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.

Genetic factors in treatment-related cardiovascular complications in survivors of childhood acute lymphoblastic leukemia.

Aim: Cardiovascular disease represents one of the main causes of secondary morbidity and mortality in patients with childhood cancer. Patients & methods: To further address this issue, we analyzed cardiovascular complications in relation to common and rare genetic variants derived through whole-exome sequencing from childhood acute lymphoblastic leukemia survivors (PETALE cohort). Results: Significant associations were detected among common variants in the TTN gene, left ventricular ejection fraction (p ≤ 0.0005), and fractional shortening (p ≤ 0.001). Rare variants enrichment in the NOS1, ABCG2 and NOD2 was observed in relation to left ventricular ejection fraction, and in NOD2 and ZNF267 genes in relation to fractional shortening. Following stratification according to risk groups, the modulatory effect of rare variants was additionally found in the CBR1, ABCC5 and AKR1C3 genes. None of the associations was replicated in St-Jude Lifetime Cohort Study. Conclusion: Further studies are needed to confirm whether the described genetic markers may be useful in identifying patients at increased risk of these complications.

Maximal cardiopulmonary exercise testing in childhood acute lymphoblastic leukemia survivors exposed to chemotherapy.

PURPOSE: The purpose of this study was to demonstrate if childhood acute lymphoblastic leukemia (ALL) survivors exposed to chemotherapy (i.e., doxorubicin) are able to achieve a safe maximal cardiopulmonary exercise test (CPET). METHODS: A total of 250 childhood ALL survivors were eligible to undergo a CPET on ergocycle. Analyses were performed in 216 survivors and stratified in regard to their prognostic risk groups: 99 survivors (55 males and 44 females) at standard risk and 117 survivors (56 males and 61 females) at high risk. RESULTS: Results showed that 100% (n = 216) of survivors completed a maximal CPET confirmed by the achievement of two out of three of the following criteria: 197 survivors (91.2%) reached a peak RER value of ≥ 1.15, 197 survivors (91.2%) reached a RPE score > 7, and 210 survivors (97.2%) reached a maximal heart rate ≥ 85% of the predicted value. Linear regression analysis showed a significant association between the survivors' cumulative dose of doxorubicin and their VO2 peak measured. Two non-fatal adverse events were observed and reported at the end of the maximal CPET, while non-fatal adverse events were reported in 5 survivors during the recovery period. None of these events resulted in a long-term complication. CONCLUSION: Childhood ALL survivors with prior exposure to chemotherapy can achieve a safe maximal CPET. They were able of achieving a maximal exercise test without being limited by symptoms, potential overprotection, or musculoskeletal issues. Thus, it should be the norm to realize a CPET prior a physical activity program to propose an optimal prescription. This study provides important information regarding the maximal physiological parameters that childhood ALL survivors are able to reach and have important clinical implications in the exercise and oncology field for this population of survivors.

Contributing Factors of Unmet Needs Among Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia with Comorbidities.

Purpose: This study aimed to: (1) describe the domains and levels of unmet needs of young adult survivors of childhood acute lymphoblastic leukemia (cALL) with comorbidities, and (2) to explore the factors associated with higher levels of unmet needs. Unmet need was considered as supportive care needs not met. Methods: The most vulnerable cALL survivors from the PETALE study cohort completed the Short-Form Survivor Unmet Needs Survey, the Brief Pain Inventory and the 15D instrument of health-related quality of life. Demographic and clinical information, including comorbidities, were obtained from medical records or self-reporting. The participants' needs and contributing factors to their needs were evaluated using nonparametric tests. Results: Of the 72 participants, 9 (13%) reported moderate/high levels of overall unmet needs. "Worry about earning money" (56%) and "Dealing with feeling tired" (51%) were the most frequent unmet needs (all levels combined). The factors associated significantly with any domain of unmet needs were: having a comorbidity, reporting altered functional health status, high ALL risk status, pain, age (<26 years), and having previously received psychological support. Conclusion: A minority of young adult survivors of cALL with comorbidities interviewed reported moderate/high levels of unmet needs. However, financial concerns and emotional health and relationship are the two domains of greatest need. Survivors with altered health condition are most at risk of experiencing moderate/high levels of unmet needs. If confirmed in larger samples, interventions should target modifiable contributors of unmet needs such as physical health and comfort, fatigue, and emotional health.

Developing and validating equations to predict V˙O2 peak from the 6MWT in Childhood ALL Survivors.

INTRODUCTION: The 6-Minute Walking Test (6MWT) is a safe, standardized and well utilized method to assess the functional capacity. Recently, it was reported that the published prediction equations cannot accurately predict a valid maximal oxygen consumption (V̇O2 peak) value in cancer survivors. Thus, the aim of this study was to establish and to validate a new equation based on the 6MWT to predict V̇O2 peak in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: A total of 200 childhood ALL survivors were enrolled in this study, among which 168 participants underwent a cardiopulmonary exercise test and a 6MWT to assess their functional capacity and their cardiorespiratory fitness. In addition, participants completed a physical activity questionnaire. Participants were randomly divided in two groups to establish the equations (n = 118 (70%)) and to validate it (n = 50 (30%)). Multiple linear regression analyses were used to determine a new prediction equation for V̇O2 peak from 6MWT using clinical and specific variables related to the disease. The accuracy in between V̇O2 peak measured and V̇O2 peak predicted were assessed using the Bland and Altman method. RESULTS: The new establish clinical V̇O2 peak equation is: V̇O2 peak (mL.kg-1.min-1) = (-0.283*age(years)) - (0.099*weight(kg)) + (0.071*6MWD(meters)) -(0.135*HR end(bpm)) + 22.789 with a mean bias of 2.67 mL.kg-1.min-1 (95% CI (-9.64 to 14.98)). The new establish disease-specific V̇O2 peak equation is: V̇O2 peak (mL.kg-1.min-1) = (-0.236*age(years)) - (0.094*weight(kg)) -(0.120*HR end(bpm)) + (0.067*6MWD(meters)) + (0.065*MVLPA(min/day)) - (0.204*DT(years)) + 25.145 with a mean bias of 2.51 mL.kg-1.min-1 (95% CI (-9.98 to 15.01)). CONCLUSION: This is the first study that predicted V̇O2 peak from a 6MWT using clinical and specific variables related to the disease of childhood ALL survivors. The availability of these newly established V̇O2 peak equations makes them an accurate tool to provide a better follow-up and better adapted physical training for survivors. We invite researchers to use our assessment procedures for their further studies.IMPLICATIONS FOR REHABILITATIONIt is critical to understand the cardiorespiratory fitness of the childhood ALL survivorsThe maximal oxygen consumption (i.e., V̇O2 peak) is recognized as the gold standard to measure the patient's cardiorespiratory fitness in the field of exercise physiologyThis study is novel and reports the validation of two new VO2 peak equations, from 6MWT, by using clinical and disease-specific variables of childhood ALL survivorsThe availability of such validated equations can better facilitate the follow-up of survivors' cardiorespiratory fitness, by relevant health care professionals and exercise physiologists.

The effect of cardiorespiratory fitness and physical activity levels on cognitive functions in survivors of childhood acute lymphoblastic leukemia.

Introduction. Most childhood acute lymphoblastic leukemia (ALL) survivors develop chronic treatment-related adverse effects several years after the end of the treatment. Regular physical activity and a good cardiorespiratory fitness can decrease the risks of neurological disturbances and increase cognitive function scores. The aim of this study was to examine the effect of good cardiorespiratory fitness and physical activity levels on cognitive functions.Methods. We enrolled 219 survivors of childhood ALL. The participants underwent a cardiopulmonary exercise test, neuropsychological tests of executive functions (i.e. verbal fluency, cognitive flexibility, working memory, processing speed) and completed a physical activity questionnaire. We calculated the odds ratio to obtain the preventive fraction of physical activity and cardiorespiratory fitness levels on cognitive functions.Results. The cohort is 52% male and 48% female. A total of 182 survivors (83%) have a cardiorespiratory fitness below their predicted (<100%). Our analyses show that there is an association between good cardiorespiratory fitness and processing speed (preventive fraction of 70% for dominant hand (p < 0.01) and 65% for non-dominant hand (p < 0.01)) and with cognitive flexibility identified as the category switching measure of the D-KEFS verbal fluency (preventive fraction of 61%; p < 0.05).Conclusion. Good cardiorespiratory fitness and good levels of physical activity were associated to a preventive fraction for most cognitive function parameters measured. Good cardiorespiratory fitness levels were significantly associated with a lower prevalence of deficits in processing speed (i.e., dominant hand and non-dominant hand) and in cognitive flexibility (i.e., category switching) in childhood acute lymphoblastic leukemia survivors.

Inconsistencies between measures of cognitive dysfunction in childhood acute lymphoblastic leukemia survivors: Description and understanding.

OBJECTIVES: The frequency of cognitive difficulties in childhood cancer survivors varies according to the measurement strategy. The goal of this research is to (a) describe agreements and differences between measures of working memory and attention (b) identify contributors of these differences, such as emotional distress, affects, and fatigue. METHODS: We used data available for 138 adults successfully treated for childhood acute lymphoblastic leukemia (ALL) (PETALE cohort). Working memory and attention were assessed using subtests from the WAIS-IV and self-reported questionnaires (BRIEF-SR and CAARS-S:L). Potential contributors included emotional distress, anxiety, depression (BSI-18), affects (PANAS), and fatigue (PedsQL-MFS). We explored measurement agreements and differences using diagnostic indices and multivariate regression models. RESULTS: The frequencies of working memory and attention deficits were higher when using cognitive tests (15%-21%) than with self-reports (10%-11%). Self-reported questionnaires showed high specificity (median 0.87) and low sensitivity (median 0.10), suggesting they did not reliably identify positive cases on cognitive tests. We identified negative affectivity as a possible contributor to inconsistencies between self-report and test results. CONCLUSIONS: When measuring working memory and attention in childhood ALL survivors, cognitive test results and self-reports should not be considered equivalent. At best, self-report may be used for screening (high specificity), but not to assess prevalence in large samples. Self-reported difficulties are also probably influenced by the negative mood in this population.

The VIE study: feasibility of a physical activity intervention in a multidisciplinary program in children with cancer.

BACKGROUND: Cancer is one of the leading causes of death in the world. The physiological and psychological benefits of physical activity have been shown in children with cancer. However, almost one in two cancer patients do not follow the physical activity guidelines. The aim of this study will be to assess the feasibility of a physical activity program intervention in pediatric oncology and to assess the barriers and facilitators to the success or failure of this physical activity program. METHODS: The VIE (valorization, implication, and education) intervention is a multidisciplinary program including physical activity, nutritional, and psychological interventions in pediatric oncology. This study involves one intervention group that will be followed over 2 years (evaluations and physical activity interventions) and one control group that will participate in only one evaluation. Children from the intervention group have been diagnosed and will be undergoing treatment at the Charles-Bruneau oncology center from the Sainte-Justine University Health Center (Montreal, Canada). The feasibility of this program will be measured through a comparison between sessions performed and sessions scheduled, while the security will be measured according to the number of reported incidents. DISCUSSION: This study will examine the effects of exercise in pediatric oncology from diagnosis to the expected end of treatment (i.e., 2 years of follow-up). Currently, there are only a few longitudinal studies on physical activity and pediatric cancer. Physiological and psychological tests will allow a better knowledge of the evolution of the physical fitness and mental health of the patients during the period of care. It is necessary to document and provide complementary knowledge in the pediatric oncology field in order to engage the discourse with pediatric oncology health professionals to help patients during and after treatment. This is an important study in the exercise and oncology field to help patients and their family during and after cancer treatments.

Physical Activity and Sedentary Behaviors in Childhood Acute Lymphoblastic Leukemia Survivors.

INTRODUCTION: More than two thirds of survivors have long-term adverse effects, and no study proposes a portrait of physical activity level in childhood acute lymphoblastic leukemia survivors. The aims of this study were to present the cardiorespiratory fitness (CRF) levels of survivors detailed overview sedentary activities portrait. METHODS: A total of 247 childhood acute lymphoblastic leukemia survivors were included in our study. Survivors underwent a cardiopulmonary exercise test on ergocycle and completed physical activity and sedentary questionnaires to assess their leisure physical and sedentary activities and total daily energy expenditure. RESULTS: Up to 67% of survivors (84% below 18 y and 60% 18 y of age or above) did not fulfill the physical activity guidelines. Their CRF was reduced by almost 16% in regard to their predicted maximum oxygen consumption (VO2peak). Almost three quarters of the survivors (70% below 18 y and 76% 18 y of age or above) spent >2 hours/day in leisure sedentary activities. Adult survivors who received high doses of anthracyclines and those who received radiation therapy had decreased odds to spend ≥2 hours/day in sedentary activities. CONCLUSIONS: Our results showed that survivors, especially children, were not active enough and had a reduced CRF. This study highlights the importance of promoting physical activity in survivors, especially because they are exposed to an increased risk of chronic health problems, which could be mitigated by physical activity.

Visual short-term memory activation patterns in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Treatments against ALL might lead to later cognitive effects and alterations in brain structure in survivors but to the authors' knowledge the observed variability in the severity of neurocognitive deficits is not fully understood. The objective of the current study was to investigate abnormalities in visual short-term memory (VSTM) brain activation in survivors of childhood ALL using magnetoencephalography. METHODS: A VSTM task was completed by 40 survivors of ALL and 26 controls. VSTM capacity (Cowan K) and brain activation were assessed during the retention period of the task (400-1400 milliseconds) using a standard minimum norm source localization method. RESULTS: Performance (Cowan K) was found to be similar between survivors of ALL and controls. Atypical brain activation was found in survivors of ALL during the task, including overactivation of regions usually involved in VSTM (lateral occipital, precentral gyrus, and postcentral gyrus), recruitment of regions that typically are not involved in VSTM (superior/middle temporal gyrus and supramarginal gyrus), and lower activation of frontal brain regions (inferior frontal gyrus). These patterns of activation were modulated by the age at the time of cancer onset (P = .01) because activity was found to be reduced in participants who were younger at diagnosis. CONCLUSIONS: The results of the current study suggest a pattern of neural inefficiency and compensatory activity during VSTM in survivors of ALL.

Childhood Acute Lymphoblastic Leukemia Survivors Have a Substantially Lower Cardiorespiratory Fitness Level Than Healthy Canadians Despite a Clinically Equivalent Level of Physical Activity.

Introduction: As the survival rate of childhood acute lymphoblastic leukemia (ALL) continues to improve, the physical deconditioning is becoming an increasingly common problem in survivors. The aim of this study was to compare the cardiorespiratory fitness and physical activity levels of survivors and control participants. Methods: A total of 221 childhood ALL survivors (114 males and 107 females), diagnosed between 1987 and 2010 and treated according to Dana Farber Cancer Institute-ALL 87-01 to 05-01 protocols at Sainte-Justine University Health Center (SJUHC), Montreal (Canada), and 825 control participants (364 males and 461 females), recruited in the Canadian Health Measures Survey (cycle 2) during 2009 to 2011 by Statistics Canada, were included in our analyses. In both survivors and controls, cardiorespiratory fitness and moderate to vigorous physical activity (MVPA) were assessed. Results: Survivors' V̇O2 peak was found to be 22% lower than that of controls. Cardiorespiratory fitness was different between the survivors (32.4 ± 8.3 mL/(kg·min); ß = 0.11; 95% confidence interval [CI] 0.07-0.14) and the controls (41.6 ± 9.4 mL/(kg·min); ß = 0.16; 95% CI 0.13-0.18), despite a clinically equivalent level of MVPA [survivors (27.5 ± 27.4 min/day) and controls (33.4 ± 24.2 min/day)]. Status (being survivor) and the age of the participants were negatively associated with cardiorespiratory fitness, whereas MVPA and male gender were positively associated with cardiorespiratory fitness. Conclusion: We observed that for a clinically equivalent level of MVPA, cardiorespiratory fitness was significantly lower in survivors compared with controls. Our findings showed that female survivors were most affected, compared with male survivors. These findings allow further understanding of the physiological differences between childhood ALL survivors and control participants and have important implications for this high-risk population of survivors.

Influence of genetic factors on long-term treatment related neurocognitive complications, and on anxiety and depression in survivors of childhood acute lymphoblastic leukemia: The Petale study.

BACKGROUND: A 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. METHODS: To 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. RESULTS: Common 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. CONCLUSIONS: Current 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.

Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors.

Background: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors. Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers.  Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models.  Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616DUOX2, P=0.0002 (Pmax) and rs41270041ADAMTS4, P=0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (P≤0.02).  Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors.

Identification of genetic association between cardiorespiratory fitness and the trainability genes in childhood acute lymphoblastic leukemia survivors.

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.

Identification of a single-nucleotide polymorphism within CDH2 gene associated with bone morbidity in childhood acute lymphoblastic leukemia survivors.

Aim: To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). Patients & methods: To this end, we measured the association between reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models. Results: The minor allele of rs1944294 in CDH2 gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002). Conclusion: The variant in CDH2 gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.

Definition and improvement of the concept and tools of a psychosocial intervention program for parents in pediatric oncology: a mixed-methods feasibility study conducted with parents and healthcare professionals.

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.

Doxorubicin treatments induce significant changes on the cardiac autonomic nervous system in childhood acute lymphoblastic leukemia long-term survivors.

AIMS: Acute lymphoblastic leukemia (ALL) is one of the leading malignancies in children worldwide. The cardiotoxicity of anti-cancer treatments leads to a dysfunction of the cardiac autonomic nervous system. Protection strategies, with dexrazoxane treatments, were used to counter these adverse effects. The aim of this study was to investigate the effects of the treatments on the cardiac autonomic nervous system. METHODS AND RESULTS: A total of 203 cALL survivors were included in our analyses and were classified into 3 categories based on the prognostic risk group: standard risk, high risk with and without dexrazoxane. A 24-h Holter monitoring was performed to study the cardiac autonomic nervous system. The frequency domain heart rate variability (HRV) was used to validate the cardiac autonomic nervous system modifications. Other analyses were performed using linear HRV indexes in the time domain and non-linear indexes. A frequency domain HRV parameters analysis revealed significant differences on an overall time-period of 24 h. A repeated measures ANOVA indicated a group-effect for the low frequency (p = 0.029), high frequency (p = 0.03) and LF/HF ratio (p = 0.029). Significant differences in the time domain and in the non-linear power spectral density HRV parameters were also observed. CONCLUSION: Anti-cancer treatments induced significant changes in the cardiac autonomic nervous system. The HRV was sensitive enough to detect cardiac autonomic nervous system alterations depending on the cALL risk category. Protection strategies (i.e., dexrazoxane treatments), which were used to counter the adverse effects of doxorubicin, could prevent changes observed in the cardiac autonomic nervous system.

Psychosocial Intervention Programs for Parents of Children with Cancer: A Systematic Review and Critical Comparison of Programs' Models and Development.

Intervention programs have been developed to help parents cope with their child's cancer. Despite some studies reporting a high level of evidence, it is unclear how these programs build on each other. Appraising models of change is critical to advance scientific knowledge and provide evidence-based interventions. This review aims to identify existing programs, explicitly formulate their underlying models, evaluate how they translate into concrete activities, as well as identify and discuss their development process. Eleven programs based on models of change from cognitive-behavioral, systemic and counselling theories were identified. Many models included a sound theoretical framework, targeted outcomes, as well as implementation strategies. In most cases, preliminary development studies were conducted, but details were rarely provided on how development stages informed the redesign of intervention programs. Acceptability and treatment fidelity were not available for one-third of the programs. Future reports should document the development and design redesign stages prior to conducting efficacy trials, as this step would provide crucial details to critically appraise programs.

Prevention of Long-term Adverse Health Outcomes With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Most childhood acute lymphoblastic leukemia (ALL) survivors develop chronic treatment-related adverse effects several years after the end of therapy. A regular practice of physical activity and a good cardiorespiratory fitness have the potential to reduce the risk of chronic disease and improve quality of life. The aim of this study was to evaluate in a cohort of ALL survivors, the association between a good cardiorespiratory fitness or the respect of physical activity guidelines and major long-term health outcomes. METHODS: In total, 247 ALL survivors underwent a cardiopulmonary exercise test, completed a physical activity questionnaire and a battery of clinical examinations. We calculated the odds ratio to obtain the preventive fraction (PF) to evaluate the effects of the cardiorespiratory fitness and physical activity levels on health outcomes (ie, obesity, metabolic health, cardiac health, cognitive health and mood, bone health). RESULTS: Despite their young age, 88% of the participants presented at least one adverse health outcome, and 46% presented ≥3. Their cardiorespiratory fitness was also lower than expected with a median VO2 peak reaching 84% of the predicted value. In the analyses using cardiorespiratory fitness, statistically significant PFs were observed for obesity (0.30), low-high-density lipoprotein-cholesterol (0.21) and depression (0.26). In the physical activity level analyses, statistically significant PFs were observed for obesity, depression, and low bone mineral density, with a PF of 0.55, 0.81, and 0.60, respectively. CONCLUSIONS: Our results indicate that a good cardiorespiratory fitness and physical activity level induced a preventive action for most health outcomes studied and was associated with a lower late adverse effects prevalence in ALL survivors.

Cancer-related effects on relationships, long-term psychological status and relationship satisfaction in couples whose child was treated for leukemia: A PETALE study.

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.