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Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

LFS Variants

Secondary constitutional epimutations in LFS. A, Concordance between enrichment scores of 931 EWAS probes found significantly associated with cancer status in the discovery cohort and the validation cohort, for both the internal (left) and external (right) validation cohort. Blue = associated with cancer status and a cis-CSCE; Red = associated with cancer status but not a cis-CSCE. B, Manhattan plot of adjusted P values from meQTL association tests between the 931 EWAS probes and their most correlated rsSNP. Red line: FDR = 0.1; Blue line: FDR = 0.01; Green points: probes in cancer genes with FDR < 0.1. C, Top cis-CSCE in ETV6, TET3, MIR143, ASXL1, PARVB, and LRG1.D, Feature enrichment heatmap of the 259 significant cis-CSCE loci showing adjusted P value (p) and effect size (d). E, ROC curve of the epimutation cancer risk model on the test set. F, UMAP projection of methylation at 259 cis-CSCE for all patients, colored by cancer status. G, UMAP projection of methylation at 259 cis-CSCE for all patients, colored by clusters associated with risk. H, Kaplan–Meier survival curve demonstrating significant differences in survival probability between the three epimutation clusters.

Variants in cancer predisposition genes (class 1–2) in the wildtype and variant TP53 cohorts, annotated with cancer type, sex, LFS criteria, inheritance status, segregation, variant location, variant function, and zygosity

Pedigrees and class 1–3 variants for two wildtype TP53 families that fit the classic LFS criteria. A, Pedigree of wildtype TP53 family (WT4) that fits the classic LFS criteria with four family members sequenced, two that developed cancer and two that are cancer-free. B, Pedigree of wildtype TP53 family (WT6) that fits the classic LFS criteria with six family members sequenced: five that developed cancer and one that is cancer-free.

Genomics informed risk stratification guidelines for patients with LFS with a germline TP53 variant

Supplementary Figures

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810).Significance:Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

Germline genetic variants in LFS. A, Classification scheme for genetic variants identified from WGS. The pyramid (top) shows how genes were prioritized into four tiers from highest known cancer predisposition potential to lowest. All variants were then classified using a Cancer Variant Classification Schema (Materials and Methods) into five classes (bottom) based on pathogenicity and whether the gene fell into Tier 1–4. AD: autosomal dominant; AR: autosomal recessive; CPG: cancer predisposition gene. B, Frequency of P/LP variants in known cancer genes (class 1–3) in LFS, KiCS and 1kGP. Fisher exact test P values for comparisons between the LFS cohorts and KiCS/1kGP shown. C, Kaplan–Meier survival curve comparing patients with P/LP variants in the WNT signaling pathway (yellow), patients with at least one class 1–3 variant (red) and patients with neither WNT signaling or class 1–3 variants (blue). D, Landscape of genetic alterations in cancer genes (class 1–3) in LFS. Annotated with family, cancer type and TP53 variant status. Genetic variants are indicated as a deletion (blue), SNV or indel (red) or duplication (purple). E, The proportion of individuals in the wildtype and variant TP53 cohorts with classes 1–5 variants (Materials and Methods). F, The number of P/LP variants in cancer genes (class 1–3) in individuals that developed cancer compared with unaffected individuals, stratified by TP53 status. G, The number of P/LP variants (class 1–3) in wildtype versus variant TP53 carriers, stratified by cancer status. On the basis of the premise that variants in the WNT signaling pathway are associated with decreased cancer incidence in LFS, these variants were removed from the comparisons made in F and G.

Differential regulation of WNT signaling and LEF1 in LFS. A, Probes in the WNT signaling pathway (WNT4, SMAD3, SFRP4, SERPINF) significantly associated with cancer status. B, Probe in the body of LEF1 (cg03041109) associated with cancer status (FDR = 0.07). C, Methylation of probe in body of LEF1 (cg03041109) across members within each LFS family. Probands almost unanimously have higher LEF1 methylation than their unaffected family members. D, Plasma cfDNA methylation of the body of LEF1 (chr4:109056901-109057200), between patients with LFS and HBCs. E, Tumor methylation of the body of LEF1 (cg03041109) in CPTs, with and without a germline variant in TP53.

The LFS cohort. A, Patient cohort and characteristics (age of first cancer onset, tumor type) by TP53 status and whether profiling was performed using WGS, methylation or both. AA = adrenal adenoma; ACC = adrenocortical carcinoma; ALL = acute lymphoid leukemia; CPC = choroid plexus carcinoma; CSA = chondrosarcoma; GCT = germ cell tumor; LMS = leiomyosarcoma; MFH = malignant fibrous histiocytoma; MFS = myxofibrosarcoma; NHL = non–Hodgkin lymphoma; OS = osteosarcoma; RMS = rhabdomyosarcoma. B, Lollipop plot displaying the location and number of SNVs and indels on the canonical TP53 transcript: NM_000546, which consists of a TAD, DBD, and tetramerization domain. TP53 hotspot variants present in our cohort (175, 245, 248, 273, 282) are highlighted.

Prevalence of discrepancies between antemortem clinical diagnoses and postmortem autopsy findings is uncertain in pediatric oncology given improving diagnostic capabilities over time. Primary objective was to describe discrepancies between antemortem and postmortem diagnosis of pediatric cancer deaths. Secondary objective was to compare clinical characteristics of deaths with and without major diagnostic discrepancies. This was a retrospective study that included pediatric cancer patients diagnosed and treated in Ontario and who died from 2003 to 2012. Antemortem clinical diagnoses associated with mortality were determined by reviewing the patient's health records 2 weeks prior to death while the postmortem diagnoses were determined by the autopsy report. Discrepancies among these diagnoses were classified using the Goldman criteria where major discrepancies were directly related to the cause of death in contrast to minor discrepancies. Among the 821 patients who died, 118 (14%) had an autopsy and were included. Of these autopsies, 12 (10%) had a major diagnostic discrepancy between antemortem and postmortem diagnoses. Major discrepancies consisted of opportunistic infections (n = 5), missed cancer diagnosis (n = 3), and organ complications (n = 4). Death in a high acuity setting (12/12, 100% vs. 60/106, 57%; P = 0.003) and treatment-related mortality (12/12, 100% vs. 60/106, 57%; P = 0.003) were significantly associated with major discrepancy. Major diagnostic discrepancy was found in 10% of pediatric oncology autopsies. Missed infections and organ complications were predominant etiologies. Death in a high acuity setting and treatment-related mortality were associated with major diagnostic discrepancies. Autopsies continue to be important for improving diagnostic insight and may improve future clinical care.

Background: There is a lack of self-management tools for adolescents with cancer (AWC). This study evaluated the feasibility of Teens Taking Charge Cancer, a web-based self-management program. Methods: A pilot randomized control trial (RCT) was conducted across 4 pediatric oncology clinics. AWC (12–18 years) and their caregivers were randomized to either the intervention or control group. All were asked to complete 12 website modules over 12 weeks (at their own pace) and received monthly calls from health coaches. The intervention website was based on cognitive behavioral principals, designed as an interactive self-guided online program, while the control consisted of education and included links to 12 general cancer websites. Outcome assessments occurred at enrollment and 12 weeks post-intervention. The primary outcomes included rate of accrual and retention, adherence to the protocol, acceptability and satisfaction with intervention using questionnaire and semi-structured interviews, adverse events and engagement with the intervention. Results: Eighty-one teen-caregiver dyads were enrolled with a retention rate of 33%. In the intervention group 46% ( n = 18) logged in at least once over the 12-week period. A mean of 2.4 of 12 modules ( SD 3.0) were completed; and no one completed the program. Thirty-three percent of caregivers in the intervention logged into the website at least once and none completed the full program. Discussion: The results from this pilot study suggest that the current design of the Teens Taking Charge Cancer RCT lacks feasiblity. Future web-based interventions for this group should include additional features to promote uptake and engagement with the program.

Objectives: The number of children who survive cancer is reaching new record levels, thanks to improved management strategies. However, this population is predisposed to chronic health conditions including cardiovascular disease and type 2 diabetes, yet the full scale of these diagnoses in this population is unclear. This protocol describes the conduct of a systematic review to report on the prevalence of diabetes mellitus (DM) subtypes in childhood cancer survivors. Methods: Searches will be conducted in MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. We will also search gray literature in Theses A&I, ProQuest Dissertations, and Web of Science as well as clinicaltrials.gov. Screening search results and data abstraction will be done independently by two reviewers. We will conduct a meta-analysis if two studies have similar designs, populations, methods, and outcome measures reported. Results: The findings of this systematic review will provide insights into the scale of diabetes in childhood cancer survivors to allow the prioritization of subpopulations that need specific interventions to screen, prevent, and treat DM. This will likely lead to improved outcomes in childhood cancer survivors.

Background Meta-iodobenzylguanidine(MIBG) scans are used to detect neuroblastoma metastatic lesions at diagnosis and during posttreatment surveillance. MIBG positivity following induction chemotherapy correlates with poor outcome; however, there are reports of patients with progression-free survival despite MIBG positivity at the end of therapy. The factors distinguishing these survivors from patients who progress or relapse are unclear. FDG-positron-emission tomography (PET) scans can also detect metastatic lesions at diagnosis; however, their role in posttherapy surveillance is less well studied. Methods We performed a retrospective analysis of International Neuroblastoma Staging System (INSS) stage 4 patients to identify those with residual MIBG-avid metastatic lesions on end-of-therapy scans without prior progression. Data collected included age, disease sites, histopathology, biomarkers, treatment, imaging studies, and response. Results Eleven of 265 patients met inclusion criteria. At diagnosis three of 11 patients were classified as intermediate and eight of 11 high risk; nine of 11 had documented marrow involvement. Histologic classification was favorable for four of 10 and MYCN amplification was detected in zero of 11 cases. The median time with persistent MIBG positivity following treatment was 1.5 years. Seven patients had at least one PET scan with low or background activity. Biopsies of three of three MIBG-avid residual lesions showed differentiation. All patients remain alive with no disease progression at a median of 4.0 years since end of therapy. Conclusion Persistently MIBG-avid metastatic lesions in subsets of patients following completion of therapy may not represent active disease that will progress. Further studies are needed to determine whether MYCN status or other biomarkers, and/or PET scans, may help identify patients with residual inactive MIBG lesions who require no further therapy.

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

Simple Summary The childhood obesity epidemic is impacting tens of millions of children globally. While obesity causes several cancers in adults, its potential role in causing pediatric cancers remains unclear. In this review, we assess the potential contribution of obesity to the development of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. We review the possible mechanisms by which the adipose tissue attracts and protects leukemia cells and how it interferes with the actions of chemotherapies used in ALL treatment. We also examine adipose tissue-secreted molecules and fuels that may support leukemia development. While there are no current definite causal links between obesity and ALL, there are plausible mechanisms that need further investigation to explore the impact of obesity on causing ALL and on impacting treatment outcomes. Abstract Childhood obesity is a growing epidemic with numerous global health implications. Over the past few years, novel insights have emerged about the contribution of adult obesity to cancer risk, but the evidence base is far more limited in children. While pediatric patients with acute lymphoblastic leukemia (ALL) are at risk of obesity, it is unclear if there are potential causal mechanisms by which obesity leads to ALL development. This review explores the endocrine, metabolic and immune dysregulation triggered by obesity and its potential role in pediatric ALL’s genesis. We describe possible mechanisms, including adipose tissue attraction and protection of lymphoblasts, and their impact on ALL chemotherapies’ pharmacokinetics. We also explore the potential contribution of cytokines, growth factors, natural killer cells and adipose stem cells to ALL initiation and propagation. While there are no current definite causal links between obesity and ALL, critical questions persist as to whether the adipose tissue microenvironment and endocrine actions can play a causal role in childhood ALL, and there is a need for more research to address these questions.

Background: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome. Approximately 80% of individuals with LFS harbor a germline TP53 pathogenic variant rendering them susceptible to a wide spectrum of early-onset malignancies. A comprehensive surveillance regimen termed the ‘Toronto Protocol’, has recently been adopted for early tumor detection, demonstrating significant improvement in survival among TP53 pathogenic variant carriers. However, the protocol’s “one-size-fits-all” approach fails to consider an individual patient's risk of cancer. We built a machine learning model that predicts early-onset of primary tumors in LFS by estimating the probability of cancer onset before the age of six years, leveraging patient peripheral blood leukocyte methylation profiles. Methods: We built a gradient-boosted tree model to predict the probability of cancer onset before the age of six using methylation data from 288 TP53 pathogenic variant carriers. An external test set of 82 TP53 pathogenic variant carriers was used to validate our model. To increase the signal-to-noise ratio, methylation probes associated with TP53 status were retained and probes associated with aging were removed. In our study, we were primarily interested in minimizing the false negative rate (i.e. to reduce the number of patients who developed cancer before the age of six but were undetected by our algorithm. Findings: We correctly predicted whether the first tumor will occur before the age of six with an accuracy of 79% in our external test set. Importantly, our model classified 90% of the patients that developed cancer prior to the age of six correctly. In addition, 81% of the individuals without cancer in the external test set were predicted correctly. Interpretation: Our tool provides additional value to clinicians in stratifying patients into low- or high-risk groups of developing early-onset malignancies, and helps inform rational use of clinical surveillance tools for early cancer detection, with the ultimate aim to improve overall patient outcomes. Citation Format: Vallijah Subasri, Benjamin Brew, Lauren Erdman, Tanya Guha, Jordan R. Hansford, Elizabeth Cairney, Carol Portwine, Christine Elser, Jonathan L. Finlay, Kim E. Nichols, Wendy Kohlmann, Noa Alon, Ana Novokmet, Ledia Brunga, Anita Villani, Kelvin C. de Andrade, Payal P. Khincha, Sharon A. Savage, Joshua D. Schiffman, David Malkin, Anna Goldenberg. DNA methylation predicts early onset of primary tumor in patients with Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1428.

Objectives were to describe bothersome fatigue in children with cancer and hematopoietic stem cell (HSCT) recipients and to identify factors associated with severely bothersome fatigue. We included children ages 8–18 years treated for cancer or HSCT recipients from three groups: [1] receiving active cancer treatment and admitted to hospital for at least 3 days, [2] attending outpatient clinic for acute lymphoblastic leukemia maintenance therapy, and [3] attending outpatient clinic following treatment completion. Fatigue was measured using the Symptom Screening in Pediatrics Tool (SSPedi); severely bothersome fatigue was defined as a lot or extremely bothersome fatigue (score of 3–4 on 0–4 scale). Factors associated with severely bothersome fatigue were examined using univariate and multiple logistic regression. Of 502 children included, 414 (82.5%) reported some degree of bothersome fatigue (scores 1–4), and 123 (24.5%) reported severely bothersome fatigue (score 3 or 4). In multiple regression analysis, factors significantly associated with severely bothersome fatigue were child age 11–14 and 15–18 years vs 8–10 years (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.21–3.77 and OR 2.96, 95% CI 1.66–5.44), and inpatients receiving cancer treatment vs outpatients who had completed therapy (OR 3.85, 95% CI 2.17–7.27). We found that 82.5% of children with cancer or HSCT recipients reported bothersome fatigue and 24.5% of children reported severely bothersome fatigue. Risk factors for severely bothersome fatigue were older age and inpatients receiving active cancer treatment. Future work should evaluate systematic symptom screening in clinical practice and apply interventions to reduce fatigue.

Objectives were to describe bothersome self-reported changes in taste in pediatric oncology and hematopoietic stem cell (HSCT) patients and to identify patient and treatment-related factors associated with bothersome taste changes. We prospectively enrolled children and adolescents with cancer or pediatric HSCT recipients 8–18 years of age from three groups: inpatients receiving cancer treatments; outpatients in maintenance therapy for acute lymphoblastic leukemia (ALL); and outpatients in survivorship. Bothersome changes in taste was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi); nausea was self-reported using the Pediatric Nausea Assessment Tool (PeNAT). Among the 502 children included, 226 (45.0%) reported bothersome taste changes and 48 (9.6%) reported severely bothersome taste changes. In multiple regression, factors independently associated with severely bothersome taste changes were: inpatients receiving cancer treatments vs outpatients in survivorship (odds ratio (OR) 12.28, 95% confidence interval (CI) 2.50–222.27), ALL in maintenance vs outpatients in survivorship (OR 7.43, 95% CI 1.06–147.77), current nausea (OR 1.59, 95% CI 1.04–2.42), vomiting (OR 2.18, 95% CI 1.06–4.38), and first language not English (OR 2.09, 95% CI 0.97–4.28). We found that 45% of children with cancer and pediatric HSCT recipients reported bothersome changes in taste and these were severely bothersome in 9.6% of children. Inpatients receiving cancer treatment, those experiencing more nausea and vomiting and children whose first language was not English were at greater risk of severely bothersome changes in taste. Future work should evaluate systematic symptom screening in clinical practice and identify interventions focused on addressing bothersome taste changes.

Objectives Primary objectives were to evaluate the interrater reliability and validity of proxy-report Symptom Screening in Pediatrics Tool (SSPedi) in children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Secondary objective was to describe the interrater reliability of each SSPedi item. Methods Respondents were children aged eight to 18 years with cancer or HSCT recipients, and their parents or guardians. We enrolled two pediatric respondent groups. The more symptomatic group was receiving active treatment for cancer, admitted to hospital, and expected to be in a hospital three days later. The less symptomatic group either was in maintenance therapy for acute lymphoblastic leukemia or had completed cancer treatments. Convergent validity was evaluated by comparing proxy-reported mucositis, nausea and vomiting, pain, and total SSPedi scores, with child self-reported validated scales, and we hypothesized fair correlations. Discriminant validity was evaluated by comparing proxy-reported total SSPedi scores between groups. Interrater reliability of each SSPedi item was evaluated. Results Four hundred thirty-nine child and parent or guardian pairs were recruited. Mean difference in proxy-reported SSPedi scores between the more and less symptomatic groups was 8.2, 95% CI 6.6–9.8. All hypothesized relationships among measures were observed. Intraclass correlation coefficients for SSPedi items ranged from 0.34 (problems with thinking) to 0.80 (diarrhea). Conclusion Proxy-report SSPedi is reliable and valid in children aged 8 years to 18 years with cancer and HSCT recipients. Future work should support proxy-reported symptom assessment in clinical settings where children are not able to self-report or communicate bothersome symptoms.

Background The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Methods In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self-report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations. Results Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed. Conclusions SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery.

Survivors of Childhood Brain Tumors (SCBT) are at a higher risk of developing cardiovascular disease and type 2 diabetes compared to the general population. Adiposity is an important risk factor for the development of these outcomes, and identifying biomarkers of adiposity may help the stratification of survivors based on their cardiovascular risk or allow for early screening and interventions to improve cardiometabolic outcomes. Leptin is an adipokine that positively correlates with the adipose mass in the general population and is a predictor of adverse cardiometabolic outcomes, yet its association with adiposity in SCBT has not been studied. The aim of this study was to determine if leptin levels are associated with the adipose mass in SCBT, and to define its predictors. This cross-sectional study included 74 SCBT (n = 32 females) with 126 non-cancer controls (n = 59 females). Total adiposity was measured using Bioelectrical Impendence Analysis (BIA) and central adiposity was measured using waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). We used multivariable linear regression analysis to determine if leptin predicts adiposity in SCBT and adjusted for age, sex, puberty, and cancer status. Leptin correlated strongly with total (p

BACKGROUND: Objectives were to describe the proportion of deaths due to treatment-related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort. METHODS: We included children with cancer ⩽18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described. RESULTS: Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0-18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage. CONCLUSIONS: TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients.

ObjectiveWe previously developed the paper-based Symptom Screening in Pediatrics Tool (SSPedi) designed for paediatric cancer symptom screening. Objectives were to evaluate and refine the electronic mobile application (app) of SSPedi using the opinions of children with cancer.MethodsParticipants were children 8–18 years of age with cancer. Participants completed electronic SSPedi on their own and then responded to semistructured questions to determine whether they found electronic SSPedi easy or difficult to complete and understand, understood and liked the app features (audio and animation), and understood previously difficult to understand concepts with the introduction of a help menu. After each group of 10 children, responses were reviewed to determine whether modifications were required.Results20 children evaluated electronic SSPedi. None found electronic SSPedi difficult to complete or understand. All children understood the app features and each of the 4 more difficult to understand concepts after using the help menu. 19 of 20 children thought the app was a good way to communicate with doctors and nurses.ConclusionsWe finalised an electronic version of SSPedi that is easy to use and understand with features specifically designed to facilitate child self-report. Future work will evaluate the psychometric properties of electronic SSPedi.

Purpose: Symptom assessment is an emergent area of research in pediatric cancer. Our team previously reported on the development of a questionnaire to be completed by parents to determine symptom prevalence and bother. This exploratory study examined parental nonprobed, free-text comments about their child’s treatment-related symptoms reported on the questionnaire. Method: Participants were parents of children aged 4 to 18 years who had been diagnosed with cancer at least 2 months prior to enrolment and had received intravenous chemotherapy within the past month at 1 of 5 pediatric cancer centers. The questionnaire consisted of 69 or 71 items (based on child’s age) addressing physical and psychological sequelae. Each symptom query was accompanied by a blank space in which parents could comment on their response. Comments were analyzed guided by content analysis methodology. Results: Five major themes emerged: parental attributions for the symptoms experienced in their child; coping patterns and communication styles within the family; evidence of anticipatory, procedural, and other anxieties; interruption of daily life; and changes in the child’s physical appearance. Conclusions: These exploratory findings provide context to parental perception of their child’s treatment-related symptoms and may contribute to a better understanding of parental perception of child and the family coping and communicating style. These findings may assist in the development of psychoeducational interventions aimed at promoting open communication styles within the family and reducing child and parent burden during treatment procedures.

Purpose This study aimed to estimate the burden of morbidity, in terms of health-related quality of life (HRQL), in survivors of high-risk neuroblastoma (NBL) after myeloablative chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT). Patients and methods A national population-based survey was undertaken of survivors of high-risk NBL (N = 99), diagnosed between 1991 and 2010 and treated with HSCT. Parents completed a proxy questionnaire incorporating two HRQL measures, Health Utilities Index (HUI) 2 and 3. Children >12 years of age provided self-assessments. Clinical and demographic data were collected. Independent t-test and one-way analysis of variance were used to assess differences. Comparative data were obtained from previously published work and Statistics Canada's 1998 National Population Health Survey. Results On a scale of 0 (being dead) to 1.0 (perfect health), mean HRQL utility scores were 0.89 (SD = 0.11) in HUI2 and 0.84 (SD = 0.18) in HUI3. Parents reported morbidity in sensation (52.5%), pain (30.3%), cognition (28.0%), and emotion (24.2%) in HUI2 and in hearing (38.4%), pain (30.3%), cognition (27.3%), and speech (23.2%) in HUI3. HRQL was not significantly different compared to NBL survivors treated without HSCT, but was less than in nontransplanted survivors of acute lymphoblastic leukemia and Wilms tumor, and children in the general population, yet higher than in survivors of brain tumors. Conclusions HRQL is compromised in high-risk NBL survivors treated with and without HSCT. A differential effect on hearing reflects additional exposure to platinum-based chemotherapy. These results should inform long-term care and the development of new therapeutic interventions.

Children with acute myeloid leukemia (AML) are at high risk of life-threatening bacterial and fungal infection. However, little is known about the prevalence or severity of adenovirus infection in this population. Objective was to describe the characteristics, treatments and outcomes of adenovirus infection in children with newly diagnosed AML.We performed a retrospective chart review based upon 2 multicenter cohort studies that focused on identifying risk factors for infection in children with AML. Inclusion criteria were patients with de novo AML who were ≤18 years of age at diagnosis with a clinical specimen positive for adenovirus.Among the 235 patients with AML, 12 (5.1%) had positive adenovirus testing. The most common site of isolation was stool (n = 11, 91.6 %), and the most frequent symptom was diarrhea (n = 11, 91.6 %). Two patients received specific treatment for adenovirus, namely intravenous immunoglobulin only in 1 patient and both intravenous immunoglobulin and inhaled ribavirin in a second patient. In 11 patients, adenovirus resolved uneventfully without recurrence, including 10 that received no adenovirus-specific therapy. However, 1 patient developed sepsis syndrome in the setting of disseminated adenoviral infection and died from multiorgan failure.In children with AML, adenovirus infection was rare and typically not associated with severe disease, even without specific treatment. However, disseminated and fatal disease can occur in this population. Further investigations are needed to identify pediatric AML patients at particular risk for severe adenovirus infection and to determine optimal treatment approaches in these patients.

Objectives: The number of children who survive cancer is reaching new record levels, thanks to improved management strategies. However, this population is predisposed to chronic health conditions including cardiovascular disease and type 2 diabetes, yet the full scale of these diagnoses in this population is unclear. This protocol describes the conduct of a systematic review to report on the prevalence of diabetes mellitus (DM) subtypes in childhood cancer survivors. Methods: Searches will be conducted in MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. We will also search gray literature in Theses A&I, ProQuest Dissertations, and Web of Science as well as clinicaltrials.gov. Screening search results and data abstraction will be done independently by two reviewers. We will conduct a meta-analysis if two studies have similar designs, populations, methods, and outcome measures reported. Results: The findings of this systematic review will provide insights into the scale of diabetes in childhood cancer survivors to allow the prioritization of subpopulations that need specific interventions to screen, prevent, and treat DM. This will likely lead to improved outcomes in childhood cancer survivors.

Introduction Acute lymphoblastic leukaemia is the most common paediatric cancer. Survivors of childhood acute lymphoblastic leukaemia (SALL) are at risk of obesity and related cardiometabolic diseases including type 2 diabetes, hypertension, stroke and cardiovascular events. Therefore, it is important to address obesity in this population as this may help mitigate future cardiometabolic comorbidities. In this systematic review, we aim to assess current treatment strategies including lifestyle interventions, pharmacotherapy and bariatric surgery to manage overweight and obesity in SALL. Methods and analysis We will search the following databases for primary studies: CINAHL, SPORTDiscus, EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. In addition, unpublished primary studies will be searched in ClinicalTrials.gov as well as conference proceedings, presentations, abstracts, editorials and ProQuest Dissertations and Theses A&I. Reviewers will perform title, abstract, and full-text screening as well as data abstraction and risk of bias assessment independently with a third reviewer to be consulted to resolve disagreements. Searches will be run and updated through May 1st, 2018. The overall quality of the evidence will be determined using the Grading of Recommendations, Assessment, Development, and Evaluation criteria for each outcome. A meta-analysis will be performed if two studies deploying similar interventions, populations, and design and outcomes are identified. Ethics and dissemination As individual patient data will not be included, we do not require ethics approval. This review will be published in a peer-reviewed journal. PROSPERO registration number CRD42016051031.

Among 235 children with acute myeloid leukemia, 17 experienced 19 perianal infections. Among 12 episodes with definite abscess, 75% were severely neutropenic. Sixteen diagnostic imaging evaluations were performed; diagnostic yield was similar between computerized tomography of pelvis (5 of 10) and ultrasound (3 of 5). Consistent management approaches to perianal infection should be developed.

Opportunities for participation in clinical trials are a core component of the care of children with cancer. In Ontario, many pediatric patients live long distances from their cancer center. This paper describes the work that was done in order to allow patients participating in Children's Oncology Group trials to receive care, including research protocol related care, jointly between the tertiary pediatric cancer center and the closer-to-home satellite center. The system is a pragmatic risk-based model, supporting excellence in care while ensuring good conduct of the research in compliance with applicable regulations and guidelines, including ethics oversight.

Little is known about the impact of enrollment on therapeutic clinical trials on adverse event rates. Primary objective was to describe the impact of clinical trial registration on sterile site microbiologically documented infection for children with newly diagnosed acute myeloid leukemia (AML). We conducted a multicenter cohort study that included children aged ≤18 years with de novo AML. Primary outcome was microbiologically documented sterile site infection. Infection rates were compared between those registered and not registered on clinical trials. Five hundred seventy-four children with AML were included of which 198 (34.5%) were registered on a therapeutic clinical trial. Overall, 400 (69.7%) had at least one sterile site microbiologically documented infection. In multiple regression, registration on clinical trials was independently associated with a higher risk of microbiologically documented sterile site infection [adjusted odds ratio (OR) 1.24, 95% confidence interval (CI) 1.01-1.53; p = 0.040] and viridans group streptococcal infection (OR 1.46, 95% CI 1.08-1.98; p = 0.015). Registration on trials was not associated with Gram-negative or invasive fungal infections. Children with newly diagnosed AML enrolled on clinical trials have a higher risk of microbiologically documented sterile site infection. This information may impact on supportive care practices in pediatric AML.

Vaginal yolk sac tumor is a rare malignant germ-cell tumor occurring most commonly in young girls. The treatment has evolved over the last 3 decades from radical surgery to conservative surgery with chemotherapy to chemotherapy alone. Here we present a case of a 6-month-old girl successfully treated with upfront surgery followed by chemotherapy. We include a literature review of studies on vaginal yolk sac tumor published in the last 30 years. We discuss the role of upfront surgery where possible followed by chemotherapy as a safe alternative to chemotherapy alone for the treatment of this rare malignancy.

Keywords: symptom screening; cancer; instrument development; cognitive interview; methodology; pediatric; oncology

Using a previously developed reliable and valid treatment‐related mortality (TRM) definition, our objective was to describe the proportion of children newly diagnosed with cancer experiencing TRM and to identify risk factors for TRM in a population‐based cohort. We included children with cancer

Background Despite the high utilization of blood products by pediatric oncology patients, literature in this population remains scarce. The primary objective of this study was to assess red blood cell (RBC) and platelet (PLT) utilization rates and transfusion thresholds in pediatric oncology patients. The secondary objective was to describe transfusion-related complications including RBC alloantibody development and transfusion reactions. Study Design and Methods This epidemiologic cohort study involved pediatric oncology patients at a Canadian academic children's hospital between April 2002 and December 2011. Demographic, clinical, laboratory, and transfusion variables were collected from the Transfusion Registry for Utilization Statistics and Tracking database, a large database that captures more than 50 demographic and clinical variables as well as comprehensive transfusion information and laboratory test results. Results Of 647 pediatric oncology patients, 430 (66%) received a RBC or PLT transfusion or both during this time period. The median transfusion threshold before a RBC and PLT transfusion was a hemoglobin (Hb) value of 72 g/L (interquartile range [IQR], 68-76 g/L) and a PLT count of 16 × 109/L (IQR, 10 × 109-23 × 109/L), respectively. Ninety-two percent of the issued RBC and PLT products (7507/8154) were cytomegalovirus negative and 90% were irradiated (7299/8154). RBC alloantibody development and transfusion reactions were reported infrequently in 0.5% (2/423) and 4.5% (8/179) of the patients, respectively. Conclusion This study assessed utilization rates, transfusion thresholds, alloantibody development, and transfusion reactions in pediatric oncology patients. The descriptive results from this epidemiologic study provide baseline information to generate hypotheses to be tested in future interventional studies.

This guideline provides an approach to the prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting (CINV) in children. It was developed by an international, inter-professional panel using AGREE II methods and is based on systematic literature reviews. Evidence-based recommendations for pharmacological and non-pharmacological interventions to prevent and treat anticipatory CINV in children receiving antineoplastic agents are provided. Gaps in the evidence used to support the recommendations are identified. The contribution of this guideline to anticipatory CINV control in children requires prospective evaluation.

BACKGROUND The prevalence and severity of Clostridium difficile infection (CDI) has increased over time in adult patients, but little is known about CDI in pediatric cancer. The primary objectives were to describe the incidence and characteristics of CDI in children with de novo acute myeloid leukemia (AML). The secondary objective was to describe factors associated with CDI. METHOD We performed a multicenter, retrospective cohort study of children with de novo AML and evaluated CDI. Recurrence, sepsis and infection-related death were examined. Factors associated with CDI were also evaluated. RESULTS Forty-three CDI occurred in 37 of 341 (10.9%) patients during 42 of 1277 (3.3%) courses of chemotherapy. There were 6 children with multiple episodes of CDI. Three infections were associated with sepsis, and no children died of CDI. Only 2 children had an associated enterocolitis. Both days of broad-spectrum antibiotics (odds ratio 1.03, 95% confidence interval: 1.01 to 1.06; P = 0.003) and at least 1 microbiologically documented sterile site infection (odds ratio 10.81, 95% confidence interval: 5.88 to 19.89; P < 0.0001) were independently associated with CDI. CONCLUSIONS CDI occurred in 11% of children receiving intensive chemotherapy for AML, and outcomes were not severe. CDI is not a prominent issue in pediatric AML in terms of prevalence, incidence or associated outcomes.

Context There are no prospective pediatric trials evaluating olanzapine for chemotherapy-induced nausea and vomiting (CINV) prevention. Objective This study evaluated the feasibility of a trial of olanzapine to evaluate the contribution of olanzapine to CINV control in pediatric oncology patients. Methods Patients < 18 years receiving CINV prophylaxis with ondansetron/granisetron/palonosetron ± dexamethasone ± aprepitant were eligible to participate in this prospective, single-arm, open-label study. All patients received olanzapine (0.14 mg/kg/dose; max 10 mg/dose) once daily orally starting before the first chemotherapy dose and continuing for up to four doses after the last chemotherapy administration. A future trial was considered feasible if mean time to enroll 15 patients was ≤ 12 months/site, ≥ 12/15 took at least half of the planned olanzapine doses, and ≤ 3/15 experienced significant sedation or dizziness despite dose reduction. The proportion of children who experienced complete CINV control (no nausea, vomiting, or retching) was described. Results Fifteen patients (range 4.1-17.4 years) participated; mean recruitment period was 9.3 months/site. All patients took at least half of the planned olanzapine doses. Six patients experienced sedation which resolved with olanzapine dose reduction (N = 5) or bedtime administration (N = 1). Olanzapine was stopped in one patient with blurry vision and in another with increased plasma GGT values. In both the acute and delayed phases, eight patients experienced complete control of vomiting but almost all (14/15) had nausea. Conclusion A pediatric trial of olanzapine for CINV control is feasible. Our findings will inform the design of a future study.

Background The objective was to compare 5-year overall survival (OS) between adolescent and young adult (AYA) patients (age 15–19) with acute lymphoblastic leukemia (ALL) treated at a pediatric versus an adult center. Patients and methods This was a population-based analysis using administrative data of Ontario ALL AYA patients diagnosed between 1986–2009. We calculated predicted survival proportions (PSPs) and 95% confidence intervals (CI). We also surveyed sites to determine whether pediatric or adult-based protocols were used in each period. Results Overall, 290 patients between 15–19 years of age were diagnosed with ALL during the study period; 144 patients (49.7%) were treated at an adult center. When adjusted for gender, age, income quintile and time period, AYA patients treated at a pediatric center did not have a significantly different PSP (0.65, 95% CI: 0.56–0.75) in comparison to those treated at an adult center (0.62, 95% CI 0.52–0.73; P = 0.87). Most AYA patients treated at adult centers received pediatric protocols in the recent periods. Conclusions Using population-based data, AYA ALL patients had similar outcomes whether treated at a pediatric or an adult center. Early introduction of aggressive treatment protocols in adult centers may have negated differences in outcomes among AYA patients by site of care.

Summary Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in paediatric acute myeloid leukaemia (AML). This study describes risk factors for IFI and IFI-related sepsis in this population. We conducted a population-based, retrospective cohort study of children with AML in Canada. IFIs during chemotherapy and prior to haematopoietic stem cell transplantation, relapse, persistent disease or death were identified. Risk factors for proven or probable IFI were examined. Among courses complicated by IFI, risk factors for sepsis were also evaluated. There were 341 children with AML included of which 41 (12.0%) experienced 46 different episodes of IFI. Candida species accounted for 23 (50.0%) of IFIs and Aspergillus spp. accounted for 14 (30.4%). Days of broad-spectrum antibiotics, days of corticosteroids and neutropenia at start of the course were independently associated with IFI. Only days of fever were independently associated with IFI-related sepsis. Invasive fungal infections occurred in 12.0% of paediatric AML patients. Risk factors for IFI and IFI-related sepsis were identified. This knowledge may help to consider targeted strategies.