Dunn, J.M.; (2011) Barrett’s Oesophagus - studies of novel optical diagnostic tools and minimally invasive therapies. Doctoral thesis , UCL (University College London).

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Abstract

Dysplasia arising in Barrett’s oesophagus (BO) confers risk of progression to oesophageal adenocarcinoma (OAC), but it is variable and confounded by sampling error and diagnostic inter-observer variability. There is a need for biomarkers to accurately define risk and guide surveillance and treatment strategies. Oesophagectomy is the preferred treatment of high grade dysplasia (HGD), although this has been challenged by the emergence of endoscopic therapy. This thesis has shown image cytometric DNA ploidy analysis (ICDA) is accurate when compared to flow cytometry. In a multi centre biomarker validation study, ICDA predicted cancer risk in non dysplastic BO. ICDA also predicted relapse following photodynamic therapy (PDT). Nucleotyping (NT) is an imaging technique that evaluates textural changes of nuclei, which correlate with chromatin content and organisation. In this thesis NT was demonstrated to yield additional diagnostic information over ICDA alone, and the combination was highly accurate for dysplasia classification. In an experiment evaluating replication licensing factors in OAC, those representing the S-G2-M phases of the cell cycle correlated with aneuploidy. Polo like kinase 1 upregulation had the strongest correlation, the first time this has been shown in BO. Elastic scattering spectroscopy detected DNA ploidy abnormalities with equal accuracy using a standard or near infra-red enhanced spectrometer. In a prospective in vivo surveillance study, fewer biopsies were taken without a change in the diagnostic yield for dysplasia. A field carcinogenesis effect was also demonstrated, independent of both dysplasia and DNA ploidy abnormalities. Finally, in a randomised control trial of PDT for HGD, patients with BO less than 7cm had significantly higher efficacy and better tolerability with ALA than photofrin. Radiofrequency ablation was shown to be a safe and effective rescue therapy for patients that failed PDT. In summary these studies advance our understanding of biomedical optics for the risk stratification and treatment of Barrett’s oesophagus.

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