Tratamiento multimodal de los adenomas de hipófisis recidivantes clínicamente no funcionales. Reporte de caso y revisión de la literatura / Multimodal treatment of non-functional recidivant hypophyseal adenomas. A case report and literature review

Resumen Antecedentes: Los adenomas hipofisarios no funcionales generalmente tienen un comportamiento benigno y naturaleza no invasiva, sin embargo, pueden mostrar características de agresividad con invasión a tejidos circundantes, alto índice mitótico, un índice de Ki67 > 3%y positividad extensa para la tinción de p53, diferenciándose de los carcinomas hipofisarios por la ausencia de diseminación cerebroespinal o metástasis a distancia. Los adenomas agresivos muestran resistencia al tratamiento guirúrgico, médico y radioterapia, y los agentes guimioterapéuticos como temozolamida son una opción terapéutica prometedora de acuerdo con los reportes de la literatura médica internacional. Caso clínico: Paciente del sexo femenino en la sexta década de la vida con padecimiento caracterizado por síndrome guiasmático progresivo e hipopituitarismo ante la presencia de un macroadenoma hipofisario no funcional, con resistencia a tratamiento neuroguirúrgico inicial, tratamiento médico con un agonista dopaminérgico y análogo de receptor de la somatostatina así como radioterapia convencional fraccionada, y cumple con los criterios de agresividad. Se establece tratamiento guimioterapéutico a base de temozolamida, y durante su vigilancia muestra tanto estabilidad clínica como ausencia de progresión tumoral. Conclusiones: La determinación de agresividad es de crucial importancia para mejorar el tratamiento del paciente y, con ello, ofrecer un mejor pronóstico y efectividad terapéutica. El tratamiento de los adenomas hipofisarios no funcionales con características de agresividad es un reto clínico gue involucra un abordaje multidisciplinario. La resistencia al tratamiento quirúrgico, médico y radioterapéutico han dado lugar a la investigación de opciones terapéuticas con agentes quimioterapéuticos como la temozolamida, con tasas de respuesta prometedoras.

Abstract Background: Non-functional pituitary adenomas generally have a benign and non-invasive nature, however, it may show aggressiveness with invasion of surrounding tissues, high mitotic index, an index of Ki67> 3% and extensive positive staining for the cellular tumor antigen p53, differing from the pituitary carcinomas by the absence of craniospinal dissemination or systemic metastases. Aggressive adenomas show resistance to surgical, medical and radiation therapy, including chemotherapeutic agents such as temozolomide, a promising therapeutic option according to reports in the international literature. Case presentation: This is a woman in her 6th decade of life with a clinical presentation characterized by a progressive chiasm syndrome and hypopituitarism in the presence of non-functional pituitary macroadenoma, with initial resistance of neurosurgical treatment, medical treatment with a dopaminergic agonist plus a somatostatin receptor agonist and conventional fractionated radiotherapy, meeting the criteria of aggressive pituitary adenoma. After the treatment with temozolomide as a chemotherapy regimen, the patient showed clinical stability and absence of tumor progression during her follow-up. Conclusion: Defining aggressiveness is of crucial importance for improving the management of patients by enhancing prognostic predictions and effectiveness of treatment. The treatment of nonfunctioning pituitary adenomas with aggressiveness is a clinical challenge that involves a multidisciplinary approach. Resistance to surgical, medical and radiotherapeutic treatment have resulted in the investigation of therapeutic options with chemotherapeutic agents such as temozolomide, with promising response rates.

A resistência das células T98G e U87MG à temozolamida está correlacionada com a expressão de genes de reparo de DNA / The resistance of T98G and U87MG cell lines to temozolomide is correlated with the expression of DNA repair genes

Os gliomas são tumores cerebrais definidos patologicamente pela presença de células com características histológicas e imuno-histoquímicas que evidenciam diferenciação glial. Dentre eles, os astrocitomas são os mais frequentes em adultos. Estes tumores normalmente apresentam infiltração difusa no tecido adjacente, são resistentes aos tratamentos e têm uma tendência natural para a progressão maligna. O tratamento padrão atual consiste na realização de ressecção cirúrgica do tecido tumoral seguida de radio e quimioterapia concomitantes, porém o prognóstico permanece extremamente pobre. O quimioterápico padrão-ouro no tratamento de GBM é o agente alquilante de DNA temozolamida (TMZ). Entretanto, os danos induzidos pela TMZ podem ser revertidos pela ação da maquinaria de reparo de DNA, impedindo a morte celular e levando à resistência do GBM ao tratamento. No presente estudo correlacionamos a expressão dos genes ATM, BRCA2, BRIP1, EXO1, NEIL3, RAD54L e XRCC2, envolvidos em reparo de DNA e sabidamente superexpressos em GBM, com a resistência das linhagens celulares T98G e U87MG ao tratamento com TMZ. Mostramos que a linhagem T98G é a mais resistente ao tratamento com TMZ, e apresenta superexpressão de BRCA2, BRIP1, EXO1, NEIL3, RAD54L e XRCC2 e sub-expressão de ATM. Vimos também que a linhagem U87MG, mais sensível ao tratamento com TMZ, apresenta expressão reduzida dos genes ATM, BRCA2 e EXO1. Portanto, estes dados sugerem uma correlação positiva entre a expressão de genes de reparo de DNA e a resistência das células de GBM à TMZ.(AU)

Gliomas are brain tumors pathologically defined by the presence of cells with histological and immunohistochemical characteristics of glial differentiation. Among them, astrocytomas are the most common in adults. These tumors usually show diffuse infiltration into adjacent tissue, are resistant to treatment and have a natural tendency to malignant progression. The current standard treatment consists in surgical removal of the tumor followed by radiotherapy and concurrent chemotherapy. However, the prognosis remains extremely poor. The first line chemotherapy for GBM treatment is the DNA alkylating agent temozolamide (TMZ). Nevertheless, TMZ-induced damage can be reversed by the action of DNA repair machinery that prevents cell death and leads to relapse. In this study we correlated the expression of the DNA damage-signaling gene, ATM kinase, and the DNA repair genes BRCA2, BRIP1, EXO1, NEIL3, RAD54L and XRCC2, with the resistance of T98G and U87MG cell lines to TMZ. T98G cells were more resistant to TMZ treatment and showed overexpression of all DNA repair genes, while ATM kinase was down regulated. We also observed that U87MG cells, more sensitive to TMZ, have reduced expression of ATM, BRCA2 and EXO1. Therefore, these data suggest a positive correlation between the expression of DNA repair genes and the resistance of GBM cells to TMZ.(AU)

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.

Impacto da adição da temozolamida à radioterapia no tratamento de crianças portadoras de tumor de tronco cerebral / Impact of the addition of temozolomide to radiotherapy in the treatment of children with brain stem tumors

OBJETIVO: Analisar o impacto da adição da temozolamida à radioterapia em tumores de tronco cerebral em crianças. MATERIAL E MÉTODO: Entre 2000 e 2005 foram analisadas, retrospectivamente, 64 crianças com tumor do tronco cerebral. Dessas crianças, 32 receberam temozolamida(grupo 1) e 32 não a receberam (grupo 2). RESULTADOS: A idade mediana no grupo 1 foi de 8,2 anos e no grupo 2 foi de 7,5 anos. A localização tumoral era predominantemente difusa (53%) emambos os grupos. Todos os pacientes receberam radioterapia com doses superiores a 50 Gy. No grupo1 foram ministrados nove ciclos, em média, de quimioterapia (3û14 ciclos). O tempo de progressão de doença foi de 7,9 meses no grupo 2 versus 13,8 meses no grupo 1. A sobrevida global foi de 8,8 meses (0,3û30,9 meses) no grupo 1 e de 14,6 meses (4,3û33 meses) no grupo 2. CONCLUSÃO: A utilização da temozolamida após a radioterapia proporcionou aumento da sobrevida, deseis meses em média, nos pacientes pediátricos com tumor do tronco cerebral.

OBJECTIVE: To analyze the impact of adding temozolomide to radiotherapyin pediatric brain stem tumors. MATERIAL AND METHOD: Between 2000 and 2005, 64 children with brain stem tumor were analyzed: 32 received temozolomide (group 1) and 32 did not(group 2). RESULTS: The median age of patients in group 1 was 8.2 year-old and in group 2 was 7.5 year-old. The predominant tumoral localization was diffuse (53%) in both groups. All of the patients were submitted to radiotherapy. In group 1, the median number of temozolomide cycles was 9 (3û14 cycles). Time of disease progression was 7.9 months in group 2 versus 13.8 months in group 1. Overall survival was 8.8 months (0.3û30.9 months) in group 1 and 14.6 months (4.3û33 months) in group 2. CONCLUSION: In our institution,adding temozolomide to radiotherapy increased the overall survival in approximately six months in brain stem pediatric tumors.