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.

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.

Prognostic factors in patients with primary cutaneous anaplastic large cell lymphoma: a multicentric, retrospective analysis of the Spanish Group of Cutaneous Lymphoma.

BACKGROUND: Reliable prognostic factors for patients with primary cutaneous anaplastic large cell lymphoma (PCALCL) are lacking. OBJECTIVE: To identify prognostic factors for specific survival in patients with PCALCL. METHODS: Using the convenience sampling method, patients with PCALCL diagnosed from May 1986 to August 2017 in 16 University Departments were retrospectively reviewed. RESULTS: One hundred eight patients were included (57 males). Median age at diagnosis was 58 years. All of them showed T1-3N0M0 stages. Seventy per cent of the cases presented with a solitary lesion, mostly at the limbs. Complete response rate after first-line treatment was 87%, and no advantage was observed for any of them (surgery, radiotherapy, chemotherapy or other approaches). Nodal and visceral progression rate was 11% and 2%, respectively. 5-year specific survival (SSV) reached 93%; 97% for T1 patients and 84% for T2/T3 patients (P = 0.031). Five-year SSV for patients developing early cutaneous relapse was 64%; for those with late or no relapse, 96% (P = 0.001). Estimated median SSV for patients showing nodal progression was 103 months (95% CI: 51-155 months); for patients without nodal progression, estimated SSV did not reach the median (P < 0.001). Nodal progression was an independent predictive parameter for shorter survival (P = 0.011). CONCLUSION: Multiple cutaneous lesions at presentation, early skin relapse and nodal progression portrait worse prognosis in patients with PCALCL.

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.

First-line treatment in lymphomatoid papulosis: a retrospective multicentre study.

BACKGROUND: Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. AIM: To assess the daily clinical practice approach to LyP and the response to first-line treatments. METHODS: This was a retrospective study enrolling 252 patients with LyP. RESULTS: Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. CONCLUSIONS: Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse.

Immunohistochemical analysis of T-type calcium channels in acquired melanocytic naevi and melanoma.

BACKGROUND: Cutaneous malignant melanoma arises from transformed melanocytes de novo or from congenital or acquired melanocytic naevi. We have recently reported that T-type Ca2+ channels (TT-Cs) are upregulated in human melanoma and play an important role in cell proliferation. OBJECTIVES: To describe for the first time in formalin-fixed paraffin-embedded tissue the immunoexpression of TT-Cs in biopsies of normal skin, acquired melanocytic naevi and melanoma, in order to evaluate their role in melanomagenesis and/or tumour progression, their utility as prognostic markers and their possible use in targeted therapies. METHODS: Tissue samples from normal skin, melanocytic naevi and melanoma were subjected to immunohistochemistry for two TT-Cs (Cav3.1, Cav3.2); markers of proliferation (Ki67), the cell cycle (cyclin D1), hypoxia (Glut1), vascularization (CD31) and autophagy (LC3); BRAF V600E mutation (VE1) and phosphatase and tensin homologue (PTEN). Immunostaining was evaluated by histoscore. In silico analysis was used to assess the prognostic value of TT-C overexpression. RESULTS: TT-C immunoexpression increased gradually from normal skin to common naevi, dysplastic naevi and melanoma samples, but with differences in the distribution of both isoforms. Particularly, Cav3.2 expression was significantly higher in metastatic melanoma than in primary melanoma. Statistical correlation showed a linear interaction between PTEN loss/BRAF V600E/Cav3.1/LC3/ Ki67/cyclin D1/Cav3.2/Glut1. Disease-free survival (DFS) and overall survival correlated inversely with overexpression of Cav3.2. DFS also correlated inversely with overexpression of Cav3.1. CONCLUSIONS: TT-C immunoexpression on melanocytic neoplasms is consistent with our previous in vitro studies and appears to be related to tumour progression. TT-C upregulation can be considered as a prognostic marker using The Cancer Genome Atlas database. The high expression of Cav3.2 in metastatic melanoma encourages the investigation of the use of TT-C blockers in targeted therapies.

Corrigendum to "Calcium Channel Expression and Applicability as Targeted Therapies in Melanoma".

[This corrects the article DOI: 10.1155/2015/587135.].

Core Content for Undergraduate Medical Education in Spain: Recommendations of the Instructors' Group of the Spanish Academy of Dermatology and Venereology (AEDV).

BACKGROUND: Skin problems are among the most frequent reasons for seeking medical attention in primary care. In recent years, as a result of the process of adapting medical curricula to the requirements of the European Higher Education Area, the amount of time students spend learning the concepts of dermatology has been reduced in many universities. MATERIAL AND METHODS: In order to reach a consensus on core content for undergraduate education in dermatology, we sent a survey to the 57 members of the instructors' group of the Spanish Academy of Dermatology and Venereology (AEDV), asking their opinions on what objectives should be set for a dermatology course in Spain. A total of 131 previously selected objectives were listed. We then applied the Delphi method to achieve consensus on which ones the respondents considered important or very important (score≥4 on a Likert scale). RESULTS: Nineteen responses (33%) were received. On the second round of the Delphi process, 68 objectives achieved average scores of at least 4. The respondents emphasized that graduates should understand the structure and functions of the skin and know about bacterial, viral, and fungal skin infections, the most common sexually transmitted diseases (STDs), and the 4 main inflammatory dermatoses. Students should also learn about common complaints, such as itching and bald patches; the management of dermatologic emergencies; purpura and erythema nodosum as signs of internal disease; and the prevention of STDs and skin cancer. During clinical clerkships students should acquire the communication skills they will need to interview patients, write up a patient's medical history, and refer the patient to a specialist. CONCLUSIONS: The AEDV's group of instructors have defined their recommendations on the core content that medical faculties should adopt for the undergraduate subject of dermatology in Spain.

Calcium channel expression and applicability as targeted therapies in melanoma.

The remodeling of Ca(2+) signaling is a common finding in cancer pathophysiology serving the purpose of facilitating proliferation, migration, or survival of cancer cells subjected to stressful conditions. One particular facet of these adaptive changes is the alteration of Ca(2+) fluxes through the plasma membrane, as described in several studies. In this review, we summarize the current knowledge about the expression of different Ca(2+) channels in the plasma membrane of melanoma cells and its impact on oncogenic Ca(2+) signaling. In the last few years, new molecular components of Ca(2+) influx pathways have been identified in melanoma cells. In addition, new links between Ca(2+) homeostasis and specific cell processes important in melanoma tumor progression have been unveiled. Thus, not only do Ca(2+) channels appear to have a potential as prognostic markers, but their pharmacological blockade or gene silencing is hinted as interesting therapeutic approaches.

Evaluating clinical dermatology practice in medical undergraduates.

The acquisition of competences (the set of knowledge, skills and attitudes required to perform a job to a professional level) is considered a fundamental part of medical training. Dermatology competences should include, in addition to effective clinical interviewing and detailed descriptions of skin lesions, appropriate management (diagnosis, differentiation, and treatment) of common skin disorders and tumors. Such competences can only be acquired during hospital clerkships. As a way of certifying these competences, we propose evaluating the different components as follows: knowledge, via clinical examinations or critical incident discussions; communication and certain instrumental skills, via structured workplace observation and scoring using a set of indicators; and attitudes, via joint evaluation by staff familiar with the student.

Registro nacional de melanoma cutáneo. Características del tumor en el momento del diagnóstico: 15 años de experiencia / The Spanish National Cutaneous Melanoma Registry. Tumour characteristics at Diagnosis: 15 Years of Experience

Introducción y objetivos: El registro nacional de melanoma cutáneo (RNMC) se creó en el año 1997 con el objetivo de conocer las características del melanoma en el momento del diagnóstico. Se muestran las características de los tumores en el momento de su diagnóstico inicial. Pacientes y métodos: Registro observacional transversal, con base poblacional. Se incluyeron casos incidentes y prevalentes de melanoma con resultados de la primera biopsia disponibles. Resultados: El RNMC contiene información de 14.039 pacientes. Se analizaron las características del melanoma en los pacientes diagnosticados en el periodo 1997-2011, sumando un total de 13.628 melanomas. El 56,5% de los pacientes eran mujeres y el 43,5% hombres. La edad media fue de 57 años (IC 95%: 56,4 a 57), con mediana de 58 años. La localización más frecuente fue en el tronco (37,1%), seguido de la extremidad inferior (27,3%). El tipo clínico-patológico más observado fue el melanoma de extensión superficial en un 62,6% (n = 7.481), seguido del melanoma nodular en un 16,8% de los casos (n = 2.014). El 86,2% (n = 10.382) tenían enfermedad localizada, el 9,9% metástasis regionales (n = 1.188) y el 3,9% (n = 479) a distancia. Se observó en los hombres, independientemente de la edad de diagnóstico, un mayor espesor del tumor y una mayor proporción de tumores ulcerados, con niveles de lactatodeshidrogenasa elevados y con enfermedad metastásica (p < 0,0001). Conclusiones: Con los resultados observados las campañas preventivas deberían orientarse al colectivo masculino mayor de 50 años, en el que se observan tumores de mayor espesor, y por lo tanto de peor pronóstico (AU)

Background and objectives: The Spanish National Cutaneous Melanoma Registry (Registro Nacional de Melanoma Cutáneo [RNMC]) was created in 1997 to record the characteristics of melanoma at diagnosis. In this article, we describe the characteristics of these tumors at diagnosis. Patients and methods: This was a cross-sectional observational study of prevalent and incident cases of melanoma for which initial biopsy results were available in the population-based RNMC. Results: The RNMC contains information on 14,039 patients. We analyzed the characteristics of 13,628 melanomas diagnosed between 1997 and 2011. In total, 56.5% of the patients studied were women and 43.5% were men. The mean age of the group was 57 years (95% CI , 56.4-57 years) while median age was 58 years. The most common tumor site was the trunk (37.1%), followed by the lower limbs (27.3%). The most frequent clinical-pathologic subtype was superficial spreading melanoma (n = 7481, 62.6%), followed by nodular melanoma (n = 2014, 16.8%). Localized disease was observed in 86.2% of cases (n = 10,382), regional metastasis in 9.9% (n = 1188), and distant metastasis in 3.9% (n = 479). Independently of age at diagnosis, men had thicker tumors, more ulceration, higher lactate dehydrogenase levels, and a higher rate of metastasis than women (P < 0.001). Conclusions: Based on our findings, melanoma prevention campaigns should primarily target men over 50 years old because they tend to develop thicker tumors and therefore have a worse prognosis (AU)

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.

Melanoma characteristics at diagnosis from the Spanish National Cutaneous Melanoma Registry: 15 years of experience.

BACKGROUND AND OBJECTIVES: The Spanish National Cutaneous Melanoma Registry (Registro Nacional de Melanoma Cutáneo [RNMC]) was created in 1997 to record the characteristics of melanoma at diagnosis. In this article, we describe the characteristics of these tumors at diagnosis. PATIENTS AND METHODS: This was a cross-sectional observational study of prevalent and incident cases of melanoma for which initial biopsy results were available in the population-based RNMC. RESULTS: The RNMC contains information on 14,039 patients. We analyzed the characteristics of 13,628 melanomas diagnosed between 1997 and 2011. In total, 56.5% of the patients studied were women and 43.5% were men. The mean age of the group was 57 years (95% CI, 56.4-57 years) while median age was 58 years. The most common tumor site was the trunk (37.1%), followed by the lower limbs (27.3%). The most frequent clinical-pathologic subtype was superficial spreading melanoma (n=7481, 62.6%), followed by nodular melanoma (n=2014, 16.8%). Localized disease was observed in 86.2% of cases (n=10,382), regional metastasis in 9.9% (n=1188), and distant metastasis in 3.9% (n=479). Independently of age at diagnosis, men had thicker tumors, more ulceration, higher lactate dehydrogenase levels, and a higher rate of metastasis than women (P<.001). CONCLUSIONS: Based on our findings, melanoma prevention campaigns should primarily target men over 50 years old because they tend to develop thicker tumors and therefore have a worse prognosis.

New therapeutic targets in melanoma.

Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; c-kit tyrosine kinase activity inhibitors in melanomas carrying c-kit mutations; and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted therapy with these and other drugs in metastatic melanoma and discuss what the future holds for this field.

Functional expression of voltage-gated calcium channels in human melanoma.

The expression of voltage-gated calcium channels (VGCCs) has not been reported previously in melanoma cells in spite of increasing evidence of a role of VGCCs in tumorigenesis and tumour progression. To address this issue we have performed an extensive RT-PCR analysis of VGCC expression in human melanocytes and a range of melanoma cell lines and biopsies. In addition, we have tested the functional expression of these channels using Ca(2+) imaging techniques and examined their relevance for the viability and proliferation of the melanoma cells. Our results show that control melanocytes and melanoma cells express channel isoforms belonging to the Ca(v) 1 and Ca(v) 2 gene families. Importantly, the expression of low voltage-activated Ca(v) 3 (T-type) channels is restricted to melanoma. We have confirmed the function of T-type channels as mediators of constitutive Ca(2+) influx in melanoma cells. Finally, pharmacological and gene silencing approaches demonstrate a role for T-type channels in melanoma viability and proliferation. These results encourage the analysis of T-type VGCCs as targets for therapeutic intervention in melanoma tumorigenesis and/or tumour progression.

[Initial evaluation, diagnosis, staging, treatment, and follow-up of patients with primary cutaneous malignant melanoma. Consensus statement of the Network of Catalan and Balearic Melanoma Centers]. / Valoración inicial, diagnóstico, estadificación, tratamiento y seguimiento de los pacientes con melanoma maligno primario de la piel. Documento de consenso de la "Xarxa de Centres de Melanoma de Catalunya i Balears"

The consensus statement on the management of primary cutaneous melanoma that we present here was based on selection, discussion, review, and comparison of recent literature (including national and international guidelines). The protocols for the diagnosis, treatment, and follow-up used in the hospital centers throughout Catalonia and the Balearic Isles belonging to the Network of Catalan and Balearic Melanoma Centers were also considered. The main objective of this statement was to present the overall management of melanoma patients typically used in our region at the present time. As such, the statement was not designed to be an obligatory protocol for health professionals caring for this group of patients, and neither can it nor should it be used for this purpose. Professionals reading the statement should not therefore consider it binding on their practice, and in no case can this text be used to guarantee or seek responsibility for a given medical opinion. The group of dermatologists who have signed this statement was created 3 years ago with the aim of making our authorities aware of the importance of this complex tumor, which, in comparison with other types of cancer, we believe does not receive sufficient attention in Spain. In addition, the regular meetings of the group have produced interesting proposals for collaboration in various epidemiological, clinical, and basic applied research projects on the subject of malignant melanoma in our society.

[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.