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Background: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma., Objectives: To characterize these tumours in terms of clinical behaviour and genetic characteristics., Methods: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden., Results: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%)., Conclusions: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]., Objectives: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib., Methods: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting., Results: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged., Conclusions: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide., Objectives: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society., Methods: The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS., Results: In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors., Conclusions: ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes., (© 2017 British Association of Dermatologists.)

Background: The status of the sentinel lymph node (SLN) is an important parameter to predict the prognosis of melanoma patients but it is a matter of debate if removal of micrometastases by SLN biopsy (SLNB) influences the prognosis of melanoma patients., Objectives: We sought to investigate the impact of SLNB in melanoma patients with regard to recurrence-free survival, overall survival and metastatic pathways., Patients and Methods: We studied, retrospectively, 673 melanoma patients with a primary melanoma (tumour thickness > or = 1 mm) and without clinical evidence of metastases at the time of melanoma diagnosis. In 377 patients the melanoma was removed without SLNB between January 1995 and March 2000 (pre-SLNB group). In 296 patients the melanoma was removed with SLNB between April 2000 and March 2003 (SLNB group). Otherwise, both groups received identical surgical treatment of the primary melanoma and initial staging procedures performed by the same team of physicians. Follow-up recommendations were also identical in both groups., Results: Both groups showed no significant differences with regard to characteristics of the primary melanoma, sex and age. By Kaplan-Meier analyses, melanoma-related overall survival was comparable in both groups. However, recurrence-free survival was increased in pre-SLNB patients due to significantly fewer regional lymph node metastases, whereas frequencies of locoregional cutaneous and distant metastases were comparable in both groups., Conclusions: SLNB advances the detection of regional lymph node metastases and therefore avoids nodal recurrences but does not influence metastatic behaviour of melanoma cells and does not protect patients from melanoma-related death caused by distant metastases. Thus, our retrospective data favour the marker hypothesis for melanoma metastasation. To elucidate further if subgroups of patients benefit from SLNB, prospective randomized studies with long-term follow-up are needed.

Background: Noninfectious granulomatous skin diseases are inflammatory disorders of unknown aetiology which are often recalcitrant to common anti-inflammatory treatment regimens. Recently, in several case reports, fumaric acid esters (FAE) have proved beneficial in granulomatous skin diseases, but studies on a larger collection of consecutive patients have not yet been performed., Objectives: To investigate the therapeutic efficacy of FAE for the treatment of granulomatous skin diseases., Patients and Methods: The therapeutic efficacy and side-effects of FAE were analysed retrospectively in 32 patients with disseminated granuloma annulare (n = 13), annular elastolytic giant cell granuloma (n = 3), sarcoidosis (n = 11), necrobiosis lipoidica (n = 4), or granulomatous cheilitis (n = 1)., Results: Three patients discontinued treatment within 4 weeks because of side-effects. Of the remaining 29 patients, 18 patients responded to treatment with FAE. Marked improvement or complete clearance was seen in seven patients. We observed a slight to moderate improvement in 11 patients, and 11 patients did not respond. In patients showing a complete remission, the maximum effect was observed after 8.5 months (SD +/-6 months, range 3-20 months). In two patients with systemic sarcoidosis, the pulmonary changes improved in parallel with the skin. Side-effects were usually mild and resolved spontaneously upon dose reduction or discontinuation of the therapy., Conclusions: The data presented here indicate that FAE may be considered for the treatment of recalcitrant granulomatous skin disease.

Background: After surgical removal, anal canal condyloma (ACC) has a higher risk of recurrence compared with extragenital warts., Objectives: To reduce local recurrences of ACC using follow-up treatment with imiquimod-containing suppositories (anal tampons)., Methods: After ablation of ACC, 10 male patients received treatment with imiquimod suppositories three times weekly for 3-4 months., Results: Treatment with imiquimod anal tampons was well tolerated. Early initial recurrences in some patients cleared after treatment with the imiquimod suppositories. Within a mean follow-up of 9 months no patient demonstrated recurrence of ACC., Conclusions: These data suggest that imiquimod anal tampons may represent a new therapeutic option to prevent recurrences of ACC following ablative surgery.

Imiquimod (Aldara, 3M) is an immune response modifier used for the treatment of anogenital warts. We report a 55-year-old non-immunocompromised woman with extensive, human papillomavirus (HPV) 16-positive anogenital Bowen's disease. After 5 months of local treatment with imiquimod, the lesions completely regressed clinically and histologically, and HPV 16 DNA was no longer detectable. Moreover, DNA image cytometry revealed DNA aneuploidy (an indicator of prospective malignancy) in pretreatment samples but not in post-treatment samples. Therefore, imiquimod might be a treatment option for Bowen's disease, particularly in patients where other treatment modalities such as surgery are contraindicated.