Clonal Immunoglobulin DNA and Lymphoma Diagnosis

克隆免疫球蛋白 DNA 和淋巴瘤诊断

• 批准号: 9927306
• 负责人: RICHARD Frederick AMBINDER
• 金额: $ 17.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-13 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927306
• 关键词: AIDS-Related Lymphoma; B Cell Proliferation; B-Cell Lymphomas; Biological Assay; Biopsy; Body Weight decreased; Cancer Diagnostics; Cause of Death; Characteristics; Clinical; Clinics and Hospitals; Consumption; Cytology; DNA; Data Analyses; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease-Free Survival; Educational Activities; Excision biopsy; Failure; Fever; Fine needle aspiration biopsy; Flow Cytometry; Future; Gene Rearrangement; Genetic Markers; Goals; HIV; HIV Infections; Hyperplasia; Immunoglobulins; Incidence; Infrastructure; Investigation; Laboratories; Laboratory Procedures; Letters; Lymphatic Diseases; Lymphoma; Malignant Neoplasms; Medical; Molecular; Molecular Analysis; Morphology; Night Sweating; Nucleic Acids; Opportunistic Infections; Palpable; Pathology; Patient Triage; Patients; Performance Status; Peripheral; Plasma; Predictive Value; Process; Prospective Studies; Quality Control; Resources; Sensitivity and Specificity; Signs and Symptoms; Site; South Africa; South African; Specimen; Specimen Handling; Stretching; Suggestion; Symptoms; Techniques; Technology; Therapeutic procedure; Thinness; Time; Training Activity; Translating; Tuberculosis; Universities; Visit; chemotherapy; co-infection; experience; follow-up; improved; insight; lectures; low and middle-income countries; lymph nodes; molecular marker; next generation sequencing; rapid diagnosis; tuberculosis treatment; tumor DNA

Project Summary Aggressive lymphomas associated with HIV infection are often curable with chemotherapy. Chemotherapy failures are much more common in patients with poor performance status, which manifests as advanced stage disease and is typically associated with a delayed diagnosis. The diagnosis of lymphoma in HIV patients is particularly challenging, and often delayed, because the signs and symptoms of lymphadenopathy, fever, night sweats, and weight loss characteristic of lymphoma may also reflect HIV, or opportunistic infections such as tuberculosis (TB). In South Africa, the diagnosis of lymphoma is especially difficult because of the high incidence of TB co-infection, which is the major cause of death in HIV patients. Fine needle aspiration (FNA) is often performed on palpable and enlarged lymph nodes as a front-line diagnostic procedure. The FNA is sometimes suggestive of lymphoma or TB, and is sometimes indeterminate or non-diagnostic. Lymphadenopathy in this setting is so common, and the medical infrastructure to support excisional biopsy and pathology stretched so thin, that definitive excisional biopsies must be prioritized. Those with FNA findings suspicious for lymphoma are sent for excisional biopsy, while others are treated empirically for TB, and only proceed to biopsy if lymphadenopathy is persistent or progressive despite TB treatment. We propose an investigation of molecular markers that may serve as diagnostic adjuncts to improve prioritization for excisional biopsy. The approach involves molecular analysis of immunoglobulin DNA to detect clonal rearrangements in FNA or in plasma specimens. Several studies suggest that circulating tumor DNA can be detected in the plasma of >95% of patients with aggressive B cell lymphomas. We suspect that these rearrangements would also be frequently detected in FNA as well. We propose to study FNA and plasma specimens from 300 HIV patients with lymphadenopathy undergoing FNA for standard clinical indications at the University of the Witwatersrand-affiliated hospitals and clinics in Johannesburg, South Africa. From this group of patients we will identify at least 30 patients with definitive lymphoma (diagnosed by excisional biopsy) and 30 without lymphoma. To make these clinical determinations (lymphoma vs. no-lymphoma), we will follow patients for up to 6 months while standard diagnostic and therapeutic procedures are pursued. When 30 true positive, and corresponding true negative, cases have been identified, we will determine whether clonal immunoglobulin (cIg) DNA is present in FNA, plasma, or both in order to estimate the sensitivity, specificity, positive predictive value and negative predictive value of cIg DNA as a diagnostic adjunct. These studies will also give insight into clonal B-cell proliferations associated with HIV and coinfections. Positive findings from this preliminary study will set the groundwork for a real-time prospective study to determine whether more rapid diagnosis can improve the performance status and long-term disease- free survival of patients with HIV lymphoma.

项目概要 与 HIV 感染相关的侵袭性淋巴瘤通常可以通过化疗治愈。 化疗失败在体能状态不佳的患者中更为常见，表现为 晚期疾病，通常与延迟诊断有关。 HIV淋巴瘤的诊断 患者尤其具有挑战性，并且经常被延误，因为淋巴结肿大的体征和症状， 淋巴瘤特征的发烧、盗汗和体重减轻也可能反映艾滋病毒或机会性感染 例如结核病 (TB)。在南非，淋巴瘤的诊断尤其困难，因为淋巴瘤的发病率很高。 结核病合并感染的发生率是艾滋病毒患者死亡的主要原因。细针抽吸 (FNA) 是 通常作为一线诊断程序对可触及和肿大的淋巴结进行。 FNA 是 有时提示淋巴瘤或结核病，有时不确定或无法诊断。 在这种情况下，淋巴结病非常常见，支持切除活检和活检的医疗基础设施也很有限。 病理学如此薄弱，必须优先考虑明确的切除活检。那些有 FNA 结果的人 怀疑患有淋巴瘤的人被送去进行切除活检，而其他人则接受结核病的经验治疗，并且仅 如果结核病治疗后淋巴结肿大持续或进展，则进行活检。我们提出一个 研究可作为诊断辅助手段的分子标记，以提高切除的优先顺序 活检。该方法涉及免疫球蛋白 DNA 的分子分析，以检测免疫球蛋白 DNA 中的克隆重排。 FNA 或血浆样本。多项研究表明，可以在血浆中检测到循环肿瘤 DNA >95% 的侵袭性 B 细胞淋巴瘤患者。我们怀疑这些重新安排也将是 也经常在 FNA 中检测到。 我们提议研究 300 名患有淋巴结肿大的 HIV 患者的 FNA 和血浆样本 在威特沃特斯兰德大学附属医院接受标准临床适应症的 FNA 并 南非约翰内斯堡的诊所。从这组患者中，我们将确定至少 30 名患有以下疾病的患者： 确诊性淋巴瘤（通过切除活检诊断）和 30 例无淋巴瘤。为了使这些临床 确定（淋巴瘤与非淋巴瘤）时，我们将跟踪患者长达 6 个月，同时进行标准诊断 并进行治疗程序。当 30 个真阳性和相应的真阴性时，病例有 确定后，我们将确定 FNA、血浆或两者中是否存在克隆免疫球蛋白 (cIg) DNA 评估 cIg DNA 的敏感性、特异性、阳性预测值和阴性预测值 作为诊断的辅助手段。这些研究还将深入了解与 HIV 相关的克隆 B 细胞增殖 和合并感染。这项初步研究的积极结果将为实时前瞻性研究奠定基础 研究以确定更快速的诊断是否可以改善体能状态和长期疾病- HIV淋巴瘤患者的自由生存。