Cachexia Research Research Articles

Nutritional Mechanisms of Cancer Cachexia.

Cancer cachexia is a complex systemic wasting syndrome. Nutritional mechanisms that span energy intake, nutrient metabolism, body composition, and energy balance may be impacted by, and may contribute to, the development of cachexia. To date, clinical management of cachexia remains elusive. Leaning on discoveries and novel methodologies from other fields of research may bolster new breakthroughs that improve nutritional management and clinical outcomes. Characteristics that compare and contrast cachexia and obesity may reveal opportunities for cachexia research to adopt methodology from the well-established field of obesity research. This review outlines the known nutritional mechanisms and gaps in the knowledge surrounding cancer cachexia. In parallel, we present how obesity may be a different side of the same coin and how obesity research has tackled similar research questions. We present insights into how cachexia research may utilize nutritional methodology to expand our understanding of cachexia to improve definitions and clinical care in future directions for the field.

Longitudinal Muscle Biopsies Reveal Inter- and Intra-Subject Variability in Cancer Cachexia: Paving the Way for Biopsy-Guided Tailored Treatment.

In the rapidly evolving landscape of cancer cachexia research, the development and refinement of diagnostic and predictive biomarkers constitute an ongoing challenge. This study aims to introduce longitudinal muscle biopsies as a potential framework for disease monitoring and treatment. The initial feasibility and safety assessment was performed for healthy mice and rats that received two consecutive muscle biopsies. The assessment was performed by utilizing three different tools. Subsequently, the protocol was also applied in leiomyosarcoma tumor-bearing rats. Longitudinal muscle biopsies proved to be a safe and feasible technique, especially in rat models. The application of this protocol to tumor-bearing rats further affirmed its tolerability and feasibility, while microscopic evaluation of the biopsies demonstrated varying levels of muscle atrophy with or without leukocyte infiltration. In this tumor model, sequential muscle biopsies confirmed the variability of the cancer cachexia evolution among subjects and at different time-points. Despite the abundance of promising cancer cachexia data during the past decade, the full potential of muscle biopsies is not being leveraged. Sequential muscle biopsies throughout the disease course represent a feasible and safe tool that can be utilized to guide precision treatment and monitor the response in cancer cachexia research.

Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia.

Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28kg in men and <18kg in women), or elevated C-reactive protein levels (>5mg/L [0.5mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3-6month period and suggested a tentative cut-off value of 21kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.

Developing an Evidence and Theory Based Multimodal Integrative Intervention for the Management of Renal Cachexia: A Theory of Change.

In this study, we aimed to develop a theoretical framework for a multimodal, integrative, exercise, anti-inflammatory and dietary counselling (MMIEAD) intervention for patients with renal cachexia with reference to how this addresses the underlying causal pathways for renal cachexia, the outcomes anticipated, and how these will be evaluated. We used a Theory of Change (ToC) approach to guide six steps. Step 1 included inputs from a workshop to obtain key stakeholder views on the potential development of a multimodal intervention for renal cachexia. Step 2 included the findings of a mixed-methods study with Health Care Practitioners (HCPs) caring for individuals with End Stage Kidney Disease (ESKD) and cachexia. Step 3 included the results from our systematic literature review on multimodal interventions for cachexia management. In step 4, we used the body of our research team's cachexia research and wider relevant research to gather evidence on the specific components of the multimodal intervention with reference to how this addresses the underlying causal pathways for renal cachexia. In steps 5 and 6 we developed and refined the ToC map in consultation with the core research team and key stakeholders which illustrates how the intervention components of MMIEAD interact to achieve the intended long-term outcomes and anticipated impact. The results of this study provide a theoretical framework for the forthcoming MMIEAD intervention for those with renal cachexia and in subsequent phases will be used to determine whether this intervention is effective. To the best of our knowledge no other multimodal intervention trials for cachexia management have reported a ToC. Therefore, this research may provide a useful framework and contribute to the ongoing development of interventions for cachexia management.

Combination of Nutritional Risk Index and Handgrip Strength on the Survival of Patients with Cancer Cachexia: A Multi- Center Cohort Study.

PurposeThe nutritional risk index (NRI) and handgrip strength (HGS) are useful indicators of nutritional and physical status, respectively, both of them can predict the prognosis of many cancers; however, the predictive accuracy of a single indicator is unsatisfactory. Whether the combination of NRI and HGS could enhance the stratification of the prognosis of patients with cancer cachexia.Patients and MethodsThe study population was randomly divided into training and validation cohorts. We combined NRI and HGS and constructed the NRI–HGS score. Restricted cubic splines were used to assess the associations between NRI, HGS, and all-cause mortality. The Kaplan–Meier method was used to calculate the survival probability of the patients. The Cox proportional hazards risk model was used to analyze survival and prognostic factors.ResultsLow NRI and low HGS were independent predictors of poor prognosis in patients with cancer cachexia. The NRI–HGS score showed a better prognostic stratification than either NRI or HGS. The co-occurrence of low NRI and low HGS was associated with an approximately 1.8-fold increased risk of mortality. The NRI–HGS score could effectively distinguish patients with a poor prognosis at different pathological stages. Furthermore, we constructed a novel prognostic nomogram based on NRI and HGS. The concordance index and calibration plot confirmed that the nomogram had good prognostic accuracy. The area under the receiver operating characteristic curve of the nomogram reached >0.8, which was much higher than that of the traditional tumor–node–metastasis staging system. The nomogram provided better prognostic stratification for patients with cancer cachexia.ConclusionLow NRI and low HGS are independent prognostic indicators in cancer cachexia. The combination of NRI and HGS improve prognostic stratification for patients with cancer cachexia. Our study suggests combining nutritional and physical status in future cachexia research.

Pancreatic Ductal Adenocarcinoma Highly Expresses Activin A: Implications in Adipose Tissue and Cancer Cachexia

Background: Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer death in the United States and is projected to become the second leading cause by the year 2030. Prognosis for patients with metastatic disease remains dismal. Cancer cachexia is seen in over 85% of PDAC patients who often have the most severe degrees of cachexia and experience adipose tissue loss prior to skeletal muscle loss early in the disease process. Several factors have been proposed to induce cachectic symptoms in human patients, including inhibin subunit βA, or activin A. Hypothesis: While muscle wasting has been the most frequently studied mechanism in cachexia research, changes in adipose tissue are increasingly understood as important components of body weight loss in cachectic patients. We hypothesized that there is a correlation between the marked increase in activin A production in PDAC patients and the remodeling of adipose tissue and consequent cancer-associated cachectic state. Experimental Design: We measured serum activin A levels of a cohort of PDAC patients and analyzed the expression of activin A in tumor-derived cell lines and biopsies of both humans and mice. We further investigated the effect of activin A on remodeling of adipose tissue secondary to tumor progression in PDAC patients and an orthotopic murine model. Results: We observed that PDAC cell lines express and secrete activin A. We recognized a loss of adipose tissue mass and adipocyte diameter in PDAC patients and our orthotopic PDAC mouse model in relation to increased circulating activin A. We also noted that both exogenous activin A and conditioned medium from pancreatic tumor-derived cell lines dampened adipocyte differentiation and lipid droplet formation via reduction of PPARγ expression in mouse mesenchymal stem cells. These treatment conditions also reduced lipid droplet size without upregulating traditional markers of adipose tissue browning and lipolysis such as UCP-1 and ATGL in mature mouse adipocytes. PPARγ, UCP-1, and ATGL expression are also heavily downregulated in adipose tissue of PDAC patients. Furthermore, our studies revealed that the expression of extracellular matrix proteins such as collagen I and fibronectin is dramatically upregulated in adipose tissue of PDAC patients and our orthotopic PDAC mouse model. Thus, we found that there is a clear correlation between elevated levels of activin A and the progression of cancer-associated cachexia in PDAC. Discussion: Our results reveal an imperative role of activin A in relation to the loss and remodeling of adipose tissue in the progression of cachexia in PDAC patients.

Activin A Plays a Critical Role in Adipose Tissue Wasting in the Progression of Cancer Cachexia

Background: Nearly 50% of cancer patients suffer from cancer cachexia, a wasting syndrome with atrophy of white adipose tissue (WAT) and skeletal muscle. Cachexia leads to negative energy balance, limits cancer therapies, and reduces survival rate. It is characterized by body weight loss due to negative nutrients and energy balance from involuntary reduced food intake and abnormal metabolic conditions such as insulin resistance and hypertriglyceridemia. Cancer-driven factors such as activin A and IL-6 (interlukein-6) contribute to the occurrence of cachexia symptoms during cancer progression. While the importance of muscle atrophy has been emphasized in cachexia research, the underlying mechanism of adipose tissue wasting remains unclear. One proposed theory is that WAT switches to brown adipose tissue (BAT), characterized by the high expression level of UCP1 (uncoupling protein 1). Hypothesis: We hypothesize that activin A plays a critical role in adipose tissue wasting during cancer cachexia progression. Experiment: GDF9-iCre+; PIK3CA* female mice which shows cachexia symptoms in cancer progression were sacrificed before and after cachexia development. In addition, we injected FST288, an antagonist to activin A, for two weeks during cancer cachexia development. We harvested and analyzed multi-sites adipose tissues (gonadal, subcutaneous, interscapular and perirenal), muscle and liver. Serum activin A and IL-6 were measured using ELISA kits. DEXA and calorimetry analyses were performed, as well as immunohistochemistry, qPCR and western blotting assay. Results:GDF9-iCre+; PIK3CA* female mice started to display bilateral ovarian tumors around postnatal day (PD) 60, lose body weight around PD70 and became cachexia condition around PD80 with an increased level of serum activin A. Along with that, other body organs including liver, pancreas, muscle, and adipose tissues became dramatically small in mass. Our data proved that cachexia progression is correlated with the level of activin A rather than IL-6 in serum of GDF9-iCre+; PIK3CA* female mice. As serum activin A increased, adipocytes lost lipids and had distinct browning phenotypes in some adipocytes within WAT. Interestingly, calorimetry analysis did not display an increase in energy expenditure in cachectic mice although browning was evident in WAT. However, treatment with FST288 during cancer progression kept body weight and WAT in GDF9-iCre+; PIK3CA* female mice. Most of all, FST288 protected the size and lipid droplets of adipose tissues against WAT wasting during cachexia development. Conclusion: The progression of cancer cachexia impacts adipose tissues. Injection of FST288 supports the key role of activin A in the progress of cachexia. FST288 prevented adipose tissue wasting and cachexia development, revealing another evidence of the efficacy of activin A antagonist in preventing cancer cachexia development.

From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.

Cancer cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here, we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers and potential therapies. Both in mice and humans, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in precachexia. Inflammatory pathways, mitochondrial dysfunction and gut microbiota have recently been studied to play an important role in muscle fatigue in preclinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. Heightened inflammation within muscle, altered muscle function and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade.

Cancer-associated cachexia reduces survival, which has been attenuated by blocking the activin receptor type 2B (ACVR2B) ligands in mice. The purpose of this study was to unravel the underlying physiology and novel cachexia biomarkers by use of the colon-26 (C26) carcinoma model of cancer cachexia. Male BALB/c mice were subcutaneously inoculated with C26 cancer cells or vehicle control. Tumor-bearing mice were treated with vehicle (C26+PBS) or soluble ACVR2B either before (C26+sACVR/b) or before and after (C26+sACVR/c) tumor formation. Skeletal muscle and serum metabolomics analysis was conducted by gas chromatography-mass spectrometry. Cancer altered various biologically functional groups representing 1) amino acids, 2) energy sources, and 3) nucleotide-related intermediates. Muscle metabolomics revealed increased content of free phenylalanine in cancer that strongly correlated with the loss of body mass within the last 2 days of the experiment. This correlation was also detected in serum. Decreased ribosomal RNA content and phosphorylation of a marker of pyrimidine synthesis revealed changes in nucleotide metabolism in cancer. Overall, the effect of the experimental C26 cancer predominated over blocking ACVR2B ligands in both muscle and serum. However, the level of methyl phosphate, which was decreased in muscle in cancer, was restored by sACVR2B-Fc treatment. In conclusion, experimental cancer affected muscle and blood metabolomes mostly independently of blocking ACVR2B ligands. Of the affected metabolites, we have identified free phenylalanine as a promising biomarker of muscle atrophy or cachexia. Finally, the decreased capacity for pyrimidine nucleotide and protein synthesis in tumor-bearing mice opens up new avenues in cachexia research.

Lipid metabolism in cancer cachexia.

Cancer cachexia, characterized by losses in muscle and adipose tissue (AT), is associated with poor quality of life and prognosis, and lacks effective therapies. Both tumor- and host- derived factors disrupt normal metabolism and are vital to the catabolic drive in cancer cachexia. While muscle loss has long dominated cachexia research, recent work conducted predominantly in rodent models has begun to recognize the significance of AT lipid metabolism alterations in the development and progression of cancer cachexia. AT losses are mainly attributed to the activation of lipolytic pathways. An important recent discovery has been in the demonstration of white AT (WAT) "browning" conferring thermogenic properties to adipocytes that results in wasteful energy expenditure. Collectively, both elevated lipolysis and WAT thermogenesis play an important role in AT depletion in cancer. The purpose of this review is to highlight current knowledge related to the regulation of AT function in cancer cachexia.

Abstract B35: Molecular and phenotypic profiling of pancreatic cancer cachexia in novel murine models and patients

Abstract Background: Patients with pancreatic ductal adenocarcinoma (PDAC) suffer the highest rates of cachexia, with ~85% experiencing muscle and fat loss. Weight loss and muscle loss correlate with mortality in PDAC. Patients with cachexia experience fatigue, weakness and reduced quality of life. Cachexia impairs response to surgery, chemotherapy and radiation therapy. Currently the only effective therapy is removal of the tumor. However, pre-clinical studies demonstrate that slowing muscle or fat loss prolongs function and life, even absent effects on tumor growth. Thus anti-cachexia therapies should increase quality of life, clinical response and survival. Most cachexia research has been conducted using two classic non-PDAC mouse models, LLC lung and C26 colon cancer cell lines implanted s.c. Little genomic data are available in patients, with only 3 small gene expression studies in cachexia, none specific to PDAC. Thus whether mouse models faithfully reflect human PDAC cachexia is unknown. Methods: Mice: Cell lines derived from the KrasG12D;Trp53R172H;Pdx1-Cre (KPC) genetically engineered mouse model (GEMM) were injected orthotopically. Elastase-Cre and Pdx1-Cre KPC mice were generated. Mice were followed for tumor growth and metastasis, weight loss, body composition, strength, and muscle and fat wasting versus matched controls. A subset of models was characterized for serum cytokine levels and muscle transcriptomes. Patients: Patients undergoing surgery for PDAC (n=24) or benign conditions (n=12) donated clinical data, blood, muscle, subcutaneous adipose tissue and tumor (PDAC). Body composition was measured from CT scans. Whole blood, muscle and fat gene expression were profiled using the Ion AmpliSeq Transcriptome Panel and analyzed with Partech, Ingenuity, GSEA and NextBio. Results: Mice: We validated 9 novel murine models of PDAC cachexia. These models demonstrated considerable diversity in cachexia severity (latency to cachexia), body composition, tumor histology and metastasis, blood cytokine levels, and muscle gene expression. Orthotopic PDAC cell line and KPC GEMM models were more similar to each other than to LLC or C26 by phenotype and muscle gene expression. IL-6 and Activin, known to be elevated in human PDAC cachexia, were consistently elevated across mouse models. Inhibition of either reduced PDAC cachexia. Patients: PDAC and control groups had similar BMI, although 6-month history of weight loss and BMI-adjusted weight loss category were both greater for the PDAC group (p&amp;lt;0.0001). PDAC patients displayed reduced skeletal muscle and subcutaneous adipose tissue volume (p&amp;lt;0.05). Ampliseq (false discovery rate &amp;lt;0.05) revealed 23 differentially expressed genes in whole blood, 906 in muscle, and 2962 in adipose tissue, with ~250 overlapping genes in muscle and fat. The top predicted biofunctions increased by PDAC in both tissues were organismal death, followed by anomaly of musculoskeletal system, and hypoplasia; the most reduced biofunctions were cell movement, migration, and size of body. The top common canonical pathways increased were EIF2 signaling, and G1/S checkpoint regulation, while the most decreased were signaling from integrins, RhoGTPases, and leukocyte extravasation. Comparing mouse muscle to human muscle, “organismal death” was oppositely regulated and decreased in mouse. However, common pathways included EIF2 signaling and G1/S checkpoint regulation (increased) and cardiac hypertrophy signaling (decreased). At the gene level, substantial differences were observed between mouse and human muscle. Conclusions: Mouse models of PDAC are superior for modeling PDAC cachexia. In patients, the muscle and fat transcriptomes show a cachexia signature even in early stage (resectable) disease. Comparative molecular phenotyping of mouse and human PDAC cachexia reveal considerable overlap in pathways, albeit clear differences in gene level analysis. Thus careful characterization and application of models is warranted. Citation Format: Teresa A. Zimmers, Yanlin Jiang, Jianguo Liu, Eugene Ceppa, Atilla Nakeeb, Michael House, Nicholas Zyromski, C. Max Schmidt, Katharyn Hannaford, Daniel Schloss, Cynthia Brooks, Milan Radovich, Yunlong Lui, Guanglong Jiang, Stephen F. Konieczny, Patrick Schweickert, Brad Hancock, Joshua Kayes, Xiaoling Zhong, Christophe Poirier, Ernie Au, Andrea Bonetto, Safi Shahda, Marc Kohli, Bert O’Neil, Marianne Pons, Leonidas Koniaris.{Authors}. Molecular and phenotypic profiling of pancreatic cancer cachexia in novel murine models and patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B35.

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia.

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.

The times they are a-changin': the Cachexia Conference goes annual.

The field of cachexia and muscle wasting research has started to move, slowly but steadily, and large and small companies alike are increasing their efforts into the development of new drug therapies for cachexia, sarcopenia and frailty. Recent research has focused on novel screening tools1 and biomarker research to enable an early diagnosis of wasting,2, 3 but also on the pathophysiological understanding of the wasting process4, 5 nutrition,6, 7 exercise, particularly in cachectic cancer patients,8, 9, 10 and novel therapeutic approaches.11, 12, 13 Even though the pathophysiological understanding is making rapid progress – if not by the minute or day, then by the week for sure – recent phase III trials have failed unfortunately to translate gain in muscle mass into gain in muscle function, i.e. more exercise capacity or strength or better stair climbing power. The Cachexia Conference, closely affiliated with this journal and the Society of Sarcopenia, Cachexia and Wasting Disorders (SCWD), until recently held ist conferences only every other year in a different location. The Cachexia Conferences closely follow the rapid progress in the field of cachexia research. Therefore, as of this coming December, the conference will be held annually. Indeed, the 9th Cachexia Conference is due to take place on December 10‐11, 2016, in Berlin, Germany. Berlin is a city that is changing as quickly as the field of cachexia research. Following the lines of Bob Dylan's song The Times They Are A‐changin’, we invite researchers to come to Berlin to share their enthusiam and insight: ‘Come senators, congressmen Please heed the call Don't stand in the doorway Don't block up the hall For he that gets hurt Will be he who has stalled There's a battle outside And it is ragin'. It'll soon shake your windows And rattle your walls For the times they are a‐changin'. Bob Dylan We would like to make the conference a very hands‐on meeting with (likely) no parallel sessions and a programme made by the audience. We hereby call for your session proposals to be send to Mrs Monika Diek at the SCWD office (ofni.aixehcac@6102ecnerefnoc). Please do so by 15th April, 2016. As we start to go annual, we will still hold a big Cachexia Conference for 3 full days (as done in Paris) every 2 years, and every other 2 years the meeting is a 2‐day affair. As the field gains momentum, we may change this in the future, but fort he time being this seems tob e prudent. So please, safe the date and come to Berlin on 10/11 December, 2016. And send us your session proposals.

Hypermetabolism: should cancer types, pathological stages and races be considered in assessing metabolism and could elevated resting energy expenditure be the therapeutic target in patients with advanced cancer?

Hypermetabolism, defined as elevated resting energy expenditure (REE), was common in cancer cachectic patients1 as published before in cancer patients2 and might result in poor outcomes. In this study, there was no significant difference in age, cancer type, gender, cancer treatment and inflammation between elevated REE group and normal REE group. As authors indicated, the small sample size, the heterogeneous population and the selection bias could have some impacts on the findings. Regarding the sample size, a moderately large study, including 714 cancer patients, suggested that cancer type, pathological stage and duration of disease are contributors to metabolic activity.2 To keep the homogeneity of the study population, Wu et al. enrolled 56 male patients as newly diagnosed with esophageal cancer and showed that the rate of weight loss positively correlated with the ration of REE to body weight and high-sensitivity C-reactive protein.3 In addition, it is well known that less than 5% of cancer patients participate in clinical studies and that non-enrollment in cancer research was associated with older age and sex (female),4 which might facilitate the selection bias. In this study, hypermetabolism is more common in non-Caucasian patients than in Caucasian patients.1 Interestingly, non-Caucasian healthy subjects had a lower REE compared with Caucasian healthy subjects,5 and a similar trend was observed in obese patients.6 It is still controversial whether racial background influences metabolic response in various pathophysiological conditions such as obesity, diabetes and cancer cachexia. At present, the number of cachexia research is critically lacking compared with that of obesity research, and7 no other evidence has been published on racial differences in REE among cancer patients, in particular cancer cachectic patients. It remains unclear whether hypermetabolism could be the therapeutic target in advanced cancer patients; however, recently, Ma et al. reported that administration of omega-3 polyunsaturated fatty acids resulted in a significant decrease in REE and a significant increase in overall survival in patients with pancreatic cancer.8 As sustained hypermetabolism leads to muscle wasting, some drugs such as ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors,9 as well as physical exercise,10 which are promising for the treatment or the prevention of muscle wasting, could be the candidates as therapeutic options for this condition. To clarify the pathophysiology of hypermetabolism in cancer patients, validation studies on larger samples, various cancer types, different pathological stages and races are needed. In addition, hypermetabolism could be the therapeutic target at least in a sub-population of cancer patients. To confirm it, further research is needed.

Demystifying Nutritional Support in Cancer (FR451)

•Describe the pathophysiology and stages of the cancer-related anorexia-cachexia syndrome.•Describe methods to assess cancer-related anorexia-cachexia at the bedside.•Describe the interventions according to stages of cancer-related anorexia-cachexia. Central to managing nutrition in the cancer patient is recognizing and managing the anorexia-cachexia syndrome. Research characterizes the anorexia-cachexia syndrome as a metabolic syndrome associated with advanced cancer producing loss of muscle with or without the loss of fat mass. Its development is a turning point in the disease trajectory of a cancer patient, with continued weight loss associated with a shorter survival time, and it is responsible for death in up to 20% of cancer patients. Anorexia-cachexia is a significant cause of morbidity that manifests as weight loss, asthenia (loss of energy and strength), anemia, and alterations in immune function. Research now recognizes anorexia-cachexia as a continuum consisting of three stages, defined as precachexia, cachexia, and refractory cachexia. Not all patients traverse the entire spectrum. Interventions potentially modifying the effect of anorexia-cachexia differ according to stages. Patients are often inappropriately recommended extreme types of nutritional support according to the stage of cancer and extent of the metabolic syndrome. Patients also experience messages that force them to adhere to therapies that are no longer appropriate for the stage of anorexia-cachexia. From presenters with diverse backgrounds in oncology, nursing, cachexia research, and community palliative care, and through didactics, case presentations, and audience participation, the session will accomplish four major goals for the attendees: (1) enhance knowledge of the basic pathophysiology of the anorexia-cachexia syndrome, (2) improve clinical assessment of anorexia-cachexia with a focus on clinical bedside assessment and technological advances, (3) characterize interventions according to stage of anorexia-cachexia, and (4) develop attendees’ skills at communicating with patients and families about cancer and nutrition. When this session is completed, palliative care specialists will walk away better equipped to participate in complex nutritional decision making for cancer patients.

Abstract 1217: Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform

Abstract Cachexia is present in the majority of patients with advanced cancer progression and is not reversible through nutritional supplementation, leading to loss of skeletal muscle and adipose tissue. There are a lack of quality pre-clinical models for cachexia research. Previously, Champions Oncology reported a mouse cachexia model derived from a primary human renal cell carcinoma tumor implanted in immunocompromised mice. This model, CTG-0804, was developed using the innovative Champions TumorGraft™ platform, which preserves the biological properties of the original human tumor. The Champions TumorGraft platform demonstrated dramatic weight loss in these mice as the tumor grew. Plasma from these mice also showed elevated levels of human IL-6. We have now further characterized this TumorGraft model by evaluating standard of care (SOC) agents for renal cell carcinoma and anti-IL-6 compounds to determine the mechanism of cachexia. The SOC evaluation revealed that sorafenib, sunitinib, temsirolimus and bevacizumab as single agents provided a survival advantage by inhibiting tumor growth and preventing weight loss in these mice. Blockade of human IL-6 with tocilizumab or ALD518 did not inhibit tumor growth and weight loss still occurred, demonstrating the possibility of other pathways involved in the cachexia mechanism. In addition, the SOC data for sunitinib showed significant tumor growth inhibition, but no regression at the study end point. This correlated with the clinical profile, where sunitinib could not prevent metastasis and the patient eventually progressed. The TumorGraft model was molecularly characterized and mutation analysis revealed a KIT V530I mutation. This mutation has been reported in extra-abdominal aggressive fibromatosis (desmoid tumor) and acute myeloid leukemia patients that have responded to c-kit targeting therapies, such as imatanib and dasatinib. Further characterization of this TumorGraft is ongoing to include additional bioinformatics using gene expression and mutation pathway analyses. In summary, we have continued development of this cachexia model using the Champions TumorGraft platform, along with molecular evaluation, to produce a robust and well-characterized approach for cachexia investigation which can also be applied to other areas of drug development and cancer research. Citation Format: Nathan Anderson, Tin Khor, Andrew Feldhaus, Andreya Gatling, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2014-1217

An invitation to the 2nd Cancer Cachexia Conference, Montréal, Canada.

The National Cancer Institute in the USA has recently placed greater emphasis on cancer cachexia research by identifying this syndrome as a provocative question needing to be addressed in order to drive progress against cancer. Such funding mechanisms are expected to stimulate cutting edge approaches at both the basic and clinical science levels to advance our understanding of the underlying causes of cachexia. The goal is to identify and test lead compounds that preserve the loss of adipose and skeletal muscle tissues in pancreatic and other tumor types prone to developing cachexia. Complementing the Provocative Questions mechanism, a cancer cachexia conference was organized in 2012 in Boston, Massachusetts, USA, with the goal of creating a forum whereby basic and clinical scientists from academia and industry could freely interact to share ideas from published and unpublished work so as to advance our understanding on the factors and mechanisms driving weight loss, weakness, and fatigue in cancer patients. This first cancer cachexia conference was viewed as a success as evidenced by the high number of registrations from Ph.D. and M.D. scientists, the balanced representation from academia and industry, the quality of unpublished data presented, the breath of the science, and the positive feedback received from a solicited questionnaire. Based on these achievements and significant scientific advancements made within the last few years, the decision was made to organize a second international cancer cachexia conference. The expectation of conducting a second conference is that it brings awareness to the many fields and accelerates research leading to better diagnosis and therapies for the cancer syndrome. Therefore, on behalf of the organizing and scientific committees, and in collaboration with the Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD), it is a pleasure to announce the 2nd Cancer Cachexia Conference: Evolving Mechanisms and Therapies, which will take place at the exciting city of Montreal, Canada on September 26–28, 2014. We hope you take the opportunity to join us in what we anticipate will be another exciting conference leading to new insights that will bring researchers and physicians one step closer to effectively treating the cancer cachexia syndrome. For more information on the conference, the venue, and how to register, please visit: http://cancercachexia2014.com/ Thank you and look forward to seeing you in Montreal!

The small intestine: A critical linkage in pathophysiology of cardiac cachexia

The small intestine: A critical linkage in pathophysiology of cardiac cachexia

Adiponectin Resistance in Heart Failure and the Emerging Pattern of Metabolic Failure in Chronic Heart Failure

In recent years, an interesting shift in our understanding of chronic heart failure (CHF) pathophysiology may be observed. Beyond the traditional concepts of hemodynamic failure and neuroendocrine activation, it is increasingly appreciated that CHF is a much more complex and truly systemic disease including the peripheral organs and whole body regulatory processes as well. Novel concepts such as the systemic inflammatory immune activation and the skeletal muscle hypothesis have emerged.1 These concepts recognize the significant contribution of peripheral changes to symptomatic status, disease progression, and outcome in CHF. Article see p 185 A further novel facet in heart failure pathophysiology has emerged recently because impaired regulation of systemic metabolic balance is increasingly in the focus of clinical research. The emerging picture suggests a complex but characteristic pattern of metabolic pathways that are imbalanced, attenuated, or abnormally activated. Hormonal imbalances have been previously observed as common features in CHF, such as insulin resistance2 and growth hormone resistance3 that contribute to both morbidity and mortality of patients. The metabolic interaction of neuroendocrine activation and immune activation such as from cytokines and oxygen radical accumulation add to the complexity of these interrelated processes. In general, the findings repeat, again, the classical concept of short-term beneficial adaptive responses on acute injury or disease may eventually turn into harmful maladaptive signals on prolonged and chronic activation. The overall clinical effects that may be observed from impaired energy metabolic efficacy contribute to impaired exercise capacity, muscle fatigue, and early exhaustion—key symptoms in heart …