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Thesis (M.Res.(Med.))--University of Hong Kong, 2009. / Includes bibliographical references (p. 105-124).

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 78-84). Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 78-84). Also available online.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.

Primary liver cancer (PLC) is the second most common cause of cancer death worldwide, preceded only by lung cancer. Current models for PLC either fail to fully recapitulate tumour histology and architecture or are expensive, time consuming and do not allow for personalised drug testing. During the first part of my PhD, I have collaborated with Dr. Laura Broutier in order to established a new 3D in vitro model system for liver cancer. Based on the current knowledge on organoid cultures, we have managed to establish a system to grow primary human liver cancer cells long-term (Broutier et al., in press). Interestingly, the tumour-derived organoids (tumoroids) recapitulate the original tumour histology and genetic alterations and are also able to generate tumours in an in vivo xenograft mouse model after long-term expansion. Furthermore, we have shown that tumoroids can also be successfully used for drug testing, suggesting their use to devise new targeted therapy as well as personalised treatment strategies. Current models to investigate the role of genes in cancer rely mostly on animal studies, which can be very time consuming and cost demanding, especially if resulting in negative outcomes. To overcome this issue, I have set up a protocol for introducing mutations in healthy human liver organoids using the CRISPR-Cas9 technology. Interestingly, after mutating TP53, RNF43 and ZNRF3 either alone or in combination, human organoids undergo genetic alterations and phenotypic changes that partially resemble the ones observed in tumoroids. This data suggests that this system could be used as a screening platform to study gene function before using animal models. In the last part, I have further explored the role of RNF43 and ZNRF3 (R&Z) - two newly identified WNT pathway negative regulators mutated in many cancer types - in the liver using an in vivo mouse model. Interestingly, conditional deletion of R&Z specifically in adult mouse hepatocytes results metabolic changes that eventually lead to extensive liver damage. However, when the liver is challenged to regenerate in a chronic damage model, R&Z mutated livers fail to fully repair and show presence of multiple regenerative nodules. Later, livers develop either focal nodular hyperplasia and/or early hepatocellular carcinoma. These data suggest that R&Z have an important role in both liver metabolic homeostasis and liver regeneration and that their alteration can eventually lead to cancer formation.

The microscopic distribution of microspheres and the resulting radiation dose deposition patterns in human liver following hepatic arterial infusion of 90Y labelled microspheres have been investigated. Tissue samples from normal liver, the tumour periphery and tumour centre were taken from a patient following infusion of 3 GBq of 32 pm diameter resin microspheres labelled with 90Y as treatment for an 80 millimetre diameter metastatic liver tumour. Microspheres were found to deposit inhomogeneously in tissues, preferentially lodging in a region approximately 6 mm wide around the periphery of the tumour. A relative concentration of microspheres of 50 to 70 times that of normal hepatic parenchyma and 65 to 94 times that in the tumour centre was measured in this region. The deposition of microspheres in the tumour periphery was not uniform, and cluster analysis showed that the spheres could be classified into clusters. The number of microspheres in a cluster was skewed towards low numbers and cluster sizes varied from 20 pm to 1500 pm. Microsphere deposition in normal liver was demonstrated to be non-uniform, there being significant variations in concentration over distances on the order of 3 to 4 millimetres. The observed microsphere distributions in three dimensions were used to calculate radiation dose patterns, and the results showed that heterogeneous doses were delivered to all tissues. Within the tumour periphery average doses ranged from 200 Gy to 600 Gy with minimum doses between 70 Gy and 190 Gy. The maximum and minimum doses for the tumour centre sample were 920 Gy and 3.7 Gy respectively, the median dose was 5.8 Gy. In the normal liver sample the median dose was 7.3 Gy with maximum and minimum doses of 753 Gy and 5 Gy respectively. Less than 1% of the normal liver tissue volume received more than 30 GY, the level above which complications have resulted for ++ / whole liver exposure using external beam radiotherapy. These calculations suggest that preferential deposition of microspheres in the well vascularised periphery of large tumours will lead to a high proportion of the tumour volume receiving a therapeutic dose, with most of the normal liver tissue being spared substantial damage.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2003. / Bibliography: leaves 96-124.

Die Dissertation handelt über die Ergebnisse der Laserinduzierten Thermotherapie bei Lebertumoren aus Februar 2000 mit einem Follow up bis Februar 2002. Dabei wurden 43 Patienten mit 89 Läsionen therapiert. Betrachtet wurden Komplikationen, Liegezeiten, metastasenfreie Intervalle, Stichkanalmetastasen, Auswertungen der bildmorphologischen Ablationskontrollen und die Analyse der klinischen Verläufe. Dabei wurden die Patienten in drei Altersgruppen eingeteilt, so dass man die Ergebnisse auf das Alter beziehen konnte. Zu den Primärtumoren zählten zu 70 Prozent das Kolorektale Karzinom, zu 10 Prozent das HCC und zu 20 Prozent andere Tumoren. Liegezeit und Komplikationen waren in allen Altersklassen gleich. Die komplette Ablationsrate betrug 80 Prozent. Die Liegezeit betrug weniger als 3 Tage im Durchschnitt. Komplikationen, die zur Verlängerung der Liegezeit führten, waren intrathorakale Blutungen, subkapsuläre Hämatome und Fistelbildungen. Es wurde ein durchschnittlich sechsmonatiges metastasenfreies Intervall festgestellt. / The dissertation acts about the results of the Laser-Induced Thermotherapy of manignant liver tumors from February 2000 in follow up to February 2002. 43 patients with 89 lesions became to treat in this case. Were considered complications, time to stay in bed, metastasis-free interval, metastasis from prick in the duct, evaluations of the picture-morphological controls and the analyses of the clinical progresses. The patients were divided into 3 age-groups in this case so that one could get the results on the age. To the primary tumors counted in 70 percent the colorectal cancer, to 10 percent the HCC and to 20 percent other tumors. The time to stay in bed and complications were identical in all age-groups. The complete ablation was 80 percent. The time to stay in bed was on average little as 3 days. Complications which led to the prolongation of the time to stay in bed were pleural effusions, subcapsular hematoma and fistulae. It was found on the average an metastases-free interval for 6 month.