Dermatology Consultation Service

皮肤科咨询服务

• 批准号: 8938525
• 负责人: Edward Cowen
• 金额: $ 46.8万
• 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/8938525
• 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; Botulinum Toxins; Bronchiolitis Obliterans; 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; 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; Principal Investigator; Process; Proteins; Protocols documentation; Publishing; Pustular psoriasis; 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; 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 disorder; skin lesion; tumor

The Consult Service Staff consists of myself, Dr. John DiGiovanna, and a Nurse Practitioner, Olanda Hathaway, who joined the Branch in 2011. 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 three therapeutic 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 three protocols: Botulinum toxin for painful leiomyomas (09-C-0072), imatinib mesylate (08-C-0148) for the treatment of sclerotic chronic GVHD, and anakinra for neutrophilic pustular skin disease (13-C-0071). 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. Lastly, we are exploring the pathways involved in pustular psoriasis and related conditions through a therapeutic protocol using the anti-IL1 therapy anakinra. In this dose escalation study, 30 patients with diverse pustular skin disease manifestations will be treated, along with extensive biological studies exploring mechanism of disease.

咨询服务人员由我自己，约翰·迪吉瓦纳（John Digiovanna）博士和护士从业者奥兰达·海瑟薇（Olanda Hathaway）组成，他于2011年加入该分支机构。 NIH社区在2007年获得NIH董事奖的认可。除了见到咨询患者外，我还是其他分支机构发起的其他几项协议的副研究员，以及针对三种治疗方案的首席研究员（要分别讨论） ）。当前我是副研究人员的当前非疾病分支方案包括GVHD的自然历史；恶性淋巴瘤/白血病的强度移植降低；免疫缺乏治疗和使用无关供体的强度移植降低； DOCK8免疫缺陷的同种异体移植；慢性GVHD的Pomalidomide；第三阶段的蒙特鲁克斯特（Montelukast）用于细支气管炎； Sirolimus Cowdens疾病；用于肾细胞癌的厄洛替尼和贝伐单抗；自动炎症疾病的自然史；阿纳基纳（Behcet）疾病； Rilonacept缺乏IL-1拮抗剂。慢性移植与宿主疾病（GVHD）的合作努力是与研究GVHD自然历史的几位NCI和非NCI研究人员进行的主要多学科合作。根据我在这个小组的经验，我在皮肤GVHD上发表了几章和临床手稿，并很荣幸向全国各个小组（哈佛，塔夫特，宾夕法尼亚州，美国皮肤病学学院，地区皮肤病学学院）讲授社会和世界皮肤病学大会。）通过繁忙的咨询服务，协作临床研究非常活跃。新发现的多种周期性发烧综合征患者的吡啶基因突变，以及在由此产生的自身炎症性疾病中具有疗效的生物疗法的可用性已将一组新的患者引入了诊所。现在，我们正在系统地表征皮肤表现，并评估IL-1受体拮抗剂（DIRA）患者的爸爸综合征，Behcets和缺乏症患者对治疗的反应。我是关于三种方案的首席研究者：用于疼痛的平滑肌瘤（09-C-0072），伊马替尼甲酸酯（08-C-0148）的肉毒杆菌毒素，用于治疗硬化性慢性GVHD和ANAKINRA，用于中性粒细胞性皮肤病（13-C-C--中性粒细胞皮肤病） 0071）。皮肤肌瘤是良性肿瘤，认为是由到达的pili肌肉引起的。它们可能以孤立的丘疹而发生，也可能是作为人体区域（包括背面和伸肌表面）的分组病变。单个病变的尺寸通常从5mm到1厘米，但直径的大小可能大于几厘米。皮肤平滑肌瘤与癌症相关的金属疾病，遗传性平滑肌瘤病和肾细胞癌（HLRCC）的主要遗传性相关，这是由富马酸氢酶基因突变引起的。 HLRCC的特征是皮肤和（在女性）子宫平滑肌瘤形成以及肾细胞癌的风险增加。 HLRCC患者可能患有分离的皮肤病变，参与区域或弥漫性平滑肌瘤。偶发地发生和与HLRCC相关的皮肤平滑肌瘤通常都很痛苦。在某些情况下，刺激可能会引起严重的阵发性疼痛，例如压力或环境温度变化。皮肤立方体的使用冰立方体可以在标准化的环境中再现感染性平滑肌瘤的疼痛。1对于有症状的皮肤平滑肌瘤患者，疼痛可能足够严重以至于患者考虑自杀。疼痛症状的病因鲜为人知，但是某些患者对神经活性剂的疼痛的情节性，强烈的性质表明，对神经传导途径的操纵可能会减轻疼痛。到达的毛肌处于自主控制之下。因此，人们希望通过使用儿茶酚胺神经递质的自主神经支配这种结构引起的肿瘤。免疫组织化学研究表明，平滑肌瘤内外的神经纤维增加。乙酰胆碱酯酶内部和周围的神经肿瘤内和周围的神经表明乙酰胆碱在平滑肌瘤神经上的作用。在鼠研究中，在到达的pili肌肉中可视化的神经纤维对神经肽降钙素与基因相关肽（CGRP）具有免疫反应性。假设疼痛与病变内神经的压力，神经肽的释放或通过肌肉摄取介导的神经有关α-肾上腺素受体。与皮肤平滑肌瘤有关的阵发性疼痛的当前治疗不足。乙酰胆碱酯酶在平滑肌瘤及其周围可见，并且在到达肌肉的神经纤维中存在CGRP免疫反应性。根据BTX-A对乙酰胆碱和CGRP的报道作用，我们一直在研究具有症状性皮肤平滑肌瘤的受试者，并在BTX-A内给药的试点研究中。我是主要研究者的第二个方案是麦替尼麦甲酸酯治疗慢性GVHD的研究（08-C-0148）。伊马替尼甲酸酯是一种酪氨酸激酶抑制剂，该抑制剂是专门针对靶向抑制涉及BCR-ABL信号转导蛋白的酪氨酸磷酸化的。此外，它具有针对血小板衍生的生长因子（PDGF）和转化生长因子（TGF-）信号传导途径的高度特异性和生物学活性，细胞因子在纤维发生过程中强烈涉及。该试验中的患者在全国范围内招募，并在美国国家癌症研究所/美国国家卫生研究院的CGVHD多学科计划中进行了治疗和评估。在评估患有多样化患者人群的极其复杂的疾病时，CGVHD临床试验的进入和评估标准的标准化不佳。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共识开发项目，该项目针对慢性移植物抗宿主疾病标准的临床试验标准，并集中在定义明确的CGVHD器官表现上，具有明确定义的进入，并发治疗和评估标准。迄今为止，所有患者都符合试验的主要结果（6个月），目前将收集实验室和其他研究数据，以准备最终的手稿。最后，我们通过使用抗IL1治疗Anakinra的治疗方案探索脓疱牛皮癣和相关疾病所涉及的途径。在这项剂量升级研究中，将治疗30例具有多种脓疱性皮肤疾病表现的患者，以及广泛的生物学研究，以探索疾病的机制。