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1.
Lancet Oncol ; 21(6): e330-e336, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502459

RESUMO

Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/terapia , Determinação de Ponto Final/normas , Imagem por Ressonância Magnética/normas , Neuroimagem/normas , Idade de Início , Neoplasias do Tronco Encefálico/epidemiologia , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/epidemiologia , Glioma Pontino Intrínseco Difuso/patologia , Humanos , Gradação de Tumores , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
2.
Clin Cancer Res ; 25(24): 7303-7311, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811016

RESUMO

PURPOSE: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. PATIENTS AND METHODS: Patients ages 1 to <18 years who had BRAF V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. RESULTS: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26-62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). CONCLUSIONS: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600-mutant pLGG.

3.
Clin Cancer Res ; 25(24): 7294-7302, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31506385

RESUMO

PURPOSE: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. PATIENTS AND METHODS: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target. RESULTS: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily. CONCLUSIONS: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.

4.
Cancer ; 125(11): 1830-1836, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707764

RESUMO

BACKGROUND: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL. METHODS: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. RESULTS: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months. CONCLUSIONS: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Lenalidomida/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Quimioterapia de Manutenção , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rituximab/efeitos adversos , Translocação Genética , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
5.
Ther Innov Regul Sci ; 53(2): 270-278, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29759018

RESUMO

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.


Assuntos
Antineoplásicos , Protocolos Clínicos , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Criança , Tomada de Decisões , Humanos , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Participação dos Interessados
6.
Int J Radiat Oncol Biol Phys ; 101(5): 1234-1242, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29908790

RESUMO

PURPOSE: Brain radiation is associated with functional deficits in children. The purpose of this study was to examine white matter integrity as measured by diffusion tensor imaging and associations with region-specific radiation dose and neuropsychological functioning in children treated with cranial irradiation. METHODS AND MATERIALS: A total of 20 patients and 55 age- and sex-matched controls were included in the present study. Diffusion tensor imaging and neuropsychological assessments were conducted at baseline and 6, 15, and 27 months after treatment. The neuropsychological assessment included motor dexterity, working memory, and processing speed. White matter regions were contoured, and the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were recorded for each participant. Linear mixed effects regression models were used to prospectively compare the associations among ADC, FA, radiation dose to contoured structures, and performance on the neuropsychological assessments over time. RESULTS: The mean prescription dose was 44 Gy (range 12-54). Across visits, compared with the controls, the patients showed a significantly increased ADC across all selected regions and alterations in FA in the dorsal midbrain and corpus callosum (genu, splenium, body). An increased radiation dose to the genu and body of the corpus callosum was associated with alterations in ADC and FA and reduced neuropsychological performance, most notably motor speed and processing. CONCLUSIONS: These prospective data suggest that subcortical white matter, especially the genu and body of the corpus callosum, could be regions with increased susceptibility to radiation-induced injury, with implications for cognitive function.


Assuntos
Encéfalo/efeitos da radiação , Cognição/efeitos da radiação , Corpo Caloso/efeitos da radiação , Neurônios/efeitos da radiação , Adolescente , Anisotropia , Comportamento , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Estudos de Casos e Controles , Criança , Pré-Escolar , Corpo Caloso/patologia , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Neurônios/patologia , Testes Neuropsicológicos , Estudos Prospectivos , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos da radiação
7.
Oncotarget ; 9(27): 19177-19191, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29721192

RESUMO

Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-γ robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-γ), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

8.
Pediatr Blood Cancer ; 65(9): e27217, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29750396

RESUMO

BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. RESULTS: In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. CONCLUSIONS: The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias/tratamento farmacológico , Taxoides/uso terapêutico , Adolescente , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Criança , Pré-Escolar , Hipersensibilidade a Drogas/etiologia , Feminino , Gastroenteropatias/induzido quimicamente , Glioma/tratamento farmacológico , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/farmacocinética , Falha de Tratamento
9.
Neuro Oncol ; 20(11): 1547-1555, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-29741745

RESUMO

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


Assuntos
Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Imagem por Ressonância Magnética/métodos , Adolescente , Biópsia , Neoplasias do Tronco Encefálico/cirurgia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Seguimentos , Glioma/cirurgia , Humanos , Masculino , Morbidade , Prognóstico , Estudos Prospectivos
10.
Int J Radiat Oncol Biol Phys ; 101(1): 152-168, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29619963

RESUMO

PURPOSE: Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. METHODS AND MATERIALS: Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. RESULTS: The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. CONCLUSIONS: Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.


Assuntos
Tronco Encefálico/patologia , Tronco Encefálico/efeitos da radiação , Neoplasias Infratentoriais/radioterapia , Terapia com Prótons/efeitos adversos , Lesões por Radiação/epidemiologia , Tronco Encefálico/diagnóstico por imagem , Institutos de Câncer/estatística & dados numéricos , Criança , Florida , Humanos , Neoplasias Infratentoriais/diagnóstico por imagem , Neoplasias Infratentoriais/patologia , Transferência Linear de Energia , Massachusetts , National Cancer Institute (U.S.) , Necrose/diagnóstico por imagem , Necrose/epidemiologia , Necrose/etiologia , Necrose/prevenção & controle , Fótons/efeitos adversos , Guias de Prática Clínica como Assunto , Terapia com Prótons/métodos , Terapia com Prótons/normas , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/prevenção & controle , Radioterapia de Intensidade Modulada , Eficiência Biológica Relativa , Texas , Incerteza , Estados Unidos
12.
Neuro Oncol ; 19(11): 1542-1552, 2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-28605510

RESUMO

Background: Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response. Methods: Pediatric patients aged ≥1 to <18 years were included according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily. Results: Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients. Conclusions: Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses.


Assuntos
Compostos de Bifenilo/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Prognóstico , Piridinas/farmacocinética , Piridinas/farmacologia , Distribuição Tecidual , Adulto Jovem
13.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28544128

RESUMO

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. METHODS: Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. RESULTS: Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. CONCLUSIONS: The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrocitoma/terapia , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia/mortalidade , Glioma/terapia , Adolescente , Adulto , Astrocitoma/patologia , Neoplasias do Tronco Encefálico/patologia , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Glioma/patologia , Humanos , Irinotecano , Masculino , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Adulto Jovem
14.
Neuro Oncol ; 19(8): 1025-1034, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28371920

RESUMO

Diffuse intrinsic pontine glioma (DIPG) has proven to be one of the most challenging of all pediatric cancers. Owing to a historical reticence to obtain tumor tissue for study, and based on an erroneous assumption that the biology of DIPG would mirror that of supratentorial high-grade astrocytomas, innumerable studies have been undertaken-all of which have had a negligible impact on the natural history of this disease. More recently, improvements in neurosurgical techniques have allowed for the safe upfront biopsy of DIPG, which, together with a wider use of autopsy tissue, has led to an evolving understanding of the biology of this tumor. The discovery of a recurrent somatic gain-of-function mutation leading to lysine 27 to methionine (p.Lys27Met, K27M) substitution in histone 3 variants characterizes more than 85% of DIPG, suggesting for the first time the role of the epigenome and histones in the pathogenesis of this disease, and more unified diagnostic criteria. Along with further molecular insights into the pathogenesis of DIPG, rational targets are being identified and studied in the hopes of improving the otherwise dismal outcome for children with DIPG.


Assuntos
Astrocitoma/patologia , Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Metionina/genética , Mutação/genética , Animais , Astrocitoma/genética , Neoplasias do Tronco Encefálico/genética , Histonas/genética , Humanos
15.
Oncotarget ; 8(70): 115570-115581, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29383182

RESUMO

Pediatric spinal ependymomas (SEPN) are important albeit uncommon malignant central nervous system tumors with limited treatment options. Our current knowledge about the underlying biology of these tumors is limited due to their rarity. To begin to elucidate molecular mechanisms that give rise to pediatric SEPN, we compared the transcriptomic landscape of SEPNs to that of intracranial ependymomas using genome-wide mRNA and microRNA (miRNA) expression profiling in primary tumour samples. We found that pediatric SEPNs are characterized by increased expression of genes involved in developmental processes, oxidative phosphorylation, cellular respiration, electron transport chain, and cofactor metabolic process. Next, we compared pediatric spinal and intracranial ependymomas with the same tumours in adults and found a relatively low number of genes in pediatric tumours that were shared with adult tumours (12.5%). In contrast to adult SEPN, down-regulated genes in pediatric SEPN were not enriched for position on chromosome 22. At the miRNA level, we found ten miRNAs that were perturbed in pediatric SEPN and we identified regulatory relationships between these miRNAs and their putative targets mRNAs using the integrative miRNA-mRNA network and predicted miRNA target analysis. These miRNAs include the oncomiR hsa-miR-10b and its family member hsa-miR-10a, both of which are upregulated and target chromatin modification genes that are down regulated in pediatric SEPN. The tumor suppressor, hsa-miR-124, was down regulated in pediatric SEPN and it normally represses genes involved in cell-cell communication and metabolic processes. Together, our findings suggest that pediatric SEPN is characterized by a distinct transcriptional landscape from that of pediatric intracranial EPNs or adult tumors (both SEPNs and intracranial EPNs). Although confirmatory studies are needed, our study reveals novel molecular pathways that may drive tumorigenesis and could serve as biomarkers or rational therapeutic targets.

16.
Cancer ; 123(1): 161-168, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27571577

RESUMO

BACKGROUND: Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning. METHODS: Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses. RESULTS: Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups. CONCLUSIONS: This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2017;161-168. © 2016 American Cancer Society.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/radioterapia , Irradiação Craniana/efeitos adversos , Lobo Frontal/fisiopatologia , Lobo Frontal/efeitos da radiação , Lobo Temporal/fisiopatologia , Lobo Temporal/efeitos da radiação , Adolescente , Criança , Pré-Escolar , Cognição/efeitos da radiação , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Memória/efeitos da radiação , Testes Neuropsicológicos , Estudos Prospectivos
17.
J Clin Rheumatol ; 22(6): 320-3, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27556240

RESUMO

Atypical hemolytic uremic syndrome is characterized by the presence of thrombocytopenia, microangiopathic hemolytic anemia, and end-organ injury. In this report, we describe two patients with systemic lupus erythematosus who presented with findings compatible with atypical hemolytic uremic syndrome, complicated by acute kidney injury that was refractory to conventional therapies. Both patients exhibited a response to eculizumab, a monoclonal antibody to complement protein C5, with stabilization of their platelet count. On 1-year follow-up from their initial presentation, their hematologic disease remained in remission without recurrence.


Assuntos
Lesão Renal Aguda , Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica , Lúpus Eritematoso Sistêmico/complicações , Microangiopatias Trombóticas , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Adulto , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/etiologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Contagem de Plaquetas/métodos , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Resultado do Tratamento
18.
J Pediatr Hematol Oncol ; 38(5): 360-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27164535

RESUMO

Although many phase I trials report tumor response, formal analysis of efficacy is deferred to phase II. We reviewed paired phase I and II pediatric oncology trials to ascertain the relationship between phase I and II objective response rate (OR%). Single-agent phase I trials were paired with corresponding phase II trials (comparable study drug, dosing schedule, and population). Phase I trials without efficacy data or a matching phase II trial were excluded. OR% was tabulated for all trials, and phase II authors' subjective conclusions regarding efficacy were documented; 35 pairs of trials were analyzed. The correlation between phase I and II OR% was 0.93. Between phase II studies with a "positive" conclusion versus a "negative" one, there was a statistically significant difference in mean phase I OR% (32.0% vs. 4.5%, P<0.001). Thirteen phase II studies were undertaken despite phase I OR% of 0%; only 1 had a "positive" conclusion, and none exceeded OR% of 15%. OR% are highly correlated between phase I and II pediatric oncology trials. Although not a formal measure of drug efficacy, phase I OR% may provide an estimate of phase II response, inform phase II study design, and should be given greater consideration.


Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos Fase I como Assunto/normas , Ensaios Clínicos Fase II como Assunto/normas , Protocolos Antineoplásicos , Criança , Ensaios Clínicos como Assunto/normas , Humanos , Neoplasias/tratamento farmacológico , Razão de Chances , Pediatria/métodos , Resultado do Tratamento
19.
Childs Nerv Syst ; 32(8): 1425-30, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27179530

RESUMO

INTRODUCTION: The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. METHODS: Thirty-four patients <21 years old with intracranial LGG who were treated with RT at the Johns Hopkins Hospital were included in this retrospective analysis. Patients were evaluated for overall survival (OS), progression-free survival (PFS), recurrence patterns, and treatment toxicities using descriptive statistics, Kaplan-Meier curves, and Cox proportional hazard regressions. RESULTS: The mean age at diagnosis was 7.9 years (range 1.2-18.3 years) and mean age at RT was 9.8 years (range 3.0-28.9 years). The median follow-up time was 9.8 years after radiation (range 0.8-33.3 years). The estimated 10-year OS and PFS after RT were 92 and 74 %, respectively. Twelve patients had disease progression after RT, and all recurrences were local. Two patients died due to disease progression 2.3 and 9.1 years after RT. One patient had malignant transformation of LGG to high-grade glioma. No significant predictors of PFS were identified on uni- or multivariate analysis. Late effects of LGG and treatment seen were endocrine deficiencies in 16 patients, visual problems in 10 patients, hearing loss in 4 patients, special education requirements for 5 patients, and a vascular injury/demyelination secondary to RT in 1 patient. CONCLUSION: Our study suggests that the use of radiation in patients with intracranial LGG results in excellent OS and PFS with acceptable toxicity at long-term follow-up.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Gerenciamento Clínico , Glioma/diagnóstico , Glioma/radioterapia , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Modelos de Riscos Proporcionais , Adulto Jovem
20.
Neuro Oncol ; 18(10): 1442-50, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27006176

RESUMO

BACKGROUND: The prognosis for children with malignant glioma is poor. This study was designed to determine whether lomustine and temozolomide following radiotherapy and concurrent temozolomide improves event-free survival (EFS) compared with historical controls with anaplastic astrocytoma (AA) or glioblastoma (GBM) and whether survival is influenced by the expression of O6-methylguanine-DNA-methyltransferase (MGMT). METHODS: Following maximal surgical resection, newly diagnosed children with nonmetastatic high-grade glioma underwent involved field radiotherapy with concurrent temozolomide. Adjuvant chemotherapy consisted of up to 6 cycles of lomustine 90 mg/m(2) on day 1 and temozolomide 160 mg/m(2)/day ×5 every 6 weeks. RESULTS: Among the 108 eligible patients with AA or GBM, 1-year EFS was 0.49 (95% CI, 0.39-0.58), similar to the original CCG-945-based design model. However, EFS and OS were significantly improved in ACNS0423 compared with the 86 AA or GBM participants treated with adjuvant temozolomide alone in the recent ACNS0126 study (1-sided log-rank P = .019 and .019, respectively). For example, 3-year EFS was 0.22 (95% CI, 0.14-0.30) in ACNS0423 compared with 0.11 (95% CI, 0.05-0.18) in ACNS0126. Stratifying the comparison by resection extent, the addition of lomustine resulted in significantly better EFS and OS in participants without gross-total resection (P = .019 and .00085 respectively). The difference in EFS and OS was most pronounced for participants with GBM (P = .059 and 0.051, respectively), and those with MGMT overexpression (P = .00036 and .00038, respectively). CONCLUSION: The addition of lomustine to temozolomide as adjuvant therapy in ACNS0423 was associated with significantly improved outcome compared with the preceding COG ACNS0126 HGG study in which participants received temozolomide alone.


Assuntos
Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Lomustina/administração & dosagem , Lomustina/efeitos adversos , Masculino , Temozolomida , Adulto Jovem
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