The impact of comparative genomic hybridization/single-nucleotide polymorphism microarray in risk stratification of pediatric acute lymphoblastic leukemia.

BACKGROUND: The objective of this study is to assess the concordance and added value of combined comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH/SNP) analyses in pediatric acute lymphoblastic leukemia (ALL) risk stratification compared to conventional cytogenetic methods. PROCEDURE: This is a retrospective study that included patients aged 1-18 years diagnosed with de novo ALL at Sainte-Justine Hospital between 2016 and 2021. Results from conventional cytogenetic and molecular analyses were collected and compared to those of CGH/SNP. RESULTS: A total of 135 ALL patients were included. Sample failures or non-diagnostic analyses occurred in 17.8% cases with G-banding karyotypes versus 1.5% cases with CGH/SNP. The mean turnaround time for results was significantly faster for CGH/SNP than karyotype with 5.8 versus 10.7 days, respectively. The comparison of ploidy assessment by CGH/SNP and G-banding karyotype showed strong concordance (r = .82, p < .001, r2 = .68). Furthermore, G-banding karyotype did not detect additional clinically relevant aberrations that were missed by the combined analysis of CGH/SNP and fluorescence in situ hybridization. The most common gene alterations detected by CGH/SNP were deletions involving CDKN2A (35.8%), ETV6 (31.3%), CDKN2B (28.4%), PAX5 (20.1%), IKZF1 (12.7%), and copy-neutral loss of heterozygosity (CN-LOH) of 9p (9.0%). Among these, only ETV6 deletion was found to have a significant prognostic impact with superior event-free survival in both univariate and multivariate analyses (adjusted hazard ratio 0.08, 95% confidence interval: 0.01-0.50, p = .02). CONCLUSION: CGH/SNP provided faster, reliable, and highly concordant results than those obtained by conventional cytogenetics. CGH/SNP identified recurrent gene deletions in pediatric ALL, of which ETV6 deletion conferred a favorable prognosis.

Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship.

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.

Predictors of low and very low bone mineral density in long-term childhood acute lymphoblastic leukemia survivors: Toward personalized risk prediction.

BACKGROUND: Cohorts of childhood acute lymphoblastic leukemia (cALL) survivors reaching adulthood are increasing. Approximately 30% of survivors meet criteria for low bone mineral density (BMD) 10 years after diagnosis. We investigated risk factors for low BMD in long-term cALL survivors. METHODS: We recruited 245 cALL survivors from the PETALE (Prévenir les effets tardifs des traitements de la leucémie aiguë lymphoblastique chez l'enfant) cohort, who were treated with the Dana Farber Cancer Institute protocols, did not experience disease relapse or hematopoietic stem cell transplants, and presented with more than 5 years of event-free survival. Median time since diagnosis was 15.1 years. RESULTS: Prevalence of low DXA-derived BMD (Z-score ≤-1) ranged between 21.9% and 25.3%, depending on site (lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and between 3.7% and 5.8% for very low BMD (Z-score ≤-2). Males had a higher prevalence of low BMD than females for all three outcomes (26%-32% vs. 18%-21%), and male sex acted as a significant risk factor for low BMD in all models. Treatment-related factors such as cumulative glucocorticoid (GC) doses and cranial radiation therapy (CRT) were associated with lower BMDs in the full cohort and in females at the FN-BMD site. CONCLUSION: Low and very low BMD is more prevalent in male cALL survivors. Male sex, high cumulative GC doses, CRT, risk group, and low body mass index (BMI) were identified as risk factors for low BMD. A longer follow-up of BMD through time in these survivors is needed to establish if low BMD will translate into a higher risk for fragility fractures through adulthood.

Physical impairments, activity limitations, and participation restrictions of childhood acute lymphoblastic leukemia survivors with and without hip osteonecrosis: a PETALE cohort study.

PURPOSE: Long-term musculoskeletal complications represent a growing burden for survivors of childhood acute lymphoblastic leukemia (cALL). This study aimed to describe physical impairments, activity limitations, and participation restrictions in a high-risk subgroup of cALL survivors of the PETALE cohort. METHODS: This cross-sectional study, using observational data from the PETALE cohort, included a subgroup of survivors who presented high-risk criteria for late effects. Outcomes measures consisted of hip magnetic resonance imaging, maximal isometric muscle strength (MIMS) or torque (MIMT), range of motion (ROM), Near Tandem Balance (NTB), 6-Minute Walk Test (6MWT), Five Time Sit-to-Stand Test (FTSST), and health-related quality of life. Descriptive statistics and regression analyses were performed. RESULTS: Survivors (n = 97, 24.2 ± 6.7 years old) showed limited grip strength, FTSST, and NTB performance compared to reference values (p < 0.001). Thirteen participants (14.6%, 18 hips) had hip osteonecrosis (ON) (53.8% male). Higher severity hip ON was found in female survivors (66.7% vs. 22.2%). Survivors with hip ON had reduced hip external rotation ROM compared to those without (p < 0.05). Relationships were found between MIMS and ROM outcomes (r = 0.32, p < 0.01) and with 6MWT (r = 0.39-0.41, p < 0.001). Our multiple linear regression model explained 27.6% of the variance of the 6MWT. CONCLUSIONS: Survivors in our subgroup had clinically significant physical impairments and activity limitations, and those with hip ON showed worst hip impairment outcomes. IMPLICATIONS FOR CANCER SURVIVORS: These findings emphasize the importance of long-term follow-up including physical therapy assessment to help early identification and management of physical impairments and activity limitations in survivors of cALL.

Novel variant in Nudix hydrolase 15 gene influences 6-mercaptopurine toxicity in childhood acute lymphoblastic leukemia patients.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. 6-Mercaptopurine (6-MP) is a key component of ALL treatment. Its use, however, is also associated with adverse drug reactions, particularly myelosuppression. Thiopurine S-methyltransferase (TPMT) and, more recently, Nudix hydrolase 15 (NUDT15) deficiency, due to no-function variants in their respective genes, are well known for their role in the development of this toxicity. Two novel genetic variants, rs12199316 in TPMT and rs73189762 in the NUDT15 gene, were recently identified by targeted sequencing. The latter is particularly interesting because of its potential association with 6-MP intolerance. Here, we assessed the relationship of this variant with the risk of myelosuppression and 6-MP dose intensity in 275 patients treated with Dana Farber Cancer Institute ALL protocols at the Sainte Justine University Health Center. Carriers of the NUDT15 rs73189762 variant allele were at a higher risk of myelosuppression, as shown by absolute phagocyte count reduction during consolidation II and maintenance phases of therapy. Reduction in 6-MP dose intensity was observed in patients with both rs73189762 and known no-function variants in the NUDT15 and TPMT genes. This finding supports the initial observation and suggests that 6-MP dose reduction might be beneficial for individuals with this genotype combination.

Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.

QTc intervals at rest and during exercise assessed by group correction formulas in survivors of childhood acute lymphoblastic leukemia.

INTRODUCTION: Early signs of subclinical cardiac damage must be identified before they turn into clinical manifestations. Tailoring a formula is relevant for precise QTc evaluation in childhood acute lymphoblastic leukemia (ALL) survivors considering they are at risk of long-term cardiac problems. Therefore, we aim to develop group heart rate correction formulas for QT intervals in childhood ALL survivors at rest and during exercise, and to assess the applicability of these methods across a variety of risk groups exposed to diverse chemotherapy dosages. METHODS: Two hundred and fifty childhood ALL survivors in the PETALE study were classified into 3 groups depending on their prognostic risk group. ECG measurements (QT and RR intervals) were made at rest and during a cardiopulmonary exercise test. QT correction for heart rate was applied using 5 different formulas, which included 2 previously published formulas and 3 group-specific formulas for each sex. RESULTS: The QT/RR relation showed 2 different curves between rest and during exercise, which was worse for females. Group-specific QTc formulas allowed adequate heart rate-corrected QT interval, independently of the cumulative dose of doxorubicin received during treatment. Group-specific formulas showed significantly shorter QTc intervals than QTc from Bazett's formula. QTc (Bazett's formula) values surpassed the established clinical norm in 22 males (11%) and 22 females (11%), with a majority occurring during exercise, affecting 15 males (7.5%) and 10 females (5%). CONCLUSION: This study shows the applicability of personalized group correction of QT/RR data in childhood ALL survivors. Our comprehensive assessments (spanning rest, exercise, and recovery) is an effective approach for risk stratification of cardiac complications in childhood ALL survivors.

Contributing factors to well-being in a sample of long-term survivors of childhood acute lymphoblastic leukemia: the role of social support in emotional regulation.

Objectives: 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.

Protocol for evaluation of the feasibility and preliminary efficacy of a targeted transition readiness workshop intervention for pediatric brain tumor survivors.

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.

Transition Readiness Assessment Questionnaire: Skill gaps and psychosocial predictors of transition readiness among adolescents and young adults with chronic medical conditions.

BACKGROUND: Transferring from paediatric to adult care can be challenging. Adolescents and young adults (AYAs) with chronic health conditions need to develop a specific set of skills to ensure lifelong medical follow-up due to the chronicity of their condition. The Transition Readiness Assessment Questionnaire-French version (TRAQ-FR) is a 19-item questionnaire measuring such skills. The aims of the study were to (1) describe participant characteristics and (2) identify constructs related to, and predictors of, having learned domain-specific transition readiness skills. METHODS: Participants included 216 AYAs aged 14-20 years (M = 15.93; SD = 1.35; 54.1% male) recruited from five outpatient clinics in a Canadian tertiary hospital. AYAs completed the TRAQ-FR, the Pediatric Quality of Life Inventory 4.0 (PedsQL) and a sociodemographic questionnaire. Descriptive, bivariate and binary logistic regression analyses were conducted. RESULTS: Overall, participants reported significantly higher scores on the Talking with Providers, Managing Daily Activities and Managing Medications subscales than on the Appointment Keeping and Tracking Health Issues subscales (F[41075] = 168.970, p < .001). At the item level, median scores (on a 5-point Likert scale) suggest that AYAs had begun practising five of the 19 skills (median scores ≥4; 'Yes, I have started doing this'), while a median score of 1 ('No, I don't know how') was found for one item ('Do you get financial help with school or work?'). At the subscale level, TRAQ-FR skills and skill gaps were related to AYAs' age, sex and PedsQL scores (ps < .05). CONCLUSION: Older and female AYAs were more likely to have begun practising specific TRAQ-FR subscale skills. Better psychosocial functioning was also related to having learned specific transition readiness skills. AYAs show several gaps in transition readiness. Targeted intervention in transition readiness skill development could take into account AYAs' age, sex and psychosocial functioning for a successful transfer to adult care.

Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children.

PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.

Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.

BACKGROUND: An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors. METHODS: We analyzed associations of neurocognitive deficits, as well as anxiety and depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors. RESULTS: Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5. CONCLUSIONS: Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications. IMPACT: Our results suggest that specific genes may be related to increased neuropsychological consequences.

Prevalence, Severity, and Description of Dental Anomalies in Children Treated for Acute Lymphoblastic Leukemia.

Purpose: To assess the prevalence and severity of and describe dental anomalies in children treated for acute lymphoblastic leukemia (ALL) under recent Dana-Farber Cancer Institute (DFCI) protocols. Methods: Patients aged between 14 and 25 years old having received a diag- nosis of ALL before the age of 11 years and after September 2000 received clinical and radiographic oral examinations. Results: Dental anomalies were observed in 26 (51.0 percent) of 51 subjects. Microdontia was the most prevalent dental defect (39.2 percent). Impacted permanent second molars were observed in five (9.8 percent) patients. Being age five years or younger at diagnosis significantly increased the prevalence and severity of dental anomalies (P<0.001). Conclusions: Recent DFCI protocols showed a decreased prevalence of dental disturbances. The anomalies observed may still alter the development of the dental arches and occlusion in pediatric ALL survivors. Further research is needed to confirm the association between ALL treatment and permanent second molar impaction.

Echocardiographic Parameters Associated With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Children's exposure to chemotherapeutic agents causes several long-term adverse effects but physical activity has been evidenced to be an effective strategy to improve cardiac function. This cross-sectional study aimed to explore the association between physical activity levels, cardiorespiratory fitness, and cardiac parameters measured by echocardiography. METHODS: Participants were 216n childhood acute lymphoblastic leukemia survivors who underwent a maximal cardiopulmonary exercise test and self-reported their daily minutes of moderate to vigorous physical activity. They underwent a complete transthoracic echocardiographic assessment. Systolic and diastolic function analysis and strain images analysis were performed. The associations were studied through the preventive fraction (examined with univariate crude and adjusted logistic regression models) of regular physical activity (≥150 min·wk-1) and adequate cardiorespiratory fitness levels (above the median ≥ 32.0 mL·kg-1·min-1) on cardiac parameters. RESULTS: Crude analysis shows that regular physical activity was associated with a significant preventive fraction in mitral E/A ratio (56%; P = .013), while adjusted analyses highlighted a nonsignificant reduction of 74% to 37% in the prevalence of cardiac parameters associated with physical activity. Similar associations of adequate cardiorespiratory fitness on cardiac parameters were observed. Adjusted analyses revealed a nonsignificant reduction of 7% to 86% in the prevalence of cardiac parameters associated with cardiorespiratory fitness. CONCLUSION: This study reports that regular physical activity and adequate cardiorespiratory fitness were associated with a higher preventive fraction. Thus, engaging in physical activity prevents childhood acute lymphoblastic leukemia survivors' cardiac dysfunctions. These findings are novel and clinically relevant in pediatric cardiooncology and provide additional evidence to strengthen the benefits of exercise as long-term care in childhood cancer survivors.

Relationship between cardiac mechanical properties and cardiac magnetic resonance imaging at rest in childhood acute lymphoblastic leukemia survivors.

The characterization of cardiac mechanical properties may contribute to better understanding of doxorubicin-induced cardiotoxicity. Our study aims to investigate the relationship between cardiac mechanical properties, T1 and T2 relaxation times and partition coefficient. Fifty childhood acute lymphoblastic leukemia survivors underwent a cardiac magnetic resonance (CMR) at rest on a 3T MRI system and included a standard ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Partition coefficient, ejection fraction, end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. CircAdapt model was used to study cardiac mechanical performance (left ventricle stiffness (LVS), contractility (LVC) and pressure (Pmin and Pmax), cardiac work efficiency (CWE) and ventricular arterial coupling). In the whole cohort, our results showed that LVC (R2 = 69.2%, r = 0.83), Pmin (R2 = 62.9%, r = 0.79) and Pmax can be predicted by significant CMR parameters, while T1 (R2 = 23.2%, r = 0.48) and partition coefficient (R2 = 13.8%, r = 0.37) can be predicted by significant cardiac mechanical properties. In SR group LVS (R2 = 94.8%, r = 0.97), LVC (R2 = 93.7%, r = 0.96) and Pmin (R2 = 90.6%, r = 0.95) can be predicted by significant cardiac mechanical properties, while in HR + DEX group CWE (R2 = 49.8%, r = 0.70) can be predicted by significant cardiac mechanical properties. Partition coefficient (R2 = 72.6%, r = 0.85) can be predicted by significant CMR parameters in SR group. Early characterization of cardiac mechanical properties from CMR parameters has the potential to early detect doxorubicin-induced cardiotoxicity.

Contribution of Fatigue to Cognitive Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors.

Late effects such as neurocognitive issues and fatigue have been reported in childhood acute lymphoblastic leukemia (cALL) survivors. Yet, their association is often poorly understood. In this study, we wished to (1) describe neurocognitive difficulties and fatigue in a well-characterized cohort of long-term cALL survivors and (2) explore the risk of having neurocognitive deficits as a function of fatigue. Childhood ALL survivors (N = 285) from three Canadian treatment centers completed the DIVERGT battery of cognitive tests and the PedsQL Multidimensional Fatigue Scale. We performed logistic regressions to assess the risk of a survivor to show cognitive deficits (<2.0 SD) depending on their fatigue levels. At least one cognitive deficit on the DIVERGT was present in 31% of participants. Domains primarily affected were working memory, fine motor skills, and verbal fluency. Sleep/rest fatigue in youths was higher than norms (d = 0.35). The risk for cognitive deficits increased independently with levels of fatigue in the domains of cognitive speed and flexibility, working memory, and verbal fluency. For every 10-point increase on general or sleep/rest fatigue on the 0-100 scale, there was a median +23-35% risk of showing a deficit among the 7 tasks significantly associated with fatigue. Fatigue may constitute a complementary target when searching to mitigate cognitive issues in this population.

Substrate oxidation during exercise in childhood acute lymphoblastic leukemia survivors.

Children with acute lymphoblastic leukemia (ALL) are at high risk of developing long-term cardiometabolic complications during their survivorship. Maximal fat oxidation (MFO) is a marker during exercise of cardiometabolic health, and is associated with metabolic risk factors. Our aim was to characterize the carbohydrate and fat oxidation during exercise in childhood ALL survivors. Indirect calorimetry was measured in 250 childhood ALL survivors to quantify substrate oxidation rates during a cardiopulmonary exercise test. A best-fit third-order polynomial curve was computed for fat oxidation rate (mg/min) against exercise intensity (%V̇O2peak) and was used to determine the MFO and the peak fat oxidation (Fatmax). The crossover point was also identified. Differences between prognostic risk groups were assessed (ie, standard risk [SR], high risk with and without cardio-protective agent dexrazoxane [HR + DEX and HR]). MFO, Fatmax and crossover point were not different between the groups (p = .078; p = .765; p = .726). Fatmax and crossover point were achieved at low exercise intensities. A higher MFO was achieved by men in the SR group (287.8 ± 111.2 mg/min) compared to those in HR + DEX (239.8 ± 97.0 mg/min) and HR groups (229.3 ± 98.9 mg/min) (p = .04). Childhood ALL survivors have low fat oxidation during exercise and oxidize carbohydrates at low exercise intensities, independently of the cumulative doses of doxorubicin they received. These findings alert clinicians on the long-term impact of cancer treatments on childhood ALL survivors' substrate oxidation.

Impairment of health-related quality of life for children with acute lymphoblastic leukemia over the first year of therapy: A report from the DFCI ALL Consortium.

BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL. PROCEDURE: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue. RESULTS: Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy. CONCLUSIONS: This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase.

Cardiac Mechanical Performance Assessment at Different Levels of Exercise in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: There is a shortage of relevant studies interested in cardiac mechanical performance. Thus, it is clinically relevant to study the impact of cancer treatments on survivors' cardiac mechanical performance to improve our knowledge. The first objective of this study is to assess survivors' cardiac mechanical performance during a cardiopulmonary exercise test (CPET) using both ventricular-arterial coupling (VAC) and cardiac work efficiency (CWE) from cardiac magnetic resonance (CMR) acquisitions. The second objective is to assess the impact of doxorubicin and dexrazoxane (DEX) treatments. METHODS: A total of 63 childhood acute lymphoblastic leukemia survivors underwent a CMR at rest on a 3T magnetic resonance imaging system, followed by a CPET on ergocycle. The CircAdapt model was used to study cardiac mechanical performance. At different levels of exercise, arterial elastance, end-systolic elastance, VAC, and CWE were estimated. RESULTS: We observed significant differences between the different levels of exercise for both VAC ( P <0.0001) and CWE parameters ( P =0.001). No significant differences were reported between prognostic risk groups at rest and during the CPET. Nevertheless, we observed that survivors in the SR group had a VAC value slightly lower than heart rate (HR)+DEX and HR groups throughout the CPET. Moreover, survivors in the SR group had a CWE parameter slightly higher than HR+DEX and HR groups throughout the CPET. CONCLUSIONS: This study reveals that the combination of CPET, CMR acquisitions and CircAdapt model was sensitive enough to observe slight changes in the assessment of VAC and CWE parameters. Our study contributes to improving survivors' follow-up and detection of cardiac problems induced by doxorubicin-related cardiotoxicity.