Hepatocellular carcinoma (HCC) is characterized by high incidence, significant mortality, and marked heterogeneity, making accurate molecular subtyping essential for effective treatment. Using multi-omics data from HCC patients, we applied diverse clustering algorithms to identify three HCC subtypes (HSs) with distinct prognostic characteristics. Among these, HS1 emerged as an immune-compromised subtype associated with the poorest prognosis. Additionally, we developed a novel, robust, and highly accurate machine learning-guided prognostic signature (MLPS) by integrating multiple machine learning algorithms and their combinations. Our study also identified SLC2A1, the core gene of MLPS, as being highly expressed during advanced stages of tumor progression. Knockdown experiments demonstrated that reducing SLC2A1 expression significantly suppressed the malignant behavior of HCC cells. Furthermore, SLC2A1 expression was linked to responsiveness to dasatinib and vincristine, suggesting potential therapeutic relevance. MLPS and SLC2A1 offer promising tools for individualized prognosis prediction and targeted therapy in HCC, providing new opportunities to improve patient outcomes.

The treatment strategy for hepatocellular carcinoma (HCC) with Vp4 (main trunk) portal vein tumor thrombosis (PVTT) remains controversial due to the dismal prognosis. We aimed to investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus lenvatinib and tislelizumab in these patients.

This multicenter retrospective study included treatment-naive HCC patients with Vp4 PVTT from 2017 to 2022. They were treated with HAIC plus lenvatinib and tislelizumab (HLP group) or HAIC alone (HAIC group). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) were assessed. Propensity score matching (PSM) was performed to reduce bias.

In this study, 155 HCC patients with Vp4 PVTT were included, with 38 in the HLP group and 117 in the HAIC group, with 35 per group matched by PSM. The HLP group showed longer median OS (23.2 vs. 6.9 months; HR 0.333, p < 0.001) and PFS (6.6 vs. 2.4 months; HR 0.403, p = 0.002) than the HAIC group. Higher ORR for tumor (77.1% vs. 42.9%, p = 0.003) and PVTT (51.4% vs. 22.9%, p = 0.025) was observed in the HLP group. More patients underwent hepatectomy post-conversion therapy (15.8% vs. 0.9%). Grade 3/4 AEs were higher in the HLP group (47.4% vs. 35.0%), but there was no significant difference, and no grade 5 AEs occurred in either group.

HAIC combined with lenvatinib and tislelizumab may be a promising treatment in patients with HCC and Vp4 PVTT because of the improved prognosis and acceptable safety profile.

This study compared the relative efficacy of first-line lenvatinib, a standard-of-care treatment for unresectable hepatocellular carcinoma (uHCC), vs licensed/license in-progress comparators. Using inverse probability of treatment weighting (IPTW) and network meta-analysis (NMA), updated evidence for lenvatinib monotherapy from LEAP-002, in addition to evidence from REFLECT, was included in the analyses.

Randomized controlled trials (RCTs) were identified via systematic review. REFLECT and LEAP-002 investigated lenvatinib in uHCC, with patient-level data available for each; however, only REFLECT included a comparator arm of interest (sorafenib). The lenvatinib arm from LEAP-002 was adjusted to match aggregate data for confounding factors from REFLECT using IPTW. Weighted Cox regressions, including matching variables as covariates, were used to derive hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). These HR estimates were included in Bayesian NMAs to compare lenvatinib with comparators; survival was significantly improved if the 95% credible interval for the HR did not include 1.0. Scenario analyses explored alternative choices for IPTW estimators.

Eight RCTs (including REFLECT) and the single-arm adjusted lenvatinib data from LEAP-002 were included in the NMA base case. Lenvatinib demonstrated significant improvement in OS compared with sorafenib 400 mg twice daily (BID) and significant improvement in PFS compared with sorafenib 400 mg BID, tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks (Q4W), and durvalumab 1500 mg Q4W.

These results suggest that patients with uHCC treated with lenvatinib have similar or significantly improved OS and PFS compared with licensed/license in-progress therapies.

Colorectal cancer (CRC) is a substantial global health burden, with treatment outcomes significantly influenced by the interaction between the immune system and the tumor microenvironment.

This study aims to investigate the role of peripheral blood immune cell subpopulations, particularly CD8+ CD28+ T cells, in predicting treatment response in metastatic CRC patients receiving bevacizumab combined with chemotherapy.

A cohort of 45 CRC patients was analyzed. Flow cytometry was utilized to assess immune cell subpopulations.

Higher CD8+ CD28+ T cell counts were associated with better treatment responses, including improved objective response rates. In a murine CRC model, the combination therapy significantly inhibited tumor growth and enhanced immune cell function.

These findings highlight the importance of CD8+ CD28+ T cells as potential biomarkers for predicting treatment outcomes in CRC. They also suggest that bevacizumab, when combined with chemotherapy, can modulate immune function and improve clinical efficacy.

Camrelizumab and rivoceranib together provide a new first-line treatment approach for unresectable hepatocellular carcinoma (HCC). Meanwhile, transarterial chemoembolization (TACE) is an effective method for the local control of the HCC. The study compared the clinical benefit and safety between TACE with camrelizumab-rivoceranib and camrelizumab-rivoceranib alone for Barcelona Clinic Liver Cancer (BCLC)-C HCC patients.

This multi-center retrospective analysis included continuous BCLC-C HCC patients who received camrelizumab-rivoceranib with TACE and camrelizumab-rivoceranib alone from January 2020 to December 2022. The therapeutic response, progression-free survival (PFS), safety, and overall survival (OS) were compared. The quantitative data were compared via the t-test or Mann-Whitney U-test. Comparison of the categorical data was done by chi-square or Fisher's exact tests. The comparison of PFS with OS was compared by Log rank test. A Multivariate Cox regression test was utilized to identify risk variables for both PFS and OS.

 This analysis comprised 132 BCLC-C HCC patients who received camrelizumab-rivoceranib alone (n = 74) or combined treatment (n = 58). The combined group displayed higher partial response (44.8% vs 21.6%, p = 0.004) and total response (55.2% versus 36.5%, p = 0.032) rates than camrelizumab-rivoceranib alone group. The median PFS (13.5 months vs 10.3 months, p = 0.046) and OS (22.8 months vs 18.4 months, p = 0.041) for the combined group was significantly longer relative to the camrelizumab-rivoceranib alone group. Additional risk factors, excluding the therapy option, were a higher alpha-fetoprotein level and Eastern Cooperative Oncology Group performance status. The incident rates of camrelizumab-rivoceranib-related advents were comparable between combined and camrelizumab-rivoceranib alone groups (46.3% vs 51.4%, p = 0.572). The combined group contained 33 patients (56.9%) who experienced temporary post-embolization symptoms.

For BCLC-C HCC patients, TACE may significantly increase the therapeutic effectiveness of camrelizumab-rivoceranib without increasing the risk of camrelizumab-rivoceranib-related complications.

Disulfidptosis is a newly discovered type of cell death. We aim to identify hub genes associated with both disulfidptosis and immune infiltration in hepatocellular carcinoma (HCC) patients, and to develop an individualized risk prediction model.

The TCGA-LIHC cohort was utilized as the training set to identify molecular subtypes associated with disulfidptosis and to perform immune infiltration analysis. WGCNA, univariate Cox, and LASSO algorithm were employed to select hub genes for constructing the prognostic model. ICGC-LIRI cohort was utilized as an independent testing set. Validation of the expression of hub genes was performed in vitro using qRT-PCR and Western blot.

Cluster 1 was identified as the disulfidptosis associated molecular subtype, characterized by higher expression of disulfidptosis related genes (DRGs) and immune infiltration levels. ANXA2, MSC, and ST6GALNAC4 were identified as hub genes for calculating the risk score. The high-risk group were more likely to benefit from immunotherapy, targeted therapy and chemotherapy. A prognostic model was developed combining clinicopathological factors with satisfactory predictive accuracy. The hub genes were found upregulated in HCC cell line.

Our findings provide valuable theoretical support for prognostic prediction and the evaluation of therapeutic outcomes in relation to disulfidptosis and immune infiltration in HCC, highlighting the importance of conducting in-depth research on disulfidptosis-related mechanisms.

The prognosis of cancers is strongly connected with nitrogen metabolism (NM), which plays a critical role in the microenvironment and growth of tumors. It is unsubstantiated, however, how important NM-related genes are for the prognosis of hepatocellular carcinoma (HCC).

Using publicly available data, we examined potential mechanisms of NM-related genes in HCC, created a predictive model, and assessed immune infiltration and medication sensitivity.

A prognostic model, which included 12 NM genes (COLQ, GNE, ISCU, MSRA, SARS2, SPHK1, CBS, GOT2, CHST1, EXTL2, GCLM, YARS1), was constructed based on regression analysis. The robustness of the model was validated using multiple methods. The high-risk (HR) and low-risk (LR) groups had varying degrees of immune infiltration, according to an immunology-related study. Of these, B cells and Type_II_IFN_Response were greatly infiltrated in the LR group, whereas aCDs, Macrophages, and Treg were heavily infiltrated in the HR group (p < 0.05). Because of higher immunophenoscore, the low-risk group could benefit from immunotherapy more. Drug sensitivity predictions indicated that people with high CBS expression and low GOT2 and ISCU expression may benefit more from treatment with SCH-772984, Pimasertib, Cobimetinib (isomer1), TAK-733, LY-3214996, ARRY-162, Cladribine, Fludarabine, and Hydroxyurea.

This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening.

Regorafenib is the recommended second-line therapy for unresectable hepatocellular carcinoma (uHCC). Our study aimed to assess the effect of transition timing to second-line therapy with regorafenib on treatment outcomes in uHCC patients.

In this retrospective study, patients were categorized into prompt transition group (PT group) or delayed transition group (DT group) based on the transition timing to second-line therapy with regorafenib following the first or subsequent occurrence of progressive disease during first-line treatment. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

There were 85 and 122 patients in the PT and DT groups, respectively. The PT group demonstrated significantly better median PFS [4.5 months (95% CI 3.8-6.0) vs. 3.4 months (95% CI 2.8-4.1); HR 0.641; 95% CI 0.478-0.859; p = 0.003], ORR (24.7% vs. 9.8%, p = 0.007), DCR (69.4% vs. 54.9%, p = 0.049), and median OS [17.5 months (95% CI 13.4-not reached) vs. 10.4 months (95% CI 7.9-15.6); HR 0.613; 92% CI 0.432-0.871, p = 0.006] compared to the DT group. Moreover, the overall safety profiles were comparable between groups.

The prompt transition to second-line therapy with regorafenib following first-line treatment progression suggests better treatment outcomes and potentially longer survival than in patients who delay the transition to second-line therapy.

Liver cancer has a high recurrence rate of 50%~70% for early-stage patients. Minimal residual disease (MRD) is strongly linked to liver cancer early recurrence. Identifying MRD through reliable prognostic biomarkers, such as circulating tumor DNA (ctDNA), could significantly benefit these patients by enabling timely intervention and improved outcomes.

A prospective study enrolled 32 liver cancer patients undergoing radical surgery. Peripheral blood samples (8 mL) were collected before and after surgery. In this study, we expanded upon our previously developed multi-omics assay, initially designed for liver cancer early detection by calculating a cancer signal score (PHCC), to determine the MRD status (named SeekInCure). This process integrated protein tumor marker alpha-fetoprotein (AFP) and cancer genomic hallmarks, copy number aberration (CNA) and fragment size (FS).

Of the enrolled patients, 78.1% were in early stages, and before surgery, 87.5% of patients had successfully detected the cancer signal in blood. After radical surgery, 23 patients were MRD-negative, exhibiting better overall survival compared to the MRD-positive patients (n = 9, p < 0.01). Patients maintaining undetectable cancer signals pre- and post-surgery showed 100% survival, conversely, those keeping with detectable signals had a 55.6% mortality rate.

This prospective study highlights the prognostic value of ctDNA-based tumor-naïve MRD detection through a multi-omics assay in early-stage liver cancer patients.

Fibrolamellar hepatocellular carcinoma (FL-HCC) clinically occurs in young people aged 20-30 years, who often have a normal liver background. We propose a treatment for such cases in which a combination therapy of atezolizumab and bevacizumab is followed by sandwiching radiation therapy to release tumor antigens and then re-administering the combination therapy of atezolizumab and bevacizumab (ABC conversion therapy).

The patient is a 15-year-old girl. On April 18, 2022, she noticed skin yellowing and visited her local doctor. Computed tomography (CT) revealed a large mass in the right lobe of the liver and bile duct obstruction due to the tumor. She also had a nodule on her chest that appeared to be a metastatic tumor and was referred to Kinki University Hospital in April 2023. She was suspected to have FL-HCC based on contrast-enhanced ultrasound and CT scan results. There were findings suggestive of lung metastasis; however, she underwent a right hepatic lobectomy on May 17, 2023, considering the risk of liver failure and intra-abdominal bleeding due to the large liver tumor. A CT scan conducted on July 25, 2022, showing increased lung metastases, and she started atezolizumab/bevacizumab combination treatment on October 20, 2022. On March 15, 2023, multiple lung metastases and new intrahepatic lesions appeared, which was diagnosed as progressive disease (PD), and lenvatinib was discontinued. On November 17, 2023, radiation therapy (25 Gy/5 Fr) was administered to the lung and intrahepatic lesions to release tumor antigens, and on November 27, 2023, atezolizumab and bevacizumab combination treatment was resumed to control the tumor.

Combination therapy with atezolizumab, bevacizumab, and radiation therapy may be an option for the treatment of FL-HCC.

In the present day, hepatocellular carcinoma (HCC) remains a formidable threat to human health. Actin-related protein 10 (ACTR10) is related to tyrosine kinase inhibitor (TKI) resistance. A comprehensive analysis of ACTR10 in HCC will further our understanding of the molecular mechanisms underlying this resistance phenomenon, shedding light on potential therapeutic strategies for combating TKI resistance in HCC.

We conducted an integration of high-throughput datasets across various centers, analyzing ACTR10 expression using the Cancer Cell Line Encyclopedia (CCLE) and assessing its implications through clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen. Pathogenic mechanisms were elucidated through enrichment analysis. Prognostic assessment utilized Kaplan-Meier survival and univariate Cox analyses. An integrated analysis of gene expression profiles related to TKI in HCC was conducted, and TKI resistance mechanisms were explored through enrichment analysis. Potential therapeutic drugs were identified using the Drug Gene Budger database and molecular docking techniques.

The standardized mean difference (SMD) of 0.34 (95% confidence interval (CI): 0.22 - 0.45, P < 0.05) and ACTR10-dependent growth in HCC cells confirm its upregulation in HCC. The area under the summary receiver operating characteristic (sROC) curve was 0.69, indicating moderate discriminative ability of ACTR10 in HCC patients. ACTR10 exerts its pro-cancer effect by influencing RNA splicing, mRNA processing and nucleocytoplasmic transport. A hazard ratio of 2.19 (95% CI: 1.56 - 3.08, P < 0.05) identifies ACTR10 as an independent prognostic risk factor. Additionally, the SMD of 0.88 (95% CI: 0.01 - 0.76, P < 0.05) validates ACTR10 as a TKI-resistance gene, mediating resistance via enhanced exocytosis, autophagy, and apoptosis in HCC patients. Trichostatin A emerges as a prospective targeted agent for HCC.

The upregulation of ACTR10 accelerates HCC progression, promotes TKI resistance, and emerges as a prospective target for the treatment of HCC.

Recently, anti-programmed cell death protein-1 (anti-PD-1) and anti-PD-L1 therapies were approved for hepatocellular carcinoma (HCC). However, the effectiveness of rechallenging with one immune checkpoint inhibitor (ICI) after failure of another remains unclear. This study explores the efficacy and safety of anti-PD-L1 rechallenge in patients who failed anti-PD-1 therapy.

From January 2016 to December 2023, 65 advanced HCC patients previously treated with anti-PD-1 therapy were retrospectively enrolled and rechallenged with durvalumab (480 mg IV every 2 weeks).

Overall, 86.2% of patients received nivolumab and 13.8% pembrolizumab as prior anti-PD-1 therapy. The overall response rate (ORR) to durvalumab was 13.8%. Patients who responded to prior anti-PD-1 had a higher ORR compared to non-responders (31.3% vs. 8.7%, p = 0.04). Patients with any grade of immune-related adverse events (irAEs) from durvalumab had a higher ORR than those without irAEs (35.3% vs. 6.7%, p = 0.01). The median PFS was 5.4 months, and the median OS was 9.6 months. Responders to prior anti-PD-1 showed longer OS (33.9 vs. 8.2 months, p < 0.01) and a trend toward longer PFS (13.8 vs. 4.9 months, p = 0.07) compared to non-responders. Multivariate analysis identified prior anti-PD-1 response (HR: 0.31) as the only protective factor for death. Common irAEs were skin toxicity (13.8%) and hepatitis (7.7%); no correlation was found between irAEs from prior anti-PD-1 and durvalumab treatment.

This study provides the first, concrete evidence that durvalumab rechallenge is effective for HCC patients who are refractory to anti-PD-1 therapy, especially for those who previously responded to anti-PD-1 treatment.

Both Ku80 and Ku70 are promising drug targets for hepatocellular carcinoma (HCC) and crucial for immune regulation. However, their correlation with HCC immune signatures has not yet been investigated. Therefore, we aimed to investigate the relationship between Ku80, Ku70, and immune signatures in HCC and validate their significance in cytotoxic lymphocyte (CTL) immunotherapy.

Analyses of Ku70, Ku80, and immune signatures in public datasets was performed using R software, an online Kaplan-Meier plotter, g:Profiler, GeneTrail, and Metascape. Uniform manifold approximation and projection, correlation chord diagrams, Pearson's correlation tests, and Spearman correlation tests were used to describe various correlation levels. HCC mRNA sequencing data (n=373 tumor samples and n=50 para-tumor samples) were drawn from The Cancer Genome Atlas (TCGA) public database. Immunofluorescent staining was used to validate Ku70/Ku80 and CD8+CTL expression in 120 HCC patients from our center. Survival analysis was performed using the Kaplan-Meier survival analysis with the Log rank test and was adopted to analyze immunotherapy outcomes correlated with Ku70/Ku80 expression in various solid tumors. Multivariate analysis of HCC patient data from our center was performed using a Cox proportional hazards model.

Increased Ku70/Ku80 expression positively correlated with more enriched immune microenvironment signatures, indicating increased immune infiltration in HCC. Upregulation of Ku70/Ku80 indicated better anti-PD1 and anti-PDL1 treatment outcomes in various solid tumors. Higher Ku70/Ku80 expression with lower CD8+CTL signatures indicated worse survival outcomes, whereas lower Ku70/Ku80 expression with higher CD8+CTL signatures indicated the best prognosis.

Higher Ku70/Ku80 expression indicated an immune-hot infiltration signature in HCC. Patients with increased Ku70/Ku80 expression and high CD8+CTL signatures may potentially benefit from CTL-centered immunotherapies.

In this editorial, we comment on the article (World J Gastrointest Oncol 2024; 16: 1236-1247), which is a retrospective study of transarterial chemoembolization (TACE) combined with multi-targeted tyrosine kinase inhibitor (TKI) and programmed cell death protein-1 (PD-1) inhibitor for the treatment of unresectable hepatocellular carcinoma (HCC). Herein, we focus specifically on the mechanisms of this triple therapy, administration sequence and selection of each medication, and implications for future clinical trials. Based on the interaction mechanisms between medications, the triple therapy of TACE + TKI + PD-1 is proposed to complement the deficiency of each monotherapy, and achieve synergistic antitumor effects. Although this triple therapy has been evaluated by several retrospective trials, it is still controversial whether the triple therapy achieves better clinical benefits, due to the flawed study design and heterogeneity in medications. In addition, the administration sequence, which may greatly affect the clinical benefit, needs to be fully considered at clinical decision-making for obtaining better prognosis. We hope that this editorial could contribute to the design and optimization of future trials.

Hepatocellular carcinoma (HCC), a prevalent and aggressive form of cancer, poses significant challenges due to its limited therapeutic options. This study aims to leverage multi-omics data from liver cancer to identify potential therapeutic targets for HCC.

We employed an integrative approach by analyzing various omics datasets related to liver cancer. Through comprehensive data mining and analysis, we identified key genes that are significantly associated with HCC. To gain insights into their biological roles and underlying mechanisms, we constructed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway networks. Specifically, we focused on genes that exhibited high expression levels in HCC and were correlated with poor patient prognosis. Among these, CDK1 and DLGAP5 emerged as promising candidates and were further investigated for their potential involvement in tumor immune cell infiltration and HCC progression.

Our analysis revealed that CDK1 and DLGAP5 are highly expressed in HCC tissues compared to normal liver tissues, and their elevated expression is associated with unfavorable clinical outcomes. Furthermore, through GO and KEGG pathway analyses, we found that these genes are implicated in critical biological processes and signaling pathways relevant to HCC pathogenesis. Notably, CDK1 and DLGAP5 were shown to be associated with tumor immune cell infiltration, suggesting their potential role in modulating the tumor microenvironment and promoting HCC progression.

These findings provide valuable insights into the development of novel therapeutic approaches for HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in India. This review explores the epidemiological trends and the landscape of systemic therapy for HCC in the Indian context, acknowledging the recent shift in etiology from viral hepatitis to lifestyle-associated factors. A comprehensive review of the literature was conducted, including data from the Global Cancer Observatory and the Indian Council of Medical Research, along with a critical analysis of various clinical trials. The article investigates systemic therapies in-depth, discussing their mechanisms, efficacy, and adaptation to Indian healthcare framework. Progression-free survival with a hazard ratio of ≤0.6 compared to sorafenib, overall survival of ∼16-19 months, and objective response rate of 20-30% are the defining thresholds for systemic therapy clinical trials. Systemic therapy for advanced HCC in India primarily involves the use of tyrosine kinase inhibitors such as sorafenib, lenvatinib, regorafenib, and cabozantinib, with sorafenib being the most commonly used drug for a long time. Monoclonal antibodies such as ramucirumab and bevacizumab and immune-checkpoint inhibitors, such as atezolizumab, nivolumab, and pembrolizumab, are expanding treatment horizons. Lenvatinib has emerged as a cost-effective alternative, and the combination of atezolizumab and bevacizumab has demonstrated superior outcomes in terms of overall survival and progression-free survival. Despite these advances, late-stage diagnosis and limited healthcare accessibility pose significant challenges, often relegating patients to palliative care. Addressing HCC in India demands an integrative approach that not only encompasses advancements in systemic therapy but also targets early detection and comprehensive care models. Future strategies should focus on enhancing awareness, screening for high-risk populations, and overcoming infrastructural disparities. Ensuring the judicious use of systemic therapies within the constraints of the Indian healthcare economy is crucial. Ultimately, a nuanced understanding of systemic therapeutic options and their optimal utilization will be pivotal in elevating the standard of HCC care in India.

The prognosis of hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM) is extremely poor. This study aimed to identify prognostic factors for systemic chemotherapy of HCC with EHM. Eighty-five patients who received systemic chemotherapy for HCC with EHM between May 2014 and October 2021 were retrospectively evaluated. Patient demographic data and characteristics of hepatic tumors and EHM were assessed to identify factors that were significantly associated with prognosis. Of the 85 patients, 68 (80.0%) had pulmonary metastasis, 11 (12.9%) had abdominal lymph node metastasis, 7 (8.2%) had abdominal metastasis, and 4 (4.7%) had bone metastasis. The median overall survival (OS) was 17.0 months, and the median progression-free survival (PFS) was 5.1 months. Univariate analysis of OS showed that synchronous EHM-HCC, serum albumin level<35 g/l and number of hepatic tumors>1 were significantly associated with poorer OS. The results of the multivariate analysis indicated that the serum albumin level and number of hepatic tumors were independent prognostic factors. Subgroup analysis of patients with 0, 1, or 2 of these independent prognostic factors showed that the median OS was 24.0 months, 16.2 months and 7.7 months and that the ORR was 38.3%, 22.6% and 0, respectively. Systemic chemotherapy is beneficial for well-selected HCC patients with EHM. The number of hepatic tumors and serum albumin level were independent risk factors for prognosis, and the number of risk factors significantly influenced OS. Therefore, these factors need to be considered before administering systemic chemotherapy for HCC patients with EHM.

The prognosis of patients with advanced HCC can vary widely depending on factors such as the stage of the cancer, the patient's overall health, and treatment regimens. This study aimed to investigate survival outcomes and associated factors in patients with hepatocellular carcinoma (HCC). In this retrospective study, data from 23 medical oncology clinics were analyzed. Progression-free survival (PFS) and overall survival (OS) values were estimated using the Kaplan-Meier method. Prognostic factors associated with survival which were identified in univariate analysis were subsequently evaluated in a multivariate Cox-regression survival analysis was conducted using the backward stepwise (Conditional LR) method to determine the independent predictors of PFS and OS. Of 280 patients, 131 received chemotherapy and 142 received sorafenib, 6 received atezolizumab plus bevacizumab and 1 received nivolumab for first-line setting. The median follow-up time was 30.4 (95%CI 27.1-33.6) months. For-first line, median PFS was 3.1 (95%CI2.7-3.5) months, and it was significantly longer in patients who received sorafenib or atezolizumab-bevacizumab or nivolumab (PFS 5.8 (95%CI 4.2-7.5) than in those received chemotherapy (PFS 2.1 (95%CI 1.9-2.3) in the first-line setting (p < 0.001). Multivariate analysis revealed that male gender (HR: 2.75, 95% CI: 1.53-4.94, p = 0.01), poor ECOG performance score (HR: 1.88, 95% CI: 1.10-3.21, p = 0.02), higher baseline AFP level (HR: 2.38, 95% CI: 1.54-3.67, p < 0.001) and upfront sorafenib treatment (HR,0.38; 95% CI: 0.23-0.62, p < 0.001) were significantly associated with shorter PFS. The median OS was 13.2 (95%CI 11.1-15.2) months. It was significantly longer in patients who received sorafenib or atezolizumab-bevacizumab or nivolumab in the first-line setting followed by TKIs (sorafenib or regorafenib, OS 18.6 (95%CI 13.8-23.5)) compared to those who received chemotherapy (OS 10.3 (95%CI 6.6-14.1)) in the first-line setting. The multivariate analysis revealed that upfront chemotherapy treatment approach, male gender (HR: 1.77, 95% CI: 1.07-2.94, p = 0.02), poor ECOG performance score (HR: 1.96, 95% CI: 1.24-3.09, p = 0.004) and Child-Pugh score, presence of extrahepatic disease (HR: 1.54, 95% CI: 1.09-2.18, p = 0.01), and higher baseline AFP value (HR: 1.50, 95% CI: 1.03-2.19, p = 0.03) were significantly associated with poor prognosis. Additionally, regarding of treatment sequence, upfront sorafenib followed by regorafenib showed a significantly lower risk of mortality (HR: 0.40, 95% CI: 0.25-0.66, p < 0.001). Sorafenib followed by regorafenib treatment was associated with a significantly lower risk of mortality rather than upfront sorafenib followed by BSC group or upfront chemotherapy followed by TKIs. These findings underscore the importance of the optimal treatment sequences to improve survival in patients with advanced HCC.

The effectiveness of radiofrequency ablation (RFA) in improving long-term survival outcomes for patients with a solitary hepatocellular carcinoma (HCC) measuring 5 cm or less remains uncertain. This study was designed to elucidate the impact of RFA therapy on the survival outcomes of these patients and to construct a prognostic model for patients following RFA.

This study was performed using the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2017, focusing on patients diagnosed with a solitary HCC lesion ≤5 cm in size. We compared the overall survival (OS) and cancer-specific survival (CSS) rates of these patients with those of patients who received hepatectomy, radiotherapy, or chemotherapy or who were part of a blank control group. To enhance the reliability of our findings, we employed stabilized inverse probability treatment weighting (sIPTW) and stratified analyses. Additionally, we conducted a Cox regression analysis to identify prognostic factors. XGBoost models were developed to predict 1-, 3-, and 5-year CSS. The XGBoost models were evaluated via receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) curves and so on.

Regardless of whether the data were unadjusted or adjusted for the use of sIPTWs, the 5-year OS (46.7%) and CSS (58.9%) rates were greater in the RFA group than in the radiotherapy (27.1%/35.8%), chemotherapy (32.9%/43.7%), and blank control (18.6%/30.7%) groups, but these rates were lower than those in the hepatectomy group (69.4%/78.9%). Stratified analysis based on age and cirrhosis status revealed that RFA and hepatectomy yielded similar OS and CSS outcomes for patients with cirrhosis aged over 65 years. Age, race, marital status, grade, cirrhosis status, tumor size, and AFP level were selected to construct the XGBoost models based on the training cohort. The areas under the curve (AUCs) for 1, 3, and 5 years in the validation cohort were 0.88, 0.81, and 0.79, respectively. Calibration plots further demonstrated the consistency between the predicted and actual values in both the training and validation cohorts.

RFA can improve the survival of patients diagnosed with a solitary HCC lesion ≤5 cm. In certain clinical scenarios, RFA achieves survival outcomes comparable to those of hepatectomy. The XGBoost models developed in this study performed admirably in predicting the CSS of patients with solitary HCC tumors smaller than 5 cm following RFA.

Currently, the effectiveness of TACE, Lenvatinib, and PD-1/L1 inhibitors used alone or in combination has been thoroughly reported. However, the differences in effectiveness between these treatment protocols require further verification. To this end, this study employs a Bayesian network meta-analysis to compare the efficacy and safety of TACE, Lenvatinib, and PD-1/L1 inhibitors, whether administered by monotherapy or in combination, providing evidence-based medicine for the treatment of unresectable HCC.

This study employed a network meta-analysis to evaluate the efficacy and safety of trans-arterial chemoembolization (TACE), Programmed Cell Death Protein/Ligand 1 (PD-1/L1) inhibitors, and Lenvatinib in the treatment of advanced HCC.

Literature on the treatment of advanced HCC with TACE, PD-1/L1 inhibitors, and Lenvatinib was searched for in both Chinese and English databases, including PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library, CNKI, and Wanfang. Two researchers conducted independent screening and data extraction, and the meta-analysis was performed using R language with the gemtc package.

After retrieval and screening, a total of 21 articles were included, involving 2052 participants and six treatment modalities: Lenvatinib (L), TACE (T), TACE + Lenvatinib (TL), Lenvatinib + PD-1/L1 inhibitors (LP), TACE + Lenvatinib + PD-1/L1 inhibitors (TLP), and TACE + PD-1/L1 inhibitors (TP). In terms of objective response rate (ORR), the TLP regimen provided the optimal effect. In predicting the best ORR, TLP had the highest (75.5%) probability. In terms of disease control rate (DCR), the TLP regimen showed the best effect. In predicting the best DCR, the TLP again offered the highest (76.1%) probability. In terms of overall survival (OS), the best outcome was observed in the TLP protocol. In predicting the best OS, the TLP holds the highest (86.00%) probability. Furthermore, the best outcome in progression-free survival (PFS) was found in the TLP regimen. In predicting the best PFS, the TLP still holds the highest (97.0%) result.

The combination of TACE, Lenvatinib, and PD-1/L1 inhibitors appears to provide the maximum benefit for inoperable HCC patients.

There is limited information on combination of hepatic arterial infusion chemotherapy (HAIC) and systemic therapy for advanced hepatocellular carcinoma (Ad-HCC). We aim to compare the efficacy and safety of HAIC plus camrelizumab (a PD-1 inhibitor) and apatinib (an VEGFR-2 inhibitor) versus camrelizumab and apatinib for Ad-HCC.

From April 2019 to October 2022, 416 patients with Ad-HCC who received either HAIC plus camrelizumab and apatinib (TRIPLET protocol, n = 207) or camrelizumab and apatinib (C-A protocol, n = 209) were reviewed retrospectively. The propensity score matching (PSM) was used to reduce selective bias. Overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan-Meier method with the log-rank test. Cox regression analyses of independent prognostic factors were evaluated.

After PSM 1:1, 109 patients were assigned to two groups. The median OS of not reached in the TRIPLET group was significantly longer than that of 19.9 months in the C-A group (p < 0.001), while in the TRIPLET group, the median PFS of 11.5 months was significantly longer than that of 9.6 months in the C-A group (p < 0.001). Multivariate analyses showed that the factors significantly affected the OS were CTP grade, tumor number > 3, and TRIPLET treatment (p < 0.001). Grade 3/4 adverse events occurred at a rate of 82.1% vs. 71.3% in TRIPLET and C-A groups, respectively.

The TRIPLET protocol has promising survival benefits in the management of patients with Ad-HCC, with acceptable safety.

The study has been retrospectively registered at Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ , ChiCTR2300075828).

Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume. However, in patients with huge HCC, high lung absorbed dose often prevents them from receiving SIRT.

A 35-year-old man was admitted because of emaciation and pain in the hepatic region for about 1 month. The computed tomography scan showed a 20.2 cm × 19.8 cm tumor located in the right lobe-left medial lobes with right portal vein and right hepatic vein invasion. After the pathological type of HCC was confirmed by biopsy, two conversions were presented. The first one was drug-eluting bead transarterial chemoembolization plus hepatic arterial infusion chemotherapy and lenvatinib and sintilimab, converted to SIRT, and the second one was sequential SIRT with continued systemic treatment. The tumor size significantly decreased from 20.2 cm × 19.8 cm to 16.2 cm × 13.8 cm, then sequentially to 7.8 cm × 6.8 cm. In the meantime, the ratio of spared volume to total liver volume increased gradually from 34.4% to 55.7%, then to 62.9%. Furthermore, there was visualization of the portal vein, indicating regression of the tumor thrombus. Finally, owing to the new tumor in the left lateral lobe, the patient underwent LT instead of resection without major complications.

Patients with inoperable huge HCC with PVTT could be converted to SIRT first and accept surgery sequentially.

With continuous advancements in interventional radiology, considerable progress has been made in transarterial therapies for hepatocellular carcinoma (HCC) in recent years, and an increasing number of research papers on transarterial therapies for HCC have been published. In this editorial, we comment on the article by Ma et al published in the recent issue of the World Journal of Gastro intestinal Oncology: "Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC". We focus specifically on the current research status and future directions of transarterial therapies. In the future, more studies are needed to determine the optimal transarterial local treatment for HCC. With the emergence of checkpoint immunotherapy modalities, it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.

Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer cases and is the third leading cause of cancer death. Regorafenib is a multi-target inhibitor that dramatically prolongs progression-free survival in HCC patients who have failed sorafenib therapy. However, one of the primary factors limiting regorafenib's clinical utilization is toxicity. Using Clinical Trials.gov and PubMed, we gathered clinical data on regorafenib and conducted a extensive analysis of the medication's adverse reactions and mechanisms. Next, we suggested suitable management techniques to improve regorafenib's effectiveness.

We have reviewed the mechanisms by which regorafenib-induced toxicity occurs and general management strategies through clinical trials of regorafenib. Furthermore, by examining the literature on regorafenib and other tyrosine kinase inhibition, we summarized the mechanics of the onset of regorafenib toxicity and mechanism-based intervention strategies by reviewing the literature related to regorafenib and other tyrosine kinase inhibition.

One of the primary factors restricting regorafenib's clinical utilization and combination therapy is its toxicity reactions. To optimize regorafenib treatment regimens, it is especially important to further understand the specific toxicity mechanisms of regorafenib as a multi-kinase inhibitor.

The combination of targeted therapy and immunotherapy has improved the clinical outcomes of unresectable hepatocellular Carcinoma (HCC). However, the overall prognosis remains suboptimal. This study aims to evaluate the efficacy and safety of a novel combination of radiofrequency ablation (RFA) with lenvatinib plus sintilimab in unresectable HCC.

In this retrospective study, patients diagnosed with unresectable HCC were included and divided into two cohorts: RFA combined with lenvatinib plus sintilimab (R-L-S group) and lenvatinib plus sintilimab (L-S group). The primary efficacy endpoints were objective response rate (ORR) and progression free survival (PFS). Adverse events were analyzed to assess the safety profiles.

The median follow-up periods for the entire cohort were 14.0 months. The R-L-S group (n = 60) had a significantly higher ORR than those with L-S alone (n = 62) (40.0% vs. 20.9%; p = 0.022). Moreover, patients in the R-L-S group had improved median PFS (12 vs. 8 months; p = 0.013) and median overall survival (24 vs. 18 months; p = 0.037), as compared with lenvatinib and sintilimab alone. No significant difference in treatment related adverse event (TRAE) of any grade between the two groups. The most common TRAEs of grade ≥ 3 were fatigue 10.0% (6/60) and hand-foot skin reaction 10.0% (6/60) in the R-L-S group and hand-foot skin reaction 11.3% (7/62) in the L-S group.

In unresectable HCC patients, the incorporation of RFA to lenvatinib plus sintilimab demonstrated improved efficacy without compromising safety compared with lenvatinib plus sintilimab alone.

Cortisol, a crucial steroid hormone synthesized by the adrenal glands, has diverse impacts on multiple physiological processes, such as metabolism, immune function, and stress management. Disruption in cortisol levels can result in conditions like Cushing's syndrome and Addison's disease. This review provides an in-depth exploration of cortisol, covering its structure, various forms in the body, detection methodologies, and emerging trends in cancer treatment and detection. Various techniques for cortisol detection, including electrochemical, chromatographic, and immunoassay methods were discussed and highlighted for their merits and applications. Electrochemical immunosensing emerges as a promising approach, which offered high sensitivity and low detection limits. Moreover, the review delves into the intricate relationship between cortisol and cancer, emphasizing cortisol's role in cancer progression and treatment outcomes. Lastly, the utilization of biomarkers, in-silico modeling, and machine learning for electrochemical cortisol detection were explored, which showcased innovative strategies for stress monitoring and healthcare advancement.

This study investigated the dynamic changes in circulating immune cells following immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), and interventional therapy in hepatocellular carcinoma (HCC).

HCC patients undergoing transarterial chemoembolization (TACE), TKI, and ICI treatment were included in the treatment group. Peripheral blood samples were collected from these patients before each cycle of PD-1 blockade treatment. Flow cytometry analysis was conducted to assess the composition of peripheral immune cells and identify PD-1-expressing T cells.

The treatment group showed a median time-to-tumor progression (TTP) of 8 months and an overall survival (OS) of 19 months. In comparison, the control group had 6 months and 15 months respectively. These differences were statistically significant (P = 0.029 for TTP and P = 0.020 for OS). In HCC patients receiving Lenvatinib, more circulating natural killer (NK) cells were noted. After 1-2 cycles of PD-1 antibody treatment, a general decline in the proportion of circulating PD-1+T cells was found, indicating individual variations in response.

Circulating immune cells have the potential to serve as indicators of the response to immunotherapy, providing a means to monitor dynamic changes and optimize treatment for HCC.

The present study compared the efficacy and safety of regorafenib plus programmed death-1 inhibitors (R-P) with regorafenib monotherapy as second-line therapies for advanced hepatocellular carcinoma (HCC). A systematic search of relevant literature published in PubMed, Embase, Web of Science and Cochrane Library databases until October 2023 was conducted. Two authors independently performed data extraction and screening using standardized protocols. Stata/MP 17.0 was used for the meta-analysis to evaluate the impact of R-P treatment on major outcome indicators, including overall survival, progression-free survival (PFS), tumor response and adverse reactions, in patients with advanced HCC. The results indicated that five cohort studies involving 444 patients with advanced HCC were included. The results revealed that R-P treatment improved overall survival [hazard ratio (HR), 0.61; 95% confidence interval (CI) 0.48-0.77; I2=0.0%; P=0.663] and PFS (HR, 0.51; 95% CI 0.41-0.63; I2=17.5%; P=0.303). Additionally, it increased the objective response rate (risk ratio, 2.33; 95% CI, 1.49-3.64; I2=0.0%; P=0.994) and disease control rate (HR, 1.40; 95% CI, 1.20-1.63; I2=0.0%; P=0.892) compared with those of regorafenib. However, R-P treatment was associated with an increased incidence of adverse events, such as hypothyroidism, thrombocytopenia and rash, compared with that in regorafenib. In conclusion, R-P is superior to regorafenib monotherapy in terms of survival benefits and tumor response.

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.

The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects.

This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them.

After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference.

With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65-1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82-1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54-0.77).

A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate.

Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene transcription and translation to influence the progression of HCC. However, the regulatory relationship that exists between E3 ligases, which is a class of post-translational modifying proteins, and circRNA remains unclear.

Based on the E3 ubiquitin ligase in the competitive endogenous RNA (ceRNA) network, a circRNA-regulated E3 ubiquitin ligase signature (CRE3UL) was developed. A CRE3UL signature was created using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis and merged it with clinicopathologic characteristics to generate a nomogram for prognosis prediction. The pRRophetic algorithm was utilized and immunological checkpoints were analyzed to compare the responses of patients in the high-risk group (HRG) and low-risk group (LRG) to targeted therapy and immunotherapy. Finally, experimental research will further elucidate the relationship between E3 ubiquitin ligase signature and HCC.

HRG patients were found to have a worse prognosis than LRG patients. Furthermore, significant variations in prognosis were observed among different subgroups based on various clinical characteristics. The CRE3UL signature was identified as being an independent prognostic indicator. The nomogram that combined clinical characteristics and the CRE3UL signature was found to accurately predict the prognosis of HCC patients and demonstrated greater clinical utility than the current TNM staging approach. According to anticancer medication sensitivity predictions, the tumors of HRG patients were more responsive to gefitinib and nilotinib. From immune-checkpoint markers analysis, immunotherapy was identified as being more probable to assist those in the HRG.

We found a significant correlation between the CRE3UL signature and the tumor microenvironment, enabling precise prognosis prediction for HCC patients. Additionally, a nomogram was developed that performs well in predicting the overall survival (OS) of HCC patients. This provides valuable guidance for clinicians in devising specific personalized treatment strategies.

The incidence of primary liver cancer (PLC) has experienced a significant global increase, primarily attributed to the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC is often diagnosed in advanced stages, leaving patients with limited treatment options. Therefore, transformation therapy is a crucial approach for long-term survival and radical resection in patients with advanced HCC. Conversion therapy has demonstrated promise in the treatment of advanced HCC. When integrated with the FOLFOX regimen, hepatic artery infusion chemotherapy (HAIC) can significantly improve tumor response efficiency, leading to high conversion and resection rates.

We reviewed landmark trials of HAIC in combination with different drugs or means for the treatment of HCC to determine the clinical value of HAIC-centric translational therapies in HCC treatment. Furthermore, we specifically emphasize the advantages associated with employing FOLFOX-HAIC in the treatment of advanced HCC.

The combination of HAIC with the FOLFOX regimen can help prevent the low intratumoral accumulation and high adverse reaction rate caused by the FOLFOX alone, holding significant potential in the comprehensive treatment of future HCC patients.

Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.

Chemokines and chemokine receptors (CCRs) are involved in a variety of anti-tumour and pro-tumour immune processes in vivo, such as angiogenesis, metastasis, proliferation and invasiveness, and influence patient prognosis and response to therapy.

CCRs differentially expressed in HCC and associated with prognosis were extracted from TCGA and GEO databases, and the obtained CCRs were then used to construct signature genes, and the signature gene were selected for expression validation as well as functional experiments to explore the role of CCRs in the treatment and prognosis of HCC.

We constructed a prognostic model including five CCRs (CCL20, CCL23, CCR3, CCR10, and CXCR3) and validated the expression of signature genes. The model's risk score is an independent prognostic factor for HCC. We have also developed prognostic model nomograms for clinical use. In addition, we validated that CCR3 expression is associated with poor prognosis in HCC, and the proliferation and migration ability of HCC cells was significantly inhibited after interfering with the expression of CCR3 in MHCC-LM3. We also looked at differences in pathway enrichment, immune infiltration and immune checkpoints. Finally, we found that risk scores were also correlated with drug sensitivity, the high-risk group had a better sensitivity to sorafenib.

The CCRs-related gene signature may better assess HCC prognosis and response to immunotherapy and tyrosine kinase inhibitors such as sorafenib in HCC, providing prospective solutions for diagnosis and treatment.

Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.

Increasing data indicated that long noncoding RNAs (lncRNAs) were directly or indirectly involved in the occurrence and development of tumors, including hepatocellular carcinoma (HCC). Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues, but its role in HCC progression is unclear. Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.

To study the role of ultrasound microbubbles (UTMBs) mediated HAND2-AS1 in the progression of HCC, in order to provide a new reference for the treatment of HCC.

In vitro, we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs, and detected cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) by cell counting kit-8 assay, flow cytometry, Transwell invasion assay and Western blotting, respectively. In addition, we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior. Next, the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2 (TIMP2) overexpression vector, and we detected cell proliferation, apoptosis, invasion and EMT. In vivo, we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.

We found that UTMBs carrying HAND2-AS1 restricted cell proliferation, invasion, and EMT, encouraged apoptosis, and HAND2-AS1 silencing eliminated the effect of UTMBs. Additionally, miR-873-5p targets the gene HAND2-AS1, which also targets the 3'UTR of TIMP2. And miR-873-5p mimic counteracted the impact of HAND2-AS1. Further, miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs. We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase (MMP) 2/MMP9. In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.

LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.