Inflammatory biomarkers after an exercise intervention in childhood acute lymphoblastic leukemia survivors.

Cancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of childhood acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. Survivors of childhood ALL aged 16-30 years (n = 21) with a median age at diagnosis 4.9 (1.6-12.9) years and a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n = 21) were studied. Stored plasma samples were analyzed with Olink's 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a previous 16-week home-based exercise intervention (n = 17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. Inflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: tumor necrosis factor superfamily member 14 (TNFSF14), oncostatin M (OSM), monocyte chemoattractant protein 1 (MCP-1), MCP-2, fibroblast growth factor 21 (FGF-21), chemokine (C-C motif) ligand 4 (CCL4), transforming growth factor alpha (TGF-α), tumor necrosis factor-related apoptosis-inducing ligand 10 (TRAIL), adenosine deaminase (ADA), chemokine (C-X-C motif) ligand 6 (CXCL6), and latency-associated peptide transforming growth factor beta 1 (LAP TGF-ß1). The ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors' 16-week exercise intervention led to significant reduction in inflammatory protein levels. Physical exercise should be promoted for survivors of childhood cancer.

Asymptomatic Right Atrial Thrombosis After Acute Lymphoblastic Leukemia Treatment.

Right atrial thrombosis is a rare, but potentially serious complication of acute lymphoblastic leukemia treatment. We conducted a retrospective multicenter study to assess the incidence, treatment, and outcome of asymptomatic right atrial thrombosis detected at routine echocardiography of children after acute lymphoblastic leukemia treatment in the Nordic and Baltic countries. Eleven (2.7%, 95% confidence interval, 1.4-4.9) of 406 patients had asymptomatic right atrial thrombosis, ranging from 10 to 25 mm at detection. Three patients were treated with anticoagulation. None of the thromboses affected cardiac function, and they showed neither sign of progress nor spontaneous or treatment-related regress at follow-up.

Use of electronic patient data storage for evaluating and setting the risk category of late effects in childhood cancer survivors.

BACKGROUND: Many of the late effects of cancer treatment in childhood may occur even decades after the treatment, and only a minority of the survivors remain as healthy as their peers. Providing appropriate long-term care for childhood cancer survivors after transition to primary health care is a challenge. Both survivors and primary care providers need information on potential late effects. The lack of a systematic late effect follow-up plan may lead to excessive use of health care services or delayed intervention. While manual compilation of individual follow-up plans is time consuming for experienced clinicians, electronic algorithms may be feasible. PROCEDURE: In Finland, international guidelines for determining the risk of late effects have been implemented. Nationally, Turku University Hospital was asked with developing an automatized system for calculating the risk of late effects, based on electronic patient records saved in the hospital data lake. An electronic algorithm that uses details from exposure-based health screening guidelines published by the Children's Oncology Group was created. The results were compared with those manually extracted by an experienced clinician. RESULTS: Significant concordance between the manual and algorithm-based risk classification was found. A total of 355 patients received a classification using the algorithm, and 325 of those matched with the manual categorization, producing a Cohen's coefficient of 0.91 (95% confidence interval 0.88-0.95). CONCLUSION: Automated algorithms can be used to categorize childhood cancer survivors efficiently and reliably into late effect risk groups. This further enables automatized compilation of appropriate individual late effect follow-up plan for all survivors.

Motor Performance in Children Diagnosed with Cancer: A Longitudinal Observational Study.

Children with cancer are dealing with different side and long-term effects caused by cancer and its treatments, like vinca-alkaloids, which may have negative effects on motor performance. However, the affected areas of motor performance (aiming and catching, balance, manual dexterity) and the differences in these areas between boys and girls and diagnoses are not frequently reported in a longitudinal design. Therefore, the aim of this study was to investigate how motor performance changes over the course of cancer treatment. The study was conducted with 3-to 16-year-old children with cancer (N = 36) in 2013-2017. The five assessment points were 0, 2, 6, 12 and 30 months from diagnosis. Movement-ABC2 was used to assess motor performance. We found that aiming and catching skills decreased significantly during the follow-up (p < 0.05). Balance was affected at the 2-month measurement point (p < 0.05) and more in children with acute lymphoblastic leukemia than in children with other cancer diagnoses (p < 0.05). Girls performed better than boys in manual dexterity at 6, 12 and 30 months (p < 0.05, p < 0.05, p < 0.05, respectively). Individual monitoring of motor performance with standardized tests and physical activity/exercise programs during and after treatment are needed.

The effect of an active video game intervention on physical activity, motor performance, and fatigue in children with cancer: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of active video games in promoting physical activity and motor performance, and reducing fatigue in children with cancer. A randomized controlled trial was conducted. The intervention included playing Nintendo Wii™Fit (Nintendo Co., Ltd., Kyoto, Japan) for 30 min/day for 8 weeks. Physical activity was estimated with accelerometers, physical activity diaries and questionnaires. Movement-ABC2 and PedsQL™ were used to examine motor performance and fatigue. Intervention experiences and fidelity were examined with an interview. RESULTS: Participants (n = 36 children with cancer, 3-16 years-old) were randomly assigned to the intervention and control groups. The median [min-max] accelerometer counts/h (500 [131-1130] vs 385 [116-1012], p = 0.63) and physical activity min/day (34 [0-150] vs 23 [0-260], p = 0.95) did not differ between the groups. Change between the pre-test and post-test regarding motor performance and fatigue was similar in both groups (motor performance p = 0.77; fatigue p = 1.00). Participants experienced playing active video games meaningful, but the intervention was not followed completely as instructed. Overall, the physical activity levels were low and one fourth of the children had or were at risk of having movement difficulties. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01748058 (October 15, 2012).

Home-Based Exercise Training Improves Left Ventricle Diastolic Function in Survivors of Childhood ALL: A Tissue Doppler and Velocity Vector Imaging Study.

BACKGROUND: Advanced echocardiographic methods may reveal signs of late anthracycline cardiac toxicity (ACT) even in asymptomatic patients. We studied echocardiographic tissue Doppler imaging (TDI) and velocity vector imaging (VVI) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) before and after an exercise intervention. METHODS: Twenty-one asymptomatic, anthracycline-treated, long-term childhood ALL survivors with matched controls were studied at baseline. Seventeen of the survivors participated in a 3-month home-based exercise program. Echocardiography with TDI and VVI was performed. RESULTS: At baseline, ejection fraction (60.7 ± 4.7% vs. 62.3 ± 3.7%, P = 0.22) and fractional shortening (32.6 ± 3.1% vs. 34.0 ± 2.8%, P = 0.13) were similar in survivors and controls. Lateral early diastolic mitral annulus velocity E' (32.81 ± 5.71 cm/sec vs. 38.03 ± 6.21 cm/sec, P = 0.01), E'/A' (1.60 ± 0.48 vs. 2.07 ± 0.63, P = 0.01), and E/E' (2.78 ± 0.35 vs. 2.42 ± 0.62, P = 0.04) were impaired compared to controls. Peak circumferential strain and strain rate were attenuated at apex (-24.50 ± 3.46% vs. -28.06 ± 4.39%, P = 0.01 and -1.47 ± 0.22 sec(-1) vs. -1.68 ± 0.33 sec(-1) , P = 0.02) compared to controls. After the intervention, early diastolic mitral inflow velocity E (87.76 ± 12.54 cm/s vs. 95.28 ± 10.48 cm/s, P = 0.04) and E' increased (31.78 ± 5.50 cm/s vs. 34.96 ± 5.41 cm/s, P < 0.01). Peak circumferential systolic and diastolic strain rates at mid-level (-1.22 ± 0.21 sec(-1) vs. -1.35 ± 0.24 sec(-1) , P = 0.04 and 1.25 ± 0.25 sec(-1) vs. 1.48 ± 0.35 sec(-1) , P < 0.01) improved after the exercise program. CONCLUSIONS: A simple home-based exercise program improved cardiac function in asymptomatic childhood ALL survivors. Adding TDI in routine echocardiographic examination may improve the recognition of early signs of ACT, and VVI may bring additional information. The improvements in cardiac function after the exercise program emphasize the importance of physical activity in this population.

Late mortality among 5-year survivors of early onset cancer: a population-based register study.

To date, only few studies have been published documenting late mortality among early onset cancer survivors, especially regarding young adulthood (YA) malignancies. Our nation-wide population-based registry study provides information concerning cause-specific long-term mortality among 16,769 5-year survivors of early onset cancer (aged 0-34 years at diagnosis), with follow-up for death extending from 1971 through 2012. A sibling cohort and population data were used as reference. The overall standardized mortality ratio (SMR) of cancer patients was 4.6-fold, (95% CI 4.4-4.8). Highest SMRs were found for malignancies (12.8, 95% CI 12.3-13.3), infectious (4.8, 95%CI 2.9-6.7) and cardiovascular diseases (1.9, 95% CI 1.7-2.1). Malignancies and cardiovascular diseases accounted for the largest number of deaths. Childhood and YA cancer survivors with the same primary cancer site had a similarly elevated overall SMR with the exception of markedly higher SMRs after childhood Hodgkin lymphoma. The highest cumulative non-malignancy-related mortality was due to cardiovascular disease with a steady rise throughout the follow-up, but strongly dependent on the primary cancer site and age at diagnosis. In childhood cancer survivors, the cumulative cardiovascular mortality did not reduce over time. However, overall and malignancy-related mortality showed a declining tendency towards the most recent periods after both, childhood and YA cancer. Our findings on non-malignancy-related mortality stress the need to set up long-term individual follow-up with a focus on cardiovascular late effects for early onset cancer survivors, especially for YA cancer survivors still lacking those.

Active video games to promote physical activity in children with cancer: a randomized clinical trial with follow-up.

BACKGROUND: Low levels of physical activity, musculoskeletal morbidity and weight gain are commonly reported problems in children with cancer. Intensive medical treatment and a decline in physical activity may also result in reduced motor performance. Therefore, simple and inexpensive ways to promote physical activity and exercise are becoming an increasingly important part of children's cancer treatment. METHODS: The aim of this study is to evaluate the effect of active video games in promotion of physical activity in children with cancer. The research is conducted as a parallel randomized clinical trial with follow-up. Patients between 3 and 16 years old, diagnosed with cancer and treated with vincristine in two specialized medical centers are asked to participate. Based on statistical estimates, the target enrollment is 40 patients. The intervention includes playing elective active video games and, in addition, education and consultations for the family. The control group will receive a general recommendation for physical activity for 30 minutes per day. The main outcomes are the amount of physical activity and sedentary behavior. Other outcomes include motor performance, fatigue and metabolic risk factors. The outcomes are examined with questionnaires, diaries, physical examinations and blood tests at baseline and at 2, 6, 12 and 30 months after the baseline. Additionally, the children's perceptions of the most enjoyable activation methods are explored through an interview at 2 months. DISCUSSION: This trial will help to answer the question of whether playing active video games is beneficial for children with cancer. It will also provide further reasoning for physical activity promotion and training of motor skills during treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01748058 (October 15, 2012).

Endothelial function in long-term survivors of childhood acute lymphoblastic leukemia: effects of a home-based exercise program.

BACKGROUND: The risk for cardiovascular disease (CVD) is increased in long-term survivors of childhood acute lymphoblastic leukemia (ALL). Chemotherapy may have direct toxic effects on vascular endothelium, potentially increasing the significance of endothelial dysfunction in the development of CVD in ALL survivors. Endothelial structure and function can be measured with carotid intima media thickness (IMT) and brachial flow mediated dilation (FMD). IMT and FMD are intermediate markers of CVD. We studied endothelial function and the effects of an exercise program on vascular endothelium in long-term survivors of childhood ALL. PROCEDURE: Twenty-one 16-30 year old long-term survivors of ALL (age at diagnosis ≤16 years) and 21 healthy controls were studied at baseline, and 17 of the ALL survivors participated in a 16 week home-based exercise program. IMT and FMD were studied before and after the exercise program. RESULTS: At baseline, the ALL survivors had impaired overall FMD response (FMDauc, P = 0.02). FMDmax(%) was 22% lower (P = 0.06) and FMD at 40 seconds 44% lower (P = 0.01) compared to healthy controls. After the exercise program, FMD at 40 seconds (P < 0.01) and IMT (P = 0.02) improved. The mean overall FMD response increased by 25% after the exercise program, but this change was not statistically significant (P = 0.27). CONCLUSIONS: Our results show that the excess burden of CVD morbidity in this population may possibly be alleviated by simple means. The importance of physical activity on the health of childhood ALL survivors should be emphasized. Longer, controlled studies are needed to confirm our findings.

Effects of a home-based exercise program on metabolic risk factors and fitness in long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Long-term survivors of childhood acute lymphoblastic leukemia (ALL) have increased risk of cardiovascular disease (CVD). The prevalence of insulin resistance and other cardiometabolic risk factors is increased in ALL survivors, and insufficient physical activity (PA) and low cardiopulmonary fitness are common. The purpose of this study was to evaluate the effects of a simple, inexpensive home-based exercise program on cardiometabolic risk factors and fitness in long-term ALL survivors. PROCEDURE: Seventeen 16- to 30-year-old survivors of childhood ALL (age at diagnosis ≤16 years) were recruited to a 16-week home-based exercise program. Peak oxygen uptake (VO(2 peak)), muscle strength, and metabolic risk factors were studied before and after the exercise program. RESULTS: Fasting plasma insulin (P = 0.01), HOMA-IR (homeostasis model assessment, insulin resistance) (P = 0.002), waist circumference (P = 0.003), waist-to-hip ratio (P = 0.002), fat percent (P = 0.04), and supine diastolic blood pressure (P = 0.03) decreased during the program, while weight and body mass index remained unchanged. VO(2 peak) and maximal work load (W/kg) improved by 5% (P = 0.01 and P = 0.02, respectively) during the exercise program. The results of the Sit-Up test, Back extensor test, and Full Squatting test improved as well (P = 0.01, P = 0.002, and P = 0.0004, respectively). CONCLUSIONS: A simple home-based exercise program was effective in improving cardiometabolic risk factor status and fitness in young adult survivors of childhood ALL. Simple exercise programs should be recommended to this population with increased risk of CVD to improve metabolic risk factor status and fitness.

Auditory event related potentials as tools to reveal cognitive late effects in childhood cancer patients.

OBJECTIVE: The purpose of this study was to analyze event related potentials mismatch negativity (MMN) and P3a in childhood cancer patients at the time of diagnosis (Study 1) and after treatment (Study 2) to evaluate their clinical usefulness in screening potential treatment-related neurotoxicity. METHODS: The MMN and P3a to phonetic stimuli were examined in 27 childhood cancer patients with age- and sex-matched controls. Neuropsychological tests were also studied. RESULTS: The MMN peak amplitude was attenuated in the patient group at Study 1. Between the studies, poorer enhancement of the MMN peak amplitude correlated with deterioration in the Verbal intelligence quotient (IQ) in leukaemia patients. In addition, prolongation of the MMN peak latency correlated significantly with deterioration in the Full Scale and Performance IQ in the patient group. Deterioration in the Arithmetic subtest and Performance IQ correlated negatively with the age at diagnosis. CONCLUSIONS: The MMN changes between the studies associated with deterioration in the neuropsychological tests indicating that the method could be clinically useful. The performance of the younger patients was more likely to deteriorate during the treatment. SIGNIFICANCE: Changes in the MMN response during cancer treatment seem to be of clinical importance as indicates of the cognitive outcome of childhood cancer patients.

Physical activity and fitness in adolescent and young adult long-term survivors of childhood acute lymphoblastic leukaemia.

INTRODUCTION: There is a lack of data on physical activity (PA) and fitness of adolescent and young adult very long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: We studied 21 childhood ALL long-term survivors (aged 16-30 years, median time since diagnosis 15.9 y), diagnosed in 1986-1996, with age- and sex-matched controls. Peak oxygen uptake (VO(2 peak)) and muscle strength were measured and physical activity index (PAI; MET h/week) calculated. RESULTS: Mean VO(2 peak) of the ALL survivors was 34.8 ± 9.3 ml/kg/min. This was 14% lower than that of the controls (-5.7 ml/kg/min, 95% CI -9.4 to -1.9, p=0.01), and all the 11 female survivors performed below the age-adjusted reference values. The survivors also performed poorer in the sit-up and maximal jump tests (p=0.02 and p=0.004). Body mass index and PAI were similar in survivors and controls (p=0.34 and p=0.52). Nonetheless, as much as 30% of the male survivors and 36% of the female survivors had PAI ≤ 5 indicating very low levels of physical activity (PA). CONCLUSIONS: Insufficient PA and poor physical fitness are clinically important issues in childhood ALL long-term survivors treated with modern protocols. Girls seem to be especially at risk. PA and better physical fitness decrease cardiovascular mortality irrespective of weight. Thus, PA should be promoted throughout and after the treatment for ALL. IMPLICATIONS FOR CANCER SURVIVORS: Since insufficient PA and poor physical fitness are an issue in very long-term ALL survivors, they should be informed on the benefits of physical activity, and be strongly encouraged to adopt a physically active lifestyle.