Integrating plasma IGF-1 into novel classification of hepatocellular carcinoma

描述(由申请人提供)：在肝细胞癌(HCC)治疗中，Child-Pugh(CP)评分是目前在临床实践中评估潜在的慢性肝病(CLD)状态和在HCC治疗试验中对患者进行分层的标准工具。它也是目前最常用的肝细胞癌分期系统中的一个基本参数，尤其是意大利肝癌计划(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，即考虑进行手术切除或局部或系统治疗试验的肝细胞癌患者的CP评分必须为A[1-3]。这种选择标准有助于评估治疗效果，而不会出现潜在的肝硬变导致的肝功能衰竭和死亡等令人困惑的问题。然而，专家小组也承认有必要改进CP评分，因为它是相对定量的。评分使用五个变量：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，此外还有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，可能由其他非肝病引起，其严重程度可能因利尿剂和乳果糖的治疗而异。因此，重要的CP评分的改进对于优化肝细胞癌的治疗和改善这种疾病典型的悲惨结局是至关重要的。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，并改进了肝细胞癌患者的分层。因此，我们建议的研究的总体目标是开发一种基于非侵入性生物标记物的策略来个性化肝细胞癌分类。我们的中心假设是，基线血浆IGF-1水平是一个容易测量的肝功能障碍程度的替代预后生物标志物，可以替代腹水和肝性脑病的评估，以完善CP和肝细胞癌分类的预测能力。我们将在三个具体目标上验证这一假设：1)通过将血浆IGF-1测量整合到CP评分参数中，构建新的CP评分和新的CLIP和BCLC分期系统。2)比较原始CP Score、CLIP和BCLC分期系统与IGF集成系统的性能。3)前瞻性地验证整合了IGF-1的“CP评分、CLIP和BCLC分期”系统在一个独立的肝癌患者队列中的表现。如果我们实现了我们的目标，我们也许能够在设计更好的可比标准的临床试验中开发个性化治疗的新策略。 公共卫生相关性：我们最新发表的研究表明，测量血浆胰岛素样生长因子-1水平可能作为评估肝细胞癌患者潜在肝病状况的一种工具。我们提出的研究的目标是构建和验证整合了胰岛素样生长因子-1的肝癌分类系统。这种对肝细胞癌进行分类的方法可能导致个性化的治疗策略和卫生保健资源的分配，并将帮助研究人员设计具有可比性标准的临床试验。

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. PUBLIC HEALTH RELEVANCE: Our most recently published studies indicated the potential use of measurement of plasma insulin-like growth factor-1 levels as a tool to assess the status of underlying liver disease in patients with hepatocellular carcinoma (HCC). The goal of our proposed study is to construct and validate insulin-like growth factor-1-integrated HCC classification systems. This approach to classification of HCC may lead to personalized therapeutic strategies and allocation of health care resources and will aid researchers in designing clinical trials of comparable criteria.