Daria Ferrara, Elisabetta M Abenavoli, Thomas Beyer, Stefan Gruenert, Marcus Hacker, Swen Hesse, Lukas Hofmann, Smilla Pusitz, Michael Rullmann, Osama Sabri, Roberto Sciagrà, Lalith Kumar Shiyam Sundar, Anke Tönjes, Hubert Wirtz, Josef Yu, Armin Frille
Background: Cancer-associated cachexia (CAC) is a metabolic syndrome contributing to therapy resistance and mortality in lung cancer patients (LCP). CAC is typically defined using clinical non-imaging criteria. Given the metabolic underpinnings of CAC and the ability of [18F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computer tomography (CT) to provide quantitative information on glucose turnover, we evaluate the usefulness of whole-body (WB) PET/CT imaging, as part of the standard diagnostic workup of LCP, to provide additional information on the onset or presence of CAC.
Methods: This multi-centre study included 345 LCP who underwent WB [18F]FDG-PET/CT imaging for initial clinical staging. A weight loss grading system (WLGS) adjusted to body mass index was used to classify LCP into 'No CAC' (WLGS-0/1 at baseline prior treatment and at first follow-up: N = 158, 51F/107M), 'Dev CAC' (WLGS-0/1 at baseline and WLGS-3/4 at follow-up: N = 90, 34F/56M), and 'CAC' (WLGS-3/4 at baseline: N = 97, 31F/66M). For each CAC category, mean standardized uptake values (SUV) normalized to aorta uptake (aorta>) and CT-defined volumes were extracted for abdominal and visceral organs, muscles, and adipose-tissue using automated image segmentation of baseline [18F]FDG-PET/CT images. Imaging and non-imaging parameters from laboratory tests were compared statistically. A machine-learning (ML) model was then trained to classify LCP as 'No CAC', 'Dev CAC', and 'CAC' based on their imaging parameters. SHapley Additive exPlanations (SHAP) analysis was employed to identify the key factors contributing to CAC development for each patient.
Results: The three CAC categories displayed multi-organ differences in aorta>. In all target organs, aorta> was higher in the 'CAC' cohort compared with 'No CAC' (P < 0.01), except for liver and kidneys, where aorta> in 'CAC' was reduced by 5%. The 'Dev CAC' cohort displayed a small but significant increase in aorta> of pancreas (+4%), skeletal-muscle (+7%), subcutaneous adipose-tissue (+11%), and visceral adipose-tissue (+15%). In 'CAC' patients, a strong negative Spearman correlation (ρ = -0.8) was identified between aorta> and volumes of adipose-tissue. The machine-learning model identified 'CAC' at baseline with 81% of accuracy, highlighting aorta> of spleen, pancreas, liver, and adipose-tissue as most relevant features. The model performance was suboptimal (54%) when classifying 'Dev CAC' versus 'No CAC'.
Conclusions: WB [18F]FDG-PET/CT imaging reveals groupwise differences in the multi-organ metabolism of LCP with and without CAC, thus highlighting systemic metabolic aberrations symptomatic of cachectic patients. Based on a retrospective cohort, our ML model identified patients
{"title":"Detection of cancer-associated cachexia in lung cancer patients using whole-body [<sup>18</sup>F]FDG-PET/CT imaging: A multi-centre study.","authors":"Daria Ferrara, Elisabetta M Abenavoli, Thomas Beyer, Stefan Gruenert, Marcus Hacker, Swen Hesse, Lukas Hofmann, Smilla Pusitz, Michael Rullmann, Osama Sabri, Roberto Sciagrà, Lalith Kumar Shiyam Sundar, Anke Tönjes, Hubert Wirtz, Josef Yu, Armin Frille","doi":"10.1002/jcsm.13571","DOIUrl":"https://doi.org/10.1002/jcsm.13571","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated cachexia (CAC) is a metabolic syndrome contributing to therapy resistance and mortality in lung cancer patients (LCP). CAC is typically defined using clinical non-imaging criteria. Given the metabolic underpinnings of CAC and the ability of [<sup>18</sup>F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computer tomography (CT) to provide quantitative information on glucose turnover, we evaluate the usefulness of whole-body (WB) PET/CT imaging, as part of the standard diagnostic workup of LCP, to provide additional information on the onset or presence of CAC.</p><p><strong>Methods: </strong>This multi-centre study included 345 LCP who underwent WB [<sup>18</sup>F]FDG-PET/CT imaging for initial clinical staging. A weight loss grading system (WLGS) adjusted to body mass index was used to classify LCP into 'No CAC' (WLGS-0/1 at baseline prior treatment and at first follow-up: N = 158, 51F/107M), 'Dev CAC' (WLGS-0/1 at baseline and WLGS-3/4 at follow-up: N = 90, 34F/56M), and 'CAC' (WLGS-3/4 at baseline: N = 97, 31F/66M). For each CAC category, mean standardized uptake values (SUV) normalized to aorta uptake (<SUV<sub>aorta</sub>>) and CT-defined volumes were extracted for abdominal and visceral organs, muscles, and adipose-tissue using automated image segmentation of baseline [<sup>18</sup>F]FDG-PET/CT images. Imaging and non-imaging parameters from laboratory tests were compared statistically. A machine-learning (ML) model was then trained to classify LCP as 'No CAC', 'Dev CAC', and 'CAC' based on their imaging parameters. SHapley Additive exPlanations (SHAP) analysis was employed to identify the key factors contributing to CAC development for each patient.</p><p><strong>Results: </strong>The three CAC categories displayed multi-organ differences in <SUV<sub>aorta</sub>>. In all target organs, <SUV<sub>aorta</sub>> was higher in the 'CAC' cohort compared with 'No CAC' (P < 0.01), except for liver and kidneys, where <SUV<sub>aorta</sub>> in 'CAC' was reduced by 5%. The 'Dev CAC' cohort displayed a small but significant increase in <SUV<sub>aorta</sub>> of pancreas (+4%), skeletal-muscle (+7%), subcutaneous adipose-tissue (+11%), and visceral adipose-tissue (+15%). In 'CAC' patients, a strong negative Spearman correlation (ρ = -0.8) was identified between <SUV<sub>aorta</sub>> and volumes of adipose-tissue. The machine-learning model identified 'CAC' at baseline with 81% of accuracy, highlighting <SUV<sub>aorta</sub>> of spleen, pancreas, liver, and adipose-tissue as most relevant features. The model performance was suboptimal (54%) when classifying 'Dev CAC' versus 'No CAC'.</p><p><strong>Conclusions: </strong>WB [<sup>18</sup>F]FDG-PET/CT imaging reveals groupwise differences in the multi-organ metabolism of LCP with and without CAC, thus highlighting systemic metabolic aberrations symptomatic of cachectic patients. Based on a retrospective cohort, our ML model identified patients ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":" ","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hans-Jonas Meyer, Tihomir Dermendzhiev, Michael Hetz, Georg Osterhoff, Christian Kleber, Timm Denecke, Jeanette Henkelmann, Robert Werdehausen, Gunther Hempel, Manuel F Struck
Background: Body composition parameters provide relevant prognostic significance in critical care cohorts and cancer populations. Published results regarding polytrauma patients are inconclusive to date. The goal of this study was to analyse the role of body composition parameters in severely injured trauma patients.
Methods: All consecutive patients requiring emergency tracheal intubation and mechanical ventilation before initial computed tomography (CT) at a level-1 trauma centre over a 12-year period (2008-2019) were reanalysed. The analysis included CT-derived body composition parameters based upon whole-body trauma CT as prognostic variables for 30-day mortality, intensive care unit length of stay (ICU LOS) and mechanical ventilation duration.
Results: Four hundred seventy-two patients (75% male) with a median age of 49 years, median injury severity score of 26 and 30-day mortality rate of 22% (104 patients) met the inclusion criteria and were analysed. Regarding body composition parameters, 231 patients (49%) had visceral obesity, 75 patients had sarcopenia (16%) and 35 patients had sarcopenic obesity (7.4%). After adjustment for statistically significant univariable predictors age, body mass index, sarcopenic obesity, visceral obesity, American Society of Anesthesiologists classification ≥3, injury severity score and Glasgow Coma Scale ≤ 8 points, the Cox proportional hazard model identified sarcopenia as significant prognostic factor of 30-day mortality (hazard ratio 2.84; 95% confidence interval 1.38-5.85; P = 0.004), which was confirmed in Kaplan-Meier survival analysis (log-rank P = 0.006). In a subanalysis of 363 survivors, linear multivariable regression analysis revealed no significant associations of body composition parameters with ICU LOS and duration of mechanical ventilation.
Conclusions: In a multivariable analysis of mechanically ventilated trauma patients, CT-defined sarcopenia was significantly associated with 30-day mortality whereas no associations of body composition parameters with ICU LOS and duration of mechanical ventilation were observed.
{"title":"Body composition parameters in initial CT imaging of mechanically ventilated trauma patients: Single-centre observational study.","authors":"Hans-Jonas Meyer, Tihomir Dermendzhiev, Michael Hetz, Georg Osterhoff, Christian Kleber, Timm Denecke, Jeanette Henkelmann, Robert Werdehausen, Gunther Hempel, Manuel F Struck","doi":"10.1002/jcsm.13578","DOIUrl":"https://doi.org/10.1002/jcsm.13578","url":null,"abstract":"<p><strong>Background: </strong>Body composition parameters provide relevant prognostic significance in critical care cohorts and cancer populations. Published results regarding polytrauma patients are inconclusive to date. The goal of this study was to analyse the role of body composition parameters in severely injured trauma patients.</p><p><strong>Methods: </strong>All consecutive patients requiring emergency tracheal intubation and mechanical ventilation before initial computed tomography (CT) at a level-1 trauma centre over a 12-year period (2008-2019) were reanalysed. The analysis included CT-derived body composition parameters based upon whole-body trauma CT as prognostic variables for 30-day mortality, intensive care unit length of stay (ICU LOS) and mechanical ventilation duration.</p><p><strong>Results: </strong>Four hundred seventy-two patients (75% male) with a median age of 49 years, median injury severity score of 26 and 30-day mortality rate of 22% (104 patients) met the inclusion criteria and were analysed. Regarding body composition parameters, 231 patients (49%) had visceral obesity, 75 patients had sarcopenia (16%) and 35 patients had sarcopenic obesity (7.4%). After adjustment for statistically significant univariable predictors age, body mass index, sarcopenic obesity, visceral obesity, American Society of Anesthesiologists classification ≥3, injury severity score and Glasgow Coma Scale ≤ 8 points, the Cox proportional hazard model identified sarcopenia as significant prognostic factor of 30-day mortality (hazard ratio 2.84; 95% confidence interval 1.38-5.85; P = 0.004), which was confirmed in Kaplan-Meier survival analysis (log-rank P = 0.006). In a subanalysis of 363 survivors, linear multivariable regression analysis revealed no significant associations of body composition parameters with ICU LOS and duration of mechanical ventilation.</p><p><strong>Conclusions: </strong>In a multivariable analysis of mechanically ventilated trauma patients, CT-defined sarcopenia was significantly associated with 30-day mortality whereas no associations of body composition parameters with ICU LOS and duration of mechanical ventilation were observed.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":" ","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leticia W Ribeiro, Sara Berndt, Gregore I Mielke, Jenny Doust, Gita D Mishra
Background: Muscle strength is essential for healthy ageing. Handgrip strength (HGS) has been recommended by expert bodies as the preferred measure of muscle strength, in addition to being considered a strong predictor of overall health. Cross-sectional studies have shown several potential factors associated with HGS, but a systematic review of factors predicting HGS over time has not previously been conducted. The aim of this study is to systematically review the literature on the factors associated with adult HGS [at follow-up(s) or its rate of change] across the life course.
Methods: Searches were performed in MEDLINE via Ebsco, Embase and SPORTDiscus databases. Longitudinal studies assessing potential factors impacting adult HGS over time were included in the analyses. Based on previously established definitions of consistency of results, a semiquantitative analysis was conducted using the proportions of studies supporting correlations with HGS.
Results: A total of 117 articles were included in this review. Factors associated with HGS were grouped into 11 domains: demographic, socioeconomic, genetic, early life, body composition, health markers/biomarkers, health conditions, psychosocial, lifestyle, reproductive and environmental determinants. Overall, 103 factors were identified, of which 10 showed consistent associations with HGS over time (i.e., in at least four studies with ≥60% agreement in the direction of association). Factors associated with greater declines in HGS included increasing age, male sex, higher levels of inflammatory markers and the presence of cardiovascular diseases. Education level, medication use, and self-rated health were not associated with the rate of change in HGS. Increased birth weight was associated with a stronger HGS over time, whereas depressive symptoms were linked to a weaker HGS, and smoking habits showed null associations.
Conclusions: Comparison between studies and estimation of effect sizes were limited due to the heterogeneity in methods. Although sex and age may be the main drivers of HGS decline, it is crucial to prioritize modifiable factors such as inflammation and cardiovascular diseases in health interventions to prevent greater losses. Interventions to improve birth weight and mental health are also likely to produce positive effects on muscle strength. Our results point to the complexity of processes involving muscle strength and suggest that the need to better understand the determinants of HGS remains.
{"title":"Factors associated with handgrip strength across the life course: A systematic review.","authors":"Leticia W Ribeiro, Sara Berndt, Gregore I Mielke, Jenny Doust, Gita D Mishra","doi":"10.1002/jcsm.13586","DOIUrl":"https://doi.org/10.1002/jcsm.13586","url":null,"abstract":"<p><strong>Background: </strong>Muscle strength is essential for healthy ageing. Handgrip strength (HGS) has been recommended by expert bodies as the preferred measure of muscle strength, in addition to being considered a strong predictor of overall health. Cross-sectional studies have shown several potential factors associated with HGS, but a systematic review of factors predicting HGS over time has not previously been conducted. The aim of this study is to systematically review the literature on the factors associated with adult HGS [at follow-up(s) or its rate of change] across the life course.</p><p><strong>Methods: </strong>Searches were performed in MEDLINE via Ebsco, Embase and SPORTDiscus databases. Longitudinal studies assessing potential factors impacting adult HGS over time were included in the analyses. Based on previously established definitions of consistency of results, a semiquantitative analysis was conducted using the proportions of studies supporting correlations with HGS.</p><p><strong>Results: </strong>A total of 117 articles were included in this review. Factors associated with HGS were grouped into 11 domains: demographic, socioeconomic, genetic, early life, body composition, health markers/biomarkers, health conditions, psychosocial, lifestyle, reproductive and environmental determinants. Overall, 103 factors were identified, of which 10 showed consistent associations with HGS over time (i.e., in at least four studies with ≥60% agreement in the direction of association). Factors associated with greater declines in HGS included increasing age, male sex, higher levels of inflammatory markers and the presence of cardiovascular diseases. Education level, medication use, and self-rated health were not associated with the rate of change in HGS. Increased birth weight was associated with a stronger HGS over time, whereas depressive symptoms were linked to a weaker HGS, and smoking habits showed null associations.</p><p><strong>Conclusions: </strong>Comparison between studies and estimation of effect sizes were limited due to the heterogeneity in methods. Although sex and age may be the main drivers of HGS decline, it is crucial to prioritize modifiable factors such as inflammation and cardiovascular diseases in health interventions to prevent greater losses. Interventions to improve birth weight and mental health are also likely to produce positive effects on muscle strength. Our results point to the complexity of processes involving muscle strength and suggest that the need to better understand the determinants of HGS remains.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":" ","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Edward J Hardy, Joseph J Bass, Thomas B Inns, Mathew Piasecki, Jessica Piasecki, Craig Sale, Robert H Morris, Jonathan N Lund, Ken Smith, Daniel J Wilkinson, Philip J Atherton, Bethan E Phillips
Background: Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole-body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B-mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work.
Methods: To address this significant knowledge gap, 10 young men (22 ± years, 24.1 ± 2.3 kg/m2) underwent 15-day unilateral leg immobilization using a knee-brace and air boot. Cross-sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI.
Results: With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSAMRI vs. MTU/S and CSAU/S: r = 0.88 and 0.94, respectively, both P < 0.0001) and after (e.g., VOLMRI vs. MTU/S and CSAU/S: r = 0.90 and 0.96, respectively, both P < 0.0001) immobilization. The relationship between the methods was notably stronger for MG than TA at each time-point (e.g., CSAMRI vs. MTU/S: MG, r = 0.70, P = 0.0006; TA, r = 0.37, P = 0.10). There was no relationship between the degree of DMA determined by the two methods in either muscle (e.g., TA pre- vs. post-immobilization, VOLMRI: 136 ± 6 vs. 133 ± 5, P = 0.08; CSAU/S: 6.05 ± 0.3 vs. 5.92 ± 0.4, P = 0.70; relationship between methods: r = 0.12, P = 0.75).
Conclusions: Both MTU/S and CSAU/S provide comparable static measures of lower leg muscle size compared with MRI, albeit with weaker agreement in TA compared to MG. Although both MTU/S and CSAU/S can discern differences in DMA susceptibility between muscles, neither can reliably assess degree of DMA. Based on the growing recognition of heterogeneous atrophy profiles between muscles, and the topical importance of less commonly studied muscles (i.e., TA for falls prevention in older adults), future research should aim to optimize accessible methods to determine muscle losses across the body.
{"title":"Exploring the utility of ultrasound to assess disuse atrophy in different muscles of the lower leg.","authors":"Edward J Hardy, Joseph J Bass, Thomas B Inns, Mathew Piasecki, Jessica Piasecki, Craig Sale, Robert H Morris, Jonathan N Lund, Ken Smith, Daniel J Wilkinson, Philip J Atherton, Bethan E Phillips","doi":"10.1002/jcsm.13583","DOIUrl":"https://doi.org/10.1002/jcsm.13583","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole-body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B-mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work.</p><p><strong>Methods: </strong>To address this significant knowledge gap, 10 young men (22 ± years, 24.1 ± 2.3 kg/m<sup>2</sup>) underwent 15-day unilateral leg immobilization using a knee-brace and air boot. Cross-sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI.</p><p><strong>Results: </strong>With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSA<sub>MRI</sub> vs. MT<sub>U/S</sub> and CSA<sub>U/S</sub>: r = 0.88 and 0.94, respectively, both P < 0.0001) and after (e.g., VOL<sub>MRI</sub> vs. MT<sub>U/S</sub> and CSA<sub>U/S</sub>: r = 0.90 and 0.96, respectively, both P < 0.0001) immobilization. The relationship between the methods was notably stronger for MG than TA at each time-point (e.g., CSA<sub>MRI</sub> vs. MT<sub>U/S</sub>: MG, r = 0.70, P = 0.0006; TA, r = 0.37, P = 0.10). There was no relationship between the degree of DMA determined by the two methods in either muscle (e.g., TA pre- vs. post-immobilization, VOL<sub>MRI</sub>: 136 ± 6 vs. 133 ± 5, P = 0.08; CSA<sub>U/S</sub>: 6.05 ± 0.3 vs. 5.92 ± 0.4, P = 0.70; relationship between methods: r = 0.12, P = 0.75).</p><p><strong>Conclusions: </strong>Both MT<sub>U/S</sub> and CSA<sub>U/S</sub> provide comparable static measures of lower leg muscle size compared with MRI, albeit with weaker agreement in TA compared to MG. Although both MT<sub>U/S</sub> and CSA<sub>U/S</sub> can discern differences in DMA susceptibility between muscles, neither can reliably assess degree of DMA. Based on the growing recognition of heterogeneous atrophy profiles between muscles, and the topical importance of less commonly studied muscles (i.e., TA for falls prevention in older adults), future research should aim to optimize accessible methods to determine muscle losses across the body.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":" ","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pamela N. Klassen, Vera C. Mazurak, Jessica Thorlakson, Stephane Servais
Investigators are increasingly measuring skeletal muscle (SM) and adipose tissue (AT) change during cancer treatment to understand impact on patient outcomes. Recent meta‐analyses have reported high heterogeneity in this literature, representing uncertainty in the resulting estimates. Using the setting of palliative‐intent chemotherapy as an exemplar, we aimed to systematically summarize the sources of variability among studies evaluating SM and AT change during cancer treatment and propose standards for future studies to enable reliable meta‐analysis. Studies that measured computed tomography‐defined SM and/or AT change in adult patients during palliative‐intent chemotherapy for solid tumours were included, with no date or geographical limiters. Of 2496 publications screened by abstract/title, 83 were reviewed in full text and 38 included for extraction, representing 34 unique cohorts across 8 tumour sites. The timing of baseline measurement was frequently defined as prior to treatment, while endpoint timing ranged from 6 weeks after treatment start to time of progression. Fewer than 50% specified the actual time interval between measurements. Measurement error was infrequently discussed (8/34). A single metric (cm2/m2, cm2 or %) was used to describe SM change in 18/34 cohorts, while multiple metrics were presented for 10/34 and no descriptive metrics for 6/34. AT change metrics and sex‐specific reporting were available for 10/34 cohorts. Associations between SM loss and overall survival were evaluated in 24 publications, with classification of SM loss ranging from any loss to >14% loss over variable time intervals. Age and sex were the most common covariates, with disease response in 50% of models. Despite a wealth of data and effort, heterogeneity in study design, reporting and statistical analysis hinders evidence synthesis regarding the severity and outcomes of SM and AT change during cancer treatment. Proposed standards for study design include selection of homogenous cohorts, clear definition of baseline/endpoint timing and attention to measurement error. Standard reporting should include baseline SM and AT by sex, actual scan interval, SM and AT change using multiple metrics and visualization of the range of change observed. Reporting by sex would advance understanding of sexual dimorphism in SM and AT change. Evaluating the impact of tissue change on outcomes requires adjustment for relevant covariates and concurrent disease response. Adoption of these standards by researchers and publishers would alter the current paradigm to enable meta‐analysis of future studies and move the field towards meaningful application of SM and AT change to clinical care.
{"title":"Call for standardization in assessment and reporting of muscle and adipose change using computed tomography analysis in oncology: A scoping review","authors":"Pamela N. Klassen, Vera C. Mazurak, Jessica Thorlakson, Stephane Servais","doi":"10.1002/jcsm.13318","DOIUrl":"10.1002/jcsm.13318","url":null,"abstract":"Investigators are increasingly measuring skeletal muscle (SM) and adipose tissue (AT) change during cancer treatment to understand impact on patient outcomes. Recent meta‐analyses have reported high heterogeneity in this literature, representing uncertainty in the resulting estimates. Using the setting of palliative‐intent chemotherapy as an exemplar, we aimed to systematically summarize the sources of variability among studies evaluating SM and AT change during cancer treatment and propose standards for future studies to enable reliable meta‐analysis. Studies that measured computed tomography‐defined SM and/or AT change in adult patients during palliative‐intent chemotherapy for solid tumours were included, with no date or geographical limiters. Of 2496 publications screened by abstract/title, 83 were reviewed in full text and 38 included for extraction, representing 34 unique cohorts across 8 tumour sites. The timing of baseline measurement was frequently defined as prior to treatment, while endpoint timing ranged from 6 weeks after treatment start to time of progression. Fewer than 50% specified the actual time interval between measurements. Measurement error was infrequently discussed (8/34). A single metric (cm2/m2, cm2 or %) was used to describe SM change in 18/34 cohorts, while multiple metrics were presented for 10/34 and no descriptive metrics for 6/34. AT change metrics and sex‐specific reporting were available for 10/34 cohorts. Associations between SM loss and overall survival were evaluated in 24 publications, with classification of SM loss ranging from any loss to >14% loss over variable time intervals. Age and sex were the most common covariates, with disease response in 50% of models. Despite a wealth of data and effort, heterogeneity in study design, reporting and statistical analysis hinders evidence synthesis regarding the severity and outcomes of SM and AT change during cancer treatment. Proposed standards for study design include selection of homogenous cohorts, clear definition of baseline/endpoint timing and attention to measurement error. Standard reporting should include baseline SM and AT by sex, actual scan interval, SM and AT change using multiple metrics and visualization of the range of change observed. Reporting by sex would advance understanding of sexual dimorphism in SM and AT change. Evaluating the impact of tissue change on outcomes requires adjustment for relevant covariates and concurrent disease response. Adoption of these standards by researchers and publishers would alter the current paradigm to enable meta‐analysis of future studies and move the field towards meaningful application of SM and AT change to clinical care.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"1918-1931"},"PeriodicalIF":8.9,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10524503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicolas Collao, Donna D'Souza, Laura Messeiller, Evan Pilon, Jessica Lloyd, Jillian Larkin, Matthew Ngu, Alexanne Cuillerier, Alexander E. Green, Keir J. Menzies, Yan Burelle, Michael De Lisio
Background
Radiation-induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation-induced muscle pathology has not previously been explored.
Methods
Four-week-old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non-IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post-IR (long-term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed.
Results
Juvenile radiation exposure resulted in smaller myofibre cross-sectional area, particularly in type I and IIA myofibres (P < 0.05) and reduced the proportion of type I myofibres (P < 0.05). Skeletal muscle fibrosis (P < 0.05) was evident at 56 days post-IR. The IR-limb had fewer endothelial cells (P < 0.05) and fibro-adipogenic progenitors (FAPs) (P < 0.05) at 56 days post-IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR-limb (P < 0.05). IR induced FAP senescence (P < 0.05), increased their fibrogenic differentiation (P < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (P < 0.05) and fusion (P < 0.05).
Conclusions
Our study suggests that following juvenile radiation exposure, FAPs contribute to long-term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP-targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.
{"title":"Radiation induces long-term muscle fibrosis and promotes a fibrotic phenotype in fibro-adipogenic progenitors","authors":"Nicolas Collao, Donna D'Souza, Laura Messeiller, Evan Pilon, Jessica Lloyd, Jillian Larkin, Matthew Ngu, Alexanne Cuillerier, Alexander E. Green, Keir J. Menzies, Yan Burelle, Michael De Lisio","doi":"10.1002/jcsm.13320","DOIUrl":"10.1002/jcsm.13320","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Radiation-induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation-induced muscle pathology has not previously been explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Four-week-old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non-IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post-IR (long-term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Juvenile radiation exposure resulted in smaller myofibre cross-sectional area, particularly in type I and IIA myofibres (<i>P</i> < 0.05) and reduced the proportion of type I myofibres (<i>P</i> < 0.05). Skeletal muscle fibrosis (<i>P</i> < 0.05) was evident at 56 days post-IR. The IR-limb had fewer endothelial cells (<i>P</i> < 0.05) and fibro-adipogenic progenitors (FAPs) (<i>P</i> < 0.05) at 56 days post-IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR-limb (<i>P</i> < 0.05). IR induced FAP senescence (<i>P</i> < 0.05), increased their fibrogenic differentiation (<i>P</i> < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (<i>P</i> < 0.05) and fusion (<i>P</i> < 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study suggests that following juvenile radiation exposure, FAPs contribute to long-term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP-targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2335-2349"},"PeriodicalIF":8.9,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13320","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10516219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
James McDonald, Judith Sayers, Stefan D. Anker, Jann Arends, Trude Rakel Balstad, Vickie Baracos, Leo Brown, Asta Bye, Olav Dajani, Ross Dolan, Marie T. Fallon, Eilidh Fraser, Christine Griel, Aleksandra Grzyb, Marianne Hjermstad, Mariam Jamal-Hanjani, Gunnhild Jakobsen, Stein Kaasa, Donald McMillan, Matthew Maddocks, Iain Philips, Inger O. Ottestad, Kieran F. Reid, Mariana S. Sousa, Melanie R. Simpson, Ola Magne Vagnildhaug, Richard J. E. Skipworth, Tora S. Solheim, Barry J. A. Laird, the Cancer Cachexia Endpoints Working Group
In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.
{"title":"Physical function endpoints in cancer cachexia clinical trials: Systematic Review 1 of the cachexia endpoints series","authors":"James McDonald, Judith Sayers, Stefan D. Anker, Jann Arends, Trude Rakel Balstad, Vickie Baracos, Leo Brown, Asta Bye, Olav Dajani, Ross Dolan, Marie T. Fallon, Eilidh Fraser, Christine Griel, Aleksandra Grzyb, Marianne Hjermstad, Mariam Jamal-Hanjani, Gunnhild Jakobsen, Stein Kaasa, Donald McMillan, Matthew Maddocks, Iain Philips, Inger O. Ottestad, Kieran F. Reid, Mariana S. Sousa, Melanie R. Simpson, Ola Magne Vagnildhaug, Richard J. E. Skipworth, Tora S. Solheim, Barry J. A. Laird, the Cancer Cachexia Endpoints Working Group","doi":"10.1002/jcsm.13321","DOIUrl":"10.1002/jcsm.13321","url":null,"abstract":"<p>In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, <i>n</i> = 1184) examined megestrol and 5 (13%, <i>n</i> = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, <i>n</i> = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (<i>n</i> = 2091). The 6MWT was assessed in 12 trials (<i>n</i> = 1074) and was statistically significant in 4 (33%) trials (<i>n</i> = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"1932-1948"},"PeriodicalIF":8.9,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10217636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dinesh S. Shah, Raid B. Nisr, Gabriela Krasteva-Christ, Harinder S. Hundal
Background
Caveolins are the principal structural components of plasma membrane caveolae. Dominant pathogenic mutations in the muscle-specific caveolin-3 (Cav3) gene isoform, such as the limb girdle muscular dystrophy type 1C (LGMD-1C) P104L mutation, result in dramatic loss of the Cav3 protein and pathophysiological muscle weakness/wasting. We hypothesize that such muscle degeneration may be linked to disturbances in signalling events that impact protein turnover. Herein, we report studies assessing the effects of Cav3 deficiency on mammalian or mechanistic target of rapamycin complex 1 (mTORC1) signalling in skeletal muscle cells.
Methods
L6 myoblasts were stably transfected with Cav3P104L or expression of native Cav3 was abolished by CRISPR/Cas9 genome editing (Cav3 knockout [Cav3KO]) prior to performing subcellular fractionation and immunoblotting, analysis of real-time mitochondrial respiration or fixed cell immunocytochemistry. Skeletal muscle from wild-type and Cav3−/− mice was processed for immunoblot analysis of downstream mTORC1 substrate phosphorylation.
Results
Cav3 was detected in lysosomal-enriched membranes isolated from L6 myoblasts and observed by confocal microscopy to co-localize with lysosomal-specific markers. Cav3P104L expression, which results in significant (~95%) loss of native Cav3, or CRISPR/Cas9-mediated Cav3KO, reduced amino acid-dependent mTORC1 activation. The decline in mTORC1-directed signalling was detected by immunoblot analysis of L6 muscle cells and gastrocnemius Cav3−/− mouse muscle as judged by reduced phosphorylation of mTORC1 substrates that play key roles in the initiation of protein synthesis (4EBP1S65 and S6K1T389). S6K1T389 and 4EBP1S65 phosphorylation reduced by over 75% and 80% in Cav3KO muscle cells and by over 90% and 30% in Cav3−/− mouse skeletal muscle, respectively. The reduction in protein synthetic capacity in L6 muscle cells was confirmed by analysis of puromycylated peptides using the SUnSET assay. Cav3 loss was also associated with a 26% increase in lysosomal cholesterol, and pharmacological manipulation of lysosomal cholesterol was effective in replicating the reduction in mTORC1 activity observed in Cav3KO cells. Notably, re-expression of Cav3 in Cav3KO myoblasts normalized lysosomal cholesterol content, which coincided with a recovery in protein translation and an associated increase in mTORC1-directed phosphorylation of downstream targets.
{"title":"Caveolin-3 loss linked with the P104L LGMD-1C mutation modulates skeletal muscle mTORC1 signalling and cholesterol homeostasis","authors":"Dinesh S. Shah, Raid B. Nisr, Gabriela Krasteva-Christ, Harinder S. Hundal","doi":"10.1002/jcsm.13317","DOIUrl":"10.1002/jcsm.13317","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Caveolins are the principal structural components of plasma membrane caveolae. Dominant pathogenic mutations in the muscle-specific caveolin-3 (Cav3) gene isoform, such as the limb girdle muscular dystrophy type 1C (LGMD-1C) P104L mutation, result in dramatic loss of the Cav3 protein and pathophysiological muscle weakness/wasting. We hypothesize that such muscle degeneration may be linked to disturbances in signalling events that impact protein turnover. Herein, we report studies assessing the effects of Cav3 deficiency on mammalian or mechanistic target of rapamycin complex 1 (mTORC1) signalling in skeletal muscle cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>L6 myoblasts were stably transfected with Cav3<sup>P104L</sup> or expression of native Cav3 was abolished by CRISPR/Cas9 genome editing (Cav3 knockout [Cav3KO]) prior to performing subcellular fractionation and immunoblotting, analysis of real-time mitochondrial respiration or fixed cell immunocytochemistry. Skeletal muscle from wild-type and Cav3<sup>−/−</sup> mice was processed for immunoblot analysis of downstream mTORC1 substrate phosphorylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cav3 was detected in lysosomal-enriched membranes isolated from L6 myoblasts and observed by confocal microscopy to co-localize with lysosomal-specific markers. Cav3<sup>P104L</sup> expression, which results in significant (~95%) loss of native Cav3, or CRISPR/Cas9-mediated Cav3KO, reduced amino acid-dependent mTORC1 activation. The decline in mTORC1-directed signalling was detected by immunoblot analysis of L6 muscle cells and gastrocnemius Cav3<sup>−/−</sup> mouse muscle as judged by reduced phosphorylation of mTORC1 substrates that play key roles in the initiation of protein synthesis (4EBP1<sup>S65</sup> and S6K1<sup>T389</sup>). S6K1<sup>T389</sup> and 4EBP1<sup>S65</sup> phosphorylation reduced by over 75% and 80% in Cav3KO muscle cells and by over 90% and 30% in Cav3<sup>−/−</sup> mouse skeletal muscle, respectively. The reduction in protein synthetic capacity in L6 muscle cells was confirmed by analysis of puromycylated peptides using the SUnSET assay. Cav3 loss was also associated with a 26% increase in lysosomal cholesterol, and pharmacological manipulation of lysosomal cholesterol was effective in replicating the reduction in mTORC1 activity observed in Cav3KO cells. Notably, re-expression of Cav3 in Cav3KO myoblasts normalized lysosomal cholesterol content, which coincided with a recovery in protein translation and an associated increase in mTORC1-directed phosphorylation of downstream targets.</p>\u0000 </section>\u0000 \u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2310-2326"},"PeriodicalIF":8.9,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10516217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiahao Zhu, Dan Zhou, Yaoyao Nie, Jing Wang, Ye Yang, Dingwan Chen, Min Yu, Yingjun Li
Background
Observational studies have demonstrated a strong bidirectional association between frailty and depression, but it remains unclear whether this association reflects causality. This study aimed to examine the bidirectional causal relationship between frailty and depression.
Methods
Using genome-wide association study summary data, two-sample Mendelian randomization was performed to test for the potential bidirectional causality between frailty, as defined by both the frailty index and the frailty phenotype, and depression. Several frailty-related traits were additionally investigated, including weaker hand grip strength, slower walking pace and physical inactivity. Findings were replicated using an independent depression data source and verified using multiple sensitivity analyses.
Results
Genetically predicted higher frailty index (odds ratio [OR], 1.86; P < 0.001), higher frailty phenotype score (OR, 2.79; P < 0.001), lower grip strength (OR, 1.23; P = 0.003), slower walking pace (OR, 1.55; P = 0.027) and physical inactivity (OR, 1.44; P = 0.003) all were associated with a higher risk of depression. As for the reverse direction, genetic liability to depression showed consistent associations with a higher frailty index (beta, 0.167; P < 0.001) and a higher frailty phenotype score (beta, 0.067; P = 0.001), but not with other frailty-related traits that were investigated. The results were stable across sensitivity analyses and across depression datasets.
Conclusions
Our findings add novel evidence supporting the bidirectional causal association between frailty and depression. Improving balance and muscle strength and increasing physical activity may be beneficial in both depression and frailty.
{"title":"Assessment of the bidirectional causal association between frailty and depression: A Mendelian randomization study","authors":"Jiahao Zhu, Dan Zhou, Yaoyao Nie, Jing Wang, Ye Yang, Dingwan Chen, Min Yu, Yingjun Li","doi":"10.1002/jcsm.13319","DOIUrl":"10.1002/jcsm.13319","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Observational studies have demonstrated a strong bidirectional association between frailty and depression, but it remains unclear whether this association reflects causality. This study aimed to examine the bidirectional causal relationship between frailty and depression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using genome-wide association study summary data, two-sample Mendelian randomization was performed to test for the potential bidirectional causality between frailty, as defined by both the frailty index and the frailty phenotype, and depression. Several frailty-related traits were additionally investigated, including weaker hand grip strength, slower walking pace and physical inactivity. Findings were replicated using an independent depression data source and verified using multiple sensitivity analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Genetically predicted higher frailty index (odds ratio [OR], 1.86; <i>P</i> < 0.001), higher frailty phenotype score (OR, 2.79; <i>P</i> < 0.001), lower grip strength (OR, 1.23; <i>P</i> = 0.003), slower walking pace (OR, 1.55; <i>P</i> = 0.027) and physical inactivity (OR, 1.44; <i>P</i> = 0.003) all were associated with a higher risk of depression. As for the reverse direction, genetic liability to depression showed consistent associations with a higher frailty index (beta, 0.167; <i>P</i> < 0.001) and a higher frailty phenotype score (beta, 0.067; <i>P</i> = 0.001), but not with other frailty-related traits that were investigated. The results were stable across sensitivity analyses and across depression datasets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings add novel evidence supporting the bidirectional causal association between frailty and depression. Improving balance and muscle strength and increasing physical activity may be beneficial in both depression and frailty.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2327-2334"},"PeriodicalIF":8.9,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13319","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hidenori Arai, Keisuke Maeda, Hidetaka Wakabayashi, Tateaki Naito, Masaaki Konishi, Prasert Assantachai, Wai Tung Auyeung, Chalobol Chalermsri, Wei Chen, Justin Chew, Ming-Yueh Chou, Chih-Cheng Hsu, Allyn Hum, In Gyu Hwang, Toshimi Kaido, Lin Kang, Shahrul Bahyah Kamaruzzaman, Miji Kim, Jenny Shun Wah Lee, Wei-Ju Lee, Chih-Kuang Liang, Wee Shiong Lim, Jae-Young Lim, Yen Peng Lim, Raymond See-Kit Lo, Terence Ong, Wen-Harn Pan, Li-Ning Peng, Pornpoj Pramyothin, Nurul Huda Razalli, Masakazu Saitoh, Suzana Shahar, Han Ping Shi, Heng-Hsin Tung, Yasuhito Uezono, Stephan von Haehling, Chang Won Won, Jean Woo, Liang-Kung Chen
Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut-off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.
{"title":"Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia","authors":"Hidenori Arai, Keisuke Maeda, Hidetaka Wakabayashi, Tateaki Naito, Masaaki Konishi, Prasert Assantachai, Wai Tung Auyeung, Chalobol Chalermsri, Wei Chen, Justin Chew, Ming-Yueh Chou, Chih-Cheng Hsu, Allyn Hum, In Gyu Hwang, Toshimi Kaido, Lin Kang, Shahrul Bahyah Kamaruzzaman, Miji Kim, Jenny Shun Wah Lee, Wei-Ju Lee, Chih-Kuang Liang, Wee Shiong Lim, Jae-Young Lim, Yen Peng Lim, Raymond See-Kit Lo, Terence Ong, Wen-Harn Pan, Li-Ning Peng, Pornpoj Pramyothin, Nurul Huda Razalli, Masakazu Saitoh, Suzana Shahar, Han Ping Shi, Heng-Hsin Tung, Yasuhito Uezono, Stephan von Haehling, Chang Won Won, Jean Woo, Liang-Kung Chen","doi":"10.1002/jcsm.13323","DOIUrl":"10.1002/jcsm.13323","url":null,"abstract":"<p>Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut-off value of 21 kg/m<sup>2</sup> for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"1949-1958"},"PeriodicalIF":8.9,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10527209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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