title: Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle.
abstract: BACKGROUND
  Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system.
  
  
  METHODS
  41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and/or low muscularity (LM). Four diagnostic criteria were used >5%WL, >10%WL, LM, and LM+>2%WL. All patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, Western blots for markers of autophagy, SMAD signalling, and inflammation.
  
  
  RESULTS
  Compared with non-cachectic cancer patients, patients with LM or LM+>2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either >5%WL or LM+>2%WL. Compared with non-cachectic patients, SMAD3 protein levels were increased in patients with >5%WL (p = 0.022) and with >10%WL, beclin (p = 0.05) and ATG5 (p = 0.01) protein levels were increased. There were no differences in phospho-NFkB or phospho-STAT3 levels across any of the groups.
  
  
  CONCLUSIONS
  Muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the diagnostic criteria for cachexia are based on weight loss alone, a measure of low muscularity alone or a combination of the two. For intervention trials where the primary end-point is a change in muscle mass or function, use of combined diagnostic criteria may allow identification of a more homogeneous patient cohort, reduce the sample size required and enhance the time scale within which trials can be conducted.
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Johns
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Stephens
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Degen
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Degen
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Frieauff
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Lambert
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Ronenn
authors.initials: R
authors.lastname: Roubenoff
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Jacobi
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Kenneth C H
authors.initials: KC
authors.lastname: Fearon
mesh_terms: D000368:Aged; D001343:Autophagy; D015415:Biomarkers; D015992:Body Mass Index; D002100:Cachexia / Q000175:diagnosis* / Q000209:etiology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009369:Neoplasms / Q000150:complications*; D010641:Phenotype; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D015431:Weight Loss
chemical_list: D015415:Biomarkers; D051785:Smad Proteins