Validation of Prognostic and Diagnostic Molecular Tests in Mesothelioma

间皮瘤预后和诊断分子测试的验证

• 批准号: 8894433
• 负责人: RAPHAEL BUENO
• 金额: $ 34.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-07 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894433
• 关键词: Algorithms; Asbestos; Base Ratios; Biopsy; Biopsy Specimen; Cancer Diagnostics; Cervical; Chemotherapy-Oncologic Procedure; Clinical; Clinical Treatment; Clinical Trials; Cytology; Data; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Disease; Enrollment; Excision; Fine needle aspiration biopsy; Formalin; Freezing; Gene Expression; Genes; Heterogeneity; Human; Institutes; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant neoplasm of lung; Measures; Mediastinoscopy; Mesothelioma; Methodology; Methods; Modeling; Molecular; Molecular Diagnostic Testing; Molecular Profiling; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathological Staging; Pathology; Patients; Pilot Projects; Pleura; Pleural; Pleural Diseases; Procedures; Property; RNA; Relative (related person); Specimen; Staging; Staging System; Stratification; Subgroup; Testing; Time; Tissues; Translational Research; Translations; Tumor Volume; Tumor stage; Validation; accurate diagnosis; advanced disease; base; cohort; diagnostic accuracy; effective therapy; expectation; image guided; improved; in vivo imaging; lymph nodes; minimally invasive; mortality; novel; outcome forecast; pre-clinical; prevent; prognostic; prospective; research study; standard of care; tool; treatment center; treatment trial; tumor

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.

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。治疗往往是不充分的，并且大多数新化疗方案的临床试验并未显示出额外的益处，这可能是由于肿瘤和分期异质性所致。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。分期也受到限制，基本上需要进行大手术切除才能确定准确的病理分期。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，以便在临床试验中对患者进行更合理的治疗分层和比较。 此前，我们提出了针对 MPM 的特定预测测试，这些测试在 120 名连续接受手术的患者的前瞻性临床试验中得到了验证，并且还建立了构成足够样本的测试特性。该试验中获得的数据可以对多个预测参数进行综合分析，这些参数在该患者队列中都是独立的，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，我们能够非常准确地将患者分为具有高度统计显着性和完全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线照相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：在前瞻性临床试验中确定 MPM 患者的治疗前分期（包括用于测量肿瘤体积的 CT、用于确定淋巴结状态的颈纵隔镜检查以及用于诊断组织学亚型的胸膜活检和确定预测基因比率测试）是否可以预测生存。具体目标 2：在前瞻性临床试验中确定 MPM 患者的图像引导 FNA 与细胞学相比是否可以增强诊断，并允许准确应用 MPM 预测测试。具体目标 3：确定 MPM 诊断和预测基因比率测试是否可以在来自同一患者的石蜡包埋和冷冻标本中产生相同的结果。