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1.
Rev Esp Patol ; 50(1): 45-48, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29179964

RESUMO

Only five cases of multifocal medulloblastoma in the adult have been reported to date. We present a case in a male patient in his 50th decade of life who presented with three extra-axial lesions associated with a parenchymatous lesion of the right middle cerebellar peduncle. Sputum sample examination revealed larvae compatible with strongyloides stercoralis, which was our main differential diagnosis. Histological and immunohistochemical studies revealed the existence of a desmoplastic medulloblastoma.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Neoplasias Primárias Múltiplas/patologia , Animais , Biomarcadores Tumorais/análise , Neoplasias Cerebelares/química , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/diagnóstico por imagem , Cromograninas/análise , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Masculino , Meduloblastoma/química , Meduloblastoma/complicações , Meduloblastoma/diagnóstico por imagem , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neuroimagem , Escarro/parasitologia , Strongyloides stercoralis/isolamento & purificação , Estrongiloidíase/complicações , Estrongiloidíase/diagnóstico , Estrongiloidíase/patologia , Sinaptofisina/análise
2.
Pediatr Blood Cancer ; 64(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28598542

RESUMO

BACKGROUND: Overexpression of minichromosome maintenance (MCM) proteins 2, 3, and 7 is associated with migration and invasion in medulloblastoma (MB). However, expression profiling of all prereplication complex (pre-RC) has not been addressed in MBs. PROCEDURE: We performed mRNA expression profiling of a large set of pre-RC elements in cell lines and tumor tissues of MB. RNAi technology was employed for functional studies in MB cell lines. RESULTS: Our data showed that most of the pre-RC components are significantly overexpressed in MB. Among all pre-RC mRNAs, MCM10 showed the highest level of expression (∼500- to 1,000-fold) in MB cell lines and tissues compared to the levels detected in cerebellum. In addition, RNAi silencing of MCM10 caused reduced cell proliferation and cell viability in MB cells. CONCLUSIONS: Taken together, our study reveals that the pre-RC is dysregulated in MB. In addition, MCM10, a member of this complex, is significantly overexpressed in MB and is required for tumor cell proliferation.


Assuntos
Neoplasias Cerebelares/química , Meduloblastoma/química , Proteínas de Manutenção de Minicromossomo/fisiologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/patologia , Humanos , Imuno-Histoquímica , Meduloblastoma/patologia , Proteínas de Manutenção de Minicromossomo/análise
3.
Lab Invest ; 97(8): 946-961, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28504687

RESUMO

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. At present, there is no well-established targeted drug for majority of patients. The kinesin family member 14 (KIF14) is a novel oncogene located on chromosome 1q and is dysregulated in multiple cancers. The objectives of this study were to evaluate KIF14 expression and chromosome 1q copy number in MB, and to delineate its biological functions in MB pathogenesis. By quantitative RT-PCR and immunohistochemistry, we found KIF14 was overexpressed in MB. Increased KIF14 expression at protein level was strongly associated with shorter progression-free survival (P=0.0063) and overall survival (P=0.0083). Fluorescence in situ hybridization (FISH) analysis confirmed genomic gain of chromosome 1q in 17/93 (18.3%) of MB. Combined genetic and immunohistochemical analyses revealed that 76.5% of MB with 1q gain showed consistent overexpression of KIF14, and a tight link between chromosome 1q gain and KIF14 overexpression (P=0.03). Transient, siRNAs-mediated downregulation of KIF14 suppressed cell proliferation and induced apoptosis in two MB cell lines. Stably KIF14 knockdown by shRNAs inhibited cell viability, colony formation, migration and invasion, and tumor sphere formation in MB cells. We conclude that KIF14 is dysregulated in MB and is an adverse prognostic factor for survival. Furthermore, KIF14 is part of MB biology and is a potential therapeutic target for MB.


Assuntos
Apoptose/genética , Regulação para Baixo/genética , Cinesina/genética , Cinesina/metabolismo , Meduloblastoma/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Adolescente , Adulto , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Cinesina/análise , Masculino , Meduloblastoma/química , Proteínas Oncogênicas/análise , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Adulto Jovem
4.
Pol J Pathol ; 68(4): 364-366, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29517209

RESUMO

Medulloblastoma is the most common CNS embryonal tumor and the most common malignant tumor of childhood. Its overall incidence is 1.8 cases per 1 million people, with a childhood incidence of 6 cases per 1 million. 77 percent of patients are less than 19 years old. Medulloblastoma occurs in the 4th ventricle and usually presents with symptoms of increased intracranial pressure (headaches, nausea, vomiting) and signs of obstructive hydrocephalus. Medulloblastoma is both histologically and genetically defined with prognosis that depends on classification.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/química , Neoplasias Cerebelares/patologia , Proteínas Hedgehog/análise , Meduloblastoma/química , Meduloblastoma/patologia , Biópsia , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Imagem por Ressonância Magnética , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/cirurgia
5.
ASN Neuro ; 8(4)2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27511909

RESUMO

Harmful effects that alter the homeostasis of neural stem or progenitor cells (NSPs) can affect regenerative processes in the central nervous system. We investigated the effect of soluble factors secreted by control or (137)Cs-γ-irradiated glioblastoma or medulloblastoma cells on redox-modulated endpoints in recipient human NSPs. Growth medium harvested from the nonirradiated brain tumor cells, following 24 h of growth, induced prominent oxidative stress in recipient NSPs as judged by overall increases in mitochondrial superoxide radical levels (p < .001), activation of c-jun N-terminal kinase, and decrease in the active form of FoxO3a. The induced oxidative stress was associated with phosphorylation of p53 on serine 15, a marker of DNA damage, induction of the cyclin-cyclin dependent kinase inhibitors p21(Waf1) and p27(Kip1), and perturbations in cell cycle progression (p < .001). These changes were also associated with increased apoptosis as determined by enhanced annexin V staining (p < .001) and caspase 8 activation (p < .05) and altered expression of critical regulators of self-renewal, proliferation, and differentiation. Exposure of the tumor cells to radiation only slightly altered the induced oxidative changes in the bystander NSPs, except for medium from irradiated medulloblastoma cells that was more potent at inducing apoptosis in the NSPs than medium from nonirradiated cells (p < .001). The elucidation of such stressful bystander effects provides avenues to understand the biochemical events underlying the development or exacerbation of degenerative outcomes associated with brain cancers. It is also relevant to tissue culture protocols whereby growth medium conditioned by tumor cells is often used to support the growth of stem cells.


Assuntos
Efeito Espectador/fisiologia , Glioblastoma/química , Meduloblastoma/química , Células-Tronco Neurais/fisiologia , Estresse Oxidativo/fisiologia , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Efeito Espectador/efeitos dos fármacos , Efeito Espectador/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Transformada , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Glioblastoma/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Meduloblastoma/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo
6.
Oncotarget ; 6(36): 38827-39, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26420814

RESUMO

PURPOSE: To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial. METHODS: Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN, 9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally. RESULTS: The favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowing re-classification of 86% as favorable-risk. CONCLUSIONS: Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of chromosome 17 imbalance at the cellular level, and MBWNT, provides a strong basis for incorporation into future trials.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/química , Meduloblastoma/química , Adolescente , Adulto , Biomarcadores Tumorais/genética , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Cromossomos Humanos Par 17 , Estudos de Coortes , Feminino , Formaldeído , Humanos , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Meduloblastoma/terapia , Inclusão em Parafina , Prognóstico , Fatores de Risco , Fixação de Tecidos , Adulto Jovem
7.
Mol Biosyst ; 11(6): 1668-83, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25909245

RESUMO

A top-down/bottom-up integrated proteomic approach based on LC-MS and 2-DE analysis was applied for comparative characterization of medulloblastoma and pilocytic astrocytoma posterior cranial fossa pediatric brain tumor tissues. Although rare, primary brain tumors are the most frequent solid tumors in the pediatric age. Among them the medulloblastoma is the prevalent malignant tumor in childhood while pilocytic astrocytoma is the most common, rarely showing a malignant progression. Due to the limited availability of this kind of sample, the study was applied to pooled tumor tissues for a preliminary investigation. The results showed different proteomic profiles of the two tumors and evidenced interesting differential expression of several proteins and peptides. Top-down proteomics of acid-soluble fractions of brain tumor homogenates ascribed a potential biomarker role of malignancy to ß- and α-thymosins and their truncated proteoforms and to C-terminal truncated (des-GG) ubiquitin, resulting exclusively detected or over-expressed in the highly malignant medulloblastoma. The bottom-up proteomics of the acid-soluble fraction identified several proteins, some of them in common with 2-DE analysis of acid-insoluble pellets. Peroxiredoxin-1, peptidyl-prolyl cis-trans isomerase A, triosephosphate isomerase, pyruvate kinase PKM, tubulin beta and alpha chains, heat shock protein HSP-90-beta and different histones characterized the medulloblastoma while the Ig kappa chain C region, serotransferrin, tubulin beta 2A chain and vimentin the pilocytic astrocytoma. The two proteomic strategies, with their pros and cons, well complemented each other in characterizing the proteome of brain tumor tissues and in disclosing potential disease biomarkers to be validated in a future study on individual samples of both tumor histotypes.


Assuntos
Astrocitoma/química , Neoplasias Encefálicas/química , Meduloblastoma/química , Proteoma/análise , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Criança , Pré-Escolar , Humanos , Meduloblastoma/metabolismo , Proteínas/análise , Proteínas/química , Proteínas/metabolismo , Proteoma/química , Proteoma/metabolismo , Proteômica
8.
J Neurosurg Pediatr ; 15(3): 236-42, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25525930

RESUMO

OBJECT: While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). METHODS: The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. RESULTS: Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. CONCLUSIONS: The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/complicações , Proteínas Hedgehog/análise , Hidrocefalia/cirurgia , Meduloblastoma/complicações , Ventriculostomia/estatística & dados numéricos , Proteínas Wnt/análise , Adolescente , Canadá , Neoplasias Cerebelares/química , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Incidência , Lactente , Masculino , Meduloblastoma/química , Meduloblastoma/patologia , Valor Preditivo dos Testes , Qualidade de Vida , Estudos Retrospectivos , Índice de Gravidade de Doença , Terceiro Ventrículo , Ventriculostomia/métodos
9.
J Neurosurg Pediatr ; 14(6): 615-20, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25303160

RESUMO

Medulloblastoma is the most frequent malignant brain tumor of the posterior fossa in children and is considered an embryonal tumor. It has been suggested that medulloblastomas be categorized into 4 distinct molecular subgroups- WNT (DKK1), SHH (SFRP1), Group 3 (NPR3), or Group 4 (KCNA1)-since each subgroup is distinct and there is no overlap. The authors report on a 13-year-old boy with medulloblastoma. He presented with sudden-onset nausea and vomiting due to intratumoral hemorrhage. The medulloblastoma was thought to be in an early developmental stage because the tumor volume was extremely small. Immunohistochemical analysis showed that the tumor was mainly composed of DKK1- and NPR3-positive areas. The individual areas of the tumor stained only for DKK1 or NPR3, with no overlap-that is, DKK1 and NPR3 expression were mutually exclusive. Samples obtained by laser microdissection of individual areas and subjected to mass spectrometry confirmed that the expression patterns of proteins were different. Fluorescence in situ hybridization for chromosome 6 showed there were 2 distinct types of cells that exhibited monosomy or disomy of chromosome 6. These results demonstrated that distinct subtypes of medulloblastoma may be present within a single tumor, an observation that has not been previously reported. Our findings in this case indicate that early-stage medulloblastoma may include more than 1 distinct subtype and hint at factors involved in the origin and development of medulloblastomas.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/patologia , Peptídeos e Proteínas de Sinalização Intercelular/análise , Meduloblastoma/patologia , Receptores do Fator Natriurético Atrial/análise , Adolescente , Neoplasias Cerebelares/química , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lasers , Masculino , Espectrometria de Massas , Meduloblastoma/química , Microdissecção/instrumentação
10.
NMR Biomed ; 27(10): 1222-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25125325

RESUMO

(1)H MRS thermometry has been investigated for brain trauma and hypothermia monitoring applications but has not been explored in brain tumours. The proton resonance frequency (PRF) of water is dependent on temperature but is also influenced by microenvironment factors, such as fast proton exchange with macromolecules, ionic concentration and magnetic susceptibility. (1)H MRS has been utilized for brain tumour diagnostic and prognostic purposes in children; however, the water PRF measure may provide complementary information to further improve characterization. Water PRF values were investigated from a repository of MRS data acquired from childhood brain tumours and children with apparently normal brains. The cohort consisted of histologically proven glioma (22), medulloblastoma (19) and control groups (28, MRS in both the basal ganglia and parietal white matter regions). All data were acquired at 1.5 T using a short TE (30 ms) single voxel spectroscopy (PRESS) protocol. Water PRF values were calculated using methyl creatine and total choline. Spectral peak amplitude weighted averaging was used to improve the accuracy of the measurements. Mean PRF values were significantly larger for medulloblastoma compared with glioma, with a difference in the means of 0.0147 ppm (p < 0.05), while the mean PRF for glioma was significantly lower than for the healthy cohort, with a difference in the means of 0.0061 ppm (p < 0.05). This would suggest the apparent temperature of the glioma group was ~1.5 °C higher than the medulloblastomas and ~0.7 °C higher than a healthy brain. However, the PRF shift may not reflect a change in temperature, given that alterations in protein content, microstructure and ionic concentration contribute to PRF shifts. Measurement of these effects could also be used as a supplementary biomarker, and further investigation is required. This study has shown that the water PRF value has the potential to be used for characterizing childhood brain tumours, which has not been reported previously.


Assuntos
Água Corporal/química , Neoplasias Encefálicas/química , Glioma/química , Meduloblastoma/química , Neuroimagem/métodos , Espectroscopia de Prótons por Ressonância Magnética , Temperatura , Termometria/métodos , Microambiente Tumoral , Adolescente , Algoritmos , Biomarcadores Tumorais , Neoplasias Cerebelares/química , Criança , Pré-Escolar , Colina/análise , Creatina/análise , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Prótons , Estudos Retrospectivos , Substância Branca/química
11.
J Neurosurg Pediatr ; 14(2): 121-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24905841

RESUMO

OBJECT: Vascular endothelial growth factor (VEGF) is the major proangiogenic factor in many solid tumors. Vascular endothelial growth factor receptor (VEGFR) is expressed in abundance in pediatric patients with medulloblastoma and is associated with tumor metastasis, poor prognosis, and proliferation. Gadolinium enhancement on MRI has been suggested to have prognostic significance for some tumors. The association of VEGF/VEGFR and Gd enhancement in medulloblastoma has never been closely examined. The authors therefore sought to evaluate whether Gd-enhancing medulloblastomas have higher levels of VEGFR and CD31. Outcomes and survival in patients with enhancing and nonenhancing tumors were also compared. METHODS: A retrospective analysis of patients with enhancing, nonenhancing, and partially enhancing medulloblastomas was performed. Primary end points included risk stratification, extent of resection, and perioperative complications. A cohort of 3 enhancing and 3 nonenhancing tumors was selected for VEGFR and CD31 analysis as well as microvessel density measurements. RESULTS: Fifty-eight patients were analyzed, and 20.7% of the medulloblastomas in these patients were nonenhancing. Enhancing medulloblastomas exhibited strong VEGFR1/2 and CD31 expression relative to nonenhancing tumors. There was no significant difference in perioperative complications or patient survival between the 2 groups. CONCLUSIONS: These results suggest that in patients with medulloblastoma the presence of enhancement on MRI may correlate with increased vascularity and angiogenesis, but does not correlate with worse patient prognosis in the short or long term.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/química , Neoplasias Cerebelares/cirurgia , Meduloblastoma/química , Meduloblastoma/cirurgia , Receptores de Fatores de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/análise , Adolescente , Adulto , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Meios de Contraste , Feminino , Gadolínio , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética/métodos , Masculino , Meduloblastoma/patologia , Microcirculação , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos
12.
Toxicol Pathol ; 42(8): 1174-87, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24862798

RESUMO

Medulloblastomas (MBs) are thought to be derived from granular cell precursors in the external granular layer (EGL) of the developing cerebellum. Heterozygous patched1 (Ptch1) knockout mice develop MBs that resemble those in humans when the sonic hedgehog (Shh) signaling pathway is activated. The present study was conducted to evaluate postnatal effects of a Shh signaling inhibitor, cyclopamine, on the development of MBs in Ptch1 mice. Ptch1 and wild-type mice were treated daily with subcutaneous cyclopamine at 40 mg/kg or vehicle from postnatal day (PND) 1 to PND14, and the subsequent development of MBs and preneoplastic lesions was examined up to week 12 (W12). Proliferative lesions in the cerebellum, MBs, and preneoplastic lesions were only detected in Ptch1 mice. Cyclopamine treatment resulted in a statistically significant reduction in the incidence and/or area of proliferative lesions at PND14 and 21. The trend of decreasing preneoplastic lesions persisted up to W12. At PND7, cyclopamine treatment reduced the width and proliferation of the EGL regardless of genotype. These results indicate that inhibition of Shh signaling during cerebellar development has prolonged inhibitory potential on MB development in Ptch1 mice. This inhibitory potential might be related to inhibition of EGL proliferation, including preneoplastic MB cells.


Assuntos
Cerebelo/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/metabolismo , Alcaloides de Veratrum/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Cerebelo/química , Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Meduloblastoma/química , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
14.
Hiroshima J Med Sci ; 61(1): 1-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22702213

RESUMO

Growth hormone (GH) is essential for quality of life in both children and adults, but it is also believed to enhance the growth of various neoplasms. However, the role of GH in the brain, particularly in brain tumors, has yet to be established. To clarify these problems from the perspective of receptor expression, we examined GH receptor (GHR) expression in brain tumors using immunohistochemistry and the correlation between GHR expression and clinical features. Surgical specimens obtained from patients with brain tumors (106 pituitary adenomas, 12 craniopharyngiomas, 13 germ cell tumors, 6 medulloblastomas, and 12 malignant gliomas) were examined immunohistochemically for GHR expression. The GHR positive rate was lower in malignant tumors than in benign tumors (59% in pituitary adenomas, 73% in craniopharyngiomas, 23% in germ cell tumors, and 0% in medulloblastomas and gliomas). GHR staining in pituitary adenomas was weaker than that in normal pituitary gland. Among the GH-producing pituitary adenomas, there was no difference in size between GHR-positive and -negative tumors. However, among the non-GH-producing adenomas, GHR-positive tumors were significantly smaller. Thus, immunohistochemical GHR expression may have, at least in part, a negative impact on tumor growth potential in brain tumors.


Assuntos
Neoplasias Encefálicas/química , Proteínas de Transporte/análise , Adenoma/química , Adenoma/patologia , Adulto , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/química , Neoplasias Cerebelares/patologia , Craniofaringioma/química , Craniofaringioma/patologia , Feminino , Glioma/química , Glioma/patologia , Humanos , Imuno-Histoquímica , Japão , Masculino , Meduloblastoma/química , Meduloblastoma/patologia , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/química , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Hipofisárias/química , Neoplasias Hipofisárias/patologia , Carga Tumoral
15.
Mod Pathol ; 24(10): 1320-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21623385

RESUMO

TP63, a member of the TP53 gene family, is a nuclear marker of myoepithelial cells. Antibody against p63 is frequently used to aid in the diagnosis of prostate carcinoma, as well as in the identification of myoepithelial cells in other tissues including the breast. p63 is also a marker for squamous cell carcinoma. Recently, it was found that all p53 family members are involved in regulating the process of muscle differentiation through the retinoblastoma (RB) protein. Ablation of these p53 family functions blocks the differentiation program and promotes malignant transformation by enabling cooperating oncogenes to transform myoblasts. We therefore studied p63 expression in a number of neoplasms with myogenic differentiation. Immunohistochemical staining for p63 was performed on paraffin sections from 38 rhabdomyosarcomas, five leiomyomas, five leiomyosarcomas, five rhabdomyomas, five rhabdomyomatous Wilms tumors, three normal cardiac muscles, one medullomyoblastoma, one pleuropulmonary blastoma with rhabdomyomatous differentiation, and one teratoma with prominent rhabdomyoblasts. Each case was also stained with desmin. Unlike the nuclear staining scored in myoepithelial cells, only cytoplasmic staining for p63 was considered positive. Of 38 cases of rhabdomyosarcoma, 36 showed cytoplasmic p63 staining; 24 of these showed highlighting of cross-striations superior to that of desmin. In addition, 5/5 rhabdomyomas, 5/5 rhabdomyomatous Wilms tumors, 1/1 pleuropulmonary blastoma with rhabdomyomatous differentiation, 1/1 teratoma with atypical rhabdoblasts, and 1/1 medullomyoblastoma exhibited cytoplasmic p63 staining. Normal cardiac muscle samples (3/3) also demonstrated positive cytoplasmic staining and distinct cross-striations. Smooth muscle tumors exhibited only very focal and faint cytoplasmic staining in 5/5 leiomyomas and 4/5 leiomyosarcomas. Immunoelectron microscopic study of skeletal muscle showed p63 localization to the Z bands of sarcomeres. We conclude that p63 immunostain is a sensitive marker for skeletal muscle differentiation and highlights the cross-striations of strap cells with exceptional definition.


Assuntos
Biomarcadores Tumorais/análise , Diferenciação Celular , Citoplasma/química , Citoplasma/patologia , Imuno-Histoquímica , Microscopia Imunoeletrônica , Músculo Esquelético/química , Músculo Esquelético/patologia , Neoplasias/química , Neoplasias/patologia , Fatores de Transcrição/análise , Proteínas Supressoras de Tumor/análise , Neoplasias Cerebelares/química , Neoplasias Cerebelares/patologia , Citoplasma/ultraestrutura , Humanos , Neoplasias Renais/química , Neoplasias Renais/patologia , Leiomioma/química , Leiomioma/patologia , Leiomiossarcoma/química , Leiomiossarcoma/patologia , Meduloblastoma/química , Meduloblastoma/patologia , Músculo Esquelético/ultraestrutura , Músculo Liso/química , Músculo Liso/patologia , Miocárdio/química , Miocárdio/patologia , Neoplasias/ultraestrutura , Blastoma Pulmonar/química , Blastoma Pulmonar/patologia , Rabdomiossarcoma/química , Rabdomiossarcoma/patologia , Teratoma/química , Teratoma/patologia , Tumor de Wilms/química , Tumor de Wilms/patologia
16.
Ann Pathol ; 30(2): 135-8, 2010 Apr.
Artigo em Francês | MEDLINE | ID: mdl-20451073

RESUMO

A 26 years old patient was operated for a tumor of cerebellar vermix, and then reoperated for a relapse at the age of 35 years, with a similar histological pattern in both cases. At pathologic examination, the tumor was composed of hypercellular sheets typical of medulloblastoma, containing also sparse large cells with eosinophilic cytoplasm and round nuclei containing voluminous nucleoli. Neuroblastic cells showed expression of neurofilament protein and synaptophysin. The large cells expressed desmin, myogenin, and neurofilament. These morphological and immunohistochemical features are characteristic of medullomyoblastoma. The patient deceased 11 years after the initial surgery. Medullomyoblastoma is a rare variant of medulloblastoma with a rhabdomyoblastic differentiation. The two tumoral populations share the same genetic alterations. The main differential diagnoses are atypical teratoid/rhabdoid tumor, immature teratoma, medulloepithelioma, primitive intracranial rhabdomyosarcoma and myoneurocytoma.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Adulto , Biomarcadores Tumorais/análise , Diferenciação Celular , Neoplasias Cerebelares/química , Neoplasias Cerebelares/cirurgia , Desmina/análise , Progressão da Doença , Evolução Fatal , Humanos , Masculino , Meduloblastoma/química , Meduloblastoma/cirurgia , Células Musculares/química , Células Musculares/patologia , Miogenina/análise , Proteínas de Neoplasias/análise , Recidiva Local de Neoplasia/química , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Proteínas de Neurofilamentos/análise , Rabdomiossarcoma/patologia , Sinaptofisina/análise
17.
Neuropathology ; 29(1): 72-7, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18422908

RESUMO

Melanotic or melanocytic medulloblastoma is a rare variant of medulloblastoma, especially when the tumor shows advanced neuronal differentiation. We report a case of this tumor, which developed in the cerebellar vermis in an 8-year-old girl. Initial biopsy specimens were identified as classical medulloblastoma with a high MIB1 index. Surgical removal of the tumor was performed after chemo-radiotherapy, and black pigments were noticed on the tumor surface. Histologically, the tumor was composed of classical medulloblastoma with the presence of pigmented epithelial cells forming tubules and clusters. Immunohistochemically, the pigmented tumor cells were positive for S100 protein, HMB45, and MART1, indicating that the pigments were derived from melanosomes, and these features were compatible with melanocytic medulloblastoma. Interestingly, some of the non-pigmented or amelanotic tumor cells were also positive for HMB45 and S100 protein. Although the tumor showed an unusual cell combination, it was distinguished from atypical teratoid/rhabdoid tumor (AT/RT) by nuclear expression of INI1/BAF45 protein. The tumor also possessed ganglion-like cells within the neuropil matrix, which resembled small mature ganglion cells, and was consequently designated as ganglioneurocytoma. The melanotic medulloblastoma and part of the ganglioneurocytomatous area were fused with each other. Hence, the present case provides new information indicating that melanocytic medulloblastoma differs from AT/RT, and that it can exhibit advanced neuronal differentiation. In addition, reduction of the tumor MIB1 index was observed after chemo-radiotherapy.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Antígenos de Neoplasias/análise , Neoplasias Cerebelares/química , Neoplasias Cerebelares/terapia , Quimioterapia Adjuvante , Criança , Proteínas Cromossômicas não Histona/análise , Proteínas de Ligação a DNA/análise , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Antígeno MART-1 , Imagem por Ressonância Magnética , Meduloblastoma/química , Meduloblastoma/terapia , Melanossomas/química , Melanossomas/patologia , Proteínas de Neoplasias/análise , Neurocitoma/química , Neurocitoma/patologia , Neurocitoma/terapia , Neurônios/química , Neurônios/patologia , Neurópilo/patologia , Radioterapia Adjuvante , Proteínas S100/análise , Proteína SMARCB1 , Sinaptofisina/análise , Fatores de Transcrição/análise
18.
Magy Onkol ; 52(4): 351-5, 2008 Dec.
Artigo em Húngaro | MEDLINE | ID: mdl-19068462

RESUMO

Medulloblastoma is the most common malignant pediatric central nervous system tumor. Despite the adequate therapy the tumor often recurs. The primary medulloblastoma expresses somatostatin receptor-2 (SSTR-2), but so far we had no experience about the receptor status in recurrent tumors. The presence of SSTR-2 may have an important role in the early detection and treatment of recurrent medulloblastomas. Our aim was to examine the state of SSTR-2 expression in recurrent childhood medulloblastomas. We examined SSTR-2 expression by immunohistochemistry in primary and recurrent medulloblastoma samples of ten children treated with recurrent medulloblastoma at Semmelweis University, Departments of Pediatrics, between 1998 and 2004. All primary and recurrent tumors have been operated at the National Institute of Neurosurgery. We examined the intensity and the percentage of SSTR-2-positive tumor cells in the primary and recurrent tumor samples. All primary tumors were receptor-positive and SSTR-2 was also expressed in all recurrent medulloblastomas. In our samples the percentage of SSTR-2-positive tumor cells was 30-90%. As a positive in vivo control Octreoscan images were available in two cases. In these cases the results of immunohistochemistry and Octreoscan imaging seemed to correlate. As a conclusion, SSTR-2-positive recurrent tumors can be detected early by Octreoscan imaging, and the presence of SSTR-2 establishes the opportunity of applying somatostatin analogues (octreotide) in the treatment of recurrent childhood medulloblastoma.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/química , Meduloblastoma/química , Recidiva Local de Neoplasia/química , Receptores de Somatostatina/análise , Adolescente , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/imunologia , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Radioisótopos de Índio , Lactente , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/tratamento farmacológico , Meduloblastoma/secundário , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Octreotida/uso terapêutico , Valor Preditivo dos Testes , Receptores de Somatostatina/imunologia , Somatostatina/análogos & derivados , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto Jovem
19.
Int J Cancer ; 123(3): 594-600, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18478565

RESUMO

The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas.


Assuntos
Neoplasias Encefálicas/metabolismo , Ependimoma/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Meduloblastoma/metabolismo , Western Blotting , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/química , Estudos de Casos e Controles , Criança , Pré-Escolar , Ependimoma/sangue , Ependimoma/líquido cefalorraquidiano , Ependimoma/química , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 6 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/genética , Masculino , Meduloblastoma/sangue , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/química , Análise em Microsséries , Valor Preditivo dos Testes , Prognóstico , RNA Mensageiro/metabolismo , Radioimunoensaio , Análise de Sobrevida , Regulação para Cima
20.
J Proteome Res ; 7(5): 1932-44, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18336001

RESUMO

The human medulloblastoma cell line DAOY was transfected with Tropomyosin receptor kinase (TrkC), a marker for good prognostic outcome. Following TrkC-activation by its ligand neurotrophin-3, protein extracts from DAOY cells were run on 2DE with subsequent MALDI-TOF-TOF analysis and quantification in order to detect downstream effectors. Protein levels of translational, splicing, processing, chaperone, protein handling, and metabolism machineries were shown to depend on neurotrophin-3-induced TrkC activation probably representing pharmacological targets.


Assuntos
Meduloblastoma/química , Meduloblastoma/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neurotrofina 3/metabolismo , Receptor trkC/metabolismo , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Criança , Ativação Enzimática , Humanos , Meduloblastoma/diagnóstico , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Prognóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
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