Integrating plasma IGF-1 into novel classification of hepatocellular carcinoma

描述（由申请人提供）：在肝细胞癌（HCC）的治疗中，Child-Pugh （CP）评分是目前评估临床实践中潜在慢性肝病（CLD）状态和HCC治疗试验中患者分层的标准工具。它也是目前大多数HCC分期系统的重要参数，特别是意大利肝癌计划（CLIP）和巴塞罗那临床肝癌（BCLC）。多个专家小组的共识声明达成共识，HCC患者考虑手术切除或局部或全身治疗试验的CP评分必须为a[1-3]。这一选择标准有助于评估治疗效果，而不会出现肝功能衰竭和潜在肝硬化导致的死亡等混杂问题。然而，专家小组也承认有必要完善CP评分，因为它是相对定量的。该评分使用5个变量：三个客观的实验室参数，通过血清白蛋白水平和凝血酶原时间来评估肝脏的合成功能或通过测量血清胆红素水平来评估肝脏的消除功能，以及两个主观的临床参数，肝性脑病和腹水。后两个参数在临床上难以分级，可能由其他非肝脏疾病沉淀，并且根据利尿剂和乳果糖治疗的不同，其严重程度可能不同。因此，需要对CP评分进行重大改进，以优化HCC的管理，改善这种疾病通常令人沮丧的结局。我们最近发表的报告描述了使用血浆胰岛素样生长因子(IGF)-1水平作为评估潜在CLD状态的工具。将这一水平的测量整合到CLIP和BCLC系统中，显著提高了它们的预测能力，并改进了HCC患者分层。因此，我们提出的研究的总体目标是开发一种基于非侵入性生物标志物的策略来个性化HCC分类。我们的中心假设是，血浆IGF-1基线水平是一种容易测量的肝功能障碍程度的替代预后生物标志物，可用于代替腹水和肝性脑病的评估，以完善CP和HCC分类的预测能力。我们将从三个方面验证这一假设：1)通过将血浆IGF-1测量纳入CP评分参数，构建新的CP评分和新的CLIP和BCLC分期系统。2)比较原始CP评分、CLIP和BCLC分期系统与igf集成系统的性能。3)前瞻性验证igf -1整合“CP评分、CLIP和BCLC分期”系统在独立HCC患者队列中的表现。如果我们实现了我们的目标，我们也许能够在设计更好的类似标准的临床试验中开发出个性化治疗的新策略。

DESCRIPTION (provided by applicant): In hepatocellular carcinoma (HCC) management, the Child-Pugh (CP) score is the current standard tool for assessing the underlying chronic liver disease (CLD) status in clinical practice and stratifying patients in HCC therapeutic trials. It alo is an essential parameter in most currently used HCC staging systems, particularly Cancer of the Liver Italian Program (CLIP) and Barcelona Clinic Liver Cancer (BCLC). Multiple experts panels consensus statements reached the consensus that patients with HCC considered for surgical resection or local or systemic therapeutic trials must have a CP score of A [1-3]. This selection criterion facilitates assessment of the effect of treatment without the confounding issues of liver failure and death as a result of underlying cirrhosis. However, the panels also acknowledged the need to refine the CP score since it is relatively quantitative. The score uses five variables: three objective laboratory-based parameters that assess the synthetic function of the liver through serum albumin level and prothrombin time or the elimination function of the liver through measuring serum bilirubin level, in addition to two subjective clinical parameters, hepatic encephalopathy and ascites. The last two parameters are clinically difficult to grade, may be precipitated by other nonliver diseases, and may vary in severity according to treatment with diuretics and lactulose. Thus, major refinement of the CP score is critically needed to optimize HCC management and improve the typically dismal outcome of this disease. Our most recent published reports described the use of the plasma insulin-like growth factor (IGF)-1 level as a tool for assessing the status of the underlying CLD. Integration of measurement of this level into the CLIP and BCLC systems significantly improved their predictive ability and refined HCC patient stratification. Therefore, our overall goal for the proposed study is to develop a noninvasive biomarker-based strategy to personalize HCC classification. Our central hypothesis is that the baseline plasma IGF-1 level is an easily measured surrogate prognostic biomarker of the extent of hepatic dysfunction that can be used instead of assessment of ascites and hepatic encephalopathy to refine the predictive ability of CP and HCC classifications. We will test this hypothesis in three specific aims: 1) To construct a new CP score and new CLIP and BCLC staging systems by integrating plasma IGF-1 measurement into the CP score parameters. 2) To compare the performance of the original CP score and CLIP and BCLC staging systems with that of the IGF-integrated systems. 3) To prospectively validate the performance of the IGF-1-integrated "CP score and CLIP and BCLC staging" systems in an independent cohort of HCC patients. Should we achieve our aims we may be able to develop new strategies in personalized therapy in better designed clinical trials of comparable criteria.