A New Lab Based Algorithm for HCC Surveillance in Patients with Cirrhosis

描述（由申请人提供）：肝细胞癌（HCC）是美国癌症相关死亡上升最快的原因。存活率很低，只有少数病例能及早发现并得到可能治愈的治疗。因此，建议对肝硬化患者定期监测HCC。血清甲胎蛋白（AFP）已被广泛用作HCC检测的标志物，但其在HCC监测中的性能一般较低。然而，AFP检测特征受肝病的严重程度和活动性的影响，部分反映在AST，ALT，胆红素，血小板等血清水平上。将这些因素中的一些因素纳入调整后的AFP算法中可能会提高其在检测HCC中的预测价值。我们的初步预测logistic模型以AFP、年龄、ALT和总胆红素作为连续非线性变量和相互作用项（AFP*ALT、AFP* 胆红素），发现与单独AFP检测相比，AFP检测后6个月内HCC发生率的预测有显著改善。这项工作已被接受发表在胃肠病学。 拟议的研究将通过使用具有更长随访时间和更多HCC病例的更新的衍生数据集来优化这种有前途的初步算法的预测效用，在来自退伍军人事务部（VA）和北方加州（KPNC）的HCV相关和非HCV相关肝硬化患者的两个独立队列中验证和完善该算法，并与KPNC的肝脏超声和AFP筛查相比较，评估其在早期HCC检测中的临床实用性。 目的1（调整后AFP算法的推导）：在肝硬化和丙型肝炎感染患者的大型推导数据集中，最大限度地提高我们初步的基于AFP的模型（调整后AFP）在预测HCC发生方面的预测价值，并估计“阳性或异常”结果的截止值。 目的2（外部验证）：在两个外部队列的不同病因肝硬化患者中，检测我们调整的AFP模型在预测HCC风险中的应用。 目的3（临床实用性测试）：与标准血清AFP测试（有或无肝脏超声筛查（US）测试）相比，检查调整后的AFP算法在改善早期HCC检测方面的临床实用性。 考虑到AFP检测的广泛可用性，其实验室标准化水平高，成本低，以及缺乏有前途和容易获得的新生物标志物，我们认为，调整后的AFP算法可能会对临床实践产生直接的效用和影响。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer related deaths in the United States. Survival is dismal except in a relatively small number of cases that are detected early and subjected to potentially curative treatment. Therefore, periodic surveillance for HCC has been recommended in patients with liver cirrhosis. Serum alpha-fetoprotein (AFP) has been extensively used as a marker for HCC detection, but its performance in the surveillance for HCC has been generally low. However, AFP test characteristics are influenced by severity and activity of liver disease that are partly reflected n serum levels of AST, ALT, bilirubin, platelets, etc. Incorporating some of these factors into an adjusted AFP-based algorithm may improve its predictive value in detecting HCC. Our preliminary predictive logistic model with AFP, age, ALT, and total bilirubin as continuous non-linear variables and interaction terms (AFP*ALT, AFP*bilirubin) found marked improvement in predicting HCC occurrence in the 6 months following an AFP test compared to AFP alone. This work has been accepted for publication in Gastroenterology. The proposed study will optimize the predictive utility of this promising yet preliminary algorithm by using an updated derivation dataset with longer follow up and more HCC cases, validate and refine the algorithm in two independent cohorts of HCV- and non HCV- related cirrhosis patients from the Department of Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC), and evaluate its clinical utility in detecting early HCC in comparison to liver ultrasound- and AFP -based screening at KPNC. Aim 1 (DERIVATION OF THE ADJUSTED AFP ALGORITHM): To maximize the predictive value of our preliminary AFP based model (adjusted AFP) in predicting the occurrence of HCC and estimate cutoffs for "positive or abnormal" results in a large derivation dataset of patients with cirrhosis and hepatitis C infection. Aim 2 (EXTERNAL VALIDATION): To test the use of our adjusted AFP model in predicting the risk of HCC in two external cohorts of patients with cirrhosis due to various etiologies. Aim 3 (TESTING OF CLINICAL UTILITY): To examine the clinical utility of the adjusted AFP algorithm in improving early HCC detection compared to standard serum AFP test with or without liver ultrasound screening (US) test. Given the wide availability of AFP tests, their high level of lab standardization, low cost, and the absence of promising and readily available new biomarkers, we believe that an adjusted AFP based algorithm may have an immediate utility and impact on clinical practice.