Terapias dirigidas con inhibidores del braf en gliomas pediátricos de alto y bajo grado con la mutación brafv600e. Experiencia del hospital Prof. Dr. Juan P. Garrahan / Targeted therapies with BRAF inhibitors for pediatric low- and high-grade gliomas with BRAF v600e mutation. Prof. Dr. Juan P. Garrahan Hospital experience

Resumen La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAF V600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAF V600E mu tado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAF V600E mutado tratados con inhibidores BRAF V600E . En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.

Abstract The BRAF V600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAF V600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAF V600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAF V600E mutated low-grade gliomas treated with BRAF V600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.

Human papillomavirus-negative epithelial proliferations resembling condylomata acuminata in a patient receiving vemurafenib for Stage IV melanoma

With the discovery of v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, new treatment possibilities arose against metastatic melanoma. A frequent adverse effect of BRAF inhibitor therapy is the induction of epithelial proliferations such as cutaneous squamous cell carcinoma and verrucous papilloma. Here, we describe a case in which a patient developed extensive anal epithelial proliferations resembling condylomata acuminata, after starting vemurafenib treatment. This adverse effect has rarely been reported in the literature. Interestingly, the lesions in our patient were negative for human papillomavirus, and mutations in BRAF, Neuroblastoma rat sarcoma viral oncogene homolog (NRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Harvey rat sarcoma viral oncogene homolog (HRAS) were not detected. Different pathways can contribute to these epithelial proliferations resembling condylomata acuminata. We show the relevance of a detailed history at the beginning and during treatment, instructions, education, and dermatological follow-up (including the genital area) for patients treated with BRAF inhibitors. Condylomata acuminata can influence the quality of life and are treated, in an early stage, with cryotherapy, coagulation, imiquimod, and/or CO2 laser therapy.

Análise de custo por evento evitado (COPE) da associação de cobimetinibe e vemurafenibe e outras opções terapêuticas para o tratamento de melanoma metastático com mutação BRAF V600 / Cost of preventing an event (COPE) comparison between the association of cobimetinib and vemurafenib among other treatment options for metastatic melanoma with BRAF V600 Mutation

Objetivo: O melanoma maligno é o tipo de neoplasia de pele com pior prognóstico devido ao seu elevado potencial de gerar metástases e a sua letalidade. Algumas diretrizes internacionais recomendam a combinação de inibidores da via das proteínas quinases BRAF e MEK para o tratamento de melanoma metastático ou irressecável com mutação positiva BRAF V600 em primeira linha. Um estudo demonstrou que, em termos de sobrevida livre de progressão (SLP), a associação de cobimetinibe + vemurafenibe foi a opção terapêutica que proporcionou menor valor de número necessário para tratar (NNT) para o tratamento de melanoma metastático com mutação BRAF V600 em primeira linha. O objetivo desta análise foi de avaliar o custo por evento evitado (COPE) de cobimetinibe em associação com vemurafenibe no tratamento do melanoma irressecável ou metastático, positivos para mutações BRAF V600. Métodos: A análise econômica adotou a perspectiva do Sistema de Saúde Suplementar brasileiro. Os comparadores avaliados foram vemurafenibe monoterapia, dabrafenibe + trametinibe, nivolumabe e ipilimumabe. O COPE foi obtido pelo produto do NNT, baseado na SLP em 12 meses, reportado por Ho et al. e do custo de tratamento considerando custos de aquisição dos medicamentos e manejo de eventos adversos. Resultados: A maior eficiência da associação de cobimetinibe e vemurafenibe foi capaz de proporcionar o menor COPE (R$ 1.204.229) entre todos os comparadores da análise, demonstrando que, com um menor número de pacientes tratados, se observa um caso de sucesso com a terapia combinada, mesmo que esta apresente um custo anual de tratamento superior (R$ 626.477). Conclusão: A associação de cobimetinibe e vemurafenibe foi a mais eficiente em termos de NNT e COPE no melanoma metastático não tratado previamente.

Objective: Melanoma is a type of skin cancer with poor prognosis due to its high potential for metastasis and lethality. Some international guidelines recommend the combination of BRAF and MEK protein kinase pathway inhibitors for the first line treatment of metastatic or unresectable melanoma with BRAF V600 positive mutation. One study demonstrated that in terms of PFS, the combination of cobimetinib + vemurafenib was the first line therapeutic option that provided the lowest number needed to treat (NNT) for BRAF V600 mutated metastatic melanoma. The objective of this analysis was to evaluate the cost of preventing and event (COPE) of cobimetinib in combination with vemurafenib in the treatment of unresectable or metastatic melanoma, positive for BRAF V600 mutations. Methods: The economic analysis adopted the perspective of the Brazilian Supplementary Health System. The comparators evaluated were vemurafenib monotherapy, dabrafenib + trametinib, nivolumabe and ipilimumab. COPE was obtained from the NNT product, based on 12-month progression-free survival (PFS), reported by Ho et al., and the cost of treatment considering medication acquisition costs and adverse event management. Results: The greater efficiency of the combination of cobimetinib and vemurafenib was able to provide the lowest COPE (R$ 1,204,229) among all comparators of the analysis, demonstrating that with a lower number of treated patients a case of success was observed with the combination therapy, even if it presents a higher annual cost of treatment (R$ 626,477). Conclusion: The combination of cobimetinib and vemurafenib was the most efficient in terms of NNT and COPE for previously untreated metastatic melanoma.

Rescate quirúrgico de metástasis suprarrenal por melanoma, previo tratamiento con vemurafenib / Surgical rescue of adrenal metastasis by melanoma following treatment with vemurafenib

Presentamos el caso de una paciente con metástasis suprarrenal única de melanoma, que fue some-tida a tratamiento sistémico con vemurafenib (un inhibidor de la quinasa BRAF) en primera instancia y luego a tratamiento quirúrgico. La bibliografia actual recomienda el tratamiento quirúrgico de las metástasis de melanoma y sostenen que, en aquellos pacientes con mutación de la quinasa BRAF, los inhibidores de esta serían seguros acompañando a las metastasectomías y mejorarían el control de la enfermedad de forma más sostenida en el tempo. Conclusión: si bien, durante muchos años, la cirugía fue la única terapia para la enfermedad en estadio IV, con las terapias de drogas modernas la situación se ha vuelto más compleja; esto ha creado el desafo de determinar la combinación óptma y la secuencia de terapias adecuada; en este sentido consideramos fundamental que casos como el presentado aquí se discutan en comité de tumores.

We report the case of a patent presenting with a single melanoma metastasis in the adrenal gland, who underwent systemic treatment with vemurafenib (BRAF kinase inhibitor) in the frst instance and then underwent surgery. Current literature recommends surgical treatment of melanoma metastases and supports the use of inhibitors in patents with a BRAF kinase mutaton since they may improve disease control in a more sustained manner over tme. Although for many years surgery was the only therapy for stage IV disease, with modern drug therapies, the situaton has become more complex; this has created the challenge of determining the optmal combinaton and appropriate sequence of therapies; in this sense we consider it fundamental that cases such as the one presented here are discussed in tumor commitee meetings.

Infección necrotzante de la pared abdominal posticesárea / Necrotzing infecton of the abdominal wall following a cesarean secton

La infección necrotzante de partes blandas (INPB) es una entidad rara, que afecta principalmente a individuos con factores de riesgo específicos pero en ocasiones suele afectar a mujeres puérperas, que al poseer un estado de inmunosupresión favorecería la aparición y curso más agresivo de la enfermedad. Presentamos el caso de una mujer de 20 años edad puérpera, sin antecedentes patológicos, que desarrolla una fascits necrotzante de la pared abdominal como complicación de una cesárea. Se realizó una resección amplia de la pared abdominal, anexohisterectomía, lavado de cavidad peritoneal y cierre temporal con bolsa de Bogotá. Tras una internación prolongada en unidad de terapia intensiva se programó el cierre de la pared abdominal utlizando una malla de poliglactina en contacto con las vísceras, sobre la cual se colocó una malla de polipropileno para proporcionar resistencia. Se inicia terapia de presión negativa (TPN) con vacuum pack de Barker hasta programar la reconstrucción de la pared abdominal con injertos de piel autólogos. Luego se continúo tratamiento con sistema V.A.C. ® ATS sobre los injertos, presentando una evolución favorable. El objetivo de esta carta científica es presentar una complicación poco habitual de la operación cesárea, destacando los aspectos más importantes de la enfermedad, definiendo algunas recomendaciones y remarcando la importancia del abordaje multidisciplinario.

Necrotzing sof tssue infecton (NSTI) is a rare disease that mainly afects individuals with specific risk factors but sometmes afects postpartum women as well. These women have a state of immunosup-pression, which would favor the appearance and more aggressive course of the disease. We report the case of a 20-year-old woman with no pathological history who developed necrotzing fasciits of the abdominal wall as a complicaton of a cesarean secton. An extensive abdominal wall resecton was performed, followed by total histerectomy and bilateral adnexectomy, peritoneal cavity lavage, and temporary abdominal closure with a Bogotá bag. Afer prolonged hospitalizaton in an intensive care unit, the abdominal wall was closed using a polyglactin mesh in contact with the viscera, on which a polypropylene mesh was placed to provide resistance. Negative pressure wound therapy with a Barker´s vacuum pack was started untl the reconstructon of the abdominal wall with autolo-gous skin grafis could be programmed. Then, a V.A.C. ATS ® therapy was used on skin grafis, showing a favorable evoluton. The objective of this scientific leter is to discuss an uncommon complicaton of the cesarean secton, emphasizing the most important aspects of the disease, and defining recommendatons for the mana-gement of this pathology and its multidisciplinary approach.

Comparação entre a associação de cobimetinibe e vemurafenibe e outras opções terapêuticas para o tratamento de melanoma metastático com mutação BRAFV600: número necessário para tratar (NNT) / Number needed to treat (NNT) comparison between the association of cobimetinib and vemurafenib among other treatment options for metastatic melanoma with brafv600 mutation

Objetivo: O objetivo do estudo foi estimar e comparar o número necessário para tratar (NNT) entre a associação de cobimetinibe + vemurafenibe e outras opções terapêuticas no tratamento de melanoma metastático BRAFV600 mutado em primeira linha. Métodos: O NNT foi calculado como o inverso do risco absoluto de um medicamento em um ponto específico de tempo (12 meses). Os comparadores considerados foram o vemurafenibe monoterapia, dabrafenibe monoterapia, dabrafenibe + trametinibe, nivolumabe e ipilimumabe. O desfecho considerado foi a sobrevida livre de progressão (SLP), cujas curvas foram obtidas dos estudos coBRIM, BRIM-3, Robert, 2015, BREAK-3 e Checkmate 67. Resultados: Em 12 meses, os resultados de NNT foram: cobimetinibe + vemurafenibe = 1,92, vemurafenibe = 3,33; dabrafenibe = 4,67; dabrafenibe + trametinibe = 2,04; nivolumabe = 4,39 e ipilimumabe = 7,84. Conclusão: A associação de cobimetinibe e vemurafenibe no tratamento de pacientes com melanoma irressecável ou metastático, positivo para mutação BRAFV600 sem tratamento sistêmico prévio para a doença, apresenta resultados favoráveis em termos de NNT quando comparada a todas as outras opções terapêuticas disponíveis no mercado brasileiro para essa mesma indicação.

Objective: The objective of the study was to estimate and compare the number needed to treat (NNT) between the association of cobimetinib + vemurafenib and other therapeutic options in the first line treatment of metastatic melanoma with BRAFV600 mutation. Methods: The NNT was calculated as the inverse of absolute risk of a drug in a specific time point (12 months). The considered comparators were vemurafenib (monotherapy), dabrafenib (monotherapy), dabrafenib + trametinib, nivolumab and ipilumumab. Progression free survival (PFS) was the defined outcome, and its curves were obtained from coBRIM, BRIM-3, BREAK-3, Robert, 2015 and Checkmate 67 studies. Results: In 12 months, the NNT results were: cobimetinib + vemurafenib = 1.92; vemurafenib = 3.33; dabrafenib = 4.67; dabrafenib + trametinib = 2.04; nivolumab = 4.39 and ipilimumab = 7.84. Conclusion: The association of cobimetinib and vemurafenib in the treatment of patients with unresectable or metastatic melanoma, BRAFV600 mutated without previous systemic treatment, showed favorable results in terms of NNT when compared to the other therapeutic options available in the Brazilian market for the same indication.

Therapeutic Inhibitors against Mutated BRAF and MEK for the Treatment of Metastatic Melanoma / 전남의대학술지

Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib. These kinase inhibitors have the potential to work in tandem with MEK, PI3K/AKT, and mTOR to inhibit the activity of melanoma inducing BRAF mutations. This review summarizes the effects of the new therapeutic agents against melanoma and the underlying biology of these BRAF inhibitors.

Therapeutic Inhibitors against Mutated BRAF and MEK for the Treatment of Metastatic Melanoma / 전남의대학술지

Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib. These kinase inhibitors have the potential to work in tandem with MEK, PI3K/AKT, and mTOR to inhibit the activity of melanoma inducing BRAF mutations. This review summarizes the effects of the new therapeutic agents against melanoma and the underlying biology of these BRAF inhibitors.

Mecanismos de regulação epigenética e heterogeneidade tumoral clonal em melanoma metastático humano envolvendo gene RECK / Mechanisms of epigenetic regulation and tumor clonal heterogeneity in human metastatic melanoma involving RECK gene

Os pacientes com melanomas, em geral, apresentam extrema quimiorresistência e prognóstico ruim, com taxa de sobrevida de aproximadamente seis meses; portanto, novas estratégias terapêuticas são necessárias. As células deste tipo de tumor acumulam alterações na expressão gênica que contribuem para a proliferação descontrolada, evasão de senescência e inibição de morte celular em múltiplas rotas intracelulares. No Capítulo 1, foi explorado o controle epigenético do supressor tumoral RECK. Esse gene é largamente expresso em tecidos normais, com correlação de sua expressão com melhor prognóstico. Em tumores, RECK é inibido, incluindo em melanoma. Neste estudo, sua inibição por hipermetilação do promotor e remodelamento da cromatina por HDACs não foi o único fator inibitório nas linhagens de melanoma analisadas. Mesmo após a utilização a remoção de marcas epigenéticas associadas ao silenciamento gênico, a expressão proteica não pôde ser recuperada nas linhagens utilizadas neste trabalho. No Capítulo 2, isolou-se subpopulações clonais ao acaso a fim de modelar a heterogeneidade tumoral intrínseca. Neste modelo experimental, caracterizamos a presença de dois perfis tumorais subclonais: uma mais proliferativa, invasiva e sensível a vemurafenibe; e outra menos proliferativa, mais resistente e com maior expressão de RECK e fatores ligados a EMT. Nossos resultados, em conjunto, mostraram que as linhagens celulares parentais utilizadas apresentam diferenças entre si quanto à viabilidade celular, indução de apoptose e fosforilação de ERK após o tratamento com vemurafenibe. Segundo o nosso modelo, a resistência intrínseca ao vemurafenibe está presente e reflete a heterogeneidade do tumor inicial. Com estes resultados, pretendemos contribuir para o conhecimento sobre a composição clonal presente na heterogeneidade tumoral, além de contribuir para a função de RECK na biologia do melanoma

Patients with melanoma often present extreme chemoresistance and poor prognosis, with survival rates of approximately six months; therefore, new therapeutic strategies are necessary. Melanoma cells accumulate genotypic changes that contribute to uncontrolled proliferation, evasion of senescence and cell death inhibition in multiple cellular pathways. In Chapter 1, we have explored the epigenetic control of the tumor suppressor RECK. This gene is widely expressed in normal tissues, with correlation of its expression with better prognosis. In tumors, RECK is inhibited, including melanoma. Here, RECK inhibition by promoter hypermethylation and chromatin remodeling by HDACs was not the only inhibiting factor in the melanoma cell lines analyzed. Even after removing the epigenetic marks associated to gene expression silencing, the protein expression could not be recovered in the cell lines used in this study. In Chapter 2, it has been isolated several tumor clonal subpopulations in order to modulate the intrinsic tumor heterogeneity. In this experimental model, we have characterized the presence of two tumor subclonal profiles: a more proliferative, invasive and sensitive to Vemurafenib; and other less proliferative, less sensitive to Vemurafenib and presenting more expression of RECK and factors associated to EMT. Our results together have showed the parental cell lines used here differed from each other in terms of cell viability, induction of apoptosis, and ERK phosphorylation after treatment with Vemurafenib. According to our model, the intrinsic resistance to Vemurafenib is present and reflects the heterogeneity of the initial tumor. With these results, we intend to contribute to the knowledge of the tumor clonal subpopulations composition in tumor heterogeneity, and contributes to the RECK function in melanoma biology.

New Systemic Treatment for Malignant Melanoma / 대한내과학회지

Although early stage melanoma can be cured by complete resection, the prognosis of the patients with unresectable or metastatic disease is dismal with the overall survival less than 1 year based on resistance to chemotherapeutic agents. Dacarbazine as either a single agent or in combination regimens with other cytotoxic agents has still remained as a standard in Korea for more than three decades although it has not been associated with any survival benefit for metastatic melanoma. Recently, according to advances in molecular science and immunology, the mechanisms responsible for biology of melanoma have been elucidated and then new agents targeting these mechanisms have been introduced leading survival benefit in patients with metastatic melanoma. Unfortunately, however, it is still difficult to give those new drugs to these patients in Korea because of the health insurance guidelines still defining dacarbazine as a front line regimen and moreover high cost and unavailability in the practice. Therefore, amendment of current guidelines and an in-depth discussion with the government for the earlier use of the novel drugs are strongly needed for the patients' sake.

New Systemic Treatment for Malignant Melanoma / 대한내과학회지

Although early stage melanoma can be cured by complete resection, the prognosis of the patients with unresectable or metastatic disease is dismal with the overall survival less than 1 year based on resistance to chemotherapeutic agents. Dacarbazine as either a single agent or in combination regimens with other cytotoxic agents has still remained as a standard in Korea for more than three decades although it has not been associated with any survival benefit for metastatic melanoma. Recently, according to advances in molecular science and immunology, the mechanisms responsible for biology of melanoma have been elucidated and then new agents targeting these mechanisms have been introduced leading survival benefit in patients with metastatic melanoma. Unfortunately, however, it is still difficult to give those new drugs to these patients in Korea because of the health insurance guidelines still defining dacarbazine as a front line regimen and moreover high cost and unavailability in the practice. Therefore, amendment of current guidelines and an in-depth discussion with the government for the earlier use of the novel drugs are strongly needed for the patients' sake.