Dermatology Consultation Service

咨询服务人员由我本人、John DiGiovanna 博士和去年加入该分部的执业护士 Olanda Hathaway 组成。第三位临床医生 Emily Chu 医生于 2011 年 6 月离开分院，由于预算限制，她的职位尚未填补。如上所述，提供皮肤疾病评估和管理方面的临床专业知识对 NIH 社区来说是一项非常有价值的服务，并于 2007 年获得了 NIH 院长奖。除了会诊患者外，我还是其他分支机构发起的其他几个方案的副研究员，以及两个方案（将单独讨论）的首席研究员。 我担任副研究员的当前非皮肤病学分支协议包括 GVHD 自然史；恶性淋巴瘤/白血病的低强度移植；使用无关捐赠者进行免疫耗竭疗法和降低强度移植； DOCK8免疫缺陷的同种异体移植；泊马度胺治疗慢性 GVHD； II期孟鲁司特治疗闭塞性细支气管炎；西罗莫司治疗考登斯病；厄洛替尼和贝伐单抗治疗肾细胞癌；自身炎症性疾病的自然史；阿那白滞素（Anakinra）治疗白塞氏病； Rilonacept 用于治疗 IL-1 拮抗剂缺乏症。慢性移植物抗宿主病 (GVHD) 合作是一项重要的多学科合作，由数名 NCI 和非 NCI 研究人员研究 GVHD 的自然史。根据我在该小组的经验，我发表了多篇有关皮肤 GVHD 的文本章节和临床手稿，并荣幸地向全国各地的各个团体（哈佛大学、塔夫茨大学、宾夕法尼亚大学、美国皮肤病学会、地区皮肤病学会和世界皮肤病学大会）进行演讲。通过繁忙的咨询服务，临床合作研究非常活跃。新发现的几种周期性发热综合征患者的pyrin基因突变，以及对由此产生的自身炎症性疾病有效的生物疗法的出现，将一组新的患者引入了临床。我们现在正在系统地描述 PAPA 综合征、Behcets 和 IL-1 受体拮抗剂缺乏症 (DIRA) 患者的皮肤表现特征并评估治疗反应。我是两个方案的首席研究员：用于治疗疼痛性平滑肌瘤的肉毒杆菌毒素 (09-C-0072) 和用于治疗硬化性慢性 GVHD 的甲磺酸伊马替尼 (08-C-0148)。皮肤平滑肌瘤是良性肿瘤，被认为起源于立毛肌。它们可能以孤立的丘疹形式出现，也可能以身体各部位（包括背部和伸肌表面）的分组病变形式出现。单个病变的大小通常为 5 毫米至 1 厘米，但直径也可大至几厘米。皮肤平滑肌瘤与显性遗传性癌症相关基因皮肤病、遗传性平滑肌瘤病和肾细胞癌（HLRCC）有关，后者是由富马酸水合酶基因突变引起的。 HLRCC 的特点是皮肤和（女性）子宫平滑肌瘤形成以及肾细胞癌风险增加。 HLRCC 患者可能会出现孤立的皮肤病变、局部受累区域或弥漫性平滑肌瘤形成。散发性皮肤平滑肌瘤和 HLRCC 相关的皮肤平滑肌瘤通常都会带来疼痛。 在某些情况下，压力或环境温度变化等无害的刺激可能会引起严重的阵发性疼痛。皮肤平滑肌瘤中寒冷引起的疼痛可以通过使用冰块在标准化环境中重现。1 对于有症状的皮肤平滑肌瘤患者，疼痛可能严重到患者考虑自杀。疼痛症状的病因尚不清楚，但疼痛的间歇性、剧烈性质以及一些患者对神经活性药物的反应报告表明，操纵神经传导通路可能会减轻疼痛。 立毛肌受自主神经控制。 因此，人们预计由这种结构产生的肿瘤也将受到利用儿茶酚胺神经递质的自主神经的支配。免疫组织化学研究表明，平滑肌瘤内部和周围的神经纤维有所增加。平滑肌瘤内部和周围的神经被乙酰胆碱酯酶强烈染色，表明乙酰胆碱在平滑肌瘤神经支配中的作用。 在小鼠研究中，立毛肌中可见的神经纤维对神经肽降钙素基因相关肽 (CGRP) 产生免疫反应。据推测，疼痛与病变内神经的压力、神经肽的释放或通过 α-肾上腺素能受体介导的肌肉收缩有关。目前对与皮肤平滑肌瘤相关的阵发性疼痛的治疗是不够的。平滑肌瘤内及其周围可见乙酰胆碱酯酶染色，立毛肌的神经纤维中存在 CGRP 免疫反应性。根据已报告的 BTX-A 对乙酰胆碱和 CGRP 的影响，我们一直在病灶内施用 BTX-A 的试点研究中研究有症状的皮肤平滑肌瘤受试者。我担任首席研究员的第二个方案是甲磺酸伊马替尼治疗慢性 GVHD 的研究 (08-C-0148)。甲磺酸伊马替尼是一种酪氨酸激酶抑制剂，专门开发用于抑制参与 BCR-ABL 信号转导的蛋白质的酪氨酸磷酸化。它还对血小板衍生生长因子 (PDGF) 和转化生长因子 (TGF-) 信号通路（与纤维发生过程密切相关的细胞因子）具有高度特异性和生物活性。 该试验中的患者在全国范围内招募，并在国家癌症研究所/国家卫生研究院的 cGVHD 多学科项目中进行治疗和评估。在评估具有不同患者群体的极其复杂的疾病时，cGVHD 临床试验的进入和反应评估标准的标准化较差。这导致了临床试验数据解释的困难。诊断和反应评估基于 NIH 慢性移植物抗宿主病临床试验标准共识发展项目，重点关注明确的 cGVHD 器官表现，并明确定义进入、同步治疗和评估标准。迄今为止，所有患者均已达到试验的主要结果（6 个月）终点，目前正在收集实验室和其他研究数据以准备最终手稿。

The Consult Service Staff consists of myself, Dr. John DiGiovanna, and a Nurse Practitioner, Olanda Hathaway, who joined the Branch last year. Dr. Emily Chu, a third Clinician, left the Branch in June 2011 and her position has not been filled due to budget constraints. As mentioned above, providing clinical expertise in the assessment and management of the cutaneous disease is a highly valued service to the NIH community which was recognized by the NIH Director's Award in 2007. In addition to seeing patients in Consultation, I am an Associate Investigator on several other protocols initiated by other branches as well as a Principal Investigator on two protocols (to be discussed separately). The current non-Dermatology Branch protocols in which I am an Associate Investigator include Natural History of GVHD; Reduced intensity transplants for malignant lymphomas/leukemias; Immune-depleting therapy and reduced intensity transplant using unrelated donors; Allogeneic transplant for DOCK8 Immunodeficiency; Pomalidomide for chronic GVHD; Phase II Montelukast for bronchiolitis obliterans; Sirolimus for Cowdens disease; Erlotinib and bevacizumab for renal cell carcinoma; Natural history of auto-inflammatory diseases; Anakinra for Behcet's disease; Rilonacept for deficiency of the IL-1 antagonist. The chronic graft versus host disease (GVHD) collaborative effort is a major multidisciplinary collaboration with several NCI and non-NCI investigators studying the Natural history of GVHD. Based on my experience with this group, I have published several text chapters and clinical manuscripts on cutaneous GVHD and have been honored to lecture to various groups around the country (Harvard, Tufts, U. of Pennsylvania, the American Academy of Dermatology, regional dermatologic societies, and the World Congress of Dermatology.) Collaborative clinical research is extremely active via the busy consultation service. The newly discovered mutations in pyrin genes in patients with several periodic fever syndromes, and the availability of biologic therapies that have efficacy in the resulting autoinflammatory diseases have introduced a new group of patients to the clinic. We are now systematically characterizing cutaneous manifestations and assessing responses to treatment in patients with PAPA syndrome, Behcets and deficiency of IL-1 receptor antagonist (DIRA). I am Principal Investigator on two protocols: Botoulinum toxin for painful leiomyomas (09-C-0072) and Imatinib mesylate (08-C-0148) for the treatment of sclerotic chronic GVHD. Cutaneous leiomyomas are benign tumors thought to arise from the arrector pili muscle. They may occur as isolated papules, or present as grouped lesions over areas of the body, including the back and extensor surfaces. Individual lesions often range from 5mm to 1cm in size, but can be as large as a few cm in diameter. Cutaneous leiomyomas have been associated with a dominantly inherited cancer-related genodermatosis, hereditary leiomyomatosis and renal cell cancer (HLRCC), which is caused by a mutation in the fumarate hydratase gene. HLRCC is characterized by cutaneous and (in females) uterine leiomyoma formation as well as an increased risk of renal cell cancer. Patients with HLRCC may present with isolated cutaneous lesions, regional areas of involvement, or diffuse leiomyoma formation.Both sporadically occurring and HLRCC-related cutaneous leiomyomas are often painful. In some cases, severe paroxysmal pain may be elicited by stimuli as innocuous as pressure or a change in ambient temperature. Cold-induced pain in cutaneous leiomyomas can be reproduced in a standardized setting with application of an ice cube.1 For patients with symptomatic cutaneous leiomyomas, the pain may be severe enough that patients contemplate suicide. The etiology of the pain symptoms is poorly understood, but the episodic, intense nature of the pain and reported response in some patients to neuroactive agents suggests that manipulation of the nerve conduction pathways may ameliorate pain. The arrector pilorum muscle is under autonomic control. Thus, one would expect that tumors arising from this structure would also be innervated by autonomic nerves that utilize catecholamine neurotransmitters. Immunohistochemical studies have demonstrated an increase in nerve fibers within and surrounding leiomyomas. Nerves within and around leiomyomas stain strongly with acetylcholinesterase, suggesting a role for acetylcholine in leiomyoma innervation. In murine studies, nerve fibers visualized in the arrector pili muscle are immunoreactive to the neuropeptide calcitonin-gene related peptide (CGRP) The pain is hypothesized to be related to pressure on the nerves within the lesions, release of neuropeptides, or muscle contraction mediated via alpha-adrenergic receptors. The current treatments for the paroxysmal pain associated with cutaneous leiomyomas are inadequate. Acetylcholinesterase staining is seen in and around leiomyomas, and CGRP immunoreactivity is present in nerve fibers of arrector pili muscles. Based on the reported effects of BTX-A on acetylcholine and CGRP, we have been studying subjects with symptomatic cutaneous leiomyomas in a pilot study with intralesional administration of BTX-A. The second protocol in which I am principal investigator is the study of imatinib mesylate for the treatment of chronic GVHD (08-C-0148). Imatinib mesylate is a tyrosine kinase inhibitor that was specifically developed to target inhibition of tyrosine phosphorylation of proteins involved in BCR-ABL signal transduction. It additionally has a high degree of specificity and biological activity against both platelet-derived growth factor (PDGF) and transforming growth factor- (TGF-) signaling pathways, cytokines strongly implicated in the fibrogenesis process. Patients in this trial are recruited nationwide and treated and evaluated in the cGVHD Multidisciplinary Program at the National Cancer Institute/National Institutes of Health. In evaluating an exceedingly complex disease with a diverse patient population, cGVHD clinical trials suffer from poor standardization of entry and response-assessment criteria. This has resulted in difficulties in clinical trial data interpretation. Diagnosis and response assessment are based on the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease criteria and is focused on well-defined cGVHD organ manifestations with clearly defined entry, concurrent treatment, and evaluation criteria. To date all patients have met the primary outcome (6 month) endpoint of the trial and will are currently collecting the laboratory and other research study data in preparion of a final manuscript.