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Precancer antiviral treatment reduces microvascular invasion of early-stage Hepatitis B-related hepatocellular carcinoma.

ABSTRACT: The impact of antiviral therapy before tumorigenesis on microvascular invasion (MVI) of Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is still unknown. In this retrospective cohort study 3,276 HCC patients with early-stage who underwent curative resection were included. We investigated the effect of precancer antiviral therapy on the pathology, especially MVI, of CHB-related HCC. MVI occurrence rates of CHB-related HCC stratified by histopathologic inflammation grades of G1, G2, and G3 were 30.4%, 34.7%, and 38.6%, respectively, compared to 19.8% for CHB-negative HCC. Patients who received standard antiviral treatment showed much lower rates of MVI, higher tumor capsule integrity, less frequent satellite micronodules and lower AFP level compared to the no antiviral group. Moreover, precancer antiviral therapy prolonged the disease-free survival (DFS), which are also proved to be independent indicators of DFS. In addition, we show that antivirals may suppress early progression of HCC primarily by inhibition of HBV viral load, and influencing the expression levels of CK18, GPC3, OPN and pERK. Hence, we demonstrate that precancer antivirals significantly reduce the MVI rate of CHB-related HCC, reduce malignancy of early-stage HCC, and improve HCC prognosis. Thus, this study confirms the importance of antiviral therapy for CHB patients.

SUBMITTER: Liu K

PROVIDER: S-EPMC6379412 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Precancer antiviral treatment reduces microvascular invasion of early-stage Hepatitis B-related hepatocellular carcinoma.

Liu Kai K Duan Jicheng J Liu Hu H Yang Xinwei X Yang Jiahe J Wu Mengchao M Chang Yanxin Y

Scientific reports 20190218 1

The impact of antiviral therapy before tumorigenesis on microvascular invasion (MVI) of Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is still unknown. In this retrospective cohort study 3,276 HCC patients with early-stage who underwent curative resection were included. We investigated the effect of precancer antiviral therapy on the pathology, especially MVI, of CHB-related HCC. MVI occurrence rates of CHB-related HCC stratified by histopathologic inflammation grades of G1, G ...[more]

PMID: 30778112

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Project description:ImportanceA reduced incidence of microvascular invasion (MVI) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) may be associated with a decreased risk of early tumor recurrence and better survival after partial hepatectomy.ObjectiveTo examine the association of preoperative antiviral treatment (AVT) with the incidences of MVI and posthepatectomy early tumor recurrence in HBV-related HCC.Design, setting, and participantsData on a cohort of 2362 patients who underwent R0 resection for HBV-related HCC between January 2008 and April 2010 at the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China, were reviewed. The median (interquartile range) postoperative follow-up was 44.8 (22.8-59.3) months. Data were analyzed from June 2016 to October 2017.InterventionsPreoperative AVT and partial hepatectomy.Main outcomes and measuresOverall survival and time to recurrence after surgery were calculated and compared using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Independent risk factors of MVI presence were assessed by logistic regression analysis.ResultsAmong 2362 included patients, 1999 (84.6%) were men, and the median (interquartile range) age was 50.6 (43.1-57.3) years. A total of 2036 patients (86.2%) did not receive any preoperative AVT, while 326 (13.8%) received ongoing AVT more than 90 days before surgery. In the non-AVT group, compared with a preoperative HBV DNA level of less than 2000 IU/mL, a preoperative HBV DNA level of 2000 IU/mL or greater was associated with an increased risk of MVI (odds ratio [OR], 1.399; 95% CI, 1.151-1.701). Compared with the non-AVT group, patients receiving AVT had a lower incidence of MVI (38.7% [126 of 326] vs 48.6% [989 of 2036]; P = .001) and reduced risk of MVI (OR, 0.758; 95% CI, 0.575-0.998). A complete response to AVT was an independent protective factor of MVI (OR, 0.690; 95% CI, 0.500-0.952). Accordingly, preoperative AVT was associated with decreased 6-month, 1-year, and 2-year recurrences vs non-AVT (14.2%, 24.6%, and 38.5%, respectively, vs 23.4%, 37.1%, and 52.3%; P < .001); AVT was protective of early tumor recurrence (hazard ratio, 0.732; 95% CI, 0.605-0.886). In addition, patients in the non-AVT group were more likely to have multiple intrahepatic recurrences (49.1% [549 of 1119] vs 36.2% [54 of 149]; P = .003) and recurrences involving multiple hepatic segments compared with patients receiving AVT.Conclusions and relevanceA high preoperative HBV DNA level was an independent risk factor of MVI. Antiviral treatment administered more than 90 days before surgery was associated with reduced incidences of MVI and early tumor recurrence after partial hepatectomy for HBV-related HCC.

Project description:BackgroundThe efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation.MethodsWe retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin).ResultsA total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 μg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 μg/L.ConclusionsAdjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib.

Project description:BackgroundRadiomics has emerged as a new approach that can help identify imaging information associated with tumor pathophysiology. We developed and validated a radiomics nomogram for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC).MethodsTwo hundred and eight patients with pathologically confirmed HCC (training cohort: n = 146; validation cohort: n = 62) who underwent preoperative gadoxetic acid-enhanced magnetic resonance (MR) imaging were included. Least absolute shrinkage and selection operator logistic regression was applied to select features and construct signatures derived from MR images. Univariate and multivariate analyses were used to identify the significant clinicoradiological variables and radiomics signatures associated with MVI, which were then incorporated into the predictive nomogram. The performance of the radiomics nomogram was evaluated by its calibration, discrimination, and clinical utility.ResultsHigher α-fetoprotein level (p = 0.046), nonsmooth tumor margin (p = 0.003), arterial peritumoral enhancement (p < 0.001), and the radiomics signatures of hepatobiliary phase (HBP) T1-weighted images (p < 0.001) and HBP T1 maps (p < 0.001) were independent risk factors of MVI. The predictive model that incorporated the clinicoradiological factors and the radiomic features derived from HBP images outperformed the combination of clinicoradiological factors in the training cohort (area under the curves [AUCs] 0.943 vs. 0.850; p = 0.002), though the validation did not have a statistical significance (AUCs 0.861 vs. 0.759; p = 0.111). The nomogram based on the model exhibited C-index of 0.936 (95% CI 0.895-0.976) and 0.864 (95% CI 0.761-0.967) in the training and validation cohort, fitting well in calibration curves (p > 0.05). Decision curve analysis further confirmed the clinical usefulness of the nomogram.ConclusionsThe nomogram incorporating clinicoradiological risk factors and radiomic features derived from HBP images achieved satisfactory preoperative prediction of the individualized risk of MVI in patients with HCC.

Project description:Background and aimsThe recurrence and metastasis of hepatocellular carcinoma (HCC) are mainly caused by microvascular invasion (MVI). Our study aimed to uncover the cellular atlas of MVI+ HCC and investigate the underlying immune infiltration patterns with radiomics features.MethodsThree MVI positive HCC and three MVI negative HCC samples were collected for single-cell RNA-seq analysis. 26 MVI positive HCC and 30 MVI negative HCC tissues were underwent bulk RNA-seq analysis. For radiomics analysis, radiomics features score (Radscore) were built using preoperative contrast MRI for MVI prediction and overall survival prediction. We deciphered the metabolism profiles of MVI+ HCC using scMetabolism and scFEA. The correlation of Radscore with the level of APOE+ macrophages and iCAFs was identified. Whole Exome Sequencing (WES) was applied to distinguish intrahepatic metastasis (IM) and multicentric occurrence (MO). Transcriptome profiles were compared between IM and MO.ResultsElevated levels of APOE+ macrophages and iCAFs were detected in MVI+ HCC. There was a strong correlation between the infiltration of APOE+ macrophages and iCAFs, as confirmed by immunofluorescent staining. MVI positive tumors exhibited increased lipid metabolism, which was attributed to the increased presence of APOE+ macrophages. APOE+ macrophages and iCAFs were also found in high levels in IM, as opposed to MO. The difference of infiltration level and Radscore between two nodules in IM was relatively small. Furthermore, we developed Radscore for predicting MVI and HCC prognostication that were also able to predict the level of infiltration of APOE+ macrophages and iCAFs.ConclusionThis study demonstrated the interactions of cell subpopulations and distinct metabolism profiles in MVI+ HCC. Besides, MVI prediction Radscore and MVI prognostic Radscore were highly correlated with the infiltration of APOE+ macrophages and iCAFs, which helped to understand the biological significance of radiomics and optimize treatment strategy for MVI+ HCC.

Project description:BackgroundMicrovascular invasion (MVI) is an independent detrimental risk factor for tumor recurrence and poor survival in hepatocellular carcinoma (HCC). Competitive endogenous RNA (ceRNA) networks play a pivotal role in the modulation of carcinogenesis and progression among diverse tumor types. However, whether the ceRNA mechanisms are engaged in promoting the MVI process in patients with HCC remains unknown.MethodsA ceRNA regulatory network was constructed based on RNA-seq data of patients with HCC from The Cancer Genome Atlas (TCGA) database. In total, 10 hub genes of the ceRNA network were identified using four algorithms: "MCC," "Degree," "Betweenness," and "Stress." Transcriptional expressions were verified by in situ hybridization using clinical samples. Interactions between ceRNA modules were validated by luciferase reporting assay. Logistic regression analysis, correlation analysis, enrichment analysis, promoter region analysis, methylation analysis, and immune infiltration analysis were performed to further investigate the molecular mechanisms and clinical transformation value.ResultsThe ceRNA regulatory network featuring a tumor invasion phenotype consisting of 3 long noncoding RNAs, 3 microRNAs, and 93 mRNAs was constructed using transcriptional data from the TCGA database. Systemic analysis and experimentally validation identified a ceRNA network (PVT1/miR-1258/DUSP13 axis) characterized by lipid regulatory potential, immune properties, and abnormal methylation states in patients with HCC and MVI. Meanwhile, 28 transcriptional factors were identified as potential promotors of PVT1 with 3 transcriptional factors MXD3, ZNF580, and KDM1A promising as therapeutic targets in patients with HCC and MVI. Furthermore, miR-1258 was an independent predictor for MVI in patients with HCC.ConclusionThe PVT1/DUSP13 axis is significantly associated with MVI progression in HCC patients. This study provides new insight into mechanisms related to lipids, immune phenotypes, and abnormal epigenetics in oncology research.

Dataset Information

Precancer antiviral treatment reduces microvascular invasion of early-stage Hepatitis B-related hepatocellular carcinoma.

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Precancer antiviral treatment reduces microvascular invasion of early-stage Hepatitis B-related hepatocellular carcinoma.

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