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Title: Development of novel diagnostic tests and therapies for hepatopancreaticobiliary malignancy
Author: Ayaru, Lakshmana
ISNI:       0000 0004 2671 7085
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2007
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An assay of minichromosome maintenance (mcm) protein 5 in bile was developed to determine whether it was a more sensitive marker of pancreatic malignancy than routine biliary brush cytology. The potential for immunotherapy and photodynamic therapy (PDT) for hepatobiliary cancer was addressed. Methods: 1) Prospective study of mcm protein expression in bile and tissue sampled from biliary strictures; 2) Longitudinal and cross-sectional studies of T cell responses in patients with primary liver cancer treated with transarterial embolisation or PDT, 3) Preclinical studies of interstitial verteporfin PDT and a phase II clinical study of endoscopically delivered meso-tretrahydroxyphenylchlorin (mTHPC) PDT in patients with malignant biliary strictures. Results and Conclusions: Mcm proteins were expressed in all tissue layers in malignant biliary strictures and confined to the basal proliferative compartment in benign tissue. Mcm 5 in bile sediment, detected by an immunofluorometric test, was significantly more sensitive than routine brush cytology for the diagnosis of malignancy in biliary strictures. Tumour (alphafetoprotein)-specific CD4+ T cells were significantly expanded in-vivo in hepatocellular carcinoma patients during and after embolisation. Novel AFP-derived epitopes were identified which could be targeted in an AFP based vaccine for hepatocellular carcinoma. The unmasking of AFP-specific CD4+ T cells was significantly associated with greater tumour necrosis and an improved clinical outcome, which may provide a rational for combining immunotherapy with embolisation in HCC patients. In patients with malignant biliary obstruction, mTHPC PDT caused efficient tumour necrosis but there was a significant risk of vascular complications. Verteporfin PDT was safe in the normal hamster pancreas and had a similar efficacy to previous photosensitisers, with the advantages of a shorter drug-light interval and drug elimination time. Phase 1 studies of verteporfin PDT in patients with locally advanced pancreatic cancer are planned.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available