Publications by authors named "Adam Fleming"

55 Publications

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.

JAMA Oncol 2021 Oct 7. Epub 2021 Oct 7.

Department of Pediatrics, Centre mère-enfant Soleil du CHU de Québec-Université Laval, Québec City, Quebec, Canada.

Importance: Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment.

Objective: To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS.

Design, Setting, And Participants: In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied.

Exposures: Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results.

Main Outcomes And Measures: The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator.

Results: In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations.

Conclusions And Relevance: In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.
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http://dx.doi.org/10.1001/jamaoncol.2021.4536DOI Listing
October 2021

Childhood head trauma and the risk of childhood brain tumours: A case-control study in Ontario, Canada.

Int J Cancer 2021 Sep 14. Epub 2021 Sep 14.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population-based and hospital-based case-control study of children 0 to 15 years with newly diagnosed CBTs from 1997 to 2003 recruited across Ontario through paediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, or head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research.
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http://dx.doi.org/10.1002/ijc.33805DOI Listing
September 2021

Frosted Branch Angiitis Associated With Cytomegalovirus in a Pediatric Autologous Stem Cell Transplant Patient: Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2021 Sep 6. Epub 2021 Sep 6.

Departments of Pediatrics Ophthalmology, McMaster University Department of Ophthalmology, Hamilton Health Sciences, Hamilton Department of Pediatrics, Western University, London, ON, Canada.

Background: Frosted branch angiitis (FBA) is a rare phenomenon of panuveitis which may occur secondary to cytomegalovirus (CMV) causing acute visual disturbances. CMV infection is a known complication in allogenic stem cell transplant (SCT) patients but is uncommon following autologous SCT.

Observation: We describe a 17-month-old medulloblastoma patient with sudden onset visual impairment following second autologous SCT. The patient was CMV seropositive, polymerase chain reaction negative before second SCT. At the time of presentation with visual complaints, the patient was diagnosed with FBA associated with CMV reactivation. Treatment included antivirals and immunosuppressive medication with visual recovery.

Conclusion: FBA induced by CMV should be considered as a differential diagnosis in pediatric patients undergoing autologous bone marrow transplant with rapidly progressive visual impairment.
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http://dx.doi.org/10.1097/MPH.0000000000002318DOI Listing
September 2021

Utility of a Cancer Predisposition Screening Tool for Predicting Subsequent Malignant Neoplasms in Childhood Cancer Survivors.

J Clin Oncol 2021 Oct 12;39(29):3207-3216. Epub 2021 Aug 12.

Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Purpose: Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS.

Methods: Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development.

Results: Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation.

Conclusion: MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.
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http://dx.doi.org/10.1200/JCO.21.00018DOI Listing
October 2021

A single center experience in the management of progressive juvenile pilocytic astrocytoma.

J Neurosurg Sci 2021 Apr 16. Epub 2021 Apr 16.

McMaster Pediatric Brain Tumor Study Group, McMaster University, Hamilton, ON, Canada.

Background: Juvenile pilocytic astrocytoma (JPA) typically follows an indolent clinical course. The first-line treatment for most JPAs is surgical resection. However, a gross total resection may not be feasible for deep-seated lesions and/or infiltrative tumors, leading to multimodal treatment approaches that may be complicated by patient age and tumor location. Despite the prevalence of pediatric JPAs, there is no single approach to treating progressive disease.

Methods: We investigated the multifaceted management of progressive JPAs through a retrospective analysis of JPAs treated at a single center over an 18-year period (1998-2016). All cases were categorized according to location, whether supratentorial or infratentorial, and for each case we calculated the number of interventions and the time between interventions.

Results: We identified a total of 40 JPAs, (11 supratentorial, 29 infratentorial). Total number of interventions among all supratentorial JPA patients was 21 (average 2 interventions/patient). The total number of interventions among infratentorial JPAs was 40 (average 1.4 interventions/patient).

Conclusions: Treatment of progressive JPA is variable and may require numerous surgeries and adjuvant therapies.
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http://dx.doi.org/10.23736/S0390-5616.21.05169-9DOI Listing
April 2021

Leptin is Associated with the Tri-Ponderal Mass Index in Children: A Cross-Sectional Study.

Adolesc Health Med Ther 2021 9;12:9-15. Epub 2021 Mar 9.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

Background: Obesity is characterized by the disproportionate expansion of the fat mass and is most commonly diagnosed using the Body Mass Index (BMI) z-score or percentile in children. However, these measures associate poorly with the fat mass. This is important, as adiposity is a more robust predictor of cardiometabolic risk than BMI-based measures, but there are limited clinical measures of adiposity in children. A new measure, the Tri-ponderal Mass Index (TMI, kg/m) 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.
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http://dx.doi.org/10.2147/AHMT.S289973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955735PMC
March 2021

Canadian Pediatric Neuro-Oncology Standards of Practice.

Front Oncol 2020 22;10:593192. Epub 2020 Dec 22.

Division of Pediatric Hematology/Oncology, IWK Health Centre, Halifax, NS, Canada.

Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the absence of a clinical trial for seven of the most prevalent brain tumors in children. This allowed description of practice across the country, along with a consensus. This had a multitude of benefits, including understanding practice patterns, allowing for a basis to compare in future research and informing Health Canada of the current management of patients. This also allows all children in Canada to receive equivalent care, regardless of location.
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http://dx.doi.org/10.3389/fonc.2020.593192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783450PMC
December 2020

High molecular weight adiponectin levels are inversely associated with adiposity in pediatric brain tumor survivors.

Sci Rep 2020 10 29;10(1):18606. Epub 2020 Oct 29.

Department of Pediatrics, McMaster University, Hamilton, ON, Canada.

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.
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http://dx.doi.org/10.1038/s41598-020-75638-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596561PMC
October 2020

Post flywheel squat vs. flywheel deadlift potentiation of lower limb isokinetic peak torques in male athletes.

Sports Biomech 2020 Oct 28:1-14. Epub 2020 Oct 28.

School of Health and Sports Sciences, University of Suffolk, Ipswich, UK.

The present study investigated the post-activation performance enhancement (PAPE) of isokinetic quadriceps and hamstrings torque after flywheel (FW)-squat vs. FW-deadlift in comparison to a control condition. Fifteen male athletes were enrolled in this randomised, crossover study. Each protocol consisted of 3 sets of 6 repetitions, with an inertial load of 0.029 kgm. Isokinetic quadriceps (knee extension) and hamstrings (knee flexion) concentric peak torque (60º/s) and hamstring eccentric peak torque (-60º/s) were measured 5 min after experimental or control conditions. A significant condition (PAPE) effect was reported ( = 4.067, p = 0.008) for isokinetic hamstrings eccentric peak torque following FW-squat and FW-deadlift, but no significant differences were found for quadriceps and hamstrings concentric peak torques. The significant difference averaged 14 Nm between FW-squat vs. control (95% CI: 2, 28; = 0.75, ; p = 0.033), and 13 Nm between FW-deadlift vs. control (95% CI: 1, 25; = 0.68, ; p = 0.038). This study reported that both FW-squat and FW-deadlift exercises are equivalently capable of generating PAPE of isokinetic hamstrings eccentric torque. Practitioners may use these findings to inform strength and power development during complex training sessions consisting of flywheel-based exercises prior to a sport-specific task.
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http://dx.doi.org/10.1080/14763141.2020.1810750DOI Listing
October 2020

Validity and reliability of a flywheel squat test in sport.

J Sports Sci 2021 Mar 6;39(5):482-488. Epub 2020 Oct 6.

School of Health and Life Sciences, University of the West of Scotland, Hamilton, UK.

The aims of this study were to examine the test-retest reliability and construct validity of the flywheel (FW)-squat test. Twenty male amateur team sports athletes (mean±SD: age 23±3 years) completed one familiarization session and two testing sessions including: FW-squat test with an inertial load of 0.061 kgm, standing long jump (SLJ), countermovement jump (CMJ) and 5-m change of direction (COD-5m) tests, and isokinetic strength assessments of the knee extensor and flexor muscles. Test-retest reliability was assessed with intraclass correlation coefficient (ICC) and coefficient of variation (CV) of data collected. Construct validity was determined as the degree of relationships between the FW-squat test outputs and both athletic tests and isokinetic assessments scores computed with Pearson's correlation coefficients. Excellent relative (ICC=0.94-0.95) and acceptable absolute (CV=5.9%-6.8%) reliability scores were found for both concentric and eccentric power outputs collected during the FW-squat test. The same outputs showed to positive correlations with concentric and eccentric knee extensor and flexor muscle peak force values (r range: 0.465-0.566) measured during the isokinetic test. The FW-squat test is a valid and reliable test to assess lower limb performance given its correlation with isokinetic test, as well as its relative and absolute reliability.
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http://dx.doi.org/10.1080/02640414.2020.1827530DOI Listing
March 2021

Wnt activation as a therapeutic strategy in medulloblastoma.

Nat Commun 2020 08 28;11(1):4323. Epub 2020 Aug 28.

McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/β-catenin signaling.
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http://dx.doi.org/10.1038/s41467-020-17953-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455709PMC
August 2020

Pontine gliomas a 10-year population-based study: a report from The Canadian Paediatric Brain Tumour Consortium (CPBTC).

J Neurooncol 2020 Aug 7;149(1):45-54. Epub 2020 Jul 7.

Division of Haematology Oncology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada.

Background: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children.

Patients And Methods: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method.

Results: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS).

Conclusions: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.
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http://dx.doi.org/10.1007/s11060-020-03568-8DOI Listing
August 2020

Myalgia and Hematuria in Association with Clonidine and Arginine Administration for Growth Hormone Stimulation Tests.

Case Rep Med 2020 26;2020:4827072. Epub 2020 May 26.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

Growth hormone deficiency (GHD) in children has significant impacts on growth and metabolism. Two-agent GH stimulation tests are commonly used to diagnose GHD, and these tests are generally considered safe. We report the case of a 5-year 5-month-old boy with a history of anaplastic ependymoma who underwent GH stimulation testing for growth deceleration using clonidine and arginine. He developed bilateral calf myalgia and gross hematuria within 24 hours of the tests. Myalgia and hematuria resolved spontaneously. Importantly, the literature review and database searches for hematuria identified 6 cases with clonidine and 20 cases with arginine. This case highlights an unusual combination of adverse reactions to clonidine and arginine in children undergoing GH stimulation testing to assess for GHD. Pediatric endocrinologists need to be aware of the potential for these side effects to allow appropriate management, and further studies are needed to clarify the mechanisms and frequency of these side effects. We recommend that patients and families need to be counselled about hematuria as an association of GH testing with these medications.
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http://dx.doi.org/10.1155/2020/4827072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270994PMC
May 2020

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy.

J Pathol 2020 07 10;251(3):249-261. Epub 2020 Jun 10.

Division of Haematology/Oncology, Department of Pediatrics, University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada.

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5457DOI Listing
July 2020

Circulating leptin levels are associated with adiposity in survivors of childhood brain tumors.

Sci Rep 2020 03 13;10(1):4711. Epub 2020 Mar 13.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

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 < 0.001) and central (WHR p = 0.001; WHtR p < 0.001) adiposity in SCBT and non-cancer controls. In conclusion, leptin is a potential biomarker for adiposity in SCBT, and further investigation is needed to clarify if leptin is a predictor of future cardiometabolic risk in SCBT.
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http://dx.doi.org/10.1038/s41598-020-61520-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070034PMC
March 2020

Salvage therapy for progressive, treatment-refractory or recurrent pediatric medulloblastoma: a systematic review protocol.

Syst Rev 2020 03 4;9(1):47. Epub 2020 Mar 4.

Department of Pediatrics, Division of Hematology-Oncology, McMaster University, Hamilton, Canada.

Background: Central nervous system tumors remain the leading cause of cancer-related mortality amongst children with solid tumors, with medulloblastoma (MB) representing the most common pediatric brain malignancy. Despite best current therapies, patients with recurrent MB experience have an alarmingly high mortality rate and often have limited therapeutic options beyond inadequate chemotherapy or experimental clinical trials. Therefore, a systematic review of the literature regarding treatment strategies employed in recurrent pediatric MB will evaluate previous salvage therapies in order to guide future clinical trials. The aim of this systematic review will be to investigate the efficacy and safety of salvage therapies for the management of children with progressive, treatment-refractory, or recurrent MB.

Methods: We will conduct literature searches (from 1995 onwards) in MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Cochrane Central Register of Controlled Trials. Studies examining the survival and toxicity of therapies administered to treatment-refractory pediatric MB patients will be included. Two reviewers will independently assess the search results based on predefined selection criteria, complete data abstraction, and quality assessment. The primary outcomes of this review will be overall and progression-free survival. Secondary outcomes will include safety and toxicity of each therapy administered. The study methodological quality (or bias) will be appraised using an appropriate tool. Due to the nature of the research question and published literature, we expect large inter-study heterogeneity and therefore will use random effects regression analysis to extract the combined effect. In additional analyses, we will investigate the role of re-irradiation and mono- vs. poly-therapy in recurrent disease, and whether molecular subgrouping of MB influences salvage therapy.

Discussion: This systematic review will provide an overview of the current literature regarding salvage therapies for relapsed MB patients. Investigation of clinically tested therapies for children with recurrent MB has significant implications for clinical practice. By reviewing the efficacy and toxicity of MB salvage therapies, this study will identify effective therapeutic strategies administered to recurrent MB patients and can inform future clinical trials aimed to improve patient survivorship and quality of life.

Systematic Review Registration: PROSPERO CRD42020167421.
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http://dx.doi.org/10.1186/s13643-020-01307-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055028PMC
March 2020

Bariatric interventions in obesity treatment and prevention in pediatric acute lymphoblastic leukemia: a systematic review and meta-analysis.

Cancer Metastasis Rev 2020 03;39(1):79-90

Department of Pediatrics, McMaster University, 1280 Main Street West, HSC-3A57, Hamilton, Ontario, L8S 4K1, Canada.

Most children are surviving acute lymphoblastic leukemia (ALL) today. Yet, the emergence of cardiometabolic comorbidities in this population may impact long-term outcomes including the quality of life and lifespan. Obesity is a major driver of cardiometabolic disorders in the general population, and in ALL patients it is associated with increased risk of hypertension, dysglycemia, and febrile neutropenia when compared with lean ALL patients undergoing therapy. This systematic review aims to assess the current evidence for bariatric interventions to manage obesity in children with ALL. The primary outcome for this systematic review was the change in BMI z-score with implementation of the interventions studied. Literature searches were conducted in several databases. Ten publications addressing the study question were included in this review, and five studies were used in the meta-analysis to assess the impact of the bariatric interventions on obesity. The BMI z-score did not change significantly with the interventions. However, the quality of evidence was low, which precluded the recommendation of their use. In conclusion, prospective, rigorous, adequately powered, and high-quality longitudinal studies are urgently needed to deliver effective lifestyle interventions to children with ALL to treat and prevent obesity. These interventions, if successful, may improves cardiometabolic health outcomes and enhance the quality of life and life expectancy in children with ALL.
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http://dx.doi.org/10.1007/s10555-020-09849-yDOI Listing
March 2020

Analysis of factors that influence neurosurgical length of hospital stay among newly diagnosed pediatric brain tumor patients.

Pediatr Blood Cancer 2020 01 14;67(1):e28041. Epub 2019 Oct 14.

McMaster Pediatric Brain Tumor Study Group, McMaster University, Hamilton, Ontario, Canada.

Background: Postoperative length of stay (LOS) carries a high burden of healthcare costs. In resource-intense specialties such as neurosurgery, it is imperative to identify factors that influence LOS to improve care. The current study investigates the potential for variables that affect clinical presentation, tumor characteristics, treatment modalities, and postoperative complications to impact overall LOS in pediatric brain tumor patients.

Methods: A retrospective cohort study design was used with patients enrolled in the McMaster Pediatric Brain Tumor Study Group database. All patients up to 18 years of age, presenting with a newly diagnosed brain tumor admitted to and discharged from neurosurgery, were included. Patients were sorted into three cohorts: short LOS (≤3 days), extended LOS (≥20 days), and control LOS (4-19 days).

Results: Of the 124 patients included, 20 (65% male; median age: 9.1 years; range, 0.8-17.4 years) were considered short LOS, 28 (61% male; median age: 4.7 years; range, 0.4-14.7 years) were considered extended LOS, and 76 (57% male; median age: 8.5 years; range, 0.3-17.9 years) were considered control LOS. Variables that prolonged LOS were emesis at presentation (P < 0.001), developmental delay (P = 0.02), multiple surgeries (P = 0.004), tumor location (P < 0.05), subtotal resection (P = 0.02), feeding tube (P < 0.001), adjuvant chemoradiotherapy (P < 0.001), and posterior fossa syndrome (P = 0.004).

Conclusions: This study identifies variables related to clinical presentation, tumor characteristics, treatment modalities, and postoperative complications associated with extended LOS. These findings uncover novel predictors of LOS that can be used to guide future research and improve health resource management.
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http://dx.doi.org/10.1002/pbc.28041DOI Listing
January 2020

Predictive measures and outcomes of extent of resection in juvenile pilocytic astrocytoma.

J Clin Neurosci 2019 Dec 26;70:79-84. Epub 2019 Aug 26.

McMaster Pediatric Brain Tumor Study Group, McMaster University, Hamilton, Canada; Department of Surgery, Division of Neurosurgery, McMaster University, Hamilton, Canada. Electronic address:

Purpose: The present study aims to determine the tumor-related, clinical, and demographic factors associated with extent of resection (EOR) and post-operative outcomes in JPA patients.

Methods: All patients with JPA, identified from a single-center brain tumour data base, were included in this retrospective analysis. Pre-operative MRI scans were reviewed by a single neurosurgeon blinded to the EOR. JPA cases that exhibited no residual tumor post-operatively were assigned to the GTR group, all other tumors were assigned to the
Results: Of the 28 patients included, 15 had a GTR (46% male; median age: 7.5 years; range: 1.16-14.9) and 13 had
Conclusions: This study shows other than location of the lesion in the cerebellum, demographic, clinical and tumor-related variables are not associated with EOR in children with JPA. GTR was associated with an extended follow-up interval but not with increased perioperative morbidities compared to those with
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http://dx.doi.org/10.1016/j.jocn.2019.08.066DOI Listing
December 2019

Salvage Therapy for Childhood Medulloblastoma: A Single Center Experience.

Can J Neurol Sci 2019 07;46(4):403-414

Pediatrics,McMaster University,Hamilton, Ontario,Canada.

Introduction: Children diagnosed with medulloblastoma (MB) who are refractory to upfront therapy or experience recurrence have very poor prognoses. Although phase I and phase II trials exist, these treatments bear significant treatment-related morbidity and mortality.

Methods: A retrospective review of children diagnosed with a recurrence of MB from 2002 to 2015 at McMaster University was undertaken.

Results: Recurrent disease in 10 patients involved leptomeningeal dissemination, with 3 experiencing local recurrence. In three recurrent patients the disease significantly progressed, and the children were palliated. The remaining 10 children underwent some form of salvage therapy, including surgical re-resection, radiation, and chemotherapy, either in isolation or in varying combinations. Of the 13 children experiencing treatment-refractory or recurrent disease, 4 are currently alive with a median follow-up of 38.5 months (75.5 months). Of the eight patients with molecular subgrouping data, none of the Wnt MB experienced recurrence.

Conclusion: Recurrent MB carried a poor prognosis with a 5-year overall survival (OS) of 18.2% despite the administration of salvage therapy. The upfront therapy received, available treatment, and tolerability of the proposed salvage therapy resulted in significant heterogeneity in the treatment of our recurrent cohort.
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http://dx.doi.org/10.1017/cjn.2019.39DOI Listing
July 2019

Evaluating the prevalence of diabetes mellitus subtypes in childhood cancer survivors: a systematic review protocol.

Adolesc Health Med Ther 2019 26;10:59-65. Epub 2019 Apr 26.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

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. 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. 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.
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http://dx.doi.org/10.2147/AHMT.S199449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498089PMC
April 2019

Tri-ponderal mass index in survivors of childhood brain tumors: A cross-sectional study.

Sci Rep 2018 11 5;8(1):16336. Epub 2018 Nov 5.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

Survivors of childhood brain tumors (SCBT) face a higher risk of cardiometabolic disorders and premature mortality compared to the general population. Excess adiposity is a known risk factor for these comorbidities. However, while SCBT have higher adiposity compared to healthy controls, measuring adiposity in clinical practice involves access to specialized equipment and may impact busy clinical services. Tri-ponderal Mass Index (TMI; kg/m) may be a superior measure of adiposity when compared to Body Mass Index (BMI; kg/m). However, its use in determining adiposity in SCBT has not been assessed. This study aims to validate TMI as a clinical measure of adiposity in SCBT. This was a cross-sectional study including 44 SCBT (n = 20 female) and 137 (n = 64 female) non-cancer control children, 5-17 years of age. BMI and TMI were calculated from height and weight measurements. Fat mass percentage was assessed using bioelectrical impedance analysis and waist to hip and waist to height ratios were used to assess central adiposity. Regression analyses were adjusted for age, sex, puberty and treatment. TMI demonstrated strong correlations to measures of total and central adiposity and predicted adiposity in SCBT and non-cancer controls, with stronger trends in the latter group. TMI may serve as a reliable clinical measure of adiposity in both SCBT and healthy children.
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http://dx.doi.org/10.1038/s41598-018-34602-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218522PMC
November 2018

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218.

Pediatr Blood Cancer 2019 03 4;66(3):e27540. Epub 2018 Nov 4.

Department of Pediatrics, University of Toronto and New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children.

Procedure: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m ) and temsirolimus (15 mg/m ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected.

Results: Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m , vinblastine 4 mg/m ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months).

Conclusion: The combination of weekly temsirolimus (15 mg/m ) and vinblastine (4 mg/m ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.
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http://dx.doi.org/10.1002/pbc.27540DOI Listing
March 2019

Survival Following Tumor Recurrence in Children With Medulloblastoma.

J Pediatr Hematol Oncol 2018 04;40(3):e159-e163

Division of Pediatric Hematology/Oncology, Hospital for Sick Children, Toronto, ON.

Medulloblastoma is the most common malignant brain tumor in children. Published survival rates for this tumor are ∼70%; however, there is limited published information on outcome after disease recurrence. This was an observational study which included all persons under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada. Data collected included date of diagnosis, age at diagnosis, sex, stage, pathology, treatment, recurrence, and current status. Survival rates were determined. In total, 550 cases were ascertained meeting the study criteria. The overall survival rate at 1 year was 83.6%±1.7%, at 3 years 77.2%±1.9%, and at 5 years 72.5%±20%. The progression-free survival rates were 78%±1.9%, 70%±2.1%, and 69±2.1% at 1, 3, and 5 years from initial diagnosis. In total, 173 (31.2%) were reported to have had tumor recurrence and 23 (11.4%) of them were alive at the time of survey with an overall survival rate at 1 year of 38.3%±4%, at 2 years of 16.9%±3.3%, and at 5 years of 12.4%±2.8%. Our data confirm that children with recurrent medulloblastoma have a poor prognosis, supporting the need for novel treatment approaches for this group.
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http://dx.doi.org/10.1097/MPH.0000000000001095DOI Listing
April 2018

Birth weight and body mass index z-score in childhood brain tumors: A cross-sectional study.

Sci Rep 2018 01 26;8(1):1642. Epub 2018 Jan 26.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

Children with brain tumors (CBT) are at higher risk of cardiovascular disease and type 2 diabetes compared to the general population, in which birth weight is a risk factor for these diseases. However, this is not known in CBT. The primary aim of this study was to explore the association between birth weight and body mass measures in CBT, compared to non-cancer controls. This is a secondary data analysis using cross-sectional data from the CanDECIDE study (n = 78 CBT and n = 133 non-cancer controls). Age, sex, and birth weight (grams) were self-reported, and confirmed through examination of the medical records. Body mass index (BMI) was calculated from height and weight measures and reported as kg/m. BMI z-scores were obtained for subjects under the age of 20 years. Multivariable linear regression was used to evaluate the relationship between birth weight and BMI and BMI z-score, adjusted for age, sex, puberty, and fat mass percentage. Higher birth weight was associated with higher BMI and BMI z-score among CBT and controls. In conclusion, birth weight is a risk factor for higher body mass during childhood in CBT, and this may help the identification of children at risk of future obesity and cardiometabolic risk.
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http://dx.doi.org/10.1038/s41598-018-19924-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786044PMC
January 2018

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

J Clin Oncol 2017 Sep 20;35(25):2934-2941. Epub 2017 Jul 20.

Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara McKeown, Jim Loukides, James T. Rutka, Peter Dirks, Michael D. Taylor, Shiyi Chen, Ute Bartels, Annie Huang, Eric Bouffet, Cynthia Hawkins, and Uri Tabori, The Hospital for Sick Children, Toronto; Adam Fleming, McMaster Children's Hospital, McMaster University, Hamilton; Shayna Zelcer, Children's Hospital of Western Ontario, London, Ontario; David Eisenstat and Bev Wilson, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta; Anne Sophie Carret, Hospital Sainte Justine; Nada Jabado, McGill University, Montreal; Valerie Larouche, Centre Hospitalier Universitaire de Québec, Québec City, Quebec, Canada; Ofelia Cruz and Carmen de Torres, Hospital Sant Joan de Déu, Barcelona, Spain; Cheng-Ying Ho, University of Maryland School of Medicine, Baltimore, MD; Roger J. Packer, Children's National Health System, Washington, DC; Ruth Tatevossian, Ibrahim Qaddoumi, Julie H. Harreld, James D. Dalton, and David W. Ellison, St Jude Children's Research Hospital, Memphis, TN; Jean Mulcahy-Levy and Nicholas Foreman, Children's Hospital Colorado, Aurora, CO; Matthias A. Karajannis, Shiyang Wang, and Matija Snuderl, New York University Langone Medical Center, New York, NY; Amulya Nageswara Rao and Caterina Giannini, The Mayo Clinic, Rochester, MN; Mark Kieran and Keith L. Ligon, Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, MA; Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, and Alessandro Raso, Istituto Giannina Gaslini, Genoa, Italy; Sabine Mueller and Theodore Nicolaides, University of California, San Francisco, San Francisco, CA; Karen Silva and Romain Perbet, Hospices Civils de Lyon; Alexandre Vasiljevic, Cécile Faure Conter, and Didier Frappaz, Institute of Pediatric Hematology and Oncology, Lyon, France; Sarah Leary and Courtney Crane, Seattle Children's Hospital, Seattle, WA; Aden Chan and Ho-Keung Ng, The Chinese University of Hong Kong, Hong Kong; Zhi-Feng Shi and Ying Mao, Huashan Hospital, Fudan University, Shanghai, People's Republic of China; Elizabeth Finch, University of North Carolina, School of Medicine, Chapel Hill, NC; Peter Hauser, Semmelweis University, Budapest, Hungary; and David Sumerauer and Lenka Krskova, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.
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http://dx.doi.org/10.1200/JCO.2016.71.8726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791837PMC
September 2017

Analysis of surgical and MRI factors associated with cerebellar mutism.

J Neurooncol 2017 Jul 19;133(3):539-552. Epub 2017 May 19.

McMaster Pediatric Brain Tumor Study Group, McMaster University, Hamilton, Canada.

The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. Therefore, we aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with individuals who did not acquire CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). A total of 22 patients (11 with and 11 without CM) were included. Medulloblastoma was the most common pathology among CM patients (91%); the remaining 9% were diagnosed with a pilocytic astrocytoma. Tumor attachment to the floor of the fourth ventricle (OR 6; 95% CI 0.7-276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9-315.5), and post-operative peri-ventricular ischemia on MRI (OR 5; 95% CI 0.5-236.5) were found to have the highest measures of association with CM. Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia have a relatively higher prevalence in patients with CM. Collectively, our work calls for a larger multi-institutional cohort study of CM patients to encourage further investigation of the determinants and management of CM in order to potentially minimize its development and predict onset.
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http://dx.doi.org/10.1007/s11060-017-2462-4DOI Listing
July 2017

Urine biomarkers of acute kidney injury in noncritically ill, hospitalized children treated with chemotherapy.

Pediatr Blood Cancer 2017 Oct 18;64(10). Epub 2017 Apr 18.

Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

Background: Cisplatin (Cis), carboplatin (Carb), and ifosfamide (Ifos) are common nephrotoxic chemotherapies. Biomarkers of tubular injury may allow for early acute kidney injury (AKI) diagnosis.

Procedure: We performed a two-center (Canada, United States) pilot study to prospectively measure serum creatinine (SCr), urine neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) in children receiving Cis/Carb (27 episodes), Ifos (30 episodes), and in 15 hospitalized, nonchemotherapy patients. We defined AKI using the Kidney Disease Improving Global Outcomes (KDIGO) definition. We compared postchemotherapy infusion NGAL and IL-18 concentrations (immediate postdose to 3 days later) to pre-infusion concentrations. We calculated area under the receiver operating characteristic curve (AUC) for postinfusion biomarkers to discriminate for AKI.

Results: Prechemotherapy infusion NGAL and IL-18 concentrations were not higher than nonchemotherapy control concentrations. Increasing chemotherapy dose was associated with increasing postinfusion (0-4 hr after infusion) NGAL (P < 0.05). Post-Ifos, immediate postdose, and daily postdose NGAL and IL-18 were significantly higher than pre-infusion biomarker concentrations (P < 0.05), during AKI episodes. NGAL and IL-18 did not rise significantly after Cis-Carb infusion, relative to predose concentrations (P > 0.05). NGAL and IL-18 measured immediately after Ifos infusion discriminated for AKI with AUCs is 0.80 (standard error = 0.13) and 0.73 (standard error = 0.16), respectively. NGAL and IL-18 were not diagnostic of Cis-Carb-associated AKI. When AUCs were adjusted for age, all biomarker AUCs (Cis-Carb and Ifos) improved.

Conclusion: Urine NGAL and IL-18 show promise as early AKI diagnostic tests in children treated with ifosfamide and may have a potential role in drug toxicity monitoring.
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http://dx.doi.org/10.1002/pbc.26538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287509PMC
October 2017

Adiposity in childhood brain tumors: A report from the Canadian Study of Determinants of Endometabolic Health in Children (CanDECIDE Study).

Sci Rep 2017 03 22;7:45078. Epub 2017 Mar 22.

Medical Sciences Program, McMaster University, Hamilton, Ontario, Canada.

Children with brain tumors (CBT) are at high risk of cardiovascular diseases and type 2 diabetes compared to the general population. Recently, adiposity has been reported to be more informative for cardiometabolic risk stratification than body mass index (BMI) in the general population. The goal of this study is to describe the adiposity phenotype in CBT, and to establish adiposity determinants. We recruited CBT (n = 56) and non-cancer controls (n = 106). Percent body fat (%FM), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were measured to determine total and central adiposity, respectively. Regression analyses were used to evaluate adiposity determinants. CBT had higher total and central adiposity compared to non-cancer controls despite having similar BMI measurements. Those with tumors at the supratentorial region had increased total and central adiposity, while those who received radiotherapy had increased total adiposity. In conclusion, CBT have increased total and central adiposity in the presence of similar BMI levels when compared to non-cancer controls. Adiposity, especially central adiposity, is a potential cardiometabolic risk factor present relatively early in life in CBT. Defining interventions to target adiposity may improve long-term outcomes by preventing cardiometabolic disorders in CBT.
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http://dx.doi.org/10.1038/srep45078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361156PMC
March 2017

Evaluating overweight and obesity prevalence in survivors of childhood brain tumors: a systematic review protocol.

Syst Rev 2017 03 3;6(1):43. Epub 2017 Mar 3.

Department of Pediatrics, McMaster University, 1280 Main Street West, HSC-3A57, Hamilton, Ontario, L8S 4K1, Canada.

Background: Overweight and obesity are well-known risk factors for cardiometabolic diseases including hypertension, myocardial infarction, stroke, and type 2 diabetes in the general population. Survivors of childhood brain tumors (SCBT) are at risk of premature mortality, and recent evidence suggests that these cardiometabolic diseases are potential emerging determinants of survival and quality of life. Therefore, the rates of overweight and obesity in this population need to be examined to assess their impact on outcomes. The objective of this systematic review is to examine the prevalence of overweight and obesity in SCBT. The secondary aim of this review is to evaluate whether SCBT have higher adiposity compared to the general population.

Methods: Searches will be conducted in MEDLINE, CINAHL, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, PubMed, and Database of Abstracts of Reviews of Effect. For gray literature, we will search ProQuest Dissertations and Theses A&I and Web of Science. Two reviewers will independently screen all articles against predetermined eligibility criteria and complete data abstraction, risk of bias, and quality assessments. The primary outcome includes the prevalence of overweight or obesity. The secondary outcomes involve waist-to-hip ratio, waist-to-height ratio, body fat percentage, and skinfold thickness. Meta-analysis will be performed when two or more studies with similar design, populations, and outcomes are available.

Discussion: This review will summarize current data on the prevalence of overweight and obesity in SCBT. This will help the development of an understanding of the scale of overweight and obesity in this population and guide the design of interventions that will improve outcomes.

Systematic Review Registration: PROSPERO CRD42016051035.
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http://dx.doi.org/10.1186/s13643-017-0439-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335753PMC
March 2017
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