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1.
Neurosurgery ; 86(2): 288-297, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892635

RESUMO

BACKGROUND: Pediatric low-grade gliomas are among the most common childhood neoplasms, yet their post-treatment surveillance remains nonstandardized, relying on arbitrarily chosen imaging intervals. OBJECTIVE: To optimize postoperative magnetic resonance imaging (MRI) surveillance protocols for pediatric low-grade gliomas. METHODS: Patients aged 0 to 21 yr with pediatric low-grade gliomas, treated between 1990 and 2016 were retrospectively analyzed. The timing of surveillance imaging and radiologic tumor outcomes were extracted, and the effect of patient age, tumor location, histology, and extent of resection as prognostic factors was studied. An algorithm was developed to analyze the detection efficacy and cost of all possible surveillance protocols. RESULTS: A total of 517 patients were included with a median follow-up of 7.7 yr (range: 2-25.1 yr) who underwent 8061 MRI scans (mean 15.6 scans per patient). Tumor recurrence was detected radiologically in 292 patients (56.5%), of whom, 143 underwent reoperation. The hazards ratio (HR) of recurrence was higher in patients who underwent biopsy (HR = 3.60; 95% confidence interval (CI): 2.45-5.30; P < .001), subtotal resection (HR = 2.97; 95% CI: 2.18-4.03; P < .001), and near-total resection (HR = 2.03; 95% CI: 1.16-3.54; P = .01), compared to patients with gross total resection (GTR). For all patients, an 8-image surveillance protocol at 0, 3, 6, 12, 24, 36, 60, and 72 mo (total cost: $13 672 per patient) yielded comparative detection rates to the current 15-image protocol ($25 635). For patients who underwent GTR, a 6-image protocol at 0, 3, 9, 24, 36, and 60 mo ($10 254) is sufficient. CONCLUSION: Our data suggest that postoperative surveillance of pediatric low-grade gliomas can be effectively performed using less frequent imaging compared to current practice, thereby improving adherence to follow-up, and quality-of-life, while reducing costs.

2.
Childs Nerv Syst ; 36(2): 291-296, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31292757

RESUMO

PURPOSE: To demonstrate the paradigm shift in management strategies of pediatric craniopharyngioma at our institution over the past six decades. METHODS: Retrospective analysis of all pediatric patients with craniopharyngioma treated at Boston Children's Hospital between 1960 and 2017. RESULTS: One hundred seventy-eight patients with craniopharyngioma were treated between 1960 and 2017; 135 (70 males and 65 females) fulfilled the inclusion criteria. Forty-five patients were treated in the old era (1960-1984) and 90 patients were treated in the new era (1985-2017). Gross total resection (GTR) was achieved in 4% and 43% of patients in old and new eras respectively. Sub-total resection (STR) and radiotherapy (XRT) were performed in 27% and 28% of patients in old and new eras respectively. STR without XRT was performed in 20% and 29% of patients in old and new era respectively. Cyst drainage and adjuvant radiotherapy were performed in 49% of patients in the old era while no patients in the new era underwent such conservative management. Aggressive surgical resection was associated with a higher risk of worsening visual outcomes (20% vs 16%), panhypopituitarism and diabetes insipidus (86% vs 53%), psycho-social impairment (42% vs 26%), and new-onset obesity (33% vs 22%). The mortality rate was higher in the old era in comparison with that of the new one (9% vs 2%). CONCLUSION: There was a paradigm shift in management strategies of pediatric craniopharyngioma over the past six decades which in turn affected the long-term outcomes and quality of life of patients.

3.
Nat Commun ; 10(1): 3731, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427603

RESUMO

Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) programme that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Células-Tronco Neurais/citologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Neoplasias Encefálicas/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oligodendroglia/citologia , Proteínas de Fusão Oncogênica/metabolismo , Células Tumorais Cultivadas
4.
Nature ; 572(7767): 74-79, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341285

RESUMO

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.


Assuntos
Genômica , Meduloblastoma/genética , Meduloblastoma/patologia , Análise de Célula Única , Transcriptoma , Adolescente , Adulto , Animais , Linhagem da Célula , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Lactente , Meduloblastoma/classificação , Camundongos , Neurônios/metabolismo , Neurônios/patologia
5.
Nat Commun ; 10(1): 2621, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197168

RESUMO

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.


Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais/metabolismo , Microfluídica/instrumentação , Anticorpos/farmacologia , Astrócitos , Barreira Hematoencefálica/citologia , Avaliação Pré-Clínica de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos/métodos , Endotélio Vascular/citologia , Humanos , Dispositivos Lab-On-A-Chip , Microfluídica/métodos , Microvasos/citologia , Pericitos , Permeabilidade , Células-Tronco Pluripotentes , Cultura Primária de Células/instrumentação , Cultura Primária de Células/métodos
6.
Neurosurgery ; 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30989228

RESUMO

BACKGROUND: The incidental discovery of brain lesions in children has increased due to greater utilization of neuroimaging. Standardized surveillance and management guidelines following the discovery of such lesions remain nonexistent. OBJECTIVE: To study the natural history and management of incidental brain lesions in children. METHODS: A retrospective analysis of pediatric patients who were treated at our institution between 2000 and 2016 with incidentally detected brain lesions that were indeterminate for neoplasm on MRI. RESULTS: We identified 445 patients with incidental brain abnormalities of whom 144 had lesions indeterminate for neoplasm. Average age at diagnosis was 11.2 (SD = 4.14) yr and average follow-up was 3.8 yr (range 1-13.2 yr). Lesions showed no progression in 112 patients (77.8%), whereas progression was detected in 31 patients (21.5%). Mean time to progression was 32.3 months (SD = 24.4). A change in management was made in 13/144 patients (9%), which included surgical resection (n = 11), biopsy (n = 1), and lumbar puncture (n = 1). Lesion size, location, multiplicity, new-onset symptoms, associated contrast enhancement, or edema were not predictive of radiologic progression. Larger lesions and those with contrast enhancement or edema were significantly more likely to undergo surgery (P < .001 each). Median geometric diameter of lesions that did not undergo surgery was 6.5 mm, whereas that of surgically resected lesions was 12.5 mm (P < .001). CONCLUSION: Most incidental brain lesions indeterminate for neoplasm have an indolent, benign course. For asymptomatic patients with radiologically stable lesions, we recommend conservative management with MRI and clinical surveillance at 6, 12, 24, 36, and 60 mo after detection.

7.
Childs Nerv Syst ; 35(6): 1089, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31025100

RESUMO

The original version of this article unfortunately contained an error. The authors apologize to have miss looked a typo of author name "Joseph Diver". The correct name is "Joseph Driver".

8.
Neuro Oncol ; 21(4): 537-546, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30883662

RESUMO

BACKGROUND: Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. METHODS: This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. RESULTS: Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. CONCLUSIONS: GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00634231.

9.
Neurosurgery ; 85(3): 375-383, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085120

RESUMO

BACKGROUND: Intraoperative electrocorticography (ECoG) has been utilized in patients with tumor-associated seizures; however, its effectiveness for seizure control remains controversial. OBJECTIVE: To evaluate clinical outcomes in pediatric patients undergoing lesionectomy with or without ECoG. METHODS: Patients undergoing brain tumor resection at Boston Children's Hospital were examined retrospectively (2005-2014). Inclusion criteria involved diagnosis of a supratentorial tumor, ≥2 unequivocal seizures, and ≥6 mo follow-up. Patients with isolated cortical dysplasia or posterior fossa tumors were excluded. Logistic regression models evaluated predictors of ECoG use, and the impact of ECoG, gross total resection, and focal cortical dysplasia with tumors on seizure freedom by Engel Class and anti-epileptic drug use (AED). RESULTS: A total of 119 pediatric patients were included (n = 69 males, 58%; median age, 11.3 yr). Forty-one patients (34.5%) had ECoG-guided surgery. Preoperative seizure duration and number and duration of AED use were significant predictors for undergoing ECoG. There were no differences in seizure freedom (Engel Class I) or improved Engel Score (Class I-II vs III-IV) in patients who did or did not have ECoG at 30 d, 6 mo, and 1, 2, or 5 yr. Patients undergoing ECoG required a greater number of AEDs at 6 mo (P = .01), although this difference disappeared at subsequent time intervals. Gross total resection predicted seizure freedom at 30 d and 6 mo postsurgery (P = .045). CONCLUSION: This retrospective study, one of the largest evaluating the use of ECoG during tumor resection, suggests that ECoG does not provide improved seizure freedom compared to lesionectomy alone for children.

10.
Neurosurgery ; 85(2): 240-249, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917093

RESUMO

BACKGROUND: While a noninvasive flow determination would be desirable in the diagnosis of cerebrospinal fluid shunt malfunction, existing studies have not yet defined a role for thermal flow detection. OBJECTIVE: To evaluate a revised test protocol using a micropumper designed to transiently enhance flow during thermal testing to determine whether thermal detection of flow is associated with progression to shunt revision surgery. METHODS: Eighty-two unique tests were performed in 71 shunts. The primary outcome, need for revision within 7 d of testing, was compared with results of micropumper-augmented thermal flow detection. Statistical analysis was based on blind interpretation of test results and raw temperature data recorded during testing. RESULTS: The test was sensitive (73%) and specific (68%) in predicting need for revision, with 5.6-fold higher probability of revision when flow was not detected. Negative predictive value in our sample was 94.2%. The probability of not requiring revision increased with increasing total temperature drop. Analysis of various possible thresholds showed that the optimal temperature cutoff may be lower than suggested by the manufacturer (0.125°C vs 0.2°C). CONCLUSION: This is the first study to report a strong association between thermal flow evaluation and a clinical impression that a shunt is not malfunctioning. The current recommended threshold may increase the false positive rate unnecessarily, and as clinicians gain experience with the method, they may find value in examining the temperature curves themselves. Multicenter studies are suggested to further define a role for this diagnostic test.

11.
J Neurosurg Pediatr ; 22(6): 678-683, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30192215

RESUMO

OBJECTIVEDiffuse intrinsic pontine glioma (DIPG) is a highly aggressive and lethal brainstem tumor in children. In the 1980s, routine biopsy at presentation was abandoned since it was claimed "unnecessary" for diagnosis. In the last decade, however, several groups have reincorporated this procedure as standard of care or in the context of clinical trials. Expert neurosurgical teams report no mortality and acceptable morbidity, and no relevant complications have been previously described. The aim of this study was to review needle tract dissemination as a potential complication in DIPG.METHODSThe authors retrospectively analyzed the incidence of dissemination through surgical tracts in DIPG patients who underwent biopsy procedures at diagnosis in 3 dedicated centers. Clinical records and images as well as radiation dosimetry from diagnosis to relapse were reviewed.RESULTSFour patients (2 boys and 2 girls, age range 6-12 years) had surgical tract dissemination: in 3 cases in the needle tract and in 1 case in the Ommaya catheter tract. The median time from biopsy to identification of dissemination was 5 months (range 4-6 months). The median overall survival was 11 months (range 7-12 months). Disseminated lesions were in the marginal radiotherapy field (n = 2), out of the field (n = 1), and in the radiotherapy field (n = 1).CONCLUSIONSAlthough surgical tract dissemination in DIPG is a rare complication (associated with 2.4% of procedures in this study), it should be mentioned to patients and family when procedures involving a surgical tract are proposed. The inclusion of the needle tract in the radiotherapy field may have only limited benefit. Future studies are warranted to explore the benefit of larger radiotherapy fields in patients with DIPG.


Assuntos
Biópsia/efeitos adversos , Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Invasividade Neoplásica/patologia , Ponte/patologia , Criança , Feminino , Humanos , Masculino
12.
Childs Nerv Syst ; 34(11): 2333-2335, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29946809

RESUMO

The authors present the case of a previously healthy 12-year-old male with intractable seizures localized to a right frontal area of encephalomalacia and porencephalic cyst who underwent resection of the seizure focus. The surgical resection cavity extended into the right lateral ventricle, and due to encountered hemorrhage, Gelfoam was used for optimal hemostasis. The patient did well following the procedure, but presented 5 months later with headaches and emesis and was discovered to have obstructive hydrocephalus on imaging studies. Endoscopic third ventriculostomy (ETV) was performed, where Gelfoam was encountered in the third ventricle, obstructing the cerebral aqueduct. After the completion of the ETV, the patient did well and continues to be asymptomatic 1 year following the procedure.


Assuntos
Esponja de Gelatina Absorvível/efeitos adversos , Hidrocefalia/etiologia , Doença Iatrogênica , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/etiologia , Criança , Humanos , Masculino , Convulsões/cirurgia
13.
Neuro Oncol ; 20(11): 1547-1555, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-29741745

RESUMO

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%). Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Imagem por Ressonância Magnética/métodos , Adolescente , Biópsia , Neoplasias do Tronco Encefálico/cirurgia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Seguimentos , Glioma/cirurgia , Humanos , Masculino , Morbidade , Prognóstico , Estudos Prospectivos
14.
Science ; 360(6386): 331-335, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29674595

RESUMO

Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.


Assuntos
Neoplasias Encefálicas/patologia , Carcinogênese/genética , Glioma/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Oncogenes , Neoplasias Encefálicas/genética , Proliferação de Células , Glioma/genética , Histonas/metabolismo , Humanos , Proteína Quinase 7 Ativada por Mitógeno/genética , Mutação , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos
15.
Neurosurgery ; 82(5): 678-685, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973637

RESUMO

BACKGROUND: Head immobilization devices (HIDs) are a staple of neurosurgical procedures, including in the intraoperative magnetic resonance imaging (iMRI) operating rooms (ORs) where material modifications were necessary for compatibility with the magnets utilized. OBJECTIVE: To present the experience in this OR environment and discuss the multifactorial nature of the observed adverse events. METHODS: A retrospective chart review was performed, utilizing the Department of Neurosurgery and iMRI OR databases to identify patients who suffered complications related to HIDs between November 2007 and March 2016. A literature review was also done to identify the magnitude of the problem and the availability of safety guidelines. RESULTS: Nine hundred and forty patients underwent surgery in the iMRI OR requiring head immobilization. Seven (0.7%) suffered complications related to the HID-depressed skull fractures (n = 7) and epidural hematomas (n = 6). Age at surgery ranged from 1.6 to 10.3 yr. All patients had posterior fossa neoplasms and associated obstructive hydrocephalus. Four patients (57%) suffered permanent neurological deficits. Six patients (86%) underwent a surgical procedure to evacuate the epidural hematomas and repair the depressed skull fracture. In contrast, 1 out of 445 patient (0.2%) suffered HID-related adverse events in the conventional ORs, aged 10.2 yr. CONCLUSION: HIDs are important to provide stability and support during neurosurgical procedures. Modifications in the material or the shape of the pins can significantly change the pressure exerted. Most of these complications are preventable if certain precautionary measures are taken especially in certain high-risk patients, and the overall benefits of HIDs continue to outweigh the risks. There is a need for consensus on guidelines for the safe use of these devices.


Assuntos
Cabeça , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Restrição Física/efeitos adversos , Criança , Pré-Escolar , Cabeça/fisiologia , Cabeça/cirurgia , Hematoma Epidural Craniano/epidemiologia , Humanos , Lactente , Imagem por Ressonância Magnética , Estudos Retrospectivos
16.
Epilepsy Behav ; 75: 25-28, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28818811

RESUMO

While brain tumors are a frequent cause of seizures, they rarely cause epileptic spasms (ES). The objective of this study was to investigate features of tumor-associated ES. We conducted a retrospective review of patients with ES and a brain tumor. Demographics; pathologic, radiologic, and EEG data; treatment response; and long-term outcome were collected. Twenty four patients were identified; 11 met inclusion criteria. Epileptic spasm (ES) onset occurred prior to tumor diagnosis in seven patients (63%), and after tumor resection in 4 patients (36%). Spasms and ictal EEG often had focal features (45%). Gross total tumor resection resulted in ES freedom in 3/7 patients. There was poor response to first-line therapy (ACTH/vigabatrin; 1/5 with ES freedom). Low grade tumors predominated (8/11) with dual pathology (associated cortical malformation) in 2 patients. All tumors involved cortex; half involved subcortical regions and/or brainstem. Ten patients developed other seizure types; eight experienced refractory epilepsy, and nine had a Modified Rankin Scale of >3. In summary, EEG in tumor-associated ES often has focal features of either the semiology or EEG. Complete tumor resection yielded ES freedom in only a subset of patients. Most patients developed refractory epilepsy and adverse developmental outcomes.


Assuntos
Neoplasias Encefálicas/complicações , Epilepsia/etiologia , Espasmo/etiologia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Espasmo/patologia , Espasmo/fisiopatologia
17.
J Neurooncol ; 135(1): 201-211, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28733870

RESUMO

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Chicago's Ann & Robert H. Lurie Children's Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.


Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/terapia , Ependimoma/epidemiologia , Ependimoma/terapia , Adolescente , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Ependimoma/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Programa de SEER , Análise de Sobrevida , Resultado do Tratamento
18.
Neuro Oncol ; 19(6): 774-785, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28082416

RESUMO

Background: Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA. Methods: A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF. Results: We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures. Conclusion: MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.


Assuntos
Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Quinases raf/antagonistas & inibidores , Animais , Astrocitoma/metabolismo , Astrocitoma/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Compostos Heterocíclicos com 3 Anéis/química , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/genética , Quinases raf/metabolismo
19.
Neuro Oncol ; 19(7): 986-996, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28104717

RESUMO

Background: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Results: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.


Assuntos
Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA , Exoma , Genômica/métodos , Medicina de Precisão/métodos , Neoplasias Encefálicas/diagnóstico , Criança , Hibridização Genômica Comparativa , Dosagem de Genes , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
20.
J Neurosurg Pediatr ; 25(6): 663-666, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27589597

RESUMO

The authors report a complex case of an 18-year-old male with a history of hydrocephalus secondary to intraventricular hemorrhage of prematurity, with more than 30 previous shunt revisions, who presented to the authors' institution with shunt malfunction. After exhausting his peritoneal cavity and pleural space as possible distal sites of shunt placement, he underwent a direct heart shunt placement when it was discovered he had thrombosis of his subclavian vein precluding a standard wire-guided atrial cannulation. His course was complicated by postoperative distal catheter migration and repeat surgery for reimplantation of the shunt directly into the atrium. At the 16-month follow-up visit, the patient showed no symptoms of shunt malfunction or pericardial effusion. Imaging studies demonstrated a functioning shunt system. This is the second reported successful ventricle to direct heart shunt placement in an adult. The authors report on the technical aspects of the case and review the relevant literature.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Derivações do Líquido Cefalorraquidiano/métodos , Coração/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/cirurgia , Adolescente , Seguimentos , Humanos , Masculino
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