United Kingdom

Introduction: The relationship between body composition and survival in locally advanced rectal cancer patients is under investigation. Methods: A retrospective study of all patients with clinical stage 2-3 rectal cancer who completed neoadjuvant chemoradiotherapy (nCRT) and surgery between 2010 and 2015 at Western Health was performed. Body composition was measured at the third lumbar vertebrae on pre-neoadjuvant treatment imaging. Skeletal muscle index (SMI), adipose tissue and mean muscle attenuation (Hounsfield units, HU) were measured. Primary outcomes were overall (OS) and diseasefree survival (DFS). Results: There were 139 patients treated for stage 2-3 low rectal cancer over 5 years. There were 32 disease recurrences and 30 deaths. Sarcopenia did not result in worse survival. Visceral obesity was predictive of OS (HR 6.43; 95% CI 1.06- 39.1). Skeletal muscle index (cm2/m2) and mean muscle attenuation (HU) were independently associated with improved OS (HR 0.83; 95% CI 0.71-0.96 and HR 0.88; 95%CI 0.78-0.99 respectively) in a multivariate model. The surface area (cm2) of subcutaneous and visceral adipose tissue was independently predictive of OS (HR 1.18; 95%CI 1.03-1.33 and HR 1.16; 95% CI 1.03-1.31 respectively) and DFS (HR 1.13; 95% CI 1.01-1.28 and HR 1.13; 95% 1.00-1.26 respectively) in a multivariate model. Conclusion: CT derived measures of adiposity, muscle mass and density can predict survival in patients with locally advanced rectal cancer undergoing multimodal curative treatment. International cut points for defining body composition phenotypes need revision and may not be suitable for this population.

ISTRC 2021 - International Sarcopenia Translational Research Conference

The association between body composition and survival in locally advanced rectal cancer: An Australian study

body compostion

sarcopenia

survival

Welcome to the inaugural International Sarcopenia Translational Research Conference.  “Where Worlds Meet” – the event brings together a broad range of researchers and practitioners in a truly interdisciplinary forum, covering discovery science through to clinical practice.

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Access to this event requires a registration. Please email Eleanor Lockhart at sarcconf@ncl.ac.uk if you have any questions regarding your registration. 

poster

Sarcopenia (‘poverty of flesh’) is the progressive degenerative loss of muscle mass and strength associated with ageing. 1) Sarcopenia is a major component of frailty and a barrier to independent living in old age. 2) The reticulospinal tract (RST) is a key neural structure in the control of balance, posture and strength. These all falter with age, but little is known about reticulospinal changes with ageing. 3) We hypothesised that age-related reductions in strength might relate to differential changes in corticospinal and reticulospinal connectivity. 4) Transcranial Magnetic Stimulation (TMS) can be used to elicit Motor Evoked Potentials (MEPs) to measure spinal pathways. 5) Contralateral and ipsilateral MEPs are carried by mainly corticospinal and reticulospinal pathways respectively.

Ipsilateral Motor Evoked Potentials as a measure of the reticulospinal tract in age-related strength changes

Background - Patients with chronic kidney disease (CKD) => loss of muscle mass (MM) and strength => Quick and easy diagnosis of MM and strength loss (sarcopenia) is warranted • Ultrasound (US) is a recommended tool to monitor muscle health in CKD [1] , however, it is unknown whether total MM can be diagnosed by a single site measurement • When choosing the anatomical site to be measured, an appropriate surrogate marker of appendicular skeletal muscle mass or total MM should be considered.
Results RF-CSA was a significant (p<0.001) predictor of total MM.

Prediction and validation of total muscle mass by a single site ultrasound measurement in chronic kidney disease patients 


Background: Dietary protein supplementation combined with resistance exercise (RE) may counteract declines in muscle strength, mass, and function (sarcopenia), but the role of whole foods rich in protein, such as milk, is less well understood. In the MIlkMAN study, we aimed to examine the feasibility and acceptability of milk+RE as an intervention for muscle function in community-dwelling older adults, and provide exploratory pilot data for future substantive research in population at risk of sarcopenia. Methods: In a parallel groups design, 30 older adults (71.7±3.6 years; 12 women) were randomised into three groups: WM (whole milk 3.6% fat)+RE, SM (skimmed milk 0.3% fat)+RE, and C (isocaloric carbohydrate drink)+RE. RE was performed twice-weekly over 6 weeks in a community gym, followed by the consumption of 500 ml of milk (~20 g protein) or carbohydrate drink immediately after exercise and a further 500 ml at home within the following 4-5 hours. The feasibility and acceptability of the study was determined by calculating recruitment and attendance rates, compliance with the intervention, rating participants' experiences, and recording adverse health events. Results: The response rate was 49% (out of 400 invitations sent), and the recruitment rate was 73.2% (30 participants recruited out of 41 screened for eligibility). Twenty-nine participants completed the intervention-an attendance rate of 97.1%; 89.7% rated their experience as 'excellent'/very good'. Compliance with taking the drinks was 97.1% (WM), 98.3% (SM), and 95.0% (C); 93.1% rated their drink intake as 'easy'/'very easy' with no adverse effects. Collection of exploratory pilot data to inform future trials was successful. Mean change in grip strength, 5-chair rises, and gait speed were 0.9±3.4 kg, 1.8±2.2 s, 0.1±0.1 m/s, respectively with no differences between the groups. Conclusions: This community-based milk+RE intervention was feasible and acceptable to older adults. The study successfully collected pilot data for future substantive research.

Milk Intervention Muscle AgeiNg (MIlkMAN) pilot study: feasibility and acceptability of a milk and resistance exercise intervention in older adults

Introduction: Lower-limb impairment is common after stroke, limiting independence of those affected. Early, accurate prediction of recovery could enable individualised rehabilitation and optimise outcomes. Previous evidence supports an effect of stroke-related damage to corticospinal tracts (CST) on functional recovery. However, effects of post-stroke sarcopenia, resultant muscle fiber-type shift and inflammation are unknown. An algorithm accounting for these changes, based on combined MRI imaging of the source-organ (brain) and end-organ (lower-limb skeletal muscle), may have superior accuracy compared with clinical assessments or isolated MRI biomarkers. We aim to assess the feasibility and utility of MRI biomarkers for predicting lower-limb recovery following stroke. Methods: 30 patients will be recruited from two North-East England NHS trusts within four weeks of their first-ever ischaemic stroke causing unilateral lower-limb weakness. Patients undergo brain and thigh muscle MRI, including volumetric sequences, lipid and oedema-based muscle imaging and diffusion tensor imaging of the CST. This is followed by baseline and 3-month clinical assessments of: lower-limb impairment (Fugl-Meyer; Motor NIHSS) strength (handheld-dynamometry) and function (Functional Ambulatory Category). Results: 10/30 participants have been recruited since 2019 and the study will close in 2021. Correlations between MRI, clinical and 3-month follow-up outcome data will assess relationships between biomarkers and outcomes to inform a predictive model incorporating baseline clinical and MRI data. Conclusion: This project will provide novel data on sarcopenia-based measures in stroke recovery. If our model has predictive value, a sample size estimate will be calculated to inform future multicentre studies with the aim of developing a robust predictive algorithm.

Study in Novel Neuro-muscular Imaging Biomarkers for Motor Outcome in Stroke

Background: Undertaking clinical trials for sarcopenia presents multiple challenges. The diagnosis is not commonly made in clinical practice in part due to the need to measure muscle mass and muscle strength. Finding participants with sarcopenia for clinical trials is therefore challenging and often requires screening large numbers of potential participants in order to identify those with sarcopenia. Sarcopenia registries are a potential method to improve recruitment to sarcopenia trials, which has proved challenging to date. We aimed to test the feasibility of setting up a UK sarcopenia registry, the feasibility of recruitment methods and to characterise the pilot registry population. Methods: Six diverse UK sites took part, selected to give a range of large and small cities, different geographies and different proportion of ethnic minority prevalence in the local population. Potential participants aged 65 and over were approached via mailshots from local primary care (GP) practices. Telephone pre-screening using the SARC-F score was followed by inperson screening and baseline visit. Comorbidities, medications, grip strength, Short Physical Performance Battery, bioimpedance analysis (Akern 101 system), Geriatric Depression Score, Montreal Cognitive Assessment and SarQoL score were performed. Permission was sought for future re-contact. We conducted an embedded randomised controlled trial of a simple intervention which aimed to boost mailshot response rates. Mailshot batches were randomised to the presence or absence of a Newcastle University logo on the mailshot envelope; we hypothesised that mailshots with the logo would be more likely to be opened and thus responded to, rather than treated as junk mail. Recruitment rates and baseline measures were analysed using descriptive statistics. For the embedded randomised trial, the primary outcome (the proportion of letters generating a positive reply (mail slip or telephone contact) was compared using Pearson's chi-squared test with 95% confidence intervals. Results: Sixteen GP practices contributed a total of 3508 letters. Details of response rates and progression through screening and recruitment for each site are given in Table 1. 150 participants were recruited (40% of those pre-screened) with 147 contributing baseline data. Conclusion: Recruitment to a multi-site UK sarcopenia registry is feasible, with high levels of consent for recontact. Different populations may require different contact approaches to maximise participation.

Developing a UK sarcopenia registry: recruitment and baseline characteristics of the SarcNet pilot

Background: Frailty in older adults is a growing challenge, further exacerbated by recent COVID-related reductions in activity. Thankfully, there is now an established evidence base for the benefit of exercise and protein supplementation in counteracting frailty. Unfortunately, this this has not yet been adequately translated into practice. The aim of this study, Diet & Exercise for FRAILty (DEFRAIL), was to develop an effective intervention suitable for widespread uptake. Our first objective was to design an intervention suitable for a wide spectrum of frailty in older adults and deliverable in a community setting. The second was to evaluate its effect on frailty and related measures. Methods: Intervention: A multi-component exercise program combined with nutritional supplementation was developed by a modified Delphi process (Figure 1). A brief pilot trial allowed participant feedback and further modifications. The final DEFRAIL program consisted of a 1-hour group class: -Warm-up x 5 mins -Stretch x 5 mins -Circuits x 15 mins each -Upper limb resistance -Lower limb resistance -Aerobic/Balance -Cool-down x 5 mins The nutritional intervention was protein-supplemented milk (250ml twice daily). Three-day food diaries were completed pre-and intraintervention to monitor the effect on micro- & macro-nutrient intake Classes were delivered by 2 instructors in group of 10-12 participants per class. Results: Participant characteristics: 28 participants (22 female, 6 male) commenced the program, of which 22 (16 female, 6 male) completed follow-up assessments. Mean age was 84.5 years, mean FFC 3.55 prior to the intervention). Statistical approach: Analysis was conducted using SPSS. The mean change in outcome measures over the control and intervention periods were compared using paired t-tests. Primary outcome measure: A statistically significant improvement in FFC of -2.05 was seen in the primary outcome measure during the intervention period, compared with the control period (mean change over control period +0.32, mean change over intervention period -1.73). The mean FFC moved from 3.23 (frail) at baseline to 3.55 (frail) after eight weeks of regular activity but fell to 1.82 (pre-frail) following completion of the intervention. Improvements were seen in the individual criteria of ”Exhaustion”, “Low activity and “Slow gait speed” but not “Weight loss” or “Low grip strength”. Secondary outcome measures: A statistically significant improvement was seen in the Timed Up & Go (TUG) test, with a mean difference of - 3.19 seconds between the change during the intervention over the control period. A significant improvement was also seen in the Geriatric Depression Scale, with a mean difference of -1.41. Based on pre- and intra-intervention three-day food diaries, a significant increase in protein intake (daily mean difference of +11.22g) was observed. No significant change was observed for measures of body mass composition, arterial stiffness, cognition, pain or quality-of-life. Conclusion: The DEFRAIL intervention is feasible for delivery without the direct input of health professionals and effective at reversing frailty in a group of community-dwelling frail older adults. We propose that it provides an effective community-based means of reversing frailty and its associated adverse outcomes. Given the growing prevalence of frailty, we feel there is an urgent need to incorporate an intervention such as this into public health policy. 

Diet and Exercise for FRAILty (DEFRAIL): The effect of a novel community-based exercise and nutritional intervention on frailty and related measures in
frail older adults

Introduction: 1) Frailty is independently associated with poor clinical outcomes such as impaired quality of life, as well as increased emergency hospital admission2 , disability 3 and earlier death. 2) Currently very few treatments, such as resistance training and nutrition high in protein have shown to have positive effects on reducing levels of frailty. 3) Given positive results in mouse studies, NAD+ supplementation may have potential as an intervention to prevent or reverse elements of poor physical function and frailty in older humans. 4) We aimed to systematically assess all available randomised controlled trials investigating effects of NAD+ precursor drugs on outcomes relevant to physical function or frailty. Methods: Figure 1. PRISMA flow chart for papers found through systematic search. 5) The Fried frailty phenotype criteria were used as a framework to construct the study’s systematic search, based on the five Fried domains: - Gait speed - Muscle strength - Fatigue and exhaustion - Physical activity - Weight loss 6) A systematic search strategy was used on several databases: MEDLINE, EMBASE, CINAHL, CENTRAL, ISRCTN, clinicaltrials.gov, NHS e-Library and Google Scholar. No language restrictions were used. Mean cohort age had to be >18 years. 7) Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. Results were grouped by phenotype domain and described through narrative synthesis. 8) All stages of the review were conducted independently by two separate authors. Results: 1) Twenty studies met the inclusion criteria; sample sizes ranged from 2 to 77 participants. • Most studies assessed only a limited number of frailty domains. Interventions were mostly short term, with 10 (50%) of studies having an intervention period of 1 week or less • Risk of bias analysis showed high risk of bias in 12/20 studies and unclear risk of bias in 7/20 studies. This was frequently due to the adverse effect of flushing which impaired masking. 2) Only 3 studies enrolled cohorts with a participant mean age >65 years. No studies assessed for intracellular NAD+ levels before or after supplementation. Conclusions: 1) The current evidence on NAD+ precursor supplementation is insufficient to ascertain effects on the frailty phenotype or physical performance. • High-quality studies are required to explore the effects of NAD+ precursor supplementation on frailty and physical function more closely. Measures of physical function and/or frailty should be primary outcomes of these studies. 2) Previous studies on NAD+ levels in humans show that older people are more likely to be deficient than younger people, and therefore may respond differently to its treatment. Future studies should consider older people as key participants of NAD+ supplementation research.

Effects of nicotinamide adenine dinucleotide precursors on physical function and frailty: a systematic review

Background and Aims: • NAFLD is the most common liver condition worldwide and is directly linked to chronic excess calorie consumption, lack of physical activity and overweight/obesity. • NAFLD can progress to non-alcoholic steatohepatitis (NASH). Incidence of NASHrelated end stage liver disease is increasing. • Concurrent with an increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) and sarcopenic obesity are rising. • There is growing evidence of a causal link between sarcopenia and the development of NAFLD. • A very low calorie diet (VLCD) has been postulated as a possible solution for NAFLD, however, there are concerns that a VLCD may induce further reduction of skeletal muscle mass (SMM). Methods: • 30 patients with advanced NAFLD were recruited to an 8-12 week VLCD (~800 kcal/day) using meal replacement products (Optifast, Nestlè Health Science). • 11 patients opted to extend the VLCD intervention beyond 8 weeks up to 12. • Anthropometrics, body composition, blood tests (liver enzymes, lipid profile, glucose, HbA1c, insulin), liver stiffness, Quality of life, and cardiovascular disease risk were measured at baseline and after the VLCD intervention. • Bioelectrical impedance analysis was used to determine body composition; fat mass (FM), fat-free mass (FFM) and skeletal muscle mass (SMM). • Anthropometrics and blood tests were also measured at weeks 1, 3, 5, 7 (and at weeks 9 and 11). • Given the intense caloric restriction, patients were not encouraged to partake in heavy exercise during a VLCD. Results: • Of the 45 patients approached to take part in this study, 30 consented to enrol. This study was fully recruited at a single site within 6 months and 27/30 retained post VLCD. • 68% of patients reached the weight loss target of 10%; mean weight loss was 13kg (3-39), equivalent to 11% (3-26). • Weight loss through an 8-12 week VLCD significantly improved (Table 1); -BMI and body composition -liver health (liver enzymes and liver stiffness) -cardiometabolic disease risk (blood pressure and QRISK2) -There was a moderate positive correlation between weight loss and change in SMM (r=0.444, p=0.034). -QOL and weight related symptom measure (WRSM) significantly improved from 44±26 to 55±20 (p=0.001) and 43±30 to 31±23 (p=0.039), respectively. Conclusions • Despite previous concerns that a VLCD may exacerbate sarcopenic characteristics, the VLCD intervention did not significantly affect SMM, but induced efficient weight loss. • it may be beneficial to encourage continuation of daily physical activity during the VLCD and an increase in physical activity/exercise after completion of the VLCD, to maintain long-term weight-loss and FFM/SMM.

The effect of a very low calorie diet on body composition in patients with non-alcoholic fatty liver disease

Background: •The increasing longevity of the world’s population together with prolonged survival in many chronic diseases means that more people have loss of mobility. •To target mobility loss effectively and thus be able to prevent it, we need valid tools that can detect and measure it in daily life (1). •It is also of vital importance that mobility outcomes are assessed in relation to other ageing syndromes, including sarcopenia and frailty. Digital technology has the potential for measuring and monitoring digital mobility outcomes in the real world, but as yet there are no robust, validated technology solutions. Methods: • The overarching objectives of Mobilise-D (“Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement”) are to: • Deliver a valid solution for real-world digital mobility assessment; • Validate digital mobility outcomes in predicting clinical outcome in a variety of disease states including Parkinson’s disease, chronic obstructive pulmonary disease, multiple sclerosis, and proximal femoral fracture; and • Obtain regulatory and health stakeholder approval for digital mobility assessment. Results: •Mobilise-D is funded by the European Innovative Medicines Initiative 2 Joint Undertaking, & includes 34 international research partners based at leading international universities and some of the world’s largest pharmaceutical and technical companies. •Mobilise-D started on 1 April 2019 and will run for five years. •Real-world walking speed and related outcomes assessed in 5 chronic disease populations to derive a device-agnostic algorithm that can be used to predict medically relevant clinical outcomes (e.g., falls, hospitalizations, disability, death) from mobility assessment •A sub-study on sarcopenia and frailty will be conducted within each cohort. Conclusion: Mobilise-D's results will directly facilitate drug development and establish the roadmap for clinical implementation of new, complementary tools to identify, stratify and monitor disability, thereby enabling widespread, cost-effective access to optimal clinical mobility management through personalised healthcare.

Connecting digital mobility assessment to sarcopenia and frailty: the Mobilise-D study

Introduction: • CT-based body composition can distinguish between lean and fat tissue, in contrast to BMI • Low skeletal muscle index (SMI) and low skeletal muscle radiodensity (SMD) are associated with survival in several cancer types • In renal cell cancer (RCC) evidence is limited and inconsistent. Methods: • Patients diagnosed with RCC from 2008-2012 were included • CT-scans at L3 level were collected to assess skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI) and subcutaneous adipose tissue (SATI) • Clinical data were retrieved from medical records • Multivariable Cox regression with restricted cubic splines were used for examining body composition and overall survival (OS) and recurrence-free survival (RFS) • Analyses were adjusted for age at diagnosis, smoking, tumor stage, Fuhrman grade (and MSKCC and mGPS for stage IV) and mutually adjusted for other body composition parameters. • Stage I-III and stage IV were analyzed separately and gender-specific results are presented. Results: • 719 stage I-III and 320 stage IV patients were included  • Median follow up was 6.35 years (interquartile range 1.41-8.23). Conclusion: • Higher SMD and higher VATI were marginally associated with better survival in RCC patients and might be useful for better prognostication. • However, the added value to current prognostic scores needs to be investigated. 

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The association between body composition and survival in locally advanced rectal cancer: An Australian study

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