Article first published online:  28 March 2019

Mitja Lainscak, Giuseppe M. C. Rosano

Cancer cachexia: an orphan with a future
no abstract

Lainscak, M., and Rosano, G. M. C. ( 2019) Cancer cachexia: an orphan with a future. Journal of Cachexia, Sarcopenia and Muscle, 10: 3– 5. https://doi.org/10.1002/jcsm.12401.

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     Article first published online:  28 March 2019

Richard J.E. Skipworth

A tale of two CT studies: the combined impact of multiple human body composition projects in cancer
no abstract

iSkipworth, R. J. E. ( 2019) A tale of two CT studies: the combined impact of multiple human body composition projects in cancer. Journal of Cachexia, Sarcopenia and Muscle, 10: 6– 8. https://doi.org/10.1002/jcsm.12406.

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     Article first published online:  17 January 2019

Katherine M. Flegal, John P.A. Ioannidis, Wolfram Doehner

Flawed methods and inappropriate conclusions for health policy on overweight and obesity: the Global BMI Mortality Collaboration meta-analysis
Guideline recommendations and health policy decisions rely on evidence from clinical and epidemiological studies. Adequate methodology and appropriate conclusions are essential to support healthcare and health policy decisions. An analysis of body mass index and mortality by the Global BMI Mortality Collaboration (GBMC) concluded that the association of excess body weight with higher mortality was similar worldwide and that overweight and obesity should be combated everywhere. To reach this conclusion, the GBMC used highly selected data, rather than a systematic approach. The GBMC initially chose individual participant data from 239 prospective studies with approximately 10.6 million participants. The GBMC then excluded over 60% of data and over 75% of fatal events by eliminating all cases with any reported disease at baseline or smoking history and all events within the first 5 years of follow-up. After applying these restrictions, the association of overweight with lower mortality was reversed and the association of obesity with higher mortality was increased. Given the major flaws in the selection process, in the adequacy of the data, in the data analysis, and in the interpretation, the GBMC conclusions should be viewed sceptically as a guide to action, either for clinical decisions or for public health in general. The flawed conclusion that overweight is uniformly associated with substantially increased risk of death and thus should be combated in any circumstances may lead not only to unjustified treatment efforts and potential harm in a wide range of clinical conditions but also to a tremendous waste of resources.

Flegal, K. M., Ioannidis, J. P. A., and Doehner, W. ( 2019) Flawed methods and inappropriate conclusions for health policy on overweight and obesity: the Global BMI Mortality Collaboration meta‐analysis. Journal of Cachexia, Sarcopenia and Muscle, 10: 9– 13. https://doi.org/10.1002/jcsm.12378.

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     Article first published online:  28 March 2019

William J. Evans, Marc Hellerstein, Eric Orwoll, Steve Cummings, Peggy M. Cawthon

D3‐Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass
Sarcopenia has been described as the age‐associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual‐energy X‐ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3‐Creatine (D3‐Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3‐Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3‐Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.

Evans, W. J., Hellerstein, M., Orwoll, E., Cummings, S., and Cawthon, P. M. ( 2019) D3‐Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass. Journal of Cachexia, Sarcopenia and Muscle, 10: 14– 21. https://doi.org/10.1002/jcsm.12390.

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     Article first published online:  28 March 2019

Markus S. Anker, Richard Holcomb, Maurizio Muscaritoli, Stephan von Haehling, Wilhelm Haverkamp, Aminah Jatoi, John E. Morley, Florian Strasser, Ulf Landmesser, Andrew J.S. Coats, Stefan D. Anker

Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review
Background
Cachexia has significant impact on the patients' quality of life and prognosis. It is frequently observed in patients with cancer, especially in advanced stages, but prevalence data for the overall population are lacking. Good quality estimates of cancer cachexia in general and for each of the major cancer types would be highly relevant for potential treatment development efforts in this field. Both the USA and European Union (EU) have implemented special clinical development rules for such rare disorders what are called ‘orphan diseases’. The cut‐off level for a disease to be considered an orphan disease in the USA is 200 000 people (0.06% of the population) and EU is 5 per 10 000 people (0.05% of the population).
Methods
For this systematic review, we searched at PubMed (from inception to 31 January 2018) to identify clinical studies that assessed the prevalence of cachexia in cancer patients at risk. Studies reporting the prevalence of either cancer cachexia or wasting disease in the top‐10 cancer types and 4 other selected cancer types known to be particularly commonly complicated by cachexia were included in this analysis (i.e. prostate cancer, breast cancer, colorectal cancer, melanoma, endometrial cancer, thyroid cancer, urinary bladder cancer, non‐hodgkin lymphoma, lung cancer, kidney and renal pelvis cancer, head and neck cancer, gastric cancer, liver cancer, and pancreatic cancer). We calculated the current burden of cancer cachexia, disease by disease, in the USA and in the EU and compared them to the current guidelines for the definition of orphan disease status.
Results
We estimate that in 2014 in the USA, a total of 527 100 patients (16.5 subjects per 10 000 people of the total population), and in 2013 in the EU, a total of 800 300 patients (15.8 subjects per 10 000 people of the total population) suffered from cancer cachexia (of any kind). In the 14 separately analysed cancer types, the prevalence of cancer cachexia in the USA ranged between 11 300 (0.4/10 000, gastric cancer) and 92 000 patients (2.9/10 000, lung cancer) and in the EU between 14 300 (0.3/10 000, melanoma of the skin) and 150 100 (3.0/10 000, colorectal cancer).
Conclusions
The absolute number of patients affected by cancer cachexia in each cancer group is lower than the defined thresholds for orphan diseases in the USA and EU. Cancer cachexia in each subgroup separately should be considered an orphan disease.

Anker, M. S., Holcomb, R., Muscaritoli, M., Haehling, S., Haverkamp, W., Jatoi, A., Morley, J. E., Strasser, F., Landmesser, U., Coats, A. J. S., and Anker, S. D. ( 2019) Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, 10: 22– 34. https://doi.org/10.1002/jcsm.12402.

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     Article first published online:  21 November 2018

Qing Zhang, Agnès Duplany, Vincent Moncollin, Sandrine Mouradian, Evelyne Goillot, Laetitia Mazelin, Karine Gauthier, Nathalie Streichenberger, Céline Angleraux, Jie Chen, Shuzhe Ding, Laurent Schaeffer, Yann-Gaël Gangloff

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis
Background
The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age-related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown.
Methods
We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle-specific mTOR knockout (mTORmKO) littermates.
Results
In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down-regulation of glycogen phosphorylase expression (0.16-fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V.
Conclusions
Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole-body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole-body homeostasis.

Zhang, Q., Duplany, A., Moncollin, V., Mouradian, S., Goillot, E., Mazelin, L., Gauthier, K., Streichenberger, N., Angleraux, C., Chen, J., Ding, S., Schaeffer, L., and Gangloff, Y.-G. (2018) Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. Journal of Cachexia, Sarcopenia and Muscle, 10: 22– 34. https://doi.org/10.1002/jcsm.12336.

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     Article first published online:  30 October 2018

Roland Veltkamp, Stefan Uhlmann, Marilena Marinescu, Carsten Sticht,Daniel Finke, Norbert Gretz, Herrmann‐Josef Gröne, Hugo A. Katus, Johannes Backs, Lorenz H. Lehmann

Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction
Background
Stroke can lead to cardiac dysfunction in patients, but the mechanisms underlying the interaction between the injured brain and the heart are poorly understood. The objective of the study is to investigate the effects of experimental murine stroke on cardiac function and molecular signalling in the heart.
Methods and results
Mice were subjected to filament‐induced left middle cerebral artery occlusion for 30 or 60 min or sham surgery and underwent repetitive micro‐echocardiography. Left ventricular contractility was reduced early (24–72 h) but not late (2 months) after brain ischaemia. Cardiac dysfunction was accompanied by a release of high‐sensitive cardiac troponin (hsTNT (ng/ml): d1: 7.0 ± 1.0 vs. 25.0 ± 3.2*; d3: 7.3 ± 1.1 vs. 52.2 ± 16.7*; d14: 5.7 ± 0.8 vs. 5.2 ± 0.3; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); reduced heart weight (heart weight/tibia length ratio: d1: 6.9 ± 0.2 vs. 6.4 ± 0.1*; d3: 6.7 ± 0.2 vs. 5.8 ± 0.1*; d14: 6.7 ± 0.2 vs. 6.4 ± 03; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); resulting from cardiomyocyte atrophy (cardiomyocyte size: d1: 12.8% ± 0.002**; d3: 13.5% ± 0.002**; 14d: 6.3% ± 0.003*; 60 min. MCAO vs. sham; mean ± SEM; **p < 0.01; *p < 0.05), accompanied by increased atrogin‐1 and the E3 ubiquitin ligase murf‐1. Net norepinephrine but not synthesis was increased, suggesting a reduced norepinephrine release or an increase of norepinephrine re‐uptake, resulting in a functional denervation. Transcriptome analysis in cardiac tissue identified the transcription factor peroxisome proliferator‐activated receptor gamma as a potential mediator of stroke‐induced transcriptional dysregulation involved in cardiac atrophy.
Conclusions
Stroke induces a complex molecular response in the heart muscle with immediate but transient cardiac atrophy and dysfunction.

Veltkamp, R., Uhlmann, S., Marinescu, M., Sticht, C., Finke, D., Gretz, N., Gröne, H.‐J., Katus, H. A., Backs, J., and Lehmann, L. H. (2018) Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction. Journal of Cachexia, Sarcopenia and Muscle, 10: 54– 62 https://doi.org/10.1002/jcsm.12335.

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     Article first published online:  25 October 2018

Daryl P. Fields, Brandon M. Roberts, Alec K. Simon, Andrew R. Judge, David D. Fuller, Gordon S. Mitchell

Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia
Background
Cancer cachexia is an insidious process characterized by muscle atrophy with associated motor deficits, including diaphragm weakness and respiratory insufficiency. Although neuropathology contributes to muscle wasting and motor deficits in many clinical disorders, neural involvement in cachexia‐linked respiratory insufficiency has not been explored.
Methods
We first used whole‐body plethysmography to assess ventilatory responses to hypoxic and hypercapnic chemoreflex activation in mice inoculated with the C26 colon adenocarcinoma cell line. Mice were exposed to a sequence of inspired gas mixtures consisting of (i) air, (ii) hypoxia (11% O2) with normocapnia, (iii) hypercapnia (7% CO2) with normoxia, and (iv) combined hypercapnia with hypoxia (i.e. maximal chemoreflex response). We also tested the respiratory neural network directly by recording inspiratory burst output from ligated phrenic nerves, thereby bypassing influences from changes in diaphragm muscle strength, respiratory mechanics, or compensation through recruitment of accessory motor pools.
Results
Cachectic mice demonstrated a significant attenuation of the hypoxic tidal volume (0.26mL±0.01mL vs 0.30mL±0.01mL; p<0.05), breathing frequency (317±10bpm vs 344±6bpm; p<0.05) and phrenic nerve (29.5±2.6% vs 78.8±11.8%; p<0.05) responses. On the other hand, the much larger hypercapnic tidal volume (0.46±0.01mL vs 0.46±0.01mL; p>0.05), breathing frequency (392±5bpm vs 408±5bpm; p>0.05) and phrenic nerve (93.1±8.8% vs 111.1±13.2%; p>0.05) responses were not affected. Further, the concurrent hypercapnia/hypoxia tidal volume (0.45±0.01mL vs 0.45±0.01mL; p>0.05), breathing frequency (395±7bpm vs 400±3bpm; p>0.05), and phrenic nerve (106.8±7.1% vs 147.5±38.8%; p>0.05) responses were not different between C26 cachectic and control mice.
Conclusions
Breathing deficits associated with cancer cachexia are specific to the hypoxic ventilatory response and, thus, reflect disruptions in the hypoxic chemoafferent neural network. Diagnostic techniques that detect decompensation and therapeutic approaches that support the failing hypoxic respiratory response may benefit patients at risk for cancer cachectic‐associated respiratory failure.

Fields, D. P., Roberts, B. M., Simon, A. K., Judge, A. R., Fuller, D. D., and Mitchell, G. S. (2018) Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia. Journal of Cachexia, Sarcopenia and Muscle, 10: 63– 72 https://doi.org/10.1002/jcsm.12348.

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     Article first published online:  18 October 2018

Tateaki Naito Shuichi Mitsunaga Satoru Miura Noriatsu Tatematsu Toshimi Inano Takako Mouri Tetsuya Tsuji Takashi Higashiguchi Akio Inui Taro Okayama Teiko Yamaguchi Ayumu Morikawa Naoharu Mori Toshiaki Takahashi Florian Strasser Katsuhiro Omae Keita Mori Koichi Takayama

Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non‐small‐cell lung cancer
Background
Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme.
Methods
This was a multicentre prospective single‐arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first‐line chemotherapy for newly diagnosed, advanced pancreatic, or non‐small‐cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder®, Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home‐based low‐intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched‐chain amino acids (Inner Power®, Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety.
Results
The median patient age was 75 years (range, 70–84). Twelve patients (40%) were cachectic at baseline. Twenty‐nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient).
Conclusions
The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non‐small‐cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.

Naito, T., Mitsunaga, S., Miura, S., Tatematsu, N., Inano, T., Mouri, T., Tsuji, T., Higashiguchi, T., Inui, A., Okayama, T., Yamaguchi, T., Morikawa, A., Mori, N., Takahashi, T., Strasser, F., Omae, K., Mori, K., and Takayama, K. (2018) Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non‐small‐cell lung cancer. Journal of Cachexia, Sarcopenia and Muscle, 10: 73– 83 https://doi.org/10.1002/jcsm.12351.

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     Article first published online:  29 October 2018

Brianna Bourgeois, Bo Fan, Neil Johannsen, Maria Cristina Gonzalez, Bennett K. Ng, Markus J. Sommer, John A. Shepherd, Steven B. Heymsfield

Improved strength prediction combining clinically available measures of skeletal muscle mass and quality
Background
Measures of skeletal muscle function decline at a faster rate with ageing than do indices of skeletal muscle mass. These observations have been attributed to age‐related changes in muscle quality, another functional determinant separate from skeletal muscle mass. This study tested the hypothesis that improved predictions of skeletal muscle strength can be accomplished by combining clinically available measures of skeletal muscle mass and quality.
Methods
The participants included 146 healthy adult (age ≥ 18 years, range 18–77 years; X ± SD 47 ± 17 years and body mass index 16.5–51.8 kg/m2; 27.7 ± 6.2 kg/m2) men (n = 60) and women (n = 86) in whom skeletal muscle mass was estimated as appendicular lean soft tissue (LST) measured by dual‐energy X‐ray absorptiometry and skeletal muscle quality as bioimpedance analysis‐derived phase angle and B‐mode‐evaluated echogenicity of mid‐thigh skeletal muscle. Strength of the right leg and both arms was quantified as knee isokinetic extension and handgrip strength using dynamometers. The statistical significance of adding phase angle or echogenicity to strength prediction multiple regression models that included extremity‐specific LST and other covariates (e.g. age and sex) was evaluated to test the study hypothesis.
Results
Right leg LST mass alone was significantly (P < 0.0001) correlated with isokinetic right leg strength (R2 = 0.57). The addition of segmental phase angle measured in the right leg at 50 kHz increased the R2 of this model to 0.66 (P < 0.0001); other phase angle frequencies (5 and 250 kHz) did not contribute significantly to these models. Results were similar for both right and left arm handgrip strength prediction models. Adding age and sex as model covariates increased the R2 values of these models further (e.g. right leg strength model R2 increased to 0.71), but phase angle continued to remain a significant (all P < 0.01) predictor of extremity strength. Similarly, when predicting isokinetic right leg strength, mid‐thigh skeletal muscle echogenicity added significantly (P < 0.0001) to right leg LST, increasing R2 from 0.57 to 0.64; age was a significant (P < 0.0001) covariate in this model, increasing R2 further to 0.68.
Conclusions
The hypothesis of the current study was confirmed, strongly supporting and extending earlier reports by quantifying the combined independent effects of skeletal muscle mass and quality on lower‐body and upper‐body measures of strength. These observations provide a clinically available method for future research aimed at optimizing sarcopenia and frailty risk prediction models.

Bourgeois, B., Fan, B., Johannsen, N., Gonzalez, M. C., Ng, B. K., Sommer, M. J., Shepherd, J. A., and Heymsfield, S. B. (2018) Improved strength prediction combining clinically available measures of skeletal muscle mass and quality. Journal of Cachexia, Sarcopenia and Muscle, 10: 84– 94 https://doi.org/10.1002/jcsm.12353.

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     Article first published online:  4 October 2018

Maria Conte, Andrea Armani, Giuseppe Conte, Andrea Serra, Claudio Franceschi, Marcello Mele, Marco Sandri, Stefano Salvioli

Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy
Background
Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments.
Methods
By mean of in vivo Plin2 down-regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery.
Results
We found that Plin2 down-regulation was sufficient to induce a 30% increase of myofiber cross-sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients.
Conclusions
Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

Conte, M., Armani, A., Conte, G., Serra, A., Franceschi, C., Mele, M., Sandri, M., and Salvioli, S. (2018) Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy. Journal of Cachexia, Sarcopenia and Muscle, 10: 95– 110 https://doi.org/10.1002/jcsm.12355.

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     Article first published online:  20 November 2018

Ross D. Dolan, Arwa S. Almasaudi, Ly B. Dieu, Paul G. Horgan, Stephen T. McSorley, Donald C. McMillan

The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer
Introduction
Colorectal cancer is the fourth leading cause of cancer mortality in developed countries. There is evidence supporting a disproportionate loss of skeletal muscle as an independent prognostic factor. The importance of the systemic inflammatory response as a unifying mechanism for specific loss of skeletal muscle mass in patients with cancer is increasingly recognized. The aim of the present study was to delineate the relationship between the systemic inflammatory response, skeletal muscle index (SMI), skeletal muscle density (SMD), and overall survival in patients with colorectal cancer.
Materials and methods
The study included 650 patients with primary operable colorectal cancer. Computed tomography scans were used to define the presence of visceral obesity, sarcopenia (low SMI), and myosteatosis (low SMD). Tumour and patient characteristics were recorded. Survival analysis was carried out using univariate and multivariate Cox regression.
Results
A total of 650 patients (354 men and 296 women) were included. The majority of patients were over 65 years of age (64%) and overweight or obese (68%). On univariate survival analysis, age, ASA, TNM stage, modified Glasgow Prognostic Score (mGPS), body mass index, subcutaneous fat index, visceral obesity, SMI, and SMD were significantly associated with overall survival (all P < 0.05). A low SMI and SMD were significantly associated with an elevated mGPS (<0.05). On multivariate analysis, SMI (Martin) [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.04–2.18, P = 0.031], SMD (Xiao) (HR 1.42, 95% CI 0.98–2.05, P = 0.061), and mGPS (HR 1.44, 95% CI 1.15–1.79, P = 0.001) were independently associated with overall survival. SMD but not SMI was significantly associated with ASA (P < 0.001).
Conclusions
This study delineates the relationship between the loss of quantity and quality of skeletal muscle mass, the systemic inflammatory response, and survival in patients with operable colorectal cancer.

Dolan, R. D., Almasaudi, A. S., Dieu, L. B., Horgan, P. G., McSorley, S. T., and McMillan, D. C. (2018) The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer. Journal of Cachexia, Sarcopenia and Muscle, 10: 111– 122 https://doi.org/10.1002/jcsm.12357.

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     Article first published online:  31 October 2018

David P.J. van Dijk, Matthew Krill, Farshad Farshidfar, Ting Li, Sander S. Rensen, Steven W.M. Olde Damink, Elijah Dixon, Francis R. Sutherland, Chad G. Ball, Vera C. Mazurak, Vickie E. Baracos; Oliver F. Bathe

Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases
Background
Most prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well‐described host phenotypes in cancer.
Methods
Clinical data and pre‐operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre‐operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C‐reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis.
Results
Skeletal muscle was significantly correlated with VAT (r = 0.46, P < 0.001). Of patients with sarcopenia, 35 (65%) also had low VAT. C‐reactive protein was elevated (≥5 mg/mL) in 42 patients (43.3%). Elevated CRP was more common in patients with sarcopenia (73.8% vs. 51.1%, P = 0.029). The most significant prognostic factors were the coincidence of elevated CRP and adverse body composition features (sarcopenia and/or low VAT; hazard ratio 4.3, 95% confidence interval 1.5–13.0, P = 0.008), as well as Fong clinical prognostic score (hazard ratio 2.9, 95% confidence interval 1.5–5.5, P = 0.002).
Conclusions
Body composition in patients with CRLM is not directly linked to the presence of systemic inflammation. However, when systemic inflammation coincides with sarcopenia and/or low VAT, prognosis is adversely affected, independent of the Fong clinical prognostic score.

van Dijk, D. P. J., Krill, M., Farshidfar, F., Li, T., Rensen, S. S., Olde Damink, S. W. M., Dixon, E., Sutherland, F. R., Ball, C. G., Mazurak, V. C., Baracos, V. E., and Bathe, O. F. (2018) Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases. Journal of Cachexia, Sarcopenia and Muscle, 10: 123– 130 https://doi.org/10.1002/jcsm.12358.

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     Article first published online:  5 November 2018

Maria Papageorgiou, Thozhukat Sathyapalan, Rudolph Schutte

Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women
Background
Despite several muscle mass measures being used in the current definitions of sarcopenia, their usefulness is uncertain because of limited data on their association with health outcomes. The aim of the study was to compare the performance of different muscle mass measures for predicting incident osteoporosis in postmenopausal women.
Methods
This study included data from 149 166 participants (aged 60.3 ± 5.5 years) as part of the UK Biobank cohort. Body composition was assessed using bioelectrical impedance. The muscle mass measures included were total body skeletal muscle mass (SMM) and appendicular SMM (aSMM) divided by height squared (ht2), derived residuals, SMM, SMM adjusted for body mass (SMM/bm × 100), and aSMM normalized for body mass index (aSMM/BMI). Diagnoses of the events were confirmed by primary care physicians and coded according to the World Health Organization's International Classification of Diseases 10th Revision (ICD‐10: M80‐M82).
Results
Over a median follow‐up of 6.75 (5th to 95th percentile interval, 1.53 to 8.37) years, 394 newly diagnosed cases of osteoporosis occurred, with 40 (10.2%) cases being associated with a pathological fracture. SMM/ht2, aSMM/ht2 residual, and SMM were lower in postmenopausal women with osteoporosis compared with women without (all P < 0.0001), while SMM/bm × 100 (P = 0.003), but not aSMM/BMI (P = 0.59), was higher in the osteoporosis group. The unadjusted rates of osteoporosis increased with decreasing quintiles for SMM/ht2, aSMM/ht2, residuals, and SMM (all P trend <0.0001), while the incidence of osteoporosis increased with increasing SMM/bm × 100 (P trend =0.001), but not for aSMM/BMI (P = 0.45). After minimally adjusting for age and after full adjustment, SMM/ht2, aSMM/ht2, and SMM were the only measure that consistently predicted osteoporosis in the total group of postmenopausal women [hazard ratio (HR) 0.65–0.67, all P ≤ 0.0001], in lean women (HR 0.62–0.68; all P ≤ 0.001), and women with increased adiposity (HR 0.64–0.68; all P ≤ 0.01). In fully adjusted models, the changes in the R2 statistic were 13.4%, 11.6%, and 15.3% for the SMM/ht2 (aSMM/ht2), residual, and SMM, but only 4.9% and 1.3% for SMM/bm × 100 and aSMM/BMI.
Conclusions
Muscle mass measures adjusted for height only (SMM/ht2, aSMM/ht2) appear to be better muscle‐relevant risk factors for incident osteoporosis in postmenopausal women, including when stratified into lean participants and participants with increased adiposity.

Papageorgiou, M., Sathyapalan, T., and Schutte, R. (2018) Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women. Journal of Cachexia, Sarcopenia and Muscle, 10: 131– 139 https://doi.org/10.1002/jcsm.12359.

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     Article first published online:  24 January 2019

Fabrizio Pin, Rafael Barreto, Marion E. Couch, Andrea Bonetto, Thomas M. O'Connell

Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism
Background
Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer‐induced and chemotherapy‐induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments.
Methods
The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer‐induced cachexia. In vivo administration of Folfiri (5‐fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy‐induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance‐based and mass spectrometry‐based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling.
Results
The study involved four groups of CD2F1 male mice (n = 4–5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (−3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (−38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (−47% in CC vs. V; P < 0.001) and depletion of liver glucose (−51% in CC vs. V; P < 0.001) and glycogen (−74% in CC vs. V; P < 0.001). The cancer‐induced and chemotherapy‐induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β‐oxidation pathways. Cancer‐induced cachexia was uniquely characterized by a dramatic elevation in low‐density lipoprotein particles (+6.9‐fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001).
Conclusions
The results of this study demonstrated for the first time that cancer‐induced and chemotherapy‐induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer‐induced and chemotherapy‐induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.

Pin, F., Barreto, R., Couch, M. E., Bonetto, A., and O'Connell, T. M. (2018) Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism. Journal of Cachexia, Sarcopenia and Muscle, 10: 140– 154 https://doi.org/10.1002/jcsm.12360.

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     Article first published online:  30 November 2018

Junting Liu. Yinkun Yan, Bo Xi, Guimin Huang, Jie Mi on behalf of China Child and Adolescent Cardiovascular Health (CCACH) Study Group

Skeletal muscle reference for Chinese children and adolescents
Background
Skeletal muscle as an essential body composition component plays an important role in maintenance of normal growth and development as well as systemic glucose metabolism in children. No nationwide reference data for skeletal muscle mass for Chinese youths are available in China. We aimed to establish the sex-specific and age-specific percentile reference values of skeletal muscle mass for Chinese children and adolescents.
Methods
This study consisted of 10 818 children and adolescents aged 3–17 years in Chinese urban area during 2013–15. Dual-energy X-ray absorptiometry scan was performed to measure whole body muscle mass and appendicular skeletal muscle mass. Lambda-mu-sigma method was used to obtain the sex-specific and age-specific percentile curves of muscle mass indices.
Results
Overall, whole body muscle mass and appendicular skeletal muscle mass indices showed an increasing trend with age for both sexes, with boys vs. girls having higher values of all muscle mass indices. Whole body muscle mass index in boys increased slightly before age 9 years and then increased rapidly until 15 years and slowed down thereafter, while the mean values in girls increased slightly before age 8 years, increased rapidly until 14 years and remained stable thereafter. Appendicular skeletal muscle mass index increased rapidly until age 16 years and then increased slightly for boys; by contrast, for girls, the mean values increased consistently before age 14 years but showed a slightly decreasing trend after that.
Conclusions
This study established sex-specific and age-specific percentile reference values for skeletal muscle mass for Chinese children and adolescents aged 3–17 years. These reference values can be used to evaluate the muscular development in Chinese children and adolescents.

Liu, J., Yan, Y., Xi, B., Huang, G., Mi, J., and on behalf of China Child and Adolescent Cardiovascular Health (CCACH) Study Group (2018) Skeletal muscle reference for Chinese children and adolescents. Journal of Cachexia, Sarcopenia and Muscle, 10: 155– 164 https://doi.org/10.1002/jcsm.12361.

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     Article first published online:  31 October 2018

Huang‐Jen Chen, Ching‐Chia Wang, Ding‐Cheng Chan, Chen‐Yuan Chiu, Rong‐Sen Yang, Shing‐Hwa Liu

Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass
Background
Acrolein is an extremely electrophilic aldehyde. Increased urinary acrolein adducts have been found in type 2 diabetic patients and people with a smoking habit. The increased blood acrolein was shown in patients who received the cancer drug cyclophosphamide. Both diabetes and smoking are risk factors for skeletal muscle wasting or atrophy. Acrolein has been found to induce myotube atrophy in vitro. The in vitro and in vivo effects and mechanisms of acrolein on myogenesis and the in vivo effect of acrolein on muscle wasting still remain unclear.
Methods
C2C12 myoblasts were used to assess the effects of low‐dose acrolein (0.125–1 μM) on myogenesis in vitro. Mice were exposed daily to acrolein in distilled water by oral administration (2.5 and 5 mg/kg) for 4 weeks with or without glycerol‐induced muscle injury to investigate the effects of acrolein on muscle wasting and regeneration.
Results
Non‐cytotoxic‐concentration acrolein dose dependently inhibited myogenic differentiation in myoblasts (myotube formation inhibition: 0.5 and 1 μM, 66.25% and 46.25% control, respectively, n = 4, P < 0.05). The protein expression for myogenesis‐related signalling molecules (myogenin and phosphorylated Akt: 0.5 and 1 μM, 85.15% and 51.52% control and 62.63% and 56.57% control, respectively, n = 4, P < 0.05) and myosin heavy chain (MHC: 0.5 and 1 μM, 63.64% and 52.53% control, n = 4, P < 0.05) were decreased in acrolein‐treated myoblasts. Over‐expression of the constitutively active form of Akt in myoblasts during differentiation prevented the inhibitory effects of acrolein (1 μM) on myogenesis (MHC and myogenin protein expression: acrolein with or without constitutively active Akt, 64.65% and 105.21% control and 69.14% and 102.02% control, respectively, n = 5, P < 0.05). Oral administration of acrolein for 4 weeks reduced muscle weights (5 mg/kg/day: 65.52% control, n = 6, P < 0.05) and cross‐sectional area of myofibers in soleus muscles (5 mg/kg/day: 79.92% control, n = 6, P < 0.05) with an up‐regulation of atrogin‐1 and a down‐regulation of phosphorylated Akt protein expressions. Acrolein retarded soleus muscle regeneration in a glycerol‐induced muscle regeneration mouse model (5 mg/kg/day: 49.29% control, n = 4, P < 0.05). Acrolein exposure reduced muscle endurance during rotarod fatigue performance in mice with or without glycerol‐induced muscle injury (5 mg/kg/day without glycerol: 30.43% control, n = 4, P < 0.05). Accumulation of acrolein protein adducts could be detected in the soleus muscles of acrolein‐treated mice.
Conclusions
Low‐dose acrolein significantly inhibited myogenic differentiation in vitro, which might be through inhibition of Akt signalling. Acrolein induced muscle wasting and retarded muscle regeneration in mice. These results suggest that acrolein may be a risk factor for myogenesis and disease‐related myopathy.

Chen, H.‐J., Wang, C.‐C., Chan, D.‐C., Chiu, C.‐Y., Yang, R.‐S., and Liu, S.‐H. (2018) Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass. Journal of Cachexia, Sarcopenia and Muscle, 10: 165– 176 https://doi.org/10.1002/jcsm.12362.

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     Article first published online:  22 November 2018

William A. Cuellar, Leigh Blizzard, Julie A. Hides, Michele L. Callisaya, Graeme Jones, Flavia Cicuttini, Anita E. Wluka, Changhai Ding, Tania M. Winzenberg

Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial
Background
The effect of vitamin D supplementation on postural muscles of the trunk is of particular interest because low 25-hydroxyvitamin D [25(OH) D] levels are associated with decreased postural balance and increased risk of falls. Understanding the role of vitamin D supplementation plays in trunk muscle function of older adults is necessary, as this is a potentially modifiable factor to improve postural muscle function and decrease the risk of falling of older adults. The objective of this randomized controlled trial was to evaluate the effect of 12 months of vitamin D supplementation compared with placebo, on morphology and function of the trunk muscles of adults aged 50 to 79 years with low serum 25(OH) D levels.
Methods
This was a secondary analysis of a randomized, placebo-controlled, and double-blind clinical trial conducted between June 2010 and December 2013 in Tasmania, Australia. The clinical trial was registered with the Australian New Zealand clinical trial registration agency, ClinicalTrials.gov identifier: NCT01176344; Australian New Zealand Clinical Trials Registry: ACTRN 12610000495022. Participants were aged 50–79 years with ongoing symptoms of knee osteoarthritis and with low serum [25(OH) D] (12.5 to 60 nmol/L, 5.2 to 24 ng/mL). Participants were randomly assigned to either monthly 50 000 IU oral vitamin D3 (n = 104) or an identical placebo (n = 113) for 24 months as per clinical trial protocol. The primary outcomes in this pre-specified secondary analysis were between-group differences in change in size of rectus abdominis, transversus abdominis, internal oblique, external oblique, and lumbar multifidus muscles and function (assessed by change in thickness on contraction) of these muscles (excepting rectus abdominis) from baseline to 12 months. Muscle size was assessed using ultrasound imaging.
Results
Of 217 participants (mean age 63 years, 48% women), 186 (85.7%) completed the study. There were no significant between-group differences in change in size or function of the abdominal or multifidus muscles after 12 months of vitamin D supplementation.
Conclusions
A monthly dose of 50 000 IU of vitamin D3 alone for 12 months does not affect the size or ability to contract trunk muscles of independent community-dwelling older adults with symptomatic knee osteoarthritis and low serum 25(OH) D levels regardless of body mass index status or degree of vitamin D deficiency. An effect of vitamin D supplementation on other aspects of trunk muscle function such as strength, power, or physical function cannot be ruled out.

Cuellar, W. A., Blizzard, L., Hides, J. A., Callisaya, M. L., Jones, G., Cicuttini, F., Wluka, A. E., Ding, C., and Winzenberg, T. M. (2018) Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial. Journal of Cachexia, Sarcopenia and Muscle, 10: 177– 187 https://doi.org/10.1002/jcsm.12364.

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     Article first published online:  28 March 2019

Juan Luis Sánchez‐Sánchez, Asier Mañas, Francisco José García‐García, Ignacio Ara, Jose Antonio Carnicero, Stefan Walter, Leocadio Rodríguez‐Mañas

Sedentary behaviour, physical activity, and sarcopenia among older adults in the TSHA: isotemporal substitution model
Background
The associations between free‐living physical activity (PA) and sedentary behaviour (SB) and sarcopenia in older people and its determinants are controversial. Self‐reporting, the use of one‐size‐fits‐all cut‐points for intensity categorization when using accelerometers and the absence of a clear sarcopenia definition hampered explorations. The aim of this study is to describe the associations between objectively measured PA patterns and sarcopenia and its determinants.
Methods
Subjects aged >65 with valid accelerometry and sarcopenia‐related measures from Toledo Study of Healthy Aging (TSHA) were included. Muscle mass (MM) was estimated by dual‐energy X‐ray absorptiometry. Handgrip strength (HS) was measured by dynamometry. Physical performance assessment relied on gait speed (GS). Sarcopenia presence was ascertained using Foundation for the National Institutes of Health (FNIH) criteria. PA and SB were estimated by ActiTrainer worn for 1 week and classified into time spent in SB and different PA intensity bands [light PA (LPA) and moderate‐to‐vigorous PA (MVPA)] using age‐specific cut‐points. Different multivariate linear and logistic regression models [(i) single‐parameter, (ii) partition, and (iii) isotemporal substitution models] were used for estimating associations between PA, SB, and sarcopenia determinants and sarcopenia rates, respectively. All models adjusted for age, sex, co‐morbidities (Charlson index), and functional ability (Katz and Lawton indexes).
Results
Five hundred twelve subjects from the TSHA had available data (78.08 ± 5.71 years of age; 54.3% women). FNIH sarcopenia assessment was performed in 497 subjects (23.3% were sarcopenic). In the linear regression, the single‐parameter model showed an association between MVPA and all sarcopenia determinants. In the partition model, MVPA was associated with greater MM and GS. The isotemporal substitution showed that reallocating 1 h/day of MVPA displacing SB was associated with greater values in MM [β = 0.014; 95% confidence interval (CI) = 0.004, 0.024; P < 0.01], GS (β = 0.082; 95% CI = 0.054, 0.110; P < 0.001), and HS (β = 0.888; 95% CI = 0.145, 1.631; P < 0.05). In the logistic regression, the single‐parameter model yielded a significant association between 1 h/day increase in MVPA and sarcopenia reduction [odds ratio (OR) = 0.522; 95% CI = 0.367, 0.726; P < 0.001], as did the partition model (OR = 0.555; 95% CI = 0.376, 0.799; P < 0.01). The reallocation of 1 h/day SB only yielded a significant lower sarcopenia risk by almost 50% when it was substituted with MVPA, whereas the substitution of 15 min/day yielded a significant lower sarcopenia risk by 15% (P < 0.001) but did not show any association when it was substituted with LPA.
Conclusions
An increase in MVPA replacing SB and LPA was associated with a reduction in sarcopenia prevalence and better performance across its determinants (MM, GS, and HS). LPA did not show any significant effect.

Sánchez‐Sánchez, J. L., Mañas, A., García‐García, F. J., Ara, I., Carnicero, J. A., Walter, S., and Rodríguez‐Mañas, L. ( 2019) Sedentary behaviour, physical activity, and sarcopenia among older adults in the TSHA: isotemporal substitution model. Journal of Cachexia, Sarcopenia and Muscle, 10: 188– 198. https://doi.org/10.1002/jcsm.12369.

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     Article first published online:  21 January 2019

Willemieke P.M. Dijksterhuis, Maarten J. Pruijt, Stephanie O. van der Woude, Remy Klaassen, Sophie A. Kurk, Martijn G.H. van Oijen, Hanneke W.M. van Laarhoven

Association between body composition, survival, and toxicity in advanced esophagogastric cancer patients receiving palliative chemotherapy
Background
Palliative systemic treatment in patients with advanced or metastatic esophagogastric cancer may result in improved overall survival and quality of life but can also lead to considerable toxicity. In various cancer types, severe muscle mass depletion (sarcopenia) and poor muscle strength are associated with decreased survival and increased chemotherapy-related toxicity. The aim of this study is to determine the impact of body composition on survival and chemotherapy toxicity in esophagogastric cancer patients treated with first-line palliative chemotherapy.
Methods
A total of 88 patients with advanced esophagogastric cancer treated with standard first-line palliative systemic therapy consisting of capecitabine and oxaliplatin (CapOx) between January 2010 and February 2017 were included. Skeletal muscle index (SMI), reflecting muscle mass, and skeletal muscle density (SMD), associated with muscle strength, were measured using pre-treatment of all patients and evaluation computed tomography scans after three treatment cycles of 65 patients and were used to determine sarcopenia and sarcopenic obesity (i.e. sarcopenia and body mass index >25 kg/m2). The associations between body composition (SMI, SMD, sarcopenia, and sarcopenic obesity) and survival and toxicity were assessed using univariable and multivariable Cox and logistic regression analyses, respectively.
Results
Of 88 patients, 75% was male, and median age was 63 (interquartile range 56–69) years. The majority of patients had an adenocarcinoma (83%). Before start of treatment, 49% of the patients were sarcopenic, and 20% had sarcopenic obesity. Low SMD was observed in 50% of patients. During three cycles CapOx, SMI significantly decreased, with a median decrease of 4% (interquartile range -8.6–-0.4). Median progression-free and overall survival were 6.9 and 10.1 months. SMI, SMD, sarcopenia, and sarcopenic obesity (both pre-treatment and after three cycles) were neither associated with progression-free nor overall survival. Pre-treatment SMD was independently associated with grade 3–4 toxicity (odds ratio 0.94; 95% confidence interval 0.89–1.00) and sarcopenic obesity with grade 2–4 neuropathy (odds ratio 3.82; 95% confidence interval 1.20–12.18).
Conclusions
Sarcopenia was not associated with survival or treatment-related toxicity in advanced esophagogastric cancer patients treated with CapOx. Pre-treatment sarcopenic obesity was independently associated with the occurrence of grade 2–4 neurotoxicity and skeletal muscle density with grade 3–4 toxicity.

Dijksterhuis, W. P. M., Pruijt, M. J., van der Woude, S. O., Klaassen, R., Kurk, S. A., van Oijen, M. G. H., and van Laarhoven, H. W. M. (2019) Association between body composition, survival, and toxicity in advanced esophagogastric cancer patients receiving palliative chemotherapy. Journal of Cachexia, Sarcopenia and Muscle, 10: 199– 206. https://doi.org/10.1002/jcsm.12371.

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     Article first published online:  28 March 2019

MT. Cederholm, G.L. Jensen, M.I.T.D. Correia, M.C. Gonzalez, R. Fukushima, T. Higashiguchi, G. Baptista, R. Barazzoni, R. Blaauw, A.J.S. Coats, A.N. Crivelli, D.C. Evans, L. Gramlich, V. Fuchs‐Tarlovsky, H. Keller, L. Llido, A. Malone, K.M. Mogensen, J.E. Morley, M. Muscaritoli, I. Nyulasi, M. Pirlich, V. Pisprasert, M.A.E. de van der Schueren, S. Siltharm, P. Singer, K. Tappenden, N. Velasco, D. Waitzberg, P. Yamwong, J. Yu, A. Van Gossum, C. Compher, GLIM Core Leadership Committee, GLIM Working Group

GLIM criteria for the diagnosis of malnutrition – A consensus report from the global clinical nutrition community
Rationale
This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.
Methods
In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face‐to‐face meetings, telephone conferences, and e‐mail communications.
Results
A two‐step approach for the malnutrition diagnosis was selected, i.e., first screening to identify “at risk” status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology‐related diagnosis categories.
Conclusion
A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re‐considered every 3–5 years.

Cederholm, T., Jensen, G. L., Correia, M. I. T. D., Gonzalez, M. C., Fukushima, R., Higashiguchi, T., Baptista, G., Barazzoni, R., Blaauw, R., Coats, A. J. S., Crivelli, A. N., Evans, D. C., Gramlich, L., Fuchs‐Tarlovsky, V., Keller, H., Llido, L., Malone, A., Mogensen, K. M., Morley, J. E., Muscaritoli, M., Nyulasi, I., Pirlich, M., Pisprasert, V., Schueren, M. A. E., Siltharm, S., Singer, P., Tappenden, K., Velasco, N., Waitzberg, D., Yamwong, P., Yu, J., Van Gossum, A., Compher, C., and GLIM Core Leadership Committee, GLIM Working Group ( 2019) GLIM criteria for the diagnosis of malnutrition – A consensus report from the global clinical nutrition community. Journal of Cachexia, Sarcopenia and Muscle, 10: 207– 217. https://doi.org/10.1002/jcsm.12383.

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     Article first published online:  28 March 2019

Nicole Ebner, Stefan D. Anker, Stephan von Haehling

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference
This article highlights the updates from preclinical and clinical studies into the field of wasting disorders that were presented at the 11th Cachexia Conference held in Maastricht, the Netherlands, in December 2018. Herein, we summarize the biological and clinical significance of different markers and new diagnostic tools and cut‐offs for the detection of skeletal muscle wasting, including micro‐RNAs, siRNAs, epigenetic targets, the ubiquitin–proteasome system, mammalian target of rapamycin signalling, news in body composition analysis including the D3‐creatine dilution method, and electrocardiography that was modified to enable segmental impedance spectroscopy. Of particular interest were the beneficial effects of BIO101 on muscle cell differentiation, hypertrophy of myofibers associated with mammalian target of rapamycin pathways activation, and the effect of metal ion transporter ZIP14 loss that reduces cancer‐induced cachexia. The potential of anti‐ZIP14 antibodies and zinc chelation as anti‐cachexia therapy should be tested in patients with cancer cachexia. Big randomized studies were presented such as RePOWER (observational study of patients with primary mitochondrial myopathy), STRAMBO (influence of physical performance assessed as score and clinical testing), MMPOWER (treatment of elamipretide in subjects with primary mitochondrial myopathy), FORCE (examined differences in relative dose intensity and moderate and severe chemotherapy‐associated toxicities between a strength training intervention and a control group), and SPRINTT (effectiveness of exercise training in healthy aging). Effective treatments were urothelin A, rapamycin analogue treatment, epigenetic factor BRD 4 and epigenetic protein BET, and the gut pathobiont Klebsiella oxytoca. Clinical studies that investigated novel approaches, including urolithin A, the role of gut microbiota, metal ion transporter ZIP14, lysophosphatidylcholine and lysophosphatidylethanolamine, and BIO101, were described. It remains a fact, however, that effective treatments of cachexia and wasting disorders are urgently needed in order to improve patients' quality of life and their survival.

Ebner, N., Anker, S. D., and Haehling, S. ( 2019) Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference. Journal of Cachexia, Sarcopenia and Muscle, 10: 218– 225. https://doi.org/10.1002/jcsm.12408.

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     Article first published online:  28 March 2019

Nicole Ebner, Stefan D. Anker, Stephan von Haehling

Abstracts of the 11th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Maastricht, The Netherlands, 7–9 December 2018 (Part 2)


Ebner, N., Anker, S. D., and Haehling, S. ( 2019) Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference. Journal of Cachexia, Sarcopenia and Muscle, 10: 218– 225. https://doi.org/10.1002/jcsm.12408.

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