Online First Article

Volume 6

Number 1 / March 2015

     Page 1

Stephan von Haehling, Stefan D. Anker

 
 
von Haehling, S., and Anker, S. D. (2015), More colour to the Journal: new style, new publisher, but still Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle, 6, 1.

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     Page 2 - 31

 
 
(2015), Abstracts of the 2nd Cancer Cachexia Conference, Montreal, Canada, 26–28 September 2014. J Cachexia Sarcopenia Muscle, 6, 2–31.

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     Page 32 - 44

Joyce Faber, Madeleen .J. Uitdehaag, Manon Spaander, Sabine van Steenbergen-Langeveld, Paul Vos, Marloes Berkhout, Cor Lamers, Hans Rümke, Hugo Tilanus, Peter Siersema, Ardy van Helvoort, Ate van der Gaast

Improved body weight and performance status and reduced serum PGE2 levels after nutritional intervention with a specific medical food in newly diagnosed patients with esophageal cancer or adenocarcinoma of the gastro-esophageal junctionBackground
The majority of cancer patients loses weight and becomes malnourished during the course of their disease. Metabolic alterations and reduced immune competence lead to wasting and an increased risk of infectious complications. In the present study, the effect of a nutritionally complete medical food, which is high in protein and leucine and enriched with fish oil and specific oligosaccharides, was investigated on immune function, nutritional status, and inflammation in patients with esophageal cancer and compared with routine care.
Methods
In this exploratory double-blind study, 64 newly diagnosed esophageal cancer patients were randomized. All patients received dietary counselling and dietary advice. In the Active group, all patients received the specific medical food for 4 weeks before the start of anticancer therapy. In the routine care control arm, patients with <5% weight loss received a non-caloric placebo product, and patients with weight loss ≥5% received an iso-caloric control product to secure blinding of the study. The required study parameters of body weight and performance status were recorded at baseline and after 4 weeks of nutritional intervention, and patients were asked to complete quality of life questionnaires. In addition, blood samples were taken for the measurement of several immune, nutritional, and safety-parameters.
Results
No effect of the specific nutritional intervention could be detected on ex vivo stimulations of blood mononuclear cells. By contrast, body weight was significantly increased (P < 0.05) and ECOG performance status was improved after intervention with the specific medical food (P < 0.05). In addition, serum Prostaglandin E2 (PGE2) levels were significantly decreased in the specific medical food group and increased in the control group (P = 0.002).
Conclusions
Nutritional intervention with the specific medical food significantly increased body weight and improved performance status compared with routine care in newly diagnosed esophageal cancer patients. This effect was accompanied by significantly reduced serum PGE2 levels.

 

 

Faber, J., Uitdehaag, M. J., Spaander, M., vanSteenbergen-Langeveld, S., Vos, P., Berkhout, M., Lamers, C., Rümke, H., Tilanus, H., Siersema, P., vanHelvoort, A., and van derGaast, A. (2015), Improved body weight and performance status and reduced serum PGE2 levels after nutritional intervention with a specific medical food in newly diagnosed patients with esophageal cancer or adenocarcinoma of the gastro-esophageal junction. J Cachexia Sarcopenia Muscle, 6, 32–44.

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     Page 45 - 52

Joyce Faber, Madeleen .J. Uitdehaag, Manon Spaander, Sabine van Steenbergen-Langeveld, Paul Vos, Marloes Berkhout, Cor Lamers, Hans Rümke, Hugo Tilanus, Peter Siersema, Ardy van Helvoort, Ate van der Gaast

Influence of cancer cachexia on drug liver metabolism and renal elimination in ratsBackground
Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats.
Methods
Nine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5—D5), and when rats were severely cachectic (Day 10—D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters.
Results
All three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (−80.5%, −79.8%, and −72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019).
Conclusions
Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events.

 

Cvan Trobec, K., Kerec Kos, M., Trontelj, J., Grabnar, I., Tschirner, A., Palus, S., Anker, S. D., Springer, J., and Lainscak, M. (2015), Influence of cancer cachexia on drug liver metabolism and renal elimination in rats. J Cachexia Sarcopenia Muscle, 6, 45–52.

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     Page 53 - 61

Nathan A. Stephens, Richard J. E. Skipworth, Iain J. Gallagher, Carolyn A. Greig, Denis C. Guttridge, James A. Ross, Kenneth C. H. Fearon

Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patientsBackground
In order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.
Methods
One hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time–polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n  = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581–1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively.
Results
Cancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P  = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008).
Conclusions
The present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.
 
 
Stephens, N. A., Skipworth, R. J. E., Gallagher, I. J., Greig, C. A., Guttridge, D. C., Ross, J. A., and Fearon, K. C. H. (2015), Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients. J Cachexia Sarcopenia Muscle, 6, 53–61.

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     Page 62 - 72

Yae Matsuo1, Konstanze Gleitsmann, Norman Mangner, Sarah Werner, Tina Fischer, T Scott Bowen, Angela Kricke, Yasuharu Matsumoto, Masahiko Kurabayashi, Gerhard Schuler, Axel Linke, Volker Adams

Fibronectin type III domain containing 5 expression in skeletal muscle in chronic heart failure—relevance of inflammatory cytokinesBackground
Chronic heart failure (CHF) is commonly associated with muscle atrophy and increased inflammation. Irisin, a myokine proteolytically processed by the fibronectin type III domain containing 5 (FNDC5) gene and suggested to be Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α activated, modulates the browning of adipocytes and is related to muscle mass. Therefore, we investigated whether skeletal muscle FNDC5 expression in CHF was reduced and if this was mediated by inflammatory cytokines and/or angiotensin II (Ang-II).
Methods
Skeletal muscle FNDC5 mRNA/protein and PGC-1α mRNA expression (arbitrary units) were analysed in: (i) rats with ischemic cardiomyopathy; (ii) mice injected with tumour necrosis factor-α (TNF-α) (24 h); (iii) mice infused with Ang-II (4 weeks); and (iv) C2C12 myotubes exposed to recombinant cytokines or Ang-II. Circulating TNF-α, Ang-II, and irisin was measured by ELISA.
Results
Ischemic cardiomyopathy reduced significantly FNDC5 protein (1.3 ± 0.2 vs. 0.5 ± 0.1) and PGC-1α mRNA expression (8.2 ± 1.5 vs. 4.7 ± 0.7). In vivo TNF-α and Ang-II reduced FNDC5 protein expression by 28% and 45%, respectively. Incubation of myotubes with TNF-α, interleukin-1ß, or TNF-α/interleukin-1ß reduced FNDC5 protein expression by 47%, 37%, or 57%, respectively, whereas Ang-II had no effect. PGC-1α was linearly correlated to FNDC5 in all conditions. In CHF, animals circulating TNF-α and Ang-II were significantly increased, whereas irisin was significantly reduced. A negative correlation between circulating TNF-α and irisin was evident.
Conclusion
A reduced expression of skeletal muscle FNDC5 in ischemic cardiomyopathy is likely modulated by inflammatory cytokines and/or Ang-II via the down-regulation of PGC-1α. This may act as a protective mechanism either by slowing the browning of adipocytes and preserving energy homeostasis or by regulating muscle atrophy.
 

Matsuo, Y., Gleitsmann, K., Mangner, N., Werner, S., Fischer, T., Bowen, T. S., Kricke, A., Matsumoto, Y., Kurabayashi, M., Schuler, G., Linke, A., and Adams, V. (2015), Fibronectin type III domain containing 5 expression in skeletal muscle in chronic heart failure—relevance of inflammatory cytokines. J Cachexia Sarcopenia Muscle, 6, 62–72.

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     Page 73 - 83

Lamia Slimani, Emilie Vazeille, Christiane Deval, Bruno Meunier, Cécile Polge, Dominique Dardevet, Daniel Béchet, Daniel Taillandier, Didier Micol, Anne Listrat, Didier Attaix Lydie Combaret

The delayed recovery of the remobilized rat tibialis anterior muscle reflects a defect in proliferative and terminal differentiation that impairs early regenerative processesBackground
The immobilization-induced tibialis anterior (TA) muscle atrophy worsens after cast removal and is associated with altered extracellular matrix (ECM) composition. The secreted protein acidic and rich in cysteine (Sparc) is an ECM component involved in Akt activation and in β-catenin stabilization, which controls protein turnover and induces muscle regulatory factors (MRFs), respectively. We hypothesized that ECM alterations may influence these intracellular signalling pathways controlling TA muscle mass.
Methods
Six-month-old Wistar rats were subjected to hindlimb cast immobilization for 8 days (I8) or not (I0) and allowed to recover for 1 to 10 days (R1–10).
Results
The TA atrophy during remobilization correlated with reduced fibre cross-sectional area and thickening of endomysium. mRNA levels for Sparc increased during remobilization until R10 and for integrin-α7 and -β1 at I8 and R1. Integrin-linked kinase protein levels increased during immobilization and remobilization until R10. This was inversely correlated with changes in Akt phosphorylation. β-Catenin protein levels increased in the remobilized TA at R1 and R10. mRNA levels of the proliferative MRFs (Myf5 and MyoD) increased at I8 and R1, respectively, without changes in Myf5 protein levels. In contrast, myogenin mRNA levels (a terminal differentiation MRF) decreased at R1, but only increased at R10 in remobilized muscles, as for protein levels.
Conclusions
Altogether, this suggests that the TA inefficiently attempted to preserve regeneration during immobilization by increasing transcription of proliferative MRFs, and that the TA could engage recovery during remobilization only when the terminal differentiation step of regeneration is enhanced
 
 
 
Slimani, L., Vazeille, E., Deval, C., Meunier, B., Polge, C., Dardevet, D., Béchet, D., Taillandier, D., Micol, D., Listrat, A., Attaix, D., and Combaret, L. (2015), The delayed recovery of the remobilized rat tibialis anterior muscle reflects a defect in proliferative and terminal differentiation that impairs early regenerative processes. J Cachexia Sarcopenia Muscle, 6, 73–83.

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     Page 84 - 94

Jvalini T. Dwarkasing, Mark V. Boekschoten, Joseph M. Argilès, Miriam van Dijk, Silvia Busquets, Fabio Penna, Miriam Toledo, Alessandro Laviano, R. F. Witkamp, Klaske van Norren

Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling
Background
Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation.
Methods
Two tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips).
Results
In both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion.
Conclusions
Altered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a therapeutic target to prevent the development of cancer-induced eating disorders.

 

Dwarkasing, J. T., Boekschoten, M. V., Argilès, J. M., vanDijk, M., Busquets, S., Penna, F., Toledo, M., Laviano, A., Witkamp, R. F., and vanNorren, K. (2015), Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling. J Cachexia Sarcopenia Muscle, 6, 84–94.

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     Page 95 - 98

Rony Dev, David Hui, Gary Chisholm, Marvin Delgado-Guay, Shalini Dalal, Egidio Del Fabbro, Eduardo Bruera

Hypermetabolism and symptom burden in advanced cancer patients evaluated in a cachexia clinicBackground
Elevated resting energy expenditure (REE) may contribute to weight loss and symptom burden in cancer patients.
Aims
The aim of this study was to compare the velocity of weight loss, symptom burden (fatigue, insomnia, anxiety, and anorexia—combined score as measured by the Edmonton Symptom Assessment Score), high-sensitivity C-reactive protein, and survival among cancer patients referred to a cachexia clinic with hypermetabolism, elevated REE > 110% of predicted, with normal REE.
Methods
A retrospective analysis of 60 advanced cancer patients evaluated in a cachexia clinic for either >5% weight loss or anorexia who underwent indirect calorimetry to measure REE. Patients were dichotomized to either elevated or normal REE. Descriptive statistics were generated, and a two-sample Student's t-tests were used to compare the outcomes between the groups. Kaplan–Meier and Cox regression methodology were used to examine the survival times between groups.
Results
Thirty-seven patients (62%) were men, 41 (68%) were White, 59 (98%) solid tumours, predominantly 23 gastrointestinal cancers (38%), with a median age of 60 (95% confidence interval 57.0–62.9). Thirty-five patients (58%) were hypermetabolic. Non-Caucasian patients were more likely to have high REE [odds ratio = 6.17 (1.56, 24.8), P = 0.01]. No statistical difference regarding age, cancer type, gender, active treatment with chemotherapy, and/or radiation between hypermetabolic and normal REE was noted. The velocity of weight loss over a 3 month period (−8.5 kg vs. −7.2 kg, P = 0.68), C-reactive protein (37.3 vs. 55.6 mg/L, P = 0.70), symptom burden (4.2 vs. 4.5, P = 0.54), and survival (288 vs. 276 days, P = 0.68) was not significantly different between high vs. normal REE, respectively.
Conclusion
Hypermetabolism is common in cancer patients with weight loss and noted to be more frequent in non-Caucasian patients. No association among velocity of weight loss, symptom burden, C-reactive protein, and survival was noted in advanced cancer patients with elevated REE.
 
 
Dev, R., Hui, D., Chisholm, G., Delgado-Guay, M., Dalal, S., Del Fabbro, E., and Bruera, E. (2015), Hypermetabolism and symptom burden in advanced cancer patients evaluated in a cachexia clinic. J Cachexia Sarcopenia Muscle, 6, 95–98.

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     Page 99 - 111

Christine Cooper, Sorrel T. Burden, Huilin Cheng, Alex Molassiotis

Understanding and managing cancer-related weight loss and anorexia: insights from a systematic review of qualitative researchThe aim of this study was to summarize the existing qualitative literature in order to develop the evidence base for understanding and managing weight loss and anorexia, in order to make recommendations for clinical practice. A systematic search was performed to retrieve English language studies using electronic search and manual checks of selected reference lists. Keywords included qualitative, cancer cachexia, weight loss, anorexia, appetite, malnutrition, food, eating, and drinking. The selection and appraisal of papers were undertaken by two reviewers. Twenty-one qualitative articles were included in the review. There were three major findings emerging from the previous qualitative studies including ‘the multidimensionality of weight loss and anorexia experience’, ‘patients and caregivers' responses to coping with weight loss and anorexia’, and ‘clinical assessment and management of weight loss and anorexia’. The literature review revealed the multidimensional nature of cachexia and weight loss experience by patients and caregivers, which was not recognized and adequately managed by healthcare professionals. Future research in this area would be helpful in enabling a deeper understanding of the complexity of cachexia and weight loss experience in order to move forward to develop an optimal model of supportive care for patients and caregivers
 
 
Cooper, C., Burden, S. T., Cheng, H., and Molassiotis, A. (2015), Understanding and managing cancer-related weight loss and anorexia: insights from a systematic review of qualitative research. J Cachexia Sarcopenia Muscle, 6, 99–111.

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     Page 112 - 113

Britta Stemmler, Joseph M. Argilés

 


Stemmler, B., and Argilés, J. M. (2015), Open source in cachexia?. J Cachexia Sarcopenia Muscle, 6, 112–113.

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Number 2 / June 2015

      Page 115124

John P. Sasso,Neil D. Eves,Jesper F. Christensen,Graeme J. Koelwyn,Jessica Scott, Lee W. Jones

A framework for prescription in exercise-oncology researchThe field of exercise-oncology has increased dramatically over the past two decades, with close to 100 published studies investigating the efficacy of structured exercise training interventions in patients with cancer. Of interest, despite considerable differences in study population and primary study end point, the vast majority of studies have tested the efficacy of an exercise prescription that adhered to traditional guidelines consisting of either supervised or home-based endurance (aerobic) training or endurance training combined with resistance training, prescribed at a moderate intensity (50–75% of a predetermined physiological parameter, typically age-predicted heart rate maximum or reserve), for two to three sessions per week, for 10 to 60 min per exercise session, for 12 to 15 weeks. The use of generic exercise prescriptions may, however, be masking the full therapeutic potential of exercise treatment in the oncology setting. Against this background, this opinion paper provides an overview of the fundamental tenets of human exercise physiology known as the principles of training, with specific application of these principles in the design and conduct of clinical trials in exercise-oncology research. We contend that the application of these guidelines will ensure continued progress in the field while optimizing the safety and efficacy of exercise treatment following a cancer diagnosis.
 
 
Sasso, J. P., Eves, N. D., Christensen, J. F., Koelwyn, G. J., Scott, J., and Jones, L. W. (2015), A framework for prescription in exercise-oncology research. Journal of Cachexia, Sarcopenia and Muscle, 6, 115124.

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      Page 125 - 131

Sitaramachandra M. Nyasavajjala, Beth E. Phillips, Jon N. Lund, John P. Williams

Creatinine and myoglobin are poor predictors of anaerobic threshold in colorectal cancer and health
Aims

Myoglobin is a haem protein produced in skeletal muscles. Serum concentrations of myoglobin have been proposed as a surrogate marker of muscle mass and function in both cachectic cancer patients and healthy non-cancer individuals. Creatinine, a metabolite of creatine phosphate, an energy store found in skeletal muscle, is produced at a constant rate from skeletal muscle. Urinary and plasma creatinine have been used in clinical practice as indicators of skeletal muscle mass in health and disease. Our study aimed to test the hypothesis that plasma myoglobin and creatinine concentration could accurately predict skeletal muscle mass and aerobic capacity in colorectal cancer (CRC) patients and matched healthy controls and thereby an indicative of aerobic performance.

Methods

We recruited 47 patients with CRC and matching number of healthy volunteers for this study. All participants had their body composition measured by dual-energy X-ray absorptiometry scan, aerobic capacity measured to anaerobic threshold (AT) by cardiopulmonary exercise testing and filled in objective questionnaires to assess the qualitative functions. This study was carried out in accordance with the Declaration of Helsinki, after approval by the local National Health Service (NHS) Research Ethics Committee.

Results

Age-matched groups had similar serum myoglobin and creatinine concentrations in spite of differences in their aerobic capacity. AT was significantly lower in the CRC group compared with matched controls (1.18 ± 0.44 vs. 1.41 ± 0.71 L/min; P < 0.01). AT had significant correlation with lean muscle mass (LMM) among these groups, but myoglobin and creatinine had poor correlation with LMM and AT.

Conclusions

Serum myoglobin is a poor predictor of muscle mass, and serum myoglobin and creatinine concentrations do not predict aerobic performance in CRC patients or healthy matched controls.

 

Nyasavajjala, S. M., Phillips, B. E., Lund, J. N., Williams, J. P. (2015), Creatinine and myoglobin are poor predictors of anaerobic threshold in colorectal cancer and health. Journal of Cachexia, Sarcopenia and Muscle, 6, 125131

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      Page 132143

Ji-an Chen, Andres Splenser, Bobby Guillory, Jiaohua Luo, Meenal Mendiratta, Blaga Belinova, Tripti Halder, Guohua Zhang, Yi-Ping Li, Jose M. Garcia

Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved
Background

A higher serum phosphate level is associated with worse outcome. Energy-demanding intracellular transport of phosphate is needed to secure anion bioavailability. In heart failure (HF), energy starvation may modify intracellular and serum levels of phosphate. We analysed determinants of serum phosphates in HF and assessed if catabolic/anabolic balance (CAB) was associated with elevation of serum phosphate.

Methods

We retrospectively reviewed data from 1029 stable patients with HF and have calculated negative (loss) and positive (gain) components of weight change from the onset of HF till index date. The algebraic sum of these components was taken as CAB. The univariate and multivariable predictors of serum phosphorus were calculated. In quintiles of CAB, we have estimated odds ratios for serum phosphorus above levels previously identified to increase risk of mortality. As a reference, we have selected a CAB quintile with similar loss and gain.

Results

Apart from sex, age, and kidney function, we identified serum sodium, N-terminal fragment of pro-brain-type natriuretic peptide, and CAB as independent predictors of serum phosphorus. The odds for serum phosphorus above thresholds found in literature to increase risk were highest in more catabolic patients. In most catabolic quintile relative to neutral balance, the odds across selected phosphorus thresholds rose, gradually peaking at 1.30 mmol/L with a value of 3.29 (95% confidence interval: 2.00–5.40, P < 0.0001) in an unadjusted analysis and 2.55 (95% confidence interval: 1.38–2.72, P = 0.002) in a fully adjusted model.

Conclusions

Metabolic status is an independent determinant of serum phosphorus in HF. Higher catabolism is associated with serum phosphorus above mortality risk-increasing thresholds.
 
 
Chen, J.-a., Splenser, A., Guillory, B., Luo, J., Mendiratta, M., Belinova, B., Halder, T., Zhang, G., Li, Y.-P., and Garcia, J. M. (2015), Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved. Journal of Cachexia Sarcopenia Muscle, 6, 132143.

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       Page 144154

Charlotte Dupuy, Valérie Lauwers-Cances, Sophie Guyonnet, Catherine Gentil, Gabor Abellan Van Kan, Olivier Beauchet, Anne-Marie Schott, Bruno Vellas, Yves Rolland

Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS study
Background

The diversity of definitions proposed for sarcopenia has been rarely tested in the same population, and so far, their clinical utilities for predicting physical difficulties could not be clearly understood. Our objective is to report the prevalence of sarcopenia and the characteristics of sarcopenic community-dwelling older women according to the different definitions of sarcopenia currently proposed. We also assessed these definitions for their incremental predictive value over currently standard predictors for some self-reported difficulties in physical function and knee extension strength.

Methods

Cross-sectional analysis included data from 3025 non-disabled women aged 75 years or older without previous history of hip fracture from the inclusion visit of the EPIDémiologie de l'OStéoporose study. A total body composition evaluation was available for 2725 women. Sarcopenia was defined using six different definitions of sarcopenia based on different muscle mass, gait speed, and grip strength cut-offs. Self-reported difficulties in physical function and knee extension strength were collected. Logistic regression and multiple linear regression models were built for each physical dysfunction, and the predictive capacity of sarcopenia (one model for each definition) was studied using the C-statistic, the net reclassification index, or adjusted R2.

Results

The estimated prevalence of sarcopenia ranged from 3.3–20.0%. Only 85 participants (3.1%) were identified having sarcopenia according to all definitions. All definitions were, to some degree, associated with self-reported difficulties in physical function and knee extension strength, but none improved the predictive ability of the self-reported difficulties in physical function. Conversely, all definitions accounted for a small but significant amount of explained variation for predicting knee extension strength.

Conclusions

Prevalence of sarcopenia varies widely depending on the definition adopted. Based on this research, the current definitions for sarcopenia does not substantially increment the predictive value of clinical characteristics of patients to predict self-reported physical difficulties and knee extension strength.

 

Dupuy, C., Lauwers-Cances, V., Guyonnet, S., Gentil, C., Abellan Van Kan, G., Beauchet, O., Schott, A.-M., Vellas, B., and Rolland, Y. (2015), Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS study. Journal Cachexia Sarcopenia Muscle, 6, 144154.

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       Page 155163

Toine M. Lodewick, Anjali A.J. Roeth, Steven W.M. Olde Damink, Patrick H. Alizai, Ronald M. van Dam, Nikolaus Gassler, Mark Schneider, Simon A.W.G. Dello, Maximilian Schmeding, Cornelis H.C. Dejong, Ulf P. Neumann

Sarcopenia, obesity and sarcopenic obesity  effects on liver function and volume in patients scheduled for major liver resection
Background

Sarcopenia, obesity and sarcopenic obesity have been linked to impaired outcome after liver surgery. Preoperative liver function of sarcopenic, obese and sarcopenic-obese patients might be reduced, possibly leading to more post-operative morbidity. The aim of this study was to explore whether liver function and volume were influenced by body composition in patients undergoing liver resection.

Methods

In 2011 and 2012, all consecutive patients undergoing the methacetin breath liver function test were included. Liver volumetry and muscle mass analysis were performed using preoperative CT scans and Osirix® software. Muscle mass and body-fat% were calculated. Predefined cut-off values for sarcopenia and the top two body-fat% quintiles were used to identify sarcopenia and obesity, respectively. Histologic assessment of the resected liver gave insight in background liver disease.

Results

A total number of 80 patients were included. Liver function and volume were comparable in sarcopenic(-obese) and non-sarcopenic(-obese) patients. Obese patients showed significantly reduced liver function [295 (95–508) vs. 358 (96–684) µg/kg/h, P = 0.018] and a trend towards larger liver size [1694 (1116–2685) vs. 1533 (869–2852) mL, P = 0.079] compared with non-obese patients. Weight (r = −0.40), body surface area (r = −0.32), estimated body-fat% (r = −0.43) and body mass index (r = −0.47) showed a weak but significant negative (all P  < 0.05) correlation with liver function. Moreover, body-fat% was identified as an independent factor negatively affecting the liver function.

Conclusion

Sarcopenia and sarcopenic obesity did not seem to influence liver size and function negatively. However, obese patients had larger, although less functional, livers, indicating dissociation of liver function and volume in these patients.

 

Lodewick, T. M., Roeth, A. A., Olde Damink, S. W., Alizai, P. H., van Dam, R. M., Gassler, N., Schneider, M., Dello, S. A., Schmeding, M., Dejong, C. H., Neumann, U. P. (2015), Sarcopenia, obesity and sarcopenic obesity: effects on liver function and volume in patients scheduled for major liver resection. Journal of Cachexia, Sarcopenia and Muscle, 6, 155163.

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       Page 164173

Piotr Rozentryt, Jacek T. Niedziela, Bartosz Hudzik, Andrzej Lekston, Wolfram Doehner, Ewa A. Jankowska, Jolanta Nowak, Stephan von Haehling, Robert Partyka, Tomasz Rywik, Stefan D. Anker, Piotr Ponikowski, Lech Poloński

Preserved muscle oxidative metabolic phenotype in newly diagnosed non-small cell lung cancer cachexia
Background

Cachexia augments cancer-related mortality and has devastating effects on quality of life. Pre-clinical studies indicate that systemic inflammation-induced loss of muscle oxidative phenotype (OXPHEN) stimulates cancer-induced muscle wasting. The aim of the current proof of concept study is to validate the presence of muscle OXPHEN loss in newly diagnosed patients with lung cancer, especially in those with cachexia.

Methods

Quadriceps muscle biopsies of comprehensively phenotyped pre-cachectic (n = 10) and cachectic (n = 16) patients with non-small cell lung cancer prior to treatment were compared with healthy age-matched controls (n  = 22). OXPHEN was determined by assessing muscle fibre type distribution (immunohistochemistry), enzyme activity (spectrophotometry), and protein expression levels of mitochondrial complexes (western blot) as well as transcript levels of (regulatory) oxidative genes (quantitative real-time PCR). Additionally, muscle fibre cross-sectional area (immunohistochemistry) and systemic inflammation (multiplex analysis) were assessed.

Results

Muscle fibre cross-sectional area was smaller, and plasma levels of interleukin 6 were significantly higher in cachectic patients compared with non-cachectic patients and healthy controls. No differences in muscle fibre type distribution or oxidative and glycolytic enzyme activities were observed between the groups. Mitochondrial protein expression and gene expression levels of their regulators were also not different.

Conclusion

Muscle OXPHEN is preserved in newly diagnosed non-small cell lung cancer and therefore not a primary trigger of cachexia in these patients.

 

Op den Kamp, C. M., Gosker, H. R., Lagarde, S., Tan, D. Y., Snepvangers, F. J., Dingemans, A. C. C., Langen, R. C., and Schols, A. M. (2015), Preserved muscle oxidative metabolic phenotype in newly diagnosed non-small cell lung cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 6, 164173.

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       Page 174180

Masaaki Konishi, Loes Pelgrim, Anika Tschirner, Anna Baumgarten, Stephan von Haehling, Sandra Palus, Wolfram Doehner, Stefan D. Anker, Jochen Springer

Febuxostat improves outcome in a rat model of cancer cachexiaBackground

Activity of xanthine oxidase is induced in cancer cachexia, and its inhibition by allopurinol or oxypurinol improves survival and reduces wasting in the Yoshida hepatoma cancer cachexia model. Here, we tested the effects of the second-generation xanthine oxidase inhibitor febuxostat compared with placebo in the same model as used previously by our group.

Methods

Wistar rats (~200 g) were treated daily with febuxostat at 5 mg/kg/day or placebo via gavage for a maximum of 17 days. Weight change, quality of life, and body composition were analysed. After sacrifice, proteasome activity in the gastrocnemius muscle was measured. Muscle-specific proteins involved in metabolism were analysed by western blotting.

Results

Treatment of the tumour-bearing rats with febuxostat led to a significantly improved survival compared with placebo (hazard ratio: 0.45, 95% confidence interval: 0.22–0.93, P = 0.03). Loss of body weight was reduced (−26.3 ± 12.4 g) compared with placebo (−50.2 ± 2.1 g, P < 0.01). Wasting of lean mass was attenuated (−12.7 ± 10.8 g) vs. placebo (−31.9 ± 2.1 g, P  < 0.05). While we did not see an effect of febuxostat on proteasome activity at the end of the study, the pAkt/Akt ratio was improved by febuxostat (0.94 ± 0.09) vs. placebo (0.41 ± 0.05, P < 0.01), suggesting an increase in protein synthesis.

Conclusions

Febuxostat attenuated cachexia progression and improved survival of tumour-bearing rats.

 

Konishi, M., Pelgrim, L., Tschirner, A., Baumgarten, A., von Haehling, S., Palus, S., Doehner, W., Anker, S. D., and Springer, J. (2015), Febuxostat improves outcome in a rat model of cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 6, 174180.

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       Page 181191

Robert Kob,Claudia Fellner,Thomas Bertsch,Astrid Wittmann,Daria Mishura,Cornel C. Sieber,Barbara E. Fischer,Christian Stroszczynski, Cornelius L. Bollheimer

Gender-specific differences in the development of sarcopenia in the rodent model of the ageing high-fat ratBackground

Sarcopenia is linked to functional impairments, loss of independence, and mortality. In the past few years, obesity has been established as being a risk factor for a decline in muscle mass and function. There are several molecular pathological mechanisms, which have been under discussion that might explain this relationship. However, most studies were conducted using male animals and for a short period of time.

Methods

In this study, the gender-specific effect of long-term, high-fat content feeding in Sprague–Dawley rats was examined. Development of the quadriceps muscle of the animals was monitored in vivo using magnetic resonance. The results of these measurements and of the biochemical analysis of the aged muscle were compared.

Results

Surprisingly, only male but not female rats showed a decline in muscle cross-sectional area at 16 months of age as a result of a chronic oversupply of dietary fats. This loss of muscle mass could not be explained by either de-regulation of the anabolic Akt pathway or by up-regulation of the main ubiquitin ligases of muscle, MAFbx and MuRF-1. However, fusion of satellite cells to myotubes was induced by the high-fat diet in male rats, possibly as a result of an increased need for compensatory regeneration processes. Caspase-3-dependent apoptosis induction, irrespective of diet, seems to be the major determinant of muscle decline during ageing in male but not female rats.

Conclusion

Taken together, activation of the apoptosis-inducing Caspase-3 seems to be the most important trigger for the age-related muscle loss. Male rats were more prone to the decline of muscle during ageing than female animals, which was further enforced by a long-term, high fat diet.

 

Kob, R., Fellner, C., Bertsch, T., Wittmann, A., Mishura, D., Sieber, C. C., Fischer, B. E., Stroszczynski, C., and Bollheimer, C. L. (2015), Gender-specific differences in the development of sarcopenia in the rodent model of the ageing high-fat rat. Journal of Cachexia, Sarcopenia and Muscle, 6, 181–191.

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       Page 192

Xiao-Hui Sun, Hai-Zhu Yu*, Meng-Meng Yang, Yi-Meng Yang, Zhi-Min Dang

CorrigendumNo abstract

 

This article corrects:

The affiliation of the authors Anker and von Haehling was rendered wrongly in the following papers: Morley et al. (2014), and Anker and von Haehling (2014), and for Anker and Springer in Toledo et al. (2014), and Cvan Trobec et al. (2015).

The correct affiliation is as given here:

Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.

Sun, X.-H., Yu, H.-Z., Yang, M.-M., Yang, Y.-M., and Dang, Z.-M. (2015), Corrigendum. Journal of Cachexia, Sarcopenia and Muscle, 6, 192.

 

 

 
Number 3 / September 2015

     Page 197207

Stephan von Haehling, Stefan D. Anker

Moving on up: the Journal of Cachexia, Sarcopenia and MuscleNo abstract

 

von Haehling, S., and Anker, S. D. (2015) Moving on up: the Journal of Cachexia, Sarcopenia and Muscle. Journal of Cachexia, Sarcopenia and Muscle, 6: 193–196

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     Page 197207

T. Scott Bowen, Gerhard Schuler, Volker Adams

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise trainingSkeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Transmission of external stimuli to intracellular effector proteins via signalling pathways is a highly regulated and controlled process that determines muscle mass by balancing protein synthesis and protein degradation. An impaired balance between protein synthesis and breakdown leads to the development of specific myopathies. Sarcopenia and cachexia represent two distinct muscle wasting diseases characterized by inflammation and oxidative stress, where specific regulating molecules associated with wasting are either activated (e.g. members of the ubiquitin-proteasome system and myostatin) or repressed (e.g. insulin-like growth factor 1 and PGC-1α). At present, no therapeutic interventions are established to successfully treat muscle wasting in sarcopenia and cachexia. Exercise training, however, represents an intervention that can attenuate or even reverse the process of muscle wasting, by exerting anti-inflammatory and anti-oxidative effects that are able to attenuate signalling pathways associated with protein degradation and activate molecules associated with protein synthesis. This review will therefore discuss the molecular mechanisms associated with the pathology of muscle wasting in both sarcopenia and cachexia, as well as highlighting the intracellular effects of exercise training in attenuating the debilitating loss of muscle mass in these specific conditions.

 

Bowen, T. S., Schuler, G., and Adams, V. (2015) Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. Journal of Cachexia, Sarcopenia and Muscle, 6: 197207.

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     Page 208211

Antonio Jose Grande, Valter Silva, Matthew Maddocks

Exercise for cancer cachexia in adults: Executive summary of a Cochrane Collaboration systematic reviewBackground

Cancer cachexia is a complex syndrome characterized by an ongoing loss of skeletal muscle mass and progressive functional impairment. A proactive management approach is recommended, including physical exercise to maintain function via modulation of muscle metabolism, insulin sensitivity and levels of inflammation. The review aimed to determine the safety, acceptability and effectiveness of exercise in adults with cancer cachexia. Secondary aims, subject to the data availability, were to compare effectiveness according to the characteristics of the study intervention or population.

Methods

We sought randomised controlled trials (RCTs) in adults meeting international criteria for cancer cachexia, comparing a programme of exercise as a sole or adjunct intervention to usual care or an active control. CENTRAL, MEDLINE, EMBASE, DARE and HTA, ISI Web of Science, LILACS, PEDro, SciVerse SCOPUS, Biosis Previews PreMEDLINE and Open Grey databases were searched up to June 2014. Two authors independently assessed studies for eligibility.

Results

We screened 3154 separate titles and abstracts, and reviewed 16 full-texts. Corresponding authors were contacted to determine if samples met cachexia staging criteria. Most authors did not explore this concept. No trial met review eligibility criteria. We were unable to perform a meta-analysis to determine any effects from exercise intervention.

Conclusion

Despite a strong rationale for the use of exercise, there is insufficient evidence to determine safety and effectiveness in patients with cancer cachexia. Findings from ongoing studies are awaited. Assessment of cachexia domains, ideally against international criteria, is required for future trials of exercise and supportive care interventions.

 

Grande, A. J., Silva, V., and Maddocks, M. (2015) Exercise for cancer cachexia in adults: Executive summary of a Cochrane Collaboration systematic review. Journal of Cachexia, Sarcopenia and Muscle, 6: 208211.

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     Page 212221

David P.J. van Dijk, Marcel C.G. van de Poll, Alastair G.W. Moses, Thomas Preston, Steven W.M. Olde Damink, Sander S. Rensen, Nicolaas E.P. Deutz, Peter B. Soeters, James A. Ross, Kenneth C.H. Fearon, Cornelis H.C. Dejong

Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patientsBackground
Although commonly observed, malnutrition is poorly characterized and frequently underdiagnosed in patients with metastatic renal cell carcinoma (RCC). The ability of nutritional screening tools to predict overall survival (OS) in patients with RCC has not been adequately validated. The objective of this study was to investigate the performance of nutritional screening tools and their additional prognostic value in patients with metastatic RCC treated with targeted therapies.
Methods
Patients were prospectively recruited from three tertiary hospitals between 2009 and 2013. Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI) and the Mini Nutritional Assessment–Short Form (MNA–SF). Their OS and early grade 3/4 adverse events were recorded as outcomes of interest, and their associations with nutritional status were assessed using Cox regression and logistic regression, respectively. The incremental value in prognostication was evaluated using concordance index and decision curve analyses.
Results
Of the 300 enrolled patients, 95 (31.7%) and 64 (21.3%) were classified as being at risk of malnutrition according to the GNRI and MNA–SF, respectively. Both GNRI and MNA–SF were independent predictors of OS in multivariate analyses and provided significant added benefit to Heng risk classification. Compared with the MNA–SF, the GNRI contributed a higher increment to the concordance index (0.041 vs. 0.016). Nutritional screening, however, was not associated with early grade 3/4 adverse events in multivariate analyses. Further investigations are needed using more comprehensive and accurate assessment tools.
Conclusions
This prospective study confirmed the importance of nutritional screening tools in survival prognostication in patients with metastatic RCC. The standardized and objective measurements would allow clinicians to identify metastatic RCC patients at risk of poor survival outcomes. Individualized nutritional assessment and intervention strategies may be included in the multidisciplinary treatment.
 
 
van Dijk, D. P. J., van de Poll, M. C. G., Moses, A. G. W., Preston, T., Olde Damink, S. W. M., Rensen, S. S., Deutz, N. E. P., Soeters, P. B., Ross, J. A., Fearon, K. C. H., and Dejong, C. H. C. (2015) Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 6: 212221.

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     Page 222230

Weijie Gu,Guiming Zhang,Lijiang Sun,Qi Ma,Yue Cheng,Hailiang Zhang,Guohai Shi,Yao Zhu, Dingwei Ye

Nutritional screening is strongly associated with overall survival in patients treated with targeted agents for metastatic renal cell carcinomaBackground
Although commonly observed, malnutrition is poorly characterized and frequently underdiagnosed in patients with metastatic renal cell carcinoma (RCC). The ability of nutritional screening tools to predict overall survival (OS) in patients with RCC has not been adequately validated. The objective of this study was to investigate the performance of nutritional screening tools and their additional prognostic value in patients with metastatic RCC treated with targeted therapies.
Methods
Patients were prospectively recruited from three tertiary hospitals between 2009 and 2013. Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI) and the Mini Nutritional Assessment–Short Form (MNA–SF). Their OS and early grade 3/4 adverse events were recorded as outcomes of interest, and their associations with nutritional status were assessed using Cox regression and logistic regression, respectively. The incremental value in prognostication was evaluated using concordance index and decision curve analyses.
Results
Of the 300 enrolled patients, 95 (31.7%) and 64 (21.3%) were classified as being at risk of malnutrition according to the GNRI and MNA–SF, respectively. Both GNRI and MNA–SF were independent predictors of OS in multivariate analyses and provided significant added benefit to Heng risk classification. Compared with the MNA–SF, the GNRI contributed a higher increment to the concordance index (0.041 vs. 0.016). Nutritional screening, however, was not associated with early grade 3/4 adverse events in multivariate analyses. Further investigations are needed using more comprehensive and accurate assessment tools.
Conclusions
This prospective study confirmed the importance of nutritional screening tools in survival prognostication in patients with metastatic RCC. The standardized and objective measurements would allow clinicians to identify metastatic RCC patients at risk of poor survival outcomes. Individualized nutritional assessment and intervention strategies may be included in the multidisciplinary treatment.
 
 
 
Gu, W., Zhang, G., Sun, L., Ma, Q., Cheng, Y., Zhang, H., Shi, G., Zhu, Y., and Ye, D. (2015) Nutritional screening is strongly associated with overall survival in patients treated with targeted agents for metastatic renal cell carcinoma. Journal of Cachexia, Sarcopenia and Muscle, 6: 222230.

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     Page 231236

Johann Dréanic, Marion Dhooge, Maximilien Barret, Catherine Brezault, Olivier Mir, Stanislas Chaussade, Romain Coriat

Anti-epidermal or anti-vascular endothelial growth factor as first-line metastatic colorectal cancer in modified Glasgow prognostic score 2' patientsBackground

In metastatic colorectal cancer, the modified Glasgow prognostic score (mGPS) has been approved as an independent prognostic indicator of survival. No data existed on poor prognosis patients treated with molecular-targeted agents.

Methods

From January 2007 to February 2012, patients with metastatic colorectal cancer and poor predictive survival score (mGPS = 2), treated with 5-fluorouracil-based chemotherapy in addition to an anti-epidermal growth factor receptor (EGFR) or anti-vascular epidermal growth factor (VEGF) therapy, were included to assess the interest of targeted therapy within mGPS = 2' patients.

Results

A total of 27 mGPS = 2' patients were included and received a 5-fluorouracil-based systemic chemotherapy in addition to an anti-EGFR treatment (cetuximab; n = 18) or an anti-VEGF treatment (bevacizumab; n  = 9). Median follow-up was 12.1 months (interquartile range 4.9–22). Patients were Eastern Cooperative Oncology Group (ECOG) Performance Status 1, 2, and 3 in 66% (n = 18), 26% (n = 7), and 8% (n  = 2), respectively. Comparing anti-EGFR and anti-VEGF groups, median progression-free survival was 3.9 and 15.4 months, respectively, and was significantly different (P = 0.046). Conversely, the median overall survival was not significantly different between the two groups (P = 0.15).

Conclusion

Our study confirmed the poor survival of patients with mGPS = 2 despite the use of targeted therapy and identified the superiority of an anti-VEGF treatment in progression-free survival, without a significant benefit in the overall survival compared with the anti-EGFR therapy. Our results deserved confirmation by a prospective clinical trial.
 
 
 
Dréanic, J., Dhooge, M., Barret, M., Brezault, C., Mir, O., Chaussade, S., and Coriat, R. (2015) Anti-epidermal or anti-vascular endothelial growth factor as first-line metastatic colorectal cancer in modified Glasgow prognostic score 2' patients. Journal of Cachexia, Sarcopenia and Muscle, 6: 231236.

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     Page 237241

Izumi Haruta, Yuki Fuku, Kazuhisa Kinoshita, Koichi Yoneda, Akinori Morinaga, Marie Amitani, Haruka Amitani, Akihiro Asakawa, Hideki Sugawara, Yasuo Takeda, Cyril Y. Bowers, Akio Inui

One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patientBackground
In Japan, growth hormone releasing peptide-2 (GHRP-2) is clinically used as a diagnostic agent for growth hormone secretion deficiency, but the therapeutic application of GHRP-2 has not been studied in anorexia nervosa. GHRP-2 reportedly exhibits agonistic action for ghrelin receptor and increases food intake.
Methods
We administered GHRP-2 to a patient with a 20-year history of anorexia nervosa to determine whether GHRP-2 treatment increases food intake and body weight. GHRP-2 was administered before every meal by an intranasal approach for 1 year.
Results
Although the patient reported a decreased fear of eating and decreased desire to be thin by our previous treatment, she was unable to increase food intake or body weight because of digestive tract dysfunction. Vomiting after meals caused by delayed gastric emptying and incurable constipation were prolonged, and sub-ileus and hypoglycemia were observed. GHRP-2 increased the feeling of hunger and food intake, decreased early satiety and improved hypoglycemia. The patient's body weight gradually increased by 6.7 kg (from 21.1 kg to 27.8 kg) in 14 months after starting GHRP-2 administration. The fatigability and muscle strength improved, and the physical and mental activities were also increased. No obvious side effects were observed after long-term intranasal administration of GHRP-2.
Conclusions
Patients with a long-term history of eating disorder occasionally recover from the psychological problems such as fear for obesity but remain emaciated. We believe that ghrelin agonists such as GHRP-2 may be promising agents for the effective treatments of severe anorexia nervosa in a chronic condition.
 
 
 
Haruta, I., Fuku, Y., Kinoshita, K., Yoneda, K., Morinaga, A., Amitani, M., Amitani, H., Asakawa, A., Sugawara, H., Takeda, Y., Bowers, C. Y., and Inui, A. (2015) One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patient. Journal of Cachexia, Sarcopenia and Muscle, 6: 237241.

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     Page 242252

Evelien Gielen, Terence W. O'Neill, Stephen R. Pye, Judith E. Adams, Frederick C. Wu, Michaël R. Laurent, Frank Claessens, Kate A. Ward, Steven Boonen, Roger Bouillon, Dirk Vanderschueren, Sabine Verschueren

 

Endocrine determinants of incident sarcopenia in middle-aged and elderly European menBackground
In men, the long-term consequences of low serum levels of sex steroids, vitamin D metabolites, and insulin-like growth factor 1 (IGF-1) on the evolution of muscle mass, muscle strength, or physical performance are unclear. Moreover, there are no data about the relationship between these hormones and incident sarcopenia defined as low muscle mass and function. The aim of this study was to determine whether the baseline levels of sex hormones, vitamin D metabolites, and IGF-1 predict changes in muscle mass, muscle strength, physical performance, and incident sarcopenia.
Methods
In 518 men aged 40–79 years, recruited for participation in the European Male Ageing Study, total, free, and bioavailable testosterone (T), oestradiol (E), sex hormone-binding globulin, IGF-1, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone were assessed at baseline. Appendicular lean mass (aLM), gait speed, and grip strength were measured at baseline and after a mean follow-up of 4.3 years. Sarcopenia was defined by the definition of Baumgartner (relative aLM ≤7.26 kg/m2), the International Working Group on Sarcopenia (IWGS), and the European Working Group on Sarcopenia in Older People (EWGSOP).
Results
aLM significantly decreased from age 50 years, while gait speed and grip strength significantly decreased from age 70 years. The incidence of sarcopenia by the definitions of Baumgartner, IWGS, and EWGSOP was 8.1%, 3.0%, and 1.6%, respectively. After adjustment for age, centre, body mass index, smoking, and number of comorbidities at baseline, baseline levels of T and vitamin D metabolites were not associated with change in aLM, gait speed, and/or grip strength, while a high baseline level of total E2 was associated with a greater decrease in aLM. In men aged ≥70 years, low IGF-1 was associated with a greater decrease in gait speed. Baseline endocrine variables were not independently associated with an increased risk of incident sarcopenia by any definition.
Conclusions
Low levels of T and 25OHD do not predict loss of muscle mass, gait speed, or grip strength in middle-aged and elderly community-dwelling European men. Low IGF-1 predicts change in gait speed in men aged ≥70 years.

 

F., Ward, K. A., Boonen, S., Bouillon, R., Vanderschueren, D., and Verschueren, S. (2015) Endocrine determinants of incident sarcopenia in middle-aged and elderly European men. Journal of Cachexia, Sarcopenia and Muscle, 6: 242252.

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     Page 253268

Klaske van Norren, Fenni Rusli, Miriam van Dijk, Carolien Lute, Jolanda Nagel, Francina J. Dijk, Jvalini Dwarkasing, Mark V. Boekschoten, Yvette Luiking, Renger F. Witkamp, Michael Müller, Wilma T. Steegenga

Behavioural changes are a major contributing factor in the reduction of sarcopenia in caloric-restricted ageing miceBackground

In rodent models, caloric restriction (CR) with maintenance of adequate micronutrient supply has been reported to increase lifespan and to reduce age-induced muscle loss (sarcopenia) during ageing. In the present study, we further investigated effects of CR on the onset and severity of sarcopenia in ageing male C57BL/6 J mice. The aim of this study was to investigate whether CR induces changes in behaviour of the animals that could contribute to the pronounced health-promoting effects of CR in rodents. In addition, we aimed to investigate in more detail the effects of CR on the onset and severity of sarcopenia.

Methods

The mice received either an ad libitum diet (control) or a diet matching 70 E% of the control diet (C). Daily activity, body composition (dual energy X-ray absorptiometry), grip strength, insulin sensitivity, and general agility and balance were determined at different ages. Mice were killed at 4, 12, 24, and 28 months. Skeletal muscles of the hind limb were dissected, and the muscle extensor digitorum longus muscle was used for force-frequency measurements. The musculus tibialis was used for real-time quantitative PCR analysis.

Results

From the age of 12 months, CR animals were nearly half the weight of the control animals, which was mainly related to a lower fat mass. In the control group, the hind limb muscles showed a decline in mass at 24 or 28 months of age, which was not present in the CR group. Moreover, insulin sensitivity (oral glucose tolerance test) was higher in this group and the in vivo and ex vivo grip strength did not differ between the two groups.

In the hours before food was provided, CR animals were far more active than control animals, while total daily activity was not increased. Moreover, agility test indicated that CR animals were better climbers and showed more climbing behaviours.

Conclusions

Our study confirms earlier findings that in CR animals less sarcopenia is present. The mice on the CR diet, however, showed specific behavioural changes characterized by higher bursts of activity within a short time frame before consumption of a 70 E% daily meal. We hypothesize that the positive effects of CR on muscle maintenance in rodents are not merely a direct consequence of a lower energy intake but also related to a more active behaviour in a specific time frame. The burst of activity just before immediate start of eating, might lead to a highly effective use of the restricted protein sources available.
 
 
van Norren, K., Rusli, F., van Dijk, M., Lute, C., Nagel, J., Dijk, F. J., Dwarkasing, J., Boekschoten, M. V., Luiking, Y., Witkamp, R. F., Müller, M., and Steegenga, W. T. (2015) Behavioural changes are a major contributing factor in the reduction of sarcopenia in caloric-restricted ageing mice. Journal of Cachexia, Sarcopenia and Muscle, 6: 253268.

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Number 4 / December 2015

 

     Page 269271

Stefan D. Anker, John E Morley

Cachexia: a nutritional syndrome?Cachexia leads to nutritional deficits including anorexia and loss of fat and muscle mass. In persons with precachexia or early cachexia, for example, old persons with weight loss and chronic obstructive pulmonary disease, there is strong evidence that nutritional support improves outcomes. Limited evidence suggests that this may be true for heart failure and chronic kidney disease. The evidence for nutritional support in refractory cachexia is, not surprisingly, less dramatic. It would appear that early in the cachectic process, nutrition, coupled with exercise, may be an important therapeutic approach.

 

Anker, S. D., and Morley, J. E. (2015) Cachexia: a nutritional syndrome?. Journal of Cachexia, Sarcopenia and Muscle, 6: 269–271. doi: 10.1002/jcsm.12088.

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     Page 272273

KCH Fearon, JM Argiles, VE Baracos, R Bernabei, AJS Coats, J Crawford, NE Deutz, W Doehner, WJ Evans, L Ferrucci, JM Garcia, RJ Gralla, A Jatoi, K Kalantar-Zadeh, M Lainscak, JE Morley, M Muscaritoli, MI Polkey, G Rosano, F Rossi-Fanelli, AM Schols, F Strasser, B Vellas, S von Haehling, SD Anker

Request for regulatory guidance for cancer cachexia intervention trialsno abstract

 

Fearon, K., Argiles, J., Baracos, V., Bernabei, R., Coats, A., Crawford, J., Deutz, N., Doehner, W., Evans, W., Ferrucci, L., Garcia, J., Gralla, R., Jatoi, A., Kalantar-Zadeh, K., Lainscak, M., Morley, J., Muscaritoli, M., Polkey, M., Rosano, G., Rossi-Fanelli, F., Schols, A., Strasser, F., Vellas, B., von Haehling, S., and Anker, S. (2015) Request for regulatory guidance for cancer cachexia intervention trials. Journal of Cachexia, Sarcopenia and Muscle, 6: 272–273. doi: 10.1002/jcsm.12083.

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     Page 275277

Stefan D. Anker, Andrew J. S. Coats, John E. Morley

Evidence for partial pharmaceutical reversal of the cancer anorexia–cachexia syndrome: the case of anamorelinA major component of the cancer anorexia-cachexia syndrome is a decline in food intake. Up until now none of the drugs that improve appetite also improve skeletal muscle. Recent studies have suggested that the oral ghrelin-analog, anamorelin, increased food intake and muscle mass. Unfortunately, it does not increase muscle power. Its regulatory future is uncertain, although it has important clinical effects.

 

Anker, S. D., Coats, A. J. S., and Morley, J. E. (2015) Evidence for partial pharmaceutical reversal of the cancer anorexia–cachexia syndrome: the case of anamorelin. Journal of Cachexia, Sarcopenia and Muscle, 6: 275–277. doi: 10.1002/jcsm.12063.

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     Page 278286

Riccardo Calvani, Federico Marini, Matteo Cesari, Matteo Tosato, Stefan D. Anker, Stephan von Haehling, Ram R. Miller, Roberto Bernabei, Francesco Landi, Emanuele Marzetti and the SPRINTT consortium

Biomarkers for physical frailty and sarcopenia: state of the science and future developmentsPhysical frailty and sarcopenia are two common and largely overlapping geriatric conditions upstream of the disabling cascade. The lack of a unique operational definition for physical frailty and sarcopenia and the complex underlying pathophysiology make the development of biomarkers for these conditions extremely challenging. Indeed, the current definitional ambiguities of physical frailty and sarcopenia, together with their heterogeneous clinical manifestations, impact the accuracy, specificity, and sensitivity of individual biomarkers proposed so far. In this review, the current state of the art in the development of biomarkers for physical frailty and sarcopenia is presented. A novel approach for biomarker identification and validation is also introduced that moves from the ‘one fits all’ paradigm to a multivariate methodology.

 

Calvani, R., Marini, F., Cesari, M., Tosato, M., Anker, S. D., von Haehling, S., Miller, R. R., Bernabei, R., Landi, F., Marzetti, E., and , (2015) Biomarkers for physical frailty and sarcopenia: state of the science and future developments. , doi: 10.1002/jcsm.12051.

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     Page 287302

Chukwuemeka Charles Ezeoke, John E. Morley

Pathophysiology of anorexia in the cancer cachexia syndromeAnorexia is commonly present in persons with cancer and a major component of cancer cachexia. There are multiple causes of anorexia in cancer. Peripherally, these can be due to (i) substances released from or by the tumour, e.g. pro-inflammatory cytokines, lactate, and parathormone-related peptide; (ii) tumours causing dysphagia or altering gut function; (iii) tumours altering nutrients, e.g. zinc deficiency; (iv) tumours causing hypoxia; (v) increased peripheral tryptophan leading to increased central serotonin; or (vi) alterations of release of peripheral hormones that alter feeding, e.g. peptide tyrosine tyrosine and ghrelin. Central effects include depression and pain, decreasing the desire to eat. Within the central nervous system, tumours create multiple alterations in neurotransmitters, neuropeptides, and prostaglandins that modulate feeding. Many of these neurotransmitters appear to produce their anorectic effects through the adenosine monophosphate kinase/methylmalonyl coenzyme A/fatty acid system in the hypothalamus. Dynamin is a guanosine triphosphatase that is responsible for internalization of melanocortin 4 receptors and prostaglandin receptors. Dynamin is up-regulated in a mouse model of cancer anorexia. A number of drugs, e.g. megestrol acetate, cannabinoids, and ghrelin agonists, have been shown to have some ability to be orexigenic in cancer patients.

 

Ezeoke, C. C., and Morley, J. E. (2015) Pathophysiology of anorexia in the cancer cachexia syndrome. Journal of Cachexia, Sarcopenia and Muscle, 6: 287–302. doi: 10.1002/jcsm.12059.

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     Page 303311

Cathleen Drescher, Masaaki Konishi, Nicole Ebner, Jochen Springer

Loss of muscle mass: current developments in cachexia and sarcopenia focused on biomarkers and treatmentLoss of muscle mass arises from an imbalance of protein synthesis and protein degradation. Potential triggers of muscle wasting and function are immobilization, loss of appetite, dystrophies, and chronic diseases as well as aging. All these conditions lead to increased morbidity and mortality in patients, which makes it a timely matter to find new biomarkers to get a fast clinical diagnosis and to develop new therapies. This mini-review covers current developments in the field of biomarkers and drugs on cachexia and sarcopenia. Here, we reported about promising markers, e.g. tartate-resistant acid phosphatase 5a, and novel substances like epigallocatechin-3-gallate. In summary, the progress to combat muscle wasting is in full swing, and perhaps diagnosis of muscle atrophy and of course patient treatments could be soon support by improved and more helpful strategies.

 

Drescher, C., Konishi, M., Ebner, N., and Springer, J. (2015) Loss of muscle mass: current developments in cachexia and sarcopenia focused on biomarkers and treatment. Journal of Cachexia, Sarcopenia and Muscle, 6: 303–311. doi: 10.1002/jcsm.12082.

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     Page 312314

KCH Fearon, JM Argiles, VE Baracos, R Bernabei, AJS Coats, J Crawford, NE Deutz, W Doehner, WJ Evans, L Ferrucci, JM Garcia, RJ Gralla, A Jatoi, K Kalantar-Zadeh, M Lainscak, JE Morley, M Muscaritoli, MI Polkey, G Rosano, F Rossi-Fanelli, AM Schols, F Strasser, B Vellas, S von Haehling, SD Anker

Rapid screening for sarcopeniano abstract

 

Morley, J. E., and Cao, L. (2015) Rapid screening for sarcopenia. Journal of Cachexia, Sarcopenia and Muscle, 6: 312–314. doi: 10.1002/jcsm.12079.

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     Page 315318

Stefan D. Anker, Andrew J. S. Coats, John E. Morley

Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2015This article details the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM). At the time of submission to JCSM, the corresponding author, on behalf of all co-authors, needs to certify adherence to these principles. The principles are as follows:

1    all authors listed on a manuscript considered for publication have approved its submission and (if accepted) publication as provided to JCSM;
2    no person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript;
3   no person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript;
4   the submitted work is original and is neither under consideration elsewhere nor that it has been published previously in whole or in part other than in abstract form;
5   all authors certify that the work is original and does not contain excessive overlap with prior or contemporaneous publication elsewhere, and where the publication reports on cohorts, trials, or data that have been reported on before these other publications must be referenced;
6   all original research work are approved by the relevant bodies such as institutional review boards or ethics committees;
7   all conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively, and relevant sources of funding have been duly declared in the manuscript;
8   the manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true; and
9   If any of the aforementioned statements ceases to be true, the authors have a duty to notify the Editors of JCSM as soon as possible so that the available information regarding the published article can be updated and/or the manuscript can be withdrawn.

 

von Haehling, S., Morley, J. E., Coats, A. J. S., and Anker, S. D. (2015) Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2015. Journal of Cachexia, Sarcopenia and Muscle, 6: 315–316. doi: 10.1002/jcsm.12089.

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     Page 317324

Lorena Lerner, Teresa G. Hayes, Nianjun Tao, Brian Krieger, Bin Feng, Zhenhua Wu, Richard Nicoletti, M. Isabel Chiu, Jeno Gyuris, Jose M. Garcia

Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patientsBackground
Cancer-related weight loss is associated with increased inflammation and decreased survival. The novel inflammatory mediator growth differentiation factor (GDF)15 is associated with poor prognosis in cancer but its role in cancer-related weight loss (C-WL) remains unclear. Our objective was to measure GDF15 in plasma samples of cancer subjects and controls and establish its association with other inflammatory markers and clinical outcomes.
Methods
We measured body weight, appetite, plasma GDF15, and other inflammatory markers in men with cancer-related weight loss (C-WL, n = 58), weight stable patients with cancer (C-WS, n = 72), and non-cancer controls (Co, n  = 59) matched by age and pre-illness body mass index. In a subset of patients we also measured handgrip strength, appendicular lean body mass (aLBM), Eastern Cooperative Oncology Group (ECOG), and Karnofsky performance scores.
Results
GDF15, interleukin (IL)-6 and IL-8 were increased in C-WL versus other groups. IL-1 receptor antagonist, IL-4, interferon–gamma, tumour necrosis factor alpha, and vascular endothelial growth factor A were increased in C-WL versus C-WS, and Activin A was significantly downregulated in Co versus other groups. C-WL patients had lower handgrip strength, aLBM, and fat mass, and Eastern Cooperative Oncology Group and Karnofsky performance scores were lower in both cancer groups.
GDF15, IL-6, and IL-8 significantly correlated with weight loss; GDF15 negatively correlated with aLBM, handgrip strength, and fat mass. IL-8 and Activin A negatively correlated with aLBM and fat mass. GDF15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression P < 0.001 for both).
Conclusion
GDF15 and other inflammatory markers are associated with weight loss, decreased aLBM and strength, and poor survival in patients with cancer. GDF15 may serve as a prognostic indicator in cancer patients and is being evaluated as a potential therapeutic target for cancer-related weight loss.
 
 
Lerner, L., Hayes, T. G., Tao, N., Krieger, B., Feng, B., Wu, Z., Nicoletti, R., Chiu, M. I., Gyuris, J., and Garcia, J. M. (2015) Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 6: 317–324. doi: 10.1002/jcsm.12033.

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     Page 325334

Piotr Rozentryt, Jacek T. Niedziela, Bartosz Hudzik, Andrzej Lekston, Wolfram Doehner, Ewa A. Jankowska, Jolanta Nowak, Stephan von Haehling, Robert Partyka, Tomasz Rywik, Stefan D. Anker, Piotr Ponikowski, Lech Poloński

Higher serum phosphorus is associated with catabolic/anabolic imbalance in heart failureBackground
A higher serum phosphate level is associated with worse outcome. Energy-demanding intracellular transport of phosphate is needed to secure anion bioavailability. In heart failure (HF), energy starvation may modify intracellular and serum levels of phosphate. We analysed determinants of serum phosphates in HF and assessed if catabolic/anabolic balance (CAB) was associated with elevation of serum phosphate.
Methods
We retrospectively reviewed data from 1029 stable patients with HF and have calculated negative (loss) and positive (gain) components of weight change from the onset of HF till index date. The algebraic sum of these components was taken as CAB. The univariate and multivariable predictors of serum phosphorus were calculated. In quintiles of CAB, we have estimated odds ratios for serum phosphorus above levels previously identified to increase risk of mortality. As a reference, we have selected a CAB quintile with similar loss and gain.
Results
Apart from sex, age, and kidney function, we identified serum sodium, N-terminal fragment of pro-brain-type natriuretic peptide, and CAB as independent predictors of serum phosphorus. The odds for serum phosphorus above thresholds found in literature to increase risk were highest in more catabolic patients. In most catabolic quintile relative to neutral balance, the odds across selected phosphorus thresholds rose, gradually peaking at 1.30 mmol/L with a value of 3.29 (95% confidence interval: 2.00–5.40, P < 0.0001) in an unadjusted analysis and 2.55 (95% confidence interval: 1.38–2.72, P = 0.002) in a fully adjusted model.
Conclusions
Metabolic status is an independent determinant of serum phosphorus in HF. Higher catabolism is associated with serum phosphorus above mortality risk-increasing thresholds.
 
 
Rozentryt, P., Niedziela, J. T., Hudzik, B., Lekston, A., Doehner, W., Jankowska, E. A., Nowak, J., von Haehling, S., Partyka, R., Rywik, T., Anker, S. D., Ponikowski, P., and Poloński, L. (2015) Higher serum phosphorus is associated with catabolic/anabolic imbalance in heart failure. J Cachexia Sarcopenia Muscle, 6: 325–334. doi: 10.1002/jcsm.12026.

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     Page 335342

Anders Nedergaard, Ulrik Dalgas, Hanne Primdahl, Jørgen Johansen, Jens Overgaard, Kristian Overgaard, Kim Henriksen, Morten Asser Karsdal, Simon Lønbro

Collagen fragment biomarkers as serological biomarkers of lean body mass – a biomarker pilot study from the DAHANCA25B cohort and matched controlsBackground
Loss of muscle mass and function is an important complication to ageing and a range of pathologies, including, but not restricted to, cancer, organ failures, and sepsis. A number of interventions have been proposed ranging from exercise to anabolic pharmacological therapy, with varying success. Easily applicable serological biomarkers of lean and/or muscle mass and change therein would benefit monitoring of muscle mass during muscle atrophy as well as during recovery. We set out to validate if novel peptide biomarkers derived from Collagen III and VI were markers of lean body mass (LBM) or change therein in head and neck cancer patients in the Danish Head and Neck Cancer Group(DAHANCA) 25B cohort subjected to resistance training as well as in an age-matched and gender-matched control group.
Methods
Blood samples and dual X-ray absorptiometry data were measured at baseline, after 12 and 24 weeks in 41 HNSCC subjects of the DAHANCA 25B cohort of subjects recovering from neck and head cancer (stages provided in Table 1), and at baseline only in 21 healthy age-matched and gender-matched controls. Serum from blood was analyzed for the ProC3, IC6, and C6M peptide biomarkers and LBM were derived from the dual X-ray absorptiometry scans.
Results
We were not able to show any correlation between biomarkers and LBM or C6M and anabolic response to exercise in recovering head and neck cancer patients. However, we did find that the biomarkers IC6, IC6/C6M, and ProC3 are biomarkers of LBM in the control group subjects (R2/P of 0.249/0.035, 0.416/0.007 and 0.178 and P = 0.057, respectively),
Conclusion
In conclusion, the IC6, ProC3, and IC6/C6M biomarkers are indeed biomarkers of LBM in healthy individuals of both genders, but not in HNSCC patients.
 
 
 
Nedergaard, A., Dalgas, U., Primdahl, H., Johansen, J., Overgaard, J., Overgaard, K., Henriksen, K., Karsdal, M. A., and Lønbro, S. (2015) Collagen fragment biomarkers as serological biomarkers of lean body mass – a biomarker pilot study from the DAHANCA25B cohort and matched controls. Journal of Cachexia, Sarcopenia and Muscle, 6: 335–342. doi: 10.1002/jcsm.12027.

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     Page 343350

Frédérick Moryoussef, Marion Dhooge, Julien Volet, Coralie Barbe, Catherine Brezault, Christine Hoeffel, Romain Coriat, Olivier Bouché

Reversible sarcopenia in patients with gastrointestinal stromal tumor treated with imatinibBackground
Imatinib is a long-term, oral, targeted therapy for high-risk resected and advanced gastrointestinal stromal tumours (GIST). It is known that sarcopenia affects prognosis and treatment tolerance in patients with various solid cancers. We analysed lumbar skeletal muscle index changes in imatinib-treated GIST patients. Imatinib tolerance was also assessed to evaluate the influence of pre-treatment sarcopenia.
Methods
Thirty-one patients with advanced (n = 16) or high-risk resected (n = 15) GIST treated with imatinib (400 mg/day) were analysed retrospectively. Lumbar skeletal muscle indexes were evaluated on computed tomography images obtained before starting imatinib for all patients and at 6 months for those initially sarcopenic. Sarcopenia was defined using consensual cutoffs. Imatinib-induced toxicities were assessed after 3 months of administration.
Results
Twelve (38.7%) of the 31 patients were sarcopenic, including one unassessable at 6 months. Seven (63.6%) of the 11 assessable sarcopenic patients became non-sarcopenic after 6 months of imatinib. Pre-treatment sarcopenia was not associated with grades 3–4 toxicities, but the mean number of all-grade toxicities per sarcopenic patient was significantly higher for those non-sarcopenic (4.1 vs. 1.7, respectively, p < 0.01) after 3 months of treatment. Grades 1–2 anaemia and grades 1–2 fatigue were more frequent for sarcopenic than non-sarcopenic patients (83% vs. 26%, P < 0.01 and 42% vs. 5%, P = 0.02, respectively).
Conclusions
Sarcopenia is reversible in some GIST patients treated with imatinib. Pre-imatinib sarcopenia is predictive of non-severe toxicities, particularly anaemia and fatigue.

 

Moryoussef, F., Dhooge, M., Volet, J., Barbe, C., Brezault, C., Hoeffel, C., Coriat, R., and Bouché, O. (2015) Reversible sarcopenia in patients with gastrointestinal stromal tumor treated with imatinib. Journal of Cachexia, Sarcopenia and Muscle, 6: 343–350. doi: 10.1002/jcsm.12047.

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     Page 351357

Hidetaka Wakabayashi,Masato Matsushima,Rimiko Uwano,Naoko Watanabe,Hideyuki Oritsu, Yoshitaka Shimizu

Skeletal muscle mass is associated with severe dysphagia in cancer patientsBackground
The purpose of this study was to assess the association between skeletal muscle mass, activities of daily living (ADLs) and severe dysphagia in cancer patients.
Methods
A nested case-control study was performed in 111 consecutive cancer patients with dysphagia who were prescribed speech therapy. Skeletal muscle mass comprising the cross-sectional area of the left and right psoas muscles was assessed via abdominal computed tomography at the third lumbar vertebral level. ADLs were evaluated by the Barthel Index. The severity of dysphagia was assessed by the Food Intake Level Scale and was characterized by non-oral feeding or oral food intake at discharge. Univariate and logistic regression analyses were applied to examine the associations between dysphagia, skeletal muscle index (SMI) and ADLs.
Results
There were 86 men and 25 women (mean age, 70 years). The mean SMI was 5.68 ± 1.74 cm2/m2 in men and 4.43 ± 1.21 cm2/m2 in women. The median Barthel Index score was 20. Thirty-three patients were on non-oral feeding at discharge. The mean SMI did not differ significantly between non-oral feeding and oral food intake groups in t-test. The median Barthel Index score was lower in the non-oral feeding group in Mann–Whitney U test. Logistic regression analysis of the severity of dysphagia adjusted for age, sex, SMI, Barthel Index score, serum albumin, cancer type and stage, and vocal cord paralysis showed that SMI was associated independently with oral food intake at discharge. Barthel Index score showed a tendency to be associated with oral food intake.
Conclusions
Skeletal muscle mass is associated with severe dysphagia in cancer patients. ADLs show a tendency to be associated with severe dysphagia in cancer patients.

 

Wakabayashi, H., Matsushima, M., Uwano, R., Watanabe, N., Oritsu, H., and Shimizu, Y. (2015) Skeletal muscle mass is associated with severe dysphagia in cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 6: 351–357. doi: 10.1002/jcsm.12052.

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     Page 358364

Malgorzata Ponikowska, Malgorzata Tupikowska, Monika Kasztura, Ewa A. Jankowska, Jacek C. Szepietowski

Deranged iron status in psoriasis: the impact of low body massBackground
Iron deficiency (ID) frequently complicates inflammatory-mediated chronic disorders, irrespective of anaemia. Psoriasis is a chronic, immune-mediated skin disease with systemic pro-inflammatory activation; thus, these patients may be prone to develop ID. ID adversely affects immune cells function, which can further contribute to disease progression. This study investigates iron status in psoriasis.
Methods
Serum concentrations of ferritin, transferrin saturation (Tsat), soluble transferrin receptor (sTfR), and hepcidin were assessed as the biomarkers of iron status in 39 patients with psoriasis (17 men, age: 47 ± 10 years) and 44 healthy subjects (30 men, age: 53 ± 6 years).
Results
Compared with healthy controls, patients with psoriasis demonstrated similar haematologic status but deranged iron status as evidenced by decreased Tsat and elevated sTfR (negative tissue iron balance) and low levels of hepcidin (depleted iron stores) (all P < 0.05 vs. controls). In patients, the levels of interleukin-6 (level of pro-inflammatory activation) significantly correlated with hepcidin (R = 0.54), but not with ferritin, Tsat, and sTfR. Biomarkers reflecting ID were not associated with the severity of the disease (assessed with the Psoriasis Area and Severity Index) but significantly correlated low body mass index (BMI). Patients with BMI < 24 kg/m2 compared with those with BMI ≥ 24 kg/m2 demonstrated lower levels of ferritin (40 ± 30 vs. 186 ± 128 ng/mL, P < 0.001) and hepcidin (4.9 ± 2.3 vs. 10.7 ± 6.7 ng/mL, P = 0.03).
Conclusion
Psoriasis is associated with deranged iron status characterized by depleted iron stores with concomitant unmet cellular iron requirements. The magnitude of these abnormalities is particularly strong in patients with low body mass index. Whether iron deficiency may become a therapeutic target in psoriasis needs to be investigated.

 

Ponikowska, M., Tupikowska, M., Kasztura, M., Jankowska, E. A., and Szepietowski, J. C. (2015) Deranged iron status in psoriasis: the impact of low body mass. Journal of Cachexia, Sarcopenia and Muscle, 6: 358–364. doi: 10.1002/jcsm.12061.

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     Page 365380

Francesco Elia Marino, Gail Risbridger, Elspeth Gold

Activin-βC modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathwaysBackground
Cancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy.
We previously showed that activin-βC, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin α-KO mouse). This study aimed to identify the molecular mechanism by which activin-βC increases survival and abolishes cancer-associated cachexia in α-KO mice. We hypothesized that overexpression of activin-βC modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways.
Methods
Male and female ActC++, α-KO, and α-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed.
Results
Increased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the α-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- βC antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. α-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival.
Conclusion
Our findings show for the first time a specific effect of activin-βC on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-βC may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.

 

Marino, F. E., Risbridger, G., and Gold, E. (2015) Activin-βC modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways. Journal of Cachexia, Sarcopenia and Muscle, 6: 365–380. doi: 10.1002/jcsm.12031.

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     Page 381390

Norman Mangner, Bettina Weikert, T. Scott Bowen, Marcus Sandri, Robert Höllriegel, Sandra Erbs, Rainer Hambrecht, Gerhard Schuler, Axel Linke, Stephan Gielen, Volker Adams

Skeletal muscle alterations in chronic heart failure: differential effects on quadriceps and diaphragmBackground
Chronic heart failure (CHF) results in limb and respiratory muscle weakness, which contributes to exercise intolerance and increased morbidity and mortality, yet the molecular mechanisms remain poorly understood.
Therefore, we aimed to compare parameters of antioxidative capacity, energy metabolism, and catabolic/anabolic balance in diaphragm and quadriceps muscle in an animal model of CHF.
Methods
Ligation of the left anterior descending coronary artery (n = 13) or sham operation (n = 11) was performed on Wistar Kyoto rats. After 12 weeks, echocardiography and invasive determination of maximal rates of left ventricular (LV) pressure change were performed. Antioxidative and metabolic enzyme activities and expression of catabolic/anabolic markers were assessed in quadriceps and diaphragm muscle.
Results
Ligated rats developed CHF (i.e. severe LV dilatation, reduced LV ejection fraction, and impaired maximal rates of LV pressure change; P < 0.001). There was a divergent response for antioxidant enzymes between the diaphragm and quadriceps in CHF rats, with glutathione peroxidase and manganese superoxide dismutase activity increased in the diaphragm but reduced in the quadriceps relative to shams (P < 0.01). Metabolic enzymes were unaltered in the diaphragm, but cytochrome c oxidase activity (P < 0.01) decreased and lactate dehydrogenase activity (P < 0.05) increased in the quadriceps of CHF animals. Protein expression of the E3 ligase muscle ring finger 1 and proteasome activity were increased (P < 0.05) in both the diaphragm and quadriceps in CHF rats compared with shams.
Conclusion
Chronic heart failure induced divergent antioxidative and metabolic but similar catabolic responses between the diaphragm and quadriceps. Despite the quadriceps demonstrating significant impairments in CHF, apparent beneficial adaptations of an increased antioxidative capacity were induced in the diaphragm. Nevertheless, muscle ring finger 1 and proteasome activity (markers of protein degradation) were elevated and oxidative enzyme activity failed to increase in the diaphragm of CHF rats, which suggest that a myopathy is likely present in respiratory muscle in CHF, despite its constant activation.
 
 
Mangner, N., Weikert, B., Bowen, T. S., Sandri, M., Höllriegel, R., Erbs, S., Hambrecht, R., Schuler, G., Linke, A., Gielen, S., and Adams, V. (2015) Skeletal muscle alterations in chronic heart failure: differential effects on quadriceps and diaphragm. Journal of Cachexia, Sarcopenia and Muscle, 6: 381–390. doi: 10.1002/jcsm.12034.

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     Page 391392

Junichi Ishida, Masaaki Konishi, Masakazu Saito, Jochen Springer

Hypermetabolism: should cancer types, pathological stages and races be considered in assessing metabolism and could elevated resting energy expenditure be the therapeutic target in patients with advanced cancer?
no abstract

 

Ishida, J., Konishi, M., Saito, M., and Springer, J. (2015) Hypermetabolism: should cancer types, pathological stages and races be considered in assessing metabolism and could elevated resting energy expenditure be the therapeutic target in patients with advanced cancer?. Journal of Cachexia, Sarcopenia and Muscle, 6: 391–392. doi: 10.1002/jcsm.12080.

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     Page 393

Michiyoshi Hatanaka, Masaaki Konishi, Junnichi Ishida, Masakazu Saito, Jochen Springer

Novel mechanism of ghrelin therapy for cachexiano abstract

 

Hatanaka, M., Konishi, M., Ishida, J., Saito, M., and Springer, J. (2015) Novel mechanism of ghrelin therapy for cachexia. Journal of Cachexia, Sarcopenia and
Muscle, 6: 393. doi: 10.1002/jcsm.12084.

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     Page 394395

Masakazu Saitoh, Junichi Ishida, Masaaki Konishi, Jochen Springer

Concern regarding quality and quality of muscleno abstract

 

Saitoh, M., Ishida, J., Konishi, M., and Springer, J. (2015) Concern regarding quality and quality of muscle. Journal of Cachexia, Sarcopenia and Muscle, 6: 394–395. doi: 10.1002/jcsm.12081.

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     Page 396397

Masaaki Konishi, Junichi Ishida, Masakazu Saito, Jochen Springer

Irisin - a myokine potentially bridging muscle and fat tissue in cachexiano abstract

 

Konishi, M., Ishida, J., Saito, M., and Springer, J. (2015) Irisin – a myokine potentially bridging muscle and fat tissue in cachexia. Journal of Cachexia, Sarcopenia and Muscle, 6: 396–397. doi: 10.1002/jcsm.12085.

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     Page 398509

Nadja Scherbakov

Abstracts of the 8th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Paris, France, 4-6 December 2015no abstract

 

Scherbakov, N. (2015) Abstracts of the 8th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Paris, France, 4-6 December 2015. Journal of Cachexia, Sarcopenia and Muscle, 6: 398–509. doi: 10.1002/jcsm.12087.

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