Current concepts in the pathology and genetics of gliomas.

In recent years, there has been a marked improvement in our understanding of molecular genetics of gliomas. These advancements offer hope for development of tailored therapies targeting a tumor's unique molecular profile, and may also translate into improved classification and identification of newer prognostic markers. This review focuses on the neuropathological features of different types of glial neoplasms according to the World Health Organization classification, and the recent advances in their molecular biology with emphasis on the genetic mechanisms underlying tumor progression, diagnostic and prognostic markers and potential therapeutic targets.

Current concepts and newer developments in the treatment of malignant gliomas.

Primary malignant brain tumors account for only 2% of all adult cancers but they cause a disproportionately high cancer-related disability and death. Survival of malignant glioma patients has changed only modestly over the past three decades despite the emergence of new treatment strategies for these tumors. In this review, we describe the standard treatment modalities for malignant glioma, which include surgery, radiation therapy and chemotherapy, as well as the status of novel therapies that have been developed to target various aspects of glioma cell biology. We also address this issue of drug delivery as a factor limiting the efficacy of systemic administration of therapeutics and attempts to overcome this barrier. Further progress towards a cure for malignant gliomas will require a greater understanding of the underlying mechanisms driving the growth, and resistance to therapy, of these challenging tumors.

Mutation analysis of gene PAX6 in human gliomas

Gliomas are the most common tumors of the central nervous system. In spite of the marked advances in the characterization of the molecular pathogenesis of gliomas, these tumors remain incurable and, in most of the cases, resistant to treatments, due to their molecular heterogeneity. Gene PAX6, which encodes a transcription factor that plays an important role in the development of the central nervous system, was recently recognized as a tumor suppressor in gliomas. The objective of the present study was to analyze the mutational status of the coding and regulating regions of PAX6 in 94 gliomas: 81 astrocytomas (11 grade I, 23 grade II, 8 grade III, and 39 grade IV glioblastomas), 5 oligodendrogliomas (3 grade II, and 2 grade III), and 8 ependymomas (5 grade II, and 3 grade III). Two regulating regions (SX250 and EIE) and the 11 coding regions (exons 4-13, plus exon 5a resulting from alternative splicing) of gene PAX6 were analyzed and no mutation was found. Therefore, we conclude that the tumor suppressor role of PAX6, reported in previous studies on gliomas, is not due to mutation in its coding and regulating regions, suggesting the involvement of epigenetic mechanisms in the silencing of PAX6 in these tumors.

Oligodendrogliomas: impact of molecular genetics on treatment.

The interest in oligodendrogliomas has increased since it became evident that a subset of these tumors respond to chemotherapy or radiation. This interest was augmented when the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 was identified as a powerful prediction factor for response. Lack of stringent morphological criteria allow high-interobserver variation with regard to classification and grading of oligodendroglial tumors. The prospect of beneficial chemotherapy prompted neuropathologists to diagnose more 'oligodendroglioma' than before. Therefore, there is great demand for unambiguous classification of oligodendroglial tumors. Supplementary analysis of the integrity of chromosomal arms 1p and 19q may greatly assist diagnostic characterization of tumors with oligodendroglial phenotype. The underlying mechanisms for these deletions are not known. Tumor suppressor genes on 1p and 19q relevant for oligodendroglioma have not yet been identified. Knowledge of these genes and the mechanisms of their inactivation might help to understand why oligodendroglial tumors do respond better to chemotherapy and radiotherapy than astrocytomas. This review compiles clinical, pathological and molecular genetic findings on oligodendrogliomas and oligoastrocytomas of WHO Grades II and III to present a brief overview on recent developments.

Tratamiento actual de los oligodendrogliomas: fundamentos patólogicos y de biología molecular / Present treatment of oligodendrogliomas: pathological foundations and of molecular biology

El estudio de los oligodendrogliomas ha generado gran interés en los últimos 15años, debido que se trata de tumores primarios del cerebro, que son quimiosensibles, a diferencia del resto de los gliomas característicamente quiimioresistentes. Los rápidos avances tecnológicos, permiten el estudio y una mejor comprensión de los cambioscromosómicos y las mutaciones de los ácidos desoxiribonucleicos, que llevan a la activación de los proto-oncógenos y a la perdida de la función de los genes supresores de tumor. Algunos cambioscomo las deleciones del brazo corto p del cromosoma 1 y del brazo largo q del cromosoma 19, y especialmente cuando se dan en forma simultanea, son considerados prácticamente específicospara el diagnóstico de oligodendroglioma. Esto ha permitido demostrar, que estos tumores son muchomas frecuentes que lo que se estimaba hace unos 10 años atrás, y que por lo tanto, el estudio genético molecular es un complemento diagnóstico fundamental al estudio histológico ehistoquimico convencional de este tipo de tumor, que como sabemos muchas veces no permite distinguirlode otros gliomas. Esta caracterización molecular de los gliomas, adquiere gran relevancia ya que permite diagnosticar un mayor número de oligodendrogliomas u otros gliomas con componente oligodendroglial que pueden ser tratados con quimioterapia.

The study of oligodendrogliomas has generated great interest in the last fifteen years, because it refers about primary tumors of the brain, that are quimiosensitive, opposed to the rest of the gliomas, that are characteristicaly quimiorresistent. The rapid advances in technology, allows the study and a better understanding of the chromosomalchanges and the deoxyribonucleic acid mutations, that lead to the activation of proto-oncogenes and loss of function of tumor suppresor genes. Some changes, like deletions in the short arm (p) of the chromosome 1, and the long arm (q) of the chromosome 19, specially when specially when they are simultaneous, are considered practicaly specific for thediagnosis of oligodendroglioma. This fact has lead us to demostrate, that this tumors are much more frequent,than considered 10 years ago, and that is why the genetic molecular study is an essencial complement to the conventional hystologycal and hystochemichal study of this kind of tumors, that as we know, many times, it not allow us to distinguish from othergliomas. This molecular characterization of gliomas, acquieres great relevance allowing to diagnose a greater numberof oligodendrogliomas or other gliomas with oligodendroglial component that can be treated whith quimiotherapy.

Familial gliomas : a case report.

Two non-twin brothers were found to have intracranial malignant neoplasms. The age of presentation was third and fourth decade but the onset was simultaneous, at the same time. Diagnosis in each of them was made by computed tomography and confirmed by histopathology. Elder among them had cellular ependymoma and the younger had oligodendroglioma. Both the brothers received radiotherapy post operatively and were surviving asymptomatically without any neurological deficit, leading active life as police constable, 12 months after surgical treatment.

Loss of heterozygosity on chromosome 10, 13q(Rb), 17p, and p53 gene mutations in human brain gliomas

Using the methods of restriction fragment length polymorphism (RFLP) and single strand conformation polymorphism (SSCP) analyses, we have examined 33 cases of human gliomas with various malignant grades to detect the deletions of putative tumor suppressor gene loci, chromosome 10, 13q(retinoblastoma gene, Rb), 17p, and p53 mutation. We observed loss of heterozygosity (LOH) at loci on chromosome 10 (36%), 13q(Rb) (54%), and 17p(50%) in malignant gliomas. There, however was no allelic loss on chromosome 10 and 17p in low-grade gliomas. Rb gene deletions were seen in low-grade gliomas, including oligodendroglioma and ependymoma. This finding suggests that Rb inactivation may be an early genetic event in the development and progression of gliomas. We correlated the results of LOH on chromosome 17p and p53 mutation. Among the 8 cases which showed LOH on chromosome 17p, only three cases (38%) revealed p53 mutations. Low incidence of p53 mutations in cases with chromosome 17p deletions suggests that some other tumor suppressor genes may be located on chromosome 17p.

Cytogenetic investigation of four low grade gliomas

Four low-grade gliomas - two oligodendrogliomas and two astrocytomas - were analyzed cytogenetically. All cases exhibited monosomies of chromosomes 10 and 11. The astrocytomas shared monosoniies of chromosomes 8, 9, 1O, 11, 12, 18 and 20. Losses of chromosomes 3, 5, 6, 10 and I I were present in both oligodendrogliomas, and except for monosomy of chromosome 6, were also identified in the pilocytic astrocytoma.