Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 221
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Acta Neuropathol ; 139(2): 277-286, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31732806

RESUMO

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

2.
Clin Cancer Res ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744830

RESUMO

PURPOSE: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy. EXPERIMENTAL DESIGN: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti-PD-L1) therapy in a preclinical model of Cushing disease. RESULTS: Herein, treatment with anti-PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade-susceptible tumors. CONCLUSIONS: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.

3.
J Neuropathol Exp Neurol ; 78(9): 780-787, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361005

RESUMO

Infratentorial glioneuronal neoplasms are overall quite rare and are more commonly low-grade with surgical excision usually being curative. Multiple distinct histologic entities have been described including rosette-forming glioneuronal tumor, papillary glioneuronal tumor, neurocytoma, dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease), cerebellar liponeurocytoma, and ganglioglioma. While each of these entities has distinct findings, in some instances a tumor may demonstrate overlapping histologic features with mixed components. Herein, we report 2 unusual adult cases of a fourth ventricular glioneuronal tumor with features of ganglioglioma and neurocytoma, with one coming from a surgical resection and one found incidentally at autopsy. To the best of our knowledge, this specific histologic combination has not previously been described. As such, the clinical significance is unknown although in both cases the neoplasms were circumscribed and appeared to be low grade. The presence of the gangliogliomatous component was of particular interest since these are extremely rare occurrences in the fourth ventricle and we provide a comprehensive review of infratentorial gangliogliomas.

4.
Cancer Res ; 79(13): 3383-3394, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31040154

RESUMO

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP-null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133+ cells in MTAP-null GBM can be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.

5.
Am J Forensic Med Pathol ; 40(3): 275-278, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30958386

RESUMO

Primary central nervous system tumors are an extremely rare cause of sudden, unexpected death in children as most patients develop symptoms because of increased intracranial pressure and seek medical attention. Rarely, a forensic pathologist may encounter a primary intracranial neoplasm in a pediatric decedent that was not suspected before death. Herein, we present a case of a supratentorial neuroepithelial tumor found at autopsy in a 3-year-old African American boy without any reported significant medical history. The tumor had significant mass effect and caused cerebral edema, which ultimately resulted in transtentorial herniation and death. The gross, histopathological, immunohistochemical, and ultrastructural findings were most consistent with an anaplastic ependymoma.


Assuntos
Morte Súbita/etiologia , Ependimoma/patologia , Neoplasias Supratentoriais/patologia , Pré-Escolar , Humanos , Imuno-Histoquímica , Masculino , Microscopia , Microscopia Eletrônica de Transmissão
6.
Acta Neuropathol Commun ; 7(1): 42, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876455

RESUMO

Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAFV600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAFV600E status, is necessary for important prognostic and possible treatment implications.

7.
Nat Commun ; 10(1): 1023, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833574

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Astrocitoma/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Genoma Humano/genética , Glioma/metabolismo , Histonas/metabolismo , Receptores de Ativinas Tipo I/genética , Animais , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Histonas/genética , Humanos , Camundongos , Mutação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
8.
Neuro Oncol ; 21(4): 440-450, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30346624

RESUMO

BACKGROUND: Mutations in telomerase reverse transcriptase promoter (TERTp) and isocitrate dehydrogenase 1 and 2 (IDH) offer objective markers to assist in classifying diffuse gliomas into genetic subgroups. However, traditional mutation detection techniques lack sensitivity or have long turnaround times or high costs. We developed GliomaDx, an allele-specific, locked nucleic acid-based quantitative PCR assay to overcome these limitations and sensitively detect TERTp and IDH mutations. METHODS: We evaluated the performance of GliomaDx on cell line DNA and frozen tissue diffuse glioma samples with variable tumor percentage to mimic use in clinical settings and validated low percentage variants using sensitive techniques including droplet digital PCR (ddPCR) and next-generation sequencing. We also developed GliomaDx Nest, which incorporates a high-fidelity multiplex pre-amplification step prior to allele-specific PCR for low-input formalin-fixed paraffin embedded (FFPE) samples. RESULTS: GliomaDx detects the TERTp and IDH1 alterations at an analytical sensitivity of 0.1% mutant allele fraction, corresponding to 0.2% tumor cellularity. GliomaDx identified TERTp/IDH1 alterations in a cohort of frozen tissue samples with variable tumor percentage of all major diffuse glioma histologic types. GliomaDx Nest is able to detect these hotspot mutations with similar sensitivity from pre-amplified samples and was successfully tested on a cohort of clinical FFPE samples. Testing of a cohort of previously identified TERTpWT-IDHWT gliomas (by Sanger sequencing) revealed that 26.3% harbored low-percentage mutations. Analysis by ddPCR and whole exome sequencing of these tumors confirmed the low mutant fraction of these alterations and overall mutation-based tumor purity. CONCLUSIONS: Our results show that GliomaDx can rapidly detect TERTp/IDH mutations with high sensitivity, identifying cases that might be missed due to the lack of sensitivity of other techniques. This approach may facilitate more objective classification of diffuse glioma samples in clinical settings such as intraoperative diagnosis or in testing cases with low tumor purity.

9.
J Neuropathol Exp Neurol ; 78(1): 57-64, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500933

RESUMO

Glioma therapeutic resistance to alkylating chemotherapy is mediated via O6-methylguanine-DNA methyltransferase (MGMT). We hypothesized that a CD45/HAM56/MGMT double-stained cocktail would improve MGMT discrimination in tumor cells versus inflammatory and endothelial cells (IEC). Total MGMT protein was quantified by IHC on 982 glioblastomas (GBM) and 199 anaplastic astrocytomas. Correcting for IEC was done by a CD45/HAM56/MGMT 2-color cocktail. Lowest IEC infiltrates (IEC "cold spots") were identified to quantitate MGMT as well as the percentage of IEC% in the IEC cold spots. MGMT promoter methylation (PM) was also determined. Among the GBM biopsies, mean uncorrected and corrected MGMT% were 19.87 (range 0-90) and 16.67; mean IEC% was 18.65 (range 1-80). Four hundred and fifty one (45.9%) GBM biopsies were positive MGMT PM. Both uncorrected and corrected MGMT% positivity correlated with PM. All 3 MGMT scores correlated with overall survival (OS) in GBM's. Cold spot IEC% was also positively associated with OS. These effects remained in a multivariate model after adjusting for age and disease status. Prognosis determined by correcting MGMT% score for IEC% is not improved in this analysis. However, IEC COLD SPOT score does provide additional prognostic information that can be gained from this correction method.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Imuno-Histoquímica/métodos , Proteínas Supressoras de Tumor/análise , Adulto , Idoso , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor/genética
10.
Am J Clin Pathol ; 151(3): 241-254, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30551183

RESUMO

Objectives: The list of tumors involving the pituitary gland has been expanded to include a variety of neuronal and paraneuronal tumors in the 2017 World Health Organization tumor classification of endocrine organs. All the entities included in this category are distinctly rare, with limited case reports in the literature. Methods: We illustrate two extraordinary sellar tumors with neuronal differentiation: a sellar paraganglioma and a sellar neurocytoma, with thorough literature review and comparison of the clinicopathologic features of these entities. Results: Both entities are exceptionally rare and tend to be misdiagnosed as pituitary adenoma preoperatively. Both entities demonstrate frequent clinical recurrence compared with pituitary adenoma, as well as the rare occurrence of metastatic disease. Conclusions: In evaluating a sellar tumor with an uncommon morphology and neuroendocrine differentiation, an increased awareness of the unusual entities that may involve the sellar region and a judicious panel of immunohistochemical studies should improve the diagnosis.


Assuntos
Adenoma/patologia , Tumores Neuroendócrinos/patologia , Paraganglioma/patologia , Neoplasias Hipofisárias/patologia , Adenoma/classificação , Adenoma/diagnóstico por imagem , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/diagnóstico por imagem , Paraganglioma/classificação , Paraganglioma/diagnóstico por imagem , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/diagnóstico por imagem , Sela Túrcica/diagnóstico por imagem , Sela Túrcica/patologia , Organização Mundial da Saúde
11.
J Neuropathol Exp Neurol ; 78(2): 187-190, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561708

RESUMO

Rare pilocytic astrocytomas (PA) have been described to arise in the ventricles of children. They are even less common in this location for the adult population. We present the case of a 44-year old man presenting with vision and mental status changes. Brain imaging revealed an intraventricular mass within the right ventricular atrium, most consistent with a meningioma. Microscopic examination revealed a neoplasm composed of elongated to plump bipolar astrocytes arranged in a fascicular architecture, accompanied by foci containing numerous Rosenthal fibers. By immunohistochemistry, the tumor cells were positive for vimentin and glial fibrillary acid protein, whereas negative for epithelial membrane antigen. Isocitrate dehydrogenase 1 (R132H) was also negative. By fluorescence in situ hybridization, we detected a KIAA1549/BRAF fusion gene. These findings supported the diagnosis of intraventricular PA arising in an adult.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Neoplasias do Ventrículo Cerebral/genética , Neoplasias do Ventrículo Cerebral/patologia , Proteínas de Fusão Oncogênica/genética , Adulto , Humanos , Masculino
12.
Semin Oncol Nurs ; 34(5): 430-442, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30409555

RESUMO

OBJECTIVE: To explain several biomarkers used in primary adult brain tumor diagnosis and the methodologies for their application. DATA SOURCES: Peer-reviewed literature. CONCLUSION: In the past few years, several biomarkers have been touted as providing reliable and objective assays of histogenesis, prognosis, and therapeutic sensitivity. A number of these markers have failed the test of time and rigorous practice applications. More recently, assays with diagnostic applications have been reported and validated from multiple laboratories using large numbers of patients in routine clinical practices. IMPLICATIONS FOR NURSING PRACTICE: This article provides a reference for biomarker tests for gliomas. There is a greater need for nurses to understand the translational interface between basic science and clinical medicine to determine the applications of these biomarkers for the best interests of their patients.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Glioma/classificação , Glioma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
13.
Clin Neuropathol ; 37(5): 221-227, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30079884

RESUMO

INTRODUCTION: Edema is a significant cause of neuromorbidity in children and adults with brain tumors. Agents used to control this effect, such as corticosteroids, have their own associated morbidities. Sulfonylurea receptor 1 (SUR1) is a transmembrane protein that regulates the activity of ion channels in neurons, glia, and endothelial cells. SUR1 expression is upregulated in neuroinflammatory conditions. Inhibition of SUR1 with glyburide decreases edema and neuroinflammation by countering cytotoxic edema and apoptosis in rodent models of subarachnoid hemorrhage, stroke, trauma, and cerebral metastases. However, the expression of SUR1 in human brain tumors has not been elucidated. The purpose of this study was to determine SUR1 expression and cellular colocalization in a variety of human brain tumor specimens. MATERIALS AND METHODS: Six glioblastoma, 12 cerebral metastases, 11 medulloblastoma, 9 supratentorial ependymoma, and 8 posterior fossa ependymoma specimens were analyzed using immunofluorescence. SUR1 expression and colocalization with blood vessels, neurons, and glial cells was analyzed and compared using ANOVA. RESULTS: SUR1 expression was found in all specimens examined as a percentage of the total tissue area (mean ± SD): glioblastoma 3.9 ± 4, cerebral metastases 4.1 ± 3.1, medulloblastoma 8.2 ± 7.2, supratentorial ependymoma 9.1 ± 7, and posterior fossa ependymoma 8.1 ± 5.9. SUR1 expression was greater in supratentorial ependymoma compared to glioblastoma and metastases (p < 0.05) and greater in medulloblastoma compared to glioblastoma (p < 0.05). SUR1 colocalized most reliably with the neuronal marker, NeuN, in glioblastoma, metastases, and posterior fossa ependymoma samples (p < 0.05). SUR1 colocalized most reliably with the endothelial cell marker, CD31, in medulloblastoma samples (p < 0.05). CONCLUSION: SUR1 is a putative therapeutic target to reduce neuroinflammation in adult and pediatric brain tumors. Inhibition of SUR1 may result in neuronal stabilization in glioblastoma, cerebral metastases, and posterior fossa ependymoma and reduced edema in medulloblastoma.
.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Receptores Sulfonilureia/biossíntese , Receptores Sulfonilureia/genética , Adulto , Edema Encefálico/etiologia , Edema Encefálico/patologia , Neoplasias Encefálicas/complicações , Criança , Células Endoteliais/metabolismo , Humanos , Inflamação/patologia , Metástase Neoplásica , Neuroglia/metabolismo , Neurônios/metabolismo , Receptores Sulfonilureia/antagonistas & inibidores
14.
Brain Tumor Pathol ; 35(4): 202-208, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30159860

RESUMO

Ollier disease (OD) and Maffucci syndrome are rare conditions due to a post-zygotic somatic mutation that results in mosaicism. In addition to enchondromas and hemangiomas, some of these patients also develop other unrelated tumors, such as gliomas, that harbor IDH mutations, suggesting that an IDH mutation is a common genetic event in the tumorigenesis in this group of patients. We illustrate an interesting case of multifocal IDH-mutant astrocytomas in an OD patient with 8 years of follow-up. We first demonstrated identical IDH mutations in the brain tumor samples from various locations in this patient, but different 1p,19q results by fluorescent in-situ hybridization, different whole genome copy number profiles by OncoScan analysis, and a discrepant IDH2M131I mutation unique to one tumor, supporting a multifocal disease process in the setting of somatic IDH mosaicism.


Assuntos
Astrocitoma/etiologia , Neoplasias Encefálicas/etiologia , Encondromatose/complicações , Encondromatose/genética , Isocitrato Desidrogenase/genética , Mosaicismo , Adulto , Astrocitoma/diagnóstico por imagem , Astrocitoma/patologia , Astrocitoma/cirurgia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Encondromatose/diagnóstico por imagem , Encondromatose/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
15.
Acta Neuropathol ; 136(2): 227-237, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30019219

RESUMO

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.


Assuntos
Variações do Número de Cópias de DNA/genética , Ependimoma/classificação , Ependimoma/genética , Neoplasias Infratentoriais/classificação , Neoplasias Infratentoriais/genética , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Metilação de DNA/genética , Ependimoma/patologia , Ependimoma/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/cirurgia , Estimativa de Kaplan-Meier , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
16.
Neuropathology ; 38(5): 542-548, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30039530

RESUMO

Central neurocytoma is a rare neuronal tumor that typically occurs in young adults. Infrequently, these tumors exhibit advanced neuronal maturation and glial differentiation, giving rise to a histologically diverse tumor, in contrast to a typical central neurocytoma. We present a novel case of intraventricular central neurocytoma with prominent gangliogliomatous differentiation that developed atypical features upon recurrence after 10 years of follow up in a 10-year-old boy. Our case provides insight into the divergent differentiation capability of a neurocytic tumor and illustrates the diverse histological features of this rare entity.


Assuntos
Neoplasias do Ventrículo Cerebral/patologia , Ganglioglioma/patologia , Recidiva Local de Neoplasia/patologia , Neurocitoma/patologia , Diferenciação Celular , Criança , Seguimentos , Humanos , Masculino , Adulto Jovem
17.
J Clin Neurosci ; 56: 163-168, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30041899

RESUMO

Convection Enhanced Delivery (CED) infuses therapeutic agents directly into the intracranial area continuously under pressure. The convection improves the distribution of therapeutics such as those aimed at brain tumors. Although CED successfully delivers small therapeutic agents, this technique fails to effectively deliver cells largely due to cell sedimentation during delivery. To overcome this limitation, we have developed a low viscosity hydrogel (LVHydrogel), which is capable of retaining cells in suspension. In this study, we evaluated whether LVHydrogel can effectively act as a carrier for the CED of tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells were resuspended in saline or LVHydrogel carriers, loaded into syringes, and passed through the CED system for 5 h. CAR T cells submitted to CED were counted and the efficiency of delivery was determined. In addition to delivery, the ability of CAR T cells to migrate and induce cytotoxicity was evaluated. Our studies demonstrate that LVHydrogel is a superior carrier for CED in comparison to saline. The efficiency of cell delivery in saline carrier was only ∼3-5% of the total cells whereas delivery by the LVHydrogel carrier was much higher, reaching ∼45-75%. Migration and Cytotoxicity was similar in both carriers in non-infused samples but we found superior cytotoxicity in LVHydrogel group post-infusion. We demonstrate that LVHydrogel, a biodegradable biomaterial which does not cause acute toxicity on preclinical animal models, prevents cellular sedimentation during CED and presents itself as a superior carrier to the current carrier, saline, for the CED of CAR T cells.


Assuntos
Ácido Hialurônico/química , Hidrogéis/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/transplante , Animais , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Feminino , Humanos , Hidrogéis/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos Quiméricos/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Viscosidade
18.
J Neuropathol Exp Neurol ; 77(9): 846-852, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30053065

RESUMO

Diagnosis and classification of poorly differentiated tumors with primitive features of the central nervous system heavily relies on molecular and genetic findings of the tumors. Although RB1 gene mutation underlies the development of retinoblastoma and many other systemic cancers, RB1 gene mutation in a brain tumor is mainly limited to infiltrating gliomas. We describe what we believe to be a hitherto unreported case of sellar/suprasellar embryonal tumor with distinctive Flexner-Wintersteiner rosette formation, and somatic RB1 gene mutation in a 5-month-old infant. There were no molecular features associated with the embryonal tumor with multi-layered rosettes, and there were no histological or genetic features of a germ cell tumor. A follow up of 14 months duration showed good clinical response to VETOPEC regimen and no development of retinal disease. Our case shows an interesting association between RB1 mutation and Flexner-Wintersteiner rosettes in an embryonal tumor of the central nervous system and underscores the utility of large scale next generation sequencing in helping to identify the genetic aberrations that may help in clinical pathologic correlations of unusual or out-of-place histologic findings.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Retinoblastoma/patologia , Antígenos CD/metabolismo , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Proteínas de Neoplasias/metabolismo , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Proteínas do Tecido Nervoso/metabolismo , Retinoblastoma/diagnóstico por imagem
19.
J Neuropathol Exp Neurol ; 77(8): 696-702, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29878245

RESUMO

Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect, propagate, and inhibit cell proliferation. CD155 expression in pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, and anaplastic ependymoma specimens was assessed. The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation. PVR mRNA expression was evaluated in 763 medulloblastoma and 1231 normal brain samples. CD155 was expressed in all 12 patient specimens and in PXA and medulloblastoma cell lines. One-step growth curves at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5-10 hours. PVSRIPO infection significantly decreased cellular proliferation in 2363, 645, and D341 cell lines at 48 hours (p < 0.05) and resulted in cell death. PVR expression was highest in medulloblastoma subtypes Group 3γ, WNTα, and WNTß (p < 0.001). This proof-of-concept in vitro study demonstrates that PVSRIPO is capable of infecting, propagating, prohibiting cell proliferation, and killing PXA and Group 3 medulloblastoma.


Assuntos
Astrocitoma/metabolismo , Neoplasias Cerebelares/metabolismo , Regulação Neoplásica da Expressão Gênica , Meduloblastoma/metabolismo , Receptores Virais/biossíntese , Adolescente , Adulto , Astrocitoma/genética , Astrocitoma/patologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Receptores Virais/genética , Adulto Jovem
20.
N Engl J Med ; 379(2): 150-161, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29943666

RESUMO

BACKGROUND: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. RESULTS: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).


Assuntos
Glioblastoma/terapia , Imunoterapia , Recidiva Local de Neoplasia/terapia , Terapia Viral Oncolítica , Poliovirus , Rhinovirus , Adulto , Idoso , Quimera , Feminino , Glioblastoma/mortalidade , Humanos , Infusões Intralesionais , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA