J.A. Gómez-Moreta

Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

BackgroundGliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs) are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow in vitro forming neurospheres and that can be isolated in vivo using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM.MethodsEight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA;ResultsGene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders). Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups of samples: those discriminated by tumour location and, the most importantly, the group discriminated by their proliferative potential;ConclusionsPrimary glioblastomas could be sub-classified according to the properties of their CD133+ cells. The molecular characterization of these potential stem cell populations could be critical to find new therapeutic targets and to develop an effective therapy for these tumours with very dismal prognosis.

Multiple meningiomas of the fourth ventricle in infancy: case report.

Meningiomas are uncommon tumors in infancy. Intraventricular meningiomas do occur more frequently in infancy than in adulthood, although the establishment and growth of such tumors in the fourth ventricle is exceptional in children. The occurrence of multiple meningiomas is currently estimated to be less than 8%. We present the case of a girl who displayed two meningiomas in the fourth ventricle. Five years later, the child had four more meningiomas detected and extirpated from the same site. Eighteen months later, a new tumor appeared in the lower third of the clivus; after resection this was found to be another meningioma. The presence in a child of the repeated occurrence of multiple meningiomas, both in the fourth ventricle and in other areas of the posterior fossa, have led the authors to consider that the case is both curious and rare. Twelve similar cases of meningiomas developing exclusively in the fourth ventricle have been published; of these, only 3 occurred during infancy. A discussion is offered concerning the etiology and pathogenesis of these tumors; in which the possibility of unknown neuro-oncogenic factors that might induce meningiomas is postulated.

Analysis of DNA repair gene polymorphisms in glioblastoma

BACKGROUND Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite several factors such as ionizing radiation exposure or rare genetic syndromes have been associated with the development of glioblastoma, no underlying cause has been identified for the majority of cases. We thus aimed to investigate the role of DNA repair polymorphisms in modulating glioblastoma risk. METHODS Genotypic and allelic frequencies of seven common polymorphisms in DNA repair genes involved in nucleotide excision repair (ERCC1 rs11615, ERCC2 rs13181, ERCC6 rs4253079), base excision repair (APEX1 rs1130409, XRCC1 rs25487), double-strand break repair (XRCC3 rs861539) and mismatch repair (MLH1 rs1800734) pathways were analyzed in 115 glioblastoma patients and 200 healthy controls. Haplotype analysis was also performed for ERCC1 rs11615 and ERCC2 rs13181 polymorphisms, located on the same chromosomal region (19q13.32). RESULTS Our results indicated that carriers of the ERCC2 Gln/Gln genotype were associated with a lower glioblastoma risk (OR=0.32, 95% CI 0.12-0.89; P=0.028), whereas carriers of the MLH1 AA genotype were associated with an increased risk of glioblastoma (OR=3.14, 95% CI 1.09-9.06; P=0.034). Furthermore, the haplotype containing the C allele of ERCC2 rs13181 polymorphism and the T allele of ERCC1 rs11615 polymorphism was significantly associated with a protective effect of developing glioblastoma (OR=0.34, 95% CI 0.16-0.71; P=0.004). CONCLUSIONS These results pointed out that MLH1 rs1800734 and ERCC2 rs13181 polymorphisms might constitute glioblastoma susceptibility factors, and also suggested that the chromosomal region 19q could be important in glioblastoma pathogenesis.

Integrated Analysis of Mismatch Repair System in Malignant Astrocytomas

Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1 -93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.

Ventriculostomía endoscópica: influencia de factores predisponentes al fallo y evolución del tamaño ventricular

Resumen Introduccion La ventriculostomia endoscopica es en nuestro centro el tratamiento de primera eleccion para la hidrocefalia no comunicante. Hay una serie de factores favorecedores de un fracaso de la intervencion. El objetivo de este trabajo ha sido analizar su influencia en nuestra serie. Material y metodos Cincuenta y seis pacientes (edad media 48.5 anos) han sido tratados mediante ventriculostomia endoscopica durante el periodo 1997–2002. Se han diferenciado formas agudas (68%) y formas cronicas de hidrocefalia. La etiologia se clasifico en lesiones ocupantes de espacio (59%), estenosis primaria del acueducto (34%) y malformacion de Chiari (7%). Consideramos los siguientes factores predisponentes al fracaso: edad inferior a 12 meses, antecedentes de mielomeningocele, radioterapia, craneotomia, infeccion de liquido cefalorraquideo (LCR), hemorragia intracraneal y tratamiento previo de la hidrocefalia con un shunt. Se analizo la evolucion de cuatro indices de tamano ventricular comparando la ultima imagen postoperatoria con la preoperatoria. Resultados Despues de un periodo de seguimiento medio de 26 meses, la intervencion ha sido efectiva en el 71.4% de los pacientes. La hidrocefalia secundaria a metastasis localizadas en areas que dificultan la circulacion de LCR se asocia con fracaso de la ventriculostomia (p=0.006). Ninguno de los factores predisponentes al fallo ha mostrado relacion con el resultado de la intervencion. La evolucion del tamano ventricular depende de la eficacia. El indice de Evans, indice del tercer ventriculo, indice de celia media y el indice ventricular global disminuyen si la ventriculostomia es eficaz y aumentan en caso de fallo (p Conclusion En la hidrocefalia secundaria a metastasis cerebrales la eficacia de una ventriculostomia endoscopica es menor por una probable implicacion de otros mecanismos fisiopatologicos, ademas de una obstruccion en la circulacion de LCR. La evolucion del tamano ventricular se relaciona con el resultado de la ventriculostomia.

Expression of VAV1 in the tumour microenvironment of glioblastoma multiforme

Even though much progress has been made towards understanding the molecular nature of glioma, the survival rates of patients affected by this tumour have not changed significantly over recent years. Better knowledge of this malignancy is still needed in order to predict its outcome and improve patient treatment. VAV1 is an GDP/GTP exchange factor for Rho/Rac proteins with oncogenic potential that is involved in the regulation of cytoskeletal dynamics and cell migration. Here we report its overexpression in 59 patients diagnosed with high-grade glioma, and the associated upregulation of a number of genes coding for proteins also involved in cell invasion- and migration-related processes. Unexpectedly, immunohistochemical experiments revealed that VAV1 is not expressed in glioma cells. Instead, VAV1 is found in non-tumoural astrocyte-like cells that are located either peritumouraly or perivascularly. We propose that the expression of VAV1 is linked to synergistic signalling cross-talk between cancer and infiltrating cells. Interestingly, we show that the pattern of expression of VAV1 could have a role in the neoplastic process in glioblastoma tumours.

VRK2 identifies a subgroup of primary high-grade astrocytomas with a better prognosis.

BackgroundMalignant astrocytomas are the most common primary brain tumors and one of the most lethal among human cancers despite optimal treatment. Therefore, the characterization of molecular alterations underlying the aggressive behavior of these tumors and the identification of new markers are thus an important step towards a better patient stratification and management.Methods and resultsVRK1 and VRK2 (Vaccinia-related kinase-1, -2) expression, as well as proliferation markers, were determined in a tissue microarray containing 105 primary astrocytoma biopsies. Kaplan Meier and Cox models were used to find clinical and/or molecular parameters related to overall survival. The effects of VRK protein levels on proliferation were determined in astrocytoma cell lines. High levels of both protein kinases, VRK1 or VRK2, correlated with proliferation markers, p63 or ki67. There was no correlation with p53, reflecting the disruption of the VRK-p53-DRAM autoregulatory loop as a consequence of p53 mutations. High VRK2 protein levels identified a subgroup of astrocytomas that had a significant improvement in survival. The potential effect of VRK2 was studied by analyzing the growth characteristics of astrocytoma cell lines with different EGFR/VRK2 protein ratios.ConclusionHigh levels of VRK2 resulted in a lower growth rate suggesting these cells are more indolent. In high-grade astrocytomas, VRK2 expression constitutes a good prognostic marker for patient survival.

Hematoma subdural crónico. Estudio de la expansión cerebral utilizando la inyección espinal de suero fisiológico durante la cirugía

Resumen Se estudian 31 pacientes con H.S.C. tratados mediante trepanos e inyeccion espinal de suero fisiologico, utilizando la tecnica descrita por LaLonde y Gardner. La edad media fue de 70 anos. La reexpansion cerebral intraoperatoria se mantuvo solamente en nueve ocasiones produciendose nuevo colapso cerebral en el resto, como se constataba por TAC. Los mejores resultados se obtuvieron en los casos de coleccion unilateral, edad por debajo de los 51 anos y que precisaron menos de 70 cc. de suero fisiologico para conseguir la expansion cerebral durante la intervencion. Tras el tratamiento se obtuvo reexpansion cerebral completa en todos los casos, a los 10 dias en nueve colecciones unilaterales, a los 58 dias en otras quince y a los 82 dias en seis bilaterales. Seis pacientes fueron reintervenidos, cinco de ellos con coleccion bilateral en el momento del ingreso. Hubo un exitus. Presentamos las complicaciones del metodo y se discuten los resultados.

Quistes espinales meníngeos extradurales gigantes: Consideraciones etiológicas y quirúrgicas☆

Resumen Los quistes espinales meningeos que den lugar a alteraciones neurologicas no se observan con frecuencia y es menos habitual que estos quistes adquieran grandes proporciones; sin embargo es interesante conocerlos en tanto en cuanto son procesos absolutamente benignos que pueden determinar graves trastornos neurologicos. Su origen y mecanismo de produccion, aunque incierto en algunos casos, parece estar ligado a un trastorno del desarrollo embrionario y habitualmente se asocian a otras malformaciones congenitas. Uno de los problemas diagnosticos es determinar si comunican o no con el espacio subaracnoideo. Para ello es de mayor utilidad el estudio con mielo-TAC que los datos proporcionados por la RNM. El tratamiento debe ser quirurgico con extirpacion total del quiste y cierre del defecto dural si se quiere llegar a resultados satisfactorios. Apoyando la teoria congenita se describe el caso de un quiste espinal meningeo extradural gigante con otras anormalidades congenitas, del que se hizo reseccion total.

Meningiomas de la región parasellar

Resumen Objetivos Hacer una valoracion del tratamiento quirurgico de los meningiomas parasellares. Material y metodos En los ultimos 12 anos han sido revisadas de forma retrospectiva las historias clinicas e iconografia de 33 pacientes diagnosticados de meningioma que asentaban en la region parasellar. Bajo esta denominacion se ha considerado un area que rodea la silla turca y que esta constituida por estructuras situadas profundamente, por lo tanto de dificil acceso, y cuya lesion tiene un alto grado de morbi-mortalidad. Resultados Se ha conseguido una extirpacion macroscopica completa en el 84.84%, con aparicion de recidiva en tres pacientes suponiendo un 9.1%, durante un seguimiento medio de 39.75 meses. El porcentaje preoperatorio de afectacion de pares craneales se redujo en un 15.6%. La mortalidad postquirurgica es de un 9.1%, con una mortalidad global durante todo el seguimiento del 21.21%, siendo la causa mas importante de morbi-mortalidad el tromboembolismo pulmonar. Como complicaciones neurologicas en el postoperatorio aparecieron tres hemiparesias y 15 nuevos pares craneales en nueve pacientes en su mayoria de caracter reversible. El 60.60% de los casos (20 pacientes) no presentaron ningun tipo de complicacion ni neurologica ni general. Al final del seguimiento el 75% de los enfermos presentaron un Karnofski entre 90 y 100 pudiendo realizar sus actividades preoperatorias con normalidad. Conclusiones La cirugia de estos tumores a pesar de su volumen, generalmente importante, y la afectacion de estructuras como los pares craneales y vasos del poligono de Willis, puede presentar unos resultados aceptables de morbi-mortalidad. Si se consigue una extirpacion completa macroscopica del tumor, las posibilidades de recidiva son bajas, ensombreciendose el pronostico del paciente de forma importante si no se consigue una exeresis completa o aparece una recidiva. Finalmente se valora el papel de la radiocirugia y la radioterapia convencional como tratamiento complementario de estos tumores.