No description available.

Errata pasted onto t.p. verso. / Bibliography: leaves 129-148. / 148 leaves : [3] col. ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates the relationship between folate states and colorectal cancer risk using the rat AOM intestinal cancer model. Results indicate that folate status can play an important role in modulating colorectal carcinogenesis. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2000

Background: It is well recognized that not all patients with stage C colorectal cancer (CRC) derive a survival benefit from adjuvant chemotherapy. It would therefore be advantageous to identify factors that define a target group for treatment. It has been suggested that those most likely to benefit are women with proximal tumours. Recent work has suggested microsatellite instability (MSI) may be a useful marker however the limited studies performed are conflicting. Aim: To determine if gender, site, tumour histology or microsatellite (MSI) status predict survival benefit from 5FU-based adjuvant chemotherapy in stage C CRC. Method: Data was collated on stage C colorectal cancer cases that underwent curative resection over a 20-year period (inclusive of years prior to standard chemotherapy). Pathology was re-evaluated, DNA extracted from the formalin fixed paraffin specimen and MSI status established. Primary endpoint was cancer-related death. Kaplan-Meier curves were constructed for univariate analysis and differences analysed by log rank test. Multivariate analysis was performed using Cox proportional hazard model adjusting for age, gender, site, distinct pathological variables and MSI. A compounding effect between these factors and chemotherapy benefit was measured by interaction testing Results: 811 unselected cases were included in the study. Thirty-seven percent received chemotherapy. Chemotherapy significant improved cancer-specific survival (HR of dying 0.66 (95% CI 0.52-0.83 p=0.0003). Female gender offered a survival advantage overall (HR 0.81 95% CI 0.68-0.97; p=0.02) however site did not influence outcome (HR 1.03). On interaction testing, gender, site and tumour histology did not significantly influence the survival effect of chemotherapy. 802 cases were included in the MSI analysis of which 77 exhibited MSI. MSI status did not influence prognosis (HR of cancer death 1.45, 95% CI 0.90-2.21; p= 0.13). However, in the non-chemotherapy cohort, MSI conferred a significantly less favourable outcome (HR 1.89, 95%CI 1.13-3.16; p= 0.02). Chemotherapy produced a survival benefit in both the MSI (HR 0.08 95% CI 0.02-0.27; p=<0.0001) and the microsatellite stable (MSS) cohort (HR 0.62, 95% CI 0.47-0.81; p=0.001). On interaction testing, neither compounded the benefit of chemotherapy, however of all the tested parameters, MSI came closest to significance (p=0.08). Conclusion: These results suggest that 5FU-based adjuvant chemotherapy for stage C colorectal cannot be targeted using gender, tumour site, histological characteristics or MSI. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1522132 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010

Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1999. / Bibliography: leaves 214-236.

Thesis (Ph. D.)--University of New South Wales, 1999. / Also available online.

Thesis (Ph. D.)--University of Toronto, 2007. / Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2991.

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

Thesis (M.S. in Cancer Biology)--Vanderbilt University, Aug. 2007. / Title from title screen. Includes bibliographical references.

Colorectal cancer (CRC) is one of the most common forms of neoplasia in Western populations but is uncommon in sub-Saharan Africa. In developing countries such as South Africa, differences in lifestyles and environment exist between the various population groups. These differences and the diverse patterns of cancer that exist, provide an ideal opportunity to study the pathogenesis of colorectal cancer. In South Africa, the incidence of CRC in black patients is approximately ten fold lower than that of white South African patients. The majority of black South African CRC patients presents with tumours without macroscopic polyps. Recently five genes involved in DNA mismatch repair (MMR) have been implicated in hereditary nonpolyposis colorectal cancer (HNPCC). In this retrospective study, paraffin-embedded normal and tumour tissues from 109 black, and 110 Caucasian CRC patients were studied. To screen for the possible involvement of DNA mismatch repair genes, the presence of microsatellite instability (MSI) was investigated. In total 40 patients presented with MSI-H tumours, 27/109 (24,8%) tumours from black patients and 13/110 (11,8%) tumours from Caucasian patients. The proportion of MSI-H tumours from black patients attending Chris Hani Baragwanath Hospital (CHB) (12,2%; 5/41) and that of Caucasian patients is in accordance to published results on sporadic tumours. However the finding that 32,4% of black patients attending Kalafong and Pretoria Academic Hospitals, have tumours with MSI-H is much higher than is commonly reported in Western populations and is significantly higher than that of the Caucasian patients (p = 0.002; χ2-test). It has been observed that patients who present at CHB live mainly in urban Johannesburg/Soweto, in comparison to those seen at KPH who are mostly from peri-urban and rural areas. Failure of PCR amplification, owing to the absence of high quality tissue, allowed 32 of the 40 MSI-H tumours to be fully screened for mutations in hMLH1 and hMSH2 using exon-by-exon PCR single strand conformation polymorphism (SSCP) analysis. Sixteen pathogenic mutations were found in 14 tumours, 10/22 (45%) from black patients and 4/10 (40%) from caucasian patients. Five tumours presented with two mutations each, one is a compound heterozygote and the other four tumours are double heterozygotes. Ten of the sixteen mutations identified, are novel. Five (5/32; 16%) of the pathogenic mutations are germline in origin, four (4/22; 18%) of which were detected in tumours from black patients. Thus HNPCC was diagnosed in ~0,93% (1/107) of Caucasian and 3,85% (4/104) of black patients via germline mutations. The frequency of recognised DNA repair gene mutations in black patients with HNPCC is four times higher than that in Caucasian patients with HNPCC. This is consistent with the notion that penetrance of HNPCC cancer is independent of environmental factors which is true as the frequency of HNPCC in a low incidence population (black South Africans) is much higher than that of a high incidence population (Caucasian South Africans). A missense mutation in hMSH2 (codon 127) was identified in three black patients. It is listed in the ICG-HNPCC database as a pathogenic mutation (in a Nigerian family). However, further investigation demonstrated that this is a polymorphic change exclusive to black Africans. Somatic mutations were detected in 6 (27%) tumours from black and 3 (30%) tumours from Caucasian patients. In conclusion, the observed microsatellite instability and mutations in hMLH1 and hMSH2 thus clearly implicate the involvement of DNA mismatch repair genes in the pathogenesis of colorectal cancers of black and Caucasian South African patients. This study represents the first investigation of DNA mismatch repair genes in tumours from both population groups. It is also the first report of black South Africans with HNPCC. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2005. / Genetics / unrestricted

Ce travail de thèse est centré sur l'établissement de modèles prédictifs de toxicité radio-induite et sur l’étude de leur intérêt en cas de radiothérapie par modulation d’intensité. Six modèles NTCP ont été implémentés et leur paramètres identifiés pour la prédiction des toxicités rectale et vésicale tardives dans le cancer de la prostate. Leur capacité prédictive a été démontrée pour les deux organes. Par ailleurs, le modèle LKB a été utilisé pour la prédiction de l’œsophagite aiguë en cas de radiothérapie du cancer bronchique non à petites cellules. Ensuite, le bénéfice tiré de l’incorporation du paramètre de dose équivalent uniforme (EUD) pour la planification inverse de la radiothérapie par modulation d’intensité (IMRT) a été évalué. L’évaluation de cette approche a montré une baisse significative de la dose dans les parois vésicale et rectale. L’incorporation de plusieurs modèles biologiques dans le processus d’optimisation de l’IMRT a aussi été réalisée. Des fonctions objectif ont été établies pour les différents facteurs biologiques comme le NTCP, l’EUD et le TCP. Les résultats dosimétriques obtenus montrent la supériorité de l’optimisation basée sur des facteurs biologiques sur celle reposant uniquement sur des facteurs physiques. Enfin, les modèles NTCP classiques ont été améliorés en intégrant un paramètre radiobiologique supplémentaire, le rapport α/β. Ce rapport α/β a été identifié pour différents types de toxicité. Avec ce nouveau paramètre, les modèles NTCP peuvent finalement être étendus à des patients traités suivant différents fractionnements, les traitements hypofractionnés étant de plus en plus utilisés. / This thesis is focused on the predictive models of irradiation induced toxicities in intensity modulated radiotherapy. Six different NTCP models were implemented and their parameters were identified at predicting late rectal and bladder toxicities in prostate cancer. Their predictive skills have been demonstrated on both organs. Second, LKB model was used to predict the irradiation induced acute esophagitis after nun-small-cell lung cancer. Then, the benefit of using EUD in prostate cancer IMRT inverse planning was evaluated. The evaluation of the proposed approach proved that the use of EUD significantly decreased both the dose in the bladder and rectum walls. Then, the incorporation of different biological models in IMRT optimization process has been realized. Objective functions were established for different biological factors like NTCP, EUD and TCP. Obtained results show the superiority of the optimization based on biological factors over the optimization relying only on physical factors. Finally, classical NTCP models were corrected to deal with another radiobiological parameter, the α/β ratio. With this additional factor, NTCP models can be extended to predict toxicity for patients with different dose fractionation, these kinds of treatments being more and more clinically used.