Surgery (Austin & Northern Health) - Theses
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ItemThe role of zinc in prostate cancer( 2018)Prostate cancer (PCa) is the most common cancer amongst Australian men. Zinc is an essential metal and is vital for normal function of the prostate gland. Castrate-resistant prostate cancer (CRPC) is becoming increasingly resistant and treatment options are limited in number and often associated with poor clinical outcomes. Therefore a pertinent clinical issue is to develop more effective treatment regimes. Zinc appears to play a role in PCa, but a true understanding leading to therapeutic developments is yet to be achieved. In particular evidence regarding cell proliferation and zinc uptake and levels in PCa cells is conflicting. HIF1α is a well-known prognostic marker in PCa associated with poor prognosis, resistance to treatment and development of metastatic disease, however the cause over-expression in CRPC remains a mystery. Therefore the ability of PCa cells to uptake and store zinc, and the role of zinc in PCa cell proliferation, tumour growth and HIF1α mediated survival was investigated in this thesis. CRPC-like human PC3 cells are significantly resistant to docetaxel chemotherapy and overexpress HIF1α protein, compared to normal prostate epithelial control cells (PNT1A). Cell proliferation assays (MTT) demonstrated that physiological zinc administered to PC3 cells significantly slowed growth compared to normal PNT1A and androgen-sensitive PCa (LNCaP) cells. The effect of zinc supplementation or zinc chelation (by TPEN) does not affect macroscopic growth in PC3 xenograft tumours. There is no significant difference in baseline total zinc concentration (measured by ICP-MS) between cell lines normal (PNT1A), androgen sensitive (LNCaP) and CRPC (DU145 and PC3) cells. However, CRPC-like PC3 cells contain significantly higher unbound free Zn2+ and Immunofluorescence Microscopy (IFM) subcellular distribution of Zn2+ in PC3 cells is unlike that seen in normal prostate epithelial cells. PC3 cells are resistant to oxidative stress injury. Zinc strongly induces HIF1α protein expression in these cells in a time and dose dependent manner. Zinc mediated oxidative protection in PC3 cells is a HIF1α dependent as demonstrated in a PC3 HIF1α-KD model. No such zinc protection was seen PNT1A cells. Zinc could be essential in the resistant nature of CRPC cells as Zn2+ ions rescue HIF1α protein expression and are implicated in the normoxic stabilisation of the HIF1α protein by competing with Fe2+ ions at the PHD binding sites. Therefore zinc dysregulation in CRPC cells is an important factor in the development of resistance, as well as potentially progression to metastatic disease and poor prognosis in PCa.
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ItemCharacterisation of tumour-infiltrating lymphocytes in benign and malignant prostate tissues( 2018)Over the past decade, we have seen a significant advancement in the treatment of metastatic castrate-resistant prostate cancer (PC). Cancer immunotherapy is now a reality, but the information on tumour infiltrating lymphocytes (TILs) in human prostate tissues is still limited. This project aims to evaluate and compare T cell characteristics in blood and tissues from patients with benign and malignant prostate conditions using flow-cytometry. Patients with benign prostatic hyperplasia (BPH) and normal prostate (NP) were used as controls and compared with patients with PC. We also examined the effects of androgen deprivation therapy (ADT) on systemic immune responses and immune regulation in patients with advanced/metastatic PC. The T cell characteristics evaluated were: (1) The proportion of regulatory T cell (Treg) and CD8/Treg ratio; (2) The percentage of activated cytotoxic lymphocytes (CTLs); and (3) The T cell maturation status. We found that the proportion of Treg in PC tissue was 5.6%, consistent with other studies. We did not find any differences in the proportion of Treg or CD8/Treg ratio in tissues for the three patient groups. When evaluating PC involved vs PC non-involved tissues, as an internal control comparison, PC involved tissues were found to have a higher percentage of Treg (6.89% vs 4.15%, p-value of 0.045) and a lower CD8+/Treg ratio (54 vs 119, p-value of 0.0032) than PC non-involved tissues. Despite a small number of 6 cases, the differences were statistically significant. These findings support the hypothesis of local immunosuppression in PC-involved tissues, and that such immunosuppression might be compartmentalised even to the level of specific lobes of the prostate. In this compartmentalised environment, PC cells can evade and survive the immune system’s defences. This study did not find any correlation between Gleason scores and the percentage of Treg in the CD4+ T cell subset or the CD8/Treg ratio either in PBMC or PC tissue. In the PC group, the same percentages of CD8+ T cells were found in both tissues and peripheral blood for majority of the patients. This showed that CD8+ T cells were not expelled or excluded from the tumour micro-environments, therefore the PC tissues were of the T-inflamed phenotype. When comparing tissue with PBMC, the levels of Treg are two times higher in tissues (both benign and malignant) than in peripheral blood. This could be a phenomenon across all tissue types and not exclusive to the prostate. Their role presumably is to maintain peripheral tolerance. We also found that the percentage of activated CD8+ T cells was ~20 times higher in tissues than in blood, regardless of the tissue type. Again, it is possible that this is not exclusive to the prostate. Profiling the immune infiltrates of other tissue types will help to clarify this. Using PCR, we have assessed the cytokine profiles in benign and malignant prostate tissues, and there were no significant differences in the levels of IFNγ, TNFα, TGFβ and IL-10 expressions. Our assays did not detect IL-4, IL-5 and IL-13 in any sample. To assess the impact of ADT on T cells, we evaluated the T cell characteristics in peripheral blood of 15 patients before ADT, at 3 months and then at 9-12 months after ADT. There was a significant reduction in the percentage of Treg by 15% after 3 months of ADT. This suggested there was an initial reduction in immune suppression during the first year of ADT. There was a significant decreased in the proportion of naïve T after 9-12 months of ADT. This suggested naïve T cells might have developed into other more mature T cell subsets after ADT.
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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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ItemThromboembolism and neoadjuvant chemoradiation for rectal cancer( 2015)Thromboembolism (TE) is one of the leading causes of morbidity and mortality in cancer, is an independent predictor of reduced survival, and the overall rate of TE in cancer patients is increasing. Assessing the TE risk of an individual patient at a given time point and the benefit of thromboprophylaxis (TP) can be complex, involving widely variable TE rates according to tumour related factors (such as cancer subtype and disease stage), as well as patient and treatment related factors. Some, such as surgery and hospitalisation are well recognised and appropriately targeted with mechanical and pharmacological thromboprophylaxis (TP) strategies backed by Level I evidence. There is evidence that TP after hospital discharge following surgery (extended TP) is also beneficial. Recently, subgroups such as those with metastases receiving palliative chemotherapy have been shown to be at equally high risk, and also benefit from primary TP. Both chemotherapy and central venous access devices (CVAD) have been shown to be independently associated with development of TE. In addition, early studies examining neoadjuvant radiotherapy (nRT) in rectal cancer reported higher rates of TE however this finding was not repeated in subsequent studies using modern radiotherapy techniques. Extrapolating these findings raises the question of TE risk and the potential benefit of TP during neoadjuvant radiotherapy (nRT) or chemoradiotherapy (nCRT) for rectal cancer. This thesis explores the current evidence and contemporary guidelines concerning TE risk during nCRT, demonstrating considerable uncertainty and a lack of robust data. Randomised trials examining nCRT in rectal cancer are systematically reviewed to determine rates of TE, demonstrating a failure to capture TE events due to inadequate complication reporting frameworks. Existing attitudes and prescribing practices of specialist rectal cancer surgeons are surveyed, as well as barriers to TP prescribing. Issues of equipoise, ownership and logistical problems with outpatient TP prescribing were identified. The historical TE rate and epidemiology over a prolonged follow-up period in rectal cancer patients, as well as the relationship to nCRT is examined at both Peter MacCallum Cancer Centre in Australia and the Cleveland Clinic in the United States. These studies demonstrated that most TE events occurred in patients with metastatic disease receiving ambulatory palliative chemotherapy, and that the overall rate of TE in patients treated with nCRT was not elevated over those patients who had surgery alone. Finally, a prospective study of thrombogenic biomarkers in patients with rectal cancer was undertaken demonstrating significant coagulation abnormalities in colorectal cancer patients at baseline, but no major alteration during neoadjuvant chemoradiation. Marked and prolonged procoagluant abnormalities were demonstrated in the post-operative phase. Thus the current literature, attitudes of treating clinicians, historical rates, as well as candidate biomarkers for prospective TE risk were examined in nCRT for rectal cancer for the first time, identifying future potential research questions aimed at reducing this common complication of cancer care.
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ItemIntravenous lignocaine followed by a 24-hour postoperative subcutaneous infusion shortens length of hospital stay after open radical retropubic prostatectomy: a blinded, randomised, placebo-controlled multicentre trial( 2014)Introduction: An alternative method of administering lignocaine for its beneficial anti-inflammatory and analgesic effects to improve and accelerate postoperative recovery is to administer the local anaesthetic solution by a continuous intravenous infusion. However, in patients undergoing major abdominal surgery, intravenous lignocaine combined with a 24-hour continuous subcutaneous infusion has not been systematically examined for efficacy and safety. A subcutaneous infusion of lignocaine may be an effective strategy to continue systemic lignocaine into the early postoperative period. Subcutaneous delivery may be more advantageous than an intravenous infusion, being technically easier to deliver, safer and cost-effective. Drug tolerance may also be less likely to develop. A significant advantage of subcutaneous infusions over intravenous drug delivery methods is that plasma levels are more stable, and symptom control may be achieved without the toxic effects of peaks and troughs resulting from episodic drug administration or a prolonged continuous intravenous infusion. However, it is unknown whether this intervention will impact clinically on important postoperative outcomes, such as length of hospital stay and accelerated postoperative rehabilitation. Before a combination of intravenous lignocaine and subcutaneous lignocaine is adopted as a feasible and efficacious technique for patients undergoing major abdominal surgery, it needs to be investigated in a randomised controlled clinical trial to measure its benefits and harm, and to better define its role in therapy. Study aims: The aims of this study are to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing length of hospital stays, improving analgesia, and reducing opioid consumption compared to placebo. This study will also quantify the safety of this technique in a perioperative setting. The study was designed to test the hypothesis that perioperative systemic lignocaine infusion in this combination enhances recovery and shortens length of hospital stay after an open radical retropubic prostatectomy. Methods: The Austin and Box Hill Human Research Ethics Committees approved this study. This was a blinded, randomised, placebo-controlled, multicentre trial at two university teaching hospitals. Patients undergoing open radical retropubic prostatectomy were randomised to receive intravenous lignocaine (bolus injection 1.5 mg/kg), then an intravenous infusion (1.5 mg/kg/hr) during surgery, followed by iv subcutaneous infusion for 24 hours (1.5 mg/kg/hr) (Lignocaine group), or a Placebo group who received an equal volume of normal saline delivered at the same infusion rates and over the same time period. General anaesthesia, including the use intraoperative opioids, was standardized, and no patient received regional analgesia or anaesthesia, surgical wound catheters, or infiltration of the surgical wound with local anaesthetic solutions. All patients received morphine patient-controlled analgesia postoperatively in a standardized dosing regime. The primary aim of this study is to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing the length of hospital stay compared to placebo. Important secondary outcomes included comparing intraoperative haemodynamics (heart rate, blood pressure), Bispectral index (BIS), and end-tidal sevoflurane concentrations required to maintain 1 MAC of anaesthesia. In addition, postoperative pain using a Visual Analogue Scale at the incision site measured at rest and with coughing, morphine and rescue analgesia consumption, need for rescue anti-emetic therapy, and patient satisfaction were also evaluated. Opioid-related and lignocaine-related side effects were critically examined including the measurement of plasma lignocaine levels performed in the immediate postoperative period and at 24 hours prior to the discontinuation of the lignocaine subcutaneous infusion. Results: The Lignocaine group had 37 patients and the control group had 38 patients. Patient demographics were similar between groups. The mean duration for surgery was 155.7 minutes (SD: 34.2) for the Lignocaine group and 141.6 minutes (SD: 44.6) for the Placebo group (estimated difference: 14.1 minutes, 95% CI: -4.27 to 32.47, p = 0.13). In the Lignocaine group, the mean highest heart rate recorded was 97.5 beats/minute vs. 103.8 beats/minute in the Placebo group (estimated difference: 6.3 beats/minute; 95% CI: 2.4 to 10.3 beats/minute, p = 0.001). Intraoperatively, the Lignocaine group had lower heart rates [52.1 beats/minute vs. 59.0 beats/minute; estimated difference: 6.8 beats/minute; 95% CI: 3.3 to 10.3 beats/minute, p = 0.001]. The mean BIS is the Lignocaine group was lower than that in the Placebo group (43.4% vs. 49.8%; estimated difference 6.3%, 95% CI: 3.0% to 9.7%, p = 0.001). Despite the BIS being lower in the Lignocaine group, the average concentration of sevoflurane required to maintain 1 MAC of anaesthesia was lower in the Lignocaine group [1.49% vs. 1.89%; estimated difference 0.39%, 95% CI: 0.26% to 0.5%, p = 0.001]. The Lignocaine group had a shorter length of hospital stay [3.3 days (SD: 0.8) vs. 4.7 days (SD: 3.2), estimated difference 1.3 days; 95% CI: 0.2 to 2.4, p = 0.02]. The Lignocaine group required less morphine during the first 24 hours [mean 38 mg (SD: 24) vs. 52 mg (SD: 27); estimated difference 14 mg; 95% CI 2 to 26 mg, p = 0.02]. The mean Visual Analogue Scores for pain at rest one hour postoperatively were 3.73 units for the Placebo group and 1.93 units for the Lignocaine group. On average, the Placebo group scored 1.80 units higher than the Lignocaine group at this time point (95% CI: 0.73 to 2.88, p = 0.001). There was no difference in rest pain at 24 hours. There were also no significant differences in pain on movement over the 24-hour period. Among secondary endpoints, the time taken to tolerate free fluids and a light ward diet were shorter in the Lignocaine group. Time to mobilize was also shorter in the Lignocaine group. Other secondary endpoints were similar. In the Lignocaine group, the mean plasma lignocaine level after surgery was 1.36 mcg/mL (SD: 0.48), range 0.5 mcg/mL to 2.19 mcg/mL; and at 24 hours postoperatively was 3.1 mcg/mL (SD: 0.95); range 1.1 mcg/mL to 4.96 mcg/mL. Lignocaine levels in the Placebo group were always less than 0.5 mcg/mL. No patient experienced complications associated with lignocaine infusion. Conclusions: Intravenous lignocaine followed by a 24-hour subcutaneous infusion resulted in a shorter length of hospital stay and accelerated acute rehabilitation after open radical retropubic prostatectomy. Furthermore, subcutaneous infusion of lignocaine was an effective strategy to continue systemic lignocaine into the early postoperative period. To date, this is the first randomised clinical trial evaluating the use of subcutaneous lignocaine in this setting, and therefore adds to the growing body of literature supporting the use of lignocaine via this route for open abdominal surgery.
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ItemPrognostic factors in urological malignancies( 2014)BACKGROUND: The management of urologic cancers relies heavily on the implicit or explicit application of prognostic models. This may range from the appropriate selection of diagnostic tests based upon the pre-test probability of a positive finding, to an informed decision on choice of treatment modality or enrolment in suitable clinical trials. While some prognostic factors such as stage and grade are time-tested, others such as molecular and immunohistochemical markers or surgical approach are new and evolving. Furthermore, the literature abounds with nomograms, models, risk tables or groups which utilize varying combinations of predictor variables to prognosticate on myriad outcomes of interest. The aim of this body of work was to enhance our understanding of prognostication in urologic malignancies, particularly prostate cancer, renal cancer and urothelial cancer of the bladder, in various clinical settings. METHODS: Details of methodology vary – specifics are outlined in the relevant chapters. In general terms, an appropriate study population was defined based upon the hypothesis. Variables of interest were extracted from suitable database and / or clinical records, or assessed in the laboratory. Associations between predictors and outcomes were analysed using univariate and (where suitable) multivariate regression techniques. PRINCIPAL RESULTS: • PSA kinetics provide important prognostic information in various clinical settings, including prior to surgical treatment and after hormonal therapy • A persistently detectable PSA following radical prostatectomy is associated with a greater risk of progression and death, but with a long natural history • Younger patients with prostate cancer have less aggressive features, but a proportionately greater risk of progression and death despite curative surgical treatment • Obese patients with prostate cancer have more adverse pathologic features, but similar oncological outcomes compared to those of normal weight • A positive family history is associated with an increased risk of developing prostate cancer, but similar oncologic outcomes following surgical treatment • Gleason scoring has evolved over time, with consequent changes in the prognostic implications thereof • So-called “insignificant” prostate cancer has similar oncological outcomes to low-risk cancers overall, following surgical treatment • Patient suitability for brachytherapy as a single modality can be judged based on the clinically assessed risk of lymph node or seminal vesicle involvement • Clinical factors can predict the risk of nodal metastasis, thus allowing the rational selection of patients for pelvic lymphadenectomy at the time of radical prostatectomy • RALRP is associated with a lower rate of +SM compared to ORP, even after adjusting for known clinical and pathological risk factors • Renal cancers in solitary kidneys associated with vena caval extension may be treated by nephron-sparing surgery where technically suitable, although a high risk of disease progression and death remains • The pre-operative erythrocyte sedimentation rate provides independent prognostic information in patients with renal cancer • Renal lesions with low nephrometry score as measured using the R.E.N.A.L. have a greater likelihood of having benign or indolent histology • Histologic coagulative tumour necrosis within renal cancers is associated with poorer oncological outcomes after surgical treatment • Expression of the oncogene c-kit is rare within high-grade or sarcomatoid renal cancers • Muscle invasive urothelial cancers of the bladder are often infiltrated by profuse numbers of lymphocytes with a variety of phenotypes, although they appear not to impact on the risk of progression or death after surgical treatment • Peri-operative chemotherapy has been increasing in its use over recent years, and appears to reduce the risk of recurrence after surgical treatment of urothelial cancer of the bladder CONCLUSIONS: Many of the findings summarized above have had important implications for practice. For instance: • PSA kinetics are now in widespread use at various stages of prostate cancer management • Gleason scores from patients treated some time ago are often re-interpreted according to revised criteria
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ItemProfiling tumour infiltrating lymphocytes in prostate cancer( 2013)The purpose of this study was to understand the T cell processes that take place in prostate pathology. The subset of T cells and their functional and activational status was determined using flow cytometry and immunohistochemistry. Furthermore the use of androgen deprivation therapy (ADT) on the impact on T cells was also determined. The three main conditions of prostate pathology investigated were benign prostatic hyperplasia (BPH), chronic abacterial prostatitis (CAP) and prostate cancer (PCa). Patients with BPH were used as the control group. The results in CAP showed a trend of an active immune process, where there was an influx of CD4+ T lymphocytes cells (9.45%, p 0.1407) in prostate tissue and a reduction in T regulatory (Treg) cells (2.32%, p 0.0675) in the tissue and the blood (3.13%, p 0.0042). In PCa tissue there was an influx of both CD4+ T lymphocytes (9.63%, p 0.0296) and CD8+ lymphocytes (12.81%, p 0.0063). Correspondingly a trend was seen with an increase in Treg cells in prostate tissue (2.12%, p 0.2480). This resulted in the ratios between CD4:CD8, CD4:Treg and CD8:Treg in PCa to be similar to BPH indicating a net homeostasis in immune action. The use of Treg cells as a prognostic indicator was compared to current pathological markers, where a higher number of Treg cells was seen in patients with extraprostatic spread (3.52%, p 0.0371), seminal vesicle extension (10.74%, p 0.0249), PSA relapse (4.39%, p 0.0162) and higher Gleason score (3.89%, p 0.0376). Despite showing a homeostatic picture in PCa, the functional status of CD8+ T lymphocytes was assessed. There were lower proportions of naïve T cells (9.86%, p 0.0068) and central memory T cells (8.60%, p 0.0258) in PCa tissue. While there was an increase in terminal effector T cells (12.06%, p 0.0019) and effector memory T cells (8.63%, p 0.0253). This implied that the tumour cells had been recognized and a shift in the dynamics towards a local cytotoxic environment. These cytotoxic T lymphocytes were activated as demonstrated by increased expression of CD69 (13.35%, p 0.0083). Despite showing activation, the effectiveness of these cells in the implementation of an anti-tumour response was assessed by evaluating the distribution of cytokines IFNγ, TGFβ and IL-10. However no clear pattern was seen, but it will require further investigation with a larger sample population. The use of ADT has been shown to reverse thymic involution and restore peripheral T cell population. However from this study there was no difference seen in the subset numbers, functional and activational status of T lymphocytes. From this study, the profile of prostatic pathology is better understood. The T cell profile especially in the in the local tumour environment of PCa shows a dynamic process between cytotoxic and immunosuppressive cells. This will allow for the development of further studies to understand the immune interaction with PCa.
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ItemClinical application of evidence-based surgery: the role of audits in surgical practice( 2008)Evidence-Based Medicine (EBM) is the integration of clinical practice with research evidence. The development aims to respond to the limitations of traditional expert recommendations as a guide to clinical practice. It has become a paradigm shift in the way clinicians learn and practice medicine [1-3]. Audit has been recognized as a form of EBM. Although the basic form has been practiced by some great surgeons since last century, often surgical practice has been based on ‘the tradition‘. The universal acceptance and practice of audits in surgery is only recent [4-6]. The aim of the project was to conduct audits for current surgical practice, and observe whether the evidence influence its practice. To achieve the aim, the thesis consisted of six studies, which were designed to investigate three aspects of surgical practice, including quality care assurance, cost-effectiveness of healthcare resources in surgical practice, and validation of a new surgical technique.
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ItemThe role of a Medical Emergency Team in a teaching hospital( 2009)Modern hospitals treat patients with increasing co-morbidity and complexity. Multiple studies have shown that up to 17% of patient admissions are complicated by a serious adverse event. Such events are often not related to the patients underlying medical condition and may result in morbidity, permanent disability, and in up to 10% of cases, death. Serious adverse events are often foretold by the development of new complaints that manifest in derangements of commonly measured vital signs. The Medical Emergency Team is a team of intensive care doctors and nurses with skills in reviewing and treating patients who have become acutely unwell on the hospital wards. The team is summoned when a patient fulfil one ore more predefined criteria for activation. The chapters in this thesis present original research related to the role of the Medical Emergency Team in identifying, reviewing and treating acutely unwell ward patients, primarily at the Austin Hospital in Melbourne, Australia. The literature relating to the incidence and antecedents to serious adverse events is reviewed. The rationale behind the Medical Emergency Team and the history of its evolution in Australia and The Austin Hospital is then discussed. In the subsequent chapters, the effect of introduction of the Medical Emergency Team on the outcome of a number of patient cohorts is review including 1). the long term mortality following major surgery; 2) the incidence of cardiac arrests in patients admitted for more than 24 hours; and 3) the inhospital mortality of medical and surgical patients admitted for more than 24 hours. In addition, a survey of nurse’s attitudes to the Medical Emergency Team and potential barriers to its activation is presented. The change in Medical Emergency Team utilization with time at the Austin and Alfred Hospitals is described. Finally, the causes for Medical Emergency Team activation are examined, as is the role of the team in end of life care planning.