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

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

Adult childhood cancer survivors' perceptions of factors that influence their ability to be physically active.

PURPOSE: Studies indicate that adult childhood cancer survivors do not achieve recommended physical activity levels. A deeper understanding of factors that influence their ability to be physically active is essential to identify individuals in need of support. The aim was to explore factors that influence adult childhood cancer survivor's ability to be physically active. METHOD: Semi-structured interviews were conducted from June to October 2020 with 20 adult childhood cancer survivors with a median age of 31 (min-max 20-47) years. Interviews were transcribed verbatim and analyzed with qualitative content analysis. RESULTS: Four main categories: "The impact of environmental factors," "Personal factors of importance," "Consequences of the treatment or disease," and "The impact of support from healthcare" and 10 sub-categories, were identified. Participants described how family habits and encouragement from others influenced their present ability to be physically active. Experienced benefits of physical activity were described as a facilitator for current physical activity while suffering from late complications was identified as a barrier. Participants highlighted the importance of specific and individualized physical activity recommendations. CONCLUSION: This study includes adult childhood cancer survivors several years after completion of treatment, hence highlighting the importance for support both during treatment and follow-up to sustain their physical activity. Healthcare providers need to identify individuals suffering from late complications, even several years after treatment; provide individualized physical activity recommendations; and educate families and schools about the importance of physical activity in childhood cancer survivorship. TRIAL REGISTRATION: This research project was registered in the Swedish National Database of Research and Development, identifier 273320, December 6, 2019 ( https://www.researchweb.org/is/vgr/project/273320 ).

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.

Heart rate response and chronotropic incompetence during cardiopulmonary exercise testing in childhood acute lymphoblastic leukemia survivors.

Cardiopulmonary exercise tests (CPET) focusing on analyses of heart rate (HR) responses and chronotropic incompetence (CI) could provide early information about treatment's negative cardiac effects. We examined childhood acute lymphoblastic leukemia (ALL) survivors' HR response during maximal CPET and identified survivors with CI. A total of 250 childhood ALL survivors underwent a CPET on ergocycle to assess their HR response. We used a multiparametric structure of three methods to assess survivors' CI, as follows: 1) age-predicted HRmax (APMHR): failure to achieve 85% of the APMHR at the peak of CPET; 2) HR reserve (HRR): failure to achieve 80% of the HRR at the peak of CPET; and 3) metabolic chronotropic relationship (MCR): failure to reach an MCR slope ratio >0.8 at each stage of the CPET. Among 250 childhood ALL survivors, 216 survivors performed a maximum CPET. We observed that 73 males and 74 females did not achieve their predicted HRmax. We found that 6 survivors did not achieve 85% of their APMHR (80.9 ± 3.9%) and had an MCR below 80% (53.9 ± 13.8%). In addition, 16 survivors did not achieve 80% of their HRR (71.0 ± 7.4%) and among them, 15 survivors had an MCR below 80% (61.0 ± 12.1%). Survivors with CI had a significantly lower cardiorespiratory fitness than those without CI. This study shows that survivors are at risk of developing altered HR responses and CI many years after the end of their cancer treatments. These findings highlight the importance of early detection of cardiac damage due to cancer treatments.

Male and Female Sexual Dysfunction in Pediatric Cancer Survivors.

BACKGROUND: Pediatric cancer survivors suffer indirect long-term effects of their disease; however, there is a paucity of data regarding the effect of pediatric cancer survivorship on sexual function. AIM: To assess the prevalence and risk factors associated with sexual dysfunction among pediatric cancer survivors. METHODS: Pediatric cancer survivors were recruited to complete an online survey using the Female Sexual Function Index (FSFI) or the International Index of Erectile Function (IIEF-5), both validated questionnaires to assess female sexual dysfunction (FSD) and erectile dysfunction (ED). Patient demographics, oncologic history, prior treatment, and sexual habits were also queried. Logistic regression was used to evaluate risk factors for sexual dysfunction, and Mann-Whitney U test was used to identify factors associated with individual domains of the FSFI. OUTCOMES: The main outcome measures were FSFI and IIEF-5 score, which are used to diagnose FSD (FSFI<26.55) and ED (IIEF-5<22). RESULTS: A total of 21 (72.4%) female respondents and 20 (71.4%) male respondents were sexually active and completed the survey and FSFI or IIEF-5 questionnaire, respectively. Mean (±SD) age was 23.7 (4.1) years, and average age at diagnosis was 9.1 (5.0), with no difference between genders. Overall, 25.0% (5/20) of male and 52.4% (11/21) of female pediatric cancer survivors reported sexual dysfunction (P = .11). Oncologic history and prior treatment were not associated with sexual function. Females who reported difficulty relaxing during intercourse in the last 6 months had higher odds of reporting sexual dysfunction (odds ratio: 13.6, 95% confidence interval: 1.2-151.2, P = .03). Subgroup analysis of FSFI domains found that previous radiation therapy was correlated with decreased lubrication and satisfaction during intercourse, whereas previous treatment to the pelvic region significantly reduced satisfaction and increased pain during intercourse. CLINICAL IMPLICATIONS: Female pediatric cancer survivors have higher odds of reporting sexual dysfunction after treatment and should be screened appropriately to provide early intervention and to mitigate risk. STRENGTH & LIMITATIONS: Our study includes validated questionnaires to assess FSD and ED and queries specific characteristics to assess their association with sexual dysfunction. However, the study is limited by sample size and its cross-sectional survey design. CONCLUSIONS: The prevalence of female sexual dysfunction in this cohort is higher than that in the general population of equivalent-aged individuals, and clinicians should be aware of these potential long-term sequelae. Greenberg DR, Khandwala YS, Bhambhvani HP, et-al. Male and Female Sexual Dysfunction in Pediatric Cancer Survivors. J Sex Med 2020;17:1715-1722.

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.

Who is a survivor? Perceptions from individuals who experienced pediatric cancer and their primary support persons.

PURPOSE: The purpose of this research was to examine the lived experiences of individuals who had cancer as children, as well as lived experiences of their current primary support persons. METHODS: Based on van Manen's "new" interpretive phenomenology, interviews were conducted with ten pediatric cancer survivors and nine of their support persons to gain a more holistic understanding of the pediatric cancer experiences of children and their families. RESULTS: Four themes emerged from the data; however, only the topic of the use of the term "survivor" and identification with the term will be discussed. All participants in the study described their personal definition of the term survivor and what it meant to be a survivor. Additionally, all individuals in the study discussed the concept of being a survivor and if they would consider themselves, or their loved ones, to be "survivors." CONCLUSIONS: The results of this study provide health care professionals, family members, and individuals fundraising or advocating for cancer causes with insights on how the term survivor may be interpreted. This study may provide insight to individuals who had cancer as children, in showing that their personal perspective shapes their identity; although "survivor" is common cancer vernacular, individuals can choose not to identify with their illness experiences.

Development of a Primary Care-Based Clinic to Support Adults With a History of Childhood Cancer: The Tactic Clinic.

PURPOSE: Describe the development and evolution of a primary-care-based, multidisciplinary clinic to support the ongoing care of adult survivors of childhood cancer. METHODS: A consultative clinic for adult survivors of childhood cancer has been developed that is located in an adult, academic internal medicine setting and is based on a long-term follow-up clinic model available at Children's Hospital Colorado. RESULTS: The clinic opened in July 2008. One hundred thirty-five patients have been seen as of April 2014. Referrals and clinic capacity have gradually increased over time, and a template has been developed in the electronic medical record to help facilitate completion of individualized care plan letters. CONCLUSIONS: A primary care-based, multidisciplinary consultative clinic for adults with a history of childhood cancer survivor is feasible and actively engages adult primary care resources to provide risk-based care for long-term pediatric cancer survivors. This model of care planning can help support adult survivors of pediatric cancer and their primary care providers in non-academic, community settings as well.

Cardiac electrical abnormalities in childhood acute lymphoblastic leukemia survivors: a systematic review.

PURPOSE: The aim was to provide evidence about the prevalence, incidence, and risk factors of cardiac electrical abnormalities in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: We included all original studies reporting the incidence and/or prevalence of cardiac electrical abnormalities and/or risk factors associated with cardiac electrical abnormalities in childhood ALL survivors (< 21 years old at the time of their initial cancer diagnosis) who were post-treatment. Searches of the databases PubMed, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions(R), Ovid All EBM Reviews, Ovid Embase, and ISI Web of Science were completed in May 2023. The risk of bias was assessed using the standard JBI critical appraisal checklists. RESULTS: The 11 studies included in this review (N = 1,264 participants) evaluated various parameters, including different cardiac electrical abnormalities. Five studies reported heart rate abnormalities (0-68%), six reported repolarization disorders (0-30%), two reported depolarization disorders (0-1%), seven reported rhythm disturbances or abnormalities (0-100%), four reported conduction disorders (0-10%), and three reported unclassified abnormalities (1-38%). No risk factors were reported. CONCLUSIONS: Electrical heart problems have been observed in childhood ALL survivors after completion of treatment. Large prospective studies in childhood ALL survivors, clear definitions of cardiac electrical abnormalities, and comparison with a control group are warranted. IMPLICATIONS FOR CANCER SURVIVORS: Cardiac electrical abnormalities induced by chemotherapy-related cardiotoxicity in the growing population of childhood ALL survivors need to be better characterized to ensure better long-term follow-up and improve overall survival rate.

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.

Sex and Gender Considerations After Surviving Acute Lymphoblastic Leukemia: An Exercise Oncology Context.

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in children worldwide. The distinction between sex (i.e., biological parameters) and gender (i.e., sociocultural and behavior) is not always taken into consideration in an exercise oncology context, despite its importance for the patient's care. A recent study showed that female survivors were more affected than males by low cardiorespiratory fitness several years after the end of their cancer treatments. This is all the more worrying considering that for a clinically equivalent level of moderate to vigorous physical activities, cardiorespiratory fitness is significantly lower in female survivors, compared with healthy females. Thus, the need for studies that help to better understand the physical deconditioning of female survivors after ALL is an essential aspect of exercise and oncology research. Because female survivors' cardiorespiratory fitness is directly impacted for many years, this article aims at discussing these aspects in an exercise and oncology context with sex and gender consideration.

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.