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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.)

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.)

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.)

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.)

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.)

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).)

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.

Objective: The impact of the coronavirus disease 2019 (COVID-19) on hepatocellular carcinoma (HCC) care is unclear. This study reports on HCC patterns during the COVID-19 pandemic in the Netherlands., Methods: Patients diagnosed with HCC between 2017 and 2020 were identified from the Netherlands Cancer Registration. Monthly incidence rates were compared between 2020 and 2017-2019. Patient, tumor, process, and treatment characteristics and survival were compared between 2020 and 2017-2019, and between COVID-high (April and May 2020) and COVID-low (June and July 2020) months., Results: The incidence of HCC was lower in May 2020 (IRR 0.56, P = 0.001) and higher in June 2020 (IRR 1.32, P = 0.05) compared to the same months in 2017-2019. In 2017-2019, 2134 patients presented with HCC, compared to 660 in 2020. Time-to-treatment was shorter in 2020 (median 60 vs. 70 days, P < 0.001). The percentage of patients undergoing any treatment did not differ, yet if treatment was not performed this was more commonly due to comorbidity in 2020 (52 vs. 39%, P < 0.001). No other differences were found in patient, tumor, process and treatment characteristics and survival between COVID-high and COVID-low months., Conclusions: This study demonstrated no impact of the COVID-19 pandemic on HCC patients, despite a decrease in HCC diagnoses.

HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC., (© 2024. The Author(s).)

Sorafenib (SRF) is recognized as the primary treatment for hepatocellular carcinoma (HCC), yet the emergence of SRF resistance in many HCC patients results in unfavorable outcomes. Enhancing the efficacy of SRF in HCC remains a significant challenge. SRF works in inducing ferroptosis, a form of cell death, in cancer cells through the inhibition of glutathione peroxidase 4 (GPX4). The effectiveness of this process is limited by the low levels of cellular iron and reactive oxygen species (ROS). A promising approach to circumvent this limitation is the use of intracellular magnetic hyperthermia (MH) mediated by magnetic iron oxide nanomaterials (MIONs). When MIONs are subjected to an alternating magnetic field (AMF), they heat up, enhancing the Fenton reaction, which in turn significantly increases the production of ROS within cells. In this study, we explore the capability of MH facilitated by high-performance ferrimagnetic vortex-domain iron oxide nanoring (FVIO) to enhance the effectiveness of SRF treatment in HCC. The increased iron uptake facilitated by FVIO significantly enhances the sensitivity of HCC cells to SRF-induced ferroptosis. Moreover, the nanoheat generated by FVIO in response to an AMF further elevates ROS levels and stimulates lipid hydroperoxide (LPO) production and GPX4 inactivation, thereby intensifying ferroptosis. Both in vitro and in vivo animal studies demonstrate that combining FVIO-mediated MH with SRF significantly reduces cell viability and inhibits tumor growth, primarily through enhanced ferroptosis, with minimal side effects. The effectiveness of this combination therapy is affected by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The combination treatment of FVIO-mediated MH and SRF offers a strategy for HCC treatment by promoting accelerated ferroptosis, presenting a different perspective for the development of ferroptosis-based anticancer therapies.

Background: Recent studies have highlighted that TACE in conjunction with Lenvatinib (TACE-L) offers a promising adjunct therapy for advanced HCC patients, outperforming TACE plus Sorafenib (TACE-S). However, there has been a lack of research comparing these two regimens for intermediate HCC., Aims: This study aims to address the research gap by evaluating the efficacy of TACE-L versus TACE-S in intermediate HCC patients., Methods: A retrospective analysis was conducted on a cohort of consecutive intermediate HCC patients who received either TACE-L or TACE-S from November 2018 to December 2022. Portal vein width was assessed using abdominal NMRI or Doppler ultrasonography, and inflammatory markers were derived from routine blood counts. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse drug reactions (ADRs)., Results: The study included 117 patients, with 56 in the TACE-S group and 61 in the TACE-L group. The TACE-S group demonstrated superior OS (HR = 1.704, 95% CI: 1.012-2.870, p = 0.045) compared to the TACE-L group. No significant difference was observed in PFS (HR:1.512, 95% CI: 0.988-2.313, p = 0.057) between the two groups. Subgroup analyses revealed that male patients, those with cirrhosis, and those with more than four tumors had better OS and PFS in the TACE-S group than in the TACE-L group. Inflammatory markers were comparable between the groups. The TACE-S group experienced a higher incidence of palmar-plantar erythrodysesthesia syndrome (PPE) (14/56 [25%] vs. 5/61 [8.1%], p = 0.014) but a lower incidence of hypertension (3/56 [5.3%] vs. 11/61 [18%], p = 0.035) compared to the TACE-L group., Conclusions: In patients with intermediate HCC, TACE-S was found to be more effective in terms of OS than TACE-L. No significant disparity was noted in PFS between the two treatment groups., (© 2024. The Author(s).)

This study aimed to assess the effectiveness and safety of 5-Fluorouracil (5-Fu) combined with conventional transarterial chemoembolization (cTACE) compared to 5-Fu combined with drug-eluting bead transarterial chemoembolization (DEB-TACE) using CalliSpheres for the treatment of unresectable hepatocellular carcinoma (HCC) using propensity score weighting methods. This retrospective analysis included 131 patients with HCC treated with 5-Fu combined with cTACE (5-Fu-cTACE group, n = 65) or DEB-TACE (5-Fu-DEB-TACE group, n = 66) at the Affiliated Hospital of North Sichuan Medical College from January 2019 to December 2022. Based on the baseline data and laboratory indicators, propensity score weighting was used to reduce confounding bias. Modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate clinical efficacy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the disease control rate (DCR), objective response rate (ORR) and adverse events (AEs). PFS was assessed using Kaplan‒Meier analysis and Cox proportional hazards models. The ORRs at 1 month (M1) after treatment in the 5-Fu-DEB-TACE group and 5-Fu-cTACE group were 90.9% and 76.9%, respectively (P = 0.029), while at this time, the DCRs were 93.9% in the 5-Fu-DEB-TACE group and 90.8% in the 5-Fu-cTACE group (P = 0.494). At 3 months (M3) after treatment, the 5-Fu-DEB-TACE group had a higher ORR (84.8% vs. 56.9%, P < 0.001) and DCR (84.8% vs. 72.3%, P = 0.08). The ORR at 6 months (M6) was also higher in the 5-Fu-DEB-TACE group than in the 5-Fu-cTACE group (72.7% vs. 50.8%, P = 0.01). The median PFS after treatment with 5-Fu-DEB-TACE was longer than that after treatment with 5-Fu-cTACE (11 months vs. 6 months) (P = 0.004). Cox proportional hazards regression analysis indicated that 5-Fu-DEB-TACE (HR = 0.590, P = 0.044), Model for End-Stage Liver Disease (MELD) intermediate risk (HR = 2.470, P = 0.010), BCLC stage B (HR = 2.303, P = 0.036), BCLC stage C (HR = 3.354, P = 0.002) and ascitic fluid (HR = 2.004, P = 0.046) were independent predictors of PFS. No treatment-related deaths occurred in this study. The 5-Fu-DEB-TACE group had a greater incidence of abdominal pain (72.7% vs. 47.7%, P = 0.003). However, the incidence of postoperative elevated transaminase levels was higher in the 5-Fu-cTACE group (83.1% vs. 66.6%, P = 0.031). Subgroups analysis showed patients receiving 5-Fu-DEB-TACE have better PFS compared to those receiving 5-Fu-cTACE in the BCLC stage A group (P = 0.0093), BCLC stage B group (P = 0.0096), multifocal group (P = 0.0056), Child-Pugh stage A group (P<0.001), non- extrahepatic metastasis group (P = 0.022), non-vascular invasion group (P = 0.0093), and the group with a largest tumor diameter ≥ 5 cm (P = 0.0048). At M1, M3, and M6, patients with preserved liver function and in some cases of low tumor burden had higher Objective Response Rate (ORR) and Disease Control Rate (DCR) (P < 0.05). Compared with 5-Fu-cTACE, 5-Fu-DEB-TACE has superior therapeutic efficacy, prolongs PFS, and reduces hepatotoxicity. However, it is associated with an increased incidence of postoperative abdominal pain., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer in the world and its incidence and mortality are increasing year by year, frequently diagnosed at an advanced stage. Traditional treatments such as surgery, chemotherapy, and radiotherapy have limited efficacy, so new diagnostic and treatment strategies are urgently needed. Recent research has discovered that intratumoral microbiota significantly influences the development, progression, and metastasis of HCC by modulating inflammation, immune responses, and cellular signaling pathways. Intratumoral microbiota contributes to the pathologic process of HCC by influencing the tumor microenvironment and altering the function of immune system. This article reviews the mechanism of intratumoral microbiota in HCC and anticipates the future possibilities of intratumoral microbiota-based therapeutic strategies for HCC management. This emerging field provides fresh insights into early diagnosis and personalized approaches for HCC while holding substantial clinical application potential to improve patient outcomes and tailor interventions to individual tumor profiles., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity globally, and with the prevalence of metabolic-related diseases, the incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) related hepatocellular carcinoma (MAFLD-HCC) continues to rise with the limited efficacy of conventional treatments, which has created a major challenge for HCC surveillance. Immune checkpoint inhibitors (ICIs) and molecularly targeted drugs offer new hope for advanced MAFLD-HCC, but the evidence for the use of both types of therapy in this type of tumour is still insufficient. Theoretically, the combination of immunotherapy, which awakens the body's anti-tumour immunity, and targeted therapies, which directly block key molecular events driving malignant progression in HCC, is expected to produce synergistic effects. In this review, we will discuss the progress of immunotherapy and molecular targeted therapy in MAFLD-HCC and look forward to the opportunities and challenges of the combination therapy., 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 B.V.)

The clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) is significantly limited by the low immunogenicity of the tumor. Recent studies have revealed that both pyroptosis and photothermal therapy can effectively induce tumor immunogenic cell death (ICD) in liver cancer cells. Polyphyllin II (PPII), the major active component of Rhizoma Paridis, has been demonstrated for the first time to induce pyroptosis in tumor cells, while IR780 is activated by 808 nm laser to transform light energy into heat energy, effectively eliminating tumor cells. However, both PPII and IR780 are afflicted with challenges such as low solubility and poor targeting, significantly limiting their utilization. To address these problems, the pyroptosis inducer PPII and photosensitizer IR780 were co-loaded in PLGA nanoparticles by precipitation method, and the aptamer AS1411 was modified on the surface of nanoparticles to construct the targeting nanoparticles (Apt/PPII/IR780-NPs). The nanoparticles exhibit a pH/NIR dual-response intelligent release feature, which realizes the targeted and controlled release of drugs in tumor site. Furthermore, it can rapidly release PPII to induce cell pyroptosis under laser irradiation, combining with IR780-based photothermal therapy exert a significant synergistic anti-tumor effect in vitro and in vivo. This process not only promotes maturation of DCs and activates effector T cells, thereby initiating adaptive immunity, but also generates enduring and effective immune memory. In addition, Apt/PPII/IR780-NPs significantly improved the Anti-PD-1 efficacy. In summary, chemo-photothermal therapy based on Apt/PPII/IR780-NPs can significantly enhance tumor ICD, which provides a promising new strategy for HCC immunotherapy., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is usually diagnosed in patients at the age of > 45 years. We aimed to determine the prognosis of patients with HCC at the age of 30-44 years compared with that of patients at a more senior age., Methods: Based on the Sun Yat-sen University Cancer Center database, a total of 1745 patients with HCC were retrospectively enrolled and were assigned to three age groups (30-44, 45-59, and 60-70 years). The primary endpoint was overall survival. Among baseline characteristics, five variables including sex, serum albumin level, total bilirubin level, the maximum tumor diameter, and the number of tumor nodules were adjusted using propensity score matching., Results: Patients aged 30-44 years presented a worse overall survival, a greater number of HCC nodules, a greater maximum tumor diameter, and higher serum alpha-fetoprotein (AFP) concentration than those aged 45-59 years in a crude analysis (p < 0.05). Using propensity score matching, the difference in overall survival between the two cohorts was canceled (p > 0.05)., Conclusion: The prognosis of patients with HCC at age 30-44 years was equal to that of patients aged 45-59 years., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: The purpose of this study was to interpret real-world clinical data to analyze the surgical safety and survival outcomes of patients with initial unresectable hepatocellular carcinoma (uHCC) after conversion therapy., Methods: A retrospective analysis was performed on 2984 hepatocellular carcinoma (HCC) patients hospitalized in Shandong Cancer Hospital Affiliated to Shandong First Medical University from June 1st, 2019 to June 1st, 2023. Clinicopathological features, response to systemic and/or loco-regional treatments, surgical resection rate after conversion therapy, surgical safety, and postoperative recurrence were analyzed., Results: A total of 38 patients were successfully converted to obtain surgical resection. 35 patients underwent radical resection. A high objective response rate (ORR) (52.6% under RECIST v1.1 and 78.9% under mRECIST criteria) was observed in patients under conversion therapy, and the disease control rate (DCR) was 100%. Pathologic complete response (pCR) was 42.9%. Treatment-related adverse events (TRAEs) of any grade were observed in 37 patients (97.4%). Safety of conversion or direct surgery continues to improve. The median follow-up time was 19.3 months. The 1-year Disease-free survival (DFS) rate of patients with direct surgery and patients with conversion surgery were 91.4% and 86.8%, respectively., Conclusions: With conversion therapy, a small percentage (1.81%) of uHCC patients are likely to be converted to radical resection. Local combined systemic therapy is a relatively safe and effective conversion therapy, and the safety of surgery is gradually improved after successful conversion. Preliminary follow-up data showed satisfactory survival benefits for patients undergoing conversion surgery., Trial Registration: This was a retrospective study and it did not interfere with treatment decisions., (© 2024. The Author(s).)

Immune checkpoint inhibitors (ICIs), such as durvalumab, tremelimumab, and atezolizumab, have emerged as a significant therapeutic option for the treatment of hepatocellular carcinoma (HCC). In fact, the efficacy of ICIs as single agents or as part of combination therapies has been demonstrated in practice-changing phase III clinical trials. However, ICIs confront several difficulties, including the lack of predictive biomarkers, primary and secondary drug resistance, and treatment-related side effects. Herein, we provide an overview of current issues and future challenges in this setting., Competing Interests: The authors declare no conflicts of interest.

Background: Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors., Methods: Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry., Results: In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells., Conclusions: Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) poses a significant global health challenge due to its poor prognosis and limited therapeutic modalities. Anoikis and ErbB signaling pathways are pivotal in cancer cell proliferation and metastasis, but their relevance in HCC remains insufficiently explored., Methods: This study evaluates the prognostic significance of anoikis and ErbB signaling pathways in HCC by utilizing data from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), three additional independent validation cohorts, and an in-house cohort. Advanced bioinformatics analyses and 167 machine learning models based on leave-one-out cross-validation (LOOCV) were used to predict HCC prognosis and assess outcomes of immune-targeted therapies. Additionally, key biological processes of the anoikis and ErbB signaling pathways in HCC were further investigated., Results: The single sample Gene Set Enrichment Analysis revealed a strong correlation between upregulated ErbB signaling in high anoikis-expressing tumors and poor clinical outcomes. The development of the Anoikis-ErbB Related Signature (AERS) using the LASSO + RSF model demonstrated robust predictive capabilities, as validated across multiple patient cohorts, and proved effective in predicting responses to immune-targeted therapies. Further investigation highlighted activated NOTCH signaling pathways and decreased macrophage infiltration was associated with resistance to sorafenib and immune checkpoint inhibitors, as evidenced by bulk and single-cell RNA sequencing (scRNA-seq)., Conclusion: AERS provides a novel tool for clinical prognosis and paves the way for immune-targeted therapeutic approaches, underscoring the potential of integrated molecular profiling in enhancing treatment strategies 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 Fang, Chen, Zhong, Wu, Ke, Huang, Wang and Zhang.)

Background: The impact of clinical factors and social determinants of health on treatment patterns and health care costs among patients with HCC is unknown., Methods: Using 100% Medicare Fee-For-Service claims and a commercial multipayor claims database, we identified patients diagnosed with HCC from January 1, 2017, to December 31, 2020. Surveillance receipt was defined 12 months prior to HCC diagnosis, whereas treatment and health care costs were assessed post-HCC diagnosis. Multinomial logistic regression was used to assess the association between demographics, social determinants of health, and surveillance or HCC treatment. Multivariable generalized linear regression was used to identify factors associated with total health care costs., Results: Of the 32,239 patients with HCC (mean age 68 y, 67% male, 73% White), 70% received surveillance and only half (51%) received any treatment. Curative treatment receipt was higher among those with prior surveillance (24% with CT/MRI and 18% with ultrasound vs. 9% with no surveillance). Curative treatment was independently associated with HCC surveillance and inversely associated with Black race, lower education level, and diagnosis in the year 2020 (COVID-19 year). Higher health care costs were independently associated with Black race, low English proficiency, living alone, and diagnosis in 2018-2020, and inversely associated with CT/MRI-based surveillance., Conclusions: Race and social determinants of health were independently associated with curative treatment receipt and health care costs. Increasing access to high-quality HCC surveillance may improve treatment receipt and reduce health disparities among patients with HCC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Evidences regarding the feasibility of transcatheter arterial chemoembolization (TACE)-based therapy for unresectable hepatocellular carcinoma (uHCC) remains limited. This study aimed to investigate the efficacy and safety of TACE combined with envafolimab and lenvatinib for uHCC. Eligible patients with uHCC received envafolimab and lenvatinib after TACE until disease progression, conversion to surgery, intolerable toxicities, or death. The primary endpoint was the objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Between March 2022 and July 2022, 38 patients were included for safety analysis, and 36 patients were included for efficacy analysis. As of the data cutoff (13 December 2023), the median follow-up was 16.9 months. The ORR was 50%, and disease control rate (DCR) was 83.3% per RECIST 1.1 (ORR and DCR of both 83.3% per modified RECIST (mRECIST)). The median progression-free survival (PFS) was 7.58 months. Of 36 patients, 17 patients were converted to resectable HCC with a surgical conversion rate of 47.2%, and 16 patients underwent surgery with R0 resection rate of 100%, pathologic complete response (pCR) rate of 31.3%. Overall incidences of treatment-related adverse events (TRAEs) of any grade was 97.4%. Grade ≥ 3 TRAEs were observed in 52.6% patients. No treatment-related deaths occurred. Image mass cytometry (IMC) analysis revealed that combined treatment improved the immune status of the tumor microenvironment, and resident macrophages had the potential to predict efficacy of this treatment. Envafolimab plus lenvatinib and TACE yielded promising survival outcomes and conversion efficiency with a tolerable safety profile. Trial registration Clinical trials: NCT05213221., (© 2024. The Author(s).)

This study aimed to evaluate how the timing of transarterial chemoembolization (TACE) relative to systemic therapy (tyrosine-kinase inhibitors [TKIs] and immune checkpoint inhibitors [ICIs]) influences oncological outcomes in patients with hepatocellular carcinoma (HCC). A retrospective analysis was conducted on HCC patients treated with TACE plus TKIs and ICIs from January 2018 to February 2023. We compared objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) between patients receiving TACE before versus after systemic therapies. Multivariate Cox regression analyses identified potential prognostic factors. Of the 194 patients enrolled, 111 received TACE before systemic therapies, and 83 after. The median age at diagnosis was 52.8 years. There were no significant differences in ORR (40.72% vs. 30.41%, p = 0.989) or DCR (48.45% vs. 35.57%, p = 0.770) between the groups. Likewise, OS (18.73 vs. 18.20 months, p = 0.091) and PFS (11.53 vs. 10.05 months, p = 0.336) were similar regardless of treatment sequence. In the result of Cox analysis, a 20% decrease in AFP from baseline at one month was associated with improved OS (HR = 0.35, 95% CI 0.17-0.70, p = 0.003) and PFS (HR = 0.69, 95% CI 0.49-0.96, p = 0.028). Large tumor size (≥ 10 cm) was a poor prognostic factor for OS (HR = 2.12, 95% CI 1.07-4.21, p = 0.032), and the presence of portal vein tumor thrombus adversely affected PFS (HR = 2.31, 95% CI 1.47-3.62, p < 0.001). The sequencing of TACE and systemic therapies does not significantly impact the prognosis of advanced HCC. A 20% reduction in AFP within one month of treatment commencement emerges as a protective prognostic factor for HCC., (© 2024. The Author(s).)

Objective: This study investigates the impact of transvascular antitumor interventional therapies on immune cell dynamics and its correlation with disease control and progression-free survival (PFS) in hepatocellular carcinoma (HCC) patients., Methods: A single-center observational case-control study was conducted with 119 HCC patients. Transvascular antitumor interventional therapy were administered based on patient-specific evaluations. Peripheral blood samples were collected before and within 28 days after the first treatment to analyze lymphocyte subsets and other immune cells., Results: Higher counts of total white blood cells (WBCs), lymphocytes, monocytes, and basophils were significantly associated with disease control rate. Subgroup analysis revealed that abnormal BMI, diabetes, infection, and multiple lesions were significantly associated with T cell abnormalities. Age, abnormal BMI, hypertension, and abnormal AFP were linked to total T cell abnormalities. NK cells, B cells, Th cells, Tc/Ts cells, and CD4/CD8 ratios did not show significant differences in PFS probabilities., Conclusion: Higher counts of WBCs, lymphocytes, monocytes, and basophils, play a crucial role in the effectiveness of HCC interventional therapy., 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 Sun, Zhang, Li, Zhou and Han.)

Background: Surgical resection (SR) following transarterial chemoembolization (TACE) is a promising treatment for unresectable hepatocellular carcinoma (uHCC). However, biomarkers for the prediction of postoperative recurrence are needed., Purpose: To develop and validate a model combining deep learning (DL) and clinical data for early recurrence (ER) in uHCC patients after TACE., Methods: A total of 511 patients who received SR following TACE were assigned to derivation (n = 413) and validation (n = 98) cohorts. Deep learning features were taken from the largest tumor area in liver MRI. A nomogram using DL signatures and clinical data was made to forecast early recurrence risk in uHCC patients. Model performance was evaluated using area under the curve (AUC)., Results: A total of 2278 subsequences and 31,346 slices multiparametric MRI including contrast-enhanced T1WI, T2WI and DWI were input in the DL model simultaneously. Multivariable analysis identified three independent predictors for the development of the nomogram: tumor number (hazard ratio [HR]:3.42, 95% confidence interval [CI]: 2.75-4.31, P = 0.003), microvascular invasion (HR: 9.21, 6.24-32.14; P < 0.001), and DL scores (HR: 17.46, 95% CI: 12.94-23.57, P < 0.001). The AUC of the nomogram was 0.872 and 0.862 in two cohorts, significantly outperforming single-subsequence-based DL mode and clinical model (all, P < 0.001). The nomogram provided two risk strata for cumulative overall survival in two cohorts, showing significant statistical results (P < 0.001)., Conclusions: The DL-based nomogram is essential to identify patients with uHCC suitable for treatment with SR following TACE and may potentially benefit personalized decision-making., (© 2024. The Author(s).)

Background & Aims: The benefit of postoperative adjuvant transcatheter arterial chemoembolization (pTACE) for patients with hepatocellular carcinoma (HCC), especially those with Child-Pugh (CP) B, remains controversial. This study aimed to assess the survival benefit of pTACE for HCC patients with CP B., Methods: Data from 297 HCC patients with CP B7 or B8 were analyzed, dividing them into groups with and without pTACE (70, 23.6% vs. 227, 76.4%). Propensity score matching (PSM) was used to control for confounding bias, and competing-risk regression was applied to address bias from non-cancer-specific death (NCSD)., Results: Preliminary findings suggest that pTACE did not increase the incidence of severe complications in HCC patients with CP B7 or B8. Survival analysis indicated that the group receiving pTACE had better overall survival and recurrence-free survival than the group without pTACE after PSM. Furthermore, competitive risk analysis revealed that pTACE was an independent prognostic factor associated with reduced cancer-specific death incidence (subdistribution hazard ratio [SHR] 0.644, 95%CI: 0.378-0.784, P = 0.011) and recurrence (SHR 0.635, 95% CI: 0.379-0.855, P = 0.001). Importantly, pTACE did not increase NCSD. Subgroup analysis corroborated these results., Conclusion: Adjuvant TACE demonstrates the potential to significantly enhance the long-term prognosis of HCC patients with CP B7 or B8 following hepatectomy, particularly those with multiple tumors, large tumor size, macrovascular or microvascular invasion, and narrow resection margin. Hence, pTACE should be considered for patients at high risk of recurrence following thorough evaluation., (© 2024. The Author(s).)

Background: Primary liver cancer is the sixth most common cancer worldwide, with hepatocellular carcinoma (HCC) being the most prevalent form. Despite the current availability of multiple immune or immune combination treatment options, the prognosis is still poor, so how to identify a more suitable population is extremely important., Aim: To evaluate the clinical effectiveness of combining lenvatinib with camrelizumab for patients with hepatitis B virus (HBV)-related HCC in Barcelona Clinic Liver Cancer (BCLC) stages B/C, considering various body mass index (BMI) in different categories., Methods: Retrospective data were collected from 126 HCC patients treated with lenvatinib plus camrelizumab. Patients were divided into two groups based on BMI: The non-overweight group (BMI < 25 kg/m 2 , n = 51) and the overweight/obese group (BMI ≥ 25 kg/m 2 , n = 75). Short-term prognosis was evaluated using mRECIST criteria, with subgroup analyses for non-overweight (BMI: 18.5-24.9 kg/m 2 ), overweight (BMI: 25-30 kg/m 2 ), and obese (BMI ≥ 30 kg/m 2 ) patients. A Cox proportional hazards regression analysis identified independent prognostic factors for overall survival (OS), leading to the development of a column-line graph model., Results: Median progression-free survival was significantly longer in the obese/overweight group compared to the non-overweight group. Similarly, the median OS was significantly prolonged in the obese/overweight group than in the non-overweight group. The objective remission rate and disease control rate for the two groups of patients were, respectively, objective remission rate (5.88% vs 28.00%) and disease control rate (39.22% vs 62.67%). Fatigue was more prevalent in the obese/overweight group, while other adverse effects showed no statistically significant differences ( P > 0.05). Subgroup analysis based on BMI showed that obese and overweight patients had better progression-free survival and OS than non-overweight patients, with obese patients showing the best outcomes. Multifactorial regression analysis identified BCLC grade, alpha-fetoprotein level, portal vein tumor thrombosis, and BMI as independent prognostic factors for OS. The column-line graph model highlighted the importance of BMI as a major predictor of patient prognosis, followed by alpha-fetoprotein level, BCLC classification, and portal vein tumor thrombosis., Conclusion: BMI is a long-term predictor of the efficacy of lenvatinib plus camrelizumab, and obese/overweight patients have a better prognosis., 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 aim of this study was to conduct a systematic review and meta-analysis to comprehensively evaluate the performance and methodological quality of artificial intelligence (AI) in predicting recurrence after single first-line treatment for liver cancer., Methods: A rigorous and systematic evaluation was conducted on the AI studies related to recurrence after single first-line treatment for liver cancer, retrieved from the PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The area under the curve (AUC), sensitivity (SENC), and specificity (SPEC) of each study were extracted for meta-analysis., Results: Six percutaneous ablation (PA) studies, 16 surgical resection (SR) studies, and 5 transarterial chemoembolization (TACE) studies were included in the meta-analysis for predicting recurrence after hepatocellular carcinoma (HCC) treatment, respectively. Four SR studies and 2 PA studies were included in the meta-analysis for recurrence after intrahepatic cholangiocarcinoma (ICC) and colorectal cancer liver metastasis (CRLM) treatment. The pooled SENC, SEPC, and AUC of AI in predicting recurrence after primary HCC treatment via PA, SR, and TACE were 0.78, 0.90, and 0.92; 0.81, 0.77, and 0.86; and 0.73, 0.79, and 0.79, respectively. The values for ICC treated with SR and CRLM treated with PA were 0.85, 0.71, 0.86 and 0.69, 0.63,0.74, respectively., Conclusion: This systematic review and meta-analysis demonstrates the comprehensive application value of AI in predicting recurrence after a single first-line treatment of liver cancer, with satisfactory results, indicating the clinical translation potential of AI in predicting recurrence after liver cancer treatment., (© 2024. The Author(s).)

As a first-line chemotherapeutic agent, albumin-bound paclitaxel (PA) has a considerable effect on the treatment of various cancers. However, in chemotherapy for hepatocarcinoma, the sensitivity to PA is low owing to the innate resistance of hepatocarcinoma cells; the toxicity and side effects are severe, and the clinical treatment impact is poor. In this study, we present a unique nanodrug delivery system. The ultraviolet (UV)-induced tumor-cell-derived extracellular vesicles (EVs) were isolated and purified by differential centrifugation. Then, PA was loaded by coextrusion to create a vesicle drug delivery system (EVPA). By employing the EV-dependent enhanced retention effect and specific homing effect, EVPA would passively and actively target tumor tissues, activate the immune response to release PA, and achieve the combination therapeutic effect of chemo-immunotherapy on hepatocarcinoma. We demonstrated that the tumor-killing effect of EVPA is superior to that of PA, both in vivo and in vitro and that EVPA can be effectively taken up by hepatocarcinoma and dendritic cells, activate the body's specific immune response, promote the infiltration of CD4+ and CD8+ T cells in tumor tissues, and exert a precise killing effect on hepatocarcinoma cells via chemo-immunotherapy.

Objective: Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC)., Design: We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in TERT promoter, CTNNB1 , TP53 , PIK3CA and NFE2L2 by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples., Results: In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p<0.001). In active HCC, we identified 27.5% of mutations in TERT promoter, 21.3% in TP53 , 13.1% in CTNNB1 , 0.4% in PIK3CA and 0.2% in NFE2L2, most of the times similar to those identified in the corresponding tumour. CtDNA mutation rate increased with advanced tumour stages (p<0.001). In 103 patients treated by percutaneous ablation, the presence and number of mutations in the ctDNA before treatment were associated with higher risk of death (p=0.001) and recurrence (p<0.001). Interestingly, cfDNA concentration and detectable mutations increased 24 hours after a locoregional treatment. Among 356 plasmas collected in 53 patients treated by systemic treatments, we detected mutations at baseline in 60.4% of the cases. In patients treated by atezolizumab-bevacizumab, persistence of mutation in ctDNA was associated with radiological progression (63.6% vs 36.4% for disappearance, p=0.019). In two patients progressing under systemic treatments, we detected the occurrence of mutations in CTNNB1 in the plasma that was subclonal in the tumour for one patient and not detectable in the tumour for the other one., Conclusion: ctDNA offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide HCC clinical management., Competing Interests: Competing interests: PN has received honoraria from and/or consults for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen and Roche. He received research grants from AstraZeneca, AbbVie, Bristol–Myers Squibb and Eisai. NGC received travel and congress fees, consulting fees or honoraria for lectures, presentations, speakers’ bureaus from Abbvie, Bayer, Gilead, Ipsen, Intercept and Roche. J-CN received research funding from Bayer and Ipsen. CC, SI, GC, MZ, TZH, SR, BN, KH, SS, OS, VT, PL-P and JZ-R have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expression in adult tissues. Its re-expression in hepatocellular carcinoma (HCC) and secretion into the serum highlights its potential as a diagnostic marker. GPC-3 is involved in important cellular processes such as proliferation, metastasis, apoptosis, and epithelial-mesenchymal transition through various signaling pathways including Wnt, IGF, YAP, and Hedgehog. To review the structure, biosynthesis, and post-translational modifications of GPC-3, and to elucidate its signaling mechanisms and role as a pro-proliferative protein in HCC, emphasizing its diagnostic and therapeutic potential. A comprehensive literature review was conducted, focusing on the expression of GPC-3 in various tumors, with a special emphasis on HCC. The review synthesized findings from experimental studies and clinical trials, analyzing the overexpression of GPC-3 in HCC, its differentiation from other liver diseases, and its potential as a diagnostic and therapeutic target. GPC-3 overexpression in HCC is linked to aggressive tumor behavior and poor prognosis, including shorter overall and disease-free survival. Additionally, GPC-3 has emerged as a promising therapeutic target. Ongoing investigations, including immunotherapies such as monoclonal antibodies and CAR-T cell therapies, demonstrate potential in inhibiting tumor growth and improving clinical outcomes. The review details the multifaceted roles of GPC-3 in tumorigenesis, including its impact on tumor-associated macrophages, glucose metabolism, and epithelial-mesenchymal transition, all contributing to HCC progression. GPC-3's re-expression in HCC and its involvement in key tumorigenic processes underscore its value as a biomarker for early diagnosis and a target for therapeutic intervention. Further research is warranted to fully exploit GPC-3's diagnostic and therapeutic potential in HCC management., (© 2024. The Author(s).)

Backgroud: Mediator complex subunit 19 (MED19), a member of the mediator complex, has been demonstrated to involve in tumorigenesis of hepatocellular carcinoma (HCC). However, the regulation mechanisms of MED19, the immune landscape linking MED19 to HCC and its predictive value of immunotherapy treatment in HCC are so far unknown., Methods: Here, we analyzed data from The Cancer Genome Atlas and other databases to assess the expression of MED19 and its prognosis and therapeutical-targets impact in HCC., Results: MED19 expression was upregulated in HCC tissues compared to non-tumorous liver tissues and that its upregulation was positively associated with advanced clinicopathology features. The multivariate analysis showed that MED19 was an independent predictor of outcome in HCC. In vitro experiments revealed that MED19 knockdown suppressed hepG2 cells proliferation, colony forming and invasion and induced apoptosis. Furthermore, MED19 inhibition resulted in G0/G1 phase arrest in hepG2 cells. We screened differentially expressed genes between low and high MED19 expression groups. Enrichment analyses showed that these genes were mainly linked to nuclear division and cell cycle. The pattern of tumor-infiltrating immune was demonstrated to be related with MED19 expression in HCC. TIDE analyses showed that patients in the low-expression group presented significantly better immunotherapy. Moreover, we developed a predicted model for HCC patient's prognosis. Receiver operating characteristic analyses revealed that this model processed a favorable performance in predicting the prognosis of HCC patients. Finally, a nomogram was built for predicting survival probability of individual HCC patient., Conclusion: These findings suggest that MED19 as a novel biomarker that has significant association with immune landscape and immunotherapy response in HCC. The proposed prediction model composed of MED19 and pathological stage has a better role in determining prognosis and stratifying of HCC., (© 2024. The Author(s).)

Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut microbiome, which interacts with the liver through the "gut-liver axis". This bidirectional relationship between the gut and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites and immune responses being central to these processes. Our review consolidates the latest research on how gut microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut microbiota's roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine diagnostic techniques and develop targeted therapies that exploit the microbiome's capabilities, aiming to enhance patient care in liver diseases., (© 2024. The Author(s).)

Background: Hepatocellular Carcinoma (HCC) is a highly aggressive, prevalent, and deadly type of liver cancer. With the advent of deep learning techniques, significant advancements have been made in simplifying and optimizing the feature selection process., Objective: Our scoping review presents an overview of the various deep learning models and algorithms utilized to address feature selection for HCC. The paper highlights the strengths and limitations of each approach, along with their potential applications in clinical practice. Additionally, it discusses the benefits of using deep learning to identify relevant features and their impact on the accuracy and efficiency of diagnosis, prognosis, and treatment of HCC., Design: The review encompasses a comprehensive analysis of the research conducted in the past few years, focusing on the methodologies, datasets, and evaluation metrics adopted by different studies. The paper aims to identify the key trends and advancements in the field, shedding light on the promising areas for future research and development., Results: The findings of this review indicate that deep learning techniques have shown promising results in simplifying feature selection for HCC. By leveraging large-scale datasets and advanced neural network architectures, these methods have demonstrated improved accuracy and robustness in identifying predictive features., Conclusions: We analyze published studies to reveal the state-of-the-art HCC prediction and showcase how deep learning can boost accuracy and decrease false positives. But we also acknowledge the challenges that remain in translating this potential into clinical reality., (© 2024. The Author(s).)