Primary Extra-axial Glioblastoma: Case Report and Literature Review

Glioblastoma multiforme (GBM) is the most frequent and most aggressive primary brain tumor in adults,mainly located in the cerebral hemispheres. In the literature, few cases of primary GBM have been reported to have radiographic and intraoperative features of extra-axial lesions, leading to a diagnostic dilemma. Despite the advances in imaging modalities, the diagnosis of GBM can be challenging, and it is mainly based on the histopathologic confirmation of the excised tumor. We describe the case of a 76- year-old previously healthy female patient who presented to our hospital due to speech disturbances and cognitive impairment. The diagnosis of the tumor type on magnetic resonance imaging (MRI) was difficult, as the findings were suggestive of a malignant meningioma due to the heterogeneous enhancement of a dural-based mass with a dural tail sign. Moreover, the intraoperative findings revealed an extra-axial mass attached to the dura. A histological examination confirmed the diagnosis of glioblastoma with arachnoid infiltration. The patient underwent adjuvant radiotherapy and concomitant temozolomide treatment, she had clinical improvement postoperatively, and was stable during the six months of follow-up. Glioblastoma should be considered in the differential diagnosis of primary extra-axial mass with atypical and malignant features, especially in elderly patients.

Magnetic hyperthermia therapy in glioblastoma tumor on-a-Chip model / Terapia de magneto-hipertermia no modelo de tumor de glioblastoma on-a-Chip

ABSTRACT Objective: To evaluate the magnetic hyperthermia therapy in glioblastoma tumor-on-a-Chip model using a microfluidics device. Methods: The magnetic nanoparticles coated with aminosilane were used for the therapy of magnetic hyperthermia, being evaluated the specific absorption rate of the magnetic nanoparticles at 300 Gauss and 305kHz. A preculture of C6 cells was performed before the 3D cells culture on the chip. The process of magnetic hyperthermia on the Chip was performed after administration of 20μL of magnetic nanoparticles (10mgFe/mL) using the parameters that generated the specific absorption rate value. The efficacy of magnetic hyperthermia therapy was evaluated by using the cell viability test through the following fluorescence staining: calcein acetoxymethyl ester (492/513nm), for live cells, and ethidium homodimer-1 (526/619nm) for dead cells dyes. Results: Magnetic nanoparticles when submitted to the alternating magnetic field (300 Gauss and 305kHz) produced a mean value of the specific absorption rate of 115.4±6.0W/g. The 3D culture of C6 cells evaluated by light field microscopy imaging showed the proliferation and morphology of the cells prior to the application of magnetic hyperthermia therapy. Fluorescence images showed decreased viability of cultured cells in organ-on-a-Chip by 20% and 100% after 10 and 30 minutes of the magnetic hyperthermia therapy application respectively. Conclusion: The study showed that the therapeutic process of magnetic hyperthermia in the glioblastoma on-a-chip model was effective to produce the total cell lise after 30 minutes of therapy.

RESUMO Objetivo: Avaliar a terapia de magneto-hipertermia em modelo de tumor de glioblastoma on-a-Chip. Métodos: As nanopartículas magnéticas recobertas com aminosilana foram utilizadas para a terapia da magneto-hipertermia, sendo avaliada a taxa de absorção específica das nanopartículas magnéticas em 300 Gauss e 305kHz. Uma pré-cultura de células C6 foi realizada e, seguidamente, foi feito o cultivo das células 3D no chip. O processo de magneto-hipertermia no chip foi realizado após administração de 20μL de nanopartículas magnéticas (10mgFe/mL), utilizando os parâmetros que geraram o valor da taxa de absorção específica. A eficácia da terapia de magneto-hipertermia foi avaliada pela viabilidade celular por meio dos corantes fluorescentes acetoximetiléster de calceína (492/513nm), para células vivas, e etídio homodímero-1 (526/619nm), para células mortas. Resultados: As nanopartículas magnéticas, quando submetidas ao campo magnético alternado (300 Gauss e 305kHz), produziram um valor médio da taxa de absorção específica de 115,4±6,0W/g. A cultura 3D das células C6 avaliada por imagem de microscopia de campo claro mostrou a proliferação e a morfologia das células antes da aplicação da terapia de magneto-hipertermia. As imagens de fluorescência mostraram diminuição da viabilidade das células cultivadas no organ-on-a-Chip em 20% e 100% após 10 e 30 minutos, respectivamente, da aplicação da terapia de magneto-hipertermia. Conclusão: O processo terapêutico da magneto-hipertermia no modelo de tumor glioblastoma on-a-chip foi eficaz para produzir lise total das células após 30 minutos de terapia.

Patterns of recurrence and outcomes of glioblastoma multiforme treated with chemoradiation and adjuvant temozolomide

OBJECTIVES: To assess the patterns of failure and prognostic factors in Brazilian patients with glioblastoma multiforme (GBM) treated with radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). METHODS: Patients with diagnosed GBM post-resection received postoperative RT. TMZ was administered concurrently at 75 mg/m2/day for 28 consecutive days and adjuvant therapy at 150-200 mg/m2/day for 5 days every 28 days. Radiographic failure was defined as any new T1-enhancing lesion or biopsy-confirmed progressive enhancement inside of the radiation field. When possible, patients with recurrence were salvaged with metronomic TMZ, either in combination with a local treatment or alone (surgery or re-irradiation). Several prognostic factors were evaluated for overall survival (OS). Univariate and multivariate analyses were performed to identify significant factors. A p-value <0.05 was considered significant. RESULTS: This study included 50 patients. The median follow-up time was 21 months. The median RT dose was 60 Gy and all patients received concomitant TMZ. During follow-up, 41 (83.6%) failures were observed, including 34 (83%) in-field, 4 (9.7%) marginal, and 3 (7.3%) distant failures. Metronomic TMZ was used as salvage treatment in 22 (44%) cases and in combination with local treatment in 12 (24%) cases. The median OS and progression-free survival times for the entire cohort were 17 and 9 months, respectively. In univariate analysis, the following factors were significant for better OS: maximal surgical resection (p=0.03), Karnofsky Performance Score (KPS)>70 at diagnosis (p=0.01), metronomic TMZ treatment (p=0.038), recursive partitioning analysis class III (p=0.03), and time to failure >9 months (p=0.0001). In multivariate analysis, the following factors remained significant for better OS: metronomic TMZ (p=0.01) and time to failure >9 months (p=0.0001). CONCLUSION: The median OS of Brazilian patients with GBM treated with RT and TMZ was satisfactory. Although TMZ therapy has become the standard of care for patients with newly diagnosed GBM, the recurrence rate is extremely high. Metronomic TMZ as salvage treatment improved survival in these patients.

Avances neuroquirúrgicos y biología molecular en el tratamiento del glioblastoma multiforme / Neurosurgical advances and molecular biology in the treatment of glioblastoma multiforme

RESUMEN A pesar de los avances en radioterapia, quimioterapia y los tratamientos de resección quirúrgica agresiva en el glioblastoma multiforme, el pronóstico sigue siendo sombrío. Con la presente revisión se describen, en un marco actual, las principales alternativas de tratamiento del glioblastoma multiforme. Se revisaron los principales artículos publicados en inglés, en revistas de alto impacto a nivel mundial, acerca de los principales avances en el tratamiento de este tumor. Se abordaron los importantes progresos neuroquirúrgicos en la resección del glioblastoma así como las implicaciones de las células madres tumorales en la génesis y control de la proliferación tumoral y el efecto de la hipoxia sobre la dinámica celular tumoral. Se explican las alteraciones del ADN que ocasionan tumorogénesis y las mutaciones del PTEN en el glioblastoma (AU).

SUMMARY Despite advances in radiotherapy, chemotherapy and aggressive surgical resection treatments in glioblastoma multiforme, the prognosis remains discouraging. With the current review, the main alternatives for the treatment of glioblastoma multiforme are described in a current context. The authors reviewed the main articles published in English, in high impact journals worldwide, on the main advances in the treatment of this tumor. The main neurosurgical advances in the resection of glioblastoma were addressed, as well as the implications of tumor stem cells in the genesis and control of tumor proliferation, as well as the effect of hypoxia on tumor cell dynamics. DNA alterations causing tumor genesis and PTEN mutations in glioblastoma are also explained (AU).

Therapeutic evaluation of magnetic hyperthermia using Fe3O4-aminosilane-coated iron oxide nanoparticles in glioblastoma animal model / Avaliação terapêutica da técnica de magneto-hipertermia utilizando nanopartículas de Fe3O4 recobertas com aminosilana em modelo animal de glioblastoma

ABSTRACT Objective: To evaluate the potential of magnetic hyperthermia using aminosilane-coated superparamagnetic iron oxide nanoparticles in glioblastoma tumor model. Methods: The aminosilane-coated superparamagnetic iron oxide nanoparticles were analyzed as to their stability in aqueous medium and their heating potential through specific absorption rate, when submitted to magnetic hyperthermia with different frequencies and intensities of alternating magnetic field. In magnetic hyperthermia in vitro assays, the C6 cells cultured and transduced with luciferase were analyzed by bioluminescence in the absence/presence of alternating magnetic field, and also with and without aminosilane-coated superparamagnetic iron oxide nanoparticles. In the in vivo study, the measurement of bioluminescence was performed 21 days after glioblastoma induction with C6 cells in rats. After 24 hours, the aminosilane-coated superparamagnetic iron oxide nanoparticles were implanted in animals, and magnetic hyperthermia was performed for 40 minutes, using the best conditions of frequency and intensity of alternating magnetic field tested in the in vitro study (the highest specific absorption rate value) and verified the difference of bioluminescence before and after magnetic hyperthermia. Results: The aminosilane-coated superparamagnetic iron oxide nanoparticles were stable, and their heating capacity increased along with higher frequency and intensity of alternating magnetic field. The magnetic hyperthermia application with 874kHz and 200 Gauss of alternating magnetic field determined the best value of specific absorption rate (194.917W/g). When these magnetic hyperthermia parameters were used in in vitro and in vivo analysis, resulted in cell death of 52.0% and 32.8%, respectively, detected by bioluminescence. Conclusion: The magnetic hyperthermia was promissing for the therapeutical process of glioblastoma tumors in animal model, using aminosilane-coated superparamagnetic iron oxide nanoparticles, which presented high specific absorption rate.

RESUMO Objetivo: Avaliar o potencial da técnica de magneto-hipertermia utilizando nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana em modelo de tumores de glioblastoma. Métodos: As nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana foram avaliadas quanto à sua estabilidade em meio aquoso e a seu potencial de aquecimento pela taxa de absorção específica, quando submetidas à magneto-hipertermia, com diferentes frequências e intensidades de campo magnético alternado. Nos ensaios de magneto-hipertermia in vitro, as células C6 cultivadas e transduzidas com luciferase foram avaliadas por bioluminescência na presença/ausência do campo magnético alternado, como também com e sem nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana. No estudo in vivo, a medida de bioluminescência foi adquirida no 21º dia após indução do glioblastoma com células C6 nos ratos. Após 24 horas, as nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana foram implantadas no animal, tendo sido realizada a magneto-hipertermia por 40 minutos, nas melhores condições de frequência e intensidade de campo magnético alternado testado no estudo in vitro (maior valor da taxa de absorção específica); foi verificada a diferença do bioluminescência antes e após a magneto-hipertermia. Resultados: As nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana se mostraram estáveis, e sua capacidade de aquecimento aumentou com o incremento da frequência e da intensidade de campo magnético alternado. A aplicação da magneto-hipertermia, com 874kHz e 200 Gauss do campo magnético alternado, determinou o melhor valor da taxa de absorção específica (194,917W/g). Quando utilizados, estes parâmetros de magneto-hipertermia in vitro resultaram em morte celular de 52,0% e in vivo de 32,8% por bioluminescência. Conclusão: A técnica de magneto-hipertermia foi promissora para o processo terapêutico de tumores de glioblastoma no modelo animal utilizando as nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana recobertas com aminosilana, que apresentaram alta taxa de absorção específica.

Survival Analysis in Elderly Patients with Glioblastomas: The Influence of Clinical Status, Tumor and Surgical Features

Introduction Glioblastomas are malignant neoplasms, notorious for their poor prognosis. We have conducted a survival analysis in a sample of elderly patients with glioblastomas. Methods The sample of the present study consisted of elderly patients consecutively admitted from January 2014 to January 2016 (24 months) at the Hospital do Servidor Público Estadual de São Paulo. We have evaluated the impact of age, Karnofsky scale (KS) score, tumor location, and occurrence of perioperative complications. Results A total of 42 patients were analyzed. Of these, 23 (54.7%) were men, and 19 (45.3%) were women. Patients > 60 years old, with low KS score, deep-seated tumors, and those with perioperative complications had worst outcomes. Discussion and conclusion Surgery, perioperative chemotherapy and radiotherapy add survival time and quality of life to these patients. In patients with low KS score, isolated radiotherapy and/or chemotherapy might be adequate. Decreasing perioperative complications is essential to adequately deliver adjuvant therapy in elderly patients.

Relevant coexpression of STMN1, MELK and FOXM1 in glioblastoma and review of the impact of STMN1 in cancer biology / Coexpressão relevante de STMN1, MELK e FOXM1 em glioblastoma e revisão do impacto de stmn1 na biologia do câncer

OBJECTIVE: To analyze the associated expression of STMN1, MELK and FOXM1 in search of alternative drugable target in glioblastoma (GBM) and to review relevant functional roles of STMN1 in cancer biology. METHOD: STMN1, MELK and FOXM1 expressions were studied by quantitative PCR and their coexpressions were analyzed in two independent glioblastoma cohorts. A review of articles in indexed journals that addressed the multiple functional aspects of STMN1 was conducted, focusing on the most recent reports discussing its role in cancer, in chemoresistance and in upstream pathways involving MELK and FOXM1. RESULTS: Significant associated expressions of MELK and FOXM1 were observed with STMN1 in GBM. Additionally, the literature review highlighted the relevance of STMN1 in cancer progression. CONCLUSION: STMN1 is very important to induce events in cancer development and progression, as cellular proliferation, migration, and drug resistance. Therefore, STMN1 can be an important therapeutic target for a large number of human cancers. In glioblastoma, the most aggressive brain tumor, the MELK/FOXM1/STMN1 presented significant associated expressions, thus pointing MELK and FOXM1 as alternative targets for therapy instead of STMN1, which is highly expressed in normal brain tissue. Continuous functional research to understand the STMN1 signaling pathway is worthwhile to improve the therapeutic approaches in cancer.

OBJETIVO: Analisar as expressões associadas de STMN1, MELK e FOXM1 na procura de alvos alternativos de tratamento em glioblastoma (GBM) e revisar os papeis funcionais relevantes de STMN1 na biologia do câncer. MÉTODO: As expressões de STMN1, MELK e FOXM1 foram estudadas por PCR quantitativo e suas coexpressões foram analisadas em dois coortes independentes de GBM. A revisão dos artigos publicados em revistas indexadas na procura dos aspectos funcionais múltiplos de STMN1 foi conduzida focando-se nos estudos mais recentes discutindo o seu papel em câncer, quimiorresistência e vias de sinalização envolvendo MELK e FOXM1. RESULTADOS: Observou-se expressões associadas significantes de MELK e FOXM1 com STMN1. Adicionalmente, a revisão da literatura salientou a relevância do STMN1 na progressão do câncer. CONCLUSÃO: STMN1 é muito importante nos eventos relacionados ao desenvolvimento e progressão do câncer, como proliferação celular, migração e resistência ao tratamento. Desta forma, STMN1 pode ser um forte alvo terapêutico em um grande número de cânceres humanos. Em GBM, o tumor cerebral mais agressivo, MELK/FOXM1/STMN1 apresentaram significativa associação em suas expressões gênicas, indicando, portanto, MELK e FOXM1 como alvos alternativos para terapia em substituição ao STMN1, que apresenta alta expressão no tecido cerebral normal. Perseverar nos estudos funcionais para o entendimento da via de sinalização do STMN1 é relevante para melhorar os esquemas terapêuticos para câncer.

Performance of adjuvant treatment correlates with survival in reoperated glioblastomas / Uso de tratamento adjuvante é relacionado ao aumento da sobrevida em pacientes com glioblastoma submetidos à reoperação

ABSTRACT Objective To analyze cases of recurrent glioblastoma subjected to reoperation at a Brazilian public healthcare service. Methods A total of 39 patients subjected to reoperation for recurrent glioblastoma at the Department of Neurosurgery, São Paulo Hospital, Federal University of São Paulo, from January 2000 to December 2013 were retrospectively analyzed. Results The median overall survival was 20 months (95% confidence interval – CI = 14.9–25.2), and the median survival after reoperation was 9.1 months (95%CI: 2.8–15.4). The performance of adjuvant treatment after the first operation was the single factor associated with overall survival on multivariate analysis (relative risk – RR = 0.3; 95%CI = 0.2–0.7); p = 0.005). Conclusion The length of survival of patients subjected to reoperation for glioblastoma at a Brazilian public healthcare service was similar to the length reported in the literature. Reoperation should be considered as a therapeutic option for selected patients.

RESUMO Objetivo Analisar o papel da reoperação em pacientes com glioblastoma recidivado em um serviço público no Brasil. Métodos Foram analisados retrospectivamente 39 pacientes submetidos à reoperação por recorrência de glioblastoma no Departamento de Neurocirurgia da Universidade Federal de São Paulo, no período de janeiro de 2000 até dezembro de 2013. Resultados A sobrevida global mediana foi de 20 meses (IC 95% = 14.9–25.2), e a sobrevida mediana após a reoperação foi de 9.1 meses (IC 95% = 2.8–15.4). A realização de tratamento adjuvante após a primeira cirurgia foi o único fator associado com a sobrevida global numa análise multivariada (RR = 0.3; IC 95% = 0.2–0.7; p = 0.005). Conclusão A sobrevida dos pacientes submetidos à reoperação em um serviço público no Brasil é semelhante à reportada pela literatura. A reoperação deve ser considerada como uma opção terapêutica em pacientes selecionados.

Análisis de costo-efectividad de la radioterapia sola, del protocolo Stupp y del protocolo Stupp más bevacizumab para pacientes con reciente diagnóstico de glioma maligno (GBM) en Colombia / Cost-effectiveness analysis of radiotherapy alone, the Stupp protocol and the Stupp plus bevacizumab protocol for patients with a recent diagnosis of malignant glioma (GBM) in Colombia

Problema de investigación: Evaluar la RICE de la radioterapia (medida la efectividad en AVAC), el PS y el PS+BEV para el tratamiento de pacientes mayores de edad con diagnóstico reciente de GBM confirmado \r\nhistológicamente y con resección macroscópica completa. Tipo de evaluación económica: Análisis de costo\r\n-efectividad. Población objetivo: Pacientes mayores de 18 años con diagnóstico reciente de GBM confirmado histológicamente y con resección macroscópica completa. Intervención y comparadores: Comparación 1: PS comparado con radioterapia, Comparación 2: PS+BEV comparado con PS. Horizonte temporal: Se consideró un horizonte temporal de dos años, con ciclos de 1 mes de duración. Tasa de descuento: La tasa de descuento del caso base fue del 5 % y se llevaron a cabo análisis para tasas de 0 %, 3,5 %, 7 % y 12 %. Estructura del modelo: Se diseñó un modelo de Markov con tres estados de salud (estable, progresión y muerte). Fuentes de datos de efectividad y seguridad: Los datos de efectividad y seguridad fueron obtenidos de cuatro estudios clínicos multicéntricos; la información acerca de la valoración de los desenlaces fue obtenida de una ETES. Desenlaces y valoración: Las ponderaciones para la calidad de vida percibida por los pacientes en cada estado de salud fueron obtenidas de una ETES publicada previamente, y fueron utilizadas para calcular los AVAC. Costos incluidos: Fueron incluidos los costos que generan un gasto directo al SGSSS en Colombia. No se incluyeron costos de cuidadores, costos de pérdidas de productividad ni \r\ncostos de transporte. Fuentes de datos de costos: La valoración de los costos se hizo mediante el uso de \r\nSISMED y de la Circular 03 de 2015 de precios máximos en el caso de los medicamentos, y del manual tarifario ISS 2001 para el caso de los procedimientos. Resultados del caso base: La RICE del PS comparado con la radioterapia es de $ 55.410.625, lo que resulta en que no sería una alternativa costo-efectiva para el país. La RICE del PS+ BEVvs. PS ($ 1.795.371.090) comparado con tres veces el PIB per cápita hace que \r\nesta no se considere una estrategia costo-efectiva para el contexto colombiano. Análisis de sensibilidad:\r\nCuando el costo de la dosis de TMZ concomitante con radioterapia es igual a $ 136.868,6 o menos, el PS se \r\nvuelve una tecnología en salud costo-efectiva para Colombia comparado con la RT. Y solo resulta costo-efectivo a su precio actual si el umbral de disponibilidad a pagar fuera mayor a $ 50.000.000. Bajo ningún escenario de disponibilidad a pagar entre 1 y 3 PIB per cápita, el PS+BEV tendría probabilidad de ser costo-efectivo en Colombia al ser comparado con el PS. Conclusiones y discusión: Aunque las diferencias en términos de AVAC no son amplias entre las diferentes tecnologías, el uso de TMZ (es decir, el PS) es el que mejores resultados reporta frente a la radioterapia sola y frente a la inclusión del BEV al PS (aunque el uso del BEV en esta indica ción es off-label en Colombia).(AU)

EGFR, p53, IDH-1 and MDM2 immunohistochemical analysis in glioblastoma: therapeutic and prognostic correlation / Análise imunoistoquímica para EGFR, p53, IDH-1 e MDM2 em glioblastoma: correlação terapêutica e prognóstica

We studied 36 glioblastoma cases at HC-UNICAMP from 2008 to 2012 and classified the immunohistochemical distribution of the wild-type epidermal growth factor receptor (EGFR), mutated forms of p53 protein and isocitrate dehydrogenase-1 (IDH-1) and murine double protein 2 (MDM2). Immunostaining findings were correlated with clinical data and response to treatment (surgery, chemotherapy and radiotherapy). About 97% of the tumors were primary, most of them localized in the frontal lobe. Mean time free of clinical or symptomatic disease and free time of radiological disease were 7.56 and 7.14 months, respectively. We observed a significant positive correlation between expressions of p53 and MDM2, EGFR and MDM2. Clinical, radiological and overall survivals also showed a significant positive correlation. p53 staining and clinical survival showed a significant negative correlation. The current series provides clinical and histopathological data that contribute to knowledge on glioblastoma in Brazilians.

Estudamos 36 casos de glioblastoma acompanhados no HC-UNICAMP de 2008 a 2012 e classificamos a marcação imunoistoquímica da forma selvagem do receptor do fator de crescimento epidérmico (EGFR), formas mutantes da proteína p53 e isocitrato desidrogenase-1 (IDH-1) e proteína murina dupla 2 (MDM2). Os resultados de imunoistoquímica foram correlacionados com dados clínicos e resposta ao tratamento (cirurgia, quimioterapia e radioterapia). Cerca de 97% dos tumores foram primários, grande parte localizada no lobo frontal. O tempo médio livre de doença clínica ou sintomática e o tempo livre de doença radiológica foram de 7.56 e 7.14 meses, respectivamente. Observou-se correlação positiva entre a expressão das proteínas p53 e MDM2, EGFR e MDM2. Sobrevivências clínica, radiológica e global também mostraram correlação positiva e significativa. A expressão para p53 e sobrevivência clínica mostrou correlação negativa. O estudo fornece dados clínicos e histopatológicos que contribuem para o conhecimento sobre glioblastoma em brasileiros.

Estudio de una cohorte uruguaya de pacientes portadores de Glioblastoma tratados con radioterapia y Temozolamida / Analysis of a Uruguayan cohort of patients with Glioblastoma treated with radiotherapy and Temozalamide

Objetivos: conocer la sobrevida a dos años de pacientes con diagnóstico de Glioblastoma multiforme (GBM) tratados con Temozolamida con cobertura del Fondo Nacional de Recursos (FNR), evaluar la seguridad del tratamiento y los factores pronósticos. Metodología: cohorte de pacientes portadores de GBM, tratados con Temozolamida entre mayo de 2009 y diciembre 2011. Fuente de información: base de datos del FNR. Resultados: Se incluyeron 81 pacientes. La mediana de sobrevida global fue de 18 meses. Vivos a dos años: 33 de los pacientes. El análisis multivariado encontró a la edad y al peor estado funcional del paciente como los factores de riesgo para mortalidad. 8 pacientes tuvieron efectos adversos severos. Discusión: Se presentan los primeros resultados nacionales vinculados al tratamiento combinado de los GBM. La sobrevida fue similar a la reportada en los estudios de referencia internacionales y mayor que la descripta para el tratamiento radiante exclusivo. El beneficio es mayor en aquellos pacientes jóvenes con buena capacidad funcional previa al inicio del tratamiento. Su seguridad fue considerada como aceptable.

Objectives: find out the two-year survival of patients diagnosed with Multiform Glioblastoma (MGB) treated with Temozolamide funded by the National Resource Fund (FNR), and evaluate the safety of therapy and prognostic factors. Methodology: cohort of patients with MGB, treated with Temozolamide between May 2009 and December 2011. Data source: database of the FNR. Results: the 81 patients included had a median overall survival of 18 months; 33 of them were still alive at two years. The multivariate analysis found that the patient’s age and functional status were the risk factors for mortality. Eight patients had severe adverse effects. Discussion: Presentation of the first national results related to the combined therapy of MGB. Survival was similar to that reported in the international reference studies and greater than that described for radiation therapy alone. Benefits were greater in young patients presenting with a good functional capacity before starting therapy. The safety of therapy was deemed acceptable.

Glioblastoma multiforme em idosos: uma revisão sobre seu tratamento com ênfase na abordagem cirúrgica / Glioblastoma multiforme in the elderly: a review on their treatment with emphasis in the surgical approach

O glioblastoma multiforme (GBM) é o tumor primário mais comum do sistema nervoso central (SNC). Em virtude do envelhecimento populacional, entre outros fatores, sua ocorrência em faixas etárias avançadas tem se mostrado crescente nas últimas décadas. Os objetivos da ressecção do GBM incluem: alívio do efeito de massa, citorredução tumoral, diagnóstico histopatológico, controle dos sintomas e melhoria nas taxas de sobrevivência. Por muito tempo acreditou-se que a idade seria fundamental na decisão pelo tratamento, embora alguns autores afirmem que a extensão da ressecção cirúrgica constitui o principal fator determinante do prognóstico, sobretudo para pacientes que foram eleitos para radioterapia e quimioterapia. A ressecção de mais de 98% do volume tumoral é capaz de interferir na sobrevivência, e ressecções menores proporcionaram sobrevivência semelhante à dos pacientes não abordados. O presente trabalho tem por objetivo realizar uma revisão da literatura atual a respeito do tratamento do GBM nos idosos, com enfoque especial na abordagem cirúrgica...

The glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system (CNS). Due to the aging population, among other factors, its occurrence in older age groups has shown increasing in recent decades. The goals of resection of GBM include: relieve mass effect, tumor debulking, histopathological diagnosis, symptom control and improvement in survival rates. For a long time it was believed that age would be crucial in deciding the treatment, although some authors state that the extent of surgical resection is the main determinant of prognosis, especially for patients who were elected to radiotherapy and chemotherapy. The resection of more than 98% of the tumor volume can interfere with the survival and minor resections provided similar to survival of patients not operated. This paper aims to review the current literature regarding the treatment of GBM in the elderly, with special focus on surgical approach...

[Dendrosomal curcumin upregulates expression of the long noncoding RNA gene MEG3 in U87MG glioblastoma cells]

Glioblastoma is an invasive tumor of the central nervous system. Epigenetic therapy of cancer is potentially very useful in reversing some of cancer defects due to reversibility of epigenetic alterations. MEG3 is a tumor suppressor long non-coding RNA [lncRNA] that expresses in the majority of normal tissues. Methylation of the MEG3 promoter region elicits a decrease in its expression in glioblastoma cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status. Herein, we aim to investigate the epigenetic-based role of dendrosomal-curcumin [DNC] in upregulation of MEG3 expression in glioblastoma cells. We evaluated DNC entrance to U87MG cells with the use of the fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on cell viability. The ability of DNC to boost expression of MEG3 in DNA methylation regulation was accomplished by a study of the relative expressions of MEG3 and DNA methylation regulator enzymes, DNA methyltransferases [DNMT1, DNMT3A and 3B] using semi-quantitative and quantitative PCR. We observed the entrance of DNC into U87MG cells. DNC significantly caused U87MG cell death in a time and dose-dependent manner. However dendrosome did not show any toxic effect on this cell line. Data acquired from gene expression assays determined that DNC upregulated MEG3 expression [P<0.05] and downregulated DNMT3B expression [P<0.05]. There was no significant effect on DNMT1, 3A expression in U87MG cells. The data showed that DNC could awaken epigenetically silenced tumor suppressor genes through an ambiguous route in glioblastoma cells. Notwithstanding, DNA hypomethylation has occurred by downregulation of DNMTs, inactive DNA demethylation and or active DNA demethylation, subsequently tumor suppressor genes such as MEG3 a cell growth regulator overexpressed. We concluded that DNC has useful characteristics in epigenetic therapy of glioblastoma

Glioblastoma: approach to treat elderly patients / Glioblastoma: enfoque no tratamento de pacientes idosos

Treating elderly cancer patients is a challenge for oncologists, especially considering the several therapeutic modalities in glioblastoma. Extensive tumor resection offers the best chance of local control. Adequate radiotherapy should always be given to elderly patients if they have undergone gross total resection and have maintained a good performance status. Rather than being ruled out, chemotherapy should be considered, and temozolomide is the chosen drug. A comprehensive geriatric assessment is a valuable tool to help guiding treatment decisions in elderly patients with glioblastoma.

O tratamento de idosos com câncer é um desafio para a prática oncológica, especialmente no que se refere à terapêutica multimodal do glioblastoma. Nessa população, a ressecção ampla do tumor oferece a melhor chance de controle local e, naqueles pacientes que mantenham um bom performance status, a radioterapia complementar deve sempre ser levada em consideração. A quimioterapia também tem um papel no tratamento, sendo a temozolomida a droga de eleição. Frente à heterogeneidade desses pacientes, uma avaliação geriátrica ampla é um instrumento valioso no auxílio da decisão terapêutica em idosos com glioblastoma.

Glioblastoma multiforme cerebral hemisférico: análisis de sobrevida de 65 casos tratados en el Departamento de Oncología del Hospital de Clínicas, desde 1980 a 2000 / Glioblastoma multiforme in the cerebral hemisphere: survival analysis of 65 cases seen at the Oncology Department of the Clínicas Hospital from 1980 through 2000

Introducción: el glioblastoma multiforme (GBM) representa la forma más agresiva de los gliomas. La sobrevida a cinco años con el tratamiento quirúrgico exclusivo es nula. El agregado radioterapia (RT) y quimioterapia (QT) prolongan la so-brevida. Objetivo: evaluar el impacto del tratamiento en la sobrevida de pacientes portadores de GBM.Pacientes y métodos: se incluyeron los pacientes con diagnóstico histológico de GBM asistidos en la Unidad de Neuro-Oncología del Hospital de Cínicas, de 1980 a 2000. Se recabaron datos patronímicos, clínicos, paraclínicos y evolutivos de las historias clínicas. Se calculó la sobrevida mediante el método de Kaplan Meier y Mantel Cox.Resultados: se estudiaron 65 pacientes con una edad mediana de 58 años (rango: 6-79). Recibieron cirugía 100%(completa en 22 pacientes, subtotal en 9, parcial en 32 y biopsia en 2). El 92% recibió RT posoperatoria y 25% QT. La mediana de sobrevida fue de 46,6 semanas y la sobrevida global al año fue de 28%. La probabilidad de sobrevida al año fue 0 en los pacientes que recibieron cirugía exclusiva; 0,23 en los que se agregó RT, y 0,62 en los tratados con QT (p=0,0001). El análisis multivariable identificó como variables independientes: el tratamiento multimodal incluyendo quimioterapia(p=0,003) y buen estado neurológico posoperatorio (p=0,007).Conclusiones: la mediana de sobrevida de esta serie fue similar a lo descrito en la literatura, existiendo una sobrevida mayor en los pacientes con buen estado neurológico tratadoscon cirugía seguida de RT y QT.

Introduction: glioblastoma multiforme (GBM) is the most agressive kind of gliomas. The 5-year survival rate for exclusive surgical treatment is null. Additional chemotherapy and radiotherapy increases survival.Objective: to evaluate the impact of treatment in the survival of patients suffering from GBM.Method: patients with a histological diagnosis of GBM who were seen at the Neuro-Oncology Unit of the Clínicas Hospital, from 1980 through 2000. Clinical, paraclinical and patronymic data was collected, the same as information on the evolution of medical records. Survival rates were calculated through the Kaplan Meier and Mantel Cox method. Results: 65 patients with an average age of 58 years old were studied, (range: 6-79). All of them underwent surgery (complete in 22 patients, subtotal in 9, partial in 32 and biopsy in 2 patients). Ninety two percent of patients were treated with radiotherapy and 25% with chemotherapy. Median survival was 46.6 weeks and global survival one year after was 28%. The probability for survival one year after was 0 in patients who were treated only with surgery; 0.23 in those who also received radiotherapy and 0.62 with chemotherapy QT (p=0,0001).Multivariable analysis identified the following independent variables: multimodal treatment including chemotherapy (p=0,003) and a good postoperative general condition (p=0,007). Conclusions: median survival in this series was similar to that described in literature, there existing a longer survival rate for patients with a good neurologic condition who are treated with radiotherapy and chemotherapy after surgery.

Introdução: o glioblastoma multiforme (GBM) é a forma mais agressiva dos gliomas. A sobrevida a os cinco anos é nula quando o paciente recebe exclusivamente tratamento cirúrgico. Observa-se um aumento da sobrevida quando ademais da cirurgia se agrega radioterapia (RT) e quimioterapia (QT).Objetivo: avaliar o impacto do tratamento na sobrevida de pacientes portadores de GBM. Pacientes e métodos: foram incluídos todos os pacientes com diagnóstico histológico de GBM atendidos na Unidade de Neuro-Oncologia do Hospital de Clínicas, de 1980 a 2000. Dos prontuários dos pacientes foram coletados os dados de identificação, clínicos, resultados de exames e estudos e os relacionados com a evo-lução do caso. A sobrevida foi calculada utilizando o método de Kaplan Meier e Mantel Cox.Resultados: foram estudados 65 pacientes com idade média de 58 anos (rango: 6-79 anos). Todos os pacientes (100%) foram submetidos à cirurgia (completa em 22 pacientes, subtotal em 9, parcial em 32 e biopsia em 2). Noventa e dois por centos (92%) receberam RT pós-operatória e 25% QT. A mediana de sobrevida foi de 46,6 semanas e a sobrevida global aos 12 meses foi de 28%. A probabilidade de sobrevida aos 12 meses foi zero nos pacientes que foram submetidos exclusivamente à cirurgia; 0,23 nos que se agregaram RT, e 0,62 nos tratados com QT (p=0,0001). A análise multivariada identificou como variáveis independentes: o tratamento multimodal incluindo quimioterapia (p=0,003) e bom estado neurológico pós-operatório (p=0,007).Conclusões: a mediana de sobrevida desta serie foi similar às descritas na literatura, existindo uma sobrevida maior nos pacientes com bom estado neurológico tratados com cirurgia seguida de RT e QT.

Combination hyperbaric oxygen and temozolomide therapy in c6 rat glioma model / Terapia combinada de oxigênio hiperbárico e temozomida no modelo C6 de glioma em ratos

PURPOSE: Temozolomide (TMZ) has anti-tumor activity in patients with malignant glioma. Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are limited because of the hypoxic tumor microenvironment. We examined the combined effects of TMZ-HBO in a rat glioma model. METHODS: After stereotactic injection of C6/LacZ rat glioma cells into the Wistar rats brain, the rats were randomly assigned to three treatment groups [group 1, control treatment; group 2, TMZ alone; group 3, a combination of TMZ and HBO]. Rats were sacrificed 18 days after treatment, and number of intra-/peri-tumoral vessels, microendothelial proliferations, immunohistochemistry and necrotic area were evaluated. RESULTS: Tumoral tissue was stained only sparsely with GFAP. Temozolomide treatment was significantly decreased in tumor tissue intratumoral vessel number / total tumor area level. The level of Ki67 was significantly decreased in the tumor tissue of the group 3. Additionally, the total necrotic area / total tumor volume (%) was decreased significantly in tumor tissue of the group 3 rats compared to group1 and 2. CONCLUSION: The combination of hyperbaric oxygen with temozolomide produced an important reduction in glioma growth and effective approach to the treatment of glioblastoma.

OBJETIVO: A temozolomida (TMZ) tem atividade anti-tumoral em pacientes com glioma maligno. Oxigênio hiperbárico (HBO) pode aumentar a eficácia de terapias que são limitadas devido a um microambiente do tumor hipóxico. Foram examinados os efeitos combinados de TMZ-HBO em um modelo de glioma em rato. MÉTODOS: Após a injeção estereotáxica de células de glioma de rato C6/LacZ no cérebro de ratos Wistar, os ratos foram distribuídos aleatoriamente em três grupos de tratamento: Grupo 1: tratamento de controle. Grupo 2: TMZ sozinho. Grupo 3: uma combinação de TMZ e HBO. Os ratos foram sacrificados 18 dias após o tratamento. Foram avaliados o número de vasos intra-/peri-tumoral, proliferação microendotelial, imunohistoquímica e área necrótica . RESULTADOS: O tecido tumoral foi marcado apenas esparsamente com GFAP. O tratamento com temozolomida diminuiu significativamente o tecido intratumoral e a área total do tumor. O nível de Ki67 foi significativamente diminuído no tecido do tumor do grupo 3. Além disso, a superfície necrótica total / volume total do tumor (%) diminuiu significativamente no tecido do tumor do grupo 3 em comparação com grupo 1 e 2. CONCLUSÃO: A combinação de oxigênio hiperbárico com temozolomida produziu uma redução importante no crescimento do glioma podendo ser abordagem eficaz para o tratamento do glioblastoma.

Desarrollo de glioblastoma multiforme tras una hemorragia intracerebral: reporte de un caso / Development of glioblastoma multiforme after intracerebral hemorrhage: case report

Varios factores han sido implicados como posibles causantes del desarrollo de tumores cerebrales; son pocos los autores que han proporcionado evidencia de la etiología traumática de un tumor cerebral. Presentamos el caso de un paciente masculino de 30 años quien se presento con un cuadro clínico de cefalea intensa de 15 días de evolución. Los estudios imagenológicos (TAC, RMN) revelaron lesión frontal intra axial. Se le realizo resección total de la lesión, cuyo resultado de patología fue compatible con glioblastoma multiforme. El paciente tenía antecedente de hemorragia intracerebral espontanea hacia 7 meses en el mismo lugar del tumor. Basados en la literatura en relación a glioblastoma multiforme y lesión traumática o vascular cerebral, hacemos una revisión crítica de ella.

Treatment of recurrent glioblastoma with intra-arterial BCNU [1, 3-bis (2-chloroethyl)-1-nitrosourea] / Tratamento do glioblastoma recorrente com BCNU [1, 3-bis (2-chloroethyl)-1-nitrosourea] intra arterial

Contemporary therapies for patients with glioblastomas remain marginally efficient, and recurrence following surgery, radiation therapy and adjuvant chemotherapy is practically universal. The major obstacles to the successful use of chemotherapy for CNS tumors are the drug delivery to the tumor site and the infusion of chemotherapeutic agents directly into the arterial supply of a tumor. The latter could provide a pharmacokinetic advantage by enhancing drug delivery to the tumor. Sixteen patients with recurrent unilateral glioblastomas treated with intra-arterial BCNU were evaluated retrospectively. During the infusion, eleven patients referred pain in the ipsilateral eye, five patients were nauseated, three reported headache, one patient presented mental confusion, while two presented focal signs. There were two deaths during the course of therapy. Four patients achieved temporary clinical improvement, seven showed disease stability, and three presented clinical deterioration. The median total survival time was 87.9 weeks. Unilateral vision loss and focal signs were observed as delayed complications of this treatment. This study has confirmed previous reports indicating that arterial chemotherapy is clearly not curative, and presents serious toxicity. Only through a randomized prospective study performed in a large series of patients can the questions concerning survival period increment be answered properly.

Os tratamentos atuais para pacientes com glioblastoma permanecem pouco eficientes e a recorrência, acompanhando cirurgia, radioterapia e quimioterapia, é a regra geral. O maior obstáculo para o sucesso da quimioterapia para os tumores do SNC é a disponibilização da droga no sitio do tumor sendo que a infusão do agente quimioterápico diretamente na trama arterial da lesão pode proporcionar vantagens por maior liberação da substância diretamente no tumor. Estudamos retrospectivamente dezesseis pacientes com glioblastomas recorrentes, unilaterais, que foram tratados com BCNU intra-arterial; durante a infusão, onze pacientes sentiram dor no olho ipsilateral, cinco ficaram nauseados, três queixaram-se de cefaléia, um apresentou confusão mental e dois apresentaram sinais focais. Ocorreram duas mortes durante a terapia. Quatro pacientes apresentaram melhora clinica temporária, sete apresentaram estabilização e três apresentaram deterioração. A média de sobrevida total foi de 87,9 semanas. Perda da visão unilateral e sinais focais foram complicações tardias. Este estudo confirmou trabalhos anteriores indicando que a quimioterapia intra-arterial claramente não é curativa, séria toxicidade pode ocorrer e somente um estudo prospectivo e randomizado, realizado em uma serie maior de pacientes, poderá responder questões sobre o aumento do tempo de sobrevida de forma adequada.

Evidence-based adjuvant therapy for gliomas: current concepts and newer developments.

The incidence of gliomas is increasing worldwide, including India. Of the 18,820 new cases of primary central nervous system (CNS) tumors diagnosed annually in the United States, gliomas account for over 60% with 30-40% of them being glioblastoma multiforme (GBM), 10% being anaplastic astrocytoma (AA), and 10% being low grade gliomas (LGGs). This is in contrast to one study from West Bengal, India, in which only 7.9% of the brain tumors were GBMs, while 46.8% were astrocytomas. Of all adult primary CNS tumors, GBM is the most common and the most malignant with about 7,000 to 8,000 new cases annually in the United States. Given poor outcomes, a number of treatment approaches have been investigated. Common to these approaches is the use of adjuvant radiation therapy, even as surgery alone, with or without chemotherapy, may be the mainstay for some lower grade and low-risk gliomas. Today, treatment typically involves external beam radiation, with concurrent and adjuvant chemotherapy for more aggressive histologies. Although gliomas are relatively uncommon, active research is ongoing. Results of landmark trials along with some of the recently published trials are presented. These trials and management strategies as well as evolving concepts are found by reviewing over 200 articles in the National Library Medical (NLM) database, PubMed, more than 60 of which are refrenced. Specifically, the database is searched using the following keywords, with various combinations: glioma, low-grade, anaplastic, astrocytoma, oligodendroglioma, oligoastrocytoma, glioblastoma multiforme, chemotherapy, radiation, new concepts, phase III, MGMT, CDX-110 (Celldex), temozolomide, 1p/19q deletion, and bevacizumab.