Fearon, Kenneth

Preston, Tom

MacDonald, Alisdair John

2016-09-07T15:17:28Z

2016-09-07T15:17:28Z

2015-07-04

Cachexia occurs commonly and is a significant cause of morbidity and up to 20% mortality in patients with cancer. Loss of muscle mass occurs as part of the cachexia wasting process and low muscle mass is a key element of the most recent consensus cachexia definition. Measuring muscle mass and changes in skeletal muscle is important to phenotype cachectic individuals and to monitor response to anti-cachectic treatments. This thesis investigates minimally invasive or burdensome methods of measuring muscle mass and muscle protein kinetics for use in a clinical or research setting. Quantification of muscle area on routine diagnostic cross-sectional imaging offers a novel and relatively non-invasive method of assessing both regional (and by extrapolation) whole body muscle mass. The need for such a direct measurement of muscle mass was demonstrated by showing that simple anthropometric formulae are unable to predict muscularity accurately (within 25%) when compared with estimates derived from patients diagnostic CT scans. It may be that qualitative changes in muscle may be more sensitive indices of the wasting process rather than qualitative change. Myosteatosis (infiltration of muscle by fat) is known to occur in both cachexia and age related sarcopenia and can be quantified using the Hounsfield spectrum observed on routine diagnostic CT scans. However, not all patients undergo routine CT scanning and there is a need for a biomarker derived from urine or blood. Consequently, cross sectional imaging was used to phenotype patients in a proteomic analysis of urine with the aim of identifying protein or peptide biomarkers associated with myosteatosis in cancer cachexia. A biomarker model for myosteatosis was developed with good sensitivity (97%) but poor specificity (71%). Many of the potential protein / peptide markers identified had poor associations with known mechanisms of muscle wasting and further study of the identified peptides in an extended cohort would help determine the validity of the present findings. However, two proteins with potential roles in muscle repair or neuromuscular function (Agarin and Cathepsin C) were identified and these may warrant targeted investigation with evaluation against sequential measures of muscle mass to determine their value in defining muscle loss over time. As different regional measures of muscularity are available, trunk (L3 CT) and limb muscle (quadriceps MRI) cross sectional measurements were compared with functional assessments to determine the optimal site for measurement. Neither measure proved superior to the other but appeared to reflect different aspects of function. Quadriceps muscle area correlated with quadriceps strength and power whilst truncal muscle area correlated more with complex movements such as the timed-up-and-go test. Changes in regional muscle area in patients with upper gastrointestinal cancer were assessed by upper and lower limb MRI before and after surgery and by L3 CT cross sectional area before and after neo-adjuvant chemotherapy. No change in limb muscularity was seen at 220 days post operatively compared with pre-op measurements. During neo-adjuvant chemotherapy a significant loss of truncal muscle occurred in the absence of significant weight loss suggesting that sequential cross sectional imaging is capable of detecting changes in body composition that may not be apparent clinically. Whilst sequential scans may document changes in muscularity, they do not describe the underlying levels of muscle synthesis or degradation that may regulate muscle volume. The final section of this thesis describes the development of a novel tracer method to measure skeletal muscle synthesis and its application in a study of patients with cancer and healthy volunteers. This novel method was able to measure skeletal muscle fractional synthetic rate (FSR) over a longer time-period than previous methods (weeks rather than hours) and reduced the burden on the patient by the use of a single oral tracer dose and single muscle biopsy. Comparison of synthesis rates in quadriceps and rectus abdominis showed higher rates in quadriceps, 0.067% per hour vs 0.058% per hour respectively. Despite a net loss of muscle as measured by serial CT scans, skeletal muscle FSR appeared to be marginally increased in weight losing patients with cancer compared with weight stable patients and healthy controls. When FSR was combined with measures of muscle mass it was demonstrated that only small differences between synthesis and degradation are required to see the levels of muscle wasting seen in patients with cancer. In summary, routine cross sectional imaging provides a useful and unique measure of muscularity that is associated with function in patients with cancer Sequential scans can provide additional information about changes in body composition even in the absence of weight loss. There are significant regional variations in both muscle wasting and skeletal muscle fractional synthetic rate. The combination of sequential estimates of muscle mass from diagnostic CT scans along with estimates of FSR allow assessment of the contribution of altered synthesis and degradation to muscle loss. In patients with upper GI cancer it would appear that increased degradation may be more important that altered synthesis. The relative change in either process to account for absolute loss of muscle mass is small. Such findings have implications for the targeted therapy of muscle wasting in cancer patients.

http://hdl.handle.net/1842/16455

en

The University of Edinburgh

Gallagher IJ, Stephens NA, MacDonald AJ, Skipworth RJ, Husi H, Greig CA, et al. Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies. Clin Cancer Res. 2012;18(10):2817-27.

MacDonald AJ, Greig CA, Baracos V. The advantages and limitations of crosssectional body composition analysis. Curr Opin Support Palliat Care. 2011;5(4):342-9.

Stephens NA, Skipworth RJ, Macdonald AJ, Greig CA, Ross JA, Fearon KC. Intramyocellular lipid droplets increase with progression of cachexia in cancer patients. J Cachexia Sarcopenia Muscle. 2011;2(2):111-7.

Stephens NA, Gray C, MacDonald AJ, Tan BH, Gallagher IJ, Skipworth RJ, et al. Sexual dimorphism modulates the impact of cancer cachexia on lower limb muscle mass and function. Clin Nutr. 2012;31(4):499-505.

A novel oral tracer procedure for measurement of habitual myofibrillar protein synthesis A. J. MacDonald, A. C. Small, C. A. Greig, H. Husi, J. A. Ross, N. A. Stephens, K. C. H. Fearon, T. Preston Rapid Communications in Mass Spectrometry. 2013, 27, 1769–1777

Habitual myofibrillar protein synthesis is normal in patients with upper GI cancer cachexia A.J. MacDonald, N. Johns, N.A. Stephens, C.A. Greig, J.A. Ross, A.C Small, H. Husi, K.C.H. Fearon, T. Preston Clinical Cancer Research, Nov 2014, PMID 25370466

Can baseline muscle mass be predicted in weight stable patients with cancer? A. J. Macdonald, N. Stephens, C. Greig, H. Husi, K. C. Fearon, T. Preston Clinical Nutrition Supplements 2011 Volume 6, Issue 1 , Pages 41-42,

Upper and lower limb muscle mass in patients undergoing surgery for upper GI cancer A. J. Macdonald, M. Esposito, C. Gray, N. A. Stephens, C. Greig, K. C. Fearon Clinical Nutrition Supplements (2011) Volume: 6, Issue: 1, Pages: 42

Loss of fat free mass occurs during neo-adjuvant chemotherapy for upper GI cancer A. J. Macdonald, N. Stephens, M. Esposito, J. Ross, L. Wall, C. Greig, V. Baracos, K. C. Fearon Clinical Nutrition Supplements 2011 Volume 6, Issue 1 , Page 42,

cachexia

computed tomography

sarcopenia

Assessment of muscle wasting

Thesis or Dissertation

Doctoral

MD Doctor of Medicine