Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors.

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

How Cancer Harms the Developing Brain: Long-Term Outcomes in Pediatric Cancer Survivors.

Survival rates for pediatric cancer are improving, resulting in a rising need to understand and address long-term sequelae. In this narrative review, we summarize the effects of cancer and its treatment on the developing brain, with a focus on neurocognitive function in leukemia and pediatric brain tumor survivors. We then discuss possible mechanisms of brain injury and management considerations.

Visual outcomes after bevacizumab-based therapy for optic pathway glioma.

In optic pathway glioma (OPG), bevacizumab-based therapy (BBT) has promising effects on radiographic tumor burden, but the impact on vision is less clear. This single-institution study characterized visual acuity (VA) and visual field (VF) outcomes in 17 pediatric OPG patients treated with BBT. VA was stable or improved in 14 patients. Nine patients had evaluable VF data, six of whom experienced stability or improvement. Among six patients with vision deterioration as a treatment indication, stable or improved was observed for both VA and VF in five patients. In summary, BBT was associated with favorable visual outcomes in this cohort of patients with OPG.

Successful Endovascular Therapy in COVID-19 Associated Pediatric Ischemic Stroke.

Cerebrovascular diseases attributed to coronavirus disease 2019 (COVID-19) are uncommon but can result in devastating outcomes. Pediatric acute ischemic strokes are themselves rare and with very few large vessel occlusion related acute ischemic strokes attributed to COVID-19 described in the literature as of date. COVID-19 pandemic has contributed to acute stroke care delays across the world and with pediatric endovascular therapy still in its infancy, it poses a great challenge in facilitating good outcomes in children presenting with acute ischemic strokes in the setting of COVID-19. We present a pediatric patient who underwent endovascular therapy for an internal carotid artery occlusion related acute ischemic stroke in the setting of active COVID-19 and had an excellent outcome thanks to a streamlined stroke pathway involving the vascular neurology, neuro-interventional, neurocritical care, and anesthesiology teams.

Reducing Prescribing Errors in Hospitalized Children on the Ketogenic Diet.

BACKGROUND: Children on the ketogenic diet must limit carbohydrate intake to maintain ketosis and reduce seizure burden. Patients on ketogenic diet are vulnerable to harm in the hospital setting where carbohydrate-containing medications are commonly prescribed. We developed clinical decision support to reduce inappropriate prescription of carbohydrate-containing medications in hospitalized children on ketogenic diet. METHODS: A clinical decision support alert was developed through formative and summative usability testing. The alert warned prescribers when they entered an order for a carbohydrate-containing medication in patients on ketogenic diet. The alert was implemented using a quasi-experimental design with sequential crossover from control to intervention at two tertiary care pediatric hospitals within a single health system. The primary outcome was carbohydrate-containing medication orders per patient-day. RESULTS: During the study period, there were 280 ketogenic diet patient admissions totaling 1219 patient-days. The carbohydrate-containing medication order rate declined from 0.69 to 0.35 orders per patient-day (absolute rate reduction 0.34, 95% confidence interval 0.25-0.43), corresponding to 256 inappropriate orders prevented. The alert fired 398 times and was accepted (i.e., the order was removed) 227 times for an overall acceptance rate of 57%. CONCLUSIONS: Implementation of a clinical decision support alert at order-entry resulted in a sustained reduction in carbohydrate-containing medication orders for hospitalized patients on ketogenic diet without an increase in alert burden. Clinical decision support developed with user-centered design principles can improve patient safety for children on ketogenic diet by influencing prescriber behavior.

Use of a wearable device to assess sleep and motor function in Duchenne muscular dystrophy.

INTRODUCTION: Rest-activity disruption is an important feature of Duchenne muscular dystrophy (DMD). We sought to describe sleep impairment and its relationship to quality of life (QOL) and to evaluate associations between rest-activity, sleep quality, and 6-minute walk test (6MWT) in DMD. METHODS: Sleep impairment and its relationship to QOL was assessed by questionnaire in 54 children (33 ambulatory, 21 nonambulatory) with DMD. Rest-activity characteristics were calculated for 23 of these children (14 ambulatory, nine nonambulatory) by actigraphy. RESULTS: Pathologic sleep was reported in 11 (20%) participants and correlated with lower QOL but not with ambulatory status. In ambulatory participants who completed actigraphy, rest-activity rhythm fragmentation was associated with subjective sleep impairment. Habitual daytime activity level was associated with 6MWT performance. DISCUSSION: Children with DMD experience substantial sleep impairment that is related to QOL. Wrist actigraphy may be a parsimonious tool for monitoring both sleep and motor impairment in ambulatory children with DMD.

Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma.

Host genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology, are limited. Here, we evaluated variation in host genome of long-term survivors of medulloblastoma and its association with neurocognitive outcome. Whole-genome sequencing was conducted on peripheral blood of long-term survivors of pediatric medulloblastoma who also completed neuropsychological testing. Cognitively impaired and less impaired survivors did not differ in exposure to chemoradiation therapy or age at treatment. Unsupervised consensus clustering yielded two distinct variant clusters that were significantly associated with neurocognitive outcome. Interestingly, 34 of the 36 significant variants were found in noncoding DNA regions with unknown regulatory function. A separate unsupervised cluster analysis of variants within DNA repair genes identified discrete variant groups that were not associated with neurocognitive outcome, suggesting that variations in genes corresponding to a single functional group may be insufficient to predict long-term outcome alone. These findings are supportive of the presence of a genetic diathesis for treatment-related neurocognitive morbidity in medulloblastoma that may be driven by variation in noncoding regulatory elements.

Impact of a Daily PICU Rounding Checklist on Urinary Catheter Utilization and Infection.

INTRODUCTION: In critically ill children, inappropriate urinary catheter (UC) utilization is associated with increased morbidity, including catheter-associated urinary tract infections (CAUTIs). Checklists are effective for reducing medical errors, but there is little data on their impact on device utilization in pediatric critical care. In this study, we evaluated UC utilization trends and CAUTI rate after implementing a daily rounding checklist. METHODS: A retrospective review of our checklist database from 2006 through 2016 was performed. The study setting was a 36-bed pediatric intensive care unit in a quaternary-care pediatric hospital. Interventions included the "Daily QI Checklist" in 2006, ongoing education regarding device necessity, and a CAUTI prevention bundle in 2013. UC utilization and duration were assessed via auto-correlated time series models and Cochran-Armitage tests for trend. Changes in CAUTI rate were assessed via Poisson regression. RESULTS: UC utilization decreased from 30% of patient-days in 2006 to 18% in 2016 (P < 0.0001, Cochran-Armitage trend test), while duration of UC use (median, 2.0 days; interquartile range, 1-4) did not change over time (P = 0.18). CAUTI rate declined from 9.49/1,000 UC-days in 2009 to 1.04 in 2016 (P = 0.0047). CONCLUSIONS: Implementation of the checklist coincided with a sustained 40% reduction in UC utilization. The trend may be explained by a combination of more appropriate selection of patients for catheterization and improved timeliness of UC discontinuation. We also observed an 89% decline in CAUTI rate that occurred after stabilization of UC utilization. These findings underscore the potential impact of a checklist on incorporating best practices into daily care of critically ill children.

Elevated viral restriction factor levels in cortical blood vessels in schizophrenia.

BACKGROUND: Higher tissue transcript levels of immune-related markers-including the recently discovered viral restriction factor interferon-induced transmembrane protein (IFITM), which inhibits viral entry and replication-have been reported in the prefrontal cortex in schizophrenia. Interestingly, mouse models of neuroinflammation have higher IFITM levels and deficits in γ-aminobutyric acid (GABA)-related markers that are similar to findings in schizophrenia, suggesting that a shared pathogenetic process might underlie diverse cortical pathology in the disorder. However, the cell types that overexpress IFITM messenger RNA (mRNA) in schizophrenia are unknown, and it is unclear whether higher IFITM mRNA levels are associated with lower GABA-related marker levels in the same schizophrenia subjects. METHODS: We used quantitative polymerase chain reaction and in situ hybridization with film and grain counting analyses to quantify IFITM mRNA levels in prefrontal cortex area 9 of 57 schizophrenia and 57 healthy comparison subjects and in antipsychotic-exposed monkeys. RESULTS: Quantitative polymerase chain reaction and in situ hybridization film analysis revealed markedly elevated IFITM mRNA levels (+114% and +117%, respectively) in prefrontal gray matter in schizophrenia. Interestingly, emulsion-dipped, Nissl-stained sections from schizophrenia and comparison subjects revealed IFITM mRNA expression in pia mater and blood vessels. The IFITM grain density over blood vessels was 71% higher in schizophrenia. The IFITM mRNA levels were negatively correlated with GABA-related mRNAs in the same schizophrenia subjects. CONCLUSIONS: The finding that schizophrenia subjects with higher IFITM mRNA levels in cortical blood vessels have greater disturbances in cortical GABA neurons suggests that these cell-type distinct pathological disturbances might be influenced by a shared upstream insult that involves immune activation.

Endocannabinoid metabolism in the prefrontal cortex in schizophrenia.

Adolescent cannabis use is associated with greater relative risk, increased symptom severity, and earlier age of onset of schizophrenia. We investigated whether this interaction may be partly attributable to disease-related disturbances in metabolism of the major cortical endocannabinoid 2-arachidonoylglycerol (2-AG). Transcript levels for the recently discovered 2-AG metabolizing enzyme, α-ß-hydrolase domain 6 (ABHD6), were assessed using quantitative PCR in the prefrontal cortex of schizophrenia and healthy subjects (n=84) and antipsychotic- or tetrahydrocannabinol-exposed monkeys. ABHD6 mRNA levels were elevated in schizophrenia subjects who were younger and had a shorter illness duration but not in antipsychotic- or tetrahydrocannabinol-exposed monkeys. Higher ABHD6 mRNA levels may increase 2-AG metabolism which may influence susceptibility to cannabis in the earlier stages of schizophrenia.