Cetoacidosis diabética como debut de diabetes mellitus inmunomediada en paciente en tratamiento con inhibidores de checkpoint / Diabetic ketoacidosis as debut of immune-mediated diabetes mellitus in a patient in treatment with immune checkpoint inhibitors

Los inhibidores de checkpoint (ICP) son anticuerpos usados en inmunoterapia contra el cáncer. Uno de sus blancos de acción es el receptor de muerte celular programada-1 (PD-1), el cual es importante para mantener la tolerancia inmunitaria. Sin embargo, este mecanismo se asocia a riesgo de eventos adversos relacionados a la inmunidad que pueden afectar a múltiples órganos incluyendo el sistema endocrino. Se describe el caso inhabitual de un paciente que a los 18 meses de terapia con ICP debutó con cetoacidosis diabética (CAD).

Immune checkpoint inhibitors consist in antibodies used in immunotherapy against cancer. One of their targets is the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, this mechanism is associated with a risk for immune-related adverse events potentially affecting multiple organs, including the endocrine system. We describe the unusual case of a patient who, after 18 months of treatment with an immune checkpoint inhibitor, debuted with diabetic ketoacidosis

Multi-target combinatory strategy to overcome tumor immune escape / 医学前沿

Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.

Interleukins in the treatment of melanoma / 中华医学杂志(英文版)

Interleukins (ILs) and associated cytokines serve as the means of communication for immune cells and non-immune cells. The use of ILs in harnessing the immune system to cancer treatment has been a promising approach. ILs not only nurture an environment enabling cancer growth but also simultaneously trigger a productive tumor-directed immune response. These properties of ILs are increasingly being explored as a strategy to improve the outcomes of cancer. Here, we describe recently innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacies of IL-2, 15, 10, and 18 in the treatment of melanoma. Furthermore, the combination of ILs and immune checkpoint inhibition may synergize to reshape the tumor environment, thus yielding better clinical benefits in the future.

EGCG and ECG induce apoptosis and decrease autophagy via the AMPK/mTOR and PI3K/AKT/mTOR pathway in human melanoma cells / 中国天然药物

Catechins have been proven to exert antitumor effects in different kinds of cancers. However, the underlying mechanisms have not been completely clarified yet. This study aimed to assess the effects and mechanisms of (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) on human melanoma skin A375 cells. Results showed that EGCG and ECG inhibited the proliferation of A375 cells and ECG showed better inhibitory effect. Flow cytometry analysis had shown that EGCG and ECG induced apoptosis and led to cell cycle arrest. EGCG and ECG decreased Bcl-2 expression and upregulated Caspase-3 protein level, indicating the development of apoptosis. Furthermore, EGCG and ECG could decreased mitochondrial membrane potential of A375 cells. In addition, the expression of Beclin-1, LC3 and Sirt3 were downregulated at protein levels, which known to be associated with autophagy. After autophagy was increased by rapamycin, the apoptotic trend was not change, indicating that apoptosis and autophagy are independent. Mechanistically, EGCG and ECG treatments decreased phosphorylated-AMPK (p-AMPK) and increased the ratios of p-PI3K, p-AKT and p-mTOR in melanoma cells. Conclusively, EGCG and ECG induced apoptosis via mitochondrial signaling pathway, downregulated autophagy through modulating the AMPK/mTOR and PI3K/AKT/mTOR signaling pathway. It indicated that EGCG and ECG may be utilized in human melanoma treatment.

Case of large lentigo maligna melanoma of the scalp treated with 5% and 3. 75% Imiquimod

Abstract The paper presents a case of lentigo maligna melanoma of the scalp in an elderly patient treated for the nodular part with surgery and the residual melanoma in situ with 5% Imiquimod and subsequently with 3.75% Imiquimod (each concentration for 4 months, 5 times per week), with complete regression of the lesion. 3.75% Imiquimod, which is already used for the treatment of actinic keratosis, could be a useful weapon with the same effectiveness and fewer side effects compared to 5% Imiquimod.

Melanoma: un desafío para el pediatra. Dos casos clínicos / Melanoma: A pediatric challenge. A two cases report

El melanoma es la forma más grave de cáncer de piel. La morbimortalidad es variable, ya que se relaciona con las medidas de prevención implementadas, la detección temprana y el acceso al tratamiento temprano. La incidencia ha aumentado en los últimos años a pesar de la mayor concientización con respecto a la exposición a la luz solar y la utilización de cremas protectoras. A su vez, el rango etario se ha ampliado, y esta enfermedad afecta a individuos cada vez más jóvenes. Se estima que del 1 % al 4 % de todos los casos de melanoma ocurren en menores de 20 años.Se presentan dos casos pediátricos, con evolución prolongada y diagnóstico inicial erróneo. Es fundamental para el pediatra general, primer contacto del paciente con el sistema de salud, conocer las características de estas lesiones. Un alto índice de sospecha permitiría la derivación al especialista de forma temprana.

Melanoma is the most serious skin cancer. Morbimortality is variable as it is related to the preventive measures, early detection, and access to early treatment. The incidence has increased in recent years, despite the raise in awareness of avoiding sun exposure and the use of sunscreen. What is more, the disease age range has expanded, affecting increasingly younger individuals. It is estimated that 1 to 4 % of all melanoma cases occurred in people younger than twenty years old.We present two pediatric cases with prolonged evolution and wrong initial diagnosis. Since the general pediatrician is the patient's first contact with the health system, it is extremely important to know the characteristics of these lesions. A high index of suspicion would allow an early referral to the specialist.

The current role of surgery in the treatment of cardiac metastases from malignant melanoma: an educational presentation

Abstract A 71 year-old male with a history of multiple excisions of an initial Clark's level V melanoma of the breast followed by combined radiation and interferon treatment, as well as a recurrence, 3 years later, of a BRAF-positive tumor of the shoulder, with subsequent therapy with dabrafenib and trametinib, presented again with progressive intracardiac masses causing significant right ventricular outflow obstruction. Additionally, the patient complained of dyspnea and fatigue on exertion, thus he was scheduled for surgical resection.

Effect of piceatannol against malignant melanoma / 华西口腔医学杂志

OBJECTIVES@#To study the antitumor effect of piceatannol (PIC) on malignant melanoma @*METHODS@#B16F10 cells were cultured @*RESULTS@#The cell viability of B16F10 decreased with increasing PIC concentration. The results of the Transwell assay showed that invasion ability decreased with increasing PIC concentration, and healing time was prolonged at increased PIC concentration in the wound healing assay. Western blot results showed that PIC mainly inhibited the phosphorylation of Syk and inhibited the expression of MMP-2, MMP-9, and VEGF. RNA interference pointed out that blocking the expression of Syk can reveal the same inhibition effect on B16F10 cells as PIC. @*CONCLUSIONS@#PIC might block the progression of malignant melanoma by inhibiting spleen tyrosine kinase.

Melanoma de escroto en un paciente de mediana edad / Scrotum melanoma in a middle-age patient

Se describe el caso clínico de un paciente de 42 años de edad, de piel negra, que asistió a la consulta de Cirugía de Tumores Periféricos en el Hospital Oncológico Docente Provincial Conrado Benítez García de Santiago de Cuba, por presentar una lesión oscura hiperpigmentada en el lado izquierdo del escroto, próxima a la región del rafe, de aproximadamente 4 mm y bordes irregulares, que no elevaba la piel ni dolía. Se realizó exéresis de la lesión y el estudio histopatológico reveló la existencia de un melanoma, sin ulceración ni satelitosis, con crecimiento radial, por lo que se profundizó en el área operada en busca de márgenes sin afectación y se resecaron los ganglios linfáticos inguinales bilaterales de manera profiláctica. Luego se indicó quimioterapia e inyecciones de interferón. El paciente mantenía una evolución favorable hasta el año y medio después de operado.

The case report of a 42 years, black skin patient is described, he attended the Peripheral Tumors Surgery Service in Conrado Benítez García Teaching Provincial Cancer Hospital in Santiago de Cuba, due to a hyperpigmented dark lesion in the left side of the scrotum, next to the raphe region, of approximately 4 mm and irregular borders that didn't elevate the skin or hurted. An excision of the lesion was carried out and the histological and pathological study revealed the existence of a melanoma, without ulceration or satelitosis, with radial growth, reason why there was a deep examination of the operated area in search of margins without affectation and the bilateral groin lymph nodes were dried up in a prophylactic way. Then chemotherapy and interferon injections were indicated. The patient maintained a favorable clinical course until a year and a half after the surgery.

Paniculitis secundaria a terapia target en paciente con melanoma, lo que el dermatólogo debe saber: reporte de un caso / Panniculitis in association with target therapy in melanoma patient, what the dermatologist should know: a case report

Las terapias target constituyen hoy en día una alternativa terapéutica cada vez más utilizada para el manejo de pacientes con melanoma metastásico. Sin embargo, se han descrito múltiples efectos farmacológicos adversos asociados a su uso, siendo los cutáneos los de mayor prevalencia. Se presenta el caso de un hombre de 55 años con diagnóstico de melanoma cutáneo metastásico etapa IV, BRAFV600E mutado, en tratamiento con dabrafenib/trametinib que consultó por desarrollo de lesiones nodulares eritematosas sensibles en extremidades superiores e inferiores, asociadas a sensación febril durante el curso del tratamiento. Se descartó alguna infección sobreagregada. Se realizó una biopsia de las lesiones cutáneas, con confirmación diagnóstica histopatológica de una paniculitis mixta de predominio septal, granulomatosa y con vasculitis leucocitoclástica. La paniculitis asociada a esta terapia ha sido descrita en la literatura y se ha considerado un efecto farmacológico inmunomediado adverso, relacionándose a un mejor pronóstico para el melanoma metastásico en tratamiento. Por lo tanto, así como en el caso presentado, se evita la suspensión del fármaco y se asocia terapia sintomática en caso de mayores molestias del paciente. Es de alta relevancia para el dermatólogo conocer e interpretar adecuadamente este efecto adverso farmacológico, y así indicar el manejo más adecuado para el paciente.

Target therapies are currently a therapeutic option increasingly used for the management of patients with metastatic melanoma. However, there are multiple adverse pharmacological effects associated with their use that have been described. Cutaneous adverse reactions are the most frequent. We report the case of a 55-year-old man with a diagnosis of stage IV BRAFV600E-mutated metastatic cutaneous melanoma undergoing treatment with dabrafenib/trametinib, who consulted due to the development of erythematous nodular lesions in the upper and lower limbs associated with febrile sensation during the course of treatment. Infection was ruled out and a biopsy of the skin lesions was done, which provided the histopathological confirmation of a predominantly septal, granulomatous with leukocytoclastic vasculitis, mixed panniculitis. Panniculitis associated with this therapy has been described in the literature and has been considered an immune-mediated pharmacological adverse effect. It is considered to be related to a better prognosis in the treatment of metastatic melanoma. Consequently, as shown in this case report, target therapy should not be discontinued and symptomatic medication should be given to alleviate patient discomfort. The dermatologist should know and properly interpret this adverse effect and prescribe the most appropriate management for the patient.

Efectos adversos inmunomediados por inhibidores de PD-1 / PD-1 inhibitors immune-mediated side effects

Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)

Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)

Primary scrotal melanoma: it is time to destigmatize genital lesions

Abstract Primary male genital melanomas are very rare; they are associated with high mortality and late detection. Scrotal melanoma is the least common presentation and only 23 cases have been reported. Herein, the authors present a 30-year-old patient with stage IIIC (T4b, N2a, M0) scrotal melanoma in order to report the characteristics, treatment, and outcome, as well as to emphasize the importance of examination of the genitals, education of patients about self-examination and destigmatizing genital lesions to increase the likelihood of earlier detection.

Effects of ranibizumab and amfenac on the functional abilities and radiosensitivity of uveal melanoma cells / Efeitos do ranibizumabe e do amfenac nas habilidades funcionais e na radiossensibilidade de células de melanoma uveal

ABSTRACT Purpose: To evaluate the effects of ranibizumab and amfenac in human uveal melanoma cell lines and to explore the ability of these compounds to sensitize uveal melanoma cells to radiation therapy. Methods: The 92.1 human uveal melanoma cell line was cultured and subjected to the proposed treatment (ranibizumab, amfenac, and a combination of both). Proliferation, migration, and invasion assays of the 92.1 uveal melanoma cell line were assessed after pretreatment with ranibizumab (125 mg/mL), amfenac (150 nM), or a combination of both. In addition, proliferation rates were assessed after treatment with ranibizumab and amfenac, and the cells were subsequently exposed to various radiation doses (0, 4, and 8 Gy). Results: Proliferation assay: cells treated with a combination of ranibizumab and amfenac had lower proliferation rates than controls (p=0.016) and than those treated with only ranibizumab (p=0.033). Migration assay: a significantly lower migration rate was observed in cells treated with amfenac than the control (p=0.014) and than those treated with ranibizumab (p=0.044). Invasion assay: there were no significant differences among the studied groups. Irradiation exposure: in the 4 Gy dose group, there were no significant differences among any groups. In the 8 Gy dose group, treatment with ranibizumab, amfenac, and their combination prior to application of the 8 Gy radiation led to a marked reduction in proliferation rates (p=0.009, p=0.01, and p=0.034, respectively) compared with controls. Conclusion: Combination of ranibizumab and amfenac reduced the proliferation rate of uveal melanoma cells; however, only amfenac monotherapy significantly decreased cell migration. The radiosensitivity of the 92.1 uveal melanoma cell line increased following the administration of ranibizumab, amfenac, and their combination. Further investigation is warranted to determine if this is a viable pretreatment strategy to render large tumors amenable to radiotherapy.

RESUMO Objetivo: Avaliar os efeitos do ranibizumabe em associação com o amfenac nas células de melanoma uveal humano e explorar a capacidade desses compostos em sensibilizar as células de melanoma uveal à radioterapia. Métodos: Células de melanoma uveal humano do tipo 92.1 foram cultivadas e submetidas ao tratamento proposto (ranibizumabe, amfenac e a combinação de ambos). Ensaios de proliferação, migração e invasão com as células de melanoma uveal do tipo 92.1 foram avaliados após tratamento com ranibizumabe (125 mg/ml), amfenac (150 nM) e a combinação de ambos. Além disso, as taxas de proliferação foram avaliadas após tratamento com ranibizumabe e amfenac com subsequente exposição das células a diferentes doses de radiação (0 Gy, 4 Gy e 8 Gy). Resultados: Ensaio de proliferação: células tratadas com ranibizumabe e amfenac combinados apresentaram taxas de proliferação inferiores em comparação ao grupo controle (p=0,016), do que as tratadas apenas com ranibizumabe (p=0,033). Ensaio de migração: foi observada uma taxa de migração significativamente mais baixa nas células tratadas com amfenac do que no grupo controle (p=0,014) e do que nas tratadas com ranibizumabe (p=0,044). Ensaio de invasão: não houve diferenças significativas entre os grupos estudados. Exposição à irradiação: no grupo da dose de 4 Gy, não houve diferença significante entre os grupos. No grupo da dose de 8 Gy, o tratamento com ranibizumabe, afenac e sua combinação antes da aplicação da radiação de 8 Gy levou a uma redução acentuada nas taxas de proliferação (p=0,009, p=0,01 e p=0,034, respectivamente) em comparação aos grupos controle. Conclusão: A combinação de ranibizumabe e amfenac reduziu a taxa de proliferação das células de melanoma uveal; no entanto, apenas o amfenac diminuiu significativamente a migração celular. A radiossensibilidade das células de melanoma uveal do tipo 92.1 aumentou após a administração de ranibizumabe, amfenac e sua combinação. Mais investigações são necessárias para determinar se esta é uma estratégia de pré-tratamento viável para tornar grandes tumores passíveis de radioterapia.

Terapia-alvo versus dacarbazina no tratamento de primeira linha do melanoma avançado não cirúrgico e metastático: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde, 2018-2020 / Terapia dirigida versus dacarbazina en el tratamiento de primera línea del melanoma avanzado no quirúrgico y metastásico: análisis de impacto presupuestario en la perspectiva del Sistema Nacional de Salud de Brasil, 2018-2020 / Target therapy versus dacarbazine in first-line treatment of advanced non-surgical and metastatic melanoma: budget impact analysis from the perspective of the Brazilian National Health System, 2018-2020

Objetivo: estimar o impacto orçamentário incremental da terapia-alvo para tratamento de primeira linha do melanoma avançado não cirúrgico e metastático, em comparação à dacarbazina. Métodos: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde (SUS) do Brasil; a partir de dados demográficos e estimativas da incidência, foi delimitada a população no horizonte temporal de três anos (2018-2020) e estimados os custos diretos médicos; foi considerado cenário de referência o tratamento com dacarbazina, e como cenários alternativos a terapia-alvo com vemurafenibe, dabrafenibe, vemurafenibe + cobimetinibe e dabrafenibe + trametinibe; a avaliação das incertezas foi conduzida mediante análise por cenários. Resultados: o impacto orçamentário incremental variou de R$ 451.867.881,00 a R$ 768.860.968,00, representando 0,70 a 1,53% dos gastos anuais totais com medicamentos ambulatoriais no SUS; no melhor e no pior cenário, os resultados variaram de R$ 289.160.835,00 a R$ 1.107.081.926,00. Conclusão: a terapia-alvo, comparada à dacarbazina, implica impacto excessivo no orçamento, desfavorecendo eventual incorporação.

Objetivo: estimar el impacto presupuestario incremental de la terapia dirigida para tratamiento de primera línea del melanoma avanzado no quirúrgico y metastásico comparado con la dacarbazina. Métodos: análisis de impacto presupuestario, en la perspectiva del Sistema Único de Salud (SUS) de Brasil; a partir de datos demográficos y estimaciones de incidencia se delimitó la población en un horizonte temporal de tres años (2018-2020) y se estimaron los costos directos médicos. El escenario de referencia fue el tratamiento con dacarbazina y los escenarios alternativos la terapia dirigida con vemurafenib, dabrafenib, vemurafenib + cobimetinib y dabrafenib + trametinib; la evaluación de incertidumbre se llevó a cabo mediante análisis por escenarios. Resultados: el impacto presupuestario incremental varió de R$ 451.867.881,00 a R$ 768.860.968,00, representando 0,70 a 1,53% de gastos anuales totales con medicamentos de ambulatorios en el SUS; en el mejor y el peor escenario los resultados variaron de R$ 289.160.835,00 a R$ 1.107.081.926,00. Conclusión: el uso de terapia dirigida comparado a la dacarbazina implica en impacto excesivo en el presupuesto, desfavoreciendo una eventual incorporación.

Objective: to estimate the incremental budget impact of target therapy for first-line treatment of advanced non-surgical and metastatic melanoma compared to dacarbazine treatment. Methods: budget impact analysis, from the Brazilian National Health System (SUS) perspective; based on demographic data and incidence estimates, the population over a three-year time horizon (2018-2020) was delimited and the direct medical costs were estimated; the reference scenario was treatment with dacarbazine, and the alternative scenarios were target therapy with vemurafenib, dabrafenib, vemurafenib + cobimetinib and dabrafenib + trametinib; uncertainty assessment was conducted through scenario analysis. Results: the incremental budget impact ranged from R$ 451,867,881.00 to R$ 768,860,968.00, representing 0.70 to 1.53% of total SUS annual outpatient drugs expenditure; in best and worst scenario, results ranged from R$ 289,160,835.00 to R$ 1,107,081,926.00. Conclusion: the use of target therapy compared to dacarbazine implies an excessive impact on the budget, this bring unfovorable to its possible incorporation.

Tratamiento con vemurafenib: indicación de mapeo corporal y seguimiento digital dermatoscópico / Vemurafenib treatment: indication of body mapping and dermoscopic digital follow-up

El Vemurafenib es un inhibidor de la enzima serina/treonina quinasa BRAF utilizado en el tratamiento de pacientes con melanoma con diseminación loco-rregional y enfermedad metastásica, portadores de la mutación V600E del gen BRAF. Se ha asociado a múltiples efectos adversos cutáneos de los cuales se destaca la posibilidad de generar cambios en los nevos melanocíticos, aparición de nuevos nevos e incluso de segundos melanomas. El seguimiento digital dermatoscópico con mapeo corporal, ha demostrado utilidad en el diagnóstico precoz de melanoma.Presentamos dos casos clínicos de pacientes con ante-cedentes de melanoma en tratamiento con inhibido-res de BRAF (BRAFi) e inhibidores de BRAF y MEK (MEKi) en quienes se realizó seguimiento digital der-matoscópico con mapeo corporal. Se detectaron cambios en nevos melanocíticos preexistentes, aparición segundos melanomas y metástasis cutáneas.El grupo de pacientes con antecedentes de melanoma y en tratamiento con BRAFi o combinación de BRA-Fi y MEKi se beneficia especialmente del control der-matológico con seguimiento digital dermatoscópico y mapeo corporal.

Vemurafenib is an inhibitor of the serine / threonine kinase BRAF enzyme currently used in the treatment of patients with locoregional spread and metastatic melanoma carriers of the mutationV600E of the BRAF gene. It has been associated with multiple cu-taneous adverse effects including changes in melanocytic nevi, appearance of new nevi and even second melanomas. Dermoscopic digital follow-up with total body mapping has proven useful in the early diagnosis of melanoma.We present two cases of patients with a history of me-lanoma in treatment with BRAF inhibitors (BRAFi) and inhibitors of BRAF and MEK (MEKi) in whom a digital dermoscopic follow-up was performed with body mapping. Changes in preexisting melanocytic nevi, second melanomas and cutaneous metastases were detected.The group of patients with a history of melanoma and in treatment with BRAFi or a combination of BRAFi and MEKi especially benefits from dermato-logical surveillance with digital dermoscopic follow-up and total body mapping.

Diphencyprone as a therapeutic option in cutaneous metastasis of melanoma. A single-institution experience

Abstract: Diphencyprone has been reported as a local immunotherapy for cutaneous melanoma metastases. We aim to report cases of melanoma patients treated with diphencyprone in a single Brazilian institution and highlight their outcomes. Since 2012, we have treated 16 melanoma patients with cutaneous metastases with topical diphencyprone. To date, we have had 37.5% of complete response, 25% of partial responses, and 31.25% patients without any response. Treatment was well tolerated and local toxicity was easily controlled. We believe topical diphencyprone is a feasible treatment that can be another option for treating melanoma patients, especially in cases of in-transit or extensive disease.

Treatment of advanced melanoma - A changing landscape / Tratamento de melanoma avançado - Um panorama em transformação

Summary Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival. As a result, new drugs have been approved for clinical use in the United States and Europe, including the immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review the results of studies that brought new approaches to the bedside and discuss how these developments are being incorporated into the care of patients in Brazil.

Resumo Após décadas de ostracismo, os recentes avanços no tratamento do melanoma trouxeram uma nova realidade para pacientes, médicos e pesquisadores. Enquanto anticorpos monoclonais voltados a moléculas envolvidas na modulação da interação entre células do melanoma e do sistema imune consolidaram o uso da "imunoterapia", um melhor conhecimento acerca das aberrações genômicas envolvidas na carcinogênese do melanoma viabilizaram o desenvolvimento de inibidores da via mitogen-activated protein kinase pathway (MAPK), o que também resultou em ganhos significativos em taxas de resposta e sobrevida. Consequentemente, novas modalidades de tratamento foram aprovadas para uso clínico nos Estados Unidos e na Europa, incluindo os bloqueadores de correceptores imunes ipilimumabe, nivolumabe e pembrolizumabe, o herpesvírus oncolítico talimogene laherparepvec (T-VEC), e os agentes-alvo vemurafenibe, dabrafenibe, cobimetinibe e trametinibe. Nesse artigo, revisamos os resultados que trouxeram novas alternativas para a prática clínica e discutimos a incorporação desses avanços ao cuidado de pacientes no Brasil.

Effects of nivolumab in peritoneal carcinamatosis of malign melanoma in mouse model

Abstract Purpose: To evaluate the efficacy of nivolumab and comparison with dacarbazine (DTIC) on peritoneal carcinomatosis of malignant melanoma in mouse model. Methods: Mouse skin melanoma cells was injected under the capsule of the peritoneal surface in the left side of the abdomen. On postoperative day ten, mouses randomised into three groups. Group 1: Control, Group 2: HIPEC (Hyperthermic intraperitoneal chemotherapy) with DTIC and Group 3: HIPEC with Nivolumab. After the sacrification on postoperative day fifteen, peritoneum evaluated macroscopically and histopathologically by using peritoneal regression grading score (PRGS). Results: In the 15th day exploration, all animals developed extensive intraperitoneal tumor growth in Group 1. In Group 2 and Group 3 median tumor size was 0.7±0.3cm and 0.3±0.2cm respectively (p: 0.023). Peritoneal carcinomatosis index (PCI) were significantly lower in Group 3 than other groups (p: 0.019). The lowest total tumor nodules in group 3 was 4 ± 2. The PGRS score was found significantly lower in Group 3 than other groups (p: 0.03). Lymphocytic response rate was found higher in the Group 3. Conclusions: It has been found that nivolumab significantly better than DTIC on peritoneal metastases of malign melanoma in mouse models. Nivolumab treatment gives promising results with pathological evidence in the treatment of metastatic disease of malignant melanoma.

Cancer immunology and melanoma immunotherapy

Abstract: The stimulation of the immune system, in order to generate an attack against cancer cells, similarly to that which occurs in infectious disease, has long been matter of interest in oncology; however, only limited success has been achieved, with different treatment strategies tested in recent years. The development of new immune checkpoint inhibitors is currently changing this scenario, and immunotherapy is becoming a real choice among traditional cytotoxic treatments to fight cancer. Recent reports have shown efficacy and safety with the use of pembrolizumab, nivolumab, and ipilimumab for the treatment of different neoplasms, especially melanoma. In this article, we propose a review of the mechanisms of action involved in cancer immunology, the response evaluation of immunotherapies, and its toxicity profile, as well as a summary of the main clinical trials that led to the adoption of these new drugs for melanoma treatment.

An extremely rare case of concurrent BRAF V600E mutation driven hairy cell leukemia and melanoma: case report and review of literature

BRAF protein is a serine/threonine kinase with 766 amino acids. Approximately 15% of human cancers harbor BRAF mutations as well as other BRAF anomalies (amplifications, fusions). Somatic mutations mainly occur in the catalytic kinase domain (CR3), and the predominant mutation is p.V600E which is the substitution of glutamic acid (E) for valine (V) as result of a mutation at codon 600 of the kinase domain. To our knowledge, the vast majority of the cancers have non-germline BRAF mutations. Here we describe a case of a 60-year-old female with a history of hairy cell leukemia (HCL) who presented with aphasia and forgetfulness. A follow-up Brain CT scan showed three distinct brain lesions which were found to be diagnostic of melanoma (confirmed by immunohistochemistry) with no evidence of a concurrent brain involvement by a B-cell neoplasm. Molecular studies confirmed the same BRAF p.V600E mutation in both malignancies (hairy cell leukemia and melanoma). Thereafter the patient was started on BRAF inhibitor treatment and is now symptom-free after one year of follow up. Having two concurrent malignancies with a shared BRAF mutation is extremely rare and makes this an excellent example of a genomic marker-driven treatment in two histologically and immunophenotypically distinct tumors.