Treatment Of Hepatocellular Carcinoma Research Articles

Percutaneous microwave ablation of HCC: comparison between 100 and 150W technology systems.

To evaluate the differences in efficacy and safety between the 100 and 150W percutaneous microwave ablation (MWA) systems in the treatment of hepatocellular carcinoma (HCC). We retrospectively reviewed all patients who underwent percutaneous MWA (Emprint™ HP Ablation System, Medtronic) between January 2021 and May 2023. We divided the cohort into two groups: Group 1, treated with MWA at 100 W power system, and Group 2, treated with 150 W one. Effectiveness was defined as the absence of residual disease at 1-month CT follow-up; safety was defined as the absence of grade II-VI complications. A total of 135 HCC nodules were treated with MWA in 87 patients with a median age of 66 ± 10years: 76 procedures in 42 patients were carried out in group 1, while 59 procedures in 45 patients in group 2. Cases treated with 150 W had a shorter ablation time (p: 0.002; mean 227.37 ± 92.5 vs 180.51 ± 75.6s (100 vs 150W)) and a larger ablation volume (p 0.008; mean 13,920.0 ± 10,723.2 vs 21,241.4 ± 18,374.7 mm3 (100 vs 150W)), and a major effectiveness at 1-month CT follow-up (p: 0.013). A higher rate of complications (grade II and III) was observed in Group 2 (p < 0.001). In conclusion, these preliminary results showed a good correlation between intended-to-treat area and ablation volume and intended-to-treat area and ablation time for both Groups. A minor ablation time, and major ablation volume, but also a higher incidence of complications was observed in 150 W Group.

Fibroblast Heterogeneity in Hepatocellular Carcinoma and Identification of Prognostic Markers Based on Single-cell Transcriptome Analysis.

HCC is a malignant tumor with high morbidity and mortality. Fibroblasts play a key role in the tumor microenvironment (TME). However, the transcriptional regulatory mechanisms of fibroblasts remained unclear in HCC. The aim of this study was to explore the complex role of fibroblasts in hepatocellular carcinoma (HCC) and to reveal their transcriptional regulatory mechanisms. The goal of this study was to discover potential prognostic markers for HCC by analyzing the genetic variations and differentiation process of fibroblasts. Single-cell transcriptome data from the non-tumor liver site and primary tumor site of HCC were acquired from GSE149614, processed, and clustered using the Seurat pipeline. The inferCNV algorithm was applied to infer copy number variations (CNVs) in fibroblasts. Subsequently, the mechanism underlying the interaction between fibroblasts and other cells in the TME of HCC was analyzed using CellChat software. The trajectory of cellular differentiation of fibroblasts from normal state to malignant state was examined using Monocle 2. SCENIC analysis was performed to identify key transcription factors (TFs) in fibroblasts and assess their correlation with HCC prognosis. Finally, qRT-PCR and Transwell assays were carried out to analyze the mRNA expression and cell metastasis. We identified a total of nine different cell types (B cells, cycling cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, macrophages, plasma cells, and T cells) based on the single-cell transcriptomic data of HCC. Among them, fibroblasts were highly enriched at the primary tumor site, and their number increased with advanced stages. In addition, significant deletions were detected on chromosome 6p of fibroblasts, and genes in this region were remarkably enriched in pathways associated with antigen processing and presentation. Intercellular communication showed that epithelial cells regulated fibroblasts the most. The differentiation of fibroblasts was mainly accompanied by a transition from normal to malignant state. Importantly, CEBPD and FOSB, the TFs most associated with the putative timing of fibroblasts, were under-expressed in human hepatocytes and showed a significant correlation with HCC prognosis. Overexpressed CEBPD inhibited HCC cell migration and invasion. In conclusion, our study revealed that fibroblast recruitment and differentiation, as well as copy number loss at chromosome 6p, were associated with a higher degree of malignancy and immune dysfunction in HCC. The current discoveries provided new insights into the clinical treatment and diagnosis of HCC.

Combination CXCR4 and PD1 blockade enhances intratumoral dendritic cell activation and immune responses against hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in just a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DCs) in liver malignancies. Here, we tested combination blockade of programmed death receptor 1 (PD1) and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors. Using orthotopic grafted and autochthonous HCC models with underlying liver damage, we evaluated treatment feasibility and efficacy. In addition, we examined the effects of treatment using immunofluorescence, flow cytometric analysis of DCs in vivo and in vitro, and RNA-sequencing. Combination anti-CXCR4 and anti-PD1therapy was safe and significantly inhibited tumor growth and prolonged survival in all murine preclinical models of HCC tested. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the potential role of conventional type 1 DCs (cDC1s) in the HCC microenvironment. Moreover, DC reprogramming enhanced anticancer immunity by facilitating CD8+ T-cell accumulation and activation in the HCC tissue. The effectiveness of anti-CXCR4/PD1 therapy was compromised entirely in Batf3-KO mice deficient in cDC1s. Thus, combined CXCR4/PD1 blockade can reprogram intra-tumoral cDC1s and holds the potential to potentiate antitumor immune response against HCC.

Hepatitis B Virus-Induced Resistance to Sorafenib and Lenvatinib in Hepatocellular Carcinoma Cells: Implications for Cell Viability and Signaling Pathways

Background/Objectives: Sorafenib and lenvatinib are tyrosine kinase inhibitors used in hepatocellular carcinoma (HCC) treatment. This study investigates how hepatitis B virus (HBV) infection affects their efficacy in HepG2 hepatoma cells. Methods: HepG2 and HBV-infected HepG2/2215 cells were treated with varying concentrations of both drugs. The cell viability, cell cycle gene expression, cycle progression, and phosphorylation levels of ERK and AKT were analyzed. Results: The HBV-infected cells showed significant alterations in their cell cycle gene expressions, with an 80-fold increase in CCND2 expression and a higher proportion of cells in the G2/M phase, indicating enhanced proliferation. While both drugs decreased HepG2 cell viability in a concentration-dependent manner, HBV infection conferred resistance, as evidenced by the increased viable cells in the HepG2/2215 cultures. Sorafenib and lenvatinib decreased key cyclin and cyclin-dependent kinase expressions in uninfected cells, with less effect on the HBV-infected cells. Both drugs lowered the pERK and pAKT levels in the HepG2 cells. In the HBV-infected cells, sorafenib reduced the pERK and pAKT levels to a lesser extent. However, treatment with lenvatinib elevated the levels of pERK and pAKT. Conclusions: In conclusion, HBV infection increases resistance to both sorafenib and lenvatinib in hepatoma cells by influencing the cell cycle regulatory genes and critical signaling pathways. However, the resistance mechanisms likely differ between the two medications.

Implementing palliative care in hepatocellular carcinoma ambulatory clinics—study protocol for Accelerated translational research in PRImary liver CAncer (APRICA) randomised controlled palliative care trial

BackgroundIntegration 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.MethodsThis 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.DiscussionThis 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 registrationACTRN12623000010695. Registered on September 1, 2023.

N6-methyladenosine regulators in hepatocellular carcinoma: investigating the precise definition and clinical applications of biomarkers

BackgroundAccurately identifying effective biomarkers and translating them into clinical practice have significant implications for improving clinical outcomes in hepatocellular carcinoma (HCC). In this study, our objective is to explore appropriate methods to improve the accuracy of biomarker identification and investigate their clinical value.MethodsConcentrating on the N6-methyladenosine (m6A) modification regulators, we utilized dozens of multi-omics HCC datasets to analyze the expression patterns and genetic features of m6A regulators. Through the integration of big data analysis with function experiments, we have redefined the biological roles of m6A regulators in HCC. Based on the key regulators, we constructed m6A risk models and explored their clinical value in estimating prognosis and guiding personalized therapy for HCC.ResultsMost m6A regulators exhibit abnormal expression in HCC, and their expression is influenced by copy number variations (CNV) and DNA methylation. Large-scale data analysis has revealed the biological roles of many key m6A regulators, and these findings are well consistent with experimental results. The m6A risk models offer significant prognostic value. Moreover, they assist in reassessing the therapeutic potential of drugs such as sorafenib, gemcitabine, CTLA4 and PD1 blockers in HCC.ConclusionsOur findings suggest that the mutual validation of big data analysis and functional experiments may facilitate the precise identification and definition of biomarkers, and our m6A risk models may have the potential to guide personalized chemotherapy, targeted treatment, and immunotherapy decisions in HCC.

Construction and validation of a prognostic signature based on microvascular invasion and immune-related genes in hepatocellular carcinoma

Background: Microvascular invasion (MVI) is an independent risk factor of poor prognosis in hepatocellular carcinoma (HCC) and can be used to guide the diagnosis and treatment of HCC. The immune system serves as an integral role in the incidence and progression of HCC. However, the molecular biology correlation between MVI and tumor immunity and the value of combining the two parameters to predict patient prognosis and HCC response to treatment remain to be evaluated. Results: In this study, we used univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis to establish the MVI and immune-related gene index (MIRGPI) including eight genes. We demonstrated that the MIRGPI was an independent risk factor in predicting the prognosis of HCC. Subsequently, our research established a nomogram model combining pathologic characteristics and verified its good clinical application value. In addition, our study found that the TP53 gene had a higher mutation frequency and a lower degree of immune infiltration in the high-risk group. The low-risk group had higher sensitivity to immunotherapy, sorafenib, and TACE treatment, and the high-risk group had higher sensitivity to common chemotherapeutic agents. Finally, SEMA3C was found to facilitate the proliferation, migration and invasive ability of HCC by in vitro and in vivo experiments, and its mechanism may be associated with the activation of the NF-Κb/EMT signaling pathway. Conclusions: In summary, the MIRGPI signature we developed is a reliable marker for the prediction of prognosis and treatment response, and is important for the prognostic assessment and individualized treatment of HCC.

Decoding the possible mechanism of action of Paeoniflorigenone in combating Aflatoxin B1-induced liver cancer: an investigation using network pharmacology and bioinformatics analysis

Moutan cortex has demonstrated antitumor properties attributed to its bioactive compound Paeoniflorigenone (PA). Nevertheless, there is limited research on the efficacy of PA in the prevention and treatment of hepatocellular carcinoma (HCC). We aimed to investigate the potential pharmacological mechanisms of PA in the treatment of Aflatoxin B1 (AFB1)-induced hepatocarcinogenesis using network pharmacology and bioinformatics analysis approaches. Through various databases and bioinformatics analysis approaches, 34 shared targets were identified as potential candidate genes for PA in fighting liver cancer caused by AFB1. Pathway analysis revealed involvement in cell cycle, HIF-1, and Rap1 pathways. A risk assessment model was developed using LASSO regression, showing an association between the identified genes and the tumor immune microenvironment. The genes within the risk model were found to be linked to the immune response in liver cancer. Molecular docking studies indicated that PA interacts with its targets through hydrogen bonding and hydrophobic interactions. This study provides insights into the possible mechanisms of PA in liver cancer treatment and offers a predictive model for assessing the risk level of individuals with liver cancer. These findings have significant implications for the therapeutic strategies in managing liver cancer patients.

Impact of IL-8 on survival after TARE in HCC: a comprehensive investigation and external validation from the SORAMIC trial.

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. 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. 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). 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.

CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges

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.

Clinical outcomes of modified transarterial chemoembolization vs. drug-eluting bead transarterial chemoembolization as initial treatment for single hepatocellular carcinoma: a propensity score matching analysis.

Optimizing transarterial chemoembolization (TACE) can enhance treatment efficacy for hepatocellular carcinoma (HCC). This study compares modified TACE (M-TACE), which combines a lipiodol-based emulsion and drug-eluting beads, with drug-eluting bead TACE (DEB-TACE) as initial therapies for solitary HCC. In this retrospective study, 185 patients undergoing M-TACE or DEB-TACE were evaluated. Propensity score matching was used to create 69 balanced pairs. Initial tumor response, repeated treatments within six months, local tumor progression (LTP), overall survival (OS), and adverse events (AEs) were assessed. M-TACE exhibited significantly higher initial complete response (CR) rates (39.1% vs. 23.2%, p = 0.043) and fewer repeated treatments within six months (1.7 ± 0.9 vs. 2.1 ± 0.7; p = 0.033) compared to DEB-TACE. LTP rates were notably lower with M-TACE at 12 months (39.1% vs. 65.2%, p = 0.002), and median time to LTP was prolonged with M-TACE (13.3 vs. 8.2 months, p = 0.038). Stratified analysis revealed a significantly longer OS in individuals achieving a CR after the initial M-TACE (50.5 vs. 33.4 months, p = 0.043). However, the overall study population did not exhibit a significant difference in OS between the two groups. Comparable AEs (all p > 0.05) were observed. M-TACE showed higher initial CR rates, lower LTP rates, and extended time to LTP compared to DEB-TACE, indicating its potential to enhance TACE effectiveness for solitary HCC.

Iberverin Downregulates GPX4 and SLC7A11 to Induce Ferroptotic Cell Death in Hepatocellular Carcinoma Cells

Ferroptosis, a recently elucidated style of regulated cell death, has emerged as a significant area of investigation in cancer biology. Natural active compounds that have anti-cancer effects are promising candidates for cancer prevention. Iberverin, a natural compound derived from Brassica oleracea var. capitata, has been shown to exert anti-tumor activities in some cancers. However, its role in hepatocellular carcinoma (HCC) cells and the molecular mechanisms are still poorly understood. In this study, we proved that iberverin can induce intracellular reactive oxygen species (ROS) generation to inhibit cell proliferation and initiate ferroptotic cell death in HCC cells, which can be eradicated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) or deferoxamine mesylate (DFO) and ROS scavenger (GSH or NAC). Mechanistically, iberverin treatment can simultaneously downregulate SLC7A11 mRNA level and degrade GPX4 through the ubiquitination pathway, leading to lipid peroxidation and ferroptotic cell death in HCC cells. Significantly, a low dose of iberverin can remarkably increase the sensitivity of HCC cells to ferroptosis induced by canonical ferroptosis inducers RSL3 and imidazole ketone erastin (IKE). This study uncovers a critical function of iberverin in preventing HCC through ferroptosis and provides a promising strategy for HCC treatment either via iberverin alone or in combination with canonical ferroptosis inducers in the future.

Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma.

Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.

Use of albumin and CRP related immuno-nutritional markers for prediction of locoregional response to treatment in unresectable hepatocellular carcinoma

Objective:We analysed the relationship between albumin and CRP related inflammation markers (Controlling nutritional status(Conut)score, lymphocyte albumin factor(LA), albumin-bilirubin score (ALBI), highly sensitive modified Glasgow prognostic score (Hs-mGPS), Glasgow prognostic score(GPS)) and locoregional treatment response in HCC. Materials and methods:Among 180 HCC patients, 63 patients who underwent locoregional therapy were included in this study. Albumin and CRP related immuno-nutrition scores were calculated by recording routine laboratory tests between the fourth and eighth week after treatment. The predictive and prognostic value of these markers for overall survival(OS) and disease free survival after treatment(DFS) were analysed. Results:The mean age was 63 years (min-max:26-87) and 59 (93.7%) of the patients were male. The mean follow up period was 25 months and 53 patients were deceased (84.1%). mOS: 18.56 months (min-max: 13.13-23.99); mDFS: 7 months (min-max: 3.63-10.37) after locoregional treatment. Cut-off values of prognostic markers were determined by Roc analysis. Statistically significant correlation was found between age(p=0.019), Conut(p=0.001), GPS(p=0.028), Hs-mGPS(p=0.012), LA(p=0.017) and ALBI(p=0.002) and mOS. The relationship between Conut(p=0.002), GPS(p

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis.

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

Celastrol-Loaded Hyaluronic Acid/Cancer Cell Membrane Lipid Nanoparticles for Targeted Hepatocellular Carcinoma Prevention.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its prevention and treatment face severe challenges. It is crucial to improve the targeting of drugs on tumor cells and tissues. Celastrol (CeT), as an active ingredient of traditional Chinese medicine, possesses strong antitumor effects, especially in triggering apoptosis of HCC. However, due to its toxicity and lack of targeting, its application is greatly limited. HMCLPs, a nano-biomimetic platform carrying CeT with controllable drug release, enhanced targeting, and immunocompatibility, were developed for the first time, which can be used for the treatment of HCC. By utilizing homologous cell membranes and hyaluronic acid (HA), HMCLPs can precisely target tumor regions and release CeT in a controlled manner. Both in vitro and in vivo studies have demonstrated that HMCLPs loaded with CeT significantly increased the accumulation of reactive oxygen species (ROS), induced mitochondrial damage, and triggered apoptosis of HCC cells, resulting in effective treatment with minimal adverse reaction. The development of HMCLPs as a nanocarrier system for CeT delivery offers a promising therapeutic strategy for HCC. This innovative approach improves the targeted delivery and bioavailability of CeT, dramatically induces apoptosis in HCC cells, and exerts its powerful antitumor effects while minimizing systemic toxicity. The present study highlights the potential of combining innovative nanocarriers with powerful natural compounds such as CeT to enhance efficacy and reduce toxicity.

New Scenarios in Liver Transplantation for Hepatocellular Carcinoma.

Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.

Cancer immunogenic cell death via pyroptosis with CXCR4-targeted nanotoxins in hepatocellular carcinoma

IntroductionCytotoxic agents have shown limited benefits in hepatocellular carcinoma (HCC), mediated in part by the lack of targeting. As cell-penetrating peptides (CPPs) are capable of delivering various biologically active molecules into cells, including protein, peptides, small chemo-drugs, and nucleic acid with or without targeting, we developed T22-PE24, a CXCR4-targeted self-assembling cytotoxic nanotoxin, to effectively induce HCC pyroptosis.MethodsT22 incorporating enhanced green fluorescent protein (EGFP) or PE24 was purified from DE3 bacterial cells and characterized using transmission electron microscopy, the Zetasizer Nano®, and SEC-HPLC. The internalization effect of T22-EGFP was detected by flow cytometry system (FCS) in CXCR4+/LM3(CXCR4−) HCC cells. The CCK8, lactate dehydrogenase (LDH) release, Western blot, and nude mice HCC models were used to estimate the cell viability of T22-PE24. The complete-immunity HCC tumor-bearing mice model was used to assess the immune response of T22-PE24.ResultsThe round shape under transmission electron microscopy, 49.4 nm hydrodynamic diameter, and −33.33 mV zeta potential indicated that T22-PE24 self-assembled into nanoparticles. T22 incorporating EGFP selectively internalized in CXCR4+ HCC cells and showed no accumulation in CXCR4-knockout HCC cells. The T22-PE24 nanotoxin induced HCC pyroptosis via the caspase-3/GSDME signaling pathway and suppressed tumor growth in the absence of histological alterations in normal organs. Using the complete-immunity HCC tumor-bearing mice model, we found that T22-PE24 nanotoxin effectively induces the global reprogramming of cell components of the immune tumor microenvironment, leading to enhanced antitumor effects compared to those observed in immunodeficient mice.ConclusionOur findings demonstrate the activation of the innate immune response in HCC by inducing pyroptosis with T22-PE24 nanotoxin treatment and support an implementation of this strategy for HCC treatment.

Real-World Effectiveness of All-Oral Direct-Acting Antivirals in Patients With Hepatitis C Virus-Related HCC.

The association between direct-acting antiviral (DAA) treatment and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is currently unclear. Hence, we aim to assess the association between DAA treatment and mortality rate among Medicare beneficiaries with HCV-related HCC. This retrospective cohort study screened 19,813 adults in 2013-2019 Surveillance, Epidemiology, and End Results data linked with Medicare data. Patients with HCV-related HCC initiating DAA therapy after their first HCC diagnosis were compared with patients with HCV-related HCC who received no HCV treatment. After inverse probability treatment weighting, multivariable Cox proportional hazards models compared mortality rates between the groups. Subgroup and sensitivity analyses were based on HCC stage (early vs. advanced), type of HCC treatment (curative, palliative, none), and DAA treatment duration. In total 3,777 patients with HCV-related HCC were identified (mean age: 68.2 years, 75.2% male, 61.8% White), of whom 19% initiated DAA therapy. Crude incidence mortality rates were 17.9 and 90.7 deaths per 100 person-years in the DAA and HCV-untreated groups, respectively. Cox regression models indicated that DAA therapy was associated with decreased risk of all-cause mortality (adjusted hazard ratio, 0.33; 95% CI 0.31-0.36). Median survival time was 45.7 (95% CI 40.9-57.9) months in the DAA group and 7.7 (95% CI 7.3-8.2) months in the HCV-untreated group (P < 0.001). All subgroup and sensitivity analyses were consistent with the main analyses. DAA therapy was associated with survival benefits for patients with HCV-related HCC regardless of the stage or type of HCC treatment and should not be withheld from this population of Medicare beneficiaries.

TLR3 activation enhances antitumor effects of sorafenib in hepatocellular carcinoma by activating NK cell functions through ERK and NF-κB pathways

Background Sorafenib is a standard therapeutic agent for advanced hepatocellular carcinoma (HCC). However, its efficacy is moderate, as the survival of patients is prolonged for only a few months, and the response rate is low. The mechanism of low efficacy remains unclear. In this study, we investigated the effect of Toll-like receptor 3 (TLR3) on the effects of sorafenib on HCC. Methods Polyinosinic-polycytidylic acid [poly(I: C)] was used as a double-stranded RNA analog and TLR3 agonist in subsequent experiments. After orthotopic implantation of HCC tumors in BALBc nu/nu or C57BL/6 mice, survival time, tumor growth, and metastasis in the abdomen and lungs were analyzed. Flow cytometry and cytotoxicity assays were used to analyze NK cells isolated from the spleen or peripheral blood. ELISA was used to detect the expression of plasma interferon (IFN)-γ and monocyte chemoattractant protein (MCP)-1. In addition, the expression of phosphorylated-extracellular regulated kinase 1/2 (pERK1/2), phosphorylated-protein kinase B (pAKT), ERK1/2 and AKT was analyzed by Western blotting. Results Sorafenib reduced the number and activity of NK cells in tumor-bearing mice and simultaneously decreased the levels of MCP-1 and IFN-γ in the plasma. The combination of sorafenib and poly(I: C) synergistically inhibited tumor growth and metastasis in tumor xenograft mice and prolonged survival. Poly(I: C) not only exerts a direct inhibitory effect on tumor growth and metastasis by targeting the TLR3 receptor on tumor cells but also facilitates the proliferation and activation of NK cells, indirectly impeding tumor progression. Mechanistically, poly(I: C) decreased the sorafenib-induced inhibition of ERK phosphorylation and increased the phosphorylation of IκB in NK cells, thereby enhancing NK cell function. Conclusion Activation of TLR3 can enhance the antitumor effect of sorafenib on HCC. The combination of a TLR3 activator and sorafenib may be a new strategy for the treatment of HCC.