Surgery (Austin & Northern Health) - Theses

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    Harnessing cell-free epigenetic and mitochondria-derived DNA signatures to enhance precision in liver transplantation care
    Cox, Daniel Robert Anthony ( 2023-07)
    Background: Liver transplantation (LT) is a life-saving procedure for people with end-stage liver disease. Ensuring successful, durable health outcomes for LT recipients requires long-term surveillance and monitoring of graft function. The existing, non-invasive techniques used in clinical practice to diagnose complications post-LT are imprecise and lack disease specificity. Ultimately, an invasive graft biopsy is often required to diagnose or exclude complications. The analysis of graft-derived cell-free DNA (gdcfDNA) in plasma has shown promise as an alternative, non-invasive approach for monitoring graft health following solid-organ transplantation. gdcfDNA detection has previously relied on identifying mismatched genotypes in organ donor and recipient DNA. The analysis platforms and laboratory workflows required to perform this genotyping and quantify gdcfDNA are, at present, complex and laborious. This has delayed translation of this technology into clinical practice. Objectives: Hypothesis: gdcfDNA analysis using epigenetic and non-genotyping based techniques is feasible, and might offer a more practical laboratory approach to help facilitate the incorporation of gdcfDNA monitoring into routine LT care. This thesis aimed to develop an assay that harnessed graft-specific epigenetic motifs to detect gdcfDNA in plasma, and then to evaluate its diagnostic accuracy and clinical utility in a study involving LT recipients. A further objective was to explore a role for gdcfDNA analysis to enhance precision in LT care, outside of the milieu of diagnosing or excluding graft immune rejection. Main findings: A novel gdcfDNA quantification assay, based on the detection of liver-specific DNA methylation patterns in plasma cell-free DNA (cfDNA), was developed and validated in a pilot clinical cohort study (Chapter 2). A new laboratory workflow, involving the introduction of a synthetic DNA standard to plasma samples, was implemented to improve pre-analytical quality control prior to gdcfDNA analysis (Chapter 3). In a prospective, cross-sectional clinical study (Chapter 4), plasma gdcfDNA measurement using liver-specific DNA methylation signatures, significantly outperformed conventional liver function tests in the non-invasive prediction of biopsy-proven acute graft rejection following LT. At a cut off of <33% of the total plasma cfDNA fraction, liver methylation-specific gdcfDNA had a 97% specificity for predicting biopsy proven acute rejection requiring treatment (tBPAR); correctly excluding tBPAR in 30/31 LT patients. gdcfDNA monitoring, through the quantification of mitochondria-derived cfDNA, was also demonstrated to act as a potentially useful molecular tool to inform management in other contexts within LT care (Chapters 4 and 5). The analysis of mitochondria-derived cfDNA from plasma and bile during ex-vivo normothermic machine perfusion, prior to LT, was shown to be feasible with a high degree of technical precision. Trends in gdcfDNA levels in this context varied significantly between grafts that were viable for LT and those that were not transplanted (Chapter 5). Conclusions: The detection of liver-specific methylation patterns in cfDNA is shown to represent a non-invasive, precise, rapid-turnover and cost-effective approach for quantifying gdcfDNA in patients following LT. The technique has major practical advantages over previous gdcfDNA quantification methods, particularly as it does not require prior genotyping or sequencing, lending it greater feasibility for translation into LT care. gdcfDNA monitoring has the potential to act as a “second-tier” non-invasive test to stratify the risk of developing tBPAR in LT patients, prior to undertaking an invasive biopsy. This potential clinical niche warrants further study in multi-centre, interventional trials. gdcfDNA monitoring may have a useful role for monitoring graft health in LT, outside of contexts outside of the diagnosis of acute rejection. gdcfDNA monitoring during ex-vivo machine perfusion prior to LT is feasible with a high degree of technical precision, and should be studied further to establish whether monitoring may aid in the evaluation of graft suitability for successful LT.
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    Metabolic and Morphological Tissue Assessment and Evaluation using multimodal Spectroscopy and Computation
    Sharma, Varun ( 2023-05)
    Over the last century, there has been a shift in the leading causes of mortality, with reduced rates of infectious and neonatal conditions being replaced by non-communicable diseases. Fundamental to these diseases is the process of fibrosis, the extent of which determines the nature of disease diagnosis, treatment and prognosis. The diagnosis of fibrosis is challenging as the gold standard is tissue biopsies, which are marred by the need for a tissue biopsy, resource-intensive processing, and being time-consuming. Vibrational spectroscopy (VS) is an emerging clinical technology that overcomes these shortcomings using non-ionizing Near-Infrared (NIRS), Mid-Infrared (MIR) or Raman (RS) spectroscopy to generate chemical signatures based on tissue absorption or scattering patterns. This thesis explores multimodal spectroscopy to evaluate bone, liver, and cardiac tissues, focusing on fibrosis. In analysing bone, we demonstrated the following key findings. It demonstrates that NIRS can non-destructively quantify in-depth micro-architectural properties of fresh human bone, including bone volume fraction, thickness, and porosity, with less than 3 seconds scan times. The chemical signatures acquired from the surface of bone can quantify, with small margins of error, both superficial properties, such as cortical thickness, and penetrate deep into the bone to accurately quantify bone volume fraction. Detailed assessment of the NIRS spectra can provide insight into the specific biochemical composition of bone. Lastly, we showed that NIR instrumentation has evolved to an extent where point-of-care use is possible through a hand-held miniaturised spectrophotometer system. In liver tissue, this thesis used a custom-made fibre optic NIRS probe to analyse non-diseased liver tissue from explanted livers and compare them to findings of conventional histopathology, with the following key results. The chemical signatures for advanced cirrhosis and healthy liver can be differentiated at a crude visual level. When spectral data is combined with machine learning algorithms, it has an accuracy of 96% in identifying cirrhosis and greater than 93% in grading or classifying the degree of fibrosis. This technique accurately predicts both immature and mature fibrosis (R2 > 0.80) to within 10% (Root Mean Square Error, RMSE <10%). In cardiac tissue, this thesis adopted a “multi-modal” approach, combining both handheld NIRS and Raman Spectroscopy (RS) instruments to generate “multimodal spectroscopic signatures” (MSS) for analysis of human cardiac tissue. The thesis demonstrates that the key differences in MSS of Ischaemic Heart Disease (IHD), Dilated Cardiomyopathy (DCM) and healthy patients are in regions associated with myocardial fibrosis and collagen deposition. In principal component analysis, a handful of key differences (principal components, PC) in the MSS explain the majority of the variance. Broken into individual components, NIRS explains 99.2% of the variance in 4 PCs; in RS, 81.6% with 10 PCs; and 99.0% with 26 PCs in the final combined MSS scans (NIR + Raman). When data were entered into a machine learning (ML) model, MSS has excellent accuracy, with a precision of 94.4%, recall of 93.1%, specificity of 96.9% and AUC of 1.00. When implemented as a diagnostic instrument, MSS demonstrates a classification accuracy of 100% in identifying abnormal patients.
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    Low tidal volume ventilation and postoperative outcomes after major surgery
    Karalapillai, Sudharshan Christie ( 2022)
    Millions of surgeries are undertaken every year worldwide. Mechanical ventilation is an essential component of many of these.Despite the essential nature of its use the ideal approach to mechanical ventilation is currently not known. Data from the critical care literature primarily in patients with acute respiratory distress syndrome suggest that low tidal volume ventilation is associated with significant improvement in outcomes.Whether this confers benefit in operative patients is unknown. This thesis sought to identify how Australian anaesthetists set the ventilator and administer oxygen during surgery. The impact of intra-operative low tidal volume ventilation, 6mL per kilogram versus conventional tidal volume strategy, 10mL per kilogram on a variety of postoperative outcomes was also studied. We found that in 2014 Australian anaesthetists set a conventional tidal volume of 10mL per kilogram lean body mass and administered high inspired fractions of oxygen during surgery.In a randomised controlled trial we found that low tidal volume ventilation did not reduce postoperative pulmonary or non pulmonary complications relative to a conventional ventilation strategy. This thesis suggests that a physiologic tidal volume of 6mL per kilogram is appropriate during major surgery given the absence of benefit of a supra-physiologic tidal volume.
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    Role of Nephrectomy in Metastatic Renal Cancer
    Silagy, Andrew William ( 2022)
    Nephrectomy is one of multiple treatment modalities available for managing renal cancer. As more effective systemic therapies emerge, the optimal approach to treat renal cancer needs re-evaluation. While surgery is the gold standard for curative management of localised renal cell carcinoma, the role in metastatic disease is more complex. In 2001, two seminal clinical trials from the United States and Europe established the role for cytoreductive nephrectomy in the cytokine era. Then, in 2018, the CARMENA trial reported non-inferiority for upfront sunitinib compared with nephrectomy followed by sunitinib. At the time of the trial’s publication, immune checkpoint blockade rather than sunitinib was the standard of care for metastatic renal cell carcinoma, further obfuscating the role for surgery. In this thesis, I aimed to analyse how a cytoreductive nephrectomy alters the natural history of metastatic renal cell carcinoma. First, I reviewed the literature relating to the natural history of renal cell carcinoma and the information gaps about the role of the cytoreductive nephrectomy in the evolving multimodal setting. I addressed this question by focusing on five components that were not evaluated in the aforementioned prospective trial: 1. Do cytoreductive nephrectomy outcomes vary depending on the metastatic picture? 2. Do cytoreductive nephrectomy outcomes vary depending on the histology? 3. Why are some patients not selected for a cytoreductive nephrectomy? 4. What role do anaesthesia and kidney disease have on nephrectomy outcomes? 5. What are the biologic effects of a cytoreductive nephrectomy? Studies of renal cell carcinoma often quantify disease burden by the size of the primary tumour and the location of metastases. My research team identified that the primary tumour size was independently prognostic in cytoreductive nephrectomy. However, a more nuanced approach was needed to assess the overall burden and distribution of disease. Therefore, in collaboration with the radiology department we used semi-automated segmentation analysis to measure the 3-dimensional burden of both the primary tumour and metastases in patients undergoing cytoreductive nephrectomy. We determined that primary tumour volume resected was prognostic whereas the proportion resected and the residual volume of disease were of equivocal significance. Due to the heterogeneity of renal cell carcinomas, patients with non-clear cell histology were not assessed in the cytoreductive clinical trials. Therefore, we compiled the largest single-institution series of non-clear cell cytoreductive nephrectomies. In conjunction with genitourinary pathologists, a comprehensive review of histological subtypes enabled us to identify clinicopathological characteristics with prognostic implications: tumours with papillary features were associated with favourable outcomes and tumours displaying sarcomatoid dedifferentiation were associated with adverse outcomes. We further evaluated sarcomatoid features by exploring outcomes across treatment eras, noting that while survival continues to improve, the combination of non-clear cell histology and sarcomatoid dedifferentiation represents a very aggressive phenotype with distinct metastatic patterns and very poor survival outcomes. A recurrent limitation of these retrospective studies was that I was looking at populations selected for surgery. To address this selection bias, I used a ground-based theory to develop a framework of oncological and patient-fitness factors outlining why some patients were not selected for surgery. The specific reason for not operating on a patient carried prognostic implications and is potentially generalisable to other cancers. In altering the disease course of renal cancer, a nephrectomy may also alter renal function. Indeed, one factor for reduced case selection was poor renal function. Therefore, we evaluated the impact of a nephrectomy for patients with chronic kidney disease. Patients with grade 3A chronic kidney disease were able to maintain their renal function postoperatively. Conversely, patients with grade 3B or worse chronic kidney disease slowly declined after surgery, although all groups had very low rates of dialysis. While many studies explored how newer surgical approaches can improve perioperative and oncological outcomes, few had looked at the role of anaesthetic techniques. Onco-anaesthesia is a nascent field and no clinical paper to date had researched the role of intraoperative opioids on outcomes following renal cell carcinoma surgery. We identified that increased intraoperative opioids were associated with adverse oncological outcomes. This finding highlights the importance of assessing both surgical and anaesthetic techniques in future clinical trials. The natural history of metastatic renal cell carcinoma ranges from indolent to rapidly progressive disease. To determine whether a cytoreductive nephrectomy alters this trajectory, we assessed validated biomarkers prior to and following surgery. We identified significant changes in these biomarkers with corresponding changes in survival outcomes. The novel finding of this study was to demonstrate variable responses to cytoreductive nephrectomy at the biomarker level. By characterising these distinct phenotypes, we provide a basis for a prospective trial aiming to refine case selection. This thesis covers cytoreductive nephrectomy in an historical context, provides granularity about tumour burden, explores rarer tumour phenotypes, evaluates case selection, analyses perioperative factors, and characterises the biological effects of surgery. Further work can continue to be undertaken to refine surgical selection and the integration of cytoreductive nephrectomy with emerging systemic therapies.
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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.
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    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.
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    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.
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    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.
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    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.
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    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.