Cáncer de piel: melanoma. Revisión de la literatura / Skin cancer: melanoma. Literature review

Skin cancer is usually classified into melanoma (SCM) and non-melanoma (SCNM), with different cell origins; being the SCM responsible for the highest mortality. In Chile, an incidence (2008) of 434 new cases is estimated, obtaining a standardized rate of 2.2 cases per 100,000 habitants. There are multiple associated risk factors, the main ones being exposure to UV radiation and sunburn. The strategies to prevent this pathology fall on these same factors. The clinical evaluation of the lesions with ABCD mnemonics added to the use of dermoscopy increases the diagnostic sensitivity and specificity; however, the definitive confirmation is through biopsy, which must include the necessary parameters to define prognosis of disease. The definitive treatment is Surgical. There are alternatives such as the use of the sentinel lymph node to define lymph node dissections. Regarding systemic therapies, the use of immunotherapy has shown results that improve survival in these patients.

Indolamina 2, 3-dioxigenase (IDO) em melanoma: regulação frente ao inibidor de BRAF e sua expressão na progressão da doença / Indoleamine 2, 3-dioxygenase (IDO) in melanoma: regulation against BRAF inhibitor and its expression in disease progression

Os inibidores de BRAF (iBRAFs) e de MEK (iMEK), inauguraram uma nova classe de medicamentos, a terapia direcionada, no combate ao melanoma metastático. Entretanto, os pacientes adquirem resistência ao tratamento em poucos meses. Além disso, a imunoterapia vem ganhando espaço no tratamento do câncer, incluindo o melanoma, porém, com alguns aspectos inexplorados. Dentro deste tema, a enzima IDO vem despertando um grande interesse pela participação nos mecanismos de imunotolerância, imunoescape e progressão tumoral. A IDO é responsável pelo consumo e depleção do triptofano, produzindo a quinurenina. Ela está presente em diversos tipos celulares, incluindo células do sistema imune e células tumorais. Este trabalho objetivou avaliar a expressão de IDO durante a progressão da doença - desde do nevo até o melanoma metastático e também avaliar a regulação de IDO induzido por IFN-γ após tratamento com iBRAF em linhagens parentais e resistentes ao iBRAF, buscando-se os mecanismos moleculares. Por fim, objetivou-se entender os efeitos do 1-metil-triptofano (1-MT), um inibidor de IDO, tanto na sua capacidade de inibir a atividade de IDO quanto na sua influência na capacidade clonogênica. O estudo de bioinformática sobre o repositório público GSE12391 mostrou que o nível de expressão gênica de IDO foi superior nos estágios mais avançado da doença. Além disso, todas amostras de melanoma primário de pacientes apresentaram a imunomarcação de IDO, enquanto que nenhuma amostra de nevo apresentou tal marcação. Adicionalmente, a ocorrência de IDO se deu nos infiltrados linfoides, em células mononucleares do sistema imune. Duas análises de bioinformática de expressão gênica demonstraram que a IDO estava expressa positivamente na fase de resistência ao iBRAF. Ademais, os resultados de expressão proteica mostraram que a inibição de via MAPK (tanto por iBRAF quanto por iMEK) conseguiu modular a expressão de IDO, sendo que a maioria das linhagens apresentou uma diminuição de IDO. A atividade de IDO, medida através da produção de quinurenina, por HPLC se mostrou em consonância com os resultados de expressão proteica, exceto pela linhagem WM164 que não apresentou atividade enzimática, embora a proteína estivesse presente. Por fim, o 1-MT conseguiu inibir de maneira eficiente a enzima IDO, bloqueando a produção de quinurenina. Além de que, o 1-MT reduziu a capacidade clonogênica de maneira dose-dependente. Portanto, conclui-se que a expressão de IDO é crescente conforme a progressão do melanoma, que a inibição da via MAPK regulou a expressão de IDO e que o 1-MT reduz a capacidade clonogênica, além da sua função primária de inibir IDO

BRAF and MEK inhibitors (BRAFi and MEKi) has launched a new class of medication, the target therapy, to combat metastatic melanoma. Nevertheless, patients acquired resistance to the treatment in few months. Additionally, immunotherapy has been gaining space in cancer treatment, including melanoma, but some aspects need to be explored. Inside this theme, IDO enzyme has called the attention due to its participation in the mechanisms of immune tolerance, scape and tumor progression. IDO is responsible for tryptophan consume e depletion, producing kynurenine. It is present in different cells, including cells from immune system and tumor cells. This work purposed evaluate IDO expression during disease progression - since nevus until metastatic melanoma and also, evaluate IFN-γ-induced IDO regulation after BRAFi treatment in parental and resistant melanoma cell lines, seeking the molecular mechanisms. Lastly, it was evaluated the effects of 1-methyltryptopahn (1-MT), an IDO inhibitor, by its ability to inhibit IDO and also by its influency on the clonogenic capability. Bioinformatic study performed on GSE12391 showed that gene expression level of IDO was superior in the most advanced stages of the disease. Additionally, all sample of patient's primary melanoma presented IDO immunostaining, whereas, no nevus samples presented such staining. Besides, IDO occurrence was in the lymphoid infiltrates, in mononuclear cells from immune system. Two bioinformatic analysis of gene expression demonstrated that IDO was differentially overexpressed during BRAFi resistance stage. Moreover, protein expression results presented that MAPK pathway inhibition (both by BRAFi and by MEKy) was able to modulate IDO expression, and most of the cell lines presented an IDO downregulation. IDO activity, measured through kynurenine production, by HPLC was consonant with protein expression results, except by WM164 cell line, which did not present enzymatic activity, albeit the protein was present. By the end, 1-MT could inhibit efficiently IDO enzyme, blocking kynurenine production. Furthermore, 1-MT reduced clonogenic capability in a dosedependent manner. Therefore, it was concluded that IDO expression increases along with melanoma progression, MAPK pathway inhibition regulated IDO expression and 1-MT reduced clonogenic capability, besides its primary function of IDO inhibitor

Importancia del seguimiento de lesiones melanocíticas con dermatoscopia digital para el diagnóstico temprano de melanoma / Importance of monitoring melanocytic lesions with digital dermatoscopy for diagnosis early melanoma

La dermatoscopia digital es una herramienta que permite el diagnóstico de melanomas en estadios tempranos, por medio del seguimiento de las lesiones pigmentarias a largo plazo. Se comunican tres casos de pacientes con alto riesgo de melanoma, en los cuales ‒a través del seguimiento con dermatoscopia digital‒ se realizó el diagnóstico de la enfermedad mediante la detección de cambios morfológicos, arquitecturales y de pigmentación de las lesiones estudiadas. (AU)

Digital dermoscopy is a tool that allows the early diagnosis of melanomas, through the long-term follow up of pigmentary skin lesions. We report three cases of patients with high-risk of melanoma, in which the diagnosis had been made by morphological, arquitectural and pigmentary changes observed by the digital dermoscopy follow-up. (AU)

Avaliação do potencial de superação da quimioresistência do melanoma aos inibidores de BRAFV600E (Vemurafenibe) e de MEK (Trametinibe) utilizando terapia combinatória com 4-nerolidilcatecol (4-NC) / Evaluation of the potential of overcoming the chemoresistance of melanoma to BRAFV600E (Vemurafenib) and MEK (Trametinib) inhibitors using combinatory therapy with 4-nerolidylcatechol (4-NC)

Embora o melanoma represente apenas 4% das neoplasias malignas da pele, é considerado a mais grave por ser altamente etal. Em virtude da via MAPK (Mitogen activated protein kinase) estar intimamente ligada ao descontrole da proliferação celular, especialmente em melanoma, esta via se tornou um alvo para o desenvolvimento de terapias direcionadas a oncogenes, como os potentes quimioterápicos Vemurafenibe (inibidor da mutação V600E em BRAF - BRAFV600E) e Trametinibe (inibidor de MEK). Cada vez mais, melhores taxas de respostas vêm sendo alcançadas com os novos medicamentos, porém a maioria dos pacientes está sujeita a recidivas após 7 meses de tratamento devido ao desenvolvimento de quimioresistência, justificando a constante busca por novos compostos terapêuticos. Dados de nosso laboratório indicam que 4-nerolidilcatecol (4-NC) induz aumento na expressão de p53, produção de ROS e dano ao DNA, culminando em apoptose dependente de caspase-3 em células de melanoma por ser um inibidor proteassomal. Além disto, o 4-nerolidilcatecol (4- NC) demonstrou efeito inibitório na proliferação de células de melanoma em modelo de cultura organotípica de pele. Desta forma, este projeto visa avaliar a possibilidade de superação da quimioresistência aos inibidores de BRAF e de MEK, utilizando terapias combinatórias com 4-NC em células de melanoma humano resistentes a estes inibidores. Primeiramente, linhagens celulares de melanoma resistentes aos inibidores de BRAF (R) e BRAF/MEK (DR) foram geradas a partir de células parentais BRAF mutadas (P) e caracterizadas por MTT, microscopia de fluorescência e western blotting. Estas células foram submetidas ao tratamento com 4-NC que apresentou citotoxicidade na concentração de 30µM, inibição de formação de colônias e diminuição na invasão em modelos in vitro de culturas 2D e 3D em todas as linhagens estudadas (P, R e DR). O 4-NC foi ainda capaz de induzir estresse de retículo endoplasmático com indução de apoptose. Visando a explorar o efeito terapêutico in vivo do 4-NC, outro estudo foi conduzido em animais submetidos a enxerto xenográfico com células parentais de melanoma NRAS mutadas. Após desenvolvimento do tumor, os animais foram tratados 3 vezes por semana durante 3 semanas com 4-NC (10 mg/kg) por via i.p. O 4-NC foi capaz de inibir em até 4 vezes o crescimento dos tumores xenográficos (4/10) quando comparado com os controles, com remissão completa do tumor em um animal. A expressão de p53 e PARP clivada foi aumentada nos tumores dos animais tratados, sugerindo apoptose. A expressão gênica de MMP2 e MMP14 estava diminuída nas mesmas amostras, demonstrando o papel do 4-NC na inibição da invasão do melanoma in vivo. Finalmente, a toxicidade sistêmica do 4-NC foi avaliada nas mesmas doses empregadas no ensaio in vivo de tumorigênese. A baixa toxicidade observada nos ensaios toxicológicos com tratamentos sub-crônicos com 4-NC e a citotoxicidade demonstrada em modelos xenográficos nos leva a considerar este composto como promissor para estudos futuros e sua aplicação no tratamento do melanoma cutâneo humano, incluindo pacientes resistentes aos inibidores de BRAF e MEK

Melanoma accounts for only 4% of malignant neoplasms of the skin, but is considered the most serious because it is highly deadly. Because the MAPK (Mitogen activated protein kinase) pathway is closely linked to the lack of control of cell proliferation, especially in melanoma, this pathway has become a target for the development of oncogene-targeted therapies, such as the potent chemotherapeutic agents Vemurafenib (V600E mutation inhibitor in BRAF - BRAFV600E) and Trametinib (MEK inhibitor). Increasingly, better response rates have been achieved with the new drugs, but most patients are subject to relapses after 7 months of treatment due to several mechanisms, which justify the constant search for new therapeutic compounds. Data from our laboratory indicate that 4-nerolidylcatechol (4-NC) induces increased p53 expression, ROS production and DNA damage, culminating in caspase-3 dependent apoptosis in melanoma cells. The 4-NC compound demonstrated an inhibitory effect on melanoma cell proliferation in an organotypic skin culture model. Thus, this project aims to evaluate the possibility of overcoming the existing chemoresistance to BRAF and MEK inhibitors, using 4-NC combinatory therapies in human melanoma cells resistant to these inhibitors. Firstly, melanoma cell lines resistant to BRAF (R) and BRAF / MEK (DR) inhibitors were generated from naive cells mutated BRAF (N) and characterized by MTT, fluorescence microscopy and western blotting. These cells were submitted to 4-NC treatment that showed cytotoxicity with 30 µM, inhibition of colony formation and decrease in invasion in 2D and 3D in vitro models in all cell line studied (N, R and DR). Furthermore, 4-NC was able to induce endoplasmic reticulum stress with apoptosis induction. In order to explore the in vivo therapeutic effect of 4-NC, an additional study was conducted using xenograft model with NRAS-mutated melanoma cell line. After tumor development, the animals were treated 3 times per week for 3 weeks with 4-NC (10 mg / kg) by i.p. injection. 4-NC was able to inhibit up to 4- fold the growth of xenograft tumors (4/10) when compared to controls, with complete tumor remission in one animal. Cleaved PARP and p53 expression were increased in the tumors of treated animals, suggesting apoptosis. MMP2 and MMP14 gene expression were decreased in the same samples, demonstrating the role of 4-NC in inhibiting melanoma invasion in vivo. Finally, the systemic toxicity of 4-NC was evaluated at the same doses employed in the in vivo tumorigenesis assay. The low toxicity observed in the toxicological assays with sub-chronic 4- NC treatments and the demonstrated cytotoxicity in xenograft models leads us to consider this compound as promising for future studies and its application in the treatment of cutaneous human melanoma, including patients resistants to BRAF and MEK inhibitors

Prevalence of photoprotection and its associated factors in risk group for skin cancer in Teresina, Piauí

Abstract: Background: The incidence of skin cancer has increased worldwide, particularly melanoma rates, which had a mean development of 2.6 % a year in the last 10 years. The agreement on the relation between long-term or chronic exposure to the sun and the emergence of these neoplasias has made several workers who perform activities exposed to solar radiation to form a risk group for the development of skin cancer, community health agents included. OBJECTIVES: To analyze the prevalence of sunscreen-use-related factors to skin cancer in a labor risk group. METHODOLOGY: Cross-sectional study with community health agents selected through simple random sampling. After collecting data using semi-structured interviews, a descriptive analysis was performed for the qualitative variables, bivariate analysis was employed for checking the association between sunscreen use and sociodemographic, occupational and knowledge about skin variables, and multivariate analysis was conducted to check independent variables associated to sunscreen use. A 5% significance level was used. Results: Of 261 health gents selected, 243 were able to participate in the study. The prevalence rate of sunscreen use was 34.2% (95% CI: 28.2-40.2). Factors associated with sunscreen use were female sex, advanced age, use of sunscreen in situations when the skin got burnt, knowledge of the negative effects of the sun on the skin and skin cancer history. Conclusions: The prevalence found reveals that there is a need for implementing educational strategies in health services regarding photoprotection.

In vivo antitumor potential of extracts from different parts of Bauhinia variegata linn. Against b16f10 melanoma tumour model in c57bl/6 mice

Background: Melanoma is a metastatic type of skin cancer that is difficult to treat and the majority of efforts are directed to the design of new drugs. Medicinal Plants have been the primary source of medicines since life on earth; more than 50% of existing cancer treatments is derived from plants. Bauhinia variegata is well-known medicinal plant used from the ancient era to till date for their medicinal values. Scientific literatures have not documented any evidence of the antitumour potential of Bauhinia variegata against B16F10 melanoma tumor model in C57BL mice. The present investigation was undertaken to explore the antitumour activity of Leaf, stem bark and flower extract of Bauhinia variegata against B16F10 melanoma tumour model in C57BL mice. Methods: Hydro-methanolic extract prepared from the leaf, stem bark and flower of Bauhinia variegata were assessed for their antitumor activity. The extracts at doses of 500 and 750 mg/kg b.wt. were given orally along with cyclophosphamide (chemotherapeutic drug) for 40 days for exploring antitumor activity against melanoma tumor (B16F10) in C57BL mice. Inhibition of tumor growth, increase in survival time of animal with treatment, histopathological studies and antioxidant parameter were determined. Results: The Present investigation showed significant effect of the B. variegata L. in preventing melanoma tumor by B16F10 cell line in C57BL/6 mice. As compared with the tumour control group, the remarkable results especially in the group which received B. variegata extract and cyclophosphamide together were obtained for all of the measured parameters. Dose dependent response was observed in tumor volume, inhibition rate, life span time and antioxidant parameter of extracts. Combination treatment of cyclophosphamide and B. variegata extracts showed more pronounced effect. Conclusions: These findings suggest that B. variegata hydromethanolic extract may contain bioactive compounds of potential therapeutic significance which are relatively safe from toxic effects, and can compromise the medicinal use of this plant in folk medicine (US)

Occupational skin cancer: Systematic review / Câncer de pele ocupacional: revisão sistemática

SUMMARY Objective: To analyze the epidemiological profile, risk factors in the workplace environment and prevention methods for professionals at risk of skin cancer. Method: A systematic review of articles on occupational skin cancer, published in the Lilacs, Scielo, Medline and Cochrane Library from January 1st, 2008, to December 31st, 2013, was performed. The search included the following terms: “neoplasias cutâneas” (DeCS), “exposição ocupacional” (DeCS), “epidemiologia” (DeCS) as well as the keyword “prevenção”, and their equivalents in English. Results: After analyzing the titles and summaries of articles, the search strategy resulted in 83 references, of which 22 articles met the eligibility criteria. Discussion: We found that sun exposure is the main occupational risk factor for skin cancer, causing outdoor workers to be the most vulnerable to developing occupational skin cancer. Professionals with low levels of education and European descent are at increased risk of developing this cancer. Conclusion: Outdoor workers are more vulnerable to developing occupational skin cancer, estimating that professionals with low level of education and European descent are at increased risk of developing this cancer. Therefore, companies need to invest more in the health of workers by providing protective equipment and thus preventing occupational skin cancer.

RESUMO Objetivo: analisar o perfil epidemiológico, os fatores de risco no ambiente de trabalho e os métodos de prevenção dos profissionais de risco para câncer de pele. Método: foi realizada uma revisão sistemática de artigos sobre o câncer de pele ocupacional, publicados entre 1 de janeiro de 2008 e 31 de dezembro de 2013, nas bases de dados Lilacs, Scielo, Medline e Biblioteca Cochrane. A pesquisa baseou-se na intersecção dos seguintes termos: “neoplasias cutâneas” (DeCS), “exposição ocupacional” (DeCS), “epidemiologia” (DeCS) e a palavra-chave “prevenção” e seus equivalentes em inglês. Resultados: após a análise dos títulos e resumos dos artigos, a estratégia de busca resultou em 83 referências, das quais 22 artigos preencheram os critérios de elegibilidade. Discussão: a exposição solar é o principal fator de risco ocupacional para câncer de pele e os trabalhadores ao ar livre são os mais vulneráveis a desenvolvê-lo. Aqueles com baixo nível de escolaridade e ascendência europeia apresentam maior risco de desenvolver a neoplasia. Conclusão: os trabalhadores ao ar livre são mais vulneráveis a desenvolver câncer de pele ocupacional. Os profissionais com baixo nível de escolaridade e ascendência europeia apresentam maior risco de desenvolver a neoplasia. São necessários mais investimentos das empresas na saúde dos trabalhadores por meio de fornecimento de equipamentos de proteção, a fim de prevenir o câncer de pele ocupacional.

Vitamin D axis and its role in skin carcinogenesis: a comprehensive review

Vitamin D (VD) is a secosteroid hormone that is mainly synthesized in the skin upon exposure to UVB radiation. VD is widely known for its role in calcium metabolism; however, multiple endocrine, paracrine and autocrine functions of VD have been described, including a prominent role on carcinogenesis. In recent years, multiple associations between VD deficiency and different types of cancer have been described, supported by evidence of anti-proliferative, anti-angiogenic, pro-apoptotic, cell-differentiating and anti-invasive effects of this hormone. An immunomodulatory role of VD associated to cancer microenvironment has also been suggested. Regarding skin cancer, it has been shown that VD inhibits tumor development in basal cell carcinoma, squamous cell carcinoma, and melanoma in vitro. Some studies have suggested that lower VD levels may be a risk factor for skin cancer, while others have shown the opposite; there is also preliminary evidence on the role of VD supplementation for the prevention of melanoma in vivo. In this review, we explore the mechanisms of VD effects on carcinogenesis and the available scientific evidence of the interplay between VD and the genesis of both non-melanoma and melanoma skin cancer. (AU)

Suspected melanoma only when the lesion is greater than 6mm may harm patients / Considerar diâmetro apenas maior que 6mm como suspeita de malignidade de melanoma pode prejudicar pacientes

ABSTRACT Objective To analyze the distribution of larger diameter in the pathological report of cutaneous melanoma patients. Methods Data were obtained from patients seen from 1994 to 2015. Date, sex, age, maximum diameter, histological subtype, primary site, microscopic thickness, mitoses, ulceration, vertical growth phase, and regression were the variables studied. This study was approved by the National Ethics Committee - Brazil Platform. Patients were grouped into smaller diameter (≤6mm) and larger diameter (>6mm). The statistical analysis used the χ2test (p<0.05). Results Of the 292 patients analyzed, 123 were seen between 1994 and 2004, and 169 between 2005 and 2015; in that, 151 women and 141 men, mean age of 52 years. The diameters ranged from 2 to 76mm (mean of 14mm), 81 patients with smaller diameter (≤6mm) and 211 with larger diameter (>6mm). Out of 81 patients with smaller diameter, 29 had invasive melanoma, while 179 of the 211 with larger diameter were invasive. A difference was observed in frequency of vertical growth phase. Conclusion Pigmented skin lesions with diameter smaller than 6mm should not be an excluding factor for biopsies, especially when patients present risk of developing skin cancer.

RESUMO Objetivo Analisar a distribuição do maior diâmetro reportado no laudo histopatológico de portadores de melanoma cutâneo. Métodos Os dados foram obtidos de pacientes atendidos de 1994 a 2015. Data, sexo, idade, diâmetro máximo, subtipo histopatológico, sítio primário, espessura microscópica, mitoses, ulceração, fase de crescimento e regressão foram as variáveis estudadas. O estudo foi aprovado pela Comissão Nacional de Ética em Pesquisa na Plataforma Brasil. Os pacientes foram agrupados em diâmetro menor (≤6mm) e maior (>6mm). Análise estatística utilizou o teste χ2 (p<0,05). Resultados Dos 292 pacientes analisados, 123 foram atendidos entre 1994 e 2004, e 169 entre 2005 e 2015, sendo 151 mulheres e 141 homens, com média de idade de 52 anos. Os diâmetros variaram de 2 a 76mm (média de 14mm), sendo 81 pacientes com diâmetro menor que 6mm e 211 com diâmetro maior. Dos 81 pacientes com diâmetro menor, 29 apresentavam melanoma invasivo, enquanto 179 dos 211 com diâmetro maior eram invasivos. Houve também diferença de frequência da fase de crescimento vertical. Conclusão Diâmetro de lesões pigmentadas menor que 6mm não deve ser fator excludente para realização de biópsias, especialmente para paciente de risco para câncer de pele.

Lesões cutâneas malignas e pré-malignas: conhecimentos, hábitos e campanhas de prevenção solar / Malignant and premalignant skin lesions: knowledge, habits and sun protection campaigns

Objetivo determinar a morbilidade de lesões malignas e pré-malignas da pele e o conhecimento da população sobre prevenção solar e hábitos perigosos. Métodos aplica-se um estudo longitudinal retrospetivo e outro descritivo transversal a uma população de 25.956 habitantes utilizando o programa Abucasis® e realizando 201 inquéritos a doentes do serviço de urgências; posteriormente utiliza-se o programa SPSS 15.0 para Windows. Resultados em seis anos registaram-se 228 casos de queratose actínica, 26 de melanoma e 32 de neoplasias malignas da pele. Encontramos que 63,7% da população crê que não se realizam suficientes campanhas de prevenção solar, 50,2% desconhece os sinais de alarme do cancro de pele e a medida de proteção mais utilizada é a utilização de filtros solares. Conclusão A morbilidade de lesões malignas e pré-malignas da pele na população de Manises quadruplicou e o conhecimento acerca da prevenção solar é insuficiente...

Objective To determine the morbidity of malignant and pre-malignant skin lesions and people’s knowledge about preventing sun exposure and dangerous habits. Methods A retrospective longitudinal study and one descriptive transversal study were conducted with a population of 25,956 inhabitants using the Abucasis® program, and 201 questionnaires were administered to patients in an emergency department; SPSS 15.0 for Windows program was then used. Results In six years there were 228 cases of actinic keratosis, 26 melanoma and 32 malignant neoplasms of the skin. It was found that 63.7% of the population believed that sufficient solar prevention campaigns were not performed, 50.2% were unaware of the warning signs of skin cancer, and the most widely used measure used for protection was the use of sunscreens. Conclusion The morbidity of malignant and premalignant skin lesions in the Manises population quadrupled and the knowledge about preventing sun exposure is insufficient...

Metabolismo de triptofano em melanomas: o que dizem as células do microambiente? / Tryptophan metabolism in melanomas: what do microenvironment cells can say?

O melanoma é composto por células malignas e também por um estroma de sustentação que inclui fibroblastos, células imunológicas, endoteliais, matriz extracelular, dentre outros fatores. Assim, os tumores não são entidades independentes, eles interagem ativamente com o microambiente adjacente de forma bidirecional através de sinais moleculares que modulam o fenótipo maligno. Um dos sinais bioquímicos para desenvolvimento desse fenótipo se dá pelo catabolismo de Trp pela via das quinureninas, que gera compostos com diversas atividades biológicas, que no tumor estão envolvidas com tolerância e imunoescape e, logo, com prognóstico ruim para os pacientes. Até o presente momento apenas o consumo de Trp e a formação de um único metabólito, a quinurenina (KYN), tem sido associada a malignidade dos melanomas. A fim de ampliar e elucidar os mecanismos bioquímicos do metabolismo desse aminoácido em melanomas, estudamos mais de quinze compostos de todas as rotas catabólicas de Trp em células da pele, células imunológicas, linhagens tumorais e amostras clínicas de melanoma. De forma inédita pudemos observar que as células da pele tem maior habilidade de sintetizar KYN quando comparadas às linhagens tumorais, demonstrando que o catabolismo de Trp peritumoral pode ser responsável pelos fenômenos de imunotolerância e escape. Além disso, o metabolismo de Trp pode estar envolvido nos mecanismos de homeostasia da pele, já que especificamente essas células produzem compostos com atividade biológica nesse órgão. As células imunológicas possuem um perfil metabólico completamente diferente umas das outras: monócitos, macrófagos e dendríticas possuem maior ativação da via KYN enquanto linfócitos e neutrófilos possuem maior indução da rota que gera serotonina e melatonina. Mesmo nos diferentes fenótipos de macrófagos, M1 e M2a, foram observadas marcações especificas de metabolismo, que podem estar relacionadas às atividades anti- ou pró-tumoral dessas células no microambiente. Em amostras clínicas, apesar da principal diferença entre nevos e melanomas ser a concentração de KYN, diversas outras alterações no metabolismo de tiptofano foram observadas, o que mostra a complexa magnitude deste metabolismo na fisiopatologia da pele

Melanoma is composed of malignant cells and also by a stromal support that includes fibroblasts, immune cells, endothelial cells, extracellular matrix, among other factors. Thus, tumors are not separate entities; they actively interact with the surrounding microenvironment bi-directionally through molecular signals that modulate the malignant phenotype. One of biochemical signals for the development of this phenotype occurs by Trp catabolism through kynurenine pathway, that generates compounds with diverse biological activities, which in tumors are involved with tolerance and imunoescape and therefore with poor prognosis for patients. To date only the consumption of Trp and formation of a single metabolite, kynurenine (KYN), has been associated with malignant melanomas. In order to enlarge and clarify the biochemical mechanisms of this amino acid metabolism in melanomas, we have studied more than fifteen compounds of all catabolic routes of Trp in skin cells, immune cells, tumor cell lines and clinical samples of melanoma. In an unique way we could observe that the skin cells has superior ability to synthesize KYN when compared to tumor cell lines, demonstrating that the peritumoral catabolism of Trp may be responsible for the phenomena of immune tolerance and escape. Furthermore, the Trp metabolism may be involved in skin homeostasis mechanisms, since these cells produce specific compounds with biological activity in this organ. The immune cells have a completely different metabolic profile among them: monocytes, macrophages and dendritic cells have greater KYN pathway activation, and lymphocytes and neutrophils possess greater induction of the route that generates serotonin and melatonin. Even in different macrophages phenotypes, M1 and M2a, we observed specific metabolic marks, which may be related to the anti- or pro-tumoral activity of these cells in the tumor microenvironment. In clinical samples, although the main difference between nevi and melanomas is the concentration of KYN, a range of other changes in Trp metabolism were observed, which shows the complex magnitude of this metabolism in the skin pathophysiology

Avaliação dos efeitos da terapia fotodinâmica utilizando compostos fenotiazínicos sobre melanoma in vitro / Assessment of the effects of photodynamic therapy using phenothiazine compounds on in vitro melanoma

O câncer é considerado a segunda maior causa de morte em países ocidentais. Nos Estados Unidos da América (EUA) as mortes por câncer anualmente superam a soma das mortes provocadas em guerras como Vietnã, Coreia e as Grandes Guerras Mundiais. Apresentando-se como a mais agressiva das neoplasias dermatológicas, o melanoma cutâneo está associado à cerca de 75% das causas de morte por câncer de pele. Um dos tratamentos estudados para aplicação em pacientes com esta e outras patologias é a Terapia Fotodinâmica (TFD), que é baseada no uso de corantes de baixa toxicidade, que tem seletividade por alguns tecidos ou células e quando ativados por baixas doses de luz visível induzam alterações celulares como a produção ERO. Os fenotiazínicos são moléculas catiônicas com, absorção de luz na região entre 620-660nm, espectro que permite maior penetração nos tecidos, promovendo maior ação do composto em tecidos mais profundos. A irradiação foi feita com luz lazer com λ= 660nm, com potência de 100 mW, densidade de energia de 150 J/cm2 por 1 min. As quantificações de viabilidade celular foram feitas por método colorimétrico, e realizada a leitura em leitor de microplaca a 655 nm. A determinação das IC50 do Azul de Metileno e Azul de Toluidina O foi 2,5 μM e 8,4 μM, respectivamente. Utilizando a TFD observamos que os efeitos citotóxicos dos compostos fenotiazínicos apresentam significância estatística (p<0,05) tanto em AM quanto em ATO. Em microscopia óptica com coloração por May-Grunwald-Giemsa observamos que existe uma aparente diminuição do conteúdo citoplasmático e preservação nuclear nas células tratadas com TFD, além da diminuição da quantidade de células por campo. A avaliação ultraestrutural por Microscopia de varredura mostra células com visível extração citoplasmática após a TFD, apontando uma lesão membranar. Novas avaliações precisam ser feitas como estabelecer um melhor protocolo para aumentar os efeitos da TFD.

Cancer is considered the second leading cause of death in Western countries. In the United States of America (USA) cancer deaths annually exceed the total of deaths in wars like Vietnam, Korea and the Great World Wars. Presenting as the most aggressive of the skin neoplasms, cutaneous melanoma is associated with circa 75% of the deaths from skin cancer. One of the therapies used in patients with melanoma and other pathologies is Photodynamic Therapy (PDT), which is based upon the use of dyes of low toxicity, which has selectivity for certain tissues or cells and low doses when activated by visible light induce cellular changes such as ROS production. The phenothiazic dyes are cationic molecules, absorption of light in the region between 620-660 nm, allowing greater spectrum tissue penetration, promoting higher activity of the compound in deeper tissues. The irradiation was performed with laser light with λ = 660 nm with 100 mW, energy density of 150 J/cm2 for 1 min. Quantification of cell viability was performed by the colorimetric method, and performed a reading in a microplate reader at 655nm. Determination of IC50 of Methylene Blue and Toluidine Blue O was 2.5 μM and 8.4 μM respectively. Using the protocol of PDT observed that there is one of the cytotoxic effects of phenothiazine compounds with statistical significance (p <0.05) in both MB and in TBO. Through optical microscopy by staining with fast Panotic was observed that there is an apparent decrease in the cytoplasm in cells treated with MB and TBO as well as reduced number of cells per field. The Scanning Electron Microscopy, shows cells with cytoplasm extraction, after PDT, indicated possibility, membrane damage. New assessments need to be made to establish a better protocol to potentiate the effects of PDT.

Cáncer de piel y radiación solar: experiencia peruana en la prevención y detección temprana del cáncer de piel y melanoma / Skin cancer and sun radiation: peruvian experience in the prevention and early detection of skin cancer and melanoma

La excesiva exposición a la radiación solar, específicamente la ultravioleta (RUV), ha sido causa de diferentes enfermedades, en especial de cáncer de piel. En 1995 el Círculo Dermatológico del Perú realizó la primera “Campaña de Educación, Prevención y Detección Temprana de Cáncer de Piel y Melanoma” denominada el “Día del Lunar”. Fue oficializada por el Ministerio de Salud, y cuenta con la participación del Seguro Social de Salud (EsSalud). Es una campaña gratuita que se realiza cada año a nivel nacional, en ella, desde 1995 al 2011 se atendieron a 118 092 personas, en 76 sedes distribuidas en 18 ciudades de todo el país, en el 2,8% de estas se pudo identificar alguna lesión cutánea sospechosa de malignidad, de las cuales el 64,9% correspondió a carcinoma basocelular, 26,7% a melanoma cutáneo y 8,4% a carcinoma espinocelular. Estas campañas destacan en importancia no solo por la práctica asistencial en ellas realizada, sino por las actividades educativas orientadas a fomentar una cultura de prevención en favor de las poblaciones más vulnerables. Finalmente, consideramos que es fundamental seguir educando a la población en la prevención del cáncer de piel, crear conciencia en las autoridades para que participen activamente en la realización de estas actividades, además de solicitar a todos los médicos que se sumen coordinadamente a este esfuerzo para seguir avanzando y mejorar lo logrado en beneficio de nuestro país.

The excessive exposure to sun radiation, especially to ultraviolet radiation (UV), has led to various diseases, in particular to skin cancer. In 1995, the Peruvian Dermatological Association conducted the first “Campaign for Education, Prevention and Early Detection of Skin Cancer and Melanoma” called “Mole’s Day”. The Ministry of Health has turned it into an official event, and the Health Social Security (EsSalud) also participates. This is a free campaign that takes place every year nationwide. 118,092 people attended from 1995 to 2011 in 76 sites distributed in 18 cities throughout the country. A cutaneous lesion were malignancy was suspected was identified in 2.8% of people attending, out of which 64.9% corresponded to basal cell carcinoma, 26.7% to cutaneous melanoma, and 8.4% to squamous cell carcinoma. These campaigns are highly important not only because of the assistance given, but also because of the educational activities aimed at promoting a prevention culture in favor of the most vulnerable populations. Finally, we believe it is important to continue educating the population on skin cancer prevention, to build awareness among the authorities so that they actively participate in the performance of these activities, and to ask all physicians to coordinately join this initiative, in order to continue growing, and to improve all that has been attained for the benefit of our country.

Perceived Relevance of Educative Information on Public (Skin) Health: A Cross-sectional Questionnaire Survey / 예방의학회지

OBJECTIVES: Unprotected leisure time exposure to ultraviolet radiation from the sun or artificial tanning beds is the most important environmental risk factor for melanoma, a malignant skin cancer with increasing incidences over the past decades. The aim of the present study was to assess the impact of skin health information provided by several sources and different publishing issues on knowledge, risk perception, and sun protective behavior of sunbathers. METHODS: A cross-sectional questionnaire survey was conducted among Austrian residents (n=563) spending leisure time outdoors in August 2010. RESULTS: Print media, television, and family were perceived as the most relevant sources of information on skin health, whereas the source physician was only ranked as fourth important source. Compared to other sources, information provided by doctors positively influenced participants' knowledge on skin risk and sun protective behavior resulting in higher scores in the knowledge test (p=0.009), higher risk perception (p<0.001), and more sun protection (p<0.001). Regarding gender differences, internet was more often used by males as health information source, whereas females were more familiar with printed information material in general. CONCLUSIONS: The results of this survey put emphasis on the demand for information provided by medical professionals in order to attain effective, long-lasting promotion of photoprotective habits.

Fotoproteção tópica na infância e na adolescência / Topical photoprotection in childhood and adolescence

OBJETIVO: A exposição à luz solar na infância ocorre, frequentemente, de forma mais intensa do que em muitos adultos. Dados da literatura comprovam de maneira inequívoca a associação desse comportamento social com o risco de desenvolvimento do melanoma maligno e do câncer cutâneo não melanoma mesmo na vida adulta. Além disso, o fotoenvelhecimento cutâneo é semeado já na infância com a exposição solar inadequada. Esta revisão tem como objetivo orientar os pediatras nas medidas adequadas de fotoproteção tópica nas crianças e adolescentes, o que irá alterar de maneira positiva o futuro desses pacientes. FONTES DOS DADOS: Realizou-se uma revisão da literatura indexada na base de dados MEDLINE/PubMed entre os anos de 1999 e 2012 sobre fotoproteção na infância, selecionando-se como fonte os artigos de revisão mais relevantes, do ponto de vista de abrangência do tema fotoproteção em crianças e adolescentes, fotoproteção e vitamina D, fototerapia na neonatologia e impacto no câncer cutâneo, bronzeamento artificial e câncer cutâneo. SÍNTESE DOS DADOS: Crianças e adolescentes devem adotar medidas adequadas de fotoproteção para diminuir o risco de câncer cutâneo melanoma e não melanoma. CONCLUSÕES: Há dados na literatura que suportam a associação de hábitos de exposição solar segura e uso de fotoprotetores tópicos em crianças e adolescentes com a redução da ocorrência do câncer cutâneo.

OBJECTIVE: Exposure to sunlight in childhood is often more intense than in adults. Literature data unequivocally show the association between this social behavior and the risk for developing malignant melanoma and non-melanoma skin cancer, even in adulthood. Furthermore, skin photoaging begins already in childhood through inadequate sun exposure. This review aims to guide pediatricians on appropriate measures of topical photoprotection in children and adolescents, which will positively change the future of these patients. SOURCES: A review of the literature indexed in MEDLINE/PubMed between the years 1999 and 2012 on photoprotection in childhood was conducted. The most relevant review articles on photoprotection in children and adolescents, photoprotection and vitamin D in neonatal phototherapy and impact on skin cancer, artificial tanning and skin cancer were selected as sources. SUMMARY OF THE FINDINGS: Children and adolescents should adopt appropriate measures of photoprotection in order to decrease the risk of melanoma and non-melanoma skin cancer. CONCLUSIONS: There are published data that support the association between sun exposure habits and safe use of topical sunscreens in children and adolescents on the one hand and a reduced occurrence of skin cancer on the other.

Câncer de pele: o papel da exposição solar como fator causal e da fotoproteção na prevenção / Skin cancer: the sun exposure as a causal factor and photoprotection prevention

O câncer de pele se tornou, nas últimas décadas, um problema de saúde pública no Brasil, corespondendo a 25% do total dos tumores malignos registrados. Constata-se a necessidade de se estabalecer estratégias que visem minimizar os problemas relacionados às dificuldades na adoção de ações preventivas, bem como motivar as pessoas para a adesão às medidas de fotoproteção. Grande parte da população mundial se expõe ao sol de forma irracional, isto aliado à mudança de hábitos de vida, à diminuição da camada de ozônio e ao descuido quanto ao uso de fotoprotetores. Todos estes fatores têm contribuído significativamente para o aumento da incidência de câncer de pele e de outras alterações cutâneas relacionadas à exposição solar inadequada. O tipo de câncer de pele mais frequentemente encontrado na população brasileira é o não melanoma, representado pelos carcinomas basocelular e espinocelular. O melanoma de pelo corresponde a apenas 4% dos tumores cutâneos; entretanto, sua letalidade é alta. Quando a exposição passa a ser prolongada e irracional, o risco de alterações cutâneas relacionadas à exposição solar passa a ser maior, principalmente em pessoas de pele clara. Os filtros solares são comumente usados como proteção contra os danos solares. Eles reduzem a penetração de ondas ultravioleta solares na pele, pela reflexão ou por absorvê-las. A aplicação apropriada de filtro solar é fundamental como estratégia eficaz de saúde pública para prevenção do câncer de pele. Além do uso de fotoprotetores, medidas educativas de prevenção, como conscientização da proteção solar desde a infância, são necessárias pra se tentar diminuir a incidência dos cânceres de pele.

Skin cancer in recent decades has become a public health problem in Brazil, accounting for 25% of all malignant tumors recorded. There is a need to establish strategies for minimizing the problems hindering the adoption of preventive actions. as well as motivate people to adhere to measures for effective photoprotection. The solar exposure has been occurred in an irrational way by most of the people all over the world along with habit changes of everyday life, decreasing the ozone layer and careless to the use of photoprotectors as well. All these factors have contributed meaningfully for the increase of incidence of skin cancer and other cutaneous changes related to inadequate solar exposure. The type of skin cancer most often found in the Brazilian population is not melanoma, basal cell carcinomas and squamous cell carcinomas. The skin melanoma accounts for only 4% of skin tumors, but its mortality is high. When the exposure becomes prolonged and unreasonable risk of developing skin changes related to sun exposure becomes greater, expecially in people with white skin. Sunscreens are commonly used as protection against sun damage. They reduce the penetration of solar ultraviolet waves in the skin by reflecting or absorbing them. Proper application of sunscreen is essential to effective public health strategy for prevention of skin cancer. Besides the use of sunscreens, prevention and educational measures, awareness of sun protection from childhood are necessary to decrease the incidence of skin cancers.

Experiência de um ano de modelo de programa de prevenção contínua do melanoma na cidade de Jaú-SP, Brasil / One year experience of a model for melanoma continuous prevention in the city of Jaú (São Paulo), Brazil

FUNDAMENTO: A incidência do melanoma aumentou nos últimos anos mais rapidamente do que qualquer outro câncer. Embora represente apenas 4 por cento dos cânceres de pele, é o responsável por 60 por cento das mortes por esta neoplasia. Isto torna o melanoma um problema de saúde pública. OBJETIVOS: O presente estudo propôs o desenvolvimento de um Programa Contínuo de Prevenção do Melanoma, por meio da realização da prevenção primária e do diagnóstico precoce desta neoplasia. MÉTODOS: Foi tomada como piloto uma cidade de aproximadamente 130.000 habitantes. Uma equipe de enfermagem esteve presente por cerca de 30 dias em cada um dos 13 postos de saúde da cidade de Jaú (SP), realizando orientações quanto ao autoexame da pele, fotoproteção e sinais precoces do melanoma. O paciente com lesão suspeita era encaminhado imediatamente ao hospital de referência para dermatoscopia e triagem médica, sendo excisada quando suspeita. RESULTADOS: Foram diagnosticados 4 casos de melanoma em fase inicial e 3 nevos displásicos. Dos entrevistados, 74 por cento trabalham expostos ao sol, variando de meio período ao completo, e mais de 60 por cento nunca fizeram uso de filtro solar. CONCLUSÃO: Este modelo de programa de prevenção é inédito, exclusivo e demonstrou ser eficaz na prevenção e diagnóstico precoce do melanoma em uma cidade de 130.000 habitantes do Estado de São Paulo. Com esclarecimento à população e orientação à equipe de saúde, realiza-se uma rápida triagem e identificam-se lesões suspeitas de melanoma para que, com o diagnóstico em suas fases iniciais, o paciente apresente melhor prognóstico.

BACKGROUND: Worldwide incidence of melanoma has increased in recent years faster than any other cancer. Although it represents only 4 percent of skin cancers it is nevertheless responsible for 60 percent of skin cancer deaths. This makes melanoma a public health problem. OBJECTIVES: The aim of this study was the development of a continuous program for melanoma prevention and early detection. METHODS: A city of around 130,000 inhabitants in the state of São Paulo, Brazil, was chosen for the development of a pilot project covering primary prevention and early diagnosis of melanoma. A nursing team worked for approximately 30 days in each of the 13 health centers in the city of Jaú (SP), providing guidance on self-examination of the skin, photoprotection and recognition of early signs of melanoma. Patients with suspicious lesions were immediately sent to the reference hospital for medical and dermoscopic screening. Excisional biopsies were performed on suspected melanomas. RESULTS: 4 four cases of early stage melanoma and 3 dysplastic nevi were diagnosed. Of the people interviewed, 74 percent worked either part-time or full-time exposed to sun and over 60 percent claimed to never use sunscreen. CONCLUSION: This is a new and effective model for melanoma prevention and early diagnosis. In short, the melanoma prevention program is able to quickly identify suspicious lesions, leading to early diagnosis and better chances of survival.

intervention based on protection motivation theory in reducing skin cancer risk

Skin cancer is one of the most preventable, curable and treatable of all other cancers. In the past decade, the rates for most cancers, specially the skin cancers increased visibly. Sun exposure is a major causative factor for skin cancer for which prevention is possible. Protection motivation theory [PMT] provides one model for increasing healthy behavior through persuasive communication. We apply this theory for skin cancer prevention behavior. This was an experimental study. Participants were 360 female students from four high schools in Yazd city, Iran that divided in two groups [180 in case and 180 in control group]. A self-report questionnaire was used to assess the variables in the PMT model at pretest, post-test and follow-up. The questionnaire was distributed before the intervention [pre-test] and afterwards [post-test] and following at a 2 month lag. For data analysis ANOVA, T-test, Wilcoxon, Pearson's correlation and coefficient were used. A significant difference between all variables except fear was noted in the case and control groups in follow-up [p=0.00]. There was significant difference between mean grades score of all of variables in case group, in pre-test and follow up. No significant difference was seen between mean grade scores of variables in control group in pre-test and follow up. There is significant difference between using methods for prevention skin cancer in case and control group after intervention. Results support the effectiveness of a PMT-based intervention to change the attitude and behavior associated with skin cancer risk. Theory-based intervention can motivate people to alert their attitudes and behaviors regarding sun exposure