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

Due to recent biological and technical advances, the list of potentially useful candidate genes is rapidly expanding in the study of brain tumors. However, traditional methods of screening individual genes in individual samples are slow and tedious, often with consumption of precious resources after only a few experiments. This study evaluates the feasibility of high-throughput molecular analysis using fluorescence in situ hybridization (FISH) on glioma tissue microarrays (TMA). A single microarray paraffin block was constructed using 65 WHO grade III and IV astrocytomas, sampled in duplicate with 0.6-mm-diameter punch cores. FISH was used to detect common alterations, such as EGFR amplification, chromosome 7, 9, and 10 aneusomies and deletions of 1p, 19q, PTEN, DMBT1, and p16. Of 585 hybridization sets, 508 (87%) yielded interpretable data, with hybridization failure in 33 (5.5%) and dislodged tissue in 44 sets (7.5%), respectively. Glioblastomas harbored significantly more alterations than anaplastic astrocytomas, with the overall frequencies of alterations similar to those reported using other techniques. The overall concordance rate between paired tumor core samples was 93%. We conclude that TMA-FISH is an efficient and reliable method for detecting molecular alterations in high-grade astrocytomas.
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PMID:High-throughput molecular profiling of high-grade astrocytomas: the utility of fluorescence in situ hybridization on tissue microarrays (TMA-FISH). 1248 70

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
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PMID:Targeted molecular therapy of GBM. 1258 May 45

Glioblastoma multiform is one of the most devastating primary tumors in neurooncology. We analyzed prognosis factors in patients with grade IV glioblastoma treated between 1993 and 1997. The 22 long-term survival patients (survival over 26 months) were extracted from our 30 years archives and the 2 populations are compared. The incidence was 2.6/100,000h/year, 62% male and 38% female, mean age 59 years, mean survival 12 months, median survival time 9 months. Multivariate analysis showed that younger age, surgical treatment and radiotherapy were all dependent prognosis factors for better survival. Statistically, survival was best for total surgical removal of tumors, followed by tumor gross resection then biopsy. Clinical status and inextirpable tumor location were also prognosis factors. The free interval time between total surgery and tumor reappearance was strongly correlated with survival (r=0.94). This suggests that some grade IV gliomas follow a quicker course, others exhibiting slow growth. Each of the prognosis factors was confirmed in the long-survival patients. Prevalence of all glioblastomes was 4.3%. Their mean age was 42 and mean survival 62 months. A larger proportion of these patients had total surgery and radiotherapy. The time lapse before tumor reappearance was longer. Deep tumor locations were less frequent. The proportion of secondary versus primary glioblastomas was the greatest difference between the long-term and regular survivors. Secondary glioblastomas were found in only 4% of the standard population and in 23 to 41% in the long-term survivors (p<0.01). Primary glioblastomas typically show EGFR over expression and mutation (variant III). The pathway to secondary glioblastoma involves early P53 mutation. Despite the fact that the anatomopathologist regards similar tissues under the microscope, these subtypes of glioblastomas are distinct disease entities which evolve through different genetic pathways and exhibit different outcomes.
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PMID:[Glioblastomas: clinical study and search for prognostic factors]. 1259 6

This article reviews studies on the correlation between genetic abnormalities in malignant astrocytic tumors and patient survival. It is almost certain that alterations of PTEN on chromosome 10 represent a significant unfavorable prognostic factor in glioblastoma patients. The association of alterations in p53, MDM2, p16 or EGFR with the survival of patients with anaplastic astrocytoma or glioblastoma remains controversial. It is possible that the p16 alteration and EGFR amplification are associated with poor survival in certain groups of patients and that there might be a relationship with age. Malignant transformation of astrocytic cells are driven by the sequential acquisition of genetic alteration. Therefore, it is reasonable to subgroup gliomas by their patterns of genetic alterations. However the studies that correlated the multiple genetic alterations with survival are still limited. Further studies on large cohorts are necessary to elucidate the genetic factors that affect the prognosis and response to therapy of patients with malignant gliomas and to develop effective management strategies.
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PMID:Correlation of molecular genetic analysis of p53, MDM2, p16, PTEN, and EGFR and survival of patients with anaplastic astrocytoma and glioblastoma. 1270 Jan 22

Recent advances in cytogenetic and molecular methodologies have elucidated certain principal characteristics of oncogenesis in glioblastoma multiforme. The earliest clues implicate gene sequence alterations, such as gene amplification and numerical gain or loss of function in specific chromosomes. Genetic classification and expression patterns have thus been constructed, conferring the likelihood of two types of glioblastoma, primary (de novo) as opposed to secondary (evolving from a pre-existing low-grade glioma). The former group of tumors exhibits more frequent occurrences of EGFR gene amplification, whereas the latter group relies strongly on TP53 gene inactivation. Many other tumor suppressor genes and oncogenes have been discovered. Most gene alterations induce cell cycle dysfunction on a complex molecular level. Further insight into tumor genesis by means of genomic assays may aid in predicting the clinical behavior of glioblastoma and in providing individualized potential targets for therapeutic agents.
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PMID:Classification of glioblastoma multiforme in adults by molecular genetics. 1278 73

Glial tumors are the most common tumors of the nervous system, affecting individuals at any age. Since understanding of the molecular pathologies underlying human gliomas is still very poor, the treatment and therefore prognosis of this malignancy could not yet be improved. In order to determine whether different glioblastoma-associated genomic aberrations may serve as prognostic markers in combination with histopathological findings, 20 primary glioblastoma multiforme tumors were screened by comparative genomic hybridization, and the results were compared with histopathological and clinical features. All tumors showed genomic copy aberrations detected by comparative genomic hybridization. Regional and numerical increases in chromosome 7 copy number were the most frequently seen abnormality (10/20 tumors), followed by loss of chromosome 10 (8/20). Both of these aberrations were associated with shorter surveillance time. Chromosome 12q amplification was detected in seven tumors. Loss of 17p, 1p, and 19q in combination was seen in three cases. One of them was a giant cell GBM, whereas the remaining two cases were still alive. Combination of chromosome 1p and 19q deletions was also seen in a case with long surveillance. According to the preliminary findings of this study, in addition to the EGFR gene, amplification of other genes on chromosome 7 and the deletion of PTEN gene and other cancer-related genes on chromosome 10 appeared important to the development of glioblastoma multiforme and were associated with poor prognosis, whereas the combination of chromosome 1p and 19q deletions seems to be an informative molecular marker for better prognosis. The clinical features and genetic alterations of primary and secondary glioblastoma multiforme should be compared in large series to clarify the effective prognostic markers; and further molecular analyses focused on chromosomes 7 and 10 will be very helpful for understanding the molecular mechanisms underlying the progression of glioblastoma.
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PMID:The importance of genomic copy number changes in the prognosis of glioblastoma multiforme. 1284 40

The objective of this study was to determine the immunoexpression pattern of the mitogen-activated protein kinase (MAPK), and related signalling proteins [protein kinase C (PKC), phospholipase Cgamma (PLCgamma)], in glioblastoma multi-forme, and to investigate their prognostic value. Paraffin-embedded biopsy samples from 26 patients [13 patients with long-term survival (LTS; N=13; median 28 months, range 13-76 months), and, for comparison, 13 patients with short-term survival (STS; N=13; median 7 months, range 1-12 months)] were investigated for the immunoexpression of MAPK, the activated pMAPK, PKC, PLCgamma, EGFR, and PTEN. Additionally, the MIB-1 proliferation index was determined. The immunoexpression pattern were related to clinical data, including analysis of their prognostic value using the Cox-proportional hazard model. No significant differences were found between STS and LTS in terms of age, Karnofsky performance status, and treatment. Whereas EGFR expression did not differ between STS and LTS and does not influence survival, expression of MAPK and activated pMAPK was significantly correlated with survival time. The percentage of pMAPK expressing cells correlated strongly with the percentage of MIB-1 positive cells. Furthermore, survival in patients with tumors expressing PKC or PLCgamma was significantly shorter. No differences were found for PTEN expression. Our findings indicate that the MAPK pathway is correlated with proliferation in gliomas, and that patient subgroups exist, in which expression of MAPK-related signalling proteins (PKC, PLCgamma) is associated with poorer prognosis. These patient subgroups may benefit from additional chemotherapeutic agents which specifically inhibit these signalling proteins.
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PMID:Prognostic relevance of MAPK expression in glioblastoma multiforme. 1288 99

The overexpression of epidermal growth factor receptors, EGFR, in glioblastomas is well documented. Hence, the EGFR can be used as target structure for a specific targeting of glioblastomas. Both radiolabeled anti-EGFR antibodies and the natural ligand EGF are candidate agents for targeting. However, EGF, which has a rather low molecular weight (6 kDa), might have better tissue penetration properties through both normal tissue and tumors in comparison with anti-EGF antibodies and their fragments. The aim of this study was to prepare and evaluate in vitro an EGF-based antiglioma conjugate with residualizing label. Human recombinant EGF (hEGF) was coupled to isothiocyanate-benzyl-DTPA. The conjugate was purified from unreacted chelator using solid-phase extraction and labeled with (111)In. The labeling yield was 87% +/- 7%. The label was reasonably stable; the transchelation of (111)In to serum proteins was about 5% after incubation at 37 degrees C during 24 hours. The obtained [(111)In]benzyl-DTPA-hEGF conjugate was characterized in vitro using the EGFR expressing glioma cell line U343MGaCl2:6. The binding affinity, internalization, and retention of the conjugate were studied. The conjugate had receptor specific binding and the radioactivity was quickly internalized. The intracellular retention of radioactivity after interrupted incubation with conjugate was 71% +/- 1% and 59% +/- 1.5% at 24 and 45 hours, respectively. The dissociation constant was estimated to 2.0 nM. The results indicate that [(111)In]benzyl-DTPA-hEGF is a potential candidate for targeting glioblastoma cells, possibly using locoregional injection.
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PMID:[(111)In]Bz-DTPA-hEGF: Preparation and in vitro characterization of a potential anti-glioblastoma targeting agent. 1450 60

Aberrations of genes/proteins regulating cell cycle and growth, increased proliferation and telomerase activity (TA) are documentable in glioblastoma multiforme. TA is more frequently detectable in secondary glioblastoma, which is also characterized by p53 mutation/overexpression. Discordant telomere (Te) length values have been reported in glioblastomas with and without TA. In 31 glioblastomas, in which pre-existing astrocytoma was not documented, we compared cases with and without TA for the expression of p53, EGFR, c-Myc, MIB-1 and Topoisomerase IIalpha; p53 mutations were also investigated by SSCP-PCR. Correlations were made with Te parameters [TePs: number (TeNo), length and area] as evaluated by image analysis in interphase nuclei of fluorescence in situ hybridization (FISH)-processed sections. We found no differences in the expression of the proteins evaluated and in TePs, except Te/nuclear area %, which was significantly lower in TA+ cases (p=0.02). TePs were, instead, inversely correlated with TA (p=0.0001). TA was positively correlated with MIB1 staining index in the TA+ cases (p=0.033), which also showed a positive correlation between TeNo and EGFR expression (p=0.042), and a trend towards a negative correlation between TeNo and p53 expression (p=0.05). Tumors overexpressing EGFR had a significantly shorter lifetime (p=0.0001). TeNo seems to be inversely correlated to tumor proliferation and lifetime in glioblastoma multiforme.
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PMID:In situ detection of telomeres by fluorescence in situ hybridization and telomerase activity in glioblastoma multiforme: correlation with p53 status, EGFR, c-myc, MIB1, and Topoisomerase IIalpha protein expression. 1461 23

Glioblastoma (GB) often has loss of heterozygosity on the chromosomes, 1p, 10p, 10q, 11p, 17p, 19q, 22q, and several others. In the case of chromosome 12q, however, it remains to be seen whether LOH occurs. Apaf-1, the apoptotic protease activating factor-1, located at chromosome 12q22-23, is a major effecter of the p53 mediated apoptosis pathway, and Apaf-1 inactivation due to chromosome 12q22-23 LOH and hypermethylation may be involved in some of the neoplasms in malignancy. However, little is known about the frequency of the 12q22-23 LOH or the state of Apaf-1 in GB. To elucidate their involvement in GB, we analyzed a series of 33 GBs for chromosome 12q22-23 LOH, Apaf-1 mRNA expression, and Apaf-1 protein expression, using microsatellite analysis, reverse transcription (RT)-PCR analysis, and immunohistochemical (IHC) analysis, respectively. We also evaluated if and how the 12q22-23 LOH correlated with the p53 gene mutation and EGFR gene amplification. Chromosome 12q22-23 LOH was detected in 14 (42%) of 33 cases. Among the examined cases with LOH at 12q22-23, a low expression of Apaf-1 mRNA was detected in 9 (69%) of 13 cases, and a low expression of Apaf-1 protein was detected in 12 (86%) of 14 cases. The 12q22-23 LOH was significantly correlated with low expression of mRNA and protein (p<0.05, p<0.001 respectively). The p53 gene mutation and EGFR gene amplification were found in 13 cases (39%) and 8 cases (24%), respectively, and these gene alterations were inversely correlated. However, 12q22-23 LOH had no correlations with the p53 gene mutation or EGFR gene amplification. Six of 9 GBs (67%) with neither p53 gene mutation nor EGFR gene amplification tested positive for 12q22-23 LOH. These GBs are likely to belong to another subset independent from the 2 common genetic subsets in GB (one with p53 gene mutation and without EGFR gene amplification, and the other with EGFR gene amplification and without p53 gene mutation). Twenty-three (70%) out of the 33 GBs with the 12q22-23 LOH also tested positive for Apaf-1 inactivation or p53 gene mutation. This high frequency of alterations in the apoptosis-associated factors prompts a speculation that abrogation of the Apaf-1 and p53 mediated apoptosis pathway may play an important role in the tumorigenesis of GB.
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PMID:Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. 1519 36


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