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Title: Radiological, clinical and laboratory based studies in the pathogenesis of desmoid tumours in familial adenomatous polyposis
Author: Bhandari, Santosh
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Around 10% of desmoid tumours (DT) in familial adenomatous polyposis (FAP) patients grow relentlessly, causing major morbidity and mortality. Radiological, clinical or cellular predictors of aggressive DT are yet to be identified. The work described in this dissertation aimed to identify such predictors by radiological studies, and to develop management guidelines and identify possible targets for therapy. Nine FAP patients with DT underwent 64 multi detector computed tomography (64-MDCT), 1.5 Telsa magnetic resonance imaging (1.5T MRI), Diffusion Tensor Imaging (DTI), Dynamic Contrast Enhanced MRI (DCE-MRI) and Fluorine-18 Flurodeoxyglucose Positron Emission Tomography (18F-FDG PET CT). Direct comparision between 1.5T MRI and 64-MDCT found that MRI was at least equivalent to MDCT in the assessment of DT. DTI was feasible and detected an anisotropic diffusion, which was less directional than in muscle. Metabolic (FDG PET) and vascular imaging (DCE-MRI) of DT demonstrated a spectrum of findings and found that DT were generally hypovascular and poorly glucose avid. A review of nine FAP patients with intra-abdominal desmoid (IAD) and air-fluid level (AFL) on cross sectional imaging found that either a direct communication or translocation of microorganism from bowel led to the development of AFL. Some of these patients could be treated successfully with antibiotics and/or a percutaneous drain; however, the majority ultimately required complex surgery. Full sequence APC mutation analysis performed in three primary DT cell lines detected ‘second hit’ somatic mutation in only one, confirming the establishment of a true DT cell line. A study of choline metabolism using choline kinase alpha (CHKA) as a marker for activation, however, failed to demonstrate up regulation of choline metabolism in desmoid tumour cells. Studies of the Wnt signalling pathways confirmed the activation of canonical Wnt signalling in DT. Interestingly Wnt11, a non-canonical Wnt, was also up regulated in DT.
Supervisor: Clark, Sue ; Phillips, Robin Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral