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1.
J Neurooncol ; 167(3): 447-454, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38443693

RESUMEN

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.


Asunto(s)
Neurofibromatosis 1 , Pruebas Neuropsicológicas , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/administración & dosificación , Masculino , Femenino , Adolescente , Niño , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/psicología , Adulto Joven , Preescolar , Glioma/tratamiento farmacológico , Glioma/psicología , Glioma/complicaciones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/psicología , Neoplasias Encefálicas/complicaciones , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/efectos adversos
2.
Childs Nerv Syst ; 39(8): 2095-2104, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37022464

RESUMEN

OBJECTIVE: To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS: Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS: There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS: This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Niño , Humanos , Masculino , Preescolar , Femenino , Estudios Retrospectivos , Proteínas Hedgehog , Meduloblastoma/tratamiento farmacológico , Neoplasias Cerebelosas/tratamiento farmacológico , Recurrencia
4.
Pediatr Blood Cancer ; 68(10): e29172, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34125480

RESUMEN

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.


Asunto(s)
Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Germinoma , Ganglios Basales/patología , Neoplasias Encefálicas/radioterapia , Germinoma/radioterapia , Humanos , Recurrencia Local de Neoplasia , Dosificación Radioterapéutica , Estudios Retrospectivos , Tálamo/diagnóstico por imagen
5.
Pediatr Dev Pathol ; 24(4): 309-317, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33749384

RESUMEN

INTRODUCTION: The World Health Organization currently classifies medulloblastoma (MB) into four molecular groups (WNT, SHH, Group 3 and Group 4) and four histologic subtypes (classic, desmoplastic nodular, MB with extensive nodularity, and large cell/anaplastic). "Classic" MB is the most frequent histology, but unfortunately it does not predict molecular group or patient outcome. While MB may exhibit additional histologic features outside of the traditional WHO subtypes, the clinical significance of such features, in a molecular context, is unclear. METHODS: The clinicopathologic features of 120 pediatric MB were reviewed in the context of NanoString molecular grouping. Each case was evaluated for five ancillary histologic features, including: nodularity without desmoplasia (i.e., "biphasic", B-MB), rhythmic palisades, and focal anaplasia. Molecular and histological features were statistically correlated to clinical outcome using Chi-square, log-rank, and multivariate Cox regression analysis. RESULTS: While B-MB (N = 32) and rhythmic palisades (N = 12) were enriched amongst non-WNT/SHH MB (especially Group 4), they were not statistically associated with outcome. In contrast, focal anaplasia (N = 12) was not associated with any molecular group, but did predict unfavorable outcome. CONCLUSION: These data nominate B-MB as a surrogate marker of Groups 3 and particularly 4 MB, which may earmark a clinically significant subset of cases.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Cerebelosas/patología , Proteínas Hedgehog/metabolismo , Meduloblastoma/patología , Proteínas Wnt/metabolismo , Canadá , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/mortalidad , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/metabolismo , Meduloblastoma/mortalidad , Pronóstico , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de Matrices Tisulares
6.
J Neurooncol ; 149(3): 523-532, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33034840

RESUMEN

PURPOSE: The purpose of this study is to describe the long-term toxicities of intracranial germ cell tumor (IGCT) in the adolescent and young adult (AYA) population. METHODS: We report late toxicities of a multi-center cohort of AYA patients treated for IGCT between 1975 and 2015. Charts were retrospectively reviewed for hormone deficiency, ototoxicity, seizure disorder, visual deterioration, cerebrovascular events, second neoplasm, psychiatric illness, and neurocognitive impairment. Statistical analysis was performed for late toxicities to evaluate the influence of select factors. RESULTS: Our patient cohort included 112 patients with IGCTs; 84% of patients had a germinoma as opposed to a non-germinomatous germ cell tumor (NGGCT), median age at radiotherapy (RT) was 19 years, and median follow-up was 8.3 years. Of the 94 patients with germinoma, 32 (34%) received both chemotherapy and RT as part of their upfront treatment, while 62 (66%) received RT alone. All 18 patients with NGGCT received chemotherapy and RT. The most common late toxicity following IGCT treatments was physician-reported neurocognitive impairment, with a 10-year cumulative incidence (CI) of 38.5%. Ten-year CI of treatment-induced ototoxicity was 39.2% for patients who received cisplatin, compared to 3.6% for those who received carboplatin but no cisplatin (p < 0.005). Suprasellar/hypothalamic tumor location was associated with 10-year CI of treatment-induced hormone deficiency (36.1 vs 6.2%, p < 0.005). CONCLUSIONS: A significant proportion of AYAs treated for IGCTs experience late effects from treatment, including neurocognitive impairment, ototoxicity, and hormone deficiency. Suprasellar/hypothalamic tumor location and cisplatin were associated with a higher risk of treatment-induced hormone deficiency and ototoxicity, respectively.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/terapia , Quimioradioterapia/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Germinoma/terapia , Neoplasias de Células Germinales y Embrionarias/terapia , Traumatismos por Radiación/etiología , Adolescente , Adulto , Neoplasias Encefálicas/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Estudios de Seguimiento , Germinoma/patología , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Traumatismos por Radiación/patología , Estudios Retrospectivos , Adulto Joven
7.
J Neurooncol ; 149(1): 45-54, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32632896

RESUMEN

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. PATIENTS AND METHODS: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). CONCLUSIONS: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.


Asunto(s)
Neoplasias del Tronco Encefálico/terapia , Quimioradioterapia/mortalidad , Glioma Pontino Intrínseco Difuso/terapia , Adolescente , Neoplasias del Tronco Encefálico/epidemiología , Neoplasias del Tronco Encefálico/patología , Canadá/epidemiología , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/epidemiología , Glioma Pontino Intrínseco Difuso/patología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo
8.
J Neurooncol ; 147(3): 721-730, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32297094

RESUMEN

PURPOSE: Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon of paradoxical growth of a germ cell tumor (GCT) during treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of iGTS in Western countries. METHODS: Pediatric patients from 22 North American and Australian institutions diagnosed with iGTS between 2000 and 2017 were retrospectively evaluated. RESULTS: From a total of 777 cases of central nervous system (CNS) GCT, 39 cases of iGTS were identified for an overall frequency of 5%. Pineal region was a more frequent location for iGTS as compared to cases of GCT without iGTS (p < 0.00001). In patients with an initial tissue diagnosis of GCT, immature teratoma was present in 50%. Serum AFP or ßhCG was detectable in 87% of patients (median values 66 ng/mL and 44 IU/L, respectively). iGTS occurred at a median of 2 months (range 0.5-32) from diagnosis, in the majority of patients. All patients underwent surgical resection, leading to gross total resection in 79%. Following surgery, all patients resumed adjuvant therapy or post treatment follow-up for GCT. At a median follow-up of 5.3 years (range 0.2-11.8), 37 (95%) of patients are alive, including 5 with stable residual mass. CONCLUSION: iGTS occurs in 5% of patients with GCT in Western countries. Tumors of the pineal region and GCT containing immature teratoma appear to be associated with a higher risk of developing iGTS. Complete surgical resection is the mainstay of treatment. Overall survival of patients developing iGTS remains favorable.


Asunto(s)
Neoplasias de Células Germinales y Embrionarias/epidemiología , Teratoma/epidemiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias de Células Germinales y Embrionarias/complicaciones , Pinealoma/complicaciones , Pinealoma/epidemiología , Estudios Retrospectivos , Teratoma/complicaciones , Resultado del Tratamiento , Adulto Joven
9.
Pediatr Dev Pathol ; 23(4): 326-331, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32282273

RESUMEN

Embryonal tumor with multilayered rosettes (ETMR) is a rare and highly aggressive embryonal central nervous system tumor that primarily affects young children. It is characterized by (1) amplification of the C19MC miRNA cluster at 19q13.42 and (2) immunohistochemical tumor cell positivity for LIN28A. We describe the case of a 3-year-old girl who presented with a 2-week history of multiple neurological deficits. Based primarily on imaging findings that revealed a large pontine tumor, biopsy was not performed and the patient was clinically diagnosed with a "diffuse intrinsic pontine glioma." She was subsequently treated with radiation and concurrent adjuvant temozolomide, but unfortunately there was minimal response and the patient died 6 months after diagnosis. Autopsy revealed an ETMR that was confirmed via C19MC fluorescence in situ hybridization and LIN28 immunohistochemistry. Although widespread central nervous system dissemination was observed, large portions of the main pontine mass exhibited evidence of extensive glial and neuronal maturation (ie, differentiation). We consider this tissue "maturation" to have been induced by chemotherapy and radiation. Herein, we discuss the importance of antemortem biopsy of intrinsic pontine tumors and the clinical significance of glial and neuronal maturation post therapy in the context of ETMR.


Asunto(s)
Neoplasias del Tronco Encefálico/patología , Tronco Encefálico/patología , Neoplasias de Células Germinales y Embrionarias/patología , Neuroglía/patología , Neuronas/patología , Autopsia , Tronco Encefálico/fisiología , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/terapia , Diferenciación Celular , Quimioradioterapia , Preescolar , Resultado Fatal , Femenino , Humanos , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/terapia , Neuroglía/fisiología , Neuronas/fisiología
10.
BMC Cancer ; 19(1): 1250, 2019 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-31881853

RESUMEN

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. METHODS: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. DISCUSSION: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.


Asunto(s)
Glioma/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neurofibroma Plexiforme/tratamiento farmacológico , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Adolescente , Antineoplásicos/uso terapéutico , Canadá , Niño , Preescolar , Glioma/metabolismo , Humanos , Lactante , Neurofibroma Plexiforme/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Adulto Joven
11.
J Neurooncol ; 143(2): 289-296, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30937607

RESUMEN

INTRODUCTION: The study objectives were to describe patterns of practice for intracranial germ cell tumors (IGCT) in adolescents and young adults (AYA) and to determine factors associated with practice patterns. METHODS: A survey was written containing questions on the management of two 17-year old males, one with localized pineal germinoma and the other with localized pineal non-germinomatous germ cell tumor (NGGCT). An invitation to participate anonymously in the survey was e-mailed to 119 oncologists who treat brain tumors across Canada. RESULTS: Seventy-two (61%) of the 119 oncologists participated in the study. For the germinoma case, the most common treatment approaches were whole ventricular radiotherapy (WVRT) and chemotherapy (CH) (56%), WVRT alone (15%), and craniospinal radiotherapy (CSRT) alone (10%); for physicians recommending WVRT + CH, most frequently selected whole ventricular doses were 24 Gy (57%) and 18 Gy (20%). Chemotherapy was included in the treatment of germinoma by 96% of pediatric physicians vs. 54% of adult physicians (P = 0.001). The most common treatment approaches for NGGCT were CSRT + CH (44%), WVRT + CH (21%), and pineal gland RT + CH (15%). The selection of craniospinal vs. smaller-volume RT was not associated with the physicians' specialty, percentage of practice treating brain tumors, number of IGCTs seen, or size of institution. CONCLUSIONS: There is wide variation in the management of IGCT in AYA across Canada. A 17-year old male with a localized pineal germinoma is highly likely to receive chemotherapy if managed by a pediatric oncologist, while the same patient is much less likely to receive chemotherapy if managed by an adult oncologist.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/terapia , Quimioradioterapia/métodos , Irradiación Craneana/métodos , Neoplasias de Células Germinales y Embrionarias/terapia , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Adulto , Neoplasias Encefálicas/patología , Canadá , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Pronóstico
12.
Acta Neuropathol ; 136(2): 227-237, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30019219

RESUMEN

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


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Ependimoma/clasificación , Ependimoma/genética , Neoplasias Infratentoriales/clasificación , Neoplasias Infratentoriales/genética , Adolescente , Adulto , Factores de Edad , Niño , Estudios de Cohortes , Metilación de ADN/genética , Ependimoma/patología , Ependimoma/cirugía , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Infratentoriales/patología , Neoplasias Infratentoriales/cirugía , Estimación de Kaplan-Meier , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Adulto Joven
13.
Psychooncology ; 27(1): 91-98, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28124799

RESUMEN

BACKGROUND: To determine if a group social skills intervention program improves social competence and quality of life (QOL) in pediatric brain tumor survivors (PBTS). METHODS: We conducted a randomized control trial in which PBTS (8-16 years old, off therapy for over 3 months) were allocated to receive social skills training (eg, cooperation, assertion, using social cognitive problem solving strategies, role playing, games, and arts and crafts) in 8 weekly 2-hour sessions, or an attention placebo control (games and arts and crafts only). Outcomes were self-reported, proxy-reported (caregiver), and teacher-reported using the Social Skills Rating System (SSRS), to measure social competence, and the Pediatric Quality of Life (PedsQL4.0, generic) to measure QOL at baseline, after intervention, and at 6 months follow-up. At baseline, SSRS were stratified into low and high scores and included as a covariate in the analysis. RESULTS: Compared to controls (n = 48), PBTS in the intervention group (n = 43) reported significantly better total and empathy SSRS scores, with improvements persisting at follow-up. The PBTS in the intervention group who had low scores at baseline reported the greatest improvements. Proxy and teacher reports showed no intervention effect. CONCLUSIONS: Participating in group social skills intervention can improve self-reported social competence that persisted to follow up. The PBTS should be given the opportunity to participate in social skills groups to improve social competence.


Asunto(s)
Terapia Conductista/métodos , Neoplasias Encefálicas/psicología , Cuidadores/psicología , Ajuste Social , Conducta Social , Habilidades Sociales , Sobrevivientes/psicología , Adolescente , Neoplasias Encefálicas/mortalidad , Niño , Práctica Clínica Basada en la Evidencia , Femenino , Humanos , Relaciones Interpersonales , Solución de Problemas , Calidad de Vida/psicología
14.
Pediatr Blood Cancer ; 65(6): e26988, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29369515

RESUMEN

OBJECTIVE: Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach. METHOD: We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT. RESULTS: Since January 2011, we identified 16 patients with progressive DIPG who received rRT. Median time from diagnosis to progression was 10.5 months (range, 4-37 months). rRT was given focally in 14 patients at a dose ranging from 21.6 to 36 Gy. rRT was well tolerated by all children but one. All but three patients showed neurological improvement. With a median follow-up from original diagnosis of 19.2 months, all patients died, with a median time from rRT to death of 6.48 months (range, 3.83-13.26 months). When compared to a historic cohort of 46 consecutive patients, the median time from progression to death was 92 days in the non-reirradiated patients versus 218 days in the reirradiated ones (P = 0.0001). CONCLUSION: In this limited experience, rRT was safe and feasible in patients with progressive DIPG, providing neurological improvement and a prolonged life span in most patients. Prospective Canadian rRT protocols are ongoing to further assess the benefit of this approach, including quality of life assessment.


Asunto(s)
Neoplasias del Tronco Encefálico/radioterapia , Glioma/radioterapia , Calidad de Vida , Reirradiación , Adolescente , Neoplasias del Tronco Encefálico/patología , Canadá , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glioma/patología , Humanos , Masculino , Pronóstico , Estudios Retrospectivos
15.
Acta Neuropathol ; 134(5): 705-714, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28733933

RESUMEN

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.


Asunto(s)
Ependimoma/metabolismo , Neoplasias Infratentoriales/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Niño , Preescolar , Supervivencia sin Enfermedad , Ependimoma/mortalidad , Ependimoma/patología , Femenino , Humanos , Lactante , Neoplasias Infratentoriales/mortalidad , Neoplasias Infratentoriales/patología , Masculino , Pronóstico , Sistema de Registros , Tasa de Supervivencia
16.
J Neurooncol ; 132(1): 155-162, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28102486

RESUMEN

While 2/3 of patients with ATRT are less than 3 years at diagnosis, the literature suggests younger children present with more aggressive disease and poorer outcome. However, little data exist on characteristics and outcome of patients diagnosed with ATRT in the first year of life. In particular, it is unclear whether they access similar treatments as do older children. We compared the cohort of patients ≤12 months from the Canadian ATRT registry to all cases extracted from the literature reported between 1996 and 2014 to describe their clinical and treatment characteristics, and potential prognostic factors. Twenty-six (33.7%) patients from the Canadian registry were ≤12 months at diagnosis as were 120 cases identified in the literature. Post-operatively, 46% of the registry's patients underwent palliation as opposed to 10.8% in the literature cohort. Palliative patients were significantly younger than those who received active therapy (3.3 vs. 6.6 months). While the use of high-dose chemotherapy (HDC) was relatively similar in both cohorts (42.9 and 35.5% respectively), radiotherapy (RT) use was significantly lower in the Canadian cohort (14.3 vs 44.9%). Children ≤6 months, who received active therapy, had a worst outcome than older ones. Gross total resection, HDC and adjuvant RT were associated with better outcomes. Eighty percent of the tested patients had evidence of germline mutation of INI1. While 1/3 of ATRT occurs within the first year of life, a large proportion only received palliative therapy. Even when actively treated, children ≤6 months fare worse. Some selected patients benefit from HDC.


Asunto(s)
Tumor Rabdoide/epidemiología , Teratoma/epidemiología , Canadá , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Cuidados Paliativos/estadística & datos numéricos , Radioterapia Adyuvante , Sistema de Registros , Tumor Rabdoide/radioterapia , Tumor Rabdoide/cirugía , Teratoma/radioterapia , Teratoma/cirugía , Resultado del Tratamiento
17.
Pediatr Blood Cancer ; 64(9)2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28296130

RESUMEN

INTRODUCTION: To describe the quality of life (QOL) of pediatric brain tumor survivors (PBTSs) prospectively and to identify potential medical, personal and family contextual factors associated with QOL. METHODS: Ninety-one PBTSs (8-16 years) who were off treatment and attending a regular classroom participated. Self- and caregiver-proxy-reported on QOL at baseline, 2 and 8 months. At baseline, cognitive, executive function, attention and memory, medical and demographics information were attained. RESULTS: Significant improvements over time in PBTS's emotional QOL were self- and proxy-reported (P < 0.01) and global QOL proxy-reported (P = 0.04). Receiving cranial irradiation therapy (CIT) and poor behavioral regulation predicted poor global QOL scores reported by both informants (P < 0.017). Poor behavioral regulation also predicted poor self-reported school functioning, and poor proxy-reported emotional and social QOL (P < 0.037). Boys reported better emotional QOL (P = 0.029), and PBTSs over 11 years old were reported to have better emotion and school-related QOL. Finally, being non-White and having low income predicted poor self-reported global and emotional QOL (P = 0.041). CONCLUSIONS: Receiving CIT, having poor behavioral regulation, being a female, under 11 years old and coming from low-income, non-White families place PBTSs at risk for poor QOL.


Asunto(s)
Neoplasias Encefálicas , Sobrevivientes/psicología , Adolescente , Neoplasias Encefálicas/psicología , Neoplasias Encefálicas/terapia , Niño , Irradiación Craneana/efectos adversos , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Calidad de Vida
18.
Support Care Cancer ; 25(9): 2891-2898, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28411324

RESUMEN

PURPOSE: This prospective study describes disease/treatment, personal characteristics, and social/family contextual variables as risk and resilience factors that predict social competence in pediatric brain tumor survivors (PBTS). METHODS: Ninety-one PBTS (51% male, mean age 11.21 years, off-treatment, attending a regular classroom >50% of the time) participated. PBTS and their primary caregivers (proxy) completed the Social Skills Rating System (SSRS) to assess social competence at baseline, 2, and 8 months follow-up. At baseline, medical information (e.g., tumor type and location, cranial irradiation therapy (CIT)), personal characteristics (e.g., child's age and gender, intelligence, executive function, attention, and memory), and social/family factors (family income and ethnicity) were obtained. RESULTS: Using mixed model multivariable analyses with a longitudinal component, tumor type (medulloblastoma) (p < 0.01) and poor executive function, specifically, emotional control, were the best predictors of low total and assertion self-reported SSRS scores (p < 0.02). Receiving CIT was associated with low proxy-reported assertion (p = 0.035), and cooperation score (p = 0.02). Poor emotional control was associated with low proxy-reported total (p = 0.032), assertion (p = 0.023), and self-control scores (p = 0.007). Being non-White was associated with low proxy-reported total (p = 0.016), self-control (p = 0.040), responsibility (p = 0.035), and cooperation scores (p = 0.002). There were no significant changes over time. CONCLUSIONS: This study supports a multifactorial model of insult and non-insult factors (medical, personal, and social context) as determinants of social competence in PBTS. Data from both informants identify determinants of social competence. These factors need to be considered in future interventions to help children better improve their social competence.


Asunto(s)
Neoplasias Encefálicas/psicología , Cuidadores/psicología , Sobrevivientes/psicología , Neoplasias Encefálicas/mortalidad , Niño , Femenino , Humanos , Masculino , Estudios Prospectivos , Conducta Social , Habilidades Sociales
19.
Neuropediatrics ; 47(4): 263-7, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27104484

RESUMEN

We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Discapacidades del Desarrollo/tratamiento farmacológico , Distrofias Retinianas/inducido químicamente , Succionato-Semialdehído Deshidrogenasa/deficiencia , Vigabatrin/efectos adversos , Niño , Electrorretinografía , Femenino , Humanos , Masculino , Distrofias Retinianas/tratamiento farmacológico , Distrofias Retinianas/fisiopatología , Taurina/uso terapéutico
20.
Childs Nerv Syst ; 32(2): 269-80, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26597682

RESUMEN

BACKGROUND: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. METHODS: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. RESULTS: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53% of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13% for unithalamic tumors compared to 37 ± 32% for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. CONCLUSION: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.


Asunto(s)
Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Ependimoma/terapia , Tálamo , Adolescente , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Canadá , Quimioterapia Adyuvante , Niño , Preescolar , Ependimoma/diagnóstico , Ependimoma/genética , Femenino , Glioma/genética , Glioma/terapia , Humanos , Lactante , Estimación de Kaplan-Meier , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Análisis Multivariante , Procedimientos Neuroquirúrgicos , Proteínas de Fusión Oncogénica/genética , Pronóstico , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Estudios Retrospectivos , Resultado del Tratamiento
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