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: 9974283
• 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/9974283
• 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; Proteins; Publishing; ROC Curve; Race; Research; Risk; Risk Factors; Role; Sensitivity and Specificity; Series; Serum; Signal Transduction; Stress; Surveillance Methods; Testing; Therapeutic Intervention; Transplantation; Treatment Efficacy; 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; outcome forecast; patient population; performance tests; preservation; response; specific biomarkers; standard of care; 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.

肝细胞癌是一种原发于肝脏的恶性肿瘤，最常发生于 肝硬变背景(1，2)。丙型肝炎病毒(丙型肝炎病毒)感染仍然是导致肝硬化的主要原因 美国退伍军人中的肝癌(3，4)。抗病毒治疗的最新进展使越来越多的 无干扰素(干扰素)的直接作用抗病毒药物(DAAs)治愈的肝硬变患者的比例(5，6)。在即将到来的时候 几年来，根除丙型肝炎有望降低但不是消除肝硬变患者患肝癌的风险 (7，8)。晚期纤维化或肝硬变患者丙型肝炎病毒清除后，肝细胞癌的风险仍较高 其他风险因素，如日常饮酒、肥胖、代谢综合征、糖尿病、 和种族(非裔美国人或西班牙裔)(7-16)。早期发现的肝细胞癌可以有效地治疗 移植、切除甚至局部治疗，但晚期发现的肝细胞癌预后较差。 目前的肝细胞癌监测方法包括每六个月一次的肝脏超声，并选择血清甲胎蛋白。 (AASLD指南)。然而，这些方法缺乏在早期发现肝细胞癌所需的特异性和敏感性。 舞台。因此，一种基于血清的非侵入性生物标志物的开发将使肝癌的早期检测和治疗成为可能。 有效的治疗干预。这项多中心拨款申请建议测试肝脏的性能- 特定的血清生物标志物，以及包括肝脏超声、甲胎蛋白在内的标准护理测试 (AFP)AFP-L3和DCP用于肝细胞癌检测以监测肝硬变患者的肝细胞癌风险。这项验证研究 将通过从6个不同的VA医疗机构招募2000名肝硬变VA患者(丙型肝炎和非丙型肝炎)来执行 中锋。根据肝硬变人群中肝癌的发病率，我们预计&gt；50例肝癌病例将 在早期阶段被发现。我们的假设是，不能解决内质网应激的肝硬变患者 反应将继续增加患肝癌的风险，因此继续分泌肝细胞癌特异的外切体， 富含Glypcan-3和HSC70(热休克相关蛋白70)进入血液。因为压力反应 耗尽miRNA-122转录，我们假设对血清miRNA-122水平的测量将提供 强大的器官特异性生物标志物可用于早期预测丙型肝炎治愈后肝硬变的消退。此应用程序将 探索肝癌特异性外体生物标记物miRNA-122的性能及其对血清的额外益处 AFP检测和肝脏超声检查，以提高对肝癌的监测和肝细胞癌的早期发现。这一假设 将使用以下特定目标进行测试：目标1将确定血清胞外体货物的性能 (Glypcan-3、HSC70和CD63)与肝脏超声、AFP、AFP-L3、DCP作为联合生物标志物平台 应用纵向多中心研究对丙型肝炎治愈后的退伍军人肝硬变患者肝细胞癌的早期检测 学习。AIM 2将开展一项纵向多中心研究，以确定早期肝癌监测的益处 胞外体生物标志物(Glypcan-3、HSC70和CD63)、血清miRNA-122和非胞外体的联合检测 肝超声、AFP、AFP-L3、DCP在退伍军人肝硬变相关性肝细胞癌早期诊断中的应用 非酒精性脂肪性肝病(NAFLD)。目标3将调查肝脏特异性miRNA的测量是否 血清中的122水平与非侵入性检查(FIB-4指数、APRI评分和纤维扫描)一起可能会增加 早期评估丙型肝炎治愈后肝硬化消退或持续性肝硬变风险的能力 患有肝硬变的退伍军人。如果选择该申请作为资助，基于外显体的生物标记物平台将 可用于肝硬变VA患者的早期肝细胞癌检测。