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1.
Hum Mol Genet ; 22(2): 226-38, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23049073

RESUMO

Mitochondrial DNA (mtDNA) mutations leading to the disruption of respiratory complex I (CI) have been shown to exhibit anti-tumorigenic effects, at variance with those impairing only the function but not the assembly of the complex, which appear to contribute positively to cancer development. Owing to the challenges in the analysis of the multi-copy mitochondrial genome, it is yet to be determined whether tumour-associated mtDNA lesions occur as somatic modifying factors or as germ-line predisposing elements. Here we investigated the whole mitochondrial genome sequence of 20 pituitary adenomas with oncocytic phenotype and identified pathogenic and/or novel mtDNA mutations in 60% of the cases. Using highly sensitive techniques, namely fluorescent PCR and allele-specific locked nucleic acid quantitative PCR, we identified the most likely somatic nature of these mutations in our sample set, since none of the mutations was detected in the corresponding blood tissue of the patients analysed. Furthermore, we have subjected a series of 48 pituitary adenomas to a high-resolution array comparative genomic hybridization analysis, which revealed that CI disruptive mutations, and the oncocytic phenotype, significantly correlate with low number of chromosomal aberrations in the nuclear genome. We conclude that CI disruptive mutations in pituitary adenomas are somatic modifiers of tumorigenesis most likely contributing not only to the development of oncocytic change, but also to a less aggressive tumour phenotype, as indicated by a stable karyotype.


Assuntos
Adenoma/genética , Transformação Celular Neoplásica/genética , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/genética , Instabilidade Genômica , Mutação , Neoplasias Hipofisárias/genética , Adenoma/patologia , Sequência de Aminoácidos , Transformação Celular Neoplásica/metabolismo , Variações do Número de Cópias de DNA , DNA Mitocondrial/química , DNA Mitocondrial/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Fenótipo , Neoplasias Hipofisárias/patologia , Alinhamento de Sequência
2.
J Neurooncol ; 116(3): 533-41, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24293233

RESUMO

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6% (95% CI 29.3-55.2) and a median PFS of 5.2 months (95% CI 3.8-6.6). The median OS was 9.1 months (95% CI 7.3-10.3). Twenty-eight patients (52%) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60%). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76%), while the diffuse non-enhancing progression accounted for 9.5%. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22%) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4%) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Nitrosoureia/uso terapêutico , Compostos Organofosforados/uso terapêutico , Idoso , Bevacizumab , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Proteínas Supressoras de Tumor/metabolismo
3.
Cell Biochem Funct ; 32(2): 164-76, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23836332

RESUMO

Glioblastomas (GBMs) are the most lethal primary brain tumours. Increasing evidence shows that brain tumours contain the population of stem cells, so-called cancer stem cells (CSCs). Stem cell marker CD133 was reported to identify CSC population in GBM. Further studies have indicated that CD133 negative cells exhibiting similar properties and are able to initiate the tumour, self-renew and undergo multilineage differentiation. GBM is a highly heterogeneous tumour and may contain different stem cell populations with different functional properties. We characterized five GBM cell lines, established from surgical samples, according to the marker expression, proliferation and differentiation potential. CD133 positive cell lines showed increased proliferation rate in neurosphere condition and marked differentiation potential towards neuronal lineages. Whereas two cell lines low-expressing CD133 marker showed mesenchymal properties in vitro, that is high proliferation rate in serum condition and differentiation in mesenchymal cell types. Further, we compared therapy resistance capacity of GBM cell lines treated with hydroxyurea. Our results suggest that CSC concept is more complex than it was believed before, and CD133 could not define entire stem cell population within GBM. At least two different subtypes of GBM CSCs exist, which may have different biological characteristics and imply different therapeutic strategies.


Assuntos
Neoplasias Encefálicas/genética , Heterogeneidade Genética , Glioblastoma/genética , Células-Tronco Neoplásicas/fisiologia , Fenótipo , Antígeno AC133 , Adulto , Idoso , Antígenos CD/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Diferenciação Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Glioblastoma/patologia , Glicoproteínas/genética , Humanos , Hidroxiureia/farmacologia , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Peptídeos/genética , Células Tumorais Cultivadas
4.
Cell Rep ; 42(8): 112816, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37505981

RESUMO

Glioblastoma (GBM) is known as an intractable, highly heterogeneous tumor encompassing multiple subclones, each supported by a distinct glioblastoma stem cell (GSC). The contribution of GSC genetic and transcriptional heterogeneity to tumor subclonal properties is debated. In this study, we describe the systematic derivation, propagation, and characterization of multiple distinct GSCs from single, treatment-naive GBMs (GSC families). The tumorigenic potential of each GSC better correlates with its transcriptional profile than its genetic make-up, with classical GSCs being inherently more aggressive and mesenchymal more dependent on exogenous growth factors across multiple GBMs. These GSCs can segregate and recapitulate different histopathological aspects of the same GBM, as shown in a paradigmatic tumor with two histopathologically distinct components, including a conventional GBM and a more aggressive primitive neuronal component. This study provides a resource for investigating how GSCs with distinct genetic and/or phenotypic features contribute to individual GBM heterogeneity and malignant escalation.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Neoplasias Encefálicas/metabolismo , Amplificação de Genes , Células-Tronco Neoplásicas/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral
5.
Hum Mol Genet ; 19(6): 1019-32, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20028790

RESUMO

We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors of the thyroid and kidney. We here report a high frequency of homoplasmic disruptive mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicates disassembly of respiratory complex I in vivo which in turn contributes to the inability of oncocytic tumors to stabilize HIF1alpha and to display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced the shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 gene. Such shift is associated with a profound metabolic impairment leading to the imbalance of alpha-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1alpha stabilization. We conclude that the main hallmarks of oncocytic transformation, namely the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1alpha stabilization.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia Celular , Respiração Celular , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/metabolismo , Fumarato Hidratase/genética , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Ácidos Cetoglutáricos/metabolismo , Mutação/genética , NADH Desidrogenase/genética , Fenótipo , Biossíntese de Proteínas , Estabilidade Proteica , RNA de Transferência/genética , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/genética , Ácido Succínico/metabolismo
6.
Mol Med ; 18: 1147-51, 2012 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-22714714

RESUMO

Aquaporin-4 (AQP-4), the most important water channel in the brain, is expressed by astrocyte end feet abutting microvessels. Altered expression levels of AQP-4 and redistribution of the protein throughout the membranes of cells found in glioblastoma multiforme (GBM) lead to development of the edema often found surrounding the tumor mass. Dysregulation of AQP-4 also occurs in hippocampal sclerosis and cortical dysplasia in patients with refractory partial epilepsy. This work reports on analysis of the relationship between AQP-4 expression and the incidence of epileptic seizures in patients with GBM. Immunohistochemical and polymerase chain reaction techniques were used to evaluate AQP-4 in biopsy specimens from 19 patients with GBM, 10 of who had a history of seizures before surgery. AQP-4 mRNA levels were identical in the two groups of patients, but AQP-4 expression was more frequently detected on the GBM membranes from specimens of patients with seizures than from individuals without (10 versus 2, P < 0.001). We conclude that reduced expression of cell surface AQP-4 is characteristic of GBM patients without seizures, likely attributable to a posttranslational mechanism.


Assuntos
Aquaporina 4/genética , Aquaporina 4/metabolismo , Glioblastoma/complicações , Glioblastoma/genética , Convulsões/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/complicações , Edema Encefálico/genética , Edema Encefálico/patologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Demografia , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Convulsões/patologia
7.
Neuropathology ; 32(2): 133-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21978279

RESUMO

The Ras signaling pathway, consisting of mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling, is a prominent oncogenic pathways in adult diffuse gliomas, but few studies have evaluated such pathways in pediatric malignant gliomas. We investigated by immunohistochemistry MAPK and AKT signaling in a series of 28 pediatric high-grade gliomas (WHO grade III and IV). We sought a possible association of phospho-ERK (p-ERK) and phospho-AKT (p-AKT) with expression of other proteins involved in the Ras pathway, that is, YKL40, epidermal growth factor receptor (EGFR), EGFR vIII and c-Met. Moreover we correlated the expression of p-ERK and p-AKT with prognosis. No cases showed expression for c-Met and EGFR, and only one case was positive for EGFR vIII. YKL-40 protein was expressed in 43% of cases. We detected expression of p-ERK and p-AKT in 61% and 57%, respectively, of pediatric high grade gliomas. Statistical analysis comparing the two groups in term of high and low p-ERK and p-AKT expression showed a trend toward worse overall survival in patients with high expression of p-AKT. The activation of ERK and AKT suggest a possible role of this protein in inducing activation of the Ras signaling pathway in pediatric high-grade gliomas. Moreover high levels of p-AKT are associated with worse overall survival.


Assuntos
Adipocinas/biossíntese , Astrocitoma/diagnóstico , Astrocitoma/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , Lectinas/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese , Adipocinas/metabolismo , Adolescente , Astrocitoma/enzimologia , Criança , Pré-Escolar , Proteína 1 Semelhante à Quitinase-3 , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Seguimentos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Lectinas/metabolismo , Masculino , Fosforilação/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sobrevida
8.
Childs Nerv Syst ; 27(12): 2077-85, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21717155

RESUMO

OBJECTIVE: The purpose of this study is to detect different protein profiles in medulloblastoma (MDB) that may be clinically relevant and to check the correspondence of histological classification of MDB with proteomic profiles. MATERIALS AND METHODS: Surgical specimens, snap frozen at the time of neurosurgery, entered the proteomic study. Eight samples from patients (age range, 4 months-26 years) with different MDB histotypes (five classic, one desmoplastic/nodular, one with extensive nodularity, and one anaplastic) were analyzed by two-dimensional gel electrophoresis. One sample for each histotype was further characterized by matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. RESULTS: Eighty-six unique proteins were identified and compared to histology, with the determination of proteins expressed by single histotypes and of a smaller number of proteins shared by two or three histotypes. The sharp difference of protein expression was found to be in agreement with WHO histological classification, with the identification of type-specific proteins with limited overlapping between histotypes. CONCLUSION: Proteomic analysis confirmed and strengthened the difference between histotypes as biologically relevant. Cluster analysis enhanced the distance of extensive nodularity MDB from other histotypes. Possible innovative approaches to therapy may rely upon a proteomic-based classification of MDB tightly correlated to histology. The utility of snap freezing tumoral samples must be stressed and should become a mandatory task for pathologists.


Assuntos
Neoplasias Cerebelares/metabolismo , Eletroforese em Gel Bidimensional/métodos , Meduloblastoma/metabolismo , Proteínas/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adolescente , Adulto , Neoplasias Cerebelares/classificação , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/classificação , Peroxirredoxinas/análise , Peroxirredoxinas/metabolismo , Proteômica , Estatmina/análise , Estatmina/metabolismo , Adulto Jovem
9.
J Neurosurg Sci ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34763393

RESUMO

BACKGROUND: Medulloblastoma is a highly malignant, embryonal tumor, which is rare in adults, and shows distinct clinical, histopathological, molecular and treatment response features. METHODS: We retrospectively investigated 44 adults (age 17-48 years) with an histological diagnosis of medulloblastoma, and in 23 immunohistochemistry was used to identif y the molecular subgroups. We analyzed demographic, diagnostic, therapeutic and cognitive data, and correlated with PFS (progression-free-survival) and OS (overall survival). RESULTS: We observed a male prevalence and a median age of 31 years. Symptoms at onset were related to infratentorial location, while myeloradicular and/or cranial nerve involvement was rare. Histological examination showed the classic variant in 75% of patients, the desmoplastic/nodular in 23% and the anaplastic in one. As for molecular diagnosis, 17 patients were SHH and 6 non-WNT/non-SHH (5 group 4 and 1 group 3), while no WNT subgroup was found. The SHH subgroup had a prevalence of high-risk patients and leptomeningeal involvement. Patients underwent grosstotal or subtotal/partial resection, and craniospinal irradiation, followed in 20 cases by adjuvant chemotherapy. Median OS and PFS were 16.9 and 12 years, respectively. Metastatic disease at presentation and subtotal/partial resection were associated with worse prognosis, while the addition of chemotherapy did not yield a significant advantage over radiotherapy alone. Cognitive impairment in long-term survivors was limited and late relapses occurred in 15% of patients. CONCLUSIONS: Future studies with adequate sample size and long-term follow-up should prospectively investigate the role of surgery and adjuvant therapies across the different molecular subgroups to see whether a personalized approach is feasible.

10.
Neuro Oncol ; 23(5): 848-857, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33135735

RESUMO

BACKGROUND: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features. METHODS: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. RESULTS: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). CONCLUSIONS: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.


Assuntos
Neoplasias Encefálicas , Ependimoma , Hematologia , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Ependimoma/genética , Ependimoma/terapia , Feminino , Seguimentos , Humanos , Itália , Masculino , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos
11.
J Neurooncol ; 99(1): 141-6, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20066474

RESUMO

Ependymomas are glial tumours representing approximately 5-10% of all intracranial tumours and are the third most common primary brain tumour in childhood. Only a few karyotypic studies on paediatric ependymomas have been published and no specific chromosomal aberration has been specifically related to this type of cancer. We performed cytogenetic analysis of an ependymoma in an 11-year-old boy. Our patient showed a complex karyotype, characterized by a near-tetraploidy and a sole structural unbalanced aberration: der(2)t(2;11)(q11.2;q13.1), which has not been described before. We here discuss such cytogenetic findings, comparing our data with those reported in the literature.


Assuntos
Neoplasias Encefálicas/genética , Ependimoma/genética , Cariotipagem/métodos , Translocação Genética , Criança , Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Humanos , Masculino
12.
Cell Biochem Funct ; 28(5): 343-51, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20535838

RESUMO

Glioblastoma Multiforme (GBM) is an incurable malignancy. GBM patients have a short life expectancy despite aggressive therapeutic approaches based on surgical resection followed by adjuvant radiotherapy and concomitant chemotherapy. Glioblastoma growth is characterized by a high motility of tumour cells, their resistance to both chemo/radio-therapy, apoptosis inhibition leading to failure of conventional therapy. Cancer Stem Cells (CSCs), identified in GBM as well as in many other cancer types, express the membrane antigen prominin-1 (namely CD133). These cells and normal Neural Stem Cells (NSC) share surface markers and properties, i.e. are able to self-renew and differentiate into multiple cell types. Stem cell self-renewal depends on microenvironmental cues, including Extracellular Matrix (ECM) composition and cell types. Therefore, the role of microenvironment needs to be evaluated to clarify its importance in tumour initiation and progression through CSCs. The specific microenvironment of CSCs was found to mimic in part the vascular niche of normal stem cells. The targeting of GMB CSCs may represent a powerful treatment approach. Lastly, in GBM patients cancer-initiating cells contribute to the profound immune suppression that in turn correlated with CSCs STAT3 (CD133 + ). Further studies of microenvironment are needed to better understand the origin of GMB/GBM CSCs and its immunosuppressive properties.


Assuntos
Glioblastoma/terapia , Células-Tronco Neoplásicas/metabolismo , Antígeno AC133 , Antígenos CD/metabolismo , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/imunologia , Glicoproteínas/metabolismo , Humanos , Células-Tronco Neoplásicas/citologia , Peptídeos/metabolismo
13.
Pediatr Blood Cancer ; 52(7): 875-7, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19061219

RESUMO

We present the case of a 6-year-old male affected by an infratentorial tumor. Histological diagnosis was melanotic medulloblastoma. Immunohistochemistry showed in the melanin rich areas positive cells for HMB45. We performed a proteomic study to compare protein profiles in melanotic versus non-melanotic areas. Protein profiles of different areas of the tumor displayed similarity, with the exception of seven proteins. In accordance with the hypothesis that melanotic medulloblastomas produce oculo-cutaneous melanin, proteomic analysis showed melanocytic-associated antigens and epidermal autoantigen 450K in the pigmented nodule; both these proteins have a significant role as markers of melanotic elements.


Assuntos
Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Melaninas/metabolismo , Proteínas de Neoplasias/metabolismo , Proteômica , Neoplasias Cerebelares/patologia , Criança , Eletroforese em Gel de Poliacrilamida , Humanos , Técnicas Imunoenzimáticas , Masculino , Espectrometria de Massas , Meduloblastoma/patologia
14.
Childs Nerv Syst ; 25(12): 1627-31, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19554334

RESUMO

INTRODUCTION: We describe a case of genetically proven atypical teratoid/rhabdoid tumor (ATRT), showing ultrastructural evidence of ependymal differentiation. Such differentiation has not been reported so far in ATRT. CONCLUSION: This finding supports the concept that ATRTs as the majority of central nervous system embryonal tumors may derive from an immature and pluripotent neuroectodermal cell capable of differentiating along multiple lineages.


Assuntos
Neoplasias do Ventrículo Cerebral/ultraestrutura , Epêndima/ultraestrutura , Tumor Rabdoide/ultraestrutura , Teratoma/ultraestrutura , Neoplasias do Ventrículo Cerebral/genética , Neoplasias do Ventrículo Cerebral/cirurgia , Criança , Citogenética , Epêndima/cirurgia , Humanos , Masculino , Microscopia Eletrônica , Mutação , Tumor Rabdoide/genética , Tumor Rabdoide/cirurgia , Teratoma/genética , Teratoma/cirurgia
15.
J Pediatr Endocrinol Metab ; 32(10): 1193-1197, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31490776

RESUMO

Background Pheochromocytomas (PCCs) and paragangliomas (PGLs) are known to physicians as the "great mimickers" because of their variable presentation, especially in the pediatric population. Rarely, they co-secrete other hormones. Case presentation An 11-year-old boy presented with severe hypertension (HTN) with cardiac target organ damage. Signs of genital and cutaneous androgenization were observed, but the gonadal volume was prepubertal (2 mL). Urine normetanephrine and norepinephrine levels were elevated. Increased beta-human chorionic gonadotropin (ß-HCG) and pubertal testosterone values with suppressed values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) suggested an androgenization secondary to HCG hyperproduction. Imaging revealed a right adrenal mass, suggestive for PCC. Histopathology confirmed a PCC with positive staining for ß-HCG. Postoperative resolution of symptoms of ß-HCG and catecholamine excess and normalization of hormonal levels confirmed the diagnosis. Conclusions Ectopic hormone secretion from PCC is possible, even if rare. Signs and symptoms attributable to ectopic hormones should be investigated in PCC patients. To date, this is the first case of a ß-HCG-secreting PCC.


Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Catecolaminas/metabolismo , Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Hiperandrogenismo/patologia , Hipertensão/patologia , Feocromocitoma/complicações , Índice de Gravidade de Doença , Neoplasias das Glândulas Suprarrenais/metabolismo , Adrenalectomia , Criança , Humanos , Hiperandrogenismo/etiologia , Hiperandrogenismo/cirurgia , Hipertensão/etiologia , Hipertensão/cirurgia , Masculino , Feocromocitoma/metabolismo , Prognóstico
16.
European J Pediatr Surg Rep ; 7(1): e104-e109, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788410

RESUMO

Lipoblastomas are rare benign mesenchymal tumors that arise from embryonal fat cells. They are usually discovered in infants and children under 3 years of age, and mostly occur in the trunk (from 10 to 60%, depending on the study) and extremities (from 40 to 45%), while head and neck localizations are rare, with only five cases described to date. We report on three cases of lipoblastomas in infants younger than 4 years, with unusual localizations: one intra-abdominal, discovered during a laparotomy for an intussusception; one pelvic, misdiagnosed as an ovarian mass; and one gluteal with a pelvic extension. All children underwent magnetic resonance imaging as preoperative workup. All tumors were completely resected with free surgical margins and ultrasonographic follow-up was uneventful for all patients.

17.
J Neuropathol Exp Neurol ; 78(3): 248-256, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689922

RESUMO

Higher-grade meningiomas (WHO grade II and III) represent a diagnostic and prognostic challenge. We assessed the pathological and molecular characteristics of 94 higher-grade meningiomas (85 grade II, 9 grade III) to identify novel prognostic parameters. Higher mitotic count (p = 0.018), diffuse (≥50%) prominent nucleoli (p < 0.001), and sheeting (p < 0.001) were associated with recurrence. Lower SSTR2a-positive cells median rate (p = 0.048) and TERT promoter mutations (p = 0.014) were associated with recurrence and patient death, respectively; further analyses did not identify other outcome associations. Presence of Ki67 hot spots was associated with a shorter progression-free survival (PFS), independently of WHO grade at multivariate analysis (HR = 3.35, p = 0.008). Necrosis was related to a poorer overall survival (OS) at univariate (focal: HR = 4.55, p = 0.041 and diffuse: HR = 7.38, p = 0.020) and Kaplan-Meier analyses. A prognostic score was designed based on previous results: Presence of diffuse (≥50%) prominent nucleoli (0/1 point), diffuse (≥50%) sheeting (0/1 point), focal (<50%) or diffuse (≥50%) necrosis (0/1/2 points), and Ki67 hot spots (0/1 point). A total score ≥4 predicted poorer PFS and OS by Kaplan-Meier (PFS: 1.7 vs 6.4 years, p < 0.001 and OS: 5.2 vs 10.8 years, p = 0.001) and multivariate (PFS: HR = 5.98, p < 0.001 and OS: HR = 2.99, p = 0.048) analyses. These results were confirmed in an independent series of 58 grade II meningiomas (PFS: HR = 7.22, p = 0.002 and OS: HR = 9.69, p = 0.003). These associations and the integrated score could complement WHO grading.


Assuntos
Progressão da Doença , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
18.
Am J Surg Pathol ; 43(1): 56-63, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29266023

RESUMO

Ependymomas (EPs) are tumors of the brain and spinal cord constituting ∼10% of the childhood central nervous system neoplasms and about 30% in children aged <3 years. Their anatomic distribution varies according to the age, with those arising in the supratentorial (ST) compartment, spinal cord being more common in older children and adults, and those at the infratentorial location are more common and occurring more frequently in infants and children. Recently, molecular classification of EP subgroups has been proposed and a supratentorial ependymoma subgroup characterized by RELA-fusion genes (ST-EP-RELA) has been established. It would be useful to define a standardized, robust method for the diagnosis of these relevant fusion genes. We used real-time polymerase chain reaction, conventional real-time polymerase chain reaction, and Sanger sequencing to characterize RELA fusion status in formalin-fixed paraffin-embedded samples from 42 ST-EPs (12 adults and 30 pediatric). We tested p65/RELA and L1CAM protein immunohistochemistry for their ability to predict RELA-fusion status. We reviewed clinical data to assess significant associations in this anatomic subgroup. Of the 42 patients, we identified RELA-fusion genes in 17 cases. L1CAM immunostaining displayed 94% sensitivity, 76% specificity, 73% positive predictive value (PPV), 95% negative predictive value (NPV). The p65/RELA immunostaining displayed 100% sensitivity, 92% specificity, 89.5% PPV, 100% NPV. Concordant double immunostaining improves PPV to 92.5% and maintains 100% NPV. Immunohistochemistry using both p65/RELA and L1CAM antibodies is valuable for ST-EP-RELA diagnosis: the negativity with both antibodies consistently predicts the absence of RELA fusions, whereas verification of fusion transcripts by molecular analyses is warranted only in single-positive or double-positive staining cases.


Assuntos
Ependimoma/genética , Imuno-Histoquímica/métodos , Proteínas/genética , Neoplasias Supratentoriais/genética , Fator de Transcrição RelA/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ependimoma/diagnóstico , Ependimoma/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neuropatologia/métodos , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Neoplasias Supratentoriais/diagnóstico , Neoplasias Supratentoriais/patologia
19.
Clin Epigenetics ; 11(1): 100, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288858

RESUMO

BACKGROUND: Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, ß- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation. RESULTS: In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours. CONCLUSIONS: Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers.


Assuntos
Caderinas/genética , Metilação de DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Ilhas de CpG , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Família Multigênica , Regiões Promotoras Genéticas , Análise de Sequência de DNA
20.
J Pediatr Gastroenterol Nutr ; 47(5): 618-22, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18979585

RESUMO

OBJECTIVES: Celiac disease (CD)-related lesions have been reported in duodenal bulb biopsies, sometimes the bulb mucosa being the only one affected. The aim was to verify in a significant series whether histological lesions are always present in the bulb of celiac patients, what is the prevalence of lesions when isolated to the bulb, and if similar lesions are present in nonceliac subjects. METHODS: We studied 665 children with CD (241 males, range 9 months-15 years, 8 months), at diagnosis on a gluten-containing diet, and 348 age- and sex-matched gastroenterological controls submitted to upper endoscopy for gastroenterological complaints. During endoscopy, multiple biopsies (1 bulb and 4 distal duodenum samples) were taken. Anti-endomysium antibodies were evaluated by immunofluorescence method, anti-human tissue-transglutaminase antibodies by an enzyme-linked immunosorbent assay or radioimmunoassay. Human leukocyte antigen-DRB1, -DQA1, and -DQB1 genes were typed by polymerase chain reaction sequence-specific primers repeat method. RESULTS: In all of the patients with CD, histological lesions were present in the bulb sample; in 16 of them, the lesions were present only in the bulb. Patchy villous atrophy was found in 20 children. All of the patients with CD were anti-endomysium and/or antitransglutaminase positive. The controls showed neither autoantibody positivity nor mucosal changes compatible with CD. CONCLUSIONS: This study demonstrated that CD-related histological lesions are always present in the bulb; sometimes this specific site is the only one affected. Therefore, we suggest taking 2 biopsies from the bulb and 2 from the distal duodenum for CD diagnosis.


Assuntos
Doença Celíaca/diagnóstico , Doença Celíaca/patologia , Duodeno/patologia , Mucosa Intestinal/patologia , Adolescente , Biópsia , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Criança , Pré-Escolar , Dieta Livre de Glúten , Duodeno/citologia , Feminino , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Lactente , Mucosa Intestinal/citologia , Masculino , Reação em Cadeia da Polimerase , Valores de Referência , Sensibilidade e Especificidade
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