Prognostic Markers for HIV-Postive Diffuse Large B-Cell Lymphoma

HIV 阳性弥漫性大 B 细胞淋巴瘤的预后标志物

• 批准号: 7691293
• 负责人: Chun R. Chao
• 金额: $ 50.35万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691293
• 关键词: AIDS-Related Lymphoma; Acquired Immunodeficiency Syndrome; Affect; Age; Apoptotic; Archives; B-Cell Activation; BCL2 gene; Biological Factors; California; Caring; Cell Cycle; Cessation of life; Characteristics; Clinical; Complement 3d Receptors; Cyclin E; Data Analyses; Databases; Decision Making; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; Environment; Equation; Gender; HIV; HIV Infections; Herpesviridae; Heterogeneity; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Integrated Health Care Systems; Kaposi Sarcoma; Knowledge; Logistic Regressions; Malignant Neoplasms; Medical Records; Molecular; Morbidity - disease rate; Outcome; PRKCB1 gene; Pathogenesis; Patients; Pattern; Persons; Population; Probability; Prognostic Marker; Proliferation Marker; Protein p53; Proteins; Recommendation; Research; Resistance; Risk; Role; SKP2 gene; Specimen; Staining method; Stains; Survival Analysis; Techniques; Therapeutic; Tissue Microarray; Treatment Protocols; Tumor Markers; Tumor stage; United States; Variant; Viral; Virus Diseases; activation-induced cytidine deaminase; antiretroviral therapy; clinical care; cohort; comparison group; cyclin D2; design; insight; large cell Diffuse non-Hodgkin' s lymphoma; member; molecular marker; mortality; neoplasm registry; novel; novel therapeutics; outcome forecast; prognostic; protein kinase C beta; public health relevance; response; survivin; therapeutic development; therapeutic target; therapy development; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): This application is submitted in response to the PA-07-173 entitled Research on Malignancies in AIDS and Acquired Immune Suppression. HIV-related diffuse large B-cell lymphoma (DLBCL) is known to be clinically more aggressive and less responsive to therapy compared to non HIV-related DLBCL. In the era of combination antiretroviral therapy (ART), HIV-related DLBCL is no longer invariably fatal and is heterogeneous in clinical outcomes. Despite the availability of potentially effective regimens for the treatment of DLBCL, more than 50% of patients continue to succumb to the disease. Therefore, understanding factors underlying HIV-related DLBCL aggressiveness and heterogeneity is critical to risk- stratified patient management and novel therapeutic development. Although clinical factors (e.g., tumor stage) are predictive for HIV-related DLBCL outcomes in the ART era, they fail to accurately predict outcome for a sizeable portion of cases and provide little therapeutic insight. Yet, knowledge on biologic factors predisposing HIV-related DLBCL prognosis is scarce. The broad objective of this study is therefore to investigate the prognostic significance of several viral and molecular factors for HIV-related DLBCL to advance clinical care and provide insight for new molecular therapeutic targets for DLBCL. The three main aims are: (1) to investigate the prognostic significance of tumor viral infection (EBV, KSHV) and several molecular agents (mutagenic molecules, cell cycle regulators, B-cell activation markers, and anti-apoptotic proteins) for HIV-related DLBCL prognosis; (2) to investigate the effect of HIV infection on viral/molecular pathogenesis in DLBCL prognosis; and (3) to build a prediction equation, incorporating both clinical factors and tumor markers, for predicting probability of disease progression for HIV-related DLBCL. The proposed study employs an observational cohort design and will include: (1) all incident HIV-related DLBCL cases diagnosed between 1996 and 2006 (expected n=192), and (2) an age- gender- and diagnosis year-matched cohort of non HIV-related DLBCL cases. Patients will be identified from Kaiser Permanente Southern and Northern California, which are integrated health care systems serving ~25% of insured Californians. Kaiser Permanente has long-standing HIV and cancer registries in addition to >80 administrative and clinical databases to perform these studies. This research will utilize archived tumor specimens available at Kaiser Permanente to assess tumor expression of selected markers via the construction of tissue microarrays and immunohistochemical staining. Patients will be followed for overall survival and disease progression through December 2009 by a standardized review of the medical records. Analytical techniques including survival analysis and logistic regression will be used to analyze data for the proposed aims. The proposed study will serve to identify tumor- related biologic factors affecting HIV-related DLBCL aggressiveness, and provide insights for novel molecular therapeutic targets. Furthermore, the study will provide a prediction equation for predicting DLBCL progression in HIV-infected patients, which will assist clinicians to evaluate both tumor characteristics and clinical factors when making therapeutic recommendations for patients. PUBLIC HEALTH RELEVANCE: This project will contribute to the understanding of tumor-related biological factors underlying the HIV- related diffuse large B-cell lymphoma aggressiveness and heterogeneity in clinical outcomes. Our results may also help to identify new molecular therapeutic targets for resistant tumor and assist with the building of an outcome prediction equation for risk-stratified patient management.

描述（由申请人提供）：本申请是为了响应标题为“艾滋病和获得性免疫抑制中的恶性肿瘤的研究”的 PA-07-173 而提交的。与非 HIV 相关的弥漫性大 B 细胞淋巴瘤 (DLBCL) 相比，已知在临床上更具侵袭性且对治疗的反应较差。在联合抗逆转录病毒治疗 (ART) 时代，HIV 相关的 DLBCL 不再总是致命的，并且临床结果存在异质性。尽管存在治疗 DLBCL 的潜在有效方案，但超过 50% 的患者仍然死于该疾病。因此，了解 HIV 相关 DLBCL 侵袭性和异质性的潜在因素对于风险分层患者管理和新疗法开发至关重要。尽管临床因素（例如肿瘤分期）可以预测 ART 时代 HIV 相关 DLBCL 的结果，但它们无法准确预测相当一部分病例的结果，并且提供的治疗见解很少。然而，关于导致 HIV 相关 DLBCL 预后的生物学因素的知识却很少。因此，本研究的广泛目标是调查几种病毒和分子因素对 HIV 相关 DLBCL 的预后意义，以推进临床护理并为 DLBCL 的新分子治疗靶点提供见解。三个主要目标是：（1）研究肿瘤病毒感染（EBV、KSHV）和几种分子制剂（诱变分子、细胞周期调节剂、B 细胞激活标记物和抗凋亡蛋白）对 HIV 的预后意义。相关DLBCL预后； (2) 探讨HIV感染对DLBCL预后中病毒/分子发病机制的影响； (3) 建立一个结合临床因素和肿瘤标志物的预测方程，用于预测 HIV 相关 DLBCL 疾病进展的概率。拟议的研究采用观察性队列设计，包括：(1) 1996 年至 2006 年间诊断的所有与 HIV 相关的 DLBCL 病例（预期 n=192），以及 (2) 年龄、性别和诊断年份匹配的队列非 HIV 相关 DLBCL 病例。患者将来自 Kaiser Permanente 南加州和北加州，这是为约 25% 的加州参保人提供服务的综合医疗保健系统。 Kaiser Permanente 拥有长期的 HIV 和癌症登记，以及超过 80 个用于执行这些研究的管理和临床数据库。这项研究将利用凯撒医疗机构提供的存档肿瘤标本，通过构建组织微阵列和免疫组织化学染色来评估选定标记物的肿瘤表达。截至 2009 年 12 月，将通过病历的标准化审查来跟踪患者的总体生存率和疾病进展情况。包括生存分析和逻辑回归在内的分析技术将用于分析数据以实现拟议的目标。拟议的研究将有助于确定影响 HIV 相关 DLBCL 侵袭性的肿瘤相关生物学因素，并为新的分子治疗靶点提供见解。此外，该研究还将提供预测 HIV 感染患者 DLBCL 进展的预测方程，这将有助于临床医生在为患者提出治疗建议时评估肿瘤特征和临床因素。 公共健康相关性：该项目将有助于了解 HIV 相关弥漫性大 B 细胞淋巴瘤侵袭性和临床结果异质性背后的肿瘤相关生物学因素。我们的结果还可能有助于确定耐药肿瘤的新分子治疗靶点，并有助于建立风险分层患者管理的结果预测方程。