Targeted Exercise Training for Cancer Patients: Moving beyond Generic Exercise Guidelines in Clinical Oncology

Targeted Exercise Training for Cancer Patients: Moving beyond Generic Exercise Guidelines in Clinical Oncology Ciaran M Fairman1 and Jesper F Christensen()2,3 1Department of Exercise Science, University of South Carolina, USA 2Center for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark 3Department of Sports Science and Clinical Biomechanics, Faculty of Health Sciences, University of Southern Denmark, Denmark © The Authors Abstract The field of exercise oncology has rapidly evolved over the past 30 years. Initial investigations of safety and feasibility have progressed towards efficacy and effectiveness trials with a variety of health-related outcomes in mind. More recently, it has been recognized that interventions aimed at modifying physical activity behavior (i.e. behavioral interventions to increase participation in un/structured physical activity) are distinctly different from those aiming to target a clinically relevant outcome (using a specific exercise prescription). There is a strong rationale for the latter, where cancer/treatment toxicities can result in musculoskeletal, cardiopulmonary, and/or hematological declines with important prognostic implications. Treatment intolerance, unfavorable tumor response and heightened risk of mortality are all consequences of leaving these impairments unaddressed. Importantly, the control/reversal of the decline in these systems is more likely to occur through a targeted exercise prescription, specifically designed to target the impairment, rather than interventions trying to change behavior. This requires careful consideration in the study design in exercise oncology in relation to the selection of clinically relevant outcomes, decisions on methods of assessments and ensuring the exercise is targeted to the outcome. The objective of this review is to 1) conceptualize and provide a clinical rationale for targeted exercise interventions in exercise oncology, and 2) provide a framework for consideration in the design and execution in targeted exercise interventions in oncology. We hope that this framework can encourage research into targeted exercise interventions in oncology and that our framework can be used to inform the design of future trials.

Physical Activity and Fatigue in Multiple Sclerosis: Secondary Outcomes from a Double-blinded Randomized Controlled Trial of Cocoa Flavonoid Drinks

Physical Activity and Fatigue in Multiple Sclerosis: Secondary Outcomes from a Double-blinded Randomized Controlled Trial of Cocoa Flavonoid Drinks Maedeh Mansoubi()1,2, Shelly Coe1,2,3, Jo Cossington1, Johnny Collet1,2, Miriam Clegg4, Jacqueline Palace5, Ana Cavey5, Gabriele C DeLuca5, Martin Ovington1 and Helen Dawes1,2,6 1Center for Movement, Occupational and Rehabilitation Sciences, Oxford Institute of Nursing, Midwifery and Allied Health Research, Oxford Brookes University, Oxford, United Kingdom 2Oxford Clinical Allied Technology and Trial Services Unit (OxCATTS), Oxford, United Kingdom 3Oxford Brookes Center for Nutrition and Health, Oxford Brookes University, Oxford, United Kingdom 4Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, University of Reading, Reading, United Kingdom 5Department of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom 6Oxford Health NHS Foundation Trust, United Kingdom © The Authors Abstract Fatigue is a common and pervasive symptom reducing physical activity in people with multiple sclerosis (pwMS). Exercise may reduce fatigue, although evidence to guide optimal prescription is limited. Specifically, supportive evidence for the timing of exercise for fatigue management or the impact of dietary supplements is unavailable. We performed intensive phenotyping of the interrelation of time of day, physical activity levels, and fatigue to evidence exercise prescription in 40 pwMS participating in a six week randomized controlled trial of morning flavonoid intake (n=19) or a control (n=21). Physical activity was measured over seven days by using an accelerometer at baseline, week three and week six. Participants self-reported their fatigue on a 1–10 rating scale at 10 am, 3 pm, and 8 pm daily. Physical activity levels were calculated for 2.5 h before and after fatigue was reported. Generalized estimating equations were used to explore the time of day fatigue profiles, the relationship of physical activity to fatigue, and the effect of morning flavonoids on this relationship. Participants experienced higher fatigue at 8 pm (4.64±2.29) than at 3 pm (4.39±2.28) and 10 am (3.90±2.10) (P<0.001). Higher fatigue was shown to predict subsequent lower physical activity behavior (P=0.015), but physical activity did not predict higher subsequent fatigue (P>0.05). Morning flavonoid cocoa consumption reduced the relationship of fatigue to physical activity (P=0.049) and fatigue to time of the day (P<0.001). Fatigue levels increased during the day and higher fatigue reduced physical activity in pwMS, but physical activity did not increase fatigue. In addition, morning cocoa reduced daytime fatigue and the relationship of fatigue to subsequent physical activity levels. Therefore morning exercise prescription is indicated; in combination with dietary flavonoids, it may optimize exercise and physical activity potential in pwMS. Trial registration: ISRCTN69897291, https://doi.org/10.1186/ISRCTN69897291 Registration name: A study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing-remitting multiple sclerosis (RRMS). Consort Statement: In this study, we adhered to CONSORT guidelines. As this paper is a secondary analysis, we therefore did not repeat some parts in the methods, results, diagrams, or tables that have been published in the first paper authored by Coe et al. 2019.

Resistance Training for Rehabilitation in Patients with Idiopathic Pulmonary Fibrosis

Resistance Training for Rehabilitation in Patients with Idiopathic Pulmonary Fibrosis Baruch Vainshelboim()1 and Jonathan Myers2 1Cardiovascular and Metabolic Disease Research Institute, Mountain View, CA, USA 2Cardiology Division, Veterans Affairs Palo Alto Health Care System / Stanford University, Palo Alto, CA, USA © The Authors Abstract Idiopathic pulmonary fibrosis (IPF) is a debilitating condition that causes severe symptoms, impaired functional capacity and poor quality of life. Exercise training has been shown to be a safe and effective therapy for improving physical function, dyspnea and quality of life in patients with IPF. However, due to pathophysiological limitations and symptom burden, conducting safe and effective exercise interventions is challenging; optimal program components and training modalities are yet to be established. Resistance training (RT) is a well-established exercise modality for combating effects of aging, disuse and chronic diseases, although there are scarce data available among patients with IPF. The current review briefly summarizes the pathophysiology and clinical manifestations of IPF and describes the numerous health and clinical benefits of RT among older adults and patients with respiratory disease. It then explores the potential RT mechanisms for overcoming exercise limitations in IPF, which may provide a therapeutic opportunity for rehabilitation. Finally, the review suggests practical RT recommendations for pulmonary rehabilitation programs in patients with IPF.

Exercise, Pharmaceutical Therapies and Type 2 Diabetes: Looking beyond Glycemic Control to Whole Body Health and Function

Exercise, Pharmaceutical Therapies and Type 2 Diabetes: Looking beyond Glycemic Control to Whole Body Health and Function Thomas Yates()1,2, Joseph Henson1,2, Jack Sargeant1,2, James A King2,4, Ehtasham Ahmad1, Francesco Zaccardi1,3 and Melanie J Davies1,2 1Diabetes Research Center, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, UK 2NIHR Leicester Biomedical Research Center, University Hospitals of Leicester NHS Trust and University of Leicester, UK 3Leicester Real World Evidence Unit, Diabetes Research Center, University of Leicester, Leicester, UK 4National Center for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, UK © The Authors Abstract Exercise is a powerful therapy for improving glycemic control and increasing cardiorespiratory fitness in adults with type 2 diabetes mellitus (T2DM). However, there is a dearth of evidence investigating interactions or synergies between exercise and most pharmaceutical therapies. This is important as exercise is rarely prescribed in isolation of other background medications used to manage T2DM. Therefore understanding which exercise and drug combinations optimize or blunt responses is crucial. This narrative review discusses advances in weight loss management in diabetes and highlights research opportunities and challenges for combining exercise therapies with newer generations of glucose-lowering therapies with weight loss effects, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is). We discuss the role of exercise in preserving lean mass and increasing physical function along with other potential areas of synergy. We conclude that until the evidence base investigating areas of interaction or synergy between exercise and other glucose-lowering or weight loss therapies is developed, exercise will remain a generic rather than a tailored therapy in the management of T2DM.

Translational Medicine and Exercise Prescription (TMEP): Advancing the Era of Exercise Medicine

Translational Medicine and Exercise Prescription (TMEP): Advancing the Era of Exercise Medicine Sulin Cheng1,2,3,4, Moritz Schumann()2,4 and Wilhelm Bloch4 1Exercise, Health and Technology Center, Department of Physical Education, Shanghai Jiao Tong University, Shanghai, China 2Exercise Translational Medicine Center, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China 3Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland 4Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany © The Authors "Exercise is medicine" has gained popularity worldwide after the American Medical Association and the American College of Sports Medicine co-launched their ground-breaking health initiative in 20071 . This initiative was aimed at improving population health and well-being, mainly by raising the awareness of healthcare providers to regard performing physical activity (PA) as one of the vital signs. Ever since, this concept has spread worldwide and PA has been proposed as an essential part of treatment for chronic diseases2 . In their pioneering work, Pedersen and Saltin provided compelling evidence for the role of exercise as the first- or second-line therapy for at least 26 diseases2 . These findings are further corroborated by meta-epidemiological data, indicating exercise interventions to be as effective as drug interventions, such as during rehabilitation after stroke and for the treatment of heart failure3 . However, the overall effect appears to be strongly correlated with important determinants of the exercise program performed (i.e. dose of training [frequency, volume, intensity], type of exercise and adherence to the training program) and disease-related specifics4 , thus requiring not only clinical expertise but also an in-depth understanding of exercise physiology and biology. In this new journal-Translational Medicine and Exercise Prescription (TMEP), we are aiming to bring together the fields of exercise physiology and biology, sports medicine and the science of physical training and testing to bridge the gap between mechanistic research and clinical practice. The journal covers nine sections, including obesity, diabetes, cancer, cardiovascular diseases, neurological and psychiatric diseases, pulmonary diseases, musculoskeletal diseases, endocrine disorders as well as advanced exercise prescription and health maintenance. In this first issue of TMEP, we are delighted to present seven papers from different areas of translational research performed in humans on specific themes related to the treatment and prevention of chronic diseases. Appropriate selection of primary and secondary endpoints is critical for successfully designing translational studies. In the first paper of this issue, TMEP Section Editor, Jörn Rittweger provides his thoughts on "What Are Good Muscle Endpoints for Translational Studies?". In his important work, he highlights the importance of muscles for our health because of their size, their involvement in energy metabolism and their relevance for locomotion. He further suggests that at least eight different muscle functions are important to health. Well accepted methods exist for three relevant muscular endpoints, namely for power, strength and muscle mass, and these endpoints are utilized in clinical studies. However, such validated methods lack a number of additional muscle functions that are not yet fully scientifically explored. This applies foremost to not only the metabolic functions of muscles, but also to their role in storage and dissipation of mechanical energy. His work concludes by emphasizing how physiological knowledge can be an important base for the guidance of clinical diagnostics. Following this important message, the group of TMEP Section Editor Pieter de Lange shares their work entitled "Exercise with Energy Restriction as a Means of Losing Body Mass While Preserving Muscle Quality and Ameliorating Comorbidities: Towards A Therapy for Obesity?". Obesity and related comorbidities have reached pandemic proportions worldwide, particularly during the past decade. Therefore, finding effective intervention strategies not only requires scientific focus but these strategies are also of public interest. Based on both human and animal studies, this narrative review summarizes the effects of dietary and exercise-based programs on loss of different body mass components. Furthermore, both the gain and lack of loss of lean mass in view of muscle quality maintenance are discussed and data related to the mechanisms underlying the conservation of functional muscle mass provided. They also provide evidence of the interaction between energy restriction by diet and exercise-induced metabolic demands at the molecular level. This insight into the mechanisms underlines the relevance of translational considerations for personalized exercise prescription. Obesity and an unhealthy lifestyle are also known to be among the risk factors for type 2 diabetes (T2DM). The research group of TMEP Section Editor Thomas Yates highlights research opportunities and challenges for combining exercise and medical therapies by means of a narrative review entitled "Exercise, Pharmaceutical Therapies and Type 2 Diabetes: Looking beyond Glycemic Control to Whole Body Health and Function". The authors provide evidence on newer generations of glucose-lowering therapies that also induce concomitant weight loss, particularly on glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is). Based on current knowledge, they stress the importance of investigating the interaction or synergy between exercise and other glucose-lowering or weight loss therapies, to make exercise a tailored therapy rather than a generic treatment in the management of T2DM. This review, therefore, clearly highlights the need of precise exercise prescription, originating from an in-depth mechanistic understanding of the effects of exercise. Cancer is another important metabolic and chronic inflammatory disease that may also be associated with obesity. TMEP Section Editor Jesper F Christensen and Associate Editor Ciaran M Fairman provide a very interesting viewpoint in their article,"Targeted Exercise Training for Cancer Patients: Moving beyond Generic Exercise Guidelines in Clinical Oncology". This paper aims to update the current knowledge and the clinical rationale for targeted exercise interventions in exercise oncology. Moreover, a framework for systematic guidance of the design and execution of targeted exercise interventions in oncology is presented. The authors hope that their framework can encourage further research into targeted exercise interventions in oncology and may also be used as a guideline for the design of future trials to increase quality and impact. The group of TMEP Section Editor Helen Dawes, shares their original data in the context of neurological and psychiatric diseases in the article entitled "Physical Activity and Fatigue in Multiple Sclerosis: Secondary Outcomes from a Double-blinded Randomized Controlled Trial of Cocoa Flavonoid Drinks". In this study, they performed intensive phenotyping of the inter-relationships of the time of day, physical activity levels and fatigue to determine exercise prescription in a group of people with multiple sclerosis (MS) participating in a six-week randomized controlled trial of morning flavonoid intake. It was found that fatigue levels increased during the day and higher levels of fatigue reduced physical activity; yet physical activity itself did not lead to increased fatigue. Additionally, morning cocoa intake reduced daytime fatigue and fatigue related to subsequent physical activity. Therefore, combined prescription of morning exercise and dietary flavonoids may optimize the exercise and physical activity potential in people with MS. This study nicely demonstrates the importance of understanding and considering possible covariants such as nutrition and chronobiology to determine an optimal exercise prescription model. TMEP Section Editor Jonathan Myers and colleague Baruch Vainshelboim present a narrative review on "Resistance Training for Rehabilitation of Patients with Idiopathic Pulmonary Fibrosis". In this paper, the pathophysiology and clinical manifestations of Idiopathic Pulmonary Fibrosis (IPF) are summarized with an emphasis on the numerous health and clinical benefits of resistance training among older adults and patients with this respiratory disease. This article effectively explores the potential mechanisms by which systematic resistance training may help overcome exercise limitations in IPF, providing a therapeutic opportunity for rehabilitation. Furthermore, the authors provide important recommendations for pulmonary rehabilitation programs that are based on resistance training for patients with IPF. With this paper, the authors highlight that disease-adapted exercise prescription requires a pathophysiological understanding to justify the inclusion of specific exercise regimens. In the final paper of this special issue, the research group of Section Editor Anthony C Hackney shares their original data on the "Energy Availability and RED-S Risk Factors in Competitive, Non-elite Male Endurance Athletes". This paper particularly emphasizes the entire spectrum of TMEP, that is more than just the most common types of non-communicable diseases, but also includes chronic conditions that may be for example induced by athletic training. In this study, the authors assessed the associations of energy availability and risk factors of relative energy deficiency in sport (RED-S) in 60 competitive, recreationally trained male endurance athletes. They found that hormonal and bone biomarkers were within normal clinical ranges, even when the energy availability was low. The authors further state that athletes are considered at a high risk for RED-S if their energy availability is low (<30 kcal/kg FFM), which is based primarily upon research in women. However, the included recreationally trained male endurance athletes were below this criterion but displayed no RED-S symptomology. Thus, the authors suggest that the <30 kcal/kg FFM criterion may not be a valid categorization for a high risk of RED-S in non-elite male endurance athletes, highlighting the importance of using other criteria. While the purpose of this first issue is to stimulate further discussion on the topic of translational medicine and exercise prescription from different disciplines, we wish to highlight that these topics are not exhaustive and there are many more questions that must be addressed. With TMEP, we aim to introduce a platform for the transparent dissemination of research findings, where special consideration will be given to novel types of exercise prescriptions, including technology-based intervention approaches as well as mechanism-driven studies with translation to exercise prescription. Moreover, TMEP encourages submissions of "negative findings" and/or possible reports of harmful adverse events (e.g. if trials are terminated prematurely) as long as the quality of the study can be assured (i.e. indicated by relevance/novelty of the question, rigorous methodology, transparency and reproducibility). We strongly encourage submissions from all parts of the world to further improve our understanding on exercise prescription based on mechanistic approaches and by that commence a new era of evidence-based precision exercise medicine.

Energy Availability and RED-S Risk Factors in Competitive, Non-elite Male Endurance Athletes

Energy Availability and RED-S Risk Factors in Competitive, Non-elite Male Endurance Athletes Amy R Lane1, Anthony C Hackney()1, Abbie E Smith-Ryan1, Kristen Kucera1, Johna K Register-Mihalik1 and Kristin Ondrak1 1Department of Exercise & Sport Science, University of North Carolina, Chapel Hill, NC 27599, USA © The Authors Abstract Relative Energy Deficiency in Sport (RED-S) is predicated on the assumption that low energy availability (EA) induces deficiencies-dysfunction in multiple physiologic systems. However, research on RED-S and EA in male athletes is limited in comparison to women. The aim of this study is to investigate EA and the risk factors for RED-S, and their potential associations in non-elite male endurance athletes. Laboratory assessments for resting metabolic rate (RMR), bone mineral density (BMD), blood hormonal biomarkers and maximal aerobic capacity were conducted on 60 competitive, recreationally trained male endurance athletes (age=43.4±11.6 years [mean±SD], training=10.9±2.7 h/wk, 7.1±8.8 years). Participants provided 7-days of training logs and 4-days of diet records. Diet and training records were used to calculate EA. Correlations were used to examine associations between EA and RMR, BMD, stress fractures and reproductive, metabolic and bone biomarkers. Mean EA was 28.7±13.4 kcal/kg fat free mass (FFM), which categorized our sample as low EA (based upon published criterion, < 30 kcal/kg FFM) and at a high risk for RED-S. Hormonal and bone biomarkers were in normal clinical ranges, even though EA was low. The only interesting significant association was EA being negatively associated with total body BMD (r=–0.360, P=0.005), opposite of expectations. On average our subjects displayed a state of low EA based upon the criterion which has been primarily developed from female-based research. Nonetheless, our participants displayed no major hormonal or bone health disturbances found in athletes diagnosed with RED-S. A value of < 30 kcal/kg FFM to diagnose low EA may not be appropriate for non-elite endurance trained men.

Exercise with Energy Restriction as a Means of Losing Body Mass while Preserving Muscle Quality and Ameliorating Co-morbidities: Towards a Therapy for Obesity?

Exercise with Energy Restriction as a Means of Losing Body Mass while Preserving Muscle Quality and Ameliorating Co-morbidities: Towards a Therapy for Obesity? Antonia Giacco1*, Elena Silvestri1*, Rosalba Senese2, Federica Cioffi1, Arianna Cuomo2, Assunta Lombardi3, Maria Moreno1, Antonia Lanni2 and Pieter de Lange()2 1Dipartimento di Science e Tecnologie, Università degli Studi del Sannio, Benevento, Italy 2Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli," Caserta, Italy 3Dipartimento di Biologia, Università degli Studi di Napoli "Federico II," Napoli, Italy © The Authors Abstract Obesity and related co-morbidities are a major public health threat worldwide, and efforts to counteract obesity by means of physiological interventions are currently being explored and applied. Here we present an overview of the literature on the effect of dietary/exercise-based programs on loss of different components of body mass. We also discuss gain or lack of loss of lean mass in view of muscle quality maintenance, which is an important aspect to consider when employing weight-loss strategies to tackle obesity. By comparing results obtained in participants with mild to severe obesity with those obtained in lean participants, we highlight variations in the success of these interventions. Furthermore, we briefly address the observation that although certain interventions may not always affect body composition they can nevertheless ameliorate co-morbidities (insulin resistance, non-alcoholic fatty liver disease). Based on what is currently known, in this narrative review we include data from human and animal studies related to the process of unravelling the mechanisms underlying conservation of functional muscle mass.

What Are Good Muscle Endpoints for Translational Studies?

What Are Good Muscle Endpoints for Translational Studies? Jörn Rittweger()1,2 1Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany 2Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany © The Author Abstract Muscles matter to our health because of their size, their involvement in energy metabolism and their relevance for locomotion. Adequate selection of good endpoints is crucial for successfully designing translational studies. At least eight different muscle functions matter to health, namely the mechanical functions of exerting force, velocity, power, elastic storage and braking power, the two metabolic functions of substrate uptake (e.g. carbohydrates, lipids and amino acids) and substrate provision (e.g. lactate and amino acids) and secretory functions. However, specific endpoint tests have been validated for muscle force and power only. Walking speed and grip strength demonstrate good predictive value for hard clinical endpoints, such as disability, loss of autonomy and death. Vertical jump power also has good ecological validity and construct validity, and it depicts excellent test-retest reliability, which is an important advantage with regard to the study of power. Assessment of muscle mass, e.g. by magnetic resonance imaging, dual energy X-ray absorptiometry or bioelectrical impedance, should be considered as an important secondary endpoint to enhance construct validity. Further secondary endpoints should be included wherever they are likely to enhance the plausibility of the study outcome and assessment of test-retest reliability at baseline is always recommended. Well-established methods exist for three relevant muscular endpoints, namely power, strength and muscle mass, and these endpoints lend themselves to utilization in clinical studies. However, such validated methods lack a number of additional muscle functions that are scientifically only emerging. This applies foremost to the metabolic function of muscles but also to its role in storage and dissipation of mechanical energy.