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1.
AJNR Am J Neuroradiol ; 33(1): 69-76, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22095961

RESUMO

BACKGROUND AND PURPOSE: Quantifying MVA rather than MVD provides better correlation with survival in HGG. This is attributed to a specific "glomeruloid" vascular pattern, which is better characterized by vessel area than number. Despite its prognostic value, MVA quantification is laborious and clinically impractical. The DSC-MR imaging measure of rCBV offers the advantages of speed and convenience to overcome these limitations; however, clinical use of this technique depends on establishing accurate correlations between rCBV, MVA, and MVD, particularly in the setting of heterogeneous vascular size inherent to human HGG. MATERIALS AND METHODS: We obtained preoperative 3T DSC-MR imaging in patients with HGG before stereotactic surgery. We histologically quantified MVA, MVD, and vascular size heterogeneity from CD34-stained 10-µm sections of stereotactic biopsies, and we coregistered biopsy locations with localized rCBV measurements. We statistically correlated rCBV, MVA, and MVD under conditions of high and low vascular-size heterogeneity and among tumor grades. We correlated all parameters with OS by using Cox regression. RESULTS: We analyzed 38 biopsies from 24 subjects. rCBV correlated strongly with MVA (r = 0.83, P < .0001) but weakly with MVD (r = 0.32, P = .05), due to microvessel size heterogeneity. Among samples with more homogeneous vessel size, rCBV correlation with MVD improved (r = 0.56, P = .01). OS correlated with both rCBV (P = .02) and MVA (P = .01) but not with MVD (P = .17). CONCLUSIONS: rCBV provides a reliable estimation of tumor MVA as a biomarker of glioma outcome. rCBV poorly estimates MVD in the presence of vessel size heterogeneity inherent to human HGG.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Glioma/patologia , Glioma/cirurgia , Angiografia por Ressonância Magnética/métodos , Microvasos/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Determinação do Volume Sanguíneo , Neoplasias Encefálicas/irrigação sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/prevenção & controle , Neovascularização Patológica/patologia , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como Assunto , Técnicas Estereotáxicas , Resultado do Tratamento
2.
AJNR Am J Neuroradiol ; 31(1): 40-8, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19749223

RESUMO

BACKGROUND AND PURPOSE: Relative cerebral blood volume (rCBV) accuracy can vary substantially depending on the dynamic susceptibility-weighted contrast-enhanced (DSC) acquisition and postprocessing methods, due to blood-brain barrier disruption and resulting T1-weighted leakage and T2- and/or T2*-weighted imaging (T2/T2*WI) residual effects. We set out to determine optimal DSC conditions that address these errors and maximize rCBV accuracy in differentiating posttreatment radiation effect (PTRE) and tumor. MATERIALS AND METHODS: We recruited patients with previously treated high-grade gliomas undergoing image-guided re-resection of recurrent contrast-enhancing MR imaging lesions. Thirty-six surgical tissue samples were collected from 11 subjects. Preoperative 3T DSC used 6 sequential evenly timed acquisitions, each by using a 0.05-mmol/kg gadodiamide bolus. Preload dosing (PLD) and baseline subtraction (BLS) techniques corrected T1-weighted leakage and T2/T2*WI residual effects, respectively. PLD amount and incubation time increased with each sequential acquisition. Corresponding tissue specimen stereotactic locations were coregistered to DSC to measure localized rCBV under varying PLD amounts, incubation times, and the presence of BLS. rCBV thresholds were determined to maximize test accuracy (average of sensitivity and specificity) in distinguishing tumor (n = 21) and PTRE (n = 15) samples under the varying conditions. Receiver operator characteristic (ROC) areas under the curve (AUCs) were statistically compared. RESULTS: The protocol that combined PLD (0.1-mmol/kg amount, 6-minute incubation time) and BLS correction methods maximized test AUC (0.99) and accuracy (95.2%) compared with uncorrected rCBV AUC (0.85) and accuracy (81.0%) measured without PLD and BLS (P = .01). CONCLUSIONS: Combining PLD and BLS correction methods for T1-weighted and T2/T2*WI errors, respectively, enables highly accurate differentiation of PTRE and tumor growth.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico , Glioma/cirurgia , Angiografia por Ressonância Magnética/métodos , Angiografia por Ressonância Magnética/normas , Adulto , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes
3.
AJNR Am J Neuroradiol ; 30(3): 552-8, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19056837

RESUMO

BACKGROUND AND PURPOSE: Differentiating tumor growth from posttreatment radiation effect (PTRE) remains a common problem in neuro-oncology practice. To our knowledge, useful threshold relative cerebral blood volume (rCBV) values that accurately distinguish the 2 entities do not exist. Our prospective study uses image-guided neuronavigation during surgical resection of MR imaging lesions to correlate directly specimen histopathology with localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging (DSC) measurements and to establish accurate rCBV threshold values, which differentiate PTRE from tumor recurrence. MATERIALS AND METHODS: Preoperative 3T gradient-echo DSC and contrast-enhanced stereotactic T1-weighted images were obtained in patients with high-grade glioma (HGG) previously treated with multimodality therapy. Intraoperative neuronavigation documented the stereotactic location of multiple tissue specimens taken randomly from the periphery of enhancing MR imaging lesions. Coregistration of DSC and stereotactic images enabled calculation of localized rCBV within the previously recorded specimen locations. All tissue specimens were histopathologically categorized as tumor or PTRE and were correlated with corresponding rCBV values. All rCBV values were T1-weighted leakage-corrected with preload contrast-bolus administration and T2/T2*-weighted leakage-corrected with baseline subtraction integration. RESULTS: Forty tissue specimens were collected from 13 subjects. The PTRE group (n = 16) rCBV values ranged from 0.21 to 0.71, tumor (n = 24) values ranged from 0.55 to 4.64, and 8.3% of tumor rCBV values fell within the PTRE group range. A threshold value of 0.71 optimized differentiation of the histopathologic groups with a sensitivity of 91.7% and a specificity of 100%. CONCLUSIONS: rCBV measurements obtained by using DSC and the protocol we have described can differentiate HGG recurrence from PTRE with a high degree of accuracy.


Assuntos
Neoplasias Encefálicas/patologia , Circulação Cerebrovascular , Glioma/patologia , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/patologia , Radioterapia/efeitos adversos , Biópsia , Volume Sanguíneo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Terapia Combinada , Craniotomia , Diagnóstico Diferencial , Glioma/radioterapia , Glioma/cirurgia , Humanos , Imageamento por Ressonância Magnética/normas , Neuronavegação , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
4.
Oncogene ; 27(4): 441-9, 2008 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-17637744

RESUMO

Human neuroblastoma remains enigmatic because it often shows spontaneous regression and aggressive growth. The prognosis of advanced stage of sporadic neuroblastomas is still poor. Here, we investigated whether genomic and molecular signatures could categorize new therapeutic risk groups in primary neuroblastomas. We conducted microarray-based comparative genomic hybridization (array-CGH) with a DNA chip carrying 2464 BAC clones to examine genomic aberrations of 236 neuroblastomas and used in-house cDNA microarrays for gene-expression profiling. Array-CGH demonstrated three major genomic groups of chromosomal aberrations: silent (GGS), partial gains and/or losses (GGP) and whole gains and/or losses (GGW), which well corresponded with the patterns of chromosome 17 abnormalities. They were further classified into subgroups with different outcomes. In 112 sporadic neuroblastomas, MYCN amplification was frequent in GGS (22%) and GGP (53%) and caused serious outcomes in patients. Sporadic tumors with a single copy of MYCN showed the 5-year cumulative survival rates of 89% in GGS, 53% in GGP and 85% in GGW. Molecular signatures also segregated patients into the favorable and unfavorable prognosis groups (P=0.001). Both univariate and multivariate analyses revealed that genomic and molecular signatures were mutually independent, powerful prognostic indicators. Thus, combined genomic and molecular signatures may categorize novel risk groups and confer new clues for allowing tailored or even individualized medicine to patients with neuroblastoma.


Assuntos
Perfilação da Expressão Gênica , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Análise de Sequência com Séries de Oligonucleotídeos , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 17 , Análise por Conglomerados , Amplificação de Genes , Humanos , Lactente , Recém-Nascido , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/classificação , Neuroblastoma/mortalidade , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Prognóstico , Risco , Análise de Sobrevida
5.
Cancer Res ; 61(20): 7683-8, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11606412

RESUMO

Astrocytomas are brain tumors with variable responses to radiation and chemotherapy. Tumor grade and patient age are important prognostic factors but do not account for the variability in clinical outcome. We hypothesized that genetic subgroups play a role in the outcome of grade III astrocytomas and studied 80 grade III astrocytomas by comparative genomic hybridization. Some chromosomal aberrations (+7p/q, -9p, -10q, -13q, +19q) were related to aberrations that are frequent in grade IV astrocytoma, whereas others (+10p, -11q, +11p, -Xq) were more frequent in grade III astrocytoma. +7p, +19 and -4q were more frequent in tumors from older patients while -11p was more frequent in tumors from younger patients. Finally, gains of 7p and 7q were associated with shorter patient survival, independent of age. Our results indicate that genetic events underlie the well-known effects of age on survival in grade III astrocytoma and demonstrate the importance of molecular classification in astrocytic tumors.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos , Progressão da Doença , Feminino , Dosagem de Genes , Glioblastoma/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Hibridização de Ácido Nucleico , Prognóstico , Taxa de Sobrevida
6.
Mod Pathol ; 14(9): 842-53, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11557779

RESUMO

Comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), polymerase chain reaction-based microsatellite analysis, and p53 sequencing were performed in paraffin-embedded material from 18 oligodendrogliomas and histologically similar astrocytomas. The study was undertaken because of evidence that concurrent loss of both the 1p and 19q chromosome arms is a specific marker for oligodendrogliomas. Of the six lesions with a review diagnosis of oligodendroglioma, all had the predicted loss of 1p and 19q seen by CGH, FISH, and polymerase chain reaction. Other lesions, including some considered oligodendroglioma or mixed glioma by the submitting institution, did not. There were no p53 mutations in any of the six oligodendrogliomas, whereas 5 of the 10 remaining, successfully studied cases did have p53 mutations. The results suggest that CGH and FISH performed on current or archival tissue can aid in classification of infiltrating gliomas such as oligodendrogliomas and astrocytomas. The results of the p53 studies are consistent with findings of previous investigations that such mutations are less common in oligodendrogliomas than they are in astrocytomas.


Assuntos
Neoplasias Encefálicas/genética , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Oligodendroglioma/genética , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Análise Mutacional de DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Microtomia , Pessoa de Meia-Idade , Mutação , Hibridização de Ácido Nucleico , Oligodendroglioma/diagnóstico , Oligodendroglioma/metabolismo , Inclusão em Parafina , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/genética
7.
Med Pediatr Oncol ; 36(1): 5-10, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11464905

RESUMO

PROCEDURE: Analysis of comparative genomic hybridization (CGH) data of 120 tumors from four different studies, and data of 84 previously unpublishied tumors, allowed delineation of at least six different genetic subsets of neuroblastomas. RESULTS AND CONCLUSIONS: A small number of tumors show no detectable imballances. A second group of tumors presents with gains and losses of whole chromosomes and is found predominantly in prognostically favorable stage 1 and 2 tumors. The remaining groups are characterized by the presence of partial chromosome imbalances, and are found mostly in stage 3, 4, and 4S tumors. The third group shows 17q gain without 11q loss, 1p loss, or MYCN amplification (MNA). The fourth group has 1p deletion or MNA, and finally, a fifth group shows 11q loss without 1p deletion or MNA, and is found mainly in stage 4 tumors. The latter group is significantly associated with losses of 3p, 4p, and 14q.


Assuntos
Aberrações Cromossômicas , DNA de Neoplasias/análise , Neuroblastoma/genética , Deleção Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos/ultraestrutura , Humanos , Perda de Heterozigosidade , Estadiamento de Neoplasias , Neuroblastoma/classificação , Neuroblastoma/mortalidade , Hibridização de Ácido Nucleico , Prognóstico , Trissomia
8.
J Mol Diagn ; 3(2): 62-7, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11333301

RESUMO

We amplified various amounts of DNA derived from frozen SF210 and U251NCI human glioblastoma cells, carried out comparative genomic hybridization (CGH) using degenerate oligonucleotide primed-PCR (DOP-PCR) products as test probes, and compared results to analyses performed with probes prepared by standard nick translation. Next we extracted DNA from hematoxylin-eosin (HE)- and methyl green (MG)-stained, microdissected sections of formalin-fixed and paraffin-embedded U251NCI cells, amplified and labeled it by DOP-PCR, and subjected it to CGH. Finally, we used the same methods in multiple samples from a single human mixed glioma tissue. DOP-PCR products from 50 pg to 250 ng of DNA were equally effective in generating the same CGH profiles as the standard method. DOP-PCR products from microdissected pieces of MG-stained cells were effective probes for CGH, but HE-stained samples were not desirable. As the proportion of HE-stained sample increased, CGH profiles deteriorated. DOP-PCR products from microdissected pieces of MG-stained paraffin sections of glioma tissue produced CGH profiles compatible with their histological features. CGH performed with DOP-PCR products from microdissected paraffin blocks allows for the accurate investigation of the cytogenetic characteristics from invasive tumors and of cytogenetic heterogeneity within neoplastic tissue.


Assuntos
Aberrações Cromossômicas , Reação em Cadeia da Polimerase/métodos , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , DNA/metabolismo , Eletroforese em Gel de Ágar , Humanos , Hibridização de Ácido Nucleico , Células Tumorais Cultivadas
9.
Int J Cancer ; 91(5): 680-6, 2001 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11267980

RESUMO

We have studied the occurrence and association of 11q deletions with other chromosomal imbalances in Stage 4 neuroblastomas. To this purpose we have performed comparative genomic hybridization (CGH) analysis on 50 Stage 4 neuroblastomas and these data were analyzed together with those from 33 previously published cases. We observed a high incidence of 11q deletion in Stage 4 neuroblastoma without MYCN amplification (59%) whereas 11q loss was only observed in 15% of neuroblastomas with MYCN-amplification (p = 0.0002) or 11% of cases with 1p deletion detected by CGH (p = 0.0001). In addition, 11q loss showed significant positive correlation with 3p loss (p = 0.0002). Event-free survival was poor and not significantly different for patients with or without 11q deletion. Our study provides further evidence that Stage 4 neuroblastomas with 11q deletions represent a distinct genetic subgroup that typically shows no MYCN-amplification nor 1p deletion. Moreover, it shows that neuroblastomas with 11q deletion also often present 3p deletion. This genetic subgroup shows a similar poor prognosis as MYCN amplified 4 neuroblastomas.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11 , Genoma Humano , Neuroblastoma/genética , Hibridização de Ácido Nucleico , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 3 , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Modelos Genéticos , Estudos Multicêntricos como Assunto , Mutação , Metástase Neoplásica , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Prognóstico , Fatores de Tempo , Células Tumorais Cultivadas
10.
Am J Pathol ; 158(3): 1137-43, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11238062

RESUMO

Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization. The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13. Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.


Assuntos
Neoplasias Encefálicas/classificação , Aberrações Cromossômicas , Ependimoma/classificação , Neoplasias da Medula Espinal/classificação , Adolescente , Adulto , Idoso , Aneuploidia , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Análise Citogenética , Ependimoma/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias da Medula Espinal/genética
11.
Brain Pathol ; 10(3): 342-52, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10885653

RESUMO

Astroblastomas are uncommon brain tumors whose classification and histogenesis have been debated. Precise criteria for diagnosis have been described only recently, but have not found wide acceptance. We report the clinical, radiographic, and histopathologic features of 20 astroblastomas, and the chromosomal alterations in seven cases as detected by comparative genomic hybridization (CGH). The tumors occurred both in children and young adults (average age, 14 years), most often as well circumscribed, peripheral, cerebral hemispheric masses. Radiographically, the lesions were contrast-enhancing and solid, often with a cystic component. All were characterized histologically by astroblastic pseudorosettes, and most displayed prominent perivascular hyalinization, regional hyaline changes, and pushing borders in regard to adjacent brain. Tumor cells were strongly immunoreactive for S-100 protein, GFAP, and vimentin. Staining for EMA was focal. Ten of 20 astroblastomas were classified as "well differentiated" and 10 were classified as "malignant," largely on the basis of hypercellular zones with increased mitotic indices, vascular proliferation, and necrosis with pseudopalisading. All 10 well differentiated lesions and 8 of 10 malignant lesions were completely resected. None of the well differentiated astroblastomas recurred within the limited follow-up period. Three malignant astroblastomas recurred, including two incompletely resected tumors, and one that had been totally resected. One patient died of disease following recurrence. The most frequent chromosomal alterations detected by CGH were gains of chromosome arm 20q (4/7 tumors) and chromosome 19 (3/7). The combination of these gains occurred in three, including two well differentiated and one malignant astroblastoma. Other alterations noted in two tumors each were losses on 9q, 10, and X. These chromosomal alterations are not typical of ependymoma or infiltrating astrocytic neoplasms, and suggest that astroblastomas may have a characteristic cytogenetic profile in addition to their distinctive clinical, radiographic, and histopathologic features.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Aberrações Cromossômicas , Transtornos Cromossômicos , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Criança , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/cirurgia , Hibridização de Ácido Nucleico , Radiografia
12.
Am J Clin Pathol ; 112(6): 801-9, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10587703

RESUMO

Inactivation of the p53 gene is a common early event of astrocytoma tumorigenesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes have been implicated in malignant progression, detection of losses or amplifications of these genes in gliomas could be diagnostically, prognostically, and therapeutically important. We obtained smear preparations from 96 diffuse gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and CEN12/CDK4 were performed and revealed expected frequencies of abnormalities, except for p53 losses, which were low (7%). The latter supports the concept that p53 inactivation usually occurs by mitotic recombination. Detected abnormalities of the p16/RB/CDK4 pathway were highly associated with astrocytic differentiation and were univariately associated with decreased patient survival. However, only patient age and histologic classification retained statistical significance on multivariate analysis. We conclude that in diffuse gliomas, p16/RB/CDK4 abnormalities are markers of astrocytic phenotype. Thus, their detection by fluorescence in situ hybridization may have diagnostic usefulness in cases with equivocal morphologic features. Although our numbers are small, we find no additional prognostic significance to these genetic abnormalities one age, grade, and oligodendroglial histology are taken into account.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Quinases Ciclina-Dependentes/genética , Deleção de Genes , Genes do Retinoblastoma/genética , Genes p53/genética , Glioma/genética , Proteínas Proto-Oncogênicas , Adulto , Astrócitos/patologia , Diferenciação Celular , Quinase 4 Dependente de Ciclina , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Oligodendroglia/patologia , Taxa de Sobrevida
14.
Oncogene ; 18(28): 4144-52, 1999 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10435596

RESUMO

Allelic alterations of chromosomes 1 and 19 are frequent events in human diffuse gliomas and have recently proven to be strong predictors of chemotherapeutic response and prolonged survival in oligodendrogliomas (Cairncross et al., 1998; Smith et al., submitted). Using 115 human diffuse gliomas, we localized regions of common allelic loss on chromosomes 1 and 19 and assessed the association of these deletion intervals with glioma histological subtypes. Further, we evaluated the capacity of multiple modalities to detect these alterations, including loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH). The correlation coefficients for detection of 1p and 19q alterations, respectively, between modalities were: 0.98 and 0.87 for LOH and FISH, 0.79 and 0.60 for LOH and CGH, and 0.79 and 0.53 for FISH and CGH. Minimal deletion regions were defined on 19q13.3 (D19S412-D19S596) and 1p (D1S468-D1S1612). Loss of the 1p36 region was found in 18% of astrocytomas (10/55) and in 73% (24/33) of oligodendrogliomas (P < 0.0001), and loss of the 19q13.3 region was found in 38% (21/55) of astrocytomas and 73% (24/33) of oligodendrogliomas (P = 0.0017). Loss of both regions was found in 11% (6/55) of astrocytomas and in 64% (21/33) of oligodendrogliomas (P < 0.0001). All gliomas with LOH on either 1p or 19q demonstrated loss of the corresponding FISH probe, 1p36 or 19q13.3, suggesting not only locations of putative tumor suppressor genes, but also a simple assay for assessment of 1p and 19q alterations as diagnostic and prognostic markers.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Glioma/genética , Deleção de Sequência , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 19/ultraestrutura , Glioma/classificação , Glioma/patologia , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade , Oligodendroglioma/genética , Oligodendroglioma/patologia
15.
Cancer ; 86(2): 331-9, 1999 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10421270

RESUMO

BACKGROUND: Intracranial primitive neuroectodermal tumors (PNETs) occur in the supratentorial and infratentorial regions of the brain. Although histologically similar, the natural history of the tumor at each site differs. The study goal was to determine whether there was evidence of a genetic difference between supratentorial and infratentorial PNETs. METHODS: Using comparative genomic hybridization (CGH), 53 PNETs were analyzed to determine copy number aberrations. Forty-three tumors were located in the cerebellum (IPNETs), and ten were supratentorial PNETs (SPNETs). All samples were reviewed to confirm the diagnosis. Each specimen had at least 50% tumor. RESULTS: Six of the 43 cases of IPNET had no copy number aberrations. In contrast, each case of SPNET had copy number aberrations detected by CGH. Statistically significant differences in copy number aberrations of chromosomes 14, 17, and 19 were detected in the two groups. The most common copy number aberration in the IPNETs was gain of chromosome 17q, which was observed in 16 of 43 cases (37%). However, no case of SPNET had gain of 17q. Loss of 14q was detected in four of ten SPNETs but was not detected in any of the IPNET cases. Loss of 19q was detected in 4 of 10 SPNETs and in only 1 of 43 IPNETs. CONCLUSIONS: These results indicate that the genetic aberrations of IPNETs differ from the genetic aberrations of SPNETs. Although they are similar histologically, SPNETs and IPNETs appear to be biologically distinct entities.


Assuntos
Neoplasias Encefálicas/genética , Aberrações Cromossômicas/genética , Tumores Neuroectodérmicos Primitivos/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Transtornos Cromossômicos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Hibridização de Ácido Nucleico
16.
Clin Cancer Res ; 5(6): 1435-43, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10389929

RESUMO

Glioblastoma multiforme (GM) is the most common and most malignant astrocytoma in adults. After surgery, radiation therapy extends patient survival; however, in vivo response to radiation therapy is variable. The purpose of this investigation was to determine whether the cytogenetic abnormalities of GM differ according to patient response to radiation therapy. Radiation response was defined by either progression [radiation-resistant (RR)] or resolution [radiation-sensitive (RS)] of tumor at the first postradiation radiographic imaging evaluation. Twenty RR and 10 RS frozen tissue specimens were subjected to cytogenetic analysis by comparative genomic hybridization. RS and RR specimens had different cytogenetic aberrations that mapped predominantly to chromosomes 7, 9, 10, 13, and 19. Relative gain of 7 occurred in 70% of the RR and 30% of the RS cases and was the most significant difference involving a single change between the two groups (P = 0.06). RR and RS specimens also differed in their patterns of simultaneous cytogenetic aberrations. A simultaneous gain of chromosomes 7 and 19 was found in 30% of the RR cases but was absent in the RS group. Concurrent loss of 9p23-24 and 13q14 regions was absent in the RS cohort but occurred in 30% of the RR series. This latter cytogenetic pattern was also associated with older age. Amplifications were more common in the RR series, but the difference did not reach statistical significance. The data suggest that GM with different in vivo responses to radiation therapy also differ cytogenetically.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Aberrações Cromossômicas/genética , Glioblastoma/genética , Glioblastoma/radioterapia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Transtornos Cromossômicos , Mapeamento Cromossômico , Estudos de Coortes , Progressão da Doença , Feminino , Amplificação de Genes , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Deleção de Sequência , Taxa de Sobrevida , Resultado do Tratamento
17.
J Neurosurg ; 90(2): 306-14, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9950502

RESUMO

OBJECT: This study was conducted to determine whether comparative genomic hybridization (CGH) is a more sensitive method for detecting genetic aberrations than other tests currently in use. METHODS: The authors used CGH to examine 40 primary and 13 recurrent adenomas obtained from 52 patients for loss and gain of genetic material. Copy number aberrations (CNAs) were detected in 25 (48%) of the 52 patients studied. The chromosomes affected were, in order of decreasing frequency, 11, 7, X, 1, 8, 13, 5, 14, 2, 6, 9, 10, 12, 3, 18, 21, 4, 16, 15, 19, 22, and Y. Endocrinologically active adenomas were more likely to contain (p = 0.009) and had a greater number (p = 0.003) of CNAs. Of 26 adenomas with CNAs, 18 showed multiple aberrations involving entire chromosomes or chromosome arms. The most frequent CNA involving a chromosome subregion, which was present in four (8%) of 53 adenomas, was the loss of all chromosome 11 material except for a preserved common segment containing 11q13. Immunoperoxidase staining did not detect cyclin D1 expression in those four cases, making cyclin D1 an unlikely target of this rearrangement. CONCLUSIONS: These findings indicate that genetic abnormalities are present in pituitary adenomas at a higher rate than previously reported, are associated with endocrinological activity, and often involve several chromosomes. Rearrangement at 11q13 may inactivate a tumor suppressor gene or activate an oncogene that is important in the initiation or progression of sporadic pituitary adenomas.


Assuntos
Adenoma/genética , Aberrações Cromossômicas/genética , Cromossomos Humanos Par 11 , Rearranjo Gênico/genética , Neoplasias Hipofisárias/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Ciclina D1/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Neoplasias Hipofisárias/metabolismo , Sensibilidade e Especificidade
18.
Cytometry ; 32(2): 120-31, 1998 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-9627225

RESUMO

erbB2, a member of the epidermal growth factor (EGF) receptor-type tyrosine kinase receptor family, is overexpressed in breast carcinomas with poor prognosis. We examined the cell surface association of this receptor with itself and with other cell surface proteins by the Förster-type fluorescence resonance energy transfer using whole antibodies and Fab fragments. We found that erbB2 molecules homoassociate in unstimulated SK-BR-3, BT474 and BT474-M (a metastatic version of the parent BT474 line) breast tumor cells, and that the interaction was enhanced by EGF treatment in suspensions of SK-BR-3 and BT474-M cells. BT474 cells (with low EGF receptor expression) and attached SK-BR-3 cells do not respond to EGF. Image microscopic energy transfer measurements found considerable pixel-by-pixel heterogeneity in the homoassociation state of erbB2. In accordance with the EGF-induced redistribution of erbB2, EGF receptor was found to be in close proximity to erbB2 in FRET measurements. By labeling different epitopes on erbB2 and the lipid bilayer, we were able to prepare an epitope map of erbB2 molecule. Our data suggest the existence of dynamic cell surface patterns of erbB2 and point to functions fulfilled by these molecular complexes.


Assuntos
Neoplasias da Mama/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/biossíntese , Receptor ErbB-2/biossíntese , Carcinoma de Células Escamosas/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Transferência de Energia , Feminino , Citometria de Fluxo/métodos , Humanos , Modelos Moleculares , Receptor ErbB-2/química , Receptores da Transferrina/análise , Receptores da Transferrina/química , Células Tumorais Cultivadas
19.
Genes Chromosomes Cancer ; 21(3): 195-206, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9523194

RESUMO

We analyzed 72 primary and 25 recurrent glioblastoma multiforme (GBM) samples for DNA sequence copy number abnormalities (CNAs) by comparative genomic hybridization (CGH). The number of aberrations per tumor ranged from 2 to 23 in primary GBM and 5 to 25 in recurrent GBM. There were 26 chromosome regions with CNAs in more than 20% of tumors. 7q22-36 was the most common gain and 10q25-26 was the most common loss; each occurred in more than 70% of tumors. Of 27 amplification sites, epidermal growth factor receptor (EGFR) was the most common; it was observed in 25% of primary GBMs. Statistical analysis based on pairwise correlation of CNAs indicated that there is more than one class of primary GBM.


Assuntos
Glioblastoma/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Amplificação de Genes , Deleção de Genes , Dosagem de Genes , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Hibridização de Ácido Nucleico
20.
J Neurooncol ; 36(2): 113-21, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9525811

RESUMO

The polyamine inhibitor DL-alpha-difluoromethylornithine (DFMO) is a specific irreversible inhibitor of ornithine decarboxylase which is a rate-limiting enzyme in the polyamine bio-synthesis pathway. The present study describes the effects of DFMO on glioma cell proliferation, migration and invasion using multicellular spheroids from three glioma cell lines (GaMg, U-251 Mg and U-87 Mg). 10 mM DFMO reduced cell migration in the three cell lines by about 30-50%. 1 mM putrescine, added together with DFMO inhibited the DFMO effect. A stronger effect was observed in the growth assay where 10 mM DFMO reduced the spheroid growth, for all cell lines, by 90%. This effect was also reversed by adding 1 mM of putrescine. In vitro tumor cell invasion experiments indicated after 3 days of confrontation, an extensive invasion also after 10 mM DFMO treatment. The brain aggregate volumes were reduced to about the same extent as in the absence of drug, suggesting essentially no effects of DFMO on the invasive process. It is concluded that the tumor spheroids retained their ability to invade normal brain tissue even after DFMO exposure. However, DFMO inhibited spheroid growth and cell migration which supports the notion that cell growth, migration and invasion are biological properties that are not necessarily related to each other.


Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Eflornitina/farmacologia , Glioma/patologia , Adulto , Animais , Divisão Celular/efeitos dos fármacos , Feminino , Glioma/tratamento farmacológico , Humanos , Invasividade Neoplásica , Ratos , Ratos Wistar , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Células Tumorais Cultivadas
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