Quality of life in patients with myositis is associated with functional capacity, body composition, and disease activity-Baseline data from a randomized controlled trial.

OBJECTIVE: To investigate the potential associations between functional capacity, muscle strength, body composition, and disease-related measures and quality of life in patients with myositis. METHODS: Baseline measures of functional capacity (functional index 3 (FI3), 2-minute walk test (2MWT), timed up and go (TUG) and 30-s sit-to-stand (30-STS)), muscle strength (incl. leg and handgrip strength), maximal leg extensor power, body composition (appendicular lean mass, fat percentage/mass) and disease-related measures (disease activity & damage core sets) were examined for their associations with quality of life (physical- and mental component summary scores, Short Form 36 questionnaire (SF-36)) by means of Spearman's correlation analysis. RESULTS: A total of 32 patients with myositis were included. Positive correlations between SF-36 physical component summary score (PCS) and FI3, 30-STS, TUG, 2MWT, leg extensor power, leg strength, bench press strength, and handgrip strength were observed. In contrast, fat percentage and fat mass correlated negatively with PCS. In disease-related measures, Extramuscular global assessment, health assessment questionnaire, physician global damage, and patient global damage scores were negatively associated with SF-36 PCS. No correlations to the mental component summary score of SF-36 were observed. CONCLUSION: All measures of functional capacity were positively related to the SF-36 physical component summary score, indicating higher functional capacity positively affects quality of life in patients with myositis. Health assessment questionnaire and patient global damage scores demonstrated the strongest correlations with SF-36 physical component summary scores, further supporting these patient-reported outcomes as viable monitoring tools in patients with myositis.

Harms of exercise training in patients with cancer undergoing systemic treatment: a systematic review and meta-analysis of published and unpublished controlled trials.

Background: Exercise is recommended for people with cancer. The aim of this study was to evaluate the harms of exercise in patients with cancer undergoing systemic treatment. Methods: This systematic review and meta-analysis included published and unpublished controlled trials comparing exercise interventions versus controls in adults with cancer scheduled to undergo systemic treatment. The primary outcomes were adverse events, health-care utilization, and treatment tolerability and response. Eleven electronic databases and trial registries were systematically searched with no date or language restrictions. The latest searches were performed on April 26, 2022. The risk of bias was judged using RoB2 and ROBINS-I, and the certainty of evidence for primary outcomes was assessed using GRADE. Data were statistically synthesised using pre-specified random-effect meta-analyses. The protocol for this study was registered in the PROESPERO database (ID: CRD42021266882). Findings: 129 controlled trials including 12,044 participants were eligible. Primary meta-analyses revealed evidence of a higher risk of some harms, including serious adverse events (risk ratio [95% CI]: 1.87 [1.47-2.39], I2 = 0%, n = 1722, k = 10), thromboses (risk ratio [95% CI]: 1.67 [1.11-2.51], I2 = 0%, n = 934, k = 6), and fractures (risk ratio [95% CI]: 3.07 [3.03-3.11], I2 = 0%, n = 203, k = 2) in intervention versus control. In contrast, we found evidence of a lower risk of fever (risk ratio [95% CI]: 0.69 [0.55-0.87], I2 = 0% n = 1109, k = 7) and a higher relative dose intensity of systemic treatment (difference in means [95% CI]: 1.50% [0.14-2.85], I2 = 0% n = 1110, k = 13) in intervention versus control. For all outcomes, we downgraded the certainty of evidence due to imprecision, risk of bias, and indirectness, resulting in very low certainty of evidence. Interpretation: The harms of exercise in patients with cancer undergoing systemic treatment are uncertain, and there is currently insufficient data on harms to make evidence-based risk-benefits assessments of the application of structured exercise in this population. Funding: There was no funding for this study.

Exercise training to increase tumour natural killer-cell infiltration in men with localised prostate cancer: a randomised controlled trial.

OBJECTIVES: To explore the effects of preoperative high-intensity interval training (HIIT) compared to usual care on tumour natural killer (NK)-cell infiltration in men with localised prostate cancer (PCa), as NK-cell infiltration has been proposed as one of the key mechanisms whereby exercise can modulate human tumours. PATIENTS AND METHODS: A total of 30 patients with localised PCa undergoing radical prostatectomy (RP) were randomised (2:1) to either preoperative aerobic HIIT four-times weekly (EX; n = 20) or usual care (CON; n = 10) from time of inclusion until scheduled surgery. Tumour NK-cell infiltration was assessed by immunohistochemistry (CD56+ ) in diagnostic core needle biopsies and corresponding prostatic tissue from the RP. Changes in cardiorespiratory fitness, body composition, blood biochemistry, and health-related quality of life were also evaluated. RESULTS: The change in tumour NK-cell infiltration did not differ between the EX and CON groups (between-group difference: -0.09 cells/mm2 , 95% confidence interval [CI] -1.85 to 1.66; P = 0.913) in the intention-to-treat analysis. The total number of exercise sessions varied considerably from four to 30 sessions. The per-protocol analysis showed a significant increase in tumour NK-cell infiltration of 1.60 cells/mm2 (95% CI 0.59 to 2.62; P = 0.004) in the EX group. Further, the total number of training sessions was positively correlated with the change in NK-cell infiltration (r = 0.526, P = 0.021), peak oxygen uptake (r = 0.514, P = 0.035) and peak power output (r = 0.506, P = 0.038). CONCLUSION: Preoperative HIIT did not result in between-group differences in tumour NK-cell infiltration. Per-protocol and exploratory analyses demonstrate an enhanced NK-cell infiltration in PCa. Future studies are needed to test the capability of exercise to increase tumour immune cell infiltration.

Effects of acute exercise training on tumor outcomes in men with localized prostate cancer: A randomized controlled trial.

Postdiagnosis physical activity is associated with improved cancer outcomes, but biological mechanisms mediating anticancer effects remain unclear. Recent findings suggest that physiological adaptations to acute exercise comprise potential anticancer effects, but these remain poorly explored in clinical settings. The objective of this study was to explore the effects of a single exercise bout on tumor oxygenation and immune cell infiltration in patients with prostate cancer. Thirty patients with localized prostate cancer were randomized (2:1) to either one high-intensity interval training bout or no exercise on the day before radical prostatectomy. Immunohistochemical analyses were performed on prostatic tissue from surgery and assessed for tumor hypoxia, natural killer (NK) cell infiltration, and microvessel density (MVD). Acute systemic response in blood lymphocytes, epinephrine, norepinephrine, IL-6, tumor necrosis factor, cortisol, lactate, and glucose was also evaluated. We did not find between-group differences in tumor hypoxia (Mann-Whitney U test, U = 83.5, p = 0.604) or NK cell infiltration (U = 77.0, p = 0.328). Also, no significant correlation was found between MVD and tumor hypoxia or NK cell infiltration. One exercise bout is likely insufficient to modulate tumor hypoxia or NK cell infiltration. Future studies may elucidate if an accumulation of several exercise bouts can impact these outcomes (NCT03675529, www.clinicaltrials.gov).

The effects of acute exercise and inflammation on immune function in early-stage prostate cancer.

Background: The immune system plays a vital role in cancer development and progression. Strategies mobilizing cytotoxic cells of the immune system to combat immunosuppression in cancer may help to improve the treatment response of patients. To this end, we aimed to characterize the anti-cancer effect of acute exercise, including the involvement of inflammatory signals. Patients and methods: Twenty patients with early-stage prostate cancer (PCa) scheduled to undergo prostatectomy performed one bout of acute exercise consisting of a watt-max test and four high-intensity intervals. Natural Killer (NK), NKT-like and T cell phenotype, NK cell cytotoxic activity (NKCA), and NKCA per-cell against cell lines of leukemia (K562) and prostate cancer origin (LNCaP and PC-3) were assessed. Inflammatory markers (TNF-α, IL-6, and CRP) were measured in plasma. Results: Exercise increased NK, NKT-like, and CD8 T cell concentration in the circulation. Furthermore, exercise shifted immune cells towards a mature and cytotoxic phenotype e.g., NK cells exhibited higher CD57 as well as lower NKG2A expression. NKT-like and CD8 cells exhibited elevated CD57, TIGIT and Granzyme-B expression. Exercise significantly improved NKCA against K562 (+16% [5%; 27%]; p = 0.002) and LNCaP (+24% [14%; 34%]; p < 0.001) but not PC-3. NKCA per NK cell decreased during exercise and increased 1-h post exercise compared to baseline in K562, LNCap, and PC-3 cell lines. Baseline IL-6 correlated with lymphocyte, monocyte and T cell concentration pre-exercise and inversely correlated with the fold-change of mobilized lymphocytes and CD8 T cells during exercise. Furthermore, baseline IL-6 and TNF-α inversely correlated with NKCA against PC-3 cells during exercise. Conclusions: Acute exercise mobilized cytotoxic immune cells and improved NKCA in patients with PCa whereas low-grade inflammation might impair the response. Whether the observed improvements impact long-term outcomes warrant further investigation. Clinical trial number: NCT03675529.

Amino Acid Metabolism and Protein Turnover in Lean and Obese Humans During Exercise-Effect of IL-6 Receptor Blockade.

CONTEXT: Interleukin-6 (IL-6) is implicated in skeletal muscle wasting and in regulating skeletal muscle hypertrophy in the healthy state. OBJECTIVE: This work aimed to determine the role of IL-6 in regulating systemic protein and amino acid metabolism during rest, exercise, and recovery in lean and obese humans. METHODS: In a nonrandomized, single-blind design, 12 lean and 9 obese individuals were infused first with 0.9% saline (Saline), secondly with the IL-6 receptor antibody tocilizumab (Acute IL-6R ab), and 21 days later with saline while still under tocilizumab influence (Chronic IL-6R ab). Outcome measures were determined before, during, and after 90 minutes of exercise at 40% Wattmax by isotope dilution technique, using primed continuous infusion of L-[ring-D5]phenylalanine and L-[D2]tyrosine. Main outcomes measures included systemic protein turnover and plasma amino acid concentrations. RESULTS: We saw no effect of acute or chronic IL-6 receptor blockade on protein turnover. In lean individuals, chronic IL-6 receptor blockade increased plasma concentrations of total amino acids (rest Δ + 186 µmol/L; 95% CI, 40-332; recovery Δ + 201 µmol/L; 95% CI, 55-347) and essential amino acids (rest Δ + 43 µmol/L; 95% CI, 12-76; recovery Δ + 45 µmol/L; 95% CI, 13-77) independently of exercise but had no such effect in obese individuals (total amino acids rest Δ + 63 µmol/L; 95% CI, -170 to 295, recovery Δ - 23 µmol/L, 95% CI, -256 to 210; essential amino acids rest Δ + 26 µmol/L; 95% CI, -21 to 73, recovery Δ + 11 µmol/L; 95% CI, -36 to 58). CONCLUSION: IL-6 receptor blockade has no effect on protein turnover in fasting lean and obese humans during rest, exercise, and recovery. Chronic IL-6 receptor blockade increases total and essential amino acid concentrations only in lean individuals.

Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men.

Lack of interleukin-6 (IL-6) leads to expansion of adipose tissue mass in rodents and humans. The exact underlying mechanisms have not been identified. In this placebo-controlled, non-randomized, participant-blinded crossover study, we use the IL-6 receptor antibody tocilizumab to investigate the role of endogenous IL-6 in regulating systemic energy metabolism at rest and during exercise and recovery in lean and obese men using tracer dilution methodology. Tocilizumab reduces fatty acid appearance in the circulation under all conditions in lean and obese individuals, whereas lipolysis (the rate of glycerol appearance into the circulation) is mostly unaffected. The fact that fatty acid oxidation is unaffected by IL-6 receptor blockade suggests increased re-esterification of fatty acids. Glucose kinetics are unaffected. We find that blocking endogenous IL-6 signaling with tocilizumab impairs fat mobilization, which may contribute to expansion of adipose tissue mass and, thus, affect the health of individuals undergoing anti-IL-6 therapy (Clinicaltrials.gov: NCT03967691).

Cardiorespiratory fitness and physical performance after childhood hematopoietic stem cell transplantation: a systematic review and meta-analysis.

The effects of childhood hematopoietic stem cell transplantation (HSCT) on key organs can impair cardiorespiratory fitness, muscle strength, and physical performance. We aimed to provide an overview of childhood HSCT survivors' status on these parameters compared with healthy controls and discuss current insights into clinical risk factors. We performed a systematic search in six scientific databases, including studies published before April 2019 and performed a meta-analysis on cardiorespiratory fitness. Muscle strength and physical performance status were presented narratively. We included ten studies embodying 517 childhood HSCT survivors (mean 17.8 years at follow-up). The meta-analysis (n = 4 studies) showed that childhood HSCT survivors have lower cardiorespiratory fitness compared with healthy controls (Standard mean difference (SMD) -1.32 [95% CI -1-58 to -1.07]; I2 2%, p < 0.00001). Collectively, the studies indicated that childhood HSCT survivors have lower muscle strength (n = 4 studies) and physical performance (n = 3 studies) compared with healthy controls. Childhood HSCT survivors have impaired cardiorespiratory fitness years after ended treatment. Muscle strength and physical performance seem to be impaired, although these measures are insufficiently investigated. Associations between HSCT-specific clinical risk factors and cardiorespiratory fitness, muscle strength, and physical performance are required.

Assessment of sarcopenia in patients with upper gastrointestinal tumors: Prevalence and agreement between computed tomography and dual-energy x-ray absorptiometry.

BACKGROUND & AIMS: Sarcopenia is associated with an increased risk of complications to treatment and lower survival rates in patients with cancer, but there is a lack of agreement on cut-off values and assessment methods. We aimed to investigate the prevalence of sarcopenia assessed by dual-energy x-ray absorptiometry (DXA) and computed tomography (CT) as well as the agreement between the methods for identification of sarcopenia. METHODS: This cross-sectional study pooled data from two studies including patients scheduled for surgery for gastrointestinal tumors. We assessed sarcopenia using two different cut-off values derived from healthy young adults for DXA and two for CT. Additionally, we used one of the most widely applied cut-off values for CT assessed sarcopenia derived from obese cancer patients. The agreement between DXA and CT was evaluated using Cohen's kappa. The mean difference and range of agreement between DXA and CT for estimating total and appendicular lean soft tissue were assessed using Bland-Altman plots. RESULTS: In total, 131 patients were included. With DXA the prevalence of sarcopenia was 11.5% and 19.1%. Using CT, the prevalence of sarcopenia was 3.8% and 26.7% using cut-off values from healthy young adults and 64.1% using the widely applied cut-off value. The agreement between DXA and CT in identifying sarcopenia was poor, with Cohen's kappa values ranging from 0.05 to 0.39. The mean difference for estimated total lean soft tissue was 1.4 kg, with 95% limits of agreement from -8.6 to 11.5 kg. For appendicular lean soft tissue, the ratio between DXA and CT was 1.15, with 95% limits of agreement from 0.92 to 1.44. CONCLUSIONS: The prevalence of sarcopenia defined using DXA and CT varied substantially, and the agreement between the two modalities is poor.

Interval Walking Improves Glycemic Control and Body Composition After Cancer Treatment: A Randomized Controlled Trial.

CONTEXT: Patients with colorectal cancer have increased risk of metabolic diseases including diabetes. Exercise training may counteract metabolic dysregulation, but the impact of exercise training on glycemic control, including postprandial glycemia, has never been explored in patients with colorectal cancer. OBJECTIVE: To examine the effects of home-based interval walking on aerobic and metabolic fitness and quality of life in patients with colorectal cancer. DESIGN: Randomized controlled trial. SETTING: Clinical research center. PARTICIPANTS: Thirty-nine sedentary (<150 minutes moderate-intensity exercise per week) patients with stage I to III colorectal cancer who had completed primary treatment. INTERVENTION: Home-based interval walking 150 min/wk or usual care for 12 weeks. MAIN OUTCOME MEASURES: Changes from baseline to week 12 in maximum oxygen uptake (VO2peak) by cardiopulmonary exercise test, glycemic control by oral glucose tolerance test (OGTT), body composition by dual-energy x-ray absorptiometry scan, blood biochemistry, and quality of life. RESULTS: Compared with control, interval walking had no effect on VO2peak [mean between-group difference: -0.32 mL O2 · kg-1 · min-1 (-2.09 to 1.45); P = 0.721] but significantly improved postprandial glycemic control with lower glucose OGTT area under the curve [-126 mM · min (-219 to -33); P = 0.009], 2-hour glucose concentration [-1.1 mM (-2.2 to 0.0); P = 0.056], and improved Matsuda index [1.94 (0.34; 3.54); P = 0.01]. Also, interval walking counteracted an increase in fat mass in the control group [-1.47 kg (-2.74 to -0.19); P = 0.025]. CONCLUSION: A home-based interval-walking program led to substantial improvements in postprandial glycemic control and counteracted fat gain in posttreatment patients with colorectal cancer, possibly providing an effective strategy for prevention of secondary metabolic diseases.

Exercise-mediated improvement of depression in patients with gastro-esophageal junction cancer is linked to kynurenine metabolism.

Background: Exercise may improve depression in cancer patients, yet the molecular mechanism behind this protection is poorly understood. Here, we aimed to explore the link between exercise and regulation of kynurenine (Kyn) metabolism and inflammation in patients with operable gastro-esophageal junction (GEJ) cancer patients, who improved significantly in depression score with exercise training. Material and Methods: Fifty GEJ cancer patients were allocated to 12 weeks of supervised training twice weekly including interval-based aerobic exercise and resistance training, or standard care. Depression score was evaluated by HADS, and blood samples and muscle biopsies were collected for determination of Kyn metabolism and inflammation across the intervention. Results: Depression scores decreased by -1.3 points in the exercise group (p < 0.01), whereas no changes were observed in the control group. Plasma 3-hydroxykynurenine (HK), a Kyn metabolite giving rise to other neurotoxic metabolites, increased by 48% (p <0.001) in the control group, while exercise training attenuated this accumulation. The production of HK is induced by inflammation, and while we observed no differences in systemic pro-inflammatory cytokines, exercise training ameliorated the treatment-induced intramuscular inflammation. Moreover, exercise has been suggested to convert Kyn to the neuroprotective metabolite, kynurenic acid (KA), but despite marked functional and muscular exercise-mediated adaptations, we did not observe any enhancement of KA production and related enzyme expression in the muscles of GEJ cancer patients. Conclusion: Exercise training reduced symptoms of depression in patients with GEJ cancer, and this effect was associated with an exercise-dependent attenuation of the inflammation-induced conversion of Kyn to neurotoxic metabolites.

Exercise Training in Cancer Control and Treatment.

Exercise training is playing an increasing role in cancer care, as accumulating evidence demonstrates that exercise may prevent cancer, control disease progression, interact with anti-cancer therapies, and improve physical functioning and psychosocial outcomes. In this overview article, we present the current state of the field of exercise oncology, which currently comprises of nearly 700 unique exercise intervention trials with more than 50,000 cancer patients. First, we summarize the range of these interventions with regard to diagnoses, clinical setting, timing, and type of intervention. Next, we provide a detailed discussion of the 292 trials, which have delivered structured exercise programs, outlining the impact of exercise training on cancer-specific, physiological, and psychosocial outcomes in the light of the challenges and physiological limitations cancer patients may experience. In summary, the safety and feasibility of exercise training is firmly established across the cancer continuum, and a wide range of beneficial effects on psychosocial and physiological outcomes are well documented. Many of these beneficial effects are linked to the general health-promoting properties of exercise. However, it is becoming increasing evident that exercise training can have direct effects on cancer and its treatment. This calls for future exercise oncology initiatives, which aim to target cancer-specific outcomes, and which are integrated into the concurrent cancer trajectory. Here, the field must bridge extensive knowledge of integrative exercise physiology with clinical oncology and cancer biology to provide a basis of individualized targeted approaches, which may place exercise training as an integrated component of standard cancer care. © 2019 American Physiological Society. Compr Physiol 9:165-205, 2019.

Sarcopenia and Postoperative Complication Risk in Gastrointestinal Surgical Oncology: A Meta-analysis.

OBJECTIVE: The aim of the study was to evaluate sarcopenia as a predictor of postoperative risk of major and total complications after surgery for gastrointestinal cancer. BACKGROUND: Sarcopenia is associated with poor survival in gastrointestinal cancer patients, but the role of sarcopenia as prognostic tool in surgical oncology has not been established, and no consensus exists regarding assessment and management of sarcopenic patients. METHODS: We performed a systematic search for citations in EMBASE, Web of Science, and PubMed from 2004 to January 31, 2017. Random effects meta-analyses were used to estimate the pooled risk ratio for postoperative complications by Clavien-Dindo grade (total complications: grade ≥2; major complications: grade ≥3) in patients with sarcopenia versus patients without sarcopenia. Stratified analyses were performed by sarcopenia criteria, cutoff level, assessment methods, study quality, cancer diagnosis, and "Enhanced Recovery After Surgery" care. RESULTS: Twenty-nine studies (n = 7176) were included with sarcopenia prevalence ranging between 12% and 78%. Preoperative incidence of sarcopenia was associated with increased risk of major complications (risk ratio 1.40; 95% confidence interval, 1.20-1.64; P < 0.001; I = 52%) and total complications (risk ratio 1.35; 95% confidence interval, 1.12-1.61; P = 0.001; I = 60%). Moderate heterogeneity was found for both meta-analyses. Subgroup analyses showed that sarcopenia remained a consistent risk factor across stratification by sarcopenia criteria, assessment methods, study quality, and diagnoses. CONCLUSIONS: Sarcopenia was associated with an increased risk of complications after gastrointestinal tumor resection, but lack of methodological consensus hampers the interpretation and clinical utilization of these findings. Combining assessment of muscle mass with measures of physical function may increase the prognostic value and accuracy in preoperative risk stratification.