Adam Fleming

Background: Central nervous system (CNS) tumors in infants are rare, pose unique clinical challenges, and lack large‐scale evidence‐based data to guide management. This study seeks to describe CNS tumors in Canadian infants and to compare their outcomes with those of older children. Methods: We conducted a retrospective cohort study using the Cancer in Young People in Canada (CYP‐C) database, a population‐based childhood cancer surveillance program in Canada. The study included all children under 10 years with newly diagnosed CNS tumors between 2001 and 2020. Cox proportional hazards models were employed to compare event‐free survival (EFS) and overall survival (OS) between infants (n = 157, 51.7%, including 95 infants [31.3%] with low‐grade and 36 infants [11.8%] with high‐grade gliomas), followed by atypical teratoid/rhabdoid tumors ( n = 45, 14.8%), choroid plexus tumors ( n = 33, 10.8%), ependymomas ( n = 31, n = 10.2%), and medulloblastomas ( n = 15, 5.3%). Infants had significantly more metastatic disease compared to older children (15.0% vs. 8.7%; p < 0.001). Treatment approaches differed significantly between infants and older children, with infants receiving radiotherapy far less frequently (6.9% vs. 22.2%; p < 0.001). Compared with older children, infants had worse 5‐year EFS (43.9% [95% CI: 35.9–50.1] vs. 57.7% [95% CI: 55.6–59.8]; p < 0.001) and worse 5‐year OS (52.8% [95% CI: 45.3–59.8] vs. 66.7% [95% CI: 64.7–68.7]; p < 0.001). In multivariable analyses adjusting for CNS tumor subtype and metastatic status, infants had significantly poorer EFS (adjusted HR [aHR] 1.55, 95% CI: 1.29–1.87; p < 0.001) and OS (aHR 1.64, 95% CI: 1.34–2.01; p < 0.011). Stratified by tumor subtypes, infants with low‐grade gliomas (OS HR 3.41, 95% CI: 1.76–6.63; p < 0.001), medulloblastomas (OS HR 2.47, 95% CI: 1.15–5.30; p = 0.02), and atypical teratoid/rhabdoid tumors (OS HR 2.69, 95% CI: 1.71–4.23; p  < 0.001) demonstrated significantly inferior outcomes compared to older children. Conclusion: Infants account for 8.4% of all children under 10 years with CNS tumors in Canada. Their outcomes are significantly worse than those of older children, particularly among patients with low‐grade gliomas, medulloblastomas, and atypical teratoid/rhabdoid tumors.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Background Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child’s early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs. Methods The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0–15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child’s demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times. Results Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17–6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35–21.63) and 24-month (OR 6.04, 95% CI 2.06–17.70) lead time before diagnosis. No associations for other medications were found. Conclusions This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted.

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

There has been a significant rise in the number of emergency department (ED) visits over the past 15 years despite the number of ED providers and treatment spaces remaining fixed (M. P. Lin et al., 2018). A hospital's need to quickly initiate care upon patient arrival is of paramount importance to combat these ED overcrowding trends. A teleprovider in triage (TPIT) program without a standardized operating protocol leads to significant provider practice variations and limits effectiveness of a TPIT program. The intention of this health care project was to reduce ED time metrics and reduce the number of patients who left before evaluation by implementing a standardized TPIT protocol. This standardization allowed for a more predictable experience for the patient and ED staff. This quality improvement project involved developing and implementing a standardized TPIT protocol to improve TPIT efficiency and throughput. Patient ED visit metrics were collected during the pre- and postimplementation periods to evaluate for any improvement in throughput due to the TPIT protocol. The TPIT advanced practice providers (APPs) showed significant improvement in knowledge following the TPIT protocol education with an increase in provider comfort ( p < 0.05). Time spent by the TPIT provider on each patient encounter was reduced by 23%, demonstrating increased provider efficiency. Improvements in discharge lengths of stay (LOS) ( p = 0.68) and room to discharge LOS ( p < 0.05) were noted following the implementation of the TPIT protocol. Conclusions: The implementation of the TPIT protocol provided improvements in APP knowledge and understanding of the process while increasing provider efficiency. Improvements were identified in specific ED patient metrics demonstrating the significance of the TPIT protocol on patient care.

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identified binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Background: Obesity is characterized by the disproportionate expansion of the fat mass and is most commonly diagnosed using the Body Mass Index (BMI) z-score or percentile in children. However, these measures associate poorly with the fat mass. This is important, as adiposity is a more robust predictor of cardiometabolic risk than BMI-based measures, but there are limited clinical measures of adiposity in children. A new measure, the Tri-ponderal Mass Index (TMI, kg/m³) has recently demonstrated robust prediction of adiposity in children. The aim of this study is to explore the association of leptin, a validated biomarker of the fat mass, with TMI. Methods: One hundred and eight children and adolescents were included in this cross-sectional study. Height and weight were used to calculate TMI. Plasma leptin was measured using ELISA. Multivariable regression analysis was applied to determine the predictors of TMI. Results: The age range of participants included in this study was 8.00– 16.90 years (female n=48, 44%). Leptin correlated with BMI percentile (r=0.64, p-value < 0.0001) and TMI (r=0.71, p-value < 0.0001). The multivariable regression analysis revealed that BMI percentile (Estimated Beta-coefficient 0.002, 95% CI 0.002– 0.003, p-value < 0.0001) and Leptin (Estimated Beta-coefficient 0.05, 95% CI 0.02– 0.07, p-value 0.013) were associated with TMI. Conclusion: Leptin is associated with TMI in healthy children. The TMI is a feasible clinical measure of adiposity that may be used to stratify children and adolescents for further assessments and interventions to manage and attempt to prevent cardiometabolic comorbidities.