Combined exercise intervention in a mouse model of high-risk neuroblastoma: effects on physical, immune, tumor and clinical outcomes.

Background: Exercise might exert anti-tumoral effects in adult cancers but this question remains open in pediatric tumors, which frequently show a different biology compared to adult malignancies. We studied the effects of an exercise intervention on physical function, immune variables and tumoral response in a preclinical model of a highly aggressive pediatric cancer, high-risk neuroblastoma (HR-NB). Methods: 6-8-week-old male mice with orthotopically-induced HR-NB were assigned to a control (N = 13) or exercise (5-week combined [aerobic+resistance]) group (N = 17). Outcomes included physical function (cardiorespiratory fitness [CRF] and muscle strength), as well as related muscle molecular indicators, blood and tumor immune cell and molecular variables, tumor progression, clinical severity, and survival. Results: Exercise attenuated CRF decline (p=0.029 for the group-by-time interaction effect), which was accompanied by higher muscle levels of oxidative capacity (citrate synthase and respiratory chain complexes III, IV and V) and an indicator of antioxidant defense (glutathione reductase) in the intervention arm (all p≤0.001), as well as by higher levels of apoptosis (caspase-3, p=0.029) and angiogenesis (vascular endothelial growth factor receptor-2, p=0.012). The proportion of 'hot-like' (i.e., with viable immune infiltrates in flow cytometry analyses) tumors tended to be higher (p=0.0789) in the exercise group (76.9%, vs. 33.3% in control mice). Exercise also promoted greater total immune (p=0.045) and myeloid cell (p=0.049) infiltration within the 'hot' tumors, with a higher proportion of two myeloid cell subsets (CD11C+ [dendritic] cells [p=0.049] and M2-like tumor-associated macrophages [p=0.028]), yet with no significant changes in lymphoid infiltrates or in cirulating immune cells or chemokines/cytokines. No training effect was found either for muscle strength or anabolic status, cancer progression (tumor weight and metastasis, tumor microenvironment), clinical severity, or survival. Conclusions: Combined exercise appears as an effective strategy for attenuating physical function decline in a mouse model of HR-NB, also exerting some potential immune benefits within the tumor, which seem overall different from those previously reported in adult cancers.

Physical exercise effects on metastasis: a systematic review and meta-analysis in animal cancer models.

Physical exercise is considered a well-tolerated adjuvant therapy to mitigate cancer-related side effects, but its impact on metastasis is unclear. The present systematic review and meta-analysis aimed to summarize the evidence on the effects of exercise on metastasis in animal cancer models. A systematic search was conducted to identify controlled studies in animals analyzing the impact of exercise interventions on any marker of metastasis incidence or severity. The pooled mean differences (PMD) were calculated for those endpoints for which a minimum of three studies used the same assessment method. We also calculated the pooled odds ratio (OR) of metastases. Twenty-six articles were included in the systematic review, of which 12 could be meta-analyzed. Exercise training in murine cancer models did not significantly modify the number of metastatic foci (PMD = - 3.18; 95% confidence interval [CI] - 8.32, 1.97; p = 0.23), the weight of metastatic tumors (PMD = - 0.03; 95% CI - 0.10, 0.04; p = 0.41), or the risk of developing metastasis (OR = 0.64; 95% CI 0.10, 4.12; p = 0.64). These findings suggest that exercise has no overall influence on any marker of cancer metastasis incidence or severity in animal models. However, the wide methodological heterogeneity observed between studies might be taken into account and the potential exercise effects on metastasis development remain to be determined in pediatric tumors.

What are the effects of exercise training in childhood cancer survivors? A systematic review.

This systematic review aimed to summarize evidence on the effects of physical exercise interventions in childhood cancer survivors (CCS) who had finished anticancer therapy ≥ 1 year before the study. Relevant articles were identified in the electronic databases PubMed, Web of Science, and SPORTDiscus (from inception to June 27, 2019). The PEDro scale was used to assess methodological quality. Twelve studies including 109 CCS met all inclusion criteria and were included in the systematic review. The quality of the included studies was overall low. Physical exercise improved endothelial function, reduced waist circumference, and waist-to-hip ratio and increased physical activity levels. Preliminary evidence was found regarding benefits on brain volume and structure after exercise interventions in childhood brain tumor survivors. Only two studies reported exercise-related adverse events. Physical exercise seems to be safe and effective for improving several health markers in CCS, but further high-quality research and especially randomized controlled trials are needed to confirm these results.

Benefits of exercise and immunotherapy in a murine model of human non-small-cell lung carcinoma.

BACKGROUND: Lung cancer has the highest incidence and mortality rate in the world. One of the most promising new cancer therapies in recent years is immunotherapy, which is based on the blockade of immune checkpoints such as programmed cell death protein 1 (PD-1). Exercise training is beneficial to maintain and improve the quality of life of cancer patients, and it might also modulate the anti-tumoral efficiency of some chemotherapeutic agents. However, the potential of exercise combined with immunotherapy as a cancer therapy remains to be elucidated. Here, we examined the effects of exercise on tumor growth and its possible adjuvant effects when combined with anti-PD-1 immunotherapy (nivolumab) in a patient derived xenograft (PDX) model of non-small-cell lung carcinoma (NSCLC). METHODS: We generated a PDX model using NOD-SCID gamma mice with subcutaneous grafts from tumor tissue of a patient with NSCLC. Animals were randomly assigned to one of four groups: non-exercise + isotype control (n=5), exercise + isotype control (n=5), non-exercise + nivolumab (n=6) or exercise + nivolumab (n=6). The animals undertook an 8- week moderate-intensity training regimen (treadmill aerobic exercise and strength training). Immunotherapy (nivolumab) or an isotype control was administered 2 days/week, for 6 weeks. Several tumor growth and microenvironment parameters were measured after the intervention. RESULTS: Improvements in aerobic capacity and muscle strength (p=0.027 and p=0.005) were noted in exercised animals. Exercise alone reduced the tumor growth rate with respect to non-exercised mice (p=0.050). The double intervention (exercise + nivolumab) increased tumor necrosis and reduced apoptosis with respect to controls (p=0.026; p=0.030). All interventions achieved a reduction in proliferation compared with the control group (p=0.015, p=0.011, and p=0.011). Exercise alone increased myeloid tumor infiltrates (mostly neutrophils) with respect to the nivolumab only group (p=0.018). Finally, Vegf-a expression was higher in the nivolumab groups (in combination or not with exercise) than in exercise + isotype control group (p=0.045 and p=0.047, respectively). No other significant effects were found. CONCLUSIONS: Our results would suggest that aerobic and strength training should be studied as an adjuvant to cancer immunotherapy treatment.

Inhospital exercise benefits in childhood cancer: A prospective cohort study.

Childhood cancer patients are at risk of developing important adverse effects, mortality and disease relapse after treatments, which has a substantial economic impact on healthcare systems. The objective of this study was to determine the effects of supervised inhospital exercise on clinical endpoints during childhood cancer treatment. 169 children with a new diagnosis of cancer were divided into an exercise intervention (n = 68, 11 ± 4 years) or a control group (n = 101, 11 ± 3 years). The cohort was followed up from the start of treatment for up to five years. Supervised inhospital exercise intervention was performed during the neoadjuvant (for solid tumors) or intensive chemotherapy treatment period (for leukemias). The median duration of the intervention was 22 (interquartile range, 14-28) weeks. We assessed survival, risk of disease relapse or metastasis, and days of hospitalization (primary outcomes), and cardiovascular function, anthropometry and blood variables (secondary outcomes). No exercise-related adverse events were noted. The exercise group had significantly less days of hospitalization than the control group (P = .031), resulting in a lower (~-17%) mean total economic cost of hospitalization in the former. Moreover, echocardiography-determined left ventricular function (ejection fraction and fractional shortening) was significantly impaired in the control group after treatment compared with baseline, whereas it was maintained in the exercise group (P = .024 and .021 for the between-group differences, respectively). In conclusion, supervised inhospital exercise intervention is safe and plays a cardioprotective role, at least in the short term, in children with cancer, also reducing hospitalization time, and therefore alleviating the economic burden.

Reply: Letter to the Editor: Exercise Interventions and Cardiovascular Health in Childhood Cancer: A Meta-Analysis.

Dear EditorWe sincerely appreciate the nice comments by Drs. P.V. da Costa Ghignatti and R. Pereira de Lima 1 concerning our recent meta-analysis assessing the effects of physical exercise interventions on cardiovascular endpoints in childhood cancer survivors 2. They are quite right to remain that even non-significant improvements in cardiorespiratory fitness (CRF) might be clinically relevant. Indeed, we still do not know if CRF increments of a theoretically low magnitude (i. e., <1 metabolic equivalent) might have a prognostic value in the context of pediatric cancer and treatment-associated cardiotoxicity. We also agree that unsupervised exercise interventions are unlikely to be as effective as tailored programs, especially because the latter allow for intensity to being adequately controlled and thus gradually increased. It is indeed our opinion, after long years of experience working with children with cancer as well as with other debilitated clinical populations, that there is always room for physiological improvement and ideally loads should be gradually improved instead of remaining stable.

Exercise Interventions and Cardiovascular Health in Childhood Cancer: A Meta-analysis.

This study analyzed the effects of physical exercise interventions on cardiovascular endpoints in childhood cancer survivors. Relevant articles were systematically searched in PubMed, CINAHL, and Web of Science databases (since inception to 11th September 2019). We performed a meta-analysis (random effects) to determine the mean difference (expressed together with 95% confidence intervals) between pre- and post-intervention values for those cardiovascular endpoints reported in more than three studies. Twenty-seven studies (of which 16 were controlled studies) comprising 697 participants were included. Only three studies reported adverse events related to exercise interventions. Exercise resulted in an increased performance on the 6-minute walk distance test (mean difference=111 m, 95% confidence interval=39-183, p=0.003) and a non-significant trend (mean difference=1.97 ml∙kg-1∙min-1, 95% confidence interval=-0.12-4.06, p=0.065) for improvement in peak oxygen uptake. Furthermore, left ventricular ejection fraction was preserved after exercise interventions (mean difference=0.29%, 95% confidence interval=-1.41-1.99, p=0.738). In summary, exercise interventions might exert a cardioprotective effect in childhood cancer survivors by improving - or attenuating the decline of - physical capacity and cardiovascular function. Further studies, particularly randomized controlled trials, are needed to confirm these benefits.

Physical exercise and Prader-Willi syndrome: A systematic review.

OBJECTIVE: The aim of this systematic review was to summarize evidence on the acute responses of individuals with Prader-Willi syndrome (PWS) to physical exercise, and on the effectiveness of long-term exercise interventions to improve the clinical manifestations of this syndrome. DESIGN/METHODS: Relevant articles were identified in the electronic databases PubMed, Medline, CINAHL and SPORTDiscus (from inception to December 2018). Twenty-two studies including a total of 356 patients with PWS met all inclusion criteria and were included in the review. RESULTS: Patients with PWS present with a decreased physical performance and impaired cardiorespiratory (maximal oxygen consumption, heart rate recovery after exercise) and hormonal (growth hormone release) responses to exercise. Most long-term exercise interventions have proven to decrease body mass while improving physical performance. Some benefits have also been reported in biochemical (glucose homeostasis, lipid profile) and biomechanical (gait pattern) variables, although there is controversy regarding the effects on body composition. No exercise-related adverse events have been reported in patients with PWS. CONCLUSION: Physical exercise seems to be safe and effective for improving several phenotypes in PWS, notably physical fitness. However, further research is needed to confirm these results and especially to corroborate whether exercise per se or combined with dietary intervention is an effective coadjuvant treatment for reducing body mass in these patients.

On- Versus Off-Bike Power Training in Professional Cyclists: A Randomized Controlled Trial.

PURPOSE: To compare the effectiveness of resistance power training (RPT, training with the individualized load and repetitions that maximize power output) and cycling power training (CPT, short sprint training) in professional cyclists. METHODS: The participants (20 [2] y, peak oxygen uptake 78.0 [4.4] mL·kg-1·min-1) were randomly assigned to perform CPT (n = 8) or RPT (n = 10) in addition to their usual training regime for 7 weeks (2 sessions/wk). The training loads were continuously registered using the session rating of perceived exertion. The outcomes included endurance performance (8-min time trial and incremental test), as well as measures of muscle strength/power (1-repetition maximum and mean maximum propulsive power on the squat, hip thrust, and lunge exercises) and body composition (assessed by dual-energy X-ray absorptiometry). RESULTS: No between-group differences were found for training loads or for any outcome (P > .05). Both interventions resulted in increased time-trial performance, as well as in improvements in other endurance-related outcomes (ie, ventilatory threshold, respiratory compensation point; P < .05). A significant or quasi-significant increase (P = .068 and .047 for CPT and RPT, respectively) in bone mineral content was observed after both interventions. A significant reduction in fat mass (P = .017), along with a trend (P = .059) toward a reduced body mass, was observed after RPT, but not CPT (P = .076 for the group × time interaction effect). Significant benefits (P < .05) were also observed for most strength-related outcomes after RPT, but not CPT. CONCLUSION: CPT and RPT are both effective strategies for the improvement of endurance performance and bone health in professional cyclists, although the latter tends to result in greater improvements in body composition and muscle strength/power.

Is health status impaired in childhood cancer survivors? A systematic review and meta-analysis.

BACKGROUND: An increase in survival rates of childhood cancer is associated with long-term health issues in survivors. METHODS: We conducted a systematic review and meta-analysis comparing health status-related endpoints in childhood cancer survivors (CCS) versus controls. RESULTS: Eighty-six studies (n = 98,480 participants, 62% CCS) were included in the review. Of these, 73 studies (n = 96,550, 63% CCS) could be meta-analyzed. CCS showed a lower left ventricular ejection and fractional shortening (SMD=-0.59 and -0.55, respectively, both p < 0.01 [n=1,824 and 1,880]), a lower HDL-cholesterol concentration (SMD=-0.48, p<0.001, n=1,378) and a higher waist-to-hip ratio (SMD=0.61, p < 0.01, n=229) than their healthy peers. No significant differences were found for the remaining endpoints. CONCLUSIONS: CCS is associated with a lower left ventricular function and HDL-cholesterol level, and a higher waist-to-hip ratio than healthy controls. These findings support the need to closely monitor the cardiometabolic health status of CCS and to implement preventive lifestyle interventions for this population.

Exercise training in childhood cancer: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Physical capacity and quality of life (QoL) are typically impaired in children/adolescents with cancer. Our primary objective was to examine the effects of exercise training performed after diagnosis of any type of pediatric cancer on physical capacity-related endpoints, survival, disease relapse and adverse effects. METHODS: (a) Search and selection criteria: Systematic review in Pubmed and Web of Science (until August 2018) of randomized controlled trials (RCTs) of exercise interventions in children with cancer during treatment or within one year after its end. (b) Data collection: Two authors independently identified studies meeting inclusion criteria, extracted data, and assessed risk of bias using standardized forms. When needed, we contacted authors to request clarifications or additional data. (c) Statistical Analysis: The pooled standardized mean differences (SMD) were calculated for those endpoints for which a minimum of three RCTs used the same assessment method. We also calculated the pooled odds ratio (OR) of dying or having a tumor relapse. RESULTS: Eight RCTs (n = 283 patients) were included in the systematic review. Of these, five studies (n = 173) could be meta-analyzed. Exercise training during pediatric cancer treatment significantly improves patients' functional mobility, as assessed with the timed up and down stairs test (SMD: -0.73, p < 0.001) and does not affect mortality (OR: 0.85, p = 0.76) or relapse risk (OR: 0.96, p = 0.94). CONCLUSIONS: Exercise training in children with cancer improves functional mobility. More RCTs analyzing the effects of supervised exercise interventions are needed, as well as the development of a core-set of outcomes in pediatric oncology exercise research.

Inhospital Exercise Training in Children With Cancer: Does It Work for All?

Purpose: Physical exercise training might counteract the weakening effects of both pediatric cancer and anti-cancer treatment. We aimed to analyze the prevalence of "responders" and "non-responders" to inhospital exercise training in children with cancer and to identify the factors that could influence responsiveness, which might help personalize exercise interventions for this patient population. Methods: We performed an ancillary analysis of the randomized controlled trial "Physical activity in Pediatric Cancer" (NCT01645436), in which 49 children with solid tumors were allocated to an inhospital exercise intervention or control group. The present study focused on the children in the former group (n = 24, 10 ± 4 years), who performed 3 weekly training sessions (aerobic + strength exercises). The intervention lasted 19 ± 8 weeks (i.e., from the start to the end of neoadjuvant chemotherapy treatment). A responder-vs-non-responder analysis was performed for physical capacity-related endpoints (five-repetition maximum strength, functional mobility tests, and cardiorespiratory fitness [CRF]). Only those participants showing improvements in a given test of a magnitude greater than both the random error and the threshold for clinically meaningful changes were considered responders. Results: Most participants improved their performance in the strength tests, with 80, 88, and 93% of total showing a positive response for seated bench press, lateral row, and leg press, respectively (p < 0.001). No significant improvements were observed for the functional mobility tests or CRF (p > 0.05, rate of responsiveness ≤ 50%). No differences between responders and non-responders were observed for sex, age, type of cancer, or treatment (i.e., including or not anthracyclines/radiotherapy). However, significant differences (p < 0.05) were observed between responders and non-responders for baseline performance in all the tests, and a significant (p < 0.05) inverse relationship was found between baseline performance and relative improvement for most endpoints. Conclusions: Although most children improved their muscle strength after the exercise intervention, a considerable individual variability was observed for the training responsiveness of functional mobility and CRF. A lower baseline performance was associated with a higher responsiveness for all the study endpoints, with the fittest children at the start of treatment showing the lowest responses. Efforts to individualize exercise prescription are needed to maximize responsiveness in pediatric cancer patients.