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

描述(申请人提供)：本申请是为响应PA-07-173《艾滋病和获得性免疫抑制中的恶性病变研究》而提交的。HIV相关弥漫性大B细胞淋巴瘤(DLBCL)与非HIV相关DLBCL相比，临床上更具侵袭性，对治疗的反应较差。在联合抗逆转录病毒治疗(ART)的时代，HIV相关的DLBCL不再总是致命的，临床结果是不同的。尽管有可能有效的治疗DLBCL的方案可用，但仍有超过50%的患者死于这种疾病。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的治疗开发至关重要。虽然临床因素(如肿瘤分期)可以预测ART时代HIV相关DLBCL的预后，但它们无法准确预测相当大一部分病例的预后，也提供了很少的治疗洞察力。然而，关于易患HIV相关性DLBCL预后的生物因素的知识很少。因此，本研究的主要目的是探讨几种病毒和分子因素对HIV相关性DLBCL预后的意义，以促进临床治疗，并为DLBCL的新的分子治疗靶点提供见解。本研究的三个主要目的是：(1)探讨肿瘤病毒感染(EBV、KSHV)和多种分子因子(诱变分子、细胞周期调节因子、B细胞活化标志物和抗凋亡蛋白)对HIV相关性DLBCL预后的预测意义；(2)探讨HIV感染对DLBCL预后的病毒/分子发病机制的影响；(3)建立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的疾病进展概率。拟议的研究采用观察性队列设计，将包括：(1)1996至2006年间诊断的所有与艾滋病毒相关的DLBCL病例(预计为192例)，以及(2)与HIV相关的DLBCL病例的年龄、性别和诊断年份匹配的队列。患者将从Kaiser Permanente南加州和北加州确定，这是一种综合医疗保健系统，服务于约25%的参保加州人。Kaiser Permanente除了&gt；80个行政和临床数据库外，还有长期存在的艾滋病毒和癌症登记系统来进行这些研究。这项研究将利用Kaiser Permanente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。2009年12月将通过对医疗记录的标准化审查来跟踪患者的总体生存和疾病进展情况。将使用包括生存分析和Logistic回归在内的分析技术来分析拟议目标的数据。这项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因素，并为新的分子治疗靶点提供见解。此外，这项研究将提供一个预测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供治疗建议时评估肿瘤特征和临床因素。 公共卫生相关性：该项目将有助于理解HIV相关弥漫性大B细胞淋巴瘤的侵袭性和临床结果的异质性背后的肿瘤相关生物学因素。我们的结果也可能有助于确定耐药肿瘤的新的分子治疗靶点，并有助于建立风险分层患者管理的结果预测方程。

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.