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: 8120890
• 负责人: Chun R. Chao
• 金额: $ 30.14万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120890
• 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; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; Environment; Equation; Gender; HIV; HIV Infections; Herpesviridae; Heterogeneity; Human Herpesvirus 4; Human Herpesvirus 8; Immunosuppression; 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; clinical decision-making; 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; 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）：此申请是针对PA-07-173提交的，标题为“艾滋病中的恶性肿瘤研究和获得的免疫抑制”。与非HIV与HIV相关的DLBCL相比，已知与HIV相关的大型B细胞淋巴瘤（DLBCL）在临床上更具侵略性，对治疗的反应较低。在组合抗逆转录病毒疗法（ART）的时代，与HIV相关的DLBCL不再是致命的，并且在临床结果中是异质的。尽管可用于治疗DLBCL的潜在有效方案，但超过50％的患者继续屈服于该疾病。因此，了解与HIV相关的DLBCL的侵略性和异质性对风险分层的患者管理和新型治疗性发育至关重要。尽管临床因素（例如，肿瘤阶段）可以预测与HIV相关的DLBCL在ART时代的结果，但它们无法准确预测大量病例的结果，并且几乎没有治疗见解。然而，关于生物学因素的知识偏见与HIV相关的DLBCL预后很少。因此，这项研究的广泛目的是研究与HIV相关DLBCL的几种病毒和分子因子的预后意义，以提高临床护理并为DLBCL的新分子治疗靶标提供见解。三个主要目的是：（1）研究肿瘤病毒感染（EBV，KSHV）和几种分子剂（诱变分子，细胞周期调节剂，B细胞激活标记和抗凋亡蛋白）的预后意义； （2）研究HIV感染对DLBCL预后中病毒/分子发病机理的影响； （3）构建一个预测方程，并结合了临床因素和肿瘤标记，以预测HIV相关DLBCL疾病进展的概率。拟议的研究采用了观察队列设计，将包括：（1）所有与HIV相关的DLBCL事件诊断为1996年至2006年（预期n = 192），以及（2）（2）年龄和诊断的年龄和诊断性的与HIV与HIV相关的DLBCL病例的年龄和诊断群体。将从Kaiser Permanente南部和北加州鉴定出患者，这些综合保健系统为加利福尼亚州的约25％提供服务。 Kaiser Permanente除了80个行政和临床数据库外，还拥有长期的HIV和癌症注册机构，以进行这些研究。这项研究将利用Kaiser Permanente可用的存档肿瘤标本来评估通过组织微阵列和免疫组织化学染色的肿瘤表达。通过对医疗记录的标准化审查，将遵循患者的整体生存和疾病进展。包括生存分析和逻辑回归在内的分析技术将用于分析所提出的目标的数据。拟议的研究将旨在鉴定影响与HIV相关DLBCL侵略性的肿瘤相关的生物学因素，并为新型分子治疗靶标提供见解。此外，该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与HIV相关的大型B细胞淋巴瘤侵袭性和临床结果中异质性的肿瘤相关生物学因素。我们的结果还可能有助于确定用于抗性肿瘤的新分子治疗靶标，并有助于建立风险分层患者管理的结果预测方程。

项目成果

Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell Lymphoma.

• DOI: 10.1158/1078-0432.ccr-11-3169
• 发表时间: 2012-09-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chao C;Silverberg MJ;Martínez-Maza O;Chi M;Abrams DI;Haque R;Zha HD;McGuire M;Xu L;Said J
• 通讯作者: Said J