Virus-related Hepatocellular Carcinoma Patients Research Articles

Impact of hepatic inflammation and fibrosis on the recurrence and long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after hepatectomy

BackgroundUnderlying liver disease is correlated with hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV) infection. However, the impact of hepatic inflammation and fibrosis on the patients’ prognoses remains unclear.MethodsThe clinicopathological data of 638 HBV-infected patients with early-stage HCC between 2017 and 2019 were prospectively collected. Hepatic inflammation and fibrosis were evaluated by experienced pathologists using the Scheuer score system. Survival analysis was analyzed using the Kaplan–Meier analysis.ResultsApplication of the Scheuer scoring system revealed that 50 (7.9%), 274 (42.9%), and 314 (49.2%) patients had minor, intermediate, and severe hepatic inflammation, respectively, and 125 (15.6%), 150 (23.5%), and 363 (56.9%) patients had minor fibrosis, advanced fibrosis, and cirrhosis, respectively. Patients with severe hepatitis tended to have a higher rate of HBeAg positivity, higher HBV-DNA load, elevated alanine aminotransferase (ALT) levels, and a lower proportion of capsule invasion (all Pp < 0.05). There were no significant differences in the recurrence-free and overall survival among the three groups (P = 0.52 and P = 0.66, respectively). Patients with advanced fibrosis or cirrhosis had a higher proportion of HBeAg positivity and thrombocytopenia, higher FIB-4, and larger tumor size compared to those with minor fibrosis (all P < 0.05). Patients with minor, advanced fibrosis, and cirrhosis had similar prognoses after hepatectomy (P = 0.48 and P = 0.70). The multivariate analysis results indicated that neither hepatic inflammation nor fibrosis was an independent predictor associated with prognosis.ConclusionsFor HBV-related HCC patients receiving antiviral therapy, hepatic inflammation and fibrosis had little impact on the post-hepatectomy prognosis.

Abstract 2534: Single-cell dissection of heterogeneity and dynamics of tumor ecosystem upon immune-checkpoint blockade in hepatocellular carcinoma

Abstract Background: Therapy-induced alteration of tumor ecosystem poses a major barrier for cancer regression. As the majority of patients with hepatocellular carcinoma (HCC) develops resistance to immune checkpoint blockade (ICB) therapy, we aimed to characterize heterogeneity and dynamics of multicellular tumor ecosystem following anti-PD-1 treatment using scRNA-seq. Methods: In a phase II clinical trial of pembrolizumab on advanced hepatitis B virus-related HCC patients (NCT03419481), we performed a comprehensive single-cell transcriptomic profiling of biopsy samples from 26 patients before and during treatment. The composition and distribution of immune aggregates in responsive tumors was characterized by scRNA-seq and spatial transcriptome analyses. The anti-tumor efficacy of combined therapy with anti-PD-1 and inhibition of immunosuppressive macrophage were further determined in RIL-175-derived PD-1-resistant mouse model. Results: After initial data processing and quality control, we obtained 353,329 high-quality cells that included tumor cells, myeloid cells, lymphoid cells, endothelial cells and fibroblasts. Our analysis revealed that baseline tumor-reactive CD8+T cells exhibited a strong association with improved prognosis. Notably, treatment-induced expansion and differentiation of tumor-reactive CD8+T cells with memory-like phenotype highly correlated with durable ICB response. Moreover, we observed a co-occurrence pattern of key anti-tumor immune subsets in the tumor microenvironment (TME), which associated with ligand-receptor pair interactions. Spatial transcriptome analysis further validated the presence of immune aggregates in responsive tumors. Importantly, we derived an responsive signature from immune aggregates, which showed a strong association with improved prognosis in pan-cancer ICB datasets. Paired comparisons of pre- and on-treatment macrophage percentages in non-responders revealed a specific expansion of an immunosuppressive macrophage subset. Inhibition of this macrophage subset could overcome ICB resistance by enhancing T cell function in our PD-1 resistant model. We further observed that a tumorous epithelial-mesenchymal transition (EMT) program might contribute to therapeutic resistance via TME remodeling. Conclusions: Our study suggests that tumor-reactive CD8+T cells and immune aggregates may be associated with durable ICB response, while ICB-induced upregulation of immunosuppressive macrophages and EMThi tumor cells contributed to therapeutic evasion. These findings provide valuable insights for identification of predictive biomarkers and therapeutic strategies for ICB therapy of HCC. This project is supported by the General Research Fund (14119023, 14120621 and 14115820), the Li Ka Shing Foundation, and the CUHK Strategic Seed Funding for Collaborative Research Scheme. Citation Format: Alfred S. L. Cheng, Zhewen Xiong, Haoran Wu, Jianquan Cao, Zhixian Liang, Jingying Zhou, Joseph Jao-Yiu Sung, Kevin Yip, Stephen Chan. Single-cell dissection of heterogeneity and dynamics of tumor ecosystem upon immune-checkpoint blockade in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2534.

Prediction of immunocyte infiltration and prognosis in postoperative hepatitis B virus-related hepatocellular carcinoma patients using magnetic resonance imaging.

The immune microenvironment (IME) is closely associated with prognosis and therapeutic response of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). Multi-parametric magnetic resonance imaging (MRI) enables non-invasive assessment of IME and predicts prognosis in HBV-HCC. We aimed to construct an MRI prediction model of the immunocyte-infiltration subtypes and explore its prognostic significance. HBV-HCC patients at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) with radical surgery (between 1 October and 30 December 2021) were prospectively enrolled. Patients with pathologically proven HCC (between 1 December 2013 and 30 October 2019) were retrospectively enrolled. Pearson correlation analysis was used to examine the relationship between the immunocyte-infiltration counts and MRI parameters. An MRI prediction model of immunocyte-infiltration subtypes was constructed in prospective cohort. Kaplan-Meier survival analysis was used to analyse its prognostic significance in the retrospective cohort. Twenty-four patients were prospectively enrolled to construct the MRI prediction model. Eighty-nine patients were retrospectively enrolled to determine its prognostic significance. MRI parameters (relative enhancement, ratio of the apparent diffusion coefficient value of tumoral region to peritumoral region [rADC], T1 value) correlated significantly with the immunocyte-infiltration counts (leukocytes, T help cells, PD1+Tc cells, B lymphocytes). rADC differed significantly between high and low immunocyte-infiltration groups (1.47 ± 0.36 vs 1.09 ± 0.25, P = 0.009). The area under the curve of the MRI model was 0.787 (95% confidence interval 0.587-0.987). Based on the MRI model, the recurrence-free time was longer in the high immunocyte-infiltration group than in the low immunocyte-infiltration group (P = 0.026). MRI is a non-invasive method for assessing the IME and immunocyte-infiltration subtypes, and predicting prognosis in post-operative HBV-HCC patients.

Effect of multidisciplinary team care on patient survival in chronic hepatitis B or C hepatocellular carcinoma.

Multidisciplinary team care coordinates with medical teams to improve the quality of cancer care. This study explored multidisciplinary team care in hepatitis B or hepatitis C virus-related hepatocellular carcinoma patients from the time of diagnosis to the first-time treatment interval and investigated treatment outcomes and prognosis. This retrospective cohort study included data from a nationwide population from 2007 to 2016. Data were collected from the Taiwan Cancer Registry Database, linked to the Taiwan National Health Insurance Research Database. Propensity score matching was applied at a ratio of 1:2 to reduce the selection bias. A multiple regression model with generalized estimating equations was used to analyze whether multidisciplinary team care affected the diagnosis-to-treatment interval. The stratified Cox proportional hazards model examined whether involvement in multidisciplinary team care influenced survival status. A total of 10,928 and 21,856 patients with hepatocellular carcinoma received multidisciplinary and non-multidisciplinary care, respectively. Participants with multidisciplinary care had a longer diagnosis-to-treatment interval but a lower risk of cumulative cancer death (HR=0.88, 95% CI:0.84-0.92). In patients with intermediate- to advanced-stage hepatocellular carcinoma, multidisciplinary team care has obvious benefits for improving survival. Patients with hepatocellular carcinoma who participated in multidisciplinary team care had a longer diagnosis-to-treatment interval but a lower risk of cancer death. Patients with intermediate- to advanced-stage hepatocellular carcinoma who received multidisciplinary team care significantly benefited from this outcome. Hospitals should provide HCC patients with multidisciplinary team care to improve cancer care.

Establishment of nucleic acid sensing pathways-based model in predicting response to immunotherapy and targeted drug in hepatitis virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) accounts for 80% of liver cancers, while 70%-80% of HCC developed from chronic liver disease with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as the major etiology. Immunotherapy is assuming a role as a pillar of HCC treatment, but the remarkable immune-mediated responses are restricted in a minority of patients. Nucleic acid sensing (NAS) pathways are the central pathway of the innate immune system and antiviral immune response to viral infection, but their role in hepatitis virus-related HCC remains undetermined. In our study, we performed a comprehensive bioinformatics analysis based on transcriptomic data of hepatitis virus related-HCCtissues collected from multiple public data sets. Two subgroups were validated based on NAS-relatedgenes in virus-related HCC patients, which were defined as NAS-activatedsubgroups and NAS-suppressed subgroups based on the expression of NAS-related genes. On this basis, a NAS-related risk score (NASRS) predictive model was established for risk stratification and prognosis prediction in the hepatitis virus-related HCC (TCGA-LIHCand ICGC cohorts). The predictive values of the NASRS in prognosis and immunotherapy were also verified in multiple data sets. A nomogram was also established to facilitate the clinical use of NASRS and demonstrate its effectiveness through different approaches. Additionally, six potential drugs binding to the core target of the NAS signature were predicted via molecular docking strategy. We subsequently evaluated the cytotoxic capabilities of potential drug in vitro and in vivo. Based on these results, we conclude that the NASRS model could serve as a power prognostic biomarker and predict responses to immunotherapy, which is meaningful in clinical decision-making of hepatitis virus-related HCC patients.

Diagnosis and monitoring of hepatocellular carcinoma in Hepatitis C virus patients using attenuated total reflection Fourier transform infrared spectroscopy

BackgroundCurrent diagnostic methods for assessment of hepatitis C virus related hepatocellular carcinoma and subsequent categorization of hepatocellular carcinoma into non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma, to establish appropriate treatment strategies, are costly, invasive and requires multiple screening steps. This demands alternative diagnostic approaches that are cost-effective, time-efficient, and minimally invasive, while maintaining their efficacy for screening of hepatitis c virus related hepatocellular carcinoma. In this study, we propose that attenuated total reflection Fourier transform infrared in conjunction with principal component analysis – linear discriminant analysis and support vector machine multivariate algorithms holds a potential as a sensitive tool for the detection of hepatitis C virus-related hepatocellular carcinoma and the subsequent categorization of hepatocellular carcinoma into non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma. MethodsFreeze-dried sera samples collected from 31 hepatitis c virus related hepatocellular carcinoma patients and 30 healthy individuals, were used to acquire mid-infrared absorbance spectra (3500–900 cm-1) using attenuated total reflection Fourier transform infrared. Chemometric machine learning techniques were utilized to build principal component analysis – linear discriminant analysis and support vector machine discriminant models for the spectral data of hepatocellular carcinoma patients and healthy individuals. Sensitivity, specificity, and external validation on blind samples were calculated. ResultsMajor variations were observed in the two spectral regions i.e., 3500–2800 and 1800–900 cm-1. IR spectral signatures of hepatocellular carcinoma were reliably different from healthy individuals. Principal component analysis – linear discriminant analysis and support vector machine models computed 100% accuracy for diagnosing hepatocellular carcinoma. To classify the non-angio-invasive hepatocellular carcinoma/ angio-invasive hepatocellular carcinoma status, diagnostic accuracy of 86.21% was achieved for principal component analysis – linear discriminant analysis. While the support vector machine showed a training accuracy of 98.28% and a cross-validation accuracy of 82.75%. External validation for support vector machine based classification observed 100% sensitivity and specificity for accurately classifying the freeze-dried sera samples for all categories. ConclusionsWe present the specific spectral signatures for non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma, which were prominently differentiated from healthy individuals. This study provides an initial insight into the potential of attenuated total reflection Fourier transform infrared to diagnose hepatitis C virus related hepatocellular carcinoma but also to further categorize into non-angio-invasive and angio-invasive hepatocellular carcinoma.

An inflammation-related gene landscape predicts prognosis and response to immunotherapy in virus-associated hepatocellular carcinoma.

Due to the viral infection, chronic inflammation significantly increases the likelihood of hepatocellular carcinoma (HCC) development. Nevertheless, an inflammation-based signature aimed to predict the prognosis and therapeutic effect in virus-related HCC has rarely been established. Based on the integrated analysis, inflammation-associated genes (IRGs) were systematically assessed. We comprehensively investigated the correlation between inflammation and transcriptional profiles, prognosis, and immune cell infiltration. Then, an inflammation-related risk model (IRM) to predict the overall survival (OS) and response to treatment for virus-related HCC patients was constructed and verified. Also, the potential association between IRGs and tumor microenvironment (TME) was investigated. Ultimately, hub genes were validated in plasma samples and cell lines via qRT-PCR. After transfection with shCCL20 combined with overSLC7A2, morphological change of SMMC7721 and huh7 cells was observed. Tumorigenicity model in nude mouse was established. An inflammatory response-related gene signature model, containing MEP1A, CCL20, ADORA2B, TNFSF9, ICAM4, and SLC7A2, was constructed by conjoint analysis of least absolute shrinkage and selection operator (LASSO) Cox regression and gaussian finite mixture model (GMM). Besides, survival analysis attested that higher IRG scores were positively relevant to worse survival outcomes in virus-related HCC patients, which was testified by external validation cohorts (the ICGC cohort and GSE84337 dataset). Univariate and multivariate Cox regression analyses commonly proved that the IRG was an independent prognostic factor for virus-related HCC patients. Thus, a nomogram with clinical factors and IRG was also constructed to superiorly predict the prognosis of patients. Featured with microsatellite instability-high, mutation burden, and immune activation, lower IRG score verified a superior OS for sufferers. Additionally, IRG score was remarkedly correlated with the cancer stem cell index and drug susceptibility. The measurement of plasma samples further validated that CCL20 upexpression and SLC7A2 downexpression were positively related with virus-related HCC patients, which was in accord with the results in cell lines. Furthermore, CCL20 knockdown combined with SLC7A2 overexpression availably weakened the tumor growth in vivo. Collectively, IRG score, serving as a potential candidate, accurately and stably predicted the prognosis and response to immunotherapy in virus-related HCC patients, which could guide individualized treatment decision-making for the sufferers.

Should associating liver partition and portal vein ligation for staged hepatectomy be applied to hepatitis B virus-related hepatocellular carcinoma patients with cirrhosis? A multi-center study

BackgroundIt is unclear whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can be performed in hepatitis B virus-related hepatocellular carcinoma (HCC) patients with cirrhosis. We explored the efficacy of ALPPS in HCC patients. MethodsData of 54 patients who underwent ALPPS between August 2014 and July 2020 at three centers were collected. Adverse factors affecting their prognosis were analyzed and subsequently compared with 184 patients who underwent transcatheter arterial chemoembolization (TACE). ResultsOverall survival rates of the ALPPS group at 1, 3, and 5 years were 70.6%, 38.4%, and 31.7%, respectively; corresponding disease-free survival rates were 50.5%, 22.4%, and 19.2%, respectively. The ALPPS group had a significantly greater long-term survival rate than the TACE group (before propensity score matching, P < 0.001; after propensity score matching, P = 0.002). Multivariate analysis demonstrated that multifocal lesions (P = 0.018) and macroscopic vascular invasion (P = 0.001) were prognostic factors for HCC patients who underwent ALPPS. After the propensity score matching, the multifocal lesions (P = 0.031), macroscopic vascular invasion (P = 0.003), and treatment type (ALPPS/TACE) (P = 0.026) were the factors adversely affecting the prognosis of HCC patients. ConclusionALPPS was feasible in hepatitis B virus-related HCC patients with cirrhosis and resulted in better survival than TACE.

Comparison of effectiveness and safety of camrelizumab between HBV-related and non-B, non-C hepatocellular carcinoma: A retrospective study in China.

Purpose: This study aimed to compare the clinical outcomes of camrelizumab in hepatitis B virus-related hepatocellular carcinoma (HBV–HCC) patients and non-HBV, non-HCV hepatocellular carcinoma (NBNC–HCC) patients in China. Materials and methods: A total of 54 patients with hepatocellular carcinoma who received camrelizumab were included in this retrospective study from January 2019 to December 2021. The patients were assigned to the HBV–HCC group (n = 28) and the NBNC–HCC group (n = 26). The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Multivariate analysis using Cox proportional hazard regression was used to identify independent prognostic factors. A nomogram model was subsequently established based on independent prognostic factors. Results: The mean duration of follow-up was 12.7 ± 3.6 months. The median OS was not determined. The median PFS in the HBV–HCC group was significantly longer than that in the NBNC–HCC group (9.2 vs. 6.7 months, p = 0.003). The ORR and DCR in the HBV–HCC group were significantly higher than those in the NBNC–HCC group (ORR, 28.6% vs. 7.7%, p = 0.048; DCR, 71.4% vs. 42.3%, p = 0.031). No significant differences in the total incidence of AEs were found between the HBV–HCC group and the NBNC–HCC group (75.0% vs. 69.2%, p = 0.224). Multivariate regression analysis identified etiology, AFP level, and vascular invasion as independent prognostic factors (all p < 0.05). Conclusion: Our findings demonstrate that camrelizumab is more effective in HBV–HCC patients than in NBNC–HCC patients, with manageable safety.

Well-Controlled Viremia Predicts the Outcome of Hepatocellular Carcinoma in Chronic Viral Hepatitis Patients Treated with Sorafenib.

Simple SummaryPrevious studies reported hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) patients might have better prognosis than hepatitis B virus-related HCC (HBV-HCC) patients at using sorafenib. However, the information about status of viremia was limited in these studies. We defined well-controlled viremia as patients who had undetectable viremia, or who had been receiving antivirals at least six months before sorafenib. We reported 116 (65.2%) HBV-HCC patients and 62 (34.8%) HCV-HCC patients who received sorafenib, and progression-free survival and overall survival (OS) rates between these two groups were not different. Before sorafenib, 56% of HBV-HCC patients and 54.8% of HCV-HCC patients had well-controlled viremia and their OS was superior to those who had uncontrolled viremia (15.5 vs. 11.1 months, p = 0.001). Besides, well-controlled viremia was associated with mortality in multivariate analysis (Hazard ratio: 0.63, 95% confidence interval: 0.42–0.93, p = 0.022). The significance of our study is the first research to confirm the prognostic value of well-controlled viremia between HBV-HCC and HCV-HCC patients receiving sorafenib. Besides, HBV or HCV infection was not associated with the outcome, neither in univariate nor in multivariate analysis.Without analyzing the status of viremia, hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) patients are proposed to have better prognosis than hepatitis B virus-related HCC (HBV-HCC) patients using sorafenib. We aimed to elucidate the efficacy of concurrent sorafenib and anti-viral treatment for HCC patients with HBV or HCV infection in real world. Between January 2018 and January 2021, 256 unresectable HCC patients receiving first-line sorafenib were evaluated. High-potency nucleoside analogs were used for HBV control, whereas direct-acting antivirals were administered for HCV eradication. Well-controlled viremia was defined as patients who had undetectable viremia, or who had been receiving antivirals at least 6 months before sorafenib. We recruited 116 (65.2%) HBV-HCC patients and 62 (34.8%) HCV-HCC patients. Using sorafenib, progression-free survival and overall survival (OS) rates between these two groups were not different. Before sorafenib, 56% of HBV-HCC patients and 54.8% of HCV-HCC patients had well-controlled viremia and their OS was superior to those who had uncontrolled viremia (15.5 vs. 11.1 months, p = 0.001). Dividing our patients into four subgroups as well-controlled HCV viremia, well-controlled HBV viremia, uncontrolled HCV viremia, and uncontrolled HBV viremia, their OS rates were distributed with a significantly decreasing trend as 21.9 months, 15.0 months, 14.2 months, and 5.7 months (p = 0.009). Furthermore, well-controlled viremia was associated with mortality in multivariate analysis (Hazard ratio: 0.63, 95% confidence interval: 0.42–0.93, p = 0.022). In real-life, HBV or HCV infection did not contribute to the prognosis of HCC patients receiving sorafenib; however, whether viremia was controlled or not did contribute.

Developmental artificial neural network model to evaluate the preoperative safe limit of future liver remnant volume for HCC combined with clinically significant portal hypertension.

Background & aims: Finding a way to comprehensively integrate the presence and grade of clinically significant portal hypertension, amount of preserved liver function and extent of hepatectomy into the guidelines for choosing appropriate candidates tohepatectomy remained challenging. This study sheds light on these issues to facilitate precise surgical decisions for clinicians. Methods: Independent risk factors associated with grade B/C post-hepatectomy liver failure were identified by stochastic forest algorithm and logistic regression in hepatitis B virus-related hepatocellular carcinoma patients. Results: The artificial neural network model was generated by integrating preoperative pre-ALB, prothrombin time, total bilirubin, AST, indocyanine green retention rate at 15 min, standard future liver remnant volume and clinically significant portal hypertension grade. In addition, stratification of patients into three risk groups emphasized significant distinctions in the risk of grade B/C post-hepatectomy liver failure. Conclusion: The authors' artificial neural network model could provide a reasonable therapeutic option for clinicians to select optimal candidates with clinically significant portal hypertension for hepatectomy and supplement the hepatocellular carcinoma surgical treatment algorithm.

Acyl-CoA Binding Domain Containing 4 Polymorphism rs4986172 and Expression Can Serve as Overall Survival Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Patients After Hepatectomy.

BackgroundThe aim of our study was to evaluate the potential of expression and single nucleotide polymorphism of Acyl-CoA binding domain containing 4 (ACBD4) gene as prognosis biomarkers in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after hepatectomy.MethodsHBV-related HCC patients from the First Affiliated Hospital of Guangxi Medical University and GSE14520 were included in the current study, as well as The Cancer Genome Atlas (TCGA) HCC verification cohort. Prognostic analysis and multiple functional enrichment analysis methods were used to evaluate the prognostic value and potential biological functions of the ACBD4 gene in HBV-related HCC.ResultsWe found that ACBD4 gene is highly expressed in normal liver tissues and markedly down-regulated in HBV-related HCC tissues. ACBD4 gene was significantly related to overall survival (OS) of HCC in TCGA and GSE14520 cohorts, and patients with low ACBD4 expression were markedly related to poor OS. Rs4986172 was observed as an OS biomarker after hepatectomy in the Guangxi HBV-related HCC cohort. The OS of rs4986172 GG genotype was worse than that of HCC patients with A allele (AA and AG genotypes). Multifunctional enrichment analysis suggested that ACBD4 gene is closely related to the metabolic, peroxisome proliferator-activated receptor and cytochrome P450 pathway. Through connectivity map, we also identified eight compounds that may be used as targeted therapeutic agents for ACBD4 gene in HBV-related HCC; these compounds were scopoletin, alfaxalone, bephenium hydroxynaphthoate, apramycin, 4,5-dianilinophthalimide, DL-thiorphan, aminohippuric acid and quinidine. Immune microenvironment analysis revealed that there were significant differences in immune scores of HBV-related HCC tumor tissues with different ACBD4 expression levels.ConclusionOur study reveals that ACBD4 expression and rs4986172 can be serve as biomarkers of OS in HBV-related HCC patients after hepatectomy.

Prognostic Model for the Risk Stratification of Early and Late Recurrence in Hepatitis B Virus-Related Small Hepatocellular Carcinoma Patients with Global Histone Modifications.

Background and AimTo assess the profile of global histone modifications in small hepatocellular carcinoma (small HCC) and identify its prognostic value in predicting recurrence.MethodsThe expression profiles of global histone modifications, including H2AK5AC, H2BK20AC, H3K4me2, H3K9AC, H3K18AC, H4K12AC, and H4R3me2, were evaluated with immunohistochemistry in 335 HBV related small HCC patients. Two histone signature classifiers were then developed using least absolute shrinkage and selection operator Cox regression. A nomogram was built using the classifier and independent risk factors. The performances of the classifier and nomogram were assessed by receiver operating characteristic curves.ResultsHistone modifications were more pronounced in tumor tissues than in adjacent liver tissues. In tumor tissues, the risk score built based on the seven-histone signature exhibited satisfactory prediction efficiency, with an AUC = 0.71 (0.63–0.79) for 2-year survival in the training cohort. Patients with a high risk score had shorter recurrence-free survival than those with a low risk score (HR: 1.96, 95% CI: 1.24–3.08, p = 0.004; HR: 1.95, 95% CI: 1.12–3.42, p = 0.019; and HR: 1.97, 95% CI: 1.39–2.80, p < 0.001 for the training, validation and total cohorts, respectively). Furthermore, the statistical nomogram built using the histone classifier for early recurrence had a C-index = 0.68. In non-neoplastic liver tissues, the hepatic signature based on H3K4me2 and H4R3me2 was related to late recurrence (HR: 2.00, 95% CI: 1.15–3.48, p = 0.01).ConclusionGlobal histone modifications in tumor and adjacent liver tissues are novel predictors of early and late recurrence, respectively, in HBV-related small HCC patients.

Impact of Interferon on the Prognosis of Hepatitis C Virus-Related Hepatocellular Carcinoma Patients with a Sustained Virological Response -An Additional Comparison Between Preoperative and Postoperative Sustained Virological Response.

Several studies have reported that interferon (IFN) therapy improves the prognosis of patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), especially for patients who have achieved a sustained virological response (SVR). We retrospectively evaluated the clinicopathological outcomes of patients who acquired an SVR through IFN therapy pre- or post-hepatectomy for treatment naïve HCC. Among the 305 HCV-related HCC patients entered in this study, 59 patients (SVR group) achieved an SVR after IFN therapy and received hepatectomy either after or before achieving an SVR (n=36 and n=23, respectively), while the remaining 179 patients (control group) did not receive IFN therapy, or did not achieve an SVR through IFN therapy (n=67). In the SVR group, the overall survival (OS) and disease-free survival (DFS) rates were significantly higher than in the control group. We evaluated the prognosis of patients with an SVR achieved pre- or post-hepatectomy separately. There were no significant differences in OS and DFS. This result suggests that the prognosis of naïve HCC may be improved by additional INF therapy to achieve SVR status after hepatectomy.

Exosome‐derived differentiation antagonizing non‐protein coding RNA with risk of hepatitis C virus‐related hepatocellular carcinoma recurrence

Differentiation antagonizing non-protein coding RNA is associated with various types of neoplasms. Hepatitis C virus-related hepatocellular carcinoma has a high risk of recurrence. Here we determined the role of differentiation antagonizing non-protein coding RNA in hepatitis C virus-related hepatocarcinogenesis and identified potential therapeutic targets and non-invasive prognostic markers for long-term outcome of hepatitis C virus-related hepatocellular carcinoma after surgical resection. Differentiation antagonizing non-protein coding RNAs relevant to hepatitis C virus-related hepatocellular carcinoma were identified through comparative RNA-sequencing of tumour and adjacent non-tumour (ANT) tissues in a screening set, and were validated using real-time polymerase chain reaction. Target long non-coding RNAs (lncRNAs) in tissues and serum exosomes were used to predict the recurrence of hepatitis C virus-related hepatocellular carcinoma after curative surgical resection in a large application cohort from 2005 to 2012. We confirmed that differentiation antagonizing non-protein coding RNA was upregulated following hepatitis C virus infection and identified as the lncRNA most relevant to hepatitis C virus-related hepatocellular carcinoma in tumour tissues as compared to that in ANT tissues. In 183 hepatitis C virus-related hepatocellular carcinoma patients followed for 10years after curative HCC resection, the expression level of circulating exosomal differentiation antagonizing non-protein coding RNA was positively associated with HCC recurrence and was the most predictive factor associated with HCC recurrence and mortality (hazard ratio/95% confidence intervals: 7.0/4.3-11.6 and 2.7/1.5-5.1 respectively). Differentiation antagonizing non-protein coding RNA is highly relevant to disease progression of hepatitis C virus-related hepatocellular carcinoma. Our finding indicated that circulating exosomal differentiation antagonizing non-protein coding RNA might serve as a non-invasive prognostic biomarker for hepatitis C virus-related hepatocellular carcinoma.

Predictive value of preoperative and postoperative peripheral lymphocyte difference in hepatitis B virus-related hepatocellular cancer patients: Based on the analysis of dynamic nomogram.

Inflammation plays an important role in the progression and prognosis of hepatocellular carcinoma (HCC). Our aim is to explore the prognostic value of preoperative and postoperative peripheral lymphocyte differences and to develop a dynamic prognosis nomogram in hepatitis B virus-related HCC patients. Important indicators related to overall survival (OS) are screened out by Cox proportional hazard models. The receiver operating characteristic curves, decision curve analysis curves, net reclassification improvement, and integrated discrimination improvement were used to evaluate the performance of the model. Lymphocyte (L) difference was an independent risk factor. It was further verified that the performance of the nomogram was significantly improved after the L difference was incorporated into the nomogram. The nomogram generated had the area under curves of 0.779, 0.775, and 0.793 at 3, 5, and 7 years after surgery, respectively. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models. And online webserver and scoring system table was built based on the proposed nomogram for convenient clinical use. It is newly found that L difference is an effective predictor of OS, and the nomogram based on this indicator can accurately predict the prognosis of HCC patients.

Albumin-to-Alkaline Phosphatase Ratio Associates with Good Prognosis of Hepatitis B Virus-Positive HCC Patients.

PurposeThe aim of this study was to investigate the prognostic significance of preoperative AAPR in hepatitis B virus-related hepatocellular carcinoma patients after curative hepatectomy.Patients and MethodsA total of 221 patients with hepatitis B virus-related HCC patients who received curative liver resection were included. After propensity matching analysis, 188 patients were enrolled in the final analysis. COX regression analyses were used to analyze the prognosis value of AAPR and other prognostic factors. The overall survival (OS) and recurrence-free survival (RFS) curves were constructed and compared between different groups.ResultsThe optimal cutoff of AAPR was defined as 0.40 with X-tile software. According to cutoff value, patients were divided into low-AAPR group (≤0.40) and high-AAPR group (>0.40). The cumulative 1-, 3-, and 5-year OS rates were 97.1%, 78.2%, and 67.3% in patients with AAPR>0.40 group, respectively, which were significantly higher than those in the AAPR≤0.40 group (80.2%, 54.4%, and 40.1%, respectively) (P <0.001). In the multivariate COX regression analysis, AAPR, tumor number, ascites, and portal vein tumor thrombus (PVTT) were independent risk factors for OS and RFS.ConclusionAAPR shows promise as a reliable prognostic factor in patients with hepatitis B virus-related HCC after curative hepatectomy, which could be used as a routine inspection of HCC patients before surgery.

Expression of hepatitis B surface antigen in liver tissues can serve as a predictor of prognosis for hepatitis B virus-related hepatocellular carcinoma patients after liver resection.

Background:Hepatitis B surface antigen (HBsAg) is a detectable index after hepatitis B virus (HBV) infection, which is a risk factor of hepatocellular carcinoma (HCC). However, few studies have focused on the expression of HBsAg in HCC patients’ liver tissues. This study aimed to explore the potential utility of using HBsAg protein expression in normal liver tissues as a prognostic factor for HCC patients who underwent liver resection.Study design:The study enrolled 100 HCC patients with seropositivity for HBsAg. The liver tissues were collected, and tissue microarrays were constructed. The expression of HBsAg in liver tissues were measured by immunohistochemistry (IHC). Relevant clinical data and follow-up records were collected for analysis.Results:HBsAg expressions was detected in 29 patients (positive group) and was unable to be detected in the remaining 71 patients (negative group). The patients in the positive group had higher HBV DNA levels (P < 0.05) than the patients in the negative group. The overall survival (OS) rate of the positive group was worse than the OS rate of the negative group (P = 0.013). The OS rates after resection at 1 and 2 years in negative group were 90.1% and 85.7%, respectively, while the value in the positive group were 79.3% and 65.5%, respectively. Multivariate analysis showed that HBsAg expression in liver tissues, ascites and alpha-fetoprotein levels were independent factors influencing OS. Similarly, after propensity score matching (PSM), the OS was worse in the positive group than in the negative group, and HBsAg expression could also serve as a predictor for OS (P = 0.039). The OS rates after resection and PSM at 1 and 2 years were 93.2% and 85.9% in the negative group, while the value in the positive group were 79.3% and 65.5%.Conclusion:As determined according to grouping based on immunohistochemistry staining results for HBsAg, this study indicated that HBsAg expression in liver tissues could predict the OS of HBV-related HCC patients after liver resection.

Impact of Pringle’s maneuver on postoperative serum inflammatory mediator levels and prognosis of HBV-related HCC patients

Objective To analyze the impact of Pringle’s maneuver on postoperative serum inflammatory mediator levels and prognosis in hepatitis B virus-related hepatocellular carcinoma (HBV related HCC) patients. Methods A retrospective study was conducted on 157 HBV related HCC patients who underwent treatment at the Chinese PLA General Hospital from January 2016 to December 2017. There were 128 males and 29 females. The mean age was (54.5±12.1) years. These patients were divided into 106 patients who underwent Pringle’s maneuver (the Pringle’s maneuver group). The remaining patients were in the Occlusion-free group. All patients were detected inflammatory mediator levels including the various interleukins (IL) and were regularly followed up. The recurrence-free survival was evaluated by the Kaplan-Meier method, and compared with the log-rank test. The relationship between the Pringle’s maneuver and risks of postoperative tumor recurrence of these patient were estimated by the univariate and multivariate Cox regression models. Results On postoperation day 1 and day 3, the serum IL-1 and IL-6 levels of the Pringle’s maneuver group were significantly higher than the Occlusion-free group [5.0(5.0, 12.0)ng/L vs. 5.0(5.0, 5.0)ng/L], [122.0(74.5, 173.8)ng/L vs. 80.0(40.0, 120.0)ng/L]; [5.0(5.0, 10.0)ng/L vs. 5.0(5.0, 5.0)ng/L], [78.3(42.8, 138.5)ng/L vs. 48.1(30.1, 75.0)ng/L]. On day 5, the serum IL-1 and IL-8 levels were also significantly higher than the Occlusion-free group [5.0(5.0, 5.3)ng/L vs. 5.0(5.0, 5.0)ng/L], [100.6 (44.2, 186.5)g/L vs. 68.0(36.3, 112.0)ng/L] (all P 0.05). The multivariate Cox regression model suggested that there was no significant correlation between Pringle’s maneuver and recurrence free survival of these patients with HBV related HCC. Conclusions Pringle’s maneuver could significantly elevate the postoperative serum IL-1, IL-6, IL-8 levels, but it was not related with an increased risk of postoperative tumor recurrence. Key words: Carcinoma, hepatocellular; Hepatitis B virus; Prognosis; Pringle maneuver; Inflammatory mediator

A scoring model combining serum alpha-fetoprotein and tumor size and number predicts prognosis in hepatitis B virus-related hepatocellular carcinoma patients after curative hepatectomy.

BackgroundMore in-depth models, such as biomarker and anatomical information, are needed to predict individualized prognoses of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative liver resection. alpha-fetoprotein (AFP) has conflicting value in predicting prognosis. We aimed to investigate the significance of an AFP score model as a potential predictor of prognosis after radical resection in patients with HBV-related HCC.MethodsThis study retrospectively analyzed 397 patients with HBV-related HCC who underwent hepatic resection between 2001 and 2013. Serum AFP level, tumor size, and tumor number were calculated by adding individual points for the AFP score model. Patient and tumor characteristics were tested for prognostic significance using ANOVA and chi-squared test, respectively. The receiver operating characteristic (ROC) curve was used to identify the AFP score model with or without other risk factors to discriminate patients. Kaplan-Meier and Cox’s analyses were performed to pinpoint risk factors for overall survival (OS) and disease-free survival (DFS) in the patients.ResultsThe cutoff value for the AFP score model was set at 2 using the ROC curve, with good specificity and sensitivity for OS and DFS. According to the AFP score model, 185 patients were in the AFP score >2 group, and 212 were in the AFP score ≤2 group. The median OS in the AFP score ≤2 and AFP score >2 groups were 173.4±1.00 vs. 50.30±8.67 m, respectively (P=0.000). The median DFS in the AFP score ≤2 and AFP score >2 groups were 17.20±3.66 vs. 73.7±10.39 m (P=0.000), respectively. Analyses from Cox’s multivariate proportional hazard model indicated that AFP score (HR =0.563, 95% CI: 0.398–0.798, P=0.001), MVI (HR =0.653, 95% CI: 0.441–0.967, P=0.033), and cirrhosis (HR =0.358, 95% CI: 0.185–0.696, P=0.002) were risk factors for OS. The multivariate Cox model identified MVI (HR =1.589, 95% CI: 1.496–2.854, P=0.003) and AFP score (HR =0.876, 95% CI: 0.404–0.925, P=0.040) as risk factors of DFS. According to the stratification by the AFP score with MVI, the mean OS in the AFP score >2 group combined with the MVI group was significantly shorter, compared with that in the AFP score >2 group without the MVI group (65.58±9.18 vs. 94.21±8.25 m, P=0.024). The mean OS in the AFP score >2 group combined with the cirrhosis group is significantly shorter than that in the AFP score ≤2 group without the cirrhosis group (64.08±7.38 vs. 145.31±8.38 m, P=0.000).ConclusionsThe AFP score model categorizes HCC patients with relatively good liver function after radical resection with low- and high-risk prognosis.