Article first published online:  27 August 2019

Stephan von Haehling, Nicole Ebner, Stefan D. Anker

The Journal of Cachexia, Sarcopenia and Muscle in 2019
no abstract

von Haehling, S., Ebner, N., and Anker, S. D. ( 2019) The Journal of Cachexia, Sarcopenia and Muscle in 2019, Journal of Cachexia, Sarcopenia and Muscle, 10, 715– 720, XXX, doi: https://doi.org/10.1002/jcsm.12482.

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     Article first published online:  23 April 2019

Leocadio Rodriguez-Mañas, Olga Laosa, Bruno Vellas, Giuseppe Paolisso, Eva Topinkova, Juan Oliva-Moreno, Isabelle Bourdel-Marchasson, Mikel Izquierdo, Kerry Hood, Andrej Zeyfang, Giovanni Gambassi, Mirko Petrovic, Tim C. Hardman, Mark J. Kelson, Ivan Bautmans, Gabor Abellan, Michelangela Barbieri, Luz M. Peña-Longobardo, Sophie C. Regueme, Riccardo Calvani, Stefanie De Buyser, Alan J. Sinclair on behalf of the European MID-Frail Consortium

Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus
Background
Type 2 diabetes, a highly prevalent chronic disease, is associated with increasing frailty and functional decline in older people. We aimed to evaluate the effectiveness of a multimodal intervention on functional performance in frail and pre-frail participants aged =70 years with type 2 diabetes mellitus.
Methods
The MID-Frail study was a cluster-randomized multicenter clinical trial conducted in 74 trial sites across seven European countries. The trial recruited 964 participants who were aged >70 years [mean age in intervention group, 78.4 (SD 5.6) years, 49.2% male and 77.6 (SD 5.29) years, 52.4% male in usual care group], with type diabetes mellitus and determined to be frail or pre-frail using Fried's frailty phenotype. Participants were allocated by trial site to follow either usual care (UCG) or intervention procedures (IG). Intervention group participants received a multimodal intervention composed of (i) an individualized and progressive resistance exercise programme for 16 weeks; (ii) a structured diabetes and nutritional educational programme over seven sessions; and (iii) Investigator-linked training to ensure optimal diabetes care. Short Physical Performance Battery (SPPB) scores were used to assess change in functional performance at 12 months between the groups. An analysis of the cost-effectiveness of the intervention was undertaken using the incremental cost-effectiveness ratio (ICER). Secondary outcomes included mortality, hospitalization, institutionalization, quality of life, burden on caregivers, the frequency and severity of hypoglycaemia episodes, and the cost-effectiveness of the intervention.
Results
After 12 months, IG participants had mean SPPB scores 0.85 points higher than those in the UCG (95% CI, 0.44 to 1.26, P < 0.0001). Dropouts were higher in frail participants and in the intervention group, but significant differences in SPPB between treatment groups remained consistent after sensitivity analysis. Estimates suggest a mean saving following intervention of 428.02 EUR (2016) per patient per year, with ICER analysis indicating a consistent benefit of the described health care intervention over usual care. No statistically significant differences between groups were detected in any of the other secondary outcomes.
Conclusions
We have demonstrated that a 12 month structured multimodal intervention programme across several clinical settings in different European countries leads to a clinically relevant and cost-effective improvement in the functional status of older frail and pre-frail participants with type 2 diabetes mellitus.

Rodriguez‐Mañas, L., Laosa, O., Vellas, B., Paolisso, G., Topinkova, E., Oliva‐Moreno, J., Bourdel‐Marchasson, I., Izquierdo, M., Hood, K., Zeyfang, A., Gambassi, G., Petrovic, M., Hardman, T. C., Kelson, M. J., Bautmans, I., Abellan, G., Barbieri, M., Peña‐Longobardo, L. M., Regueme, S. C., Calvani, R., De Buyser, S., Sinclair, A. J., and on behalf of the European MID‐Frail Consortium ( 2019) Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus, Journal of Cachexia, Sarcopenia and Muscle, 10, 721– 733, https://doi.org/10.1002/jcsm.12432.

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     Article first published online:  23 April 2019

Tobias Wollersheim, Julius J. Grunow, Niklas M. Carbon, Kurt Haas, Johannes Malleike, Sara F. Ramme, Joanna Schneider, Claudia D. Spies, Sven Märdian, Knut Mai, Simone Spuler, Jens Fielitz, Steffen Weber-Carstens

Muscle wasting and function after muscle activation and early protocol-based physiotherapy: an explorative trial
Background
Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)-cohort. We aimed to investigate clinical and molecular benefits or detriments of early mobilization and muscle activating measures in a high-risk ICU-acquired weakness cohort.
Methods
Fifty patients with a SOFA score =9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole-body vibration in addition to early protocol-based physiotherapy (intervention) or early protocol-based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow-up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol-based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU-acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier.
Results
ICU-acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median [IQR]: CPP 3.3 [3.0–4.3]; control 3.0 [2.7–3.4]; intervention 3.0 [2.1–3.8]; P > 0.05 for all), ICU discharge (MRC median [IQR]: CPP 3.8 [3.4–4.4]; control 3.9 [3.3–4.0]; intervention 3.6 [2.8–4.0]; P > 0.05 for all), and 12 month follow-up (MRC median [IQR]: control 5.0 [4.3–5.0]; intervention 4.8 [4.3–5.0]; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross-sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up-regulated gene expression for myosin heavy chains (fold change median [IQR]: MYH1 2.3 [1.1–2.7]; MYH2 0.7 [0.2–1.8]; MYH4 5.1 [2.2–15.3]) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32.
Conclusions
In our patients with sepsis syndrome at high risk for ICU-acquired weakness muscle activating measures in addition to early protocol-based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow-up. Yet it prevented muscle atrophy.

Wollersheim, T., Grunow, J. J., Carbon, N. M., Haas, K., Malleike, J., Ramme, S. F., Schneider, J., Spies, C. D., Maerdian, S., Mai, K., Spuler, S., Fielitz, J., and Weber‐Carstens, S. ( 2019) Muscle wasting and function after muscle activation and early protocol‐based physiotherapy: an explorative trial, Journal of Cachexia, Sarcopenia and Muscle, 10, 734– 747, doi: https://doi.org/10.1002/jcsm.12428.

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     Article first published online:  03 May 2019

Douglas W. Gould, Emma L. Watson, Thomas J. Wilkinson, Joanne Wormleighton, Soteris Xenophontos, Joao L. Viana

Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI
Background
Chronic kidney disease (CKD) is a catabolic condition associated with muscle wasting and dysfunction, which associates with morbidity and mortality. There is a need for simple techniques capable of monitoring changes in muscle size with disease progression and in response to interventions aiming to increase muscle mass and function. Ultrasound is one such technique; however, it is unknown how well changes in muscle cross-sectional area (CSA) measured using ultrasound relate to changes in whole muscle volume measured using magnetic resonance imaging. We tested whether rectus femoris CSA (RF-CSA) could be used as a valid indication of changes in quadriceps muscle volume as a single measure of muscle size and following a 12 week exercise intervention that resulted in muscle hypertrophy.
Methods
Secondary analysis of data was collected from the ExTra CKD study (ISRCTN 36489137). Quadriceps muscle size was assessed from 36 patients with non-dialysis CKD before and after 12 weeks of supervised exercise that resulted in muscle hypertrophy.
Results
Strong positive correlations were observed between RF-CSA and quadriceps volume at baseline (r2 = 0.815, CI 0.661 to 0.903; P < 0.001) and following 12 week exercise (r2 = 0.845, CI 0.700 to 0.923; P < 0.001). A moderate positive association was also observed between changes in RF-CSA and quadriceps following exercise training (rho = 0.441, CI 0.085 to 0.697; P = 0.015). Bland–Altman analysis revealed a small bias (bias 0.6% ± 12.5) between the mean percentage changes in RF-CSA and quadriceps volume but wide limits of agreement from -24 to 25.
Conclusions
Rectus femoris CSA appears to be a reliable index of total quadriceps volume as a simple measure of muscle size, both as a single observation and in response to exercise training in non-dialysis CKD patients.

Wollersheim, T., Grunow, J. J., Carbon, N. M., Haas, K., Malleike, J., Ramme, S. F., Schneider, J., Spies, C. D., Maerdian, S., Mai, K., Spuler, S., Fielitz, J., and Weber‐Carstens, S. ( 2019) Muscle wasting and function after muscle activation and early protocol‐based physiotherapy: an explorative trial, Journal of Cachexia, Sarcopenia and Muscle, 10, 734– 747, doi: https://doi.org/10.1002/jcsm.12428.

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     Article first published online:  02 April 2019

Yen‐Chung Lin, Yi‐Jen Lai, Yi‐Chun Lin, Chiung‐Chi Peng, Kuan‐Chou Chen, Ming‐Tsang Chuang, Mai‐Szu Wu, Tzu‐Hao Chang

Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR‐TMU study
Background
Weight‐reduction therapies, including bariatric surgery (BS), are standard treatments for severely obese patients with type 2 diabetes; however, the outcomes of these therapies are inconclusive for obese patients with chronic kidney disease (CKD). This study aimed to investigate the effects of BS or non‐surgical interventions on the estimated glomerular filtration rate (eGFR) and to determine whether BS can be recommended for renal function preservation based on body mass index (BMI) and eGFR changes in obese patients with CKD.
Methods
This study used data from the weight Reduction Intervention on GFR in Obese Patients with Renal Impairment‐Taipei Medical University (TMU) study, which was a large, long‐term, propensity score‐matched cohort study based on clinical data from patients who registered at weight‐reduction centres at TMU and its affiliated hospitals from 2008 to 2016. The patients were stratified according to whether they had undergone BS and into the mild, moderate, and high CKD risk groups using the Kidney Disease: Improving Global Outcomes guidelines. The primary outcome was the eGFR calculated using the Taiwan Chronic Kidney Disease‐Epidemiology Collaboration equation. Cox regression models were used to determine hazard ratios (HRs) for eGFR decreases ≥25%.
Results
A total of 4332 obese patients were enrolled in this study. After propensity score matching, 1620 patients, including 60.2% women, with a mean age of 36.5 (9.9) years were divided into BS or non‐surgery groups (n = 810 per group). The overall mean eGFRs increased by 4.4 (14) mL/min·1.73 m2 and decreased by 6.4 (16.0) mL/min·1.73 m2 in the BS and non‐surgery groups, respectively. The decrease in BMI in the BS and non‐surgery groups were 2.5 and 1.3 kg/m2, respectively. In the moderate/high CKD risk BS group, a significant correlation was evident between an increased eGFR and a reduced BMI (Spearman's correlation −0.229, P < 0.001). The Cox regression analysis showed that the BS group had a significantly lower risk of an eGFR decline ≥25% at 12 months [adjusted HR (aHR) 0.47, P = 0.03). After BS, obese patients with hypertension or albuminuria had significantly lower risks of eGFR declines ≥25% (aHR 0.37, P = 0.02 and aHR 0.13, P = 0.0018, respectively).
Conclusions
Bariatric surgery was associated with eGFR preservation in all obese patients and, particularly, in those with moderate‐to‐high CKD risks. A longer term outcome study is warranted to determine the benefits of BS for CKD patients.

Lin, Y.‐C., Lai, Y.‐J., Lin, Y.‐C., Peng, C.‐C., Chen, K.‐C., Chuang, M.‐T., Wu, M.‐S., and Chang, T.‐H. ( 2019) Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR‐TMU study, Journal of Cachexia, Sarcopenia and Muscle, 10, 756– 766, doi: https://doi.org/10.1002/jcsm.12423.

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     Article first published online:  10 April 2019

Ashley J. Smuder, Aaron B. Morton, Stephanie E. Hall, Michael P. Wiggs, Bumsoo Ahn, Nicholas R. Wawrzyniak, Kurt J. Sollanek, Kisuk Min, Oh Sung Kwon, W. Bradley Nelson, Scott K. Powers

Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation
Background
Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator‐induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity‐induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF‐κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise‐induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise‐induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD.
Methods
Cause and effect was determined by inhibiting the endurance exercise‐induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV‐HSP72) or pharmacological (BGP‐15) overexpression is sufficient to prevent VIDD.
Results
Our results demonstrate that the exercise‐induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV‐HSP72 and BGP‐15‐induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF‐κB and FoxO target genes.
Conclusions
HSP72 overexpression in the diaphragm is an effective intervention to prevent MV‐induced oxidative stress and the transcriptional activity of NF‐κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD.

Smuder, A. J., Morton, A. B., Hall, S. E., Wiggs, M. P., Ahn, B., Wawrzyniak, N. R., Sollanek, K. J., Min, K., Kwon, O. S., Nelson, W. B., and Powers, S. K. ( 2019) Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation, Journal of Cachexia, Sarcopenia and Muscle, 10, 767– 781, https://doi.org/10.1002/jcsm.12427. .

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     Article first published online:  01 April 2019

Sami Antoun, Hugues Morel, Pierre‐Jean Souquet, Veerle Surmont, David Planchard, Franck Bonnetain, Pascal Foucher, Thomas Egenod, Ivan Krakowski, Hélène Gaudin, Didier Debieuvre

Staging of nutrition disorders in non‐small‐cell lung cancer patients: utility of skeletal muscle mass assessment

Background
An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia [skeletal muscle mass (SMM) loss], inflammation, and anorexia. The aim of this study was to stage CAX in non‐small‐cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters.
Methods
This was a cross‐sectional and non‐interventional multicentre study. SMM was assessed by analysing L3 computed tomography‐scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ‐C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ).
Results
Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0–1, and the tumour stage was mainly IIIB‐IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre‐CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K‐RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre‐CAX patients. Overall, 43.8% of pre‐CAX patients had only sarcopenia with limited weight loss (≤2%) and no anorexia.
Conclusions
This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX.

Antoun, S., Morel, H., Souquet, P.‐J., Surmont, V., Planchard, D., Bonnetain, F., Foucher, P., Egenod, T., Krakowski, I., Gaudin, H., and Debieuvre, D. ( 2019) Staging of nutrition disorders in non‐small‐cell lung cancer patients: utility of skeletal muscle mass assessment, Journal of Cachexia, Sarcopenia and Muscle, 10, 782– 793, https://doi.org/10.1002/jcsm.12418.

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     Article first published online:  29 April 2019

Seung Bae Yoon, Moon Hyung Choi, Meiying Song, Ju Hyun Lee, In Seok Lee, Myung Ah. Lee, Tae Ho Hong, Eun Sun Jung, Myung-Gyu Choi

Impact of preoperative body compositions on survival following resection of biliary tract cancer
Background
Although surgical resection is the only potentially curative treatment for biliary tract cancer, the prognosis remains poor after a major operation such as pancreatoduodenectomy or hepatectomy. We aimed to investigate the impact of preoperative body compositions on long-term survival of patients undergoing resection of biliary tract cancer.
Methods
We analysed data of patients diagnosed with biliary tract cancer who underwent surgery from 2009 to 2015. Skeletal muscle area, skeletal muscle radiation attenuation, and visceral and subcutaneous adipose tissue areas were measured from the computed tomography images at L3 vertebral levels obtained before resection of cancer. Patients were divided into two groups based on the sex-specific median values for each parameter, and long-term survival was compared between the groups.
Results
A total of 371 patients (women, 39.6%; mean age, 66.2 ± 9.6 years) were finally included in the analysis. Patients with low skeletal muscle index (SMI) had significantly shorter median survival than those with high SMI (29 vs. 39 months; P = 0.026). Patients with low skeletal muscle attenuation (SMA) also showed reduced survival compared with those with high SMA (median survival 25 vs. 60 months; P = 0.002). Combining these two factors, survival was highest in the high SMI/high SMA group (reference) and lowest in the low SMI/low SMA group (hazard ratio, 2.18; 95% confidence interval, 1.44–3.30). Visceral and subcutaneous adipose tissue areas were not associated with long-term survival.
Conclusions
Low SMI and low SMA on computed tomography scan have a negative impact on survival after resection of biliary tract cancer. They can be used in preoperative risk assessment to assist in treatment decision making.

Yoon, S. B., Choi, M. H., Song, M., Lee, J. H., Lee, I. S., Lee, M. A., Hong, T. H., Jung, E. S., and Choi, M.‐G. ( 2019) Impact of preoperative body compositions on survival following resection of biliary tract cancer, Journal of Cachexia, Sarcopenia and Muscle, 10, 794– 802, doi: https://doi.org/10.1002/jcsm.12431.

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     Article first published online:  15 May 2019

Sophie Kurk, Petra Peeters, Rebecca Stellato, B. Dorresteijn, Pim de Jong, Marion Jourdan, Geert‐Jan Creemers, Frans Erdkamp, Felix de Jongh, Peter Kint, Lieke Simkens, Bea Tanis, Manuel Tjin‐A‐Ton, Ankie Van Der Velden, Cornelis Punt, Miriam Koopman, Anne May

Skeletal muscle mass loss and dose‐limiting toxicities in metastatic colorectal cancer patients
Background
Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first‐line maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose‐limiting toxicities (DLTs) during CAP‐B and CAPOX‐B.
Methods
Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs.
Results
One hundred eighty‐two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP‐B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX‐B. At the start of CAP‐B and CAPOX‐B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non‐sarcopenic at the start of CAP‐B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX‐B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2). Sarcopenia at the start of CAP‐B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64–1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01–1.66)]. At the start of subsequent CAPOX‐B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06–3.01)] or sarcopenia [1.75 (1.08–2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX‐B [sarcopenia vs. non‐sarcopenic: 0.86 (0.69–1.08) and SMI loss vs. stable/gain: 0.83 (0.65–1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs.
Conclusions
In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.

Kurk, S., Peeters, P., Stellato, R., Dorresteijn, B., de Jong, P., Jourdan, M., Creemers, G.‐J., Erdkamp, F., de Jongh, F., Kint, P., Simkens, L., Tanis, B., Tjin‐A‐Ton, M., Van Der Velden, A., Punt, C., Koopman, M., and May, A. ( 2019) Skeletal muscle mass loss and dose‐limiting toxicities in metastatic colorectal cancer patients, Journal of Cachexia, Sarcopenia and Muscle, 10, 803– 813, doi: https://doi.org/10.1002/jcsm.12436.

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     Article first published online:  15 May 2019

Jie Lee, Jhen‐Bin Lin, Meng‐Hao Wu, Ya‐Ting Jan, Chih‐Long Chang, Chueh‐Yi Huang, Fang‐Ju Sun, Yu‐Jen Chen

Muscle radiodensity loss during cancer therapy is predictive for poor survival in advanced endometrial cancer
Background
Treatment‐related toxicities and decreased levels of patient performance during cancer therapy might contribute to body composition changes and thereby impact outcomes. However, the effect of longitudinal body composition changes on outcomes in patients with advanced endometrial cancer is unknown. This study investigated the association between body composition changes during staging surgery and adjuvant chemoradiotherapy and outcomes in patients with stage III endometrial cancer.
Methods
Pretreatment and post‐treatment computed tomography (CT) images of 131 patients with stage III endometrial cancer who were treated between 2008 and 2016 were analysed. All CT images were contrast enhanced and acquired according to the standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured from two sets of CT images obtained at the level of the third lumbar vertebra. The skeletal muscle gauge was calculated by multiplying SMI by SMD (SMI × SMD). Predictors of overall survival and progression‐free survival were identified using Cox regression models.
Results
The median follow‐up was 50.6 (range 12.1–117.0) months. Overall, body mass index (BMI) changes during treatment were 0.4% per 210 days (95% confidence interval: −0.6 to 1.4; P = 0.41), and patients experienced an average SMD loss of 2.1% per 210 days (95% confidence interval: −4.0 to −0.2; P = 0.03). Weight loss and SMD loss ≥5% were observed in 23 (17.6%) and 54 (41.2%) patients, respectively. The changes in SMD did not correlate with those in BMI (Spearman's ρ for SMD, −0.13; P = 0.13). SMD change (per 1 Hounsfield unit/210 days decrease) was independently associated with poorer overall survival (hazard ratio: 1.32, 95% confidence interval: 1.14–1.52; P < 0.001) and progression‐free survival (hazard ratio: 1.28, 95% confidence interval: 1.12–1.43; P < 0.001). Our results did not show association between survival and pretreatment myosteatosis and sarcopenia or changes in SMI and total adipose tissue index during treatment. The pretreatment skeletal muscle gauge was associated with treatment modifications such as delays, dose reductions, and discontinuation of chemotherapy.
Conclusions
Skeletal muscle radiodensity decreased significantly during treatment and was independently associated with poorer survival in patients with stage III endometrial cancer who underwent staging surgery and adjuvant chemoradiotherapy. SMD loss was occult and occurred independently of BMI change.

Lee, J., Lin, J.‐B., Wu, M.‐H., Jan, Y.‐T., Chang, C.‐L., Huang, C.‐Y., Sun, F.‐J., and Chen, Y.‐J. ( 2019) Muscle radiodensity loss during cancer therapy is predictive for poor survival in advanced endometrial cancer, Journal of Cachexia, Sarcopenia and Muscle, 10, 814– 826, doi: https://doi.org/10.1002/jcsm.12440.

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     Article first published online:  12 April 2019

Aditi Narsale, Rosa Moya, Jasmin Ma, Lindsey J. Anderson, Daniel Wu, Jose M. Garcia, Joanna D. Davies

Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study
Background
Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4+ precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti-cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer.
Methods
The frequency of circulating CD4+ and CD8+ naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real-time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one-repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual-energy X-ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses.
Results
Our data show significant correlations between (i) higher frequencies of CD8+ naïve (P = 0.02) and effector memory (P = 0.003) T cells and lower frequencies of CD8+ central memory T cells (P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index (P = 0.04), (iii) lower frequency of CD8+ T cells that express CD95 with greater stair climb power (P = 0.003), (iv) higher frequency of T cells that co-express CD197 and CD45RA and greater one-repetition maximum knee extension strength (P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment (P = 0.004) in people with cancer.
Conclusions
We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow-up study with a larger cohort to test the validity of the findings.

Narsale, A., Moya, R., Ma, J., Anderson, L. J., Wu, D., Garcia, J. M., and Davies, J. D. ( 2019) Cancer‐driven changes link T cell frequency to muscle strength in people with cancer: a pilot study, Journal of Cachexia, Sarcopenia and Muscle, 10, 827843, doi: https://doi.org/10.1002/jcsm.12424.

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     Article first published online:  29 April 2019

Daniel I. Brierley, Joe R. Harman, Natasha Giallourou, Emma Leishman, Anna Emily Roashan, Ben A.D. Mellows, Heather B. Bradshaw, Jonathan R. Swann, Ketan Patel, Benjamin J. Whalley, Claire M. Williams

Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol
Background
Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality. Extracts of Cannabis sativa, and analogues of the major phytocannabinoid ?9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss. We recently established that the non-psychoactive phytocannabinoid cannabigerol (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin.
Methods
An acute cachectic phenotype was induced in adult male Lister-hooded rats by 6 mg/kg (i.p.) cisplatin. In total 66 rats were randomly allocated to groups receiving vehicle only, cisplatin only, or cisplatin and 60 or 120 mg/kg CBG (po, b.i.d.). Feeding behavior, bodyweight and locomotor activity were recorded for 72 hours, at which point rats were sacrificed for post-mortem analyses. Myofibre atrophy, protein synthesis and autophagy dysregulation were assessed in skeletal muscle, plasma metabolic profiles were obtained by untargeted 1H-NMR metabonomics, and levels of endocannabinoid-like lipoamines quantified in plasma and hypothalami by targeted HPLC-MS/MS lipidomics.
Results
CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Y=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Y=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment.
Conclusions
Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models.

Brierley, D. I., Harman, J. R., Giallourou, N., Leishman, E., Roashan, A. E., Mellows, B. A. D., Bradshaw, H. B., Swann, J. R., Patel, K., Whalley, B. J., and Williams, C. M. ( 2019) Chemotherapy‐induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol, Journal of Cachexia, Sarcopenia and Muscle, 10, 844– 859, doi: https://doi.org/10.1002/jcsm.12426.

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     Article first published online:  21 May 2019

Malcolm A. West, David P.J. van Dijk, Fredrick Gleadowe, Thomas Reeves, John N. Primrose, Mohammed Abu Hilal, Mark R. Edwards, Sandy Jack, Sander S.S. Rensen, Michael P.W. Grocott, Denny Z.H. Levett, Steven W.M. Olde Damink

Myosteatosis is associated with poor physical fitness in patients undergoing hepatopancreatobiliary surgery
Background
Body composition assessment, measured using single‐slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia (i.e. low skeletal muscle mass), myosteatosis [i.e. low skeletal muscle radiation attenuation (SM‐RA)], and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post‐operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery.
Methods
A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single‐slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold ( urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0001O2 at AT), oxygen uptake at peak exercise ( urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0002O2 peak), skeletal muscle mass, and SM‐RA.
Results
Of 123 patients recruited [77 men (63%), median age 66.9 ± 11.7, median body mass index 27.3 ± 5.2], 113 patients had good‐quality abdominal CT scans available and were included. Of the CT body composition variables, SM‐RA had the strongest correlation with urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0003O2 peak (r = 0.57, P < 0.001) and urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0004O2 at AT (r = 0.45, P < 0.001) while skeletal muscle mass was only weakly associated with urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0005O2 peak (r = 0.24, P < 0.010). In the multivariate analysis, only SM‐RA was associated with urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0006O2 peak (B = 0.25, 95% CI 0.15–0.34, P < 0.001, R2 = 0.42) and urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0007O2 at AT (B = 0.13, 95% CI 0.06–0.18, P < 0.001, R2 = 0.26).
Conclusions
There is a positive association between preoperative CT SM‐RA and preoperative physical fitness ( urn:x-wiley:21905991:media:jcsm12433:jcsm12433-math-0008O2 at AT and at peak). This study demonstrates that myosteatosis, and not sarcopenia, is associated with reduced aerobic physical fitness. Combining both myosteatosis and physical fitness variables may provide additive risk stratification accuracy and guide interventions during the perioperative period.

West, M. A., van Dijk, D. P. J., Gleadowe, F., Reeves, T., Primrose, J. N., Abu Hilal, M., Edwards, M. R., Jack, S., Rensen, S. S. S., Grocott, M. P. W., Levett, D. Z. H., and Olde Damink, S. W. M. ( 2019) Myosteatosis is associated with poor physical fitness in patients undergoing hepatopancreatobiliary surgery, Journal of Cachexia, Sarcopenia and Muscle, 10, 860– 871, doi: https://doi.org/10.1002/jcsm.12433.

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     Article first published online:  24 April 2019

Savina Apolloni, Susanna Amadio, Paola Fabbrizio, Giovanna Morello, Antonio Gianmaria Spampinato, Emanuele Claudio Latagliata, Illari Salvatori, Daisy Proietti, Alberto Ferri, Luca Madaro, Stefano Puglisi-Allegra, Sebastiano Cavallaro, Cinzia Volonté

Histaminergic transmission slows progression of amyotrophic lateral sclerosis
Background
Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti-inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine-mediated therapeutic strategy in ALS mice.
Methods
We adopted an integrative multi-omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)-G93A mice that recapitulate key ALS features, with the brain-permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1-G93A motor neuron-like cells.
Results
We identified 13 histamine-related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine-related genes overlapped with genomic regions disrupted by DNA copy number and with ALS-linked pathogenic variants. Histidine treatment in SOD1-G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro.
Conclusions
Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine-related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi-gene network responsible for ALS and, furthermore, in the drug development process.

Apolloni, S., Amadio, S., Fabbrizio, P., Morello, G., Spampinato, A. G., Latagliata, E. C., Salvatori, I., Proietti, D., Ferri, A., Madaro, L., Puglisi‐Allegra, S., Cavallaro, S., and Volonté, C. ( 2019) Histaminergic transmission slows progression of amyotrophic lateral sclerosis, Journal of Cachexia, Sarcopenia and Muscle, 10, 872– 893, doi: https://doi.org/10.1002/jcsm.12422.

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     Article first published online:  24 April 2019

Yeonhee Hong, Jong Han Lee, Kwang Won Jeong, Cheol Soo Choi, Hee-Sook Jun

Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy
Background
Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exendin-4 (Ex-4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP-1R agonist for muscle wasting and the mechanisms involved.
Methods
Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex-4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex-4 in a Dex-induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex-4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)-induced muscle atrophy model. Furthermore, we evaluated the effect of a long-acting GLP-1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J-mdx mice, a Duchenne muscular dystrophy model.
Results
Ex-4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F-box only protein 32 (atrogin-1) and muscle RING-finger protein-1 (MuRF-1) in Dex-treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP-1R. In addition, Ex-4 treatment inhibited glucocorticoid receptor (GR) translocation by up-regulating the proteins of GR inhibitory complexes. In a Dex-induced muscle atrophy model, Ex-4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex-4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long-acting GLP-1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J-mdx mice.
Conclusions
GLP-1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP-1R-mediated signalling pathways. These novel findings suggest that activating GLP-1R signalling may be useful for the treatment of atrophy-related muscular diseases.

Hong, Y., Lee, J. H., Jeong, K. W., Choi, C. S., and Jun, H.‐S. ( 2019) Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy, Journal of Cachexia, Sarcopenia and Muscle, 10, 903– 918, doi: https://doi.org/10.1002/jcsm.12434.

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     Article first published online:  08 May 2019

Arthur Goron, Frédéric Lamarche, Sandrine Blanchet, Pascale Delangle, Uwe Schlattner, Eric Fontaine, Christophe Moinard

Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis
Background
Animal studies and clinical data support the interest of citrulline as a promising therapeutic for sarcopenia. Citrulline is known to stimulate muscle protein synthesis, but how it affects energy metabolism to support the highly energy-dependent protein synthesis machinery is poorly understood.
Methods
Here, we used myotubes derived from primary culture of mouse myoblasts to study the effect of citrulline on both energy metabolism and protein synthesis under different limiting conditions.
Results
When serum/amino acid deficiency or energy stress (mild uncoupling) were applied, citrulline stimulated muscle protein synthesis by +22% and +11%, respectively. Importantly, this increase was not associated with enhanced energy status (ATP/ADP ratio) or mitochondrial respiration. We further analysed the share of mitochondrial respiration and thus of generated ATP allocated to different metabolic pathways by using specific inhibitors. Our results indicate that addition of citrulline allocated an increased share of mitochondrially generated ATP to the protein synthesis machinery under conditions of both serum/amino acid deficiency (+28%) and energy stress (+21%). This reallocation was not because of reduced ATP supply to DNA synthesis or activities of sodium and calcium cycling ion pumps.
Conclusions
Under certain stress conditions, citrulline increases muscle protein synthesis by specifically reallocating mitochondrial fuel to the protein synthesis machinery. Because ATP/ADP ratios and thus Gibbs free energy of ATP hydrolysis remained globally constant, this reallocation may be linked to decreased activation energies of one or several ATP (and GTP)-consuming reactions involved in muscle protein synthesis.

Goron, A., Lamarche, F., Blanchet, S., Delangle, P., Schlattner, U., Fontaine, E., and Moinard, C. ( 2019) Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis, Journal of Cachexia, Sarcopenia and Muscle, 10, 919– 928, doi: https://doi.org/10.1002/jcsm.12435.

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