Abstracts of the 2nd Cancer Cachexia Conference, Montreal, Canada, 26–28 September 2014

s of the 2nd Cancer Cachexia Conference, Montreal, Canada, 26-28 September 2014 Published online 31March 2015 inWiley Online Library (wileyonlinelibrary.com)  Body composition and prognostication in cancer Vickie Baracos Department of Oncology, University of Alberta, Edmonton Alberta, Canada Cancer cachexia contributes to poor prognosis through progressive depletion of the body’s energy and protein reserves; research is revealing the impact of the quantitly of these reserves on survival. Our group has exploitated computed tomography (CT) images to study body composition in cancer patients. We argue that CT taken for the purposes of diagnosis and routine follow-up can be used to derive clinically useful information on skeletal muscle and fat amount and distribution. Population-based data sets have been analyzed, revealing wide variation in individual proportions of fat and muscle (Prado et al. Lancet Oncology 2008;9:629–35; Martin et al. . Muscle loss during aging is well known and is prognostic of frailty, falls, fractures, loss of independence, increased length of hospital stay, infectious complications in hospital and mortality. Muscle depletion is not limited to people who appear underweight and it may be a hidden condition in normal weight, overweight or obese people (i.e. sarcopenic obesity). Disparate behaviour of skeletal muscle and fat was acknowledged by an international consensus of experts on cancer cachexia, defined as being characterized by loss of skeletal muscle with or without loss of fat mass. Within the large interindividual variation of body composition in cancer patients, several consistent themes are emerging. Skeletal muscle depletion is a powerful predictor of cancer related mortality as well as of severe toxicity during systemic chemotherapy. Distinct from skeletal muscle, the fat mass is an important reserve of energy. High fat mass (i.e. obesity) appears to confer a survival advantage in patients with diseases associated with wasting, including cancer, rather than a disadvantage as understood from studies of all-cause mortality. The larger energy reserve of obese persons is thought to confer this advantage. Obesity predicted higher survival especially strongly when sarcopenia is absent. To specifically understand the relationships between body composition and cancer utcomes, we have reviewed several thousand clinical CT images. We used statistical methods (i.e. optimal stratification) to define muscle mass cutpoints that relate significantly to increased mortality and evaluated them in survival models alongside conventional covariates including cancer site, stage and performance status. Muscle depletion is associated with mortality in diverse tumor groups including patients with cancers of the pancreas, lung, breast and gastrointestinal tract, liver, bladder and kidney. Cancer patients who are cachexic by conventional criteria (involuntary weight loss) and by the additional criterion of severe muscle depletion share a very poor prognosis, regardless of overall body weight. Severe muscle depletion was identified in patients with cancers of the breast, colon, lung, kidney, liver, head & neck and lymphoma and these consistently had worse toxicity resulting in dose reductions or definitive termination of therapy when treated with 5-FU, capecitabine, sorafenib, sunitinib, carboplatin, cisplatin or a regimen (5FU with epirubicin & cyclophosphamide; 5FUwith oxaliplatin or CPT 11). Reduced treatment may explain excess early mortality in patients affected by severe muscle depletion. Survival models including cachexia and body weight/composition characteristics showed excellent fit (i.e. concordance statistics >0.9) and outperformed prediction models using only conventional cancer related covariates (C-statistics 0.75-0.8). In renal cell carcinoma muscle depletion was independent of the frequently used Memorial Sloan Kettering Cancer Center prognostic score and similar results were seen for muscle depletion in lymphoma independent of the FLIPI prognostic score. 1–02 Myostatin as a marker of cachexia in gastric cancer Maurizio Muscaritoli, Zaira Aversa and Filippo Rossi Fanelli Department of Clinical Medicine Sapienza, University of Rome, Rome, Italy Myostatin, also known as growth and differentiation factor-8 (GDF-8), is a negative regulator of muscle mass, belonging to the TGF-β superfamily. Myostatin is secreted as an inactive propeptide that is cleaved to generate a mature ligand, whose activity may be regulated in vivo by association and dissociation with binding proteins, including propeptide itself as well as follistatin or related molecules. Active myostatin binds the activin type II B receptor (ActRIIB) and, to a lesser extent, the related ActRIIA, resulting in the phosphorylation and consequent recruitment of the low-affinity type I receptor ALK (activin receptor like-kinase)-4 or ALK-5. This binding induces phosphorylation and activation of the transcription factors SMAD2 and 3 [mammalian homologue of Drosophila MAD (MothersAgainst-Decapentaplegic gene)], which translocate into the nucleus and together with SMAD 4 regulate the expression of target genes. In addition, myostatin has been suggested to exert its action through different pathways, such as the extracellular signal-regulated kinase (ERK)/ mitogen activated protein kinase (MAPK) cascade. Moreover, cross-talking between myostatin pathway and the IGF-1 axis has been postulated. Inactivating mutations of myostatin gene have been found in the “double-muscled cattle phenotype” as well as in humans. Myostatin null mice are characterized by marked muscle enlargement (~100 to 200% more than controls), exhibiting both fiber hypertrophy and hyperplasia, whereas systemic administration of myostatin in adult mice induces profound muscle and fat loss. Moreover, high myostatin protein levels have been reported in conditions associated with muscle depletion, such as aging, denervation atrophy, or mechanical unloading. Results from our laboratory have shown that myostatin signaling is enhanced in skeletal muscle of tumor-bearing rats and mice. Similarly, others have shown that myostatin inhibition, either by antisense oligonucleotides or by  Although the reason of this result is not known at present, a possible explanation could be that myostatin increase is paralleled by a concomitant rise in the expression of follistatin, a physiological inhibitor of myostatin. This would result in a myostatin/follistatin ratio similar to controls, thereby maintaining the myostatin signaling in basal conditions. In addition, unchanged levels of pSmad 2/3, despite increased myostatin protein expression, also may reflect a modulation of other molecules acting through the activin receptor type IIB, such as activin A. Interestingly enough, we found that the expression levels of muscle myostatin mRNA are significantly reduced in gastric cancer patients. Although the reason for these apparently contradictory results is not known at present, it is conceivable that the differences may at least in part be due to posttranscriptional mechanisms, such as increased myostatin synthesis secondary to increased translational efficiency or reduced degradation of myostatin. Based on the available data, it may be concluded that myostatin signaling is perturbed in the skeletal muscle of patients with gastric cancer. Changes occur even in early disease stage and in the absence of significant weight loss, supporting the view that the molecular changes contributing to muscle wasting and cancer cachexia are operating since the early phases of cancer. Myostatin signaling is complex and may be affected by the interplay of inhibitors such as follistatin and/or other members of the TGFβ superfamily. Myostatin may represent a suitable target for future pharmacological interventions aimed at the prevention and treatment of cancer-related muscle loss. 1-03 Role of Activin A in human cancer cachexia (ACTICA study) A Loumaye, M de Barsy, M Nachit, L Frateur, P Lause, A Van Maanen, JP Thissen Cancer Center of the Cliniques Universitaires St-Luc; Radiology, Cliniques Universitaires St-Luc; Endocrinology, Diabetology and Nutrition Dept, IREC, Université Catholique de Louvain and Cliniques Universitaires St-Luc, Brussels, Belgium Cachexia is a complex metabolic syndrome associated with underlying illness, characterized by loss of skeletal muscle and not reversible by nutritional support. Recent animal observations suggest that the production of Activin A (ActA), a member of the TGFß superfamily, by some tumors might contribute to cancer cachexia. This hypothesis seems attractive since inhibitors of ActA have been developed. Nevertheless, the role of ActA in the development of cancer cachexia has never been investigated in humans. Our goal was to demonstrate the role of ActA as a mediator of the human cancer cachexia and to assess its potential use as a biomarker of cachexia. Patients with colorectal or lung cancer were prospectively evaluated. All patients had clinical, nutritional and functional assessment. The skeletal muscle mass was measured by bioimpedance (BIA) and abdomen CT-scan (CT). Blood samples were collected in standardized conditions to measure circulating levels of ActA. One-hundred fifty-two patients were recruited (59 lung