Mechanical suppression of osteolytic bone metastases in advanced breast cancer patients: A randomised controlled study protocol evaluating safety, feasibility and preliminary efficacy of exercise as a targeted medicine

Background: Skeletal metastases present a major challenge for clinicians, representing an advanced and typically incurable stage of cancer. Bone is also the most common location for metastatic breast carcinoma, with skeletal lesions identified in over 80% of patients with advanced breast cancer. Preclinical models have demonstrated the ability of mechanical stimulation to suppress tumour formation and promote skeletal preservation at bone sites with osteolytic lesions, generating modulatory interference of tumour-driven bone remodelling. Preclinical studies have also demonstrated anti-cancer effects through exercise by minimising tumour hypoxia, normalising tumour vasculature and increasing tumoural blood perfusion. This study proposes to explore the promising role of targeted exercise to suppress tumour growth while concomitantly delivering broader health benefits in patients with advanced breast cancer with osteolytic bone metastases. Methods: This single-blinded, two-armed, randomised and controlled pilot study aims to establish the safety, feasibility and efficacy of an individually tailored, modular multi-modal exercise programme incorporating spinal isometric training (targeted muscle contraction) in 40 women with advanced breast cancer and stable osteolytic spinal metastases. Participants will be randomly assigned to exercise or usual medical care. The intervention arm will receive a 3-month clinically supervised exercise programme, which if proven to be safe and efficacious will be offered to the control-arm patients following study completion. Primary endpoints (programme feasibility, safety, tolerance and adherence) and secondary endpoints (tumour morphology, serum tumour biomarkers, bone metabolism, inflammation, anthropometry, body composition, bone pain, physical function and patient-reported outcomes) will be measured at baseline and following the intervention. Discussion: Exercise medicine may positively alter tumour biology through numerous mechanical and nonmechanical mechanisms. This randomised controlled pilot trial will explore the preliminary effects of targeted exercise on tumour morphology and circulating metastatic tumour biomarkers using an osteolytic skeletal metastases model in patients with breast cancer. The study is principally aimed at establishing feasibility and safety. If proven to be safe and feasible, results from this study could have important implications for the delivery of this exercise programme to patients with advanced cancer and sclerotic skeletal metastases or with skeletal lesions present in haematological cancers (such as osteolytic lesions in multiple myeloma), for which future research is recommended. Trial registration: anzctr.org.au, ACTRN-12616001368426. Registered on 4 October 2016

Effect of exercise adjunct to radiation and androgen deprivation therapy on patient-reported treatment toxicity in men with prostate cancer: A secondary analysis of 2 randomized controlled trials

Purpose: Physical inactivity, in addition to clinical factors, has been associated with higher levels of late pelvic symptoms in patients with prostate cancer (PCa) after radiation therapy. The aim of this study was to investigate the effect of a structured multicomponent exercise program comprised of aerobic and resistance training as well as impact loading on the prevalence and severity of symptoms commonly resulting from androgen deprivation therapy (ADT) and pelvic radiation therapy. Methods and Materials: We performed a secondary analysis of pooled data from 2 randomized controlled trials that investigated the role of exercise on treatment-related side effects in patients with PCa receiving ADT. Patients were included in the analysis if they had undergone radiation therapy during the intervention in addition to ADT. Patient-reported quality of life and functional and symptom scales were assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and PR25 before and after 6 months of exercise or usual care (UC). Results: One-hundred and fifteen patients with PCa receiving ADT, aged 47 to 84 years, who also underwent radiation therapy were included in the analysis (exercise, n = 72; UC, n = 43). There was a significant reduction in physical functioning (P = .019) and increased fatigue (P = .007) in the control group, with no change observed in the exercise group. Similarly, there was a trend toward reduced sexual activity in the control group (P = .064), with a mean adjusted change of -7.1 points. Furthermore, the prevalence of clinically important pain at 6 months was lower in the exercise group compared with UC (18.1 vs 37.2%, P = .022). No between-group differences were found for urinary (P = .473) or hormonal treatment-related symptoms (P = .552). Conclusions: Exercise during concomitant hormone and radiation treatment for men with PCa may mitigate some adverse changes in patient-reported fatigue, physical functioning, and possibly sexual activity. The promotion and provision of exercise to counter a range of treatment-related adverse effects in patients with PCa undergoing radiation therapy and ADT should be actively encouraged

Nationwide industry-led community exercise program for men with locally advanced, relapsed, or metastatic prostate cancer on androgen-deprivation therapy

Purpose Androgen-deprivation therapy in patients with prostate cancer (PCa) is associated with considerable side effects and secondary comorbidities such as overweight/obesity and cardiovascular disease. The aim of thisstudy was to investigate the effectiveness of an industry-led, treatment-integrated, community-based exercise program on outcomes of body weight, cardiovascular health, and physical function. Patients and Methods PCa patients with locally advanced, relapsed, or metastatic disease receiving leuprorelin acetate were enrolled across multiple sites in Australia and assigned supervised group exercise undertaken weekly or biweekly (ie, 16 exercise sessions in total) for 10-18 weeks, consisting of aerobic and resistance training performed at moderate-to-vigorous intensity. Results Between 2014 and 2020, 760 participants completed the baseline and follow-up assessment. Participants were age 48-94 years, and most were either overweight (42.1%) or obese (38.1%). Program compliance was high, with 90% of participants completing all 16 exercise sessions. There was a small but significant reduction in waist circumference (–0.9 cm; 95% CI [–1.2 to –0.5]; P \u3c .001) and no change in weight or body mass index. Systolic (–3.7 mmHg; 95% CI [–4.8 to –2.6]; P \u3c .001) and diastolic (–1.7 mmHg; 95% CI [–2.3 to –1.0]; P \u3c .001) blood pressure were significantly lower after the program. Furthermore, significant improvements were seen in cardiorespiratory fitness and muscle strength (P \u3c .001). For most of the investigated outcomes, participants with poorer initial measures had the greatest benefit from participating in the program. Conclusion The community exercise program was feasible and effective in preventing weight gain, reducing blood pressure, and improving physical function in patients with PCa on androgen-deprivation therapy

Examining the effects of creatine supplementation in augmenting adaptations to resistance training in patients with prostate cancer undergoing androgen deprivation therapy: A randomised, double-blind, placebo-controlled trial

INTRODUCTION: Creatine supplementation has consistently been demonstrated to augment adaptations in body composition, muscle strength and physical function in a variety of apparently healthy older adults and clinical populations. The effects of creatine supplementation and resistance training in individuals with cancer have yet to be investigated. This study aims to examine the effects of creatine supplementation in conjunction with resistance training on body composition, muscle strength and physical function in prostate cancer patients undergoing androgen deprivation therapy. METHODS AND ANALYSIS: This is a randomised, double-blind, placebo-controlled trial designed to examine the effects of creatine supplementation in addition to resistance training in patients with prostate cancer receiving androgen deprivation therapy. Both supplement and placebo groups will receive a 12-week supervised exercise programme comprising resistance training undertaken three times per week. The primary endpoint (fat-free mass) and secondary endpoints (fat mass, per cent body fat, physical fitness, quality of life and blood biomarkers) will be assessed at baseline and immediately following the intervention. ETHICS AND DISSEMINATION: The Human Research Ethics Committee of Edith Cowan University approved this study (ID: 22243 FAIRMAN). If the results of this trial demonstrate that creatine supplementation can augment beneficial adaptations of body composition, physical function and/or psychosocial outcomes to resistance training, this study will provide effect sizes that will inform the design of subsequent definitive randomised controlled trials. The results of this study will be published in peer-reviewed journals and presented at various national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000099123

Does exercise impact gut microbiota composition in men receiving androgen deprivation therapy for prostate cancer? A single-blinded, two-armed randomised controlled trial

Introduction: A potential link exists between prostate cancer (PCa) disease and treatment and increased inflammatory levels from gut dysbiosis. This study aims to examine if exercise favourably alters gut microbiota in men receiving androgen deprivation therapy (ADT) for PCa. Specifically, this study will explore whether: (1) exercise improves the composition of gut microbiota and increases the abundance of bacteria associated with health promotion and (2) whether gut health correlates with favourable inflammatory status, bowel function, continence and nausea among patients participating in the exercise intervention. Methods and analysis: A single-blinded, two-armed, randomised controlled trial will explore the influence of a 3-month exercise programme (3 days/week) for men with high-risk localised PCa receiving ADT. Sixty patients will be randomly assigned to either exercise intervention or usual care. The primary endpoint (gut health and function assessed via feacal samples) and secondary endpoints (self-reported quality of life via standardised questionnaires, blood biomarkers, body composition and physical fitness) will be measured at baseline and following the intervention. A variety of statistical methods will be used to understand the covariance between microbial diversity and metabolomics profile across time and intervention. An intention-to-treat approach will be utilised for the analyses with multiple imputations followed by a secondary sensitivity analysis to ensure data robustness using a complete cases approach. Ethics and dissemination: Ethics approval was obtained from the Human Research Ethics Committee of Edith Cowan University (ID: 19827 NEWTON). Findings will be reported in peer-reviewed publications and scientific conferences in addition to working with national support groups to translate findings for the broader community. If exercise is shown to result in favourable changes in gut microbial diversity, composition and metabolic profile, and reduce gastrointestinal complications in PCa patients receiving ADT, this study will form the basis of a future phase III trial. Trial registration number: ANZCTR12618000280202

Exercise Preserves Physical Function in Prostate Cancer Patients with Bone Metastases

The presence of bone metastases has excluded participation of cancer patients in exercise interventions and is a relative contraindication to supervised exercise in the community setting due to concerns of fragility fracture. We examined the efficacy and safety of a modular multi-modal exercise program in prostate cancer patients with bone metastases.Between 2012 and 2015, 57 prostate cancer patients (70.0±8.4 years; BMI 28.7±4.0 kg/m) with bone metastases (pelvis 75.4%, femur 40.4%, rib/thoracic spine 66.7%, lumbar spine 43.9%, humerus 24.6%, other sites 70.2%) were randomised to multi-modal supervised aerobic, resistance and flexibility exercises undertaken thrice weekly (EX, n=28) or usual care (CON, n=29) for 3 months. Physical function subscale of the SF-36 was the primary endpoint as an indicator of patient-rated physical functioning. Secondary endpoints included objective measures of physical function, lower body muscle strength, body composition and fatigue. Safety was assessed by recording the incidence and severity of any adverse events, skeletal complications, and bone pain throughout the intervention.There was a significant difference between groups for self-reported physical functioning (3.2 points, 95% CI 0.4-6.0 points; p=0.028) and lower body muscle strength (6.6 kg, 95% CI 0.6-12.7; p =0.033) at 3 months favouring EX. However, there was no difference between groups for lean mass (p=0.584), fat mass (p=0.598), or fatigue (p=0.964). There were no exercise-related adverse events or skeletal fractures and no differences in bone pain between EX and CON (p=0.507).Multi-modal modular exercise in prostate cancer patients with bone metastases led to self-reported improvements in physical function and objectively measured lower body muscle strength with no skeletal complications or increased bone pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal

H3K18 lactylation marks tissue-specific active enhancers

Background: Histone lactylation has been recently described as a novel histone post-translational modification linking cellular metabolism to epigenetic regulation. Results: Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG island-containing promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. Conclusions: Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers. Keywords: Adipocyte; CUT&Tag; ChromHMM; Embryonic stem cell; Enhancer; Epigenetics; H3K18la; Histone post-translational modification; Lactate; Lactylation; Macrophage; Muscle; Promoter

The International Cancer Expert Corps: A Unique Approach for Sustainable Cancer Care in Low and Lower-Middle Income Countries

The growing burden of non-communicable diseases including cancer in low- and lower-middle income countries (LMICs) and in geographic-access limited settings within resource-rich countries requires effective and sustainable solutions. The International Cancer Expert Corps (ICEC) is pioneering a novel global mentorship–partnership model to address workforce capability and capacity within cancer disparities regions built on the requirement for local investment in personnel and infrastructure. Radiation oncology will be a key component given its efficacy for cure even for the advanced stages of disease often encountered and for palliation. The goal for an ICEC Center within these health disparities settings is to develop and retain a high-quality sustainable workforce who can provide the best possible cancer care, conduct research, and become a regional center of excellence. The ICEC Center can also serve as a focal point for economic, social, and healthcare system improvement. ICEC is establishing teams of Experts with expertise to mentor in the broad range of subjects required to establish and sustain cancer care programs. The Hubs are cancer centers or other groups and professional societies in resource-rich settings that will comprise the global infrastructure coordinated by ICEC Central. A transformational tenet of ICEC is that altruistic, human-service activity should be an integral part of a healthcare career. To achieve a critical mass of mentors ICEC is working with three groups: academia, private practice, and senior mentors/retirees. While in-kind support will be important, ICEC seeks support for the career time dedicated to this activity through grants, government support, industry, and philanthropy. Providing care for people with cancer in LMICs has been a recalcitrant problem. The alarming increase in the global burden of cancer in LMICs underscores the urgency and makes this an opportune time fornovel and sustainable solutions to transform cancer care globally