ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .

Association of strength, power, and function with muscle thickness, echo intensity, and lean tissue in older males.

Dual-energy X-ray absorptiometry (DXA) appendicular lean tissue is used to screen older adults for sarcopenia. However, emerging data indicates that ageing-related muscle atrophy largely occurs within specific muscles, which may be masked using appendicular lean tissue. Comparisons between appendicular lean tissue and site-specific measures of muscle in relation to strength and physical function are needed to advance our understanding of these features in the context of poor muscle function in aged adults. Our primary objective was to compare correlations between lean tissue and site-specific muscle characteristics in relation to strength and physical function in older males. Older males (≥65 years) were evaluated for muscle strength, physical function (6-minute walk and 30-second sit-to-stand), and muscle size (appendicular and site-specific) and composition (echo intensity) using DXA and ultrasound. Of the 32 older males (75.4 ± 7.9 years), 12 had low appendicular lean tissue. All DXA and ultrasound muscle characteristics were associated (r = 0.39 to 0.83, p < 0.05) with torque or power producing capabilities. Except for the knee flexors, no differences in correlation coefficients were observed between muscle thickness or regional lean tissue in relation to muscle strength. Neither DXA nor ultrasound muscle characteristics were associated with physical function. In older males, ultrasound-based muscle thickness and DXA lean tissue provided similar associations with strength. Novelty: Lean tissue and muscle thickness provide similar associations with strength. Muscle thickness can distinguish low and normal appendicular lean tissue in older adults.

Altered features of body composition in older adults with type 2 diabetes and prediabetes compared with matched controls.

BACKGROUND: Ageing is accompanied by muscle loss and fat gain, which may elevate the risk of type 2 diabetes (T2D). However, there is a paucity of data on the distribution of regional lean and fat tissue in older adults with T2D or prediabetes compared with healthy controls. The objective of this study was to compare regional body composition [by dual-energy x-ray absorptiometry (DXA)], muscle and subcutaneous adipose tissue (SAT) thicknesses (by ultrasound), and ultrasound-based muscle texture features in older adults with T2D or prediabetes compared with normoglycaemic controls. METHODS: Eighteen adults > 60 years with T2D or prediabetes (T2D group) were individually matched to normoglycaemic participants [healthy matched (HM) group] for age (±5 years), sex, and body fat (±2.5%). In a single study visit, all participants received a whole-body DXA scan and ultrasound assessment of the abdomen and anterior thigh. At these two landmarks, we used ultrasound to measure muscle and SAT thickness, as well as texture features of the rectus femoris and rectus abdominis. We also conducted an exploratory subanalysis on a subset of participants (n = 14/18 in the T2D group and n = 10/18 in the HM group) who underwent additional assessments including strength testing of the knee extensors (using a Biodex dynamometer), and a fasting blood sample for the measurement of circulating markers of glucose metabolism [glucose, insulin, c-peptide, and the homoeostatic model assessment of insulin resistance (HOMA-IR)]. RESULTS: The T2D group was 72 ± 8 years old (mean ± SD), predominantly male (n = 15/18; 83%), and overweight (BMI: 27.8 ± 4.2 kg/m2 , 33.2 ± 5.3% body fat). DXA-derived upper arm lean mass was 0.4 kg greater (P = 0.034), and leg fat mass was 1.4 kg lower (P = 0.048), in the T2D vs. HM group. Ultrasound-based texture features were distinct between the groups [rectus abdominis blob size: 0.07 ± 0.06 vs. 0.30 ± 0.43 cm2 , P = 0.045; rectus femoris local binary pattern (LBP) entropy: 4.65 ± 0.05 vs. 4.59 ± 0.08 A.U., P = 0.007]. When all participants who underwent additional assessments were pooled (n = 24), we observed that certain ultrasound-based muscle texture features correlated significantly with muscle strength (rectus abdominis histogram skew vs. power during an isokinetic contraction at 60°/s: r = 0.601, P = 0.003) and insulin resistance (rectus femoris LBP entropy vs. HOMA-IR: r = 0.419, P = 0.042). CONCLUSIONS: Our findings suggest a novel body composition phenotype specific to older adults with T2D or prediabetes. We are also the first to report that ultrasound-based texture features correspond with functional outcomes. Future larger scale studies are needed to uncover the mechanisms underpinning these regional body composition differences.

Body size normalization of ultrasound measured anterior upper leg muscle thickness in younger and older males and females.

BACKGROUND: Ultrasound measurements of the anterior upper leg muscle thickness are often used to quantify muscle mass; however, the ideal normalization approach is unclear. Our primary objective was to examine how the anterior upper leg muscle thickness scales with indices of body size in younger and older adults. Our secondary objectives were to examine how normalization with body size alters the identification of low muscle thickness and associations with strength and physical function. METHODS: Younger (<45 years) males (n = 38) and females (n = 24) and older (≥60 years) males (n = 53) and females (n = 24) were evaluated for anthropometrics and anterior upper leg muscle thickness. Allometric models were used to examine how body size metrics scale with anterior upper leg muscle thickness. A subset of older males was evaluated for strength and function. RESULTS: Weight and BMI scaled with anterior upper leg muscle thickness with coefficients less than 1 (0.58 to 0.82, r2 = 0.15 to 0.31, p < 0.05) for both younger and older males and females. Compared to absolute anterior upper leg thickness, normalized indices identified a greater proportion of older adults with low muscle thickness (p < 0.05). Absolute muscle thickness provided stronger associations with strength compared to weight normalized indices. CONCLUSIONS: Scaling exponents less than 1 for weight and BMI for the anterior upper leg muscle thickness indicate that allometric normalization is the ideal approach to develop body size independent metrics. However, allometric normalization of muscle thickness increases the proportion of older adults classified as low muscle mass but decreased the associations with strength.

Influence of Subcutaneous Adipose Tissue and Skeletal Muscle Thickness on Rectus Femoris Echo Intensity in Younger and Older Males and Females.

OBJECTIVES: Ultrasound measurements of muscle echo intensity are commonly used surrogates of muscle composition (eg, intramuscular adipose tissue). However, given that soundwaves are increasingly attenuated with tissue depth, the interpretation of echo intensity may be confounded by adipose and skeletal muscle thickness. Our objectives are to compare the associations between adipose or muscle tissue thickness and rectus femoris echo intensity in younger and older males and females. METHODS: Participants included in this analysis were derived from 3 previously published cohorts of younger (<45 years) and older (≥60 years) males and females. Ultrasound images of the rectus femoris were evaluated for muscle thickness, echo intensity, and subcutaneous adipose tissue thickness. RESULTS: Older adults (n: 49 males, 19 females) had a higher body mass index (P = .001) compared with younger adults (n: 37 males, 49 females). Muscle thickness was negatively associated with echo intensity in older males (r = -0.59) and females (r = -0.53), whereas no associations were observed in younger males (r = 0.00) or females (r = -0.11). Subcutaneous adipose tissue thickness displayed no associations with echo intensity in any group. CONCLUSIONS: Despite the known influence of subcutaneous adipose tissue thickness on beam attenuation, we observed no association with muscle echo intensity, indicating that adipose tissue correction may be required to better understand muscle echo intensity across differences in adiposity. The negative associations between muscle thickness and echo intensity in older, but not younger adults, suggests these associations may be related to the co-occurrence of skeletal muscle atrophy and intramuscular adipose tissue infiltration with advancing age.

Low-frequency exercise training improves cardiovascular fitness and strength during treatment for breast cancer: a single-arm intervention study.

Aerobic and resistance exercise during and after cancer treatment are important for health-related outcomes, however treatment-specific barriers may inhibit adherence. We explored the effect of lower-frequency exercise training on fitness, body composition, and metabolic markers (i.e. glucose and lipids) in a group of recently diagnosed breast cancer patients. Fifty-two females ≥ 18 years with stage I-IIIB breast cancer were instructed to attend 2 cardiovascular and strength training sessions/week over 12 weeks, but program length was expanded as needed to accommodate missed sessions. Pre- and post-intervention, we measured: (1) cardiovascular fitness, (2) isometric strength, (3) body composition (dual-energy X-ray absorptiometry), and (4) fasting glucose, insulin, c-peptide, and lipids. Pre-intervention, participants were 53 ± 10 years old (mean ± SD) and overweight (BMI: 27.5 ± 5.4 kg m-2, 40.1 ± 6.5% body fat). Forty participants completed the program over a median 20 weeks (range: 13-32 weeks, median frequency: 1.2 sessions/week), over which predicted VO2peak improved by 7% (2.2[0.1-4.4] mL/kg/min) (delta[95% CI]), and strength increased by 7-9% (right arm: 2.3[0.1-4.5] N m; right leg: 7.9[2.1-13.7] N m; left leg: 7.8[1.9-13.7] N m). Body composition and metabolic markers were unchanged. An exercise frequency of 1.2 sessions/week stimulated significant improvements in fitness, and may represent a practical target for patients during active treatment.

Associations between skeletal muscle echo intensity and thickness in relation to glucose homeostasis in healthy and glucose impaired older males.

BACKGROUND: Aging-related changes in muscle composition and mass may predispose older adults to developing insulin resistance. Ultrasound echo intensity and thickness are surrogates of muscle composition and mass, however, their associations with glucose homeostasis are not well established. We examined how muscle echo intensity and thickness correlate with markers of glucose homeostasis in older (≥65 years) males with normal (n = 22) or impaired (n = 10) glucose control. METHODS: Echo intensity was measured for the biceps brachii, rectus abdominis, and rectus femoris. Muscle thickness was evaluated for the biceps brachii + brachioradialis, rectus abdominis, and rectus femoris + vastus intermedius. Glucose homeostasis was evaluated using a 2-h oral glucose tolerance test. RESULTS: In older males with normal glucose homeostasis, higher echo intensity of the rectus abdominis and rectus femoris was moderately (r = 0.36 to 0.59) associated with 2-h glucose. On the contrary, higher muscle echo intensity of the rectus abdominis, biceps brachii, and rectus femoris was moderately-to-strongly (r = -0.36 to -0.79) associated with indices of better glucose homeostasis in the impaired group. Rectus abdominis muscle thickness was moderately associated (r = 0.36) with better glucose tolerance in the normal glucose homeostasis; however, in the glucose impaired group, muscle thickness was associated with (r = 0.37 to 0.73) with poorer glucose homeostasis. CONCLUSIONS: Muscle echo intensity displays divergent associations with glucose homeostasis in older males with normal compared to impaired glucose control. Larger muscle thickness was associated with poorer glucose homeostasis in the glucose impaired group, but rectus abdominis muscle thickness was correlated with better homeostasis in healthy older males.

Older males exhibit reduced anterior upper leg and anterior abdominal muscle thickness compared to younger males when matched for relative appendicular lean tissue.

Background Ageing-related muscle atrophy does not occur uniformly across the body; rather, atrophy occurs to a greater extent in specific muscle groups compared to others. However, site-specific comparisons of muscle mass between older and younger adults typically do not account for relative muscle mass (i.e., matched for age- and sex-specific percentiles), which may confound site-specific differences. Furthermore, the uniformity of ageing-related differences in muscle composition (e.g., intramuscular adipose tissue) across the body are not well characterized. Purpose To examine site-specific muscle mass and composition differences between younger and older males matched for relative muscle mass. Methods Younger (18-44 years old, n = 19) and older (≥65 years old, n = 19) males were matched for relative appendicular lean tissue index (NHANES age- and sex-specific Z-scores) measured using dual-energy x-ray absorptiometry. Site-specific differences in skeletal muscle size (thickness) and composition (echo-intensity) were evaluated using ultrasound for 8 distinct landmarks across the body. Results Relative appendicular lean tissue mass was well matched between younger and older males (Z-score difference: -0.02, p = 0.927). Compared with younger males, older males had smaller muscle thickness for the anterior upper leg (difference: -1.08 cm, p < 0.001) and anterior abdomen (difference: -0.53 cm, p < 0.001). However, older adults displayed higher echo intensity across all muscles (p < 0.05), except for the posterior upper arm (p = 0.377), in comparison to the younger males. Conclusions When matched for relative appendicular lean tissue, muscle thickness differences between younger and older males are not-uniform across the body, whereas echo intensity was more uniformly higher in the older males.

Ultrasound image resolution influences analysis of skeletal muscle composition.

INTRODUCTION: Analysis of muscle composition using ultrasound requires standardization of several equipment settings (i.e. gain). However, the influence of image resolution, which is altered by imaging depth, on measures of muscle composition is unknown. METHODS: We analysed rectus femoris muscle composition using ultrasound images captured from 32 males and females (aged 28 ± 5 years) at depths of 9.0, 7.3, 5.9 and 4.7 cm. The transducer's orientation was fixed using a clamp during image acquisition to minimize movement. Across each image resolution, a region of interest encompassing the same anatomical area within the muscle was used for muscle composition analysis. Muscle composition was analysed using a combination of first-, second- and higher-order texture features. Muscle composition agreement across image resolutions was evaluated using a one-way ANOVA and intraclass correlation coefficients (ICC). RESULTS: Most muscle composition features displayed differences due to image resolution (p < .05). ICCs demonstrated poor-to-good agreement across different image resolutions. In general, higher resolution images (i.e. shallower imaging depth) demonstrated better agreement (ICC > 0.90) compared to lower resolution images. CONCLUSIONS: Ultrasound image resolution influences muscle composition analysis. Image resolution should be fixed within and between individuals when evaluating muscle composition using ultrasound.

Screening for low muscularity in colorectal cancer patients: a valid, clinic-friendly approach that predicts mortality.

BACKGROUND: Low skeletal muscle quantified using computed tomography (CT) scans is associated with morbidity and mortality among cancer patients. However, existing methods to assess skeletal muscle from CT are time-consuming, expensive, and require training. Clinic-friendly tools to screen for low skeletal muscle in cancer patients are urgently needed. METHODS: We included 807 scans from non-metastatic colorectal cancer patients. With the digital ruler available in most radiological software, we implemented an abbreviated method to assess skeletal muscle area at the third lumbar vertebra (L3), which consisted of assessing the height and width of the psoas and paraspinal muscles and computing their combined 'linear area' in centimetres squared (cm2 ). A subset of CT scans was assessed twice by two analysts to compute intra-rater and inter-rater reliability. We derived cut-points for 'low' linear area using optimal stratification and then calculated the sensitivity and specificity of these cut-points relative to standard methods (total L3 cross-sectional area assessed with Slice-O-Matic research software). We further evaluated the association of low linear area with death from any cause after colorectal cancer diagnosis in Cox proportional hazards models adjusting for demographics, smoking, body mass index category, and tumour characteristics. RESULTS: The linear area was highly correlated with total cross-sectional area assessed using standard methods [r = 0.92; 95% confidence interval (CI): 0.91, 0.93] overall and within subgroups defined by age, sex, and body mass index group. Intra-rater and inter-rater reliability were equally high (both intra-class correlations = 0.98). Cut-points for low linear area were sensitive (0.75; 95% CI: 0.70, 0.80) and specific (0.77; 95% CI: 0.73, 0.80) for identifying low skeletal muscle relative to the standard of total L3 cross-sectional area. The hazard ratio and 95% CI for death associated with a low linear area were hazard ratio = 1.66; 95% CI: 1.22, 2.25. CONCLUSIONS: Clinic-friendly methods that assess linear area from CT scans are an accurate screening tool to identify low skeletal muscle among non-metastatic colorectal cancer patients. These linear measures are associated with mortality after colorectal cancer, suggesting they could be clinically useful both to improve prognostication and to provide a practical screening tool to identify cancer patients who require nutrition or exercise intervention.

Clinically Practical Approach for Screening of Low Muscularity Using Electronic Linear Measures on Computed Tomography Images in Critically Ill Patients.

BACKGROUND: Computed tomography (CT) scans performed during routine hospital care offer the opportunity to quantify skeletal muscle and predict mortality and morbidity in intensive care unit (ICU) patients. Existing methods of muscle cross-sectional area (CSA) quantification require specialized software, training, and time commitment that may not be feasible in a clinical setting. In this article, we explore a new screening method to identify patients with low muscle mass. METHODS: We analyzed 145 scans of elderly ICU patients (≥65 years old) using a combination of measures obtained with a digital ruler, commonly found on hospital radiological software. The psoas and paraspinal muscle groups at the level of the third lumbar vertebra (L3) were evaluated by using 2 linear measures each and compared with an established method of CT image analysis of total muscle CSA in the L3 region. RESULTS: There was a strong association between linear measures of psoas and paraspinal muscle groups and total L3 muscle CSA (R2 = 0.745, P < 0.001). Linear measures, age, and sex were included as covariates in a multiple logistic regression to predict those with low muscle mass; receiver operating characteristic (ROC) area under the curve (AUC) of the combined psoas and paraspinal linear index model was 0.920. Intraclass correlation coefficients (ICCs) were used to evaluate intrarater and interrater reliability, resulting in scores of 0.979 (95% CI: 0.940-0.992) and 0.937 (95% CI: 0.828-0.978), respectively. CONCLUSIONS: A digital ruler can reliably predict L3 muscle CSA, and these linear measures may be used to identify critically ill patients with low muscularity who are at risk for worse clinical outcomes.