M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors.

BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.

Descriptive study of naevus involution in a series of 74 patients with atypical naevus syndrome under SIAscopy digital follow-up.

BACKGROUND: Characterization of nevi involution could help to understand the biological behaviour of melanocytic neoplasms. OBJECTIVE: To describe the frequency and morphology of naevus involution in a series of patients with atypical naevus syndrome under digital follow-up with a SIAscopy program and, in a small sample of fading nevi, to analyse histopathological features and immunohistochemical biomarkers. METHODS: Seventy-four patients registered from April 2007 to July 2014 in the SIAscopy system of the Department of Dermatology of Hospital Arnau de Vilanova of Lleida, Spain, were reviewed. Fourteen naevus cases with fading features were prospectively excised during follow-up. Eleven already excised naevus controls were randomly selected from our archive. RESULTS: We observed that 81% of patients showed, at least, one involutive naevus and 25% of recorded nevi presented this phenomenon; the mean time of involution was 46.7 months. The predominant structural pattern was reticular (>70%), and the most frequently observed regression structures were vascular (33.8%). Histopathological significant higher intensity of inflammatory infiltrate in controls and higher presence of laminar and compact fibrosis and increase of vessels in cases were demonstrated. Regarding immunohistochemical biomarkers, only higher expression of cytoplasmic activated caspase 3 in controls was significant. CONCLUSIONS: Naevus involution is a common phenomenon in patients with dysplastic naevus syndrome. It is usually a slow process, more frequent in naevus with reticular pattern. SIAscopy regression structures are uncommon, with the exception of vascular ones. Histologically, fading involutive pattern is characterized by scarce inflammatory infiltrate and melanophages, delicate fibrosis and increase of vessels.

Unilateral milia-type intradermal tophi associated with underlying urate subcutaneous deposition: an uncommon cutaneous presentation of gout.

Tophi develop during the most advanced clinical stage of gout, and are usually located on or around the joints. However, unusual skin features caused by intradermal and/or subcutaneous deposition of tophaceous material at locations other than articular regions have been reported. We present the case of a patient with a condition that has been recently termed 'miliarial gout'. which is only the second such case, to our knowledge. A 51-year-old woman, who had a chronic joint disease that had been diagnosed and treated as psoriatic arthritis, presented with multiple asymptomatic, yellowish-white, firm papules (1-3 mm in size) on erythematous areas on the outside of her left leg. On histological examination of a skin biopsy, uric acid crystals were seen in the dermis and subcutis. The patient also had a raised level of serum urate, consistent with a diagnosis of gout. Treatment with allopurinol led to rapid improvement. Intake of corticosteroids and diuretics was a possible triggering factor for the development of cutaneous tophi in this patient.

[Scarring alopecia]. / Alopecias cicatriciales.

Scarring alopecia refers to a group of disorders of various etiologies that cause permanent hair loss. In this article, we focus on primary cicatricial alopecia, a group of diseases in which the hair follicle is the main target of the inflammatory process. These disorders are currently classified as lymphocytic, neutrophilic, or mixed according to the cells that make up the inflammatory infiltrate. The pathogenesis of the majority of these conditions is not fully understood and they may have similar clinical features, often making it necessary to perform 1 or more skin biopsies in order to reach a diagnosis. Management depends on early and accurate diagnosis and aggressive treatment in some cases in order to prevent follicular destruction and scarring.

Abdominal tumors in patients with neurofibromatosis type I: Genotype-phenotype relationships.

BACKGROUND: Gastrointestinal stromal tumors have been detected in 25% of the necropsies performed on NF1 patients, but have been reported only in 7% of NF1 patients in the largest series. Such data imply an important gap between the true presence of tumors and those diagnosed. Few genotype-phenotype relationships have been described but to date none referring to abdominal tumors. OBJECTIVES: Evaluate retrospectively the efficacy of a regular and proactive follow-up of NF1 patients to early diagnose abdominal tumors and report their mutations. METHODS: Cohort study performed between 2010 and 2020, with 43 NF1 adult patients followed at our Dermatology department. RESULTS: Eight abdominal tumors were diagnosed in six patients, meaning that 14% of the followed patients developed an abdominal tumor. Five patients (83%) were asymptomatic. Five (83.3%) had a family history of NF1 with abdominal tumors (patients 1,2 and 3,4,5 were relatives). CONCLUSIONS: Although currently gastrointestinal routine screening investigations for asymptomatic patients are not recommended in the guidelines, the family aggregation in our series suggests it should be considered a close follow-up of the relatives of a patient with an NF1-related abdominal tumor. Also, for the first time, two mutations [c.2041C > T (p.Arg681Ter) and c.4537C > T (p.Arg1513*)] have been associated with family aggregation of abdominal tumors in NF1 patients.

[Portfolios: a tool for the training and assessment of residents in dermatology, part 1]. / El portafolio como herramienta de formación y evaluación de los residentes de Dermatología (I).

The medical resident's portfolio is a collection of materials that show reflective learning in the context of clinical practice. A portfolio contains documents (such as case histories and questionnaires the resident has used), images, and video recordings that reveal that an individual has acquired the competencies needed for professional practice. A portfolio is an assessment tool that simultaneously supports learning and gives evidence for certifying competence. It encourages independent continuing professional development that is incremental and centered on answering questions about what one has learned, how it might be applied, what still needs to be learned, and what must be done to reach one's goal. Answering such questions provides evidence of competencies that have been acquired and what is still lacking, allowing the trainee to develop a plan for personal improvement and evaluate subsequent achievements. The first step in creating a portfolio is to list required skills and abilities, along with the actions that will allow the resident to acquire them during each year of residency training. The ultimate goal is to define the resident's professional competence. We describe a model on which to base a training and assessment portfolio for residents in dermatology.

[Portfolios: a tool for the training and assessment of residents in dermatology, part 2]. / El portafolio como herramienta de formación y evaluación de los residentes de dermatología (II).

A portfolio is a collection of material documenting reflection about practice. It contains documents (eg, case histories and questionnaires the resident has used), images, and video recordings that reveal that an individual has acquired the competencies needed for professional practice. This assessment tool simultaneously supports learning and provides evidence for certifying competence. The adoption of portfolio use by a dermatology department requires the support of both the training supervisor and the chief of department. The learning objectives defined by the National Board for Medical-Surgical Dermatology and Venereology must be taken into consideration so that ways to assess each objective can be included; this approach supports holistic ongoing education as well as the certification of competencies the resident finally achieves. Use of portfolios in medical residency training can improve on current assessment methods, which we believe lack precision. We propose that portfolios gradually begin to replace the resident's training log. We are currently developing an online software application that will facilitate the use of portfolios.

Population-based incidence of basal cell carcinoma in a Spanish Mediterranean area.

BACKGROUND: Considering the latitude of Spain, the reported age-adjusted incidence rates of basal cell carcinoma (BCC) in this country, similar to those of Northern Europe, are lower than expected. OBJECTIVES: To estimate the actual incidence of BCC in a Mediterranean population from the eastern coast of Spain. METHODS: A registry of BCC cases newly diagnosed between 16 January 2006 and 16 January 2007 was established for the population of residents in the Barcelonès Nord county (369,622 inhabitants). All dermatologists of this area agreed to register their patients. All tumours were registered as 'definite' or 'probable' BCC cases according the existence or not of a proven microscopic diagnosis. If a patient had more than one tumour at different sites, each was counted and registered separately. Sex-specific, age-specific and age-standardized incidence rates were calculated by direct standardization to the World and European Standard Population. RESULTS: Among the 936 cases registered, 81.2% were classified as 'definite' BCC and 18.8% as 'probable' BCC. The overall crude incidence rate was 253.2 per 100,000 person-years, and was 128 per 100,000 person-years and 195.5 per 100,000 person-years after standardizing for the World and European population, respectively. After the age of 65 years, the BCC age-adjusted incidence rates showed a significantly higher increase in men than in women (P = 0.01). CONCLUSIONS: The incidence rates found in our study are higher than those previously reported in Spain. Age-adjusted incidence rates revealed that BCC increases with age in both sexes, this increase being particularly evident in men older than 65 years.

[Normal cutaneous flora and secondary bacterial infection]. / Flora cutánea normal e infección bacteriana secundaria.

Normal skin microflora consists of those micro-organisms which are usually present on the skin, without causing infection. The infant's skin colonization starts during birth and after the first months of life the skin microbiota is composed of the same micro-organisms as in the adult. The skin microflora is composed of bacteria, mostly gram-positives Staphylococcus species, yeasts which the most prevalent is Malassezia, viruses and arthropods like Demodex folliculorum. In the last years, the development of molecular microbiology and specially techniques like amplification and comparison of 16S rRNA, have demonstrated that cutaneous microbiota is composed of a higher diversity of bacteria than the traditionally observed in culture methods. We also review the main secondary bacterial skin infections.

[Use of www.dermatoweb.net to support undergraduate teaching of dermatology]. / www.dermatoweb.net. Una web docente para el aprendizaje de la Dermatología en el pregrado.

Dermatoweb is a website to aid undergraduate dermatology training. It includes the dermatology program of the Lerida Faculty of Medicine, and is based principally on clinical presentations, tables with the differential diagnosis of the 20 most common reasons for dermatologic consultation, about 200 clinical test cases to stimulate self-training, and a subject list with the 32 topics that make up the dermatology syllabus in many faculties of medicine. Thanks to this website, some of our students achieve high marks in dermatology despite hardly coming to classes. In addition, therapeutic guidelines for the common dermatoses can be found on the site, and an atlas with more than 5,300 photographs and almost 100 videos on the more common dermatological procedures; these can serve as a visual aid for family doctors, residents in dermatology in the initial years, and practicing dermatologists.

[Childhood dermatosis in a dermatology clinic of a general university hospital in Spain]. / Dermatosis infantiles en la consulta de Dermatología de un hospital general universitario en España.

BACKGROUND AND OBJECTIVES: Pediatric dermatology is a relatively new subspecialty for which few epidemiological studies are available. We aimed to determine the work load associated with this subspecialty and the most common presenting complaints among pediatric patients in the general dermatology clinic of our hospital. METHODS: A descriptive study was performed based on hospital records to analyze patients aged 16 years or under seen in our department in 2005 and their diagnoses. RESULTS: Pediatric dermatology accounts for 12.1 % of the work load in our department (1,329/10,998 patients were

Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines.

BACKGROUND: Cutaneous malignant melanoma is an aggressive type of skin cancer which causes disproportionate mortality in young and middle-aged adults. Once disseminated, melanoma can be considered an incurable disease, highly resistant to standard antineoplastic treatment, such as chemotherapy or radiation therapy. The proteasome represents a novel target for cancer therapy that can potentially be used in melanoma. OBJECTIVES: To assess the effect of four structurally different proteasome inhibitors on human cutaneous melanoma-derived cell lines. METHODS: Sixteen human cutaneous melanoma-derived cell lines which are original were obtained from patients who were treated by two of the authors. Cells were cultured, exposed to proteasome inhibitors (bortezomib, ALLN, MG-132 and epoxomicin) and then assayed for cell cycle and cell death analyses. RESULTS: Proteasome inhibitors inhibited the in vitro growth of melanoma cells, and this effect was due to a reduction in cell proliferation rate and an induction of both caspase-dependent and caspase-independent cell death. Moreover, release of apoptosis-inducing factor was observed in the presence of the broad-specificity caspase inhibitor BAF (Boc-D-fmk). In addition, the four different proteasome inhibitors induced caspase 2 processing. CONCLUSIONS: This study provides information regarding the in vitro effects of proteasome inhibitors on melanoma cell lines, and the molecular mechanisms involved. It also gives support to the future use of such inhibitors in the treatment of patients with melanoma, either administered alone or in combination with other drugs.