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published_or_final_version / abstract / toc / Clinical Oncology / Doctoral / Doctor of Philosophy

Complexes of the radionuclides (^67)Ga and (^III)In, or of the paramagnetic contrast agent Gd, used in MRI, provide a means of imaging tumours. The stability of the (^71)Ga- NOTA complex was verified by in vivo NMR spectroscopy. The novel phosphinic acid NOTA analogue, bearing an isopropyl substituent on phosphorus was prepared and its lipophilicity and (^III)In biodistribution in mice determined. The crystal structure of the yttrium complex of N,N"-bis(benzylcarbamoylmethyl)diethylenetriamine-N,N',N"-triacetic acid revealed amide carbonyl ligation in a distorted mono-capped square antiprismatic structure, with one metal-bound water. The biodistribution of the analogous Gd complex was examined. A novel series of 9N3 based ligands incorporating three further N donor atoms, carboxymethyl groups and a potentially larger cavity size were synthesised. The analogous series containing phosphinic acid groups and the 12N3 counterparts were also prepared. The former series formed complexes with Gd and the biodistribution in mice was studied. The 12N3 analogues failed to form Gd complexes.2-Nitroimidazoles are known to selectively target hypoxic tumour tissue. Two conjugates of 2-nitroimidazole for tumour imaging were prepared, the Gd complex of a DTPA-bis(2-nitroimidazole) amide and the (^III)In complex of a C-functionalised NOTA- nitroimidazole conjugate. The biodistribution in mice of each was studied and luminescence experiments on the Tb complex of the former revealed one metal bound water molecule. Novel conjugates of the tetrapeptide tuftsin and a complexing agent based on the 12N4 skeleton and an N-linked NOTA derivative were synthesised. Biodistributions of the Gd and In complexes respectively are being carried out. Acridine intercalators reversibly bind DNA, possibly enhancing the effectiveness of tumour targeting conjugates. Novel multifunctionally labelled acridines based on tris(2- aminoethyl) amine were sought. The p-nitrophenolate active ester of 9-acridine carbamoyl-2-(2-aminoethyl)-2-methyl amine was also prepared as a versatile agent for acridine labelling.

Background Qualitative longitudinal research (QLR) has a long history in the social sciences, where its theoretical basis is well established. Qualitative longitudinal (QL) methods are gaining popularity in health care research for exploring the dynamic experience of illness. However, methodological development of QLR is limited within the health literature, and there are very few studies examining the experience of people with colorectal cancer (CRC). Moreover, such studies describe the experiences of those surviving CRC and the voices of those with advanced disease who are approaching the end of their lives remain largely unheard. Aim and objective This study explores the potential of QL interviewing to examine the experiences of those with advanced, metastatic, CRC. I investigate how QL interviews can be best utilised to explore the participants’ accounts of their experiences. I specifically examine the added value and costs of a flexible approach with regard to the frequency and timing of longitudinal interviews. Analytical approaches to QL data are examined to determine their overall value. Methods Sixteen patients with metastatic CRC and eight of their family carers participated in narrative interviews at three time points over the course of a year. The study was designed to include two groups of participants. The first, a routine interval group where interviews were carried out at regular intervals of six months; the second, a flexible interval group where there was an interview at baseline followed by monthly phone calls to track changes in the participants’ circumstances, with a view to conducting the interview as change was occurring. The data were analysed at each time point, and longitudinally using narrative and thematic techniques. Findings The QL design enabled a trusting relationship to evolve, such that private accounts of experience were disclosed. Thus, a nuanced and contextualised understanding of the experience of metastatic CRC materialised. Overall the accounts of CRC were characterised by uncertainty, yet at the same time death was a certainty. Over time, this dual narrative led to participants feeling themselves to be in an ambiguous and liminal state. Some participants described a loss of sense of self, yet others maintained their identity. The work that participants carried out to manage their sense of self changed, as they moved from a collective to an individual identity. In the flexible interval group, monthly telephone calls produced an even more profound research relationship and further enriched the accounts. However, early interviews were only conducted on two occasions and more ethical issues arose as a result of the increased contact. Conclusions By exploring the potential of QL methods, this study has developed the methodology for researching the experiences of those with serious illness. QL interviewing elicits a deep understanding of metastatic CRC that appreciates notions of temporality, process and change. Regular contact with participants between interviews can further enrich the accounts, and is a useful strategy for tracking changes given the unpredictable nature of advanced disease. This thesis showcases the cross-sectional and longitudinal opportunities that QL analysis presents; yet also highlights how longitudinal narrative analysis allows a story to unfold over time which reflects the beginning, the middle and for some the end of the illness experience. Although QL analysis is time consuming, and more contact can amplify ethical issues, the benefits outweigh the constraints.

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