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Severe cutaneous adverse reactions (SCARs) [Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic syndrome (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed eruption (GBFE)] are severe drug reactions that often require hospitalization and could be fatal. BRAF and MEK inhibitors (BRAF/MEKi) are a standard of care in patients with BRAF-mutated metastatic melanomas. These agents are administered until disease progression or unacceptable toxicity occurs. This review has focus on BRAF/MEKi-induced SCARs. A systematic search of the following terms: 'vemurafenib', 'cobimetinib', 'dabrafenib', 'trametinib', 'encorafenib', 'binimetinib', 'Acute Generalized Exanthematous Pustulosis', 'Stevens Johnson syndrome', 'Toxic Epidermal Necrolysis', 'Generalized Bullous Fixed Eruption' 'Drug Hypersensitivity Syndrome', and 'DRESS' in simple combination (every drug with each disease) and all in combination, was performed on MEDLINE, EMBASE, Web of Knowledge and The Cochrane Library repositories, with no restriction on language, for original studies. One hundred sixty-eight original articles were found, 26 (retrospective series, case reports and conference abstracts) were selected, and 21 were included in the qualitative synthesis. A total of 31 SCAR cases (23 DRESS and 8 SJS/TEN - 1 SJS and 7 TEN -) were identified. Vemurafenib was the culprit drug in all but one case, which was dabrafenib-induced. Mean time to SCAR onset from drug intake was 15.5 and 11.4 days, for SJS/TEN and DRESS, respectively. For the DRESS cases, hepatic involvement occurred in 96% and renal alterations in 87% of patients. Overall, BRAF/MEKi-induced SCARs are rare. Among them, vemurafenib is the drug that requires more close monitoring for SCARs. Prior immunotherapy can favour SCARs. Vemurafenib DRESS is likely to occur within the first fifteen days of treatment accompanied by hepatic and renal involvement. Following vemurafenib-induced SCAR resolution, switching to dabrafenib seems to be a safe alternative for these patients' treatment.

Apremilast is a phosphodiesterase-4 inhibitor taken orally. Little information about its use in routine clinical practice is available. We aimed to assess treatment safety and persistence rates in patients on apremilast for different forms of plaque psoriasis. This observational retrospective study included 30 patients with psoriasis who were treated with apremilast between January 2016 and December 2017 in our hospital. Twelve patients had palmar-plantar psoriasis, 8 had plaque psoriasis mainly on the scalp, and 10 had plaque psoriasis in other locations. The probable period of treatment persistence in patients in the 50th percentile was 18.5 months according to survival analysis of the series overall. Our experience suggests that apremilast is effective and safe for treating palmar-plantar psoriasis and plaques at other locations but not for treating scalp psoriasis. Adverse effects that compromise treatment occur in nearly two-thirds of the patients.

Resumen El apremilast es un inhibidor via oral de la fosfodiesterasa-4 con pocos datos de practica clinica habitual. Nuestro objetivo fue evaluar la persistencia y la seguridad del apremilast en la practica clinica en distintas formas clinicas de psoriasis. Se realizo un estudio observacional retrospectivo de los 30 pacientes con psoriasis que recibieron el farmaco entre enero de 2016 y diciembre de 2017 en nuestro centro, 10 con psoriasis en placas, 8 con placas predominantemente en el cuero cabelludo y 12 palmo-plantares. El tiempo global de probabilidad de supervivencia del 50% fue de 18,5 meses. En nuestra experiencia, el apremilast es un farmaco efectivo y seguro para la psoriasis en placas y palmo-plantar, no asi para la afectacion del cuero cabelludo. Los efectos secundarios ocurren en casi dos tercios de los pacientes comprometiendo la persistencia del tratamiento.

Resumen Introduccion y objetivos La telomerasa es una enzima implicada en el mantenimiento de los telomeros y la senescencia celular. Numerosos estudios han demostrado que en mas del 90% de las neoplasias malignas se detecta actividad telomerasica. El objetivo del presente estudio es analizar la expresion de telomerasa por inmunohistoquimica en una serie de neoplasias melanociticas. Material y metodos Estudio observacional retrospectivo realizado en una serie de 85 melanomas primarios, 12 metastasicos y 22 nevus melanociticos. La expresion de telomerasa se analizo empleando el anticuerpo monoclonal hTERT (Rockland). El analisis de los datos se realizo con el programa SPSS. Resultados En todas las neoplasias melanociticas analizadas se demostro expresion de telomerasa. En el caso de los melanomas predomino el patron de expresion heterogeneo, y la expresion moderada o intensa. En los nevus resulto mas frecuente una expresion homogenea con intensidad leve. El patron de expresion heterogeneo se asocio a los melanomas de rapido crecimiento (p = 0,028), con Breslow > 4 mm (p = 0,004), con mitosis (p = 0,032), y con mutaciones en el gen TERT (p = 0,002). En el caso de los nevus, la intensidad fue menor en los nevus intradermicos, seguidos de los compuestos y de los diplasicos (p = 0,054). Conclusiones La expresion de telomerasa esta presente en la totalidad de las neoplasias melanociticas, con mayor expresion en los melanomas que en los nevus. En el caso de los melanomas, la expresion de forma heterogenea se asocia a un fenotipo de mayor agresividad.

Background Some studies have suggested a relationship between type 2 diabetes mellitus (T2DM) and increased incidence of melanoma. Efforts are under way to identify preventable and treatable factors associated with greater melanoma aggressiveness, but no studies to date have examined the relationship between T2DM and the aggressiveness of cutaneous melanoma at diagnosis. Objectives To explore potential associations between T2DM, glycaemic control and metformin treatment and the aggressiveness of cutaneous melanoma. Methods We conducted a cross-sectional multicentric study in 443 patients diagnosed with cutaneous melanoma. At diagnosis, all patients completed a standardized protocol, and a fasting blood sample was extracted to analyse their glucose levels, glycated haemoglobin concentration and markers of systemic inflammation. Melanoma characteristics and aggressiveness factors [Breslow thickness, ulceration, tumour mitotic rate (TMR), sentinel lymph node (SLN) involvement and tumour stage] were also recorded. Results The mean (SD) age of the patients was 55 center dot 98 (15 center dot 3) years and 50 center dot 6% were male. The median Breslow thickness was 0 center dot 85 mm. In total, 48 (10 center dot 8%) patients were diagnosed with T2DM and this finding was associated with a Breslow thickness > 2 mm [odds ratio (OR) 2 center dot 6, 95% confidence interval (CI) 1 center dot 4-4 center dot 9; P = 0 center dot 004)] and > 4 mm (OR 3 center dot 6, 95% CI 1 center dot 7-7 center dot 9; P = 0 center dot 001), TMR > 5 per mm(2) (OR 4 center dot 5, 95% CI 1 center dot 4-13 center dot 7; P = 0 center dot 009), SLN involvement (OR 2 center dot 3, 95% CI 1-5 center dot 7; P = 0 center dot 038) and tumour stages III-IV (vs. I-II) (OR 3 center dot 4, 95% CI 1 center dot 6-7 center dot 4; P = 0 center dot 002), after adjusting for age, sex, obesity, alcohol intake and smoking habits. No significant associations emerged between glycated haemoglobin levels, metformin treatment and melanoma aggressiveness. Conclusions T2DM, rather than glycaemic control and metformin treatment, is associated with increased cutaneous melanoma aggressiveness at diagnosis.

Resumen Introduccion La enfermedad de injerto contra huesped cronica (EICHc) es la causa mas importante de mortalidad tardia no relacionada con la recidiva del trasplante alogenico de celulas progenitoras hematopoyeticas. La EICHc esclerodermiforme suele ser refractaria a los corticosteroides y supone todo un reto terapeutico. Se han descrito anticuerpos activadores contra el RFCDP en pacientes con EICHc esclerodermiforme. Estos anticuerpos inducen la fosforilacion del RFCDP, produciendo fibrosis. Hay cada vez mas evidencias de la efectividad de imatinib, un inhibidor de la tirosina cinasa, en el tratamiento de la EICHc esclerodermiforme. Objetivo Evaluar la respuesta de la EICHc esclerodermiforme al imatinib. Materiales y metodos Estudio retrospectivo de 18 pacientes con EICHc cutanea esclerodermiforme refractaria a inmunosupresores tratada con imatinib en un unico centro. La evaluacion de la respuesta al tratamiento se realizo mediante valoracion clinica del dermatologo y percepcion subjetiva del paciente tras uno, 3, 6, 9, 12 y 18 meses de iniciar el tratamiento con imatinib. La respuesta fue valorada como completa, parcial, significativa, sin cambios o progresion. El descenso de la dosis de esteroides se catalogo como completo, parcial o no posible. Resultados En nuestra serie, 4 (22%) pacientes lograron una respuesta completa, 9 (50%) alcanzaron una respuesta parcial, 2 (11%) tuvieron un grado significativo de respuesta, 2 (11%) no presentaron ningun cambio y uno (6%) experimento avance de la enfermedad en el ultimo seguimiento que se llevo a cabo. El tiempo medio transcurrido desde el inicio del imatinib hasta mostrar algun grado de respuesta fue de 2,75 meses (rango 1-9 meses). Conclusiones Este estudio apoya la evidencia de la utilidad del imatinib en el tratamiento de la EICHc esclerodermiforme.

Introduction and objectives Cutaneous chronic graft-vs-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. Phototherapy is a therapeutic option for patients with skin involvement and for those who require high doses of corticosteroids. We analyze the cases treated in our department and review the literature. Material and methods All patients with GVHD treated with phototherapy in the dermatology department of Hospital Universitario y Politecnico la Fe in Valencia, Spain between March 2011 and October 2014 were identified. Data were gathered retrospectively. Results There were 16 patients: 10 treated with psoralen–UV-A and 6 with narrowband–UV-B. Complete response was achieved in 9 patients and partial response in 7; 2 patients with partial responses relapsed after treatment. Ten patients were able to decrease their dose of corticosteroids during treatment, and a further 3 decreased the number of other immunosuppressant drugs. No serious adverse effects occurred. Conclusions Phototherapy is a good therapeutic option for patients with chronic GVHD with extensive cutaneous involvement, as well as for those who fail to respond to topical treatment or who have become steroid-dependent. The main benefits are that, as the treatment targets the skin, it reduces corticosteroid requirements and has a good safety profile. Treatment must be individualized and, in our experience, both the initial dose and the maximum dose per session can be lower than for other diseases.

Resumen Introduccion y objetivos La enfermedad injerto contra huesped (EICH) cronica cutanea es una complicacion frecuente tras un trasplante de progenitores hematopoyeticos. La fototerapia es una modalidad terapeutica para pacientes con afectacion cutanea o para aquellos que precisan altas dosis de corticoesteroides (CE). El objetivo de este estudio es revisar los casos tratados en nuestro servicio y hacer una revision de la literatura. Material y metodos Recogida de datos de manera retrospectiva de todos los casos tratados desde marzo de 2011 a octubre de 2014 en el Servicio de Dermatologia del Hospital Universitario y Politecnico la Fe de Valencia. Resultados Recogimos un total de 16 pacientes, 10 tratados con PUVA y 6 con UVB-BE. Nueve pacientes obtuvieron una respuesta completa y 7 una respuesta parcial, aunque 2 recidivaron tras el tratamiento. Diez pacientes pudieron disminuir la dosis de CE durante el tratamiento y 3 pudieron disminuir el numero de otros inmunosupresores. No se presentaron efectos adversos graves. Conclusiones La fototerapia es una buena opcion terapeutica para pacientes con EICH cronica con gran afectacion cutanea, para aquellos que no responden al tratamiento topico o para pacientes corticodependientes. Su mayor beneficio es el de ser un tratamiento dirigido a la piel que permite ahorrar CE y que presenta un buen perfil de seguridad. La pauta de tratamiento se realiza de manera individualizada y, segun nuestra experiencia, con dosis iniciales y dosis maximas por sesion menores que para otras enfermedades.

Resumen El melanoma mucoso es un subtipo infrecuente de melanoma que difiere del melanoma cutaneo en su biologia, clinica y manejo. El diagnostico suele realizarse de forma tardia debido a su localizacion en zonas de dificil acceso a la exploracion fisica y a la falta de signos especificos y tempranos. La cirugia es el tratamiento de eleccion en caso de enfermedad localizada. El papel de la biopsia selectiva de ganglio centinela y de la linfadenectomia permanece todavia incierta. La radioterapia se puede emplear como tratamiento adyuvante con el fin de controlar localmente la enfermedad. Existe un mayor porcentaje de mutaciones en c-KIT que en otros tipos de melanoma, lo que ha llevado a avances significativos en el tratamiento de la enfermedad metastasica con imatinib.

BackgroundPromoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. ObjectivesThis is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival. Materials and methodsDNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method. ResultsIn the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS. ConclusionsAberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice. What's already known about this topic? Epigenetic aberrations have recently been implicated in the development and progression of many human cancers. Regarding melanoma, over 100 genes have been identified to be aberrantly hypermethylated. What does this study add? Aberrant methylation of tumour suppressor gene promoters is associated with aggressive clinicopathological features and poorer melanoma survival. What is the translational message? DNA methylation may represent a potential prognostic biomarker for the management of patients with melanoma in routine practice. Linked Comment:van Doorn. Br J Dermatol 2018; 179:250-251. Respond to this article

Introduction Chronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor. Objective To evaluate the response of cutaneous sclerodermatous cGVHD to imatinib. Materials and methods Retrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians’ assessment and patients’ subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible. Results In our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months). Conclusions This study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD.

Chronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor.To evaluate the response of cutaneous sclerodermatous cGVHD to imatinib.Retrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians' assessment and patients' subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible.In our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months).This study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD.

Background Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) are heterocyclic compounds used as preservatives in cosmetic and industrial products. They continue to be common allergens, causing positive patch test reactions in 2% to 4% of patients tested. Material and methods We searched the database at our skin allergy unit for all cases of sensitization to MCI/MI and MI diagnosed between January 1980 and March 2013. Results Patch tests were performed with MCI/MI in 8705 patients and with MI in 404 patients. In total, 222 patients (2.55%) were sensitized to MCI/MI and 21 (5.19%) were sensitized to MI. The incidence of MCI/MI cases peaked between 1998 and 2005 and again between 2009 and 2013. Of the 222 patients with MCI/MI sensitization, 142 were women (64%) and 49 were men (36%); the mean age was 43 years. The most frequently affected areas were the hands (54% of cases), the arms (36%), and the face (35%); 75.67% of cases were due to cosmetics and 2.25% were due to paint. Of the 21 patients with MI sensitization (mean age, 50 years), 12 were women (57%) and 9 were men (43%). The most common site of involvement in this group was the face (71% of cases), followed by the arms (38%) and the hands (29%). All the cases were due to cosmetics. Conclusions Our data show that sensitization to the combination of MCI and MI and MI alone has increased in recent years. It would appear to be necessary to add MI to the baseline patch test series, although the test concentration has yet to be determined.

Mucosal melanoma is a rare melanoma subtype that differs from the cutaneous form of the tumor in its biology, clinical manifestations, and management. Diagnosis is usually late due to a lack of early or specific signs and the location of lesions in areas that are difficult to access on physical examination. Surgical excision is the treatment of choice for localized disease. The value of sentinel lymph node biopsy and lymphadenectomy is still unclear. Radiotherapy can be used as adjuvant therapy for the control of local disease. c-KIT mutations are more common than in other types of melanoma and this has led to significant advances in the use of imatinib for the treatment of metastatic mucosal melanoma.

Epstein-Barr virus-positive (EBV) diffuse large B-cell lymphoma (DLCBL) of the elderly is a newly described lymphoproliferative disorder that arises in elderly patients without a predisposing immunodeficiency. Clinical features at presentation may include lymphadenopathy, B-symptoms and extranodal involvement. The main sites of extranodal involvement are the skin, lung, tonsil and stomach. Histopathological findings include atypical large lymphoid cells with variable amounts of reactive cells, such as small lymphocytes, plasma cells and histiocytes. The neoplastic cells are positive for CD20, and in situ hybridization for EBV-encoded RNA is positive in the majority of neoplastic cells. We present a new case of EBV-positive DLBCL in an 85-year-old man, who presented to our clinic with a 2-month history of asymptomatic cutaneous lesions involving his face and scalp.

Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) are heterocyclic compounds used as preservatives in cosmetic and industrial products. They continue to be common allergens, causing positive patch test reactions in 2% to 4% of patients tested.We searched the database at our skin allergy unit for all cases of sensitization to MCI/MI and MI diagnosed between January 1980 and March 2013.Patch tests were performed with MCI/MI in 8705 patients and with MI in 404 patients. In total, 222 patients (2.55%) were sensitized to MCI/MI and 21 (5.19%) were sensitized to MI. The incidence of MCI/MI cases peaked between 1998 and 2005 and again between 2009 and 2013. Of the 222 patients with MCI/MI sensitization, 142 were women (64%) and 49 were men (36%); the mean age was 43 years. The most frequently affected areas were the hands (54% of cases), the arms (36%), and the face (35%); 75.67% of cases were due to cosmetics and 2.25% were due to paint. Of the 21 patients with MI sensitization (mean age, 50 years), 12 were women (57%) and 9 were men (43%). The most common site of involvement in this group was the face (71% of cases), followed by the arms (38%) and the hands (29%). All the cases were due to cosmetics.Our data show that sensitization to the combination of MCI and MI and MI alone has increased in recent years. It would appear to be necessary to add MI to the baseline patch test series, although the test concentration has yet to be determined.