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1.
West Afr J Med ; 36(2): 172-175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31385604

RESUMO

BACKGROUND AND OBJECTIVES: Brainstem gliomas are relatively rare tumours of the central nervous system which have varying presentations and clinical course. This study aims to analyse the clinical profile and challenges of management of these tumours in a resource-limited country. METHIODS: We retrospectively analysed the data from the records of the patients managed for briainstem glioma between January 2010 and July 2017. RESULTS: There were 11 patients in the study (7 males and 4 females). The median age at diagnosis was 9 years. Eight of the patients were less than 15 years. The duration of symptoms ranged from 1 month to 2 years. All the patients had cranial nerve deficits at presentation, while 7 patients had cerebellar signs. Hydrocephalus was present in 4 patients. The lesion was pontine in 9 patients and tectal in 2. Three of the patients with hydrocephalus had ventriculoperitoneal shunt insertion while one patient refused surgery. Only one of the patients had radiotherapy. None of the patients received chemotherapy. A patient was dishcarged against medical advice. One patient is still alive after 4 years while another patient is alive after 2 years. The other 9 patients are dead with a mean survival period of 6 months. CONCCLUSION: Most of the tumours in this series were located in the pons and ran aggressive courses. Majority of our patients did not have access to radiotherapy while none had chemotherapy.


Assuntos
Neoplasias do Tronco Encefálico/mortalidade , Nervos Cranianos/fisiopatologia , Glioma/mortalidade , Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/terapia , Criança , Feminino , Glioma/diagnóstico , Glioma/terapia , Humanos , Hidrocefalia/etiologia , Masculino , Estudos Retrospectivos
2.
Nat Commun ; 10(1): 2235, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138805

RESUMO

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).


Assuntos
Adenoviridae , Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Simulação por Computador , Modelos Animais de Doenças , Glioma/patologia , Humanos , Técnicas In Vitro , Camundongos , Gradação de Tumores , Ensaios Antitumorais Modelo de Xenoenxerto
3.
BMJ Case Rep ; 12(4)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30996066

RESUMO

Brainstem gliomas are rare tumours in adults, accounting for only 1%-2% of all intracranial gliomas. They are recognised as a heterogeneous group, in which most are malignant tumours. Brainstem gliomas are classified into four major groups according to the growth pattern on imaging, namely diffuse, focal, exophytic and cervicomedullary. Such a classification system is also useful for surgical decision making. The exophytic variant is extremely rare having anecdoctal reports in the literature. We report the case of an adult patient affected by an exophytic glioblastoma of the pons, which was submitted to subtotal resection followed by radiation therapy and chemotherapy with a longer overall survival. To the best of our knowledge, this is the seventh adult patient reported of an exophytic brainstem glioblastoma.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Tronco Encefálico/patologia , Doenças dos Nervos Cranianos/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Neuroimagem , Ponte/patologia , Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia , Doenças dos Nervos Cranianos/etiologia , Doenças dos Nervos Cranianos/fisiopatologia , Evolução Fatal , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Hidrocefalia/fisiopatologia , Hemorragias Intracranianas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Ponte/diagnóstico por imagem , Fatores de Tempo
4.
J Neurooncol ; 143(1): 107-113, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830679

RESUMO

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. METHODS: The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). RESULTS: All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. CONCLUSIONS: Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia , Glioma/terapia , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Quimiorradioterapia/efeitos adversos , Criança , Pré-Escolar , Progressão da Doença , Feminino , Glioma/diagnóstico por imagem , Humanos , Masculino , Ponte , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
5.
J Neurooncol ; 143(1): 49-56, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852713

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a high fatality pediatric brain cancer without effective treatment. The field of electrotherapeutics offers new potential for other forms of glioma but the efficacy of this strategy has not been reported for DIPG. This pilot study evaluated the susceptibility of patient-derived DIPG cells to low intensity electric fields delivered using a developing technology called intratumoral modulation therapy (IMT). METHODS: DIPG cells from autopsy specimens were treated with a custom-designed, in vitro IMT system. Computer-generated electric field simulation was performed to quantify IMT amplitude and distribution using continuous, low intensity, intermediate frequency stimulation parameters. Treatment groups included sham, IMT, temozolomide (TMZ) chemotherapy and radiation therapy (RT). The impact of single and multi-modality therapy was compared using spectrophotometric and flow cytometry viability analyses. RESULTS: DIPG cells exhibited robust, consistent susceptibility to IMT fields that significantly reduced cell viability compared to untreated control levels. The ratio of viable:non-viable DIPG cells transformed from ~ 6:1 in sham-treated to ~ 1.5:1 in IMT-treated conditions. The impact of IMT was similar to that of dual modality TMZ-RT therapy and the addition of IMT to this treatment combination dramatically reduced DIPG cell viability to ~ 20% of control values. CONCLUSIONS: This proof-of-concept study provides a novel demonstration of marked DIPG cell susceptibility to low intensity electric fields delivered using IMT. The potent impact as a monotherapy and when integrated into multi-modality treatment platforms justifies further investigations into the potential of IMT as a critically needed biomedical innovation for DIPG.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Terapia por Estimulação Elétrica , Glioma/terapia , Antineoplásicos Alquilantes/farmacologia , Neoplasias do Tronco Encefálico/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Criança , Pré-Escolar , Terapia Combinada , Campos Eletromagnéticos , Glioma/patologia , Humanos , Projetos Piloto , Ponte , Cultura Primária de Células , Estudo de Prova de Conceito , Radioterapia , Temozolomida/farmacologia
6.
Pediatr Blood Cancer ; 66(3): e27561, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30484948

RESUMO

BACKGROUND: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9-11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. PROCEDURE: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. RESULTS: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. CONCLUSION: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia , Dieta Cetogênica/métodos , Glioma/terapia , Recidiva Local de Neoplasia/dietoterapia , Radioterapia , Adolescente , Neoplasias do Tronco Encefálico/complicações , Neoplasias do Tronco Encefálico/patologia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Estudos de Viabilidade , Seguimentos , Glioma/complicações , Glioma/patologia , Humanos , Incidência , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Países Baixos/epidemiologia , Prognóstico , Estudos Prospectivos , Segurança , Taxa de Sobrevida
7.
J Neurooncol ; 141(2): 253-263, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30446898

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. METHODS: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. RESULTS: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). CONCLUSION: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.


Assuntos
Neoplasias do Tronco Encefálico/fisiopatologia , Neoplasias do Tronco Encefálico/terapia , Glioma/fisiopatologia , Glioma/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Neoplasias do Tronco Encefálico/genética , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Glioma/genética , Histonas/genética , Humanos , Camundongos , Mutação , Estudos Retrospectivos
8.
J Neurosurg Pediatr ; 23(3): 333-342, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544335

RESUMO

OBJECTIVE In this clinical trial report, the authors analyze safety and infusion distribution of IL13-Pseudomonas exotoxin, an antitumor chimeric molecule, administered via intratumoral convection enhanced delivery (CED) in pediatric patients with diffuse intrinsic pontine glioma (DIPG). METHODS This was a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via single-catheter CED into 5 pediatric DIPG patients. IL13-PE38QQR was administered to regions of tumor selected by radiographic findings. Two escalating dose levels were evaluated: 0.125 µg/mL in cohort 1 and 0.25 µg/mL in cohort 2. Real-time MRI was performed during intratumoral infusions, and MRI and MR spectroscopy were performed before and after the infusions. Clinical evaluations, including parent-reported quality of life (QOL), were assessed at baseline and 4 weeks post-infusion. RESULTS Direct infusion of brainstem tumor with IL13-PE using the CED technique in patients with DIPG produced temporary arrest of disease progression in 2 of 5 patients, both of whom subsequently received a second infusion. All 5 patients showed signs of disease progression by 12 weeks after initial infusion. Two patients experienced transient cranial nerve deficits and lethargy after infusion, and these deficits resolved with corticosteroid treatment in both cases. No patient had radiographic evidence of acute or long-term treatment toxicity. Parent-reported QOL was consistent with medical outcomes. CONCLUSIONS Even though IL13-PE delivered by CED did not reach the entire MRI-defined tumor volume in any patient, short-term radiographic antitumor effects were observed in 2 of the 5 patients treated. The patients' performance status did not improve. Drug delivery using multiple catheters may produce improved outcomes. Clinical trial registration no.: NCT00088061 (clinicaltrials.gov) ABBREVIATIONS CED = convection-enhanced delivery; DIPG = diffuse intrinsic pontine glioma; IL-13 = interleukin 13; IL13R = IL-13 receptor; IPI = Impact of Pediatric Illness; KPS = Karnofsky Performance Status; LPS = Lansky Performance Status; MRS = MR spectroscopy; NAA = n-acetyl aspartate; QOL = quality of life; Vd = volume of distribution; Vi = volume of infusion.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Exotoxinas/administração & dosagem , Exotoxinas/efeitos adversos , Glioma/terapia , Interleucina-13/administração & dosagem , Interleucina-13/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Criança , Progressão da Doença , Glioma/diagnóstico por imagem , Humanos , Infusões Intralesionais/métodos , Imagem por Ressonância Magnética Intervencionista/métodos , Espectroscopia de Ressonância Magnética , Pseudomonas , Qualidade de Vida , Retratamento , Fatores de Tempo
9.
Anticancer Res ; 38(8): 4897-4900, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061266

RESUMO

This case report presents the first known case of a brainstem glioblastoma multiforme (GBM) in a patient with neurofibromatosis type 1 (NF1). While research has proposed that larger germ-line mutations in NF1 may be the driving factor that predisposes patients with NF1 to high-grade astrocytomas, this patient had a nonsense mutation in the NF1 gene, suggesting a variant tumorigenesis. Limited data on targeted immunotherapy for NF1 patients with a GBM have been reported and more data are required before targeted therapies could be proven as second-line treatment options.


Assuntos
Astrocitoma/genética , Neoplasias do Tronco Encefálico/genética , Glioblastoma/genética , Neurofibromina 1/genética , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/patologia , Astrocitoma/terapia , Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia/métodos , Códon sem Sentido/genética , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , Temozolomida , Adulto Jovem
10.
World Neurosurg ; 119: e1006-e1015, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30138731

RESUMO

BACKGROUND: Pediatric high-grade brainstem gliomas are aggressive tumors with dismal prognoses. Large-scale studies are needed to further characterize these tumors and determine factors influencing cancer-specific mortality and survival at varying time points. METHODS: We used the SEER (Surveillance Epidemiology and End Results) database to conduct a population-based study of pediatric patients with histologically confirmed anaplastic astrocytoma or glioblastoma tumors located within the brainstem. Multivariate analyses incorporating patient demographics, tumor characteristics, and treatments were used to determine predictors of cancer-specific mortality and survival at 6 months, 9 months, 1 year, and 2 years. RESULTS: We included 154 patients from the SEER database: 72 patients with anaplastic astrocytoma (47%) and 82 (53%) with glioblastoma. Median survival for the entire cohort was 10.0 months. Glioblastoma histology, developmental stage, and large tumor size were significantly associated with cancer-specific mortality. Six-month, 9-month, 1-year, and 2-year survival was 75%, 57%, 42%, and 20%, respectively. Glioblastoma histology was associated with worsened survival at 6 months (odds ratio [OR], 0.19; P = 0.0081), 9 months (OR, 0.18; P < 0.001), 1 year (OR, 0.19; P < 0.001), and 2 years (OR, 0.14; P = 0.0055). Radiation therapy was associated with improved survival at 6 (OR, 8.53; P = 0.0012) and 9 months (OR, 3.58; P = 0.035) but not at 1 or 2 years. Radiation therapy was associated with improved survival in glioblastoma (9.0 vs. 3.0 months; P < 0.001). CONCLUSIONS: This population-based study showed that glioblastoma histology is associated with a poor prognosis in pediatric patients with high-grade brainstem gliomas. Regardless of histology, radiation therapy improved survival at 6 and 9 months but not long-term.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/mortalidade , Glioma/diagnóstico , Glioma/mortalidade , Adolescente , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Glioma/patologia , Glioma/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Programa de SEER
11.
Neurosurg Focus ; 44(6): E15, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29852760

RESUMO

OBJECTIVE Tectal gliomas constitute a rare and inhomogeneous group of lesions with an uncertain clinical course. Because these supposedly benign tumors are frequently followed up by observation over many years, the authors undertook this analysis of their own case series in an effort to demonstrate that the clinical course is highly variable and that there is a potential for a progressive biology. METHODS Clinical data analysis of 23 cases of tectal glioma (involving 9 children and 14 adults) was performed retrospectively. Radiographic data were analyzed longitudinally and MR images were evaluated for tumor volume, contrast enhancement, and growth progression. Quality of life was assessed using the EORTC BN20 and C30 questionnaires during follow-up in a subgroup of patients. RESULTS The patients' mean age at diagnosis was 29.2 years. The main presenting symptom at diagnosis was hydrocephalus (80%). Six patients were treated by primary tumor resection (26.1%), 3 patients underwent biopsy followed by resection (13.1%), and 3 patients underwent biopsy only (13.1%). For additional treatment of hydrocephalus, 14 patients (60.9%) received shunts and/or endoscopic third ventriculostomy. Radiographic tumor progression was observed in 47.9% of the 23 cases. The mean time between diagnosis and growth progression was 51.5 months, and the mean time to contrast enhancement was 69.7 months. Histopathological analysis was obtained in 12 cases (52.2%), resulting in 5 cases of high-grade glioma (3 cases of glioblastoma multiforme [GBM], grade IV, and 2 of anaplastic astrocytoma, grade III), 5 cases of pilocytic astrocytoma, 1 diffuse astrocytoma, and 1 ganglioglioma. Malignant progression was observed in 2 cases, with 1 case progressing from a diffuse astrocytoma (grade II) to a GBM (grade IV) within a period of 13 years. Quality-of-life measurements demonstrated distinct functional deficits compared to a healthy sample as well as glioma control cohorts. CONCLUSIONS Analysis of this case series shows that a major subpopulation of tectal gliomas show progression and malignant transformation in children as well as in adolescents. These tumors therefore cannot be considered inert lesions and require histological confirmation and close follow-up. Quality-of-life questionnaires show that tectal glioma patients might benefit from special psychological support in emotional, social, and cognitive functionality.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/terapia , Gerenciamento Clínico , Progressão da Doença , Qualidade de Vida , Teto do Mesencéfalo/diagnóstico por imagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
14.
J Clin Oncol ; 36(19): 1963-1972, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29746225

RESUMO

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Sobreviventes de Câncer/estatística & dados numéricos , Glioma/diagnóstico , Adolescente , Adulto , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/terapia , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Sistema de Registros , Adulto Jovem
15.
Mol Cancer Ther ; 17(7): 1504-1514, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29654065

RESUMO

Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2-M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504-14. ©2018 AACR.


Assuntos
Neoplasias Encefálicas/terapia , Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Telomerase/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Meduloblastoma/terapia , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Prognóstico , Telomerase/uso terapêutico , Telômero/efeitos dos fármacos , Telômero/genética , Tionucleosídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Neurooncol ; 138(1): 147-153, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29397521

RESUMO

The end-of-life management of children with diffuse intrinsic pontine glioma (DIPG) is challenging. Families cope with debilitating symptoms and make complex decisions regarding their child's care. However, there is little evidence guiding palliative care provision for these children. Our objective was to describe the dying trajectory of children with DIPG, their symptoms, the care they require and the end-of-life decisions made for them. This retrospective cohort study analyzed the end-of-life care of 41 consecutive patients with DIPG who died between January 2001 and June 2010. All patients died of disease progression, experiencing a significant symptom burden prior to death. Despite this, the majority of patient days at the end of life were spent at home. However, 60% of patients were hospitalized at least once in their final 3 months, often close to the time of death. A wide range of healthcare professionals were involved, providing a range of medicinal/non-medicinal interventions. Chemotherapy was given to 30% of patients in their final month. Thirty of 33 families approached (91%) agreed to a "Do not resuscitate" order. A small subset of families opted for intensive treatment towards the end of life including cardiopulmonary resuscitation, intensive care admission and mechanical ventilation. Children with DIPG have complex needs and require intensive multidisciplinary support. This paper describes the end-of-life choices made for these children and discusses how these choices influence our institutional model for palliative care. We believe this approach will be useful to clinicians caring for similar patients.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Assistência Terminal/métodos , Adolescente , Criança , Pré-Escolar , Tomada de Decisão Clínica , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Cuidados Paliativos , Análise de Sobrevida
17.
Childs Nerv Syst ; 34(3): 431-439, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29299687

RESUMO

PURPOSE: Incidence of BS primitive neuroectodermal tumors (BS-PNET) in children is not reported to date. Our main objectives were to estimate the incidence and report the outcome of BS-PNET in children. METHODS: Data were collected using the Surveillance Epidemiology and End Results cancer registry. RESULTS: From 1973 to 2013, we identified 83 pediatric patients (aged 0-21 years). Patients were divided into two age groups (0-3 years and 4-21 years). Median overall survival was 53 months. Patients in the older age group had a significant survival advantage (P < 0.001), as did those who received three modalities of therapy (surgery, chemotherapy, and radiation therapy) (P < 0.001) and patients with gross or subtotal tumor resection (P < 0.001). CONCLUSIONS: This study presents the first estimate of incidence and the largest cohort of pediatric BS-PNETs to date. A high index of suspicion of BS-PNET in similar cases is crucial for diagnosis, treatment, and outcome.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/epidemiologia , Análise de Dados , Tumores Neuroectodérmicos Primitivos/diagnóstico por imagem , Tumores Neuroectodérmicos Primitivos/epidemiologia , Programa de SEER/tendências , Adolescente , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Tumores Neuroectodérmicos Primitivos/terapia , Adulto Jovem
18.
Neurosurgery ; 83(5): 1050-1056, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29088386

RESUMO

BACKGROUND: There are no effective treatments for diffuse intrinsic pontine gliomas (DIPGs); these tumors cannot be surgical resected, and diagnosis is based on magnetic resonance imaging. As a result, tumor tissues for molecular studies and pathologic diagnosis are infrequent. New clinical trials are investigating novel medications and therapeutic techniques in an effort to improve treatment of patients with DIPGs. OBJECTIVE: To determine the safety, tolerability, and toxicity of an oncolytic adenovirus, DNX-2401, injected into the cerebellar peduncle in pediatric subjects with DIPG and to collect tumor samples of this type of tumor. METHODS: Phase I, single-center, uncontrolled trial. A tumor biopsy will be performed through the cerebellar peduncle, and DNX-2401 will be injected immediately after the biopsy. Standard therapy consisting of radiotherapy and chemotherapy will follow in 2 to 6 wk. EXPECTED OUTCOMES: Improvement of overall survival and quality of life in patients with DIPG and collection of tumor specimens to study the molecular profiling of these tumors. DISCUSSION: The aims of this trial are to contribute to the sample collection of DIPG and to offer treatment during the tumor tissue biopsy using the virus. If this virus works as expected, it could kill the tumor cells with no damage to healthy tissue, functioning as a targeted therapy. It is important to note that edema has not been observed with this virus in all trials performed to date. The information obtained through this and other similar studies may be useful for developing or improving new therapies in the battle against DIPG.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Terapia Viral Oncolítica/métodos , Projetos de Pesquisa , Criança , Humanos , Imagem por Ressonância Magnética , Masculino , Terapia Viral Oncolítica/efeitos adversos
19.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29090526

RESUMO

BACKGROUND: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). PATIENTS AND METHODS: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. RESULTS: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. CONCLUSION: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Capecitabina/administração & dosagem , Quimiorradioterapia , Glioma/terapia , Administração Oral , Adolescente , Neoplasias do Tronco Encefálico/diagnóstico , Criança , Pré-Escolar , Feminino , Seguimentos , Glioma/diagnóstico , Humanos , Masculino , Estudos Prospectivos , Comprimidos
20.
Childs Nerv Syst ; 34(3): 449-455, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29151166

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. METHODS: Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SDTumor) normalized to the genu of the corpus callosum (SDCorpus Callosum). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. RESULTS: MR images from 18 patients with DIPG were evaluated. The mean survival ± standard deviation was 13.8 ± 13.7 months. T2-weighted images had the highest HI (mean ± SD, 5.1 ± 2.5) followed by contrast-enhanced T1-weighted images (3.7 ± 1.5), FLAIR images (3.0 ± 1.1), and ADC maps (1.6 ± 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p < 0.01) and ADC (p < 0.0001). Following radiotherapy, T2-weighted and contrast-enhanced T1-weighted image HI values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). CONCLUSIONS: For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with increased cellularity and thus may represent a putative target for CED catheter placement in future clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/normas , Adolescente , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Feminino , Glioma/mortalidade , Glioma/terapia , Humanos , Aumento da Imagem/métodos , Aumento da Imagem/normas , Imagem por Ressonância Magnética/mortalidade , Masculino , Taxa de Sobrevida/tendências
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