Prevention Of Cachexia Research Articles

Abstract 6610: Metabolic patterns of pancreatic cancer cachexia: Cross-tissue lipid networks predict cachexia progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancer types. A key — yet poorly understood — facet in the disease state is cachexia, a multi-organ pathological state characterized by physical wasting and tissue catabolism. It occurs in 80% of PDAC patients, and to date there are no preventative or early detection methods. Cachexia leads to limited tolerance to anti-cancer therapy and contributes to disease lethality. Here, we present the first-of-its-kind systemic metabolomic analysis across cachectic stages to better understand disease progression. We used the well-established mutant KRASG12D(LSL/+) mutant p53 inducible mouse model of PDAC. Model physiology faithfully recaptures human cachexia: we observe progressive overall weight loss as well as loss of skeletal muscle and adipose tissue. As with human disease, weight loss occurs prior to loss of appetite in the animals, suggesting physiological changes independent of nutrition. Importantly, our model captures the period prior to weight loss (pre-CAC), as well as early-CAC (<10% weight loss) and late-CAC (>10% weight loss). We profiled the metabolomes of the pancreas, interstitial fluid, plasma, liver, 3 different adipose tissues, and 3 skeletal muscles, from male and female mice, control and tumor-bearing, across all 3 stages of cachexia. Each tissue has a unique metabolic trajectory across cachexia stages; pathway and correlation analyses showed a particular emphasis on lipid alterations in peripheral tissues. Strikingly, we find systemic metabolic changes prior to tissue wasting, including rewiring in the liver before the presence of metastases. This indicates systemic alterations as early as pre-CAC. We therefore used computational modeling to identify metabolites that may be participating in cross-tissue networks. A key finding, confirmed by 13C tracing, was the circulation of lactate and glucose and their uptake by the liver and pancreas. Network maps also suggest lipid rewiring in distal tissues, changes in abundances of these same lipid species in plasma, and their consequent alterations in the tumor and liver. A fundamental question remains: can we predict cachexia development before the manifestation of symptoms? We used feature selection algorithms based on statistical learning, training the models only on a subset of data. Specific sphingolipids and triglycerides were the key lipid species that distinguished control and pre-CAC. We find that the model — trained only on pre-CAC — is able to determine early-CAC with an 85% accuracy and late-CAC with a 90% accuracy. Thus, a limited set of metabolites that are altered in pre-CAC could have predictive value for future cachexia development. Overall, our work provides a resource for the field and advances our understanding of systemic metabolism in PDAC cachexia. We hope this will lay the foundation for cachexia prevention and treatment. Citation Format: Deepti Mathur, Blanca Majem, Courtney Beaulieu, Lucas Dailey, Sarah Jeanfavre, Joao Xavier, Clary Clish, Nada Kalaany. Metabolic patterns of pancreatic cancer cachexia: Cross-tissue lipid networks predict cachexia progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6610.

Cancer-Cachexia-Induced Human Skeletal Muscle Myotube Degeneration Is Prevented via Cannabinoid Receptor 2 Agonism In Vitro.

Cachexia syndrome, leading to reduced skeletal muscle and fat mass, is highly prevalent in cancer patients, resulting in further negative implications for these patients. To date, there is no approved therapy for cachexia syndrome. The objective of this study was to establish an in vitro model of cancer cachexia in mature human skeletal muscle myotubes, with the intention of exploiting the cell model to assess potential cachexia therapeutics, specifically cannabinoid related drugs. Having cultured and differentiated primary human muscle myoblasts to mature myotubes, we successfully established two cancer cachexia models using conditioned media (CM) from human colon adenocarcinoma (SW480) and from non-small-cell lung carcinoma (H1299) cultured cells. The cancer-CM-induced extensive myotube degeneration, demonstrated by a significant reduction in mature myotube diameter, which progressed over the period studied. Myotube degeneration is a characteristic feature of cancer cachexia and was used in this study as an index of cachexia. Expression of cannabinoid 1 and 2 receptors (CB1R and CB2R) was confirmed in the mature human skeletal muscle myotubes. Subsequently, the effect of cannabinoid compounds on this myotube degeneration were assessed. Tetrahydrocannabinol (THC), a partial CB1R/CB2R agonist, and JWH133, a selective CB2R agonist, proved efficacious in protecting mature human myotubes from the deleterious effects of both (SW480 and H1299) cancer cachexia conditions. ART27.13, a full, peripherally selective CB1R/CB2R agonist, currently being trialled in cancer cachexia (IRAS ID 278450, REC 20/NE/0198), was also significantly protective against myotube degeneration in both (SW480 and H1299) cancer cachexia conditions. Furthermore, the addition of the CB2R antagonist AM630, but not the CB1R antagonist Rimonabant, abolished the protective effect of ART27.13. In short, we have established a convenient and robust in vitro model of cancer-induced human skeletal muscle cachexia. The data obtained using the model demonstrate the therapeutic potential of ART27.13 in cancer-induced cachexia prevention and provides evidence indicating that this effect is via CB2R, and not CB1R.

Insights on discovery, efficacy, safety and clinical applications of ghrelin receptor agonist capromorelin in veterinary medicine.

Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the pituitary through a specific G-protein coupled receptor (GPCR) called growth hormone secretagogue receptor 1a expressed in the hypothalamus. Ghrelin is a peptide hormone released from the cells in the stomach, which stimulates appetite and food intake in mammals, regulates gut motility, gastric acid secretion, taste sensation, circadian rhythm, learning and memory, oxidative stress, autophagy, glucose metabolism etc. When the release of the endogenous ligand GHSR-1a, i.e., ghrelin is malfunctioned or stopped, external substitutes are administrated to induce the stimulation of growth hormone and appetite. A class of compound known as ghrelin receptor agonists are developed as an external substitute of ghrelin for regulation and stimulation of growth hormone in frailty, for body weight gain, muscle mass gain, prevention of cachexia and for the treatment of chronic fatigue syndromes. Capromorelin [Entyce™ (Aratana Therapeutics, Leawood, KS, USA)] is the only FDA (Food and Drug Administration) approved (May 2016) drug used for stimulating appetite in dogs and was marketed in the fall of 2017. In 2020, USFDA approved Capromorelin [Elura™ (Elanco US Inc.)] for the management of weight loss in chronic kidney disease of cats. This article reviews the discovery of the ghrelin receptor agonist capromorelin, its efficacy, safety, clinical applications and aims to delineate its further scope of use in veterinary practice.

Pyruvate prevents the onset of the cachectic features and metabolic alterations in myotubes downregulating STAT3 signaling.

Cachexia is a systemic disease associated with several pathologies, including cancer, that leads to excessive weight loss due to enhanced protein degradation. Previously, we showed that cachectic features in myotubes are provoked by a metabolic shift toward lactic fermentation. Our previous results led us to hyphotesise that increasing pyruvate concentration could impede the metabolic modifications responsible for induction of cachexia in myotubes. Here, we demonstrated that the addition of sodium pyruvate in conditioned media from CT26 colon cancer cells (CM CT26) prevents the onset of either phenotypic and metabolic cachectic features. Myotubes treated with CM CT26 containing sodium pyruvate show a phenotype similar to the healthy counterpart and display lactate production, oxygen consumption, and pyruvate dehydrogenase activity as control myotubes. The use of the Mitochondrial Pyruvate Carrier inhibitor UK5099, highlights the importance of mitochondrial pyruvate amount in the prevention of cachexia. Indeed, UK5099-treated myotubes show cachectic features as those observed in myotubes treated with CM CT26. Finally, we found that sodium pyruvate is able to decrease STAT3 phosphorylation level, a signaling pathway involved in the induction of cachexia in myotubes. Collectively, our results show that cachexia in myotubes could be prevented by the utilization of sodium pyruvate which impedes the metabolic modifications responsible for the acquisition of the cachectic features.

Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma‐1 receptor (σ‐1R) is a ligand‐operated protein that exhibits pro‐survival and anti‐apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease‐modifying effects of pridopidine, a σ‐1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine‐treated SOD1 G93A mice showed genotype‐specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS‐associated cachexia and motor deficits in a SOD1 G93A mouse model.

Enteral Nutrition Combined with Improved-Sijunzi Decoction Shows Positive Effect in Precachexia Cancer Patients: A Retrospective Analysis.

Background Cancer has been considered as the leading cause of death in the world. In patients with cancer, up to 80% display a cachectic period after diagnosis. Cachexia is known to have a negative impact on function, treatment tolerance, higher rates of hospitalizations, and mortality. Anorexia is often used as a warning sign of precachexia. Long-term anorexia may lead to malnutrition and, then, accelerate the occurrence of cachexia. A safe and effective treatment, which can both improve appetite and assist nutritional support for precachexia cancer patients shows its particular important role. Methods A retrospective analysis comparing the different therapeutic effects on precachexia cancer patients with anorexia-malnutrition. We recorded 46 patients with the improved-Sijunzi decoction combined with enteral nutrition emulsion (ISJZ group) and 35 patients with single enteral nutrition emulsion (SEN group). The different therapeutic effects of the two groups were observed by recording indicators before and 2 weeks after treatment, including patient-generated subjective global assessment score, quality of life score, Karnofsky performance status scale, Eastern cooperative oncology group scale standard and traditional Chinese medicine syndrome, daily total dietary intake, red blood cells, hemoglobin, prealbumin, albumin, total protein cholinesterase, C-reactive protein, leukocytes, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea nitrogen, and creatinine. Results ISJZ group exhibited prominent improvement of traditional Chinese medicine syndrome (TCMS), nutritional condition, and quality of life compared with the SEN group (QOL: p=0.0001, PG-SGA: p=0.019, dietary intake: p=0.0001, TCMS: p=0.0001). The levels of HGB (p=0.006), PAlb (p=0.001), Alb (p=0.0001), TP (p=0.008), and ChE (p=0.0001) in the ISJZ group were higher than the SEN group after treatment. Moreover, the ratios of CRP/ALB (p=0.028) and CRP/PALB (p=0.005) in the two groups have obvious differences; they were lower for the ISJZ group than the SEN group. Conclusions Enteral nutrition combined with ISJZ decoction is an effective treatment in precachexia cancer patients for the prevention of cachexia. This treatment therapy can alleviate the inflammatory response, improve malnutrition state, and promote the performance status. Tianjin Medical University Cancer Institute and Hospital approved this study (Trial No. 1913).

Front Cover: Fish Oil Diet during Pre‐mating, Gestation, and Lactation in Adult Offspring Rats on Cancer Cachexia Prevention

Front Cover: Fish Oil Diet during Pre‐mating, Gestation, and Lactation in Adult Offspring Rats on Cancer Cachexia Prevention

Fish Oil Diet during Pre-mating, Gestation, and Lactation in Adult Offspring Rats on Cancer Cachexia Prevention.

Nutritional supplementation of the maternal diet can modify the cancer susceptibility in adult offspring. Therefore, the authors evaluate the effects of a fish-oil diet administered to a long-term, during pre-mating, gestation, and lactation, in reducing cancer-cachexia damages in adult Walker-256 tumor-bearing offspring. Female rats receive control or fish oil diet during pre-mating, gestation, and lactation. After weaning, male offspring are fed the control diet until adulthood and distributed in (C) control adult-offspring; (W) adult tumor-bearing offspring; (OC) adult-offspring of maternal fish oil diet; (WOC) adult tumor-bearing offspring of maternal fish oil diet groups. Fat body mass is preserved, muscle expression of mechanistic target of rapamicin (mTOR) and eukariotic binding protein of eukariotic factor 4E (4E-BP1) is modified, being associated with lower 20S proteasome protein expression, and the liver alanine aminotransferase (ALT) enzyme content maintained in the WOC group. Also, the OC group shows reduced triglyceridemia. In this experimental model of cachexia, the long-term maternal supplementation is a positive strategy to improve liver function and lipid metabolism, as well as to modify muscle proteins expression in the mTOR pathway and also reduce the 20S muscle proteasome protein, without altering the tumor development and muscle wasting in adult tumor-bearing offspring.

Nutritional Interventions in Cancer Cachexia Prevention and Treatment

Cancer cachexia contributes to 30% of cancer-related deaths. There is currently no treatment or standard of care for cancer cachexia. Many nutritional interventions show promise for the treatment and or prevention of cachexia. Supplementation with omega-3 fatty acids, protein and vitamins either alone or in combination has shown some beneficial effects in the prevention and treatment of cancer cachexia. The mechanisms through which many nutritional interventions work to attenuate cachexia are just beginning to be understood. Therefore, the purpose of this review is to examine several nutritional strategies that have been investigated in the prevention and or treatment of cancer cachexia and provide evidence for the use of additional nutritional interventions to combat cachexia.

Prevenção e Tratamento da Caquexia no Câncer de Mama por Probiótico e Curcumina

O objetivo desse artigo é realizar uma revisão sistêmica sobre o tratamento e a prevenção da caquexia no câncer de mama (CM) com o uso de probióticos e curcumina, o processo no qual ocorre degradação proteica, lipólise excessiva e inflamação crônica através de estímulos de HIF-1/IL-6/TGF-β/TNF/NF-kB, desencadeando angiogênese, invasão e metástase tumoral, levando a um pior prognóstico do câncer de mama. Para atingir o objetivo foi realizada uma revisão sobre os mecanismos bioquímicos pelos quais a caquexia atinge os pacientes com CM e a inibição desses através da utilização de probióticos e curcumina. Os probióticos inibem as vias STAT/NF-kB/COX-2 e estimulam PPARγ, inibindo a inflamação crônica e a lipólise excessiva. A curcumina é eficiente na captação de espécies reativas ao oxigênio (ERO) e na inibição do fator induzível por hipóxia 1 (HIF-1), consequentemente inibindo o estresse oxidativo total do organismo, melhorando a sensibilidade a radioterapia de células neoplásicas e causando diminuição do metabolismo tumoral. De acordo com os artigos estudados, os probióticos e a curcumina são duas estratégias eficientes na prevenção e tratamento da caquexia no CM, melhorando o prognóstico da doença. Os estudos analisados descrevem que, tanto os probióticos como a curcumina são seguros, para administração em pacientes com câncer durante tratamento radioterápico e quimioterápico.

Understanding the Role of Exercise in Cancer Cachexia Therapy.

Cachexia, the unintentional loss of body weight, is prevalent in many cancer types, and the associated skeletal muscle mass depletion increases patient morbidity and mortality. While anorexia can be present, cachexia is not reversible with nutritional therapies alone. Pharmacological agents have been proposed to treat this condition, but there are currently no approved treatments. Nonetheless, the hallmark characteristics associated with cancer cachexia remain viable foundations for future therapies. Regular physical activity holds a promising future as a nonpharmacological alternative to improve patient survival through cachexia prevention. Evidence suggests exercise training is beneficial during cancer treatment and survival. However, the mechanistic examination of cachectic skeletal muscle's response to exercise is both needed and justified. The primary objective of this review is to discuss the role of exercise for the prevention and treatment of cancer-associated muscle wasting. Initially, we provide an overview of systemic alterations induced by cancer and their role in the regulation of wasting processes during cachexia progression. We then discuss how exercise could alter disrupted regulatory pathways related to growth and metabolism during cancer-induced muscle atrophy. Last, we outline current exercise prescription guidelines and how exercise could be a potential behavioral therapy to curtail cachexia development in cancer patients.

Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial).

BackgroundCancer cachexia is a major cause of morbidity and mortality with no widely approved treatment.MethodsThe ACT‐ONE trial is a randomized, double‐blind, parallel group, placebo‐controlled, phase II multicentre trial in patients (25‐80 years) with stages III or IV colorectal cancer or non‐small cell lung cancer‐related cachexia that tested two doses of espindolol (a novel non‐selective β blocker with central 5‐HT1a and partial β2 receptor agonist effects). The primary endpoint was the difference in the rate of weight change over 16 weeks (linear mixed‐effect model for repeated measures) between high‐dose espindolol and placebo.ResultsEighty‐seven patients were randomized centrally in blocks in a ratio 3:2:1 [42 high dose, 10 mg twice daily (bd):31 placebo:14 low dose, 2.5 mg bd]. High‐dose espindolol produced a statistically and clinically significant weight gain (+0.54 kg/4 weeks, 95% CI 0.38–0.70) compared with a weight loss on placebo (−0.21 kg/4 weeks, 95% CI ‐0.37–0.05); P < 0.0001. High‐dose espindolol produced a statistically significant increase in lean body mass, whilst changes in fat mass were neutral. Hand grip strength significantly (high dose −1.15 ± 0.7 kg, placebo −3.51 ± 0.8 kg change per 4 weeks; P = 0.0134), stair climbing power, and 6‐min walk test non‐significantly were all directionally in favour of high‐dose espindolol. There were no clinically significant differences in safety signals or survival between treatment groups, although a numerical excess of dyspnoea was seen with high‐dose espindolol (19.1%) compared with placebo (3.2%).ConclusionsThis positive trial showed that espindolol 10 mg bd significantly reversed weight loss, improved fat free mass, and maintained fat mass in advanced colorectal cancer and non‐small cell lung cancer‐related cachexia. This was associated with a significant improvement in handgrip strength, supporting the further investigation of 10 mg bd espindolol for the treatment of cancer cachexia. Although not powered to look at dose response, most treatment effects for low dose lay between high dose and placebo, suggesting that there may be a dose response in the effects of espindolol.

Can the Serum Level of Myostatin be Considered as an Informative Factor for Cachexia Prevention in Patients with Medullary Thyroid Cancer?

Thyroid cancer, the most common endocrine neoplasia, consists of four main types of carcinomas: papillary, follicular, and anaplastic, all with thyroid follicular origin, and medullary thyroid cancer (MTC) related to para-follicular cells. Cronic diseases such as diverse cancers may be associated with cachexia, especially at advanced stage. Cancer-induced cachexia is associated with diminished quality of life, functional performance, reduced response to antitumor therapy, and increased morbidity and mortality. Myostatin (Mst) is one of the outstanding molecules in the skeletal muscle loss process in cancer and it may be released by both skeletal muscle and cachexia-inducing tumors. Recently changes in serum levels of Mst have been identified as an important factor of cancer-induced cachexia. The goal of this study was to assessserum Mst levels in MTC patients. In this descriptive and case-control study, 90 participants were selected, comprising 45 MTC patients (20 males, 29±13.9 years, 25 females, 29±14.5 years) and 45 control individuals (25 males, 23.1±11.6 years, 20 females, 31.5±14.4 years). Serum Mst was determined using an ELISA kit and body mass index (BMI) was calculated by weight and height measurements. The Kolmogorov Simonov test showed a normal distribution for log transformed Mst serum levels in both case and control groups. Geometric means were 5.9 and 8.2 ng/ml respectively, and a significant difference was found according to the independent t-test results (P<0.01) . There was also a significant difference mean of Mst between females in control and MTC groups, but not for the males. Pearson correlation test showed no correlation between age and BMI with Mst serum levels. The findings of this study support the hypothesis that Mst serum levels may have a potential ability for early diagnosis of cachexia in MTC patients, especially in females.

Identification of neutrophil-derived proteases and angiotensin II as biomarkers of cancer cachexia.

Background:Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre-cachexia (no cachexia but high CRP levels: ⩾5 mg l−1) and no cachexia (no cachexia and CRP: <5 mg l−1).Methods:A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software.Results:In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (⩾1.5-folds) in mRNA expression of neutrophil-derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (P=0.005 and P=0.02, respectively), TGFβ1 (P=0.042 and P<0.0001, respectively) and CRP (both P<0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (P=0.005), IL-8 (P=0.001) and absolute neutrophil counts (P=0.007).Conclusions:Ang II, TGFβ1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia.

Beneficial bacteria inhibit cachexia.

Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny.

Cardiac Cachexia: Perspectives for Prevention and Treatment.

Cachexia is a prevalent pathological condition associated with chronic heart failure. Its occurrence predicts increased morbidity and mortality independent of important clinical variables such as age, ventricular function, or heart failure functional class. The clinical consequences of cachexia are dependent on both weight loss and systemic inflammation, which accompany cachexia development. Skeletal muscle wasting is an important component of cachexia; it often precedes cachexia development and predicts poor outcome in heart failure. Cachexia clinically affects several organs and systems. It is a multifactorial condition where underlying pathophysiological mechanisms are not completely understood making it difficult to develop specific prevention and treatment therapies. Preventive strategies have largely focused on muscle mass preservation. Different treatment options have been described, mostly in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reducing intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimens. Currently, nonpharmacological therapy such as nutritional support and physical exercise are considered central to cachexia prevention and treatment.

The Evaluation of Nutrition Status and its Relationship to Exercise Tolerance in Heart Failure Patients after Device Implantation

Cardiac cachexia is one of the prognostic factors in patients with advanced heart failure (HF). Because inflammatory cytokines promote the proteolysis in skeletal muscle and cachexia accompanied with malnutrition, rehabilitation and nutrition management are important for the prevention of cachexia. Average of calorie intake(A) during hospital stay was calculated and compared with the nutrition requirement(B) calculated by Harris Benedict Equation ×Af1.4 ×Sf1.0, and the nutrition status was evaluated by GNRI formula in 21 patients (76 ± 11years old, male 17) who admitted for the treatment of HF exacerbation. 43% of patients showed A/B and GNRI <99%. These findings meant some part of CHF patients had the risk of malnutrition. Furthermore, the nutrition status among 30 patients(72 ±8years old, male 22, CRT-D 21) who had undergone CRT/CRT-D implantation was also evaluated by GNRI formula. 10% of the patients showed moderate malnutrition risk and 33% of them showed mild malnutrition risk. In the 15 patients who underwent CPX, the relationship between nutrition status and exercise tolerance was evaluated. PeakVO2 was correlated to serum Alb (r=0.601, p <0.05), and total lymphocyte count (r=0.731, p <0.01). ATVO2 was correlated to serum Alb (r=0.790, p <0.01). GNRI was negatively correlated to VE/VCO2 slope (r=-0.629, p <0.05). We should care the nutrition management and plan the optimal rehabilitation to the patients with advanced heart failure.

487P - Survival and Quality of Life Data from the Act One Randomised, Double-Blind, Placebo-Controlled, Phase Ii Study of Espindolol for the Treatment and Prevention of Cachexia in Patients with Stage III / Iv Non-Small Cell Lung Cancer or Colorectal Cancer

ABSTRACT Aim: Neurohormonal overactivity is implicated in the progression of cachexia and BBs are proposed as a potential therapy. Retrospective studies suggest that s-blockers (BBs) may have a beneficial effect on survival in cancer patients but to date randomised prospective data has been lacking. These effects may depend upon the receptor specificities of the BB used and espindolol (eP) has been shown in preclinical studies to have superior effects compared to other BBs. Methods: 87 subjects with stage III or IV NSCLC or CRC who met a consensus definition of cachexia (including weight loss >5% in 12 months) were recruited. Excessive weight loss and significant pre-existing cardiac disease were exclusion criteria. Subjects were randomised 3:1:2 to high dose eP (HD = 10mg bd), low dose eP (LD = 2.5 mg bd) or placebo (P) and treated for 16 weeks. EQ-5D was assessed at days 0, 28, 55, 84 and 112. Survival was monitored to the date of last subject last visit. Results: Baseline characteristics, tolerability, weight change and functional improvement data have all been presented previously (1).There were no statistically significant differences or trends in quality of life as measured by the EQ-5D instrument on any individual parameter, the VAS score or the EQ-5D Index (using UK TTO value set). Median overall survival was longer for treated subjects (HD = 61.0 wks; LD = 50.9 wks; P = 42.3 wks) and the % of responders (alive and without weight loss at day 112) was higher (HD = 43.33% vs P = 24%) but these differences were not statistically significant. This new data is supportive of the previously presented data showing statistically significant weight gain and functional improvement for eP treated subjects. Conclusions: This study provides the first prospective randomised data on the effect of a BB on survival in cancer patients and is consistent with previously reported retrospective data. This new data for eP is also consistent with the previously reported data on weight gain and functional improvement in cancer cachexia patients. Disclosure: J. Beadle: I am a Director, an office bearer, an Employee and a stock owner; A. Coats: I am a paid consultant and a stock owner; R. Brown: I am an employee and a stock owner; S. Anker: I am a paid consultant and stock owner.All other authors have declared no conflicts of interest.

Enobosarm (GTx-024, S-22): A Potential Treatment for Cachexia

Muscle loss and wasting occurs with aging and in multiple disease states including cancer, heart failure, chronic obstructive pulmonary disease, end-stage liver disease, end-stage renal disease and HIV. Cachexia is defined as a multifactorial syndrome that is associated with anorexia, weight loss and increased catabolism, with increased morbidity and mortality. Currently no therapy is approved for the treatment or prevention of cachexia. Different treatment options have been suggested but many have proven to be ineffective or associated with adverse events. Nonsteroidal selective androgen receptor modulators (SARMs) are a new class of anabolic agents that bind the androgen receptor and exhibit tissue selectivity. Enobosarm (GTx-024, S-22) is a recently developed SARM, developed by GTx, Inc. (TN, USA), which has been tested in Phase I, II and III trials with promising results in terms of improving lean body mass and measurements of physical function and power. Enobosarm has received fast track designation by the US FDA and results from the Phase III trials POWER1 and POWER2 will help determine approval for use in the prevention and treatment of muscle wasting in patients with non-small-cell lung cancer. This article provides an introduction to enobosarm as a new therapeutic strategy for the prevention and treatment of cachexia. A review of the literature was performed using search terms 'cachexia', 'sarcopenia', 'SARM', 'enobosarm' and 'GTx-024' in September 2013 using multiple databases as well as online resources.

Prevention of Cachexia in Cancer

The cachexia syndrome is seen across a wide range of chronic diseases and is especially evident in the cancer patient. Weight loss causes difficulties for the patient and clinician alike as it reduces quality of life and also reduces tolerance of anti-cancer therapy. It is now recognised that cachexia exists through a range of phases (pre-cachexia, cachexia syndrome and refractory cachexia); however, not all patients traverse the entire spectrum. The risk of progression varies and depends on numerous clinical factors that should be taken into account when risk stratifying and counselling patients about weight loss and possible interventions. Tumour type, tumour stage, co-morbidities, systemic inflammation, low food intake and response to anti-cancer therapy all play roles in determining whether a patient will be at risk of cachexia progression. The acknowledgement that multiple components are responsible for the development of cachexia has led to the view that any cachexia intervention strategy should target all components i.e. multimodal therapy for a multimodal problem. There is growing acceptance that anti-cachexia therapy must form a major component of supportive oncology and be given along with anti-cancer therapy. The critical concern remains when to start such treatment and in which individuals?