Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.

Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti-oncogenic effects of exercise were associated with the exercise-mediated release of myokines such as interleukin (IL)-15. However, no study has quantified the acute IL-15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high-intensity interval exercise (HIIE) [4×4 min at 85-95% heart rate (HR) peak, 3 min at 50-70% HR peak] before and after 7 months of three times weekly high-intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL-15, IL-6, IL-10, IL-1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL-15 concentrations (pre-intervention: 113%; P = 0.013, post-intervention: 102%; P = 0.005). Post-exercise IL-15 concentrations were associated with all other post-exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre- or post-HIIE IL-15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL-15 and other myokines including IL-6, IL-10 and IL-1ra which may be clinically relevant in the anti-oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. KEY POINTS: Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise-induced myokines (IL-6 and IL-15). High-intensity interval exercise significantly increased myokines associated with the anti-oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL-15 has been implicated in the anti-oncogenic effect of exercise and is being explored as an immunotherapy agent, high-intensity interval exercise may improve outcomes for people living beyond cancer through IL-15-mediated pathways. Interventions that increase lean mass may also enhance this response.

Technical and biological reliability of pQCT measured bone and muscle tissue quality across the age-span.

INTRODUCTION: Reliable peripheral quantitative computed tomography (pQCT) assessment is essential to the accurate longitudinal reporting of bone and muscle quality. However, the between-day reliability of pQCT and the influence of age on outcome reliability is currently unknown. OBJECTIVE: To quantify the same- and between-day reliability of morphological pQCT at proximal and distal segments of the forearm, shank, and thigh, and explore the influence of participant body size, age, and sex on outcome reliability. METHODS: Men and women (49 % female, 18-85 years, n=72-86) completed two consecutive-day pQCT testing sessions, where repeat measurements were conducted on day-one for technical error, and between-day for biological error quantification. Testing was undertaken following best practice body composition testing guidance, including standardized presentation and consistent time-of-day. RESULTS: All measurements of bone were classified as having 'good' to 'excellent' reliability [intraclass correlation coefficient (r=0.786- 0.999], as were measurements of muscle area (ICC r=0.991-0.999) and total fat (r=0.996-0.999). However, between- and same-day muscle density measurements at the thigh and forearm were classified as 'poor' (r=0.476) and 'moderate' (r=0.622), respectively. Likewise, intramuscular fat area at the thigh was classified as 'moderate' (r=0.737) for between-day measurement. Biological error was inflated compared to technical error by an average of 0.4 % for most measurements. Error values tended to increase proportionally with the amount of tissue quantified and males had significantly greater biological error for measurement of distal tibial bone (p<0.002) and trabecular area (p<0.002). Biological error was inflated among older adults for measurement of forearm muscle density (p<0.002). CONCLUSIONS: Most pQCT outcomes can be implemented with confidence, especially outcomes that assess bone area and density at any of the radial, tibial, and femoral sites investigated herein. However, it is important to account for the influence of biological measurement error in further studies, especially for muscle and intramuscular fat outcomes derived by pQCT.

Exercise and the gut microbiome: implications for supportive care in cancer.

PURPOSE: Growing recognition of the gut microbiome as an influential modulator of cancer treatment efficacy and toxicity has led to the emergence of clinical interventions targeting the microbiome to enhance cancer and health outcomes. The highly modifiable nature of microbiota to endogenous, exogenous, and environmental inputs enables interventions to promote resilience of the gut microbiome that have rapid effects on host health, or response to cancer treatment. While diet, probiotics, and faecal microbiota transplant are primary avenues of therapy focused on restoring or protecting gut function in people undergoing cancer treatment, the role of physical activity and exercise has scarcely been examined in this population. METHODS: A narrative review was conducted to explore the nexus between cancer care and the gut microbiome in the context of physical activity and exercise as a widely available and clinically effective supportive care strategy used by cancer survivors. RESULTS: Exercise can facilitate a more diverse gut microbiome and functional metabolome in humans; however, most physical activity and exercise studies have been conducted in healthy or athletic populations, primarily using aerobic exercise modalities. A scarcity of exercise and microbiome studies in cancer exists. CONCLUSIONS: Exercise remains an attractive avenue to promote microbiome health in cancer survivors. Future research should elucidate the various influences of exercise modalities, intensities, frequencies, durations, and volumes to explore dose-response relationships between exercise and the gut microbiome among cancer survivors, as well as multifaceted approaches (such as diet and probiotics), and examine the influences of exercise on the gut microbiome and associated symptom burden prior to, during, and following cancer treatment.

Immunomodulatory Function of Interleukin-15 and Its Role in Exercise, Immunotherapy, and Cancer Outcomes.

Exercise has been shown to improve physical and psychosocial outcomes for people across the cancer care continuum. A proposed mechanism underpinning the relationship between exercise and cancer outcomes is exercise-induced immunomodulation via secretion of anti-inflammatory myokines from skeletal muscle tissue. Myokines have the potential to impair cancer growth through modulation of natural killer (NK) cells and CD8+ T cells while improving the effectiveness of cancer therapies. Interleukin-15 (IL-15), one of the most abundant myokines found in skeletal muscle, has a key immunoregulatory role in supporting the proliferation and maturation of T cells and NK cells, which have a key role in the host's immune response to cancer. Furthermore, IL-15 is being explored clinically as an immunotherapy agent with doses similar to the IL-15 concentrations released by skeletal muscle during exercise. Here we review the role of IL-15 within the immune system, examine how IL-15 is produced as a myokine during exercise, and how it may improve outcomes for people with cancer, specifically as an adjuvant or neoadjuvant to immunotherapy. We summarize the available evidence showing changes in IL-15 in response to both acute exercise and training, and the results are inconsistent; higher quality research is needed to advance the understanding of how exercise-mediated increases in IL-15 potentially benefit those who are being treated for, or who have had, cancer.

Between-day reliability of cytokines and adipokines for application in research and practice.

Purpose: This study assessed the biological reliability of peripheral human cytokines and adipokines, and the influence of participant characteristics on total error. This has essential application to interventional cytokine measurement to ensure that reported results are interpreted with confidence. Methods: Participants (49% female, 18-85 years, n = 84) completed two consecutive-day testing sessions. Participants provided a venous blood sample at the same time of day across two consecutive days, under standardized participant presentation, including 24-h rested and 12-h fasted conditions. Multiplex immunoassay was used to assess inflammatory analytes from samples (predominantly plasma). Repeat measurements were conducted between-day for total precision quantification, and technical (technique) error was negated from the total to provide an estimate of biological (attributed to participant presentation) error. Results: Whilst there was no evidence of statistically significant biological error, a small amount of biological error was consistently present across most analytes (∼3.3%/0.07 pg/ml), which was largest for measurement of leptin (7.3%/210 pg/ml). There was also an influence of sex on reliability of leptin and adiponectin (total model explained 6-7% of error variation), where females demonstrated the greatest error. Conclusion: Biological error reported in this study should be applied to any future study or individual with a repeated measurement of cytokine concentrations over time that maintain best practice procedures (12-h fasted, 24-h rested). In most cases, raw error should be used, with exceptions for women for measurement of leptin and adiponectin. This approach will ensure that results are reported with certainty for improved reporting of intervention efficacy.

Accuracy of body composition measurement techniques across the age span.

This study investigated the acceptable accuracy of common body composition techniques compared with the reference 4-compartment (4C-R) model, which has not been investigated in a sample with diverse characteristics, including age and sex. Techniques included components of the 4C-R model [dual-energy X-ray absorptiometry, air displacement plethysmography, deuterium dilution (DD)] and surrogate compartment models, which utilised bioelectrical impedance spectroscopy (BIS) rather than DD. Men and women (sex = 1:1, 18-85 years, n = 90) completed body composition testing under best-practice guidance. For measurement of individuals, only the reference 3-compartment (3C-R) equation met acceptable error limits (<5% error among individuals) within the a priori cut-point (80%) for fat-free mass (FFM; CV = 0.52%) and fat mass (FM; CV = 1.61%). However, all investigated techniques reached equivalency to the 4C-R model for FFM on average (CV = 0.52-4.31%), but for FM only the 3C and 4C equations that included quantification of total body water (TBW) by DD or BIS reached equivalency overall (CV = 1.61-6.68%). Sex and age minimally influenced accuracy. Only the 3C-R or 4C-R equations are supported for acceptable individual accuracy for both FFM and FM. For group estimates any investigated technique could be used with acceptable accuracy for FFM; however, for FM, inclusion of TBW measurement within a compartment model is necessary. Novelty: Only the referent 3C and 4C models (including deuterium dilution) provide accurate body composition results that are acceptable for measurement of individuals in the general population. For group estimates of lean mass in the general population, compartments models that include TBW must be used for accurate measurement.

How body composition techniques measure up for reliability across the age-span.

BACKGROUND: Reliability of body composition measurement techniques is essential to the accurate reporting of intervention outcomes. However, the between-day precision error of commonly used techniques, as well as the reference multi-compartment model, in a population-representative sample are currently unknown. OBJECTIVES: To quantify technical and biological precision error of body composition techniques in comparison to the referent 4-compartment (4C) model. METHODS: Men and women (1:1 ratio; 18-85 years old; n = 90) completed 2 consecutive-day body composition testing sessions, including individual components of the referent 4C model. Testing was undertaken in accordance with best practice guidance for each technique, including standardized presentation and a consistent time of day. Repeat measurements were conducted on day 1 for technical precision, and between-day measurements were conducted for biological precision quantification. RESULTS: On average, all measurements met acceptable error limits and presented typically low technical and biological error [<2% fat-free mass (FFM) and < 3% fat mass (FM) precision error]. For technical precision of FFM, all techniques met a priori cut points (80%; CV = 0.45-0.81%). For FM, all techniques were equivalent to the best-rating method on average (CV = 0.78-1.35%), except air displacement plethysmography (CV = 2.13%). For biological precision, only 3-compartment (3C) and 4C equations sufficiently met the a priori determined cut point for estimates for FFM (CV = 0.77-0.79%), and only DXA met the 80% cut point (CV = 1.17%) for FM. CONCLUSIONS: The primary purpose of a study design is imperative when deciding on body composition assessment techniques used for longitudinal measurements. If reliable longitudinal assessments of FFM are central, a 3C or 4C model may be indicated. If FM is a primary outcome, DXA may be preferable. However, considering the low error rates presented within the current study across a broad age span of healthy adults with implementation of best-practice guidelines, any technique assessed here may be used, provided that strict protocols are adhered to.