Medicine (St Vincent's) - Theses
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ItemAdenocarcinoma of the lung: an exploration of the relationships between histopathology, molecular pathology and inflammatory markers and their relationship to patient outcomes( 2017)Lung cancer remains the most common cause of cancer related death worldwide, with nearly 1.4 million deaths in 2008 globally. Adenocarcinoma is the most common type of lung cancer, and its frequency compared to other histologic subtypes is increasing. The simplicity of the label “adenocarcinoma” hides its significant pathologic and clinical heterogeneity. This thesis explores a number of clinicopathologic correlates in lung adenocarcinoma specimens obtained from patients treated at St Vincent’s Hospital in Melbourne, Australia. In 2011 the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) proposed a new classification system for pulmonary adenocarcinoma. This was subsequently adopted in the 2015 edition of the World Health Organisation Classification of Tumours of the Lung, Pleura, Thymus and Heart. Multiple groups demonstrated that the new classification had prognostic significance following resection of pulmonary adenocarcinoma independent of stage. The impact of the classification in metastatic disease was not known. This thesis found that it was possible to identify the adenocarcinoma patterns of solid with mucin, papillary, micropapillary and acinar in each specimen taken from a metastatic site and semi-quantitatively assess each component. Further, the identification of a major pattern was not prognostic, but did predict for differences in survival time for patients treated with systemic therapy. The worst outcomes were observed for patients with tumours with a major solid pattern. The major solid pattern was also found to have infrequent occurrence of activating epidermal growth factor receptor (EGFR) mutations. As this is the first time that this novel finding has been reported. Validation from other groups is required. The presence of the IASLC/ATS/ERS classification as a robust new tool with clinical relevance has led to further research to define other clinicopathologic correlates. Oncogene driver mutations in genes such as EGFR and Kirsten RAS (KRAS) are critical in selection of therapy in advanced disease. This thesis examined relationships between adenocarcinoma subtype and mutation status for patients who had resected lung adenocarcinoma. Patients with solid predominant adenocarcinoma were significantly less likely to have EGFR mutations, while KRAS mutation was a frequent event in invasive mucinous adenocarcinoma. No other significant associations were found. The findings were consistent with those recently reported by other groups from centres located in predominantly Caucasian countries. EGFR inhibition and the discovery of EGFR mutations was the starting point for a major change in the approach to treatment of advanced lung adenocarcinoma, however resistant to treatment occurs. It had been suggested that upregulation of phosphorylated STAT3 (pSTAT3) via interleukin 6 (IL6) and Janus Kinase (JAK) may be linked to EGFR mutation status in the absence of treatment with EGFR tyrosine kinase inhibitors and therefore may offer a rational target to delay resistance to such therapies. In the patient cohort studied the presence of EGFR or KRAS mutation status did not enrich for activation of IL6, JAK1 or pSTAT3 as determined by immunohistochemistry. Further, there was no clinicopathologic or prognostic correlates of note found by the IL6, JAK1 or pSTAT3 activation state. The assessment of IL6, JAK1 and pSTAT3 in the same samples and by two methods to assess positivity was a unique feature of this study. In conclusion this contributes new knowledge on the relevance of pathologic subtyping in advanced lung adenocarcinoma. It confirms and consolidates recent reports oncogene mutation status and adenocarcinoma subtype following surgical resection. It examines the IL6 / JAK1 / pSTAT3 pathway in detail in resected pulmonary adenocarcinoma. Translational research that explores why adenocarcinoma subtypes have different outcomes by treatment may allow clinicians to direct therapies differently or unlock new pathways for targeting lung adenocarcinoma with therapeutic effect.
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ItemA health and economic impact analysis of robotic surgery for the treatment of localised prostate cancer in the Victorian public health system( 2017)Background: The rising prevalence of prostate cancer in Australia will increasingly contribute significant morbidity, mortality and economic burden on society. Radical prostatectomy is the mainstay of treatment for localised prostate cancer, and robotic prostatectomy the dominant surgical approach to management in the United States and Europe. Large systematic reviews have demonstrated some perioperative and functional benefits of robotic over open and laparoscopic approaches, however no differences in oncological outcomes have been demonstrated to date. The cost of the robot is undoubtedly greater than open and laparoscopic approaches however studies have shown a significant cost offset due to reduced length of stay and other improved clinical outcomes. We aim to perform a comprehensive health and economic impact analysis of robotic surgery for the treatment of localised prostate cancer in the Victorian public health system since the introduction of the da Vinci surgical robot to Peter MacCallum Cancer Centre (Peter Mac) in July 2010. Methods: To compare patterns of care and perioperative outcomes of robotic prostatectomy to other approaches, we utilised a large dataset from the Victorian Admitted Episodes Dataset (VAED) including all prostatectomy patients performed in the Victorian public sector since the installation of the da Vinci robot. Additionally the RARP series of perioperative, complication, oncological, functional and quality of life (QOL) outcomes at Peter Mac was compared to local, national and international literature. We then created an economic model to evaluate the incremental cost of robotic-assisted radical prostatectomy (RARP) versus open radical prostatectomy (ORP) and laparoscopic radical prostatectomy (LRP), incorporating the cost-offset from differences in length of stay and blood transfusion rate. The economic model constructs estimates of the diagnosis-related group (DRG) costs of ORP and LRP, adds the gross cost of the surgical robot (capital, consumables, maintenance and repairs), and manipulates these DRG costs to obtain a DRG cost per day, which can be used to estimate the cost-offset associated with RARP in comparison with ORP and LRP. Economic modelling was performed around a base-case scenario assuming a 7-year robot lifespan and 124 RARPs performed per financial year. One and two-way sensitivity analyses were performed for the four-arm da Vinci S HD, Si and Si dual console surgical systems. Results: The robotic surgical approach has become the dominant technique to radical prostatectomy for localised prostate cancer in the Victorian health system over ORP and LRP. The introduction of a surgical robot to the Victorian public system has resulted in centralisation of prostatectomy to Peter Mac with huge institutional growth since its instillation. Length of hospital stay and blood transfusion rates are significantly improved with the robotic approach. Positive surgical margin rates with RARP are improved compared to prior Victorian data consisting of primarily an ORP cohort. Complication and oncological outcomes of RARP are comparable between surgical approaches and to large international RARP series. Definitive comparison of RARP functional and QOL outcomes between approaches was difficult without a comparative cohort however compared favourably with previous literature. Improvements in length of stay and blood transfusion rates offset most of the additional cost of the robot in the base case scenario where 124 robotic cases are performed per year. RARP can become cost-equivalent with ORP where ~140 cases are performed in the base-case scenario. Increasing the surgical volume, lifespan of the robot and reducing the cost of the consumables can ameliorate cost. Conclusions: The da Vinci surgical robot has been safely introduced into the Victorian public health system at Peter Mac. The addition of the robot has significantly altered the way we treat patients with localised prostate cancer in Victoria. The robotic approach confers some clinical advantages compared to laparoscopic and open prostatectomy consistent with international literature, and the reduction in length of stay offsets much of the increased cost of the robotic procedure.
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ItemSelection and management of men for active surveillance in low risk prostate cancer( 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.
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ItemAdvanced characterisation of pulmonary hypertension: Assessment of right ventricular diastolic function and pulmonary artery wave reflection( 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.
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ItemBreast cancer risk assessment and risk management:: Development of a personalised, web- based, decision support tool (iPrevent®)( 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.