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Brianna Empringham,1,2 William J Jennings,1,2 Raeesha Rajan,1– 3 Adam J Fleming,1,4 Carol Portwine,1,4 Donna L Johnston,5 Shayna M Zelcer,6 Shahrad Rod Rassekh,7 Victoria Tran,1,2 Sarah Burrow,8 Lehana Thabane,3,9– 11 M Constantine Samaan1– 3 1Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; 2Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 3Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada; 4Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 5Division of Pediatric Hematology/Oncology, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 6Pediatric Hematology Oncology, Children’s Hospital, London Health Sciences Center, London, Ontario, Canada; 7Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, British Columbia’s Children’s Hospital, Vancouver, BC, Canada; 8Division of Orthopedic Surgery, Department of Surgery, McMaster University Medical Centre, Hamilton, Ontario, Canada; 9Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada; 10Centre for Evaluation of Medicines, St. Joseph’s Health Care, Hamilton, Ontario, Canada; 11Biostatistics Unit, St Joseph’s Healthcare-Hamilton, Hamilton, Ontario, CanadaCorrespondence: M Constantine SamaanDepartment of Pediatrics, McMaster University, Division of Pediatric Endocrinology, McMaster Children’s Hospital, 1280 Main Street West, 3A-57, Hamilton, Ontario, L8S 4K1 Tel +001-905-521-2100, ext. 75926Fax +001-905-308-7548Email samaanc@mcmaster.caBackground: 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.Keywords: Tri-ponderal mass index, adiposity, leptin, children

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10 -8 ) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006)., (© 2024. The Author(s).)

Dexamethasone use during hematopoietic cell transplant (HCT) conditioning varies between pediatric centers. This study aimed to estimate the difference in 1-year treatment-related mortality (TRM) between patients who did or did not receive dexamethasone during HCT conditioning. Secondary objectives were to estimate the difference between dexamethasone-exposed and dexamethasone-unexposed groups in 1-year event-free survival (EFS), time to neutrophil engraftment, acute graft-versus-host disease (aGVHD), and invasive fungal disease (IFD) at day + 100. This was a seven-site, international, retrospective cohort study. Patients < 18 years old undergoing their first allogeneic or autologous myeloablative HCT for hematologic malignancy or aplastic anemia between January 1, 2012, and July 31, 2017, were included. To control for potential confounders, propensity score weighting was used to calculate the standardized mean difference for all endpoints. Among 242 patients, 140 received dexamethasone during HCT conditioning and 102 did not. TRM was unaffected by dexamethasone exposure (1.7%; 95% CI - 7.4, 10.2%). Between-group differences in secondary outcomes were small. However, dexamethasone exposure significantly increased possible, probable, and proven IFD incidence (9.0%, 95% CI 0.8, 17.3%). TRM is not increased in pediatric patients who receive dexamethasone during HCT conditioning. Clinicians should consider potential IFD risk when selecting chemotherapy-induced vomiting prophylaxis for pediatric HCT patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Penicillin allergy is a common drug allergy diagnosis in pediatric patients; however, upon appropriate allergy testing, many of these patients are found not to have a true allergy. For patients with a reported allergy, alternative antibiotics are prescribed, which are less effective, more toxic, or more expensive. There is a lack of data evaluating allergies in hospitalized children and comparing allergy assessments conducted by pediatric allergists and pharmacists., Objective: To estimate the percentage of pediatric patients admitted with reported penicillin allergy who did not have a true penicillin allergy., Methods: This single-centre prospective cohort study included inpatients between 6 months and 17 years of age, with a documented penicillin allergy, who were admitted to the general pediatric and oncology units of a tertiary care children's hospital between November 2019 and March 2023. The allergy history, evaluation, and risk categorization were performed by pharmacists. The history was reviewed with the allergist, and the patient was then referred, underwent skin testing, or received oral amoxicillin challenge with monitoring for 1 hour., Results: Thirty patients were included, of whom 29 (97%) had delabelling of their penicillin allergy. Four patients (13%) had delabelling on the basis of history alone, without risk assessment. Twenty-five (83%) of the patients were assessed as having low risk; 24 of these had delabelling following oral challenge, and 1 did not complete the oral challenge because of transfer to another hospital. One patient (3%) was assessed as having moderate risk, with delabelling on the basis of results of skin testing and oral challenge. The pharmacist's and allergist's risk assessments were in agreement in 29 (97%) of the 30 cases., Conclusions: Pediatric patients, including those with oncologic malignancies, are often mislabelled as having a penicillin allergy. Pharmacists are able to accurately determine true allergy risk and delabel penicillin allergies for pediatric patients in the hospital setting., Competing Interests: Competing interests: For activities unrelated to the study reported here, Raymond Mak has received speaker’s honoraria from ALK, Sanofi, CSL Behring, Pfizer, AstraZeneca, and Novartis; and Tiffany Wong has received speaker’s honoraria from Valeo, Pfizer, CeraVe, and Polaris Health. Dr Wong also serves as Faculty Lead for the Spread Quality Improvement initiative of the Provincial Health Services Authority (British Columbia) and Faculty Lead for Patient Safety and Quality Improvement, Postgraduate Medical Education, Faculty of Medicine, The University of British Columbia. No other competing interests were declared., (2024 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers., (© 2024. The Author(s).)

Background: Palivizumab is recommended for prevention of severe respiratory syncytial virus (RSV) disease in immunocompromised children, despite a lack of strong supporting evidence. The recent approval of substitute RSV-neutralizing monoclonal antibodies against RSV, offers an opportunity to synthesize the most current evidence supporting the palivizumab standard of care., Objective: To evaluate the efficacy of palivizumab in preventing acute respiratory tract infection- or RSV-related hospitalization, or mortality in immunocompromised children., Methods: We searched Ovid MEDLINE and EMBASE for published clinical studies that investigated outcomes of palivizumab use in children. We included clinical trials, cohort studies, and case-control studies. The primary outcomes were RSV-related or respiratory viral infection-related hospitalizations, or RSV-related mortality. This systematic review was registered in PROSPERO (ID CRD42021248619) and is reported in accordance with the PRISMA guidelines., Results: From the 1993 records, six studies were eligible and included, for a total of 625 immunocompromised children with an heterogeneous composition of primary and acquired immunodeficiencies enrolled from palivizumab programs. There were no intervention studies. None of the studies included a control group. RSV hospitalizations were infrequent (0%-3.1% of children). Most children included received palivizumab, although one study (n = 56) did not specify how many received palivizumab. RSV mortality was neither observed, in three studies, nor reported, in three other studies., Conclusions: The evidence supporting the use of palivizumab for prevention of severe RSV disease in immunocompromised children remains extremely limited and appears insufficient to justify prioritizing this intervention as the current standard of care over alternative interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers., Methods: We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV))., Primary Outcome: serum creatinine (SCr)-defined AKI (≥ stage 1)., Results: At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine) 2 /1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70)., Conclusions: TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance., Methods: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified., Results: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance., Conclusions: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk., Competing Interests: Several authors on this article (B. Brooks, S.R. Rassekh, C. J. D. Ross, and B. C. Carleton) were authors on published studies discussed in this systematic review; however, transparent grading criteria were employed to limit bias. All authors declare no other conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite the widespread use of medical cannabis, little is known regarding the safety, efficacy, and dosing of cannabis products in children with cancer. The objective of this study was to systematically appraise the existing published literature for the use of cannabis products in children with cancer., Methods: This systematic review, registered with the International Prospective Register of Systematic Reviews (CRD42020187433), searched four databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library. Abstracts and full texts were screened in duplicate. Data on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, and clinical and demographic details as well as reported efficacy outcomes were extracted. Data on cannabinoid-related adverse events were also summarized., Results: Out of 34,611 identified citations, 19 unique studies with a total of 1927 participants with cancer were included: eight retrospective chart reviews, seven randomized controlled trials, two open-label studies, and two case reports. The included studies reported the use of various cannabis products for the management of symptoms. Cannabinoids were commonly used for the management of chemotherapy-induced nausea and vomiting (11 of 19 [58%]). In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids. Across all included studies, no serious cannabis-related adverse events were reported., Conclusions: Although there is evidence to support the use of cannabis for symptom management, in children with cancer, there is a lack of rigorous evidence to inform the dosing, safety, and efficacy of cannabinoids. Because of the increasing interest in using cannabis, there is an urgent need for more research on medical cannabis in children with cancer., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach., Methods: Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020., Results: There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9)., Conclusions: This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT., (© 2023. Crown.)

Published outcomes for children with cancer with coronavirus disease 2019 (COVID-19) have varied. Outcome data for pediatric oncology patients in Canada, outside of Quebec, have not been reported. This retrospective study captured patient, disease, and COVID-19-related infectious episode characteristics and outcome data for children, 0 to 18 years, diagnosed with a first COVID-19 infection between January 2020 to December 2021 at 12 Canadian pediatric oncology centers. A systematic review of pediatric oncology COVID-19 cases in high-income countries was also undertaken. Eighty-six children were eligible for study inclusion. Thirty-six (41.9%) were hospitalized within 4 weeks of COVID-19; only 10 (11.6%) had hospitalization attributed to the virus, with 8 being for febrile neutropenia. Two patients required intensive care unit admission within 30 days of COVID-19 infection, neither for COVID-19 management. There were no deaths attributed to the virus. Of those scheduled to receive cancer-directed therapy, within 2 weeks of COVID-19, 20 (29.4%) experienced treatment delays. Sixteen studies were included in the systematic review with highly variable outcomes identified. Our findings compared favorably with other high-income country's pediatric oncology studies. No serious outcomes, intensive care unit admissions, or deaths, in our cohort, were directly attributable to COVID-19. These findings support the minimization of chemotherapy interruption after COVID-19 infection., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL., Patients and Methods: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations., Results: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021-0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011-0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection., Conclusions: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant., (©2023 American Association for Cancer Research.)

The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response. This knowledge is increasingly being translated into guidelines that inform drug dosing, monitoring for efficacy and safety, and determining the suitability of specific agents to treat patients. Health Canada and the U.S. Food and Drug Administration have recommended using genetic information to guide dosing for more than 20 drugs. There are no current, comprehensive paediatric guidelines to assist health care professionals in the use of genetics to inform medication dosing, safety, and efficacy in children, and such guidance is urgently needed. This statement helps to guide clinician understanding of the role of pharmacogenetics and how to use this information when prescribing medications in paediatrics., Competing Interests: SRR received payment for expert testimony from Knowles Intellectual Property Strategies, LLC in a patent case about an otoprotectant medication (sodium thiosulfate). Through the BC Children’s Hospital Research Institute, SRR also sits on the Data and Safety Monitoring Board for local non-industry studies (investigator initiated grants), none of which are related to this manuscript. There are no other disclosures., (© Canadian Paediatric Society 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Depuis vingt ans, le savoir médical sur le rôle des facteurs génétiques de variabilité a énormément évolué, tant à l'égard des maladies humaines que de la réponse aux médicaments. Ce savoir se traduit de plus en plus par des directives qui influent sur la posologie, la surveillance de l'efficacité et de l'innocuité et la détermination de la pertinence d'agents particuliers pour traiter les patients. Santé Canada et la Food and Drug Administration des États-Unis recommandent d'utiliser l'information génétique pour orienter la posologie de plus de 20 médicaments. Il n'existe actuellement pas de directives pédiatriques complètes pour aider les professionnels de la santé à utiliser la génétique afin d'établir la posologie, l'innocuité et l'efficacité des médicaments chez les enfants, et ces directives s'imposent d'urgence. Le présent document de principes aide le clinicien à comprendre le rôle de la pharmacogénétique et à utiliser l'information qu'il en tire pour prescrire des médicaments en pédiatrie., (© Société canadienne de pédiatrie 2023. Publié par Oxford University Press pour le compte de la Société canadienne de pédiatrie. Tous droits réservés. Pour obtenir une autorisation, écrivez à journals.permissions@oup.com.)

Background: Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss., Methods: The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT -risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups., Results: Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity ( P = 9 × 10 -7 ). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10 -5 ) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months)., Conclusions: Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT -risk alleles., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Anthracyclines, which are effective chemotherapeutic agents, cause cardiac dysfunction in up to 57% of patients. The cumulative anthracycline dose is a crucial predictor of cardiotoxicity; however, the cumulative dose alone cannot explain all cardiotoxic events. Strongly associated genetic variants in SLC28A3 , UGT1A6 , and RARG contribute to anthracycline-induced cardiotoxicity in pediatric patients and may help identify those most susceptible. This study aimed to examine how these pharmacogenetic effects are modulated by cumulative anthracycline doses in the development of cardiotoxicity., Methods: A total of 595 anthracycline-treated children were genotyped and cardiotoxicity cases were identified. A dose-stratified analysis was performed to compare the contributions of SLC28A3 rs7853758, UGT1A6 rs17863783, and RARG rs2229774 variants to the development of cardiotoxicity in low-dose (<150 mg/m 2 cumulative dose) and high-dose (>250 mg/m 2 cumulative dose) patient groups. Logistic regression was used to model the relationships between the cumulative anthracycline dose, genetic variants, and cardiotoxicity in the full cohort., Results: At < 150 mg/m 2 cumulative anthracycline dose, the SLC28A3 protective variant did not reach statistical significance [odds ratio (OR) 0.46 (95% confidence interval (CI) 0.10-1.45), P = 0.23], but it was statistically significant at doses >250 mg/m 2 [OR 0.43 (95% CI 0.22-0.78), P = 0.0093]. Conversely, the UGT1A6 and RARG risk variants were either statistically significant or approaching significance at doses <150 mg/m 2 [OR 7.18 (95% CI 1.78-28.4), P = 0.0045 for UGT1A6 and OR 2.76 (95% CI 0.89-7.63), P = 0.057 for RARG ], but not at doses >250 mg/m 2 [OR 2.91 (95% CI 0.80-11.0), P = 0.10; OR 1.56 (95% CI 0.89-2.75), P = 0.12]., Conclusions: These findings suggest that the SLC28A3 variant imparts more significant protection for patients receiving higher anthracycline doses, whereas the UGT1A6 and RARG risk variants significantly increased the risk of cardiotoxicity at low anthracycline doses., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2-6 months post-cisplatin, and (3) whether AKI is associated with 2-6-month outcomes., Methods: This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines., Results: Of 159 children (median [interquartile range [IQR]] age: 6 [2-12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76-110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2-6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2-6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04-6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2-6-month hypertension (AdjOR [95% CI]: 3.64 [1.05-12.62])., Conclusions: Severe electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children., Competing Interests: RJH and LEK served on Health Canada’s Scientific Advisory Committee on Health Products Containing Cannabis whose views are not reflected in this manuscript. RJH received a grant from the Jim Pattison Children’s Hospital Foundation for a study on medical cannabis in childhood refractory epilepsy and was Co-Chair, Health Canada Scientific Advisory Committee on Health Products Containing Cannabis (an unpaid position). EL received speaking fees from Spectrum Therapeutics and holds leadership positions in the following groups: Jamaican Medical Cannabis Corporation (unpaid position), Medical Cannabis Clinicians Society (UK), Canadian Collaborative for Childhood Cannabinoid Therapeutics, MedCan Support and Canadian Patient Advocacy & Support Services. CM-H is the controlling shareholder of a small publicly traded company that made an incremental $1.7M investment in a biotechnology company involved in medical research related to minor cannabinoids. JA has participated in an advisory board for Zyus Life Science. REB is a member of the Advisory Council, Drug-Free Kids Canada, and was Co-Chair of the Cannabis Project Advisory Group, Canadian Paediatric Society (both unpaid positions). SC holds a leadership position on the Network of Networks (N2) Board of Directors. AG reports that this article was researched and written prior to her employment at Health Canada and any views, opinions, and recommendations expressed within are those of the authors and do not reflect the position of Health Canada and/or the Government of Canada. JJ received grants from NSERC, CIHR, AMA Pediatrics, and Alberta Children’s Hospital Foundation, consulting fees from EISAI, UCB, and PENDOPHARM, payment/honoraria from EISAI, UCB, PENDOPHARM, and SUNOVION, and travel reimbursement from Neurocrine. JJ also holds leadership positions in the American Epilepsy Society, the Canadian League Against Epilepsy, and Hope for Hypothalamic Hamartomas. MJR is a member of the Paediatrics & Child Health editorial board. Another editor was responsible for overseeing the peer review of this manuscript. AS is the founder of Shackelford Pharma., an emerging medical cannabis company. There is also a provisional patent application filed, but not yet issued, on behalf of Shackelford Pharma, Inc. RV was director of the Department of Pediatric Pharmacy, Children’s Hospital of Eastern Ontario when this manuscript was written and submitted for publication but is now Vice President of Pharmacy Affairs for BCE Pharma. He has received consulting fees from Harvest Medicine Clinic and recently concluded an 8-year term as a Director of the International Pharmaceutical Federation Foundation. LEK holds a Board of Directors position at the Canadian Consortium for the Investigation of Cannabinoids and holds funding from the Canadian Institutes of Health Research, the Canadian Cancer Society, and the SickKids Foundation for C4T. She holds a Mitacs Accelerate grant for a separate project in partnership with Canopy Growth. There are no other disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society.)

Background: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2)., Objectives: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart., Methods: Rbl2 -/- mice and Rbl2 +/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies., Results: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors., Conclusions: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy., Competing Interests: This work was supported by the National Heart, Lung, and Blood Institute; National Institutes of Health (R00HL119605 and R56HL145034 to Dr Cheng; R01HL151472 to Dr Cheng and Dr Chow); National Cancer Institute, National Institutes of Health (R01CA211996 to Dr Chow); and WSU College of Pharmacy and Pharmaceutical Sciences. The SJLIFE study was supported by the National Cancer Institute, National Institutes of Health (CA195547, CA21765, and CA261898). The CPNDS work was supported by the Canadian Institutes of Health Research. Dr Xia was partially supported by T32HL007208 during manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Chow has received research funds from Abbott Laboratories for work unrelated to this project. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Various definitions used to describe cisplatin nephrotoxicity potentially lead to differences in determination of risk factors. This study evaluated incidence of kidney injury according to commonly used and alternative definitions in two cohorts of children who received cisplatin., Methods: This retrospective cohort study included children from Vancouver, Canada (one center), and Mexico City, Mexico (two centers), treated with cisplatin for a variety of solid tumors. Serum creatinine-based definitions (KDIGO and Pediatric RIFLE (pRIFLE)), electrolyte abnormalities consisted of hypokalemia, hypophosphatemia and hypomagnesemia (based on NCI-CTCAE v5), and an alternative definition (Alt-AKI) were used to describe nephrotoxicity. Incidence with different definitions, definitional overlap, and inter-definition reliability was analyzed., Results: In total, 173 children (100 from Vancouver, 73 from Mexico) were included. In the combined cohort, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity compared to pRIFLE and KDIGO criteria (82.7 vs. 63.6 vs. 44.5%, respectively). Nephrotoxicity and all electrolyte abnormalities were significantly more common in Vancouver cohort than in Mexico City cohort except when using KDIGO definition. The most common electrolyte abnormalities were hypomagnesemia (88.9%, Vancouver) and hypophosphatemia (24.2%, Mexico City). The KDIGO definition provided highest overlap of cases in Vancouver (100%), Mexico (98.6%), and the combined cohort (99.4%). Moderate overall agreement was found among Alt-AKI, KDIGO, and pRIFLE definitions (κ = 0.18, 95% CI 0.1-0.27) in which KDIGO and pRIFLE showed moderate agreement (κ = 0.48, 95% CI 0.36-0.60)., Conclusions: Compared to pRIFLE and KDIGO criteria, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity. pRIFLE is more sensitive to detect not only actual kidney injury but also patients at risk of cisplatin nephrotoxicity, while KDIGO seems more useful to detect clinically significant kidney injury. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Children with cancer are increasingly using cannabis therapeutically., Aim: The purpose of this study was to determine the perspectives and practices of pediatric oncologists and palliative care physicians regarding the use of cannabis for medical purposes among children with cancer., Methods: A self-administered, voluntary, cross-sectional, deidentified online survey was sent to all pediatric oncologists and palliative care physicians in Canada between June and August 2020. Survey domains included education, knowledge, and concerns about cannabis, views on its effectiveness, and the importance of cannabis-related research. Data were analyzed using descriptive statistics., Results: In total, 122/259 (47.1%) physicians completed the survey. Although 62.2% of the physicians completed some form of training about medical cannabis, nearly all (95.8%) desired to know more about the dosing, side effects, and safety of cannabis. Physicians identified a potential role of cannabis in the management of nausea and vomiting (85.7%), chronic pain (72.3%), cachexia/poor appetite (67.2%), and anxiety or depression (42.9%). Only four (0.3%) physicians recognized cannabis to be potentially useful as an anticancer agent. Nearly all physicians reported that cannabis-related research for symptom relief is essential (91.5%) in pediatric oncology, whereas 51.7% expressed that future studies are necessary to determine the anticancer effects of cannabis., Conclusions: Our findings indicate that most pediatric oncologists and palliative care physicians recognize a potential role for cannabis in symptom control in children with cancer. Well-conducted studies are required to create evidence for cannabis use and promote shared decision making with pediatric oncology patients and their caregivers., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies ( n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research.

Background: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication., Methods: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data., Results: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10 -4 ). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10 -7 ) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10 -7 )., Conclusions: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The use of cannabis for medical purposes by pediatric patients is expanding across Canada; however, supporting evidence, federal regulations and treatment guidelines are lacking. To understand factors affecting treatment decisions in this landscape, we sought to delineate clinician perspectives, ethics priorities and values for cannabis authorization., Methods: We sampled participants purposefully through Canadian Childhood Cannabinoid Clinical Trials listservs, which include the majority of pediatric oncologists and palliative care physicians practising in Canada, among many other pediatric physicians and clinicians. Inclusion criteria were being a practising clinician in Canada, involvement in the care of children and willingness to be interviewed regardless of stance on medical cannabis. In November and December 2020, we conducted semistructured interviews focusing on principles, values and priorities, including medical, professional, regulatory, evidentiary and social considerations, for authorizing medical cannabis to children. Interviews were recorded, transcribed and analyzed by means of deductive and inductive thematic methods., Results: We conducted 18 interviews with a diverse group of clinicians representing a range of specialties within pediatric care, including neurology, palliative care, oncology, family medicine and pharmacology. The interviews yielded 4 themes and 12 subthemes related to a priori (medical, professional, regulatory, evidentiary and social themes) and emergent themes. The 4 themes of access, relationships and relational autonomy (autonomy within relationships), medically appropriate use and research priorities were grounded in principles of harm reduction. Participants described problematic authorization procedures that negatively affect patient use. Principles associated with relational autonomy were highlighted as a feature of open clinical communication. Benefits of appropriate medical uses weighed positively over risks, even in the context of potential effects on neurodevelopment. Participants expressed that more research is essential to align medical cannabis with biomedical standards., Interpretation: Clinicians reported pursuing ethical use of medical cannabis for pediatric patients and prioritizing their safety under principles of harm reduction. There is a need for evidence about neurodevelopmental risks, support for research, treatment guidelines and greater knowledge about stakeholder perspectives to alleviate burdens related to use of medical cannabis for pediatric patients in Canada., Competing Interests: Competing interests: None declared., (© 2022 CMA Impact Inc. or its licensors.)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition estimated to affect 1 in 66 children in Canada and 1 in 270 individuals worldwide. As effective therapies for the management of ASD core and associated symptoms are limited, parents are increasingly turning to clinicians for advice regarding the use of medicinal cannabis to manage behavioural disturbances., Objective: The objective of this scoping review was to identify and map symptoms, outcomes and adverse events related to medicinal cannabis treatment for ASD-related behaviours., Methods: Ovid MEDLINE, Embase, CINAHL, PsycInfo, Web of Science Core Collection, Google Scholar and grey literature sources were searched up to 5 January 2020 for studies. Included studies met the following criteria: (1) investigate the use of medicinal cannabis, (2) at least 50% participants had ASD, (3) at least 50% of the study population was 0-18 years old and (4) any study design (published or unpublished)., Results: We identified eight completed and five ongoing studies meeting the inclusion criteria. All studies reported substantial behaviour and symptom improvement on medicinal cannabis, with 61% to 93% of subjects showing benefit. In the three studies reporting on concomitant psychotropic medication usage and with cannabis use, up to 80% of participants observed a reduction in concurrent medication use. Adverse events related to cannabis use were reported in up to 27% of participants related, and two participants had psychotic events., Conclusions: Early reports regarding medicinal cannabis in paediatric ASD symptom management are presented as positive; the evidence, however, is limited to very few retrospective cohort and observational studies. Evidence of safety and efficacy from prospective clinical trials is needed., (© 2021 John Wiley & Sons Ltd.)

Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL., Methods: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy., Results: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m 2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time., Conclusions: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle., (© 2021 American Cancer Society.)

Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide-MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers., (© 2021. Crown.)

Competing Interests: Intérêts concurrents: Richard Huntsman et Lauren Kelly sont coprésidents du Comité consultatif scientifique sur les produits de santé contenant du cannabis de Santé Canada; l’opinion du Comité n’est ni reflétée ni garantie dans cet article. Lauren Kelly détient une bourse Mitacs Accélération en partenariat avec Canopy Growth, sans lien avec le présent manuscrit. Juan Pablo Appendino déclare avoir reçu des honoraires de Pendopharm, Sunovion et UCB; il est également membre de comités ou de conseils de la Canadian League Against Epilepsy, de la Société canadienne de neurophysiologie clinique, de la Fédération des sciences neurologiques du Canada et de l’Académie ibéro-américaine de neurologie pédiatrique. Richard Bélanger fait partie du comité sur le cannabis de la Société canadienne de pédiatrie. Bruce Crooks indique avoir participé au comité de surveillance de la sécurité des données pour l’étude ReRAD et il est membre du comité consultatif pour la Nouvelle-Écosse et du comité consultatif médical de la fondation Rêves d’enfants Canada. Evan Lewis est conseiller médical bénévole auprès de JMCC Canada Corp. et déclare avoir reçu des honoraires de Spectrum Therapeutics. Alexander Repetski a occupé un poste de consultant bénévole auprès de Strainprint. Michael Rieder est membre du comité de surveillance de l’innocuité des médicaments pour une étude sur l’utilisation du cannabis médical pour traiter la céphalée chez l’enfant, et il est l’auteur principal du document de principes de la Société canadienne de pédiatrie sur le cannabis médical chez les enfants. Régis Vaillancourt déclare avoir reçu des honoraires de consultation de Harvest Medicine. Aucun financement n’a été versé pour la rédaction de ce manuscrit. Aucun autre intérêt n’a été déclaré.

Primary and secondary malignant tumors of the spine are relatively uncommon in the pediatric population but are associated with high morbidity and significantly decreased quality of life due to pain. Local management of these tumors is often challenging due to the importance of maintaining vertebral mechanical integrity as well as the spinal growth potential. Typically, surgery and/or radiation therapy have been used in the primary management of these tumors. However, treatment options become more limited when there is relapse or refractory disease, with re-resection or additional radiotherapy often not being viable therapies. Vertebroplasty is a currently underutilized modality that might provide significant pain palliation in cases of relapsed cancer in the spine., (© 2021 Wiley Periodicals LLC.)

Background: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin., Methods: Participants ( n =159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured ( 1 ) pre-cisplatin infusion, ( 2 ) post-infusion (morning after), and ( 3 ) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher)., Results: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0-232.7] versus 14.9 [5.4-29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083-9077] versus 1049 [358-3326] pg/mg creatinine; P <0.01). These markers modestly discriminated for AKI (area under receiver operating characteristic curve [AUC-ROC] range: NGAL, 0.56-0.72; KIM-1, 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROC range, 0.54-0.75) versus early infusions (AUC-ROC range, 0.48-0.65)., Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and associations with late kidney outcomes., Competing Interests: T.D. Blydt-Hansen reports having ownership interest in Apple, Hydrogenics, and Royal Bank of Canada; receiving honoraria from Astellas Canada; receiving research funding from Astellas Canada, Canadian Institutes of Health Research, Child and Family Research Institute, Children’s Hospital of Manitoba Research Institute, and Transplant Research Foundation of BC; having consultancy agreements with Astellas Canada, Horizon Canada, Novartis, and Ricordati; and serving as a scientific advisor for or member of BC Transplant, Canadian National Transplant Research Program, International Pediatric Transplant Association (council member), and North American Pediatric Transplant and Collaborative Studies. B.C. Carleton reports serving as a scientific advisor for or member of AEVI Genomic Medicine, United Health Group Pharmacogenomics (on the advisory committee); having consultancy agreements with Dynacare Specialized Diagnostics; receiving research funding from Dynacare Specialized Diagnostics (ended in June 2021) and grants from federal and provincial agencies; and having other interests/relationships with Rare Disease Society. P. Devarajan reports having consultancy agreements with Alnylam, Dicerna, Natera, and Reata; being a coinventor on patents for the use of NGAL as a biomarker of kidney injury; and serving on speakers bureaus for BioPorto Inc., Natera, and Reata. M. Pinsk reports having consultancy agreements with Canadian Agency for Drugs and Technologies in Health (as consultant); serving as an expert witness for legal consultations (multiple); and having other interests/relationships with Canadian Society of Nephrology, International Pediatric Nephrology Association, and Medical Council of Canada. K. R. Schultz reports having consultancy agreements with AVM Biotech, Celgene/Juno, Jazz, and Medpace; receiving honoraria from Bristol Myers Squibb (BMS), Celegene, and Jazz; serving on the data safety monitoring boards for BMS/Juno and Medpace; and serving as a scientific advisor or membership of Jazz. R.T. Tsuyuki reports receiving research funding from AstraZeneca, Merck Canada Inc., and Sanofi; serving as the editor-in-chief for Canadian Pharmacists Journal, and as president, chair, and on the board of directors for Hypertension Canada; receiving honoraria from Emergent Biosolutions and Merck Canada Inc.; and having consultancy agreements with Emergent Biosolutions and Shoppers Drug Mart. M. Zappitelli reports having consultancy agreements with BioPorto Inc., CytoPheryx Inc., and Eloxx Pharmaceuticals; receiving honoraria from Bioporto Inc. and Eloxx Pharmaceuticals; and having other interests/relationships with Canadian Pediatric Nephrologists Association, Canadian Society of Nephrology, and Kidney Foundation of Canada. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Malignant mesothelioma is a neoplasm of serosal surfaces, most commonly affecting the pleura. The peritoneum, pericardium, and tunica vaginalis are less frequently involved. Malignant mesothelioma with EWSR1-ATF1 fusion in young adults was recently reported in the literature. Here, we present two pediatric cases of EWSR1-ATF1 translocation-associated malignant mesothelioma in the peritoneum and pericardium respectively. Both cases lacked a known exposure history. Microscopy in both cases showed predominantly epithelioid morphology with ample eosinophilic cytoplasm, and immunohistochemistry was positive for pan-keratin, calretinin, and WT1. Both cases showed EWSR1-ATF1 gene rearrangement by RNA sequencing, which was instrumental in confirming the diagnosis of malignant mesothelioma and to exclude more common pediatric sarcomas, especially in the context of limited sampling.

Competing Interests: Competing interests: Richard Huntsman and Lauren Kelly are co-chairs of the Health Canada scientific advisory committee on health products containing cannabis, whose opinion is not reflected or guaranteed within. Lauren Kelly holds a Mitacs Accelerate award in partnership with Canopy Growth, unrelated to this manuscript. Juan Pablo Appendino reports honoraria from Pendopharm, Sunovion and UCB, as well as board or committee membership with the Canadian League Against Epilepsy, the Canadian Society of Clinical Neurophysiologists, the Canadian Neurological Sciences Federation and the Iberoamerican Academy of Pediatric Neurology. Richard Bélanger is on the cannabis committee of the Canadian Paediatric Society. Bruce Crooks reports participation on the data safety monitoring board of the ReRAD study, as well as membership with the Nova Scotia chapter advisory board and medical advisory committee of Make a Wish Foundation Canada. Evan Lewis has an unpaid position as medical advisor to the JMCC Canada Corp., and also reports honoraria from Spectrum Therapeutics. Alexander Repetski has an unpaid advisory position with Strainprint. Michael Rieder is a member of the drug safety monitoring board for a study exploring the use of medical cannabis for headache in children and is the principal author of the Canadian Paediatric Society’s statement on medical cannabis for children. Regis Vaillancourt reports consulting fees from Harvest Medicine. No funding was received to author this manuscript. No other competing interests were declared.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10 -10 , OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity., (© 2021. The Author(s).)

This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the 'voice of the clinician' dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.

Introduction: The World Health Organization currently classifies medulloblastoma (MB) into four molecular groups (WNT, SHH, Group 3 and Group 4) and four histologic subtypes (classic, desmoplastic nodular, MB with extensive nodularity, and large cell/anaplastic). "Classic" MB is the most frequent histology, but unfortunately it does not predict molecular group or patient outcome. While MB may exhibit additional histologic features outside of the traditional WHO subtypes, the clinical significance of such features, in a molecular context, is unclear., Methods: The clinicopathologic features of 120 pediatric MB were reviewed in the context of NanoString molecular grouping. Each case was evaluated for five ancillary histologic features, including: nodularity without desmoplasia (i.e., "biphasic", B-MB), rhythmic palisades, and focal anaplasia. Molecular and histological features were statistically correlated to clinical outcome using Chi-square, log-rank, and multivariate Cox regression analysis., Results: While B-MB (N = 32) and rhythmic palisades (N = 12) were enriched amongst non-WNT/SHH MB (especially Group 4), they were not statistically associated with outcome. In contrast, focal anaplasia (N = 12) was not associated with any molecular group, but did predict unfavorable outcome., Conclusion: These data nominate B-MB as a surrogate marker of Groups 3 and particularly 4 MB, which may earmark a clinically significant subset of cases.

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., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Cannabis is legal for recreational and medical use in Canada. Our aim was to explore family experiences using medical cannabis for children with severe conditions in the context of legalization., Methods: We conducted a qualitative study using semistructured interviews between April and July 2019. Participants were parents of children attending BC Children's Hospital oncology or palliative care clinics, recruited through posters, emails or referral. Participants were included if they spoke English and their child used any type of cannabis for medical purposes. Interviews included open-ended questions about the child's cannabis use. Interviews were recorded and transcribed, and thematic analysis was performed using qualitative description., Results: Ten interviews were completed with 9 mothers and 1 mother-father pair. The age range of the children was 22 months to 16 years. The primary reasons for cannabis use were epilepsy (6 children) or chemotherapy management (4 children). Five major themes were identified. 1) Child and family context, and cannabis as a last resort: children were seen as severely ill; parents sought cannabis out of desperation and responsibility to their child. 2) Varied information sources informed decision-making: parents lacked resources from health care providers and sought support from social media, industry and other families. 3) Cannabis as an ambiguous medicine: cannabis was viewed as both a serious drug that doctors should prescribe and as a natural alternative health product, safe to pursue alone. 4) Perceived effects: parents perceived medical benefits with few concerns about adverse effects. 5) Legal and financial challenges: parents were willing to obtain cannabis despite high costs and uncertain legality., Interpretation: Parents of children with severe conditions pursued medical cannabis despite obstacles and needed unbiased information to access alone. Scientific investigation is needed to develop pediatric medical guidelines to inform decisions., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

Background: Cisplatin is used to treat a wide range of childhood cancers and cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity. We aimed to address persistent knowledge gaps in CIHL by establishing benchmarks for the prevalence of and risk factors for CIHL., Methods: In this multi-institutional cohort study, children (age 0-14 years), adolescents, and young adults (age 15-39 years) diagnosed with a cisplatin-treated tumour from paediatric cancer centres, who had available cisplatin dosing information, and primary audiology data for central review from consortia located in Canada and the USA were eligible for inclusion. Audiology was centrally reviewed and CIHL graded using the consensus International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale. We assessed the prevalence of moderate or severe CIHL (SIOP grade ≥2) at latest follow-up and end of therapy, in each demographic, diagnosis, and treatment group and their relative contributions to risk for CIHL. Secondary endpoints explored associations of cisplatin dose reductions and CIHL with survival. We also examined whether cisplatin dose reductions and CIHL were associated with survival outcomes., Findings: We included 1481 patients who received cisplatin. Of the 1414 (95·5%) participants who had audiometry at latest follow-up (mean 3·9 years [SD 4·2] since diagnosis), 620 (43·8%) patients developed moderate or severe CIHL. The highest prevalence of CIHL was seen in the youngest patients (aged <5 years; 360 [59·4%] of 606 patients) and those with a CNS tumour (221 [50·9%] of 434 patients), hepatoblastoma (110 [65·9%] of 167 patients), or neuroblastoma (154 [62·1%] of 248 patients). After accounting for cumulative cisplatin dose, higher fractionated doses were associated with risk for CIHL (for each 10mg/m 2 increase per day, adjusted odds ratio [aOR] 1·15 [95% CI 1·07-1·25]; for each 50 mg/m 2 increase per cycle aOR 2·16 [1·37-3·51]). Vincristine exposure was newly identified as a risk factor for CIHL (aOR 3·55 [2·19-5·84]). Dose reductions and moderate or severe CIHL were not significantly associated with survival differences., Interpretation: Using this large, multicentre cohort, benchmarks were established for the prevalence of CIHL in patients treated with cisplatin. Variations in cisplatin dosing confer additive risk for developing CIHL and warrant investigation as a potential approach to decrease the burden of therapy., Funding: US National Institutes of Health and National Institute on Deafness and Other Communication Disorders, US National Institutes of Health and National Cancer institute, St Baldrick's Foundation, Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Canada Foundation for Innovation, University of British Columbia, British Columbia Children's Hospital Research Institute, British Columbia Provincial Health Services Authority, Health Canada, and C17 Research Network., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There is no uniform guideline for postchemotherapy vaccination of children with acute lymphoblastic leukemia (ALL). We evaluated waning immunity to 14 pneumococcal serotypes, pertussis toxin (PT), tetanus toxoid (TT) and varicella, and immunogenicity of postchemotherapy diphtheria, tetanus, pertussis, hepatitis B, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) and pneumococcal vaccination among previously vaccinated children treated for ALL., Methods: This was a multicenter trial of children with ALL enrolled 4-12 months postchemotherapy completion. Exclusion criteria included: infant ALL, relapsed ALL, and stem cell transplant recipients. Immunocompetent children were recruited as controls. Postchemotherapy participants received DTaP-IPV-Hib and 13-valent pneumococcal conjugate vaccine (PCV13) concurrently, followed by 23-valent pneumococcal polysaccharide vaccine (PPV23) 2 months later. Serology was measured at baseline, 2 and 12 months postvaccination. Adverse events were captured via surveys., Results: At enrollment, postchemotherapy participants (n = 74) were less likely than controls (n = 78) to be age-appropriately immunized with DTaP (41% vs 89%, P < .001) and PCV (59% vs 79%, P = .008). Geometric mean concentrations (GMCs) to TT, PT, PCV serotypes, and varicella were lower in postchemotherapy participants than controls after adjusting for previous vaccine doses (P < .001). Two months postvaccination, GMCs to TT, PT, and PCV serotypes increased from baseline (P < .001 for all antigens) and remained elevated at 12 months postvaccination. Antibody levels to PPV23 serotypes also increased postvaccination (P < .001). No serious adverse events were reported., Conclusions: Children treated for ALL had lower antibody levels than controls against pneumococcal serotypes, tetanus, pertussis, and varicella despite previous vaccination. Postchemotherapy vaccination with DTaP-IPV-Hib, PCV13, and PPV23 was immunogenic and well tolerated. Children with ALL would benefit from systematic revaccination postchemotherapy., Clinical Trials Registration: NCT02447718., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

While children with brain tumors are surviving at record rates, survivors are at risk of cardiovascular disease and type 2 diabetes mellitus; these conditions may be driven by excess body fat. Adiponectin in an adipokine that is inversely associated with the fat mass, and has been linked to cardiometabolic risk stratification in the general population. However, adiponectin's profile and determinants in SCBT have not been established. We tested the hypothesis that high molecular weight (HMW) adiponectin levels, the more biologically active form of adiponectin, were associated with adiposity in SCBT similarly to non-cancer controls. Seventy-four SCBT (n = 32 female) and 126 controls (n = 59 female) who were 5-17 years old were included. Partial correlations and multivariable regression analyses assessed the relationship between HMW adiponectin and adiposity. HMW adiponectin was inversely associated with total and central adiposity (FM%: β - 0.21, 95% CI - 0.15, - 0.08; p value < 0.0001; WHR: β - 0.14, 95% CI - 0.02, - 0.01; p value < 0.0001 ;WHtR: β - 0.21, 95% CI - 0.05, - 0.03; p value < 0.0001). In conclusion, HMW adiponectin is inversely correlated with adiposity in SCBT. Adiponectin may serve as a biomarker of cardiometabolic risk and response to interventions to prevent and manage obesity and its comorbidities in SCBT.

Cell-free DNA (cfDNA) has become a comprehensive biomarker in the fields of non-invasive cancer detection and monitoring, organ transplantation, prenatal genetic testing and pathogen detection. While cfDNA samples can be obtained using a broad variety of approaches, there is an urgent need to standardize analytical tools aimed at assessing its basic properties. Typical methods to determine the yield and fragment size distribution of cfDNA samples are usually either blind to genomic DNA contamination or the presence of enzymatic inhibitors, which can confound and undermine downstream analyses. Here, we present a novel droplet digital PCR assay to identify suboptimal samples and aberrant cfDNA size distributions, the latter typically associated with high levels of circulating tumour DNA (ctDNA). Our assay was designed to promiscuously cross-amplify members of the human olfactory receptor (OR) gene family and includes a customizable diploid locus for the determination of absolute cfDNA concentrations. We demonstrate here the utility of our assay to estimate the yield and quality of cfDNA extracts and deduce fragment size distributions that correlate well with those inferred by capillary electrophoresis and high throughput sequencing. The assay described herein is a powerful tool to establish quality controls and stratify cfDNA samples based on presumed ctDNA levels, then facilitating the implementation of robust, cost-effective and standardized analytical workflows into clinical practice.

Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families., (© The Author(s) 2020. Published by Oxford University Press.)