Faculty Bibliography

Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8(+)NKG2D(+) T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing CD8(+)NKG2D(+) effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8(+)NKG2D(+) T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.

BACKGROUND:Basal cell carcinoma (BCC) is the most common skin cancer. Surgical excision remains the standard of treatment, but several alternative treatment modalities exist. OBJECTIVES/OBJECTIVE:This review aims to provide a current analysis of evidence for the treatment of BCC; specifically, which treatments have the lowest recurrence rates and the best cosmetic outcomes. METHODS:We searched PubMed (January 1946 to August 2013), Ovid MEDLINE (2003-August 2013), the Cochrane Central Register of Controlled Trials (January 1993 to August 2013), and the Cochrane Database of Systematic Reviews (The Cochrane Library Issue 9, 2013) databases for randomized controlled trials, systematic reviews, or comparative studies for the treatment of BCC. RESULTS:We found 615 potential articles. Two independent reviewers selected 40 studies: 29 randomized controlled trials (RCTs), seven systematic reviews, and four nonrandomized prospective trials. Treatment modalities reviewed include surgical therapy, radiotherapy and cryotherapy, photodynamic therapy (PDT), topical imiquimod, topical 5-fluorouracil (5-FU), topical solasodine glycoalkaloids, topical ingenol mebutate, intralesional 5-FU, intralesional interferon (IFN), and oral hedgehog pathway inhibitors. CONCLUSIONS:The available data suggest that surgical methods remain the gold standard in BCC treatment, with Mohs micrographic surgery typically utilized for high-risk lesions. Suitable alternate treatment options for appropriately selected primary low-risk lesions may include PDT, cryotherapy, topical imiquimod, and 5-FU. Radiotherapy is a suitable alternate for surgical methods for treatment in older patient populations. Electrodesiccation and curettage (ED&C) is a commonly used primary treatment option for low-risk lesions; however, there were no RCTs examining ED&C that met our inclusion criteria. New hedgehog pathway inhibitors are promising for the management of advanced BCC; however, side effects are a concern for some patients, and much remains to be learned regarding optimal treatment length, risk of recurrence, and potential development of resistance. There is insufficient evidence at present to make recommendations on topical solasodine glycoalkaloids, topical ingenol mebutate, and intralesional 5-FU and IFN-α. Overall continued research on the efficacy of treatment modalities is needed. In particular, studies should include histologic ascertainment of clearance, long-term follow-up, stratification based on tumor subtype, and comparison with surgical outcomes.

IMPORTANCE/OBJECTIVE:Keratocystic odontogenic tumors (KCOTs) of the jaw affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog signaling pathway. OBSERVATIONS/METHODS:We examined the effect of vismodegib (an oral Hedgehog pathway inhibitor) on KCOT size in patients with BCNS enrolled in a clinical trial testing vismodegib for basal cell carcinoma prevention (NCT00957229), using pretreatment and posttreatment magnetic resonance imaging. Four men and 2 women had pretreatment KCOTs (mean longest diameter, 2.0 cm; range, 0.7-3.3 cm), occurring primarily in the mandible. Patients were treated with vismodegib, 150 mg/d, for a mean (SD) of 18.0 (4.8) months (range, 11-24 months). Four patients experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all patients by 1.0 cm (95% CI, 0.03-1.94; P = .02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Vismodegib shrinks some KCOTs in patients with BCNS and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.

Sporadic human basal cell carcinomas (BCC) are generally well managed with current surgical modalities. However, in the subset of high-risk patients predisposed to developing large numbers of BCCs, there is an unmet need for effective, low-morbidity chemoprevention. This population includes fair-skinned patients with extensive sun exposure and those with genodermatoses such as the basal cell nevus (Gorlin) syndrome (BCNS). Tazarotene (Tazorac, Allergan) is a topical retinoid with relative specificity for RAR-β and RAR-γ receptors. We previously demonstrated tazarotene's robust anti-BCC efficacy in Ptch1(+/-) mice, a murine equivalent of BCNS, and others have found it to have some efficacy against sporadic human BCCs. We report here results of a randomized, double-blind, vehicle-controlled study in patients with BCNS evaluating the efficacy of topically applied tazarotene for BCC chemoprevention (N = 34 subjects), along with an open-label trial evaluating tazarotene's efficacy for chemotherapy of BCC lesions (N = 36 subjects) for a maximum follow-up period of 3 years. We found that only 6% of patients had a chemopreventive response and that only 6% of treated BCC target lesions were clinically cured. Our studies provide no evidence for either chemopreventive or chemotherapeutic effect of tazarotene against BCCs in patients with BCNS.

In the United States, alopecia areata (AA) is the most prevalent autoimmune disease, affecting approximately 5.3 million people, including males and females of all ages and across all ethnic groups. AA affects more individuals than most other autoimmune diseases combined, and yet despite its prevalence, there is little information on the underlying pathogenesis and there are currently no evidence-based treatments available to treat or cure this disease. Genetics has provided a valuable tool for gaining insight into disease pathology. We recently completed the first genome-wide association study (GWAS) in AA and successfully identified at least eight regions in the genome with evidence for association to AA. Importantly, this work identifies a discrete set of genes, some of which have been well studied within the context of other autoimmune diseases and already have targeted therapies available or in development. The insight that we have gained through our GWAS sets the stage for the rational development of novel effective therapeutic approaches and heralds in an exciting new era with the commencement of translational research in AA based on genetic findings.

BACKGROUND:Mohs micrographic surgery (MMS) has a low rate of surgical site infection (SSI) without the use of prophylactic antibiotics. In the studies to date, there has been variation in the steps taken by each surgeon to prevent SSIs but in all cases sterile technique was used during wound reconstruction. OBJECTIVE:We sought to evaluate the rate of SSIs among patients undergoing MMS with the use of clean surgical technique for all steps of MMS including wound reconstruction in the absence of prophylactic antibiotics. METHODS:We prospectively evaluated 1000 patients undergoing MMS using clean surgical technique for SSIs. Clean surgical technique includes the use of clean surgical gloves and towels and a single pack of sterile instruments for all steps including wound reconstruction. RESULTS:There were 11 SSIs among 1000 patients with 1204 tumors, with an overall rate of infection of 0.91% (95% confidence interval 0.38%-1.45%). Three of the 11 infections were complications of hematomas. Four of the 11 infections occurred in flap closures, which had the highest rate of SSIs of 2.67% (4/150). LIMITATIONS/CONCLUSIONS:The study was a prospective, single-institution uncontrolled study. CONCLUSION/CONCLUSIONS:To our knowledge, this is the first study to examine the rate of SSIs with the use of clean surgical technique, in the absence of antibiotic prophylaxis, for all steps of MMS including wound reconstruction. Our rate of SSIs of 0.91% is exceedingly low, underscoring the overall safety of MMS and its performance in the outpatient setting without the use of antibiotic prophylaxis or sterile technique.

Nephrogenic fibrosing dermopathy or scleromyxedema-like illness of renal disease is a recently reported disorder. It manifests as scleromyxedema-like skin lesions without associated paraproteinemia, occurring in the setting of renal disease. In the majority of cases skin lesions of nephrogenic fibrosing dermopathy develop after hemodialysis or renal transplantation; however, the origin is still unknown. We report 4 new cases of nephrogenic fibrosing dermopathy and review the literature. The clinical and histopathologic features, differential diagnosis, possible etiology, and treatment options are reviewed.