Medicine (Austin & Northern Health) - Theses
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ItemTracking cerebral amyloid accumulation in ageing, mild cognitive impairment, Alzheimer’s disease and other dementias( 2018)Background Alzheimer’s disease (AD), the most common form of dementia in the elderly, is thought to result from the neurotoxicity of cerebral β-amyloid (Aβ) plaques. Accumulation of Aβ plaques begins years before AD dementia onset; earlier detection might improve diagnostic accuracy, which potentially translates to better clinical outcomes. We assessed the clinical utility of Aβ imaging with 18F-florbetaben (FBB) in mild cognitive impairment (MCI) by evaluating its prognostic accuracy for progression to AD, comparing semi-quantitative assessment with visual scan assessment and exploring the relationships between Aβ plaque deposition, cognition, hippocampal volume and white matter hyperintensities. Methods Forty-five MCI (mean age = 72.7 years, mean Mini-Mental State Examination score = 27.2) underwent FBB positron emission tomography (PET), magnetic resonance imaging and neuropsychological assessment at baseline and two years, and clinical follow-up at four years. Positive FBB PET (FBB+), defined by a cortical to cerebellar cortex standardised uptake value ratio (SUVR) ≥1.45, was compared with visual assessment by five readers. Amnestic MCI (aMCI) was defined by a composite episodic memory (EM) z-score of <−1.5. Correlations were adjusted for age, gender and years of education. Results At baseline, 24 (53%) MCI were FBB+. Regression analyses showed SUVR (r = -0.51, p = 0.0015) and hippocampal volume (r = 0.60, p = 0.024) both contributing to episodic memory impairment in independent fashion. White matter hyperintensities correlated with non-memory-related cognition, and this correlation was particularly associated with high Aβ burden at baseline. Majority reads agreed with SUVR classification (κ 0.96). In two years, 18 (75%) FBB+ progressed to AD compared with two (9.5%) FBB PET negative (FBB−), yielding a predictive accuracy of 83% (95% CI 61% to 94%). Four FBB− developed non-AD dementia. Predictive accuracies of hippocampal volume (58% (95% CI 42% to 73%)) and aMCI status (73% (95% CI 58% to 81%)) were lower. Combinations did not improve accuracy. By four years, 21 (87.5%) FBB+ progressed to AD whereas five (24%) FBB− developed non-AD dementia, yielding a predictive accuracy of 94% (95% CI 74% to 99%). While the strong baseline association between FBB SUVR and EM declined over two years, the association between hippocampal volume and EM became stronger. The association between SUVR and hippocampal volume also strengthened over two years. FBB SUVR increased 2.2%/year in FBB+ with no change in FBB−. Conclusions 18F-florbetaben Aβ imaging facilitates accurate detection of prodromal AD better than hippocampal volume or aMCI status. This supports the notion that biomarkers of amyloid dysregulation employed for identifying patients with incipient AD should be ordered first. In MCI, higher Aβ plaque burden is associated with more severe memory impairment and contributes to early amnestic symptoms independent of hippocampal atrophy. However, as neurodegeneration progresses, and in contrast with the early stages of the disease, hippocampal atrophy, not Aβ plaque burden, seems to drive memory decline. The latter observation might be explained by the neurotoxic effect of soluble fibrillogenic Aβ oligomers on hippocampi, upstream of the formation of Aβ plaque.
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ItemWhat factors affect the development, progression and outcome of aortic stenosis?( 2013)With the aging population, the number and complexity of patients with aortic stenosis (AS) being referred for consideration of aortic valve replacement (AVR) is increasing. Selection of appropriate candidates for AVR can be difficult as the relative prognostic importance of increasing age, haemodynamic severity and comorbidity in patients with AS is not well understood. In addition, traditional risk assessment with AS severity, symptomatic status and left ventricular ejection fraction (LVEF) has limitations and new objective markers of cardiovascular (CV) risk are required to assist with management decisions. This thesis consists of three overall studies: 1) The natural history of AS in elderly patients over long-term follow up study (Chapter 3); 2) The prospective AS cohort study (Chapters 4-7); and 3) The prospective AVR cohort study (Chapter 8). “The natural history of AS in elderly patients over long-term follow up study” (Chapter 3) aimed to document the natural history of AS with regards to haemodynamic progression, adverse cardiac events and survival in a cohort of 239 elderly patients over eighteen years of follow up. Predictors of rapid haemodynamic progression included severe renal impairment, a history of anaemia, advanced aortic valve (AV) calcification and moderate to severe AS. Survival rates were reduced across the spectrum of AS severity; however, patients who developed severe symptomatic AS and underwent AVR, experienced excellent long-term survival. Survival was strongly dependent upon age and comorbidity, with the age-adjusted Charlson comorbidity index (age-CCI) proving a strong independent predictor of all-cause mortality. “The prospective AS cohort study” (Chapters 4-7) evaluated the role of novel non-invasive cardiac imaging techniques and biomarkers in the assessment and risk stratification of AS in 146 patients over a median follow up of two years. The main aims of this study were: 1) To compare traditional versus novel trans-thoracic echocardiography (TTE) and cardiac magnetic resonance imaging (cMRI) techniques for the evaluation of AS severity (Chapter 4); and 2) To assess the capacity of novel TTE (Chapter 5), cMRI (Chapter 6) and biomarker parameters (Chapter 7) to detect clinical and subclinical left ventricular (LV) dysfunction and predict adverse clinical outcomes in patients with AS. Of the AS severity parameters assessed, energy loss index (ELI) demonstrated the strongest association with adverse clinical outcomes. cMRI successfully evaluated AV morphology and AS severity, although cMRI specific thresholds for a diagnosis of severe AS are recommended. Overall, global longitudinal strain (GLS) and plasma brain natriuretic peptide (BNP) were the most promising risk markers in patients with AS. GLS and plasma BNP demonstrated significant associations with haemodynamic severity, detected sub-clinical LV dysfunction and independently predicted adverse clinical outcomes. Myocardial fibrosis imaging with cMRI provided insights into the detrimental effects of chronic pressure overload and the quantitative fibrosis burden predicted major adverse cardiac events (MACE). The primary aim of “The prospective AVR cohort study” (Chapter 8) was to document the prevalence and predictors of adverse outcomes twelve months post AVR for severe AS (Study 8A). Persistent adverse cardiac remodeling, LV dysfunction and symptoms were common post AVR, although outcomes were more favourable in patients who received AVR prior to the development of adverse cardiac changes. Impaired GLS was a strong predictor of MACE and persistent symptoms post AVR. In a separate sub-study cMRI safely evaluated AV prosthesis function with reasonable accuracy (Study 8B). Overall, this thesis supports the routine calculation of the age-CCI and incorporation of the ELI, GLS and plasma BNP into risk stratification algorithms alongside traditional risk factors in patients with AS. This approach would enhance discussions regarding the potential risks and benefits of AVR in patients with haemodynamically significant AS and may assist with identifying the optimal timing for intervention.
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ItemTargeting therapy in colon cancer( 2011)Colon cancer is a common disease affecting Australians and is rarely curable once metastatic disease develops. Angiogenesis plays an important role in the development of metastases. In metastatic colon cancer, anti-angiogenesis agents such as bevacizumab have been integrated in to standard clinical practice. Despite only a modest benefit in delaying disease progression, these agents are expensive and associated with rare but catastrophic side effects, including cerebrovascular accident, pulmonary embolus and intestinal perforation. Standard treatments for metastatic colon cancer still consist of chemotherapy that is not targeted to cancer cells and affects all dividing cells in the body, including those in bone marrow, gastrointestinal tract and hair follicles, causing significant toxicity. In order to improve the toxicity of drugs such as doxorubicin, they have been encapsulated in nanoparticles, which are small structures usually smaller than 1µm in size. The aim of the first study was to investigate differences in the expression of angiogenic factors in the epithelium and stroma of normal colon, primary colon cancer and metastatic colon cancer. The hypothesis was that angiogenic factors would be upregulated in metastases compared with primary tumours and normal colon. Archival samples of primary colon cancer, adjacent normal colon and an associated metastasis were obtained from 32 patients. Immunohistochemistry was used to examine the tumours for vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)-2 expression. In the primary tumour, VEGF-A levels were significantly higher in tumour cells compared with the stroma but there was not a difference in expression between normal colon and cancer. The aim of the second study was to measure the changes in circulating biomarkers and circulating endothelial precursor cells (CEPC) in patients commencing treatment with chemotherapy and an angiogenesis inhibitor for metastatic colon cancer. The hypothesis was that biomarkers of angiogenesis would decrease as a result of treatment and that there would be a difference in biomarker levels between patients who responded and those who did not. Plasma biomarkers were measured in patients prior to treatment and then every two weeks for six weeks. There was a non-significant correlation between placental growth factor (PlGF) and basic fibroblast growth factor (bFGF) and tumour bulk as well as a significant correlation between CEPC and VEGF-A. In addition, CEPC fell in patients who responded poorly to treatment whereas those who did respond had low CEPC at baseline that did not change. The aim of the third study was to determine the biodistribution of a variety of hollow polymeric nanoparticles and measure the changes in biodistribution and tumour uptake that occurred as a result of coating with polyethylene glycol (pegylation) and antibody functionalisation. The hypothesis was that alteration in size and surface chemistry would affect biodistribution and that pegylation and antibody functionalisation would increase tumour uptake and reduce uptake by other organs. Biodistribution in mice of nanoparticles made using a layer-by-layer technique from poly(vinylpyrrolidone) (PVP), poly(methacrylic acid) (PMA) or DNA showed high liver and spleen uptake. This occurred despite alterations in size, polymer type and pegylation. Positron emission tomography (PET) and Gamma Camera imaging demonstrated that liver uptake of nanoparticles is nearly instantaneous and fluorescent microscopy showed that Kupffer cells were the cell-type responsible for uptake. Short circulation time appeared to be responsible for poor tumour uptake. Attaching the human A33 antibody, that specifically binds colon cancer cells, to PVP nanoparticles, appeared to reduce liver and spleen uptake but did not result in significant tumour uptake.
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ItemMolecular determinants of therapeutic response to targeted therapies in metastatic colorectal cancer( 2011)Given the high cost, optimizing survival of patients with colorectal cancer requires research into two important questions. Firstly, can there be improved efficacy of these agents by using novel combinations with existing or other new drugs? Secondly, what are the mechanisms of both innate and acquired resistance to these drugs? Restricting use from those patients who have factors that govern immediate innate resistance will enrich and maximise initial response rates (RR). Identification of mechanisms governing acquired resistance may allow novel future strategies to avoid these mechanisms and allow ongoing durable responses to therapy. This thesis aims to explore methods of optimizing the targeted treatment of the EGFR pathway and the VEGF related pathway in colorectal cancer. The biology of each pathway will be reviewed. Therapeutic options for inhibiting these pathways in colorectal cancer will be discussed, focusing on targeted agents. The concept of maximising the effect of targeting the EGFR pathway by using two drugs that target the same pathway will be reviewed. Additionally, biological characteristics of the tumour that may predict resistance and response to targeting each individual pathway will also be reviewed.