published_or_final_version / abstract / Surgery / Doctoral / Doctor of Philosophy

There are a number of existing staging systems for patients with hepatocellular carcinoma (HCC). Yet, Barcelona Clinic Liver Cancer (BCLC) staging classification is the only one which suggests treatment guidance. Although BCLC staging is widely used in Western countries, it may not fit in the management of HCC patients in Hong Kong as they mostly have different etiologies and have more aggressive treatment strategy when compared with their counterparts in Western countries. It is aimed in this thesis to develop a new prognostic staging system in conjunction with treatment guidelines for HCC patients in Hong Kong. Three thousand eight hundred and fifty six adult HCC patients presented to the Department of Surgery, Queen Mary Hospital between January 1995 and December 2008 were included. The patient data were randomly separated into a training set and a test set for scheme development and performance assessment respectively. Four established prognostic factors which have determinative roles in treatment, namely Eastern Cooperative Oncology Group performance status, Child-Pugh grade, tumor status, and presence of extrahepatic vascular invasion/metastasis, were selected in building the scheme. Cox proportional hazards regression on overall survival was used to derive a relative coefficient for each category of these four factors. Clinical knowledge in addition to the relative coefficients was involved in the proposal of the prognostic stages. Then a classification and regression tree analysis was performed to elicit a set of simple clinical decision rules given the factors. This tree-structured classifier was adjusted with clinical judgment and reconciled with the proposed prognostic staging system for treatment guidelines. This Hong Kong Combined Liver Cancer (HKCLC) prognostic classification scheme stratifies patients to stages I to V with distinct overall survival outcomes. Its performance was compared to BCLC scheme for their discriminatory ability as staging systems and effectiveness of treatment guidelines. The former used receiver operating characteristics (ROC) analysis and concordance index as measures of the ability to distinguish patients with different prognosis for overall survival. HKCLC staging had significantly larger 1-year, 3-year and 5-year area under ROC curve values and higher concordance index vis-a-vis BCLC staging. The latter compared the overall survival of patients who received different treatments. The overall survival of patients with the same BCLC stage and the same HKCLC stage but received HKCLC recommended treatments were compared with those received BCLC recommended treatments by Kaplan-Meier plots and log-rank test. HKCLC treatment guidelines had wider indications for more aggressive treatments than the BCLC treatment schedule, and demonstrated significant survival benefit in our patients. / published_or_final_version / Surgery / Master / Master of Philosophy

[Truncated abstract] Hepatocellular carcinoma (HCC) is the major malignancy complicating chronic liver disease. New therapies for the prevention of HCC are required due to the limited success and high tumour recurrence rates of existing treatments. Emerging evidence suggests that HCC arise from the transformation of adult liver progenitor cells (LPCs), which have the capacity to differentiate into hepatocytes and biliary cells during liver regeneration. LPC activation precedes neoplasia in experimental hepatocarcinogenesis. LPCs share antigenic epitopes with HCCs, including α-fetoprotein (AFP) and M2- pyruvate kinase (M2PK). In animal models of hepatocarcinogenesis, attenuation of the LPC response reduces the incidence of HCC following prolonged liver injury via a tumour necrosis factor (TNF) dependent mechanism. As TNF is a pro-inflammatory cytokine, these data suggest that anti-inflammatory agents may be effective in inhibiting LPC activation and hepatocarcinogenesis. Cyclo-oxygenase-2 (COX-2) is an inducible enzyme that mediates the production of many prostaglandins during inflammation and carcinogenesis. Recent investigations show that the administration of selective COX-2 inhibitors (SC2Is) may reduce the incidence of a variety of tumours including breast, colon and skin. The broad aim of this thesis was to conduct a series of detailed studies on the effects of a SC2I on LPC activation and the hepatic pathologies associated with hepatocarcinogenesis in order to test the hypothesis that S2CIs may be a beneficial therapy that can reduce liver injury and pre-neoplastic changes in the choline-deficient, ethionine supplemented (CDE) murine model of hepatocarcinogenesis. Administration of a SC2I (SC-236) significantly inhibited a variety of hepatic cell populations that expand during the first month of the CDE mouse model of hepatocarcinogenesis (a choline deficient, ethionine supplemented diet). Numbers of M2PK-positive LPCs (which are more hepatocytic in morphology and are also COX-2 positive) and inflammatory cells were all significantly reduced by SC-236. In contrast, numbers of A6-positive LPCs (which are more biliary cell-like in morphology and do not express COX-2) were unchanged. ... In summary, these data suggest that COX-2 inhibitors such as SC-236 inhibit LPC activation and a variety of pre-neoplastic liver pathologies as a result of COX-2 dependent and independent mechanisms that may be mediated through inhibition of Akt phosphorylation and induction of apoptosis. Moreover, SC2Is may be useful as preventative treatment strategies for HCC in patients with chronic liver disease.

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published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Master / Master of Philosophy

Li Ka Shing Prizes for best PhD theses in the Faculties of Dentistry, Engineering, Medicine and Science, 2006-2007 / published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy