No abstract

BackgroundHereditary breast and ovary cancer syndrome affects both genders but little is known about the uptake of genetic services by men. The objective of this study is to characterise the male population counselled through a multidisciplinary breast/ovarian program.MethodsDescriptive analysis of male patients counselled from January 2000 to December 2015. Data in this analysis include new cancer diagnoses during prospective follow up.ResultsFrom 4,320 families registered, 362 male patients were identified: 236 (65.2%) from hereditary cancer families (HCF) and 126 (34.8%) from non-HCF. In HCF, 121 patients (51.3%) were mutation carriers (MC): BRCA2 – 102 (84.3%), BRCA1 – 16 (13.2%), CHEK2 – 1 (0.8%) and TP53 – 2 (1.7%). Non-HCF included 126 patients: 85 (67.5%) belonged to families without pathogenic mutations or with variants of unknown clinical significance; 22 (17.5%) refused testing after counselling and 19 (15.0%) did not meet criteria for testing. Both HCF and non-HCF included patients with previous cancer diagnoses: HCF- Breast Cancer (BC) - 18; prostate cancer (PC) - 13; melanoma - 1; others - 7) and non-HCF (BC - 77; PC - 20; gastric cancer (GC) - 1; melanoma - 8; bladder cancer - 1; others - 22). From the 121 MC identified (including the TP53 and CHEK2 carriers), 97 patients (80.2%) adhered to prospective surveillance. With a median follow-up of 36.9 months, 17 cancers were diagnosed in 14 patients, PC being the most frequently diagnosed neoplasia (5 cases). Eleven patients (78.6%) are alive and three patients died of advanced cancer (2 with GC, 1 with disseminated adenocarcinoma).ConclusionWe observed a high adherence to counselling, genetic testing and active surveillance by men belonging to hereditary BC families. Male carriers of pathogenic DNA variants are at risk for several cancers and should be included in prospective follow-up studies.

Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

BACKGROUNDMost available studies on the efficacy of topical photodynamic therapy focus on short-to medium-term results. Long-term data are scarce.OBJECTIVETo evaluate the long-term efficacy of photodynamic therapy with topical methylaminolevulinate to treat Bowen's disease and basal cell carcinoma in the clinical practice setting of a dermato-oncology department.METHODSThe study included patients diagnosed with Bowen's disease or basal cell carcinoma, and who received photodynamic therapy from 2004 to 2008. Treatment protocol and clinical follow-up were standardized. The primary endpoint was clinically observed recurrence in a previous photodynamic therapy-treated area. Descriptive and survival analyses were performed.RESULTSA total of 31 Bowen's disease lesions and 44 superficial basal cell carcinoma were treated, with a median follow-up of 43.5 months. Recurrence was observed in 14 Bowen's disease lesions (53.8%) and in 11 superficial basal cell carcinoma (33.3%). Significantly higher estimates for recurrence rates were found in patients with Bowen's disease (p=0.0036) or those aged under 58 years (p=0.039). The risk of recurrence was higher in patients with Bowen's disease than in those with superficial basal cell carcinoma and younger patients.CONCLUSIONSRecurrence should be considered when choosing to treat non-melanoma skin cancer with photodynamic therapy. Younger age and Bowen's disease were independent predictors for long-term recurrence, suggesting the need to establish an extended period of follow-up for this subset of patients.

RESUMO -O conhecimento do processo de evolução tumoral é essencial para compreender os alvos terapêuticos no controle da doença. A forma como o sistema imune influência o desenvolvimento e a progressão do cancro é uma questão desafiante na área da imunologia. Atualmente reconhece-se o papel paradoxal do sistema imunológico neste processo: por um lado protege contra o crescimento tumoral, destruindo células exprimindo antigénios tumorais "aberrantes", por outro pode favorecer a sua progressão, selecionando células tumorais que escapam à vigilância imunológica e são capazes de sobreviver num hospedeiro imunocompetente. Esta observação deu origem ao conceito de "cancer immunoediting", que explica a influência do sistema imune na progressão tumoral. Tendo em conta algumas observações associadas ao melanoma, como por exemplo, o desenvolvimento de vitiligo, a possibilidade de regressão e a correlação com a imunossupressão, este tem sido considerado um exemplo de tumor imunogénico, cujo mecanismo patofisiológico reconhecido até à data se enquadra no conceito de "immunoediting". Reconhecida a importância de CTLA-4 (antigénio linfócitário T citotóxico) e PD-1 (proteína de morte celular programada) como "checkpoints" imunológicos na regulação da atividade das células T em resposta à progressão tumoral, estas moléculas têm sido considerados alvos terapêuticos importantes no tratamento do melanoma avançado. O presente artigo pretende rever sucintamente o processo de evolução tumoral e respetiva interação com o sistema imune, bem como o mecanismo de ação dos "checkpoints" inibitórios por forma a melhor compreender os novos alvos da imunoterapia no melanoma avançado, que serão revistos em trabalho futuro. PALAVRAS-CHAVE -

Epidermolysis Bullosa (EB) is a rare group of diseases caused by genetic variants in skin structural proteins. EB is characterized by varying degrees of skin fragility, blisters and impaired wound healing, and is classified based on the ultrastructural levels of skin cleavage-simplex, junctional, dystrophic, and Kindler Syndrome. Squamous cell carcinoma (SCC) is the most severe complication and most common cause of death of patients with EB, particularly in those with recessive dystrophic Epidermolysis Bullosa (RDEB). To date, the first line of treatment of SCC in patients with RDEB is surgery, despite the high risk of recurrence. Radiotherapy and systemic therapy have been avoided due to its skin toxicity. Recently, electrochemotherapy (ECT) has been proposed as a potential treatment. We report eight sessions of ECT using bleomycin for treatment of SCC in five patients with EB. After 8 weeks all patients showed an objective response. Four patients (seven ECT sessions) had a complete response. The treatment was well tolerated, with mild adverse effects, such as local pain, erythema, and ulceration. Our results demonstrate that ECT is a potential treatment for SCC in patients with RDEB.

O diagnóstico dos sarcomas cutâneos é desafiante, devido à complexidade e heterogeneidade deste gru- po de lesões, cuja apresentação nos tecidos superficiais (pele e tecido celular subcutâneo) impõe diagnóstico diferen- cial obrigatório com tumores benignos e processos inflamatórios. Apesar de serem tumores pouco frequentes alguns tipos assumem grande importância por serem localmente invasivos, com elevada morbi-mortalidade associada, taxas de recidiva local e metastização significativas. Os autores apresentam cinco casos clínico-patológicos de sarcomas cutâneos – sarcoma de Kaposi, dermatofibros- sarcoma protuberans, fibroxantoma atípico, leiomiossarcoma e angiossarcoma – e fazem uma breve revisão da literatura sobre os tipos de sarcoma cutâneo com maior interesse na Dermatologia, salientando os aspectos fisiopa- tológicos, clínicos, histopatológicos e terapêuticos particulares.PALAVRAS-CHAVE – Neoplasias da pele; Sarcoma, Sarcoma de Kaposi; Dermatofibrossarcoma protuberans; Fibro- xantoma atípico, Leiomiossarcoma; Angiossarcoma; Lipossarcoma, Neoplasia da bainha do nervo periférico.

Langerhans cell histiocytosis (LCH) is a multisystemic disorder that results from the clonal proliferation of immunophenotypically and functionally immature Langerhans cells (LC). The detection of the V600E mutation in the BRAF oncogene in LCH biopsy specimens supports previous evidence that LCH is a neoplastic disorder. This mutation is present in other cutaneous lesions including malignant melanoma and benign nevi. Single case reports of a correlation between LCH and the appearance of eruptive nevi limited to the inguinal folds after chemotherapy have previously been described in the literature. This suggested that LCH could be an additional cause of eruptive melanocytic nevi, with a specific distribution mimicking that of LCH cutaneous lesions. We present the case of a 6-year-old boy, previously treated with chemotherapy for Langerhans cell histiocytosis, with disseminated junctional nevi. Although this co-occurrence may be coincidental, the skin involvement is distinct from other previously reported clinical cases. It would be interesting to evaluate whether the BRAF mutation described in LCH cells might in fact support a genetic background for the development of nevi in these patients. LEARNING POINTS Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of immature Langerhans cells, with the V600E mutation in the BRAF oncogene present in approximately 60% of cases. The V600E mutation in the BRAF oncogene is also documented in other cutaneous lesions, namely malignant melanoma and benign nevi. There are case reports of a correlation between LCH and the appearance of eruptive nevi after chemotherapy, but it is not known whether the BRAF mutation described in LCH cells supports a genetic background for the development of nevi in these patients.