Medicine (Austin & Northern Health) - Theses

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    The therapeutics of Diabetes Mellitus : developmental and regulatory aspects
    Wang, Jue MHlthSci. (University of Melbourne, 2006)
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    The therapeutics of Diabetes Mellitus : developmental and regulatory aspects
    Wang, Jue MHlthSci. (University of Melbourne, 2006)
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    The use of humidified, warmed CO2 in cancer surgery to improve patient outcomes
    Dean, Meara ( 2018)
    Aim To investigate the effects of warmed, humidified CO2 on peritoneal inflammation and tissue damage, tumor microenvironment, and perioperative outcomes in colorectal cancer surgery. Methods • A literature review was performed on peritoneum and mesocolon anatomy and physiology, the mechanisms of colorectal cancer recurrence, and the surgical techniques that are used to help reduce colorectal cancer recurrence. • A systematic review of the literature regarding warmed, humidified CO2 in abdominal surgery was performed. • A meta-analysis of the effects of warmed, humidified CO2 on peri-operative hypothermia was performed. • An experimental study was performed to investigate the effects of warmed, humidified CO2 on peritoneal inflammation and tissue damage, and colorectal cancer in a laparoscopic surgery mouse model. • A multi-centre, randomized, controlled trial was designed, evaluating the effect of warmed, humidified CO2 on peritoneal inflammation and tissue damage as a primary outcome, and secondary outcomes of systemic inflammation, presence of systemic ctDNA, perioperative hypothermia, length of stay, cost of intervention and quality of recovery. Findings A review of the literature reveals the use of warmed, humidified CO2 for insufflation during abdominal surgery may have potential benefits for patient care. However, findings are limited by the size and quality of published studies. Meta-analysis of published studies suggests a benefit in maintaining perioperative normothermia. The results of the experimental study show the use of warmed, humidified CO2 alters the tumor microenvironment. A multicentre, randomized, controlled, clinical study has been designed to further assess the effects on peritoneal inflammation, tissue damage and other perioperative outcomes. Conclusions The use of warmed, humidified CO2 in abdominal surgery has several potential benefits including reduced peritoneal structural damage and inflammation, maintenance of perioperative normothermia and reduced postoperative pain. The findings of this experimental study have shown an effect on the tumor microenvironment. Future research should re-assess this effect in human subjects. An adequately powered, multicentre, randomized, controlled clinical trial that has been implemented will help confirm the other effects of this therapy.
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    Experimental and clinical advances in the management of kidney cancer
    Rao, Kenny ( 2014)
    Approximately 2700 new cases of kidney cancer are diagnosed in Australia each year. Kidney cancer accounts for about 2% of all Australian cancer deaths. The only known cure for localised kidney cancer is surgical removal. A common approach to kidney cancer surgery is partial removal of the affected kidney with preservation of non‐cancer affected kidney tissue. This is indicated in patients who have poor kidney function, or a tumour in a functionally or anatomically solitary kidney. The increase in early detection and apparent decrease in cancer aggressiveness at this early stage have increased the number of patients eligible for kidney preserving operations. The standard technique of partial nephrectomy requires clamping of the renal artery and vein to the affected kidney during the operation to minimise blood loss during dissection and removal of the highly vascular kidney tissue. The duration of reduced perfusion is kept to within the critical ischemia time of approximately 30 minutes at a normal core body temperature to prevent injury to the remaining kidney tissue. Another method to ensure minimal ischemic renal damage is by reducing the kidney and body temperature. Despite these measures, studies show the rate of acute renal failure following partial nephrectomy is between 5-17% in patients with previously underlying kidney disease or solitary kidneys with up to 5% requiring dialysis for chronic renal failure. There is significant potential benefit from preventing functional kidney loss in those who develop complications as a result of critical ischemia of the kidney. Preconditioning is the term used to describe the stimulation of cells to adapt, inadvance, to protect themselves against subsequent injury from ischemia. The kidney can protect itself from ischemic injury by making proteins that act as signals to produce protective substances. These proteins, which include Hypoxia Inducible Factor (HIF), gastrin and metallothionein (MT), act as master regulators to control genes that stimulate red blood cell production and other associated processes. These proteins can turn on genes that reverse the harmful effects of low oxygen and thus enable the kidney to survive in a low oxygen environment. In these situations, a preconditioning mechanism could limit the short and long term damage to the normal kidney. This has great promise for clinical application where routine pre‐operative stimulation of the affected kidney can be used to prevent functional renal loss. From previous studies undertaken by researchers in the Department of Surgery at the Austin Hospital, we know that the metal ion cobalt can protect kidneys against irreversible ischemic injury by signalling increased production of such proteins. However, cobalt toxicity is also known to cause various potential side effects such as nausea, nerve damage, and renal failure. Similarly, studies by other workers have shown that zinc can also signal production of proteins that protect brain, liver and heart cells against ischemic injury. Furthermore, because zinc is a naturally occurring metal ion found in the healthy body, it might also be less toxic to cells. To date, there have been no studies that investigate the potential protective effects of zinc on 60 minutes of kidney ischemia. Clinically, kidney cancers, and most other urological cancers are now being managed in a multidisciplinary team environment. While this trend is becoming increasingly widespread throughout the world, few studies have looked at whether or not multidisciplinary meetings (MDM) change decision-making outcomes. There is also conflicting data on the impact of these discussions on clinical decision-making. Certainly, in an era of ever increasing numbers and complexity of chemotherapeutic trials, the MDM seems to be a logical setting to discuss and facilitate formal referrals and to disseminate information amongst various medical and allied health specialties. Therefore this project aims to investigate novel experimental agents that may protect the kidney against the ischemic injury often encountered during kidney cancer surgery, and to study the impact of clinical decision-making of MDMs in the management kidney and urological cancers.
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    Selection of men for active surveillance in low risk prostate cancer
    Wong, Lih-Ming ( 2013)
    Aims: Active surveillance (AS) is a management strategy that aims to avoid over-treatment of indolent prostate cancer, monitor for development of more aggressive disease, and intervene within the window of curability. Interest in AS has increased as large randomized screening trials suggest many men with prostate cancer are over-diagnosed and over-treated. Suitability of men for AS is determined by criteria that were found to predict "insignificant tumours", defined as tumours of volume <0.5ml. However, amongst the published literature on AS, variations in eligibility criteria exist between individual institutions. The primary aim of this thesis was to examine the ability of certain published AS eligibility criteria to include only men with insignificant tumours, and avoid selection of men with more aggressive disease. Methods: To investigate eligibility criteria for AS, data on men who were suitable for AS but underwent upfront radical prostatectomy was analysed. Initially, a database from Addenbrookes Hospital, Cambridge, United Kingdom was utilized. Subsequently, a collaboration of radical prostatectomy data between Addenbrookes Hospital, United Kingdom; Vancouver Prostate Centre, Canada; and Royal Melbourne Hospital, Australia was formed. First, the Cambridge database was used to assess a National Institute for Health and Clinical Excellence (NICE) guideline. Here, it had previously been stated “men with low-risk localised prostate cancer who are considered suitable for radical treatment should first be offered active surveillance”. Subsequently, the combined database was utilized to examine two of the commonly used AS criteria (Sunnybrook Toronto and European Prostate Cancer Research International: Active Surveillance (PRIAS)). Here, the number of men suitable for AS according to each criteria, and proportions of men with upgrading and upstaging at radical prostatectomy were described. Multivariate logistical regression was done to identify predictors of more aggressive, or high-risk, disease, and analysis to create a predictive model for both indolent and high-risk disease performed. Results: When reviewing the NICE guideline, their definition of low risk prostate cancer, was applied to the Cambridge radical prostatectomy database (n=700) and 39.2% of men (n=275) deemed suitable. In this group of NICE low risk patients, 30.6% (n=84/275) of men had features of more aggressive disease (Gleason sum ≥7, pathological stage ≥ pT3) at upfront radical prostatectomy. In selecting men for AS, application of more stringent criteria was found to effectively halve the number of men suitable for AS (Sunnybrook criteria n=800, compared to PRIAS criteria n=410). The proportion of men with increase in Gleason grade (≥7) was 42.7-50.6%, and increase in stage was 12.4-17.6%. Predictors of high-risk disease included increasing age, cT2, increasing PSA and number of positive cores. More men in Cambridge, compared to Vancouver and Melbourne, were found to have pT3 disease (26% versus 12%). To assist selection of men in the UK for AS, from the Cambridge data, we generated a nomogram predicting high-risk features in patients who meet the Sunnybrook Toronto criteria (AUC of 0.72). Conclusions: In selecting men for AS, a proportion of them will harbour undiagnosed high-risk disease. Using more stringent criteria may reduce this number but at the cost of including fewer men who may benefit from AS. Predictive models may assist with selection of men but the future likely lies in better tests, be it imaging or biomarkers, to be performed at time of selection and during the course of AS.
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    Identification of genetic changes in prostate tissue of men with prostate cancer from multiple breast cancer families
    Kavanagh, Liam ( 2013)
    Introduction: Male BRCA2 mutation carriers are at higher risk of developing aggressive prostate cancer. My research looks at DNA changes in prostate cancer specimens from men positive for a BRCA2 mutation. The first project involves DNA analysis of HG PIN tissue to look for loss of heterozygosity (LOH) in those carriers of a BRCA2 mutation. The purpose of looking for LOH in HG PIN of BRCA2 positive carriers is to ascertain if this tissue is a genomic predictor for tumorigenesis in this population. We also considered that whole exome copy-number analysis (CNA) of prostate cancer tissue, as well as HG PIN and normal prostate tissue from these BRCA2 men, may provide additional insight. Another inheritable mutation associated with prostate cancer is the HOXB13 mutation. We explored our cohort of prostate cancer men from breast cancer-rich families for the incidence of this mutation and impact on survival. We also investigated the incidence of the HOXB13 mutation in breast cancer women from breast cancer-rich families. Patients and Methods: Ten BRCA2 positive participants, from the kConFab cohort of high-risk breast cancer families, were identified , with access to archival prostate tissue specimens. Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation specific PCR and sequencing of DNA from laser microdissected HG PIN. We also dispatched 15 DNA samples to Affymetrix for CNA: 9 prostate adenocarcinoma tissue DNA samples with 4 matched normal prostate tissue samples and 2 matched HG PIN samples. This data was analysed using specific software for microarray genetic analysis. For the HOXB13 study, the G84E variant was screened for using high resolution melting analysis in germ-line DNA in the index case or youngest affected member of 898 high-risk breast cancer families and in 1097 population controls. Results: Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HG PIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. For the CNA project, our samples showed common sites of amplification at 8q, as well as deletions at 10q and 13q. Six out of 898 multi-case breast cancer families had carriers of the HOXB13 G84E variant: three families had either a single or multi-case family history of prostate cancer (3/99) and three had a personal and family history of breast cancer (3/799). Conclusion: Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers. Regarding the CNA study, this is the first genomic analysis of this specific patient group, with our results have validated previous results of CNA in prostate cancer, as well as demonstrating the highly heterogenous nature of copy-number changes in this subset of patients. We confirm an association of the HOXB13 G84E variant with good prognosis prostate cancer in non BRCA1 or BRCA2 breast cancer families but we found no evidence for an increased risk of familial breast cancer.