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Title: Mechanisms of cancer cachexia
Author: Wigmore, Stephen J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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The purpose of this thesis was to investigate the mechanisms of cancer cachexia and use the information so obtained to attempt to develop effective treatment strategies using pancreatic cancer as a model of cancer cachexia. Longitudinal nutritional assessment in a group of untreated patients with pancreatic cancer demonstrated that weight loss with depletion of lean tissue and subcutaneous fat stores was an inexorable process up to death. Analysis of energy balance in a similar cohort of patients demonstrated increased resting energy expenditure (REE) compared with predicted values and reduced nutritional intake and showed that patients who had an elevated acute phase protein response (APPR) had the greatest energy deficits. An investigation was undertaken into the aetiology of the APPR in cancer. Peripheral blood mononuclear cell (PBMC) interleukin-6 (IL-6) and tumour necrosis factor (TNF) production were elevated compared with controls and the supernatants from these cells stimulated a greater intensity of APPR by isolated human hepatocytes compared with supernatants from control PBMC. Pre-treatment of PBMC with IL-4 reduced the ability of PBMC from cancer patients to produce IL-6 and TNF and reduced the potential of these supernatants to elicit an APPR in vitro. Human pancreatic cancer cell lines were found to secrete IL-6 and/or IL-8 constitutively. During investigations into the effects of pancreatic cancer cell line supernatants on APP production by hepatocytes it was observed that IL-8 could mediate APP production in vitro. Serum concentrations of both IL-6 and IL-8 were elevated in pancreatic cancer patients and IL-8 correlated with serum CRP concentration. These investigations highlight the importance of the cytokine-hepatocyte axis and the APPR in cancer cachexia. Clinical trials of drugs directed at reducing cytokine concentrations and the APPR have shown early promise and are worthy of further evaluation in the management of cancer cachexia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available