RESUMO
PURPOSE: To evaluate clinico-pathological and molecular prognostic factors in a well-defined series of posterior uveal melanoma (UM) with focus on chromosomal aberrations and mutations in the GNAQ, GNA11 and BRCA1-associated protein 1 (BAP1) genes. METHODS: Formalin-fixed paraffin-embedded (FFPE) tissue samples were obtained from 50 consecutive eyes enucleated for UM between 1993 and 2005. The material was tested for loss of chromosome 3 and gain of chromosome 8q gene signatures by selective molecular gene markers using multiplex ligation-dependent probe amplification (MLPA), and for DNA mutations in the GNAQ, GNA11 and BAP1 genes. RESULTS: After a mean follow-up of 83 months (range, 8-205 months), 21 patients had died of metastatic UM and 16 patients of other causes. Tumour diameter, ciliary body involvement, mixed/epithelioid cell types, mitotic index, Ki-67 proliferation index, loss of chromosome 3 and gain of chromosome 8q showed statistically significant associations with metastatic disease. There were no significant differences in the prevalence of GNAQ and GNA11 mutations between patients with or without metastatic disease. Mutational analysis of the BAP1 gene was performed in 32 primary UM and in five UM liver metastases. Nine different BAP1 missense mutations were identified. BAP1 mutations were not more common in metastasizing than in nonmetastasizing UM. CONCLUSION: The molecular gene markers showing loss of chromosome 3 and gain of 8q gene signatures were associated with an increased risk of metastatic disease. BRCA1-associated protein 1 (BAP1) gene mutation status had no prognostic significance. The frequency and spectrum of BAP1 mutations in UM may be more dependent on ethnicity and demographic variables than hitherto considered.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , DNA de Neoplasias/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Análise Mutacional de DNA , Feminino , Seguimentos , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Masculino , Melanoma/metabolismo , Melanoma/secundário , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Mutação , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Úvea/metabolismo , Úvea/patologia , Neoplasias Uveais/metabolismo , Neoplasias Uveais/secundário , Adulto JovemRESUMO
The transcription factor ZEB1 has gained attention in tumor biology of epithelial cancers because of its function in epithelial-mesenchymal transition, DNA repair, stem cell biology and tumor-induced immunosuppression, but its role in gliomas with respect to invasion and prognostic value is controversial. We characterized ZEB1 expression at single cell level in 266 primary brain tumors and present a comprehensive dataset of high grade gliomas with Ki67, p53, IDH1, and EGFR immunohistochemistry, as well as EGFR FISH. ZEB1 protein expression in glioma stem cell lines was compared to their parental tumors with respect to gene expression subtypes based on RNA-seq transcriptomic profiles. ZEB1 is widely expressed in glial tumors, but in a highly variable fraction of cells. In glioblastoma, ZEB1 labeling index is higher in tumors with EGFR amplification or IDH1 mutation. Co-labeling studies showed that tumor cells and reactive astroglia, but not immune cells contribute to the ZEB1 positive population. In contrast, glioma cell lines constitutively express ZEB1 irrespective of gene expression subtype. In conclusion, our data indicate that immune infiltration likely contributes to differential labelling of ZEB1 and confounds interpretation of bulk ZEB1 expression data.
Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
The expression, cellular distribution, and subcellular sorting of the microtubule (MT)-nucleating γ-tubulin small complex (γTuSC) proteins, GCP2 and GCP3, were studied in human glioblastoma cell lines and in clinical tissue samples representing all histologic grades of adult diffuse astrocytic gliomas (n = 54). Quantitative real-time polymerase chain reaction revealed a significant increase in the expression of GCP2 and GCP3 transcripts in glioblastoma cells versus normal human astrocytes; these were associated with higher amounts of both γTuSC proteins. GCP2 and GCP3 were concentrated in the centrosomes in interphase glioblastoma cells, but punctate and diffuse localizations were also detected in the cytosol and nuclei/nucleoli. Nucleolar localization was fixation dependent. GCP2 and GCP3 formed complexes with γ-tubulin in the nucleoli as confirmed by reciprocal immunoprecipitation experiments and immunoelectron microscopy. GCP2 and GCP3 depletion caused accumulation of cells in G2/M and mitotic delay but did not affect nucleolar integrity. Overexpression of GCP2 antagonized the inhibitory effect of the CDK5 regulatory subunit-associated tumor suppressor protein 3 (C53) on DNA damage G2/M checkpoint activity. Tumor cell GCP2 and GCP3 immunoreactivity was significantly increased over that in normal brains in glioblastoma samples; it was also associated with microvascular proliferation. These findings suggest that γTuSC protein dysregulation in glioblastomas may be linked to altered transcriptional checkpoint activity or interaction with signaling pathways associated with a malignant phenotype.
Assuntos
Neoplasias Encefálicas/metabolismo , Nucléolo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Anuros , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/ultraestrutura , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Galinhas , Dano ao DNA/genética , Feminino , Glioblastoma/patologia , Glioblastoma/ultraestrutura , Humanos , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Transporte Proteico , Tubulina (Proteína)/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem , Peixe-ZebraRESUMO
OBJECT: Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. METHODS: GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. RESULTS: In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P = 0.04). CONCLUSION: GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.
Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Radiocirurgia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Comportamento Animal , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Ratos , Ratos Nus , Análise de SobrevidaRESUMO
Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, long-term expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Genes erbB-1/genética , Glioblastoma/genética , Glioblastoma/patologia , Ativação Transcricional , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Cetuximab , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Amplificação de Genes , Humanos , Invasividade Neoplásica/genética , Neovascularização Patológica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Exploring the re-emergence of embryonic signaling pathways may reveal important information for cancer biology. Nodal is a transforming growth factor-ß (TGF-ß)-related morphogen that plays a critical role during embryonic development. Nodal signaling is regulated by the Cripto-1 co-receptor and another TGF-ß member, Lefty. Although these molecules are poorly detected in differentiated tissues, they have been found in different human cancers. Poor prognosis of glioblastomas justifies the search for novel signaling pathways that can be exploited as potential therapeutic targets. Because our intracranial glioblastoma rat xenograft model has revealed importance of gene ontology categories related to development and differentiation, we hypothesized that increased activity of Nodal signaling could be found in glioblastomas. We examined the gene expressions of Nodal, Cripto-1, and Lefty in microarrays of invasive and angiogenic xenograft samples developed from four patients with glioblastoma. Protein expression was evaluated by immunohistochemistry in 199 primary glioblastomas, and expression levels were analyzed for detection of correlations with available clinical information. Gene expression of Nodal, Lefty, and Cripto-1 was detected in the glioblastoma xenografts. Most patient samples showed significant levels of Cripto-1 detected by immunohistochemistry, whereas only weak to moderate levels were detected for Nodal and Lefty. Most importantly, the higher Cripto-1 scores were associated with shorter survival in a subset of younger patients. These findings suggest for the first time that Cripto-1, an important molecule in developmental biology, may represent a novel prognostic marker and therapeutic target in categories of younger patients with glioblastoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dura-Máter , Linfoma Difuso de Grandes Células B/terapia , Neoplasias Meníngeas/terapia , Idoso , Craniotomia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Meníngeas/patologia , Resultado do TratamentoRESUMO
The cuprizone model is a model of de- and remyelination secondary to oligodendrocyte death, likely to be mediated by an inhibition of mitochondrial function. The aim of this study was to characterize histopathological changes associated with de/remyelination in grey and white matter at different disease stages in C57Bl/6 mice after per oral administration of cuprizone. Oligodendrocyte loss, astrocytosis and complement activation was detected in areas of demyelination. Demyelination, astrocytosis and complement activation occurred earlier in the cerebral cortex than in the corpus callosum. There was no perivascular lymphocyte infiltration. Microglia- and macrophage activation was observed in the corpus callosum, but not in the cerebral cortex. After cuprizone exposure was stopped, remyelination was extensive in the corpus callosum, but scarce in the cortex. In conclusion, cortical demyelination and oligodendrocyte loss in the cuprizone model may be due to a direct effect on oligodendrocyte mitochondrial function, as it occurs in the absence of microglial activation. The histopathology of de/remyelination in the cuprizone treated mice show regional heterogeneities which suggest differences in the underlying pathophysiology. Cuprizone-induced demyelination is a relevant model for the study of regional heterogeneity of demyelination and lesion pathology in multiple sclerosis.
Assuntos
Cuprizona/administração & dosagem , Doenças Desmielinizantes/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteínas do Sistema Complemento/metabolismo , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Feminino , Gliose/metabolismo , Gliose/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Oligodendroglia/metabolismoRESUMO
PURPOSE: The aims of this study were to use transscleral optical spectroscopy to analyze normal and tumor-infiltrated areas of enucleated human eyes, and to characterize the spectral properties of uveal melanomas in relation to various morphological features. METHODS: Nine consecutive eyes enucleated for uveal melanoma were examined by transscleral spectroscopy, using a fiber-optic probe that exerted a fixed pressure on the scleral surface. Spectroscopic measurements, covering the wavelength range of 400-1100 nm, were sequentially performed over the uveal melanoma and on the opposite (normal) side of each eye. The eyes were then processed for histological and immunohistochemical analyses. Comparisons between spectral and morphological parameters were performed by Spearman's rank correlation coefficient and unpaired t-test. RESULTS: The average reflection intensity obtained from the normal side of the eyes was higher than that from the tumors. The spectral imprint of hemoglobin was lower and that of water was considerably stronger when compared with the tumor side. The diffuse reflection spectra from the melanomas showed a strong correlation with the degree of tumor pigmentation (Spearman's rho = -0.87, P < 0.0001). A weaker correlation was observed between the amount of hemoglobin-related absorption and the density of intratumoral blood vessels (Spearman's rho = -0.25, P = 0.023). The mean diffuse reflection intensity obtained from the spindle cell melanomas was significantly higher than that from the mixed and epithelioid cell melanomas (P < 0.0001). CONCLUSIONS: Although future in vivo studies are required, these data suggest that transscleral optical spectroscopy is a feasible method for identification and morphological assessment of choroidal tumors.
Assuntos
Melanoma/patologia , Espectrofotometria Infravermelho/métodos , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Enucleação Ocular , Feminino , Hemoglobinas/análise , Humanos , Imuno-Histoquímica , Masculino , Melanoma/irrigação sanguínea , Melanoma/química , Pessoa de Meia-Idade , Fotomicrografia , Neoplasias Uveais/irrigação sanguínea , Neoplasias Uveais/químicaRESUMO
Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg), or supplemented with low (500 IU/kg), high (6200 IU/kg) or very high (12500 IU/kg) amounts of vit D3. Cuprizone (0.2%) was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (pâ=â0.004) and attenuated microglia activation (pâ=â0.001). No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration.
Assuntos
Colecalciferol/farmacologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Suplementos Nutricionais , Animais , Colecalciferol/sangue , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/fisiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
We studied the expression and distribution of the microtubule-severing enzyme spastin in 3 human glioblastoma cell lines (U87MG, U138MG, and T98G) and in clinical tissue samples representative of all grades of diffuse astrocytic gliomas (n = 45). In adult human brains, spastin was distributed predominantly in neuronsand neuropil puncta and, to a lesser extent, in glia. Compared with normal mature brain tissues, spastin expression and cellular distribution were increased in neoplastic glial phenotypes, especiallyin glioblastoma (p < 0.05 vs low-grade diffuse astrocytomas). Overlapping punctate and diffuse patterns of localization wereidentified in tumor cells in tissues and in interphase and mitotic cells ofglioblastoma cell lines. There was enrichment of spastin in the leading edges of cells in T98G glioblastoma cell cultures and in neoplastic cell populations in tumor specimens. Real-time polymerase chain reaction and immunoblotting experiments revealed greater levels of spastin messenger RNA and protein expression in theglioblastoma cell lines versus normal human astrocytes. Functional experiments indicated that spastin depletion resulted in reduced cell motility and higher cell proliferation of T98G cells. Toour knowledge, this is the first report of spastin involvement incellmotility. Collectively, our results indicate that spastinexpression in glioblastomas might be linked to tumor cell motility, migration, and invasion.
Assuntos
Adenosina Trifosfatases/metabolismo , Neoplasias Encefálicas/enzimologia , Movimento Celular/fisiologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/enzimologia , Adenosina Trifosfatases/genética , Fatores Etários , Encéfalo/enzimologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Contagem de Células/métodos , Linhagem Celular Tumoral , Criança , Feminino , Glioblastoma/patologia , Humanos , Lactente , Masculino , Microtúbulos , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Espastina , Adulto JovemRESUMO
We analyzed the relationships among clinical variables, histology, 1p/19q status, and outcome in 95 patients with oligodendroglial tumors. The study enrolled adult patients who underwent first-time surgery for a supratentorial oligodendroglial tumor at Oslo University Hospital, Rikshospitalet. Tumors were: 27 oligodendrogliomas, WHO grade II; 32 oligoastrocytomas, WHO grade II; 16 anaplastic oligodendrogliomas, WHO grade III; 14 anaplastic oligoastrocytomas, WHO grade III; and 6 glioblastomas with a major oligodendroglial component, WHO grade IV. The clinical files were reviewed. Three neuropathologists evaluated the histological slides independently. Loss-of-heterozygosity analysis for 1p and 19q was performed by PCR. Favorable prognostic factors from univariate analyses included seizures as presenting symptom, female sex, location in the frontal lobe, low WHO grade, classic histology, absence of gemistocytic cells, and combined 1p/19q loss. Solitary 19q loss was a negative prognostic marker. 1p/19q status was of prognostic significance in both tumors with classic and nonclassic oligodendroglial histology. In the multivariate analysis, WHO grade II (P< .001), frontal tumor location (P= .002), and combined 1p/19q loss (P< .001) remained favorable prognostic variables. Our results suggest that tumor location, WHO grade, and 1p/19q status are important independent variables associated with survival in oligodendroglial tumors. The study suggests that solitary 19q loss is a negative prognostic variable and that 1p/19q loss is associated with prolonged survival also in oligodendroglial tumors without classic histology.
Assuntos
Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Oligodendroglioma/genética , Oligodendroglioma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Oligodendroglioma/patologia , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: High-grade glioma is a primary malignant brain tumour which affects about 200 Norwegian patients each year. Diagnosis and treatment of high-grade gliomas in adults has been reviewed. MATERIAL AND METHODS: The article is based on recent literature retrieved through a non-systematic search in PubMed and the authors' experience with the patient group. RESULTS: The most common symptoms are focal neurological deficits, epileptic seizures and pressure symptoms. The patients should be examined by magnetic resonance (MR) imaging and the diagnosis confirmed with biopsy. No curative treatment is currently available for high-grade gliomas. The standard treatment is surgical resection followed by radiation therapy alone or in combination with chemotherapy (temozolomid). Five-year survival is only 6.1 %. INTERPRETATION: The diagnosis is composite with both neurological symptoms and cognitive problems. This requires good communication with the patient and close cooperation between various departments and the primary health services. Symptomatic treatment and multidisciplinary follow-up is necessary.
Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Terapia Combinada , Seguimentos , Glioma/diagnóstico , Glioma/mortalidade , Glioma/terapia , Humanos , Comunicação Interdisciplinar , Imageamento por Ressonância Magnética/métodos , Estadiamento de Neoplasias , PrognósticoRESUMO
Paraneoplastic cerebellar degeneration (PCD) is often associated with Yo antibodies that are directed against human cerebellar degeneration-related protein 2 (CDR2). Such antibodies may also be found in ovarian cancer patients without PCD. We studied if there was an association between Yo antibody production and differences in CDR2 cDNA sequence, mRNA or CDR2 expression in ovarian cancers. We found similar CDR2 cDNA sequence, mRNA and protein levels in primary ovarian cancers, with or without associated Yo antibodies. CDR2 was also present in other cancers, as well as in normal ovary tissue. The results suggest that Yo antibodies are not only related to the expression of CDR2 alone, but also to immune dysregulation.
Assuntos
Anticorpos/análise , Anticorpos/imunologia , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/imunologia , Neoplasias Ovarianas/imunologia , Adulto , Idoso , Complexo Antígeno-Anticorpo/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/genética , Degeneração Paraneoplásica Cerebelar/imunologia , RNA Mensageiro/genéticaRESUMO
BACKGROUND: The vestibular nerve is the predilection site for schwannomas. Few transcriptomic studies have been performed on solely sporadic vestibular schwannomas (VSs). OBJECTIVE: To detect genes with altered expression levels in sporadic VSs. METHODS: We studied 25 VSs and 3 tibial nerves (controls) with the ABI 1700 microarray platform. Significance analysis of microarrays was performed to explore differential gene expression. Selected genes were validated with quantitative reverse transcriptase polymerase chain reaction. A tissue microarray was constructed for immunohistochemistry. Neurofibromatosis type II cDNA was sequenced for mutations. RESULTS: The VSs formed 2 clusters based on the total expression of 23,055 genes. Tumor size, previous Gamma Knife surgery, neurofibromatosis type II mutations, and cystic tumors were distributed equally in both. Significance analysis of microarrays detected 1650 differentially expressed genes. On the top 500 list, several cancer-related genes with an unrecognized role in VSs were down-regulated: CAV1, TGFB3, VCAM1, GLI1, GLI2, PRKAR2B, EPHA4, and FZD1. Immunohistochemistry showed no CAV1 expression in the VSs. The ERK pathway was the central core in the network linking the differentially expressed genes. The previously reported VS candidate genes SPARC, PLAT, and FGF1 were up-regulated. Nineteen of 25 VSs had NF2 mutations. CONCLUSION: Using microarray technology, we identified novel genes and pathways with a putative role in VSs, confirmed previous candidate genes, and found cancer-related genes with no reported role in VSs. Among these, down-regulation of CAV1 at both the mRNA and protein levels is of particular interest because this tumor suppressor normally is expressed in Schwann cells.
Assuntos
Caveolina 1/metabolismo , Regulação para Baixo/fisiologia , Perfilação da Expressão Gênica/métodos , Neuroma Acústico , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adulto , Idoso , Caveolina 1/genética , Análise Mutacional de DNA/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Mutação/genética , Neurofibromatose 2/genética , Neuroma Acústico/genética , Neuroma Acústico/metabolismo , Neuroma Acústico/fisiopatologia , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: To report the clinical course of PML in an apparently immunocompetent patient treated with cidofovir. CASE PRESENTATION: A 35-year-old immunocompetent man who developed progressive hemianopsia, aphasia, and limb weakness underwent repeated MRI scans of the brain, spinal fluid analyses, and brain biopsy. Before diagnosis was established based on brain biopsy, he was consecutively treated with methylprednisolone, acyclovir, ceftriaxone and plasmapheresis, but he deteriorated rapidly suggestive of the immune reconstitution inflammatory syndrome (IRIS). He started to recover two weeks after the initiation of treatment with cidofovir and has had no relapse at 3 1/2 years of follow-up. MRI has shown marked improvement. CONCLUSIONS: PML should be considered in immunocompetent patients with a typical clinical course and MRI findings compatible with PML. Treatment with cidofovir should be considered as early as possible in the disease course.
Assuntos
Imunocompetência/fisiologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/fisiopatologia , Adulto , Humanos , Imageamento por Ressonância Magnética/métodos , MasculinoRESUMO
Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors (n = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80-100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior.
Assuntos
Cromossomos Humanos Par 19/genética , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/genética , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/genética , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Masculino , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/cirurgia , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/cirurgia , Análise de SobrevidaRESUMO
Mutations in the catalytic subunit of the mitochondrial DNA-polymerase gamma cause a wide spectrum of clinical disease ranging from infantile hepato-encephalopathy to juvenile/adult-onset spinocerebellar ataxia and late onset progressive external ophthalmoplegia. Several of these syndromes are associated with an encephalopathy that characteristically shows episodes of rapid neurological deterioration and the development of acute cerebral lesions. The purpose of this study was to investigate the nature, distribution and natural evolution of central nervous system lesions in polymerase gamma associated encephalopathy focusing particularly on lesions identified by magnetic resonance imaging. We compared radiological, electrophysiological and pathological findings where available to study potential mechanisms underlying the episodes of exacerbation and acute cerebral lesions. We studied a total of 112 magnetic resonance tomographies and 11 computed tomographies in 32 patients with polymerase gamma-encephalopathy, including multiple serial examinations performed during both the chronic and acute phases of the disease and, in several cases, magnetic resonance spectroscopy and serial diffusion weighted studies. Data from imaging, electroencephalography and post-mortem examination were compared in order to study the underlying disease process. Our findings show that magnetic resonance imaging in polymerase gamma-related encephalopathies has high sensitivity and can identify patterns that are specific for individual syndromes. One form of chronic polymerase gamma-encephalopathy, that is associated with the c.1399G > A and c.2243G > C mutations, is characterized by progressive cerebral and cerebellar atrophy and focal lesions of the thalamus, deep cerebellar structures and medulla oblongata. Acute encephalopathies, both infantile and later onset, show similar pictures with cortical stroke-like lesions occurring during episodes of exacerbation. These lesions can occur both with and without electroencephalographic evidence of concurrent epileptic activity, and have diffusion, spectroscopic and histological profiles strongly suggestive of neuronal energy failure. We suggest therefore that both infantile and later onset polymerase gamma related encephalopathies are part of a continuum.
Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , Encéfalo/metabolismo , DNA Mitocondrial/genética , DNA Polimerase Dirigida por DNA/genética , Metabolismo Energético , Mutação , Arginina , Encéfalo/patologia , Encefalopatias/complicações , Encefalopatias/diagnóstico , Cerebelo/patologia , Cisteína , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/genética , Esclerose Cerebral Difusa de Schilder/metabolismo , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Eletroencefalografia , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/metabolismo , Glicina , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Neocórtex/patologia , Sensibilidade e Especificidade , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Acidente Vascular Cerebral/etiologia , Síndrome , Tálamo/patologia , Tomografia Computadorizada por Raios XAssuntos
Neoplasias da Coroide/patologia , Síndrome de Exfoliação/etiologia , Glaucoma de Ângulo Aberto/etiologia , Melanoma/patologia , Malha Trabecular/patologia , Doença Aguda , Idoso , Neoplasias da Coroide/diagnóstico por imagem , Enucleação Ocular , Gonioscopia , Humanos , Pressão Intraocular , Masculino , Melanoma/diagnóstico por imagem , Necrose , Ultrassonografia , Acuidade VisualRESUMO
BACKGROUND: Establishing clinically relevant animal models of glioblastoma multiforme (GBM) remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates. METHODS: In this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features. RESULTS: The tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages in vivo, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days +/- 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 in vivo passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms. CONCLUSIONS: In vivo passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to in vitro propagated cell lines for dissecting mechanisms of brain tumour progression.