published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Liver transplantation (LT) is the most effective treatment for hepatitis B virus (HBV) related liver failure and hepatocellular carcinoma (HCC). Nevertheless, HBV and HCC recurrence rate remains high after LT. Previous studies have shown that HBV reactivation is associated with HCC recurrence and poor prognosis after LT. The main objectives of this study are to investigate the risk factors for HBV and HCC recurrence after LT, the efficacy of antiviral drugs to prevent HBV reactivation and the underlying mechanisms contributing to HBV reactivation. Firstly, we investigate the risk factor for HBV and HCC recurrence in 551 HBsAg seropositive LT patients, of whom374 had no tumor and 177 had HCC. All patients received indefinite antiviral treatment after LT. The study showed that pre-LT HBV DNA levels and HCC recurrence were significantly associated with HBV reactivation after LT. Younger age, lower Child-Pugh score, beyond UCSF criteria, higher AST level, salvage LT, older donor, HBsAg seropositive at the last follow-up and HBV reactivation after LT were independent risk factors for HCC recurrence. HCC recurrence alone accounts for poor overall survival. The sequence analysis identified drug-resistant mutants as the main contributors to HBV reactivation. In addition, wild-type (antiviral drug-sensitive) HBV reactivation was identified in patients with HCC recurrence. Secondly, we investigate the efficacy of antiviral drugs monotherapy (Lamivudine or Entecavir) in preventing HBV reactivation. This study showed that patients receiving lamivudine (LAM) experienced significantly greater HBV reactivation and HCC recurrence than those receiving entecavir (ETV). In patients with no tumors, HBV reactivation was found in the LAM groups but not in the ETV groups, due to the appearance of a LAM drug-resistant mutant. In patients with HCC recurrence, HBV reactivation was found in both treatment groups. Wild-type HBV reactivation was identified in 17% (5/29) and 100% (1/1) of HCC patients receiving LAM and ETV respectively. This suggests that, although ETV had higher genetic barriers to HBV drug resistance; it still cannot prevent wild-type HBV reactivation in HCC-recurrent patients. Thirdly, we investigate the expression of HBV markers in HCC and adjacent non-tumor tissues. Origin of circulating HBV was identified using genetic distance analysis of HBV isolated from different compartments (i.e. HCC and adjacent non-tumor tissues). The study showed that, in some HCC cases, the expressions of HBsAg and HBV replicative efficiency are higher in HCC tissues than in adjacent non-tumor tissues. Moreover, through genetic distance analysis, we demonstrated that HBV reactivation could originate from recurrent HCC. These data suggest that HCC supports HBV replication and that HBV is secreted from recurrent HCC. Finally, we demonstrate that the up-regulation of drug-specific ABC-transporters is significantly associated with patients with HCC recurrence. In vitro studies also showed that the up-regulation of ABCG2 contributes to antiviral drug-resistant. Finally, we demonstrate that the up-regulation of drug-specific ABC-transporters is significantly associated with patients with HCC recurrence. In vitro studies also showed that the up-regulation of ABCG2 contributes to antiviral drug-resistant. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

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Intensity modulated radiotherapy (IMRT) can potentially increase the dose delivered to liver tumours while sparing normal tissues from dose. More complex IMRT, with more modulation of the radiation beam is more susceptible to geometric and dosimetric uncertainties than simpler radiotherapy plans. Simple breath-hold liver IMRT using few radiation beam segments (<30) was investigated in 27 patients to determine the quality of treatment in terms of tumour dose coverage and normal tissue sparing as compared to index IMRT using >30 segments. In all 27 plans number of segments was reduced to <30 without compromising tumour coverage or normal tissue dose constraints, at the expense of dose conformity. Delivered tumour and normal tissue dose did not differ statistically between IMRT plans when accounting for treatment residual geometric error. This research supports considering the use of simple IMRT for treatment of liver cancer, except when loss of dose conformation is undesirable (i.e. very high doses).

Chen, Juan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 124-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Sze, Siu Ching. / Thesis M.Phil. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 109-124). / Abstracts also in Chinese. / Title from PDF title page (viewed on 24, October, 2016).

He, Mian. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 165-188). / Abstracts also in Chinese. / Title from PDF title page (viewed on 24, October, 2016).

archives@tulane.edu / 1 / Anna Smith