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Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as â¼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.
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Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.
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Primary spinal cord high-grade gliomas, including those histologically identified as glioblastoma (GBM), are a rare entity in the pediatric population but should be considered in the differential diagnosis of intramedullary lesions. Pediatric spinal cord high-grade gliomas have an aggressive course with poor prognosis. The aim of this case report is to present a 15-year-old female adolescent with histopathologically confirmed spinal cord GBM with H3F3A K27 M mutation consistent with a diffuse midline glioma (DMG), H3 K27-altered, CNS WHO grade 4 with leptomeningeal seeding on initial presentation. As imaging features of H3 K27-altered DMGs are non-specific and may mimic more frequently encountered neoplastic diseases as well as demyelinating disorders, severe neurological deficits at presentation with short duration, rapid progression, and early leptomeningeal seeding should however raise the suspicion for a pediatric-type diffuse high-grade glioma like DMG, H3 K27-altered.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias de la Médula Espinal , Adolescente , Neoplasias Encefálicas/patología , Niño , Femenino , Glioma/patología , Histonas/genética , Humanos , Mutación , Neoplasias de la Médula Espinal/diagnóstico por imagenAsunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Ependimoma/tratamiento farmacológico , Ependimoma/genética , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias Encefálicas/patología , Niño , Ependimoma/patología , Perfilación de la Expresión Génica , Humanos , Masculino , Glicoproteínas de Membrana/genética , Recurrencia Local de Neoplasia , Pirazoles/orina , Pirimidinas/orina , Receptor trkB/genéticaRESUMEN
Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%-30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19-year-old proband with muscular dystrophy and negative clinical ES. Deep phenotypic analysis identified two critical data points: (1) the absence of emerin protein in muscle biopsy and (2) clinical features consistent with Emery-Dreifuss muscular dystrophy. Sequencing data analysis uncovered an ultra-rare, intronic variant in EMD, the gene encoding emerin. The variant, NM_000117.3: c.188-6A > G, is predicted to impact splicing by in silico tools. This case thus illustrates how better integration of clinicopathologic data into ES analysis can enhance diagnostic yield with implications for clinical practice.
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Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Adulto , Humanos , Masculino , Músculo Esquelético/metabolismo , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/metabolismo , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Craniopharyngiomas account for approximately 1.2-4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function. METHODS: The Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, nineteen patients (median age at enrollment, 13.1 y; range, 2-25 y) were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2). RESULTS: Eighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 wk). Therapy was well tolerated with no grade 4 or 5 toxicities. 2 of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than 3 months. None of the 11 stratum 2 patients had an objective radiographic response, although median progression-free survival was 19.5 months. CONCLUSIONS: Pegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression-free survival results are encouraging, warranting further studies.
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Neoplasias Encefálicas , Craneofaringioma , Interferón alfa-2/uso terapéutico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Adolescente , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Niño , Preescolar , Craneofaringioma/tratamiento farmacológico , Craneofaringioma/radioterapia , Femenino , Humanos , Lactante , Masculino , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/radioterapia , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG). METHODS: Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 µg/mL. VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy. RESULTS: From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1) months, and estimated one-year EFS was 24% (7%-45%). Four patients with glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months. CONCLUSION: Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Tronco Encefálico/terapia , Quimioradioterapia/mortalidad , Glioma Pontino Intrínseco Difuso/terapia , Adolescente , Adulto , Bevacizumab/administración & dosificación , Neoplasias del Tronco Encefálico/patología , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Tasa de Supervivencia , Ácido Valproico/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVE: To describe the findings of histopathology and genotyping studies in affected brain tissue from an individual with phacomatosis pigmentovascularis (PPV). METHODS: A retrospective chart review of a 2-year 10-month-old male with a clinical diagnosis of PPV cesiomarmorata (or type V) was performed. Clinical features, brain imaging and histopathology findings, and genotyping studies in his affected brain tissue are summarized. RESULTS: The proband had a clinically severe neurologic phenotype characterized by global developmental delay, generalized hypotonia, and recurrent episodes of cardiac asystole in the setting of status epilepticus. A somatic pathogenic variant in GNA11 (c.547C>T, p.Arg183Cys) was detected in his skin tissue but not in blood (previously published). He underwent an urgent left posterior quadrantectomy for his life-threatening seizures. Histopathology of resected brain tissue showed an increase in leptomeningeal melanocytes and abnormal vasculature, and the exact pathogenic variant in GNA11 (c.547C>T, p.Arg183Cys), previously isolated from his skin tissue but not blood, was detected in his resected brain tissue. CONCLUSIONS: The finding of this variant in affected skin and brain tissue of our patient with PPV supports a unifying genetic diagnosis of his neurocutaneous features.
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Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline POLE p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.
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Neoplasias Encefálicas/genética , Neoplasias Colorrectales/genética , ADN Polimerasa II/genética , Meduloblastoma/genética , Síndromes Neoplásicos Hereditarios/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Cerebelosas , Preescolar , Neoplasias Colorrectales/metabolismo , Reparación de la Incompatibilidad de ADN/genética , Análisis Mutacional de ADN , ADN Polimerasa II/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Células Germinativas/metabolismo , Mutación de Línea Germinal/genética , Humanos , Meduloblastoma/metabolismo , Mutación , Síndromes Neoplásicos Hereditarios/metabolismo , Fenotipo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismoRESUMEN
BACKGROUND: Pseudoprogression (PsP) is a recognized phenomenon after radiotherapy (RT) for high-grade glioma but is poorly characterized for low-grade glioma (LGG). We sought to characterize PsP for pediatric LGG patients treated with RT, with particular focus on the role of RT modality using photon-based intensity-modulated RT (IMRT) or proton beam therapy (PBT). METHODS: Serial MRI scans from 83 pediatric LGG patients managed at 2 institutions between 1998 and 2017 were evaluated. PsP was scored when a progressive lesion subsequently decreased or stabilized for at least a year without therapy. RESULTS: Thirty-two patients (39%) were treated with IMRT, and 51 (61%) were treated with PBT. Median RT dose for the cohort was 50.4 Gy(RBE) (range, 45-59.4 Gy[RBE]). PsP was identified in 31 patients (37%), including 8/32 IMRT patients (25%) and 23/51 PBT patients (45%). PBT patients were significantly more likely to have post-RT enlargement (hazard ratio [HR] 2.15, 95% CI: 1.06-4.38, P = 0.048). RT dose >50.4 Gy(RBE) similarly predicted higher rates of PsP (HR 2.61, 95% CI: 1.20-5.68, P = 0.016). Multivariable analysis confirmed the independent effects of RT modality (P = 0.03) and RT dose (P = 0.01) on PsP incidence. Local progression occurred in 10 patients: 7 IMRT patients (22%) and 3 PBT patients (6%), with a trend toward improved local control for PBT patients (HR 0.34, 95% CI: 0.10-1.18, P = 0.099). CONCLUSIONS: These data highlight substantial rates of PsP among pediatric LGG patients, particularly those treated with PBT. PsP should be considered when assessing response to RT in LGG patients within the first year after RT.
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Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Fotones/efectos adversos , Terapia de Protones/efectos adversos , Traumatismos por Radiación/patología , Adolescente , Neoplasias Encefálicas/patología , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glioma/patología , Humanos , Lactante , Masculino , Clasificación del Tumor , Traumatismos por Radiación/etiología , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. MATERIALS AND METHODS: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. RESULTS: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. CONCLUSION: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.â©.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/patología , Proteína Nuclear Ligada al Cromosoma X/genética , Adulto , Neoplasias Encefálicas/genética , Niño , ADN Helicasas/genética , Femenino , Humanos , Lactante , Masculino , Mutación/genética , Recurrencia Local de Neoplasia/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Atypical teratoid/rhabdoid tumor (ATRT) is a high-grade central nervous system tumor, with poor prognosis despite intensive multimodal therapy. Loss of nuclear immunostaining for INI1 due to inactivation of the hSNF5/INI1 tumor suppressor gene is pathognomonic of ATRT. We present a patient with congenital ATRT, who had spontaneous tumor regression without therapy, and is disease-free 4 years later. Tumor histopathology showed rhabdoid cells characteristic of ATRT, but immunohistochemistry revealed heterogeneous loss of nuclear INI1 staining. The populations of INI1-intact and INI1-deficient cells were separated by laser microdissection, for molecular analysis with DNA sequencing and fluorescence in situ hybridization. The INI1-negative cells were found to harbor a heterozygous deletion and truncating mutation of the hSNF5/INI1 locus, while the INI1-intact cells had 2 copies of the wild-type INI1 gene. To our knowledge, this is the first report of spontaneous regression of ATRT, with molecular heterogeneity for SMARCB1 inactivation, with no radiographic signs of recurrence at 4 years after diagnosis.
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Biomarcadores de Tumor/genética , Tumor Rabdoide/patología , Proteína SMARCB1/genética , Teratoma/patología , Femenino , Humanos , Recién Nacido , Remisión Espontánea , Tumor Rabdoide/congénito , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Teratoma/congénito , Teratoma/genética , Teratoma/metabolismoRESUMEN
BACKGROUND: Studies demonstrating an association between anesthesia and brain cell death (neuroapoptosis) in young animals were performed without accompanying surgery. This study tests the hypothesis that fetal surgery decreases anesthesia-induced neuroapoptosis. MATERIALS AND METHODS: Seventy-day-pregnant ewes received 2% isoflurane for 1 h (low dose [LD]) or 4% for 3 h (high dose [HD]) with or without fetal surgery (S). Unexposed fetuses served as controls (C). Fetal brains were processed for neuroapoptosis using anti-caspase-3 antibodies. Data were analyzed using ANOVA. RESULTS: Twenty-eight fetal sheep were evaluated. Dentate gyrus neuroapoptosis was lower in the HD+S group (13.1 ± 3.76 × 105/mm3) than in the HD (19.1 ± 1.40 × 105/mm3, p = 0.012) and C groups (18.3 ± 3.55 × 105/mm3, p = 0.035). In the pyramidal layer of the hippocampus, neuroapoptosis was lower in the HD+S group (8.11 ± 4.88 × 105/mm3) than in the HD (14.8 ± 2.82 × 105/mm3, p = 0.006) and C groups (14.1 ± 4.54 × 105/mm3, p = 0.019). The LD+S group showed a trend towards a significant decrease in neuroapoptosis in the pyramidal layer (LD+S 7.51 ± 1.48 vs. LD 13.5 ± 1.87 vs. C 14.1 ± 4.54 × 105/mm3, p = 0.07) but not in the dentate gyrus. Fetal surgery did not affect neuroapoptosis in the frontal cortex or endplate. CONCLUSIONS: Fetal surgery decreases isoflurane-induced neuroapoptosis in the dentate gyrus and the pyramidal layer of mid-gestational fetal sheep. Long-term effects of these observations on memory and learning deserve further exploration.
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Apoptosis , Encéfalo/patología , Fetoscopía , Isoflurano/efectos adversos , Ovinos , Animales , Caspasa 3/metabolismo , Femenino , Isoflurano/uso terapéutico , EmbarazoRESUMEN
Amish nemaline myopathy (ANM) is a severe congenital form of NM, known to be fatal in early childhood due to pulmonary insufficiency. Homozygous mutation in TNNT1 was originally ascertained in an Older Amish community in 2000. To date, only five reports with six pathogenic variants in TNNT1 have been described in both Amish and non-Amish families. Here, we describe a 16-month old female from a small Mennonite community from Mexico, presenting with congenital hypotonia and dilated cardiomyopathy, with a novel homozygous deletion of 19q13.42 of about 11â¯kb in size, encompassing TNNT1 and TNNI3. Cardiomyopathy has not been observed in association with ANM in previous reports. Conversely, homozygous mutation in TNNI3 have been described with dilated cardiomyopathy. Our report underscores the consideration of contiguous gene deletion in children with ANM who present with congenital hypotonia and cardiomyopathy. The report also expands the known spectrum of non-Amish related ANM mutations to include homozygous multi-exonic TNNT1 deletion.
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Cardiomiopatía Dilatada/genética , Eliminación de Gen , Miopatías Nemalínicas/genética , Troponina T/genética , Cardiomiopatía Dilatada/patología , Exones/genética , Femenino , Homocigoto , Humanos , Lactante , Músculo Esquelético/patología , Mutación , Miopatías Nemalínicas/patología , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.
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Purpose: Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivoExperimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and in vivo therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations in vivo and mechanism of action and resistance were also investigated.Results: AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133+ cells appears to have contributed to in vivo therapy resistance.Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133+ pGBM cells to prevent tumor recurrence. Clin Cancer Res; 24(9); 2159-70. ©2018 AACR.
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Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Azepinas/farmacología , Glioblastoma/metabolismo , Glioblastoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Biomarcadores , Biomarcadores de Tumor , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Glioblastoma/tratamiento farmacológico , Glioblastoma/mortalidad , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Clasificación del Tumor , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The treatment for childhood intracranial ependymoma includes maximal surgical resection followed by involved-field radiotherapy, commonly in the form of intensity-modulated radiation therapy (IMRT). Proton-beam radiation therapy (PRT) is used at some centers in an effort to decrease long-term toxicity. Although protons have the theoretical advantage of a minimal exit dose to the surrounding uninvolved brain tissue, it is unknown whether they have the same efficacy as photons in preventing local recurrence. METHODS: A retrospective review of medical records from September 2000 to April 2013 was performed. Seventy-nine children with newly diagnosed localized intracranial ependymomas treated with either IMRT (n = 38) or PRT (n = 41) were identified, and progression-free survival (PFS) was analyzed with Kaplan-Meier and Cox multivariate analyses. RESULTS: The median age at diagnosis was 3.7 years for all patients (range, 0.4-18.7 years). There were 54 patients with infratentorial tumors (68% of the total population). Patients treated with PRT were younger (median age, 2.5 vs 5.7 years; P = .001) and had a shorter median follow-up (2.6 vs 4.9 years; P < .0001). Gross total resection (GTR) was achieved in 67 patients (85%) and was more frequent in the PRT group versus the IMRT group (93% vs 76%; P = .043). The 3-year PFS rates were 60% and 82% with IMRT and PRT, respectively (P = .031). CONCLUSIONS: Children with localized ependymomas treated with PRT have a 3-year PFS rate comparable to that of children treated with IMRT. This analysis suggests that local control is not compromised by the use of PRT. The data also support GTR as the only prognostic factor for PFS. Cancer 2017;123:2570-78. © 2017 American Cancer Society.
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Neoplasias Encefálicas/radioterapia , Ependimoma/radioterapia , Procedimientos Neuroquirúrgicos , Terapia de Protones/métodos , Radioterapia de Intensidad Modulada/métodos , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Radioterapia Adyuvante , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p.N546K) and PIK3CA (p.H1047R) and a germline pathogenic variant in PTPN11 (p.N308S) diagnostic for Noonan syndrome. The molecular landscape of RGNT is not well-described, but these data are consistent with prior observations regarding the importance of the interconnected MAPK and PI3K/AKT/mTOR signaling pathways in this rare tumor. The co-occurrence of FGFR1, PIK3CA, and PTPN11 alterations provides further evidence for consideration of RGNT as a distinct molecular entity from pediatric low-grade gliomas and suggests potential therapeutic strategies for this patient in the event of tumor recurrence as novel agents targeting these pathways enter pediatric clinical trials. Although RGNT has not been definitively linked with cancer predisposition syndromes, two prior cases have been reported in patients with RASopathies (Noonan syndrome and neurofibromatosis type 1 [NF1]), providing an additional link between these tumors and the mitogen-activated protein kinase (MAPK) signaling pathway. In summary, this case provides an example of the potential for genome-scale sequencing technologies to provide insight into the biology of rare tumors and yield both tumor and germline results of potential relevance to patient care.