Penicillium verrucosum is a fungal pathogen capable of producing two mycotoxins of concern, ochratoxin A (OTA) and citrinin (CIT). The production profile of these two mycotoxins is not well understood but could help mitigate co-contamination in the food supply. As such, the production of OTA and CIT from P. verrucosum DAOMC 242724 was investigated under different growing conditions in liquid culture. We found that among the different liquid media chosen, liquid YES (yeast extract sucrose) medium induced the highest production of both OTA and CIT, when P. verrucosum DAOMC 242724 was cultured in stationary mode. Shake culture significantly reduced the amounts of OTA and CIT produced. Among all culture conditions tested, far greater amounts of CIT were produced compared to OTA. Consequently, upon transcriptomic data analysis, a statistically significant increase in the expression of CIT biosynthetic genes was easier to detect than the expression of OTA biosynthetic genes. Our study also revealed that the putative biosynthetic gene clusters of OTA and CIT in P. verrusocum DAOMC 242724 are likely distinct from each other. It appears that despite sharing a highly similar structure, the isocoumarin rings of OTA and CIT are each assembled by a specialized polyketide synthase enzyme. Our data identified a putative nonreducing polyketide synthase responsible for assembling the carbo-skeleton of CIT. In contrast, a highly reducing polyketide synthase appears to be involved in the biosynthesis of OTA.

AbstractBackground: 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.

Mediation analysis with a binary outcome is notoriously more challenging than with a continuous outcome. A new Bayesian approach for performing causal mediation with a binary outcome and a binary mediator, named the t-link approach, is introduced. This approach relies on the Bayesian multivariate logistic regression model introduced by O'Brien and Dunson (2004) and its Student-t approximation. By re-expressing the Mediation Formula, it is shown how to use this multivariate latent model for estimating the natural direct and indirect effects of an exposure on an outcome in any measure scale of interest (e.g., odds or risk ratio, risk difference). The t-link mediation approach has several valuable features which, to our knowledge, are not found together in existing binary-binary mediation analysis approaches. In particular, it allows for sensitivity analyses regarding the impact of unmeasured mediator-outcome confounders on the natural effects estimates. The proposed mediation approach was evaluated and compared with two other benchmark approaches using simulated data. Results revealed the usefulness of the t-link mediation approach when the sample size is small or moderate. Lastly, the t-link approach was applied for assessing the impact of cranial radiation therapy given to treat childhood acute lymphoblastic leukemia on the long-term risk of insulin resistance, where this effect is possibly mediated by obesity.

The ability to assess various cellular events consequent to perturbations, such as genetic mutations, disease states and therapies, has been recently revolutionized by technological advances in multiple "omics" fields. The resulting deluge of information has enabled and necessitated the development of tools required to both process and interpret the data. While of tremendous value to basic researchers, the amount and complexity of the data has made it extremely difficult to manually draw inference and identify factors key to the study objectives. The challenges of data reduction and interpretation are being met by the development of increasingly complex tools that integrate disparate knowledge bases and synthesize coherent models based on current biological understanding. This chapter presents an example of how genomics data can be integrated with biological network analyses to gain further insight into the developmental consequences of genetic perturbations. State of the art methods for conducting similar studies are discussed along with modern methods used to analyze and interpret the data.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer diagnosed in children. Despite the great progress achieved over the last 40 years, with cure rates now exceeding 85%, refractory or relapsed ALL still exhibit a dismal prognosis. This poor outcome reflects the lack of treatment options specifically targeting relapsed or refractory ALL. In order to address this gap, we performed whole-genome CRISPR/Cas drop-out screens on a panel of seven B-ALL cell lines. Our results demonstrate that while there was a significant overlap in gene essentiality between ALL cell lines and other cancer types survival of ALL cell lines was dependent on several unique metabolic pathways, including an exquisite sensitivity to GPX4 depletion and ferroptosis induction. Detailed molecular analysis of B-ALL cells suggest that they are primed to undergo ferroptosis as they exhibit high steady-state oxidative stress potential, a low buffering capacity, and a disabled GPX4-independent secondary lipid peroxidation detoxification pathway. Finally, we validated the sensitivity of BALL to ferroptosis induction using patient-derived B-ALL samples.

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.

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.

BACKGROUND:Childhood cancer survivors should be routinely screened for psychological distress. However, existing screening tools promoted by cancer care institutions, such as the Distress Thermometer (DT) generate high rates of errors. The aim of this study is to help refining strategies of screening psychological distress in this population by exploring two-step methods combining the DT on step #1 with one question on step #2. PROCEDURE:Data from 255 survivors of childhood acute lymphoblastic leukemia aged 13-40 years were analyzed (38% 13-18 years, 62% 19+ years, 53% females). We used the DT on step #1 and the individual emotion items from the Pediatric Quality of Life Questionnaire (PedsQL) on step #2, to detect distress, depression and anxiety as measured by standard instruments. We compared sensitivity, specificity, negative and positive predictive values, Youden index, and clinical utility indices, in newly developed two-step strategies. RESULTS:The best two-step strategies to screen anxious-depressive distress were DT ≥ 2 on step #1, with the item of Sadness on step #2, and DT ≥ 2 combined with the item of Concerns. Two-step strategies outperformed the DT alone on the correct identification of distressed survivors. However, two-step strategies did not outperform the DT used alone on the correct detection of no distressed survivors. Results were similar when predicting depression or anxiety alone. CONCLUSION:Completing the DT with one single question on emotions from the PedsQL may minimize the number of participants falsely identified as distressed, which could be particularly pertinent in resource-limited clinics.

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.

Abstract Purpose: The six-minute walk test (6MWT) is the most widely used test to assess the functional capacity of cancer patients. However, it is reported that the actual equations cannot accurately predict oxygen uptake (VO2 value) or walk distance (6MWD) in cancer survivors. Because of the importance for clinicians and physiologists to have a validated VO2 or 6MWD equation from the 6MWT to observe the predicted survivors’ value, we focused on the validation of a standard and specific equation to predict VO2 peak and 6MWD. Methods: A total of 200 survivors were enrolled in this study, among whom 168 participants underwent a cardiopulmonary exercise test and a 6MWT. They also completed a physical activity questionnaire. Participants were randomly divided in two groups to predict the equations (n=118 (70%)) and to validate them (n=50 (30%)). Multiple linear regression analyses were used to determine a new prediction equation for VO2 peak and 6MWD from 6MWT. Bland and Altman methods were used to assess the accuracy. Results: Our findings showed that without specific variables in the VO2 peak equation, the mean bias was of 2.67 mL.kg-1.min-1 and of 2.51 mL.kg-1.min-1 with specific variables. We observed a better accuracy compared to previously published equations, which reported a mean bias of 12.09 mL.kg-1.min-1. The same results were observed for the 6MWD. Conclusion: This was the first study to predict VO2 peak and 6MWD using clinical and specific variables related to the disease. Every health care professional and exercise physiologist should use both our validated equations to provide a better adapted physical training. Our findings strengthen the need to evaluate survivors’ cardiorespiratory fitness in the care process. Citation Format: Maxime Caru, Jennifer Labonté, Valérie Lemay, Simon Drouin, Laurence Bertout, Gregor Andelfinger, Nathalie Alos, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. Improvement of physical activity training in childhood acute lymphoblastic leukemia survivors: New specific equation to predict the peak oxygen uptake from the six-minute walk test [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B61.

Abstract Purpose: Cancer survivors’ exposure to chemotherapeutic agents leads to multiple long-term side effects with a decrease in their cardiorespiratory fitness. The first aim was to determine whether cardiorespiratory fitness and physical activity levels were lower among survivors than healthy Canadians, while the second aim was to report associations between genetic variants and cardiorespiratory fitness in survivors. Methods: Cardiorespiratory fitness (VO2peak) and moderate to vigorous physical activity (MVPA) were compared between childhood ALL survivors (N=221) and healthy Canadians (N=825). We performed whole-exome sequencing in survivors. Germline variants (both common and rare) in a selected set of trainability genes were analyzed for an association with cardiorespiratory fitness. Results: Survivors’ VO2 peak was found to be 22% lower than healthy Canadians. The cardiorespiratory fitness level was different between survivors and healthy Canadians despite a clinically equivalent level of MVPA. Positive associations between the cardiorespiratory fitness level and trainability genes (TTN, LEPR, IGFBPI, and ENO3 genes) were reported, especially in female survivors with a low cardiorespiratory fitness level. Conclusion: The cardiorespiratory fitness was significantly lower in survivors, which can be associated with variants in genes related to subjects’ trainability. At this time, it appears that more physical activity would be beneficial to survivors to achieve the same benefits as the healthy population. However, the optimal amount of physical activity needed to reach these benefits is not yet clear. The survivors’ responder or nonresponder status several years after the end of the treatments is unknown. This study has important implications for the field of exercise in oncology. Citation Format: Maxime Caru, Kateryna Petrykey, Mariia Samoilenko, Simon Drouin, Valérie Lemay, Laurence Kern, Lucia Romo, Patrick Beaulieu, Pascal St-Onge, Laurence Bertout, Geneviéve Lefebvre, Gregor Andelfinger, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. The need to improve exercise prescriptions to support care in pediatric oncology [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B62.

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.

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.

Abstract Purpose: Cancer is one of the leading causes of death in the world. The physiologic 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 in 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 two years (evaluations and physical activity interventions) and one control group that will participate in only one evaluation. 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. Preliminary Results: An adhesion rate of about 40% despite restrictions and organizational conflicts specific to the hospital context was reported. A minor incident in 1 of 278 sessions performed with 35 children with cancer was observed. Conclusion: This study is the first to examine the effects of exercise in pediatric oncology, from diagnosis to the expected end of treatment. At this time, our findings show the feasibility of this physical activity program in a safe context. This is an important study in the exercise and oncology field to help patients and their family during and after cancer treatments. Citation Format: Maxime Caru, Gabrielle Duhamel, Valérie Marcil, Serge Sultan, Caroline Meloche, Isabelle Bouchard, Simon Drouin, Laurence Bertout, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. Feasibility of physical activity in children with cancer: A multidisciplinary program in the context of the VIE study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A57.

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). 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 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. 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.

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.

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.

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.

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.