Surgery (Austin & Northern Health) - Theses

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Reno-protective effects of zinc against nephrotoxic injury and safety of high-dose zinc in critically ill patients

Perera, Marlon Lakmal ( 2021)

In current clinical practice, acute kidney injury (AKI) remains a significant source of morbidity and mortality. Among the commonest cause of AKI is contrast-induced nephropathy (CIN). Iodinated contrast-media may be to augment computerised tomography, allowing improved image quality, tissue differentiation and facilitates interpretation. Additionally, high volumes of contrast media are used during endovascular interventions, such as vascular and cardiac interventions. The use of contrast media appears to be growing annually with a growth rate of the industry of 6.7% between 2006 and 2013, and an estimated revenue of US$998 million. Data relating to Australian contrast-associated computerized tomography and contrast-requiring endovascular intentions have not been reported. Using epidemiological measures, we demonstrate an increasing use of contrast-media associated imaging and interventions. Changes in imaging are largely driven by increased uptake in advanced vascular imaging techniques such as digital subtraction angiography and CT coronary angiography. The increasing use of contrast media at compounding levels highlight the need to continue to develop strategies to protect patients from the sequele of contrast media administration. While the pathogenesis of CIN is complex, it has been well-studied in recent literature. Contrast media (CM) causes renal injury through both direct cellular injury (cytotoxicity) and regional vascular changes (renal hypoxia). Both of these injury mechanisms are mediated by reactive oxygen species (ROS). Zinc may be able to provide protection against CM induced cytotoxicity due to its indirect antioxidant properties and subsequent effect on ROS. Further, our group has demonstrated that zinc has protective effects against renal ischaemia and hypoxia. Thus, zinc may provide reno-protection against both pathways of renal injury following contrast administration. We aimed to determine the protective role of zinc preconditioning against contrast-induced renal injury in-vitro and in-vivo. Results from our cellular model demonstrated that zinc preconditioning reduces oxidative stress following exposure to radiographic contrast media which in turn results in increased survival of renal cells. Translation of this in vitro was not possible in the current thesis due to difficulties producing a reliable model of CIN in rats. Providing exogenous zinc to produce a sustained increase in serum zinc levels has remained a challenge. Oral zinc preparations are limited by enteral bioavailability. Previous works have demonstrated that prolonged oral preparations do not reliably increase serum zinc when compared to placebo. Further, these preparations are poorly tolerated due to gastrointestinal adverse effects and alterations of other trace elements such as copper. Accordingly, there is a need to investigate other mode of zinc administration that are better tolerated and result in a reproducible increase in serum zinc – in order to provide potential beneficial effects. In late December 2019, an outbreak of a new corona virus SARS-CoV-2 (COVID19) caused an unprecedented global pandemic of respiratory illness, leading to the death of millions of people globally. This virus had significant impact flow of the current thesis. Interestingly, zinc has been inextricably implicated in the progression of corona viruses and has been proposed as a treatment option to mitigate the pulmonary implications of this disease. Given the previous research from our department, we performed a randomized controlled trial – a combined Phase I/IIa in patients with COVID19. Our co-primary outcome measure for this trial was the safety and tolerability of high-dose intravenous zinc. The results of our trial demonstrated safety of this preparation and dosing scheme in the domains of local, hepatic, renal, cardiac, gastrointestinal and haematologic tolerability. Additionally, we reported a comprehensive assessment of the impact of intravenous zinc on electrolyte homeostasis. Despite the importance of essential metals and physiologic ions, their complex interactions with zinc poorly understood. Further research is warranted to clarify these interactions on a cellular level and further determine the effect of longer periods of high dose intravenous zinc (HDIVZn) administration.
Evaluating the Utility of 3D Printing in Endovascular Aneurysm Repair

Coles-Black, Jasamine Misty ( 2021)

3D printed patient-specific phantoms offer a new means of simulating complex procedures in vascular surgery. Despite growing interest, lack of expertise poses a barrier for adoption. I explore the potential scope of implementation of 3D printing in vascular surgery by developing a reproducible, low-cost methodology for producing 3D printed phantoms which successfully recapitulate the procedural challenges encountered during surgery. These phantoms are valuable in visualising complex anatomy, presurgical simulation, appropriate device selection, and templating physician modified stent grafts. Next steps involve larger scale translational studies to validate impacts on patient outcomes and cost savings to the healthcare system.
The Use of Prehabilitation in Colorectal Cancer Surgery

Bolshinsky, Vladimir ( 2021)

Abstract Introduction: Prehabilitation in colorectal cancer surgery is an emerging opportunity in the field of perioperative medicine designed to improve the standard of care. The thesis aim is to identify the current attitudes towards risk stratification and the delivery of prehabilitation programs to colorectal cancer patients. The impact of a “Bundle-of-Care” approach to prehabilitation prior to major GI cancer surgery has not previously been explored. Risk stratification can enable the clinician to differentiate modifiable and non-modifiable risk. Cardiopulmonary exercise testing (CPET) is the gold standard assessment of functional capacity and is therefore the most reproducible risk stratification tool. However, availability of CPET in Australasian Hospitals is limited. Furthermore, the accuracy of traditional CPET parameters is reduced in patients with sarcopenic obesity and chemotoxicity. Conventional CPET focus on VO2 at anaerobic threshold (AT), may be superseded by a holistic approach that analyses multiple physiological and biochemical parameters to not only improve risk prediction, but to optimise reversible patient factors within the prehabilitation window. As part of prehabilitation initiatives, a number of unimodal components have been investigated in isolation. Haematinic prehabilitation to optimize oxygen carrying capacity in circulating blood volume an opportunity for improvement of fitness. Methods: An electronic survey was distributed to all members of the Colorectal Surgical Society of Australia and New Zealand (CSSANZ). A comprehensive review of published trials in preoperative optimisation of GI cancer patients was conducted according to the Preferred Reporting Items or Systematic Review and Meta-Analysis (PRISMA) guidelines. A retrospective cohort of 43 consecutive patients scheduled for major cancer surgery was used to identify if the peakVO2 derived from the patient administered questionnaire, “Duke Activity Severity index (DASI)” would correlate with the CPET peakVO2. A retrospective cohort of 82 consecutive patients was used to investigate novel risk stratification variables. A further retrospective cohort of 65 cancer patients that underwent a ferric carboxymaltose (FCM) infusion prior to surgery were assessed as to the feasibility and potential haematinic optimisation following intervention. Based on the above findings, a protocol was derived for a potential randomized control trial in order to determine if the preoperative functional status (as measured by CPET) of anaemic and/or iron deficient colorectal cancer patients could be improved by preoperative intravenous infusion of FCM. Results: There does not appear to be enough robust data to make specific conclusions based on the systematic review of multimodal prehabilitation in colorectal cancer surgery. There is no harm identified with prehabilitation, however prior to routine integration of multimodal prehabilitation programs into clinical practice, adequately powered trials that utilise CPET, therefore ensuring uniform endpoints would be of benefit. Awareness of objective preoperative risk stratification and prehabilitation amongst CSSANZ members is variable and current utilisation of prehabilitation programs is low. There is growing interest in this area amongst the colorectal community, who regard implementation of prehabilitation programs as technically feasible within the majority of represented institutions. DASI-predicted peakVO2 did overpredict the actual peakVO2 values, with a more significant discrepancy for patients with higher peakVO2. The CPET-derived parameters that were most predictive of reduced overall survival included peakVO2 (corrected to body surface area) and (Ve/VCO2) at anaerobic threshold. Specifically, one in two patients with a preoperative pVO2 <710 ml/kg/m2 and Ve/VCO2 at AT >35 had died within one year of surgery. A preoperative pro-inflammatory state added significant ability to discriminate between survivors and non-survivors. Charlson Co-morbidity Index however, did not discriminate survivors from non-survivors. The overall numbers from the retrospective analysis of FCM infusion did not demonstrate any meaningful conclusions. However, FCM infusion is safe and feasible in this patient population, therefore, the proposed randomized control trial would contribute to the literature on this topic. Conclusion: The “Bundle-of-Care” approach to prehabilitation makes intuitive sense, however robust data is required prior to mass implementation. The survey of CSSANZ members does not demonstrate current use or core knowledge, but there is significant interest. Subjective assessment of functional capacity (such as DASI) is inaccurate and CPET will continue to play an integral role in risk stratification. Specific CPET parameters require further refinement, particularly in sarcopenic patients with significant co-morbidities. Haematinic optimization is safe and would benefit a significant proportion of colorectal cancer patients. A multidisciplinary approach to implementation of prehabilitation programs is key. In order to proceed, it is imperative that early triage of patients to preoperative clinics, identification of reversible comorbid disease, including deconditioning, and implementation of interventions occurs in parallel with the diagnostic work up of the surgical disease.
Tumour growth in the regenerating liver

Riddiough, Georgina Ellen ( 2021)

Post-partial hepatectomy liver regeneration (PHLR) facilitates major hepatic resection by reinstating liver volume and function. However, experimental and clinical data has linked PHLR to tumour progression and recurrence in the future liver remnant following liver resection. This presents a major hurdle for hepatobiliary surgeons seeking curative resections for their patients. This thesis explores the mechanisms underlying tumour recurrence in the regenerating liver and investigates the role of renin-angiotensin inhibitors (RASi) in attenuating the growth of colorectal liver metastasis (CRLM) using murine and human models of CRLM disease. RASi, captopril attenuated CRLM tumour burden in the regenerating liver in vivo and underlying mechanisms for this were identified and included reprogramming of the immune and metabolic responses, as well as tumour specific downregulation of the proto-oncogene c-myc. Captopril also attenuated growth of patient-derived CRLM organoids in vitro. In summary, captopril exerts an effective anti-tumour response in the regenerating liver and should be pursued as a treatment adjunct for patients undergoing liver resection for CRLM.
Exploring Treatments to Inhibit tumour recurrence Following Resection of Colorectal Liver Metastases

Kastrappis, Georgios Loizou ( 2021)

Background: Colorectal cancer (CRC) accounts for 9.2% of all cancer related deaths making it the second most common cause of cancer related death worldwide. The majority of CRC deaths are attributed to metastases, with liver being the most common metastatic site. Currently the best available treatment for colorectal liver metastasis (CRLM) that offers high survival rates and a potential for cure is liver resection surgery. However, only a small fraction of CRLM patients are eligible for surgery. Furthermore, liver resection and the ensuing liver regeneration (LR) upregulate growth factors and cytokines leading to a pro-inflammatory response, creating a favourable environment for any dormant tumours to grow. Thus, liver resected patients experience high tumour recurrence rates. Anti-inflammatory treatments administered perioperatively may reduce tumour recurrence. Previous experimental studies have shown that inhibition of the Renin Angiotensin System (RAS) classical pathway reduces tumour growth and accelerates liver regeneration together with a reduction in inflammation. This study investigates mechanisms by which captopril a RAS inhibitor (RASi) influences the environment of a regenerating liver to reduce inflammation. Additionally, it investigates the potential of a VEGFR-3 specific inhibitor, SAR131675, to inhibit tumour growth and reduce inflammation. Aims: 1) To investigate the effects Captopril, an angiotensin I converting enzyme (ACE) inhibitor, has on pro-inflammatory cytokines during LR. 2) To investigate the effect Captopril has on the global proteome and phosphoproteome of the liver during the early stages of LR 3) To investigate the effect SAR131675, a VEGFR-3 tyrosine kinase inhibitor, has on liver metastases in a CRLM mouse model and determine the likely mechanisms. Methods: Male CBA mice were used for all experiments in this study. For the liver regeneration study a 70% partial hepatectomy mouse model was used. Captopril (750mg/kg) was administered intraperitoneally and given daily starting 4 days before surgery until the endpoint (1 hour, 3 hours, 4 hours, 1 day and 2 days). Serum cytokine (IL-2, IL-6, IL-10, IL-12p70, IL-17A, TNF, IFNgamma and MCP-1) levels were assessed at the 1, 3 and 4 hour timepoints while liver regeneration was assessed at the day 1 and 2 timepoints, by measuring liver to body weight ratio and the liver regeneration rate. In addition, the 4 hour timepoint was used to conduct global proteomic and phosphoproteomic analyses. To investigate the effects SAR131675 had on CRLM and the mechanisms involved a mouse model of CRLM was used where metastases were established via intrasplenic injection of tumour cells. Immunohistochemistry was used for the analysis of proliferation, apoptosis, lymphatic and blood vessel densities, macrophage and T-cell tumour infiltration. Furthermore, FACS analysis was used to investigate changes in immune lymphoid and myeloid cell populations due to SAR131675 treatment. Results: Captopril treatment significantly reduced IL-6 levels in the serum of mice in the early phase of liver regeneration. This result was reinforced by the results of the global proteomic and phospho-proteomic study indicating that Captopril induced changes in a great number of proteins involved in inflammatory pathways in almost every cell process including cell proliferation, apoptosis transcription, translation and stress response. Interestingly, the largest proportion of protein changes were associated with lipid metabolism which is also closely associated with inflammatory pathways. SAR131675 treatment significantly reduced tumour growth in the mouse model of liver metastases. Mechanistically SAR131675 treatment changed the tumour microenvironment and promoted anti-tumour immune responses by modulating the tumour infiltrating immune cell composition; increasing the ratio of T lymphocytes to monocytes and by modifying the T-cell and myeloid cell subtype and activation to that favouring an anti-tumour immune response. Conclusion: Both Captopril and SAR131675 were able to modulate inflammatory pathways creating a microenvironment that is inhibitory towards tumour growth. These treatments have potential to be used in order to reduce tumour recurrence in patients that have undergone liver resection surgery.
Functions of CXC Ligand Family in Pancreatic Tumour Microenvironment

Lee, Nien-Hung ( 2021)

Chemoresistance is the major contributor to the low survival of pancreatic cancer (PC). PC progression is a complex process reliant on interactions between tumour and tumour microenvironment (TME). A family of structurally similar inflammatory chemokines, namely CXC ligands (CXCLs), were recently discovered to play important roles in various cancer types, including PC. This thesis aimed to investigate the role of CXCL5 in chemoresistance of PC. In both human and mice PC cell lines tested, CXCL5 expression was dramatically upregulated. The expressions of CXCL5, CXCL10 and selected CSC genes were various in gemcitabine resistant cell lines, and gemcitabine treated cells. However, in mouse xenografted tumour samples, which was generated from a patient-derived cell line, gemcitabine alone or in combination with other chemotherapeutic reagents led to increased CXCL5 protein level while CXCL10 level remained unchanged. These results suggested that expression of CXCL5 may be stimulated upon administration of gemcitabine or other chemotherapeutic reagents. Therefore, CXCL5 has a role in chemoresistance and clinical importance in PC; however, the mechanisms involved deserves a careful investigation. To determine whether CXCL5 mediates chemoresistance in PC, CXCL5 expression in MiaPaCa-2 cells was knocked down by shRNA. To determine whether CXCL5 mediated chemoresistance in vitro, two chemotherapeutic drugs, were used to treat a negative control (NC) and CXCL5 knockdown (KD) clones. In the cell proliferation assays, CXCL5 was found to mediate the resistance to gemcitabine and 5-fluouracil (5- FU). Mice carrying xenografted tumours inoculated by either NC or CXCL5 KD cells II were treated with gemcitabine. CXCL5 KD suppressed tumour growth and enhanced the inhibitory effect of gemcitabine by decreasing proliferation and promoting apoptosis These results indicated that knockdown of CXCL5 sensitized PC cell response to gemcitabine and 5-FU, suggesting that CXCL5 mediates chemoresistance in PC. Finally, the global proteomic analysis showed CXCL5 knockdown resulted in significant changes in expression of several proteins. Each of these proteins had a distinct biological function in cancer as determined with KEGG pathway analysis and NCBI. From the phosphor-proteomic analysis, CXCL5 knockdown induced significant changes of certain phosphorylated proteins. Cross-referencing with the database of NCBI clearly identified the biological functions of these proteins. Although experimental and clinical validation are necessary, CXCL5 serves as a pivotal molecular target in overcoming chemoresistance and eliminating PC tumours in clinical practices. In summary, these studies have revealed that CXCL5 plays an important role in chemoresistance and activates several intracellular pathways that contribute to resistance to therapeutic treatments and PC progression. Therefore, CXCL5 could serve as a potential molecular target in reversing chemoresistance in pancreatic cancer.
Improving Outcomes in Patients Undergoing Major Hepatobiliary-Pancreatic Surgery

Weinberg, Laurence ( 2021)

Background An estimated 300 million surgical procedures are performed each year globally. Postoperative complications are projected to occur in a small percentage of these patients and are associated with increased morbidity and mortality and high health care costs. It is desirable to identify potentially modifiable factors associated with an increased risk of major abdominal surgery complications. The careful use of intravenous fluid and vasoactive medications during surgery are essential modifiable risk factors for reducing the incidence of perioperative complications. The overarching research questions for this thesis are: 1. What are the associations between intraoperative fluid intervention and postoperative outcomes? 2. Does using an intraoperative surgery-specific, patient-specific advanced haemodynamic monitoring algorithm improve postoperative outcomes? 3. What are the costs of complications following major hepatobiliary-pancreatic surgery, and are they associated with the severity of complications? 4. What are the health costs of complications after other major abdominal surgery types, such as colorectal resections, and are they related to the severity of complications? Thirteen clinical studies and six systematic reviews were performed to answer these questions comprehensively: 1. Two retrospective study evaluating fluid amount, type and balance associations, and outcomes in patients undergoing major surgery. 2. Two retrospective observational cohort studies evaluating the effect of a surgery-specific cardiac output-guided haemodynamic algorithm on outcomes in patients undergoing liver resection and pancreaticoduodenectomy. 3. Two prospective randomised clinical trials assess whether a surgery-specific goal-directed therapy protocol improves outcomes in patients undergoing major liver resection and pancreaticoduodenectomy. 4. Two observational cohort studies evaluating the costs of complications in patients undergoing liver and pancreatic surgery. 5. Two systematic reviews assess addressing the costs of complications in patients undergoing hepatobiliary-pancreatic surgery and one integrative review of perioperative fluid management in patients undergoing major hepatic resection. 6. Two studies examine the associations of intrathecal morphine and outcomes after major hepatobiliary surgery. 7. Six other studies (two systematic reviews and 4 retrospective cohort studies) evaluating the costs of complications in patients undergoing major abdominal surgery. Results 1. There is a significant independent association between liberal fluid volumes and developing complications in patients undergoing major surgery. 2. Using a perioperative haemodynamic optimisation plan that prioritises preserving cardiac output and organ perfusion pressure by carefully using fluid therapy, vasoactive drugs and the timely application of inotropic drugs improve postoperative outcomes in patients undergoing pancreaticoduodenectomy. Larger studies are needed to confirm this finding. 3. In patients undergoing major liver resection in high-volume hepatobiliary surgical units, adding a fluid restrictive intraoperative cardiac output-guided algorithm with a standard Enhanced Recovery After Surgery (ERAS) protocol did not significantly reduce the hospital stay length or fluid-related complications. These findings are hypothesis-generating, and a larger confirmatory study is justified. 4. Major abdominal surgery carries a high incidence of complications, resulting in a substantial financial burden. 5. Hospital costs and length of stays increase with greater severity and number of complications. 6. Patients with the lowest haemoglobin concentrations incurred the highest hospital costs, strongly associated with increased blood transfusions. 7. In patients undergoing open liver resection and intrathecal morphine, in addition to conventional multimodal analgesic strategies, reduced postoperative opioid requirements and improved analgesia for twenty-four hours after surgery. This occurred without any statistically significant differences in opioid-related complications and length of hospital stay. Conclusion Findings of this thesis imply that the careful use of fluid and vasoactive medications is a core component of improving adverse outcomes after surgery. Clinicians should employ advanced haemodynamic monitoring to help rationalise the effective use of fluid and vasoactive medications. Further, these findings provide an in-depth analysis of the rate of complications that occur after major surgery. Moreover, these findings imply that complications following major surgery are common and associated with increased costs. The impact of complications on cost has a dose-response relationship to both the amount and severity of complications. This thesis highlights the importance of evaluating and preventing complications in the postoperative period. Finally, these findings allow health institutions to review their practices in addressing complications and their associated cost and encourages further studies to expand on potential identification and mitigation strategies to address complications and costs in the future.
Reprogramming tumour immune microenvironment of colorectal liver metastases with renin-angiotensin inhibitors

Vallejo Ardila, Dora Lucia ( 2021)

Background Renin-angiotensin system inhibitors (RASi) have shown anti-tumour effects that may significantly impact the response to current cancer immunotherapies and the prognosis in patients with colorectal liver metastases (CLM). RAS components are expressed by various immune cells and adult hematopoietic cells. The mechanisms by which RASi reprogram the tumour immune microenvironment toward an immunostimulatory milieu involves modulating the function of immune T lymphocytes, myeloid cells and cancer-associated fibroblasts. Experimental Design Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi captopril 750mg/kg or saline was administered to the mice daily via intraperitoneal injection, from day one post-tumour induction to the endpoint, day 15 or 21 post tumour induction. At the endpoint, tumour growth was determined, and lymphocyte and myeloid-derived infiltration and composition in the tumour and liver tissues were analyzed by flow cytometry and immunohistochemistry. At endpoint day 15, livers and tumour tissues were collected, and tissue lysates were prepared and analyzed using liquid chromatography-tandem mass spectrometry proteomic techniques to determine relative changes in protein abundance. The proteomics results were analyzed using open-source software such as MaxQuant and Perseus. A 7-plex OPAL protocol was used to assess the composition and spatial distribution of T cell markers CD3, CD8, FoxP3 and CD103 and the epithelial to mesenchymal transition markers alpha- Smooth muscle actin and E-cadherin. The protocol was manually optimized and validated in two independent cohorts of formalin-fixed, paraffin-embedded CLM patient tissues using well-established antibodies, a single spectral library, negative controls, and biological controls corroborating the staining pattern of immune infiltrates. Results Captopril significantly decreased tumour viability and impaired metastatic growth, increased the infiltration of CD3 T cells into both tissues, and the primary contributing phenotype to this influx is a CD4 and CD8 double-negative T cell subtype, while CD4 T cells decreased and CD8 T cells remained unchanged. Furthermore, clustering and functional enrichment showed that captopril modulates the expression of some of the immunoproteasome subunits, including PSMB8, PSMB10, PSMB5 and PSME1. Also, T lymphocyte phenotypes’ spatial distribution was seen in significantly higher levels in the invasive tumour margin compared to their density within the liver parenchyma or the tumour centre in human CLM. Thus, high CD3 density in the tumour core or high CD8 density in the invasive tumour margin predicts a significantly better overall survival. Moreover, high CD3 T cell density at the adjacent liver parenchyma and a high CD8 density at the tumour core segment influenced patient survival after CLM resection in patients who received RASi antihypertensive medication. In the case of myeloid cells, a significant decline in myeloid cells expressing CD31pos was induced by captopril, while the relative proportion of CD31neg cells was preserved when comparing between the liver and the tumour. RASi significantly reduces a CD31pos monocyte-derived subset F480neg Ly6C intermediate and High, which may have a pro-angiogenic and immunosuppressive function. Conclusion The work of this thesis highlights the mechanism by which RAS inhibitors decreased tumour viability and impaired metastatic growth by effectively restoring the immunogenicity of CLM toward an immunostimulatory milieu.

Surgery (Austin & Northern Health) - Theses

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