists as a dominant cause of cancer-related mortality globally, with a notably rapid escalation in mortality rates. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era in the management of liver cancer, albeit with unresolved challenges in the context of treatment beyond progression (TBP) and stratified prognosis in diverse populations. This study aimed to develop and validate a novel nomogram model to identify factors that predict the benefit of continued immunotherapy for hepatocellular carcinoma patients following disease progression in clinical practice., Methods: This study retrospectively analyzed the efficacy of ICIs in TBP, focusing on the Chinese population with advanced liver cancer. A nomogram was constructed based on four independent risk factors identified through Cox multivariate analysis, aiming to predict patient prognosis post-ICI treatment. The model was validated through receiver operating characteristic (ROC) curve analysis and categorized patients into high-, intermediate-, and low-risk groups, with further validation using calibration plots and decision curve analysis (DCA)., Results: The low-risk group demonstrated significantly enhanced overall survival (OS) compared to the high-risk group, with the nomogram predictions aligning closely with actual outcomes for 6- and 9-month OS. The model exhibited commendable predictive accuracy, achieving a C-index exceeding 0.7 in both training and validation datasets. The DCA underscored the clinical utility of the nomogram-based prognostic model, further substantiated by the area under the ROC curve (AUC)., Conclusions: The developed nomogram presents a potentially valuable tool for predicting the prognosis of HCC patients undergoing ICI therapy beyond progression, particularly within the Chinese demographic. However, the study is constrained by its retrospective, single-center nature and necessitates further validation through large-scale, multicenter clinical studies across varied populations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-646/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of sorafenib combined with best supportive care (BSC) in these patients. We enrolled 44 patients with unresectable and advanced ICC who were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12, and the secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Our results showed that the DCR was 15.9%, the median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). AEs of grades 1 and 2 events occurred in 75% of patients, and AE of grade 4 (severe) was observed in 1 patient. Therefore, sorafenib in combination with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC.