Validation of Prognostic and Diagnostic Molecular Tests in Mesothelioma

描述（由申请人提供）：恶性胸膜间皮瘤（MPM）是一种罕见但致命的恶性肿瘤。治疗往往是不够的，大多数新的化疗方案的临床试验没有显示出额外的好处，可能是由于肿瘤和阶段的异质性。手术已被证明可以提高一些早期疾病患者的生存率，但确定那些最有可能受益的患者仍然是一个重大挑战。分期也是有限的，基本上需要一个大的手术切除，以确定准确的病理阶段。目前真正缺乏的是一个全面的普遍认可的治疗前分期策略，以允许更合理的治疗分层和临床试验中患者的比较。 以前，我们提出了具体的预测测试MPM，在120例连续接受手术的患者的前瞻性临床试验中进行了验证，并建立了构成足够样本的测试属性。本试验中获得的数据允许对多个预测参数进行综合分析，这些参数在该患者队列中均为独立的，并且除了MPM预测测试之外还包括淋巴结状态、组织学亚型和肿瘤体积。通过结合这四个参数，我们能够相当准确地将患者分成具有高度统计学显著性和相当不同的生存预期的组。最重要的是，所有这些变量都可以在决定治疗之前通过放射学和微创分期程序确定。 我们建议在前瞻性临床试验中测试这种基于分子的分期模型，并将结果扩展到微创活检和福尔马林固定石蜡包埋组织的分析。为了实现我们的目标，我们将使用废弃的人类肿瘤和对照组织。具体目标1：在一项前瞻性临床试验中确定MPM患者的治疗前分期（包括测量肿瘤体积的CT、确定淋巴结状态的颈部纵隔镜检查以及用于组织学亚型诊断的胸膜活检和确定预测基因比率测试）是否可以预测生存期。具体目标二：在一项前瞻性临床试验中，确定与细胞学检查相比，图像引导下的细针穿刺活检是否能提高MPM患者的诊断率，并能准确应用MPM预测试验。具体目标3：确定MPM诊断和预测基因比率检测是否可以在来自相同患者的石蜡包埋和冷冻标本中产生等效结果。

DESCRIPTION (provided by applicant): Malignant pleural mesothelioma (MPM) is a rare but deadly malignancy. Therapy is often inadequate and most clinical trials with new chemotherapy regimens have not shown added benefit possibly due to tumor and stage heterogeneity. Surgery has been shown to improve survival in some patients with early disease, but identifying those patients most likely to benefit remain a significant challenge. Staging is also limited, essentially requiring a major surgical resection to determine the accurate pathological stage. What is truly lacking at this time is a comprehensive universally agreed-upon pre-treatment staging strategy to allow more rational treatment stratification and comparison of patients across clinical trials. Previously, we proposed specific predictive tests for MPM which were validated in a prospective clinical trial of 120 consecutive patients undergoing surgery and the test properties in terms of what constitute adequate specimens were established as well. The data obtained in this trial allowed for a comprehensive analysis of multiple predictive parameters which were all independent in this patient cohort and included in addition to the MPM predictive test, the lymph node status, histological subtype and the tumor volume. By combining these four parameters, we were able to quite accurately stratify patients into groups that had highly statistically significant and quite distinct survival expectations. Most importantly, all these variables can be determined through radiographic and minimally invasive staging procedures prior to decision on therapy. We propose to test this molecular-based staging model in a prospective clinical trial and to extend the results to the analysis of minimally invasive biopsies and formalin-fixed, paraffin-embedded tissues. To accomplish our objectives we will use discarded human tumor and control tissues. Specific Aim 1: To determine in a prospective clinical trial whether pre-treatment staging for patients with MPM which includes CT for measuring tumor volume, cervical mediastinoscopy to determine lymph node status as well as pleural biopsy for histological subtype diagnosis and determination of the predictive gene ratio test can predict survival. Specific Aim 2: To determine in a prospective clinical trial whether image-guided FNA in patients with MPM enhances diagnosis compared with cytology and allow for an accurate application of the MPM predictive test. Specific Aim 3: To determine whether the MPM diagnostic and predictive gene ratio tests can yield equivalent results in paraffin embedded and frozen specimens from the same patients.