Early Detection of HCC Among Veterans With Liver Cirrhosis

肝硬化退伍军人中肝癌的早期发现

• 批准号: 10266040
• 负责人: Srikanta Dash
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266040
• 关键词: Affinity; African American; Alcohol consumption; Antiviral Agents; Applications Grants; Area; Autophagocytosis; Autophagosome; Biological Assay; Biological Markers; Blood; Cirrhosis; Data; Detection; Development; Diabetes Mellitus; Diagnostic; Early Diagnosis; Enrollment; Enzyme-Linked Immunosorbent Assay; Excision; Fibrosis; Funding; GPC3 gene; Genetic Transcription; Guidelines; Hepatitis C; Hepatitis C virus; Hepatocyte; Hispanics; Hsc70 protein; Human; Impairment; Incidence; Interferons; Laboratories; Liver; Liver Cirrhosis; Lysosomes; Malignant - descriptor; Malignant neoplasm of liver; Measurement; Measures; Mediating; Medical center; Metabolic syndrome; Methods; MicroRNAs; Molecular Chaperones; Monitor; Multicenter Studies; Multivesicular Body; Obesity; Organ; Pathway interactions; Patients; Performance; Play; Population; Primary Infection; Primary carcinoma of the liver cells; Prognosis; Proteins; Publishing; ROC Curve; Race; Research; Risk; Risk Factors; Role; Sensitivity and Specificity; Series; Serum; Signal Transduction; Stress; Surveillance Methods; Testing; Therapeutic Intervention; Transplantation; Ultrasonography; Veterans; Virus Diseases; alpha-Fetoproteins; base; biological adaptation to stress; chronic liver disease; early detection biomarkers; endoplasmic reticulum stress; exosome; imaging modality; improved; indexing; inhibition of autophagy; liver development; non-alcoholic fatty liver disease; patient population; performance tests; preservation; response; specific biomarkers; standard of care; therapeutically effective; validation studies

Hepatocellular carcinoma (HCC) is a primary malignant cancer of the liver that most often develops in the background of liver cirrhosis (1,2). Hepatitis C virus (HCV) infection remains the major cause of liver cirrhosis and HCC among US Veterans (3,4). Recent advances in antiviral treatment have allowed an increasing number of cirrhotic patients to be cured with interferon (IFN)-free direct-acting antivirals (DAAs) (5,6). In the coming years, hepatitis C eradication is expected to decrease, but not eliminate, the risk of HCC among cirrhotic patients (7,8). The risk of HCC remains elevated post HCV clearance among patients with advanced fibrosis or cirrhosis and is also magnified by other risk factors such as daily alcohol intake, obesity, metabolic syndrome, diabetes, and race (African Americans or Hispanic) (7-16). HCC detected at an early stage can be effectively treated with transplantation, resection or even loco-regional therapies, but HCC detected at a late stage has a poor prognosis. The current HCC surveillance methods include liver ultrasound every six months with option of serum AFP (AASLD guideline). However, these methods lack the specificity and sensitivity needed to detect HCC at an early stage. Therefore, the development of a noninvasive, serum-based biomarker will allow early HCC detection and effective therapeutic intervention. This multicenter grant application proposes to test the performance of liver- specific serum biomarkers, together with standard-of-care tests including liver ultrasound, alpha-fetoprotein (AFP) AFP-L3 and DCP for HCC detection to monitor HCC risk among cirrhotic patients. This validation study will be performed by enrolling 2000 cirrhotic VA patients (HCV and non-HCV) from six different VA medical centers. Based on the incidence rate of HCC among the cirrhotic population, we anticipate >50 HCC cases will be detected at an early stage. Our hypothesis is that liver cirrhosis patients who do not resolve the ER-stress response will remain at an increased risk of HCC and therefore continue secreting HCC-specific exosomes that are enriched in glypican-3 and HSC70 (heat shock cognate protein 70) into the blood. Since the stress response depletes miRNA-122 transcription, we postulate that measurement of serum miRNA-122 levels will provide a powerful organ-specific biomarker for early prediction of cirrhosis regression after HCV cure. This application will explore the performance of HCC-specific exosome biomarkers, miRNA-122 and their additional benefit to serum AFP testing and liver ultrasound to improve surveillance of HCC and early detection of HCC. This hypothesis will be tested using the following Specific Aims: Aim 1 will determine the performance of serum exosomal cargoes (glypican-3, HSC70 and CD63) along with liver ultrasound, AFP, AFP-L3, DCP as a combined biomarker platform for the early detection of HCC among Veterans with liver cirrhosis after HCV cure using a longitudinal multicenter study. Aim 2 will develop a longitudinal multicenter study to determine the benefit of early HCC surveillance using the combination of exosomal biomarkers (glypican-3, HSC70 and CD63), serum miRNA-122 and non-exosomal (liver ultrasound, AFP, AFP-L3, DCP) for the early detection of HCC among Veterans with liver cirrhosis related to non-alcoholic fatty liver disease (NAFLD). Aim 3 will investigate whether measurement of liver specific miRNA- 122 levels in the serum along with noninvasive tests (FIB-4 index, APRI score and FibroScan) could increase the power of early assessment of cirrhosis regression or risk for persistent cirrhosis after HCV cure among Veterans with liver cirrhosis. If this application is selected for funding an exosome-based biomarker platform will be developed for early HCC detection among cirrhotic VA patients.

肝细胞癌（HCC）是一种原发性肝脏恶性肿瘤，最常发生在肝内， 肝硬化的背景（1，2）。丙型肝炎病毒（HCV）感染仍然是肝硬化的主要原因 美国退伍军人中的HCC（3，4）。抗病毒治疗的最新进展使越来越多的 用不含干扰素（IFN）的直接作用抗病毒药物（DAA）治愈腹泻患者（5，6）。在未来几 2010年，丙型肝炎根除有望降低，但不能消除，肝细胞癌患者的风险 （7，8）.在晚期肝纤维化或肝硬化患者中，HCV清除后HCC的风险仍然升高 并且还被其他风险因素放大，例如每日酒精摄入、肥胖、代谢综合征、糖尿病， 和种族（非洲裔美国人或西班牙裔）（7-16）。在早期发现的HCC可以有效地治疗， 移植、切除或甚至局部区域治疗，但晚期检测到的HCC预后不良。 目前的肝癌监测方法包括每六个月进行一次肝脏超声检查，并可选择血清AFP （AASLD指南）。然而，这些方法缺乏早期检测HCC所需的特异性和敏感性。 阶段因此，开发一种非侵入性的、基于血清的生物标志物将允许早期HCC检测， 有效的治疗干预。这项多中心拨款申请旨在测试肝脏的性能- 特异性血清生物标志物，以及标准治疗检查，包括肝脏超声、甲胎蛋白 (AFP)AFP-L3和DCP用于HCC检测，以监测HCC患者的风险。本验证研究 将通过从6个不同的VA医疗机构招募2000名丙型肝炎病毒（HCV）和非HCV的VA患者进行 中心.根据肝癌在肝癌人群中的发病率，我们预计50例以上的肝癌病例将 在早期阶段被发现。我们的假设是，肝硬化患者谁不解决ER应激 应答将保持在增加的HCC风险下，因此继续分泌HCC特异性外泌体， 富含磷脂酰肌醇蛋白聚糖-3和HSC 70（热休克同源蛋白70）进入血液。由于应激反应 耗尽miRNA-122的转录，我们假设测量血清miRNA-122水平将提供一个 一种强有力的器官特异性生物标志物，用于早期预测HCV治愈后肝硬化消退。此应用程序将 探索HCC特异性外泌体生物标志物miRNA-122的性能及其对血清的额外益处 AFP检测和肝脏超声可改善HCC的监测和HCC的早期发现。这一假设 将使用以下特定目标进行测试：目标1将确定血清外泌体货物的性能 （磷脂酰肌醇蛋白聚糖-3，HSC 70和CD 63）与肝脏超声，AFP，AFP-L3，DCP一起沿着作为联合生物标志物平台 使用纵向多中心研究， study.目标2将开展一项纵向多中心研究，以确定早期HCC监测的益处， 外泌体生物标志物（磷脂酰肌醇蛋白聚糖-3、HSC 70和CD 63）、血清miRNA-122和非外泌体生物标志物的组合 （肝脏超声，AFP，AFP-L3，DCP）用于早期发现退伍军人肝硬化相关的HCC 非酒精性脂肪肝（NAFLD）目的3将研究是否测量肝脏特异性miRNA- 血清中的122水平沿着非侵入性测试（FIB-4指数、APRI评分和FibroScan）可升高 HCV治愈后早期评估肝硬化消退或持续性肝硬化风险的能力， 有肝硬化的退伍军人。如果该申请被选中用于资助基于外泌体的生物标志物平台， 开发用于在强直性脊柱炎患者中进行早期HCC检测。