Identification of Pathway-Specific Serum Biomarkers of Response to Glucocorticoid and Infliximab Treatment in Children with Inflammatory Bowel Disease

Objective: Serum biomarkers may serve to predict early response to therapy, identify relapse, and facilitate drug development in inflammatory bowel disease (IBD). Biomarkers are particularly important in children, in whom achieving early remission and minimizing procedures are especially beneficial. Methods: We profiled protein and micro RNA (miRNA) in serum from patients pre- and post-therapy, to identify molecular markers of pharmacodynamic effect. Serum was obtained from children with IBD before and after treatment with either corticosteroids (prednisone; n=12) or anti-tumor necrosis factor-α biologic (infliximab; n=7). Over 1,100 serum proteins were assayed using aptamer-based SOMAscan proteomics, and 22 miRNAs analyzed by quantitative real time PCR. Concordance of longitudinal changes between the groups was used to identify markers responsive to treatment. Bioinformatic analysis was used to build insight into mechanisms of changes in response to treatment. Results: We identified 18 proteins and three miRNAs responsive to both prednisone and infliximab. Eight markers that decreased are associated with inflammation and have gene promoters regulated by nuclear factor (NF)-κB. Several that increased are associated with resolving inflammation and tissue damage. We also identified six markers that appear to be steroid-specific, three of which have glucocorticoid receptor binding elements in their promoter region. Conclusions: Serum markers regulated by the inflammatory transcription factor NF-κB are potential candidates for pharmacodynamic biomarkers that, if correlated with later outcomes like endoscopic or histologic healing, could be used to monitor treatment, optimize dosing, and enhance drug development. The pharmacodynamic biomarkers identified here hold potential to improve both clinical care and drug development. Further studies are warranted to investigate these markers as early predictors of response, or possibly surrogate outcomes

Investigating the Role of Hypothalamic Tumor Involvement in Sleep and Cognitive Outcomes Among Children Treated for Craniopharyngioma

Objective: Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. Methods: Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. Results: EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. Conclusion: Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity

In pediatric patients with brain tumors treated with radiation therapy

Background. Pediatric patients with brain tumors who are treated with radiation therapy (RT) are at risk for neurocognitive and psychosocial late effects. Research to date has primarily examined these outcomes at a group level and in isolation. Advanced statistical techniques allow for person-centered analyses, as well as examination of relationships between domain-specific trajectories. Methods. Patients with brain tumors (craniopharyngioma, ependymoma, low-grade astrocytoma, high-grade astrocytoma) were enrolled on a phase II clinical trial of RT.Three hundred and fifty patients completed serial neurocognitive assessments as part of their treatment monitoring, including pre-RT baseline, 6 months post-RT, and then yearly for 5 years.This secondary analysis focused on outcomes of cognition (estimated IQ, parent-reported attention problems) and psychosocial effects (parent-reported socialization and social problems) post-RT. Results. Latent growth curve modeling indicated that estimated IQ and socialization were best served by quadratic models, while attention and social problems were best served by linear models. Growth mixture modeling indicated 3-class models were the best fit for IQ and socialization, and 2-class models for attention and social problems. Baseline IQ and socialization scores were associated, but there was no association over time.Young age at diagnosis and pre-RT treatments (surgery, chemotherapy) were associated with class membership. Conclusions. Person-centered statistical analyses provide rich information regarding the variability in neurocognitive and psychosocial functioning following RT for pediatric brain tumor. While many patients do well over time, a subset are exhibiting significant cognitive and/or psychosocial deficits. Class membership was associated with some medical factors (eg, pre-radiation surgery/chemotherapy, age at diagnosis, shunted hydrocephalus)

Executive function late effects in survivors of pediatric brain tumors and acute lymphoblastic leukemia

BACKGROUND: Survivors of pediatric brain tumors (BT) and acute lymphoblastic leukemia (ALL) are at risk for neurocognitive late effects related to executive function. PROCEDURE: Survivors of BT (48) and ALL (50) completed neurocognitive assessment. Executive function was compared to estimated IQ and population norms by diagnostic group. RESULTS: Both BT and ALL demonstrated relative executive function weaknesses. As a group, BT survivors demonstrated weaker executive functioning than expected for age. Those BT survivors with deficits exhibited a profile suggestive of global executive dysfunction, while affected ALL survivors tended to demonstrate specific rapid naming deficits. CONCLUSION: Findings suggest that pediatric BT and ALL survivors may exhibit different profiles of executive function late effects, which may necessitate distinct intervention plans

Health-related quality of life, obesity, fragmented sleep, fatigue, and psychosocial problems among youth with craniopharyngioma

Objective: Youth with craniopharyngioma experience weight gain, fragmented sleep, excessive daytime sleepiness (EDS), fatigue, and psychosocial problems that negatively impact their overall health-related quality of life (HRQoL). Greater hypothalamic tumor involvement (HI) may be associated with higher rates or severity of these impairments; however, the direct and indirect impact of HI on the physical and psychosocial consequences associated with pediatric craniopharyngioma remain unclear. The purpose of the current study was to examine relations between HI, body mass index (BMI), fragmented sleep, EDS, fatigue, psychosocial problems, and HRQoL among youth with craniopharyngioma. Methods: Eighty-four youth with craniopharyngioma (Mage = 10.27 ± 4.3 years, 53.6% female, 64.3% White) were assessed with actigraphy, nocturnal polysomnography, and multiple sleep latency tests prior to proton therapy, when indicated. Caregivers completed measures of fatigue, psychosocial functioning, and HRQoL. Results: Hypothalamic tumor involvement was associated with greater BMI (Est. = 2.97, p = 0.003) and daytime sleepiness (Est. = 2.53, p = 0.01). Greater fatigue predicted more psychosocial problems (Est. = 0.29, p \u3c 0.001) and lower HRQoL (Est. = 0.23, p = 0.001). Psychosocial problems also predicted lower HRQoL (Est. = −0.34, p = 0.004). Fragmented sleep (Est. = 0.03, p = 0.04) and fatigue (Est. = 0.10, p = 0.02) indirectly predicted lower HRQoL through psychosocial problems. Conclusions: Youth with craniopharyngioma with greater HI may benefit from weight reduction interventions and management of excessive sleepiness. Patients should be prospectively monitored for sleep problems, fatigue, and psychosocial problems, as these patients may benefit from interventions targeting fatigue and psychosocial health to improve HRQoL

Clinical Importance of Free Thyroxine Concentration Decline after Radiotherapy for Pediatric and Adolescent Brain Tumors

Context: Clinical significance of a decline in free T4 (FT4) concentrations across the reference range in children with brain tumors treated with radiation therapy (RT) is uncertain. Objectives: To study trends in FT4 in children after RT and risk factors and health outcomes associated with plasma FT4 concentrations. Design and Setting: Longitudinal, single-center retrospective cohort study. Patients: Low-grade glioma or ependymoma patients (n = 267; age ≤25 years) who received RT (50.4 to 59.4 Gy) at a single institution (1996 to 2016) and followed with serial FT4 measurements. Main Outcome Measure: A linear mixed-effects model with a random intercept was used to investigate risk factors for longitudinal changes in FT4 concentrations. A two-stage mixed-effects model examined associations between clinical outcomes and plasma FT4 concentrations. Results: FT4 concentrations declined over time after RT (P < 0.001). Females (P < 0.001) and younger patients (P < 0.001) demonstrated greater declines in FT4 concentrations over time. The rate of weight gain, but not of height loss, increased with a higher FT4 decline rate (P < 0.001). At last follow-up, patients with lower baseline FT4 concentrations had increased risk of glucose disorder (OR, 19.73; P = 0.002) or dyslipidemia (OR, 19.40; P = 0.003) but not high fat mass (P = 0.18). Lower baseline FT4 concentrations were not associated with impaired scores for intelligence, attention, memory, or psychosocial functioning. Conclusions: FT4 concentrations significantly decline in children with brain tumor after RT. Variation and trends in FT4 concentration are associated with physical health outcomes. Future studies should assess whether continuous FT4 concentrations and trends, rather than population-based cut-off values, can distinguish between euthyroid and hypothyroid states