The optimal clinical management of unresectable hepatocellular carcinoma (uHCC) is challenging for clinicians. Bayesian network meta-analysis was conducted to compare the efficacy and safety of different interventional strategies for uHCC.

A systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, and CNKI databases. Bayesian network meta-analysis was applied to evaluate the disease control rate (DCR), 1-year survival rate and 2-year survival rate, as well as the incidence of serious adverse events associated with seven interventional strategies. Odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects. Treatment rankings utilized surface under the cumulative ranking curve (SUCRA), whereas heterogeneity was examined via I-square and meta-regression.

A total of 40 randomized controlled studies were included. Compared with transarterial chemoembolization (TACE) alone, all of the combination treatments, including TACE with radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), percutaneous ethanol injection (PEI), and radiotherapy (RT), significantly improved the DCR. TACE combined with RFA was observed to be superior to hepatic arterial infusion chemotherapy (HAIC) (OR: 1.91; 95% CI: 1.03-3.81) and TACE (OR: 3.85; 95% CI: 2.66-5.69), with the highest probability (SUCRA 0.836). TACE combined with HIFU ranks highest 1-year survival (SUCRA 0.919) and 2-year survival (SUCRA 0.925) rates, and also exhibited a better 1-year survival rate than HAIC (OR: 2.99; 95% CI: 1.09-9.03). Compared with TACE alone, HAIC exhibited a greater DCR (OR: 2.02; 95% CI: 1.15-3.40) and a potential advantage in 2-year survival (OR: 1.95; 95% CI: 1.02-3.78). No significant differences in serious adverse events were observed across treatments.

Compared with TACE alone, combined treatments for uHCC patients demonstrates better efficacy and survival. Moreover, compared with TACE and HAIC, TACE combined with RFA provides better efficacy, whereas TACE combined with HIFU offers the highest 1-year survival rate. HAIC alone outperforms TACE in DCR and 2-year survival rate.

Hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib (Len) and immune checkpoint inhibitor (ICI) in treating advanced hepatocellular carcinoma (HCC) still needs further confirmation. We aimed to evaluate the efficacy of HAIC combined with Len and ICI (HAIC + Len + ICI) versus Len alone in advanced HCC.

A total of 290 patients in Len group and 349 patients in HAIC + Len + ICI group were analysed. Propensity score matching (PSM), inverse probability treatment weighting (IPTW), and coarsened exact matching (CEM) analyses were used to balance the bias between two groups. Mediation analysis of treatment type in survival was performed for analysis.

The median progression-free survival (PFS) was 5.9 ± 0.2 months in Len group and 9.2 ± 0.5 months in HAIC + Len + ICI group. The HAIC + Len + ICI group demonstrated significantly better PFS than the Len group across the entire cohort (hazard ratio [HR], 0.50; 95% CI 0.43-0.60; P < 0.001). This advantage in PFS was sustained in the PSM, IPTW, and CEM cohorts. HAIC + Len + ICI group also showed better overall survival (OS) than the Len group (HR, 0.38; 95% CI 0.31-0.46; P < 0.001). The OS was also superior in the PSM, IPTW, and CEM cohorts. The objective response rate (ORR) in HAIC + Len + ICI group was twice as high as that in Len group. Further mediation analysis showed tumor response at 3 and 6 months had different mediation effect on survival.

HAIC combined with Len and ICI showed improved better OS and PFS than Len alone. This triple therapy could be considered as a first-line treatment for advanced HCC.

Hepatic artery infusion chemotherapy (HAIC) is a widely used local therapeutic approach for intermediate to advanced-stage hepatocellular carcinoma (HCC), exhibiting considerable efficacy. However, the prevalence of postoperative pain highlights the importance of pain management. Owing to the limitations inherent in existing pain management strategies, this study investigates and assesses the analgesic effectiveness of a multimodal treatment protocol in mitigating pain after HAIC procedures.

To provide patients with a more comprehensive and effective pain management strategy.

A total of 100 patients with primary HCC who underwent HAIC were randomly assigned to a control group (n = 50) and a multimodal group (n = 50). Baseline characteristics and perioperative data were collected. Upon enrollment, patients in the multimodal group received parecoxib (40 mg) 30 minutes before HAIC, followed by 48 hours of patient-controlled analgesia with sufentanil. In contrast, the control group underwent standard preoperative preparation (psychological support) and received dezocine (5 mg) intraoperatively, with intravenous flurbiprofen (100 mg) administered every 12 hours for 48 hours postoperatively.

Compared to the control group, the multimodal analgesia group exhibited significantly lower resting and movement visual analog scale pain scores at postoperative 0, 2, 4, 6, and 12 hours (P < 0.05). Furthermore, the multimodal group experienced a reduced incidence of postoperative nausea and vomiting, as well as a lower overall frequency of adverse events, compared to the control group (P < 0.05). Patient satisfaction was also significantly higher in the multimodal group than in the control group (P < 0.05).

Our study demonstrates that multimodal analgesia is effective in reducing postoperative pain, minimizing adverse reactions, and improving patient satisfaction in HCC patients undergoing HAIC. This approach provides valuable clinical strategies for optimizing pain management in this patient population.

A previous phase 3 FOHAIC-1 study demonstrated that hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimen displayed favorable outcomes in advanced hepatocellular carcinoma (HCC) patients, including those with high-risk features (main portal tumor invasion and >50% liver infiltration). This study aimed to compare the treatment efficacy of HAIC-FOLFOX versus atezolizumab-bevacizumab in HCC patients.

Individual patient data from the Chinese FOHAIC-1 study and aggregate data from the global IMbrave150 study were used to conduct an anchored matching-adjusted indirect comparison. Hazard ratios (HR) and restricted mean survival times (RMST) were calculated to assess survival differences. Landmark analysis was performed to evaluate time-sensitive treatment effects, and simulated treatment comparison (STC) was conducted as a sensitivity analysis. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.

After matching baseline characteristics, HAIC showed a numerical OS benefit (HR 0.57, 95% CI, 0.30-1.08) and similar PFS benefit (HR 0.79, 95% CI, 0.43-1.47) compared to atezolizumab-bevacizumab in the overall population. In high-risk patients, HAIC demonstrated significantly improved OS (HR 0.30, 95% CI, 0.12-0.72) and 2.89-month longer RMST compared to atezolizumab-bevacizumab (95% CI, 0.15-5.64 months). Additionally, HAIC showed superior PFS (HR 0.25, 95% CI, 0.10-0.64) and 2.88-month longer RMST over atezolizumab-bevacizumab (95% CI, 0.90-4.86). Landmark analysis in the high-risk group revealed that HAIC was associated with significant improvements in both OS (HR 0.32, 95% CI, 0.13-0.79) and PFS (HR 0.24, 95% CI, 0.09-0.63) during the 0-12 months following treatment initiation. Sensitivity analysis using the anchored STC analysis yielded consistent results. HAIC was associated with lower rates of grade 3-4 TRAEs and TRAE-related discontinuation in both the overall population and the high-risk group.

HAIC treatment provided superior survival benefits and a favorable safety profile compared to atezolizumab-bevacizumab in high-risk HCC patients.

Cancer-associated fibroblasts (CAFs) have garnered significant attention due to their ability to shape the tumor microenvironment, thereby facilitating tumor progression and metastasis. Serpin peptidase inhibitor clade H member 1 (SERPINH1) is known for its role in the proper folding and secretion of collagen. However, its biological significance in hepatocellular carcinoma (HCC) remains unclear. We observed higher levels of SERPINH1 in the conditioned medium (CM) of CAFs compared to normal fibroblasts (NFs) via ELISA assays. To investigate its impact on HCC, we knocked down SERPINH1 in CAFs by shRNA, which led to a notable reduction in HCC cell proliferation, migration, and invasion induced by CM of CAFs, measured by colony formation and Transwell assays. SERPINH1 also inhibited HCC cell apoptosis, decreased the percentage of cells arrested in the G0/G1 phase, and increased the proportion of cells in the S phase, which were detected by flow cytometry. We further performed co-injections of HepG2 cells liver orthotopic transplantation model with either shCtrl-CAFs or shSERPINH1-CAFs. Interestingly, the presence of shCtrl-CAFs significantly enhanced tumor-initiating capacity compared to HepG2 cells alone or when co-injected with shSERPINH1-CAFs. Mechanistically, CAFs-derived SERPINH1 activated the SENP3/SP1 signaling pathways, substantially promoting the growth of HCC cells. Notably, we found that the transcription factor SP1 directly binds to the SQLE promoter and activates its transcription via ChIP-qPCR assay. Inhibition of SP1 expression using the specific inhibitor plicamycin effectively reversed CAFs-derived SERPINH1-induced HCC growth in vivo. Collectively, our findings highlighted the pathological role CAFs-derived SERPINH1 played in driving malignant of HCC cells through the SENP3/SP1/SQLE signaling axis, which offered a explanation of how SERPINH1 promotes HCC progress. Besides, we also demonstrated that targeting SERPINH1 signaling shall be a promising direction to develop effective therapeutical strategies for anti-HCC clinical management.

In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.

Hepatocellular carcinoma (HCC) is increasing in prevalence globally, and cure remains limited with non-operative treatment. Surgical intervention, through resection or transplantation, offers a potential for cure for select patients. However, many patients present with advanced or unresectable disease, and recurrence rates remain high. Recent advances in systemic therapies, particularly immune checkpoint inhibitors, have demonstrated promise in treating unresectable HCC and as adjuvant therapy. Evidence from adjuvant trials highlights the synergistic potential of combined liver-directed and systemic therapies. These findings have ignited growing interest in neoadjuvant therapy across various scenarios: (1) as a bridging strategy while awaiting transplantation, (2) for downstaging disease to enable transplantation, (3) for converting unresectable disease to a resectable state, or (4) as neoadjuvant treatment in operable cases. Early-stage trials of neoadjuvant therapy in resectable HCC have reported promising outcomes. To realize the potential of neoadjuvant treatment for HCC, thoughtfully designed, adequately powered, multi-center clinical trials are essential.

Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment for unresectable hepatocellular carcinoma (HCC). However, the safety profiles of HAIC and its various combination therapies remain to be systematically evaluated.

We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to November 2024. Studies reporting adverse events (AEs) of HAIC monotherapy or combination therapies in HCC were included. The severity and frequency of AEs were analyzed according to different treatment protocols.

A total of 58 studies (11 prospective, 47 retrospective) were included. HAIC monotherapy demonstrated relatively mild toxicity, primarily affecting hepatobiliary (transaminase elevation 53.2%, hypoalbuminemia 57.2%) and hematological systems (anemia 43.0%, thrombocytopenia 35.2%). HAIC with targeted therapy showed increased adverse events, including characteristic reactions like hand-foot syndrome (48.0%) and hypertension (49.9%). HAIC combined with targeted, and immunotherapy exhibited the highest adverse reaction rates (neutropenia 82.9%, transaminase elevation 97.1%), while HAIC with anti-angiogenic and immunotherapy showed a relatively favorable safety profile. Prospective studies consistently reported higher incidence rates than retrospective studies, suggesting potential underreporting in clinical practice.

Different HAIC-based regimens exhibit distinct safety profiles requiring individualized management approaches. We propose a comprehensive framework for patient selection, monitoring strategies, and AE management. These recommendations aim to optimize treatment outcomes while minimizing adverse impacts on patient quality of life.

Hepatocellular carcinoma (HCC) with coexisting portal vein tumor thrombus (PVTT) is associated with poor patient outcomes. The efficacy and safety of neoadjuvant therapy in patients with HCC with PVTT remain a subject of debate. In the present study, a comprehensive search of electronic databases, including PubMed, Web of Science, Embase and the Cochrane Library, was conducted to identify studies evaluating the outcomes of neoadjuvant therapy in patients with HCC and PVTT. The primary outcomes assessed were overall survival (OS) and relapse-free survival (RFS), with complication rates as a secondary outcome. A total of six studies comprising 750 patients were included in the present meta-analysis. The neoadjuvant therapy group exhibited significantly superior OS [hazard ratio (HR), 0.39; P<0.001] and RFS (HR, 0.31; P<0.001) compared with the primary hepatectomy control group. Compared with the control group, neoadjuvant radiotherapy improved OS (HR, 0.34; P<0.001) and RFS (HR, 0.24; P=0.004). While the neoadjuvant intervention subgroup exhibited an improved OS compared with controls (HR, 0.37; P=0.001), no significant difference in RFS was observed (HR, 0.11; P=0.095). Geographical analysis revealed that the Chinese subgroup demonstrated a significantly improved OS and RFS (HR, 0.41 for both; P<0.001), compared with the control group. However, the Japanese and Korean subgroups showed no improvement in OS (HR, 0.25; P=0.057) compared with the control group, and the results did not reach statistical significance. There were no significant differences between the groups in terms of blood transfusion, blood loss, operation time, bile leakage, ascites, peritoneal infection, postoperative bleeding, complications or mortality (all P>0.05). Overall, neoadjuvant therapy significantly improved survival outcomes in patients with HCC and PVTT without increasing complication rates, supporting its efficacy and manageable safety profile.

With advancements in drug therapy, local treatments, and evolving concepts, conversion therapy has shown benefits for patients initially diagnosed with unresectable hepatocellular carcinoma (HCC). Over the past 10 years, the conversion therapy field has accumulated a vast amount of underutilized data, necessitating in-depth bibliometric evaluation.

This cross-sectional retrospective study collected a substantial amount of research on conversion therapy published between 2014 and 2023, adhering to strict search criteria. The primary outcomes were publication volume, citation count, and interstudy relationships. Comprehensive analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression model, and the Walktrap algorithm.

Over the past decade, conversion therapy has demonstrated significant progress, with an annual growth rate of 23.0%. Post-2020, these metrics saw a marked increase, reaching 116 publications and 1943 citations by 2023. Cluster analysis grouped 244 authors into 17 clusters, highlighting early and sustained contributions from Western authors compared with later-emerging Eastern authors. Research characteristics in HCC conversion therapy were classified into 5 clusters, with Cluster 2 (Target Therapy and Immunotherapy) emerging as a new focus. Thematic analysis categorized research characteristics into 4 quadrants, identifying "immune checkpoint inhibitor" and "combination therapy" as highly relevant and rapidly developing themes, while "hepatic arterial infusion chemotherapy" and "radioembolization" show high potential for future research.

This study highlights key contributors and emerging trends and provides important predictions for future research directions. To achieve effective conversion therapy for HCC, researchers may prioritize immunotherapy and locoregional treatments such as hepatic arterial infusion chemotherapy or radioembolization.

Hepatic arterial infusion chemotherapy (HAIC) is an advanced targeted therapeutic approach for hepatocellular carcinoma (HCC), the most common type of primary liver cancer. HAIC has demonstrated significant potential in managing advanced HCC, particularly in regions with high prevalence rates. Despite its promise, several challenges and areas for future research remain. Clinical studies have substantiated the efficacy of HAIC in enhancing survival outcomes for patients with advanced hepatic carcinoma. Notably, combination therapies involving immune checkpoint inhibitors, such as lenvatinib and programmed death-1 inhibitors, have shown substantial improvements in median overall survival and progression-free survival compared to systemic chemotherapy. These combination therapies have also exhibited superior response rates and disease control, with manageable and often less severe adverse events relative to systemic treatments. This article is based on the review by Zhou et al and aims to discuss the current status and future directions in the treatment of HCC, emphasizing the role of HAIC and its integration with novel therapeutic agents.

Hepatic arterial infusion chemotherapy (HAIC) is increasingly recognized as a primary treatment option for patients with unresectable hepatocellular carcinoma (uHCC), providing a focused treatment for localized tumors. The combination of lenvatinib, a multikinase inhibitor, with PD-1 inhibitors has demonstrated significant survival benefits in HCC. This meta-analysis aims to assess whether the integration of HAIC with lenvatinib and PD-1 inhibitors (referred to as the HAIC-L-P group) leads to better treatment effectiveness and security compared to lenvatinib and PD-1 inhibitors alone (L-P group) in uHCC.

An exhaustive search of the literature was conducted, including PubMed, the Cochrane Library, Embase, ClinicalTrials.gov, and Web of Science, from the start of each database until September 2024, to ensure a thorough and up-to-date compilation of relevant studies. Extract data on outcome measures such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Subsequently, meta-analyses were performed using RevMan 5.4 to quantitatively evaluate the aggregated effect of the HAIC-L-P regimen versus the L-P regimen alone.

In our systematic meta-analysis of eight retrospective cohort studies, the HAIC-L-P regimen demonstrated markedly enhanced OS, with an HR of 0.54 (95% CI: 0.45-0.64; p < 0.00001), and enhanced 1-year and 2-year OS rates. Superior PFS was also observed in the HAIC-L-P group, with an HR of 0.64 (95% CI: 0.55-0.75; p < 0.0001), and higher 1-year and 2-year PFS rates. Response rates were markedly higher in the HAIC-L-P group, with an ORR risk ratio of 2.15 (95% CI: 1.84-2.50; p < 0.00001) and a DCR risk ratio of 1.28 (95% CI: 1.20-1.43; p < 0.0001). The AEs classified as grade 3 or above were elevated in the HAIC-L-P group, with notable risk ratios for vomiting, elevated AST, elevated ALT, thrombocytopenia, neutropenia, and hyperbilirubinemia. No life-threatening AEs were reported.

The HAIC-L-P regimen correlated with enhanced tumor responses and prolonged survival, alongside manageable adverse effects, indicating its potential as a viable therapeutic strategy for individuals afflicted with uHCC.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024594109.

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.

Hepatocellular carcinoma (HCC) is typically diagnosed at intermediate to advanced stage, making surgical treatment unfeasible. Conversion therapy aims to reduce tumor stage, improve hepatic resection feasibility, and lower recurrence rates. Since traditional therapies are often accompanied by uncertainty of efficacy, there is an urgent need to explore new treatment strategies. Near-infrared phototheranostics technology provides a new way for HCC diagnosis and treatment by its excellent optical properties. However, complex preparation and poor biocompatibility of phototheranostics probes limit clinical application. In this study, we developed a fluorescence/magnetic resonance dual-modality imaging (FLI/MRI) as well as photothermal/photodynamic therapy (PTT/PDT) GPC3-targeted multifunctional phototheranostics probe, IR820-GPC3-Gd NPs (IGD NPs), to improve the efficiency of conversion therapy for HCC. The IGD NPs were simply prepared with the IR820 as the core. Conjugating the HCC-specific targeting molecule GPC3 peptide and the MRI agent DOTA-Gd through click chemistry. IGD NPs target HCC cells through GPC3, releasing heat and reactive oxygen species (ROS) under noninvasive 808 nm laser irradiation to reduce tumor size and achieve downstaging. High-sensitivity FLI/MRI precisely delineates tumor boundaries, providing real-time surgical navigation and prognosis assessment. This novel probe offers a feasible and effective treatment option for advanced HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with advanced stages posing significant treatment challenges. Although hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising modality for treating advanced HCC, particularly in Asian clinical practice, its adoption in Western medicine remains limited due to a lack of large-scale randomized controlled trials. This editorial reviews and comments on the meta-analysis conducted by Zhou et al, which evaluates the efficacy and safety of HAIC and its combination strategies for advanced HCC. The authors performed a comprehensive meta-analysis of various clinical trials and cohort studies comparing HAIC and its combinations to other first-line treatments, such as sorafenib and transarterial chemoembolization (TACE). In this work, HAIC showed significantly better results regarding overall survival and progression-free survival compared to sorafenib or TACE alone and their combination. HAIC in combination with lenvatinib, ablation, programmed cell death 1 inhibitors, and radiotherapy further enhanced patient outcomes, indicating a synergistic effect. This editorial focuses on the critical role of multimodal treatment strategies in managing advanced HCC. It advocates for a paradigm shift towards integrated treatment approaches to enhance survival rates and improve the quality of life in patients with advanced HCC.

The combination of local therapy with lenvatinib and programmed cell death protein-1 (PD-1) inhibitors represents an emerging treatment paradigm for unresectable hepatocellular carcinoma (uHCC). Our study sought to investigate the interrelationship between gut microbiota and intratumoral microbiota in the context of triple therapy, with a view to identifying potential biological markers.

The gut microbial community profiles of patients with primary untreated hepatocellular carcinoma (HCC) and those treated with local therapy combined with lenvatinib and PD-1 inhibitors were analyzed by 16S rRNA gene amplicon sequencing. Additionally, microbial community profiles of tumor tissues of patients with HCC and normal liver tissues were analyzed.

In our investigation, we observed that patients with HCC who received triple therapy exhibited a notable enhancement in the abundance of Actinobacteriota and a considerable decrease in Escherichia Shigella. Patients who received hepatic artery infusion chemotherapy (HAIC) in combination with levatinib and PD-1 inhibitors exhibited significantly elevated levels of Faecalibacterium prausnitzii and Bacteroides stercoris in comparison to those who received transarterial chemoembolization (TACE) in combination with levatinib and PD-1 inhibitors. Furthermore, a notable decline in microbial diversity was observed within HCC tumors in comparison to normal liver tissues. The gut and intratumoral microbiota in HCC patients exhibited a high degree of similarity to the microbes present at the phylum level.

Gut microbiota is connected to triple therapy with local therapy combined with lenvatinib and PD-1 inhibitors for HCC. These discoveries underscore the potential of utilizing gut microbiota and intratumoral microbiota as biomarkers, as well as the possibility of triple therapy in the management of HCC.

Hepatocellular carcinoma (HCC) remains a major challenge in oncology, being a leading cause of cancer-related mortality worldwide. Early-stage HCC is typically treated with surgical resection, transplantation, or ablation, while advanced-stage HCC relies on systemic therapies like sorafenib and newer combinations such as atezolizumab-bevacizumab. Despite these advancements, there is still a need for effective treatments for unresectable HCC, especially in cases with macroscopic vascular invasion. Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising outcomes in Asia for the treatment of unresectable HCC, yet its application in Western countries has been relatively limited. This letter reviews the recent meta-analysis by Zhou et al published in the World Journal of Gastrointestinal Oncology, which demonstrates the efficacy and safety of HAIC vs sorafenib. The analysis includes 9 randomized controlled trials and 35 cohort studies, highlighting significant improvements in overall survival, progression-free survival, and objective response rates with HAIC and its combinations. The editorial explores the reasons behind the limited use of HAIC in Western countries. It underscores the potential of HAIC to enhance treatment outcomes for advanced HCC and calls for more research and broader adoption of HAIC in clinical practice globally.

There is no established second-line treatment for hepatocellular carcinoma (HCC) following atezolizumab-bevacizumab (ate-beva) failure. This study assessed the efficacy of hepatic arterial infusion chemotherapy (HAIC) as a salvage therapy by comparing survival outcomes and treatment responses between HAIC as a first-line treatment and as a second-line option after ate-beva failure.

We retrospectively analyzed 100 patients with advanced HCC treated with HAIC between March 2022 and July 2024. Patients were categorized into two groups: those who received HAIC as initial therapy (first-line HAIC group) and those who received HAIC following ate-beva failure (post-ate-beva group). Survival outcomes were assessed with Kaplan-Meier curves and log-rank tests, and factors associated with survival were identified through Cox regression analysis.

The post-ate-beva group exhibited longer overall survival (OS) (median OS 12.4 months) compared to the first-line HAIC group (median OS 6.8 months) (p = 0.073). Progression-free survival (PFS) was significantly superior in the post-ate-beva group (median PFS 8.2 months) compared to the first-line HAIC group (median PFS 3.1 months) (p = 0.018). The objective response rate was also notably higher in the post-ate-beva group than in the first-line HAIC group (35.3% vs. 18.1%, p = 0.031). In multivariate analysis, HAIC following ate-beva failure, compared to first-line HAIC, was significantly associated with favorable outcomes for both OS (p = 0.014) and PFS (p = 0.006).

The superior survival outcomes and treatment responses observed in the post-ate-beva group suggest that HAIC may be an effective second-line treatment option for advanced HCC following ate-beva therapy failure. However, due to the retrospective nature and small sample size of the study, further prospective studies with larger patient populations are needed to strengthen the evidence.

Advanced hepatocellular carcinoma (HCC) has been treated with targeted therapy, immunotherapy, or a combination of both, however, the overall clinical efficacy is still unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC), as a localized treatment modality, has demonstrated favorable therapeutic efficacy in patients with advanced HCC accompanied by portal vein tumor thrombus and extensive intrahepatic metastasis. In recent years, the combination of HAIC with immune and targeted therapy has gradually gained acceptance in East Asian countries. However, further investigation is necessary to assess the efficacy and safety of this triple therapy.

PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies conducted within the past 5 years on HAIC combined with immunotherapy and targeted therapy as first-line treatment for advanced HCC. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted this meta-analysis. Additionally, the quality of included studies was assessed using the Joanna Briggs Institute (JBI) scale. Outcomes such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs)were extracted and pooled from eligible studies.

Twelve studies involving 1072 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 65.7% (95% CI, 58.7%-72.7%) (I2 = 83%, P = 0.000) and 89.2% (95% CI, 83.9%-93.6%) (I2 = 83%, P = 0.000), respectively. When analyzing PFS, the upper limit of 95% confidence interval of PFS in one study was not reached, which could potentially impact the statistical analysis. Therefore, we analyzed the remaining 11 studies a total of 1019 patients to pool mPFS, ultimately the pooled mPFS was 9.77months (95% CI, 7.73-11.80) (I2 = 93.9%, P = 0.000). Follow-up time in some studies was insufficient, only eight studies reported OS, we systematically analyzed these eight studies and extracted the pooled mOS was 16.65 months (95% CI, 14.17-19.14) (I2 = 76.9%, P = 0.000). In terms of safety, the incidence rates of any grade AEs, ranked from high to low, were as follows: aminotransferase increased (61.3%), nausea and vomiting (40.5%), hypertension (37.8%), thrombocytopenia (37.4%), hyperbilirubinemia (36.7%), abdominal pain (35.6%), leukopenia (34.6%), hypothyroidism (19.0%), rash (14.4%). Grade 3-4 AEs ranked from high to low were as follows: aminotransferase increased (10.8%), thrombocytopenia (7.9%), hypertension (7.4%), leukopenia (5.0%). No treatment-related deaths occurred, patients receiving this triple therapy demonstrated favorable tolerability.

The combination of hepatic arterial infusion chemotherapy with tyrosine kinase inhibitors and immune checkpoint inhibitors as a first-line therapy for unresectable advanced HCC demonstrates promising therapeutic efficacy and favorable safety.

Atezolizumab/bevacizumab (atezo-bev) is the first-line chemotherapy for patients with unresectable hepatocellular carcinoma (HCC). However, hepatic artery infusion chemotherapy (HAIC) can be used as an alternative. Our aim was to compare the prognosis of HAIC treatment between newly diagnosed patients and patients treated after failure of atezo-bev.

We retrospectively assessed 73 patients with HCC treated with HAIC between January 2022 and September 2023. Fifty-seven patients were treated with HAIC at initial diagnosis, while 16 were treated with HAIC after first-line atezo-bev combination chemotherapy. We evaluated tumor responses, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

No significant difference was observed in either OS or PFS between patients with HCC treated with HAIC at the initial diagnosis and those treated after atezo-bev treatment failure. However, the ORR of the initial HAIC group was 19.6% and that of the HAIC group after atezo-bev therapy failure was 43.6%, which was a statistically significantly difference.

Although no significant difference was observed for OS and PFS, the ORR of patients in the HAIC group after the failure of atezo-bev therapy was superior to that of newly diagnosed patients. HAIC may prolong survival in patients with HCC after atezo-bev treatment failure.

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti-VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) is administered when the above-described combination fails to confer sufficient clinical benefit. The present study aimed to explore the association between tumor programmed cell death-ligand 1 (PD-L1) positivity and HAIC response. A total of 40 patients with HCC who had undergone HAIC with available biopsy samples obtained between January 2020 and May 2023 were retrospectively enrolled. Tumor response, progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) were evaluated. PD-L1 expression in tumor samples was assessed using a combined positivity score. The response rates of HAIC-treated patients with advanced HCC after failure of atezolizumab/bevacizumab combination therapy were recorded. OS (P=0.9717) and PFS (P=0.4194) did not differ between patients with and without PD-L1 positivity. The objective response rate (P=0.7830) and DCR (P=0.7020) also did not differ based on PD-L1 status. In conclusion, the current findings highlight the consistent efficacy of HAIC, regardless of PD-L1 positivity.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

In inoperable hepatocellular carcinoma (HCC), chemotherapy is a common treatment strategy. However, there is a lack of reliable methods to predict the prognosis of patients with inoperable HCC after chemotherapy. Therefore, the aim of this study was to identify the clinical characteristics of patients with inoperable HCC and to establish and validate nomogram models for predicting the survival outcomes in this patient group following chemotherapy.

The data of patients diagnosed with HCC from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Logistic regression analyses were used to identify potential factors for inoperability in patients with HCC. Kaplan-Meier analyses were applied to evaluate the impact of chemotherapy on prognosis. Additionally, Cox regression analyses were performed to identify the potential risk factors associated with overall survival (OS) and cancer-specific survival (CSS) in patients with inoperable HCC treated with chemotherapy. Finally, we constructed prognostic nomograms for predicting the 1- and 3-year survival probabilities.

A total of 3,519 operable patients with HCC and 4,656 patients with inoperable HCC were ultimately included in this study. Logistic regression analyses revealed a significant association between patient age, gender, race, tumor, node, metastasis (TNM) stage, tumor size, pretreatment alpha fetoprotein (AFP) levels, and marital status with inoperability. Moreover, Kaplan-Meier analyses revealed a significant improvement in both OS and CSS with the administration of chemotherapy. Moreover, 1,456 patients with inoperable HCC were enrolled in the training group and 631 patients with inoperable HCC were enrolled in the validation group to develop and validate the prognostic models. Cox regression models indicated that TNM stage, tumor size, and pretreatment AFP were independent risk factors for predicting OS and CSS in patients with inoperable HCC receiving chemotherapy. These factors were subsequently integrated into the predictive nomograms.

We preliminarily developed survival models with strong predictive capabilities for estimating survival probabilities in patients with HCC following chemotherapy. These models hold potential for clinical application and warrant further exploration through additional studies.

The preoperative conversion therapy for advanced hepatocellular carcinoma (HCC) is still being explored. This study reported the potential of combination of transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), programmed cell death protein-1 (PD-1) inhibitors and lenvatinib as preoperative conversion therapy for nonmetastatic advanced HCC.

This retrospective study gathered data on patients with nonmetastatic advanced HCC who received this combination therapy. We used drug-eluting bead (DEB) instead of conventional iodized oil in TACE. The clinical data, conversion rate, adverse events (AEs) and short-term survival were summarized. A stratified analysis based on whether or not the patient received surgery was conducted.

A total of 28 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 64.3%. Ten (35.7%) patients eventually received R0 resection after 2 cycles of combination therapy. Patients succeeding to resection (surgery group) had significantly higher ORR (90.0% vs. 50.0%, P=0.048). The proportion of patients with alpha-fetoprotein (AFP) >1,000 µg/L was significantly lower in surgery group (10.0% vs. 66.7%, P=0.006). After combination therapy, more patients in surgery group experienced significant reduction of >90% in AFP levels (75.0% vs. 23.1%, P=0.03), as well as standardized uptake value (SUV) of 18F-fluorodeoxyglucose (18F-FDG) both in primary tumors and portal vein tumor thrombosis (PVTT) (60.0% vs. 5.6%, P=0.003; 57.1% vs. 8.3%, P=0.04). Of note, 85.7% of PVTT exhibited major pathological response (MPR) in pathological examination although only 28.6% achieved downstage in preoperative imaging examination. MPR was more commonly observed in PVTT than in main tumors (85.7% vs. 20.0%). In non-surgery group, the median overall survival (OS) was 7 months with a 1-year survival rate of 27.8%, while in surgery group, the median OS was not reached and 1-year survival rate was 60.0%.

The combination of TACE-HAIC, PD-1 inhibitors and lenvatinib showed its benefit as a preoperative conversion therapy for nonmetastatic advanced HCC. In addition to imaging evaluation, significant reduction of 18F-FDG uptake and AFP can be used as predictors of successful conversion, especially for PVTT.

Hepatocellular carcinoma (HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization (TACE) being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.

The presence of macrovascular invasion (MVI) is associated with poor prognosis in advanced hepatocellular carcinoma (HCC). This study aims to evaluate the efficacy and safety of Cinobufacini therapy via hepatic arterial infusion (HAI) in advanced HCC patients with MVI.

The clinical records of 130 consecutive patients with unresectable advanced HCC and MVI who had received Cinobufacini or cisplatin plus 5-fluorouracil (CF) treatment via HAI were retrospectively analyzed. The therapeutic efficacy, overall survival (OS), progression-free survival (PFS), and adverse events were compared between the two treatment groups.

The Cinobufacini group demonstrated significant curative effects on treatment via HAI compared with the CF group, including the objective response rate (44.9% vs 27.9%, P=0.048), the median OS (14.8 months vs 11.1 months, P=0.010), and the median PFS (10.3 months vs 6.0 months, P=0.006). Result in subgroup analysis of portal vein invasion grade supported the efficacy in Cinobufacini treatment, especially in the median OS of Vp1-2 (18.3 months vs 14.3 months, P=0.043) and Vp3 (15.0 months vs 11.4 months, P=0.046), as well as the median PFS of Vp1-2 (14.8 months vs 10.2 months, P=0.028) and Vp3 (10.8 months vs 6.6 months, P=0.033) compared with CF treatment. Cox proportional hazards model and forest plot analysis of factors confirmed the survival benefit from HAI with Cinobufacini over CF (hazard ratio [HR], 0.61; 95% CI: 0.40-0.91; P=0.010). Multivariable analysis identified portal vein invasion grade (Vp4; HR, 1.78; 95% CI: 1.03-2.16; P=0.032) and AFP (>1000; HR, 1.61; 95% CI: 1.08-1.91; P=0.039) as the independent factors for prognosis. Moreover, the total incidence of adverse events in the Cinobufacini group was significantly lower than in the CF group (60.9% vs 82.0%, P=0.009).

Cinobufacini therapy via HAI is a viable strategy for curing advanced HCC with MVI, due to prolonged survival and a superior safety profile.

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma.

Platinum-fluorouracil combination chemotherapy is the standard neoadjuvant treatment for locally advanced gastric cancer in China, but it does not improve the survival benefit of patients. In recent years, the application of immune checkpoint inhibitors and/or targeted drugs in neoadjuvant therapy for gastric cancer has achieved certain efficacy, but the survival benefit of patients is still not obvious. Intra-arterial infusion chemotherapy, as a method of regional therapy, has been widely used in the treatment of many advanced tumors and achieved remarkable curative effect. The role of arterial infusion chemotherapy in neoadjuvant therapy for gastric cancer is not clear. We describe two patients with locally advanced gastric cancer treated with continuous arterial infusion neoadjuvant chemotherapy. Two patients received continuous arterial infusion of chemotherapy drugs for 50 hours, the drugs were pumped into the main feeding artery of the tumor through the arterial catheter. A total of 4 cycles were followed, then undergone surgical resection. The postoperative pathological pCR of two patients was 100%, TRG was 0 grade, and no further anti-tumor therapy was required after operation, achieving clinical cure. During the treatment period, no serious adverse events occurred in either patient. These results suggest that continuous arterial infusion chemotherapy may be a new adjuvant therapy for locally advanced gastric cancer.

Striking advances in systemic therapy for unresectable advanced hepatocellular carcinoma (HCC) have improved the average prognosis of patients with HCC. As a result, the guidelines for the treatment of HCC have changed significantly. However, various issues have emerged in clinical practice. First, there is no established biomarker that can predict response to systemic therapy. Second, there is no established treatment regimen after primary systemic therapy, including combined immunotherapy. Third, there is no established treatment regimen for intermediate-stage HCC. These points make the current guidelines ambiguous. In this review, we present the Japanese guidelines for the diagnosis and treatment of HCC based on the latest evidence; introduce various efforts mainly in Japanese real-life practice to update these guidelines; and present our perspectives on future guidelines.

The subsequent therapy for hepatocellular carcinoma (HCC) patients with refractory to transarterial chemoembolization (TACE) is still controversial. This study was performed to evaluate the efficacy and safety of combination therapy comprising hepatic artery infusion chemotherapy (HAIC), lenvatinib, and programmed death-1 inhibitors relative to HAIC combined with lenvatinib.

In this single-center retrospective study, we analyzed data from HCC patients with refractory to TACE from June 2017 to July 2022. Primary study outcomes were overall survival (OS) and progression-free survival (PFS), while the secondary outcomes were the objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events.

We enrolled 149 patients finally, including 75 patients who received HAIC combined with lenvatinib plus PD-1 inhibitors therapy (HAIC+L+P group) and 74 patients who received HAIC combined with lenvatinib therapy (HAIC+L group). The median OS in the HAIC+L+P group (16.0; 95% CI: 13.6~18.3 months) was significantly higher compared to the HAIC+L group (9.0; 95% CI: 6.5~11.4 months) (p = 0.002), while the median PFS in the HAIC+L+P group (11.0; 95% CI: 8.6~13.3 months) was significantly higher compared to the HAIC+L group (6.0; 95% CI: 5.0~6.9 months) (p < 0.001). Significant between-group differences in DCR (p = 0.027) were found. Additionally, 48 pairs of patients were matched after propensity matching analysis. The survival prognosis between two groups before propensity matching is similar to that after propensity matching. Moreover, the percentage of patients with hypertension in the HAIC+L+P group was significantly higher compared to the HAIC+L group (28.00% vs. 13.51%; p = 0.029).

A combination therapy of HAIC, lenvatinib, and programmed death-1 inhibitors significantly improved oncologic response and prolonged survival duration, showing a better survival prognosis for HCC patients with refractory toTACE.