Caroline C. Kim

Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype

Melanoma is the most lethal skin cancer. Most deaths from melanoma result from metastases. Semaphorins have been shown to inhibit neuronal and endothelial cell migration, but the effects of semaphorins on tumor metastasis have not been documented. We found that semaphorin 3F (SEMA3F) was markedly downregulated in highly metastatic human cell lines in vitro and in vivo, which suggested that it may be a metastasis inhibitor. Metastatic human melanoma cells were transfected with SEMA3F and implanted into mice; the resultant tumors did not metastasize. Rather, the primary tumors resembled benign nevi characterized by large areas of apoptosis, diminished vascularity, inhibition of hyperplasia in overlying epidermal cells, and encapsulated tumor borders delineated by thick layers of fibroblasts and collagen matrix. This phenotype is in stark contrast to highly invasive, vascular mock-transfected tumors. In vitro, tumor cells expressing SEMA3F had a diminished capacity to adhere and migrate on fibronectin. Consistent with semaphorin-mediated chemorepulsion of neurons, tumor cells expressing SEMA3F were chemorepulsive for vascular and lymphatic endothelial cells expressing neuropilin-2 (NRP2), a novel mechanism for a tumor angiogenesis inhibitor. The repulsive activity was abrogated by NRP2 RNA interference. Together these results indicate that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells and raise the possibility of SEMA3F having therapeutic potential.

Analysis of Dermatologic Events in Vemurafenib-Treated Patients With Melanoma

BACKGROUND Vemurafenib has been approved for the treatment of patients with advanced BRAF(V600E)-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). METHODS Dermatologic AEs were assessed from three ongoing trials of BRAF(V600E) mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. RESULTS A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%-95% of patients. Rash was the most common AE (64%-75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%-63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%-10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%-26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. CONCLUSIONS Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients.

Cutaneous Granulomatous Eruption and Successful Response to Potent Topical Steroids in Patients Undergoing Targeted BRAF Inhibitor Treatment for Metastatic Melanoma

IMPORTANCE Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported. OBSERVATIONS Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy. CONCLUSIONS AND RELEVANCE We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.

Survival Is Not the Only Valuable End Point in Melanoma Screening

The impact and benefit of screening and early detection of melanoma in the general population is controversial. Discrepancies exist in recommendations across different organizations worldwide. In the US, a broad range of screening and surveillance strategies can be identified. The 2009 US Preventive Services Task Force (USPSTF) report stated that due to the limited evidence linking skin cancer screening to improved health outcomes, screening in the general primary care population could not be recommended (Wolff et al, 2009). This statement was predicated on the lack of evidence from randomized controlled studies addressing the survival benefit of screening for skin cancer based on whole body examination. Herein we will review the current data on alternative, non-survival outcomes and benefits, including: reduction of melanoma thickness at the time of diagnosis, reduced morbidity, enhanced primary and secondary prevention education, increased cost-effectiveness, and improved targeting of the highest-risk populations followed by methods to improve the effectiveness of screening. However, melanoma screening also comes with a price, which is not limited to financial implications. Some of the limitations challenging the effectiveness of screening efforts include potential “over diagnosis”, the difficulty of early identification of rapidly developing melanomas, and the challenge of reaching out to certain high-risk groups, such as older males.

Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: Pigmented Lesion Subcommittee consensus statement.

IMPORTANCE The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence. OBJECTIVES To outline key issues related to the management of CAN/DN: (1) biopsies of CAN and how positive margins arise, (2) whether incompletely excised DN evolve into melanoma, (3) current data on the outcomes of DN with positive histologic margins, (4) consensus recommendations, and (5) a proposal for future studies, including a large-scale study to help guide the management of DN with positive margins. EVIDENCE REVIEW The literature, including recent studies examining management and outcomes of DN with positive margins between 2009 to 2014, was reviewed. FINDINGS A consensus statement by the PLS of the MPWG following review of the literature, group discussions, and a structured Delphi method consensus. CONCLUSIONS AND RELEVANCE This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.

Skin cancer screening: recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Forces 2016 Draft Recommendation Statement on skin cancer screening.

Follicular malignant melanoma: A case report of a metastatic variant and review of the literature

one reported case as well as our two cases did not fulfill the diagnostic criteria of RP and involved only the auricles. This may be related to the short disease course or, alternatively, the chondritis involving only the auricles in these two patients may be a forme fruste of RP. Thus, the term ‘‘RP-like ear disease’’ was used. RP might be a condition associated with PsA. In the cartilage of patients with PsA, both apoptosis and necrosis of chondrocytes has been observed. Patients with active PsA have significantly higher serum levels of cartilage oligomeric matrix protein (COMP), which is both a biomarker of cartilage destruction and an indicator of disease activity in patients with PsA. COMP is a noncollagen protein in the matrix of the articular cartilage and is also detectable in elastic cartilage of the ear. Improvement of PsA and decreased serum concentrations of COMP after short-term treatment with infliximab has been documented. In addition, the pathogenesis of RP may involve TH1 cytokines, including tumor necrosis factor-alfa, and successful treatment of RP with a tumor necrosis factor antagonist has been reported. Our patients were treated with etanercept and significant improvement in chondritis and arthritis was noted. In conclusion, coexistent psoriasis with PsA and RP is rare. However, the therapeutic efficacy of etanercept in such cases was confirmed in our cases. More experience is needed to elucidate whether the chronic, relapsing course of RP can be altered.

What syndrome is this? Laryngo-onycho-cutaneous syndrome.

A 12-year-old Pakistani girl presented with scarring of her skin, eyes, and trachea. Shewas born one of fraternal twins to a 26-year-old G2P1 mother with an uncomplicated birth history. A slow-healing erosion was first noticed on the scalp after traumaat age 1 month, and the patient subsequently developed more erosions on her face and upper extremities. Her toenails would thicken and fall off. At 112 years of age, she developed photophobia and later, sclerocorneal lesions which ultimately led to visual impairment despite steroid eye drops and surgical procedures. The patient had always had noisy breathing and at 6 years of age she was found to have airway stenosis, eventually requiringa tracheostomy.She required repeated laryngoscopies and excision of tissue. The patient ate soft foods because of a growth in her mouth, and had iron deficiency anemia. Family history was significant for a healthy twin brother. A sibling died at 112 years of age from fever and seizures, and a paternal cousin died at 4 years of age from ‘‘epidermolysis bullosa’’ with clinical features that were similar to those of our patient. The patient’s parents denied consanguinity. Physical examination was significant for bilateral symblepheron. She had small erosions on her lower lip and nares and crusting within her nares, as well as multiple hyperpigmented sclerotic plaques on her face (Fig. 1). She had a tracheostomy. Crusted, eroded plaques were noted on her elbows (Fig. 2). A mucosalcovered firm nodule was found on her hard palate (Fig. 3). Some of her fingers and toes had anonychia, while others had thickened nailplates (Fig. 4). Laryngoscopy and tracheoscopy revealed total glottic obstructionwith a lobulated tumorwhich pathologically showed an inflammatory polyp. A skin biopsy specimen taken after rubbing normal skin with a pencil eraser revealed a small separation between the epidermis and dermis. Immunohistochemical studies of skin showed no definite cleavage planes, with normal expression of type VII collagen and laminin 5 along the dermoepidermal junction. Electron microscopy of the skin revealed a normal dermoepidermal junction, basal cells, and anchoringfibrils. The basal laminahad focal loss of basal cell hemidesmosomes. Initial mutational analyses revealed normal plectin. After careful clinical correlation with photographs, the patient was tested and found to be homozygous for the 151insG frameshift mutation.

Degree of clinical concern and dysplasia affect biopsy technique and management of dysplastic nevi with positive biopsy margins: Results from a survey of New England dermatologists

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Anticonvulsant hypersensitivity syndrome associated with Bellamine S, a therapy for menopausal symptoms

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, potentially fatal, idiosyncratic drug reaction characterized by fever, morbilliform rash, lymphadenopathy, hepatitis, and hematologic abnormalities. Aromatic antiepileptic agents, such as phenytoin, carbamazepine, and phenobarbital are the most frequent causes of this syndrome. We report a case of a previously healthy, postmenopausal woman who developed anticonvulsant hypersensitivity syndrome while taking Bellamine S (belladonna alkaloids; ergotamine; phenobarbital) for hot flashes. Although combinations of belladonna, ergotamine, and phenobarbital have been used for medical treatment of menopausal symptoms since the 1960s, this is the first known case report of its association with anticonvulsant hypersensitivity syndrome. Given the current debate about the risks of hormonal replacement therapy, more women are seeking alternative therapies for menopausal symptoms. Dermatologists need to be aware of this potential serious reaction to this phenobarbital-containing therapy for hot flashes.