Hematopathology Fellowship

血液病理学奖学金在吸引优秀申请者并为他们提供血液病理学培训方面非常成功，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业诊断工具。自2000年以来，该奖学金已获得ACGME认证，毕业研究员在美国病理学委员会进行的认证考试中有100%的通过率。毕业生们在学术医学领域建立了独立的职业生涯，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，并成功完成各种主题的研究，如下所述。我们进行了研究，以检查细胞因子微环境对滤泡性淋巴瘤（FL）的影响。由于t的作用，FL的特征是Bcl-2的组成性表达（14;18）。有证据表明，淋巴结微环境中与肿瘤内T细胞、巨噬细胞和树突状细胞相关的因素在疾病过程中发挥作用。我们生成了FL （N = 50）和滤泡增生（FH; N = 23）的蛋白质组细胞因子谱。采用超灵敏多重酶联免疫吸附法检测共10种细胞因子：il -1 β、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，各细胞因子在FL中的蛋白浓度均低于FH， IL-4在FL中的蛋白浓度是FH的近5倍（P = 0.005）。利用逆相蛋白微阵列（rpma），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。基础Erk磷酸化在FL中大约是FH的4倍（P < .001）， Mek也有类似的发现；Stat-6显示出较弱的基础磷酸化，FL的磷酸化水平大约是FH的两倍（P = 0.012）。综上所述，FL微环境中IL-4水平升高，肿瘤基础Erk磷酸化显著。这些发现表明IL-4、Erk和Stat-6可能在FL的生物学中发挥作用，并可能作为未来治疗的靶点。在另一项研究中，我们评估了FL甲基组的重塑。新兴技术允许癌症基因组相对于良性细胞的差异DNA甲基化的广泛分析。使用商用C/UpG基因分型法分析来自反应性增生或滤泡性淋巴瘤（FL）淋巴结的亚硫酸氢盐修饰DNA。在FL中鉴定了分布在183个独特基因中的259个差异甲基化靶点（DMT）。通过福尔马林固定、石蜡包埋和冷冻手术病理重复的比较，发现不同存档组织标本中癌症甲基组的完整保存。对DMT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样基因。在咨询中看到的一个新病例的例子导致一位实习同事发表了一份病例报告。移植后淋巴细胞增生性疾病（ptld）可能是接受实体器官或骨髓同种异体移植的患者免疫抑制的并发症。大多数PTLDs是b细胞谱系，而t细胞增殖是罕见的。大多数b细胞病变与eb病毒感染有关。在同一患者中同时出现b细胞和t细胞PTLDs是极其罕见的，以前只发表过6例。我们报告了一例63岁男性在心脏移植后10年开始出现2个异时性Epstein-Barr病毒相关的PTLDs。首先出现多态b细胞PTLD，部分停用免疫抑制治疗后完全消退。然后，在31个月后，形成一个单态t细胞PTLD。患者17个月后因疾病进展死亡。我们强调这种情况下的诊断挑战，需要大量的辅助研究谱系评估和分类。有免疫抑制史的患者通常需要这样的研究。

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.