Early Detection of Hepatocellular Carcinoma

 描述(申请人提供)：肝细胞癌是美国与癌症相关的死亡中增长最快的原因。确定肝癌的高危人群并制定有效的早期诊断监测策略至关重要。肝纤维化是肝细胞癌的主要危险因素。每6个月一次的超声和甲胎蛋白(α-FetoProtein，AFP)仍然是最常用于肝硬变患者的监测手段，但这些检测的敏感性和特异性都很低。我们先前在肝癌病例、肝硬变对照和肝癌诊断前样本中进行的广泛的生物标志物研究确定了用于肝癌风险预测和监测的新标志物。在这项提案中，我们将进一步评估这些新标记物和FDA批准的标记物的性能。验证研究将在一个大对比磁共振监测队列中进行，这将提供一个独特的机会来研究临床材料上的生物标记物，这些患者被严格归类为在监测环境中患有非常早期的疾病。血样的纵向采集在评估早期生物标记物如何在观察到病变直至确诊为肝细胞癌期间变为阳性将特别有价值。在对比MRI监测下的肝硬变患者(n=3500名患者)将在贝勒-圣彼得堡登记。卢克医疗中心和休斯顿卫理公会医院。数据管理、标本储存库和分子分析将在MD Anderson癌症中心进行。预计在研究期间将至少检测到150种氟氯烃，其中大多数是在早期阶段检测到的。我们将确定一组生物标志物，最好地区分早期肝细胞癌和肝硬变，因此在肝细胞癌监测中可能有用处。我们将评估新型标记物小组检测临床前疾病的能力，并确定这些生物标记物预测肝细胞癌发展的纵向变化。我们之前的研究也发现了特定的脂肪酸，可以区分在5年内发展为肝细胞癌的肝硬变患者和那些没有发展为肝细胞癌的患者。因此，这些脂肪酸可能在肝细胞癌风险评估中有用处。我们将使用相同的MRI监测队列来确定最能预测肝细胞癌发展的脂肪酸小组。最后，这项研究将评估超声和新型生物标志物面板的互补性，并确定对比增强超声是否会显著提高超声检测小肿瘤病灶的能力。这项建议在一项研究中实现了两个主要目标：早期发现和当生物标记物呈阳性时肿瘤的特征。这项研究具有许多高影响力的转化性应用：使患者不必进行不必要的成像测试；识别高危患者并在监测患者中触发执行MRI而不是超声的决定；在早期阶段发现病变，以便进行根治治疗。这种临床应用将显著降低肝细胞癌监测的成本，并提高肝细胞癌患者的存活率。

 DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related death in the United States. It is critically important to identify those at high risk for HCC and institute effective surveillance strategies for early diagnosis. Livr cirrhosis is the main risk factor for HCC. Ultrasound and α-fetoprotein (AFP) every 6 months remains the surveillance modality most frequently used on cirrhosis patients but the sensitivity and specificity of the tests are low. Our extensive prior biomarker studies in HCC cases, cirrhosis controls and HCC pre-diagnosis samples identified novel markers for HCC risk prediction and surveillance. In this proposal, we will further evaluate the performance of these novel markers together with FDA-approved markers. The validation study will be performed in a large contrast MRI surveillance cohort that provides a unique opportunity to study biomarkers on clinical material from patients rigorously classified as having a very early disease in a surveillance setting. Longitudinal collection of blood samples will be particularly valuable in assessing how early biomarkers become positive during the period when lesions are observed to a confirmed diagnosis of HCC. Cirrhotic patients under contrast MRI surveillance (n=3500 patients) will be enrolled at Baylor-St. Luke's Medical Center and Houston Methodist Hospital. Data management, specimen repository and molecular assays will be performed at MD Anderson Cancer Center. It is anticipated that at least 150 HCCs will be detected during the study with most of them detected at an early stage. We will identify the panel of biomarkers that best distinguishes between early HCC and cirrhosis and that could therefore have utility in HCC surveillance. We will evaluate the capacity of the novel marker panel to detect preclinical disease and determine longitudinal changes in these biomarkers predictive of HCC development. Our prior studies also identified specific fatty acids that discriminate between patients with cirrhosis who developed HCC within 5 years and those who didn't progress to HCC. These fatty acids may therefore have utility in HCC risk assessment. We will determine using the same MRI surveillance cohort the fatty acid panel that best predicts HCC development. Finally, this study will evaluate the complementarity performance of ultrasound and the novel biomarker panel and determine whether contrast-enhanced ultrasound results in any significant improvement in the ability of ultrasound to detect small tumor foci. This proposal achieves in one study two major goals: early detection and characteristics of tumors when biomarker becomes positive. This study has a number of high-impact translational applications: spare patients from unnecessary imaging tests; identify at-risk patients and trigger the decision to perform MRI instead of ultrasound in patients under surveillance; detect lesions at an early stage allowing for curative treatment. Such clinical applications would significantly reduce the cost of HCC surveillance and improve survival of HCC patients.