Medicine (St Vincent's) - Theses
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ItemSelection and management of men for active surveillance in low risk prostate cancerWong, Lih-Ming ( 2016)Aims: To investigate: 1. Selection of men for active surveillance of prostate cancer a. Validation of risk calculators b. Suitability for inclusion of Gleason 3+4 disease. 2. Performance of prostate biopsy during AS a. Differences in quality of diagnostic biopsy between academic and referral centres. b. Optimization of biopsy templates c. Examination of prognostic indicators for disease progression Methods: Data were obtained from several difference sources: • Men suitable for AS on prostate biopsy but undergoing upfront radical prostatectomy were pooled from 3 international academic institutions in Cambridge (UK), Toronto (Canada) and Melbourne (Australia). • Prospectively maintained AS prostate cancer database at Princess Margaret Cancer Centre (PMCC) (1997-2012). Analyses performed: • Four risk calculators were assessed for their ability to predict different definitions of insignificant prostate cancer by area under the curve (AUC) of receiver operating characteristic curves and Brier scores for discrimination, calibration curves and decision curve analysis. • Men with biopsy Gleason 3+4 disease, suitable according to modified Royal Marsden, Sunnybrook Toronto and PRIAS selection criteria, were assessed for presence of adverse pathology at upfront radical prostatectomy. • Patients on AS at a tertiary referral centre (PMCC) were dichotomized depending on where their diagnostic biopsy was performed (interval versus external). Multivariate logistic regression was performed to examine for predictors of re-classification at the second, or confirmatory, biopsy. • Mapping of all patients with pathological progression at PMCC for location of disease progression enabled comparison of hypothetical biopsy templates (sextant and standard extended) to the institutional template used. • Men on AS at PMCC were evaluated for presence of disease progression at serial biopsy in the prostate transition zone (TZ). Multivariate Cox proportional hazards regression evaluated predictors of TZ progression. • At PMCC, men were dichotomized based on presence of cancer at their confirmatory biopsy. Pathological progression was investigated using a Cox proportional hazards regression model. Results: • All 4 models predicting presence of insignificant prostate cancer had weak discrimination at best (AUC 0.618-0.664). • Presence of Gleason 3+4 at biopsy, compared to 3+3 disease, increases risk of adverse pathology at radical prostatectomy if modified Sunnybrook Toronto criteria are used (19% versus 33%, p≤0.001). Using a stricter protocol such as PRIAS, there was no statistical difference between the groups. • External biopsy predicted both grade related re-classification (OR 4.14, C.I. 2.01-8.54, p<0.001) and volume related re-classification (OR 3.43, C.I. 1.87-6.25, p<0.001). • Sextant and standard extended biopsy templates were inferior to the institutional biopsy template in detecting presence of cancer (84% and 99% versus 100%), and pathological progression (47.9% and 81.9% versus 100%). • At each subsequent biopsy during AS, 2.7-6.7% of men had disease progression only in the TZ which would not have been detected if TZ biopsy was not performed. Predictors of TZ progression were maximum % single core (HR 1.99, C.I. 1.30-3.04, p=0.002), and MRI reporting cancer (HR 3.19, C.I. 1.23-8.27, p=0.02). • Men with no cancer at confirmatory biopsy were less likely to have pathological progression (HR 0.47, CI 0.29-0.77, p=0.003). Sub-analysis showed this was predictive of volume-related progression (HR=0.36, CI 0.20-0.62, p=0.0006) and not grade-related progression. Conclusions: • Utilization of models predicting suitability for AS should be used with caution as external validation in our cohort was weak. • If considering biopsy Gleason 3+4 disease for AS, a stricter protocol such as PRIAS must be utilized. • At PMCC, patients who had their initial diagnostic prostate biopsy for AS done externally, were more likely to have worse pathological features and re-classify on the second biopsy. • For men on AS, sextant and standard extended biopsy are less likely to detect prostate cancer or disease progression than the template used at PMCC. • TZ biopsy should be considered for all men having serial biopsy on AS, in particular those with high % core involvement or positive MRI findings. • Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression.
ItemAdvanced characterisation of pulmonary hypertension: Assessment of right ventricular diastolic function and pulmonary artery wave reflectionMurch, Stuart David ( 2016)Pulmonary hypertension is the net haemodynamic consequence of a wide variety of underlying pathologies. As disease progresses, right ventricular systolic dysfunction may develop. However, by the time this occurs, prognosis is poor. Like the situation in the left ventricle, chronically increased right ventricular afterload first leads to right ventricular hypertrophy and hypothetically, diastolic dysfunction. Although there is some evidence from animal models for this, human data is limited. Theoretically, the identification of right ventricular diastolic dysfunction may assist in the earlier diagnosis of pulmonary hypertension. This thesis provides evidence that right ventricular diastolic dysfunction does exist in the setting of pulmonary hypertension, that it occurs earlier than systolic dysfunction, and that it can be identified by invasive pressure measurement in the right ventricular cavity. Although echocardiography provides a useful way to assess left ventricular diastolic function, data presented here will show that currently available echocardiographic measurement of right ventricular diastolic function may not be sensitive enough to detect abnormal function. The secondary hypothesis tested is that a pressure/time analysis of pulmonary wave reflection can provide additional information in the assessment of patients with pulmonary hypertension. Data suggests that a metric of wave reflection, the pulmonary augmentation index, is closely associated with standard measures of right ventricular afterload, and therefore may not add value. However, the time to wave reflection is related to the site of obstruction in the pulmonary circulation and could theoretically assist in identifying disease aetiology.
ItemBreast cancer risk assessment and risk management:: Development of a personalised, web- based, decision support tool (iPrevent®)Collins, Ian ( 2016)Breast cancer risk is a complex interaction of environmental factors, inheritance and genetics. Awareness of her personal breast cancer risk can allow a woman to make informed decisions regarding the management of her risk, through screening or risk reduction measures such as surgery or medication. The effect of risk factors, both inherited and modifiable, on breast cancer risk is complex but mathematical models exist to estimate an individual’s risk. These models use epidemiological data to quantify the risk for an individual, based on a range of their risk factors. As these models were developed primarily for research purposes, they are not designed for ease-of-use by a range of clinicians, nor designed to be used by those unfamiliar with estimating breast cancer risk. Once estimated, a woman’s breast cancer risk must then be explained in a way that is comprehensible to the woman, together with ways to manage that risk in a similar format. If this were achieved for all women, it may allow them to make informed choices and potentially even prevent breast cancer or reduce its impact greatly. The ultimate aim of this research was to develop a user-friendly computerised, web-based breast cancer risk assessment and risk management support tool. This tool, called iPrevent©, uses the existing mathematical models to estimate individualised breast cancer risk, but using a user friendly interface. It then goes further, and provides Cancer Australia guideline-based recommendations, based on that risk, for each individual woman. It presents the risks and befits of each evidence-based intervention in a similar manner to the risk so that women can make an informed choice regarding their breast cancer prevention strategy. Before developing iPrevent©, I first examined the other possible effects of being a carrier of a mutation in breast cancer predisposition genes, as it was hypothesised that other factors such as fertility effects, could have a large bearing on any future decisions women may make, including risk reducing surgery. I then explored current behaviours to reduce risk among women at highest risk, in an attempt to understand the magnitude of the possible benefits of iPrevent© in this highest risk group. Through focus group studies, I examined the information needs of clinicians to facilitate breast cancer risk discussions. Understanding the needs of end-user clinicians of iPrevent© ensures it could meet their needs. This usability may increase uptake and use, of both the tool and breast cancer risk management strategies where appropriate. This tool, iPrevent©, is currently undergoing clinical validation studies, outside the scope of this thesis, but will shortly become freely available with the aim of increasing individual awareness of each woman’s own breast cancer risk, enabling her to manage that risk according to the evidence, Cancer Australia guidelines and her own preferences.