Search

Background: Bevacizumab and sintilimab combined interventional treatment (BeSiIT) and L envatinib and sintilimab combined interventional treatment (LeSiIT) are two commonly used therapeutic regimens for intermediate-advanced hepatocellular carcinoma (HCC) in clinical practice., Aim: To compare the clinical efficacy and safety of BeSiIT and LeSiIT for the treatment of intermediate and advanced HCC., Methods: Patients diagnosed with intermediate-advanced HCC and initially treated with BeSiIT or LeSiIT in the Tianjin Medical University Cancer Institute and Hospital between February 2020 and July 2021 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), conversion rate, and treatment-related adverse events., Results: Total 127 patients met the inclusion criteria and were divided into BeSiIT and LeSiIT groups. Twenty-eight and fifty patients in the BeSiIT and LeSiIT groups, respectively, were assessed after 1:2 propensity score matching. PFS and OS rates were not significantly different between the two groups. No significant variations were noted in ORRs or DCRs according to the Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST. BeSiIT group showed a better conversion rate than the LeSiIT group ( P = 0.043). Both groups showed manageable toxicity profiles. Multivariate analysis showed that the independent factors associated with PFS were alpha-fetoprotein levels and carcinoembryonic antigen score., Conclusion: In intermediate-to-advanced HCC, the BeSiIT and LeSiIT groups exhibited acceptable toxicities and comparable PFS, OS, and ORR., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) treatment and its underlying mechanisms remain elusive. This study investigates the role of enzymes involved in fatty acid activation, specifically Acyl-CoA synthetase long chain 4 (ACSL4), in HCC patients treated with postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells., Methods: We examined the expression of ACSL4 and its family members in HCC clinical samples and cell lines. The clinical significance of ACSL4, particularly regarding the prognosis of patients treated with PA-TACE, was assessed using two independent HCC cohorts. We further explored the role of ACSL4 in glucose starvation-induced cell death in HCC cells and xenograft mouse models., Results: Among the family members, ACSL4 is the most up-regulated enzyme, associated with poor survival in HCC patients, particularly in post-recurrent TACE-treated patients in a Singapore cohort. ACSL4 is essential for HCC cell survival in response to glucose starvation, rather than to hypoxia or to the combination of hypoxia with doxorubicin or cisplatin. ACSL4-mediated arachidonic acid (AA) metabolism supports mitochondrial β-oxidation and energy production. CCAAT/enhancer binding protein α (CEBPA) transcriptionally regulates ACSL4 by binding 3 motifs (-623 to -613, -1197 to -1187 and -1745 to -1735) of ACSL4 upstream promoter region, enhancing its pro-survival effects. Furthermore, canagliflozin (Cana), a clinical-approved drug for type 2 diabetes, mimics glucose starvation and inhibits the growth of ACSL4-low xenograft tumors. Moreover, high ACSL4 or CEBPA expressions correlate with increased recurrence susceptibility after PA-TACE in the China-Guangxi HCC cohort., Conclusions: The CEBPA-ACSL4 pathway is critical in protecting HCC cells from glucose starvation-induced cell death, suggesting that ACSL4 and CEBPA could serve as valuable prognostic indicators and potential therapeutic targets in the context of PA-TACE treatment for HCC., Competing Interests: Declarations Ethics approval and consent to participate The studies involving two HCC cohorts were conducted with approval from the National Healthcare Group Domain Specific Review Board (NHG DSRB Ref: 2011/01580) and the Guangxi Medical University Institutional Review Board (GXMU #20160302–10). Informed consent was obtained from all patients participating in the study. All animal experiments were approved by the Guangxi Medical University Institutional Animal Care and Use Committees (#201910029) and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care guidelines. Consent for publication The consents for publication from all authors were obtained. Competing interests The authors declare that they have no conflicts of interest., (© 2024. The Author(s).)

The study aimed to develop a prognostic model for Hepatocellular Carcinoma (HCC) based on pan-apoptosis-related genes, a novel inflammatory programmed cell death form intricately linked to HCC progression. Utilizing transcriptome sequencing and clinical data from the TCGA database, we identified six crucial pan-apoptosis-related genes through statistical analyses. These genes were then employed to construct a prognostic model that accurately predicts overall survival rates in HCC patients. Our findings revealed a strong correlation between the model's risk scores and tumor microenvironment (TME) status, immune cell infiltration, and immune checkpoint expression. Furthermore, we screened for drugs with potential therapeutic efficacy in high- and low-risk HCC groups. Notably, PPP2R5B gene knockdown was found to inhibit HCC cell proliferation and clonogenic capacity, suggesting its role in HCC progression. In conclusion, this study presents a novel pan-apoptosis gene-based prognostic risk model for HCC, providing valuable insights into patient TME status and guiding the selection of targeted therapies and immunotherapies., Competing Interests: Declaration of competing interest All authors declare no competing interests. We maintain objectivity and unbiasedness in our analysis and reporting of results, and no external influences have been exerted on the research process or outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sorafenib is a recommended first-line therapy for advanced hepatocellular carcinoma (HCC). However, when used as monotherapy in patients in advanced stages, the prognosis remains suboptimal. This study aimed to evaluate the impact of transcatheter arterial chemoembolization (TACE) on survival outcomes in patients with advanced HCC treated with sorafenib, as well as to identify which subgroups may benefit most from the addition of TACE. This single-institution retrospective study included 92 patients diagnosed with Barcelona Clinic liver cancer (BCLC) stage C HCC who received sorafenib between August 2011 and December 2016. We assessed the influence of different treatment modalities on prognosis using multivariable regression analysis. Patients were categorized into three subgroups: those with vascular invasion, those with distant metastasis, and those with both risk factors. Baseline comparisons indicated no significant differences in clinical characteristics among the three groups. Survival analysis showed no statistically significant difference in overall survival (OS) between the subgroups. However, in the overall cohort of patients with BCLC stage C, multifactorial Cox regression analysis identified pre-treatment alpha-fetoprotein (AFP) levels (p = 0.020), alkaline phosphatase (ALP) levels (p = 0.034), and the absence of combination TACE therapy (p = 0.008) as independent risk factors affecting OS. Further subgroup Cox analyses revealed that the lack of combination TACE therapy was an independent risk factor for OS in both the vascular invasion group and the group with both risk factors. In conclusion, for patients with advanced HCC receiving sorafenib, the addition of TACE may enhance long-term survival, particularly in those with vascular invasion.

In recent years, with the decline in HBV and HCV infections, there has been a corresponding reduction in both the morbidity and mortality of virus-associated HCC. Nevertheless, rising living standards, coupled with the increasing prevalence of metabolic disorders like diabetes and obesity, have led to a rapid surge in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) incidence. The mechanisms underlying the progression from NAFLD to NAFLD-HCC are multifaceted and remain incompletely understood. Current research suggests that genetic predisposition, metabolic dysregulation, lipotoxicity, oxidative stress, and inflammation are key contributing factors. Given the complexity of these mechanisms and the frequent occurrence of metabolic comorbidities like type 2 diabetes mellitus (T2DM) and cardiovascular disease in NAFLD-HCC patients, there is a pressing need for tailored therapeutic strategies, along with novel prevention, monitoring, and treatment approaches that are personalized to the patient's pathophysiology. Due to the limited depth of research, incomplete understanding of pathogenesis, and insufficient clinical data on NAFLD-HCC treatment, current therapeutic approaches largely rely on tumor staging. In this review, we synthesize current research on the pathogenesis, surveillance, diagnosis, treatment, and prevention of NAFLD-HCC, and offer perspectives for future studies, particularly regarding its underlying mechanisms.

Traditional hepatocellular carcinoma-chip models lack the cell structure and microenvironments necessary for high pathophysiological correlation, leading to low accuracy in predicting drug efficacy and high production costs. This study proposed a decellularized hepatocellular carcinoma-on-a-chip model to screen anti-tumor nanomedicine. In this model, human hepatocellular carcinoma (HepG2) and human normal liver cells (L02) were co-cultured on a three-dimensional (3D) decellularized extracellular matrix (dECM) in vitro to mimic the tumor microenvironments of human hepatocellular carcinoma in vivo. Additionally, a smart nanomedicine was developed by encapsulating doxorubicin (DOX) into the ferric oxide (Fe 3 O 4 )-incorporated liposome nanovesicle (NLV/Fe+DOX). NLV/Fe+DOX selectively killed 78.59% ± 6.78% of HepG2 cells through targeted delivery and synergistic chemo-chemodynamic-photothermal therapies, while the viability of surrounding L02 cells on the chip model retained high, at over 90.0%. The drug efficacy tested using this unique chip model correlated well with the results of cellular and animal experiments. In summary, our proposed hepatocellular carcinoma-chip model is a low-cost yet accurate drug-testing platform with significant potential for drug screening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This article aims to present the single-institution outcomes of patients with Fibrolamellar Carcinoma (FLC) treated with liver-directed therapies (LDT)., Methods: In this single-center retrospective study, all patients diagnosed with FLC who underwent LDT were identified. Between July 2012 and July 2023, six patients were identified. One patient was excluded due to bleeding. Demographic and clinical parameters were recorded. Complications within 30 days of the LDT were evaluated. Radiological treatment responses at 1, 6, and 12 months were assessed per mRECIST., Results: A total of five patients, which included three females and two males, were reviewed. Three patients were treated with transarterial hepatic embolization (TAE; n = 3), transarterial radioembolization (TARE; n = 1), and combined TAE + radiofrequency ablation (n = 1). The objective response rate at one month was 80% [CR = 2 (40%), PR = 2 (40%), and SD = 1 (20%)]. At 12 months (n = 4), two patients demonstrated CR (50%) and two demonstrated PR (50%). Overall survival from LDT at five years was 50%. There was no 30-day mortality among this group of patients or any adverse event attributable to the LDT., Conclusion: TAE, TARE, and ablation are safe and effective therapeutic options for FLC. Based on this study and previously published case reports, ablation and TARE yielded the most favorable results., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 The Authors.)

This randomized, prospective, multicenter (12 centers in China) phase III trial (Chinese Clinical Trial Registry #ChiCTR2000041170) compared drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with apatinib and DEB-TACE monotherapy for patients with unresectable hepatocellular carcinoma (uHCC). Progression-free survival (PFS) was the primary endpoint. Overall survival (OS), mRECIST-based objective response rates (ORR) and disease control rates (DCR), and treatment-related adverse events (TRAEs) were secondary endpoints. Totally 243 cases were randomized, with 122 and 121 in the DEB-TACE + apatinib and DEB-TACE groups, respectively. Cases administered DEB-TACE + apatinib displayed markedly improved median PFS (7.1 months [95%CI 6.6-8.3] vs. 5.2 months [95%CI 5.0-5.9]) and OS (23.3 months [95%CI 20.7-29.6] vs. 18.9 months [95%CI 17.9-20.1] compared with those treated with DEB-TACE (both p < 0.001). Additionally, patients administered DEB-TACE + apatinib had elevated ORR (56.6% vs. 38.8%) and DCR (89.3% vs. 80.2%) versus the DEB-TACE group (both p < 0.001). Majority of TRAEs were mild and manageable. Regarding DEB-TACE-related TRAEs, the rates of hepatic artery thinning and spasms were elevated during the second DEB-TACE in cases administered DEB-TACE + apatinib vs. DEB-TACE. The commonest apatinib-related TRAEs in the DEB-TACE + apatinib group included hypertension, hand-foot syndrome, fatigue, and diarrhea. In conclusion, DEB-TACE plus apatinib demonstrates superior PFS versus DEB-TACE monotherapy in uHCC cases, maintaining a favorable safety profile with similar occurrences of AEs., Competing Interests: Competing interests The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. Ethics The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (SS-2020-017) and followed the Declaration of Helsinki. Before enrollment, all participants provided informed consent. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR2000041170)., (© 2024. The Author(s).)

Immune checkpoint inhibitor (ICI)-based immunotherapy has emerged as the most promising strategy for hepatocellular carcinoma (HCC) downstaging prior to liver transplantation (LT). However, further evidence is required to assess the feasibility and safety of pretransplant ICI exposure. We retrospective analyzed 159 HCC patients who underwent LT at our institution from June 2019 to December 2023, and 39 recipients (39/159, 24.5%) received pretransplant ICI therapy. The perioperative acute rejection rate and rejection-related mortality rate in the ICI group were 23.1% (9/39) and 12.8% (5/39), respectively, which were significantly higher than those in the non-ICI group, at 5% (6/120, P = 0.002) and 0% (0/120, P = 0.001). There was no significant difference in the 90-day post-transplant overall survival (OS) (P = 0.447) and recurrence-free survival (RFS) (P = 0.723) between these two groups. We found 37.1% (59/159) recipients were found to have microvascular invasion (MVI), no matter whether the HCC tumor is within Milan criteria or not. Notably, though MVI was identified as a risk factor for the LT recipients, pretransplant ICI exposure appeared to be a protective factor for HCC patients with MVI which benefits its overall survival. Besides, the RFS and OS in the ICI exposure recipients with MVI were comparable to the non-ICI exposure recipients without MVI. However, no synergistic anti-tumor effects were observed with pretransplant ICI immunotherapy when combined with locoregional of TACE, HAIC, RFA and systematic of lenvatinib or sorafenib downstaging treatments, nor with post-transplant adjuvant of systematic or FOLFOX chemotherapy. Further comprehensive studies are needed to balance the dual natural effects of immunotherapy by optimizing downstaging protocols and patient selection to reduce acute rejection and improve long-term survival., Competing Interests: Declarations Conflict of interest The authors of this manuscript have no conflicts of interest to disclosure., (© 2024. The Author(s).)

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy., (© 2024. The Author(s).)

Intra-tumor immune infiltration plays a pivotal role in the interaction with tumor cells in hepatocellular carcinoma (HCC). However, its phenotype and related spatial structure remained elusive. To address these limitations, we conducted a comprehensive study combining spatial data (38,191 spots from eight samples) and single-cell data (56,022 cells from 20 samples). Our analysis revealed two distinct infiltration patterns: immune exclusion and immune activation. Plasma cells emerged as the primary cell type within intra-tumor immune clusters. Notably, we observed the co-location of CCL19+ fibroblasts with plasma cells, which secrete chemokines and promote T-cell activation and leukocyte migration. Conversely, in immune-exclusion samples, this co-location was primarily observed in the adjacent normal area. This co-localization correlated with T cell infiltration and the formation of tertiary lymphoid structures, validated by multiplex immunofluorescence conducted on twenty HCC samples. Both CCL19+ fibroblasts and plasma cells were associated with favorable survival outcomes. In an immunotherapy cohort, HCC patients who responded favorably exhibited higher infiltration of CCL19+ fibroblasts and plasma cells. Additionally, we observed the accumulation of DKK1+ tumor cells within the tumor area in immune-exclusion samples, particularly at the tumor boundary, which inhibited the infiltration of CCL19+ fibroblasts and plasma cells into the tumor area. Furthermore, in immune-exclusion samples, the SPP1 signaling pathway demonstrated the highest activity in communication between tumor and immune clusters, and CCL19-CCR7 played a pivotal role in the self-communication of immune clusters. This study elucidates immune exclusion and immune activation patterns in HCC and identifies relevant factors contributing to immune resistance., (© 2024. The Author(s).)

Background: Integration of symptom and palliative care for people with advanced cancer is established in many tumour types, but its role in people with hepatocellular carcinoma (HCC) has not been clearly defined. This study aims to evaluate the clinical and cost effectiveness of an intervention involving a suite of strategies designed to assess and treat palliative care symptoms and needs in adult outpatients with HCC attending four New South Wales (NSW) metropolitan tertiary hospitals., Methods: This trial will use a pragmatic cluster-based randomised-controlled design, with ambulatory HCC services as the clusters. HCC patients will be recruited if they have Barcelona Clinical Liver Cancer (BCLC) stage A disease with active tumour or a current or prior diagnosis of BCLC stage B or C disease regardless of tumour activity. Patients with BCLC stage D disease will be excluded as palliative care is the standard of care (SOC) in this group. Cluster sites will be randomised to the study intervention or control where patients are managed according to SOC. All participants will complete the liver-specific Edmonton Symptom Assessment Scale (ESAS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire at regular ambulatory clinic appointments. At intervention sites, patients scoring ≥ 5 on any liver-specific ESAS symptom will be referred to palliative care physicians for consultation. The primary clinical outcome will be improvement in all symptoms scored ≥ 5 on the liver-specific ESAS by 50% within 3 months and the primary implementation outcome will recording the liver-specific ESAS in ≥ 80% of all participants attending clinic appointments. Caregivers of patients enrolled in the trial will be invited to perform Carer Support Needs Assessment Tool at each appointment., Discussion: This trial will inform if earlier palliative care involvement significantly reduces the symptom burden associated with HCC. If found to be effective, earlier implementation of palliative care consultation should be included in HCC treatment guidelines., Trial Registration: ACTRN12623000010695. Registered on September 1, 2023., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers worldwide, highlighting the urgent need for improved diagnostic and therapeutic methodologies. The standard treatment regimen generally involves surgical intervention followed by systemic therapies; however, the median survival rates for patients remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a pivotal advancement in cancer treatment. Both clinical and preclinical studies emphasize the notable efficacy of CAR T cells in targeting HCC. Various molecules, such as GPC3, c-Met, and NKG2D, show significant promise as potential immunotherapeutic targets in liver cancer. Despite this, employing CAR T cells to treat solid tumors like HCC poses considerable challenges within the discipline. Numerous innovations have significant potential to enhance the efficacy of CAR T-cell therapy for HCC, including improvements in T cell trafficking, strategies to counteract the immunosuppressive tumor microenvironment, and enhanced safety protocols. Ongoing efforts to discover therapeutic targets for CAR T cells highlight the need for the development of more practical manufacturing strategies for CAR-modified cells. This review synthesizes recent findings and clinical advancements in the use of CAR T-cell therapies for HCC treatment. We elucidate the therapeutic benefits of CAR T cells in HCC and identify the primary barriers to their broader application. Our analysis aims to provide a comprehensive overview of the current status and future prospects of CAR T-cell immunotherapy for HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Wei, Xu, Wu, Dou, Li, Zhang and Zhang.)

Purpose: In the treatment of hepatocellular carcinoma (HCC) with transarterial radioembolization (TARE), identifying reliable biomarkers for predicting survival outcomes remains a critical challenge. We aimed to address this gap by investigating the significance of serum cytokines associated with inflammation as potential biomarkers for the selection of patients for TARE., Methods: Our retrospective study involved 161 patients diagnosed with HCC who underwent Y90 radioembolization at our medical center between 2010 and 2020. Serum samples from a subset of 78 patients were retrospectively analyzed to determine the concentrations of pro-inflammatory cytokines. The results from the prospective SORAMIC trial were used for independent validation., Results: With a median overall survival of 36 weeks (range 4-436), our study showed the strongest correlation between 12-week survival and IL-8 levels before treatment (p < 0.001), while other relevant interleukins, interferon-α2, INF-γ, TNF-α and MCP-1 were not associated with survival. IL-8 levels below the cut-off of 190 pg/mL were significantly associated with increased 12-week and 24-week survival, with hazard ratios of 19.01 (95% CI: 2.29-157.89) and 2.57 (95% CI: 1.05-6.31), respectively (p = 0.006 and p = 0.039, respectively). In the adjusted multivariate analysis, the 190 pg/mL cut-off for IL-8 remained independently associated with 12- (p = 0.011) and 24-week survival (p = 0.039). Similarly, the SORAMIC population showed a strong association between IL-8 levels and 36-week survival (p = 0.03)., Conclusion: Our study emphasizes the pivotal role of IL-8 as a valuable parameter, demonstrating its potential for predicting treatment outcomes and assessing liver function in patients with HCC undergoing TARE. The robustness of these findings warrants further validation., (© 2024. The Author(s).)

In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma patient-derived xenografts (HCC-PDX) encounter limitations in NK cell infiltration, hindering studies on NK cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 reinstated persistent NK cell reconstitution and infiltration in HCC-PDX in humanized mice. scRNA-seq revealed NK cell and T cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights., Competing Interests: Declaration of interests Q.C. is the scientific cofounder of two biotech companies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients., Methods: Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted., Results: The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS., Conclusion: The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy., (© 2024. The Author(s).)

Objective: We aimed to characterize quality of life (QOL) trajectories among patients with intermediate and advanced hepatocellular carcinoma patients treated with immunotherapy., Methods: Barcelona Clinic Liver Cancer (BCLC) stage B-C HCC patients receiving immunotherapy at Guangxi Medical University Cancer Hospital were included. Trajectories of QOL, assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire, were identified through iterative estimations of group-based trajectory models. Associations with trajectory group membership were analyzed using multivariable multinomial logistic regression., Results: Three trajectory groups were identified (n=156): excellent (35.3%), poor (43.6%), and deteriorating (21.1%) QOL. The deteriorating trajectory group reported a mean QOL score of 124.79 (95% CI, 116.58-133.00), but then declined significantly at month-2 (estimated QOL score 98.67 [95% CI, 84.33-113.00]), and the lowest mean score is reached at month-6 (estimated QOL score 16.58 [95% CI, 0-46.07]). Factors associated with membership to the deteriorating group included no drinking (odds ratio [OR] vs yes [95% CI], 3.70 [1.28-11.11]), no received radiotherapy (OR vs yes [95% CI], 8.33 [1.41-50.00]), diabetes (OR vs no [95% CI], 6.83 [1.57-29.73]), and extrahepatic metastasis (OR vs no [95% CI], 3.08 [1.07-8.87]). Factors associated with membership to the poor group also included body mass index ≤24.0 kg/m 2 (OR vs no [95% CI], 4.49 [1.65-12.22])., Conclusions: This latent-class analysis identified a high-risk cluster of patients with severe, persistent post-immunotherapy QOL deterioration. Screening relevant patient-level characteristics may inform tailored interventions to mitigate the detrimental impact of immunotherapy and preserve QOL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 You, Lu, Li, Zhao and Huo.)

The efficacy of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the mechanisms underlying treatment resistance. Accumulating evidence indicates that tumor-associated macrophages (TAM) within the tumor microenvironment demonstrate a key role in immune evasion and treatment resistance. This study explored the role of TAMs in the HCC tumor microenvironment. Our findings reveal that TAMs expressing CX3C motif chemokine receptor 1 (CX3CR1) induced T-cell exhaustion through IL27 secretion in orthotopic models of HCC following treatment with anti-PD1. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of TAM transition to a CX3CR1+ phenotype. To augment the therapeutic response to anti-PD1 therapy, we propose targeting CX3CR1+ TAMs in addition to anti-PD1 therapy. Our study contributes to the understanding of the role of TAMs in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in patients with HCC., (©2024 American Association for Cancer Research.)

This study was to develop and validate a model for predicting who can benefit from multiple transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients.228 and 98 patients were included in the development and validation sets, respectively. The primary clinical endpoint was benefiting from consecutive multiple TACE treatments. Logistic regression analysis was used to screen the independent risk factors for the clinical endpoint. The independent risk factors were then used to construct the predictive model. The area under receiver operating characteristic (ROC) curves, calibration curves, and clinical decision curves were used to evaluate the predictive ability of the model.Multivariate Logistic regression analysis showed that complete envelope, hepatic lopes, tumor number, and alpha-fetoprotein (AFP) were independent risk factors for benefiting from multiple TACE in HCC patients. The area under the curve (AUC) of the model constructed by using independent risk factors in the development and validation sets was 0.843 (95% confidence interval [CI]: 0.784-0.902) and 0.828 (95%CI: 0.739-0.916), respectively. The calibration curves and clinical decision curves showed that the model had good predictive ability.The model established in this study has a good predictive effect on HCC patients who can benefit from multiple TACE., (© 2024. The Author(s).)

The management of hepatocellular carcinoma (HCC) is undergoing transformational changes due to the emergence of various novel immunotherapies and their combination with image-guided locoregional therapies. In this setting, immunotherapy is expected to become one of the standards of care in both neoadjuvant and adjuvant settings across all disease stages of HCC. Currently, more than 50 ongoing prospective clinical trials are investigating various end points for the combination of immunotherapy with both percutaneous and catheter-directed therapies. This review will outline essential tumor microenvironment mechanisms responsible for disease evolution and therapy resistance, discuss the rationale for combining locoregional therapy with immunotherapy, summarize ongoing clinical trials, and report on developing imaging end points and novel biomarkers that are relevant to both diagnostic and interventional radiologists participating in the management of HCC., (© RSNA, 2024.)

With the rising incidence of hepatocellular carcinoma, there has been increasing use of local-regional therapy (LRT) to downstage or bridge to transplant, for definitive treatment, and for palliation. The CT/MRI Liver Imaging Reporting and Data System (LI-RADS) Treatment Response Assessment (TRA) algorithm provides guidance for step-by-step tumor assessment after LRT and standardized reporting. Current evidence suggests that the algorithm performs well in the assessment of tumor response to arterial embolic and loco-ablative therapies and fair when assessing response to radiation-based therapies, with limited data to validate the latter. Both evidence-based and expert-based refinements of the algorithm are needed to improve its diagnostic accuracy after varying types of LRT. This review provides an overview of the challenges and limitations of the LI-RADS TRA algorithm version 2017 and discusses the refinements introduced in the updated 2024 LI-RADS algorithm for CT/MRI., (© RSNA, 2024.)

Aim: The purpose of this study was to evaluate the predictors of deterioration of the Child-Pugh classification 1 month after transcatheter arterial chemo-embolization (TACE) in patients with treatment-naive hepatocellular carcinoma (HCC)., Methods: Between 2010 and 2020, consecutive patients who underwent conventional TACE using epirubicin as the initial treatment were enrolled. Patients with Barcelona Clinic Liver Cancer stage-0, A or B and Child-Pugh class A were included. The Child-Pugh score was evaluated before treatment and 1 month after TACE. The following variables were analyzed by univariate and multivariate analyses as predictors of deterioration of the Child-Pugh class from A to B: age, sex, etiology, serum albumin, bilirubin, prothrombin time (PT), encephalopathy, ascites, largest tumor diameter, tumor number, tumor location, α-fetoprotein, protein induced by vitamin K absence or antagonist-II, epirubicin dosage, ethiodized oil dosage, and number of treated liver segments., Results: A total of 152 patients were retrospectively enrolled. The deterioration rate of the Child-Pugh class from A to B was 8.6%. Multivariable analysis showed that serum albumin ≤ 3.8 g/dL, PT ≤ 80%, and largest tumor diameter ≥ 3.8 cm were predictors of deterioration of the Child-Pugh class. The deterioration rate to Child-Pugh class B was 0% in patients with up to one of these factors, 14.3% in those with two factors, and 70% in those with three factors., Conclusions: A combination of serum albumin ≤ 3.8 g/dL, PT ≤ 80%, and largest tumor diameter ≥ 3.8 cm can predict the immediate deterioration of the Child-Pugh classification from A to B following TACE., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis., Methods: Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO 2 (HMnO 2 ). The conditions and capacity of HMnO 2 to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO 2 @DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO 2 @DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism., Findings: The high adhesion and crosslinking of Zein with HMnO 2 @DOX impart Zein-HMnO 2 @DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO 2 decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O 2 release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O 2 release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression., Interpretation: This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation., Funding: Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Due to heterogeneity of molecular biology and microenvironment, therapeutic efficacy varies among hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs). We examined combined models using clinicoradiological characteristics, mutational burden of signaling pathways, and radiomics features to predict survival prognosis., Methods: Two cohorts comprising 111 patients with HCC were used to build prognostic models. The training and test cohorts included 78 and 33 individuals, respectively. Mutational burden was calculated based on 17 cancer-associated signaling pathways. Radiomic features were extracted and selected from computed tomography images using a pyradiomics system. Models based on clinicoradiological indicators, mutational burden, and radiomics score (rad-score) were built to predict overall survival (OS) and progression-free survival (PFS)., Results: Eastern Cooperative Oncology Group performance status, Child-Pugh class, peritumoral enhancement, PI3K&#95;AKT and hypoxia mutational burden, and rad-score were used to create a combined model predicting OS. C-indices were 0.805 (training cohort) and 0.768 (test cohort). The areas under the curve (AUCs) were 0.889, 0.900, and 0.917 for 1-year, 2-year, and 3-year OS, respectively. To predict PFS, alpha-fetoprotein level, tumor enhancement pattern, hypoxia and receptor tyrosine kinase mutational burden, and rad-score were used. C-indices were 0.782 (training cohort) and 0.766 (test cohort). AUCs were 0.885 and 0.925 for 6-month and 12-month PFS, respectively. Calibration and decision curve analyses supported the model's accuracy and clinical potential., Conclusions: The nomogram models are hopeful to predict OS and PFS in patients with intermediate-advanced HCC treated with TACE plus TKIs, offering a promising tool for treatment decisions and monitoring patient progress., Competing Interests: Declarations Conflict of interest The authors declare that they have no competing interests. Ethics approval and consent to participate This retrospective study was conducted in accordance with the protocol approved by the Institutional Review Board of The First Affiliated Hospital, Sun Yat-Sen University (ethical number: No [2018] 230). Written informed consent was obtained from each patient. Consent for publication Not applicable., (© 2024. Italian Society of Medical Radiology.)

Purpose: To create and evaluate prediction models of local tumor recurrence after successful conventional transcatheter arterial chemoembolization (c-TACE) via radiomics analysis of lipiodol deposition using cone-beam computed tomography (CBCT) images obtained at the completion of TACE., Materials and Methods: A total of 103 hepatocellular carcinoma nodules in 71 patients, who achieved a complete response (CR) based on the modified Response Evaluation Criteria in Solid Tumors 1 month after TACE, were categorized into two groups: prolonged CR and recurrence groups. Three types of areas were segmented on CBCT: whole segment (WS), tumor segment (TS), and peritumor segment (PS). From each segment, 105 radiomic features were extracted. The nodules were randomly divided into training and test datasets at a ratio of 7:3. Following feature reduction for each segment, three models (clinical, radiomics, and clinical-radiomics models) were developed to predict recurrence based on logistic regression., Results: The clinical-radiomics model of WS showed the best performance, with the area under the curve values of 0.853 (95% confidence interval: 0.765-0.941) in training and 0.752 (0.580-0.924) in test dataset. In the analysis of radiomic feature importance of all models, among all radiomic features, glcm&#95;MaximumProbability, shape&#95;MeshVolume and shape&#95;MajorAxisLength had negative coefficients. In contrast, shape&#95;SurfaceVolumeRatio, shape&#95;Elongation, glszm&#95;SizeZoneNonUniformityNormalized, and gldm&#95;GrayLevelNonUniformity had positive coefficients., Conclusion: In this study, a machine-learning model based on cone-beam CT images obtained at the completion of c-TACE was able to predict local tumor recurrence after successful c-TACE. Nonuniform lipiodol deposition and irregular shapes may increase the likelihood of recurrence., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Global statistics indicate that hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer‑related death. Protein phosphatase Mg 2+ /Mn 2+ dependent 1G (PPM1G, also termed PP2Cγ) is one of the 17 members of the PPM family. The enzymatic activity of PPM1G is highly reliant on Mg 2+ or Mn 2+ and serves as a dephosphorylation regulator for numerous key proteins. PPM1G, functioning as a phosphatase, is involved in a number of significant biological processes such as the regulation of eukaryotic gene expression, DNA damage response, cell cycle and apoptosis, cell migration ability, cell survival and embryonic nervous system development. Additionally, PPM1G serves a role in regulating various signaling pathways. In recent years, further research has increasingly highlighted PPM1G as an oncogene in HCC. A high expression level of PPM1G is closely associated with the occurrence, progression and poor prognosis of HCC, offering notable diagnostic and therapeutic value for this patient population. In the present review, the regulatory role of PPM1G in diverse biological processes and signaling pathway activation in eukaryotes is evaluated. Furthermore, its potential application as a biomarker in the diagnosis and prognosis evaluation of HCC is assessed, and future prospects for HCC treatment strategies centered on PPM1G are discussed.

Although transarterial chemoembolization has improved as an interventional method for hepatocellular carcinoma, subsequent postembolization syndrome is a threat to the patients' quality of life. This study aimed to evaluate the effectiveness of a clinical decision support system in postembolization syndrome management across nurses and patient outcomes. This study is a randomized controlled trial. We included 40 RNs and 51 hospitalized patients in the study. For nurses in the experimental group, a clinical decision support system and a handbook were provided for 6 weeks, and for nurses in the control group, only a handbook was provided. Notably, the experimental group exhibited statistically significant improvements in patient-centered caring attitude, pain management barrier identification, and comfort care competence after clinical decision support system implementation. Moreover, patients' symptom interference during the experimental period significantly decreased compared with before the intervention. This study offers insights into the potential of clinical decision support system in refining nursing practices and nurturing patient well-being, presenting prospects for advancing patient-centered care and nursing competence. The clinical decision support system contents, encompassing postembolization syndrome risk prediction and care recommendations, should underscore its role in fostering a patient-centered care attitude and bolster nurses' comfort care competence., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Transarterial chemoembolization (TACE) is recommended as a palliative treatment for patients of the B stage of the Barcelona Clinic Liver Cancer (BCLC) classification., Aims: To identify clinical, biological, and radiological predictors of survival in patients undergoing TACE and develop a pre-therapeutic prognostic score., Methods: 191 adult cirrhotic patients treated for HCC with TACE at the University Hospital (UH) of Clermont-Ferrand (France) from 2007-2017 were retrospectively included. We investigated the impact of baseline liver function, patient characteristics, and tumor burden on overall survival and developed a prognostic score., Results: Patients had a median age of 66 years and 126 patients were Child A. The AFP-DIAM score distinguishes two groups with a significant difference in survival time (median OS 28.3 months in patients with a score = 0 versus 17.7 months in patients with a score > 0). AFP-DIAM was validated on an external cohort, is well calibrated, and has the best discrimination capacity (C-index) as compared to NIACE, HAP, STATE, and SIX TO TWELVE. AFP-DIAM and SIX TO TWELVE are the more easy-to-use scores. When AFP-DIAM and the SIX TO TWELVE scores were tested in the same statistical model, results confirmed a better AFP-DIAM performance., Conclusions: The AFP-DIAM is an easy-to-use score which allows to distinguish two groups with different prognosis before the first TACE session. Its use could provide further support to BCLC system to guide the therapeutic strategy of patients with HCC., Competing Interests: Declarations Conflict of interest All authors have no potential conflict of interests related to this article to declare., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking., Objective: To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol., Design, Setting, and Participants: This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued., Exposure: All patients had received stereotactic body radiotherapy followed by anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy., Main Outcomes and Measures: The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses., Results: A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P < .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR., Conclusions and Relevance: This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.

Background: The widely accepted view that portal hypertension (PHT) is a contraindication to hepatectomy for patients with hepatocellular carcinoma (HCC) is being increasingly challenged. The long-term survival outcomes and safety of partial hepatectomy versus interventional treatment using ablation with or without pre-ablation transarterial chemoembolization (TACE) in patients with HBV-related HCC within the Milan criteria and with clinically significant PHT were compared in this study., Methods: This open-label randomized clinical trial was conducted on consecutive patients with clinically PHT and hepatitis B virus (HBV)-related HCC with tumors which were within the Milan criteria. These patients were randomized 1:1 to receive either partial hepatectomy or interventional treatment between December 2012 and June 2018. The primary endpoint was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and therapeutic safety., Results: Each of the 2 groups had 80 patients. The 1-, 3- and 5-year OS rates in the partial hepatectomy group and the interventional treatment group were 95.0%, 86.2%, 69.5% versus 93.8%, 77.5%, 64.9%, respectively (P = 0.325). The corresponding RFS rates were 78.8%, 55.0%, 46.2% versus 71.3%, 52.5%, 45.0%, respectively (P = 0.783). The partial hepatectomy group had a higher complication rate compared to the interventional group (67.5% vs. 20%, P < 0.001). However, the differences were mainly in Clavien-Dindo Grade I complications (P < 0.001), while not significant in Grade II/III/IV/V (All P > 0.05)., Conclusions: This study shows that partial hepatectomy treatment did not meet prespecified significance for improved OS and RFS compared to interventional treatment for patients with HBV-related HCC within the Milan criteria and with clinically significant PHT. However, partial hepatectomy is still a safe procedure and should be considered as a treatment option rather than a contraindication., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer and the third leading cause of cancer mortality globally. Despite surgical resection being the preferred approach for early-stage HCC, most patients are diagnosed at intermediate to advanced stages, limiting treatment options to chemotherapy and immunotherapy, which often yield poor outcomes. Extracellular vesicles (EVs), minute lipid-bilayered particles released by diverse cells under various physiological and pathological conditions, are crucial for mediating communication between cells. Mounting evidence indicates that EVs sourced from different cells can profoundly influence the HCC tumor microenvironment (TME), thereby affecting the progression of HCC. Given their immunogenicity and liver-targeting properties, these EVs not only hold promise for HCC treatment but also provide avenues for advancing early diagnostic methods and assessing prognosis. This review not only describes the function of EVs within the HCC tumor microenvironment but also analyzes their therapeutic advantages and explores their significance in various therapeutic approaches for HCC, including chemotherapy, immunotherapy, combination therapy, and their role as innovative drug delivery carriers. Furthermore, it highlights the potential of EVs as biomarkers for the diagnosis and prognosis of HCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Favorable clinical outcomes have been reported with the adjunct use of beta-blockers in cancer treatment, hypothetically secondary to their anti-angiogenic/anti-proliferative effects. Hereby, we investigate whether there is synergy between beta-blockers and TACE in the treatment of HCC., Methods: 36 HCC patients on beta-blockers (mean dose of 48 mg daily) at the time of first-line treatment with TACE at our institution were retrospectively identified out of a cohort of 221 patients between 2008 and 2019. Using propensity scoring, a matched cohort of 36 patients not exposed to beta-blockers was generated based on age, gender, ethnicity, etiology of liver disease, BCLC, child Pugh score, PS/ECOG, cirrhosis, largest mass treated, type of TACE and treated liver segments. Tumor response was assessed at 1st and 2nd post-TACE imaging timepoints (1.4 and 4.1 months on average respectively). Variables were compared using chi-square test and Student's t-test. Kaplan-Meier transplant-free survival plots were generated using IBM® SPSS® software. Cox regression analysis was used to evaluate survival predictors. A p values < 0.05 was considered significant., Results: Comparing the control and beta-blocker cohorts, there were no differences in baseline characteristics, post-TACE imaging timepoints, tumor response or transplant free survival (p > 0.05). Tumor size was found to be a predictor of survival when the two cohorts were combined (p = 0.03)., Conclusion: Transplant-free survival and HCC response to first-line TACE treatment were similar in the control and beta-blocker groups. Large tumor sizes were associated with higher mortality in combined analysis of the cohorts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: This review assesses the efficacy and safety of the combination of transarterial chemoembolization (TACE) and camrelizumab for treating advanced hepatocellular carcinoma (HCC) and is to provide a goal, evidence-based medical foundation for effectively guiding clinical practice., Methods: We conducted a computerized search of six electronic databases to identify studies pertinent to the combination of TACE and camrelizumab for treating advanced HCC. For further analysis of clinical indicators and adverse events data, we utilized random or fixed-effect models to account for heterogeneity between studies., Results: As of May 30, 2023, 12 articles were included for Meta-analysis, encompassing 1123 patients with advanced HCC. The results indicated that the combined objective response rate (ORR) and disease control rate (DCR) were 51.1 % and 86.8 %, respectively. Regarding survival indicators, the combined overall survival (OS) and progression-free survival (PFS) were 24.26 months and 11.84 months, respectively. Among the adverse events observed, the highest incidence rates for TACE combined with camrelizumab were fever (all grade: 46.5 %, ≥grade III: 5.0 %), hypertension (all grade: 32.2 %, ≥grade III: 8.5 %), transaminase elevation (all grade: 34.7 %, ≥grade III: 13.4 %), and nausea and vomiting (all grade: 43.9 %, ≥grade III: 2.5 %)., Conclusions: This study demonstrated the efficacy and safety of combining TACE with camrelizumab in treating patients with advanced HCC, providing valuable evidence for its prospective clinical application. However, due to the limited availability of clinical data, it is essential to design larger-scale and multi-center clinical randomized controlled trials in the future to validate and confirm these findings definitively., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Purpose: To evaluate the effect of deep learning reconstruction (DLR) on vascular depiction, tumor enhancement, and image quality of computed tomography hepatic arteriography (CTHA) images acquired during transcatheter arterial chemoembolization (TACE)., Methods: Institutional review board approval was obtained. Twenty-seven patients (18 men and 9 women, mean age, 75.7 years) who underwent CTHA immediately before TACE were enrolled. All images were reconstructed using three reconstruction algorithms: hybrid-iterative reconstruction (hybrid-IR), DLR with mild strength (DLR-M), and DLR with strong strength (DLR-S). Vascular depiction, tumor enhancement, feeder visualization, and image quality of CTHA were quantitatively and qualitatively assessed by two radiologists and compared between the three reconstruction algorithms., Results: The mean signal-to-noise ratios (SNR) of sub-segmental arteries and sub-sub-segmental arteries, and the contrast-to-noise ratio (CNR) of tumors, were significantly higher on DLR-S than on DLR-M and hybrid-IR (P < 0.001). The mean qualitative score for sharpness of sub-segmental and sub-sub-segmental arteries was significantly better on DLR-S than on DLR-M and hybrid-IR (P < 0.001). There was no significant difference in the feeder artery detection rate of automated feeder artery detection software among three reconstruction algorithms (P = 0.102). The contrast, continuity, and confidence level of feeder artery detection was significantly better on DLR-S than on DLR-M (P = 0.013, 0.005, and 0.001) and hybrid-IR (P < 0.001, P = 0.002, and P < 0.001). The weighted kappa values between two readers for qualitative scores of feeder artery visualization were 0.807-0.874. The mean qualitative scores for sharpness, granulation, and diagnostic acceptability of CTHA were better on DLR-S than on DLR-M and hybrid-IR (P < 0.001)., Conclusions: DLR significantly improved the SNR of small hepatic arteries, the CNR of tumor, and feeder artery visualization on CTHA images. DLR-S seems to be better suited to routine CTHA in TACE than does hybrid-IR., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) presents a significant global health burden, with varying survival rates across regions. The presence of pulmonary metastases (PM) in HCC predicts a poorer prognosis, yet the global understanding of the progression and management is limited., Methods: This study aims to systematically review the burden of PM in HCC, document current treatment approaches, and evaluate treatment effectiveness through meta-analysis. A comprehensive literature search was conducted across multiple databases. Articles were screened, and data extraction was performed independently by two reviewers. Statistical analyses were conducted to synthesise data and assess treatment outcomes., Results: A total of 82 articles were included, comprising a population of 3241 participants with documented PM. Our analysis revealed a linear relationship between the HCC population size and the occurrence of PM (p < 0.005). Surgical intervention demonstrated the lowest hazard ratio (0.128) and significantly improved survival rates compared to other treatment modalities. However, data quality limitations underscore the need for further research to delineate patient subsets benefitting from surgical intervention for PM., Conclusion: Our findings advocate for continued investigation into PM management strategies, notably the role of surgical resection alongside systemic therapies, to improve outcomes in HCC patients with PM., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Gene therapy and sonodynamic therapy, as emerging treatment methods, have great potential in cancer treatment. However, there are significant challenges in the in vivo delivery of genes and sonosensitizers during the treatment process, which ultimately affects the therapeutic outcome. In this study, an ultrasound-sensitive targeted liposome nanoparticle system (MLip siBcl-2 ) is developed to deliver the sonosensitizers and siRNA for the synergistic treatment of hepatocellular carcinoma. Generation of reactive oxygen species (ROS) by MLip siBcl-2 can be initiated through ultrasound stimulation, leading to liposome rupture and release of the sonosensitizer and small interfering RNA (siRNA). Furthermore, ROS can disrupt lysosomal membranes, facilitating gene release for downregulating overexpressed antiapoptotic protein levels in cancer cells. Experimental results from in vitro and in vivo studies demonstrated the efficacy of synergistic treatment on hepatocellular carcinoma cells and the high biocompatibility of MLip siBcl-2 under ultrasound stimulation. The advancement of this ultrasound-sensitive targeted gene delivery system shows potential as a versatile therapeutic platform that is easily operable, presenting a prospect for a synergistic treatment approach across various cancer types., (© 2024 Wiley‐VCH GmbH.)

Purpose: To compare oncologic outcomes of transarterial chemoembolization (TACE) using 70-150-μm and 100-300-μm drug-eluting embolics (DEEs) to treat small hepatocellular carcinoma (HCC)., Materials and Methods: This retrospective study included 93 patients with small HCC (≤3 cm) who underwent their first TACE with DEEs: (a) 43 with 70-150-μm DEEs and (b) 50 with 100-300-μm DEEs. Initial tumor response was assessed using per-patient and per-lesion analyses. Progression-free survival (PFS) and target tumor PFS were analyzed for patients and lesions with initial complete response (CR). Overall survival (OS) and safety outcomes were also evaluated., Results: At 1 month, initial CR rates were 72.1% in the 70-150-μm group and 70.0% in the 100-300-μm group. PFS was significantly longer in the 70-150-μm group (median, 26 months) compared with that in the 100-300-μm group (median, 11 months; log-rank P = .049), with comparable OS results (P = .096, median not reached at 36 months for either group). Per-lesion analysis found that target tumor PFS was significantly longer in the 70-150-μm group (median, 30 months) compared with that in the 100-300-μm group (median, 13 months; P = .009). Subgroup analysis revealed that the 70-150-μm group had significantly longer target tumor PFS compared with the 100-300-μm group in the 1.0-2.0-cm subgroup (P = .017), but not in the 2.1-3.0-cm subgroup (P = .117). No significant differences in adverse events were observed between the 2 groups., Conclusions: The 70-150-μm and 100-300-μm DEE-TACEs resulted in comparable tumor response and short-term safety in small HCCs (≤3 cm). However, in cases where CR was achieved, treatment with smaller microspheres demonstrated longer PFS and target tumor PFS., (Copyright © 2024. Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child-Pugh class A., (© 2024. The Author(s).)

Purpose: To provide detailed reports on radiation doses during transarterial chemoembolization (TACE) in the cone-beam computed tomography (CBCT) era and to identify the associated factors., Methods: This retrospective study included 385 consecutive patients who underwent initial conventional TACE for hepatocellular carcinoma (HCC) between January 2016 and December 2017. In most cases, CBCT was performed at the common hepatic artery or celiac axis to confirm the location of the tumor and the three-dimensional hepatic artery anatomy. Superselective TACE was performed for all technically feasible cases. Information on total dose area product (DAP), total cumulative air kerma (CAK), fluoroscopy time, and DAP and CAK of each digital subtraction angiography (DSA) and CBCT scan was recorded. Multiple linear regression analysis was performed to identify the factors associated with increased DAP during TACE., Results: The mean values of total DAP and CAK were 165.2 ± 81.2 (Gy·cm²) and 837.1 ± 571.0 (mGy), respectively. The mean fluoroscopy time was 19.1 ± 10.3 min. The mean DAP caused by fluoroscopy, DSA, and CBCT was 51.8 ± 43.9, 28.0 ± 24.1, and 83.9 ± 42.1 Gy·cm², respectively. Male sex, a high body mass index, largest tumor size > 3 cm, presence of aberrant right and left hepatic arteries, and superselective TACE were identified as independent predictors of increased total DAP during TACE., Conclusion: We were able to provide detailed reports on radiation doses during TACE and associated factors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale and Objectives: To compare the treatment efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib versus TACE alone in patients with intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria., Materials and Methods: A total of 107 newly diagnosed HCC patients with Barcelona Clinic Liver Cancer stage B HCC beyond up-to-seven criteria were included in this retrospective cohort study. These patients were divided into two groups: TACE-Lenv group and TACE alone group. Propensity score matching was used to account for potential confounding factors. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), downstaging rate, liver function, and adverse events (AEs) were recorded and evaluated., Results: Both the median OS and median PFS were significantly longer in the TACE-Lenv group compared to the TACE alone group (median OS: 28.0 vs 12.0 months, P = 0.017; median PFS [mRECIST]: 8.2 vs 3.7 months, P = 0.018; median PFS [RECIST v1.1]: 8.9 vs 3.7 months, P = 0.003). Furthermore, the ORR and DCR were also significantly higher in TACE-Lenv group (ORR: 94% [30/32] vs 47% [15/32], P < 0.001; DCR: 97% [31/32] vs 62% [20/32], P < 0.001). There were no significant differences in terms of liver function and grade 3 or 4 AEs rate between two groups., Conclusion: The combination of TACE and lenvatinib provides clinical benefits for patients with intermediate HCC beyond the up-to-seven criteria, has an acceptable safety profile, shows a trend towards improving liver function, and does not increase the occurrence of grade 3-4 AEs., Key Points: The efficacy of transarterial chemoembolization in intermediate-stage hepatocellular carcinoma patients is partially unsatisfactory. Addition of lenvatinib to transarterial chemoembolization improves OS, PFS, ORR, and DCR for patients with intermediate-stage hepatocellular carcinoma beyond the up-to-seven criteria. This combination therapy is a superior treatment option for intermediate-stage hepatocellular carcinoma patients with high tumor burden., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease., Materials and Methods: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability., Results: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7)., Conclusions: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials., Competing Interests: Conflicts of interest A.L. reports receiving consulting fees from Advanz Pharma, AlfaSigma, Takeda, and Albireo Pharma, and speaker fees from Gilead, Abbvie, MSD, Intercept Pharma, AlfaSigma, GSK, and Incyte. BS received grant support from AstraZeneca and Eisai; speaker honoraria from Eisai; and travel support from AbbVie, AstraZeneca, Ipsen, and Gilead. MP received travel support from Bayer, BMS, Ipsen, Lilly, MSD, and Roche; he is a consultant for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; and he received travel support from Bayer, BMS, Ipsen, and Roche. HW received consulting and speaker fees from Roche, AstraZeneca, Eisai, and Ipsen., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. All rights reserved.)

Background: Locoregional treatment with transarterial chemoembolization (TACE) or hepatic artery infusion chemotherapy (HAIC) and systemic targeted immunotherapy with tyrosine kinase inhibitors (TKI) and programmed cell death protein-1 (PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC) have achieved promising efficacy. The retrospective study aimed to evaluate the efficacy and safety of TACE and HAIC plus TKI with or without PD-1 for uHCC., Patients and Methods: From November 2020 to February 2024, the data of 44 patients who received TACE-HAIC + TKI + PD-1 (THKP group) and 34 patients who received TACE-HAIC + TKI (THK group) were retrospectively analyzed. Primary outcomes were overall survival (OS) and progress-free survival (PFS), and secondary outcomes were objective response rate (ORR), disease control rate (DCR), conversion rates, and adverse events (AEs)., Results: A total of 78 patients were recruited in our single-center study. The patients in THKP group had prolonged median OS [25 months, 95% confidence interval (CI) 24.0-26.0 vs 18 months, 95% CI 16.1-19.9; p = 0.000278], median PFS [16 months, 95% CI 14.1-17.9 vs 12 months 95% CI 9.6-14.4; p = 0.004] and higher ORR (38.6% vs 23.5%, p = 0. 156) and DCR (88.6% vs 64.7%, p = 0.011) compared with those in THK group. Multivariate analysis showed that treatment option and alpha-fetoprotein (AFP) level were independent prognostic factors of OS and PFS. The frequency of AEs were similar between the two groups., Conclusions: The THKP group had better efficacy for uHCC than the THK group, with acceptable safety., (© 2024. Society of Surgical Oncology.)

Aim: Hepatic angiography procedures are essential in the treatment of hepatocellular carcinoma (HCC), with traditional transfemoral arterial (TFA) access being the traditional standard. Recently, transradial arterial (TRA) access has gained popularity, offering potential benefits. This study aims to conduct a systematic review and meta-analysis to compare TRA and TFA access in hepatic angiography oncologic procedures for HCC. The study investigates fluoroscopy time, radiation dose, patient preferences, and complications associated with each access method., Material and Methods: A systematic review was performed using PRISMA guidelines, with 11 studies encompassing 2535 HCC procedures included. Statistical analysis was conducted using RevMan 5.4 software. Continuous outcomes were calculated as mean differences, and binary outcomes were measured as odds ratios. Patient preferences, procedural complications, and access site success rates were assessed., Results: The meta-analysis revealed that there were no significant differences in fluoroscopy time, radiation dose, or contrast dose between TRA and TFA. Access failure rates were similar for both methods. However, the odds of adverse events, excluding access failure, were significantly higher for TFA, while the overall rate of complications was comparable. Patients strongly preferred TRA over TFA due to reduced hospital stay and post-procedure discomfort., Conclusion: This meta-analysis supports the use of TRA for hepatic angiography oncologic procedures for HCC with patient preferences in favor of TRA. Additional randomized clinical trials are encouraged to further evaluate the feasibility and benefits of both access sites., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: Transcatheter Arterial Chemoembolization (TACE) is the first choice for the treatment of advanced-stage hepatocellular carcinoma (HCC). However, TACE suffers from a lack of specificity and rapid drug release. Herein, a targeted redox-responsive peptide (TRRP) was synthesized and used as a carrier of doxorubicin (DOX) to enhance the efficacy of TACE through tumor cells targeting and controlled drug release., Methods: TRRP has a high loading capacity of DOX and a sensitive drug release behavior at high glutathione (GSH) concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models., Results: TRRP has a high loading capacity of DOX and a sensitive drug release behavior at GSH concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models., Conclusions: This study demonstrated that TRRP was a promising therapeutic agent for enhancing TACE therapy for HCC treatment., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being., Competing Interests: Declaration of interests None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Increasing evidence supports the connection between the progression of several cancers and BRK1. However, the clinical significance of aberrant BRK1 gene expression in cancer is unknown. This study is conducted to investigate the possibility and effect of BRK1 as a potential immunotherapy target, to deliver a better option for liver cancer immunotherapy. We explored the predictive role of BRK1 expression in a variety of cancers from different bioinformatics, including differential expression in different cancers, tumor microenvironment (TME), microsatellite instability (MSI), tumor mutational burden (TMB), immune checkpoint molecules, immune-related and cell cycle-related signalling pathways, and drug response sensitivity. Finally, we verified the expression of BRK1 in hepatocellular carcinoma using immunohistochemistry. BRK1 is overexpressed in multiple cancers and displays a negative association with prognosis and progression of disease in a wide range of main cancer types. Additionally, the expression of BRK1 is related to MSI and TMB of tumors. There was also a remarkable correlation between the expression of BRK1 and immune score, immune infiltration, immune checkpoint molecules and a stromal score of tumors. In hepatocellular carcinoma, BRK1 is associated with several signaling pathways and immune cell infiltration may affect several key immune-related regulatory genes, making it an excellent biomarker and may be a sensitive target for immune drugs.Our research suggests that BRK1 may be a potential prognostic marker and target for immunotherapy and may be associated with poor prognosis in diverse malignancies, including hepatocellular carcinoma.

This paper introduces catheter-directed intravascular casting hydrogels for transarterial chemo/starvation/chemodynamic embolization (TACSCE) therapy of hepatocellular carcinoma (HCC). Comprising Mn ion-crosslinked hyaluronic acid-dopamine (HD) with glucose oxidase (for glucose decomposition to H 2 O 2 in starvation therapy), doxorubicin (for chemotherapy), and iopamidol (for X-ray imaging), these hydrogels are fabricated for transarterial embolization therapy guided by X-ray fluoroscopy. Mn 4+ (from MnO 2 ) demonstrates strong coordination with the catechol group of HD, providing hypoxia relief through O 2 generation and cellular glutathione (GSH) consumption, compared to the OH radical generation potential of Mn 2+ . The gelation time-controlled, catheter-injectable, and rheologically tuned multitherapeutic/embolic gel system effectively reaches distal arterioles, ensuring complete intravascular casting with fewer complications related to organic solvents. Glucose deprivation, cascade reactive oxygen species (ROS) generation, GSH depletion, and sustained release profiles of multiple drug cargos from the hydrogel system are also achieved. The combined chemo/starvation/chemodynamic efficacies of these designed hydrogel systems are confirmed in HCC cell cultures and HCC-bearing animal models. The developed radiopaque/injectable/embolic/sol-to-gel transformable systems for TACSCE therapy may offer enhanced therapeutic efficacies compared to typical transarterial embolization and transarterial chemoembolization procedures for HCC., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Hepatocellular carcinoma (HCC) is a high-incidence, poor-prognosis malignancy worldwide, requiring new strategies for treatment. Ubiquitination, especially ubiquitination through E3 ubiquitin ligases, plays an indispensable role in the development and progression of HCC. E3 ubiquitin ligases are crucial enzymes in ubiquitination, controlling the degradation of specific substrate proteins and influencing various cellular functions, such as tumor cell proliferation, apoptosis, migration, and immune evasion. In this review, we systematically summarize the mechanisms of E3 ubiquitin ligases in HCC, with a focus on the significance of RING, HECT, and RBR types in HCC progression. The review also looks at the potential for targeting E3 ligases to modulate the tumor microenvironment (TME) and increase immunotherapy efficacy. Future studies will optimize HCC treatment by formulating specific inhibitors or approaches that will be based on gene therapy targeting E3 ligases in order to overcome resistance issues with present treatments and create optimism in the journey of treatment for HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Li, Tang, Shi, Wu, Mao, Wu, Zhang, Liu, Li and Li.)