Early Detection of Hepatocellular Carcinoma

 描述（由申请人提供）：肝细胞癌（HCC）是美国增长最快的癌症相关死亡原因。识别HCC高危人群并制定有效的早期诊断监测策略至关重要。肝硬化是HCC的主要危险因素。超声和甲胎蛋白（AFP），每6个月仍然是最常用的监测方式对肝硬化患者，但敏感性和特异性的测试是低的。我们在HCC病例、肝硬化对照和HCC诊断前样本中进行了广泛的生物标志物研究，确定了HCC风险预测和监测的新标志物。在本提案中，我们将进一步评估这些新标记物与FDA批准的标记物的性能。验证研究将在大对比度MRI监测队列中进行，该队列提供了一个独特的机会来研究在监测环境中被严格分类为患有极早期疾病的患者的临床材料的生物标志物。纵向收集血液样本将特别有价值的评估如何早期生物标志物成为积极的期间，病变被观察到确诊为肝癌。在对比MRI监测下的肝硬化患者（n=3500例患者）将在贝勒-圣卢克医疗中心和休斯顿卫理公会医院入组。将在MD安德森癌症中心进行数据管理、标本储存和分子测定。预计在研究期间将检测到至少150例HCC，其中大多数在早期阶段检测到。我们将确定一组最能区分早期HCC和肝硬化的生物标志物，从而在HCC监测中发挥作用。我们将评估新的标志物组检测临床前疾病的能力，并确定这些生物标志物预测HCC发展的纵向变化。我们之前的研究还确定了特定的脂肪酸，可以区分5年内发生HCC的肝硬化患者和未进展为HCC的患者。因此，这些脂肪酸可能在HCC风险评估中具有实用性。我们将使用相同的MRI监测队列来确定最能预测HCC发展的脂肪酸组。最后，本研究将评估超声和新型生物标志物面板的互补性能，并确定对比增强超声是否会显著改善超声检测小肿瘤病灶的能力。该提案在一项研究中实现了两个主要目标：早期检测和生物标志物呈阳性时的肿瘤特征。该研究具有许多高影响力的转化应用：使患者免于不必要的成像检查;识别有风险的患者，并触发对监测下的患者进行MRI而不是超声检查的决定;在早期阶段检测病变，以便进行治愈性治疗。这样的临床应用将显著降低HCC监测的成本并提高HCC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.