Abstract BackgroundCross‐sectional muscle area (CSMA) at the mid third lumbar vertebra (L3) can be used for sarcopenia diagnosis. The measurement of CSMA is time‐consuming and thus restricted to clinical research. We aimed to compare the automatic module ABACS (Automatic Body composition Analyser using Computed tomography image Segmentation software) with manual segmentation for CSMA assessment into clinical routine.MethodsThe study population was screened retrospectively from a computed tomography‐scan (CT‐scan) database. All consecutive participants, hospitalized at the Grenoble University Hospital (CHU Grenoble Alpes) between January and May 2018, and with an abdominal CT‐scan including sagittal reconstruction were included. The software SliceOmatic complemented with the module ABACS (ABACS‐SliceOmatic) was compared with the software ImageJ. Their agreement was determined using Lin's concordance correlation coefficient and visualized in Bland–Altman plots for the CSMA measurement or with Cohen's kappa coefficient (κ) for sarcopenia status.ResultsData from 680 participants were analysed (mean age 59 ± 19 years, %females: 45.7). The concordance correlation coefficient between both types of software was 0.93 (CI95%: 0.92 to 0.94). Mean CSMA was significantly higher with ABACS‐SliceOmatic (mean difference: 6.51 ± 10.50 cm2; P < 0.001). Kappa agreement for sarcopenia diagnosis was moderate: 0.68 (CI95%: 0.62–0.74) and 0.71 (CI95%: 0.65–0.76) for Prado's and Derstine's definitions, respectively.ConclusionsABACS‐SliceOmatic has moderate agreement with the manual software ImageJ in a routine clinical database. Our work suggests that ABACS‐SliceOmatic should be used with caution in clinical practice. To improve its reliability, we suggest to manually validate the automatic segmentation.

Abstract BackgroundCancer cachexia is characterized by impaired function of skeletal and cardiac muscle. Smooth muscle is abundantly present in the body and critical for the function of the gastrointestinal tract. Given the frequently reported gastrointestinal symptoms in cancer patients, we hypothesized that the smooth musculature could be compromised in cancer patients with sarcopenia.MethodsFull‐thickness jejunal tissue sections from 57 pancreatic cancer patients were analysed by picrosirius red stains and immunohistochemistry for α‐smooth muscle actin (α‐SMA), smoothelin, and CD117 (c‐kit). Muscle wall thickness, contractile marker expression, and collagen deposition were quantified. Patients were assigned to a sarcopenia or non‐sarcopenia group based on their skeletal muscle index.ResultsIntestinal smooth muscle wall thickness did not differ between the sarcopenia and non‐sarcopenia group (1,661 ± 125.0 vs. 1,439 ± 93.5 μm, P = 0.41). Whereas α‐SMA staining intensity was similar in both groups, staining intensity of smoothelin, a key marker of the contractile smooth muscle cell phenotype, was reduced (143.0 ± 22.6 vs. 125.4 ± 29.3 arbitrary units, P = 0.02) in sarcopenic patients. The distribution of CD117+ interstitial cells of Cajal was similar in both groups, but pronounced collagen deposition around the myenteric plexus was more often observed in patients with sarcopenia (P = 0.04).ConclusionsThese data suggest that cancer cachexia is not only associated with skeletal and cardiac muscle wasting, but also affects the intestinal smooth musculature. Reduced contractile smooth muscle marker expression and fibrosis around the myenteric plexus suggest that both contractile function of smooth muscle cells and regulation of their contractile functionality could be compromised.

Abstract BackgroundCAPARFI study explored whether sonoelastographic data collected using the acoustic radiation force impulse (ARFI) system are reliable when evaluating skeletal muscles and whether the technique can detect muscle changes with aging.MethodsTwenty young (YH; 18–30 years) and 30 old (OH; ≥70 years) healthy volunteers and 15 old patients with cancer (OP; ≥70 years) were assessed through quantitative ARFI measurements (m s−1) of the relaxed rectus femoris, tibialis anterior, and soleus muscles, and Short Physical Performance Battery (SPPB) test. The reliability in ARFI measurements was evaluated by intra‐class correlation coefficient. Among‐group differences in ARFI measurements and SPPB were evaluated using a global linear model.ResultsAcoustic radiation force impulse measurements demonstrated high reliability in all groups (intra‐class correlation coefficient > 0.82). ARFI measurements of the rectus femoris muscle were significantly lower in both the OH and OP groups than in the YH group (1.46 ± 0.12 and 1.50 ± 0.32 vs. 1.80 ± 0.35 m s−1). The ARFI measurements of the soleus muscle were significantly lower in the OP group than in the YH group (1.37 ± 0.37 vs. 1.70 ± 0.53 m s−1). No significant difference was observed for tibialis anterior muscle. Significantly lower SPPB scores were observed in the OP group (10.3 ± 1.4 out of 12) than in the YH (12.0 ± 0.0) and OH groups (11.5 ± 1.0).ConclusionsThis study demonstrated that ARFI quantitative measurements are reliable in relaxed skeletal muscle and may be reliably used to explore muscle changes with aging and/or neoplasia in clinical practice.

Abstract BackgroundSubjective global assessment (SGA) and Royal Free Hospital‐global assessment (RFH‐GA) are clinically useful for assessing malnutrition. This study aimed to investigate the relationship between sarcopenia, which predicts poor clinical outcomes in patients with chronic liver disease (CLD), and these two methods.MethodsThis retrospective study included 240 consecutive patients admitted to our hospital between October 2011 and January 2014. Sarcopenia and RFH‐GA were evaluated using anthropometric measurements and computed tomography‐based skeletal muscle area. The primary outcome was whether nutritional assessment methods could predict sarcopenia. In addition, factors associated with sarcopenia and mortality were evaluated.ResultsThe median age was 70 years, 67% were men, and 17% had sarcopenia. Malnourished patients assessed by SGA (P = 0.02) and RFH‐GA (P < 0.001) had a significantly higher prevalence of sarcopenia than did well‐nourished patients. After adjustment for age, sex, aetiology, and albumin, multivariate analysis revealed that RFH‐GA, but not SGA, was a significant predictor of sarcopenia [odds ratio, 2.47; 95% confidence interval (CI), 1.15–5.33]. During a median follow‐up of 2.7 years, 113 patients died. The overall survival rates were significantly lower in malnourished patients assessed by SGA (P < 0.001) and RFH‐GA (P < 0.001) than in well‐nourished patients. Multivariate analysis revealed that RFH‐GA [hazard ratio (HR), 1.51; 95% CI, 1.02–2.23] and SGA (HR, 1.99; 95% CI, 1.19–3.32) were independently associated with mortality.ConclusionsRoyal Free Hospital‐global assessment is a simple bedside screening tool for identifying sarcopenia and predicting mortality in patients with CLD.

Abstract BackgroundSarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre‐screening, performance of a questionnaire on physical function conducted as part of the pre‐screening telephone call, and performance of bioimpedance measurement to identify low muscle mass.MethodsHospital‐based recruitment took place through inpatient and outpatient geriatric medicine services. Local research nurses reviewed medical notes and approached potentially eligible patients. Primary care recruitment reviewed primary care lists from collaborating practices, sending mailshots to patients aged 70 and over who were not taking angiotensin‐converting enzyme inhibitors. Telephone pre‐screening was conducted either by research nurses at each site or centrally by Tayside Clinical Trials Unit. The 10‐point SARC‐F questionnaire was used for pre‐screening. De‐identified recruitment information was held on a central electronic tracking system and analysed using SPSS. Bioimpedance was measured using the Akern BIA 101 system, with the Sergi equation used to estimate lean mass.ResultsFourteen UK sites recruited to the trial. The 1202 sets of notes in hospital‐based care were reviewed at these sites; 7 participants (0.6% of total notes screened) were randomized. From primary care, 13 808 invitations were sent; 138 (1.0% of total invited) were randomized. 633/2987 primary care respondents were pre‐screened centrally; the mean number of calls per respondent was 2.3. For 10 sites where central and local pre‐screening could be compared, the conversion rate from pre‐screening to randomization was 18/588 (3.1%) for centralized calls, compared with 73/1814 (4.0%) for local pre‐screening calls (P = 0.29). A weak relationship was seen between higher (worse) SARC‐F score at screening and lower likelihood of progression to randomization (r = −0.08, P = 0.03). Muscle mass estimates generated using the Sergi equation were systematically biased, and a recalibrated equation for bioimpedance‐estimated muscle mass was derived.ConclusionsPrimary care recruitment led to higher response rates and overall numbers randomized than hospital‐based recruitment. Centralized pre‐screening saved local research nurses' time but did not improve conversion to randomization. SARC‐F did not help to target screening activity in this sarcopenia trial, and a recalibration of the equation for estimating muscle mass from bioimpedance measures may improve accuracy of the screening process.

Abstract BackgroundCachexia, a complex multi‐organ syndrome, shortens survival time of patients, particularly those with cancer. Many studies and clinical trials have been carried out to identify cachexia‐inducing factors and potential treatments for cancer cachexia over the last 20 years. Of these factors, some are promising targets for treatment in humans, owing to their expression profiles in patients. Several clinical interventions, which act on either cachexia‐inducing factors or tissues affected by cachexia, have been developed. Some have had positive effects in the treatment of cancer cachexia; however, the question remains whether these interventions reverse cancer cachexia and could be used as standard interventions for disease treatment. The aim of this review is to understand the basic mechanisms and factors that induce cancer cachexia and their efficacies in clinical trials, providing a better outlook for future studies of cancer cachexia.MethodsA systematic search was performed using PubMed and ClinicalTrials.gov databases for cachexia mediators and clinical trials.ResultsOf all databases and peer‐reviewed facts considered, 256 papers and 35 clinical trials were included in this systematic review. Twenty‐one mediators were identified, and 17 clinical interventions were reported in these studies. Outcomes of these clinical trials were assessed on changes in overall survival, body weight, lean body mass, appetite, muscle strength, muscle function, quality of life, and cytokine levels.ConclusionsThere is no current standard or successful intervention for treating cancer cachexia. Further research is needed to improve our understanding of initiators of cachexia to achieve successful outcomes in cachexia clinical trials.

Abstract BackgroundSarcopenia is the progressive generalized loss of skeletal muscle mass, strength, and function that occurs with aging. This study was undertaken to identify new biomarkers of sarcopenia by proteomics analysis of female sera.MethodsA case–control study was set up, for which 19 sarcopenic subjects and 20 control subjects, according to the European Working Group on Sarcopenia Older People criteria published in 2010 (EWGSOP1), were enrolled. All the subjects were at least 65 years old and in majority female. Biomarker screening was performed by a comparative mass spectrometry analysis. Protein expression levels between the two groups were compared. One of the identified biomarkers, cathepsin D, was measured by immunoassay on the serum of the full sample set (n = 39). Its diagnostic performance was evaluated with a receiver operating characteristic curve (ROC curve).ResultsTwo biomarkers were identified: fructose‐biphosphate aldolase A (P ≤ 0.05) and cathepsin D (P ≤ 0.05). The levels of all of them were higher in sarcopenic patients. It was confirmed by immunoassay that cathepsin D levels in serum were significantly higher in the sarcopenic group of patients (P = 0.038). An inverse correlation (−0.385) was observed between cathepsin D levels in serum and gait speed. The area under the ROC curve measurement (AUC = 0.696) demonstrated that cathepsin D levels could discriminate between sarcopenic and non‐sarcopenic subjects. A predictive model including cathepsin D, age, and body mass index was established to improve the diagnostic performance (AUC = 0.908).ConclusionsCathepsin D has been identified as a diagnostic biomarker of sarcopenia.

Abstract BackgroundCardiorespiratory fitness (CRF) has important implications for post‐operative recovery. The timed‐up‐and‐go (TUG) test is a cheap and simple method to assess a patient's functional performance; although how well TUG correlates with results of a cardiopulmonary exercise test (CPET), the gold standard measure of CRF is unknown. Therefore, the aim of this study was to assess the correlation between CPET‐derived parameters of CRF and TUG times in a group of older adults.MethodsNinety‐eight independent community dwelling older adults [mean age: 72 years (range: 61–86), mean body mass index: 26.3 ± 3.1 kg/m2, 54 male] were recruited to this study; completing 180 CPET and TUG testing sessions over a 28 month period. The correlation between CPET‐derived CRF parameters and TUG time was assessed, and receiver operating characteristic curve analysis was performed to determine clinically useful cut‐off points in TUG time.ResultsMedian TUG time was 7.1 s [interquartile range (IQR): 4–8.5], median VO2 peak was 24.4 mL/kg/min (IQR: 20.2–29.2), and the median anaerobic threshold (AT) was 13.4 mL/kg/min (IQR: 8.6–16.5). There was a statistically significant negative correlation between TUG time and AT (r = −0.317, P = <0.0001) and TUG time and VO2 peak (r = −0.4247, P < 0.0001). Receiver operating characteristic curve analysis determined a TUG time of ≥6.5 s to have an 82% sensitivity and 60% specificity to detect an AT <11.0 mL/kg/min, the point at below which perioperative mortality is known to increase.ConclusionsDespite strong evidence for the utility of pre‐operative CPET in stratifying surgical risk, CPET is not universally available. Our finding of a correlation between TUG time and CPET‐derived parameters of CRF (AT/VO2 peak) suggests that TUG may be a useful surrogate in the pre‐operative setting.

Abstract BackgroundPre‐clinical studies suggest that renin–angiotensin system blockade may improve muscle function. Clinical reports of the effect of angiotensin converting enzyme inhibitors (ACEIs) on physical functioning are inconsistent. There are no reports of the effect of angiotensin receptor blockers (ARBs) treatment in older adults.MethodsWe analysed data of 1268 participants in the Singapore Longitudinal Ageing Study (SLAS‐2) who provided information on the use of ACEI, ARB, and other antihypertensive drugs at baseline and follow‐up (mean 4.5 years later). Baseline and follow‐up outcome measures were cumulated deficits frailty index (CD‐FI), physical phenotype frailty index (PP‐FI), calf circumference (CC), knee extension strength, composite muscle mass and strength (MMS) z‐score, and gait speed (GS). In primary analyses, we compared the use and non‐use of an anti‐hypertensive drug class among participants with hypertensive and cardiac disease, and secondarily with participants having other chronic diseases, and those who reported no chronic diseases. Multi‐variable analyses adjusted for socioeconomic status, body mass index ≥30, ≥5 comorbidities, ≥5 drugs use, other non‐ARB or non‐ACEI drugs (calcium channel blockers, beta blockers, or hydrochlorothiazide), MMSE <23, Geriatric Depression Scale score, Nutrition Screening Initiative nutritional risk, physical activities, baseline frailty, and physical performance.ResultsAmong study participants, 7.8% (N = 99) were ARB users (62% used losartan), 11.7% (N = 148) were ACEI users (53% used enalapril), and 34.2% (N = 434) were users of other anti‐hypertensive drug classes. The cohort participants overall showed increases in the mean levels and changes in CD‐FI and PP‐FI and decreases in knee extension strength, GS, CC, and MMS. However, among groups, ARB users showed decreasing trends in CD‐FI and increasing trends of CC and MMS. Among participants with hypertensive and cardiovascular disease, there were significant differences in CD‐FI and PP‐FI changes, adjusted for confounding variables: ARB users compared with non‐users showed lesser declines in CD‐FI (0.013 vs. 0.028, P = 0.018) and PP‐FI (0.924 vs. 1.170, P = 0.017). ARB users also showed statistically significantly greater gains in MMS z‐scores: 0.329 vs. 0.076, P = 0.022. There was no association of ACEI or other anti‐hypertensive class use with changes in frailty, MMS, or GS.ConclusionsThe use of ARBs is associated with a reduction in frailty and age‐related loss of muscle mass and strength.

BackgroundMonoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one‐third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL0) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL0 may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL0 and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms.MethodsWe evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (Fcgrt) expression was assessed in liver using real‐time quantitative reverse transcription PCR. Non‐compartmental and mixed‐effects pharmacokinetics analyses were performed.ResultsWe observed higher pembrolizumab CL0 and decreased Fcgrt expression in whole liver tissue from tumour‐bearing vs. tumour‐free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and Fcgrt expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q.ConclusionsThese data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which Fcgrt expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn‐mediated clearance and efficacy of ICI therapies.