Medicine (Northwest Academic Centre) - Theses
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ItemSessile Serrated Adenoma/Polyps: a new target for effective colon cancer prevention( 2022)This work pertains to a Master of Medicine thesis entitled: “Sessile Serrated Adenomas: a new target for effective colon cancer screening”. Colorectal cancer screening and surveillance programs aim to detect and remove adenomatous polyps, on the basis that the adenoma-carcinoma sequence results in the development of colorectal cancers from pre-existing adenomatous polyps. However, other molecular pathways for colorectal cancer development have recently been recognised. The serrated neoplasia pathway accounts for 15-30% of all colorectal cancers and sessile serrated adenoma/polyps (SSA/P) are the principal serrated precursors of colorectal cancer. Recently, a recommended SSA detection rate during colonoscopy of at least 4% has been proposed for all practising Australian colonoscopists by the Australian Colonoscopy recertification committee. Furthermore, updated Australian colonoscopic surveillance guidelines published in 2018 have now included SSA/P as a separate entity to conventional adenomas, in their recommendations. SSA/P are often difficult to detect on colonoscopy and have unique endoscopic features. Evidence suggests that SSA/P recognition during colonoscopy and their optimal resection using colonoscopic polypectomy techniques is an acquired skill that may be separate to conventional adenomatous polyp detection. This project comprises three separate studies. The first aims to evaluate SSA/P detection rates over a 4-year audit period, for a single colonoscopist, in comparison to their adenoma detection rate (ADR). This study demonstrated a statistically significant increase in SSADR over time with learning and experience, with a relatively stable but adequate conventional ADR. The second study documented existing ADR and SSADR for a broad group of colonoscopy practitioners at Western Health during Jul-Dec 2015, to identify groups of practitioners who may benefit from targeted education to improve their SSADR. This study demonstrated variable detection rates for different categories of colonoscopy practitioners and identified non-interventional gastroenterologists and colorectal surgeons as the categories that may benefit from further education to improve their SSADR. The third and main component of this project aimed to improve SSADR for these practitioners by a targeted educational intervention, including comparing their ADR, SSADR and PSLDR (proximal serrated lesion detection rate) before and after the educational intervention. This consisted of a multimedia presentation and reinforcing posters in the endoscopy suites across Western Health. Overall, there were no statistically significant increases in ADR or SSADR following the educational intervention. However, a significant increase in ADR and a trend towards improved SSADR was seen for non-interventional gastroenterologists. Furthermore, when compared to the original control cohort from 2015, both ADR and SSADR demonstrated a statistically significant increase, suggesting that improvement in SSADR likely occurs with experience and exposure to these lesions over time, similar to results from the first study. Large multicentre longitudinal cohort studies are required to investigate whether improvements in SSADR translate to reduced mortality from colorectal cancer. However, SSA/P are now firmly established as a new target, in addition to conventional adenomatous polyps, for removal via colonoscopy, to achieve effective colon cancer prevention. Further studies are required to evaluate more effective but practical ways to improve the SSADR for Australian colonoscopists, as the results from this project suggest that there is room for further improvement.
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ItemThe management of acute decompensated heart failure in a geriatric population: evaluation of novel strategies in a contemporary hospital setting( 2020)Heart failure is a heterogeneous complex disease, with increasing prevalence in the elderly. It is a morbid disease characterized by high mortality and frequent hospital re-admissions, responsible for a significant burden to the patient and to healthcare services. This thesis will examine unique approaches to the hospital system care of acute decompensated elderly heart failure patients by two main projects. Project one is an evaluation of Western Health’s implementation of a ‘cardio-geriatric ’unit and its effect on length of stay and readmission compared to previous routine practice. This found that the intervention did not change length of stay or readmission, however uniquely described a complex group and explores reasons why it may be difficult to achieve these outcomes. Project two explores the significance of anemia and iron deficiency, and the effect on treatment of iron deficiency, a significant comorbidity in heart failure in an elderly population. It demonstrates the prevalence and patterns of iron use in this group of patients. This thesis adds to the literature an exploration of the care provided to elderly comorbid heart failure patients in the hospital setting. It demonstrates the medical complexity of this group of patients and the difficulty in curbing outcomes in this group of patients. It allows for future research to develop alternative models of care or intervention or perhaps induce a paradigm change in the approach to care for the elderly comorbid heart failure patients.
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ItemAn Examination of Heart Failure Rehospitalisation in a Western Metropolitan Melbourne Population( 2020)Heart failure is a complex clinical syndrome, associated with a significant burden of morbidity and mortality, including a high rate of rehospitalisation. Reducing the burden of rehospitalisation among patients with heart failure is a recognised priority for healthcare systems. However, in order to optimize outcomes, contemporary studies have emphasized the need for better understanding of the clinical heterogeneity of heart failure populations. Extending beyond the understanding of pathophysiological heterogeneity, the elucidation of sociodemographic factors may also reveal greater opportunities for targeted optimisation. Moreover, utilising new methods by which rehospitalisation is assessed may lead greater insights than would otherwise be captured by conventional means. This project aims to expand the understanding of rehospitalisation burden in evolving heart failure populations. It evaluates the adverse impact of cultural and linguistic diversity on rehospitalisation outcomes in patients with heart failure. A discussion of important methodological concepts into researching culturally and linguistically diverse (CALD) patient groups is carried out. In doing so, a novel operational approach to defining CALD patients is presented. This thesis also explores the measures of which rehospitalisation is evaluated in heart failure patients. It described the added value of analysing all recurrent hospital admissions (events), an approach which is very seldom performed in heart failure research. An assessment of several modelling techniques for evaluating rehospitalisation burden is performed, specifically in relation to heart failure type (i.e. heart failure with preserved vs reduced ejection fraction). In doing so, demonstrate the analysis of recurrent hospitalisations, compared to traditionally utilised first-event statistical approaches, may be a more informative and clinically relevant measure when evaluating the burden of heart failure rehospitalisation. As the prevalence of heart failure is rising and patients are becoming more diverse and complex, there is an increasing need to better characterise and understand these evolving heart failure populations. Further elucidating the heterogeneity of heart failure populations will help guide improvements to existing management approaches, as well as the direct the development of new targeted approaches.
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ItemThe pattern of expression of the receptor tyrosine kinases (RTK) EphB1, EphB2 and EphB4 in colorectal cancer( 2016)Colorectal cancer (CRC) is a global health problem. It is the second leading cause of cancer related death worldwide and in Australia. Around 25% of CRC will experience recurrences postoperatively in the absence of lymph node metastasis and liver metastasis. We need to develop better diagnostic tools and more effective therapeutics. This will come through a thorough understanding of the molecular events in CRC progression. Erythropoietin producing hepatoma (Eph) receptors are the largest family of the receptor tyrosine kinases (RTK). They are divided into two subfamilies, A and B, Together with their cognate ligands, they play integral role in different body organs during embryo development and in adulthood. EphB receptors are considered as key coordinator of proliferation and migration of the intestinal stem cells (ISCs). They are Wnt signalling target genes. They are distributed in a complimentary pattern with their ligands, ephrinB1 and ephrinB2, along the intestinal crypt axis. Adenomatous polyposis coli gene mutation is considered as the initiating step in CRC development. It leads to Wnt signalling mutation and adenoma-carcinoma progression. Despite activation of Wnt signalling pathway, EphB receptors are inactivated during adenoma-carcinoma progression EphB1 and EphB2 receptors function as tumour suppressors in CRC, whereas for the EphB4 some studies found that EphB4 receptor is underexpressed whilst others found it overexpressed with the progression of the disease. It has also been suggested EphB4 expression is up-regulated as EphB2 expression is extinguished. Using immunohistochemistry we investigated pattern of expression of the three receptors together, EphB1, EphB2 and EphB4, across three stages of CRC, SII, SIII, SIV, in lymph node metastasis, and in liver metastasis, in a total population of 148 CRC patients. We found that: The three receptors are co-ordinately under-expressed in the primary CRC. The receptors are further under-expressed in the liver metastasis. The EphB1 receptor is under-expressed in most undifferentiated CRC and in liver metastasis. The EphB4 receptors follow the same down-regulation pattern as the other two in both primary tumours and metastases. There is no evidence that EphB2 –negative tumours express EphB4. The importance of this study of EphB receptors expression pattern in CRC and in liver metastasis is that it gives a general picture about the status of the three receptors together across different stages of CRC, in lymph node metastasis, and in liver metastasis of the same patients. Understanding the pattern of expression of three receptors together in CRC, highlights the significance of these receptors in CRC, and in long term revolutionizes current anticancer drug treatment of the disease.
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ItemSun exposure and type 2 diabetes mellitus: Can sun exposure lower type 2 diabetes risk?( 2015)Background: Lower serum 25-hydroxyvitamin D (25OHD) levels have been consistently associated with increased type 2 diabetes mellitus (T2DM) prevalence and incidence in systematic reviews and meta-analyses of observational studies, however this association has not consistently been replicated in vitamin D supplementation trials. This disparity may be due to a number of different factors: lack of power in the trials due to small sample size, insufficient duration of dosing, baseline vitamin D or glycaemic status differing between studies, low supplementation compliance or insufficient vitamin D dose. Alternatively, lower 25OHD levels may be a product, rather than a cause of ill-health, or they may share pathology earlier in life or in disease progression so that supplementing with vitamin D in adulthood has no effect on disease outcome. This body of work presents another explanation: given that sun exposure is the most influential contributor to serum 25OHD levels, observational studies may be reporting an effect of sun exposure, rather than vitamin D, on T2DM. Therefore vitamin D supplementation trials may be failing to capture any additional benefits of sun exposure through non-vitamin D pathways. The aim of this body of work was to investigate the possible association between sun exposure and T2DM endpoints reported in scientific literature as well as in an original analysis. A major objective of the original analysis was to determine whether or not any association found between sun exposure and T2DM incidence was through non-vitamin D pathways. Methods: Following a literature review, a systematic review of observational studies reporting on associations between sun exposure variables and T2DM-related endpoints was conducted. The potential of an association between sun exposure- measured using ambient ultraviolet radiation (UVR), and five-year cumulative incidence of T2DM was explored using a prospective, national diabetes cohort (AusDiab). A causal mediation analysis was undertaken to explore whether or not there were effects of ambient UVR on cumulative T2DM incidence, via non-vitamin D pathways. Results: The systematic review revealed that high-level evidence for an association between sun exposure and T2DM-related outcomes was lacking. There was moderate-level evidence for greater sun exposure reducing T2DM incidence. The opposite was found in the original analysis using the AusDiab cohort: ambient UVR was associated with increased T2DM incidence (OR=1.17, 95% CI: 1.01-1.36, p=0.04). This association was independent of an effect of age, sex, body mass index, physical activity, ethnicity, smoking status and serum 25OHD levels, but was likely to be confounded by area-level determinants of health due to the nature of the exposure variable. The major limitations of this work were that the sun exposure measures were suboptimal. Time-of-year measures were the most common sun exposure variables contained in the systematic review, and ambient UVR at the site of participant recruitment was the proxy for sun exposure in the original analysis. Conclusion: There is likely to be a complex relationship between sun exposure and T2DM. The direction of the association between sun exposure and T2DM incidence, as well as delineation of the mechanistic pathways through which this association may exist, are yet to be confirmed. Future studies are encouraged to use person-level sun exposure measurements, and findings from such studies may influence sun protection policy.
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ItemTo validate a preoperative risk stratification model developed at Barwon Health for mortality and major morbidity in major colorectal surgery( 2013)Colorectal surgery is associated with significant mortality, with reported rates of 1% to 2% in elective surgery and 5% to 10% in emergency surgery. The majority of the colorectal workload is attributed to colorectal cancer and according to the National Health and Medical Research Council guidelines, being the second leading cause of cancer related death in Australia. Each year at least 12,600 new cases are diagnosed with an estimated annual increase of 0.3%. Therefore in the past decade, there has been much initiative to create a prognostic model that could predict patient’s mortality and morbidity before colorectal surgery. Currently there are three known models; Association Française de Chirurgie index score, Barwon Health 2009 model and the American College of Surgeons National Surgery Quality Improvement Program colorectal risk calculator. These prognostic models were created for the purpose of informed consent, to discuss a patient’s risk for surgery and to identify high risk patients for early medical, high dependency unit or intensive care unit admission. Although all three models have reported reliable results in predicting patient mortality, these models have never been validated with another independent dataset in Australia. The purpose of validating the prognostic models was to ensure they were reliable at predicting patient’s mortality in other institutions. However only the Association Française de Chirurgie score and the Barwon Health 2009 model were validated and neither predicted mortality accurately. The American College of Surgeons National Surgery Quality Improvement Program colorectal risk calculator was not validated as it was password protected and available only to the participating hospitals. As there were no reliable models for colorectal surgery, the Colorectal preOperative Surgical Score was created. The Colorectal preOperative Surgical Score is a 4-variable pre-operative model that predicts a patient’s mortality risk following emergency or elective colorectal surgery. This model was successfully validated at two independent institutions. We hope to use this model to guide pre-operative counselling with individual patients and as a simple tool for risk stratification of outcomes as reported in colorectal surgical audit.