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Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1.

ABSTRACT: Individuals with Neurofibromatosis Type 1 (NF1) are strongly predisposed to developing pediatric brain tumors (PBTs), especially optic pathway gliomas (OPGs). Although developmental factors have been implicated in the origins of PBTs in both human and animal studies, associations between early-life factors and PBTs have not been evaluated in individuals with NF1. Our objective was to evaluate associations between peri-gestational characteristics and PBTs in this population.We conducted a cross-sectional study, ascertaining questionnaire and medical record data for 606 individuals<18years old who enrolled in the NF1 Patient Registry Initiative (NPRI) from 6/9/2011-6/29/2015. One hundred eighty-four individuals had reported PBT diagnoses, including 65 who were identified with OPG diagnoses. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PBT and OPG diagnoses and peri-gestational characteristics (prematurity, birth weight, parental age, plurality, family history of NF1, assisted reproductive technology, maternal vitamin supplementation, and parental smoking).We observed no significant associations between any of the assessed characteristics and PBTs overall or OPGs with the exception of birth weight. After controlling for potential confounding variables, we observed a significant positive association between birth weight quartile and OPGs with a HR of 3.32 (95% CI 1.39-7.94) for the fourth (?3915.5g) compared to the first (?3020g) quartile (p for trend=0.001).Consistent with results for PBTs in the general population, these results suggest that higher birth weights increase OPG risk in individuals with NF1.

SUBMITTER: Johnson KJ

PROVIDER: S-EPMC4899111 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1.

Johnson Kimberly J KJ Zoellner Nancy L NL Gutmann David H DH

Cancer epidemiology 20160325

<h4>Background</h4>Individuals with Neurofibromatosis Type 1 (NF1) are strongly predisposed to developing pediatric brain tumors (PBTs), especially optic pathway gliomas (OPGs). Although developmental factors have been implicated in the origins of PBTs in both human and animal studies, associations between early-life factors and PBTs have not been evaluated in individuals with NF1. Our objective was to evaluate associations between peri-gestational characteristics and PBTs in this population.<h4 ...[more]

PMID: 27018750

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Project description:The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex.Sirolimus concentration-time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses.Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3-18), and mean weight was 29.8 kg (SD 16.7, range 12-85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2-24.1), and the mean dose to obtain a target trough concentration of 10-15 ng/mL was 2.0 mg/m administered twice daily (SD 0.72, range 0.77-3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r = 0.67 and 0.65, respectively).Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m twice a day was required for attainment of target trough concentrations of 10-15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1.

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Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1.

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Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1.

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