Journal of Hepatocellular Carcinoma最新文献

Aim: The prognosis of hepatocellular carcinoma with extrahepatic spread (HCC-EHS) remains poor. While systemic therapy is standard, intrahepatic progression often drives mortality. This study evaluated whether combining transarterial chemoembolization (TACE) with sorafenib (TACES) improves outcomes versus TACE alone in HCC-EHS.

Methods: In this multicenter, retrospective study, 423 HCC-EHS patients (Child-Pugh A) were categorized into TACE-alone (n = 294) or TACES (n = 129) groups. The primary endpoint was overall survival (OS). Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. Radiological response was assessed per mRECIST.

Results: After IPTW adjustment, the TACES group demonstrated significantly superior tumor response, with higher objective response (33.3% vs 16.4%, p = 0.004) and disease control rates (63.2% vs 46.3%, p = 0.008) compared to the TACE-alone group. This translated into a significant survival benefit, with a median OS of 10.4 months for TACES versus 7.0 months for TACE alone (IPTW-adjusted hazard ratio: 0.68; 95% CI: 0.52-0.88; p = 0.004). The survival advantage remained consistent in landmark analyses. Subgroup analyses indicated that the absolute benefit from combination therapy was most pronounced in patients with high intrahepatic tumor burden and preserved liver function.

Conclusion: This real-world study demonstrates that in carefully selected patients with HCC-EHS, a combination of TACE and sorafenib provides significantly better tumor control and survival outcomes than TACE monotherapy. These findings suggest that an integrated therapeutic strategy, which aggressively manages the intrahepatic disease in conjunction with systemic therapy, can improve outcomes in this challenging-to-treat population and warrants validation in prospective studies.

Background: Surgical resection and ablation therapy are both primary treatment options for very early stage hepatocellular carcinoma (HCC). Accurate risk stratification is important, since patients at higher risk of recurrence may derive greater benefit from curative resection than from ablation. We investigated whether the mitotic index is associated with early recurrence in HCC and may serve as a prognostic marker to refine risk assessment in very early stage disease.

Methods: The number of mitoses was counted in representative tumor slides from 942 cases of surgically resected HCC from Samsung Medical Center. A high mitotic index was defined as more than eight mitoses in 10 high-power fields. The relationship between mitotic index, clinicopathological characteristics, and prognosis were analyzed. External validation was performed using 112 HCC cases obtained from Hallym University Sacred Heart Hospital.

Results: High mitotic index was identified in 296 patients and was significantly associated with aggressive clinicopathological features including higher Edmondson grade, advanced American Joint Committee on Cancer T stage, and early tumor recurrence. Patients with a high mitotic index displayed a significantly shorter early recurrence-free survival (e-RFS). In subgroup analysis of patients with very early stage, the high mitotic index group showed unfavorable influences on e-RFS.

Conclusion: High mitotic index is a significant predictor of early recurrence in HCC patients and may provide useful prognostic information in very early stage disease. While its direct role in guiding primary treatment selection is limited, the mitotic index could contribute to risk stratification and postoperative management strategies.

Background: Tumor-associated macrophages (TAMs) are pivotal components of the immune cell infiltrate in tumors and cell division cycle-associated protein-3 (CDCA3) is associated with tumor progression. The role of CDCA3 in regulating TAM polarization remains uncharacterized in hepatocellular carcinoma (HCC).

Methods: CDCA3 expression, its correlation with immune cell infiltration, and prognostic significance in HCC were analyzed using the TCGA and TIMER databases. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), were performed to predict CDCA3-related pathways. The knockdown efficiency of CDCA3 in HCC cell lines was confirmed by RT-qPCR and Western blotting. Functional assays, including CCK-8, wound healing, and flow cytometry, were used to assess the role of CDCA3 in cell proliferation, migration, and apoptosis. Immunohistochemistry (IHC) was applied to evaluate the correlation between CDCA3 expression and M2 macrophage markers in clinical tissue samples.

Results: Bioinformatic analysis revealed that CDCA3 was significantly upregulated in HCC tissues, and its high expression was associated with advanced clinical stage, higher tumor grade, and poor prognosis. CDCA3 expression also correlated strongly with the level of immune infiltration. Notably, CDCA3 showed high diagnostic potential for HCC, with an area under the curve (AUC) of 0.869, cut-off value of 189.03 pg/mL, sensitivity of 81.9%, and specificity of 77.8%. Experimentally, CDCA3 knockdown significantly suppressed malignant phenotypes of HCC cells and inhibited M2 macrophage polarization.

Conclusion: Our findings suggest that CDCA3 promotes the malignant progression of HCC by driving M2-like TAM polarization, potentially through the upregulation of cytokines such as TGF-β1, VEGFA, CD40, CXCL1, and CXCL5. CDCA3 thus represents a promising diagnostic biomarker and therapeutic target for HCC.

Purpose: Circadian disruption contributes to hepatocellular carcinoma (HCC) progression. This study aimed to develop a CT-based radiomics model to non-invasively predict circadian rhythm (CR) gene expression profiles for improved prognostic assessment.

Methods: Mendelian randomization (MR) analysis revealed a significant causal association between CR disorders and the risk of HCC. In Cohort 1 (TCGA database, n = 424), 32 CR-related genes were identified from an initial set of 71 genes. Univariate Cox regression analysis identified 18 prognosis-related genes, and a risk model containing 8 genes was constructed using LASSO and multivariate Cox regression. This model was then validated in Cohort 2 (ICGC database, n = 232). The gene CRTC2 was further validated in vitro. Radiomics features were constructed based on enhanced CT images from Cohort 3 (TCIA database, n = 45) to predict CR risk genes, and the prognostic value of the model was validated in Cohort 4 (The Fourth Affiliated Hospital of Zhejiang University School of Medicine, n = 38).

Results: The CR risk gene model stratified patients into high- and low-risk groups with significantly different survival outcomes in both TCGA and ICGC cohorts (TCGA: P < 0.001; ICGC: P = 0.029). The risk score was independently associated with overall survival (HR = 3.582, 95% CI: 2.101-6.107, P < 0.001). Experimental results confirmed that knockdown of CRTC2 significantly inhibited HCC cell proliferation, migration, invasion, and induced apoptosis. The radiomics model achieved an AUC of 0.931 in the training set and 0.760 in the validation set for predicting CR gene expression. Importantly, in the clinical validation cohort, patients with low radiomics scores had significantly longer survival (P = 0.039).

Conclusion: Circadian rhythm-related gene expression, implicated in HCC development, can be non-invasively predicted via CT-based radiomics. The proposed model offers promise for prognostic stratification and personalized treatment planning in HCC.

Purpose: Tertiary lymphoid structure (TLS) has been well-established across multiple tumor types for predicting efficacy of immunotherapy and prognostic evaluation. However, its role in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains unclear. Refinement of TLS pathological assessment could potentially optimize postoperative management in these patients. This study aimed to develop a practical histopathological grading system of intratumoral TLS to improve prognostic stratification of cHCC-CCA patients.

Patients and methods: A cohort of 310 cHCC-CCA patients undergoing hepatectomy with curative intent was analyzed. Three pathologists re-evaluated pathological slides to establish a four-tier TLS grading system: TLS 0 (absent), TLS 1 (immature TLS only), TLS 2a [single mature TLS (mTLS)], and TLS 2b (multiple mTLS). Associations with recurrence-free survival (RFS), overall survival (OS), early RFS (≤1 year), late RFS (>1 year), and recurrence patterns were assessed. Predictive factors for TLS were also investigated.

Results: Patients were stratified into TLS 0 (29.4%), TLS 1 (51.6%), TLS 2a (6.8%), and TLS 2b (12.3%). Survival outcomes significantly correlated with TLS presence and maturation. Median RFS increased stepwise: 0.24 years (TLS 0), 0.49 years (TLS 1), 1.13 years (TLS 2a), and 1.16 years (TLS 2b) (P<0.001). Median OS also improved progressively: 1.32 years (TLS 0), 2.20 years (TLS 1), 3.24 years (TLS 2a), and 10.04 years (TLS 2b) (P<0.001). TLS presence was associated with increased extrahepatic recurrence. The TLS grading system emerged as an independent prognostic factor for RFS, OS, and early RFS. Smaller tumor diameter was the sole significant predictive factor for both TLS and mTLS.

Conclusion: This novel TLS grading system effectively stratifies prognosis in cHCC-CCA, with increasing intratumoral mTLS indicating better outcomes. This practical method can be integrated into routine pathological reporting to aid clinical decision-making.

Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, remains a major global health concern due to its high incidence and mortality rates. Driven by factors such as chronic hepatitis B and C infections, alcohol-related liver disease, and metabolic-associated fatty liver disease (MAFLD), HCC is often diagnosed at advanced stages, limiting therapeutic options and prognosis. Recent advances in understanding the molecular mechanisms and tumor microenvironment of HCC, particularly disruptions in key pathways like Ras-Raf-MEK, PI3K-Akt/mTOR, and Wnt/β-catenin, have catalyzed the development of novel treatment strategies. This review synthesizes findings from over 80 recent peer-reviewed studies to explore the evolution of HCC therapy, including targeted therapies, immune checkpoint inhibitors, combination regimens, surgical techniques, and locoregional treatments. Special emphasis is placed on the role of tumor immunology, emerging biomarkers, and the impact of precision medicine in tailoring treatment strategies. These innovations collectively offer promising avenues for improving survival and quality of life in patients with HCC.

Background: The influence of pyroptosis on tumors is complex and diverse. However, its specific impact on hepatocellular carcinoma (HCC) is still not well understood. Therefore, the objective of this study was to develop a prognostic signature for HCC based on pyroptosis-related genes.

Methods: The single-cell RNA sequencing (scRNA-seq) data, mRNA expression files and corresponding clinical information of HCC were obtained from the The Cancer Genome Atlas and Gene Expression Omnibus databases. Python was used to process scRNA-seq data and calculated the enrichment score of pyroptosis-related genes (PRGs). Weight Co-Expression Network Analysis was used to identify pyroptosis-related hub genes. By overlapping the PRGs from scRNA-seq analysis and bulk RNA-seq analysis, respectively. Then, Univariate cox and LASSO regression were used to construct the pyroptosis prognostic model. Multivariate cox was used to identify independent factors for HCC and then developed a nomogram. The biological functions, survival analysis, immune characteristics, therapy response, and m6A modification status were analyzed.

Results: Based on the scRNA-seq analysis and bulk RNA-seq analysis, hub PRGs were identified in HCC. Of those genes, five PRGs (ADGRE2, FCER1G, SLC9A9, CYBB, SLAMF6) were selected as a prognostic signature. The risk score established from the prognostic signature was an independent prognostic factor for HCC. The high-risk score group is associated with a poor prognosis, characterized by immunosuppressive features.

Conclusion: This study uniquely integrates single-cell and bulk transcriptomic data to systematically identify pyroptosis-related prognostic biomarkers, pinpointing their cellular origin within the tumor microenvironment.

Objective: This study aims to compare the efficacy and safety of transarterial chemoembolization (TACE) and radio-frequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC) within the Milan criteria.

Materials and methods: 162 patients with HCC who underwent TACE (n=97) or RFA (n=65) from February 2011 to December 2024. A matched cohort composed of 88 patients was included after propensity score matching (PSM). The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and safety.

Results: Baseline characteristics were balanced between the two groups after propensity score matching. Before matching, the 1-, 3-, and 5-year OS rates were 71.0%, 48.7%, 34.1%, respectively, in the TACE group and 87.0%, 69.5%, 63.1%, respectively, in the RFA group (P = 0.006). The 1-, 2-, and 3-year PFS rates were 37.1%, 25.1%, 18.3% in TACE group, and 52.6%, 43.3%, 40.6% in RFA group (P=0.009). After matching, the 1-, 3-, and 5-year OS rates were81.2%, 48.1%, 37.1%, respectively, in the TACE group and 88.6%, 65.6%, and 54.6%, respectively, in the RFA group (p=0.15). The 1-, 2-, and 3-year PFS rates were 33.3%, 20.5%, 17.5% in TACE group, and52.3%, 40.2%, 37.8% in RFA group (P=0.036). Before and after PSM, the incidence of major complications (before PSM P=0.306, after PSM P=0.08) and length of hospital stay (before PSM P=0.25, after PSM P=0.406) were similar between the two groups.

Conclusion: In the treatment of HCC within the Milan criteria, RFA demonstrated a superior median PFS compared to TACE, although there was no significant difference in OS between the two therapies.

Objective: This study aimed to evaluate the clinical efficacy and safety of combined therapy (transcatheter arterial chemoembolization [TACE] with hepatic artery infusion chemotherapy [HAIC] combined with tyrosine kinase inhibitors [TKIs] and PD-1 inhibitors) versus TACE alone in hepatocellular carcinoma (HCC) patients with concurrent portal/hepatic vein tumor thrombus (PVTT/HVTT) and arteriovenous fistula (AVF).

Materials and methods: This single-center retrospective study analyzed 301 HCC patients with PVTT/HVTT and AVF who received either combined therapy (n=177) or TACE monotherapy (n=124). Propensity score matching (PSM) was used to minimize confounding bias, yielding an average of 109 patients per group. Key outcomes compared included tumor thrombus regression rate, AVF closure rate, objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), median progression-free survival (mPFS), and adverse events (AE).

Results: After PSM, the AVF complete closure rate of the combination therapy group was significantly higher than the TACE group (63.3% vs 27.5%, p < 0.001). According to response evaluation criteria in solid tumors (RECIST) 1.1 criteria for tumor thrombus response, the combination therapy group showed higher ORR (47.7% vs 7.3%, p < 0.001) and DCR (73.4% vs 50.5%, p < 0.001) than the TACE group. The combined therapy provided longer mOS (16.70 vs 10.40 months, p < 0.0001) and mPFS (14.23 vs 8.21 months, p < 0.0001) than TACE. The incidences of grade 3/4 AE were similar in both groups, respectively, 37.6% and 33.9%, p = 0.57.

Conclusion: Compared with TACE monotherapy, the combined therapy is a promising option with acceptable safety for HCC patients with PVTT/HVTT and AVF.

Purpose: This study aims to elucidate the anti-tumor properties of rutin and its specific molecular mechanisms for inhibiting hepatocellular carcinoma (HCC) through the ferroptosis.

Methods: The effects of rutin on HuH-7 cell proliferation, migration, invasion, and cell cycle progression were evaluated through in vitro experiments. By integrating bioinformatics analysis and network pharmacology, potential ferroptosis targets influenced by rutin in HCC were identified from the TCGA-LIHC database. A prognosis-related risk-scoring model was constructed and validated in the GEO14520 cohort and ICGC-LIRI-JP. Samples were categorized into high-risk and low-risk groups based on their scores. Enriched pathways within these different risk groups were explored using Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Additionally, key targets of rutin-related ferroptosis in HCC cells were investigated through single-cell analysis and molecular docking studies.

Results: Rutin inhibited the proliferation, invasion, migration, and cell cycle progression of HCC cells in a dose-dependent manner. We constructed a risk model comprising five ferroptosis-related targets of rutin (FRTs-R): ACACA, AKR1C3, ALDH2, AR, and CDK1. This prognostic model was validated in the GEO14520 and ICGC datasets, revealing that the low-risk group had a better prognosis than the high-risk group. Furthermore, lipid metabolism pathway activity was up-regulated in the low-risk group. Single-cell analysis indicated specific expression of AKR1C3 in HCC cells, while molecular docking analysis showed that, among the five potential targets, AKR1C3 demonstrated the most stable binding affinity to rutin.

Conclusion: Our findings suggest that rutin may modulate ferroptosis in HCC, with rutin associated ferroptosis genes implicated in disease biology; moreover, the proposed risk scoring model shows promising prognostic utility in HCC.