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Bender J.G.,Columbia University | Blaney S.M.,Texas Childrens Cancer Center | Borinstein S.,Childrens Hospital at Vanderbilt | Reid J.M.,Mayo Medical School | And 8 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2. Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. ©2012 AACR.


Sills M.R.,Aurora University | Sills M.R.,Childrens Hospital | Hall M.,Child Health Corporation of America | Fieldston E.S.,University of Pennsylvania | And 11 more authors.
Emerging Infectious Diseases | Year: 2011

Quantifying how close hospitals came to exhausting capacity during the outbreak of pandemic infl uenza A (H1N1) 2009 can help the health care system plan for more virulent pandemics. This ecologic analysis used emergency department (ED) and inpatient data from 34 US children's hospitals. For the 11-week pandemic (H1N1) 2009 period during fall 2009, inpatient occupancy reached 95%, which was lower than the 101% occupancy during the 2008-09 seasonal influenza period. Fewer than 1 additional admission per 10 inpatient beds would have caused hospitals to reach 100% occupancy. Using parameters based on historical precedent, we built 5 models projecting inpatient occupancy, varying the ED visit numbers and admission rate for infl uenza-related ED visits. The 5 scenarios projected median occupancy as high as 132% of capacity. The pandemic did not exhaust inpatient bed capacity, but a more virulent pandemic has the potential to push children's hospitals past their maximum inpatient capacity.


Beverung L.M.,Medical College of Wisconsin | Strouse J.J.,Johns Hopkins University | Hulbert M.L.,University of Washington | Neville K.,University of Missouri - Kansas City | And 8 more authors.
American Journal of Hematology | Year: 2015

The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre-existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health-related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the child's health being better, was significantly greater for the transfusion group than the observation group (difference estimate = -0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy. © 2014 Wiley Periodicals, Inc.


Pina-Garza J.E.,Childrens Hospital at Vanderbilt | Schiemann-Delgado J.,UCB Inc. | Yang H.,UCB Inc. | Duncan B.,UCB Inc. | And 2 more authors.
Clinical Therapeutics | Year: 2010

Background: In a recent double-blind, placebo-controlled study, adjunctive levetiracetam (LEV) was reported to be effective and well tolerated during 5-day treatment in patients aged 1 month to <4 years with partial-onset seizures. A study was planned to fulfill the regulatory requirement to evaluate the long-term safety of LEV as adjunctive therapy for partial-onset seizures in pediatric patients.Objective: This study evaluated the long-term effectiveness and tolerability of adjunctive LEV in infants and young children with partial-onset seizures.Methods: This was a prospective, open-label, outpatient, multicenter study (N01148; ClinicalTrials.gov identifier NCT00152516) conducted as an extension of a previously published study (N01009; NCT00175890). Patients were enrolled from 3 sources, as follows: (1) patients who had completed study N01009; (2) patients who had failed screening for entry into study N01009 but fulfilled the eligibility criteria for entry into this study; and (3) patients who were directly enrolled. The study consisted of a 2- to 4-week retrospective baseline period (and a 3- to 10-day prospective baseline period for directly enrolled patients), a 2- to 8-week uptitration/conversion period, and a maintenance period. Eligible patients were required to have epilepsy with partial-onset seizures, treated with a stable regimen of 1 or 2 antiepileptic drugs. Patients received adjunctive LEV, 20 to 80 mg/kg/d, for up to 48 weeks (total study duration). The primary variable for effectiveness was the percentage reduction from baseline in the weekly frequency of partial-onset seizures, as recorded in patients' diaries. Data for effectiveness were also analyzed by age strata (1 month to <1 year, 1 to <2 years, and 2 to <4 years). Neuropsychological assessment was conducted with the Bayley Scales of Infant Development, Second Edition (BSID-II). All analyses were performed on observed data, and the last-observation-carried-forward approach was not used. The intent-to-treat (ITT) population was defined as all patients who took at least one dose of LEV during the study. Treatment-emergent adverse events (TEAEs) were assessed by observation, spontaneous reporting, standard questions, review of diary cards, and neuropsychologists' clinical reports. Additional measures included physical and neurologic examinations, vital signs, ECGs, routine blood chemistry, and routine hematology assessments.Results: The study included 152 patients in the ITT population. In total, 51.3% (78/152) of the patients were male, and mean (SD) age was 23.5 (12.4) months. The mean LEV maintenance dose was 56.1 (16.2) mg/kg/d, and the median (Q1-Q3) treatment duration was 287.8 (209.0-295.5) days. Ninety-seven patients (63.8%) completed the study. The BSID-II subpopulation included 51 patients. During maintenance, the overall median (Q1-Q3) percentage reduction from baseline in the weekly frequency of partial-onset seizures was 56.0% (-10.9% to 92.8%), which was sustained over time and appeared comparable across the age strata (1 month to <1 year, n = 25, 50.9%; 1 to <2 years, n = 48, 58.0%; and 2 to <4 years, n = 59, 55.0%). The overall responder rate (ie, ≥50% reduction from baseline in weekly partial-onset seizures) was 53.8% (71/132), was maintained over time, and was consistent across the age strata (1 month to <1 year, 52.0%; 1 to <2 years, 56.3%; and 2 to <4 years, 52.5%). Mean BSID-II raw scores for psychomotor development and behavioral functioning remained static, whereas mental development appeared to improve over time, although this was not tested statistically. At least one TEAE was reported in 143 patients (94.1%). The most frequently reported TEAEs were pyrexia (60/152; 39.5%), upper respiratory tract infection (42/152; 27.6%), and vomiting (28/152; 18.4%). The most common TEAEs affecting the central nervous system were convulsion (25/152; 16.4%), irritability (19/152; 12.5%), and somnolence (16/152; 10.5%). Most TEAEs (77.0%) were mild or moderate in intensity.Conclusion: Adjunctive LEV treatment for up to 48 weeks was associated with effective and sustained seizure control and had an acceptable tolerability profile in this small, selected population of infants and young children aged 1 month to <4 years with partial-onset seizures. © 2010 Excerpta Medica Inc.


Bacon J.L.,University of South Carolina | Romano M.E.,Childrens Hospital at Vanderbilt | Quint E.H.,University of Michigan
Journal of Pediatric and Adolescent Gynecology | Year: 2015

Labial adhesions, also known as labial agglutination, are a common finding in prepubertal adolescents. They are defined as fusion of the labia minora in the midline or are termed vulvar adhesions when they occur below the labia minora (inner labia). Patients are often asymptomatic but might present with genitourinary complaints. The decision for treatment is based on symptoms. The mainstay of treatment in asymptomatic patients is conservative, with careful attention to vulvar hygiene and reassurance to parents. In symptomatic patients, topical treatment with estrogen and/or steroid cream is often curative. Less often, corrective surgery is necessary. Recurrence is common until a patient goes through puberty. These recommendations are intended for pediatric and gynecologic health care providers who care for pediatric and adolescent girls to facilitate diagnosis and treatment. © 2015 North American Society for Pediatric and Adolescent Gynecology.


Dees E.,Childrens Hospital at Vanderbilt
Current Opinion in Pediatrics | Year: 2016

PURPOSE OF REVIEW: The study of cardiac development is critical to inform management strategies for congenital and acquired heart disease. This review serves to highlight some of the advances in this field over the past year. RECENT FINDINGS: Three main areas of study are included that have been particularly innovative and progressive. These include more precise gene targeting in animal models of disease and in moving from animal models to human disease, more precise in-vitro models including three-dimensional structuring and inclusion of hemodynamic components, and expanding the concepts of genetic regulation of heart development and disease. SUMMARY: Targeted genetics in animal models are able to make use of tissue and time-specific promotors that drive gene expression or knockout with high specificity. In-vitro models can recreate flow patterns in blood vessels and across cardiac valves. Noncoding RNAs, once thought to be of no consequence to gene transcription and translation, prove to be key regulators of genetic function in health and disease. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Roofe L.R.,Childrens Hospital at Vanderbilt | Resha D.J.,Childrens Hospital at Vanderbilt | Abramo T.J.,Childrens Hospital at Vanderbilt | Arnold D.H.,Childrens Hospital at Vanderbilt
Pediatric Emergency Care | Year: 2014

OBJECTIVE: The single-breath counting (SBC) method for assessment of asthma exacerbation severity has been evaluated in adults during exacerbations and in pediatric patients during routine settings. Single-breath counting has not been evaluated in children during exacerbations. We sought to assess criterion validity and responsiveness of SBC with percent-predicted FEV1 (%FEV1) and the Pediatric Respiratory Assessment Measure (PRAM), a validated acute asthma severity score. METHODS: We prospectively enrolled subjects aged 7 to 17 years with acute asthma exacerbations. Single-breath counting, %FEV1, and PRAM were obtained before treatment and 2 hours after initiating therapy. Multivariable linear regression models were used to examine associations of pretreatment SBC with %FEV1 and PRAM (criterion validity) and 2-hour change of these measures (responsiveness). With a 2-sided α of 0.05, SBC SD of 8.5, and 90% power to detect an adjusted R of greater than 0.36 for SBC with each outcome measure, a minimum sample of 20 participants was necessary. RESULTS: From June to November 2011, 51 participants were enrolled, with median (interquartile range) age of 8.46 years (6.92-11.4 years); male sex, n = 40 (78%); and African American race, n = 33 (64%). Before treatment, 42 (92%) were able to successfully perform SBC, and 24 (51%) %FEV1. Median pretreatment SBC obtained was 16 (10-24); %FEV1, 50 (26-71); and PRAM, 5 (1-5). CONCLUSIONS: Single-breath counting demonstrates modest criterion validity for predicting the pretreatment PRAM score and a trend for predicting %FEV1. Single-breath counting does not appear to be responsive to change of these measures in response to treatment and has limited validity as a measure of acute asthma severity. Copyright © 2014 by Lippincott Williams andWilkins.


In a recent double-blind, placebo-controlled study, adjunctive levetiracetam (LEV) was reported to be effective and well tolerated during 5-day treatment in patients aged 1 month to <4 years with partial-onset seizures. A study was planned to fulfill the regulatory requirement to evaluate the long-term safety of LEV as adjunctive therapy for partial-onset seizures in pediatric patients.This study evaluated the long-term effectiveness and tolerability of adjunctive LEV in infants and young children with partial-onset seizures.This was a prospective, open-label, outpatient, multicenter study (N01148; ClinicalTrials.gov identifier NCT00152516) conducted as an extension of a previously published study (N01009; NCT00175890). Patients were enrolled from 3 sources, as follows: (1) patients who had completed study N01009; (2) patients who had failed screening for entry into study N01009 but fulfilled the eligibility criteria for entry into this study; and (3) patients who were directly enrolled. The study consisted of a 2- to 4-week retrospective baseline period (and a 3- to 10-day prospective baseline period for directly enrolled patients), a 2- to 8-week uptitration/conversion period, and a maintenance period. Eligible patients were required to have epilepsy with partial-onset seizures, treated with a stable regimen of 1 or 2 antiepileptic drugs. Patients received adjunctive LEV, 20 to 80 mg/kg/d, for up to 48 weeks (total study duration). The primary variable for effectiveness was the percentage reduction from baseline in the weekly frequency of partial-onset seizures, as recorded in patients diaries. Data for effectiveness were also analyzed by age strata (1 month to <1 year, 1 to <2 years, and 2 to <4 years). Neuropsychological assessment was conducted with the Bayley Scales of Infant Development, Second Edition (BSID-II). All analyses were performed on observed data, and the last-observation-carried-forward approach was not used. The intent-to-treat (ITT) population was defined as all patients who took at least one dose of LEV during the study. Treatment-emergent adverse events (TEAEs) were assessed by observation, spontaneous reporting, standard questions, review of diary cards, and neuropsychologists clinical reports. Additional measures included physical and neurologic examinations, vital signs, ECGs, routine blood chemistry, and routine hematology assessments.The study included 152 patients in the ITT population. In total, 51.3% (78/152) of the patients were male, and mean (SD) age was 23.5 (12.4) months. The mean LEV maintenance dose was 56.1 (16.2) mg/kg/d, and the median (Q1-Q3) treatment duration was 287.8 (209.0-295.5) days. Ninety-seven patients (63.8%) completed the study. The BSID-II subpopulation included 51 patients. During maintenance, the overall median (Q1-Q3) percentage reduction from baseline in the weekly frequency of partial-onset seizures was 56.0% (-10.9% to 92.8%), which was sustained over time and appeared comparable across the age strata (1 month to <1 year, n = 25, 50.9%; 1 to <2 years, n = 48, 58.0%; and 2 to <4 years, n = 59, 55.0%). The overall responder rate (ie, 50% reduction from baseline in weekly partial-onset seizures) was 53.8% (71/132), was maintained over time, and was consistent across the age strata (1 month to <1 year, 52.0%; 1 to <2 years, 56.3%; and 2 to <4 years, 52.5%). Mean BSID-II raw scores for psychomotor development and behavioral functioning remained static, whereas mental development appeared to improve over time, although this was not tested statistically. At least one TEAE was reported in 143 patients (94.1%). The most frequently reported TEAEs were pyrexia (60/152; 39.5%), upper respiratory tract infection (42/152; 27.6%), and vomiting (28/152; 18.4%). The most common TEAEs affecting the central nervous system were convulsion (25/152; 16.4%), irritability (19/152; 12.5%), and somnolence (16/152; 10.5%). Most TEAEs (77.0%) were mild or moderate in intensity.Adjunctive LEV treatment for up to 48 weeks was associated with effective and sustained seizure control and had an acceptable tolerability profile in this small, selected population of infants and young children aged 1 month to <4 years with partial-onset seizures.


PubMed | Childrens Hospital at Vanderbilt and University of Massachusetts Medical School
Type: Journal Article | Journal: Journal of pediatric and adolescent gynecology | Year: 2016

Vulvovaginitis is a commonly encountered condition among prepubertal and adolescent females. The objective of this report is to provide the latest evidence regarding the diagnosis and management of vulvovaginitis in prepubertal and adolescent females. In this systematic review we used the Grading of Recommendations Assessment, Development and Evaluation evidence system. Vulvovaginal complaints are common in the pediatric and adolescent age group. The patients age in conjunction with history and associated complaints will guide evaluation, diagnosis, and treatment. Treatment should include counseling on hygiene and voiding techniques as well as therapy for any specific pathogens identified.


PubMed | Childrens Hospital at Vanderbilt
Type: Journal Article | Journal: Pediatric emergency care | Year: 2013

The single-breath counting (SBC) method for assessment of asthma exacerbation severity has been evaluated in adults during exacerbations and in pediatric patients during routine settings. Single-breath counting has not been evaluated in children during exacerbations. We sought to assess criterion validity and responsiveness of SBC with percent-predicted FEV1 (%FEV1) and the Pediatric Respiratory Assessment Measure (PRAM), a validated acute asthma severity score.We prospectively enrolled subjects aged 7 to 17 years with acute asthma exacerbations. Single-breath counting, %FEV1, and PRAM were obtained before treatment and 2 hours after initiating therapy. Multivariable linear regression models were used to examine associations of pretreatment SBC with %FEV1 and PRAM (criterion validity) and 2-hour change of these measures (responsiveness). With a 2-sided of 0.05, SBC SD of 8.5, and 90% power to detect an adjusted R of greater than 0.36 for SBC with each outcome measure, a minimum sample of 20 participants was necessary.From June to November 2011, 51 participants were enrolled, with median (interquartile range) age of 8.46 years (6.92-11.4 years); male sex, n = 40 (78%); and African American race, n = 33 (64%). Before treatment, 42 (92%) were able to successfully perform SBC, and 24 (51%) %FEV1. Median pretreatment SBC obtained was 16 (10-24); %FEV1, 50 (26-71); and PRAM, 5 (1-5).Single-breath counting demonstrates modest criterion validity for predicting the pretreatment PRAM score and a trend for predicting %FEV1. Single-breath counting does not appear to be responsive to change of these measures in response to treatment and has limited validity as a measure of acute asthma severity.

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