Hematopathology Fellowship

血液病理学奖学金

• 批准号: 7970272
• 负责人: Elaine Jaffe
• 金额: $ 71.14万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7970272
• 关键词: Affect; American; Ancillary Study; Appointment; Archives; B-Lymphocytes; Benign; Biological Assay; Biological Preservation; Biology; Case Study; Cell Lineage; Cells; Classification; Clinic; Clinical; Clinical Research; Communication; Communities; Complication; Consultations; Cytokine Receptors; DNA; DNA Methylation; Dendritic Cells; Diagnosis; Diagnostic; Diagnostic Services; Disease; Disease Progression; Emerging Technologies; Environment; Enzyme-Linked Immunosorbent Assay; Epstein-Barr Virus Infections; Exposure to; Faculty; Fellowship; Fellowship Program; Flow Cytometry; Follicular Lymphoma; Formalin; Freezing; Functional disorder; Future; Genes; Genotype; Goals; Heart Transplantation; Hematopathology; Human Herpesvirus 4; Hyperplasia; IL8 gene; Immunosuppression; Individual; Interferon Type II; Interleukin-10; Interleukin-13; Interleukin-2; Interleukin-4; Interleukin-5; International; Intracellular Signaling Proteins; Laboratories; Lesion; Lymphoproliferative Disorders; Malignant Neoplasms; Medical; Medicine; Memorial Sloan-Kettering Cancer Center; Molecular; Organ; Paraffin Embedding; Pathology; Patient Care; Patients; Phase; Philosophy; Phosphorylation; Play; Procedures; Process; Protein Microchips; Proteins; Proteomics; Publications; Publishing; Recording of previous events; Relative (related person); Reporting; Role; Solid; Specimen; Surgical Pathology; T-Cell Proliferation; T-Lymphocyte; Techniques; Therapeutic immunosuppression; Time; Tissues; Training; Training Programs; Translational Research; Tumor Necrosis Factor-alpha; United States; United States National Institutes of Health; Universities; base; bisulfite; bone marrow allograft; cancer genome; career; clinical Diagnosis; cytokine; epigenomics; experience; lymph nodes; macrophage; medical schools; novel; older men; skills; tool; tumor

The Hematopathology Fellowship has been highly successful in attracting outstanding applicants and in providing them with training in hematopathology, emphasizing outstanding clinical diagnosis, and specialized diagnostic tools including molecular diagnostics and flow cytometry. The fellowship has been ACGME accredited since 2000, and graduating fellows have had a 100% pass rate on the accrediting examination given by the American Board of Pathology. Graduating fellows gone on to establish independent careers in academic medicine, including appointments in recent years at Baylor University School of Medicine, The Mayo Clinic, Memorial Sloan Kettering Cancer Center, and the Cleveland Clinic. Fellows are encouraged to participate in clinical research, and have successfully completed studies on a variety of topics, as briefly mentioned below. We have undertaken studies to examine the influence of the cytokine microenvironment in Follicular lymphoma (FL). FL is characterized by constitutive expression of Bcl-2 as a consequence of t(14;18). Evidence suggests factors in the lymph node microenvironment, related to intratumoral T cells, macrophages, and dendritic cells, play a role in the disease process. We generated proteomic cytokine profiles of FL (N = 50) and follicular hyperplasia (FH; N = 23). A total of 10 cytokines were assayed using ultrasensitive multiplex enzyme-linked immunosorbent assays: IL-1beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-13, IL-12p70, tumor necrosis factor-alpha, and interferon-gamma. Each cytokine showed overall lower protein concentrations in FL, with the exception of IL-4, which was nearly 5 times higher in FL than FH (P = .005). Using reverse-phase protein microarrays (RPMAs), we evaluated the activation state of several intracellular signaling proteins downstream of cytokine receptors. Basal Erk phosphorylation was approximately 4 times greater in FL than FH (P < .001), with similar findings for Mek; Stat-6 showed weak basal phosphorylation that was approximately twice as high in FL than in FH (P = .012). In conclusion, the FL microenvironment contains increased levels of IL-4, with prominent tumor basal phosphorylation of Erk. These findings suggest IL-4, Erk, and possibly Stat-6 may play a role in the biology of FL and may serve as targets for future therapies. In another study we evaluated the remodeling of the FL methylome. Emerging technologies allow broad profiling of the cancer genome for differential DNA methylation relative to benign cells. Bisulfite-modified DNA from lymph nodes with either reactive hyperplasia or follicular lymphoma (FL) were analyzed using a commercial C/UpG genotyping assay. Two hundred fifty-nine differentially methylated targets (DMT) distributed among 183 unique genes were identified in FL. Comparison of matched formalin-fixed, paraffin-embedded and frozen surgical pathology replicates showed the complete preservation of the cancer methylome among differently archived tissue specimens. Analysis of the DMT profile is consistent with a pervasive epigenomic remodeling process in FL that affects predominantly nonlymphoid genes. An example of a novel case seen in consultation led to the publication of a case report by a fellow trainee. Posttransplant lymphoproliferative disorders (PTLDs) may occur as a complication of immunosuppression in patients who have received solid organ or bone marrow allografts. Most PTLDs are of B-cell lineage, whereas T-cell proliferations are rare. The majority of B-cell lesions are associated with Epstein-Barr virus infection. The occurrence of both B-cell and T-cell PTLDs in the same patient is extremely rare and only 6 cases have been previously published. We reported a case of a 63-year-old man who developed 2 metachronous Epstein-Barr virus-related PTLDs beginning 10 years after heart transplantation. A polymorphic B-cell PTLD developed first that completely regressed after immunosuppressive therapy was partially withdrawn. Then, a monomorphic T-cell PTLD developed 31 months later. The patient died 17 months later owing to disease progression. We highlight the diagnostic challenge of this case that required numerous ancillary studies for lineage assessment and classification. Such studies are often needed in patients with a history of immunosuppression.

血液病理学研究金非常成功地吸引了优秀的申请者，并为他们提供了血液病理学方面的培训，强调杰出的临床诊断，以及包括分子诊断和流式细胞术在内的专门诊断工具。该奖学金自2000年以来一直获得ACGME认证，毕业研究员在美国病理委员会颁发的认证考试中获得了100%的通过率。毕业生继续在学术医学领域建立独立的职业生涯，包括近年来在贝勒大学医学院、梅奥诊所、纪念斯隆·凯特琳癌症中心和克利夫兰诊所的任命。鼓励研究员参与临床研究，并已成功完成各种主题的研究，如下所述。我们已开始研究细胞因子微环境对滤泡性淋巴瘤(FL)的影响。作为t(14；18)的结果，FL以Bcl2的结构性表达为特征。有证据表明，与肿瘤内T细胞、巨噬细胞和树突状细胞相关的淋巴结微环境因素在疾病过程中发挥作用。我们建立了FL(N=50)和滤泡增生(FH；N=23)的蛋白质组细胞因子谱。用超灵敏的多重酶联免疫吸附试验检测10种细胞因子：IL-1β、IL-2、IL-4、IL-5、IL-8、IL-10、IL-13、IL-12p70、肿瘤坏死因子-α和干扰素-γ。除IL-4外，所有细胞因子在FL中的蛋白浓度均低于FH(P=0.005)，而FL中IL-4的含量几乎是FH的5倍。利用反相蛋白质芯片(RPMAS)，我们评估了细胞因子受体下游的几种细胞内信号蛋白的激活状态。FL的基础ERK磷酸化水平约为FH的4倍(P&lt；.001)，MEK的研究结果与此类似；Stat-6显示弱的基础磷酸化水平，FL的基础磷酸化水平约为FH的两倍(P=.012)。综上所述，FL微环境中IL-4水平升高，肿瘤细胞ERK有显著的基础磷酸化。这些发现提示IL-4、ERK和可能的Stat-6可能在FL的生物学中发挥作用，并可能成为未来治疗的靶点。在另一项研究中，我们评估了FL甲基组的重塑。新兴技术允许对癌症基因组进行广泛的剖析，以区别于良性细胞的DNA甲基化。用商业C/UPG基因分型试验分析了反应性增生或滤泡性淋巴瘤(FL)淋巴结中亚硫酸氢盐修饰的DNA。在FL中发现了259个差异甲基化靶点，分布在183个独特基因中。比较匹配的福尔马林固定的，石蜡包埋的和冷冻的手术病理复制品显示，在不同归档的组织标本中，癌症甲基组完全保存。对DMT图谱的分析与FL中普遍存在的表观基因组重塑过程一致，该过程主要影响非淋巴基因。在咨询中看到的一个新案例的例子导致发表了另一名受训人员的案例报告。在接受实质器官或骨髓移植的患者中，移植后淋巴增生性疾病(PTLDS)可能是免疫抑制的并发症。大多数PTLDs是B细胞系，而T细胞增殖很少见。大多数B细胞病变与EB病毒感染有关。在同一患者中同时发生B细胞和T细胞PTLDS是极其罕见的，以前只发表了6例。我们报告一例63岁男性心脏移植后10年开始出现2个异时性EB病毒相关PTLDS的病例。多态B细胞PTLD首先出现，在免疫抑制治疗后完全消退，部分撤销。然后，31个月后出现了单形性T细胞PTLD。患者于17个月后因病情恶化死亡。我们强调了这个病例的诊断挑战，它需要大量的辅助研究来进行谱系评估和分类。有免疫抑制病史的患者通常需要进行这样的研究。