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.

Abnormal HDL lipid and protein composition following pediatric cancer treatment: an associative study.

BACKGROUND: Long-term childhood cancer survivors (CCS) are at high risk of having dyslipidemia including low high density lipoprotein cholesterol (HDL-C). However, little is known about the prevalence of low HDL-C and the impact of therapy exposure on HDL composition early after treatment is terminated. METHODS: This associative study included 50 children and adolescents who had completed their cancer treatments (< 4 years). Clinical characteristics (demographic, diagnosis, treatment, anthropometric parameters), fasting plasma lipids, apoliporoteins (Apo) A-I and composition of HDL fractions (HDL2 and HDL3) were assessed. Data were stratified according to the presence of dyslipidemia and median doses of therapeutic agents and compared using Fisher exact or Mann-Whitney tests. Univariate binary logistic regression analyses were carried out to evaluate the associations between the clinical and biochemical characteristics and having low HDL-C. Composition of HDL2 and HDL3 particles was assessed in a sub-group of 15 patients and compared to 15 age- and sex-matched healthy controls using Wilcoxon paired test. RESULTS: Of the 50 pediatric cancer patients included in this study (mean age: 11.30 ± 0.72 y; mean time since end of treatment: 1.47 ± 0.12 y; male: 38%), 8 had low HDL-C (16%), all of which were adolescent at diagnosis. Higher doses of doxorubicin were associated with lower HDL-C and Apo A-I levels. In hypertriglyceridemic patients and compared to normolipidemics, triglycerides (TG) content was greater in HDL2 and HDL3 fractions whereas esterified cholesterol (EC) content was lower in HDL2. Enrich TG content of HDL3 and lower EC of HDL2 was found in patients exposed to ≥ 90 mg/m2 doxorubicin. Factors positively associated with the risk of having low HDL-C were age, being overweight or obese and exposure to doxorubicin ≥ 90 mg/m2. Compared to healthy controls, a sub-group of 15 patients showed higher TG and free cholesterol (FC) content of HDL2 and HDL3 and lower EC content in HDL3. CONCLUSIONS: Overall, we found abnormalities in HDL-C and Apo A-I levels and in HDL composition early after pediatric cancer treatment that are influenced by age, overweight or obesity status and exposure to doxorubicin.

Needs, Barriers and Facilitators of Adolescents Participating in a Lifestyle Promotion Program in Oncology: Stakeholders, Adolescents and Parents' Perspective.

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

Intestinal Dysbiosis and Development of Cardiometabolic Disorders in Childhood Cancer Survivors: A Critical Review.

Significance: Survivors of pediatric cancers have a high risk of developing side effects after the end of their treatments. Many potential factors have been associated with the onset of cardiometabolic disorders (CMD), including cancer disease itself, chemotherapy, hormonal treatment, radiotherapy, and genetics. However, the precise etiology and underlying mechanisms of these long-term complications are poorly understood. Recent Advances: Greater awareness is currently paid to the role of microbiota in the emergence of cancers and modulation of cancer therapies in both children and adults. Alterations in the composition and diversity of intestinal microbiota can clearly influence tumor development and progression as well as immune responses and clinical output. As dysbiosis is closely linked to the development of host metabolic diseases, including obesity, metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease, it may increase the risk of CMD in cancer populations. Critical Issues: Only limited studies targeting the profile of intestinal dysbiosis before and after cancer treatment have been conducted. Further, the exact contribution of intestinal dysbiosis to the development of CMD in cancer survivors is poorly appreciated. This review intends to clarify the influence of gut microbiota on CMD in childhood cancer survivors, elucidate the potential mechanisms, and evaluate the latest research on the interplay between diet/food supplement, microbiota, and cancer-related CMD. Future Directions: The implication of intestinal dysbiosis in late metabolic complications of childhood cancer survivors should be clarified. Intervention strategies could be developed to reduce the risk of survivors to CMD. Antioxid. Redox Signal. 34, 223-251.

Biomarkers of cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia.

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.

Diet Quality Is Associated with Cardiometabolic Outcomes in Survivors of Childhood Leukemia.

There is little information about how diet influences the health of childhood acute lymphoblastic leukemia (cALL) survivors. This study explores the associations between diet quality indices, cardiometabolic health indicators and inflammatory biomarkers among cALL survivors. Participants were part of the PETALE study (n = 241, median age: 21.7 years). Adherence to 6 dietary scores and caloric intake from ultra-processed foods were calculated. Multivariate logistirac regressions, Student t-tests and Mann-Whitney tests were performed. We found that 88% of adults and 46% of children adhered poorly to the Mediterranean diet, 36.9% had poor adherence to the World Health Organisation (WHO) recommendations and 76.3% had a diet to be improved according to the HEI-2015 score. On average, ultra-processed foods accounted for 51% of total energy intake. Low HDL-C was associated with a more inflammatory diet (E-DIITM score) and higher intake of ultra-processed foods. A greater E-DII score was associated with elevated insulin resistance (HOMA-IR), and consumption of ultra-processed foods was correlated with high triglycerides. Circulating levels of TNF-α, adiponectin and IL-6 were influenced by diet quality indices, while CRP and leptin were not. In conclusion, survivors of cALL have poor adherence to dietary recommendations, adversely affecting their cardiometabolic health.

Dietary Intakes Are Associated with HDL-Cholesterol in Survivors of Childhood Acute Lymphoblastic Leukaemia.

Survivors of childhood acute lymphoblastic leukemia (cALL) are at high risk of developing dyslipidemia, including low HDL-cholesterol (HDL-C). This study aimed to examine the associations between food/nutrient intake and the levels of HDL-C in a cohort of children and young adult survivors of cALL. Eligible participants (n = 241) were survivors of cALL (49.4% boys; median age: 21.7 years old) recruited as part of the PETALE study. Nutritional data were collected using a validated food frequency questionnaire. Fasting blood was used to determine participants' lipid profile. Multivariable logistic regression models were fitted to evaluate the associations between intakes of macro- and micronutrients and food groups and plasma lipids. We found that 41.3% of cALL survivors had at least one abnormal lipid value. Specifically, 12.2% had high triglycerides, 17.4% high LDL-cholesterol, and 23.1% low HDL-C. Low HDL-C was inversely associated with high intake (third vs. first tertile) of several nutrients: proteins (OR: 0.27, 95% CI: 0.08-0.92), zinc (OR: 0.26, 95% CI: 0.08-0.84), copper (OR: 0.34, 95% CI: 0.12-0.99), selenium (OR: 0.17, 95% CI: 0.05-0.59), niacin (OR: 0.25, 95% CI: 0.08-0.84), riboflavin (OR: 0.31, 95% CI: 0.12-0.76) and vitamin B12 (OR: 0.35, 95% CI: 0.13-0.90). High meat consumption was also inversely associated (OR: 0.28, 95% CI: 0.09-0.83) with low HDL-C while fast food was positively associated (OR: 2.41, 95% CI: 1.03-5.63) with low HDL-C. The role of nutrition in the development of dyslipidemia after cancer treatment needs further investigation.

A Bayesian multivariate latent t-regression model for assessing the association between corticosteroid and cranial radiation exposures and cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia: a PETALE study.

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

Development and relative validation of a food frequency questionnaire for French-Canadian adolescent and young adult survivors of acute lymphoblastic leukemia.

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

Insight from mitochondrial functions and proteomics to understand cardiometabolic disorders in survivors of acute lymphoblastic leukemia.

BACKGROUND: Childhood acute lymphoblastic leukemia (cALL) is the most prevalent form of cancer in children. Due to advances in treatment and therapy, young cALL subjects now achieve a 90% survival rate. However, this tremendous advance does not come without consequence since ~2/3 of cALL survivors are affected by long-term and late, severe complications. Although the metabolic syndrome is a very serious sequel of cALL, the mechanisms remain undefined. It is also surprising to note that the mitochondrion, a central organelle in metabolic functions and the main cellular energy generator, have not yet been explored. OBJECTIVES: To determine whether cALL survivors exhibit impairments in their mitochondrial functions and proteomic profiling in relationship with metabolic disorders in cALL survivors compared to healthy controls. METHODS AND RESULTS: Anthropometric measures, metabolic characteristics and lipid profiles were assessed, mitochondria isolated from peripheral blood mononuclear cells, and proteomic analyzed. Our data demonstrated that metabolically. Unhealthy survivors exhibited several metabolic syndrome components (e.g. overweight, insulin resistance, dyslipidemia, inflammation) whereas Healthy cALL survivors resemble the Controls. In line with these abnormalities, functional experiments in these subjects revealed a significant decrease in the protein expression of mitochondrial antioxidant superoxide dismutase, PGC1-α transcription factor (a key modulator of mitochondrion biogenesis), and an increase in pro-apoptotic cytochrome c. Proteomic analysis of mitochondria by mass spectrometry revealed changes in the regulation of proteins related to inflammation, apoptosis, energy production, redox and antioxidant activity, fatty acid ß-oxidation, protein transport and metabolism, and signalling pathways between groups. CONCLUSIONS: Through the use of proteomic analysis, our work demonstrated a number of significant alterations in protein expression in mitochondria of cALL survivors, especially the metabolically Unhealthy survivor group. Further investigation of these proteins may help delineate the mechanisms by which mitochondrial dysfunctions exert cardiometabolic derangements in cALL survivors.

Cardiometabolic Risk Factors in Childhood, Adolescent and Young Adult Survivors of Acute Lymphoblastic Leukemia - A Petale Cohort.

Our objectives were to assess the prevalence of cardiometabolic complications in children, adolescents, and young adult survivors of childhood acute lymphoblastic leukemia (cALL), to identify their predictors and the risk compared to the Canadian population. We performed a cardiometabolic assessment of cALL survivors from the PETALE cohort (n = 247, median age at visit of 21.7 years). In our group, overweight and obesity affected over 70% of women. Pre-hypertension and hypertension were mostly common in men, both adults (20%) and children (19%). Prediabetes was mainly present in women (6.1% of female adult survivors) and 41.3% had dyslipidemia. Cranial radiation therapy was a predictor of dyslipidemia (RR: 1.60, 95% CI: 1.07-2.41) and high LDL-cholesterol (RR: 4.78, 95% CI: 1.72-13.28). Male gender was a predictor for pre-hypertension and hypertension (RR: 5.12, 95% CI: 1.81-14.46). Obesity at the end of treatment was a predictor of obesity at interview (RR: 2.07, 95% CI: 1.37-3.14) and of metabolic syndrome (RR: 3.04, 95% CI: 1.14-8.09). Compared to the general population, cALL survivors were at higher risk of having the metabolic syndrome, dyslipidemia, pre-hypertension/hypertension and high LDL-cholesterol, while the risk for obesity was not different. Our results support the need for early screening and lifestyle intervention in this population.

Lipid and lipoprotein abnormalities in acute lymphoblastic leukemia survivors.

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