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The aim was to determine the impact of time to diagnosis (TTD) on morbidity and mortality and to identify factors associated with overall survival (OS) in pediatric patients with malignant central nervous system (CNS) tumors.This is a retrospective review of all malignant CNS tumors presenting to 2 tertiary care pediatric hospitals from 2000 to 2019. Cox proportional hazard model analysis outcomes included TTD and OS as well as morbidity; stratified by tumor category, age, relapse, and presence of metastatic disease.There were 197 children with malignant CNS tumors (mean age 8.7 y, 61% male). Tumors included medulloblastoma (N=58, 29.4%), ependymoma (N=27, 13.7%), high-grade glioma (N=42, 21.3%), germ cell tumors (N=47, 23.9%), and other embryonal tumors (N=23, 11.7%). Median TTD from symptom onset was 62 (interquartile range: 26.5 to 237.5 d) and 28% had metastatic disease. Three-year progression free survival was 55% and 3-year OS was 73.1%. Increased OS was associated with increased TTD (parameter estimate 0.12; confidence interval [CI]: 0.019-7.06; P=0.019), high-grade glioma (hazard ratio [HR]: 2.46; CI [1.03-5.86]; P=0.042), other embryonal tumor (HR: 2.84; CI [1.06-7.56]; P=0.037), relapse (HR: 10.14; CI: 4.52-22.70; P0.001) and metastatic disease (HR: 3.25; CI: 1.51-6.96; P=0.002). Vision change (HR: 0.58; CI: 0.313-1.06; P=0.078), hearing loss (HR: 0.71; CI: 0.35-1.42; P=0.355), and cognitive impairment (HR: 0.73; CI: 0.45-1.19; P=0.205) were not associated with TTD in this model.Increased median TTD is associated with higher OS in pediatric patients treated for malignant CNS tumors. Tumor biology and treatment modality are more important factors than TTD for predicting morbidity and long-term outcomes in pediatric patients with CNS tumors.

Purpose To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. Methods We report on six patients with NF‐1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. Results Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4–28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life‐threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1–2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. Conclusion Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients., Here, we report on response to Trametinib, a MEK inhibitor in children with NF‐1. Our experience presented in this report demonstrates that Trametinib is an effective therapy for advanced, life‐threatening PNF, and treatment‐refractory PLGG in patients with NF‐1 and is well tolerated in children.

Background: B7-H3 expression on central nervous system (CNS) tumors offers a potential therapeutic target for adoptive cellular therapy. Methods: A 3+3 statistical design was employed to assess the safety of repeated B7-H3 chimeric antigen receptor (CAR) T cells administered into the intracranial ventricular system (ICV) using an intrapatient dose escalation without lymphodepleting chemotherapy in pts 1-26 years of age with recurrent/refractory CNS tumors including (non-pontine) diffuse midline glioma (DMG) (NCT04185038, Arm B). Primary endpoints were feasibility to manufacture sufficient CARs and safety of weekly infusions for 3 weeks of 4-week cycles for 2 cycles. Secondary endpoints were best overall response (BOR) and correlatives of CAR activity. Results: CAR manufacturing was achieved in 20/22 (91%) enrolled pts. Eight pts were inevaluable (rapidly progressive exam precluding initial infusion (n=5), removal from protocol therapy due to progressive disease (n=2), and lack of evaluable disease prior to initial infusion (n=1)). No dose limiting toxicities were observed, identifying the maximally tolerated dose regimen (MTDR) as DR3 (maximum dose: 10 × 107 B7-H3CARs). Subjects received 98 ICV doses (median: 6 doses/patient, range: 3-13). For evaluable patients, the most common adverse events were headache (12/12, 100%), fatigue (9/12, 75%), nausea/vomiting (7/12, 58%), and fever (6/12, 50%). There was no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging analysis is ongoing with current BOR being stable disease. CAR T cells were detected in the CSF in 9/12 evaluable pts (75%). Serial CSF/serum cytokine analysis and mass spectrometry are in process. Conclusion: Repeated ICV administration of B7-H3 CAR T cells is tolerable with circulating CAR T cells detectable in the CSF post infusion. Further investigation is warranted, along with future studies interrogating iterative enhancements such as modifications for enhanced potency and multi-antigen targeting. Citation Format: Nicholas A. Vitanza, Juliane Gust, Rebecca Ronsley, Ashley L. Wilson, Wenjun Huang, Kristy Seidel, Catherine M. Albert, Navin Pinto, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. BrainChild-03: Intraventricular B7-H3 CAR T cells for recurrent/refractory central nervous system tumors and non-pontine diffuse midline glioma in children and young adults [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 LB121.

Alopecia totalis (AT) is a chronic disease that results in non-scarring hair loss of the entire scalp. This results from an autoimmune reaction involving the hair follicles due to genetic and environmental factors. The clinical course of AT is highly unpredictable. There are limited effective durable treatment options. Resolution of alopecia has been reported post-autologous and allogenic hematopoietic stem cell transplantation (HSCT). However, no cases of AT remission following chemotherapy alone have been described. Here, we present a case of complete remission of AT following chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL) in a pediatric patient.

Alopecia totalis (AT) is a cosmetically debilitating chronic disease characterized by non-scarring hair loss of the entire scalp. The clinical course of AT is highly unpredictable, and effective durable treatment options are limited. The resolution of alopecia has been reported post-autologous and allogeneic hematopoietic stem cell transplantation; however, no cases of AT remission following chemotherapy alone have been described. Herein, we present a case of complete remission of AT following chemotherapy for B-cell acute lymphoblastic leukemia in a pediatric patient.

Treatment of pediatric oncology patients generally results in significant immunosuppression and when the COVID-19 pandemic arose, there was concern among pediatric oncologists about the implications of this virus. We reviewed the literature and describe all pediatric oncology patients with COVID-19 reported worldwide. Within this review, it is striking that CNS tumors are reported at low numbers (27/466 pediatric oncology patients with COVID-19). This may be related to decreased inpatient care when compared to other pediatric cancers. Additional work is needed to understand the risk of infection in this population and gain insight into the effect on delivery of oncology care.

Type 1 diabetes (T1D) increases the risk of chronic kidney disease (CKD) development. The primary objective of this study was to assess the prevalence of abnormalities in estimated glomerular filtration rate (eGFR) in children with T1D. As a secondary objective, we sought to explore the relationship between clinical characteristics and abnormalities in eGFR.This cross-sectional study involved children ≤18 years of age with T1D followed in the diabetes clinic at a pediatric tertiary care centre. Data were collected from health records between 2016 and 2020. Using the Bedside Schwartz, Chronic Kidney Disease in Children Under 25 (CKiD U25) and European Kidney Function Consortium (EKFC) equations, eGFR was categorized as CKD (60 mL/min/1.73 mOf the 420 participants, 225 were male (54%); the median age at diagnosis and duration of T1D were 6.1 and 4.8 years, respectively. The proportion of participants with mildly decreased eGFR was similar regardless of eGFR equation, with 11% to 14% of participants with an eGFR90 mL/min/1.73 mA notable proportion of children with T1D demonstrates eGFR abnormalities early in their T1D course. This finding along with evidence of lower eGFR in adolescence is concerning for long-term risk of CKD and warrants systematic serum creatinine monitoring at diagnosis and regular intervals thereafter in children with T1D.

OBJECTIVE The objective of this study was to describe the management of hydrocephalus in a cohort of pediatric patients with germinoma. METHODS The authors conducted a retrospective chart review of patients with germinoma and symptomatic hydrocephalus treated at the Hospital for Sick Children between 2002 and 2020. Descriptive data included tumor location, CSF diversion procedure (external ventricular drain [EVD], endoscopic third ventriculostomy [ETV], ventriculoperitoneal [VP] shunt) and outcomes. The frontooccipital horn ratio (FOR) method was used to determine the presence of ventriculomegaly. RESULTS Of 39 patients with germinoma, 22 (73% male) had symptomatic hydrocephalus at diagnosis (11 pineal, 4 suprasellar, and 7 bifocal). Management of hydrocephalus included EVD (n = 5, 22.7%), ETV (n = 5, 22.7%), and combination ETV and EVD (n = 7, 31.8%), whereas 5 patients (22.7%) did not undergo surgical intervention. The median FOR at diagnosis was 0.42 (range 0.38–0.58), which correlated with moderate to severe ventriculomegaly. Carboplatin and etoposide–based chemotherapy induced fast tumor shrinkage, avoiding CSF diversion (n = 5) and resolving hydrocephalus with a transient EVD (n = 5). The median duration until EVD removal was 7 days (range 2–10 days). Two of 12 patients with EVD ultimately required a VP shunt. Kaplan-Meier overall survival was 100% and progression-free survival was 96.4% at a median follow-up of 10.4 years. CONCLUSIONS Timely initiation of chemotherapy is imperative to rapidly reduce tumor bulk in children with germinoma and limits the need for VP shunt insertions. In children in whom CSF diversion is required, hydrocephalus may be successfully managed with a temporary EVD ± ETV.

Background Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA. Methods Our institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs). Results Two patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children’s Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%). Conclusions The natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

The objective of this study was to estimate the comparative effectiveness of bisphosphonate therapy on bone mineral density (BMD) in patients with corticosteroid-treated Duchenne muscular dystrophy (DMD). A retrospective, comparative effectiveness study evaluating changes in BMD and fragility fractures in patients with DMD presenting to British Columbia Children’s Hospital from 1989 to 2017 was conducted. Marginal structural generalized estimating equation models weighted by stabilized inverse-probability of treatment weights were used to estimate the comparative effectiveness of therapy on BMD. Of those treated with bisphosphonates (N = 38), 7 (18.4%), 17 (44.7%), and 14 (36.8%) cases were treated with pamidronate, zoledronic acid, or a combination of both, respectively, while 36 cases of DMD were untreated. Mean age of bisphosphonate initiation was 9.2 (SD 2.7) years. Mean fragility fractures declined from 3.5 to 1.0 following bisphosphonate therapy. Compared to the treated group, the untreated group had an additional 0.63-SD decrease (95% confidence interval [CI]: −1.18, −0.08, P = .026) in total BMD and an additional 1.04-SD decrease (95% CI: −1.74, −0.34; P = .004) in the left hip BMD, but the change in lumbar spine BMD (0.15, 95% CI: −0.36, 0.66; P = .57) was not significant. Bisphosphonate therapy may slow the decline in BMD in boys with corticosteroid-treated DMD compared to untreated counterparts. Total number of fragility fractures decreased following bisphosphonate therapy.

The objective of this study was to describe hypersensitivity reactions with and without the use of in-line filters during intravenous etoposide therapy in pediatric oncology patients. This was a retrospective review of all patients treated in the Division of Oncology/Hematology/Bone Marrow Transplant at British Columbia Children's Hospital with intravenous etoposide between December 1, 2013 and February 1, 2018. Hypersensitivity reactions and anaphylaxis associated with etoposide infusions were compared over time, including 12 months prior to, 27 months during the use of, and for 12 months after the discontinuation of in-line filtration. There were 192 patients (median age 6.0 (IQR 2.8-13.0) years treated with etoposide and 486 etoposide infusions including 137 (28%) before, 261 (54%) during and 88 (18%) after use of in-line filters at our center. Twenty-six of 486 (5%) and 13/486 (3%) of infusions resulted in a type I hypersensitivity reaction and anaphylaxis, respectively. There were 2/137 (1%), 36/261 (14%) and 1/88 (1%) infusion reactions prior to, during and after in-line filter use, respectively. Infusion reactions during the in-line filter period were higher than during the pre-filter (Z = 3.978; p 0.001) and post-filter (Z = 3.335; p 0.001) periods of the study. These data suggest that the use of in-line filtration may be associated with increased frequency of hypersensitivity reactions to etoposide in pediatric cancer patients.

Objective To review adherence to a provincial diabetic ketoacidosis (DKA) protocol and to assess factors associated with intravenous fluid administration and the length time on an insulin infusion. Methods A retrospective chart review was conducted of all DKA admissions to British Columbia Children's Hospital (BCCH) during September 2008 to December 2013. Data collection included diabetes history, estimation of dehydration, insulin and fluid infusion rates, and frequency of laboratory investigations. Markers of adherence included appropriate use of a fluid bolus, normal saline and insulin infusion time, fluid intake and outputs, and the frequency of blood work during the insulin infusion. A log-linear regression model was fitted to assess the factors associated with insulin infusion duration. Results Of 157 children (median [interquartile range] age: 10.6 years [5.0, 13.8]) hospitalized for DKA, 45% (n = 70) were male, 55% (n = 86) were transferred from other hospitals, and 26% (n = 40) were admitted to intensive care unit. Thirty-five percent of subjects estimated to have mild or moderate dehydration received fluid boluses. In the adjusted analysis, the average duration on DKA protocol was 39% (95% confidence interval [CI]: 12%, 67%) longer for children admitted with severe dehydration (compared to those with mild dehydration). Conclusions Health care providers’ adherence to the BCCH DKA protocol is poor. More severe dehydration at presentation is associated with longer duration of insulin infusion. Further knowledge translation initiatives focused on accurate estimation of volume depletion to ensure appropriate initial fluid resuscitation—as well as careful monitoring during DKA hospitalization—are important, especially in community centers.

OBJECTIVE To determine the impact of time to diagnosis on disease related morbidity and mortality. METHODS This is a retrospective review of all diagnoses of malignant CNS tumors in children presenting to BC Children’s Hospital (BCCH) from 2000-2019. Analyses were conducted to assess the relationship between time to diagnosis and overall survival as well as long-term morbidity; stratified by tumor type, age and presence of metastatic disease. RESULTS From 2000-2019, there were 116 children diagnosed with malignant CNS tumors at BCCH (mean age 9.5 years, 67% male). Tumors included medulloblastoma (27, 23.3%), ependymoma (14, 12.1%), high grade gliomas (19, 16.4%), CNS germ cell tumors (40, 34.4%), and other embryonal CNS tumors (16, 13.8%). Median time to diagnosis from first symptom onset was 63 days (IQR 26.5 – 237.5 days). 18% had metastatic disease. Within this cohort, 3-year EFS was 57%, and 5-year overall survival was 78.4%. 64% of patients were alive with no evidence of disease at median follow up from treatment completion of 4.31 years (IQR 1.77 – 6.15 years). Long-term morbidity included panhypopituitarism (20.7%), vision loss(22.4%), hearing loss(30.2%), learning disability(17.2%) and cognitive impairment (19.8%). In a cox proportional hazards model, overall survival was associated with time to diagnosis(estimate 0.0271;SE=1.6500;p=0.028), high grade glioma(estimate 8.3200; SE=0.6650; p=0.001), age at diagnosis(estimate 0.8590; SE=0.0532; p=0.004), relapse (estimate 4.9600; SE=0.6100; p=0.009) and metastatic disease (estimate 9.1700; SE=0.5660; p< 0.001). Vision loss was also significantly correlated with time to diagnosis (estimate 0.542; SE=0.2940; p=0.038). CONCLUSION Median time to diagnosis is associated with overall survival and long-term morbidity in pediatric patients treated for malignant CNS tumors. These data highlight that knowledge translation to the public, primary care and emergency room professionals should be a priority in order to promote early connection with medical care and mitigate morbidity and mortality in those with pediatric CNS tumors.

Puberty is initiated by hormonal changes in the adolescent body that trigger physical and behavioral changes to reach adult maturation. As these changes occur, some adolescents experience concerning pubertal symptoms that are associated with dysfunction of the autonomic nervous system (ANS). Vasovagal syncope (VVS) and Postural Orthostatic Tachycardia Syndrome (POTS) are common disorders of the ANS associated with puberty that are related to orthostatic intolerance and share similar symptoms. Compared to young males, young females have decreased orthostatic tolerance and a higher incidence of VVS and POTS. As puberty is linked to changes in specific sex and non-sex hormones, and hormonal therapy sometimes improves orthostatic symptoms in female VVS patients, it is possible that pubertal hormones play a role in the increased susceptibility of young females to autonomic dysfunction. The purpose of this paper is to review the key hormonal changes associated with female puberty, their effects on the ANS, and their potential role in predisposing some adolescent females to cardiovascular autonomic dysfunctions such as VVS and POTS. Increases in pubertal hormones such as estrogen, thyroid hormones, growth hormone, insulin, and insulin-like growth factor-1 promote vasodilatation and decrease blood volume. This may be exacerbated by higher levels of progesterone, which suppresses catecholamine secretion and sympathetic outflow. Abnormal heart rate increases in POTS patients may be exacerbated by pubertal increases in leptin, insulin, and thyroid hormones acting to increase sympathetic nervous system activity and/or catecholamine levels. Given the coincidental timing of female pubertal hormone surges and adolescent onset of VVS and POTS in young women, coupled with the known roles of these hormones in modulating cardiovascular homeostasis, it is likely that female pubertal hormones play a role in predisposing females to VVS and POTS during puberty. Further research is necessary to confirm the effects of female pubertal hormones on autonomic function, and their role in pubertal autonomic disorders such as VVS and POTS, in order to inform the treatment and management of these debilitating disorders.

Background: Preclinical studies show that TLR9 agonists can eradicate leukemia by induction of immune responses in vivo against AML and ALL. These studies demonstrated that TLR9 agonists induce an immediate NK response followed by adaptive T and B cells responses resulting in long term anti-leukemia immunity. Methods: The Therapeutic Advances in Childhood Leukemia and Lymphoma Phase I consortium performed a pilot study on 3 patients with MRD positive acute leukemia after an initial remission on conventional chemotherapy (TACL T2009-008) with the TLR 9 agonist (GNKG168). To guide future trial development, we evaluated the impact of GNKG168 by Nanostring on the expression 608 genes before and 8 days after initiation of GNKG168 therapy. Results: Twenty-three out of 578 markers on the nanostring panel showed significant difference (p ≤ 0.05). We focused on 8 markers that had the greatest differences with p < 0.01. Two genes were increased, promyelocytic leukemia protein (PML) and H-RAS, and 6 were decreased, Single Ig and TIR Domain containing (SIGIRR, IL1R8), interleukin 1 receptor 1 (IL1RL1, ST2), C-C Motif chemokine receptor 8 (CCR8), interleukin 7 R (IL7R), cluster of differentiation 8B (CD8B), and cluster of differentiation 3 (CD3D). Tumor inhibitory pathways were downregulated including the SIGIRR (IL1R8), important in IL-37 signaling and NK cell inhibition. TLR9 can induce IL-33, which is known to downregulate ST2 (IL1RL1) a receptor for IL-33. Conclusion: GNKG168 therapy is associated with immunologic changes in pediatric leukemia patients. Further work with a larger sample size is required to assess the impact of these changes on disease treatment and persistence of leukemia remission.

The objective was to conduct a program evaluation of the Centre for Healthy Weights—Shapedown BC (CHW-SB), a family-centered, multidisciplinary program for obese children, by assessing the change in weight trajectories from program intake to completion. Secondary outcomes included changes in clinical, biochemical and psychological parameters, and in physical activity (PA) levels. The CHW-SB program was evaluated over 10 weeks. Data collection included anthropometric, metabolic, PA and psychological measures. Longitudinal mixed effects regression was performed to evaluate weight change from Phase 1 (before program on waitlist) to Phase 2 (during program). 238 children < 18 years of age were referred to the program of which 119 were eligible for participation. There was a significant decrease in weight trajectory in children following program entry. Participants experienced an average .89% monthly increase before program entry, compared to a .37% monthly decline afterwards, a drop of 1.26% (p < 0.0001, 95%CI 1.08 to 1.44). zBMI (2.26 ± 0.33 to 2.20 ± 0.36, p < 0.001), waist circumference (99 ± 15.7 to 97 ± 16 cm, p < 0.0001) and fasting insulin (137 ± 94.8 to 121 ± 83.4 pmol/L, < 0.001) also decreased in participants who attended the final visit. Significant improvements were seen in all measures of PA, self-concept, and anxiety. CHW-SB, a government-funded program, is the first obesity-treatment program to be evaluated in Canada. While short-term evaluation revealed significant improvements in adiposity, PA, and psychological measures, the lack of full follow-up is a limitation in interpreting the clinical effectiveness of this program, as drop-out may be associated with lack of success in meeting program goals. These data also emphasize the need for ongoing evaluation to assess the long-term implications of this unique program and ultimately optimize utilization of governmental resources.

OBJECTIVE Pleomorphic xanthoastrocytoma (PXA) with anaplasia is a rare histological subtype of central nervous system astrocytoma and generally treated as high grade gliomas. The optimal extent of therapy required is unknown. Here we report on 3 pediatric cases of PXA with anaplasia. We also describe molecular features and methylation profile of PXA with anaplasia compared to age-matched PXA without anaplasia. METHODS Our institutional database was queried for cases of PXA since 1998 and 3 cases with anaplasia were identified and records reviewed. RESULTS 2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of PXA with anaplasia was made. Immunohistochemistry demonstrated that two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation. All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients received concurrent temozolamide with radiation followed by maintenance chemotherapy with temozolamide and lomustine for 6 cycles as per the Children’s Oncology Group Protocol ACNS0423. These two patients had a continued complete response. The third patient received temozolamide following radiation and subsequently had recurrent disease at the end of treatment and went on to have a re-resection GTR and achieved complete response after 6 cycles of lomustine, vincristine and procarbazine. All are alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%). CONCLUSIONS This rare pediatric tumor is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.

Delayed diagnosis of CNS tumors in children is well documented, partially due to challenges in recognizing rare diagnoses. Our objective was to describe Canadian family physicians’ attitudes and confidence in diagnosing and managing pediatric CNS tumors. A standardized questionnaire was administered at a Canadian national family physicians’ conference. Items were based on observations from our institutional study of prediagnostic symptomatic interval in pediatric CNS tumors. 449 surveys were completed. 302/443 (68%) physicians practice in cities. 153/447 (34%) report encountering parents that inquire about their children having brain tumors. 261/449 (58%) have not managed a pediatric brain tumor. 153/447 (34%) report they are not confident, 255/447 (57%) somewhat confident and 39/447 (9%) confident in managing a suspected brain tumor in a stable child. 259/447 (58%) would refer directly to a hospital/specialist. The reported median time for suspicion of a brain tumor was 8–14 days for children with vomiting and/or headache and 1 day for children with seizure and/or ataxia. 410/447 (97%) report not knowing any guidelines to help with management. 235/447 (53%) suggested barriers they experience to include 52/235 (22%) wait times for imaging/specialists, 37/235 (16%) geographical location of the child, 27/235 (12%) knowledge, 25/235 (11%) access to imaging/specialist, and 15/235 (6%) patient-related factors or system barriers, and 8/235 (3%) specialist attitudes. 68/235 (29%) identified no barriers in their practice. This study provides insight into family physicians’ perceived challenges and barriers in diagnosing and managing new suspected pediatric CNS tumors. Educational effort and overcoming systemic perceived barriers may increase physicians’ confidence.

BACKGROUND Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear. METHODS Retrospective multi-institutional analysis was conducted across 18 institutions in four countries. RESULTS For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT. CONCLUSION In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.

Objectives To evaluate the clinical impact of a congenital adrenal hyperplasia (CAH) newborn screening program and incremental costs relative to benefits in screened vs unscreened infants. We hypothesized that screening would lead to clinical benefits and would be cost effective. Study design This was an ambispective cohort study at British Columbia Children's Hospital, including infants diagnosed with CAH from 1988-2008 and 2010-2018. Data were collected retrospectively (unscreened cohort) and prospectively (screened cohort). Outcome measures included hospitalization, medical transport, and resuscitation requirements. The economic analysis was performed using a public payer perspective. Results Forty unscreened and 17 screened infants were diagnosed with CAH (47% vs 53% male). Median days to positive screen was 6 and age at diagnosis was 5 days (range, 0-30 days) and 6 days (range, 0-13 days) in unscreened and screened populations, respectively. In unscreened newborns, 55% required transport to a tertiary care hospital, 85% required hospitalization, and 35% required a fluid bolus compared with 29%, 29%, and 12% in screened infants, respectively. The cost of care was $33 770 per case in unscreened vs $17 726 in screened newborns. In the screened cohort, the incremental cost-effectiveness ratio was $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided. Conclusions Compared with unscreened newborns, those screened for CAH were less likely to require medical transport and had shorter hospital stays. Screening led to a decrease in hospitalization costs. Although screening did not result in cost savings, it was assessed to be cost effective considering the clinical benefits and incremental cost-effectiveness ratio.

During the last 2 decades, prescriptions of atypical or SGAs to children and adolescents have increased significantly.1–3 From 1996 to 2011, SGA prescriptions in BC increased from 0.33/1000 children (

Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole-genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding. Identification of oncogenic drivers in recurrent pediatric PTC may facilitate targeted therapy while avoiding repeated RAI.

Objective: To compare the rates of obesity, impaired fasting glucose (IFG), and type 2 diabetes between second-generation antipsychotic (SGA)-treated and -naive youth. Methods: A retrospective chart review was conducted for all child and adolescent psychiatry emergency admissions over 2.5 years. Data collected included age, sex, psychiatric diagnosis, medications, height, weight, fasting glucose, and lipid profile. Body mass index (BMI) was standardized for age and sex and converted to a z score. Overweight was defined as a BMI between the 85th and 95th percentile and obese as a BMI at the 95th percentile or greater for age and sex. The 2007 American Diabetes Association criteria for IFG and type 2 diabetes were used. Results: Among the 432 admissions, 167 (39%) had both height and weight measured, and 145 (34%) had fasting glucose measured. The mean zBMI was higher in the SGA-treated ( n = 68), compared with the SGA-naive group ( n = 99) (mean difference 0.81; 95% CI 0.46 to 1.16). In the SGA-treated group, 31% were obese and 26% were overweight, compared with 15% and 8%, respectively, in the SGA-naive group ( P < 0.01). In the SGA-treated group ( n = 65), 21.5% had IFG or type 2 diabetes, compared with 7.5% in the SGA-naive group ( n = 80) ( P = 0.01). Conclusions: Youth treated with SGAs have significantly higher rates of obesity and glucose intolerance than SGA-naive youth. These data emphasize the need for consistent metabolic monitoring of youth with psychiatric disorders who are prescribed SGAs.

Second-generation antipsychotic (SGA) prescriptions for children have steadily increased over the past two decades. This is in part due to the perception of a reduction in neurological side effects with SGAs as compared to first-generation antipsychotics. However, the current literature shows that children treated with SGAs are at risk for metabolic side effects including central obesity, impaired glucose tolerance, hypertension, dyslipidemia, and metabolic syndrome. To ensure the safety of children treated with SGAs, it is important that (1) these medications are used for evidence-based indications only; (2) prescribing physicians monitor metabolic changes at regular time intervals per the current recommendations; and (3) metabolic complications are identified early and treated through promotion of a healthy lifestyle, use of the lowest effective dose of the SGA, and reduction in the use of multiple medications.

Importance Acute kidney injury (AKI) in children is associated with poor short-term and long-term health outcomes; however, the frequency of AKI in children hospitalized for diabetic ketoacidosis (DKA) has not been previously examined. Objectives To determine the proportion of children hospitalized for DKA who develop AKI and to identify the associated clinical and biochemical markers of AKI. Design, Setting, and Participants This medical record review of all DKA admissions from September 1, 2008, through December 31, 2013, was conducted at British Columbia Children’s Hospital, the tertiary pediatric hospital in British Columbia, Canada. Children aged 18 years or younger with type 1 diabetes and DKA and with complete medical records available for data analysis were included (n = 165). All data collection occurred between September 8, 2014, and June 26, 2015. Data analysis took place from August 25, 2015, to June 8, 2016. Main Outcomes and Measures Acute kidney injury was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria. Multinomial logistic regression was used to identify potential factors associated with AKI. Results Of the 165 children hospitalized for DKA, 106 (64.2%) developed AKI (AKI stage 1, 37 [34.9%]; AKI stage 2, 48 [45.3%]; and AKI stage 3, 21 [19.8%]). Two children required hemodialysis. In the adjusted multinomial logistic regression model, a serum bicarbonate level less than 10 mEq/L (compared with ≥10 mEq/L) was associated with a 5-fold increase in the odds of severe (stage 2 or 3) AKI (adjusted odds ratio [aOR], 5.22; 95% CI, 1.35-20.22). Each increase of 5 beats/min in initial heart rate was associated with a 22% increase in the odds of severe AKI (aOR, 1.22; 95% CI, 1.07-1.39). Initial corrected sodium level of 145 mEq/L or greater (compared with 135-144 mEq/L) was associated with a 3-fold increase in the odds of mild (stage 1) AKI (aOR, 3.29; 95% CI, 1.25-8.66). There were no cases of mortality in patients with or without AKI. Conclusions and Relevance This study is the first to date to document that a high proportion of children hospitalized for DKA develop AKI. Acute kidney injury was associated with markers of volume depletion and severe acidosis. Acute kidney injury is concerning because it is associated with increased morbidity and mortality as well as increased risk of chronic renal disease, a finding that is especially relevant among children who are already at risk for diabetic nephropathy. Strategies are needed to improve the diagnosis, management, and follow-up of AKI in children with type 1 diabetes.

Objective: To determine whether implementation of a metabolic monitoring training program (MMTP) in an urban community-based setting improved monitoring in children treated with second-generation antipsychotics (SGAs) and changed prescription rates of SGAs to children. Method: The MMTP was implemented in the Vancouver Coastal Health Child and Youth Mental Health Teams (CYMHTs) on January 1, 2009. A retrospective review of paper charts and electronic records for children seen at the CYMHTs from September 1, 2007, to May 1, 2010, was performed to collect the following data: age, sex, foster care, immigrant status, Axis I diagnosis, and medications. In SGA-treated children, anthropometric measurements and blood work completed at baseline and 3, 6, and 12 months were also collected. Results: Among the 1114 children seen pre-MMTP and 1262 children seen post-MMTP implementation, 174 (15.4%) and 81 (6.4%), respectively, were SGA-treated ( P < 0.001). Among the SGA-treated children seen at the CYMHTs after MMTP implementation, 38.3% had a copy of the MMTP in their paper chart. Metabolic monitoring increased by up to 40% at baseline ( P < 0.01), 20% at 3 ( P < 0.01) and 6 months ( P < 0.01), and 18% at 12 months after MMTP implementation. Conclusions: Implementation of an MMTP was associated with significantly improved monitoring rates of anthropometric and blood work parameters at baseline and the 3- and 6-month time points, with a trend for improvement at the 12-month time point, in SGA-treated children cared for in urban community mental health clinics. In addition, a 56% decrease in SGA prescriptions was observed following MMTP implementation in this population.

Objective: To compare the prevalence of metabolic syndrome (MetS) and its components in second-generation antipsychotic (SGA)-treated and SGA-naive children; and to explore the utility of clinical markers, such as waist circumference (WC) and body mass index (BMI), as screening tools for MetS. Methods: Subjects were prospectively recruited from the Psychiatry Emergency Unit at British Columbia Children's Hospital. As part of a quality-assurance project, a metabolic monitoring protocol was implemented, including collection of anthropomorphic and laboratory data. Results: From January 2008 to February 2010, there were 117 SGA-treated and 217 SGA-naive children recruited. The overall prevalence of MetS was 19.0% (16/84; median treatment duration = 14 months) in SGA-treated and 0.8% (1/127) in SGA-naive children (OR 29.7; 95% CI 3.85 to 228.40, P < 0.001), with an increased prevalence of all components except high-density lipoprotein cholesterol (HDL-C), respectively: elevated WC (40.7% and 10.1%; P < 0.001); hypertriglyceridemia (33.7% and 18.8%; P = 0.01); impaired fasting glucose (12.5% and 0.7%; P = 0.005); and elevated blood pressure (41.2% and 16.5%; P < 0.001). SGA treatment was the strongest predictor of MetS (OR 19.2; 95% CI 2.30 to 160.44, P = 0.006) followed by male sex (OR 5.7; 95% CI 1.08 to 30.62, P = 0.04). Presence of abdominal obesity was more sensitive (92.9%) than BMI (68.8%), while fasting glucose of 5.6 mmol/L or more and HDL-C of 1.03mmol/L or less were most specific (94.1%) in correctly identifying MetS. Conclusions: SGA treatment confers a significantly increased risk for MetS over the long term. WC measurement is a simple and sensitive screening tool for determining MetS risk in SGA-treated children. These data highlight the dangers of SGA treatment and the importance of standardized metabolic monitoring using sex- and age-adjusted tables in this population.

1) To review SSRI prescribing patterns for children and adolescents in our hospital and provincial prescription database and 2) To evaluate whether prescribing practices are consistent with expectations, based on published evidence and practice recommendations.A PubMed online search was conducted to obtain all randomized controlled trials assessing efficacy of SSRI use in children and adolescents. The inpatient hospital pharmacy database at BC Children's Hospital (BCCH) and the BC Pharmacare database were used to identify all unique patients (under 19 years of age) seen in the inpatient department of psychiatry at BCCH or as outpatients in the province of BC receiving SSRI prescriptions between 2005-2009.Fluoxetine, citalopram, escitalopram and sertraline have evidence supporting their efficacy in the treatment of depressive disorders. Fluoxetine, fluvoxamine, sertraline, paroxetine and venlafaxine have evidence for use in the treatment of anxiety disorders. Between 2005-2009, BCCH inpatient data revealed that fluoxetine is the most frequently prescribed SSRI, followed by citalopram, sertraline, fluvoxamine, venlafaxine, paroxetine and escitalopram. In the community outpatients, fluoxetine was most frequently prescribed SSRI followed by citalopram, venlafaxine, sertraline, paroxetine, fluvoxamine and escitalopram.Prescribing patterns for SSRIs at BC Children's Hospital are consistent with the available evidence in the pediatric population. Furthermore, with the exception of citalopram, provincial outpatient and inpatient prescriptions appear to follow published national guidelines. Hospital SSRI usage more closely reflects the available literature than outpatient community usage does.

To review the evidence for efficacy and metabolic effects of atypical antipsychotics (AAPs), and to propose a metabolic monitoring protocol for AAP use in children and adolescents.A PubMed search was performed to obtain all studies related to efficacy, metabolic side-effects, and monitoring in those less than 18 years of age.There are no approved indications for AAP use in children and adolescents in Canada. Based on US Food and Drug Administration approvals and a review of randomized controlled trials, we identified 7 indications for AAP use that target specific symptoms in youth including schizophrenia, bipolar I disorder, autism, pervasive developmental disorder, disruptive behaviour disorders (including conduct disorder and ADHD), developmental disabilities and Tourette Syndrome. A wide range of metabolic effects including weight gain, increased waist circumference, dysglycemia, dyslipidemia, hypertension, elevated hepatic transaminases and prolactin levels have been reported. We have developed a proposal for metabolic monitoring that includes anthropometric measurements and laboratory testing at baseline and appropriate intervals thereafter.There is an urgent need for national clinical practice guidelines that provide, not only appropriate treatment algorithms for AAP-use based on evidence, but also address metabolic monitoring and subsequent management of complications in this vulnerable population.

Second-generation antipsychotics (SGAs) are increasingly being used to treat children with a variety of psychiatric illnesses. Metabolic syndrome (MetS), a risk factor for cardiovascular disease, is a side-effect of SGA-treatment. We conducted a cross-sectional study and assessed the association of the methylenetetrahydrofolate reductase (MTHFR) C677T variant with features of MetS in SGA-treated (n=105) and SGA-naïve (n=112) children. We targeted the MTHFR C677T variant, because it is associated with risk for cardiovascular disease, and features of MetS in adults without psychiatric illness. MetS in children is based on the presence of any three of the following: waist circumference ≥ 90th percentile for age and sex; plasma triglyceride ≥ 1.24 mmol l(-1); plasma high-density lipoprotein-cholesterol ≤ 1.03 mmol l(-1); systolic or diastolic blood pressure ≥ 90th percentile for age, sex, and height; and fasting glucose ≥ 5.6 mmol l(-1). We found that 15% of SGA-treated children had MetS compared with 2% of SGA-naïve children (OR 8.113, P0.05). No effect of the MTHFR C677T variant on psychiatric diagnosis was observed. The MTHFR 677T allele was associated (P0.05) with MetS (OR 5.75, 95% CI= 1.18-28.12) in SGA-treated children. Models adjusted for duration of SGA treatment, ethnicity, sex, age and use of other medications revealed a positive relationship between the MTHFR 677T allele and diastolic blood pressure Z-scores (P=0.001) and fasting plasma glucose (P0.05) in SGA-treated children. These findings illustrate the high prevalence of MetS in SGA-treated children and suggest metabolic alterations associated with the MTHFR C677T variant may have a role in the development of MetS features in SGA-treated children.