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The 2014 Ebola virus disease outbreak triggered concerns about health-care worker (HCW) readiness. Two hundred and forty-five HCWs at a children's hospital were surveyed. Knowledge scores were lower for nurses than physicians (50-61%, P = 0.001). Despite HCWs lacking Ebola virus disease knowledge, their perceived lack of institutional preparedness and their own lack of training, most HCWs wanted to believe that they would be safe and were willing to provide care.

Background: Thoracic aortic dissection (TAD) is a highly lethal cardiovascular disease. Injury to the intima and media allows pulsatile blood to enter the media, leading to dissection formation. Inflammatory cells then infiltrate the site of aortic injury to clear dead cells and damaged tissue. This excessive inflammation may play a role in aneurysm formation after dissection. Methods: Using immunohistochemistry, we compared aortic tissues from patients with acute TAD (n = 11), patients with chronic TAD (n = 35), and donor controls (n = 20) for the presence of CD68+ macrophages, neutrophils, mast cells, and CD3+ T lymphocytes. Results: Tissue samples from patients with acute or chronic TAD generally had significantly more inflammatory cells in both the medial and adventitial layers than did the control samples. In tissues from patients with acute TAD, the adventitia had more of the inflammatory cells studied than did the media. The pattern of increase in inflammatory cells was similar in chronic and acute TAD tissues, except for macrophages, which were seen more frequently in the adventitial layer of acute TAD tissue than in the adventitia of chronic TAD tissue. Conclusions: The inflammatory cell content of both acute and chronic TAD tissue was significantly different from that of control tissue. However, the inflammatory cell profile of aneurysmal chronic TAD was similar to that of acute TAD. This may reflect a sustained injury response that contributes to medial degeneration and aneurysm formation.

Children with probable community-associated Staphylococcus aureus skin and soft tissue or invasive infections were randomized to routine daily hygienic measures with or without "bleach baths" twice a week for 3 months. Within 12 months, a medically attended recurrence occurred in 84 of 495 (17%) children using bleach baths compared to 103 of 492 (21%) of control participants (P = .15).

The prevalence of HIV-positive pregnant women in relationships with HIV-negative men in the United States is unclear. The purpose of this study was to calculate the prevalence of HIV-positive pregnant women with a serodiscordant (HIV-negative) partner within a single clinic population, assess disclosure of their HIV status, and examine factors associated with disclosure. All HIV-positive pregnant women who received prenatal care at the Harris County Hospital District Women's Program at Northwest Health Center in Houston TX between 1/1/2006 and 4/1/2011 were identified. Data were obtained from electronic medical records. Prevalence of serodiscordance and disclosure was calculated, and predictors of disclosure were evaluated. We identified 212 HIV-positive pregnant women. About 40% had a serodiscordant partner, and 34% had a partner with an unknown HIV status. Disclosure occurred in over 90% of women with a serodiscordant partner and in 68% of women with partners whose HIV status was unknown. Among pregnant women who knew their HIV status prior to the current pregnancy and had a serodiscordant partner, 92% reported disclosing their status prior to conception. Our data indicated that serodiscordant relationships are common in our clinic population. Suboptimal disclosure rates were observed, especially among women who have a partner with an unknown HIV status. Further research is needed to evaluate the prevalence of serodiscordance and disclosure in other United States populations.

BackgroundEchocardiographic screening for rheumatic heart disease in asymptomatic children may result in early diagnosis and prevent progression. Physician-led screening is not feasible in Malawi. Task shifting to mid-level providers such as clinical officers may enable more widespread screening.HypothesisWith short-course training, clinical officers can accurately screen for rheumatic heart disease using focussed echocardiography.MethodsA total of eight clinical officers completed three half-days of didactics and 2 days of hands-on echocardiography training. Clinical officers were evaluated by performing screening echocardiograms on 20 children with known rheumatic heart disease status. They indicated whether children should be referred for follow-up. Referral was indicated if mitral regurgitation measured more than 1.5 cm or there was any measurable aortic regurgitation. The κ statistic was calculated to measure referral agreement with a paediatric cardiologist. Sensitivity and specificity were estimated using a generalised linear mixed model, and were calculated on the basis of World Heart Federation diagnostic criteria.ResultsThe mean κ statistic comparing clinical officer referrals with the paediatric cardiologist was 0.72 (95% confidence interval: 0.62, 0.82). The κ value ranged from a minimum of 0.57 to a maximum of 0.90. For rheumatic heart disease diagnosis, sensitivity was 0.91 (95% confidence interval: 0.86, 0.95) and specificity was 0.65 (95% confidence interval: 0.57, 0.72).ConclusionThere was substantial agreement between clinical officers and paediatric cardiologists on whether to refer. Clinical officers had a high sensitivity in detecting rheumatic heart disease. With short-course training, clinical officer-led echo screening for rheumatic heart disease is a viable alternative to physician-led screening in resource-limited settings.

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

To define the mortality and long-term outcomes of children undergoing tracheostomy.Retrospective chart and Texas Department of Health Bureau of Vital Statistics review of patients admitted to a Pediatric Intensive Care Unit who underwent a tracheostomy between 2001 and 2011. Mortality and decannulation rates were compared based on tracheostomy indication and age.A total of 426 patients admitted to a Pediatric Intensive Care Unit in a large tertiary children's hospital.The median patient age was 1.5 years (3 days-24 years). Primary indications for tracheostomy included (a) airway obstruction, (b) congenital neurologic disease, (c) acquired neurologic disease, (d) congenital respiratory disease, and (e) acquired respiratory disease. Overall, 98 patients (23%) died during the study period, and 75th percentile survival time was 5.9 years (95%CI: 3-8). Patients undergoing a tracheostomy for airway obstruction were the least likely to die; while patients with acquired neurologic disease were most likely to die. A total of 163 patients (38%) were decannulated, and 50% were decannulated at 1.2 years (95%CI: 0.9-1.5). Patients with congenital neurologic disease were the least likely to undergo decannulation. Over half of the patients were discharged from the hospital requiring some form of mechanical respiratory support in addition to their tracheostomy.In this largest cohort of long-term follow-up to date, we have shown the overall risk of mortality varied according to the indication for the tracheostomy. We were unable to determine exact causes of death. The likelihood of being decannulated also correlates with the underlying indication for the tracheostomy. Pediatr Pulmonol. 2017; 52:946-953. © 2017 Wiley Periodicals, Inc.

Rheumatic heart disease (RHD) is the largest cardiac cause of morbidity and mortality in the world's youth. Early detection of RHD through echocardiographic screening in asymptomatic children may identify an early stage of disease, when secondary prophylaxis has the greatest chance of stopping disease progression. Latent RHD signifies echocardiographic evidence of RHD with no known history of acute rheumatic fever and no clinical symptoms.Determine the prevalence of latent RHD among children ages 5-16 in Lilongwe, Malawi.This is a cross-sectional study in which children ages 5 through 16 were screened for RHD using echocardiography.Screening was conducted in 3 schools and surrounding communities in the Lilongwe district of Malawi between February and April 2014.Children were diagnosed as having no, borderline, or definite RHD as defined by World Heart Federation criteria. The primary reader completed offline reads of all studies. A second reader reviewed all of the studies diagnosed as RHD, plus a selection of normal studies. A third reader served as tiebreaker for discordant diagnoses. The distribution of results was compared between gender, location, and age categories using Fisher's exact test.The prevalence of latent RHD was 3.4% (95% CI = 2.45, 4.31), with 0.7% definite RHD and 2.7% borderline RHD. There was no significant differences in prevalence between gender (P = .44), site (P = .6), urban vs. peri-urban (P = .75), or age (P = .79). Of those with definite RHD, all were diagnosed because of pathologic mitral regurgitation (MR) and 2 morphologic features of the mitral valve. Of those with borderline RHD, most met the criteria by having pathological MR (92.3%).Malawi has a high rate of latent RHD, which is consistent with other results from sub-Saharan Africa. This study strongly supports the need for a RHD prevention and control program in Malawi.

OBJECTIVE Research has shown that patients transported by nonpediatric teams have higher rates of morbidity and mortality. There is currently a paucity of pediatric standardized ongoing medical education for emergency medical service providers, thus we aimed to develop a model curriculum to increase their knowledge regarding pediatric respiratory distress and failure. METHODS The curriculum was based on the Kolb Learning Cycle to optimize learning. Target learners were flight nurses (registered nurse) and emergency medical technicians of a private helicopter emergency transport team. The topics included were pediatric stridor, wheezing, and respiratory failure. Online modules were developed for continued spaced education. Knowledge gained from the interventions was measured by precurricular and postcurricular testing and compared with paired t tests. A linear mixed regression model was used to investigate covariates of interest. RESULTS Sixty-two learners attended the workshop. Fifty-nine learners completed both precurricular and postcurricular testing. The mean increase between pretest and posttest scores was 12.1% (95% confidence interval, 9.4, 14.8; P < 0.001). Type of licensure (private emergency medical technician vs registered nurse) and number of years experience had no association with the level of knowledge gained. Learners who had greater than 1 year of pediatric transport experience scored higher on their pretests. There was no significant retention shown by those who participated in spaced education. CONCLUSIONS The curriculum was associated with a short term increased knowledge regarding pediatric respiratory distress and failure for emergency helicopter transport providers and could be used as an alternative model to develop standardized ongoing medical education in pediatrics. Further work is needed to achieve knowledge retention in this learner population.

Purpose Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT. Patients and Methods IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined. Results In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342). Conclusion PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors.

Self-injurious behaviors (SIB) are problematic for many children with autism spectrum disorders (ASD). Existing models to explain factors contributing to SIB fail to account for a large proportion of variance in SIB. This study attempted to explain a greater proportion of variance in SIB by addressing methodological/theoretical limitations in previous research using a sample of 2341 youth with ASD. The model comprised of predictors identified by the prior study continued to explain only a small proportion of variance in the SIB score (R (2) = .13). Revisions to the model failed to substantially improve model fit. Results suggest that psychological, cognitive, and behavioral factors alone do not adequately explain common measures of SIB and highlight the need for further research.

An estimated 6000 patients who are undocumented immigrants have end-stage renal disease (ESRD) and routinely present to public safety-net hospitals for life-saving emergent dialysis treatments. Because these patients lack a dialysis unit, they often do not have access to medication management consistently coordinated by a nephrologist, and this can result in more frequent emergency department (ED) utilization and cost of care. We hypothesized that patients who were taking loop diuretics had fewer ED visits for emergency dialysis. Loop diuretics can potentially take advantage of residual renal function and mitigate excess fluid gain that can induce heart failure and high potassium, the two most common indications for emergency dialysis. In our univariable analysis, patients on furosemide had 3.1 fewer ED visits on average compared with patients who are not on furosemide. After adjusting for vintage and serum potassium measures, the average number of ED visits was about 1.1 visits less in furosemide-treated patients compared with patients not receiving furosemide (95% confidence interval, -4.4 to 2.1). These results suggest that loop diuretics may have an important role in undocumented patients with ESRD with residual renal function. Further study to develop practical approaches to the care of undocumented patients with ESRD is greatly needed.

Young children 2 years of age with chronic end-stage liver disease (YC2) are a uniquely vulnerable group listed for liver transplantation, characterized by a predominance of biliary atresia (BA). To investigate wait-list mortality, associated risk factors, and outcomes of YC2, we evaluated United Network for Organ Sharing registry data from April 2003 to March 2013 for YC2 listed for deceased donor transplant (BA = 994; other chronic liver disease [CLD] = 221). Overall, wait-list mortality among YC2 was 12.4% and posttransplant mortality was 8%, accounting for an overall postlisting mortality of 19.6%. YC2 demonstrated 12.2%, 18.7%, and 20.6% wait-list mortality by 90, 180, and 270 days, respectively. YC2 with CLD demonstrated significantly higher wait-list mortality compared with BA among YC2 (23.9% versus 9.8%; P 0.05). Multivariate analyses revealed that listing Pediatric End-Stage Liver Disease [PELD] 21 (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.6-6.5), lack of exception (HR, 5.8; 95% CI, 2.8-11.8), listing height 60.6 cm (HR, 2.1; 95% CI, 1.4-3.1), listing weight 10 kg (HR, 3.8; 95% CI, 1.5-9.2), and initial creatinine 0.5 (HR, 6.8; 95% CI, 3.4-13.5) were independent risk factors for YC2 wait-list mortality (P 0.005 for all). Adjusting for all variables, the risk of death among CLD patients was 2 (95% CI, 1.3-3.1) times greater than patients with BA + surgery (presumed Kasai). Furthermore, the risk of death in BA without surgery was 1.9 (95% CI, 1‐3.4) times greater than BA with presumed Kasai. Our data highlight unacceptably high wait-list and early post-liver transplant mortality in YC2 not predicted by PELD and suggest key risk factors deserving of further study in this age group. Liver Transplantation 22 1584-1592 2016 AASLD.

Optimal care of the pediatric chronic kidney disease/end stage renal disease (CKD/ESRD) patient must now incorporate health-related quality of life (HRQOL) assessment and management.This study reports the first data on longitudinal change in global (PedsQL(TM)4.0) and disease-specific (PedsQL(TM)3.0 ESRD Module) HRQOL pediatric ESRD patient and proxy ratings over four assessment periods spanning approximately a 2-year period. General linear mixed modeling was used to analyze associations between patient demographics, medical variables, and patient and proxy HRQOL scores.Self-reported and/or proxy data were available for at least two time-points for 53 patients (age 2-18 years; 60 % male), of whom 27 were receiving in-center hemodialysis.Patient ratings on global health and physical activity, emotional, and social and disease-specific worry and communication domains were higher (i.e., better) than parent-proxy ratings, confirming the importance of obtaining both sources of information. Patients on dialysis longer, particularly females, reported worse emotional functioning; females also reported more physical appearance concerns. Parents rated older children and those on dialysis longer as functioning worse on multiple global and disease-specific (e.g., fatigue, relationship) domains. Parents also rated children as functioning increasingly worse in school over time. Further, patient ESRD history (acute onset vs. medically managed) impacted how parents viewed the burden of ESRD on their child over time.

Bilateral myringotomy and placement of ventilating tubes (BMT) is one of the most common pediatric surgical procedures in the United States. Many children who undergo BMT develop behavioral changes in the postanesthesia care unit (PACU) and require rescue pain medication. The incidence of these changes is lower in children receiving intraoperative opioids by the nasal, IM, or IV route compared with placebo. However, there are no data to indicate which route of administration is better. Our study was designed to compare the immediate postoperative analgesic and behavioral effects of 3 frequently used intraoperative techniques of postoperative pain control for patients undergoing BMT under general anesthesia.One hundred seventy-one ASA physical status I and II children scheduled for BMT were randomized into 1 of 3 groups: group 1-nasal fentanyl 2 μg/kg with IV and IM saline placebo; group 2-IV morphine 0.1 mg/kg with nasal and IM placebo; or group 3-IM morphine 0.1 mg/kg with nasal and IV placebo. All subjects received a standardized general anesthetic with sevoflurane, N(2)O, and O(2) and similar postoperative care. The primary end point of the study was the pain scores measured by the Faces, Legs, Activity, Cry, and Consolability (FLACC) scale in the PACU.There were no significant differences in peak FLACC pain among the 3 groups (mean [95% CI] 2.0 [1.2-2.8] for intranasal fentanyl, 2.7 [1.7-3.6] for IV morphine, and 2.9 [2.1-3.7] for IM morphine, respectively). There were no differences in the scores on the Pediatric Anesthesia Emergence Delirium (PAED) scale, incidence of postoperative emergence delirium (PAED score ≥ 12), emesis, perioperative hypoxemia, or need for airway intervention, and postoperative rescue analgesia. There were also no differences in the duration of PACU stay or parental satisfaction among the groups.In this double-blind, double-dummy study, there was no difference in the efficacy of intranasal fentanyl, IM and IV morphine in controlling postoperative pain and emergence delirium in children undergoing BMT placement. The IM route is the simplest and avoids the potential for delays to establish vascular access for IV therapy and the risks of laryngospasm if intranasal drugs pass through the posterior nasopharynx and irritate the vocal cords.

Intervention trials such as studies on smoking cessation may observe multiple, discrete outcomes over time. When the outcome is binary, participant observations may alternate between two states over the course of the study. The generalized estimating equation (GEE) approach is commonly used to analyze binary, longitudinal data in the context of independent variables. However, the sequence of observations may be assumed to follow a Markov chain with stationary transition probabilities when observations are made at fixed time points. Participants favoring the transition to one particular state over the other would be evidence of a trend in the observations. Using a log-transformed trend parameter, the determinants of a trend in a binary, longitudinal study may be evaluated by maximizing the likelihood function. A new methodology is presented here to test for the presence and determinants of a trend in binary, longitudinal observations. Empirical studies are evaluated and comparisons are made with the GEE ap...

Transversus abdominis plane (TAP) block has been shown to reduce pain and analgesic requirements after abdominal surgery. Our hypothesis was that bilateral TAP blocks decrease pain after laparoscopic cholecystectomy when compared with local anesthetic infiltration of trocar insertion sites.Eighty patients undergoing laparoscopic cholecystectomy were randomized to receive either bilateral TAP blocks or local anesthetic infiltration of trocar insertion sites with ropivacaine 0.5%. Postoperative pain scores and analgesic use for the first 24 hrs were recorded.Eighty patients were enrolled in the study. After exclusions, data were analyzed on 39 patients in group T (bilateral TAP block) and 35 patients in group I (infiltration). There was no statistically significant difference in pain scores on the numeric analog scale (0-10) between the groups at 4 hrs after surgery (P = 0.18) or during the 24 hrs after surgery (P = 0.23). The time interval from anesthesia start to surgery start was greater in group T than group I (48 vs 35 mins, P0.001). There was no significant difference found in analgesic use during the first 24 hrs after surgery.Bilateral ultrasound-guided TAP block is equivalent to local anesthetic infiltration of trocar insertion sites for overall postoperative pain in a heterogeneous group of patients undergoing laparoscopic cholecystectomy.

Introduction: Low Von Willebrand factor (VWF) activity, considered a bleeding risk factor, is prevalent in some adolescents with heavy menstrual bleeding (HMB), wherein upfront hemostatic therapy may not be readily considered. There is a need to better define this patient subset phenotypically and genotypically, to stratify their risk to bleed, and to tailor their therapy in hopes of preventing complications. In adolescents with HMB and low VWF, we hypothesized that a significant proportion will have disease-causing sequence variations in the VWF gene and/or modifier genes that affect hemostasis, thrombosis or vascular biology, and these will correlate with their bleeding phenotype. Methods: The objectives of this multi-center, single arm, observational cohort study were to 1) study the genotype of adolescent females with HMB and low VWF (≥ 30 and ≤ 50 IU/dL), 2) correlate genotype with bleeding phenotype by Pictorial Blood Assessment Chart (PBAC) score and ISTH bleeding assessment tool (BAT) score. Post-menarchal females < 21 years, with HMB (defined as PBAC score >100) and low VWF were eligible for the study. Patients who did not meet these criteria or diagnosed with other bleeding disorders were ineligible. Members of the Foundation for Women and Girls with Blood Disorders are participating centers in the study. Clinical phenotype data including HMB characteristics, PBAC, BAT, response to desmopressin challenge, management details, clinical outcomes, and laboratory values were obtained. Blood samples were collected for analysis of a 142 gene array that includes VWF, genes involved in hemostasis, thrombosis and vascular biology. DNA sequencing of all exons and intron/exon boundaries was performed; variants were called presumably pathogenic if categorized as damaging by the pipeline with allele frequency Results: 63 subjects were enrolled to date; 1 subject was later found to be ineligible due to detection of another bleeding disorder. The mean age was 16 years (range 11.5-20.2). The median BAT score was 5.0 (N=61; 2-20), median PBAC score was 481 (N=62; 114-8150). 11/48 (23%) had hemoglobin Conclusion: Our study confirms the feasibility of a multi-center study in adolescent females with HMB and low VWF. All subjects had significant bleeding phenotype with elevated BAT and PBAC scores, with complications including anemia, iron deficiency, transfusion requirement, and hospitalization. Response to DDAVP challenge in subjects tested was good and sustained. Potential pathogenic gene variants, not only in VWF, but also in CF and PLT genes were found in 51% of the subjects, which may account for their bleeding phenotype. The separate or the combined presence of VWF, PLT and CF damaging gene variants does not appear to correlate with the subjects' bleeding severity in this interim analysis. A larger sample size and further analysis of gene variants may provide more information regarding the phenotype/genotype correlation in this patient population. Study supported by an investigator-initiated research grant from Baxalta US Inc., now part of Shire Disclosures Srivaths: Shire: Research Funding. Kulkarni:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octa Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kedrion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; BPL: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mullins:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ragni:Sangamo: Research Funding; Bioverativ: Consultancy, Research Funding; Shire: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Novo Nordisk: Research Funding. Kouides:Octapharma: Research Funding; UniQure: Other: DSMB.

Ramucirumab (RAM) is a high affinity, humanized, monoclonal antibody that binds to the extra-cellular domain of the vascular endothelial growth factor receptor (VEGFR). RAM prevents the binding of VEGF ligands with VEGFR-2, the most potent receptor of the VEGF tumor angiogenesis pathway. RAM is FDA approved for adults with NSCLC, as well as for gastric and colorectal adenocarcinoma where higher exposure was associated with better outcomes. Based on population pharmacokinetic (PK) analysis of the adult data, a minimum steady state concentration (Cmin ss) of ≥ 50 µg/ml of RAM was considered the target concentration for pediatrics. The Children's Oncology Group (COG) conducted a phase 1 study using a rolling six design to define the maximum tolerated dose (MTD) and /or a recommended phase 2 dose (RP2D), evaluate toxicities and explore circulating angiogenic cells as a biomarker for RAM monotherapy in children with recurrent/refractory solid tumors. The starting dose of 8 mg/kg IV q2 weeks (DL1) was chosen based on the adult safety profile and effective Cmin ss. Since adult data suggested that lower body weight was associated with lower Cmin ss, dose escalation to 12 mg/kg IV q2 weeks (DL2) was planned provided the MTD was not exceeded in DL1 and up to 16 mg/kg IV q2 weeks (DL3) if Cmin ss was < 50 µg/ml in 1 of 6 subjects on DL2 without exceeding the MTD. An expansion cohort was planned at the lowest dose where at least 5 of 6 subjects exceeded the target in order to generate PK data in at least 6 additional subjects < 12 years of age. In the absence of an MTD, the RP2D was defined as the dose achieving Cmin ss ≥ 50 µg/ml on day 42 ± 2, after 3 doses of RAM administered IV every 2 weeks, in at least 10 of 12 subjects. Sixteen subjects (15 eligible; 7 females), median age of 14 years (3-21 yrs.) have been enrolled. Of the 7 subjects on DL1, two had insufficient PK sampling to establish Cmin ss, including 1 who experienced grade 2 proteinuria (DLT). In the remaining 5, the median (range) Cmin ss was 66 (40-136) µg/ml; 2/5 did not achieve the target of ≥ 50 µg/ml. Of the 8 subjects on DL2, two had insufficient PK sampling, including 1 with grade 2 proteinuria (DLT). In the remaining 6, the median (range) Cmin ss was 64 (51-101) µg/ml, all ≥ 50 µg/ml; thus 12mg/kg IV q2 weeks was identified for the expansion cohort. The most common RAM related non-DLT toxicities were grade 1/2 headache in 6 subjects, grade 1/2 elevation in aspartate aminotransferase in 7 subjects and grade 2/3 hypertension in 2 subjects. Due to low participation, circulating angiogenic cells could not be analyzed. This is the first COG study in which dose escalation and RP2D for a targeted agent incorporated a primary PK endpoint (Cmin ss) based upon efficacy data from adult studies and paves the way for similar study design for future phase-1 studies. Citation Format: Kamnesh Pradhan, Stacey L. Berg, Xiaowei Liu, Charles G. Minard, James Croop, Joel M. Reid, Elizabeth Fox, Brenda J. Weigel. A dose escalation and toxicity study using pre-determined target concentration of Ramucirumab, a novel anti-angiogenic agent in children with recurrent / refractory solid tumors: A report from the children's oncology group phase I/ pilot consortium (ADVL1416) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT054.

10556Background: Histone modification plays a key role in oncogenesis and progression of malignancy. Histone deacetylase (HDAC) inhibition has shown promise as anti-cancer therapy. Entinostat is an...

Background We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Methods Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Results Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m2 /day. At 40 mg/m2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). Conclusions A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m2 /day. A phase 2 study of cabozantinib is being conducted.

BACKGROUND Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation. METHODS Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (

Malawi, Africa has a high prevalence of rheumatic heart disease (RHD). Echocardiographic (echo) screening for RHD in asymptomatic children may enable early diagnosis and treatment in order to prevent progression of RHD. Malawi has few physicians, and no pediatric cardiologists in the country. Therefore, physician-led RHD screening is not feasible. Clinical officers (CO’s) are mid-level providers who may be able to perform RHD echo screening. Hypothesis: After training, CO’s will have similar results in identifying RHD by echocardiography as a pediatric cardiologist. Methods: 8 CO’s with no previous echo experience completed 3 half-days of didactic and computer-module based training as well as 2 days of clinical attachments at a local school. On the attachments, CO’s completed an average of 60 mentored RHD screening echos with a Philips portable CX50 echo machine. CO’s were evaluated by performing screening echos on 20 children with and without RHD who were screened in the previous year. They indicated whether the children should be referred for follow-up. Screening protocol called for referral if a mitral regurgitation jet measured more than 1.5 cm or an aortic regurgitation jet measured more than 1 cm. Kappa statistic was calculated based on agreement with a pediatric cardiologist’s screening result (referral vs. no referral). Sensitivity and specificity were estimated using a generalized linear mixed model. Results: The mean kappa statistic comparing CO reads to the pediatric cardiologist was 0.72 (95% CI: 0.62, 0.82). Kappa ranged from a minimum of 0.57 to a maximum of 0.90. Overall, sensitivity was 0.92 (95% CI: 0.86, 0.95), and specificity was 0.80 (95% CI: 0.68, 0.88). Conclusion: There is substantial agreement between the CO and pediatric cardiologist diagnoses. In addition, CO’s had a high sensitivity in detecting RHD. With short-course training, CO-led echo screening for RHD is a viable alternative to physician-led screening in resource-limited settings.

Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported. Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes. Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living. The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype–phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies. Genet Med 18 11, 1111–1118.

Collagen Metabolism Biomarkers and Health Related Quality of Life in Pulmonary Arterial Hypertension Objectives: The goal of this study was to investigate the association between collagen metabolism biomarkers and health related quality of life (HRQoL) in PAH patients. Methods: We prospectively enrolled 68 stable idiopathic, anorexigen-associated, and hereditary PAH subjects and 37 healthy controls. Serum samples were analyzed for N-terminal propeptide of type III procollagen (PIIINP), c-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). The Minnesota Living with Heart Failure (MLWHF), EQ-5D (EQ-5D), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and Short Form (SF-36) general health survey were administered at the time of blood draw. General linear models, as well as logistic regression models were used to assess associations between variables. Results: CITP, PIIINP, MMP9, and TIMP1 levels, and all HRQoL domains were significantly different between controls and PAH patients (p

Objective: The aim of this study is to analyze the body composition of patients receiving emergent dialysis and compare their body cell mass (BCM) and fat-free mass (FFM) with those of normal subjects. The care of patients receiving sporadic, emergent dialysis treatment is a growing public health concern and the magnitude of muscle wasting that occurs in this population is not known. Design and Methods: We used a cross-sectional design with matching to determine differences in total body potassium - an indicator of both BCM and FFM - between emergent dialysis patients and healthy normal subjects. We studied 22 subjects using a 40K counter that measures BCM and FFM and compared them to controls after matching with sex, height and weight. Results: In the matched comparison, BCM and FFM were significantly lower in subjects with end-stage renal disease (ESRD). Unadjusted BCM was 4.7 kg lower and FFM was 8.8 kg lower for those with ESRD compared to those without ESRD (p < 0.001, p < 0.001, respectively). Comparison with unmatched controls who underwent 40K analysis also revealed significantly lower BCM (4.1 kg) and FFM (7.7 kg) in the ESRD subjects (p = 0.004). After adjusting for age, height, weight and gender, BCM and FFM were lower by 4.2 and 7.8 kg, respectively (p < 0.001). Repeated observations were available for a subset of ESRD subjects, and the rate of FFM loss over time was significant, with the ESRD subjects demonstrating 2.2 kg per year decline (p = 0.01). Conclusion: We conclude that among other consequences, muscle wasting indicated by decline in BCM and FFM is a significant concern in the growing emergent dialysis population.

Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age- and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly +/- splenomegaly; (2) >6 months elevation of ALT (>1.5x upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cut-off values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60; P = 0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score >0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC] = 0.91; P < 0.001). Conclusion: This is the first liver biopsy-validated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages. (Hepatology 2015;62:1576-1583)

OBJECTIVE: To investigate the association of neonatal hypoglycaemia and hyperglycaemia with outcomes in infants with hypoxic ischaemic encephalopathy (HIE).DESIGN: Post hoc analysis of the CoolCap Study.SETTING: 25 perinatal centres in the UK, the USA and New Zealand during 1999-2002.PATIENTS: 234 infants at ≥36 weeks' gestation with moderate-to-severe HIE enrolled in the CoolCap Study. 214 (91%) infants had documented plasma glucose and follow-up outcome data.INTERVENTION: Infants were randomised to head cooling for 72 h starting within 6 h of birth, or standard care. Plasma glucose levels were measured at predetermined time intervals after randomisation.MAIN OUTCOME MEASURE: The unfavourable primary outcome of the study was death and/or severe neurodevelopmental disability at 18 months. Hypoglycaemia (≤40 mg/dL, ≤2.2 mmol/L) and hyperglycaemia (>150 mg/dL, >8.3 mmol/L) during the first 12 h after randomisation were investigated for univariable and multivariable associations with unfavourable primary outcome.RESULTS: 121 (57%) infants had abnormal plasma glucose values within 12 h of randomisation. Unfavourable outcome was observed in 126 (60%) infants and was more common among subjects with hypoglycaemia (81%, p=0.004), hyperglycaemia (67%, p=0.01) and any glucose derangement within the first 12 h (67%, p=0.002) compared with normoglycaemic infants (48%) in univariable analysis. These associations remained significant after adjusting for birth weight, Apgar score, pH, Sarnat stage and hypothermia therapy.CONCLUSIONS: Both hypoglycaemia and hyperglycaemia in infants with moderate-to-severe HIE were independently associated with unfavourable outcome. Future studies are needed to investigate the prognostic significance of these associations and their role as biomarkers of brain injury.TRIAL REGISTRATION NUMBER: (ClinicalTrials.gov NCT00383305).

Objectives: It is not known whether aldosterone levels are associated with increased mortality in patients with pulmonary arterial hypertension (PAH). The primary goal of this study was to determine whether circulating aldosterone levels predict severity of PAH in terms of hemodynamic characteristics and mortality. Methods: Patients with stable PAH were enrolled at the Baylor PH program. The plasma levels of aldosterone and BNP were measured. Clinical, hemodynamic, and outcome data was collected by chart review. Mean follow up time from study enrollment was 39 ± 102 months. Cox proportional hazards model was used to assess time to death. Results: There were 125 PAH patients with plasma aldosterone levels. Median aldosterone level was 9.9 pg/ml (25th-75th percentile: 4.1 pg/ml, 27.1 pg/ml) and median brain natriuretic peptide (BNP) level was 67.5 pg/ml (25th- 75th percentile: 31 pg/ml, 225 pg/ml). Aldosterone levels were not significantly associated with BNP levels, six-minute walk distance, Borg dyspnea score, right ventricular systolic pressure, cardiac output and cardiac index. However, the association between aldosterone and right atrial pressure was dependent on mineralocorticoid receptor blocker treatment (Coef.=2.88, 95CI: 1.19, 4.56, p=0.001). By log-rank statistic there was no statistical difference between the survival of patients divided by median aldosterone level (p=0.914). However, there was a significant difference in patient survival between the BNP categories (p 180 pg/mL) had a shorter survival time. conclusions: The aldosterone level was not associated with increased mortality in PAH but was a marker of disease severity.

Background. Peritoneal dialysis (PD) is an underutilized dialysis modality in the United States, especially in urban areas with diverse patient populations. Technique retention is a major concern of dialysis providers and might influence their approach to patients ready to begin dialysis therapy.Methods. Records from January 2009 to March 2014 were abstracted for demographic information, technique duration, and the reasons for withdrawal.Results. The median technique survival of the 128 incident patients during the study window was 781 days (2.1 years). The principle reasons for PD withdrawal were repeated peritonitis (30%); catheter dysfunction (18%); ultrafiltration failure (16%); patient choice or lack of support (16%); or hernia, leak, or other surgical complications (6%); and a total of 6 patients died during this period. Of the patients who did not expire and were not transplanted, most transferred to in-center hemodialysis and 8% transitioned to home-hemodialysis.Conclusions. Our findings suggest measures to ensure proper catheter placement and limiting infectious complications should be primary areas of focus in order to promote technique retention. Lastly, more focused education about home-hemodialysis as an option may allow those on PD who are beginning to demonstrate signs of technique failure to stay on home therapy.

BACKGROUND The objective of this study was to evaluate the effects of polymorphisms in 2 genes in the glutathione S-transferase (GST) family and the mutagen-sensitivity phenotype on the risk of second primary tumors (SPTs) in patients with previously diagnosed early-stage head and neck squamous cell carcinoma. Data were available for 303 patients who were enrolled in a placebo-controlled chemoprevention trial of low-dose 13-cis-retinoic acid to reduce the occurrence of SPTs. METHODS A Cox proportional hazards model and survival tree analysis were used to evaluate the association between specified genetic variations and the development of SPTs. The average number of bleomycin-induced chromatid breaks per cell was used to quantify mutagen sensitivity as an individual patient's degree of sensitivity to genotoxicity. RESULTS The GST-M1 null genotype was associated with an increased risk for any SPTs (hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.11-3.56) and for tobacco-related SPTs (HR, 2.16; 95% CI, 1.01-4.62) after adjusting for covariates. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with a statistically significant increased risk for SPTs or tobacco-related SPTs after similar adjustment. Simultaneous nonnull status for both GST genotypes was associated with a decreased risk for any SPTs (HR, 0.52; 95% CI, 0.28-0.96) and tobacco-related SPTs (HR, 0.50; 95% CI, 0.22-1.11) compared with null status for GST-M1 accompanied by nonnull status for GST-T1. CONCLUSIONS An association was observed between the development of SPTs and the GST-M1 null genotype after successful treatment for early-stage head and neck squamous cell carcinoma. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with an increased risk, and no significant interactions were identified. Cancer 2006. © 2006 American Cancer Society.

Background Non-typhoidal Salmonella (NTS) causes approximately 1.2 million illnesses per year in the United States. There are very few pediatric studies which has investigated the risk factors for NTS bacteremia in healthy children with NTS gastroenteritis (NTS-AGE). Methods This was a retrospective study of children admitted to Texas Children’s Hospital, Houston, TX, with NTS-AGE from 2007–2016. Exclusion criteria included: patients aged ≤3 m or > 18 years, immunodeficiencies, hemoglobinopathies, extraintestinal manifestations or those in whom blood cultures were not obtained. Demographics, clinical and laboratory data were collected from electronic medical records. Patients with NTS bacteremia (NTS-B) were compared with patients who were non-bacteremic (NTS-NB). Results Of 350 patients reviewed, 83 patients met inclusion criteria: 53 with NTS-B and 30 NTS-NB. The median age of diagnosis was 1.58 years (range 3.5 months-18 years). Thirty-nine patients (47.0%) were female and 44 (53.0%) were male. Majority of patients were non-Hispanic White (n = 70; 84.3%). The most common serotype was Salmonella Group C (n = 41(49.4%). There was no difference in risk factors between NTS-B vs. NTS-NB in terms of age, duration of diarrhea prior to admission, travel or pet exposure, prior antibiotic exposure or white blood cell count at presentation. Duration of fever prior to admission was statistically significant with median duration for NTS-B being 6.11 days compared with NTS-NB at 1.97 days (P = 0.0000006). There was an increased trend for bacteremia in males and Salmonella Group C bacteremia (P = 0.07 and P = 0.08 respectively). Conclusion To our knowledge this is first pediatric study in the United States to evaluate risk factors for NTS bacteremia in healthy children with NTS-AGE. Duration of fever prior to admission was associated with increased risk of NTS-B along with increased trend with males and infection with Group C Salmonella. These risk factors should prompt clinicians to monitor patients with NTS-AGE closely and help in deciding whether antimicrobials are warranted or not. Disclosures All authors: No reported disclosures.

Background Although previous single-center studies report the rate of anaphylaxis for oral food challenges (OFCs) as 9% to 11%, little is known regarding the epidemiology of clinical OFCs across multiple centers in the United States. Objective To examine the epidemiology, symptoms, and treatment of clinical low-risk OFCs in the nonresearch setting. Methods Data were obtained from 2008 to 2013 through a physician survey in 5 food allergy centers geographically distributed across the United States. Allergic reaction rates and the association of reaction rates with year, hospital, and demographics were determined using a linear mixed model. Meta-analysis was used to pool the proportion of reactions and anaphylaxis with inverse-variance weights using a random-effects model with exact confidence intervals (CIs). Results A total of 6,377 OFCs were performed, and the pooled estimate of anaphylaxis was 2% (95% CI, 1%-3%). The rate of allergic reactions was 14% (95% CI, 13%-16%) and was consistent during the study period ( P = .40). Reaction rates ranged from 13% to 33%. Males reacted 16% more frequently than females (95% CI, 4%-37.5%; P = .04). Foods challenged in 2013 varied geographically, with peanut as the most challenged food in the Northeast, Midwest, and West and egg as the most challenged in the South. Conclusion As the largest national survey of allergic reactions of clinical open OFCs in a nonresearch setting in the United States, this study found that performing clinical nonresearch open low-risk OFCs results in few allergic reactions, with 86% of challenges resulting in no reactions and 98% without anaphylaxis.

Background: Inhibition of the WEE1 kinase by AZD1775 potentiates replicative stress induced by oncogenes or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. A pediatric phase I dose escalation study of AZD1775 in combination with irinotecan was completed within the COG DVL consortium. Methods: Patients age 1-21 years with relapsed/refractory solid or CNS tumors were eligible. Both agents were administered orally once daily on days 1-5 of a 21-day cycle with a step-wise inter-patient dose escalation of both agents. AZD1775 dose levels (DL) were 50 mg/m2 (DL1), 65 mg/m2 (DL 2 and 3), 85 mg/m2 (DL4) and 110 mg/m2 (DL5). Irinotecan, 70 mg/m2 day (DL 1-2), or 90 mg/m2/day (DL3-5), was administered with cefixime for diarrheal prophylaxis. Toxicity was graded according to CTCAE v4.0. Results: Thirty-one eligible patients, median age 14 years (range 5-20) were enrolled; 29 (93%) received prior chemotherapy (median 3 regimens) and 25 (81%) received prior radiation therapy. Sixteen patients had a primary CNS malignancy: malignant glioma (9), ependymoma (4), medulloblastoma (2) and CNS Ewings sarcoma (1). Fifteen patients had extracranial solid tumors: soft tissue sarcoma (6), neuroblastoma (2), carcinoma (4), osteosarcoma (2) and Wilms’ Tumor (1). The most common toxicities were hematologic and gastrointestinal (nausea, vomiting, diarrhea). Two patients experienced dose limiting toxicity, grade 3 diarrhea and dehydration at DL5 (AZD1775 110 mg/m2 and irinotecan 90 mg/m2). Conclusion: This is the first pediatric clinical trial of AZD1775 in combination with chemotherapy. The maximum tolerated dose in children and adolescents with solid tumors was AZD1775 85 mg/m2/day in combination with irinotecan 90 mg/m2/day for five days every 21 days. Accrual is ongoing for a pediatric PK expansion, PD analysis and Phase 2 expansion in patients with neuroblastoma or medulloblastoma / CNS PNET. Clinical trial information: NCT02095132 Citation Format: Kristina A. Cole, Joel M. Reid, Xiaowei Liu, Charles G. Minard, John M. Maris, Elizabeth Fox, Brenda J. Weigel. Pediatric phase I trial of the WEE1 inhibitor AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT144. doi:10.1158/1538-7445.AM2017-CT144

10526 Background: Checkpoint inhibitors have produced impressive responses in cancer. We report results of a Phase 1 study of nivolumab (nivo) alone and in combination with ipilumumab (ipi) in children with relapsed/refractory solid tumors and activity of nivo in patients with osteosarcoma (OS) and Ewing sarcoma (EWS) treated with the RP2D. Methods: Children with relapsed/refractory solid tumors (excluding CNS tumors or metastases) were eligible for Phase I Cohorts A and C. Using a rolling 6 design, Cohort A tested nivo at the adult RP2D, 3mg/kg Q14d (cycle = 28d). Cohort C tested nivo + ipi at 2 dose levels (DLs): DL1 nivo 1mg/kg + ipi 1mg/kg and DL2 nivo 3mg/kg + ipi 1mg/kg Q21d x 4 then nivo alone Q14d. At the RP2Ds, 6 additional patients were enrolled in each cohort for pharmacokinetics (PK). Phase II expansion cohorts enrolled patients with measurable OS (Cohort B2, n = 10) or EWS (Cohort B4, n = 10) respectively to assess activity of the RP2D of single agent nivo. Results: Twelve evaluable patients enrolled in Cohort A, none had DLTs. The pediatric RP2D of nivo alone was identified as 3 mg/kg Q14d. Five evaluable patients enrolled in Cohort C:DL1 without DLT, then 12 patients enrolled in Cohort C:DL2 with one DLT within the 21d reporting period (Gr 2 creatinine increase), defining the RP2D of nivo 3mg/kg + ipi 1mg/kg at the schedule above. In 39 patients treated in cohorts A, B2, B4 and C, pleural effusions occurred in 7 with variable attributions to drug, leading to a protocol amendment mandating supportive care and corticosteroids for pleural effusions on study. Common toxicities included anemia, elevated liver enzymes, rash, fatigue, and nausea, generally Grade 1. In Cohort A, nivo Cmax, t1/2 and Clpvalues were 63.2±15.7 mg/mL, 10.7±1.8 d and 0.196±0.075 ml/h/kg, respectively. In the Phase II expansion cohorts, no objective responses were observed in OS or EWS. Conclusions: Nivo alone or with ipi at the doses tested is safe in pediatric patients with relapsed/refractory solid tumors. The pediatric RP2D of nivo is 3mg/kg alone or in combination with ipi 1mg/kg. Single agent nivo did not have antitumor activity in OS or EWS. Enrollment to other expansion cohorts with nivo or nivo/ipi is ongoing. Clinical trial information: NCT02304458.

Opera performance is physiological and emotional, and singing performers utilize their larynges in often strenuous ways. Historically, the training of a classical voice has been considered the paragon of healthy singing. However, the natural history of a performing larynx has not been studied systematically. There is paucity of scientific studies to guide practice patterns, particularly with regard to the course and extent of post-performance physiologic and acoustic changes.A prospective case series was carried out.Principal singers in the Houston Grand Opera's 2012-2013 repertory were enlisted, for a total of seven singers. Stroboscopy was performed prior to the start of rehearsals, and at the completion of the opera's run. Data points included erythema, edema, masses or lesions, mucosal waveform, supraglottic posture; acoustic measurements were also performed.There were statistically significant differences (P 0.05) in the mucosal wave on pre- and postperformance stroboscopic examinations. Acoustical measures did not achieve statistical significance, but there was a trend toward increased harmonic-to-noise ratio in postperformance measures, as well as decreased frequency range and reading FThis pilot study describes physiologic and acoustic changes that may occur over the course of a series of rehearsals and performances in the operatic larynx. In so doing, it highlights a need for larger studies with increased frequency of serial examinations to study in a systematized way what may be natural reactive changes that occur during performance.

Perioperative respiratory complications after adenotonsillectomy (TA) are common and have been described to occur more frequently in children below 3 years of age, those with cranio-facial abnormalities, Down syndrome, obstructive sleep apnea, morbid obesity, and failure to thrive.To investigate the association between awake vs deep tracheal extubation and perioperative respiratory conditions.The primary outcome was any perioperative respiratory complication. Major complications included the need for airway reinstrumentation, continuous or bi-level positive airway pressure (CPAP or BiPAP) and ventilation, or pharmacologic intervention for managing airway obstruction. Minor respiratory complications included persistent hypoxemia defined as oxygen saturation (SpO2 )92% for ≥30 s or postoperative oxygen dependence for hypoxemia for ≥15 min. There was no statistically significant difference in the incidence of any perioperative respiratory complication in children undergoing an awake vs deep extubation (18.5% and 18.9% for awake and deep extubation, respectively (P = 0.93)). Only low weight (≤14 kg) was associated with increased perioperative respiratory complications (P = 0.005). In this study, factors found not to be statistically significant with perioperative respiratory complications included age; presence of Down syndrome, cranio-facial abnormality, or cerebral palsy; obstructive sleep apnea confirmed by polysomnography; diagnosis of obstructive sleep apnea by clinical history; presence of an upper respiratory tract infection (URI) within 2 weeks of presentation; history of reactive airway disease; status at extubation; endtidal sevoflurane and carbon dioxide concentrations at extubation; total intraoperative opioids administered in morphine equivalents (mg·kg(-1) ); administration of propofol at extubation; and intraoperative administration of an anticholinergic drug.There was no difference in the incidence of perioperative respiratory complications in children undergoing a TA following an awake vs deep extubation. Only weight ≤14 kg was associated with increased perioperative respiratory complications.

Death in tertiary care neonatal intensive care units is a common occurrence. Despite recent advances in pediatric palliative education, evidence indicates that physicians are poorly prepared to care for dying infants and their families. Numerous organizations recommend increased training in palliative and end-of-life care for pediatric physicians. The purpose of this study is to develop a structured end-of-life curriculum for neonatal-perinatal postdoctoral fellows based on previously established principles and curricular guidelines on end-of-life care in the pediatric setting. Results demonstrate statistically significant curriculum effectiveness in increasing fellow knowledge regarding patient qualification for comfort care and withdrawal of support (P = .03). Although not statistically significant, results suggest the curriculum may have improved fellows' knowledge of appropriate end-of-life medical management, comfort with addressing the family, and patient pain assessment and control.