Abstracts of the 10th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Rome, Italy, 8‐10 December 2017 (Part 2)

s of the 10th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Rome, Italy, 8-10 December 2017 (Part 2) 1–07 Comparison of sarcopenia and cachexia in men with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF) Amir Emami, Masakazu Saitoh, Miroslava Valentova, Anja Sandek, Ruben Evertz, Nicole Ebner, Goran Loncar, Jochen Springer, Wolfram Doehner, Mitja Lainscak, Gerd Hasenfuß, Stefan D. Anker & Stephan von Haehling Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany, Cardiology Department, Clinical Hospital Zvezdara, Belgrade, Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia, Center for Stroke Research Berlin, Charite University Medical School, Germany, Division of Cardiology, General Hospital Murska Sobota, Slovenia, Faculty of Medicine, University of Ljubljana, Slovenia, Division of Cardiology and Metabolism – Heart Failure, Cachexia & Sarcopenia, Department of Cardiology, Campus Virchow-Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany Objectives: The aim of the present study was to compare the functional impact of changes in body composition as exemplified by heart failure (HF) patients who have cachexia and/or sarcopenia with patients without body wasting. Methods: We prospectively enrolled 207 ambulatory male patients with clinically stable chronic HF who were subgrouped into four groups; (I) patients with sarcopenia without cachexia (sarcopenic HF group), (II) patients with cachexia without sarcopenia (cachectic HF group), (III) patients with cachexia and sarcopenia (sarcopenic cachexia group), and (IV) patients with neither type of wasting (no wasting group). Results: Cachexia was present in 39 (18.8%) of 207 Patients, 14 of whom also fulfilled the characteristics of sarcopenia (sarcopenic cachexia group, 6.7%), whereas 25 did not (cachectic HF group, 12.1%). Sarcopenia without cachexia was present in 30 patients (sarcopenic HF group, 14.4%). Handgrip strength, peak VO2, distance walked in the 6-MWT, SPPB score, and EQ-5D index score results were lowest in the sarcopenic cachexia group, with significant differences compared to the no wasting group (all p < 0.05). Besides, the sarcopenic cachexia group had the lowest values in quadriceps strength in comparison to the other three groups (all p < 0.05). Likewise, the sarcopenic HF group showed lower handgrip strength, quadriceps strength, 6MWT, peak VO2, SPPB score and EQ-5D index score results, with significant differences compared to the no wasting group (all p < 0.05). Haemoglobin and IL-6 levels were significantly reduced in the sarcopenic cachexia group, as compared with the no wasting group (both p < 0.05). Conclusions: Losing muscle with or without weight loss appears to have a more pronounced role than weight loss alone, in decreasing functional capacity and QOL among male patients with chronic HF. 1–10 Serial changes in fat, muscle, and bone mass in patients with repeat hospitalization due to worsening heart failure Masaaki Konishi, Eiichi Akiyama, Yasushi Matsuzawa, Nobuhiko Maejima, Noriaki Iwahashi, Kiyoshi Hibi, Masami Kosuge, Kazuo Kimura & Kouichi Tamura Yokohama City University Medical Center, Yokohama, Japan Introduction: Loss of body weight in patients with heart failure (HF) is known as cachexia and associated with poor prognosis. However, there is a paucity of data regarding changes in body composition, namely, fat, muscle, and bone mass. Methods: We retrospectively analysed 32 consecutive patients with heart failure (56% men, left ventricular ejection fraction(LVEF) 41 + 14%, NYHA2.0 + 0.5), who experienced re-hospitalization due to worsening HF and had two or more results in dual-energy X-ray absorptiometry (DXA). To minimize influences by excess fluid in body, DXA was measured at stable state after decongestion therapy. Results: Twenty-two (69%) patients had an ischemic aetiology and 13 (41%) was categorized as heart failure with preserved LVEF (LVEF > =50). Median interval between the two measurements of DXA was 415 (IQR: 263, 763) days. In the first measurement, low muscle mass defined by the Asian Working Group for Sarcopenia (i.e., <7.0 kg/m2 in men and <5.4 kg/m2 in women) was ABSTRACTS © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders Journal of Cachexia, Sarcopenia and Muscle 2018; 9: 183–212 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.12284 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. observed in 72% of patients. During follow-up period, 69%, 72%, 56%, and 88% of patients experienced weight loss, fat loss, appendicular skeletal muscle loss, and bone loss, defined as any loss of body weight or each body component, respectively. Weight loss was correlated with fat loss (r = 0.77, p < 0.001) and appendicular skeletal muscle loss (r = 0.35, p = 0.047), but not with bone loss (r = 0.08, p = 0.67). Eleven patients with longer history of HF (>5 years) showed greater weight loss than 21 patients with shorter history ( 6.5 + 5.7 vs 0.4 + 8.0%, p = 0.03) whereas none of age, LVEF, and biomarkers (serum albumin, creatinine, lymphocyte count, C-reacting protein, B-type natriuretic peptide) could not predict weight loss, fat loss, and skeletal muscle loss. Conclusions:Weight loss was frequently observed in patients with heart failure requiring repeat hospitalization. Gain and loss of body weight was strongly associated with changes in fat mass in these patients. 1–12 Phase angle measured by bioelectrical impedance analysis in monitoring body composition changes related to treatment and to parenteral nutrition in patients irradiated due of HNC Teresa Małecka-Massalska, Paweł Gołębiowski, Radosław Mlak, Tomasz Powrózek, Monika Prendecka, Anna Brzozowska & Maria Mazurkiewicz Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11 Street, 20–080, Lublin, Poland, Department of Oncology, Medical University of Lublin, Jaczewskiego 7 Street, 20–090, Lublin, Poland Introduction: Every year, over 600 thousands new cases of Head and Neck Cancer (HNC) are diagnosed. Progressive weight loss and malnutrition are generally found in those patients, especially under treatment (surgery, radiotherapy [RTH], chemotherapy [CTH]) conditions. Nutritional deficiencies have a significant influence on mortality and quality of life in patients with HNC. Bioelectrical impedance phase angle (PA) obtained by bioelectrical impedance analysis (BIA), as a measurable indicator of the body condition at the cellular level, is an alternative parameter to laboratory and anthropometric methods to measure and monitor nutritional status of patients with cancer. The aim of the study was to monitor the changes of PA in adult patients with HNC before each RTH cycle classified as well-nourished, moderately malnourished and severely malnourished according to the SGA scale and the effect of nutritional intervention on the value of PA. Methods: HNC patients were included in the study (n = 30, men, stages: I-IV). All participants were irradiated using IMRT technique (doses: 50-70Gy). Baseline assessment included: demographic, tumour related, nutritional and clinical evaluation as well as laboratory tests (albumin, prealbumin, transferrin, total protein), subjective global assessment (SGA) and PA measured by BIA at 4 frequencies (5/50/100/ 200 kHz) before each RTH cycle. Results: Significantly higher values of PA (50 kHz) have been found in SGA C patients when compared to those SGA A or B, before 6-th (5.48 vs 4.45; p = 0.0418) and 7th cycle of RTH (5.56 vs 4.37; p = 0.0095). In patients treated with parenteral nutrition significantly higher values of PA (50 kHz) measured before 4-th (5.72 vs 4.25; p = 0.0124) and 5-th (5.48 vs 4.38; p = 0.0411) cycle of RTH were found. Conclusions: Our results have shown potential usefulness of PA measured by BIA in monitoring body composition changes related to treatment and to parenteral nutrition in patients irradiated due of HNC. 2–06 Anti-sarcopenic effect suggested by combination of ARB and statin in patients with cardiovascular disease Haruhito Harada, Ryo Shibata, Kazunori Yamaji, Hiroshi Niiyama, Atsushi Katoh & Hisashi Kai Department of Cardiology, Kurume University Medical Center, Kurume, Japan Introduction: Reduction of skeletal muscle mass is the most important component on diagnosis of sarcopenia. Aging and chronic heart failure due to cardiovascular diseases (CVDs) accelerates reduction of skeletal muscle. We previously reported the possibility of statin to treat sarcopenia with CVD. On the other hand, some angiotensin receptor blockers (ARBs), such as telmisartan and irbesartan, induce the activation of PPARγ and the increase of adiponectin, which are known to promote muscle performance and protect skeletal muscle against inflammation and injury. The purpose of this study was to assess the effectiveness of statin and ARB for an anti-sarcopenic effect in patients with CVD. Methods: Study design was a single center retrospective cross-sectional analysis. 670 in-patients with CVD were divided into four groups including patients taking neither stain nor ARB (control), statin alone, ARB alone and both ARB and stain (ARB/statin) for more than 4 weeks. Skeletal muscle volume was assessed by bioelectrical impedance assay. Skeletal muscle index (SMI) and other variables were statistically compared among four groups. Results: No significance in SMI was found in statin and ARB groups compared with control group. However, SMI was significantl

Introduction: Loss of body weight in patients with heart failure (HF) is known as cachexia and associated with poor prognosis. However, there is a paucity of data regarding changes in body composition, namely, fat, muscle, and bone mass. Methods: We retrospectively analysed 32 consecutive patients with heart failure (56% men, left ventricular ejection fraction(LVEF) 41 + À14%, NYHA2.0 + À0.5), who experienced re-hospitalization due to worsening HF and had two or more results in dual-energy X-ray absorptiometry (DXA). To minimize influences by excess fluid in body, DXA was measured at stable state after decongestion therapy. Results: Twenty-two (69%) patients had an ischemic aetiology and 13 (41%) was categorized as heart failure with preserved LVEF (LVEF > =50). Median interval between the two measurements of DXA was 415 (IQR: 263, 763) days. In the first measurement, low muscle mass defined by the Asian Working Group for Sarcopenia (i.e., <7.0 kg/m2 in men and <5.4 kg/m2 in women) was observed in 72% of patients. During follow-up period, 69%, 72%, 56%, and 88% of patients experienced weight loss, fat loss, appendicular skeletal muscle loss, and bone loss, defined as any loss of body weight or each body component, respectively. Weight loss was correlated with fat loss (r = 0.77, p < 0.001) and appendicular skeletal muscle loss (r = 0.35, p = 0.047), but not with bone loss (r = 0.08, p = 0.67). Eleven patients with longer history of HF (>5 years) showed greater weight loss than 21 patients with shorter history (À6.5 + À5.7 vs À0.4 + À8.0%, p = 0.03) whereas none of age, LVEF, and biomarkers (serum albumin, creatinine, lymphocyte count, C-reacting protein, B-type natriuretic peptide) could not predict weight loss, fat loss, and skeletal muscle loss. Conclusions: Weight loss was frequently observed in patients with heart failure requiring repeat hospitalization. Gain and loss of body weight was strongly associated with changes in fat mass in these patients. [1][2][3][4][5][6][7][8][9][10][11][12] Phase angle measured by bioelectrical impedance analysis in monitoring body composition changes related to treatment and to parenteral nutrition in patients irradiated due of HNC Introduction: Every year, over 600 thousands new cases of Head and Neck Cancer (HNC) are diagnosed. Progressive weight loss and malnutrition are generally found in those patients, especially under treatment (surgery, radiotherapy [RTH], chemotherapy [CTH]) conditions. Nutritional deficiencies have a significant influence on mortality and quality of life in patients with HNC. Bioelectrical impedance phase angle (PA) obtained by bioelectrical impedance analysis (BIA), as a measurable indicator of the body condition at the cellular level, is an alternative parameter to laboratory and anthropometric methods to measure and monitor nutritional status of patients with cancer. The aim of the study was to monitor the changes of PA in adult patients with HNC before each RTH cycle classified as well-nourished, moderately malnourished and severely malnourished according to the SGA scale and the effect of nutritional intervention on the value of PA. Methods: HNC patients were included in the study (n = 30, men, stages: I-IV). All participants were irradiated using IMRT technique (doses: 50-70Gy). Baseline assessment included: demographic, tumour related, nutritional and clinical evaluation as well as laboratory tests (albumin, prealbumin, transferrin, total protein), subjective global assessment (SGA) and PA measured by BIA at 4 frequencies (5/50/100/ 200 kHz) before each RTH cycle. Results: Significantly higher values of PA (50 kHz) have been found in SGA C patients when compared to those SGA A or B, before 6-th (5.48 vs 4.45; p = 0.0418) and 7th cycle of RTH (5.56 vs 4.37; p = 0.0095). In patients treated with parenteral nutrition significantly higher values of PA (50 kHz) measured before 4-th (5.72 vs 4.25; p = 0.0124) and 5-th (5.48 vs 4.38; p = 0.0411) cycle of RTH were found. Conclusions: Our results have shown potential usefulness of PA measured by BIA in monitoring body composition changes related to treatment and to parenteral nutrition in patients irradiated due of HNC. Background: Several definitions are used to describe sarcopenia, a progressive decrease in muscle that occurs with aging. Definitions include a measure of muscle mass, and may also include a measure of muscle strength and/or physical function. Each measure can be operationalized using numerous methods and thresholds. The goal of this review was to estimate the prevalence of sarcopenia for each definition in community-dwelling older adults, and to explore potential sources of heterogeneity observed in studies using the same definition.
Methods: A systematic review was conducted searching for sarcopenia and muscle mass terms. Screening and data extraction were conducted in duplicate. Overall prevalence for each sarcopenia definition was estimated using a DerSimonian and Laird's random effect model and stratified by sex and ethnicity. Secondary analyses explored potential sources of heterogeneity within definitions including participant age, muscle mass measurement techniques, and thresholds for muscle mass and gait speed. Results: Using data from the 109 included articles, the lowest pooled prevalence (%, 95% confidence interval) estimates were for the European Working Group on Sarcopenia/Asian Working Group on Sarcopenia (12.9%, 9.9-15.9), International Working Group on Sarcopenia (9.9%, 3.2-16.6), and Foundation for the National Institutes of Health (18.6%, 11.8-25. 5 Conclusions: The prevalence of sarcopenia ranged between 9.9% and 40.4%, depending on the definition, suggesting that the definitions may not be measuring the same underlying construct. Within definitions, participant age and the muscle mass cut points may potentially explain differences in prevalence. Overall, this review suggests that there is significant heterogeneity between and within sarcopenia definitions that needs to be better understood prior to using sarcopenia in a clinical context.

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Sarcopenia and sarcopenic obesity in women with and without breast cancer, Brazil Objective: To estimate the prevalence of sarcopenia and sarcopenic obesity in women with and without breast cancer.
Methods: A transversal with group control study carried out in a reference center for diagnosis and treatment for breast cancer. Classification of stages of sarcopenia pre-sarcopenia, relative skeletal muscle index (RSMI) <5.45 kg/m 2 ; Sarcopenia, RSMI <5.45 kg/m 2 associated with manual grip <20 kg (dynamometry) or walking speed <0.8 m/s; And severe sarcopenia, RSMI <5.45 kg/m 2 associated with manual grip <20 kg and walking speed <0.8 m/s. The diagnosis of sarcopenic obesity was confirmed in those with sarcopenia or severe sarcopenia concomitant with the percentage of total fat mass (DXAbeam absorptiometry method) greater than 38%. For each menopausal status (pre / post-menopausal), two groups (case-cancer and control-without cancer) were matched by age (30 to 80 years).
Results: A total of 262 women participated in the study, of which 46.6% were premenopausal women. The mean age of participants was 51.4 years (± 11.3); The premenopausal group was younger (p < 0.001). The prevalence of sarcopenia was 5% (n = 13), similar between status and also between groups; When pre-sarcopenia was added (n = 13), the prevalence was 9.9%. The prevalence of sarcopenic obesity was 4.2% (n = 11) in the total sample. In both menopausal status, there was an association between sarcopenia and sarcopenic obesity (premenopausal = 100.0% and postmenopausal = 83.3%), with no significant difference when comparing this prevalence between the statuses or between the groups.
Conclusions: The prevalence of pre-sarcopenia was equal to the prevalence of sarcopenia and there was no association with menopausal status or even with the presence of the disease. Obesity-related sarcopenia was associated with the presence of sarcopenia in both groups and among status. The menopausal status and presence of breast cancer were not associated with the analysed variables.

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High muscle mass associated with reduced prognosis among patients with acute calculous cholecystitis Eyal Leibovitz 1 , Nadav Ben-David 2 , Lea Shibanov 2 , Sorin Elias 3 & Mordechai Shimonov 2,4 1 Department of internal medicine "A", Yoseftal hospital, 2 Department of Surgery "A" at the Wolfson Medical Center, 3 Department of radiology at the Wolfson Medical center, Holon, 4 The Sackler school of medicine, Tel Aviv University, Israel Background: Sarcopenia and low muscle mass are considered a bad prognostic marker for many patient populations. We studied body composition and hospital prognosis of patients admitted because of acute calculous cholecystitis (ACC We also demonstrated that TNF-α is associated with low ASMI in CHC patients.

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MRI-based body composition profiling of sarcopenia shows association with prior health care burden in a large-scale population study Introduction: Sarcopenia is often defined using appendicular lean tissue normalized with height 2 , measured by DXA. An alternative approach may be the use of MRI-based thresholds, particularly as a combination with emerging body composition profiling techniques. In the current study, MRI-based thresholds were used to define sarcopenia in a large-scale population study, and associations of body composition measurements with prior health care burden were calculated. Methods: 5.681 subjects (3.086 females, 2.595 males) were included from the imaging sub-cohort of UK Biobank. All subjects were scanned using a neck-to-knee Dixon MRI protocol on a 1.5 T MR-scanner. Body composition profiling was performed with AMRA® Profiler (AMRA‚ Sweden) measuring visceral adipose tissue index (VATi = VAT/ height 2 ), abdominal subcutaneous adipose tissue index (ASATi = ASAT/height 2 ), total thigh muscle volume index (TTVi = TTV/height 2 ), liver proton density fat fraction (PDFF), and intra-muscular fat in the anterior thigh muscles (IMAT). Gender-specific TTVi thresholds for sarcopenia, based on comparisons with DXA, were used (TTVi <3.64 l/m 2 for men and TTVi <2.76 l/m 2 for women) maximizing sensitivity and specificity. Finally, associations between the MRI-acquired body composition measurements and prior health care burden were calculated, controlling for sex and age. Health care burden was defined as number of night's hospitalization up to ten years prior to the MRIscan, truncated at 30 nights, excluding gestational-related hospitalization.
Results: 986 subjects were defined as Sarcopenic using MRIbased TTVi thresholds, sensitivity and specificity compared to DXA was 0.88. In this group VATi and IMAT were associated with prior health care burden (p = 0.011, OR = 0.34 and p < 0.001, OR = 1.99 respectively). No significant associations were found for ASATi, TTVi or liver fat fraction.
Conclusions: MRI-based defined sarcopenia allow the inclusion in rapid body composition MR-scans enabling a detailed view of the patient's disease state. Body composition profiling revealed a strong association between IMAT and prior health care burden for the sarcopenic group. Background: We aimed to assess the association between sarcopenic obesity and functional capacity, clinical outcome in patients with heart failure (HF) using different diagnostic criteria for obesity. Methods: We studied 251 patients with HF (51 females, 67 ± 11 years) were recruited as a part of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) program. Sarcopenia was defined as either a gait speed of <0.8 m/s or reduced handgrip strength (<30 kg in males and <20 kg in females), together with loss of skeletal muscle mass, i.e., appendicular skeletal muscle mass two standard deviations below the mean of a healthy reference group aged 18-40 years. Obesity was defined by three different diagnostic criteria, 1) body mass index (BMI > 30 kg/m 2 ), 2) waist circumference (WC; >90 cm in males and >85 cm in females), and 3) body fat percentage (% fat; >30% in males and >40% in females). Sarcopenic obesity was considers as he combination of sarcopenia and obesity according to each definition. Functional capacity was assessed as peak oxygen uptake (peak VO 2 ), 6-minute walk test, and short physical performance battery (SPPB). Results: Prevalence of sarcopenic obesity was 2.8% (BMI criteria), 6.8% (% fat criteria), and 11.7% (WC criteria). Sarcopenic obesity defined by WC and %fat criteria had significantly lower value of peak VO 2 , 6-minute walk distance, and SPPB score than normal and obese alone group (all p < 0.05). There were 28 deaths during a 24-month followup. Sarcopenic obesity by any diagnostic criteria was not statistically significantly associated with all-cause mortality during follow-up.
Conclusions: Sarcopenic obesity defined by WC and body fat diagnostic criteria for obesity was associated with impaired functional capacity in patients with HF, however sarcopenic obesity defined by any diagnostic criteria were not sufficient to increase mortality.

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Muscle-derived exosome/miRNA-26a attenuates skeletal muscle wasting and cardiomyopathy in chronic kidney disease mice Introduction: Uremic cardiomyopathy and muscle atrophy contribute to CKD-induced morbidity and mortality. Exosomes, natural carriers of many signal molecules including microRNA (miR), mediate organ to organ communication. We hypothesized that miR-26 would benefit both CKD-induced muscle wasting and cardiomyopathy through exosomemediated muscle-heart crosstalk. Methods: We used an engineered exosome vector which contains an exosomal membrane protein gene Lamp2b fused with muscle specific surface peptide for targeting delivery. Exosome encapsulated miR-26a precursor RNA (Exo/miR26) were generated in muscle satellite cells and injected into the tibialis anterior (TA) muscle of CKD mice (5/6 subtotal nephrectomy) for 12 weeks. NanoSight instrument was used to quantify exosomes. A miR deep sequencing assay and qPCR were used to identify microRNA expression. Cardiac ultrasound was used to detect heart size and function. In-Vivo Xtreme camera system was used to detect exosome in vivo.
Results: miR-26a was decreased in skeletal muscle and heart of CKD mice. Uremic serum enhanced secretion of miR-26a exosomes in cultured C2C12 skeletal and H9C2 cardiac muscle cells. The intervention of Exo/miR26a increased the expression of miR-26a in skeletal muscle and heart, as well as increased muscle cross-section area and decreased CKDinduced upregulation of atrogin-1 and MuRF1. Curiously, cardiac fibrosis lesion was partially depressed, and FoxO1, α-SMA, connect tissue growth factor (CTGF), fibronectin and collagen1α were decreased in CKD mice with intramuscular injection of Exo/miR-26a. Echocardiography showed that the percentage of ejection fraction was increased in CKD mice treated with Exo/miR26a. Using fluorescence dye labeled Exo/miR26a, we found that the fluorescence intensity in heart was correlated with skeletal muscle, examined by linear regression. We found that miR-26a directly inhibits FoxO1 and CTGF, which provided mechanism for inhibition of muscle atrophy and cardiac fibrosis by Exo/miR26a. Conclusions: overexpression of miR-26a in muscle prevents CKD-induced muscle loss and attenuates cardiac fibrosis via exosome-mediated muscle-heart crosstalk. Funding: NIH R01 AR060268.

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Blunted activation of satellite cells in parallel with up-regulated proliferation of connective tissue fibroblasts in ageing human skeletal muscle undergoing acute regrowth and regeneration Background/aims: The cellular mechanisms responsible for the attenuated regenerative capacity in ageing human skeletal muscle are not fully understood. Here we examined the acute activation of muscle satellite cells (SC) and connective tissue fibroblast (Tcf4) in young and older human subjects after 4 days of immobility-induced muscle atrophy and again after 6 days of re-ambulation. Methods: Myofiber atrophy was induced by knee-bracing for a period of 4 days in young (YM,~20 yrs., n = 9) and aged (OM,~70 yrs., n = 9) male adults. Muscle regrowth after atrophy was induced by 6 days of re-ambulation supplemented by 2 sessions of supervised unilateral resistance training for the disused leg. Measures of SC and Tcf4 expression were analysed in muscle biopsies (VL) obtained Pre, after 4 days immobility (4d-Imob) and after additional 6 days of re-mobilization (6d-REmob). SCs were quantified and expressed as a percentage of total myonuclei (SC/MN) in MHC-I and MHC-II sensitive immunoflourescent stainings of muscle cross sections to determine fiber type, with Pax-7 as a marker of SCs, and DAPI and laminin stainings performed to verify the spatial location of SC and myonuclei. Results: We report that SC in type I fibers increased in YM and OM at 6d-REmob compared to Pre and 4d-Imob (P < 0.01). Further, SC in type II fibers increased in YM with no change in OM at 6d-REmob compared to Pre and 4d-Imob (P < 0.01). An overall effect of age was found for SC cell content in relation to type I and type II fibers (P < 0.01), thus demonstrating blunted SC proliferation in OM, indicating an impaired regenerative capacity. To further describe the SC pool, we determined the proportion of active SCs using NCAM, Ki67 and DAPI staining, with activated SCs identified as both NCAM and Ki67 positive (NCAM + /Ki67 + ). NCAM + /Ki67 + SC's increased at 6d-REmob in YM but not OM (4d-Imob:YM 0.6 ± 0.5/100 fibers; OM 0.2 ± 0.4/100 fibers & 6d-Rmob: YM 2.5 ± 1.2/100 fibers; OM 0.6 ± 0.5/100 fibers. P < 0.05). However, a markedly elevated expression of NCAM À /Ki67 + cells was noted in OM after remobilization. Further analysis of Tcf4 expression revealed that connective tissue fibroblast (Tcf4 + /Ki67 + ) became markedly more activated in OM compared to YM at 6d-REmob compared to 4d-Imob (4d-Imob: OM 1.1 ± 1.3 /100 fibers; YM 2.6 ± 1.5/100 fibers & 6d-Rmob: OM 7.2 ± 7.5/100 fibers; YM 2.8 ± 1.7/100 fibers. P < 0.05).
Conclusions: The present study demonstrates a blunted activation of skeletal muscle satellite cells in parallel with up-regulated proliferation of Tcf4 connective tissue fibroblasts in ageing human skeletal muscle with acute regeneration. Our data support the proposition that progressive fibrosis with ageing may inhibit proliferation of myogenic progenitor cells (SC's) and thereby contribute to the progressive impairment in regenerative capacity of human skeletal muscle with aging and disease.

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Molecular characterization of novel serous ovarian cancer variant associated with myosteatosis Introduction: Ovarian cancer is the fifth most common cause of cancer death in women. Decreased muscle radiodensity is a consequence of ovarian cancer associated with truncated disease-free and overall survival. We postulated that the molecular features of the tumour drive changes in muscle radiodensity/myosteatosis. Methods: Microarray and RNASeq data from serous ovarian cancer patients (n = 514) was obtained from The Cancer Genome Atlas Project. Body composition analysis was conducted for patients with available computed tomography scans at L3 (n = 112). Myosteatosis was assigned if patients had an L3 mean muscle radiodensity <30 HU. A predictive model was built to classify patients without a scan as myosteatosis-associated variant positive (MAV+) or negative (MAV-), using orthogonal partial least squares discriminant analysis. We then studied transcriptional differences between MAV+ and MAV-. Results: MAV+ patients had significantly decreased disease free and overall survival (Log rank p-value <0.05) and did not significantly differ in muscle or adipose surface area at L3. A model distinguishing MAV+ and MAV-patients (R2 = 0.954; Q2 = 0.802; CV-ANOVA p = 1.17E-32) was validated using two independent external validation datasets. Differential expression showed tumors from MAV+ patients had increased cell cycle progression, increased proliferation, increased survival, decreased apoptosis, increased insulin signaling, decreased triacylglycerol degradation, increased lipid biosynthesis.

Conclusions:
We have identified a novel variant of serous ovarian carcinoma associated with a bad prognosis and with gross effects on the health of the host (myosteatosis). We provide a picture of the molecular features of ovarian cancers that are associated with this novel variant. Our data suggests tumors from MAV+ patients are more proliferative, resistant to cell death and have altered energy metabolism compared to tumors from MAV-patients. If this variant preferentially uses lipids as fuel, then inhibition of related metabolic pathways would not only inhibit tumour growth, but also simultaneously enhance the health of the host. Introduction: Life-long regeneration of healthy muscle by cell transplantation is an ideal therapy for patients with degenerative muscle diseases. Yet, obtaining muscle stem cells from patients is very limited due to their exhaustion in disease condition. Thus, development of a method to obtain healthy myogenic stem cells is required.
Results: The iMSCs showed effective differentiation into multinucleated myotubes and also higher proliferation capacity than muscle derived stem cells both in vitro and in vivo. The iMSCs do not lost their proliferation capacity though the passaging number is increased. We further isolated CD106-negative and α7-integrin-positive iMSCs (sort-iMSCs) showing higher potent myogenic differentiation capacity than iMSCs. Moreover, genome-wide transcriptomic analysis of iMSCs and sort-iMSCs, followed by network analysis, revealed the genes and signaling pathways associated with enhanced proliferation and differentiation capacity of iMSCs and sort-iMSCs, respectively. Conclusions: The stably expandable iMSCs provide new source for drug screening and muscle regenerative therapy for muslce wasting disease including sarcopenia.

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Relationship between muscle mass and usual walking speed mediated by muscle strength, depression, and respiration in younger elderly women: preliminary study Introduction: Gender-related differences in sociodemographic, medical, psychological and functional conditions were evaluated in older adults living in the community.
Methods: This multicenter study was conducted as part of the VERISAÚDE project, a prospective cross-sectional population-based study of community-dwelling individuals aged 65 years and over enrolled in senior community centers of North West Spain (n = 749). From 2013 to 2014, a comprehensive gerontological assessment (CGA) was used to assess the social, medical, psychological and functional needs and risk factors of this representative population.
Results: Significant gender-related differences were not found in visual impairment, self-rated health and instrumental activities of daily living. Males showed significantly higher prevalence than females of hearing impairment, toxic habits, comorbidity, and better social resources and quality of life, while females showed a higher prevalence of frailty, higher risk of malnutrition, more drug consumption and polypharmacy, poor cognitive scores, and higher depressive scores. Significant gender-related differences were not found in visual impairment, self-rated health and instrumental activities of daily living. Conclusions: Gender differences were observed in different health variables. We conclude that CGA is a valid multidimensional diagnostic instrument to identify, quantify and manage the needs of older adults living in the community. Importantly, gender-related differences should be specifically explored and taking into account when developing sociosanitary measures to promote active aging and improve the quality of life of older adults. In future longitudinal studies, it should be explored whether these differences are the result of the different level of contact with risk factors, or if they result from a different gender-related reaction to the same risk factors. This work was supported by the Xunta de Galicia, FrailNet network IN607C 2016/08.

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Age-and gender-related differences in myosin heavy chain isoforms with muscle strength, quality and function , and muscle quality (24.8%, p < 0.01), whereas the women showed a significant lower only in isometric strength (24.2%, p < 0.05) and isotonic power (28.3%, p < 0.01) with aging. In addition, the proportion of MHC IIa was significantly lower in both OM (p < 0.05) and OW (p < 0.05) than in YM and YW, respectively. However, only OM showed a significant larger in MHC-I (p < 0.01) than YM, and high proportion of MHC-I found in both younger and older women. Also, there was negative correlation between MHC-I isoform and isokinetic strength and muscle quality.
Conclusions: These results show that gender related to differences seem to exist in muscle mass, strength, and function with advancing the aging. The influence of muscle strength and function on aging significant affects in men, not women. Larger proportion of MHC-I are associated with lower muscle strength and function, especially in women with younger age.

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Sexual dimorphism in the skeletal muscle transcriptome and urinary proteome indicate sex specific pathways involved in regulation of muscularity in cancer patients Introduction: Sexual dimorphism exists in skeletal muscle mass, fiber type, fiber size and response to diseases such as cancer. Our hypothesis is that variations in muscularity in men and women with cancer are associated with different molecular signatures. Methods: Molecular data were obtained from 41 K Agilent microarray analysis of rectus abdominus muscle samples (n = 94, 55♂, 39♀) and LC-MS analysis of urine samples (n = 112, 63♂, 49♀) from patients with cancer. Computed tomography images were used to measure the skeletal muscle index (SMI) for all patients in the study. Female and male patients were classified as sarcopenic if their SMI <38.5 cm 2 /m 2 and <52.4 cm 2 /m 2 , respectively. Differentially abundant features were identified and studied using pathway analysis software. Results: Men were significantly more muscular (p < 0.0001) and had greater variation in muscularity than women. Table 1 shows a summary of results. We found little overlap in differentially abundant features in men and women. Muscularity was positively associated with proliferative pathways including JAK/STAT signaling in men and growth hormone signaling in women. Muscularity was negatively associated with mismatch DNA repair in men but not women, and with ER mediated phagocytosis in women but not in men.
As with the muscle transcriptome, the urine proteome suggested altered carbohydrate metabolism in women, but not men. Finally, inflammation was associated with low muscle regardless of sex or data level. While we identified similar downstream features (e.g. NFkB signaling), there were differences in upstream signaling molecules. For example, sarcopenia was associated with increased IL25 expression and IL6 expression in men and women, respectively.
Conclusions: Cancer associated muscle wasting involves decreased anabolism and increased catabolism. While our results agree with this, we find different anabolic and catabolic pathways are altered in sarcopenic muscle in men and women. Development of interventions for cancerassociated wasting would benefit from a sex-specific approach.

3-41
Proportion of single frailty criteria in frail and pre-frail older adults Introduction: Frailty geriatric syndrome is a dynamic process of increased vulnerability to stressors exposing the individual to a higher risk of negative health-related outcomes. This status may represent a transition phase between successful aging and disability. In order to illustrate the extent to which pre-frail older adults differed from frail older adults, the proportion of single frailty criteria met was compared between groups. Methods: A cross-sectional study was carried out covering a representative sample (n = 749) of older adults aged ≥65 years (mean age = 75.8 ± 7.2). Frailty status was diagnosed based on Fried's phenotypic definition (unintentional weight loss, exhaustion, low physical activity, low walking speed, and low grip strength). This instrument classifies people into pre-frail (if they met 1-2 criteria), non-frail (if no criteria were present), and frail (≥3 criteria) categories. Comparisons between pre-frail and frail groups were performed by Chi-square tests.
Results: As expected, results showed that the proportion of individual criteria was significantly higher in frailty compared with pre-frailty (all ps < .001). "Low grip strength" was the most frequent criterion in the pre-frail population (95.0%), followed by "slow-walking time" (13.2%), "exhaustion" (6.7%), "unintentional weight loss" (4.6%), and "low physical activity" (1.7%). Low grip strength and slow walking time were also the two most frequent physical alterations in the frail group and the proportion of all criteria except low grip strength was strongly increased in frailty.
Conclusions: The fact that low grip strength was the criterion with more positive cases is relevant since weakness is considered as a warning sign of increasing vulnerability in early frailty development, and it has been shown to be a manifestation of the sarcopenia, possibly predicting dismobility syndrome. Thus, the prevention of sarcopenia is relevant for reducing the risk of frailty in elderly. This work was supported by the Xunta de Galicia, FrailNet network IN607C 2016/08.

3-43
Association between computed tomography assessment of skeletal muscle index and muscle attenuation and chemotherapy intolerance in patients with head and neck cancer: preliminary results Background: It is unclear whether muscle mass depletion is associated with chemotherapy intolerance in head and neck cancer (HNC) patients. We aimed to assess the association between pre-treatment computed tomography (CT) body composition measurements and chemotherapy intolerance in HNC patients. Skeletal muscle aging is associated with a progressive decline in muscle mass and strength, a biological process known as sarcopenia. A growing body of evidence indicates that mitochondrial dysfunction is causally involved in the development of sarcopenia. Calorie restriction (CR) is amongst the most efficient interventions to attenuate sarcopenia, and this strategy is thought to mediate its effects through its impact on mitochondria. However, many of the specific effects of CR on mitochondrial biology, especially in aged skeletal muscle, remain unclear or unknown.
In particular, the effects of aging and CR on skeletal muscle mitochondrial morphology, which is known to greatly impact mitochondrial function, remain largely under investigated.
The objectives of the present study were (i) to investigate the effects of aging on mitochondrial morphology in glycolytic and oxidative skeletal muscles and (ii) to define whether CR can attenuate the effects of aging on mitochondrial morphology. The following 3 groups of male Sprague Dawley rats were studied: 1-adult (9-month-old) ad-libitum fed (AL); 2-old (21-month-old) AL fed and; 3-old (21-month-old) calorie restricted (CR; 40% reduction in food intake during 13 months) rats. The morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria was assessed using a 2-dimensional approach in the oxidative soleus (SOL) and glycolytic white gastrocnemius (WG) skeletal muscles. In the SOL, our results indicated that aging is associated with a fragmentation of both SS and IMF mitochondria. CR in the SOL seems to attenuate the agingrelated increase in mitochondrial fragmentation. In the WG, our results indicate that aged muscle displays enlarged SS mitochondria and more complex and branched IMF mitochondria. In the WG, CR did not attenuate the effects of aging. Our results therefore indicate that the effects of aging and calorie restriction on mitochondrial morphology are muscle specific.

3-45
Role of dietary protein and exercise on tryptophan-kynurenine metabolism in older patients during muscle disuse Introduction: Old age and frailty are associated with increased immune activation and alterations in tryptophankynurenine metabolism. The activated immune system can be detected by increased neopterin and kynurenine to tryptophan concentrations. The aim of this prospective study was to evaluate the effect of a protein optimized diet on biomarkers of immune activation and tryptophan metabolism in older patients with hip fracture. Methods: Forty participants (mean age: 79.5 yrs.) were randomly assigned to an intervention group (n = 20) or to a control group (n = 20). During hospitalization (mean length of stay: 16.4 d), the intervention group received a protein optimized diet (1.5 g/kg per day) and was instructed to moderate resistance training. The Mini Nutritional Assessment was used to assess malnutrition. Hand-grip strength was measured using the JAMAR Dynamometer. Serum concentrations of tryptophan and kynurenine were determined by HPLC and immune system biomarker neopterin by ELISA at admission, discharge and at 1-month follow-up. Results: At admission, 10.5% of the patients were malnourished and another 26.3% were at risk of malnutrition. The intervention group consumed more protein during hospitalization compared with the control group (p < 0.001): 70.5(SD 13.5)g/d vs. 52.3(SD 13.9)g/d. Older patients with hip fracture exhibit higher degrees of immune system activation as indicated by biomarker concentrations compared with reference values obtained from a healthy population ( Table 1). None of the outcomes showed a significant intervention effect or interaction of intervention and time effect. Improvements in maximum hand-grip strength after intervention were related to lower neopterin and higher tryptophan levels (p = 0.0113 and p < 0.0001, respectively). Conclusions: Protein enrichment enabled older patients to increase protein intake to levels that are 80% of their opti-mized intake of 1.5 g/kg per day, however, did not affect immune-systems biomarker and tryptophan metabolism during the early postoperative period. Muscularity may affect biochemical pathways which are linked to immune activation responses following injury.

3-46
Challenge for the identification of new biomarkers for the diagnosis of Sarcopenia While it is recognized that cachexia effects profound metabolic changes in a broad range of tissues, it is poorly understood how the resultant cachectic metabolome affects the inducing cancer biology. Recent studies characterizing aggressive cancers highlight novel lipid metabolism processes as essential for sustaining aggressive features and cancer cell survival. In this study, we used IPA extraction and RP/C8 + mode MS methodology for the isolation and unbiased detection of lipid metabolites in conditioned media from differentiated human adipocytes previously exposed to cachexia-inducing vs non-inducing cancer cells. Of the more than 120 lipid metabolites detected, we focused on the lysophospholipids that have been implicated in aggressive cancer metabolism from other studies. Fourteen of these metabolites were detected in all samples with 5 of the 6 significantly elevated metabolites in the cachexia-inducing exposure precisely matching the known lysophospholipids species to be taken up and utilized by mKRAS cancer cells. Through this focused study, we demonstrate that aggressive cancer states induce cachectic metabolic changes in primary human adipocytes, resulting in the release of specific lysophospholipid metabolites that cancer cells can uptake and utilize to support drug resistance and survival. These findings expand our understanding of fundamental cancer biology and new targetable dependencies for therapeutic development in the most challenging cancers.

5-15
Myonuclear number after xenograft-induced cancer cachexia is unchanged Introduction: Cachexia is a severe wasting disorder that involves severe weight loss and muscle atrophy, often resulting in immobility and cardiac/respiratory failure. In skeletal muscle, the atrophy has been reported to be accompanied by apoptosis, contributing to the atrophy. In our study, we have investigated whether myonuclei are lost during prostate cancer-induced atrophy in skeletal muscle. Methods: We induced cachexia by xenografting prostate PC-3 cells to nu/nu mice. Six weeks after the injections, we used in vivo microscopy to measure the cross-sectional area and myonuclei number in extensor digitorum longus muscle (EDL). Additionally, the EDL, soleus and tibialis muscles were harvested for ongoing ex vivo immunohistochemical analysis of myosin heavy chain, cross-sectional area and myonuclei numbers. TUNEL-labelling was performed for the presence of apoptosis in the tissue. We also investigated the general muscle condition by HE-staining. Results: Following the injections, the mice had lost 12% their peak body weight and 16% body weight compared with control animals. In vivo measurements of EDL showed a 25% decrease in myofibre CSA (p = 0.0022) with no apparent loss of myonuclei. This was substantiated by the finding that TUNEL-labelling in the cachectic muscles was similar to control muscles. We also observed a decrease in heart wet weight and increased size of the spleen, accompanied by an overall 14% decrease in wet weight of the muscles analysed. HE-sections did not differ between the groups. Conclusions: Our data indicate that cancer cachexia causes no loss of myonuclei. The absence of apoptosis and abnormal HE-staining indicate that cachexia is not a degenerative process, and the potential for recovery is latent in the muscle tissue. Cachexia is a leading predictor of mortality across chronic diseases. However, there are no widely efficacious interventions to reverse disease progression. As with many diseases of complex aetiology, the long-term cachexia observed in the clinic has proven difficult to model in the lab with chemical or surgical insults. To address this need, our approach is to study the evolutionarily relevant host-parasite interaction between mice and Toxoplasma gondii where cachexia develops as a natural part of chronic infection. We have recently shown that adult mice infected with Toxoplasma loose 20% of their body mass and sustain inflammation, muscle and adipose loss over 5 months despite regaining eating. Toxoplasma cachexia is robust, observed across sexes, several mouse strains and animal facilities. Using a combination of host and parasite genetic tools we show that mice deficient in components of the IL-1 pathway are protected from chronic cachexia. The liver and the brain are sites of sustained IL-1 production and IL-1RÀ/À mice have reduced inflammation in these tissues and reduced circulating IL-6, TNF and IFN-y. Importantly, parasite burden is unchanged in IL-1RÀ/À animals, consistent with the hypothesis that IL-1 functions as a master regulator of host homeostasis rather than as a pathogen restriction mechanism. This is consistent with the observation that cachectic mice are rely on beta-oxidation as an energy source but this metabolic shift is rescued in IL-1RÀ/À animals. Importantly, the lipid metabolism program is primarily upregulated in the liver, rather than the muscle or adipose depots. Ongoing work is aimed at pinpointing how liver-brain cross talk regulates contributes to cachexia biology.

5-17
Improved muscle fiber diameter and motoneuron number by s-oxprenolol treatment in a mouse model of amyotrophic lateral sclerosis (ALS) Degeneration of upper and lower motoneurons in spinal cord, brainstem and motor cortex result in progressive neurodegenerative paralysis and death in amyotrophic lateral sclerosis (ALS), which also causes a form of cachexia. Currently, only riluzole is approved for the treatment of ALS. Here, we tested novel therapeutic options (beta blockers vs riluzole or placebo) in an internationally standardized and established model using male and female transgenic G93A ALS mice. Survival after birth was significantly improved by treatment (table 1). In a second set of experiments, effects of compounds were tested on body weight, biochemical parameter, myocyte diameter and motoneuron number 41 days after first symptoms of ALS (Table 2). In summary, S-oxprenolol improves survival by protecting mononeurons, reducing loss of body weigt and lean mass via downregulation of wasting related signaling.

6-11
Skeletal muscle mitochondrial energy metabolism in cancer cachexia: Clinical and mechanistic approaches We also use an in vitro model of mouse skeletal muscle cells, C2C12 for the mechanistic analyses of muscle atrophy. Results: Our preliminary data on muscle biopsies seem to show a decrease of mitochondrial oxygen consumption linked to ATP synthesis (35%), energy wasting (30%) and maximal respiratory capacity (25%) in cachectic patients in comparison to non-cachectic patients. This suggests a global reduction in mitochondrial bioenergetics in cachexia that can be explained by specific respiratory complex alteration and/or decrease in mitochondrial content.
In vitro, we show that TNFα, a proinflammatory cytokine, induces a dose-dependent atrophy of differentiated C2C12 myotubes. Treating C2C12 with 125 ng/mL of TNFα for 48 h resulted in a significant myotube atrophy by 32%, without affecting mortality. Conclusions: Our data in skeletal muscle of cachectic patients seem to confirm mitochondrial bioenergetics alterations as described in murine models. Furthermore, our in vitro model of muscle atrophy will permit us to determine the links between muscle atrophy, mitochondrial energy metabolism and sarcoplasmic reticulum stress.  : p < 0.05 vs respective doses of r-oxprenolol.

6-12
The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study Introduction: Little is known about the brain mechanisms underlying cancer-associated weight loss (C-WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that C-WL patients have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward. Methods: In 12 cancer patients and 12 healthy controls, resting state functional connectivity (RSFC, resting brain activity observed through changes in blood flow in the brain which creates a blood-oxygen-level dependent [BOLD] signal that can be measured using functional magnetic resonance imaging[fMRI]) was used to compare three brain regions hypothesized to play a role in C-WL: the hypothalamus (homeostatic), the nucleus accumbens (hedonic), and the habenula (an important regulator of reward). In addition, the brain reward response to sweet juice was studied.
Participants included twelve patients with histological diagnosis of incurable cancer (solid tumors), a European Cooperative Oncology Group (ECOG) performance status of 0-2, and a ≥ 5% involuntary body weight loss from preillness over the previous 6 months and 12 non-cancer controls matched for age, sex, and race. RSFC between the hypothalamus, nucleus accumbens, and habenula, and brain striatum activity as measured by functional MRI during sweet juice reward delivery events were the main outcome measures. Results: After adjusting for BMI and compared to matched controls, C-WL patients were found to have reduced RSFC between the habenula and hypothalamus (p = 0.04) and between the habenula and nucleus accumbens (p = 0.014). C-WL patients also had reduced reward responses in the striatum compared to controls.
Conclusions: In C-WL patients, reduced connectivity between both homeostatic and hedonic brain regions and the habenula, and reduced reward to sweetness were observed. The habenula and striatum are potential therapeutic targets in C-WL. Introduction: Myostatin and activin A, two members of the superfamily TGF-β, have been shown to play a role on skeletal muscle mass regulation. In Humans, high plasma concentrations of activin A were observed in cancer patients, especially in cachectic subpopulations. The main objective of our study was to determine the modifications of blood myostatin, activin A and follistatin concentrations associated with head and neck cancers. Methods: 55 patients were included in the study: 32 in the cancer group (only squamous cell carcinoma) and 23 in the control group. The patients underwent a complete nutritional assessment and multiple samples: blood before and 7 days after surgery, skeletal muscle biopsies, tumour biopsies. Plasma concentrations of myostatin, activin and follistatin were measured before and after tumour removal surgery. Concentrations of myostatin, activin and follistatin were also measured in an incubation medium of a tumour biopsy. Results: Activin A and follistatin plasma concentrations were significantly increased in the cancer group (320 vs. 203 pg/ml; p < 0.001) (3593 vs 2148 pg/ml; p < 0.001), while myostatin plasma concentration was significantly decreased in this group (1542 vs. 2100 pg/ml; p = 0.010). Surprisingly, data of the 7th postoperative day showed an increase in plasma activin A concentration (379 vs 320 pg /ml; p < 0.001) while concentrations of myostatin and follistatin were not modified. A high postoperative systemic inflammation could explain these results. Myostatin, activin A and follistatin proteins were systematically detected in the medium of tumour a 48 hour-incubation period, providing a strong proof of the tumour production of these factors by squamous cell carcinoma.
Conclusions: The activin A/myostatin/follistatin is modified in the context of head and neck cancer. Activin A particularly seems to play a role in the occurrence of cachexia while follistatin could have a protective role for skeletal muscle mass.

6-17
The impact of race/ethnicity on the prognostic associations between general and visceral obesity and breast cancer outcomes Conclusions: Our study demonstrates racial/ethnic differences in the associations between obesity and BC outcomes, with high VAT and low BMI being independent prognostic for poorer outcomes only in white patients.

6-18
Intractable nausea and anorexia with weight loss in a patient with advanced breast cancer

Ronny Dev
University of Texas MD Anderson Cancer Center, Houston, TX, USA Aim: Highlight benefits of olanzapine for the control of nausea, anorexia resulting in weight loss in a patient with advanced breast cancer being evaluating in an outpatient Anorexia-Cancer Cachexia Clinic. Case Presentation: A 72 year old female with metastatic breast cancer involving the bilateral breasts, sternum and left proximal femur, who had initially undergone a rightsided mastectomy and subsequently had recurrence noted in left breast, sternum and left proximal femur which was receiving active treatment with letrozole, palboiciclib and denosumab at an outside institution. She presents for consultation with intractable nausea (rated 10/10) with occasional vomiting, anorexia (rated 7/10) with 35 pound weight loss. Nausea was triggered by overeating, movement and associated with diaphoresis above the neck. Previous workup included unremarkable upper and lower endoscopy and normal computed tomography scan of abdomen and gastro-motility studies. Patient's nausea was extensively treated with ondansetron, promethazine, meclizine, and amitriptyline without benefits. Subsequently, she was treated with keppra followed by topiramate for possible migraines induced nausea by a neurologist, which were ineffective in controlling symptoms. Patient denied rumination or anxiety triggering nausea but acknowledged that her quality of life had declined due to her symptom burden. For symptomatic treatment of nausea, patient was prescribed olanzapine 2.5 mg by mouth every 12 hours as needed. She was also advised to follow-up with neurologist and recommended weaning off topiramate which had been ineffective. At 1 and 3 month follow-up, patient rating of nausea was 0/10 without anorexia and was gaining weight while tolerating treatment.
Conclusions: Olanzapine, an atypical antipsychotic, has potent anti-nausea effects via blocking multiple neuronal receptors. Olanzapine has potent 5-HT3 inhibitory effects with a longer half-life than ondansetron as well as antianxiety effects. Olanzapine should be considered for chemotherapyrelated and advanced cancer-related nausea and more research is needed with double-blind studies comparing with other class of anti-emetics.

6-19
Serum exosomal MicroRNA-21 could revolutionise the early molecular diagnosis of cancer cachexia Background and aims: Cancer cachexia is a devastating systemic tissue wasting syndrome elicited by tumour presence in up to 80% of late stage patients and estimated to account for 20% of cancer-related deaths. This starvation-like response occurs despite sufficient feeding and is characterized by insulin resistance, metabolic changes, fatigue, and gradual degradation of carbon and lipid sources, in particular from muscle and adipose tissue. The cellular response in target tissues is a switch from an anabolic to catabolic state. The systemic responses of cancer cachexia are believed to be in part a consequence of inflammatory signaling initiated by and from the tumour, but mechanistic studies in in vivo model systems has been limited. Our aim is to establish a genetic model where we can mechanistically dissect the mechanisms of cachexia, and if cachectic wasting contributes to tumour growth and nutrient remobilization fueling tumour growth.
Methods: The animal model system, Drosophila melanogaster, is a powerful model to study molecular, genetic and cellular mechanisms of cancer in vivo. In this system, genetically defined organ-specific tumors can be produced, and metabolic changes and somatic cellular responses to tumour presence can be studied in target muscle and adipose tissues. Results: Using transgenic organ-specific markers and dyes, we have been able to identify and quantify organ size of muscle and adipose tissue, as well as tumour growth over time by microscopy. Our studies have shown that Ras v12 ;scrib tumors but not Ras v12 ;control tumors cause cachexia in the distal tissues: muscle and fat body. Conclusions: Drosophila melanogaster can be used as a model for cancer cachexia. This model will be used to study the moleculargenetic mechanism of cachexia.

7-21
Dietary protein intake and lean mass in patients with lung or colorectal cancer Introduction: Low lean mass (LM) is a common issue among cancer patients and can negatively affect their prognosis 1 . Although an adequate supply of protein is essential to sustain LM, protein intake of patients recently diagnosed with cancer has not been extensively examined. Therefore, our objective was to evaluate the amount and type of protein consumed and to explore the association between LM and protein intake in patients with advanced solid tumors. Methods: Patients were recruited from the Cross Cancer Institute (Edmonton, Alberta). Dietary intake was evaluated using a three-day food record and analysed for protein amount and source. Protein intake was compared to the Recommended Dietary Allowance (RDA, 0.8 g/kg/day) and the body weight (BW) adjusted European Society for Clinical Nutrition and Metabolism (ESPEN, minimum 1.0 g/kgBW/ day, target of 1.2-2 g/kgBW/day) protein guidelines. Protein intake was divided into animal and plant sources. Body composition was measured by dual energy x-ray absorptiometry (DXA). Results: In this preliminary analysis, a total of 51 patients with metastatic lung (N = 24) or colorectal cancer (N = 27) were included. No differences in protein intake were observed between cancer groups. Mean protein intake for all patients was 90 ± 24 g/day, and 1.15 ± 0.32 g/kg BW/day; 90% met the RDA and 39% met ESPEN guidelines target protein intake of ≥1.2 g/kgBW/d. Only 1 patient consumed ≥2.0 g/kgBW/day. Animal sources accounted for 62% of total protein intake. A wide variation was observed in protein intake per unit LM with a weak relationship between these variables (r 2 = 0.208, p < 0.001). Conclusions: Less than 40% of patients met the target protein recommendation for cancer reflecting the need for additional nutrition support/intervention as low protein intake could potentially increase the risk for low lean mass or sarcopenia. As LM drives protein requirements, understanding the protein intake profile of cancer patients may enable the development of protein recommendations and future targeted interventions.

7-22
Oligonol, a low-molecular weight polyphenol, alleviates aging related sarcopenia in senescence-accelerated mice Sarcopenia is an aging-related disease with a significant reduction in mass and strength of skeletal muscle due to the imbalance between protein synthesis and protein degradation. Oligonol, a low molecular weight polyphenol derived from lychee, exhibited anti-diabetic and anti-obesity properties, suggesting being a proper supplement for attenuating age-related muscle loss. Sarcopenia was investigated in senescence-accelerated mice supplemented without and with Oligonol (200 mg/kg) for 8 weeks. Oligonol supplementation significantly increased muscle mass, muscle strength and fiber cross-sectional areas by up-regulating protein synthesis via phosphorylation of mTOR and P70 S6K in SAMP8 mice. In addition, Oligonol prevented nuclear translocation of NFκB and FoxO1a, thereby suppressing Atrogin-1 and MuRF1 expression. Oligonol reduced inflammatory mediators and inhibited autophagy by decreasing the levels of LC3II/LC3I. In conclusions, our results suggest oligonol as a supplement for alleviating sarcopenia evidenced by improving protein synthesis via mTOR and P70 S6K and suppressing protein degradation via NFκB and FoxO1a in SAMP8 mice. Introduction: The orexigenic effect of cannabinoids has been extensively studied in patients with cancer and HIV/AIDS. 1,2 However, there is little published evidence of the orexigenic effects of synthetic (e.g., dronabinol) and natural cannabinoids (e.g., delta-9-tetrahydrocannabinol (Δ9-THC) and/or cannabidiol (CBD)). [3][4][5] This retrospective study aimed to explore the effect of medical cannabis on appetite and weight. Methods: We conducted a retrospective chart review of all adult patients who were assessed at Santé Cannabis Clinic between August 2016 and July 2017, and who had "increase of appetite" as a treatment goal. Santé Cannabis Clinic is the only medical cannabinoid clinic located in the province of Quebec, Canada. Patient characteristics, "lack of appetite" item (0 = no lack of appetite to 10 = complete lack of appetite) from the revised Edmonton Symptom Assessment System (r-ESAS), and weight (kg) were considered our primary outcomes. Results: A total of one hundred and eleven patients were identified as suffering from anorexia from different chronic conditions, but only forty patients had complete information available at baseline and at three months follow-up. The r-ESAS score for lack of appetite significantly improved by 2.3 ± 3.4 points (p < 0.05 by Wilcoxon rank test); no statistically significant change in the mean weights (baseline vs three month; 74.7 ± 22.7 kg vs 75.1 ± 23.6 kg; p = 0.121) was found in our sample. The most common route of administration was a combination of oral and inhaled medical cannabis (50%). Forty percent of the patients received THC-rich products. Overall, 27.5% of the subjects reported only mild side effects (i.e., not impacting function nor requiring discontinuation of cannabis) such as anxiety, fatigue, dizziness and dry mouth. Conclusions: Chronic administration of medical cannabis may safely improve appetite and help with weight maintenance in patients suffering anorexia from cancer as well as nonmalignant chronic diseases. experimental cancer (Nissinen et al. SCWD Berlin 2016) but the mechanisms are unknown. The aim of this followup study was investigate skeletal muscle metabolome of cachectic mice with or without activin receptor administration.
Methods. BALB/c male mice were randomized into 4 groups: 1) healthy controls (CTRL) with placebo treatment (PBS) and C26 tumour-bearing mice treated with 2) placebo (C26 + PBS), 3) sACVR2B-Fc treatment only before C26 tumour formation (C26 + sACVb), and 4) sACVR2B-Fc treatment both before and after the C26 tumour formation (C26 + sACVc). Gastrocnemius muscles were collected on day 11 after C26 cell inoculation when the loss of body weight most successfully predicted survival in our previous survival experiment. Metabolites were analysed by gas chromatography-mass spectrometry (GC-MS), and further bioinformatic searches were performed with Ingenuity software. Statistical significance was set at P < 0.05 and fold change >1.3. Results. In the cachectic C26 muscle the most altered metabolites and pathways were related to protein synthesis and amino acid metabolism. These effects were in part attenuated by continued activin receptor ligand blocking (C26 + sACVc). Of the single metabolites other than amino acids, beta-glycerophosphoric acid and iminodiacetic acid were among the most altered ones in cancer while glucose-6-phosphate and L-aspartic acid were the most affected by activin receptor ligand blocking. Conclusions. Skeletal muscle metabolome is altered in C26 cancer cachexia and this is affected, in part, by the blocking of activin receptor ligands. The role and significance of the altered metabolites will be investigated in further detail in the future. This work was supported by Academy of Finland grant No. 275922.

8-22
Activin receptor ligand blocking in tumour-bearing mice: effects on acute phase response and spleen expansion and others have found that blockade of activin receptor type IIB (ACVR2B) ligands is associated with improved survival in cachectic mice. The aim of this study was to investigate the effects of C26 tumour and ACVR2B ligand blocking on liver proteins/APR and splenic MDSC content. Methods. BALB/c mice were injected with vehicle (control) or C26 cancer cells and treated with PBS or soluble ACVR2B (sACVR2B-Fc, 5 mg/kg twice a week, three injections before and three injections after C26 cell injection). Spleen and liver samples were collected on days 11-13 after C26 cell injection. Statistical significance was set at P < 0.05. Results. C26-induced muscle wasting was blocked by sACVR2B-Fc. Liver mass was unaltered in the experimental groups, but liver protein synthesis was increased in PBStreated tumour-bearing mice, while sACVR2B-Fc attenuated this effect. Increased liver protein synthesis was associated with higher phosphorylation of Stat3 and accumulation of fibrinogen and serpinA3N, known markers of APR, in tumour-bearing mice. APR was attenuated in some but not all sACVR2B-Fc treated mice. Spleen mass was increased in tumour-bearing mice and this effect was partly blocked by sACVR2B-Fc. Preliminary transcript and immunofluorescence analyses suggest an increase in splenic MDSCs in tumourbearing mice without attenuation by sACVR2B-Fc administration.
Conclusions. These results suggest that blocking ACVR2B ligands improves survival independently from splenic MDSC content. By contrast, prevention of cachexia by sACVR2B-Fc might be associated with attenuated liver APR. Further investigation is required in order to clarify the importance of this finding with respect to survival. This work was supported by Academy of Finland grant No. 275922, Jenny and Antti Wihuri Foundation and the Finnish Concordia Fund.

9-04
Targeted medical nutrition for cachexia in NSCLC: a randomized, controlled trial randomized trial evaluated the safety and efficacy of targeted medical nutrition (TMN) in (pre-)cachectic patients with NSCLC. Methods: Patients receiving first-line chemotherapy for NSCLC with involuntary weight loss or low BMI were randomized 1:1 to receive TMN (~200 kcal; 10 g whey protein; > 2.0 g eicosapentaenoic acidÀ/docosahexaenoic acid-containing fish oil; and 10 μg 25-hydroxy-vitamin D3) or a milk-based isocaloric comparator (~200 kcal; sunflower oil in place of fish oil; no vitamin D3) twice daily for 12 weeks (http://clinicaltrials.gov Identifier: NCT02515032). Primary safety endpoints included number and type of adverse events and changes in vital signs and laboratory parameters. Secondary efficacy endpoints included changes in body weight, body composition, exercise capacity, inflammatory and metabolic biomarkers and HRQoL. Chemotherapyrelated outcomes were exploratory endpoints. Statistical analyses were performed for the full analysis set and a predefined per protocol set (study completers with >70% compliance). Results: Fifty-five patients were randomized to receive TMN (n = 26; mean 64.4 ± 7.7 years) or isocaloric comparator (n = 29; mean 66.0 ± 8.0 years). TMN was well tolerated; the TMN group experienced fewer adverse events (64 vs 87), including fewer cases of neutropenia (0 vs 4), than the comparator group. Heart rate decreased from baseline in the TMN group and increased in the comparator group in highly compliant patients at week 12 (p < 0.05). Triglyceride levels also decreased in the TMN group and increased in the comparator group in the per protocol patients (À0.28 mmol/ L vs +0.43 mmol/L; p = 0.0027). Body weight increased to a similar extent in both groups and body composition remained similar. The omega-3:omega-6 ratio and vitamin D3 levels were higher in the TMN versus the comparator group at study end (both p < 0.0002). There were no other significant differences between the groups, including in chemotherapyrelated outcomes of tumour size, dose-limiting toxicity and dose reductions. Conclusions: TMN is well tolerated in (pre-)cachectic patients with NSCLC. Both study groups gained weight, and TMN had an additional positive impact on vital signs and lipid profiles. In addition, this study showed signs of improved chemotherapy tolerability in the TMN group. Thus, TMN could be beneficial for the nutritional support of lung cancer patients receiving chemotherapy.

9-05
Bovine Lactoferrin for treatment of anaemia associated with cachexia, pilot study for a randomised controlled trial Ayman Aboda 1 , Wafaa Taha 2 , Iman Abdelgawad 2 & Jagat Rakesh Kanwar 1 1 Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Centre for Molecular and Medical Research (C-MMR), Deakin University, 75 Pigdons Road, Waurn Ponds, VIC3220, Australia, 2 National Cancer Institute, Cairo University, Fom El Khalig, Cairo11796, Egypt Background: Cachexia is defined as loss of muscle due to serious sickness such as chronic heart failure, cancer, chronic renal failure and chronic obstructive pulmonary disease. Lactoferrin is well known as multifunctional protein, bovine Lactoferrin has several biological function, such as its effect in improvement of immunity, antimicrobial and anticancer effects. Method/Design: A prospective randomized controlled trail (pilot study) was conducted on 40 participants (30 patients with cancer cachexia and 10 participants apparent healthy) to check the effect of bovine Lactoferrin to improve anaemia in cancer cachexia patients with underlying stage IV nonsmall cell lung cancer and in healthy participants. Results: Both groups were matched regarding age, and sex. After 12 weeks, there was significant difference in haemoglobin concentration, serum iron level and red blood cells count in participants who received 250 mg/day bovine Lactoferrin in comparison to those who received placebo as P value was <0.001. Also there was significant difference in haemoglobin concentration between those who received 250 mg bovine Lactoferrin in comparison to those received 5oo mg bovine Lactoferrin as P value was <0.003.
Conclusions: Oral bovine Lactoferrin should be included in the multimodal therapy for treatment of cancer cachexia.

9-06
Investigating the safety and impact on muscle mitochondria of orally administered Urolithin A: a randomized, double-blind, placebo controlled Phase 1 clinical trial in elderly Background: Age associated muscle and physical decline leading to frailty and sarcopenia has become a growing public health concern. This has led to the search for novel nutritional interventions that can delay or mitigate its progression. Urolithin A (UA), is a first-in-class food derived metabolite that has recently been shown to improve mitochondrial function and exercise capacity in animal models of age-related decline of muscle function (Nature Medicine 22, 879-888 (2016). The current study was designed to investigate the safety and impact on mitochondrial biomarkers with an orally administered, synthetically produced UA in a Phase 1 clinical trial in elderly.