RESUMO
Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Glioma/genética , Mutação/genética , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Epigênese Genética/genética , Receptores ErbB/genética , Feminino , Glioma/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Inibidores de Proteínas Quinases/farmacologiaRESUMO
This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Sequenciamento do Exoma/métodos , Análise de Sequência de RNA/métodos , Sequenciamento Completo do Genoma/métodos , Adolescente , Adulto , Neoplasias do Tronco Encefálico/genética , Criança , Pré-Escolar , DNA Tumoral Circulante , Glioma Pontino Intrínseco Difuso/genética , Estudos de Viabilidade , Feminino , Histonas/genética , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Projetos Piloto , Medicina de Precisão , Adulto JovemRESUMO
Pediatric embryonal brain tumor patients treated with craniospinal irradiation (CSI) are at risk for adverse effects, with greater severity in younger patients. Here we compare outcomes of CSI vs. high-dose chemotherapy (HD), stem cell transplant (SCT) and delayed CSI in newly diagnosed patients. Two hundred one consecutive patients treated for medulloblastoma (72 %), supratentorial primitive neuroectodermal tumor (sPNET; 18 %) or pineoblastoma (10 %) at two institutions between 1988 and 2014 were retrospectively identified. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank tests. Adjuvant CSI regimens were used for 56 % of patients (upfront-CSI), and HD/SCT regimens were used in 32 % of patients. HD/SCT patients were significantly younger than those receiving upfront-CSI (2.9 vs. 7.8 years; P < 0.0001). There were no differences in metastases, extent of resection, or CSI dose between upfront-CSI and HD/SCT patients, but median follow-up was shorter in the HD/SCT group (6.2 vs. 3.9 years; P = 0.007). There were no significant outcome differences between upfront-CSI and HD/SCT patients who received CSI as a prophylaxis or following relapse (OS 66 % vs. 61 %, P = 0.13; PFS 67 % vs. 62 %, P = 0.12). Outcomes were equivalent when restricting analyses to HD/SCT patients who received prophylactic CSI prior to relapse (OS 66 % vs. 65 %, P = 0.5; PFS 67 % vs. 74 %, P = 0.8). At last follow-up, 48 % of HD/SCT patients had received neither definitive nor salvage radiotherapy. In this retrospective cohort, outcomes with adjuvant HD/SCT followed by delayed CSI are comparable to upfront-CSI for carefully surveyed pediatric embryonal brain tumor patients. Future prospective studies are required to validate this finding, and also to assess the impact of delayed CSI on neurocognitive outcomes.
Assuntos
Neoplasias Encefálicas/terapia , Radiação Cranioespinal , Transplante de Células-Tronco , Adolescente , Adulto , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Predisposição Genética para Doença/genética , Glioma/patologia , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa/genética , Glioma/genética , Humanos , Masculino , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose, describe dose-limiting toxicities (DLT) and characterize the pharmacokinetic profile of PTC299 in children with recurrent CNS tumors. PTC299 was administered orally twice or three times daily, depending on the regimen. Four regimens were evaluated using the rolling 6 design, starting with 1.2 mg/kg/dose twice daily and escalating to 2 mg/kg/dose three times daily. Pharmacokinetic studies were performed during the first two courses. Twenty-seven children (14 male, median age 11.2, range 5.5-21 years) with recurrent brain tumors were treated; 21 were fully evaluable for toxicity assessment. Therapy was well-tolerated, and the only DLT was grade 3 hyponatremia. Grade three and grade four toxicities were uncommon in subsequent cycles. Median AUC0-Tlast values at the 2 mg/kg were similar to those observed in adults. The study was terminated while patients were being treated at the highest planned dose, due to hepatotoxicity encountered in the ongoing adult phase I studies. No complete or partial responses were observed. Two patients with low-grade gliomas were noted to have minor responses, and at the time of the study's closure, 5 children with low-grade gliomas had been on therapy for 8 or more courses (range 8-16). PTC299 was well-tolerated at the highest dose level tested (2 mg/kg/dose TID) in children with recurrent brain tumors and prolonged disease stabilization was seen in children with low-grade gliomas.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Imidazóis/administração & dosagem , Tiazóis/administração & dosagem , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Hiponatremia/induzido quimicamente , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors. METHODS: Children and adolescents <22 years were enrolled into one of two strata: stratum Ithose not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum IIthose receiving EIACDs. Dose-level selection was based on the continual reassessment method (CRM). RESULTS: Thirty-six eligible patients with median age of 12.7 years (range, 5.4-21.7 years) in stratum I (24 males) and 12 patients (7 males) in stratum II with median age of 13.4 years (range, 8.9-19.5 years) were initially assessed over a 4-week DLT evaluation period, modified to 6 weeks during the study. An MTD of 32 mg/m(2)/day was declared; however, excessive toxicities (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) in the expansion cohort treated at this dose suggested that it might not be tolerated over a longer time period. An expansion cohort at 20 mg/m(2)/day also demonstrated poor longer-term tolerability. Diffusion and perfusion MRI and PET imaging variables as well as biomarker analysis were performed and correlated with outcome. At 20 mg/m(2)/day, the median plasma area under the concentration-time curve at steady state was lower than that observed in adults at similar dosages. CONCLUSIONS: While the MTD of once daily oral cediranib in children with recurrent or progressive CNS tumors was initially defined as 32 mg/m(2)/day, this dose and 20 mg/m(2)/day were not considered tolerable over a protracted time period.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Administração Oral , Adolescente , Disponibilidade Biológica , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Estatística como Assunto , Fatores de Tempo , Adulto JovemAssuntos
Glioma/genética , Histonas/genética , Mutação/genética , Neoplasias da Medula Espinal/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Medula Espinal/patologia , Neoplasias da Medula Espinal/patologia , Adulto JovemRESUMO
To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of the central nervous system (CNS). We reviewed a historical cohort of 79 patients between the ages of 3-35 years who received definitive treatment for newly diagnosed, pure CNS germinoma between 1985 and 2010 at the University of California, San Francisco (UCSF). Median age at diagnosis was 15 years (interquartile range, IQR 12-20 years) and 61 (77.2 %) patients were male. Median follow-up for the cohort was 111.1 months (IQR 45.7-185.1 months). Five-year PFS rate was 86.4 % (95 % CI 76.1-92.4) and 5 year OS rate was 93.0 % (95 % CI 84.1-97.1). Median PFS was 104.6 months (IQR 41.4-170.1 months). Fourteen patients progressed and 8 died of their disease. Patients who received focal irradiation (XRT) and chemotherapy had a significantly higher rate of progression compared to those who received whole brain irradiation (WBI) or whole ventricle irradiation (WVI). Three of 8 patients had a PR to chemotherapy and received focal XRT progressed whereas only 1 of 9 patients who had a CR to chemotherapy who went on to receive focal XRT progressed. Elevation of hCGß > 50 mIU/ml was not significantly associated with disease progression (HR 5.64, 95 % CI 0.97-32.7, p = 0.054). Patients treated with WBI or WVI with or without chemotherapy achieve better disease control compared to patients treated with focal XRT + chemotherapy.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Germinoma/tratamento farmacológico , Germinoma/radioterapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Recidiva , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. This report describes the adverse events in a recently completed large phase 2 trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system tumors. METHODS: Pediatric Brain Tumor Consortium trial-022 evaluated the efficacy and toxicity of BVZ (10 mg/kg administered intravenously) as a single agent for 2 doses given 2 weeks apart and then combined with CPT-11 every 2 weeks (1 course = 4 weeks) in children with recurrent central nervous system tumors. Children were treated until they experienced progressive disease, unacceptable toxicity or completed up to a maximum of 2 years of therapy. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients who received at least 1 dose of BVZ were included for toxicity assessment. RESULTS: Between October 2006 and June 2010, 92 patients evaluable for toxicity were enrolled and received 687 treatment courses. The most common toxicities attributable to BVZ included grade I-III hypertension (38% of patients), grade I-III fatigue (30%), grade I-II epistaxis (24%), and grade I-IV proteinuria (22%). Twenty-two patients (24%) stopped therapy due to toxicity. CONCLUSIONS: The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting, and manageable.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Adolescente , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab , Camptotecina/administração & dosagem , Criança , Pré-Escolar , Esquema de Medicação , Fadiga/induzido quimicamente , Hemorragia/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Lactente , Injeções Intravenosas , Irinotecano , Recidiva Local de Neoplasia , Proteinúria/induzido quimicamente , Adulto JovemRESUMO
PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are rapidly progressive and aggressive tumors that usually arise in children. Their anatomic location makes gross total surgical resection impossible, and fewer than 10% of patients survive more than 2 years after diagnosis. Often, these lesions are treated based on imaging characteristics alone. However, despite aggressive chemotherapy and radiation treatments available, prognosis remains poor. There is therefore a need for new therapies directed by biologic profiling. This necessitates a tissue diagnosis and, therefore, surgical biopsy. We have reviewed the results of biopsy for DIPGs in children at a single institution and compared our results to those available in the literature to elucidate the utility of biopsy for DIPGs. METHODS: A historical cohort study was performed using medical records of patients under the age of 18 who underwent surgical biopsy of a DIPG at a single institution. RESULTS: Nine patients were included, four males and five females. Age at presentation ranged from 8 months to 10 years (average 5.7 years). Pathologic diagnoses included five high grade (WHO grade III or IV) gliomas and four low grade (WHO grade II) astrocytomas. There were no intraoperative complications, and only one patient developed a new postoperative neurologic deficit. CONCLUSIONS: Stereotactic biopsy of DIPGs is essential to obtain a pathologic diagnosis and is associated with low morbidity. This technique is important to elucidate biological characteristics of these tumors in order to direct multidisciplinary treatment plans possibly involving chemotherapy, radiation therapy, or other future clinical trial interventions for children with DIPGs.
Assuntos
Neoplasias do Tronco Encefálico/cirurgia , Glioma/cirurgia , Biópsia , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Glioma/diagnóstico , Glioma/epidemiologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Morbidade , Estudos RetrospectivosRESUMO
BACKGROUND: The objective of this study was to determine the safety, tolerability, and distribution of MTX110 (aqueous panobinostat) delivered by convection-enhanced delivery (CED) in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT). METHODS: Patients with DIPG (2-21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across 7 dose levels (DL) (30-90 µM; volumes ranging from 3 mL to 2 consecutive doses of 6 mL). An accelerated dose escalation design was used. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4-8 weeks. Quality-of-life (QoL) assessments were obtained at baseline, every 3 months on therapy, and end of therapy. RESULTS: Between May 2018 and March 2020, 7 patients who received a total of 48 CED infusions, were enrolled (median age 8 years, range 5-21). Three patients experienced dose-limited toxicities. Four grade 3 treatment-related adverse events were observed. Most toxicities were transient new or worsening neurologic function. Median overall survival (OS) was 26.1 months (95% confidence interval: 14.8-not reached). Progression-free survival was 4-14 months (median, 7). Cumulative percentage of tumor coverage for combined CED infusions per patient ranged from 35.6% to 81.0%. Increased CED infusions were negatively associated with self-reported QoL assessments. CONCLUSION: Repeat CED of MTX110 with real-time imaging with gadoteridol is tolerable for patients with DIPG. Median OS of 26.1 months compares favorably with historical data for children with DIPG. The results support further investigation of this strategy in a larger cohort.
Assuntos
Antineoplásicos , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Humanos , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Panobinostat/uso terapêutico , Antineoplásicos/uso terapêutico , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Neoplasias do Tronco Encefálico/patologia , Qualidade de Vida , Convecção , Glioma/patologia , Inibidores de Histona Desacetilases/uso terapêuticoRESUMO
The prognosis for diffuse infiltrating pontine gliomas (DIPG) remains extremely poor, with the majority of patients surviving less than 2 years. Here, we have adapted standard xenograft techniques to study glioma growth in the mouse brainstem, and have utilized the mouse model for studying a relevant therapeutic for treating DIPGs. bioluminescence imaging monitoring revealed a progressive increase in signal following the injection of either of two tumor cell types into the brainstem. Mice with orthotopic GS2 tumors, and receiving a single 100 mg/kg dose of temozolomide showed a lengthy period of decreased tumor luminescence, with substantially increased survival relative to untreated mice (P < 0.001). A small molecule inhibitor that targets cdk4/6 was used to test AM-38 brainstem xenograft response to treatment. Drug treatment resulted in delayed tumor growth, and significantly extended survival. Our results demonstrate the feasibility of using an orthotopic brainstem tumor model in athymic mice, and for application to testing therapeutic agents in treating DIPG.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Ponte/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias do Tronco Encefálico/patologia , Caspase 3/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Substâncias Luminescentes , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias/métodos , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Proteína do Retinoblastoma/metabolismo , Temozolomida , Fatores de Tempo , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Diffuse intrinsic pontine gliomas arise almost exclusively in children, and despite advances in treatment, the majority of patients die within 2 years after initial diagnosis. Because of their infiltrative nature and anatomic location in an eloquent area of the brain, most pontine gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and molecular biologic abnormalities associated with pontine gliomas, and is a substantial obstacle for the preclinical testing of targeted therapeutic agents for these tumors. We have established a human glioma cell line that originated from surgical biopsy performed on a patient with a pontine glioma. To insure sustainable in vitro propagation, tumor cells were modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase), and with a luciferase reporter to enable non-invasive bioluminescence imaging. The hTERT modified cells are tumorigenic in athymic rodents, and produce brainstem tumors that recapitulate the infiltrative growth of brainstem gliomas in patients.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Ponte , Animais , Biomarcadores Tumorais/metabolismo , Western Blotting , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/terapia , Criança , Feminino , Perfilação da Expressão Gênica , Glioma/genética , Glioma/terapia , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Ratos , Ratos Nus , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The purpose of this study is to evaluate the roles of resection extent and adjuvant radiation in the treatment of craniopharyngiomas. We reviewed the records of 122 patients ages 11-52 years who received primary treatment for craniopharyngioma between 1980 and 2009 at the University of California, San Francisco (UCSF). Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were development of panhypopituitarism, diabetes insipidus (DI), and visual field defects. Of 122 patients, 30 (24%) were treated with gross total resection (GTR) without radiation therapy (RT), 3 (3%) with GTR + RT, 41 (33.6%) with subtotal resection (STR) without RT, and 48 (39.3%) with STR + RT. Median age at diagnosis was 30 years, with 46 patients 18 years or younger. Median follow-up for all patients was 56.4 months (interquartile range 18.9-144.2 months) and 47 months (interquartile range 12.3-121.8 months) for the 60 patients without progression. Fifty six patients progressed, 10 have died, 6 without progression. Median PFS was 61.1 months for all patients. PFS rate at 2 years was 61.5% (95% CI: 52.1-70.9). OS rate at 10 years was 91.1% (95% CI 84.3-97.9). There was no significant difference in PFS and OS between patients treated with GTR vs. STR + XRT (PFS; p = 0.544, OS; p = 0.735), but STR alone resulted in significantly shortened PFS compared to STR + RT or GTR (p < 0.001 for both). STR was associated with significantly shortened OS compared to STR + RT (p = 0.050) and trended to shorter OS compared to GTR (p = 0.066). GTR was associated with significantly greater risk of developing DI (56.3 vs. 13.3% with STR + XRT, p < 0.001) and panhypopituitarism (54.8 vs. 26.7% with STR + XRT, p = 0.014). In conclusion, for patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection.
Assuntos
Craniofaringioma/radioterapia , Craniofaringioma/cirurgia , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Adolescente , Adulto , Criança , Terapia Combinada , Craniofaringioma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/mortalidade , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Ciclofosfamida/análogos & derivados , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Lactente , Injeções Espinhais , Masculino , Estadiamento de Neoplasias , Projetos Piloto , Radioterapia ConformacionalRESUMO
PURPOSE: PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). PATIENTS AND METHODS: Patients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). RESULTS: Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. CONCLUSIONS: Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , DNA Tumoral Circulante , Glioma Pontino Intrínseco Difuso , Glioma , Biologia , Biomarcadores , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/terapia , Criança , DNA Tumoral Circulante/genética , Glioma Pontino Intrínseco Difuso/genética , Feminino , Instabilidade Genômica , Glioma/genética , Glioma/metabolismo , Glioma/terapia , Humanos , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to test whether a physician-supervised web-based app, integrated with an electronic medical record, helps in improving blood pressure (BP) management in clinical practice. MATERIALS AND METHODS: An observational study of 1633 patients seen at a hypertension clinic managed by an endocrinologist with two cohorts (726 adopted the app and 907 had not). The app allowed patients and doctors to monitor BP, blood sugar and other vital signs. Patients decided whether to opt in to using the app and how often to upload their readings. The provider could offer feedback and communicate with patients through the app. We evaluated the change in office-based BP measurement before and after app adoption (at least 12 months apart). We performed a difference-in-difference analysis along with matching based on patient-individual characteristics. RESULTS: The difference-in-difference estimates were 6.23âmmHg systolic [95% confidence interval (95% CI) 0.87-11.59] for patients with SBP 150âmmHg or above, 4.01âmmHg systolic (95% CI 1.11-6.91) for patients with SBP 140âmmHg or above, 4.37âmmHg diastolic (95% CI 1.06-7.68) for patients with DBP 90âmmHg or above, 1.89âmmHg systolic (95% CI 0.58-3.2) and 0.87âmmHg diastolic (95% CI 0.17-1.57) overall for an average patient. Higher frequency of app usage was also associated with a greater reduction in BP. CONCLUSION: Use of an mHealth app in a clinical practice, was associated with a significant reduction in BP for average patients as well as high-severity patients. Physician-supervised mHealth apps in a clinical practice could be instrumental in managing patient BP.
Assuntos
Hipertensão , Aplicativos Móveis , Telemedicina , Pressão Sanguínea , Estudos de Coortes , Humanos , Hipertensão/diagnóstico , Hipertensão/terapiaRESUMO
BACKGROUND: Radiation therapy (RT) is essential to the management of many brain tumors, but has been known to lead to cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs). PURPOSE: In a subset of children, adolescents, and young adults recruited from a larger trial investigating arteriopathy and stroke risk after RT, we evaluated the prevalence of CMBs after RT, examined risk factors for CMBs and cognitive impairment, and related their longitudinal development to cognitive performance changes. METHODS: Twenty-five patients (mean 17 years, range: 10-25 years) underwent 7-Tesla MRI and cognitive assessment. Nineteen patients were treated with whole-brain or focal RT 1-month to 20-years prior, while 6 non-irradiated patients with posterior-fossa tumors served as controls. CMBs were detected on 7T susceptibility-weighted imaging (SWI) using semi-automated software, a first use in this population. RESULTS: CMB detection sensitivity with 7T SWI was higher than previously reported at lower field strengths, with one or more CMBs detected in 100% of patients treated with RT at least 1-year prior. CMBs were localized to dose-targeted brain volumes with risk factors including whole-brain RT (p = 0.05), a higher RT dose (p = 0.01), increasing time since RT (p = 0.03), and younger age during RT (p = 0.01). Apart from RT dose, these factors were associated with impaired memory performance. Follow-up data in a subset of patients revealed a proportional increase in CMB count with worsening verbal memory performance (r = -0.85, p = 0.03). CONCLUSIONS: Treatment with RT during youth is associated with the chronic development of CMBs that evolve with memory impairment over time.
Assuntos
Neoplasias Encefálicas , Disfunção Cognitiva , Adolescente , Encéfalo , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Hemorragia Cerebral , Criança , Disfunção Cognitiva/etiologia , Humanos , Imageamento por Ressonância Magnética , Adulto JovemRESUMO
BACKGROUND: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. METHODS: We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses. RESULTS: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash. CONCLUSIONS: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.
Assuntos
Neoplasias Encefálicas , Neurofibromatose 1 , Glioma do Nervo Óptico , Benzimidazóis , Neoplasias Encefálicas/tratamento farmacológico , Criança , Humanos , Glioma do Nervo Óptico/tratamento farmacológicoRESUMO
High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.