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1.
Lancet Oncol ; 24(3): e133-e143, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36858729

RESUMO

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.


Assuntos
Neoplasias , Estados Unidos , Humanos , National Cancer Institute (U.S.) , Imunoterapia , Processamento de Imagem Assistida por Computador , Oncologia
2.
Pediatr Blood Cancer ; 70 Suppl 4: e30147, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36519599

RESUMO

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers.


Assuntos
Neoplasias Encefálicas , Ressonância de Plasmônio de Superfície , Humanos , Criança , Neoplasias Encefálicas/patologia , Imageamento por Ressonância Magnética/métodos , Sistema Nervoso Central/patologia , Encéfalo/patologia
3.
J Comput Assist Tomogr ; 47(5): 820-832, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37707414

RESUMO

ABSTRACT: Complications of cancer therapy in children can result in a spectrum of neurologic toxicities that may occur at the initiation of therapy or months to years after treatment. Although childhood cancer remains rare, increasing survival rates mean that more children will be living longer after cancer treatment. Therefore, complications of cancer therapy will most likely occur with increasing frequency.At times, it is very difficult to differentiate between therapeutic complications and other entities such as tumor recurrence, development of secondary malignancy, and infection (among other conditions). Radiologists often play a key role in the diagnosis and evaluation of pediatric patients with malignancies, and thus, awareness of imaging findings of cancer complications and alternative diagnoses is essential in guiding management and avoiding misdiagnosis. The aim of this review article is to illustrate the typical neuroimaging findings of cancer therapy-related toxicities, including both early and late treatment effects, highlighting pearls that may aid in making the appropriate diagnosis.


Assuntos
Neoplasias , Humanos , Criança , Neoplasias/complicações , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Neuroimagem
4.
Pediatr Radiol ; 53(13): 2723-2741, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37864711

RESUMO

The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group includes neuroradiologists, neuro-oncologists, neurosurgeons, radiation oncologists, and clinicians in various additional specialties. This review paper will summarize the imaging recommendations from RAPNO for the six RAPNO publications to date covering pediatric low-grade glioma, pediatric high-grade glioma, medulloblastoma and other leptomeningeal seeding tumors, diffuse intrinsic pontine glioma, ependymoma, and craniopharyngioma.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Criança , Diagnóstico por Imagem , Glioma/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia
5.
Lancet Oncol ; 23(8): e393-e401, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35901835

RESUMO

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Ependimoma , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Neoplasias do Sistema Nervoso Central/patologia , Criança , Ependimoma/diagnóstico por imagem , Ependimoma/terapia , Humanos , Imageamento por Ressonância Magnética
6.
Pediatr Blood Cancer ; 68(4): e28879, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33405376

RESUMO

BACKGROUND: Disruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. METHODS: Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. RESULTS: A total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75 mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy. CONCLUSIONS: Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Progressão da Doença , Feminino , Humanos , Masculino , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Adulto Jovem
7.
J Neurooncol ; 143(1): 79-86, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810873

RESUMO

BACKGROUND AND PURPOSE: Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium-PBTC). MATERIALS AND METHODS: MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio). RESULTS: A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI 0.79, 52.79, p = 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI 0.09, 0.82, p = 0.022). There was no significant association between fDM derived metrics and overall survival. CONCLUSIONS: Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Adolescente , Algoritmos , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/radioterapia , Criança , Imagem de Difusão por Ressonância Magnética/métodos , Estudos de Viabilidade , Feminino , Glioma/mortalidade , Glioma/radioterapia , Humanos , Masculino , Ponte , Estudos Retrospectivos , Análise Espaço-Temporal , Análise de Sobrevida , Resultado do Tratamento
8.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29090526

RESUMO

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


Assuntos
Neoplasias do Tronco Encefálico/terapia , Capecitabina/administração & dosagem , Quimiorradioterapia , Glioma/terapia , Administração Oral , Adolescente , Neoplasias do Tronco Encefálico/diagnóstico , Criança , Pré-Escolar , Feminino , Seguimentos , Glioma/diagnóstico , Humanos , Masculino , Estudos Prospectivos , Comprimidos
9.
J Neurooncol ; 129(3): 443-451, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27350411

RESUMO

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioma/tratamento farmacológico , Indóis/uso terapêutico , Niacinamida/análogos & derivados , Telomerase/metabolismo , Adolescente , Alanina Transaminase/metabolismo , Contagem de Células Sanguíneas , Neoplasias do Sistema Nervoso Central/cirurgia , Criança , Pré-Escolar , Feminino , Glioma/cirurgia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Niacinamida/uso terapêutico , Oligonucleotídeos , Telomerase/genética , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Childs Nerv Syst ; 31(9): 1433-45, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26188774

RESUMO

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 Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-39179297

RESUMO

With the full FDA approval and centers for Medicare & Medicaid services (CMS) coverage of lecanemab and donanemab, a growing number of practices are offering anti-amyloid immunotherapy to appropriate patients with cognitive impairment (MCI) or mild dementia due to amyloid-positive Alzheimer's disease (AD). The goal of this paper is to provide updated practical considerations for radiologists, including implementation of MR imaging protocols, workflows and reporting and communication practices relevant to anti-amyloid immunotherapy and monitoring for amyloid-related imaging abnormalities (ARIA). Based on consensus discussion within an expanded ASNR Alzheimer's, ARIA, and Dementia study group, we will: (1) summarize the FDA guidelines for evaluation of radiographic ARIA; (2) review the three key MRI sequences for ARIA monitoring and standardized imaging protocols based on ASNR-industry collaborations; (3) provide imaging recommendations for three key patient scenarios; (4) highlight the role of the radiologist in the care team for this population; (5) discuss implementation of MRI protocols to detect ARIA in diverse practice settings; and (6) present results of the 2023 ASNR international neuroradiologist practice survey on dementia and ARIA imaging.ABBREVIATIONS: AD = Alzheimer's disease; ARIA = amyloid-related imaging abnormalities; APOE = apolipoprotein-E; CMS = centers for Medicare & Medicaid services; MCI = mild cognitive impairment.

12.
Cancer ; 119(23): 4180-7, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24104527

RESUMO

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 Jovem
13.
J Neurooncol ; 106(3): 643-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21968943

RESUMO

To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Guanina/análogos & derivados , Adolescente , Neoplasias do Tronco Encefálico/mortalidade , Criança , Pré-Escolar , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/uso terapêutico , Quimioterapia Combinada/métodos , Feminino , Glioma/mortalidade , Guanina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Temozolomida , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
14.
Childs Nerv Syst ; 27(1): 11-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21052693

RESUMO

PURPOSE: To assess changes in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in brainstem gliomas (BSG) in children and to observe the temporal evolution of changes in the white matter tracts following therapy using diffusion tensor imaging (DTI) analysis. METHODS: Serial ADC and FA measurements were obtained in three patients with newly diagnosed BSG on two approved treatment protocols. Values were compared with a set of normative ADC, FA, and eigenvalues of age-matched children of the corticospinal, transverse pontine and medial lemniscal tracts. Fiber tracking of the tracts coursing through the brainstem was performed using standard diffusion tractography analysis. RESULTS: We found increased ADC values within tumor at baseline compared to age-matched controls, with subsequent drop following treatment and subsequent increase with recurrence. Correspondingly, FA values were reduced at presentation, but transiently recovered during the phase of tumor response to treatment, and finally decreased significantly during tumor progression. These changes were concordant with the tractography analysis of white matter tracts in the brainstem. Based on these results, we suggest that initial changes in ADC and FA values reflects tract infiltration by tumor, but not complete disruption, whereas tumor progression results in complete loss of anisotropy possibly due to tract disruption. CONCLUSION: Serial changes in ADC and FA values and tractography data in pediatric BSG suggest initial tumor infiltration, with transient improvement on treatment and subsequent loss of tract anisotropy during tumor progression. This technique may have potential use in assessing response to treatment regimens for pediatric BSG.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Tronco Encefálico/patologia , Glioma/patologia , Interpretação de Imagem Assistida por Computador/métodos , Adolescente , Anisotropia , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Imagem de Tensor de Difusão , Gefitinibe , Glioma/terapia , Humanos , Masculino , Fibras Nervosas Mielinizadas/patologia , Quinazolinas/uso terapêutico , Quinolonas/uso terapêutico , Radioterapia
15.
Neuro Oncol ; 23(10): 1777-1788, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631016

RESUMO

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 farmacológico
16.
Med Phys ; 37(7): 3660-6, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20831073

RESUMO

PURPOSE: The purpose of this study was to evaluate the variability in quantitation of positron emission tomography (PET) data acquired within the context of a multicenter consortium. METHODS: PET quantitation phantoms designed by American Association of Physicists in Medicine/ Society of Nuclear Medicine Task Group 145 were sent to the ten member sites of the Pediatric Brain Tumor Consortium (PBTC), a NIH-funded research consortium investigating the biology and therapies for brain tumors in children. The phantoms were water-filled cylinders (18.6 cm inside height and 20.4 cm inside diameter) based on the standard ACR phantom with four small, "hot" cylinders of varying diameters (8, 12, 16, 25 mm, all with 38 mm height), consisting of an equilibrium mixture of 68Ge/68Ga in an epoxy matrix. At each site, the operator added the appropriate amount of 18F to the water in the background in order to attain a feature-to-background ratio of roughly 4:1. The phantom was imaged and reconstructed as if it were a brain PET scan for the PBTC. An approximately 12 mm circular region of interest (ROI) was placed over each feature and in a central area in the background. The mean and maximum pixel values for each ROI were requested from local sites in units of activity concentration (Bq/ml) and the standard uptake value (SUV) (g/mL) based on bodyweight. The activity concentration was normalized by the decay-corrected known activity concentration for the features, and reported as the absolute recovery coefficient (RC). In addition, central analyses were performed by two observers RESULTS: The ten sites successfully imaged the phantom within 5 months and submitted the quantitative results and the phantom image data to the PBTC Operations and Biostatistics Center. The local site-based and central analyses yielded similar mean values for RC. Local site-based SUV measurements of the hot cylindrical features yielded greater variability than central analysis (COV range of 29.9%-42.8% compared to 7.7%-23.2%). Correcting for miscalculations in the local site reported SUVs substantially reduced the variation to levels similar to the central analysis (COV range of 8.8%-18.4%) and also led to the local sites providing a similar mean of the SUV values to those from the central analysis. In the central analysis, the use of mean SUV in place of maximum SUV for an ROI of fixed size substantially reduced the variation in the SUV values (COV ranges of 7.7%-11.3% vs. 9.3%-23.2%). CONCLUSIONS: Based on this investigation, a SUV variability in the range of 10%-25% due solely to instrument and analysis factors can be expected in the context of a multicenter consortium if a central reading is used and quality assurance and quality control procedures are followed. The overall SUV variability can be expected to be larger than this due to biological and protocol factors.


Assuntos
Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Criança , Humanos , Estudos Multicêntricos como Assunto , Imagens de Fantasmas
18.
Neuro Oncol ; 22(6): 875-885, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32009149

RESUMO

BACKGROUND: A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series. METHODS: Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity. RESULTS: Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively. CONCLUSION: Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG. TRIAL REGISTRATION: NCT01514201.


Assuntos
Neoplasias Encefálicas , Neoplasias do Tronco Encefálico , Glioma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/radioterapia , Criança , Humanos , Temozolomida/uso terapêutico
20.
Pediatr Blood Cancer ; 52(2): 169-76, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19065567

RESUMO

SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110 mg/m(2) while stratum II started at 48 mg/m(2). Thirty-three eligible patients were treated on stratum I (n = 23) and stratum II (n = 10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas, and 2 choroid plexus carcinomas. The MTD in stratum I was initially estimated to be 110 mg/m(2). The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m(2) dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia, and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in stratum I were 26.1 +/- 12.5 l/hr/m(2), 41.9 +/- 21.4 l/m(2), and 1.11 +/- 0.41 hr, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum I patients.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Indóis/administração & dosagem , Pirróis/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adolescente , Inibidores da Angiogênese/uso terapêutico , Anticonvulsivantes/uso terapêutico , Artralgia/induzido quimicamente , Criança , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Alucinações/induzido quimicamente , Humanos , Indóis/farmacocinética , Indóis/toxicidade , Fígado/enzimologia , Masculino , Dose Máxima Tolerável , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/farmacocinética , Pirróis/toxicidade , Resultado do Tratamento , Adulto Jovem
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