Surgery (Austin & Northern Health) - Theses
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ItemThe Haemodynamic Effects of Mannitolcontaining Intravenous Paracetamol: A Pilot Program( 2019)The haemodynamic effects of intravenous paracetamol: overview of clinical significance In households worldwide, paracetamol is an over-the-counter drug synonymous with its safety and efficacy for its antipyretic (fever relieving) and analgesic (pain relieving) properties. It is readily available to the public in both enteral (oral) and rectal formulations. In the hospital setting, with 100% bioavailability and ease of administration, the intravenous (IV) formulation of paracetamol is an attractive option for patients undergoing major surgery and the critically ill, where oral and rectal administration may be challenging. Studies have found IV paracetamol is often used in multimodal postoperative pain management and has been shown to improve pain, opioid consumption and overall patient satisfaction in the postoperative setting for both major and minor surgeries. As such, IV paracetamol is one of the most commonly ordered medications for surgery and critical care patients. However, there is a paucity of evidence-based research surrounding its safety profile in these patient subgroups. Emerging clinical data suggests it may have the propensity to produce hypotension in surgical patients and the critically ill. Intraoperative hypotensive events have been associated with morbidity and longer hospital stays. Additionally, maintenance of haemodynamic stability is a requirement for a patient to be discharged from intensive care. Despite the concern of such a significant, and potentially underreported side effect, the current corpus of science relating to the haemodynamic effects of IV paracetamol is limited. It is also worth noting an underappreciated excipient of IV paracetamol is mannitol. Mannitol is added to the IV paracetamol formulation as a stabilizing compound but is present in quantities close to 4% in the majority of IV paracetamol formulations available. Recent advances in invasive and non-invasive haemodynamic monitoring have allowed for the accurate measurement of variables that determine blood pressure, namely cardiac output and systemic vascular resistance. For this thesis, state-of-the-art haemodynamic monitoring will be used to quantify the haemodynamic impact of IV paracetamol by measuring the fundamental components of blood pressure. In order to understand the effects of IV paracetamol on blood pressure and the potential for mannitol to play a role in any haemodynamic alterations, this thesis will aim to investigate the haemodynamic effects of IV paracetamol by means of a comprehensive paracetamol program. This program will be specifically tailored to examine these effects in patient subgroups of varying baseline haemodynamic stability. This comprehensive paracetamol haemodynamic program involves the following: Stage 1 – Literature review: Comprehensive literature review to identify, evaluate and critically analyse the current knowledge base of the haemodynamic effects of IV paracetamol. Stage 2 – STUDY 1 Healthy volunteer study: To assess the haemodynamic effects of IV paracetamol in a healthy, normotensive population. Stage 2 – STUDY 2 Cardiac surgery patients (preoperative) study: To assess the haemodynamic effects of IV paracetamol in patients with pre-existing cardiac disease. Stage 2 – STUDY 3 Cardiac surgery patients (postoperative) study: To assess the haemodynamic effects of IV paracetamol in patients who have undergone major surgery and who are at greater risk of haemodynamic instability. Stage 2 – STUDY 4 Chronic liver disease patients study: To assess the haemodynamic effects of IV paracetamol in patients with pre-existing derangements of their systemic vascular system (similar to shock). It is hoped that this thesis will synthesize high quality results to add to the growing body of evidence that IV paracetamol may cause hypotension. Analyzing the haemodynamic effects in such different patient populations, may offer insight as to which individuals may be at greater risk of developing hypotension after the administration of IV paracetamol.
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ItemPopulation-based studies In urologic cancer( 2019)Introduction Long-term data on cancer outcomes are frequently based on large series from single- or multi-institutional databases, and whilst study numbers may be large, the study population and outcomes are often not truly reflective of community practice. Furthermore, very few of these studies, especially in urologic oncology, include patients diagnosed and treated in Australia. Using a population-based cancer registry, we sought to evaluate long-term survival outcomes in men with prostate cancer treated with surgery in Victoria, and identify the clinicopathologic and sociodemographic factors that influenced survival. Furthermore, we sought to evaluate the practice patterns of management of renal cell carcinoma (RCC) in Victoria, and identify potential differences in management between metropolitan and regional areas. Methods All eligible cases were identified from the Victorian Cancer Registry (VCR). There is a statutory requirement that all diagnoses of invasive cancer, excluding non-melanoma skin cancer, be reported to the VCR. The Victorian Radical Prostatectomy Register (VRPR) is a whole of population series of men who underwent radical prostatectomy for the treatment of prostate cancer between 1995 and 2000 in Victoria. Eligible cases were identified from the VCR and relevant clinicopathologic data was obtained via medical record review. Follow-up PSA and death data were obtained via record-linkage to pathology laboratories and the Victorian Registry of Births, Deaths and Marriages. All cases of RCC diagnosed in Victoria between 1 January 2009 and 31 December 2009 and registered with the VCR were identified. Trained data managers extracted relevant data by retrospective review of medical records and pathology reports. Data extracted included: mode of presentation, diagnostic and staging investigations, clinical and pathological disease stage, socioeconomic data, first line treatment, enrolment in clinical trials, and provision of multidisciplinary care. Case residency was categorised as metropolitan or regional/rural based on the Department of Human Services Integrated Cancer Services regions. Results Between 1995-2000, 2154 men underwent radical prostatectomy in Victoria. During a median follow-up of 10.2 years, 74 men died from prostate cancer. In addition to Gleason score and pathological stage, symptomatic presentation was associated with increased prostate cancer-specific mortality (PCSM). After adjusting for stage and PSA, no difference in PCSM was found between men with Gleason = 6 and Gleason 3+4 = 7 (p=0.649). Men with Gleason 4+3 had significantly greater cumulative incidence of PCSM compared to men with Gleason 3+4 (SHR = 2.79, 95% CI 1.40 – 5.54, p = 0.003). 695 men experienced biochemical recurrence during follow-up, of which 82% occurred within 5 years of radical prostatectomy. Men with combined high Gleason sum (>4+3) and extra-prostatic (>pT3a) disease had substantially increased mortality rate with early biochemical recurrence (BCR), while those experiencing BCR after a longer interval had significantly lower mortality. Men with combined low Gleason sum (<3+4) and organ-confined disease (
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ItemCharacteristics, management and outcomes of acute liver failure in australasian intensive care units( 2019)Introduction Acute liver failure (ALF) is a form of rapidly progressive liver injury. It induces encephalopathy, cerebral oedema, deranged haemostasis, haemodynamic compromise, renal failure, and metabolic abnormalities. Emergency liver transplantation (ELT) is sometimes necessary for survival. Unfortunately, little is known about ALF in Australia and New Zealand (ANZ). Aims To develop a comprehensive description of ALF in ANZ. Methods Data for ALF patients were obtained from the ANZ Intensive Care Society Centre for Outcomes and Resource Evaluation Adult Patient Database and the ANZ Liver Transplant Registry. The Australasian Management of Acute Liver Failure Investigator group was formed and contributed data from all six liver transplant ICUs in ANZ. Analyses of these data were used to develop a broad and representative understanding of ALF across ANZ. The approach to key management challenges was evaluated and outcomes were described. Results ALF is rare but increasing in incidence across ANZ. Illness severity and mortality are higher than the general ICU population and most cases due to paracetamol overdose. Deranged measures of haemostasis are universal, with hypofibrinogenaemia and thrombocytopaenia more strongly associated with bleeding risk than the international normalised ratio. Blood products are often administered but without clear correlation with bleeding complications. Continuous renal replacement therapy is provided in most cases, and often in the absence of classical renal failure indications but with effective correction of hyperammonemia. Hypertonic saline is often administered to induce hypernatraemia, fever is uncommon, and ventilatory strategies achieve a low normal PaCO2 in most patients. Despite low ELT utilisation compared to other regions, outcomes are similar. Conclusions These studies form the most comprehensive evaluation of ALF across ANZ to date. They identify key aetiologies, patterns of illness, current management, utility of prognostic criteria and clinical outcomes. These findings can be used to inform the evolution of practice in this field.
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ItemProtection of the kidney against Ischaemia-Reperfusion injury using zinc( 2019)Acute kidney injury (AKI) continues to be a major cause of morbidity and mortality worldwide. Septic shock, hypovolaemia, and renal ischaemia related to major surgeries are the primary contributors to AKI in hospitalised patients. AKI is associated with a four-fold increase in mortality in hospitalised patients, and a two-fold increase in the likelihood of discharge to a short- or long-term care facility. As a result, the estimated healthcare costs associated with AKI in hospitalised patients in the US alone exceeds US$10billion per year. Studies have also demonstrated that AKI resulting from ischaemia-reperfusion (IR) is a causative determinant in the development, and progression, of chronic kidney disease (CKD). Despite major medical advances to the current day, short of supportive measures there is still no definitive therapeutic option available to prevent AKI in these settings. Preconditioning (PC) against renal IR injury has been heralded as a promising solution to abrogate this major healthcare problem, and an extensive volume of research has amassed in this area. Preconditioning is a phenomenon whereby an innate tissue adaptation occurs in response to a sublethal stimulus, which leads to protection of an organ or tissue against a subsequent insult. PC was first discovered in the context of ischaemic PC (IPC), where brief sublethal periods of ischaemia led to protection against a subsequent more sustained period of ischaemia in the canine heart. Since the discovery of the IPC phenomenon in 1986, tissue protection against ischaemia by means of IPC has been demonstrated by a number of methods in a variety of tissues, including the heart, brain, liver, kidney, and striated smooth muscle. The promise of these findings has also prompted research into the use of alternative methods of tissue PC, and studies have since investigated the use of pharmaceutical agents to promote these tissue adaptations by pharmacological preconditioning (PPC). The race for a pharmaceutical agent capable of eliciting protective adaptations against tissue ischaemia has involved many classes of pharmaceutical compounds, endogenous proteins, and trace elements. Zinc (Zn) is a metal that is essential to many biological functions, including cell growth and survival. The omnipresence of Zn in cellular interactions, and its importance in so many biological processes has led to the investigation of augmenting Zn homeostasis as a means of protection against tissue ischaemia. This is the primary topic of this thesis. The promise of enabling organ protection against IR injury has major clinical implications, spanning many areas of medicine. However, despite the extensive volume of clinical and basic science research in this area, there is still currently no effective method of PC that will protect the human kidney against IR injury. The aims of this thesis are to investigate if parenteral Zn can be used as a therapeutic strategy to protect the kidney against IR injury. The body of research on the topic of tissue PC has highlighted some potential targets for PC agents, however to date a definitive mechanism has not been elucidated, and therefore a further aim of this thesis is to investigate the potential mechanisms through which Zn effects renal tubular and glomerular epithelial cell survival in the setting of renal IR.
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ItemThe oncological outcomes of dose escalated radiotherapy and its impact on biochemical control and toxicity in men with prostate cancers( 2019)Introduction: Radiation therapy (RT) for prostate cancer (PC) has steadily evolved over many years, with improvement in biochemical relapse free survival (bRFS). An association between overall survival and doses greater than or equal to 75.6 Gray in men with intermediate and high-risk PC has been reported in population-based studies. Contemporary RT techniques such as image guided radiotherapy, intensity modulated radiotherapy, and stereotactic body radiotherapy, has facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially and can be delivered in combination with external beam radiation therapy (EBRT). However, dose escalation can come with increased gastrointestinal (GI) toxicity and new devices such as rectum spacers have been developed to spare this critical normal structure. Methods: Our large prospective brachytherapy database, that I created, which included patients treated with low dose rate (LDR) and high dose rate (HDR) brachytherapy was interrogated to determine the long-term oncological outcomes. In addition, I was one of the first radiation oncologists in Australia to use a novel polyethylene glycol hydrogel rectal spacer and its iodinated counterpart. We were able to implement its use as a fiducial marker in the post-prostatectomy setting and its use as a tissue expander in the intact prostate for EBRT with or without high dose rate brachytherapy as well as in the post-prostatectomy setting. Results: I found that the use of LDR and HDR brachytherapy with or without EBRT to be safe and efficacious. The bRFS for LDR brachytherapy alone for low to intermediate risk PC was excellent as was its use in combination with EBRT for men with predominantly unfavorable intermediate risk PC. In addition, the use of HDR brachytherapy in combination with EBRT for men with intermediate and high-risk PC also yielded excellent bRFS comparable to any other series reported in the literature. I successfully introduced the use of hydrogel spacers into our practice with marked reduction in rectal volumes irradiated to high radiation doses which allowed appropriate dose escalation of EBRT with or without HDR brachytherapy. This has translated to a marked reduction in late GI toxicity. In addition, we also successfully used hydrogel spacers in the post-prostatectomy setting both as a spacer to allow for ultra-high dose radiation therapy and as a fiducial marker with hydrogel spacer in its iodinated form. Conclusion: Although the use of brachytherapy has declined in the last few years, our results confirm its outstanding efficacy in PC and as such we will continue to advocate for its use. We will continue to support a brachytherapy unit for the treatment of PC. In addition, my work on hydrogel spacers has resulted in its use as standard practice in all PC patients who require EBRT.
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ItemDevelopment of a cell-free DNA methodology to assess organ rejection after liver transplantation( 2019)Background: Liver transplantation has revolutionised the prognosis of patients with fulminant liver failure, chronic liver disease, and liver cancer. Although liver transplantation is safe, organ rejection is a common complication after such a procedure. The gold-standard for diagnosing organ rejection after liver transplantation is a tissue biopsy. Liver biopsies are invasive. There is thus an unmet clinical need for accurate blood tests to diagnose the episodes of organ rejection after liver transplantation. Donor-specific cell-free DNA (dscfDNA) is an emerging biomarker of organ rejection. Measuring dscfDNA using current methodologies such as next generation sequencing can be both complex and expensive. Novel tests that overcome these limitations would favour adoption of such methodologies for the quantification of dscfDNA and implementation for the surveillance of organ rejection after transplantation. Objectives: The first objective of this thesis was to develop a cell-free DNA based assay for the accurate quantification of dscfDNA that could overcome some of the limitations of existing methodologies. The second objective of this thesis was to deploy this assay to monitor episodes of organ rejection in a prospective cohort of recipients. Main findings: A probe-free droplet digital PCR-based methodology was developed. The methodology overcame some of the common limitations that were observed in next generation sequencing-based and other PCR-based methodologies. The newly developed approach was accurate, economical, and rapid which facilitated the rapid turnaround of results as well as enabled early clinical decision-making (Chapters 3 and 4). The application of this approach to measure dscfDNA was shown to be feasible for the monitoring of dscfDNA in a prospective cohort of forty recipients after liver transplantation (Chapter 5). The levels of dscfDNA were reflective of organ health. Furthermore, a calculated threshold of 898 copies of dscfDNA per mL of recipient plasma identified majority of the recipients with biopsy-proven acute rejection requiring treatment. The diagnostic performance of dscfDNA, in this cohort, was superior compared to routine liver function tests in identifying organ rejection. Conclusion: This thesis presented the application of a novel cfDNA methodology to measure dscfDNA in a prospective cohort of recipients after liver transplantation. The results demonstrated the promising utility of dscfDNA as a marker of organ rejection after liver transplantation. These pertinent findings warrant further validation with a view towards clinical implementation.
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ItemTargeting p21-activated kinases in the treatment of pancreatic cancer( 2019)Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies worldwide, with a very poor prognosis and a 5-year survival rate less than 9%. This dismal outcome is largely due to lack of early diagnosis, quick disease progression, high rate of post-surgery recurrence and resistance to conventional therapies. Oncogenic Kras mutation is a well-defined hallmark of pancreatic cancer. It is presented in over 95% cases and leads to constitutively active form of Kras protein. Kras still remains as an undruggable target due to absence of a well-defined drug-binding domain. With the aim to fight against Ras-driven cancers, high priority has been given to the novel therapeutic strategies targeting Ras-dependent signalling. P21-activated kinases (PAKs) are a family of serine/threonine kinases that are important down-stream effectors of multiple small GTPases including Ras, Rac1 and Cdc42. Based on the difference in the structure and sequence, all the six members of PAK family are divided into two groups: group I (PAK1-3) and group II (PAK4-6). PAK1 and PAK4 are the most widely studied members and have been reported to be up-regulated in PDA. PAK1 is situated at the convergence of multiple signalling pathways that are associated with cell proliferation, survival/apoptosis, migration/invasion and cytoskeletal regulation. Immunotherapy is now emerging as a promising treatment in the era of personalised anti-cancer therapeutics. However, it can only bring limited clinical benefits for PDA patients, which is largely attributed to the immunosuppressive tumour microenvironment (TME). The role of PAK1 has not been fully elucidated in pancreatic cancer, especially its involvement in re-programming TME. The work presented in this thesis investigated the role of PAK1 in tumour biology and therapeutic regimens, with a focus on its linkage to stroma modulation and anti-tumour immune response. Firstly, the anti-tumour effect of a potent PAK inhibitor (PF-3758309) was determined on a panel of clinical patient-derived PDA cell lines (TKCC 2.1, TKCC15, TKCC18, TKCC22, TKCC23, TKCC26). PF-3758309 treatment inhibited cell proliferation and sensitized PDA cells to different chemotherapies (fluorouracil, gemcitabine and nab-paclitaxel) with a synergistic effect, which was associated with reduction in PAK1 and PAK4 activity and down-regulation of HIF-1α, α-SMA and palladin in vitro. Combination of PF-3758309 and gemcitabine maximally suppressed tumour growth in vivo and had a comparable or even greater therapeutic efficacy compared to combination of gemcitabine and nab-paclitaxel. As mentioned above, the expression of α-SMA was observed in PDA cells. All-trans retinoid acid (ATRA), a well-known compound that induced quiescence of pancreatic stellate cell (PSC) by decreasing the expression of α-SMA, was utilized to investigate its anti-tumour effect and association with PAK protein and α-SMA in PDA cells. Inhibitory effect of ATRA on PDA cell growth and migration and its synergism with gemcitabine was observed in both wildtype and gemcitabine-resistant PDA cell lines. Expression of PAK1, PAK2, PAK4 and α-SMA was down-regulated by ATRA. Inhibition of PAK1 by shRNA knockdown or PF-3758309 sensitized PDA cells to ATRA. This was the first study to demonstrate the role of PAK proteins in ATRA treatment. The role of PAK1 in tumour immune response was evaluated using an orthotopic mouse model of pancreatic cancer. Inhibition of PAK1 by PF-3758309 or genetic knockout up-regulated intra-tumoural infiltration of CD3+ lymphocytes and splenic CD3+ or CD8+ lymphocytes. Combination of PF-3758309 and gemcitabine synergistically inhibited PDA cell growth in vitro and in vivo. This study not only confirmed the anti-tumour effect of PF-3758309 and its synergism with gemcitabine, but also revealed the potential role of PAK1 in anti-tumour immunity. Finally, the underlying mechanisms of PAK1 in regulating anti-tumour immunity was investigated. Immunohistochemistry was performed on human tissue microarray and KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice samples. PAK1 was identified to be a negative prognostic marker and positively correlated with α-SMA expression. Depletion of PAK1 decreased PSC activity, reduced PSC-stimulated PDA cell proliferation and migration and increased intra-tumoural infiltration of CD4+ or CD8+ lymphocytes. Inhibition of PAK1 decreased both intrinsic and PSC-stimulated PD-L1 expression in PDA cells, which could enhance lymphocyte-induced PDA cell death. This was the first study to demonstrate the important role of PAK1 in regulating PSC activity and PD-L1 expression in PDA. In a summary, these studies revealed the importance of PAK signalling in PDA development, the therapeutic value of PAK inhibitors and its synergism with gemcitabine in PDA treatment. Most importantly, PAK1 is emerging as a potential target to enhance anti-tumour immunity and to facilitate the development of novel immunotherapies.
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ItemThe effects of cannabinoid derivatives on pancreatic cancer( 2019)Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant solid tumours and its treatment has not been efficiently improved during the last decade. The overall 5-year survival rate of pancreatic cancer is 9%, which is expected to become the second major cause of cancer-related mortality by 2030. Chemotherapy has been used as the main treatment of choice in the majority of patients bearing either locally advanced or metastatic tumours. Gemcitabine alone or gemcitabine-based combination chemotherapy is commonly used worldwide for the treatment of pancreatic cancer. The poor treatment response to chemotherapy might be related to a dense stroma that is associated with these cancers. However, more effective treatment techniques and novel targets are urgently needed to improve the treatment response. Plant-derived cannabinoids have been used for medical purposes for over a thousand years. The main active cannabinoid components are tetrahydrocannabinol (THC) and cannabidiol (CBD) that are obtained from Cannabis sativa and Cannabis indica. THC exerts its effects via a receptor dependent mechanism, while CBD can act through a receptor and receptor independent mechanisms. CBD can modulate the adverse effects of THC such as its psychoactive effects. To date, three cannabinoids receptors have been identified, CB1, CB2, and GPR55, which are located on the cell membrane and members of the G-protein coupled receptor (GPCR) family. Cannabinoid receptors play an important role in biological and pathological activities such as inflammation, oxidative stress, metabolism, fibrosis, appetite control, memory and emotion. The main aims of this study were to look at the expression of cannabinoid receptors in pancreatic cancer cell lines and pancreatic cancer specimens, detect the correlation of cannabinoid receptors expression with patient’s outcome, determine the effect of cannabinoids alone or in combination with chemotherapy on pancreatic cancer cells in vivo and in vitro. Methods: Western blot assay, SRB-assay, immunohistochemistry staining, wound healing assay and an animal model were the main methods used in this study. Results: The expression of CB1 and CB2 receptors were shown in all the human and murine pancreatic cancer cell lines, stellate cells, and the gemcitabine resistant cell lines. The significant correlation between high expression of GPR55 and worsened PDAC patients’ outcome were demonstrated. In addition, the positive surgical margin and moderate to dense stromal status are associated with a poorer and prolonged survival in patients, respectively. Both CBD and THC dose-dependently inhibited cell proliferation of pancreatic cancer cells, although CBD was more effective than THC. All the different combination ratios of CBD to THC showed significant effects on the inhibition of cancer cell proliferation compared with a single treatment of drugs, although a 1:1 ratio of THC to CBD demonstrated the maximal inhibitory effect on cell proliferation and migration. Synergistic inhibition was observed for combined THC and CBD treatments, and when THC/CBD was combined. with gemcitabine (combination index < 1; using the Chou-Talalay method). In this study, cannabis oil, which contained a 1:1 ratio of CBD to THC and other cannabinoid components has been used for in vitro and in vivo experiments. The effects of this oil on pancreatic cancer cell proliferation and migration was less than either the pure CBD or THC alone. Moreover, cannabis oil alone or in combination with gemcitabine did not significantly inhibit tumour growth in a xenograft model. Bioavailability and absorption patterns of this oil are unknown and further studies are required. Conclusion: Cannabinoid receptors are highly expressed in pancreatic cancer cell lines. The high intensity of GPR55 was correlated with poor patients’ outcome. The 1:1 ratio of THC to CBD provided a significant inhibitory effect on pancreatic cancer proliferation and migration. Combination of cannabinoids with gemcitabine had a synergistic effect on pancreatic cancer inhibition in in vitro study. The cannabis oil used in our in vitro study showed a lesser effect on blocking proliferation and migration of cancer cells than purified THC and CBD. We could not determine the clinically significant effect on pancreatic cancer in our in vivo study using cannabis oil. No absorption characteristics of studied cannabis oil have been reported, therefore more in vivo bioavailability studies are required for the future work.