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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The median survival of glioblastoma patients is approximately 12 months. However, 3-5% of the patients survives for more than 3 years and are referred to as long-term survivors. The clinical and molecular factors that contribute to long-term survival are still unknown. To identify specific parameters that might be associated with this phenomenon, we performed a detailed clinical and molecular analysis of 55 primary glioblastoma long-term survivors recruited at the six clinical centres of the German Glioma Network and one associated centre. An evaluation form was developed and used to document demographic, clinical and treatment-associated parameters. In addition, environmental risk factors, associated diseases and occupational risks were assessed. These patients were characterized by young age at diagnosis and a good initial Karnofsky performance score (KPS). None of the evaluated socioeconomic, environmental and occupational factors were associated with long-term survival. Molecular analyses revealed MGMT hypermethylation in 28 of 36 tumours (74%) investigated. TP53 mutations were found in 9 of 31 tumours (29%) and EGFR amplification in 10 of 38 tumours (26%). Only 2 of 32 tumours (6%) carried combined 1p and 19q deletions. Comparison of these data with results from an independent series of 141 consecutive unselected glioblastoma patients registered in the German Glioma Network revealed significantly more frequent MGMT hypermethylation in the long-term survivor group. Taken together, our findings underline the association of glioblastoma long-term survival with prognostically favourable clinical factors, in particular young age and good initial performance score, as well as MGMT promoter hypermethylation.
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PMID:Long-term survival with glioblastoma multiforme. 1778 46

Glioblastomas frequently express oncogenic EGFR and loss of the Ink4a/Arf locus. Bmi1, a positive regulator of stem cell self renewal, may be critical to drive brain tumor growth. In this issue of Cancer Cell, Bruggeman and colleagues suggest that brain tumors with these molecular alterations can be initiated in both neural precursor and differentiated cell compartments in the absence of Bmi1; however, tumorigenicity is reduced, and tumors contain fewer precursor cells. Surprisingly, tumors appear less malignant when initiated in precursor cells. Bmi1-deficient tumors also had fewer neuronal lineage cells, suggesting a role for Bmi1 in determination of cell lineage and tumor phenotype.
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PMID:Bmi1 and cell of origin determinants of brain tumor phenotype. 1793 58

Even though glioblastoma, WHO grade IV (GBM) is one of the most devastating adult cancers, current treatment regimens have not led to any improvements in patient life expectancy or quality of life. The constitutively active EGFRvIII receptor is one of the most commonly mutated proteins in GBM and has been linked to radiation and chemotherapeutic resistance. To define the mechanisms by which this protein alters cell physiology, we have recently performed a phosphoproteomic analysis of EGFRvIII signaling networks in GBM cells. The results of this study provided important insights into the biology of this mutated receptor, including oncogene dose effects and differential utilization of signaling pathways. Moreover, clustering of the phosphoproteomic data set revealed a previously undescribed crosstalk between EGFRvIII and the c-Met receptor. Treatment of the cells with a combination employing both EGFR and c-Met kinase inhibitors dramatically decreased cell viability in vitro. In this perspective, we highlight the use of systems biology as a tool to better understand the molecular basis of GBM tumor biology as well as to uncover non-intuitive candidates for therapeutic target validation.
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PMID:Uncovering therapeutic targets for glioblastoma: a systems biology approach. 1798 64

Studies support involvement of the erbB/HER (human epidermal growth factor receptor) family, comprising the c-erbB-1/2/3/4 receptor proteins, in the tumourigenesis of human gliomas, raising their potential role in diagnostic and therapeutic approaches to these tumours. Reliable detection systems for these molecules in glioma tissue are therefore needed. Formalin-fixed and paraffin-embedded sections from twenty-one human glioblastomas were investigated by standard immunohistochemical procedures for expression of c-erbB-1/2/3/4 receptor proteins using commercial antibodies. All the antibodies used worked satisfactorily on paraffin-sections. For EGFR (epidermal growth factor receptor) two antibodies reactive against the external and internal domain were used. The first revealed positive immunoreactivity in 13 of 21 tumours (62 %), whereas all were positive with the latter. All glioblastomas were negative for the mutated variant of EGFR (i.e. EGFRvIII). Nine of 21 tumours (43 %) were immunoreactive for c-erbB-2, 19 of 20 tumours (95 %) for c-erbB-3, and 21 of 21 for c-erbB-4. Kaplan-Meier plots as a function of growth factor receptor expression did not show any significant association with survival among the glioblastoma patients. In conclusion, immunohistochemistry is well suited for detection of erb receptor proteins in glioblastoma tissue and demonstrated abundant and simultaneous immunoreactivity of these receptors.
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PMID:Coexpression of c-erbB 1-4 receptor proteins in human glioblastomas. An immunohistochemical study. 1798 95

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and elucidation of its underlying genetics has advanced diagnostic screening, early detection, and treatment. Because CRC genomes are characterized by numerous non-random chromosomal structural alterations, we sought to delimit regions of recurrent amplifications and deletions in a collection of 42 primary specimens and 37 tumor cell lines derived from chromosomal instability neoplasia and microsatellite instability neoplasia CRC subtypes and to compare the pattern of genomic aberrations in CRC with those in other cancers. Application of oligomer-based array-comparative genome hybridization and custom analytic tools identified 50 minimal common regions (MCRs) of copy number alterations, 28 amplifications, and 22 deletions. Fifteen were highly recurrent and focal (<12 genes) MCRs, five of them harboring known CRC genes including EGFR and MYC with the remaining 10 containing a total of 65 resident genes with established links to cancer. Furthermore, comparisons of these delimited genomic profiles revealed that 22 of the 50 CRC MCRs are also present in lung cancer, glioblastoma, and/or multiple myeloma. Among 22 shared MCRs, nine do not contain genes previously shown genetically altered in cancer, whereas the remaining 13 harbor 35 known cancer genes, of which only 14 have been linked to CRC pathogenesis. Together, these observations point to the existence of many yet-to-be discovered cancer genes driving CRC development, as well as other human cancers, and show the utility of high-resolution copy number analysis in the identification of genetic events common and specific to the development of various tumor types.
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PMID:Common and distinct genomic events in sporadic colorectal cancer and diverse cancer types. 1800 16

Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anapalsic astrocytoma (secondary glioblastoma). The molecular alteration most frequent in these tumor-like types is the loss of heterozygosity on chromosome 10, in which several genes have been identified as tumors suppressor. The TP53/MDM2/P14arf and CDK4/RB1/ P16ink4 genetic pathways involved in cycle control are deregulated in the majority of gliomas as well as genes that promote the cellular division, EGFR. Finally the increase of growth and angiogenics factors is also involved in the development of glioblastomas. One of the objectives of molecular biology in tumors of glial ancestry is to try to find the genetic alterations that allow to approach better the classification of glioblastomas, its evolution prediction and treatment. The new pathmolecular classification of gliomas should improve the old one, especially being concerned about the oncogenesis and heterogeneity of these tumors. It is desirable that this classification had clinical applicability and integrates new molecular findings with some known histological features with pronostic value. In this paper we review the most frequent molecular mechanisms involved in the patogenesis of glioblastomas.
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PMID:[Biology molecular of glioblastomas]. 1800 11

To improve activity of a recombinant IL-13 cytotoxin (CT) comprised of IL-13 spliced to truncated diphtheria toxin (DT(390)), epidermal growth factor (EGF) was added to the same single chain protein. This new recombinant bispecific CT, called DTEGF13, enhanced the killing potency against the human glioblastoma lines, U87MG (0.015 nM) and U118MG (0.02 nM). A similar enhancement was observed against the lung carcinoma cell line, Calu-3 (0.0018 nM). Enhanced activity could not be explained by an increased number of cytokines available for binding since a combination of monospecific DTEGF and DTIL13 did not cause the same enhanced activity. Enhanced activity was dependent on the presence of both cytokines on the same single chain molecule and killing was receptor specific since target receptor negative leukemia cells were unaffected by the highly selective DTEGF13 and cytotoxicity could be blocked with anti-EGFR and anti-IL-13 antibodies. In a xenograft flank tumor model, intratumoral injection of DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established U87 tumors in nude mice (P < 0.04). In this model, the human EGF and IL-13 components of DTEGF13 are reactive with mouse EGFR and IL-13R, respectively. These studies show that a new co-targeting agent that simultaneously recognizes EGFR and IL-13R is more effective than its monospecific counterparts and that DTEGF13 has therapeutic advantages for glioblastoma.
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PMID:Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model. 1808 21

Glioblastoma is the most malignant and frequent of the glial tumors. A minor fraction of glioblastoma may contain areas showing oligodendroglioma-like tumor cell differentiation. Several authors have described such tumors as glioblastoma with oligodendroglial component (GBMO). GBMO may represent the ultimate level of malignancy in the oligodendroglial lineage. The oligodendroglial component and combined loss of chromosomal arm 1p and 19q in glioblastoma indicate increased survival. In our study, we analyzed 1p and 19q status in a series of 12 glioblastoma and 8 oligodendroglial tumors using fluorescence in situ hybridization (FISH) on paraffin-embedded tissues. In each case, hybridization status was classified as deletion, imbalance, polysomy, amplification, or normal pattern. Other genetic alterations such as CDKN2A (p16), RB, and EGFR were also assessed. On histological review, 2 of 12 glioblastoma (16.7%) were classified as GBMO. Chromosome 1p/19q deletion was detected in 3 of 12 glioblastomas (25%). In contrast, all 8 oligodendroglial tumors showed 1p/19q deletion. All GBMO had 19q deletion with imbalance, whereas 1 of 10 ordinary glioblastoma (10%) demonstrated 19q deletion with imbalance. All but 1 ordinary glioblastoma (90%) showed CDKN2A (p16) deletion, but no GBMO displayed this alteration. Our results indicate that GBMO may be a distinct subtype of glioblastoma harboring a characteristic molecular profile. FISH on paraffin-embedded specimens is a useful method for subclassification of glioblastoma.
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PMID:FISH 1p/19q deletion/imbalance for molecular subclassification of glioblastoma. 1809 37

The ERK1/2 activated protein kinase (MAPK) pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation and survival, involved in malignant transformation. The purpose of this study was to determine the activation of ERK1/2 in this tumor, and to determine the relationship of ERK1/2 activation with the amplification/overexpression of EGFR as well as with 9p21 locus gene alterations, both of which are genetic factors frequently associated with glioblastoma. We used immunohistochemistry and Western blot analysis to analyze the activation of ERK1/2 in 22 patients with glioblastoma, and we studied the amplification/overexpression of EGFR; as well as the molecular alterations in 9p21 locus genes. Positive immunostaining ERK1/2 was observed in 86.4% of the tumors, displaying mainly nuclear immunolocalization; and by immunoblotting, ERK1/2 was activated in 68% of the cases. The 70% of cases with EGFR amplification presented activated ERK1/2. The joint presence of amplified EGFR and alterations in the 9p21 genes was observed in 50% of the cases, whereas the simultaneous occurrence of these two phenomena with the activation of ERK1/2 was observed in 40% of the cases. Our results suggest that the activation of ERK1/2 is implicated in the pathobiology of glioblastoma. This activation of ERK1/2 is probably related in part to the amplification of EGFR as well as to alterations in 9p21 locus genes (homozygous deletion and promoter methylation). However, the activation of ERK1/2 also involves pathways that are independent of the EGFR.
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PMID:The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFR amplification. 1841 Feb 77

Gliomas are the most frequent tumors of the central nervous system. The WHO classification, based on the presumed cell origin, distinguishes astrocytic, oligodendrocytic and mixed gliomas. A grading system is based on the presence of the following criteria: increased cellular density, nuclear atypias, mitosis, vascular proliferation and necrosis. The main histological subtype of grade I gliomas are pilocytic astrocytomas, which are benign. Diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas are low-grade (II) or high-grade (III and IV) tumors. Glioblastomas correspond to grade IV astrocytomas. C. Daumas-Duport et al. have proposed another classification based on histology and imaging data, which distinguishes oligodendrogliomas and mixed gliomas of grade A (without endothelial proliferation and/or contrast enhancement), oligodendrogliomas and mixed gliomas of grade B (with endothelial proliferation or contrast enhancement), glioblastomas and glioneuronal malignant tumors. Both classifications lack reproducibility. Many studies have searched for a molecular classification. Recurrent abnormalities in gliomas have been found. They encompassed recurrent chromosomal alterations, such as lost of chromosome 10, gain of chromosome 7, deletion of chromosome 1p and 19q, but also activation of the Akt pathway (amplification of EGFR), dysregulation of the cell cycle (deletion of p16, p53). These studies have enabled the description of two molecular subtypes for glioblastomas. De novo glioblastomas, which occur in young patients without of a prior history of brain tumor and harbor frequent amplification of EGFR, deletion of p16 and mutation of PTEN while mutation of p53 is infrequent. Secondary glioblastomas occur in the context of a preexisting low-grade glioma and are characterized by more frequent mutation of p53. On the other side, combined complete deletion of 1p and 19q as the result of the translocation t(1;19)(q10;p10) is highly specific of oligodendrogliomas. However, histological and molecular classifications do not always correspond as many alterations are shared by high-grade tumors, whatever their histological type. Besides, few molecular alterations have a prognostic value. Among them combined 1p19q loss is associated with a better prognosis and response to treatment for oligodendrogliomas. Another promising marker is MGMT, a DNA repairing enzyme. If inactivated (by methylation of the promoter of the gene) a better sensitivity is observed with nitrosoure agents. However, some concerns exist for the method of detection of this abnormality. Quality control for molecular techniques is also required before using them for therapeutic strategy. In the future, studies of gene expression profiles by cDNA-microarray as well as works in the field of neural progenitor cells will probably provide new insights in gliomagenesis.
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PMID:[Histological and molecular classification of gliomas]. 1856 48


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