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Abstract Background The progress of treatments of childhood acute lymphoblastic leukemia (ALL) has made it possible to reach a survival rate superior to 80%. However, the treatments lead to several long-term adverse effects, including cardiac toxicity. Although studies have reported associations between genetic variants and cardiorespiratory fitness, none has been performed on childhood ALL survivors. Methods We performed whole-exome sequencing in 239 childhood ALL survivors from the PETALE cohort. Germline variants (both common and rare) in selected set of genes (N = 238) were analyzed for an association with cardiorespiratory fitness. Results Our results showed that the common variant in the TTN gene was significantly associated with a low cardiorespiratory fitness level (p = 0.0005) and that the LEPR, IGFBPI and ENO3 genes were significantly associated with a low cardiorespiratory fitness level in female survivors (p ≤ 0.002). Also, we detected an association between the low cardiorespiratory fitness level in participants that were stratified to the “high risk” prognostic group and functionally predicted rare variants in the SLC22A16 gene (p = 0.001). Positive associations between cardiorespiratory fitness level and trainability genes were mainly observed in females. Conclusions For the first time, we observed that low cardiorespiratory fitness in childhood ALL survivors can be associated with variants in genes related to subjects’ trainability. These findings could allow better childhood ALL patient follow-up tailored to their genetic profile and cardiorespiratory fitness, which could help reduce at least some of the burden of long-term adverse effects of treatments.

Abstract: Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10−3 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics (KMT2A rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy. IKZF1 deletion status was retrospectively evaluated by multiplex ligation-dependent probe amplification. Between 2005 and 2011, 678 Philadelphia chromosome-negative B-ALL patients aged 1 to 18 years enrolled; 651 achieved CR and 648 received a final risk group. Among all 678 patients, 5-year event-free survival (EFS) was 87% (95% confidence interval [CI], 84-89) and overall survival 93% (95% CI, 90-94). Five-year disease-free survival of SR patients (N = 407) was 94% (95% CI, 91-96), HR (N = 176) was 84% (95% CI, 77-88), and VHR (N = 65) was 79% (95% CI, 67-87). IKZF1 deletion was present in 62 of 385 (16%) assessed patients and was associated with inferior 5-year EFS (63%; 95% CI, 49%-74% vs 88%; 95% CI, 84%-91%; P < .001), and higher 5-year cumulative incidence of relapse, including among those with low MRD (24% vs 8%, P = .001). In multivariable analysis, age ≥15 years, WBC ≥50 × 109/L, IKZF1 deletion, and MRD ≥10−4 was each associated with inferior outcome. In conclusion, risk-stratified therapy on DFCI 05-001 resulted in favorable outcomes for B-ALL patients, including those with VHR features. IKZF1 deletion was an independent predictor of inferior outcome. This trial was registered at www.clinicaltrials.gov as #NCT00400946.

Abstract: Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (ETV6-ABL1: n = 1; FOXP1-ABL1: n = 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1-altered patients, irrespective of the presence of a kinase-activating fusion.

Abstract Background Thromboembolism (TE) is a serious complication in children with acute lymphoblastic leukemia (ALL). The incidence of symptomatic thromboembolism is as high as 14% and case fatality rate of ~15%. Further, development of thromboembolism interferes with the scheduled chemotherapy with potential impact on cure rates. The exact pathogenesis of ALL-associated thromboembolism is unknown. Concomitant administration of asparaginase and steroids, two important anti-leukemic agents, is shown to increase the risk of ALL-associated TE. Dana-Farber Cancer Institute (DFCI) ALL studies reported ~10% incidence of thrombosis with significantly increased risk in older children (≥10 yrs.) and those with high-risk ALL. The majority (90%) of thromboembolic events occurred in the Consolidation phase of therapy with concomitant asparaginase and steroids when high-risk patients (including all older patients) receive higher dose steroids. Certain inherited and acquired prothrombotic defects are known to contribute to the development of TE. German investigators documented ~50% incidence of TE during therapy with concomitant asparaginase and steroids, in children with at least one prothrombotic defect. However, current evidence regarding the role of prothrombotic defects in the development of ALL-associated TE is contradictory. Although thromboprophylaxis can prevent thromboembolism, ALL and it’s therapy can increase the risk of bleeding. For judicious use of thromboprophylaxis, identifying a population at high risk for TE is important. The risk factors, including prothrombotic defects, predisposing to thrombosis in children with ALL have not been defined. Methods This prospective, observational cohort study aims to evaluate the prevalence of inherited prothrombotic defects in children with ALL treated on DFCI 05–01 protocol and the causal relationship of prothrombotic defects in combination with patient and disease-related factors to the development of TE. We hypothesize that the combination of prothrombotic defects and the intensive therapy with concomitant high dose steroids and asparaginase increases the risk of TE in older patients and patients with high-risk ALL. Discussion The results of the proposed study will help design studies of prophylactic anticoagulant therapy. Thromboprophylaxis given to a targeted population will likely reduce the incidence of TE in children with ALL and ultimately improve their quality of life and prospects for cure.

Relapsed/refractory acute lymphoblastic leukemia (ALL) is a leading cause of death by cancer in children. Our institution has switched relapse treatment strategy to improve survival. We reviewed records of first relapse/refractory childhood ALL between 1996 and 2012. Based on length of first remission, relapse site and immunophenotype, patients were classified into two groups: standard-risk relapse (SRR) and high-risk relapse and refractory (HRRR). Before 2007, all patients were uniformly treated with the same induction as at presentation, followed by hematopoietic stem cell transplantation (HSCT). Since 2007, treatment was given according to risk of failure: SRR were mostly treated with chemotherapy; HRRR patients underwent HSCT after intensive chemotherapy, aiming reduction of pre-transplant disease burden. Sixty-four patients were included. Thirty (47%) were SRR and 34 (53%) HRRR, including 11 with refractory ALL. Five-years overall survival (OS) and event-free survival (EFS) were similar for SRR, but were significantly higher with new risk-based strategy for HRRR: 56% versus 17% (P = 0.03) for OS, and 56% vs 11% for EFS (P = 0.008), respectively. In multivariate analysis, treatment strategy was significantly associated with survival. In conclusion, change for a risk-based strategy in our institution increased survival of high-risk patients to levels similar of those of standard-risk patients.

Affect recognition has emerged as a potential mechanism underlying the social competence challenges experienced by pediatric brain tumour survivors (PBTSs). However, many social interactions were altered during the pandemic, with the widespread use of masking potentially impacting affect recognition abilities. Here, we examine affect recognition in PBTSs and typically developing youth (TD) after the onset of the global pandemic. Twenty-three PBTSs and 24 TD between 8 and 16 years old were recruited and completed two performance-based affect recognition tasks (full and partial facial features) and a self-reported questionnaire on mask exposure in their social interactions. Their parents completed parent proxy questionnaires on their child’s social adjustment and sociodemographics. The scores between the PBTSs and TD did not differ significantly in full (t(45) = 1.33, p = 0.19, d = 0.39, 95% CI [−0.69, 3.40]) or partial (t(37.36) = 1.56, p = 0.13, d = 0.46, 95% CI [−0.47, 3.60]) affect recognition, suggesting similar affect recognition between the two groups. These skills were also not significantly correlated with social adjustment or mask exposure (p > 0.05). However, the combined sample had significantly better scores in affect recognition when exposed to partial facial cues versus full. Additionally, participants obtained lower scores on a measure of full facial affect recognition and higher scores on a measure of partial affect recognition compared to pre-pandemic data. The pandemic may have influenced affect recognition across youth, underscoring the importance of further research into its lasting impact on the social competence of youth.

ABSTRACTObjectives: To understand why some long-term childhood cancer survivors experience positive adjustment in the long run,[Q1] this study aimed to (1) explore associations between well-being, health status, social support, and emotion regulation (ER) strategies in a cohort of long-term childhood lymphoblastic leukemia (cALL) survivors, (2) identify the individual contribution of each ER strategy to well-being (3) and their interaction with social support.Methods: We used data from 92 participants from the PETALE cohort (51% female, aged 24 ± 7 years). Measures included well-being (WHO-5), health status (15D), social support (SSQ-6), cognitive reappraisal and expressive suppression (ERQ), and emotional processing and expression (EAC). We modeled the odds of high well-being adjusting for health status in logistic regressions and explored the moderating role of social support with bootstrap techniques. Independent of clinical history, high well-being was associated with better health status, higher social support, more frequent use of cognitive reappraisal and emotional processing.Results: We found a main contribution of emotional processing to well-being (OR = 2.12, 95% CI = 1.09-5.37). The interaction between low suppression and high social support was significant (OR = .40, 95% CI = .13-.79). Probabilities for high well-being were 96% when expressive suppression was low and social support was high. Results suggest approaching one's own emotions may contribute to well-being in long-term childhood cancer survivors.Clinical implications: Combining curbing emotional suppression with promoting supportive social environment could be a promising target for future supportive care interventions in survivors.

Abstract Childhood acute lymphoblastic leukemia (cALL) survivors suffer early-onset chronic diseases classically associated with aging. Normal aging is accompanied by organ dysfunctions, including immunological ones. We hypothesize that thymic immunosenescence occurs in cALL survivors and that its severity may correlate with early-onset chronic diseases. The PETALE study is a cALL survivor cohort with an extensive cardiovascular and metabolic evaluation. The thymic immunosenescence biomarker, signal joint T-cell receptor excision circles (TREC), was evaluated and was highly correlated with age in healthy participants (n = 281) and cALL survivors (n = 248). We observed a systematic thymic immunoage accentuation in each cALL survivor compared to controls ranging from 5.9 to 88.3 years. The immunoage gain was independent of age at diagnosis and treatment modalities and was more severe for females. Thymic aging was associated with several pathophysiological parameters, was greater in survivors suffering from metabolic syndrome, but there was no significant association with global physical condition. The decrease in TREC was independent from blood cell counts, which were normal, suggesting a segmental aging of the thymic compartment. Indeed, increased plasmatic T cell regulatory cytokines IL-6, IL-7 and GM-CSF accompanied high immunoage gain. Our data reveal that cALL or its treatment trigger a rapid immunoage gain followed by further gradual thymic immunosenescence, similar to normal aging. This leads to an enduring shift in accentuated immunoage compared to chronological age. Thus, accentuated thymic immunosenescence is a hallmark of cALL survivorship and TREC levels could be useful immunosenescence biomarkers to help monitoring the health of cancer survivors.

Abstract Background Pediatric brain tumor survivors (PBTS) are at risk of physical, cognitive, and psychosocial challenges related to their diagnosis and treatment. Routine follow-up care as adults is therefore essential to their long-term health and quality of life. In order to successfully navigate to adult healthcare, it is recommended that youth develop transition readiness skills. Existing transition readiness interventions often focus on disease management. However, PBTS are also at risk of social competence and cognitive functioning challenges. In this paper, we describe the protocol of this pilot study and the methodology that will be used for the evaluation of the feasibility, acceptability, and preliminary efficacy testing of the first targeted transition intervention workshops specifically designed to meet the needs of PBTS and their caregivers. Methods This study will use a mixed method to evaluate three 1 ½-h workshops targeted for dyads (N = 40) of PBTS (14 years or older) and their parents. Dyads will be recruited via a community pediatric cancer organization and the long-term follow-up clinic of a large pediatric hospital. Participants will complete an online survey which includes the Transition Readiness Assessment Questionnaire (TRAQ) before and after the workshops. Each workshop will cover a specific topic related to PBTS transition readiness: disease management, social competence, and cognitive functioning. Workshops will follow the same structure: topic presentation, discussion by a post-transfer survivor or parent, teaching two strategies, and workshop evaluation. Workshops will be co-led by healthcare specialists and patient partners. Feasibility and acceptability will be assessed via recruitment, attendance, retention, and Likert scales, and they will be analyzed by describing and comparing rates. Satisfaction will be measured using satisfaction surveys and audio-recorded focus groups. Qualitative data will be described through thematic content analysis. In order to test the preliminary efficacy of this study, we will compare transition readiness skills pre- and post-workshops using paired samples T test and ANCOVA to examine the impact of workshop on TRAQ skills. Discussion Results of the study will inform refinement and future broader implementation of targeted transition readiness workshops for the specific needs of pediatric brain tumor survivors.

A 2.5-month-old girl admitted for failure to thrive and severe pancytopenia was diagnosed with methylmalonic acidemia (MMA) secondary to transcobalamin II deficiency, an inborn error of vitamin B12 metabolism. Opportunistic Cytomegalovirus and Pneumocystis jirovecii pneumonia led to severe acute respiratory distress syndrome (ARDS) and immune reconstitution inflammatory syndrome (IRIS) after treatment initiation with vitamin B12 supplementation. In children with interstitial pneumonia-related ARDS, normal lymphocyte count should not delay invasive procedures required to document opportunistic infections. MMA can be associated with underlying lymphocyte dysfunction and vitamin B12 supplementation can fully reverse the associated immunodeficiency. IRIS may appear in highly treatment-responsive forms of pancytopenia in children and prompt treatment of dysregulated inflammation with high-dose corticosteroids should be initiated.

Abstract Background Long-term childhood cancer survivors (CCS) are at high risk of having dyslipidemia including low high density lipoprotein cholesterol (HDL-C). However, little is known about the prevalence of low HDL-C and the impact of therapy exposure on HDL composition early after treatment is terminated. Methods This associative study included 50 children and adolescents who had completed their cancer treatments (

Abstract Verbal fluency (VF) is a heterogeneous cognitive function that requires executive as well as language abilities. The purpose of this study was to elucidate the specificity of the resting state MEG correlates of the executive and language components. To this end, we administered a VF test, another verbal test (Vocabulary), and another executive test (Trail Making Test), and we recorded 5-min eyes-open resting-state MEG data in 28 healthy participants. We used source-reconstructed spectral power estimates to compute correlation/anticorrelation MEG clusters with the performance at each test, as well as with the advantage in performance between tests, across individuals using cluster-level statistics in the standard frequency bands. By obtaining conjunction clusters between verbal fluency scores and factor loading obtained for verbal fluency and each of the two other tests, we showed a core of slow clusters (delta to beta) localized in the right hemisphere, in adjacent parts of the premotor, pre-central and post-central cortex in the mid-lateral regions related to executive monitoring. We also found slow parietal clusters bilaterally and a cluster in the gamma 2 and 3 bands in the left inferior frontal gyrus likely associated with phonological processing involved in verbal fluency.

Introduction A healthy lifestyle could have a positive impact in reducing the incidence of some long-term sequelae secondary to pediatric cancer treatments. Motivational communication (MC) is effective at improving healthy lifestyle habits, especially when patients experience change as a challenge. To date, there is no available intervention program using MC that promotes healthy lifestyles in pediatric oncology. Objectives The aim of this study was to develop the first MC training program for professionals in pediatric oncology and assess its feasibility and acceptability. Materials and methods Following standard procedures involving professionals, we developed a professional-targeted training named the Motivation Cafés, consisting in six sessions of core MC skills for healthcare professionals who wish to positively impact lifestyles of families in pediatric oncology. We used a mixed-methods quantitative-qualitative study to assess the program feasibility and acceptability. Professionals in nutrition and physical activity (N = 16) attended two rounds of the training and completed surveys to evaluate the training. They reported self-efficacy and knowledge in MC. Participation and retention rates were used to assess acceptability and feasibility, and a thematic analysis of the open-ended questions was performed to identify strengths and weaknesses of the program to further refine the program. We used non-parametric statistics to compare pre-post changes on measures of self-efficacy and knowledge in MC. Results Attendance and retention (average 4.2/6 sessions completed) were high, suggesting very good adherence and feasibility. We also found high levels of acceptability and pertinence of the program (i.e. >90%). The results suggested probable improvements in self-efficacy and knowledge, but these were not statistically significant given the limited sample size. Conclusion The training Motivation Cafés is now ready to be pilot tested in pediatric cancer care centers.

Purpose The Health state descriptive system includes standardized self-administered instruments for measuring Health-Related Quality of Life (HRQoL) respectively among adolescents, and children. The objectives of the current study were: (1) to translate and adapt the pediatric-adolescent version 16D and 17D from English into French (Canada), (2) to demonstrate their feasibility in pediatric conditions. Methods The translation methodology combined forward and back translations, and cognitive debriefing with eight adolescents and eight children. Four bilingual translators were involved in the process. We administered the translated versions to two clinical samples, being treated for Primary immunodeficiency (PID, n = 48, aged 14.1 years, 20 girls), and having recovered from pediatric Acute Lymphoblastic Leukemia (ALL, n = 153, aged 14.7 years, 77 girls). Results Cognitive debriefing indicated that that the instructions, items, and response options were clear, easy to understand, and easy to answer. Adjustments were made for clarity. Translated versions were highly usable (measurement completion >90%). HRQoL levels were high for both samples (range 0.85–0.96). Participants reported lower levels if they were adolescents, particularly if they were girls. Older boys with PID reported a lower HRQoL than their counterparts with a history of ALL. PID and ALL patients mainly reported issues with discomfort and pain, concentration/learning, physical appearance, and psychological distress and sleeping, although to a different degree. Conclusion The French-language versions of the 16D and 17D are easy to administer and may be used to identify problematic domains. Greater availability of translated versions of short evaluation tools may facilitate broader uptake of screening practices in pediatric care.

Abstract Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity [adjusted OR = 15.7; 95% CI (6.2–39.7)], insulin resistance [20.6 (5.2–82.1)] and the metabolic syndrome [11.2 (2.6–48.7)]. Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity [3.37 (1.6–7.1) and 2.34 (1.3–4.2), respectively] whereas high C-reactive protein levels were associated with insulin resistance [3.3 (1.6–6.8)], dyslipidemia [2.6 (1.4–4.9)] and MetS [6.5 (2.4–17.9)]. Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.

Pediatric cancer survivors may experience cardiometabolic sequelae over the course of their lives as a result of the treatments they have received. While nutrition consists of an actionable target for cardiometabolic health, few nutritional interventions have been documented in this population. This study assessed the changes in diet during a one-year nutritional intervention for children and adolescents undergoing cancer treatments and the participants’ anthropometric and cardiometabolic profiles. A total of 36 children and adolescents (mean age: 7.9 years, 52.8% male) newly diagnosed with cancer (50% leukemia) and their parents underwent a one-year individualized nutrition intervention. The mean number of follow-up visits with the dietitian during the intervention was 4.72 ± 1.06. Between the initial and one-year assessments, there was an improvement in diet quality reflected by the Diet Quality Index (5.22 ± 9.95, p = 0.003). Similarly, the proportion of participants with moderate and good adherence (vs. low adherence) to the Healthy Diet Index score almost tripled after one year of intervention (14% vs. 39%, p = 0.012). In parallel, there was an increase in the mean z-scores for weight (0.29 ± 0.70, p = 0.019) and BMI (0.50 ± 0.88, p = 0.002), and in the mean levels of HDL-C (0.27 ± 0.37 mmol/L, p = 0.002) and 25-hydroxy vitamin D (14.5 ± 28.1 mmol/L, p = 0.03). Overall, this study supports that a one-year nutritional intervention deployed early after a pediatric cancer diagnosis is associated with an improvement in the diets of children and adolescents.

Abstract Background Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer. Over the past decades, treatment of cALL has significantly improved, with cure rates close to 90%. However intensive chemotherapy and cranial radiotherapy (CRT) during a critical period of a child’s development have been shown to lead to significant long-term side effects including cardiometabolic complications. Using the PETALE (Prévenir les effets tardifs des traitements de la leucémie aiguë lymphoblastique chez l’enfant) cALL survivor cohort, we investigated the association between combined cumulative corticosteroids (CS) doses and CRT exposures and obesity, insulin resistance, (pre-)hypertension, and dyslipidemia jointly. Methods A Bayesian multivariate latent-t model which accounted for our correlated binary outcomes was used for the analyses (n = 241 survivors). CS doses were categorized as low (LD) or high (HD). Combined exposure levels investigated were: 1) LD/no CRT; 2) LD/CRT, and; 3) HD/CRT. We also performed complementary sensitivity analyses for covariate adjustment. Results Prevalence of cardiometabolic complications ranged from 12.0% for (pre-)hypertension to 40.2% for dyslipidemia. The fully adjusted odds ratio (OR) for dyslipidemia associated with LD/CRT (vs. LD/No CRT) was OR = 1.98 (95% credible interval (CrI): 1.02 to 3.88). LD/CRT level also led to a 0.15 (95% CrI: 0.00 to 0.29) excess risk to develop at least one cardiometabolic complication. Except for obesity, adjusted results for the highest exposure category HD/CRT were generally similar to those for LD/CRT albeit not statistically significant. White blood cell count at diagnosis, a proxy for cALL burden at diagnosis, was found associated with insulin resistance (OR = 1.08 for a 10-unit increase (× 109/L), 95% CrI: 1.02 to 1.14). Conclusions Our results indicated that combined LD/CRT exposure is a likely determinant of dyslipidemia among cALL survivors. No evidence was found to suggest that high doses of CS lead to additional risk for obesity, insulin resistance, (pre-)hypertension, and dyslipidemia beyond that induced by CRT. The multivariate model selected for analyses was judged globally useful to assess potential exposure-related concomitance of binary outcomes.

Abstract Background Studies have shown that supporting parents in pediatric oncology reduces family distress following a cancer diagnosis. Manualized programs for parents have therefore been developed to reduce family distress. However, these programs have limitations that need to be improved, such as better defining programs’ procedures, developing interventions focusing on parents’ conjugal relationship, conducting rigorous evaluations of implementation, and proposing adaptations to various cultural dimensions. According to the Obesity-Related Behavioral Intervention Trials (ORBIT) model for the development of behavioral intervention, we improved these limitations and developed TAKING BACK CONTROL TOGETHER, a six in-person intervention sessions to support parents of children with cancer by taking the active components of two programs: Bright IDEAS and SCCIP. Referring to the redesign phase of the ORBIT model, this study aims to refine the definition of this program’s design by interviewing parents and healthcare professionals. Methods In order to refine the program, we used a sequential mixed-methods study. Parents and healthcare professionals first completed questionnaires assessing the program, and then discussed its limitations, benefits, and areas for improvement in group and/or individual interviews. We performed a descriptive thematic content analysis of the qualitative data from the open-ended questions (questionnaires and interviews) with NVivo 11 to categorize recommendations for the program refinement. Results The results showed that components seemed pertinent to final users. The main areas needing improvement were the level of complexity and understandability of the parent manual, the possibility to choose the place and time of the intervention, and the lack of ethnic/cultural diversity. Changes to the program were made accordingly. Conclusions It is necessary to include end-users when developing complex intervention programs designed for vulnerable populations and sensitive clinical contexts. Following the present refinement, we now have a treatment package, which is safe and acceptable for the target population and has a better chance of yielding a clinically significant benefit for users in a future pilot study.

Treatments for adolescent cancer can cause debilitating side effects in the short- and long-term such as nausea and malnutrition but also cardiometabolic disturbances. Although the risk for cardiometabolic complications is greater for adolescents with cancer than younger ones, adolescents typically respond poorly to family-oriented health promotion programs. This study aims to assess the needs, barriers and facilitators to healthy lifestyle promotion interventions for adolescents with cancer and how to best adapt these interventions for them. Interviews were held with adolescents treated for cancer (n = 9) and parents (n = 6), focus groups were conducted with stakeholders working in oncology (n = 12) and self-report questionnaires were sent to stakeholders involved in a health promotion intervention (n = 6). At the time of interview, mean age of adolescent participants (40% female) was 17.0 ± 1.9 years (mean age at diagnosis: 14.6 ± 1.6 years). Verbatim and responses to questionnaires were coded and analyzed using qualitative methods. Stakeholder stated that adolescents with cancer need to access activities adapted to their age, to communicate with peers going through a similar experience, and to preserve their schooling and friendships. Barriers to intervention reported by adolescents, parents and stakeholders include lack of motivation, schedule conflicts, fatigue and treatment side effects. Some of the barriers mentioned by adolescents and parents include pain, post-surgery problems, school, physical deconditioning, and lack of time. Facilitators mentioned by adolescents and parents comprise trust in stakeholders’ expertise, personalized approaches, scheduling flexibility. Stakeholders recommended to build trust in the relationship, favoring non-moralizing teachings, adapt interventions to adolescents’ limited attention span and avoiding the use of long-term health benefits as a motivator.

BackgroundAcute lymphoblastic leukemia is the most common type of pediatric cancer. Acute lymphoblastic leukemia causes an altered bone mineral homeostasis state, which can contribute to osteopenia, and bone fractures, most commonly vertebral fractures. With the increasing number of childhood cancer survivors, late adverse effects such as musculoskeletal comorbidities are often reported and are further influenced by inactive lifestyle habits. Physical activity has been shown to increase the mechanical workload of the bone, mitigating bone impairment in other cancer-specific populations. ObjectiveThis interventional pilot study aims to investigate the use of telehealth to deliver a home-based exercise intervention for early-on survivors of bone marrow–related hematological malignancies and to assess its impact on survivors’ musculoskeletal and functional health. MethodsWe aimed to recruit a group of 12 early-on survivors of acute lymphoblastic leukemia, within 6 months to 5 years of treatment, to participate in and complete the proposed telehealth intervention with a parent. The 16-week intervention included 40 potential home-based physical activity interventions supervised by a kinesiologist through a telehealth internet platform, with monthly progression. Patients were recruited to the cohort if they were able to participate in the intervention during the first month (minimum 12 weeks of intervention). Evaluation before and after the intervention protocol highlighted differences in functional capacities and musculoskeletal health of patients using mechanography, peripheral quantitative computed tomography, 6-minute walk test, and grip force test. ResultsThe recruitment rate for the intervention was low (12/57, 21% of contacted patients). Of 12 patients, 3 were excluded (1=relapse, 1=failure to meet technical requirements, and 1=abandoned). The 9 patients who completed the intervention (6 girls; mean age 10.93, SD 2.83 years; mean BMI 21.58, SD 6.55 kg/m2; mean time since treatment completion 36.67, SD 16.37 months) had a mean adherence of 89% and a completion rate of 75%. In addition, these patients showed functional improvements in lower limb muscle force and power as well as in the 6-minute walk test distance. Participants also showed improved bone health after the intervention on the following parameters: bone mineral content, stress-strain index, total and cortical cross-sectional area at the 14% site (P=.03, P=.01, P=.01, and P=.001, respectively) and 38% site of the tibia (P=.003, P=.04, P=.001, and P=.003, respectively). ConclusionsHigh adherence and participation rates suggest that telehealth is a feasible method to deliver exercise interventions to young early-on survivors of acute lymphoblastic leukemia. The proposed intervention seems promising in providing benefits to patients’ functional performance and bone health, but a large-scale study is needed to confirm this assumption.

Parental distress is a major issue in pediatric oncology. The literature shows that intervention programs aimed at supporting parents are effective in reducing parental distress following their child’s cancer diagnosis. However, most programs bear limitations, most often related to their focus on the individual (rather than the family), and their dissemination possibilities. TAKING BACK CONTROL TOGETHER is an integrative program which was developed to respond to these limitations and take the best of effective existing components. In line with development standards from behavioral medicine (ORBIT model), this 6-sessions program aims to reduce parental distress by reinforcing both Problem Solving Skills Techniques (PSST) in 4 individual sessions and communication within the couple and dyadic coping in 2 sessions with the parent couple. The program was first developed in French-language and is now being adapted in English. Because the program addresses both individual PSST and dyadic coping, it is expected to yield more benefits for parents than existing interventions. After this first phase of definition, the program should be pre-tested for refinement, and pilot-tested. This article aims to present the definition of this program, including handbooks for caregivers and parents, as well as worksheets and electronic resources.

Abstract Background Survivors of childhood acute lymphoblastic leukemia (cALL) experience cardiometabolic and bone complications after treatments. This study aimed at developing and validating an interview-administrated food frequency questionnaire (FFQ) that will serve to estimate the impact of nutrition in the development of long-term sequalea of French-Canadian cALL survivors. Methods The FFQ was developed to assess habitual diet, Mediterranean diet score, nutrients promoting bone health and antioxidants. It was validated using a 3-day food record (3-DFR) in 80 cALL survivors (50% male) aged between 11.4 and 40.1 years (median of 18.0 years). Reproducibility was evaluated by comparing FFQs from visit 1 and 2 in 29 cALL survivors. Results When compared to 3-DFR, the mean values for macro- and micronutrient intake were overestimated by our FFQ with the exception of lipid-related nutrients. Correlations between nutrient intakes derived from the FFQs and the 3-DFRs showed moderate to very good correlations (0.46–0.74). Intraclass correlation coefficients assessing FFQ reproducibility ranged from 0.62 to 0.92, indicating moderate to good reliability. Furthermore, classification into quartiles showed more than 75% of macro- and micronutrients derived from FFQs 1 and 2 classified into the same or adjacent quartile. Conclusions Overall, our results support the reproducibility and accuracy of the developed FFQ to appropriately classify individuals according to their dietary intake. This validated tool will be valuable for future studies analyzing the impact of nutrition on cardiometabolic and bone complications in French-speaking populations.

Abstract Background While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context. Methods In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models. Results Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p

Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully understood. This study aimed to characterize the plasma lipid profile, Apo distribution, and lipoprotein composition of 80 childhood ALL survivors compared with 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma triglyceride (TG) and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol, and phospholipid moieties, but less protein. Differences in Apo content were found between ALL survivors and controls for all lipoprotein fractions except HDL3. HDL2, especially, showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III1 content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors, while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders.

BackgroundA substantial number of survivors of childhood acute lymphoblastic leukemia suffer from treatment-related late adverse effects including neurocognitive impairment. While multiple studies have described neurocognitive outcomes in childhood acute lymphoblastic leukemia (ALL) survivors, relatively few have investigated their association with individual genetic constitution.MethodsTo further address this issue, genetic variants located in 99 genes relevant to the effects of anticancer drugs and in 360 genes implicated in nervous system function and predicted to affect protein function, were pooled from whole exome sequencing data of childhood ALL survivors (PETALE cohort) and analyzed for an association with neurocognitive complications, as well as with anxiety and depression. Variants that sustained correction for multiple testing were genotyped in entire cohort (n = 236) and analyzed with same outcomes.ResultsCommon variants in MTR, PPARA, ABCC3, CALML5, CACNB2 and PCDHB10 genes were associated with deficits in neurocognitive tests performance, whereas a variant in SLCO1B1 and EPHA5 genes was associated with anxiety and depression. Majority of associations were modulated by intensity of treatment. Associated variants were further analyzed in an independent SJLIFE cohort of 545 ALL survivors. Two variants, rs1805087 in methionine synthase, MTR and rs58225473 in voltage-dependent calcium channel protein encoding gene, CACNB2 are of particular interest, since associations of borderline significance were found in replication cohort and remain significant in combined discovery and replication groups (OR = 1.5, 95% CI, 1-2.3; p = 0.04 and; OR = 3.7, 95% CI, 1.25-11; p = 0.01, respectively). Variant rs4149056 in SLCO1B1 gene also deserves further attention since previously shown to affect methotrexate clearance and short-term toxicity in ALL patients.ConclusionsCurrent findings can help understanding of the influence of genetic component on long-term neurocognitive impairment. Further studies are needed to confirm whether identified variants may be useful in identifying survivors at increased risk of these complications.

OBJECTIVES:Follow-up studies suggest that the psychosocial impact of pediatric cancer on parents often extends beyond the end of their child's cancer treatments, and parents can continue to experience both individual and relationship effects. In a long-term study of parents of children who were treated for acute lymphoblastic leukemia (ALL), we aimed to: 1) describe parents' adjustment (psychological distress, relationship satisfaction; 2) describe the perceived impact of cancer on couples' relationship, and; 3) identify to what extent the perceived impact of cancer on the couple is related to both parents' long-term adjustment. METHODS:Parents of childhood ALL survivors (n = 103 couples) were surveyed as part of a cohort recall (PETALE cohort). Both parents completed questionnaires exploring adjustment (Brief Symptom Inventory-18, Dyadic Adjustment Scale) and perceived impact of cancer on the relationship (Impact of Cancer on the Couple). Mothers' and fathers' scores were compared using MANOVAs. We also examined the degree to which a parent's perceived changes in relationship dynamics following their child's cancer were associated with their own current adjustment (actor effects), and their partner's current adjustment (partner effects) using the Actor-Partner Interdependence Model (APIM). RESULTS:Frequencies of current distress were normative in parents (mothers/fathers): general distress (6.8/7.8%), anxiety (5.8/6.8%), depression (2.9/6.8%), somatization (13.6/9.7%), and relationship distress (21.4/20.4%). Mothers and fathers typically agreed on their reported relationship satisfaction, and the perceived nature of relationship changes following the illness. Dyadic analyses indicated that whereas mothers' adjustment was related to their own perceived relationship changes, fathers' adjustment was primarily related to their partner's perceptions. CONCLUSION:In long-term stable couples, mothers may act as an influential bridge connecting the illness experiences of survivors and fathers. This could explain why mothers' perceptions of relationship changes were related to their partners' long-term adjustment, which was not the case for fathers.

The introduction of multiagent treatment protocols has led to a remarkable increase in survival rates for children diagnosed with acute lymphoblastic leukemia, yet for a subpopulation of patients, resistance to chemotherapeutics remains an obstacle to successful treatment. Here we investigate the role of the mitochondrial (or intrinsic) apoptosis pathway in modulating the onset and outcomes of childhood acute lymphoblastic leukemia. Cell death is a highly regulated process that plays an essential role in regulating cell homeostasis, particularly in tissues with high intrinsic proliferating capacity such as the hematopoietic system. Following the underlying paradigm that cis-acting genetic variation can influence disease risk and outcomes by modulating gene expression, we performed a systematic analysis of the proximal promoter regions of 21 genes involved in apoptosis. Using gene reporter assays, we show that promoter variations in 11 intrinsic apoptosis genes, including ADPRT, APAF1, BCL2, BAD, BID, MCL1, BIRC4, BCL2L1, ENDOG, YWHAB, and YWHAQ, influence promoter activity in an allele-specific manner. We also show that correlated promoter variation and increased expression of MCL1 is associated with reduced overall survival among high-risk patients receiving higher doses of corticosteroid, suggesting that increased expression of this anti-apoptosis gene could lead to reduced cell death and influence treatment response in a disease- and dose-responsive manner.