RESUMO
BACKGROUND: While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. METHODS: Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. RESULTS: Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. CONCLUSIONS: Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.
Assuntos
Autopsia , Neoplasias do Sistema Nervoso Central , Obtenção de Tecidos e Órgãos/organização & administração , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto JovemRESUMO
Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.
Assuntos
Antineoplásicos/efeitos adversos , Glioma/tratamento farmacológico , Hiponatremia/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Glioma/diagnóstico , Humanos , Lactente , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêuticoRESUMO
PURPOSE: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. METHODS: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. RESULTS: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . CONCLUSIONS: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. TRIAL REGISTRATION: NCT02607124.
Assuntos
Aminopiridinas/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia/métodos , Glioma Pontino Intrínseco Difuso/terapia , Purinas/uso terapêutico , Adolescente , Adulto , Aminopiridinas/farmacocinética , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/patologia , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Prognóstico , Purinas/farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue sarcoma with an unfavorable prognosis and limited therapeutic options. MPNSTs can be sporadic, but are often associated with neurofibromatosis (NF) 1 and usually arise from preexisting neurofibromas. MPNSTs in patients with NF2 have been reported in only exceedingly rare cases, and the mechanisms underlying transformation into an MPNST have not been fully elucidated. Here, we describe the clinicopathological and genomic features of a peripheral nerve sheath tumor (PNST), with a primary diagnosis of a neurofibroma, as it transforms into a high-grade MPNST in the context of NF2.
Assuntos
Neoplasias de Bainha Neural/patologia , Neurofibromatose 2/patologia , Sarcoma/patologia , Transformação Celular Neoplásica/patologia , Criança , Humanos , Masculino , Neoplasias de Bainha Neural/genética , Neurofibromatose 2/genética , Sarcoma/genéticaRESUMO
PURPOSE: The Functional Independence Measure for children (WeeFIM) is a user-friendly functional outcomes tool that has been validated across other traditional functional scales. Historically, the significant neurologic and functional deficits of intramedullary spinal cord tumors (IMSCTs) have been monitored by coarse or overbearing functional outcomes tools that make it difficult to measure the slow improvement/decline seen in these patients. This study is the first to report WeeFIM outcomes on a series of IMSCTs with emphasis on an aggressive surgical strategy. METHODS: A retrospective review from 2005 to 2014 was performed for nine patients who underwent resective surgery for intramedullary spinal cord tumors with intraoperative ultrasound and neurophysiologic monitoring. WeeFIM scales were assessed at admission and discharge to evaluate changes in severity of disability and need for assistance. RESULTS: At the time of this submission, 7/9 patients are alive. The mean WeeFIM improvement was 27 points (8-50 points) with a mean WeeFIM efficiency of 2.0 points/day. CONCLUSIONS: The WeeFIM scale is an appropriate and useful scale for measuring postoperative improvements in patients with IMSCTs undergoing aggressive resective surgery. Attention to intraoperative spinal cord monitoring and prevention of spinal column instability may prevent morbidity related to surgery, and functional outcomes do not appear to be compromised by an aggressive surgical approach.
Assuntos
Atividades Cotidianas , Laminectomia/tendências , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Laminectomia/métodos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Prior reviews of phase I pediatric oncology trials involving primarily cytotoxic agents have reported objective response rates (ORRs) and toxic death rates of 7.9-9.6% and 0.5%, respectively. These data may not reflect safety and efficacy in phase I trials of molecularly targeted (targeted) drugs. METHODS: A systematic review of pediatric phase I solid tumor trials published in 1990-2013 was performed. The published reports were evaluated for patient characteristics, toxicity information, and response numbers. RESULTS: A total of 143 phase I pediatric clinical trials enrolling 3,896 children involving 53 targeted and 48 cytotoxic drugs were identified. A meta-analysis demonstrated that the ORR is 2.1-fold higher with cytotoxic drugs (0.066 vs. 0.031 per subject; P = 0.007). By contrast, the pooled estimate of the stable disease rate (SDR) is similar for cytotoxic and targeted drugs (0.2 vs. 0.23 per subject; P = 0.27). The pooled estimate of the dose-limiting toxicity rate is 1.8-fold larger with cytotoxic drugs (0.24 vs. 0.13 per subject; P = 0.0003). The hematologic grade 3-4 (G3/4) toxicity rate is 3.6-fold larger with cytotoxic drugs (0.43 vs. 0.12 per treatment course; P = 0.0001); however, the nonhematologic G3/4 toxicities and toxic deaths occur at similar rates for cytotoxic and targeted drugs. CONCLUSIONS: In phase I pediatric solid tumor trials, ORRs were significantly higher for cytotoxic versus targeted agents. SDRs were similar in targeted and cytotoxic drug trials. Patients treated with cytotoxic agents were more likely to experience hematologic G3/4 toxicities than those patients receiving targeted drugs.
Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Criança , Humanos , Prognóstico , SegurançaRESUMO
Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia , Glioma/terapia , Adolescente , Adulto , Bevacizumab/administração & dosagem , Neoplasias do Tronco Encefálico/diagnóstico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Seguimentos , Glioma/diagnóstico , Humanos , Irinotecano , Masculino , Gradação de Tumores , Projetos Piloto , Prognóstico , Taxa de Sobrevida , Temozolomida , Adulto JovemRESUMO
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 JovemRESUMO
OBJECTIVE: To evaluate the utility of screening brain/orbital magnetic resonance imaging (MRI) in a large population of children with neurofibromatosis type 1 (NF1) over a 20-year period. STUDY DESIGN: A retrospective analysis of clinical and imaging data from children with NF1 seen at a single center between 1990 and 2010 was performed. RESULTS: During the 20-year study period, 826 individuals with NF1 (402 females, 424 males) ages 1-9 years were screened for optic pathway gliomas (OPGs) using brain/orbital MRI; 18% were identified with OPGs with a median age at detection of 3 years. Fifteen percent of patients with OPGs had radiologic or clinical progression requiring therapy. Children with chiasmatic and postchiasmatic tumors were more likely to require therapy compared with patients with prechiasmatic OPGs (P < .0001). Patients with visual deficits at the time of diagnosis were more likely to experience visual decline despite therapy when compared with patients treated based on radiologic progression (P < .012). CONCLUSIONS: Our findings confirm that chiasmatic and postchiasmatic OPG in children with NF1 have the highest risk for progression and vision loss. Early identification of OPG by screening MRI prior to the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs.
Assuntos
Imageamento por Ressonância Magnética , Neurofibromatose 1/diagnóstico , Glioma do Nervo Óptico/diagnóstico , Neoplasias do Nervo Óptico/diagnóstico , Encéfalo/patologia , Criança , Pré-Escolar , Comorbidade , Progressão da Doença , Feminino , Humanos , Lactente , Masculino , Neurofibromatose 1/complicações , Glioma do Nervo Óptico/complicações , Neoplasias do Nervo Óptico/complicações , Estudos Retrospectivos , Transtornos da Visão/complicações , Transtornos da Visão/diagnósticoRESUMO
Pediatric tectal plate gliomas are indolent slow-growing gliomas that often present with increased intracranial pressure or incidentally on routine brain imaging. We investigated clinical outcomes, endocrinopathies, and neuropsychological sequelae associated with tectal plate gliomas. Twenty-six patients with tectal plate glioma were identified in a 20-year retrospective review. Clinical outcomes, treatments, endocrine function, neuropsychological testing outcomes and radiographic imaging were reviewed for possible signs correlating with tumor progression. Among 26 patients, 19 presented with signs or symptoms of increased intracranial pressure (73 %) versus an incidental finding in 7 (27 %). Median follow-up was 46 months (range 8-143 months). Six of 26 (23 %) experienced progressive disease after diagnosis. Five of 26 (19 %) required more than one surgical procedure due to failure of initial endoscopic third ventriculostomy. Seven of 26 had history of endocrine dysfunction, of which, five presented with endocrine dysfunction (precocious puberty or short stature), 1 developed menstrual irregularities after surgical intervention and 1 had preexisting pan hypopituitarism. Of 12 patients with available neuropsychological testing, eleven had at least one indicator of executive functioning in the low-average to impaired range. While tectal plate gliomas have been considered indolent tumors that are rarely progressive, 23 % of patients in our cohort experienced disease progression and required further therapy. Neurocognitive deficits may occur, while endocrine deficiency is uncommon. Regular multidisciplinary oncology follow-up, routine monitoring with MRI and formal neurocognitive evaluation are imperative to provide early recognition of disease progression or recurrent hydrocephalus and to improve school functioning in this population.
Assuntos
Neoplasias do Tronco Encefálico/complicações , Doenças do Sistema Endócrino/etiologia , Glioma/complicações , Procedimentos Neurocirúrgicos/efeitos adversos , Teto do Mesencéfalo/patologia , Adolescente , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/psicologia , Neoplasias do Tronco Encefálico/cirurgia , Criança , Pré-Escolar , Progressão da Doença , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/psicologia , Feminino , Seguimentos , Glioma/patologia , Glioma/psicologia , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Testes Neuropsicológicos , Prognóstico , Estudos Retrospectivos , Teto do Mesencéfalo/cirurgiaRESUMO
Juvenile pilocytic astrocytoma, the most common pediatric central nervous system (CNS) neoplasm, characteristically displays an indolent growth pattern and rarely demonstrates metastatic dissemination. Reports of infections mimicking CNS metastatic disease are also rare and can impact treatment. We report the youngest known case of a child with a CNS Nocardia farcinica infection who had a known cerebellar pilocytic astrocytoma, review other infections that may masquerade as CNS neoplasms, and discuss N. farcinica CNS infections.
Assuntos
Astrocitoma/diagnóstico , Neoplasias Encefálicas/secundário , Neoplasias Cerebelares/diagnóstico , Neoplasias Meníngeas/secundário , Meningite/diagnóstico , Nocardiose/diagnóstico , Nocardia/isolamento & purificação , Astrocitoma/microbiologia , Neoplasias Encefálicas/microbiologia , Neoplasias Cerebelares/microbiologia , Pré-Escolar , Diagnóstico Diferencial , Humanos , Masculino , Neoplasias Meníngeas/microbiologia , Meningite/microbiologia , Nocardiose/microbiologia , PrognósticoRESUMO
PURPOSE: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. RESULTS: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. CONCLUSION: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Medula Espinal/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/sangue , Criança , Pré-Escolar , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Relação Dose-Resposta a Droga , Feminino , Histonas/sangue , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Leucócitos Mononucleares/metabolismo , Masculino , Dose Máxima Tolerável , Neutropenia/sangue , Neutropenia/induzido quimicamente , Regiões Promotoras Genéticas , Recidiva , Neoplasias da Medula Espinal/sangue , Temozolomida , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Proteínas Supressoras de Tumor/metabolismo , VorinostatRESUMO
Desmoplastic infantile gangliogliomas (DIG) are intracranial tumors described in 1987 as benign lesions of infancy. A literature review and the clinical course of 3 patients reported herein suggest that the initial description should be amended. Nearly 23% of DIG cases occur in children older than 24 months. Approximately 40% of DIG cases require additional medical, radiation, and/or further surgical intervention, and 15% of infants and children develop leptomeningeal spread or die from DIG. Such adverse outcomes, combined with the recognition that DIG represents a heterogeneous disease, underscore the need for an expanded biological and molecular investigation.
Assuntos
Neoplasias Encefálicas/patologia , Ganglioglioma/patologia , Neoplasias Supratentoriais/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Ganglioglioma/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Estudos Retrospectivos , Literatura de Revisão como Assunto , Neoplasias Supratentoriais/terapiaRESUMO
Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.
RESUMO
BACKGROUND: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG. METHODS: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression. RESULTS: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations. CONCLUSIONS: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Humanos , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/radioterapia , Estudos Transversais , Glioma/patologia , Sistema de RegistrosRESUMO
BK virus (BKV) is an increasingly identified cause of pathology in immunocompromised transplant recipients. BKV is a well-known cause of graft dysfunction following renal transplantation and has also been reported in the native kidneys of other solid organ recipients. Less commonly, BKV nephropathy occurs in allogeneic stem-cell transplant (SCT) recipients. We now describe the first reported case of BKV nephropathy after pediatric autologous SCT.
Assuntos
Vírus BK/patogenicidade , Nefrite Intersticial/etiologia , Tumores Neuroectodérmicos Primitivos/complicações , Infecções por Polyomavirus/etiologia , Transplante de Células-Tronco/efeitos adversos , Infecções Tumorais por Vírus/etiologia , Antineoplásicos/uso terapêutico , Criança , Terapia Combinada , Evolução Fatal , Feminino , Humanos , Imunossupressores/uso terapêutico , Nefrite Intersticial/terapia , Tumores Neuroectodérmicos Primitivos/terapia , Infecções por Polyomavirus/terapia , Transplante Autólogo , Infecções Tumorais por Vírus/terapiaRESUMO
BACKGROUND: Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy. METHODS: We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs. RESULTS: A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects. CONCLUSIONS: In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.
Assuntos
Neurofibromatose 1 , Glioma do Nervo Óptico , Criança , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/tratamento farmacológico , Glioma do Nervo Óptico/complicações , Glioma do Nervo Óptico/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Campos VisuaisRESUMO
Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Deleção de Genes , Genoma , Genômica , Glioma/patologia , Glioma/terapia , Humanos , Lactente , Isocitrato Desidrogenase/genética , Masculino , Glicoproteínas de Membrana/genética , Gradação de Tumores , Recidiva Local de Neoplasia/terapia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myb/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor trkB/genética , Transativadores/genéticaRESUMO
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.