Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 98-111).

Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases. Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of 125I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking 125I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter 76Br by using NBI. Furthermore, it is shown that cellular uptake of 125I can be modified by stimulating EGFR (HER-1) with EGF. When labelled with the alpha emitter 211At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab. Pertuzumab was radiolabelled with the low energy beta emitter 177Lu without losing affinity or immunocompetence. [177Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with 177Lu, show promise as TRT agents.

No description available.

BACKGROUND: Organ transplantation is one of the best modalities for treating fatal organ failure. Despite the success of this procedure, an increasing incidence of cancer in this population has drawn the attention of public health officials in recent years. OBJECTIVES: The overall objective of this study is to conduct a detailed examination of adverse health outcomes among Canadian organ transplant recipients, with an emphasis on cancer incidence and mortality. METHODS: This project employed a retrospective cohort follow-up study design, whereby Canadian Organ Replacement Registry records were linked to the Canadian Mortality Database and the Canadian Cancer Registry Database. The study population consisted of more than 16,000 solid organ transplant recipients registered between January 1, 1981 and December 31, 1998. This study was designed to assess the risks of developing cancer, overall and site-specific, in transplant recipients in comparison to the general Canadian population using Standardized Incidence Ratios (SIR), Standardized Mortality Ratios (SMR), and Proportionate Mortality Ratios (PMR). In addition, Cox and logistic models were used to assess the effects of various risk factors on cancer incidence and mortality in transplant sub-populations, while cumulative incidence was used to study the patient survival pattern. Lastly, Population Attributable Risk (PAR) was used to quantify the impact of organ transplantation on cancer incidence and mortality. RESULTS: Among major causes of death, the highest PMRs are due to genitourinary diseases, followed by endocrine, nutritional and metabolic diseases, and infectious diseases. SIRs indicate that cancer incidence and mortality were relatively lower than that observed for other major causes of death, and slightly higher than that observed in the general Canadian population. Lastly, logistic regression results indicate that age, year of surgery, and smoking status were significant risk factors in mortality due to all causes, while the Cox regression model shows that age, sex and year of surgery were significant risk factors for cancer incidence. Overall, the PAR in this cohort was very minimal, indicating that the risk in mortality and cancer incidence due to organ transplantation is negligible. CONCLUSION: Life threatening diseases such as those of the genitourinary system, as well as endocrine, nutritional and metabolic diseases and infectious diseases are leading causes of death. Future research should be directed at ways of reducing incidence and subsequent mortality due to these causes.

No description available.

Abstract Ovarian cancer is the 6th most common cancer in women worldwide and mortality from this cancer is high, because early diagnosis is difficult (Sankaranarayanan et al. 2006). Thus, identification of modifiable factors contributing to its aetiology is important in reducing the burden of a very fatal form of women’s cancer. The overall aim of this thesis was to investigate the association between diet and ovarian cancer risk within the context of a framework ‘from nutrients to lifestyle’. The study examined dietary and lifestyle factors that had not previously been investigated comprehensively in four main areas: nutrients (retinol, beta-carotene, vitamins E, C, and B), foods (fruit, vegetables, dairy products, eggs, meat and liver), diet patterns and lifestyle (smoking, alcohol, and body-mass-index). The study used the data from two population-based case-control studies of women aged 18-79 years conducted in Australia 10 years apart; the Survey of Women’s Health (SWH, 1990-1993) involves 683 cases and 777 controls, and the Australian Ovarian Cancer Study (AOCS, 2002-2005) includes 1329 cases and 1397 controls. Cases were recruited from gynaecological oncology treatment centres and controls were selected at random from the electoral roll. Detailed information on non-dietary risk factors was obtained using a questionnaire and dietary information was obtained via a semi-quantitative food frequency questionnaire. Multivariable-adjusted odds ratios (ORs) (adjusting for age, parity, oral contraceptive use, education, and energy intake) for ovarian cancer risk were estimated separately for each study with logistic regression modelling and weighted pooled risk estimates for the two studies were calculated using fixed-effects models. Principal components analysis of around 40 food groups was performed to identify dietary patterns in each study separately. There was an increased risk of ovarian cancer associated with retinol intake in both studies (combined OR for the highest vs. lowest quartile =1.42, 95%CI 1.19-1.69), while intake of beta-carotene was inversely related to cancer risk (combined OR=0.80, 95%CI 0.67-0.96). The associations between retinol and beta-carotene and risk appeared to be independent. Liver was also associated with an increased risk; however this association seemed to be explained by the high levels of retinol in liver. Dairy products and eggs are other good sources of retinol, but no clear relations were seen and additional adjustment for saturated fat further attenuated the associations. High vitamin E intake (combined OR=0.73, 95%CI 0.61-0.87) was associated with a decreased risk, but no overall association was seen for vitamin C (combined OR=1.06, 95%CI 0.89-1.27). It is noteworthy that vitamin C seemed to be more beneficial for current smokers than for never/past smokers. For the B vitamins, a significant inverse association was apparent only for niacin intake (combined OR=0.69, 95%CI 0.58-0.82). While there was no association between cancer risk and sources of niacin such as total meat and red meat, other niacin-rich foods such as poultry (combined OR=0.77, 95%CI 0.66-0.89) and fish (combined OR=0.83, 95%CI 0.71-0.97) were significantly inversely associated with risk. In contrast to poultry and fish, high consumption of processed meat was associated with a 24% increase in risk (combined OR=1.24, 95%CI 1.06-1.45). Total fruit (combined OR=0.75, 95%CI 0.60-0.94) and total vegetables (combined OR=0.69, 95%CI 0.52-0.92), specifically cruciferous vegetables (combined OR=0.79, 95%CI 0.63-0.98) and green leafy vegetables (combined OR=0.79, 95%CI 0.67-0.94), were associated with a modestly decreased risk, whereas the inverse association between red/yellow vegetables and risk did not quite reach statistical significance (combined OR=0.84, 95%CI 0.64-1.08). High fruit intake was, like vitamin C intake, somewhat more beneficial for current/past smokers than for never smokers. Exclusion of women who took dietary supplements did not substantially change the observed associations between nutrients and risk. Three major eating patterns were identified: ‘snacks and alcohol’, ‘fruit and vegetable’, and ‘meat and fat’. Significant inverse associations between the snacks and alcohol pattern and risk were attenuated after further adjustment for white/red wine intake in both studies; it thus appeared that the observed association was at least partly due to wine intake. A significant association between the fruit and vegetable pattern and risk was seen only in the more recent study. A diet characterized by high meat and fat was associated with an increased risk of ovarian cancer, although the observed association was stronger in the SWH There was no evidence that the associations between diet pattern and cancer risk varied by women’s lifestyle. Although there was some variation in the analyses stratified by the histologic subtype of ovarian cancer, no consistent patterns of variation were observed for either study. These findings provide additional evidence that a healthy diet defined by high intake of fruit, vegetables, particularly cruciferous and green leafy vegetables, white meat and fish and low in meat and fat, especially processed meats might be beneficial against ovarian cancer.

Abstract Ovarian cancer is the 6th most common cancer in women worldwide and mortality from this cancer is high, because early diagnosis is difficult (Sankaranarayanan et al. 2006). Thus, identification of modifiable factors contributing to its aetiology is important in reducing the burden of a very fatal form of women’s cancer. The overall aim of this thesis was to investigate the association between diet and ovarian cancer risk within the context of a framework ‘from nutrients to lifestyle’. The study examined dietary and lifestyle factors that had not previously been investigated comprehensively in four main areas: nutrients (retinol, beta-carotene, vitamins E, C, and B), foods (fruit, vegetables, dairy products, eggs, meat and liver), diet patterns and lifestyle (smoking, alcohol, and body-mass-index). The study used the data from two population-based case-control studies of women aged 18-79 years conducted in Australia 10 years apart; the Survey of Women’s Health (SWH, 1990-1993) involves 683 cases and 777 controls, and the Australian Ovarian Cancer Study (AOCS, 2002-2005) includes 1329 cases and 1397 controls. Cases were recruited from gynaecological oncology treatment centres and controls were selected at random from the electoral roll. Detailed information on non-dietary risk factors was obtained using a questionnaire and dietary information was obtained via a semi-quantitative food frequency questionnaire. Multivariable-adjusted odds ratios (ORs) (adjusting for age, parity, oral contraceptive use, education, and energy intake) for ovarian cancer risk were estimated separately for each study with logistic regression modelling and weighted pooled risk estimates for the two studies were calculated using fixed-effects models. Principal components analysis of around 40 food groups was performed to identify dietary patterns in each study separately. There was an increased risk of ovarian cancer associated with retinol intake in both studies (combined OR for the highest vs. lowest quartile =1.42, 95%CI 1.19-1.69), while intake of beta-carotene was inversely related to cancer risk (combined OR=0.80, 95%CI 0.67-0.96). The associations between retinol and beta-carotene and risk appeared to be independent. Liver was also associated with an increased risk; however this association seemed to be explained by the high levels of retinol in liver. Dairy products and eggs are other good sources of retinol, but no clear relations were seen and additional adjustment for saturated fat further attenuated the associations. High vitamin E intake (combined OR=0.73, 95%CI 0.61-0.87) was associated with a decreased risk, but no overall association was seen for vitamin C (combined OR=1.06, 95%CI 0.89-1.27). It is noteworthy that vitamin C seemed to be more beneficial for current smokers than for never/past smokers. For the B vitamins, a significant inverse association was apparent only for niacin intake (combined OR=0.69, 95%CI 0.58-0.82). While there was no association between cancer risk and sources of niacin such as total meat and red meat, other niacin-rich foods such as poultry (combined OR=0.77, 95%CI 0.66-0.89) and fish (combined OR=0.83, 95%CI 0.71-0.97) were significantly inversely associated with risk. In contrast to poultry and fish, high consumption of processed meat was associated with a 24% increase in risk (combined OR=1.24, 95%CI 1.06-1.45). Total fruit (combined OR=0.75, 95%CI 0.60-0.94) and total vegetables (combined OR=0.69, 95%CI 0.52-0.92), specifically cruciferous vegetables (combined OR=0.79, 95%CI 0.63-0.98) and green leafy vegetables (combined OR=0.79, 95%CI 0.67-0.94), were associated with a modestly decreased risk, whereas the inverse association between red/yellow vegetables and risk did not quite reach statistical significance (combined OR=0.84, 95%CI 0.64-1.08). High fruit intake was, like vitamin C intake, somewhat more beneficial for current/past smokers than for never smokers. Exclusion of women who took dietary supplements did not substantially change the observed associations between nutrients and risk. Three major eating patterns were identified: ‘snacks and alcohol’, ‘fruit and vegetable’, and ‘meat and fat’. Significant inverse associations between the snacks and alcohol pattern and risk were attenuated after further adjustment for white/red wine intake in both studies; it thus appeared that the observed association was at least partly due to wine intake. A significant association between the fruit and vegetable pattern and risk was seen only in the more recent study. A diet characterized by high meat and fat was associated with an increased risk of ovarian cancer, although the observed association was stronger in the SWH There was no evidence that the associations between diet pattern and cancer risk varied by women’s lifestyle. Although there was some variation in the analyses stratified by the histologic subtype of ovarian cancer, no consistent patterns of variation were observed for either study. These findings provide additional evidence that a healthy diet defined by high intake of fruit, vegetables, particularly cruciferous and green leafy vegetables, white meat and fish and low in meat and fat, especially processed meats might be beneficial against ovarian cancer.

Abstract Ovarian cancer is the 6th most common cancer in women worldwide and mortality from this cancer is high, because early diagnosis is difficult (Sankaranarayanan et al. 2006). Thus, identification of modifiable factors contributing to its aetiology is important in reducing the burden of a very fatal form of women’s cancer. The overall aim of this thesis was to investigate the association between diet and ovarian cancer risk within the context of a framework ‘from nutrients to lifestyle’. The study examined dietary and lifestyle factors that had not previously been investigated comprehensively in four main areas: nutrients (retinol, beta-carotene, vitamins E, C, and B), foods (fruit, vegetables, dairy products, eggs, meat and liver), diet patterns and lifestyle (smoking, alcohol, and body-mass-index). The study used the data from two population-based case-control studies of women aged 18-79 years conducted in Australia 10 years apart; the Survey of Women’s Health (SWH, 1990-1993) involves 683 cases and 777 controls, and the Australian Ovarian Cancer Study (AOCS, 2002-2005) includes 1329 cases and 1397 controls. Cases were recruited from gynaecological oncology treatment centres and controls were selected at random from the electoral roll. Detailed information on non-dietary risk factors was obtained using a questionnaire and dietary information was obtained via a semi-quantitative food frequency questionnaire. Multivariable-adjusted odds ratios (ORs) (adjusting for age, parity, oral contraceptive use, education, and energy intake) for ovarian cancer risk were estimated separately for each study with logistic regression modelling and weighted pooled risk estimates for the two studies were calculated using fixed-effects models. Principal components analysis of around 40 food groups was performed to identify dietary patterns in each study separately. There was an increased risk of ovarian cancer associated with retinol intake in both studies (combined OR for the highest vs. lowest quartile =1.42, 95%CI 1.19-1.69), while intake of beta-carotene was inversely related to cancer risk (combined OR=0.80, 95%CI 0.67-0.96). The associations between retinol and beta-carotene and risk appeared to be independent. Liver was also associated with an increased risk; however this association seemed to be explained by the high levels of retinol in liver. Dairy products and eggs are other good sources of retinol, but no clear relations were seen and additional adjustment for saturated fat further attenuated the associations. High vitamin E intake (combined OR=0.73, 95%CI 0.61-0.87) was associated with a decreased risk, but no overall association was seen for vitamin C (combined OR=1.06, 95%CI 0.89-1.27). It is noteworthy that vitamin C seemed to be more beneficial for current smokers than for never/past smokers. For the B vitamins, a significant inverse association was apparent only for niacin intake (combined OR=0.69, 95%CI 0.58-0.82). While there was no association between cancer risk and sources of niacin such as total meat and red meat, other niacin-rich foods such as poultry (combined OR=0.77, 95%CI 0.66-0.89) and fish (combined OR=0.83, 95%CI 0.71-0.97) were significantly inversely associated with risk. In contrast to poultry and fish, high consumption of processed meat was associated with a 24% increase in risk (combined OR=1.24, 95%CI 1.06-1.45). Total fruit (combined OR=0.75, 95%CI 0.60-0.94) and total vegetables (combined OR=0.69, 95%CI 0.52-0.92), specifically cruciferous vegetables (combined OR=0.79, 95%CI 0.63-0.98) and green leafy vegetables (combined OR=0.79, 95%CI 0.67-0.94), were associated with a modestly decreased risk, whereas the inverse association between red/yellow vegetables and risk did not quite reach statistical significance (combined OR=0.84, 95%CI 0.64-1.08). High fruit intake was, like vitamin C intake, somewhat more beneficial for current/past smokers than for never smokers. Exclusion of women who took dietary supplements did not substantially change the observed associations between nutrients and risk. Three major eating patterns were identified: ‘snacks and alcohol’, ‘fruit and vegetable’, and ‘meat and fat’. Significant inverse associations between the snacks and alcohol pattern and risk were attenuated after further adjustment for white/red wine intake in both studies; it thus appeared that the observed association was at least partly due to wine intake. A significant association between the fruit and vegetable pattern and risk was seen only in the more recent study. A diet characterized by high meat and fat was associated with an increased risk of ovarian cancer, although the observed association was stronger in the SWH There was no evidence that the associations between diet pattern and cancer risk varied by women’s lifestyle. Although there was some variation in the analyses stratified by the histologic subtype of ovarian cancer, no consistent patterns of variation were observed for either study. These findings provide additional evidence that a healthy diet defined by high intake of fruit, vegetables, particularly cruciferous and green leafy vegetables, white meat and fish and low in meat and fat, especially processed meats might be beneficial against ovarian cancer.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "August 2007" Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 6 uppsatser.