Dermatology Consultation Service

皮肤科咨询服务

• 批准号: 8554180
• 负责人: Edward Cowen
• 金额: $ 92.42万
• 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/8554180
• 关键词: Academy; Acetylcholine; Acetylcholinesterase; Adverse effects; Adverse reactions; Allogenic; American; Angiogenesis Inhibitors; Area; Award; Back; Behcet Syndrome; Benign; Biological; Biological Response Modifier Therapy; Birt-Hogg-Dube Syndrome; Bronchiolitis Obliterans; Budgets; Calcitonin Gene-Related Peptide; Caliber; Cataloging; Catalogs; Catecholamines; Chronic Granulomatous Disease; Clinic; Clinical; Clinical Research; Clinical Research Protocols; Clinical Trials; Collaborations; Communities; Complex; Congresses; Consensus Development; Consult; Consultations; Country; Cutaneous; Cutaneous Leiomyoma; Data; Dermatofibrosarcoma; Dermatologic; Dermatology; Diagnosis; Diffuse; Disease; Dose; Enrollment; Epidermal Growth Factor Receptor; Erlotinib; Etiology; Evaluation; Female; Fever; Folliculitis; Fumarate Hydratase; Genes; Goals; Hamartoma; Hereditary Leiomyomatosis and Renal Cell Cancer; Hereditary Malignant Neoplasm; Ice; Imatinib mesylate; Immune; Immunologic Deficiency Syndromes; Individual; Inflammatory; Inherited; Institutes; Interdisciplinary Study; Interleukin-1; Interleukin-12; Job' s Syndrome; Laboratories; Left; Leiomyoma; Lesion; Lymphoma; Malignant Neoplasms; Manuscripts; Mediating; Medicine; Modality; Mus; Muscle; Muscle Contraction; Mutation; National Cancer Institute; National Human Genome Research Institute; National Institute of Allergy and Infectious Disease; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Neurological Disorders and Stroke; Natural History; Nerve; Nerve Fibers; Neural Conduction; Neuropeptides; Neurotransmitters; Nurse Practitioners; Organ; PAPA syndrome; Pain; Pain Nature; Palmar-plantar erythrodysesthesia syndrome; Pathway interactions; Patients; Pennsylvania; Phase; Pilot Projects; Platelet-Derived Growth Factor; Positioning Attribute; Principal Investigator; Process; Proteins; Protocols documentation; Publishing; Reaction; Recruitment Activity; Renal Cell Carcinoma; Reporting; Research Personnel; Research Support; Rest; Rheumatology; Risk; Role; Services; Signal Pathway; Signal Transduction; Sirolimus; Skin; Societies; Specificity; Staining method; Stains; Standardization; Stimulus; Structure; Study Subject; Suicide; Surface; Symptoms; Syndrome; Systemic disease; Temperature; Testing; Text; Therapeutic; Therapy Clinical Trials; Toxin; Transforming Growth Factors; Transplantation; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; United States National Institutes of Health; Uterine Fibroids; Variant; Wiskott-Aldrich Syndrome; adenosine deaminase deficiency; alpha-adrenergic receptor; anakinra; autonomic nerve; base; bcr-abl Fusion Proteins; bevacizumab; chronic graft versus host disease; congenital immunodeficiency; cytokine; experience; fibrogenesis; graft vs host disease; hair erector muscle; immunoreactivity; interest; lectures; leukemia/lymphoma; marenostrin; meetings; montelukast; multidisciplinary; nerve supply; patient population; pressure; primary outcome; programs; receptor; research study; response; skin lesion; tumor

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.

咨询服务人员包括我，约翰·迪吉奥瓦纳博士，以及去年加入分部的执业护士奥兰达·海瑟薇。第三位临床医生Emily Chu博士于2011年6月离职，由于预算限制，她的职位尚未得到填补。如上所述，在皮肤疾病的评估和管理方面提供临床专业知识是NIH社区高度重视的服务，并在2007年获得了NIH主任奖的认可。除了会诊患者外，我还是其他分支发起的其他几个方案的副研究员，以及两个方案的首席研究员（将单独讨论）。目前我是副研究员的非皮肤病学分支方案包括GVHD的自然史；恶性淋巴瘤/白血病的低强度移植；免疫消耗疗法和非亲属供体低强度移植；异体移植治疗DOCK8免疫缺陷波马度胺治疗慢性GVHD；孟鲁司特II期治疗闭塞性细支气管炎；西罗莫司治疗考登病；厄洛替尼和贝伐单抗治疗肾细胞癌；自身炎性疾病的自然史；阿那金用于治疗白塞氏病；利洛那接受治疗IL-1拮抗剂缺乏。慢性移植物抗宿主病（GVHD）合作是一项主要的多学科合作，由几位NCI和非NCI研究人员研究GVHD的自然史。基于我在这个小组的经验，我已经发表了几篇关于皮肤GVHD的文本章节和临床手稿，并荣幸地在全国各地的各种团体（哈佛大学，塔夫茨大学，宾夕法尼亚大学，美国皮肤病学会，区域皮肤病学会和世界皮肤病大会）演讲。通过繁忙的咨询服务，协作临床研究非常活跃。在几种周期性发热综合征患者中新发现的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可用性，将一组新的患者引入了临床。我们目前正在系统地描述PAPA综合征、Behcets和IL-1受体拮抗剂（DIRA）缺乏患者的皮肤表现，并评估对治疗的反应。我是两个方案的主要研究者：肉毒杆菌毒素治疗疼痛性平滑肌瘤（09-C-0072）和甲酸伊马替尼（08-C-0148）治疗硬化性慢性GVHD。皮肤平滑肌瘤是一种良性肿瘤，被认为起源于直毛肌。它们可表现为孤立的丘疹，也可表现为身体各部位的成组病变，包括背部和伸肌表面。单个病变的大小通常在5毫米到1厘米之间，但也可以大到直径几厘米。皮肤平滑肌瘤主要与遗传性癌症相关的遗传性皮肤病、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）子宫平滑肌瘤的形成以及肾细胞癌的风险增加。HLRCC患者可能表现为孤立的皮肤病变、局部受累或弥漫性平滑肌瘤形成。偶发的和与hlrc相关的皮肤平滑肌瘤通常都是疼痛的。在某些情况下，严重的阵发性疼痛可能由压力或环境温度变化等无害的刺激引起。皮肤平滑肌瘤的冷致疼痛可以在标准化的环境下通过冰块的应用重现对于有症状的皮肤平滑肌瘤患者，疼痛可能严重到足以使患者考虑自杀。疼痛症状的病因尚不清楚，但疼痛的发作性、强烈性和一些患者对神经活性药物的反应表明，操纵神经传导通路可能改善疼痛。额直肌受自主神经控制。因此，人们可以预期，由这种结构产生的肿瘤也会受到利用儿茶酚胺神经递质的自主神经的支配。免疫组织化学研究显示平滑肌瘤内部和周围的神经纤维增加。平滑肌瘤内部和周围的神经被乙酰胆碱酯酶强烈染色，提示乙酰胆碱在平滑肌瘤神经支配中的作用。在小鼠研究中，在立毛肌中可见的神经纤维对神经肽降钙素基因相关肽（CGRP）有免疫反应。假设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。目前治疗与皮肤平滑肌瘤相关的阵发性疼痛是不充分的。平滑肌瘤内及周围可见乙酰胆碱酯酶染色，竖毛肌神经纤维中可见CGRP免疫反应性。基于已报道的BTX-A对乙酰胆碱和CGRP的影响，我们对有症状的皮肤平滑肌瘤患者进行了一项局部内给药BTX-A的初步研究。我担任首席研究员的第二个方案是甲氨替尼治疗慢性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，专门用于抑制参与BCR-ABL信号转导的蛋白质的酪氨酸磷酸化。此外，它还对血小板衍生生长因子（PDGF）和转化生长因子- (TGF-)信号通路具有高度的特异性和生物活性，这些信号通路是与纤维形成过程密切相关的细胞因子。该试验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。在评估具有多样化患者群体的极其复杂的疾病时，cGVHD临床试验的进入标准和反应评估标准缺乏标准化。这导致了临床试验数据解释的困难。诊断和反应评估基于美国国立卫生研究院慢性移植物抗宿主病临床试验标准共识发展项目，重点关注明确定义的cGVHD器官表现，明确定义的进入、同步治疗和评估标准。到目前为止，所有患者都达到了试验的主要终点（6个月），目前正在收集实验室和其他研究数据，准备最终稿件。