Search

Purpose: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. Patients and Methods: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. Results: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. Conclusions: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

Background Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial. Methods Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. Results Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects. Conclusion GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193

Access to high quality and accessible online health information (OHI) is critical for reducing disparities, overcoming barriers, and improving the health of women with disabilities. This study aimed to understand women with physical disabilities' use of the Internet to access OHI, most often searched health topics, perceived usefulness of OHI, and self-reported eHealth literacy and challenges in OHI seeking.We conducted a national online survey with 508 women with physical disabilities who used the Internet.Respondents utilized a wide variety of OHI resources. They searched a broad array of health and disability-related topics, with bowel/bladder and finding a physician the most highly searched topics. They generally had confidence in their eHealth literacy skills and ability to understand statistics in OHI. Nevertheless, although our sample consisted of a majority of highly educated internet-users, a sizeable percentage found OHI seeking difficult and frustrating, did not find the information very helpful, and had concerns about the quality of information.This study serves as a call to action to disability and rehabilitation scientists, health care providers, and other health professionals to enhance the availability and accessibility of OHI critical to empowering women with physical disabilities to make well-informed health decisions. Implications for rehabilitationAccess to high quality online health information (OHI) is critical for reducing disparities, overcoming barriers, and improving the health of women with disabilities.Many of the women with disabilities in our study found OHI seeking difficult and frustrating, did not find the information very helpful, and had concerns about the quality of the information.Disability and rehabilitation scientists, health care providers, and public health and health policy professionals need to do more to enhance the availability and accessibility of OHI and resources critical to empowering women with physical disabilities to make well-informed health decisions.Physical medicine and rehabilitation scientists are encouraged to develop and improve assistive technologies needed for accessing OHI, which in turn can promote the independent functioning of people with disabilities.

Purpose:In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.Patients and Methods:ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed.Results:Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed.Conclusions:The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

Supplementary information

Supplementary Figure 1. Nivolumab (A) and Ipilumumab (B) peak and trough concentrations in treatment cycles 1 – 4.

STUDY OBJECTIVES: (1) To determine the sensitivity and specificity of the home sleep apnea test (HSAT) performed in typically developing children who were diagnosed with moderate to severe obstructive sleep apnea during overnight attended laboratory polysomnography (LPSG). (2) To determine the utility of a screening questionnaire to identify children at increased risk for obstructive sleep apnea. METHODS: Participants completed 2 consecutive study nights, the first night with the HSAT followed by LPSG on the second night. The SHOOTS questionnaire, composed of 6 questions (snoring, hyperactivity, obesity, observed apnea, tonsillar hypertrophy, and sleepiness) concerning sleep-disordered breathing, was administered by the clinician before the first study night. RESULTS: Thirty-eight participants completed both studies. The mean age was 13.8 ± 3.0 years. Twenty (53%) were male. Most participants were obese. The mean LPSG total sleep time was 7.34 ± 1.19 hours; the mean HSAT total recording time was 8.86 ± 1.73 hours (P < .001). The median obstructive apnea-hypopnea index for LPSG and HSAT was 6.6 and 0.8 events/h, respectively. For an obstructive apnea-hypopnea index ≥ 3.1 events/h by HSAT, the sensitivity was 71.43% (95% confidence interval, 41.9–91.6) and the specificity was 95.83% (95% confidence interval, 78.9–99.9) for identifying those with an LPSG obstructive apnea-hypopnea index of ≥ 10 events/h. For a SHOOTS score with ≥ 4 “yes” responses, the sensitivity and specificity were 85.7% (95% confidence interval, 57.2–98.2) and 54.2% (95% confidence interval, 32.8–74.4), respectively, for identifying those with an LPSG obstructive apnea-hypopnea index ≥ 10 events/h. CONCLUSIONS: Using HSAT, we clinically applied cutoff values to identify moderate to severe obstructive sleep apnea in typically developing children. The SHOOTS questionnaire may aid in identifying children at risk for obstructive sleep apnea and who are candidates for HSAT. CITATION: Revana A, Vecchio J, Guffey D, Minard CG, Glaze DG. Clinical application of home sleep apnea testing in children: a prospective pilot study. J Clin Sleep Med. 2022;18(2):533–540.

Key Points HMB is associated with rare and common variants in genes related to anemias and bleeding disorders.These are the first exome-sequencing results from patients with HMB, as well as their comparison with control exomes., Visual Abstract, Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar “pathogenic” variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar “pathogenic” variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10−6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Purpose:Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.Patients and Methods:Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.Results:Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.Conclusions:Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.

Purpose:Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration.Patients and Methods:Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study.Results:The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count.Conclusions:Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.See related commentary by Schulte and Eggert, p. 3507

S1. Patient Characteristics of eligible (n=37) and MTD/RP2D evaluable (n=27) patients S1B. Diagnosis of eligible (n=37) and MTD/RP2D evaluable (n=27) patients. S2. In Cycle 1, All Hematologic and Non-Hematologic toxicities related to protocol therapy in evaluable patients (N=27)

Supp Table 1

OBJECTIVE The optimal management of pediatric craniopharyngioma patients remains controversial, shifting from radical resection (gross-total resection [GTR]) to a more conservative approach with partial resection/biopsy followed by radiotherapy (PR+RT). To the authors’ knowledge, no previous studies have compared neurocognitive and quality-of-life (QOL) outcomes between the two main treatments. In this study, the authors compared changes in intellectual, adaptive, and QOL scores in children treated for craniopharyngioma with GTR and those treated with PR+RT. METHODS Patients underwent annual neurocognitive and QOL evaluations for up to 10 years posttreatment, including the Full-Scale IQ, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI). Child- and parent-reported QOL scores and adaptive behavior in different domains were assessed. General linear mixed models were used to examine change in scores over time by treatment group with adjustment for significant covariates. RESULTS Scores from 43 patients treated between 2009 and 2019 (21 GTR, 22 PR+RT) were examined. Within the PR+RT group, 9 patients had intensity-modulated RT and 13 had proton beam therapy. The treatment groups were similar in sex (44% male) and age (median 7.3 years). There were no significant differences in the trajectory of intellectual functioning or QOL scale scores between the two groups. However, patients who underwent GTR exhibited significant improvement over time in overall adaptive behavior (p = 0.04) and conceptual skills (p = 0.01), which was not observed in patients treated with PR+RT. CONCLUSIONS Long-term pediatric craniopharyngioma survivors treated with GTR and PR+RT have similar intellectual function and QOL. Larger studies are needed to explore small but clinically significant differences between the two groups.

Background/aimsMarkers to clinically evaluate structural changes from diabetic retinal neurodegeneration (DRN) have not yet been established. To study the potential role of peripapillary retinal nerve fibre layer (pRNFL) thickness as a marker for DRN, we evaluated the relationship between diabetes, as well as glycaemic control irrespective of diabetes status and pRNFL thickness.MethodsLeveraging data from a population-based cohort, we used general linear mixed models (GLMMs) with a random intercept for patient and eye to assess the association between pRNFL thickness (measured using GDx) and demographic, systemic and ocular parameters after adjusting for typical scan score. GLMMs were also used to determine: (1) the relationship between: (A) glycated haemoglobin (HbA1c) irrespective of diabetes diagnosis and pRNFL thickness, (B) diabetes and pRNFL thickness and (2) which quadrants of pRNFL may be affected in participants with diabetes and in relation to HbA1c.Results7076 participants were included. After controlling for covariates, inferior pRNFL thickness was 0.94 µm lower (95% CI −1.28 µm to −0.60 µm), superior pRNFL thickness was 0.83 µm lower (95% CI −1.17 µm to −0.49 µm) and temporal pRNFL thickness was 1.33 µm higher (95% CI 0.99 µm to 1.67 µm) per unit increase in HbA1c. Nasal pRNFL thickness was not significantly associated with HbA1c (p=0.23). Similar trends were noted when diabetes was used as the predictor.ConclusionSuperior and inferior pRNFL was significantly thinner among those with higher HbA1c levels and/or diabetes, representing areas of the pRNFL that may be most affected by diabetes.

BACKGROUND & AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH & RESULTS: A targeted ELISA-based panel of 9 biomarkers (lysyl oxidase (LOX), tissue inhibitor matrix metalloproteinase 1 (TIMP1), connective tissue growth factor (CTGF), interleukin-8 (IL-8), endoglin, periostin, mac-2-binding protein (mac2-BP), matrix metalloproteinase-3 and −7 (MMP-3, MMP-7) was examined in children with biliary atresia (BA, n=187), alpha-1 antitrypsin deficiency (A1AT, n=78) and Alagille syndrome (ALGS, n=65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations between LSM and endoglin (p=0.04), IL-8 (p

Aims/hypothesis TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. Methods We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0–92.2). Results Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, pp=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). Conclusions/interpretation Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals. Graphical abstract

Parents of children with autism spectrum disorder (ASD) may be at greater risk for developing antivaccine beliefs that lead to vaccine delays and/or refusals for their children. We investigated current parental vaccine hesitancy, parents’ beliefs about causes of children’s developmental delays, and children’s vaccination histories among parents of children with ASD or non-ASD developmental delays. Data were analyzed from 89/511 parents (17.4%) who completed the Parent Attitudes About Childhood Vaccines questionnaire and the Revised Illness Perception Questionnaire; 46.1% had childhood vaccination records available. Overall, 21/89 (23.6%, 95% confidence interval [CI]: 15.0-34.0) of parents were vaccine hesitant (ASD n = 19/21 [90.5%], non-ASD n = 2/21 [9.5%]). Parents of children with ASD were significantly more likely to agree with “toxins in vaccines” as a cause of their child’s developmental delays (28.4% vs 5.0%, P = .034). The odds of being vaccine hesitant were 11.9 times (95% CI 2.9-48.0) greater among parents who agreed versus disagreed that toxins in vaccines caused their children’s developmental delays. Rates of prior vaccine receipt did not differ between hesitant and nonhesitant groups.

Introduction: Tegavivint is a first in class small molecule inhibitor of Wnt-ß-catenin signaling that functions by disrupting the interaction of ß-catenin and TBL1/TBLR1 resulting in degradation of nuclear ß-catenin. Aberrant Wnt signaling has been identified as a key mechanism of cancer biology, resulting in uncontrolled transcription of pro-oncogenic Wnt target genes. Pre-clinical in vivo studies of tegavivint demonstrated anti-tumor activity in a variety of pediatric solid tumors, including osteosarcoma, Ewing sarcoma, and lymphoma. Methods: We conducted a phase 1 dose-escalation study of single agent tegavivint in children aged ≥12 months to ≤21 years with relapsed or refractory solid tumors including lymphoma and desmoid tumors. The dose escalation was conducted using a rolling six design starting with the recommended phase 2 dose (RP2D) in adults, 5 mg/kg, administered intravenously over four hours on days 1, 8 and 15 of a 28 day cycle. A single de-escalation to 4 mg/kg and escalations to 6.5 mg/kg and 8 mg/kg if pharmacokinetic (PK) parameters indicated were planned. Once the RP2D is defined a PK cohort and phase 2 cohorts including Ewing sarcoma, desmoid tumor, osteosarcoma, liver tumors, Wilms tumor and a disease agnostic cohort including cancers with Wnt alterations will be evaluated. Results: A total of 15 patients were enrolled on the phase 1 part of the study. Two patients were not treated due to pre-therapy DEXA scan demonstrating grade 1 osteoporosis; therefore, 13 patients received treatment with tegavivint on 2 dose levels (5 mg/kg and 6.5 mg/kg). The median age of treated patients was 16 years (range 3-21). Patient diagnoses included desmoid tumor (5), Wilms tumor (3), and one each of Ewing sarcoma, osteosarcoma, CIC::DUX4 sarcoma, neuroblastoma, and hepatocellular carcinoma. There were no dose limiting toxicities among 4 DLT-evaluable patients at DL1 and 6 at DL2. The maximum tolerated dose was not determined. Grade three or higher adverse events at least possibly related to treatment included anemia (2) and lymphopenia (2). A single patient had a grade 3 QT prolongation requiring cessation of tegavivint after cycle 3. At 5 mg/kg, the mean AUC was 94,900 hr*ng/mL (range 52,000-136,000), and at 6.5 mg/kg was 91,200 hr*ng/mL (range 28,400-144,000). The pediatric RP2D dose was determined to be 6.5 mg/kg based on the pre-specified objective of achieving pharmacologically relevant plasma concentrations and less than 20% difference in mean AUC between the two tested dose levels. Conclusions: Tegavivint is well tolerated in children with refractory solid tumors, the pediatric RP2D is 6.5 mg/kg demonstrating pharmacologically relevant plasma concentrations. The study is currently enrolling patients to a pharmacokinetic expansion cohort and will then proceed to phase 2. Citation Format: Sarah B. Whittle, Joseph G. Pressey, Xiaowei Liu, Charles G. Minard, Kristina Z. Denic, Joel M. Reid, Stacey L. Berg, Elizabeth Fox, Brenda J. Weigel. PEPN2011: a phase 1/2 study of tegavivint in children, adolescents, and young adults with recurrent or refractory solid tumors, including lymphomas and desmoid tumors: a report from the pediatric early phase clinical trials network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT090.

Purpose: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. Patients and Methods: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. Results: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. Conclusions: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity. See related commentary by Schulte and Eggert, p. 3507

Background Children with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress. Methods Using a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage. Results A total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3–21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control. Conclusion Adavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.

Objective: Vaccination can help prevent COVID-infection and serious health complications. This is particularly important for people with diabetes, who may be at higher risk for COVID-complications. While unvaccinated adults tend to be younger in general, there are no data on vaccine attitudes or uptake in young adults with T1D. We explored vaccine uptake in young adults with T1D across demographic and clinical factors and identified common reasons for not getting the vaccine. Methods: At baseline of an ongoing behavioral intervention trial (Feb-Dec 2021) , 35 young adults with T1D (M age= 20.2±1.6, 57% female, 54% non-Hispanic White, 23% Hispanic, 9% Black, 14% other/multiple, M A1c=8.9±2.4%) reported on vaccination status. Unvaccinated participants provided open-text comments on their reasons. Results: Overall, 69% of participants were vaccinated (2 doses) . Unvaccinated participants had higher median A1c than vaccinated participants (9.7% vs. 7.6%, p=0.03) ; every 1.0% increase in A1c was associated with 22.2% decreased odds of being vaccinated. There were no differences in vaccine uptake by age, gender, race/ethnicity, education, employment, pump or CGM use, or health insurance. The unvaccinated participants reported reasons including: distrust of the vaccine research/effectiveness (4) , uncertainty about health impacts (including T1D) /waiting to see impact on others’ health (2) , no time to get vaccinated (1) , indifference (1) , no desire for vaccination (2) , and still thinking about it (1) . Conclusion: In a small, diverse sample of young adults with T1D, COVID-vaccinations mirrored national rates. Some participants may have been vaccinated after completing surveys at baseline. Patterns of high A1c and unvaccinated status may place young adults at increased risk as the pandemic continues. Healthcare providers are well positioned to counsel young adults about vaccine information and considerations related to T1D, which may reduce misinformation and increase uptake. Disclosure K.R.Desai: None. S.Devaraj: None. C.G.Minard: None. M.E.Hilliard: None. S.A.Carreon: None. B.Duran: None. W.Levy: None. S.Lyons: None. R.Streisand: None. T.S.Tang: None. S.Mckay: None. B.Anderson: None.

Introduction: T1D management, age-related stressors and the COVID-pandemic may impair sleep for young adults with T1D. Disparities in A1c and exposure to life stressors may contribute to poorer sleep among people from minoritized racial/ethnic groups. We aimed to describe sleep, correlations with A1c, and sleep patterns across racial/ethnic groups in young adults with T1D during the pandemic. Methods: Young adults with T1D (n=37, M age=20.2±1.6 yrs, 57% female, M A1c=8.9±2.4%) completed an adapted Pittsburgh Sleep Quality Index and 1 sleep-related question from a COVID-questionnaire at baseline of a behavioral trial. Results Overall, 41% endorsed worse sleep during the pandemic, which was correlated with poorer sleep quality (r=-.69, p Conclusions: Young adults with T1D experienced disrupted sleep, worsened by the pandemic. Clinicians should counsel patients about optimizing sleep and overnight diabetes management, especially those with higher A1c. While small sizes reduced power to detect group differences, initial patterns suggest a need for future research examining disparities in sleep for young adults with T1D. Disclosure S.A.Carreon: None. B.Anderson: None. S.Devaraj: None. A.Butler: None. M.E.Hilliard: None. C.G.Minard: None. K.R.Desai: None. W.Levy: None. S.Lyons: None. B.Duran: None. R.Streisand: None. T.S.Tang: None. S.Mckay: None. Funding NIDDK RDK119246 (PI Hilliard) ; NIH/NIDDK Research Supplement to Promote Diversity in Health-Related Research (3R01DK119246-03S1, PI: Hilliard, Mentee: Carreon)

Vaccine hesitancy may be more common among parents of children with autism spectrum disorder (ASD). We examined factors associated with ASD-specific vaccine hesitancy among caregivers of children with ASD who participated in the SPARK study (Simons Foundation Powering Autism Research for Knowledge). 225 participants completed an online survey containing the Parent Attitudes About Childhood Vaccines (PACV) questionnaire (measure of vaccine hesitancy) and the Illness Perception Questionnaire revised for parents of children with ASD (IPQ-R-ASD; measure of parents' views about ASD). 65 participants (28.8%) were vaccine hesitant (PACV score ≥ 50); children of vaccine-hesitant parents (VHPs) were less likely to be first born (n = 27, 41.5%), had greater ASD-symptom severity (mean Social Communication Questionnaire score = 23.9, SD = 6.9), and were more likely to have experienced developmental regression (n = 27, 50.9%) or plateau (n = 37, 69.8%). Compared to non-hesitant parents, VHPs significantly more often endorsed accident/injury, deterioration of the child's immune system, diet, environmental pollution, general stress, parents' negative views, parents' behaviors/decisions, parents' emotional state, and vaccines as causes for ASD. VHPs also had higher scores on the Personal Control, Treatment Control, Illness Coherence, and Emotional Representations subscales of the IPQ-R than did non-hesitant parents. In the final model, ASD-related vaccine hesitancy was significantly associated with higher scores on the Emotional Representations subscale (OR = 1.13, p = 0.10), agreement with deterioration of the child's immunity as a cause of ASD (OR = 12.47, p < 0.001), the child not having achieved fluent speech (OR = 2.67, p = 0.17), and the child experiencing a developmental plateau (OR = 3.89, p = 0.002). Findings suggest that a combination of child functioning and developmental history, as well as parents' negative views about and their sense of control over ASD, influence vaccine hesitancy among parents of children with ASD.

Summary Background Immune checkpoint inhibitors targeting PD-1 have shown clinical benefit in adults with cancer, but data on these drugs in children are scarce. We did a phase 1–2 study of nivolumab, a PD-1 blocking monoclonal antibody, to determine its safety, pharmacokinetics, and antitumour activity in children and young adults with recurrent or refractory non-CNS solid tumours or lymphoma. Methods We did a multicentre, open-label, single-arm, dose-confirmation and dose-expansion, phase 1–2 trial in 23 hospitals in the USA. Eligible patients for part A (dose-confirmation phase) of the study were aged 1–18 years with solid tumours with measurable or evaluable disease (by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) regardless of histology. Eligible patients for part B (dose-expansion phase) were aged 1–30 years with measurable disease (by RECIST criteria) in the following disease cohorts: rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and melanoma. Patients in part A and were given nivolumab 3 mg/kg intravenously over 60 min on days 1 and 15 of a 28-day cycle in a rolling 6 study design with de-escalation upon dose-limiting toxicities to establish the recommended phase 2 dose. Patients in part B were given the recommended phase 2 dose. The primary outcomes were the tolerability, systemic exposure, maximum tolerated dose, and the antitumour activity of nivolumab at the adult recommended dose in children and young adults. This trial is registered with ClinicalTrials.gov , NCT02304458 , with follow-up ongoing and is closed to new participants. Findings 85 patients were enrolled between Feb 22, 2015, and Dec 31, 2018, and 75 patients were fully evaluable for toxicity. Median follow-up was 30 days (IQR 27–83). In part A, 13 patients were enrolled and 12 were evaluable for toxicity. There were no dose de-escalations or dose-limiting toxicities and nivolumab 3 mg/kg was confirmed as the paediatric recommended phase 2. 72 patients were enrolled in part B and 63 were evaluable for toxicity. Five (7%) patients in part B had dose-limiting toxicities. The most common overall toxicity was anaemia (35 [47%] of 75 patients; five patients had grade 3 or grade 4) and non-haematological toxicity was fatigue (28 [37%] patients; none had grade 3 or grade 4). Responses were observed in patients with lymphoma (three [30%] of ten with Hodgkin lymphoma and one [10%] of ten with non-Hodgkin lymphoma; all responders had PD-L1 expression). Objective responses were not observed in other tumour types. Interpretation Nivolumab was safe and well tolerated in children and young adults and showed clinical activity in lymphoma. Nivolumab showed no significant single-agent activity in the common paediatric solid tumours. This study defines the recommended phase 2 dose and establishes a favourable safety profile for nivolumab in children and young adults, which can serve as the basis for its potential study in combinatorial regimens for childhood cancer. Funding Bristol-Myers Squibb, Children's Oncology Group, National Institutes of Health, Cookies for Kids Cancer Foundation.

Fears persist despite compelling evidence refuting associations between vaccines and autism spectrum disorder (ASD). We compared vaccine hesitancy (VH) and beliefs about illness causes among parents of children in four groups: ASD, non-ASD developmental disorders, rheumatologic conditions, and the general pediatric population. VH was 19.9% overall; parents of children with ASD reported highest VH rates (29.5%) and more frequently attributed ASD to toxins in vaccines (28.9% vs. 15.7%, p=0.004). The odds of VH were increased among parents who attributed their child's condition to diet or eating habits (aOR 4.2; 95% CI: 1.6, 11.2) and toxins found in vaccines (aOR 20, 95% CI: 7.1, 55.9). Parents who attributed the condition to chance or bad luck were less likely to be vaccine hesitant (aOR 0.1; 95% CI: 0.03, 0.5).

Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors. Patients and Methods: Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed. Results: Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients. Conclusions: Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.

OBJECTIVEHigh survival rates have led to an increased emphasis on the functional outcomes of children diagnosed with low-grade glioma. Most outcomes research has focused on risks associated with radiotherapy, but less is known about neuropsychological risks for patients treated with surgery alone. Here, the authors sought to examine the neuropsychological trajectories of children diagnosed with a low-grade glioma and monitored up to 6 years postsurgery. Secondarily, they explored demographic and clinical predictors of neuropsychological performance.METHODSThe neuropsychological functioning of 32 patients (median age at diagnosis 10.0 years) was prospectively assessed annually for up to 6 years after surgery (median days from surgery at baseline = 72). Tumor location was predominately supratentorial (65.6%). A combination of performance-based and parent-reported measures was used to assess intelligence, memory, executive functioning, and fine motor control in all patients.RESULTSBinomial tests at the postoperative baseline revealed that the proportion of children falling below the average range (< 16th percentile) was significantly higher than the rate expected among healthy peers on measures of verbal memory, processing speed, executive functioning, and fine motor control (p < 0.05). Even so, linear mixed models indicated that neuropsychological functioning at the postoperative baseline did not significantly change over time for up to 6 years after surgery across all domains. A larger tumor size was associated with a slower reaction time (p < 0.01). A supratentorial tumor location and history of seizures were associated with more parent-reported executive difficulties (p < 0.01).CONCLUSIONSWhile radiotherapy is a known risk factor for neuropsychological deficits in pediatric brain tumor patients, findings in this study indicate that children treated for low-grade glioma with surgery alone (without radiotherapy or chemotherapy) remain susceptible to difficulties with memory, executive functioning, and motor functioning that persist over time. Over half of the children in the study sample required school support services to address neuropsychological weaknesses. Although low-grade glioma is often conceptualized as a benign tumor, children treated for this lesion require ongoing monitoring and intervention to address neuropsychological weaknesses resulting from the tumor itself as well as the surgery.

Cerebral edema from brain tumors can cause neurological impairment. Steroids treat edema but with possible adverse effects. We surveyed providers regarding steroid use in newly diagnosed patients with brain tumors to determine if practices are standard or markedly variable. An anonymous voluntary online survey was sent to members of neuro-oncology consortiums. Four clinical scenarios were provided and questions regarding initiation of steroids, type, dose, formulation, and duration were asked. Demographic information was collected. 369 providers received the survey, 76 responded (20.6% response rate). The proportion of providers who would start steroids significantly differed among scenarios (scenario 1 vs 2, p

BACKGROUND: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. PROCEDURE: Survivors who underwent PRT (n=38) or XRT (n=20) participated in a neurocognitive evaluation >1 year post-radiotherapy. Group differences in cognitive and social functioning were assessed using ANCOVA. Regression analyses examined predictors of peer relations and social skills. RESULTS: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p>0.05). XRT participants were younger at diagnosis (XRT M=5.0 years, PRT M=7.6 years) and further out from radiotherapy (XRT M=8.7 years, PRT M=4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p=0.01) and verbal memory (p

Current literature identifies mobile phones of staff as potential vectors for hospital-acquired infection.A pre-post, quasi-experimental study was conducted in a 20 bed intensive care unit (ICU). Surface bioburden of personal and shared mobile phones was estimated with a luminometer, expressed in Relative Light Units (RLU). Effects of a simple sanitizing wipe-based disinfection routine were measured at baseline, and at 1, 3, 6, and 12 months after implementation of the disinfection routine.Personal mobile phones and shared phones of 30 on-shift ICU nurses were analyzed at each collection. RLUs for personal phones decreased from baseline to 12 months post-intervention (Geometric mean 497.1 vs 63.36 RLU; adj P.001), while shared unit phones also demonstrated a decrease from baseline to 12 months post-intervention (Geometric mean 417.4 vs 45.90 RLU; adj P.001).No recommended practice yet exists for disinfection of mobile phones in the acute care setting. The disinfection method and routine used in this study may have implications for use in acute care settings to reduce opportunities for infectious disease transmission.

Humanity is battling a respiratory pandemic pneumonia named COVID-19 which has resulted in millions of hospitalizations and deaths. COVID-19 exacerbations occur in waves that continually challenge healthcare systems globally. Therefore, there is an urgent need to understand all mechanisms by which COVID-19 results in health deterioration to facilitate the development of protective strategies. Oxidative stress (OxS) is a harmful condition caused by excess reactive-oxygen species (ROS) and is normally neutralized by antioxidants among which Glutathione (GSH) is the most abundant. GSH deficiency results in amplified OxS due to compromised antioxidant defenses. Because little is known about GSH or OxS in COVID-19 infection, we measured GSH, TBARS (a marker of OxS) and F2-isoprostane (marker of oxidant damage) concentrations in 60 adult patients hospitalized with COVID-19. Compared to uninfected controls, COVID-19 patients of all age groups had severe GSH deficiency, increased OxS and elevated oxidant damage which worsened with advancing age. These defects were also present in younger age groups, where they do not normally occur. Because GlyNAC (combination of glycine and N-acetylcysteine) supplementation has been shown in clinical trials to rapidly improve GSH deficiency, OxS and oxidant damage, GlyNAC supplementation has implications for combating these defects in COVID-19 infected patients and warrants urgent investigation.

Background: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. Procedure: Survivors who underwent PRT (n=38) or XRT (n=20) participated in a neurocognitive evaluation >1 year post-radiotherapy. Group differences in cognitive and social functioning were assessed using ANCOVA. Regression analyses examined predictors of peer relations and social skills. Results: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p>0.05). However, XRT participants were younger at diagnosis (XRT M=5.0 years, PRT M=7.6 years) and further out from radiotherapy (XRT M=8.7 years, PRT M=4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p=0.01) and verbal memory (p

Importance Efforts are underway to incorporate retinal neurodegeneration in the diabetic retinopathy severity scale. However, there is no established measure to quantify diabetic retinal neurodegeneration (DRN). Objective We compared total retinal, macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness among participants with and without diabetes (DM) in a population-based cohort. Design/setting/participants Cross-sectional analysis, using the UK Biobank data resource. Separate general linear mixed models (GLMM) were created using DM and glycated hemoglobin as predictor variables for retinal thickness. Sub-analyses included comparing thickness measurements for patients with no/mild diabetic retinopathy (DR) and evaluating factors associated with retinal thickness in participants with and without diabetes. Factors found to be significantly associated with DM or thickness were included in a multiple GLMM. Exposure Diagnosis of DM was determined via self-report of diagnosis, medication use, DM-related complications or glycated hemoglobin level of ≥ 6.5%. Main outcomes and measures Total retinal, mRNFL and GC-IPL thickness. Results 74,422 participants (69,985 with no DM; 4,437 with DM) were included. Median age was 59 years, 46% were men and 92% were white. Participants with DM had lower total retinal thickness (-4.57 μm, 95% CI: -5.00, -4.14; p Conclusion GC-IPL was thinner among participants with DM, compared to without DM. This difference persisted after adjusting for confounding variables and when considering only those with no/mild DR. This confirms that GC-IPL thinning occurs early in DM and can serve as a useful marker of DRN.

Hospitalized children with underlying heart disease are at high risk for cardiac arrest, particularly when they undergo invasive catheterization procedures for diagnostic and therapeutic interventions. Outcomes for children experiencing cardiac arrest in the cardiac catheterization laboratory remain under-reported with few studies reporting survival beyond the catheterization laboratory. We aim to describe survival outcomes after cardiac arrest in the cardiac catheterization laboratory while identifying risk factors associated with hospital mortality after these events.Retrospective observational study of data from a multicenter cardiac arrest registry from November 2005 to November 2016. Cardiac arrest in the cardiac catheterization laboratory was defined as the need for chest compressions greater than or equal to 1 minute in the cardiac catheterization laboratory. Primary outcome was survival to discharge. Variables analyzed using generalized estimating equations for association with survival included age, illness category (surgical cardiac, medical cardiac), preexisting conditions, pharmacologic interventions, and event duration.American Heart Association's Get With the Guidelines-Resuscitation registry of in-hospital cardiac arrest.Consecutive patients less than 18 years old experiencing an index (i.e., first) cardiac arrest event reported to the Get With the Guidelines-Resuscitation.None.A total of 203 patients met definition of index cardiac arrest in the cardiac catheterization laboratory composed primarily of surgical and medical cardiac patients (54% and 41%, respectively). Children less than 1 year old comprised the majority of patients, 58% (117/203). Overall survival to hospital discharge was 69% (141/203). No differences in survival were observed between surgical and medical cardiac patients (p = 0.15). The majority of deaths (69%, 43/62) occurred in patients less than 1 year old. Bradycardia (with pulse) followed by pulseless electrical activity/asystole were the most common first documented rhythms observed (50% and 27%, respectively). Preexisting metabolic/electrolyte abnormalities (p = 0.02), need for vasoactive infusions (p = 0.03) prior to arrest, and use of calcium products (p = 0.005) were found to be significantly associated with lower rates of survival to discharge on multivariable regression.The majority of children experiencing cardiac arrest in the cardiac catheterization laboratory in this large multicenter registry analysis survived to hospital discharge, with no observable difference in outcomes between surgical and medical cardiac patients. Future investigations that focus on stratifying medical complexity in addition to procedural characteristics at the time of catheterization are needed to better identify risks for mortality after cardiac arrest in the cardiac catheterization laboratory.

BACKGROUND Pre-transplant nutrition is a key driver of outcomes following liver transplantation in children. Patients with biliary atresia (BA) may have difficulty achieving satisfactory weight gain with enteral nutrition alone, and parenteral nutrition (PN) may be indicated. While PN has been shown to improve anthropometric parameters of children with BA listed for liver transplantation, less is known about the risks, particularly infectious, associated with this therapy among this specific group of patients. AIM To describe the incidence, microbiology, and risk factors of central line-associated bloodstream infection (CLABSI) among children with BA listed for liver transplantation. METHODS Retrospective review of children aged ≤ 2-years of age with BA who were listed for primary liver transplantation at Texas Children’s Hospital from 2008 through 2015 (n = 96). Patients with a central line for administration of PN (n = 63) were identified and details of each CLABSI event were abstracted. We compared the group of patients who experienced CLABSI to the group who did not, to determine whether demographic, clinical, or laboratory factors correlated with development of CLABSI. RESULTS Nineteen of 63 patients (30%, 95%CI: 19, 43) experienced 29 episodes of CLABSI during 4800 line days (6.04 CLABSI per 1000 line days). CLABSI was predominantly associated with Gram-negative organisms (14/29 episodes, 48%) including Klebsiella spp., Enterobacter spp., and Escherichia coli. The sole polymicrobial infection grew Enterobacter cloacae and Klebsiella pneumoniae. Gram-positive organisms (all Staphylococcus spp.) and fungus (all Candida spp.) comprised 9/29 (31%) and 6/29 (21%) episodes, respectively. No demographic, clinical, or laboratory factors were significantly associated with an increased risk for the first CLABSI event in Cox proportional hazards regression analysis CONCLUSION There is substantial risk for CLABSI among children with BA listed for liver transplantation. No clinical, demographic, or laboratory factor we tested emerged as an independent predictor of CLABSI. While our data did not show an impact of CLABSI on the short-term clinical outcome, it would seem prudent to implement CLABSI reduction strategies in this population to the extent that each CLABSI event represents potentially preventable hospitalization, unnecessary healthcare dollar expenditures, and may exact an opportunity cost, in terms of missed allograft offers.

Objective: Evaluate the impact of multi-component quality improvement for pediatric asthma care focusing on serial use of an evidence-based clinical pathway via paper order sets, pathway integratio...

The relationship between age and neurocognitive functioning following proton beam radiotherapy (PRT) in low- and intermediate-grade gliomas (LIGG) has yet to be examined. Eighteen LIGG patients treated with PRT were prospectively enrolled and received annual neurocognitive evaluations of perceptual/verbal reasoning, working memory, and processing speed postradiotherapy. The median age at diagnosis was 8.2 years (range 1.0-14.7) and the median age at PRT was 9.9 years (range 4.2-17.0). Patients' neurocognitive performance did not change on any measure following PRT (p ≥ .142). We did not observe significant changes in cognitive function over time among a small group of LIGG patients treated with PRT.