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Statistics.
Differences in patient group characteristics were assessed using either Fisher’s exact test or Wilcoxon’s rank-sum test. Differences for biomarkers and liver functions between SOS yes or no were checked by 2-sample
PMC10322680
Study design and approval.
The study design and samples collection are summarized in Figure 1. The study was approved by the Institutional Review boards of all institutional participating centers. Written informed consent was obtained from all patients or their legal guardians.
PMC10322680
Author contributions
BPD, HL
SP designed and oversaw the study. YH, HL, and SP analyzed data and ensured data integrity. EDPA, RAK, JR, JLS, and SWC oversaw patient sample collection and processing at the respective centers. AB, BPD, AM, KBV, and SP were responsible for centralized sample processing, storage, and proteomic analysis with ELISAs. Al...
PMC10322680
Supplementary Material
PMC10322680
04/18/2023
In-Press Preview
PMC10322680
05/22/2023
Electronic publication
PMC10322680
Study design.
confusion
Workflow illustrating the study population, biomarkers measurements, and time points.Diagram of the optimal algorithm for risk prediction of SOS, its confusion matrix, sensitivity, specificity, PPV, and NPV.
PMC10322680
SOS cumulative incidence by day 35 stratified by high and low day 3 risk biomarkers using optimal cutpoints chosen by Youden’s index.
(
PMC10322680
Cumulative incidence of SOS stratified by the 3-biomarker score.
PMC10322680
Day 100 OS stratified by high and low day 3 risk biomarkers using optimal cutpoints chosen by Youden’s index.
(
PMC10322680
Kaplan-Meier estimates of OS stratified by the 3-biomarker score.
PMC10322680
Biomarker changes after defibrotide treatment.
PMC10322680
Patient demographics
PMC10322680
Outcome characteristics
PMC10322680
Parameter estimates and
PMC10322680
Rate of change for biomarkers after defibrotide treatment
PMC10322680
Univariate (top) and multivariate (bottom) Cox regression analyses for SOS incidence
PMC10322680
Abstract
PMC9972017
Background
toxicity, tumors
TUMORS
Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti‐...
PMC9972017
Methods
tumors
TUMORS
The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 16...
PMC9972017
Results
toxicity, Ewing sarcoma
EWING SARCOMA
Twenty‐six patients (median age 13 years, range 2–18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (
PMC9972017
Conclusions
The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m
PMC9972017
Abbreviations
Acute Lymphoblastic LeukemiaArea Under CurveCentral Nervous SystemConcentration at Steady StateComplete ResponseDose‐limiting ToxicityFood and Drug AdministrationGastrointestinalInstitutional Review BoardIntravenousMaximum Tolerated DoseOverall Response RateProgressive DiseasePharmacokineticPartial ResponseStable Disea...
PMC9972017
BACKGROUND
pneumonitis, nausea/vomiting, fatigue, abdominal pain, cancer, toxicities, malignancies, cancer deaths, tumors
PNEUMONITIS, CANCER, THROMBOCYTOPENIA, MALIGNANCIES, TUMORS, TYPE II DIABETES
Solid tumors, including central nervous system (CNS) tumors, represent approximately 60% of all childhood malignancies and account for the majority of cancer deaths in children.Irinotecan and temozolomide are frequently used in pediatric solid and CNS tumors due to clinical tolerability and preclinical evidence of syne...
PMC9972017
MATERIALS AND METHODS
PMC9972017
Objectives
tumors
SECONDARY, TUMORS
The study's primary objectives were to determine the MTD and RP2D of metformin combined with VIT in pediatric relapsed and refractory solid and CNS tumors, and to describe pharmacokinetics (PKs) of metformin in combination with VIT. The secondary objective was to describe the radiologic responses seen with this regimen...
PMC9972017
Patient eligibility
infection, tumor, allergy
TUMOR, GRAFT VERSUS HOST DISEASE, DISEASE, ALLERGY, SOLID TUMORS, INFECTION
Patients 1–18 years of age with histologically or radiographically confirmed relapsed or refractory CNS or non‐CNS solid tumors with radiographically measurable disease and no known curative therapy options were eligible. A Karnofsky/Lansky score of 50 or above was required. Prior therapy including vincristine, irinote...
PMC9972017
Study design
Tumors, Cancer
TUMORS, PEDIATRIC CANCER, CANCER
This study was completed through the Sunshine Project, a multi‐institutional clinical trial consortium sponsored by the National Pediatric Cancer Foundation. Moffitt Cancer Center was the coordinating center, and the study was approved by the Moffitt Cancer Center Institutional Review Board (IRB) and each participating...
PMC9972017
Treatment schema
Tumor, diarrhea
ADVERSE EVENTS, DISEASE, TUMOR
Initially, protocol therapy included VIT (vincristine 1.5 mg/mTrial design: (A) Schema for the original trial VIT cycle without metformin prior to addition of metformin in Cycle 2 (or 3) depending on hematologic tolerance. “Heme Recovery” signifies ANC > 1000 and Platelets >100,000 on Day 21 of a cycle. (B) Post‐amendm...
PMC9972017
Pharmacokinetic studies
pre‐dose, NMS
NMS, COLD
PK samples for metformin were drawn at Hour 0 (pre‐dose) and Hours 6, 12, and 24 following the first metformin dose on Cycle 1 Day 1. Additional PKs were drawn at Hour 0 before the Cycle 1 Day 8 dose and Hour 6 post‐dose. One ml of whole blood was shipped on cold packs overnight to NMS Labs (Willow Grove, PA) where met...
PMC9972017
Statistical considerations
Patient and clinical characteristics were summarized using descriptive statistics including median and range for continuous measures and proportions and frequencies for categorical measures.
PMC9972017
RESULTS
toxicity, Twenty‐nine
Twenty‐nine patients consented and were screened (Figure The median age was 13 years (range 2–18 years), and patients received a median of two prior lines of therapy (range 1–5; Table Demographics and patient characteristicsNumber of patients receiving treatment by dose level and numbers evaluable for toxicity and resp...
PMC9972017
Toxicity
toxicity, toxicities
Of 26 subjects enrolled, 22 received at least one dose of metformin and were included in toxicity analysis (Table Grade 3 and 4 toxicities, regardless of attribution, and percent of cycles in which each toxicity occurred for metformin‐containing and non‐metformin‐containing cycles of therapyEighteen patients were evalu...
PMC9972017
Responses
ATRT, PD, tumor, brainstem glioma
ANAPLASTIC ASTROCYTOMA, TUMOR, GLIOBLASTOMA MULTIFORME, WILMS TUMOR, DISEASE, EMBRYONAL RHABDOMYOSARCOMA, GERM CELL TUMOR, ALVEOLAR RHABDOMYOSARCOMA, MEDULLOEPITHELIOMA, ATYPICAL TERATOID/RHABDOID TUMOR OF CNS, CLEAR CELL SARCOMA, OSTEOSARCOMA, EWING SARCOMA
Nineteen patients achieved the threshold metformin exposure defined in the methods section or progressed after initiation of metformin making them evaluable for response, with 16 patients evaluable for best overall response (Figure Swimmer's plot of 26 patients treated on study, with timing of overall best response and...
PMC9972017
Pharmacokinetics
Twenty patients had sufficient PK sample collection for metformin PK analysis on Cycle 1 Day 1. As shown in Table Pharmacokinetic analysis by dose levelAbbreviations: AUC(0–12 h), area under the curve from 0–12 hr; C
PMC9972017
DISCUSSION
DLTs, neutropenia, diarrhea, toxicity, toxicities, thrombocytopenia, GI toxicity, Toxicity, type 2 diabetes mellitus
PEDIATRIC ALL, THROMBOCYTOPENIA, TYPE 2 DIABETES MELLITUS, NEUTROPENIA
This Phase I trial found the MTD was exceeded at Dose Level 5, 2000 mg/mRecommended metformin dosing for newly‐diagnosed type 2 diabetes mellitus in children 10 years and older is initially 500–1000 mg daily with escalation as high as 1000 mg twice daily.This study collected all Grade 3 and 4 toxicities and assessed at...
PMC9972017
AUTHOR CONTRIBUTIONS
PMC9972017
FUNDING INFORMATION
PEDIATRIC CANCER
This study was funded by the National Pediatric Cancer Foundation and Rally Foundation.
PMC9972017
CONFLICT OF INTEREST
The authors report no conflicts of interest with this work.
PMC9972017
Supporting information
Tables S1‐S2 Click here for additional data file.
PMC9972017
ACKNOWLEDGMENTS
PEDIATRIC CANCER
This study was generously supported by the National Pediatric Cancer Foundation (
PMC9972017
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
PMC9972017
REFERENCES
PMC9972017
Background
Current global trend of insufficient physical activity (PA) among children and adolescents highlights the necessity of finding effective ways to promote PA in childhood. Self-determination theory (SDT) has demonstrated efficacy as a conceptual framework for developing interventions aimed at promoting diverse health beh...
PMC10463639
Methods
Sixty eight students (M
PMC10463639
Results
While a statistically significant intervention effect on children’s leisure-time PA was not found, students in the intervention group reported higher, albeit marginal, perceptions of intrinsic motivation (
PMC10463639
Conclusions
Our pilot study highlights the importance of parental training and the potential for SDT-informed interventions to support children's intrinsic motivation towards physical activity. Further research is needed to test the intervention in other domains and combine interventions in several domains to have the highest impa...
PMC10463639
Trial registration
This pilot study is part of preparation for the main study, prospectively registered in ISRCTN registry as ISRCTN78373974 (15.12.2022). The current stage of the main study is ‘recruiting’.
PMC10463639
Supplementary Information
The online version contains supplementary material available at 10.1186/s12889-023-16528-4.
PMC10463639
Keywords
PMC10463639
Background
TCM
Physical activity (PA) has many known benefits for children and adolescents [PA in childhood predicts adult PA levels – being active as a child significantly increases the probability of being active as an adult [One of the prominent motivational theories frequently used in developing health interventions is the self-d...
PMC10463639
The present study
Need-Supportive
SECONDARY
In light of the empirical finding above, we developed an entirely web-based intervention program for parents, considering that self-paced online learning might be convenient for parents. The aim of the pilot study was to test the effectiveness of an online need-supportive study program to help parents interact with the...
PMC10463639
Methods
PMC10463639
Participants
RECRUITMENT, RECRUITMENT
To estimate the required sample size to test the study hypotheses, power calculation was conducted using G*Power Version 3.1.9.7 [We managed to recruit a total sample size of 68 children (28 boys, 40 girls) and one parent for each child who participated in the study. Students’ ages ranged from 11 to 15 years (Participa...
PMC10463639
Ethical considerations
The study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of the University of Tartu (code: 327/T-4, 19.10.2020). We used the CONSORT checklist when writing our report [Informed consent forms and study information were distributed by research team members, who ...
PMC10463639
Experimental design
The study adopted a cluster-randomized controlled design with two study groups. Schools were randomly assigned to either intervention or control groups. Parents and their children were assigned to either intervention group or control group respective of the children’s school. Parents in the intervention group participa...
PMC10463639
Web-based need-supportive parenting program
A web-based format was chosen for the intervention as it is scalable, enables reaching larger audiences and offers the possibility of self-paced learning for the participants. The aim of the need-supportive parenting program was to educate parents about techniques directed at promoting children’s intrinsic motivation t...
PMC10463639
Outcome measures
For the outcome measures, students completed pen-and-paper questionnaires during pre-trial, post-trial and one-month follow-up data collection points. All measures were self-reported. Responses to items were collected using 7-point scales with endpoints meaning
PMC10463639
Physical activity
The behavioural outcome measure was the children’s participation in out-of-school MVPA. The choice of MVPA as the behavioural measure was based on the many health benefits MVPA has for adolescents (e.g., better mental health, better cardio-respiratory fitness, and less fat gain) [
PMC10463639
Perceived need support
To measure students’ perceptions of their parents’ need-supportive behaviours regarding out-of-school PA, the modified versions of the perceived autonomy support scale [
PMC10463639
Psychological need satisfaction and frustration
Students’ perceptions of their autonomy, competence, and relatedness satisfaction and frustration in relation to leisure-time PA were measured by the Basic Psychological Need Satisfaction and Need Frustration Scale (BPNSNF) [
PMC10463639
Motivation towards PA
Autonomous and controlled forms of motivation towards out-of-school PA were measured using a modified version of the Perceived Locus of Causality Questionnaire [
PMC10463639
Theory of planned behaviour constructs
PBC
Students’ attitude, subjective norms, perceived behavioural control (PBC), and intention for out-of-school PA were measured using the scales developed according to the recommended guidelines [
PMC10463639
Perceived Effort
Students’ self-reported effort to do leisure-time PA was measured using the scale developed according to Hagger and Hamilton [
PMC10463639
Data analysis
The data analysis was conducted using JASP (Version 0.17.1; University of Amsterdam, Amsterdam, the Netherlands). Asymmetry values between -2 and + 2 and kurtosis values between -7 and + 7 were considered indicative of the data being normally distributed [Randomization check to examine the baseline differences between ...
PMC10463639
Results
PMC10463639
Preliminary analysis
PMC10463639
Discussion
Parental support is significantly correlated to children’s PA levels [According to SDT, satisfying the basic psychological needs enables the development of more autonomous forms of motivation [Previous research has shown that need-supportive behaviours from PE teachers and peers enhance need satisfaction and lower need...
PMC10463639
Conclusions
This study tested an online need-supportive training for parents to enhance children's leisure-time physical activity and autonomous motivation. There was a positive trend in vigorous and total MET-minutes per week for children in the intervention group, but no statistically significant intervention effect. However, th...
PMC10463639
Acknowledgements
The authors would like to thank master’s student Šerelin Bovt for her help in data collection.
PMC10463639
Authors’ contributions
HT
AK, HT and PRM designed the study. PRM, AK and HT developed the intervention. PRM drafted the manuscript. PRM, AK and HT edited the manuscript and approved the final version prior to submission.
PMC10463639
Funding
This work was supported by the University of Tartu, Institute of Sport Sciences and Physiotherapy. The project has not received external funding. Trial sponsor: University of Tartu, Institute of Sport Sciences and Physiotherapy. Contact: Priit Kaasik, Head of Institute. Address: Ujula 4, 51008 Tartu, Estonia.
PMC10463639
Availability of data and materials
OSF
The datasets generated during and analysed during the current study are available in the Open Science Framework (OSF) repository, 10.17605/OSF.IO/DG534[
PMC10463639
Declarations
PMC10463639
Ethics approval and consent to participate
Ethical approval for this study was provided by the Research Ethics Committee of the University of Tartu (code: 327/T-4, 19.10.2020). Children and parents provided informed written consent to participate in the study. All methods were performed in accordance with the relevant guidelines and regulations.
PMC10463639
Consent for publication
Not applicable.
PMC10463639
Competing interests
The authors declare that they have no competing interests.
PMC10463639
References
PMC10463639
Objective
Edited by: Daniel Adrian Gardan, Dunarea de Jos University, RomaniaReviewed by: Ezequiel Pinto, University of Algarve, Portugal; Paweł Bryła, University of Łódź, PolandWe designed a new type of ‘physical activity calorie equivalent’ (PACE) food label in Iran to compare its effect with that of the traffic light food lab...
PMC10683755
Design
Mixed-method study.
PMC10683755
Participants
Mothers of school children between the ages of 6–12 years.
PMC10683755
Setting
REGRESSIONS
In the qualitative phase, 10 focus group discussions (FGDs) were conducted with various groups of mothers, and two FGDs were conducted with food science and nutrition experts to design a new PACE label. In the quantitative phase, 496 mothers were randomly assigned to five groups: (1) no nutrition label, (2) current TLL...
PMC10683755
Results
The mothers’ perspectives were classified into two sub-themes, the PACE label’s facilitators and barriers. The new PACE label’s characteristics were divided into two subcategories: (a) appearance, and (b) nutritional information, including 14 codes. In the quantitative section, mean calories of the selected foods were ...
PMC10683755
Introduction
obesity, TLL
OBESITY
The increasing prevalence of obesity has been, and remains, a major global challenge, where rapid changes in dietary and food behaviors –and as a consequence, excess energy intake- are the main causes of this rising trend (Energy imbalances and physical inactivity in children and adolescents are of particular concern (...
PMC10683755
Methods
This study was part of a larger mixed method research in which the strengths, weaknesses, and strategies of improving the use of nutrition labels were discussed (For the qualitative phase, the participants were informed of the research objectives before the interviews. Furthermore, participants were assured that the in...
PMC10683755
Qualitative phase
A flowchart showing the study’s processes is presented in Study flowchart.
PMC10683755
FGDs with mothers as household representatives
CHILDHOOD OBESITY, RECRUITMENT
Sixty-three mothers participated in our study. The mothers’ general characteristics have been presented in Ten FGDs were conducted with mothers of school children aged 6–12 years in ten primary schools from southern, northern, eastern, western, and central Tehran. Two primary schools were randomly selected from each di...
PMC10683755
FGDs with experts
Two FGDs were held with ‘food science and nutrition experts’ (hereinafter referred to as ‘FSN experts’ for the sake of brevity). For this group, the sampling method was purposeful and FSN experts from two universities of Tehran participated in the FGDs. First, official letters were sent to the Heads of Departments of N...
PMC10683755
Label printing
After confirming the label image for print, we had to determine the size and definitions on each label. For this purpose, the information on the purchased products, such as definitions of serving, weight of each serving, total weight of the product, and the label size were entered into Excel 2010 software, and understa...
PMC10683755
Qualitative phase data analysis
The conventional content qualitative analysis approach was applied to determine the main themes (All the FGDs were transcribed verbatim and typed in Microsoft Word. Notes taken by the note taker were added to the transcription to ensure accuracy and clarity of any instances which might not have been recognized by the t...
PMC10683755
Quantitative phase
Similar to the qualitative phase, the participants were mothers of 6-12-year-old schoolchildren. Ten schools were randomly selected from the same regions used in the qualitative phase, but the schools were different this time, so the mothers would be blinded toward the study goal regarding their caloric choices. The in...
PMC10683755
Sample size calculation and randomization
Using G*Power software, sample size was calculated based on caloric choices –which is the primary outcome of our study. A sample size of 481 was calculated considering the expected effect size of 0.15, α = 0.05, and power = 90% (We applied stratified block randomization, using STATA software, where stratums were school...
PMC10683755
Study procedure
First, a pilot study was conducted in one school (on 50 mothers) to assess the likely problems, practicality, and feasibility of the study. In the second phase, mothers were randomized into five arms, including the traffic light label (TLL)- which is currently mandatory in Iran-, TLL plus the educational brochure (The ...
PMC10683755
Quantitative phase data analysis
REGRESSION
Continuous variables were analyzed by analysis of variance (ANOVA) (comparing mean calories of selected foods between the groups), and categorical variables by chi-square tests [comparing general characteristics including marital status, education, economic status, satiety status, BMI (normal/overweight/obese), and phy...
PMC10683755
Results
PMC10683755
Qualitative phase: designing a new PACE label
In this section, two main themes were defined. First, the mothers’ perspectives on PACE were examined, and then the new label’s expectations were drafted upon taking into account the viewpoints of mothers and FSN experts. The aforementioned are presented in
PMC10683755
Mothers’ perspectives as household representatives
1-no
Mothers’ perspectives were classified into two sub-themes, the physical activity label’s facilitators and barriers. The facilitators were categorized into four codes: 1- healthier food choices, 2-easy to understand, 3-suitable solution, 4-creating incentives to lose weight and be physically active. The barriers were ca...
PMC10683755
Mothers’ expectations of the new PACE label
TLL
SAID
The participants unanimously agreed that graphics were more understandable than digits. They also said that walking was the most feasible form of physical activity, as compared to other exercises, such as swimming. Colorful labels were highly recommended, especially for children. In addition, most of the mothers believ...
PMC10683755
Experts’ expectations of the new PACE label
The food science and nutrition (FSN) experts approved the graphic design of the new label, and believed it to be easily understood by the public. However, some of them suggested the PACE information to be included in the nutrition fact table.All the experts believed that using a single color instead of three would simp...
PMC10683755
Discussion
PMC10683755