Structural and molecular characteristics of weight-bearing volar skin can be reconstituted by micro skin tissue column grafting.

For patients with lower limb amputations, prostheses are immensely helpful for mobility and the ability to perform job-related or recreational activities. However, the skin covering the amputation stump is typically transposed from adjacent areas of the leg and lacks the weight-bearing capacity that is only found in the specialized skin covering the palms and soles (a.k.a. volar skin). As a result, the skin tissue in direct contact with the prosthesis frequently breaks down, leading to the development of painful sores and other complications that limit, and often preclude, the use of prostheses. Transplanting volar skin onto amputation stumps could be a solution to these problems, but traditional skin transplantation techniques cause substantial morbidity at the donor site, such as pain and scarring, which are especially problematic for volar skin given the critical functional importance of the volar skin areas. We previously developed the technology to collect and engraft full-thickness skin tissue while avoiding long-term donor site morbidity, by harvesting the skin in the form of small (~0.5 mm diameter) cores that we termed "micro skin tissue columns" (MSTCs), so that each donor wound is small enough to heal quickly and without clinically appreciable scarring or other long-term abnormalities. The goal of this study was to establish whether a similar approach could be used to confer the structural and molecular characteristics of volar skin ectopically to other skin areas. In a human-to-mouse xenograft model, we show the long-term persistence of various human plantar MSTC-derived cell types in the murine recipient. Then in an autologous porcine model, we harvested MSTCs from the bottom of the foot and transplanted them onto excision wounds on the animals' trunks. The healing processes at both the donor and graft sites were monitored over 8 weeks, and tissue samples were taken to verify volar-specific characteristics by histology and immunohistochemistry. The volar donor sites were well-tolerated, healed rapidly, and showed no signs of scarring or any other long-term defects. The graft sites were able to maintain volar-specific histologic features and expression of characteristics protein markers, up to the 8-week duration of this study. These results suggest that MSTC grafting could be a practical approach to obtain autologous donor volar skin tissue, confer volar skin characteristics ectopically to nonvolar skin areas, improve the load-bearing capacity of amputation stump skin, and ultimately enhance mobility and quality-of-life for lower limb amputees.

Diffuse vesiculobullous eruption with systemic findings.

Drug induced linear IgA bullous dermatosis (LABD) is a rare blistering disease that has been shown to be associated with the use of various medications. Although rarely seen together, some of the medications associated with LABD can lead to the syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which presents with fever, cutaneous eruption, and multi-organ involvement. We present a patient who developed fever and a generalized vesiculobullous eruption after recently starting amlodipine and meloxicam. Initial laboratory tests demonstrated elevated liver function tests, leukocystosis, and eosinophilia. Histopathologic examination of the punch biopsy revealed a bulla with sub-epidermal split and numerous neutrophils. Direct immunofluorescence demonstrated broad deposition of IgA along the dermal-epidermal junction. These findings were consistent with an overlap between LABD and DRESS. Drug induced LABD and DRESS are independently both rare diseases. It is even more uncommon to see the two concurrently in the same patient. In this patient, these two conditions were thought to be triggered by either amlodipine or meloxicam. Given the high mortality rate associated with DRESS, it is important to recognize the presentation and initiate the appropriate treatment plan as soon as possible.

Angioimmunoblastic t-cell lymphoma presenting as purpura fulminans.

Purpura fulminans is a nonspecific hematologic emergency with high initial mortality, representing a thrombotic occlusion of blood vessels leading to skin necrosis and disseminated intravascular coagulation, and often reported in the setting of sepsis. We report a case of nonfatal purpura fulminans in the context of angioimmunoblastic T-cell lymphoma (AITL).

Survey of medical student preference for simulation models for basic dermatologic surgery skills: simulation platforms in medical education.

BACKGROUND: The authors investigated the use of simulator platforms in fourth-year medical student education. OBJECTIVE: To evaluate which simulation platform students preferred for learning dermatologic procedures and to assess the effectiveness of the exercise in terms of the change in confidence that the students had performing dermatologic procedures. MATERIALS AND METHODS: After medical students were instructed on how to perform a punch biopsy and then assisted in executing the task, they were surveyed to determine their preferred simulation platform and simulator properties. Students were surveyed at the beginning and completion of the teaching block. RESULTS: One hundred fifty-seven students completed the skills laboratory, and 78 completed the preference questionnaire. Of the 11 surveyed categories, students preferred the pig foot in eight categories. Seventy students responded to a surgical skills questionnaire that assessed their overall confidence in planning and executing the procedure before and after the skills laboratory. The students had a statistically significant increase in confidence in dermatologic procedural skills as a result of the activity. CONCLUSION: Preference data show that the pig foot model is preferred for teaching dermatologic surgical skills. These results re-affirm that the pig foot model is an effective, low-cost solution for training.

Alteration of skin properties with autologous dermal fibroblasts.

Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue. They are primarily responsible for synthesizing collagen and glycosaminoglycans; components of extracellular matrix supporting the structural integrity of the skin. Dermal fibroblasts play a pivotal role in cutaneous wound healing and skin repair. Preclinical studies suggest wider applications of dermal fibroblasts ranging from skin based indications to non-skin tissue regeneration in tendon repair. One clinical application for autologous dermal fibroblasts has been approved by the Food and Drug Administration (FDA) while others are in preclinical development or various stages of regulatory approval. In this context, we outline the role of fibroblasts in wound healing and discuss recent advances and the current development pipeline for cellular therapies using autologous dermal fibroblasts. The microanatomic and phenotypic differences of fibroblasts occupying particular locations within the skin are reviewed, emphasizing the therapeutic relevance of attributes exhibited by subpopulations of fibroblasts. Special focus is provided to fibroblast characteristics that define regional differences in skin, including the thick and hairless skin of the palms and soles as compared to hair-bearing skin. This regional specificity and functional identity of fibroblasts provides another platform for developing regional skin applications such as the induction of hair follicles in bald scalp or alteration of the phenotype of stump skin in amputees to better support their prosthetic devices.

Plantar Skin Exhibits Altered Physiology, Constitutive Activation of Wound-Associated Phenotypes, and Inherently Delayed Healing.

Wound research has typically been performed without regard for where the wounds are located on the body, despite well-known heterogeneities in physical and biological properties between different skin areas. The skin covering the palms and soles is highly specialized, and plantar ulcers are one of the most challenging and costly wound types to manage. Using primarily the porcine model, we show that plantar skin is molecularly and functionally more distinct from nonplantar skin than previously recognized, with unique gene and protein expression profiles, broad alterations in cellular functions, constitutive activation of many wound-associated phenotypes, and inherently delayed healing. This unusual physiology is likely to play a significant but underappreciated role in the pathogenesis of plantar ulcers as well as the last 25+ years of futility in therapy development efforts. By revealing this critical yet unrecognized pitfall, we hope to contribute to the development of more effective therapies for these devastating nonhealing wounds.

Skin Malignancy in the Military: A Number Needed to Biopsy Analysis.

INTRODUCTION: Skin malignancy has increased in prevalence over the last 15 years and effective diagnosis is required for adequate treatment. Retrospective data analysis of skin biopsy data has shown correlation between various independent variables, but no studies have been shown to directly assess skin malignancy risks for military personnel. Assessing correlation could lead to more effective, targeted screening programs that could lead to decreased mortality from skin malignancies. We present a 1-year analysis of the number needed to biopsy (NNB) to detect skin cancer and analysis of military-specific risk factors in a military dermatology training program. The present study aims to (1) compare skin biopsy yields to civilian institutions and patient populations and (2) determine significance of exposure variables including age, gender, military beneficiary status, branch of service, and military rank. MATERIALS AND METHODS: We performed a retrospective observational study over 1 year by identifying all skin biopsies performed in the Walter Reed National Military Medical Center dermatology clinic from August 2015 to July 2016. Utilizing the pathology reports, we manually excluded biopsies performed for the purpose of ruling out inflammatory/immunologic conditions or cosmeses and focused only on encounters performed to rule out basal cell carcinoma, squamous cell carcinoma, or melanoma. We decided to exclude malignant diagnoses that were exceedingly rare or could mimic inflammatory conditions, such as cutaneous T-cell lymphoma. For uncertain diagnoses with vague context per pathology report, previous office clinic notes and pre-biopsy differential were referenced and included only if melanoma or non-melanoma skin cancer (NMSC) diagnosis was the intended indication. RESULTS: A total of 3,098 biopsies were included in the study, diagnostic for 1,084 total skin malignancy and 54 melanoma diagnoses. Melanoma comprised 4.98% of all skin malignancy diagnosed. The NNB for all skin malignancy was 2.86 (95% CI 2.76-2.96) and NNB for melanoma and NMSC was 20.93 (95% CI 19.70-22.15) and 1.91 (95% CI 1.83-2.00), respectively. Patient age, gender, and military rank significantly impacted NNB values (P < .001). CONCLUSIONS: The proportion of melanoma skin cancers is notably increased in our population compared to published population statistics with comparable total biopsy yields. Skin biopsy for purpose of screening for malignancy should be performed in the military population and consideration should be made for gender, age, and rank. Our findings can further expand on military risk factors for skin cancer and aid in further multivariant modeling.

Epidermolysis Bullosa Acquisita: A Case Report.

BACKGROUND Epidermolysis bullosa acquisita is a rare, subepithelial bullous disorder, which is distinguished from other autoimmune blistering diseases by the production of antibodies against type VII collagen. CASE REPORT Here, we describe the case of a 79-year-old male resident of the Northern Mariana Islands who presented to the clinic with multiple blistering skin lesions. CONCLUSIONS The primary focus of treatment is to prevent disease progression and serious complications of scarring (including blindness and respiratory obstruction) by avoiding physical trauma and suppressing the immune systems with agents, including corticosteroids, colchicine, dapsone, methotrexate, and cyclophosphamide. Successful treatment of the condition should involve a multidisciplinary team of medical professionals with regular monthly follow-ups during periods of active disease.

Anti-PD1 immune checkpoint inhibitor-induced bullous pemphigoid in metastatic melanoma and non-small cell lung cancer.

Anti-programmed cell death 1 (PD1) targeted immune checkpoint inhibitors such as nivolumab and pembrolizumab are increasingly used to treat advanced malignancies such as melanoma, non-small cell lung cancer, urothelial cancer, and renal cell carcinoma. A rare but increasingly reported adverse effect of anti-PD1 therapy is bullous pemphigoid (BP), an autoimmune blistering disease directed against BP antigen 1 and BP antigen 2 in the basement membrane of the epidermis. We present 3 cases of BP secondary to anti-PD1 immunotherapy in patients with melanoma and non-small cell lung cancer to highlight the diagnosis and treatment of this condition and emphasize the importance of the dermatologist in the care of patients with immunotherapy-related skin disease.

Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.

The dermatologist's role in amputee skin care.

Amputees face many challenges associated with residual limbs. Overall, amputees have an increased risk for skin disease occurring at residual limb sites. Although prosthetists and primary care physicians often accomplish routine care, the dermatologist plays a very important role within the multidisciplinary team. Many military dermatologists have unique clinical experience treating amputees, as a portion of their practice consists of providing care to soldiers with traumatic amputations from complex and dramatic blast injuries. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology is promising.

Heparin-induced bullous hemorrhagic dermatosis confined to the oral mucosa.

Unfractionated heparin (UFH) is frequently used in the treatment of venous thromboembolism and acute coronary syndrome. There are many common cutaneous adverse reactions to this medication. We present a unique case of hemorrhagic bullae limited to the oral mucosa that developed within 6 hours of a patient receiving UFH.

Bullous systemic lupus erythematosus successfully treated with rituximab.

Bullous systemic lupus erythematosus (BSLE) is a rare complication of systemic lupus erythematosus (SLE) characterized by cutaneous vesicles and bullae with a primarily neutrophilic infiltrate on histopathology. Bullous SLE is a heterogeneous disease without pathognomonic clinical features, making the diagnosis and differentiation from other blistering diseases challenging. We present the case of a single patient with SLE in whom 3 different clinical appearances of BSLE manifested over 5 years. The cutaneous eruption dramatically improved with rituximab at the initial presentation and continued to respond to rituximab during subsequent flares over the subsequent 5 years.

The Burden of Skin Disease on Deployed Servicemembers.

INTRODUCTION: Skin diseases have had a significant impact on the health of deployed military service members throughout history. Given the high prevalence historically of cutaneous disease among United States deployed servicemembers, we review the burden of skin disease on the modern military by analyzing the most common dermatologic diagnoses made in deployed settings from 2008 to 2015. Furthermore, we compare the most common dermatologic diagnoses made in the deployed setting with those made by dermatologists and nondermatologists in the civilian healthcare system to highlight the differences between the civilian and deployed military practice environment. METHODS: This study queried the Theater Medical Data Store for International Classification of Diseases, Ninth Revision (ICD-9) codes to determine the total number of dermatologic encounters as part of all medical encounters from 2008 to 2015 in a deployed setting. These data were provided by the Armed Forces Health Surveillance Branch. For all statistical tests, analyses were conducted using R statistical software, with type I error controlled at 5%. RESULTS: From 2008 to 2015, 92 dermatology-specific ICD-9 codes accounted for 429,837 dermatologic diagnoses that were made in a deployed setting, equating to 10% of all diagnoses. The top 20 dermatologic diagnoses were identified, and the percentage of total medical diagnoses (TMD) was calculated. Once the individual diagnoses were categorized, a direct comparison was made between the top 20 most prevalent disease categories among deployed military servicemembers and those of the United States (US) population as a whole, based on claims. The most prevalent diagnoses were compared amongst four different settings: Deployed military, military teledermatology, civilian dermatologists, and civilian nondermatologists. Overall comparison of the prevalence between each of these groups showed an association between setting and diagnosis prevalence. CONCLUSIONS: The total burden of disease based on diagnostic codes from 2008 to 2015 is 429,837 diagnoses. This accounts for 10% of TMD from 2008 to 2015 in the deployed setting. Diagnoses most prevalent in the deployed military setting had more in common with those made by civilian nondermatologists compared with military teledermatology and civilian dermatologists. At 10% of diagnoses made in the deployed military setting in this timeframe, skin disease accounts for a substantial burden on deployed servicemembers. Deployed servicemembers with skin disease should be supported through use of teledermatology resources and improved dermatology education for primary care and deployed medical personnel.

Amantadine-induced livedo reticularis in a child treated off label for neurobehavioral disorders.

We report the case of an 8-year-old boy who was taking amantadine off label for multiple childhood neurobehavioral disorders and subsequently developed livedo reticularis. Although this side effect is well-described in adult patients taking amantadine for Parkinson disease, it is now being seen in children as the off-label use of amantadine is expanded to this population.

Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies.

Paraneoplastic pemphigus (PNP) has been described as an antibody-mediated mucocutaneous disease occurring almost exclusively in patients with lymphocytic neoplasms. We describe 4 patients with the clinical features of the lichenoid variant of PNP in the absence of detectable autoantibodies. On the basis of these findings, we conclude that the spectrum of PNP likely includes patients with disease predominantly or exclusively mediated by cytotoxic T cells rather than autoantibodies. The pathophysiology and range of PNP disease are likely more complex than was initially believed.