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PURPOSE: Salivary gland (SG) tissue and derived neoplasms may occur in the sellar region. As the current literature is mostly limited to case reports, the puzzling case of an inflammatory SG removed by transsphenoidal surgery (TS) and mimicking a prolactinoma prompted us to perform the first systematic review of these unusual conditions. METHODS: A systematic literature search was conducted according to the PRISMA guidelines. Forty-four individual cases-non-neoplastic enlarged salivary glands (NNESG, n = 15), primary benign (n = 7) and malignant (n = 8) ectopic salivary tumours (ST) and sellar metastasis from eutopic primary ST (n = 14)-were suitable for the analysis of clinical, radiological and pathological characteristics. Therapeutic outcome was reviewed as a secondary endpoint. RESULTS: All cases were diagnosed after surgery. NNESG commonly affected young and/or female patients, typically leading to headaches and hyperprolactinemia and originating close to the neurohypophysis. Submucosal SG should be excluded before concluding to an intrasellar NNESG after TS. No gender or age predominance was found for primary ectopic ST, which present as large tumors, with histological phenotypes similar to common ST. Hypopituitarism and diabetes insipidus were more frequent in ST than in NNESG. NNESG and benign ectopic ST rarely recur. Malignant ectopic ST should be distinguished from secondary localizations of eutopic ST reaching the sella by contiguity or metastatic spread; both share a frequent unfavorable outcome. CONCLUSION: Sellar neoplasms derived from SG are rare but misleading conditions and pituitary dysfunction is likely to be more common than currently reported. Appropriate pathological evaluation and multidisciplinary approach are required.
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Neoplasias Hipofisárias/secundário , Prolactinoma/secundário , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologia , Sela Túrcica/patologia , Animais , HumanosRESUMO
AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
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Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Cromossomos Humanos Par 14/genética , Glioma/genética , Glioma/patologia , Metilação de DNA , Feminino , Humanos , Masculino , Monossomia , Neurocitoma/genética , Neurocitoma/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologiaRESUMO
Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.
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Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/citologia , Neovascularização Patológica , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Encéfalo , Criança , Pré-Escolar , Células Endoteliais , Citometria de Fluxo , Imunofluorescência , Humanos , Lactente , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
AIMS: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. METHODS: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. RESULTS: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. CONCLUSIONS: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.
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Proliferação de Células/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Glioma/genética , MicroRNAs/genética , Transdução de Sinais/genética , Neoplasias Supratentoriais/genética , Adolescente , Criança , Pré-Escolar , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Lactente , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , MicroRNAs/metabolismo , Gradação de Tumores , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/patologiaAssuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/patologia , Neoplasias Colorretais/patologia , Glioblastoma/patologia , Isocitrato Desidrogenase/genética , Neoplasias Primárias Múltiplas/patologia , Síndromes Neoplásicas Hereditárias/patologia , Astrocitoma/complicações , Astrocitoma/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/genética , Criança , Neoplasias Colorretais/complicações , Neoplasias Colorretais/genética , Feminino , Glioblastoma/complicações , Glioblastoma/genética , Humanos , Mutação , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/genética , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genéticaRESUMO
A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.
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Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Tumor Rabdoide/terapia , Transplante de Células-Tronco , Teratoma/terapia , Biópsia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/cirurgia , Pré-Escolar , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Metástase Neoplásica , Sistema de Registros , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/cirurgia , Teratoma/tratamento farmacológico , Teratoma/cirurgiaRESUMO
AIMS: Desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG) is a rare primary neuroepithelial brain tumour typically affecting paediatric patients younger than 24 months. Knowledge about genetic alterations in DIA/DIG is limited. However, a previous study on BRAF V600E mutation in paediatric glioma revealed a BRAF mutation in one of two tested DIAs/DIGs. The limited number of cases in that study did not allow any conclusion about mutation frequency of BRAF in this tumour entity. METHODS: We collected a series of 18 DIAs/DIGs for testing BRAF V600E mutational status by BRAF V600E immunohistochemistry (clone VE1). Cases with sufficient DNA were tested for BRAF V600E mutation by pyrosequencing. RESULTS: Three out of 18 DIAs/DIGs presented with VE1 binding. A considerable proportion of BRAF V600E mutated tumour cells was detected in the cortical tumour component, whereas the pronounced leptomeningeal tumoural stroma was predominantly negative for VE1 binding. Pyrosequencing confirmed BRAF V600E mutation in two of three VE1-positive cases. CONCLUSION: BRAF V600E mutation affects a subset of DIAs/DIGs and offers new therapeutic opportunities.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Ganglioglioma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Pré-Escolar , Feminino , Ganglioglioma/metabolismo , Humanos , Lactente , Masculino , Mutação , Proteínas Proto-Oncogênicas B-raf/metabolismoRESUMO
Pituitary adenomas are a diverse group of tumors arising from the pituitary gland. Typically, they are small, slow-growing, hormonally inactive lesions that come to light as incidental findings on radiologic or postmortem examinations, although some small, slow-growing lesions with excessive hormonal activity may manifest with a clinical syndrome. The family of neurotrophins plays a key role in the development and maintenance of the pituitary endocrine cell function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. The objective of our experimental study is to investigate the localization of the neurotrophins, their relative receptors and to detect the expression level of Ki-67 to determine whether all these factors participate in the transformation and development of human pituitary adenomas. A very strong expression of Neurotrophin-3 (NT-3) and its receptor TrKC was observed in the extracellular matrix (ECM) and vessel endothelium, together with a clear/marked presence of Brain-derived neurotrophic factor (BDNF), and its receptor TrKB, thus confirming their direct involvement in the progression of pituitary adenomas. On the contrary, NGF (Nerve growth factor) and its receptor TrKA and p75NTR were weakly expressed in the epithelial gland cells and the ECM.
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Adenoma/química , Adenoma Hipofisário Secretor de Hormônio do Crescimento/química , Antígeno Ki-67/análise , Fatores de Crescimento Neural/análise , Matriz Extracelular/química , Humanos , Imuno-Histoquímica , Proteínas do Tecido Nervoso/análise , Receptor trkA/análise , Receptor trkB/análise , Receptor trkC/análise , Receptores de Fator de Crescimento Neural/análiseRESUMO
Glioneuronal tumours are a group of primary brain neoplasms of relatively recent acquisition in the World Health Organization (WHO) Classification of the Central Nervous System tumours. In diagnostic practice it is still possible to encounter glioneuronal tumours that cannot be placed into any of the well-defined WHO categories despite a growing list of entities. We have recently published four paediatric cases of diffuse leptomeningeal tumours that cannot be easily classified in the currently used CNS WHO classification, but which have histological and immunohistochemical criteria to be considered as glioneuronal tumours. The clinical, neuroradiological and pathological long-term follow-up of an unusual diffuse leptomeningeal glioneuronal tumour is presented herein.
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Sistema Nervoso Central/patologia , Neoplasias Meníngeas/patologia , Neoplasias Neuroepiteliomatosas/patologia , Adolescente , Humanos , MasculinoRESUMO
Multiple sclerosis (MS) is an inflammatory CNS disease characterized by multifocal areas of demyelination; usually it arises in young adults, but can also occur in children (under the age of 10) and adolescents (under the age of 18). As in adult, pediatric MS (PMS) diagnosis is based on the demonstration of multiple demyelination episodes separated in time and spaces. Diagnostic criteria realized for childhood are similar to those employed for adults. Although clinical and imaging features of PMS can be similar to those of adults, the disease is often characterized by a more aggressive course and atypical imaging findings, with giant and pseudotumoral plaques. Differential diagnosis between PMS and ADEM could be difficult: clinical findings and MRI are necessary; sometimes MRI follow-up is required for definitive diagnosis.
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Acute post-infectious immune disorders include Acute Disseminated Encephalomyelitis (ADEM) and its variants such as Acute Hemorrhagic Encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE) of Weston Hurst, multiphasic and recurrent ADEM. Acute Necrotizing Encephalopathy of Childhood (ANE or ANEC) represents a dramatic event, consequent to viral infections, especially Influenza-A, and is now considered different from ADEM. ADEM and variants are classically described as uniphasic syndrome occurring in association with an immunization or vaccination (postvaccine encephalomyelitis) or systemic viral infection (parainfectious encephalomyelitis). However, multiphasic forms are not rare. Pathologically, there is perivascular inflammation, edema, and demyelination within the CNS. Clinical features are focal or multifocal neurologic disorder following exposure to virus or receipt of vaccine. The onset of the CNS disorder is usually rapid and include encephalopathy ranging from lethargy to coma, seizures, and focal and multifocal signs reflecting cerebral and spinal cord involvement. The mortality rate is estimated at 10 to 30 percent, with complete recovery rates of 50 percent cited. Poor prognosis is correlated with severity and abruptness of onset of the clinical syndrome. Multifocal CNS lesions are generally evident on MRI that can be similar from those observed in MS.
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Single brain metastases from cervical carcinomas are rare. We report two cases of solitary brain metastases, showing different histological types, which have been excised with microsurgical technique. Neuroendocrine differentiation does not seem to be connected to clinical behavior, indeed a poor prognosis depends on poorly differentiated histological types. In our cases, brain metastases were a late event and they have been successfully excised in microsurgery, thanks to their solitary and resectable nature, and a well-controlled primary disease.
Assuntos
Neoplasias Encefálicas/secundário , Carcinoma/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Neoplasias Encefálicas/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Papillary tumor of the pineal region (PTPR) is a rare variety of CNS neoplasms and, since its first definition in 2003, only 64 cases have been described. PTPR is a primary neoplasm morphologically characterized by papillary structure staining for cytokeratin, transthyretin, neurone-specific enolase and S-100 protein. We report on a case of about 4 years' clinical history and neuroradiological follow-up of PTPR, in a 47-year-old Indian patient, with the aim of increasing the knowledge of its natural history. We describe through CT and MRI scans the natural evolution of this neoplasm, enhancing changes and morphologic structures involved, together with the final surgical treatment and pathological details. A mean growth rate average was calculated for this kind of lesion. In conclusion, the inexorable progressive growing nature of this tumor leads us to advocate an aggressive attitude among neurosurgeons and radiotherapists, with a precocious surgical approach when the suspicion rises.
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Neoplasias Encefálicas/diagnóstico por imagem , Glândula Pineal/diagnóstico por imagem , Pinealoma/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Progressão da Doença , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/metabolismo , Tomografia Computadorizada por Raios XRESUMO
Epigenetic silencing of the O(6)-methylguanine-DNA-methyltransferase (MGMT) gene by promoter methylation is correlated with improved progression-free survival (PFS) and overall survival (OS) in adult patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. The aim of this study is to determine the correlation between MGMT and survival in elderly patients with GBM treated with radiotherapy (RT) and temozolomide (TMZ). Eighty-three patients aged 70 years or older with histologically confirmed GBM treated with RT plus TMZ between February 2005 and September 2009 were investigated in this study. The methylation status of the MGMT promoter was determined by polymerase chain reaction analysis. Median PFS and OS were 7.5 and 12.8 months, respectively. The MGMT promoter was methylated in 42 patients (50.6%) and unmethylated in 41 patients (49.4%). Median OS was 15.3 months in methylated patients and 10.2 months in unmethylated patients (P = 0.0001). Median PFS was 10.5 months in methylated tumors and 5.5 months in unmethylated tumors (P = 0.0001). On multivariate analysis MGMT methylation status emerged as the strongest independent prognostic factor for OS and PFS (P = 0.004 and P = 0.005, respectively). The results of the present study suggest that MGMT methylation status might be an important prognostic factor associated with better OS and PFS in elderly patients with GBM treated with RT and TMZ.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/análogos & derivados , Glioblastoma/genética , Glioblastoma/mortalidade , Proteínas Supressoras de Tumor/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Terapia Combinada , Metilação de DNA , DNA de Neoplasias/genética , Dacarbazina/uso terapêutico , Epigenômica , Feminino , Glioblastoma/terapia , Humanos , Masculino , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Dosagem Radioterapêutica , Taxa de Sobrevida , Temozolomida , Resultado do TratamentoRESUMO
BACKGROUND: The primitive neuroectodermal tumours of central nervous system (CNS-PNET) are a heterogeneous group of neoplasms, occurring in the CNS and composed of undifferentiated or poorly differentiated neuroepithelial cells which may display divergent differentiation along neuronal, astrocytic and ependymal lines. The WHO classification includes in this group of tumours also ependymoblastomas and medulloepitheliomas. Several groups have reported examples of CNS-PNET with combined histological features of ependymoblastoma and neuroblastoma, defined as 'embryonal tumour with abundant neuropil and true rosettes'. The presence of the amplification of chromosome region 19q13.42, common in both ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes, suggests that they represent a histological spectrum of a single biological entity. METHODS: We examined 24 cases of ependymoblastoma/embryonal tumour with abundant neuropil and true rosettes (EPBL/ETANTR) for the presence of mutations of TP53 and ß-Catenin and for amplification of c-myc/N-myc. RESULTS: The single strand conformation polymorphism-mutational screening did not identify any mutation in exons 5 to 8 of the TP53 gene. However, we found a point mutation affecting codon 34 (GGA â GTA) of ß-Catenin gene resulting in a Glycine â Valine substitution. No cases presented c-myc/N-myc amplification. CONCLUSIONS: EPBL/ETANTRs show molecular features different from other CNS-PNET and medulloblastomas. The presence of alterations in the ß-Catenin/WNT pathway seems to be noteworthy due to the close relationship between this pathway and miR-520g encoded in chromosome 19q13.42 region amplified in these tumours.
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Neoplasias Encefálicas/genética , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteína Supressora de Tumor p53/genética , beta Catenina/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Amplificação de Genes , Humanos , Lactente , Masculino , Neoplasias Embrionárias de Células Germinativas/patologia , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.
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Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Epilepsia/metabolismo , Malformações do Sistema Nervoso/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Adolescente , Adulto , Astrócitos/metabolismo , Biomarcadores/metabolismo , Western Blotting , Encéfalo/anormalidades , Encéfalo/patologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/fisiopatologia , Criança , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Ganglioglioma/complicações , Ganglioglioma/metabolismo , Ganglioglioma/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Imuno-Histoquímica , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/metabolismo , Malformações do Desenvolvimento Cortical/fisiopatologia , Microglia/metabolismo , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/fisiopatologia , RNA Mensageiro/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ativador de Plasminogênio Tecidual/análise , Ativador de Plasminogênio Tecidual/genética , Esclerose Tuberosa/complicações , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/fisiopatologia , Ativador de Plasminogênio Tipo Uroquinase/análise , Ativador de Plasminogênio Tipo Uroquinase/genética , Adulto JovemRESUMO
Targeted-therapies enhancing differentiation of glioma-initiating cells (GICs) are potential innovative approaches to the treatment of malignant gliomas. These cells support tumour growth and recurrence and are resistant to radiotherapy and chemotherapy. We have found that GICs express mGlu3 metabotropic glutamate receptors. Activation of these receptors sustained the undifferentiated state of GICs in culture by negatively modulating the action of bone morphogenetic proteins, which physiologically signal through the phosphorylation of the transcription factors, Smads. The cross-talk between mGlu3 receptors and BMP receptors was mediated by the activation of the mitogen-activated protein kinase pathway. Remarkably, pharmacological blockade of mGlu3 receptors stimulated the differentiation of cultured GICs into astrocytes, an effect that appeared to be long lasting, independent of the growth conditions, and irreversible. In in vivo experiments, a 3-month treatment with the brain-permeant mGlu receptor antagonist, LY341495 limited the growth of infiltrating brain tumours originating from GICs implanted into the brain parenchyma of nude mice. While clusters of tumour cells were consistently found in the brain of control mice, they were virtually absent in a large proportion of mice treated with LY341495. These findings pave the way to a new non-cytotoxic treatment of malignant gliomas based on the use of mGlu3 receptor antagonists.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Transdução de Sinais/fisiologia , Aminoácidos/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosforilação/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Xantenos/farmacologiaRESUMO
Basic helix-loop-helix (bHLH) transcription factors are involved in neuroendocrine cell growth and differentiation. Though NeuroD1 is viewed as corticotroph specific, its overexpression in non-corticotroph pituitary adenomas (PAs) may reflect the activation of molecular pathways involving other bHLH factors, like neurogenins. To search for neurogenin-NeuroD1 molecular pathways in the human normal and tumoural pituitary. Fifty-one PAs--22 clinically non-secreting (CNS) and 29 secreting respectively--and normal human pituitaries (NP) were studied for NeuroD1 and neurogenins (Ngn1, Ngn2 and Ngn3) gene expression by RT-PCR and quantitative real-time RT-PCR (qRT-PCR). Immunohistochemistry for Ngn2/3 was performed in some cases. NeuroD1, Ngn2, Ngn3 and Ngn1 were observed in up to 84.3, 76.5, 30.4 and 9.1% of PA respectively, only NeuroD1 and Ngn2 being frequently overexpressed when compared with NP. Whereas NeuroD1 expression was higher in corticotroph and CNS adenomas (P=0.0001 versus Pit-1-dependent PA), Ngn2 expression was higher in secreting PA, especially in Pit-1-dependent PA (P=0.007 and P=0.0006 versus CNS respectively). Pit-1-dependent PA which received pre-operative pharmacological treatment expressed higher Ngn2 levels than untreated cases (P=0.025). Nuclear Ngn2 was observed in NP and in most PA, especially ACTH- and GH-secreting adenomas. Nuclear Ngn3 was observed in a minority of secreting PA. Ngn2 is normally expressed in the anterior pituitary and frequently expressed in PA, but does not account for NeuroD1 overexpression where present. Owing to their low and inconstant expression, the biological significance of Ngn1/3 in the adult pituitary is uncertain.
Assuntos
Adenoma/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hipofisárias/metabolismo , Adolescente , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Feminino , Expressão Gênica , Hormônio do Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
We provide evidence on the expression of the transient receptor potential vanilloid type-1 (TRPV1) by glioma cells, and its involvement in capsaicin (CPS)-induced apoptosis. TRPV1 mRNA was identified by quantitative RT-PCR in U373, U87, FC1 and FLS glioma cells, with U373 cells showing higher, and U87, FC1 and FLS cells lower TRPV1 expression as compared with normal human astrocytes. By flow cytometry we found that a substantial portion of both normal human astrocytes, and U87 and U373 glioma cells express TRPV1 protein. Moreover, we analyzed the expression of TRPV1 at mRNA and protein levels of glioma tissues with different grades. We found that TRPV1 gene and protein expression inversely correlated with glioma grading, with marked loss of TRPV1 expression in the majority of grade IV glioblastoma multiforme. We also described that CPS trigger apoptosis of U373, but not U87 cells. CPS-induced apoptosis involved Ca(2+) influx, p38 but not extracellular signal-regulated mitogen-activated protein kinase activation, phosphatidylserine exposure, mitochondrial permeability transmembrane pore opening and mitochondrial transmembrane potential dissipation, caspase 3 activation and oligonucleosomal DNA fragmentation. TRPV1 was functionally implicated in these events as they were markedly inhibited by the TRPV1 antagonist, capsazepine. Finally, p38 but not extracellular signal-regulated protein kinase activation was required for TRPV1-mediated CPS-induced apoptosis of glioma cells.
Assuntos
Apoptose/fisiologia , Neoplasias Encefálicas/metabolismo , Capsaicina/farmacologia , Glioma/metabolismo , Canais de Cátion TRPV/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/fisiopatologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/fisiopatologia , Glioma/tratamento farmacológico , Glioma/fisiopatologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/genética , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacosRESUMO
OBJECTIVE AND IMPORTANCE: This study describes a case of autochthonous neurocysticercosis in a non endemic region where a differential diagnosis with more frequent single parenchymal lesions must be carried out. CLINICAL PRESENTATION: The patient presenting generalized seizures and coma status under the suspicion of cerebral neoplasia was admitted to the neurosurgery division. MRI showed the presence of an ovoidal cystic lesion in right-frontotemporal region. INTERVENTION: After right fronto-temporal osteoplastic bone flap elevation and usual dural tacking and opening, trans-scissural subaracnoid access was made possible by microsurgical strumentation in right Sylvian fissure. A cystic, translucid lesion was identified in the deep Sylvian fissure, involving the distal segment of the fissure and the frontal lobe, the cystic lesion was removed surgically. Pathological examination showed a typical picture of neurocysticercosis. CONCLUSIONS: After both surgical and chemotherapeutic treatment with albendazole the outcome was successful. The diagnosis of neurocysticercosis should be taken into account in the presence of generalized seizures possibly due to single parenchymal lesions, even in non-endemic regions for this parasitic infection.