Survival In Hepatocellular Carcinoma Research Articles

Triglyceride-glucose index predicts postoperative overall survival in hepatocellular carcinoma: a retrospective cohort study.

Insulin resistance is important in hepatocellular carcinoma (HCC) carcinogenesis and progression. The triglyceride-glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio or TyG-body mass index (TyG-BMI) are three non-invasive parameters for insulin resistance. However, their prognostic role in HCC patients undergoing hepatectomy remains unclear. HCC patients who underwent hepatectomy at the Meizhou People's Hospital from May 2011 to February 2023 were retrospectively explored. Patients were classified into high and low groups based on different TyG, TG/HDL-c, and TyG-BMI indices. The prognostic role of TyG, TG/HDL-c, and TyG-BMI was evaluated using Kaplan-Meier analysis and Cox regression models. A nomogram incorporating significant prognostic factors was constructed and validated. A lower TyG, lower TG/HDL-c, and lower TyG-BMI were linked to worse overall survival (OS) in HCC patients. Multivariate analysis indicated the TyG index, but not the TG/HDL-c and TyG-BMI index, could independently predict HCC OS. The nomogram incorporating the TNM stage and TyG index demonstrated good calibration, discriminative ability, and clinical benefit for predicting OS in HCC patients. The TyG index could independently predict HCC OS after hepatectomy in this cohort. The nomogram incorporating the TyG index may aid in the prognosis management of HCC.

CSTF2 Supports Hypoxia Tolerance in Hepatocellular Carcinoma by Enabling m6A Modification Evasion of PGK1 to Enhance Glycolysis.

Cleavage stimulation factor subunit 2 (CSTF2) is a fundamental factor in the regulation of 3'-end cleavage and alternative polyadenylation of pre-mRNAs. Previous work has identified a tumor-promoting role of CSTF2, suggesting that it may represent a potential therapeutic target. Here, we aimed to elucidate the mechanistic function of CSTF2 in hepatocellular carcinoma (HCC). CSTF2 upregulation was frequent in HCC, and elevated levels of CSTF2 correlated with poor patient prognosis. While CSTF2 inhibition did not suppress HCC growth under non-stress conditions, it supported tolerance and survival of HCC cells under hypoxic conditions. Mechanistically, CSTF2 increased PGK1 protein production to enhance glycolysis, thereby sustaining the energy supply under hypoxic conditions. CSTF2 shortened the 3' untranslated region (3' UTR) of phosphoglycerate kinase 1 (PGK1) pre-mRNA by binding near the proximal polyadenylation site (pPAS). This shortening led to a loss of N6-methyladenosine (m6A) modification sites that are bound by YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) and increase degradation of PGK1 mRNA. Concurrently, hypoxia increased m6A modification of PGK1 mRNA near the pPAS that was recognized by the YTH N6-methyladenosine RNA-binding protein C1 (YTHDC1), which recruited CSTF2 to enhance the shortening of the PGK1 3'-UTR. A small molecule screen identified masitinib as an inhibitor of CSTF2. Masitinib counteracted PGK1 upregulation by CSTF2 and suppressed the growth of HCC xenograft and patient-derived organoid models. In conclusion, this study revealed a function of CSTF2 in supporting HCC survival under hypoxia conditions through m6A modification evasion and metabolic reprogramming, indicating inhibiting CSTF2 may overcome hypoxia tolerance in HCC.

Identification of Crucial Cancer Stem Cell Genes Linked to Immune Cell Infiltration and Survival in Hepatocellular Carcinoma

Identification of Crucial Cancer Stem Cell Genes Linked to Immune Cell Infiltration and Survival in Hepatocellular Carcinoma

Genetic variants in folate metabolism-related genes, serum folate and hepatocellular carcinoma survival: the Guangdong Liver Cancer Cohort study.

Folate metabolism is involved in the development and progression of various cancers. We investigated the association of single nucleotide polymorphisms (SNP) in folate-metabolising genes and their interactions with serum folate concentrations with overall survival (OS) and liver cancer-specific survival (LCSS) of newly diagnosed hepatocellular carcinoma (HCC) patients. We detected the genotypes of six SNPin three genes related to folate metabolism: methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HR) and 95 % CI. This analysis included 970 HCC patients with genotypes of six SNP, and 864 of them had serum folate measurements. During a median follow-up of 722 d, 393 deaths occurred, with 360 attributed to HCC. In the fully-adjusted models, the MTRR rs1801394 polymorphism was significantly associated with OS in additive (per G allele: HR = 0·84, 95 % CI: 0·71, 0·99), co-dominant (AG v. AA: HR = 0·77; 95 % CI: 0·62, 0·96) and dominant (AG + GG v. AA: HR = 0·78; 95 % CI: 0·63, 0·96) models. Carrying increasing numbers of protective alleles was linked to better LCSS (HR10–12 v. 2–6 = 0·70; 95 % CI: 0·49, 1·00) and OS (HR10–12 v. 2–6 = 0·67; 95 % CI: 0·47, 0·95). Furthermore, we observed significant interactions on both multiplicative and additive scales between serum folate levels and MTRR rs1801394 polymorphism. Carrying the variant G allele of the MTRR rs1801394 is associated with better HCC prognosis and may enhance the favourable association between higher serum folate levels and improved survival among HCC patients.

A Novel Prognostic Nomogram Based on TIGIT and NKG2A Can Predict Relapse-Free Survival of Hepatocellular Carcinoma After Hepatectomy.

Hepatocellular carcinoma (HCC) is a major global health concern, and emerging evidence suggests that TIGIT and NKG2A are potential immune checkpoints with implications for HCC progression. This study aimed to evaluate the prognostic significance of TIGIT and NKG2A expression in HCC patients who underwent radical liver resection. We conducted a retrospective analysis of 144 HCC patients who underwent radical liver resection. TIGIT and NKG2A expression levels were assessed using the immunoreactive score. Cox proportional hazards models were utilized to analyze the association between TIGIT/NKG2A expression and clinical characteristics, relapse-free survival (RFS), and overall survival (OS). Prognostic models for OS and RFS was developed and validated using concordance index and calibration curves. Additionally, the random forest algorithm was employed to identify independent risk factors for OS and RFS and their correlation with predicted survival. TIGIT and NKG2A expression were identified as independent risk factors for RFS, while TIGIT expression alone significantly impacted OS. The prognostic models showed good discriminative ability, with concordance indices exceeding 0.7 for predicting 1-, 3-, and 5-year OS or RFS. Calibration curves confirmed the reliability of the nomograms for OS and RFS prediction. The areas under the ROC curve consistently exceeded 0.7 for predicting OS and RFS. Elevated levels of TIGIT and NKG2A expression were associated with diminished RFS, highlighting their importance as prognostic factors. Our study establishes the prognostic significance of TIGIT and NKG2A expression in predicting OS and RFS following radical liver resection for HCC patients. The developed prognostic models incorporating TIGIT and NKG2A expression hold promise for improving risk stratification and clinical management of HCC patients.

Identification of a pyroptosis-related long noncoding RNA signature for determining the prognosis and immune status of hepatocellular carcinoma patients.

Despite improvements in cancer screening and diagnosis, hepatocellular carcinoma (HCC) is still diagnosed at an advanced stage, and the prognosis is worse than that of early HCC patients. Therefore, better molecular markers and therapeutic targets in HCC are required. We investigated the predictive value of pyroptosis-related long noncoding RNAs (lncRNAs) in HCC and the effects of these lncRNAs on the immune microenvironment of HCC. RNA sequencing data of HCC patients were extracted from The Cancer Genome Atlas (TCGA) database to identify differentially expressed pyroptosis-related lncRNAs related to overall survival (OS). A model was established to verify the character of pyroptosis-associated lncRNAs in the tumor microenvironment, and their prognostic value was evaluated. A total of 721 PR lncRNAs were identified based on the analysis of the TCGA database. Univariate Cox analysis revealed 37 survival-related PRlncRNAs with prognostic values. As a result of least absolute shrinkage and selection operator (LASSO) regression analysis, 'ELFN-AS1', AC099850.3, AC073389.3, 'HPN-AS1', AC009283.1, and AL139289.1 showed prognostic value. Kaplan-Meier analysis indicated that the OS of the high-risk set was worse than those of the low-risk set in both the training and testing cohorts. Univariate and multivariate analyses revealed that the risk score was a better independent prognostic factor than the stage. The precision of the lncRNA signature was confirmed using receiver operating characteristic curve (ROC) analysis. Immuneand metabolism-related pathways were enriched in both the lowand high-risk groups. Gene set enrichment analysis suggested that the identified lncRNAs regulate HCC tumorigenesis and prognosis by modulating metabolism. Various algorithms were used to confirm the significant differences in immune cells between these 2 groups. These findings could contribute to the development and validation of favorable biomarkers, improve the prognosis and survival of HCC, and help in developed individualized treatment plans for HCC.

The Neoangiogenic Transcriptomic Signature Impacts Hepatocellular Carcinoma Prognosis and Can Be Triggered by Transarterial Chemoembolization Treatment.

Background/Objectives: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods: This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results: The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS- patients. By the end, 78.9% had died, with nTS- patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS- to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions: The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management.

Immune cell dynamics and the impact on the efficiency of transvascular antitumor interventional therapies in hepatocellular carcinoma patients.

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. 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. 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. Higher counts of WBCs, lymphocytes, monocytes, and basophils, play a crucial role in the effectiveness of HCC interventional therapy.

An analysis of the clinical significance of the TKI-resistant gene ZNF687 for hepatocellular carcinoma patients.

Novel treatments such as monotherapy and combined immunotherapy significantly extend overall survival (OS) for hepatocellular carcinoma (HCC) patients, but HCC is susceptible to treatment resistance during long-term therapy. The resistance mechanism to targeted drugs in HCC remains ambiguous, making research on HCC drug resistance targets crucial for the development of precision medicine. To investigate the transcriptional features, biological functions and potential clinical value of the tyrosine kinase inhibitor (TKI)-resistant gene ZNF687 in HCC. The TKI-resistant genes of HCC were identified using clustered regularly interspaced short palindromic repeats (CRISPR) in vitro screening. Then, the dependence of HCC cell lines on ZNF687 was investigated in silico. We collected global mRNA datasets of HCC tissue, integrated the mRNA expression characteristics of ZNF687 in HCC and explored the impact of ZNF687 on HCC patient prognoses using the Kaplan-Meier method (in silico). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were then conducted, and a connectivity map and molecular docking technology were applied to find the underlying agent opposing ZNF687. In vitro, the guide RNA corresponding to ZNF687 was weakly detected in HCC cells, and ZNF687 deficiency was found to inhibit growth in HCC cell lines. ZNF687 mRNA was overexpressed and had a high discriminatory ability for HCC in 2,975 HCC samples, contrasting with 2,340 non-HCC samples. Moreover, an excessive ZNF687 transcript level was related to a worse overall survival (OS) prognosis. Histone modification, spliceosome, transcription coregulator activity, and nucleocytoplasmic transport were the most significant pathways for ZNF687 differential-related gene enrichment. Chaetocin was found to be a candidate compound and presented a strong affinity to ZNF687. ZNF687 represents a TKI-resistant and growth-dependent gene for HCC, the overexpression of which indicates poor OS for HCC patients. Additionally, ZNF687 is expected to be a druggable target for overcoming TKI resistance, and chaetocin may be a candidate therapeutic compound for ZNF687.

ARL8B promotes hepatocellular carcinoma progression and inhibits antitumor activity of lenvatinib via MAPK/ERK signaling by interacting with RAB2A

Tumor recurrence and metastasis are important factors affecting postoperative survival in hepatocellular carcinoma (HCC) patients. ADP Ribosylation factor-like GTPase 8B (ARL8B) plays a crucial role in many biological processes, including lysosomal function, immune response, and cellular communication, all of which are related to the occurrence and development of tumors. However, its role in HCC remains unclear. Herein, we revealed that ARL8B is consistently elevated in HCC tissues compared to normal liver tissues, suggesting an unfavorable outcome in HCC patients. Increased ARL8B levels promoted the malignant phenotype of HCC in vitro and in vivo. Notably, ARL8B also induced epithelial-to-mesenchymal transition (EMT) in HCC cells. Mechanistically, the results of bioinformatics analysis combined with mass spectrometry revealed the potential downstream target molecule RAB2A of ARL8B. ARL8B directly interacted with RAB2A and increased the levels of GTP-bound RAB2A, thereby contributing to the activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Interestingly, knockout of ARL8B in Hep3B cells enhanced the antitumor activity of lenvatinib in vitro and in vivo. Furthermore, AAV-shARL8B enhanced the inhibition of HCC growth through lenvatinib, providing new insights into its mechanism of action in lenvatinib-insensitive patients. In conclusion, ARL8B promotes the malignant phenotype of HCC and EMT via RAB2A mediated activation of the MAPK/ERK signaling pathway and is expected to be a valuable prognostic indicator and therapeutic target for HCC patients.

Long-Term Outcomes of Patients with Liver Cirrhosis After Eradication of Chronic Hepatitis C with Direct-Acting Antiviral Drugs (DAAs).

This research was designed to determine the long-term outcomes in patients with liver cirrhosis who achieved sustained virological response (SVR) after direct-acting anti-viral drugs (DAAs) based regimens. This study involved 193 patients with HCV-related cirrhosis who had previously completed DAAs regimens and accomplished SVR. Clinical, laboratory, and radiological features at the first and 3rd-year follow-up after the end of treatment were analyzed. Overall survival (OS) and incidence of liver decompensation or hepatocellular carcinoma (HCC) were determined at the 5-year follow-up. About 68.4% of our patients with HCV-related cirrhosis were males and their mean age was 54.8 ± 7.7 years. Follow-up at the first and the 3rd-year showed significant improvements in albumin (P = 0.001), liver enzymes (P = 0.001), alpha-fetoprotein (AFP) (P < 0.001), platelet count (P = 0.001), the model for end-stage liver disease (MELD) score (P = 0.001 and 0.01), FIB4 and Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores (p < 0.001). The liver stiffness (LS) also significantly improved (p = 0.001). At the 5th year, the mean OS was 58.3 months, with 14.5% and 17.6% of patients developing de-novo HCC and decompensation, respectively. The mean OS at the 5th-year follow-up was shorter in patients who developed HCC and those with liver decompensation (p = 0.001). Alfa-fetoprotein and LS are predictive factors for HCC development. Despite achieving SVR, continuous surveillance for HCC and new-onset decompensation is mandatory in patients with liver cirrhosis.

A qualitative study identifying the navigation needs of patients with HCC.

263 Background: Hepatocellular carcinoma (HCC), the 2 nd leading cause of cancer mortality, disproportionately affects racial and ethnic minorities. Disparities in risk are compounded by profound differences in HCC treatment and survival. Black patients are consistently diagnosed at more advanced stages, least likely to receive treatment, and have the lowest survival. In other cancer types, navigation facilitates successful treatment and improves outcomes. To inform development of a longitudinal navigation program, we aimed to ascertain the needs of HCC patients, and identify obstacles limiting access to cancer treatment and supports needed for successful HCC treatment from the vantage point of patients and other stakeholders. Methods: In-depth, one-hour qualitative interviews were conducted with 40 individuals (14 patients, 7 caregivers, 8 advocates, and 11 providers) in English or Spanish. Providers included physicians, advanced practice providers, social workers, nurse navigators, and transplant coordinators involved in HCC care. We recruited patients, caregivers, and providers from the Sylvester Comprehensive Cancer Center and Jackson Health System; advocates were recruited through partnerships with Global Liver Institute and the Hepatitis B Foundation. Results: The interviews identified five overarching themes representing navigation needs of HCC patients: (1) Education/ Health Literacy, (2) Financial Resources, (3) Coordination of Care, (4) Emotional Management, and (5) Social Support. The table displays the themes and subthemes. Conclusions: This study provides valuable insight into the needs of HCC patients at the institutional and national levels. Successful navigation must include interventions that address these needs; study findings have informed our pilot navigation intervention. Navigation needs of HCC patients. Themes Subthemes Education Disease progression and prognosisTreatment optionsPreparation for various stages of disease and treatmentEducation and preparation for upcoming visitsImportance of follow-upNutrition and other health behaviors Financial Resources Insurance–treatment/medication coverage andcopaymentsTransportationHousing/ RentFoodConnection to other agencies/ community resources (Medicare/ Medicaid, funding programs, foundations/ non-profits targeting HCC, advocacy) Coordination of Care Scheduling multiple doctor/lab visitsFollow-up for attendance to visitsMedical records ordered and receivedImaging done correctly and receivedServices to manage symptoms (Nutrition, acupuncture, massage, etc.) Emotional Management Manage anxiety/ depression/ overwhelm/ confusion/ denial/ fatiguePsycho-oncology/psychiatrist referralAlcohol and substance abuse treatmentSupport groupsStress reduction/ coping strategiesMindfulness/ meditationYoga/ Movement Limited Social Support Mental healthTransportationTreatment adherence

Racial disparities in hepatocellular carcinoma (HCC) treatment and survival: A SEER-Medicare analysis.

144 Background: Between 2017-2022, approved systemic therapies for HCC increased from 1 to 10. Studies have shown racial disparities in overall survival (OS), but no studies have evaluated disparities in new systemic treatments. Methods: We identified patients in SEER-Medicare data diagnosed with HCC in 2014-2019 with claims through 2020. We identified demographics, liver disease type, cirrhosis complications (e.g, jaundice), diagnosis stage, receipt of local therapies (e.g, resection) and receipt of systemic therapies (e.g, sorafenib). We described cohort characteristics by race. OS and receipt of treatment were analyzed using Cox and logistical regression models adjusted for the above covariates. Results: The study included 8,257 patients (77.7% White, 11.9% Asian, 9.1% Black, 0.9% American Indian). Median OS for all patients was 9.1 months. Compared to White patients, Black patients had worse OS (hazard ratio [HR] 1.36, p= &lt;.0001). Black patients receiving no treatment (HR 1.24, p=0.002) and local therapy first (HR 1.29, p=0.003) also had worse survival, while Black patients receiving systemic therapy first had similar OS (HR 1.08, p=0.62) to White patients. Black patients were less likely than White patients to receive any treatment (odds ratio [OR]: 0.64, p=&lt;.0001) or curative treatment if they had early stage-HCC (OR 0.49, p=0.013), but had no difference in receipt of a new systemic therapy if receiving any systemic therapy (OR 0.72, p=0.19) (Table). Compared to White patients, Asian patients had better OS among all patients (HR 0.91, p=0.04) and among patients receiving local therapy first (HR 0.89), but similar OS among patients receiving no treatment (HR 0.90, p=0.13) or systemic therapy first (HR 1.07, p=0.60). Asian patients were as likely as White patients to receive any treatment (OR 1.07, p=0.43), curative treatment for early-stage HCC (OR 0.94, p=0.70) and novel therapies if receiving systemic therapy (OR 1.10, p=0.70). Conclusions: As new HCC therapies emerged, there were racial disparities in OS and receipt of any treatment or local therapies, but not in receipt of new systemic treatments. Targeted interventions are essential to address these disparities and ensure equitable access to care. Treatment and survival disparities, by race. All PatientsN=8,218 White N=6412 Black N=747 Asian or Pacific Islander N=983 American Indian/Alaskan Native* N=76 Median Overall survival, months 9.1 9.5 5.6 10.1 8.3 No treatment, n (%) 3213 (39.1) 2510 (39.2) 348 (46.6) 330 (33.6) 25 (32.9) Systemic first, n (%) 894 (10.9) 693 (10.8) 85 (11.4) 103 (10.5) 13 (17.1) Local first, n (%) 4111 (50.0) 3209 (50.0) 314 (42.0) 550 (56.0) 38 (50.0) Of patients with early-stage HCC, those who received curative treatment, n (%) 749 (41.7) &gt;542 (&gt;41.5) 43 (29.3) 147 (45.2) &lt;11 (&lt;40.0) Of patients receiving systemic therapy, those who got a novel therapy, n (%) 763 (44.3) &gt;581 (&gt;43.9) 63 (40.9) 103 (46.0) &lt;11 (&lt;50.0)

Ficolin-3 induces apoptosis and suppresses malignant property of hepatocellular carcinoma cells via the complement pathway

AimsFicolin 3 (FCN3) has the highest complement-activating capacity through the lectin pathway and is synthesized mainly in the liver and lung. Yet, its potential molecular mechanism in hepatocarcinogenesis is not fully understood. Materials and methodsThe expression of FCN3 in hepatocellular carcinoma (HCC) tumor and non-tumor tissues was analyzed by RT-qPCR, Western blotting and immunofluorescence staining assays. Lentivector-mediated ectopic overexpression was performed to explore the role of FCN3 in vitro and in vivo. Whether FCN3 inhibited HCC cell growth and survival via complement pathway was determined with immunocytochemical staining for C3b, membrane attack complex (MAC) formation and complement killing assay using recombinant FCN3 (rFCN3) in combination with human serum with or without heat inactivation, and with C6 blocking antibody. Key findingsThe transcript and protein of FCN3 were found to be remarkably down-regulated in HCC tumor tissues. FCN3 expression was found to be associated with better survival of HCC patients. Restoration of FCN3 expression significantly inhibited proliferation, migration and anchorage independent growth of HCC cell lines, and xenograft tumor growth. FCN3 expression induced apoptosis of HCC cells. C3 and MAC formation was stimulated by FCN3 overexpression or rFCN3 treatment. rFCN3 enhanced human serum-induced complement activation and cell death. C6 blocking antibody significantly attenuated complement-mediated cell death and restored the growth of FCN3-overexpressing HCC cells. SignificanceFCN3 has a malignant suppressor role in HCC cells. Our study provides new insights into the molecular mechanisms that drive HCC progression and potential therapeutic targets for treating HCC.

Relationship between EZH2 expression and prognosis of patients with hepatocellular carcinoma using a pathomics predictive model

BackgroundEnhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is overexpressed in hepatocellular carcinoma, promoting tumorigenesis and correlating with poor prognosis. Traditional histopathological examinations are insufficient to accurately predict hepatocellular carcinoma (HCC) survival; however, pathomics models can predict EZH2 expression and HCC prognosis. This study aimed to investigate the relationship between pathomics features and EZH2 expression for predicting overall survival of patients with HCC. MethodsWe analyzed 267 patients with HCC from the Cancer Genome Atlas database, with available pathological images and gene expression data. RNA sequencing data were divided into high and low EZH2 expression groups for prognosis and survival analysis. Pathological image features were screened using mRMR_RFE. A pathological model was constructed using a gradient boosting machine (GBM) algorithm, and efficiency evaluation and survival analysis of the model were performed. The R package “survminer” took the pathomics score (PS) cutoff value of 0.4628 to divide the patients into two groups: high and low PS expression. Survival analyses included Kaplan–Meier curve analysis, univariate and multivariate Cox regression analyses, and interaction tests. Potential pathomechanisms were explored through enrichment, differential, immune cell infiltration abundance, and gene mutation analyses. ResultEZH2 was highly expressed in tumor samples but poorly expressed in normal tissue samples. Univariate and multivariate Cox regression analyses revealed that EZH2 was an independent risk factor for HCC (hazard ratio [HR], 2.792 and 3.042, respectively). Seven imaging features were selected to construct a pathomics model to predict EZH2. Decision curve analysis showed that the model had high clinical utility. Multivariate Cox regression analysis showed that high PS expression was an independent risk factor for HCC prognosis (HR, 2.446). The Kaplan–Meier curve showed that high PS expression was a risk factor for overall survival. ConclusionEZH2 expression can affect the prognosis of patients with liver cancer. Our pathological model could predict EZH2 expression and prognosis of patients with HCC with high accuracy and robustness, making it a new and potentially valuable tool.

Lymphocyte Function in Tertiary Lymphoid Structures Predicts Hepatocellular Carcinoma Outcome

An increasing number of studies have revealed a correlation between tertiary lymphoid structures (TLSs) and the outcome of hepatocellular carcinoma (HCC). Nevertheless, the associations between the heterogeneity of cellular composition and the overall survival (OS) in HCC remain unexplored. Here, we evaluated the cancer tissues from 150 HCC individuals treated at the Tumor Hospital Affiliated with Nantong University using multiplex immunofluorescence to determine the presence and characteristics of TLS and to investigate the relationship between intra-TLS immunologic activity, TLS maturation, and intratumoral immune cell infiltration. Prognostic factors influencing the outcome were identified through both univariate and multivariate analyses. Additionally, the levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death 1, programmed death-ligand 1, and lymphocyte activation gene-3 were determined, as well as their relationship with TLS features were determined. TLS was detected in 71 (47.3%) of the 150 HCC cases and was related to higher intratumoral infiltration levels of lymphocytes. Additionally, intra-TLS lymphocyte proliferation correlated with that of intratumoral lymphocytes, and the presence of TLS and a high proportion of mature TLS demonstrated a significant correlation with better prognosis (P = .013 and P = .03, respectively). Among TLS-positive tumors, a high proportion of B cells expressing activation-induced cytidine deaminase and a high proportion of CD8+ T cells expressing CD45RO were significantly related to improved OS (P = .01 and P < .001, respectively). Comparatively, a high proportion of CD21+CD20+ B cells demonstrated a significant correlation with poorer OS (P < .002). A markedly reduced number of CTLA-4+ cells in the stromal regions in TLS-negative tumors was observed compared with TLS-positive tumors (P = .01). These findings reveal a correlation between TLS presence and improved OS in HCC patients. However, TLS exhibited significant variation in maturation state, T- and B-cell proliferation, and expression of markers related to B- and T-cell function. Notably, these characteristics were also found to possess prognostic significance, indicating that certain TLS might hinder tumor immunity by inhibiting immune cells, whereas others may foster antigen-driven immune responses, likely influenced by the composition and functional status of intra-TLS lymphocytes.

Transarterial Radioembolization Can Downstage Intermediate and Advanced Hepatocellular Carcinoma to Liver Transplantation.

Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC. Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes. Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall survival of patients receiving LT was 61% at 5 y after transplant. Tumor beyond up-to-seven criteria, alfafetoprotein >400 ng/mL, and albumin-bilirubin ≥2 were associated with death. Three risk groups were associated with different response, chances of being listed, and receiving LT. Median survival was 3 y for low-risk, 1.9 y for intermediate-risk, and 9 mo for high-risk patients (P < 0.001). In intermediate and advanced HCC, TARE allows for a 44% chance of response, 30% downstaging, and 23% probability of permitting LT. Patient's and tumor's characteristics allow for risk stratification and predict survival from TARE.

Upregulation of EFCAB7 after radiofrequency ablation promoting hepatocellular carcinoma metastasis and survival by regulating PARK7.

Radiofrequency ablation (RFA) is an established treatment for unresectable and early-stage hepatocellular carcinoma (HCC). However, in some cases, residual tumor cells undergo malignant transformation following RFA. The molecular mechanisms underlying this phenomenon remain poorly understood. EFCAB7, a member of the EF-hand structure family, is of particular interest due to its association with oncogenesis. Nevertheless, the role of EFCAB7 in oncogenesis remains unclear. Gene expression level of EFCAB7 in HCC tissues before and after RFA was measured, while in vitro and in vivo experiments were proposed for exploring the roles of EFCAB7 in tumor cell proliferation and metastasis. Mass spectrometry and CO-IP were adopted to validate the interaction between PARK7 and EFCAB7. Finally, PARK7 in EFCAB7 silencing cells was overexpressed and different functions were measured in vitro to determine regulation between two genes. EFCAB7 showed increased expression after RFA in patient samples and EFCAB7 expression correlated with poor prognosis in HCC patients from the TCGA database. Then, EFCAB7 promoted HCC tumor cell proliferation and metastasis while inhibiting apoptosis. Furthermore, Mass spectrometry and Co-IP experiments revealed a direct interaction between EFCAB7 and PARK7. Finally, when we overexpressed PARK7 in EFCAB7 knockdown tumor cells, it rescued proliferation and metastasis, indicating a functional relationship between these two genes. EFCAB7 might be a core contributor to HCC cells' malignant transformation after RFA and could be a potential novel target to provide a therapeutic strategy for the prevention of recurrence after RFA in HCC.

Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and ranks as the third leading cause of cancer-related mortality globally. The liver performs a wide range of tasks and is the primary organ responsible for metabolizing harmful substances and foreign compounds. Oxidative stress has a crucial role in growth and improvement of hepatocellular carcinoma (HCC). Nuclear factor erythroid 2 (1)-related factor 2 (Nrf2) is an element that regulates transcription located in the cytoplasm. It controls the balance of redox reactions by stimulating the expression of many genes that depend on antioxidant response elements. Nrf2 has contrasting functions in the normal, healthy liver and HCC. In the normal liver, Nrf2 provides advantageous benefits, while in HCC it promotes harmful effects that support the growth and survival of HCC. Continuous activation of Nrf2 has been detected in HCC and promotes its advancement and aggressiveness. In addition, Activation of Nrf2 may lead to immune evasion, weakening the immune cells' ability to attack tumors and thereby promoting tumor development. Furthermore, chemoresistance in HCC, which is considered a form of stress response to chemotherapy medications, significantly impedes the effectiveness of HCC treatment. Stress management is typically accomplished by activating specific signal pathways and chemical variables. One important element in the creation of chemoresistance in HCC is nuclear factor-E2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the activation and production of a group of genes that encode proteins responsible for protecting cells from damage. This occurs through the Nrf2/ARE pathway, which is a crucial mechanism for combating oxidative stress within cells.

959P Machine learning-based MRI radiomics predicts overall survival of unresectable hepatocellular carcinoma undergoing transarterial chemoembolization plus PD-(L)1 inhibitors and molecular targeted therapy

959P Machine learning-based MRI radiomics predicts overall survival of unresectable hepatocellular carcinoma undergoing transarterial chemoembolization plus PD-(L)1 inhibitors and molecular targeted therapy