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Background Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. Methods Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. Discussion The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. Trial registration anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

The incidence of hepatocellular carcinoma is rising worldwide. It is predicted that nearly half of the early-stage hepatocellular carcinoma (E-HCC) patients will develop recurrence. Dysregulated pH, a hallmark of E-HCC, is correlated with poor prognosis. The acidic microenvironment has been shown to promote the release of exosomes, the membrane vesicles recognized as intercellular communicators associated with tumor progression, recurrence, and metastasis. We, therefore, aimed to identify exosomes induced by acidic microenvironment that may regulate E-HCC progression and to explore their mechanisms and clinical significance in E-HCCs. miRNA microarray analysis and LASSO logistic statistic model were used to identify the main functional exosomal miRNAs. Invasion and scratch assays were performed to examine the migration and invasion of HCC cells. Immunoblotting and immunofluorescence were employed to detect the epithelial-to-mesenchymal transition (EMT) in HCC cells. Chromatin immunoprecipitation (ChIP) was used to analyze the binding of HIF-1α and HIF-2α to promoter regions of miR-21 and miR-10b. The acidic microenvironment in HCC was correlated with poor prognosis of patients. Exosomes from HCC cells cultured in the acidic medium could promote cell proliferation, migration, and invasion of recipient HCC cells. We identified miR-21 and miR-10b as the most important functional miRNAs in acidic HCC-derived exosomes. Also, the acidic microenvironment triggered the activation of HIF-1α and HIF-2α and stimulated exosomal miR-21 and miR-10b expression substantially promoting HCC cell proliferation, migration, and invasion both and . In E-HCC patients, serum exosomal miR-21 and miR-10b levels were associated with advanced tumor stage and HIF-1α and HIF-2α expression and were independent prognostic factors for disease-free survival of E-HCC patients. Most importantly, we developed a nano-drug to target exosomal miR-21 and/or miR-10b and examined its therapeutic effects against HCC . Our findings suggested that the exosomal miR-21 and miR-10b induced by acidic microenvironment in HCC promote cancer cell proliferation and metastasis and may serve as prognostic molecular markers and therapeutic targets for HCC.

Background Alcohol drinking and gut microbiota are related to hepatocellular carcinoma (HCC), but the specific relationship between them remains unclear. Aims We aimed to establish the alcohol drinking-gut microbiota-liver axis and develop machine learning (ML) models in predicting the occurrence of early-stage HCC. Methods Two hundred sixty-nine patients with early-stage HCC and 278 controls were recruited. Alcohol drinking-gut microbiota-liver axis was established through the mediation/moderation effect analyses. Eight ML algorithms including Classification and Regression Tree (CART), Gradient Boosting Machine (GBM), K-Nearest Neighbor (KNN), Logistic Regression (LR), Neural Network (NN), Random Forest (RF), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost) were applied. Results A total of 160 pairs of individuals were included for analyses. The mediation effects of Genus_Catenibacterium ( P  = 0.024), Genus_Tyzzerella_4 ( P  < 0.001), and Species_Tyzzerella_4 ( P  = 0.020) were discovered. The moderation effects of Family_Enterococcaceae (OR = 0.741, 95%CI:0.160–0.760, P  = 0.017), Family_Leuconostocaceae (OR = 0.793, 95%CI:0.486–3.593, P  = 0.010), Genus_Enterococcus (OR = 0.744, 95%CI:0.161–0.753, P  = 0.017), Genus_Erysipelatoclostridium (OR = 0.693, 95%CI:0.062–0.672, P  = 0.032), Genus_Lactobacillus (OR = 0.655, 95%CI:0.098–0.749, P  = 0.011), Species_Enterococcus_faecium (OR = 0.692, 95%CI:0.061–0.673, P  = 0.013), and Species_Lactobacillus (OR = 0.653, 95%CI:0.086–0.765, P  = 0.014) were uncovered. The predictive power of eight ML models was satisfactory (AUCs:0.855–0.932). The XGBoost model had the best predictive ability (AUC = 0.932). Conclusions ML models based on the alcohol drinking-gut microbiota-liver axis are valuable in predicting the occurrence of early-stage HCC. Graphical Abstract

PurposeTo assess the clinical value of drug-eluting bead trans-arterial chemoembolization (DEB-TACE) combined with microwave ablation (MWA) vs. MWA treatment alone for early stage hepatocellular carcinoma (HCC).Materials and methodsConsecutive data from 102 HCC patients at early stage who were referred to our hospital from December 2014 to May 2016 were retrospectively collected. Forty-seven patients underwent DEB-TACE combined with MWA treatment, whereas 55 patients underwent MWA alone. After 1 month of treatment, the tumour responses of the patients were assessed using the mRECIST criteria. Treatment-related complications and hepatic function were also analysed for the two groups. In addition, overall survival (OS) and progression-free survival (PFS) were calculated and compared.ResultsPatients in the combined treatment group (DEB-TACE combined with MWA) presented a better objective response rate (ORR) and disease control rate (DCR) compared with those in the monotherapy group (MWA treatment). The median OS and PFS were longer in the combined treatment group compared with the monotherapy group. Multivariate Cox’s regression further illustrated that DEB-TACE + MWA vs. MWA was an independent protective factor for PFS and OS. No serious treatment-related complications were observed in any of the patients.ConclusionCombined treatment with DEB-TACE appeared to have advantages in prolonging OS and PFS compared to MWA. Therefore, combined treatment was efficient and should be strongly recommended to early stage HCC patients.

Radiofrequency ablation (RFA) is a curative treatment for early-stage hepatocellular carcinoma (HCC) ineligible for surgery or liver transplantation. However, trans-arterial chemoembolization (TACE) might be an alternative when RFA is contraindicated due to structural problems. Here, we aimed to compare their long-term outcomes. Treatment-naive HCC patients fulfilling the Milan criteria who underwent RFA (n = 136) or TACE (n = 268) were enrolled. Complete response (CR) and 5-year recurrence-free survival (RFS) rates were higher in the RFA group than in the TACE group (94.1% vs. 71.6% and 35.8% vs. 17.0%, respectively; both p < 0.001), whereas 5-year overall survival (OS) rates were not significantly different (65.5% vs. 72.3%, respectively; p = 0.100). Multivariate analysis showed that RFA was associated with better RFS (adjusted hazard ratio [aHR] 0.628; p = 0.001) than TACE, but not with better OS (aHR 1.325; p = 0.151). The most common 1st-line treatment after recurrence were TACE (n = 53), followed by RFA (n = 21) among the RFA group and TACE (n = 150), followed by RFA (n = 44) among the TACE group. After propensity-score matching, similar results were reproduced. Hence, TACE could be an effective alternative to RFA in terms of OS rates. However, TACE should be confined only to RFA-difficult cases, given its lower CR and RFS rates and multi-disciplinary approaches are desirable in decision-making.

Background The detection rate of Barcelona Clinic Liver Cancer (BCLC) very-early-stage hepatocellular carcinoma (HCC) is increasing because of advances in surveillance and improved imaging technologies for high-risk populations. Surgical resection (SR) and radiofrequency ablation (RFA) are both first‐line treatments for very-early-stage HCC, but the differences in clinical outcomes between patients treated with SR and RFA remain unclear. This study investigated the prognosis of SR and RFA for very-early‐stage HCC patients with long‐term follow‐up. Methods This study was retrospectively collected data on the clinicopathological characteristics, overall survival (OS), and disease-free survival (DFS) of 188 very-early-stage HCC patients (≤ 2 cm single HCC). OS and DFS were analyzed using the Kaplan–Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. Results Of the 188 HCC patients, 103 received SR and 85 received RFA. The median follow‐up time was 56 months. The SR group had significantly higher OS than the RFA group (10-year cumulative OS: 55.2% and 31.3% in the SR and RFA groups, respectively). No statistically significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 45.9% and 32.6% in the SR and RFA groups, respectively). After PSM, the OS in the SR group remained significantly higher than that in the RFA group (10-year cumulative OS: 54.7% and 42.2% in the SR and RFA groups, respectively). No significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 43.0% and 35.4% in the SR and RFA groups, respectively). Furthermore, in the multivariate Cox regression analysis, treatment type (hazard ratio (HR): 0.54, 95% confidence interval (CI): 0.31–0.95; P  = 0.032) and total bilirubin (HR: 1.92; 95% CI: 1.09–3.41; P  = 0.025) were highly associated with OS. In addition, age (HR: 2.14, 95% CI: 1.36–3.36; P  = 0.001) and cirrhosis (HR: 1.79; 95% CI: 1.11–2.89; P  = 0.018) were strongly associated with DFS. Conclusion For patients with very-early-stage HCC, SR was associated with significantly higher OS rates than RFA. However, no significant difference was observed in DFS between the SR and RFA groups.

Purpose This study aims to review the current evidence on the utility of stereotactic body radiation therapy (SBRT), with or without transarterial chemoembolization (TACE), for early-stage hepatocellular carcinoma (ESHCC) patients not amenable to standard curative treatment options. Methods Literature search was conducted using PubMed, ScienceDirect, and Google Scholar. Comparative studies reporting oncologic outcomes were included in the review. Results Five studies (one phase II randomized controlled trial, one prospective cohort, three retrospective studies) compared SBRT versus TACE. Pooled analysis showed an overall survival (OS) benefit after 3 years (OR 1.65, 95% CI 1.17–2.34, p  = 0.005) which persisted in the 5-year data (OR 1.53, 95% CI 1.06–2.22, p  = 0.02) in favor of SBRT. RFS benefit with SBRT was also seen at 3 years (OR 2.06, 95% CI 1.03–4.11, p  = 0.04) which continued after 5 years (OR 2.35, 95% CI 1.47–3.75, p  = 0.0004). Pooled 2-year local control (LC) favored SBRT over TACE (OR 2.96, 95% CI 1.89–4.63, p  < 0.00001). Two retrospective studies compared TACE + SBRT versus TACE alone. Pooled analysis showed significantly improved 3-year OS (OR 5.47; 95% CI 2.47–12.11, p  < 0.0001) and LC (OR: 21.05; 95% CI 5.01–88.39, p  ≤ 0.0001) in favor of the TACE + SBRT group. A phase III study showed significantly improved LC and PFS with SBRT after failed TACE/TAE versus further TACE/TAE. Conclusions Taking into account the limitations of the included studies, our review suggests significantly improved clinical outcomes in all groups having SBRT as a component of treatment versus TACE alone or further TACE. Larger prospective studies are warranted to further define the role of SBRT and TACE for ESHCC.

Early-stage hepatocellular carcinoma (HCC) represents a critical window for curative treatment. However, treatment selection is complicated by significant heterogeneity in tumor biology, liver function, and patient performance status. This review provides a comprehensive overview of current curative-intent strategies for early-stage HCC, including liver transplantation, surgical resection, and local ablative therapies. We emphasize the importance of integrating tumor-specific characteristics-such as microvascular invasion, size, and anatomical location-with liver reserve metrics, including portal hypertension, Child-Pugh classification, and novel indices like albumin-bilirubin and albumin-indocyanine green evaluation grades. Furthermore, we discuss recent advances in non-thermal ablation techniques (eg, high-intensity focused ultrasound and irreversible electroporation), and technical innovations in radiofrequency ablation and cryoablation that are expanding the therapeutic landscape. By combining macro-level functional assessments with micro-level biological indicators, this review advocates for a personalized, evidence-based framework to optimize long-term outcomes in early HCC. The future of HCC management lies in standardizing individualized therapy.

Current options for the treatment of the early-stage HCC conforming to the Milan criteria consist of liver transplantation, hepatic resection (HR), transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) .Whether HR or RFA is the better treatment for early HCC has long been debated. The aim of our paper is to compare the therapeutic effects of radiofrequency ablation (RFA) and hepatic resection (HR) in the treatment of early-stage hepatocellular carcinoma (HCC). Controlled trials evaluating the efficacy between RFA and HR for the treatment of early-stage HCC published before June 2013 were searched electronically using MEDLINE, PubMed, Cochrane Library, and EMBASE databases. Using inclusion and exclusion criteria, two randomized controlled trials and 10 nonrandomized controlled trials were included in the meta- analysis. The results showed that the 3,5-year overall survival rates and 1,3,5 disease-free survival rates were significantly lower after RFA than after HR. However, complications after treatment were less common and the length of hospital stay was significantly shorter after RFA. Additionally, there was no significant difference in the 1-year overall survival rate between RFA and HR. The conclusions of the results show that the difference in the short-term effectiveness of RFA and HR in the treatment of small HCC is not notable, but the long-term efficacy of HR is better than that of RFA. However, HR is associated with more complications and a longer hospital stay.

Background/Aim: The SURF trial showed that surgical resection (SR) and percutaneous ultrasonographic guided radiofrequency ablation (RFA) had equal therapeutic effects for small hepatocellular carcinoma (HCC). However, consensus regarding which treatment is appropriate for initial recurrent early-stage HCC remains lacking. This study aimed to elucidate therapeutic efficacy differences between SR and RFA for initial recurrent early-stage HCC. Materials/Methods: From 2000 to 2021, 371 patients with recurrent early-stage HCC (≤3 cm, ≤3 nodules) after undergoing initial curative treatment with SR or RFA were enrolled (median age 72 years; males 269; Child–Pugh A:B, n = 328:43; SR:RFA, n = 36:335). Recurrence-free survival (RFS) and overall survival (OS) were retrospectively evaluated. Results: Although the median albumin–bilirubin (ALBI) score was better in the SR than the RFA group (−2.90 vs. −2.50, p < 0.01), there were no significant differences between them in regard to RFS (median 28.1 months, 95% CI 23.4–50.0 vs. 22.1 months, 95% CI 19.3–26.2; p = 0.34), OS (78.9 months, 95% CI 49.3—not applicable vs. 71.2 months 95% CI, 61.8–84.7; p = 0.337), or complications (8.3% vs. 9.3%; p = 1.0). In sub-analysis for RFS and OS according to ALBI grade revealed no significant differences between the SR and RFA groups (ALBI 1/2 = 28.2/17.5 vs. 24.0/23.4 months; p = 0.881/0684 and ALBI 1/2 = 78.9/58.9 vs. 115.3/52.6 months, p = 0.651/0.578, respectively). Conclusion: This retrospective study found no significant differences in regard to RFS or OS between patients in the SR and the RFA groups for initial recurrence of early-stage HCC after undergoing curative treatment. These results showing equal therapeutic efficacy of SR and RFA confirm the findings of the SURF trial.