Consenso chileno para el diagnóstico y tratamiento de gliomas del adulto / Diagnosis and treatment of glioma in adult: Chilean consensus

Resumen Los tumores cerebrales se caracterizan por su gran morbilidad y mortalidad. La gran mayoría corresponde a tumores secundarios (metástasis). Dentro de los tumores primarios del sistema nervioso central, los gliomas corresponden al 30% de éstos. En EEUU, entre el 2007-2011, se estima una incidencia aproximada de 21,4 casos por 100.000 habitantes. Los recientes avances en la comprensión molecular de la biología de estos tumores han permitido mejorar sustancialmente su clasificación, posibilitando realizar un mejor correlato con los desenlaces clínicos y el pronóstico. En esta línea, hoy en día es posible estratificar a los pacientes por riesgo y entregar tratamientos capaces de prolongar la sobrevida global entre 5-7 años, para los gliomas grado II y III. El presente consenso, elaborado por un panel multidisciplinario de expertos de diversas sociedades científicas chilenas y, por tanto, de todas las especialidades involucradas en el manejo médico-quirúrgico de las personas portadoras de gliomas cerebrales. A la luz de este nuevo conocimiento desarrollado al alero de la oncología molecular, esta propuesta ofrece un insumo de utilidad clínica real, que, articulado a una revisión actualizada en relación con el tratamiento y seguimiento de estos pacientes, permite entender la relevancia de estos biomarcadores en el manejo de precisión de la enfermedad. Cabe señalar que, este manuscrito emerge de la misma fuerza de trabajo, que elaboró el Protocolo Clínico de Gliomas del Adulto 2019, publicado por el Ministerio de Salud, y que ha diferencia de esta, que ofrece los detalles clínicos-operativos, como flujogramas y dosis, nuestra revisión intenta relevar los avances imagenológicos y moleculares y como estos impactan en el manejo actual de la enfermedad.

Brain tumors are characterized by high morbidity and mortality. The vast majority correspond to secondary tumors (metastasis). On the other hand, within the primary tumors of the central nervous system, gliomas correspond to 30% of these. In the US, between 2007-2011, an approximate incidence of 21.4 cases per 100,000 inhabitants was estimated. Recent advances in the molecular understanding of the biology of these tumors have made it possible to substantially improve their classification, allowing a better correlation with clinical outcomes and prognosis. Along these lines, today, it is possible to stratify patients by risk and deliver treatments capable of prolonging global survival between 5-7 years, for grade II and III gliomas. The present consensus, prepared by a multidisciplinary panel of experts from various Chilean scientific societies and, therefore, from all the specialties involved in the medical and surgical therapy. Enlightened from the molecular oncology, this proposal offers an input of clinical utility, which, together with an updated review in relation to the treatment and follow-up of these patients, allows us to understand the relevance of these biomarkers in precision disease management. It should be noted that this manuscript emerges from the same work force, which prepared the Clinical Protocol for Adult Gliomas 2019, published by the Ministry of Health, and that differs from it, which offers clinical-operative details, such as flowcharts and dose, our review attempts to reveal imaging and molecular advances and how they impact the current management of the disease.

Role of biomimetic nanomaterials made from glioma cell- derived extracellular vesicles in targeted delivery of STAT3-siRNA / 中南大学学报(医学版)

OBJECTIVES@#Glioma is the most common primary intracranial tumor and there is still no ideal treatment at present. Gene therapy, as one of the new methods for treating glioma, has attracted attention in recent years. But its application in treating glioma is very limited due to lack of effective delivery vectors. This study aims to investigate the feasibility of biomimetic nanomaterials made from glioma cells-derived extracellular vesicles (EV) for targeted delivery of signal transducers and activators of transcription 3 (STAT3)-small interfering RNA (siRNA) in treating glioma.@*METHODS@#First, U251 glioma cells-derived extracellular vessel (EVU251) was extracted by ultra-centrifugal method. Nanoparticle tracking analysis was used to characterize the particle size distribution, the transmission electron microscope was used to analyze the morphology, and Western blotting was used to verify the expression of srface characteristic protein. The homing ability was verified by cell uptake assay after labeling EVU251 with membrane dye kit PKH67; the EVU251 contents were removed by a low permeability method and then EVMU251 was prepared through a microporous membrane. Finally, the biomimetic nanomaterials EVMU251@STAT3-siRNA were prepared by loading STAT3-SiRNA with electro-dyeing method. The real-time quantitative PCR was used to quantify the successful encapsulation of siRNA, and the encapsulation and drug loading rate was calculated; then Cy5-labeled siRNA was used to evaluate the ability of biomimetic nanomaterials (EVMU251@CY5-siRNA) to target U251 cells. Lysosomal escape ability of the biomimetic nanomaterial was evaluated by lysosomal dye lyso-tracker green. At last, the ability of EVMU251@STAT3-siRNA to knock down STAT3 gene and selective killing of U251 cells was detected by cell experiments in vitro.@*RESULTS@#The size of EVU251 ranged from 50 nm to 200 nm with a natural disc shape. The expression of extracellular vesicle marker proteins could be detected on the membrane of EVU251. The cell uptake assay demonstrated that it had homing ability to target U251 cells. After EVU251 was prepared as EVMU251@STAT3-siRNA, the particle size was (177.9±5.0) nm, the siRNA loading rate was (33.5±2.2)% and the drug loading rate was (3.24±0.21)%. The biomimetic nanomaterial EVMU251@STAT3-siRNA still had the ability to target U251 cells and successfully deliver siRNA to the cytoplasm without lysosomal degradation. The EVMU251@STAT3-siRNA can effectively knock down the expression of STAT3 gene and produce selective killing ability in U251 cells.@*CONCLUSIONS@#The biomimetic nanomaterials EVMU251@STAT3-siRNA made from glioma U251 cells-derived extracellular vesicles can knock down STAT3 gene of U251 cells and produce selective killing effect, which can provide a new idea for the treatment of glioma.

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).

Genetic variants related to angiogenesis and apoptosis in patients with glioma / Variantes genéticas relacionadas à angiogênese e apoptose em pacientes com glioma

ABSTRACT Background Glioma, the most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. The objectives of this study were to evaluate the association of genetic polymorphisms related to angiogenesis and apoptosis with gliomas, as well as comorbidities, lifestyle, clinical profile, survival and response to treatment (temozolomide [TMZ] and radiotherapy [RT]) in patients with the disease. Methods In a total of 303 individuals, genotypes were performed by real-time PCR, and clinical data, lifestyle and comorbidities were obtained from medical records and questionnaires. The significance level was set at 5%. Results Smoking, alcohol consumption, systemic arterial hypertension, diabetes mellitus and body mass index prevailed among patients, compared to controls (p < 0.05). The heterozygous genotype rs1468727 (T/C) and the homozygous genotype rs2010963 (G/G) (p > 0.05) were observed in both groups. Lifestyle and comorbidities showed independent risk factors for the disease (p < 0.0001, p = 0.0069, p = 0.0394, respectively). Patients with low-grade gliomas had a survival rate of 80.0 ± 1.7% in three years. For the combination of TMZ+RT, survival was 78.7 ± 7.6% in 20 months, compared to TMZ only (21.9 ± 5.1%, p = 0.8711). Conclusions Genetic variants were not associated with gliomas. Specific lifestyle habits and comorbidities stood out as independent risk factors for the disease. Low-grade gliomas showed an increase in patient survival with TMZ+RT treatment.

RESUMO Introdução Glioma, tumor cerebral maligno, é altamente agressivo e associado a mau prognóstico. Os objetivos deste estudo foram avaliar a associação de polimorfismos genéticos relacionados a angiogênese e apoptose em pacientes com glioma, bem como suas comorbidades, hábitos de vida, perfil clínico, sobrevida e resposta ao tratamento (temozolomida [TMZ] e radioterapia [RT]). Métodos 303 indivíduos foram genotipados por PCR em tempo real, e foram coletados dados clínicos, hábitos de vida e comorbidades. Admitiu-se nível de significância para valor p < 0,05. Resultados Tabagismo, elitismo, hipertensão arterial sistêmica, diabetes mellitus e índice de massa corporal prevaleceram entre os pacientes, comprados aos controles (p < 0,05). O genótipo heterozigoto rs1468727 (T/C) e homozigoto rs2010963 (G/G) (p > 0,05) foram observados em ambos os grupos. Tabagismo, elitismo, hipertensão arterial sistêmica, diabetes mellitus e índice de massa corporal apresentaram fatores de risco independentes para a doença (p < 0.0001, p = 0.0069, p = 0.0394, respectivamente). Os pacientes com gliomas de baixo grau apresentaram sobrevida de 80,0 ± 1,7% em três anos. Para a combinação de RT e TMZ, a sobrevida foi de 78,7±7,6% em 20 meses, em comparação com TMZ (21,9 ± 5,1%, p = 0,8711). Conclusões As variantes genéticas não estiveram associadas aos gliomas. Hábitos de vida e comorbidades específicas destacaram-se como fatores de risco independentes para a doença. O tratamento com TMZ + RT mostrou aumento na sobrevida dos pacientes.

Análisis de impacto presupuestal de la temozolomida para el tratamiento de pacientes adultos con diagnóstico de novo de glioma maligno en Colombia / Budgetary impact analysis of temozolomide for the treatment of adult patients with de novo diagnosis of malignant glioma in Colombia

Tecnologías evaluadas: Nueva: temozolomida. Población: Pacientes mayores de 16 años con diagnóstico reciente de glioblástoma multiforme en Colombia. Perspectiva: La perspectiva del presente AIP corresponde al tercero pagador, que en este caso es el Sistema General de Seguridad Social en Salud (SGSSS) en Colombia. Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de la inclusión en el POS en el año 1. Costos incluidos: Costos de las tecnologías analizadas. Fuente de costos: Los precios de cada tecnología considerada fueron consultados en el manual tarifario ISS 2001 y ajustados con un +25%, +30% y +48%. Escenarios: Para este AIP no fueron diseñados escenarios de adopción debido a que la tecnología evaluada ya se utiliza en la práctica clínica colombiana, para toda la población objetivo del análisis. Resultados: El caso base involucraría una inversión total de $29.494.699.472\r\npara el año 1, $4.225.358.276,32 para el año 2 y $ 4.974.085.010,60 para el año 3. En el caso base se asuma la inclusión de la temozolomida en el POS.(AU)

Educational program on fatigue for brain tumor patients: possibility strategy? / Programa educativo para fadiga em pacientes com tumor cerebral: possibilidade de estratégia?

ABSTRACT Objective To evaluate the effectiveness of an educational program on improvement of fatigue and quality of life of patients with high-grade glioma during radiotherapy and chemotherapy treatment. Method This is a longitudinal, experimental study. Twenty-three patients with high-grade glioma were randomly assigned to one of two groups. Both groups completed the Functional Assessment of Cancer Therapy: Fatigue questionnaire and the Beck Depression Inventory, and one of the groups received the educational intervention. The groups did not show any change in quality of life and fatigue in this study, for this reason, the educational program did not present any significant difference. However, there was a significant difference in depressive symptoms during the educational program showing positive evidence for its applicability.

RESUMO Objetivo Verificar a efetividade de um programa educativo na melhora da fadiga e dos sintomas depressivos em pacientes com glioma de alto grau durante o tratamento com radioterapia e quimioterapia. Método Trata-se de estudo longitudinal e experimental. Foram incluídos 23 pacientes com glioma de alto grau e divididos aleatoriamente em 2 grupos. Os dois grupos responderam os questionários Functional Assessment of Cancer Therapy: Fatigue e Inventário de Depressão de Beck, porém somente um foi inserido ao programa educativo. Resultados e Conclusões Os grupos não apresentaram alteração na fadiga ao longo desse estudo, assim o programa educativo não mostrou diferença significativa, porém nos sintomas depressivos, o programa educativo trouxe diferença quando estava sendo realizado mostrando evidências positivas para sua aplicabilidade.

Efectividad y seguridad de temozolamida, en monoterapia o como terapia combinada con radioterapia, comparada con radioterapia o bevacizumab para gliomas malignos / Effectiveness and safety of temozolomide, as monotherapy or as combination therapy with radiotherapy, compared to radiotherapy or bevacizumab for malignant gliomas

Introducción: en países desarrollados la incidencia de tumores malignos del SNC es de 7,27 casos por cada 100.000 habitantes. Los gliomas representan el 28 % de todas las neoplasias del SNC y el 80% de los tumores malignos. Estos últimos son más frecuentes en hombres (55%) que en mujeres (45%), y su subtipo histológico más común es el glioblastoma (3.19 casos por cada 100.000 habitantes). El estándar actual de tratamiento para las neoplasias cerebrales consiste, para los casos en los que es posible, de una resección del tumor, seguido por un tratamiento concurrente de radioterapia y temozolamida. La administración de radioterapia, en ciclos diarios de 2 Gy hasta completar un 60 Gy, ligada a dosis diarias de temozolamida, y seguida por ciclos mensuales de esta última al término de la Radioterapia, se denomina Protocolo Stupp. Objetivo: examinar los beneficios y riesgos del uso de la temozolamida en pacientes con gliomas malignos, como uno de los criterios para informar la toma de decisiones relacionada con la posible inclusión de tecnologías en el Plan Obligatorio de Salud, en el marco de su actualización integral para el año 2015. Metodología: a partir de la pregunta PICO se establecieron los criterios de elegibilidad para la realización de la búsqueda de la evidencia científica (a ensayos clínicos, revisiones sistemáticas de estudios observacionales y estudios de cohortes analíticas), se realizó la tamización y selección de la evidencia evaluando su calidad y posteriormente se realizó la extracción de datos y la síntesis de la evidencia. Resultados: tres experimentos clínicos, abarcando un total de 745 pacientes, que evaluaron la temozolamida en combinación con radioterapia y en comparación con Radioterapia sola, para el tratamiento del glioblastoma multiforme. La temozolamida aumento Supervivencia Global [hazard ratio (HR) 0,60; intervalo de confianza del 95% (IC) 0,46 a 0,79; valor de p 0,0003] y el aumento de la Supervivencia Libre de Progresión (HR 0,63, IC del 95%: 0,43 a 0,92; valor P 0,02), en comparación con la radioterapia sola. Conclusiones: cuando la temozolamida se administra tanto en fases concomitante y adyuvante, es una terapia primaria eficaz para los glioblastomas malignos en comparación con la Radioterapia sola. Estos efectos se expresan tanto en la Supervivencia Global como en la Supervivencia Libre de Progresión. (AU)

Glioma Stem Cell-Targeted Dendritic Cells as a Tumor Vaccine Against Malignant Glioma

PURPOSE: Cancer stem cells have recently been thought to be closely related to tumor development and reoccurrence. It may be a promising way to cure malignant glioma by using glioma stem cell-targeted dendritic cells as a tumor vaccine. In this study, we explored whether pulsing dendritic cells with antigens of glioma stem cells was a potent way to induce specific cytotoxic T lymphocytes and anti-tumor immunity. MATERIALS AND METHODS: Cancer stem cells were cultured from glioma cell line U251. Lysate of glioma stem cells was obtained by the repeated freezing and thawing method. Dendritic cells (DCs) were induced and cultured from the murine bone marrow cells, the biological characteristics were detected by electron microscope and flow cytometry. The DC vaccine was obtained by mixing DCs with lysate of glioma stem cells. The DC vaccine was charactirizated through the mixed lymphocyte responses and cell killing experiment in vitro. Level of interferon-gamma (IFN-gamma) in the supernatant was checked by ELISA. RESULTS: After stimulation of lysate of glioma stem cell, expression of surface molecules of DC was up-regulated, including CD80, CD86, CD11C and MHC-II. DCs pulsed with lysate of glioma stem cells were more effective than the control group in stimulating original glioma cells-specific cytotoxic T lymphocytes responses, killing glioma cells and boosting the secretion of IFN-gamma in vitro. CONCLUSION: The results demonstrated DCs loaded with antigens derived from glioma stem cells can effectively stimulate naive T cells to form specific cytotoxic T cells, kill glioma cells cultured in vitro.

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.

Gliomas: marcadores tumorais e prognóstico / Gliomas: tumors biomarkers and prognosis

Os gliomas representam 30%-40% de todas as neoplasias intracranianas e aproximadamente 50% são glioblastomas. São classificados em graus pela OMS, de acordo com sua patologia. Apresentam altas taxas de mortalidade. Existem marcadores tumorais que podem auxiliar na detecção precoce e avaliar prognóstico. Realizada revisão sobre o tema marcadores tumorais por meio do site PubMed. MGMT é uma proteína que restaura o DNA, impedindo a sua alquilação. A metilação do MGMT por meio de fenômeno epigenético impede sua transcrição inibindo sua ação, tornando o tumor suscetível a fármacos. IDH e codeleção cromossômica 1p19q são marcadores tumorais e estão associados a melhor prognóstico. As neoplasias intracranianas apresentam altas taxas de mortalidade e sua detecção precoce por meio de marcadores e o conhecimento de alterações que conferem bom prognóstico podem auxiliar no tratamento dessa doença. A análise molecular auxilia na detecção e no tratamento de tumores.

Gliomas represent 30%-40% of all intracranial tumors and approximately 50% are glioblastomas. They are classified by the WHO in degrees, according to their pathology. Have high mortality rates. There are tumor markers may help in early detection and assess prognosis. Was performed a review about the topic tumor markers through PubMed. MGMT is a protein that restores the DNA, preventing its alkylation. Methylation of MGMT through epigenetic phenomenon prevents their transcription and inhibits its action, making the tumor susceptible to drugs. IDH and chromosomal deletion 1p19q are tumor markers and are associated with better prognosis. The intracranial tumors have high rates of mortality and early detection through biomarkers and knowledge of changes that confer a good prognosis can help in treating this disease. Molecular analysis allows the detection and treatment of tumors.

Análise de sobrevida e fatores prognósticos de pacientes pediátricos com tumores cerebrais / Analysis of survival and prognostic factors of pediatric patients with brain tumor

OBJETIVOS: Realizar análise de sobrevida e avaliar, através de análise multivariada, a influência de diversas variáveis na sobrevida, definindo fatores prognósticos de pacientes pediátricos com tumores do sistema nervoso central (SNC) tratados em um único centro. MÉTODOS: Analisamos, retrospectivamente, a sobrevida de 103 crianças portadoras de tumores cerebrais primários, diagnosticadas consecutivamente no período entre janeiro de 2000 e dezembro de 2006. Análise multivariada de fatores influenciando a sobrevida global por regressão de Cox foi usada para definir possíveis fatores prognósticos. RESULTADOS: A mediana e a média de idade foram de 7,2 e 7,6 anos. Houve predominância do sexo masculino (relação 1,22:1). A maioria dos pacientes tinha meduloblastoma ou tumores neuroectodérmicos primitivos (PNET, 38 por cento) ou astrocitomas de baixo grau (18 por cento). As topografias mais comuns foram cerebelar (49 por cento) e tronco cerebral (21 por cento). A sobrevida, 5 anos após o diagnóstico, foi de 84 por cento para astrocitomas de baixo grau e 51 por cento para meduloblastomas e PNET. Fatores prognósticos para a sobrevida global foram histopatológico (astrocitomas de alto grau e ependimomas, razão de risco entre 3,7 e 3,9), cirurgia (razão de risco 0,5 para tumores completamente ressecados) e radioterapia (razão de risco 0,5 para pacientes que receberam radioterapia). CONCLUSÕES: A sobrevida global de pacientes pediátricos com tumores cerebrais neste estudo é comparável àquela dos registros populacionais dos Estados Unidos e Europa. Os fatores de prognóstico definidos para sobrevida global também se assemelham àqueles previamente publicados.

OBJECTIVES: To estimate survival and evaluate prognostic factors of pediatric patients with central nervous system (CNS) tumors treated in a single center. METHODS: Retrospective analysis of survival of 103 children with primary brain tumors diagnosed consecutively from January 2000 to December 2006. Cox regression was used for multivariate analysis of factors that affect overall survival to define possible prognostic factors. RESULTS: Median and mean ages were 7.2 and 7.6 years. There was a male predominance (1.22:1). Most patients had medulloblastomas or primitive neuroectodermal tumors (PNET, 38 percent), or low-grade astrocytomas (18 percent). The anatomic site of most tumors was the cerebellum (49 percent) and the brain stem (21 percent). Five-year survival after diagnosis was 84 percent for low-grade astrocytomas and 51 percent for medulloblastomas and PNET. Prognostic factors for overall survival were histopathological type (high-grade astrocytomas and ependymomas; hazard ratio = 3.7 to 3.9), surgery (hazard ratio of 0.5 for completely resected tumors) and radiotherapy (hazard ratio of 0.5 for patients who underwent radiotherapy). CONCLUSIONS: Overall survival of pediatric patients with brain tumors in this study was similar to that found in populations of the United States and Europe. The prognostic factors defined for overall survival are also similar to those published in previous studies.

Complications of post-operative seizure prophylaxis in patients submitted to cranial irradiation

The clinical status of patients with malignant intracranial tumors, such as high-grade gliomas, is often aggravated by seizure activity. Phenytoin is typically employed as prophylactic anticonvulsant in this setting. In such patients, severe systemic drug reactions such as erythema multiforme (EM) may occur. However, in a subgroup of patients with brain radiation therapy, EM-like lesions appear to develop in an increased ratio. The acronym ‘EMPACT’ (E: erythema; M: multiform; associated with P: phenytoin; A: and; C: cranial, radiation; T: therapy) has been suggested to best describes this syndrome. In this article, the authors present a case report of a patient treated with phenytoin for seizure prophylaxis, during the post-operative period following resection of a malignant glioma, and who presented a severe cutaneous rash, evolving with serious consequences due to abrupt change of seizure medications. Because of these predictable complications we abandoned our routine institutional protocol which employed phenytoin for seizure prophylaxis for patients in the post-operative period following malignant tumor resection and which expect to be irradiated in the near future. Once both carbamazepine and barbiturates show cross-sensitivity with phenytoin and may interfere with serum levels of chemotherapy drugs, we now advocate, as other worldwide renown neuro-oncological centers, the use of valproate gabapentin, or alternatively, as recent literature guidelines suggests levetiracetam (keppra), for seizure prophylaxis in this select subset of patients.

El estado clínico de los pacientes con tumores malignos intracraneales, como los gliomas de alto grado, es a menudo agravado por la actividad convulsiva. La fenitoína es normalmente empleadaa como anticonvulsivante profiláctico en esto contexto. En estos pacientes, graves reacciones sistémicas, como eritema multiforme (EM) puedem ocurrir. Sin embargo, en un subgrupo de pacientes con terapia de radiación en el cerebro, lesiones de EM, parece que se desarrollan en una proporción mayor. ‘EMPACT’ La sigla (E: eritema, M: multiforme; asociados con P: fenitoína; A: y C: la radiación craneal, T: La terapia) Se ha sugerido que mejor describe este síndrome. En esto artículo, los autores presentan un caso clínico de un paciente tratado con fenitoína para la profilaxia de convulsiones, durante el período post-operatorio después de la resección de un glioma maligno, y que presenta una erupción cutánea grave, que evoluciona con consecuencias graves debido al cambio brusco de medicamentos anticonvulsivos. Debido a estas complicaciones predecibles, que abandonamos nuestro protocolo institucional de rutina que la fenitoína empleadas para la profilaxia de convulsiones en los pacientes en el período post-operatorio después de la resección del tumor maligno y que esperan ser irradiado en un futuro próximo. Una vez que ambos carbamazepina y los barbitúricos mostran sensibilidad cruzada con fenitoína y puede interferir con los niveles séricos de drogas de la quimioterapia, ahora defendemos, como otros centros de renombre mundial neuro-oncológico, el uso de gabapentina valproato, o bien, como orientación la literatura reciente sugiere levetiracetam (keppra), para la profilaxia de las convulsiones en este subgrupo seleccionado de pacientes.

The role of surgery in the management of intracranial gliomas: current concepts.

The role of surgery in the management of human gliomas has been controversial. The results from numerous neurosurgical series are inconsistent. The current adjuvant therapies have facilitated treatment of patients, and have rendered neurosurgical removal without morbidity or mortality more commonplace than ever before. Here, we investigated the role of surgery in the management of adults with low- and high-grade gliomas. Even though there is substantial evidence which claims that surgery per se has a role to play in extending patient survival, there is a paucity of randomized clinical trials on this subject, and little in the way of Class II data to support these claims. However, this should not divert patients away from surgery, because there may be additional benefits from a concerted effort to remove a tumor completely. At the present time, it seems best that clinicians continue to individualize patient treatment based on a myriad of factors that relate to the patient, the patient's tumor, and the known biology of the disease.

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.

Therapy for glioma: Indian perspective.

Central nervous system (CNS) are rare neoplasms with considerable heterogeneity and variation. The most common primary lesions of CNS are gliomas. A majority of the data about the demography and management of gliomas has emerged from the west. However, there may be considerable variation in the presentation, behavior, and response to treatment between patients in the western world and the Asian population. This article discusses gliomas with special reference to data from oncology centers in India.

Análise de metaloproteases de matriz extracelular como indicador prognóstico nos gliomas malignos / Analysis of matrix metalloproteinase as prognostic indicator in malignant gliomas

Introdução: Metaloproteases de matriz extracelular(MMP) são enzimas proteolíticas sintetizadas na fase de fenótipo mais agressivo dos gliomas malignos, degradando proteínas da matriz extracelular,ocasionando ruptura da barreira hematoencefálica e contribuindo para a resposta neuroinflamatória,angiogênese e migração.Estudos mostram expressão de gelatinase A(MMP-2)proeminentemente nas células gliais tumorais,com pouca expressão na microvasculatura,enquanto expressão de gelatinase B(MMP-9)é proeminente na microvasculatrua, com porco sinal nas células tumorais.Objetivo:Neste estudo analisamos amostras de soro de 34 pacientes com gliomas malignos recidivos,antes e durante o tratamento com álcool perílico por via inalatória para determinar se a expressão de MMP poderia ser usada como indicador prognóstico.Métodos:A atividade gelatinade (MMP-2, MMP-9)nas amostras de soro foi determinada por zimografia e a atividade enzimática relativa foi determinada utilizando-se programa de análise densitométrica.Os valores foram correlacionados com exames de imagem e sobrevida dos pacientes. Resultados:Os resultados obtidos em nosso estudo evidenciaram que os pacientes com gliomas malignos apresentaram aumento da expressão de MMP-2 e MMP-9 quando comparados com pacientes saudáveis.Expressão aumentada de MMP-2 foi proporcional à progressão tumoral,sobrevida desfavorável e área de edema peritumoral.Conclusão:Esses resultados indicam proporcionalidade entre a expressão de MMP-2 e a malignidade dos gliomas, sugerindo seu emprego como indicador prognóstico para recorrência tumoral pós-operatória e sobrevida desfavorável dos pacientes.

Estado actual de la terapia antiangiogénica en el manejo de gliomas de alto grado / Present state of the antiangiogenic therapy in the management of gliomas of high degree

High grade gliomas are lethal cancers. Despite recent advances in surgery, radiotherapy and chemotherapy, the overall survival is 15 months for glioblastoma. They are among the most vascular of human tumors, making them especially attractive targets for angiogenesis inhibitors. Most clinical trials of these agents as monotherapy have failed to demonstrate survival benefit in unselected high grade glioma patient populations. Several mechanisms of treatment failure have been postulated. In response, there are new intervention strategies on course: the combination of target therapy with classic chemotherapy, multitargeted kinase inhibitors and combinations of single-targeted kinase inhibitors and the identification of correlative biomarkers. These advances provide real opportunities for the development of effective therapies for high grade gliomas.