Surgery (Austin & Northern Health) - Theses
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ItemCommunication, technology and instruments in the modern contemporary setting of urology( 2018)The 2017 Sensis Social Media Report demonstrated an increase in Australians being involved in Social Media Platform. About 84% of Australians access the Internet on a daily basis with higher usage among the age group under 30 year old and less common among people age group of 40 and over. Delivering accurate medical information to patients or caregivers is essential in any medical practice. Having free access healthcare information with the unknown potential of having inaccurate medical information or unmoderated website for quality control while online consumers with health information-seeking behaviour could lead to false health information. Technological innovation has aided the growth in the healthcare industry. The wide expansion of modes of communication and surgical equipments, especially in urology has definitely changed the practice in the past few decades. It is one of the surgical specialty that has increasingly become a technology-driven specialty. With new innovative surgical instruments aiming to improve the outcomes for patients and the ease of accessibility of communication technology in medical practice has certainly improved in various ways within the healthcare setting. Technology has been part of medical and surgical practice and this continue to change the way medicine would be practice in the future. With regards to surgical instruments, the advancement of endoscopic procedures have shown to be a huge advantage in the surgical practice. Although it does not involve all types of surgery but it has been a turning point in some surgical cases. For example, open surgery was the conventional method of treating benign prostatic hyperplasia (BPH) but new treatments have been developed over the years without going through major surgery. BPH is a common condition for men as they get older which causes prostate enlargement which leads lower urinary tract symptoms (LUTS). The BPH prevalence examined in several autopsy studies showed that 20% for men stated to develop in their 40s, reaching between 50% to 60% for men in their 60s, and from 80% to 90% for men in their 70s and 80s. BPH If left untreated, this will eventually lead to blockage of the urinary tract, causing problems to bladder, urinary tract or kidney. The current "gold standard" of treating BPH surgically is transurethral resection of the prostate (TURP) using endoscopic method to remove prostate tissue. Although this method is an effective treatment clearing obstructive prostate tissue, the main side effects include bleeding. Laser surgical therapy for BPH was introduced for more than 20 years. To this date, there are various types of laser therapy that are readily available for surgical treatment of BPH with the unique properties of each laser to allow accurate treatment of BPH. The GOLIATH study demonstrated the GreenLightTM laser was noninferior to TURP in terms of the outcomes and had better results in length of catheterisation and length of hospital stay. The impact of technology in any surgical setting with the aim to improve outcomes in treating any disease while minimizing the risk of complication, or improving has changed significantly. With the rapid evolution of this of technology in the surgical field, however,needs thorough research to ensure high standards of care is delivered when utilizing latest surgical instruments. Essentially, the background outlined here not only highlights the core aim of this thesis: to observe the trend and understand the impact of technology in the current surgical practice. Given that this is will be a broad perspective, this thesis will be focusing on two parts, that is, one related to modes of communication using online technology and how it benefits the users and observing the risks involved. The other part of the thesis will be related to advancement of surgical instruments in urological surgery and the outcomes from the new equipments.
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ItemThe role of zinc in prostate cancer( 2018)Prostate cancer (PCa) is the most common cancer amongst Australian men. Zinc is an essential metal and is vital for normal function of the prostate gland. Castrate-resistant prostate cancer (CRPC) is becoming increasingly resistant and treatment options are limited in number and often associated with poor clinical outcomes. Therefore a pertinent clinical issue is to develop more effective treatment regimes. Zinc appears to play a role in PCa, but a true understanding leading to therapeutic developments is yet to be achieved. In particular evidence regarding cell proliferation and zinc uptake and levels in PCa cells is conflicting. HIF1α is a well-known prognostic marker in PCa associated with poor prognosis, resistance to treatment and development of metastatic disease, however the cause over-expression in CRPC remains a mystery. Therefore the ability of PCa cells to uptake and store zinc, and the role of zinc in PCa cell proliferation, tumour growth and HIF1α mediated survival was investigated in this thesis. CRPC-like human PC3 cells are significantly resistant to docetaxel chemotherapy and overexpress HIF1α protein, compared to normal prostate epithelial control cells (PNT1A). Cell proliferation assays (MTT) demonstrated that physiological zinc administered to PC3 cells significantly slowed growth compared to normal PNT1A and androgen-sensitive PCa (LNCaP) cells. The effect of zinc supplementation or zinc chelation (by TPEN) does not affect macroscopic growth in PC3 xenograft tumours. There is no significant difference in baseline total zinc concentration (measured by ICP-MS) between cell lines normal (PNT1A), androgen sensitive (LNCaP) and CRPC (DU145 and PC3) cells. However, CRPC-like PC3 cells contain significantly higher unbound free Zn2+ and Immunofluorescence Microscopy (IFM) subcellular distribution of Zn2+ in PC3 cells is unlike that seen in normal prostate epithelial cells. PC3 cells are resistant to oxidative stress injury. Zinc strongly induces HIF1α protein expression in these cells in a time and dose dependent manner. Zinc mediated oxidative protection in PC3 cells is a HIF1α dependent as demonstrated in a PC3 HIF1α-KD model. No such zinc protection was seen PNT1A cells. Zinc could be essential in the resistant nature of CRPC cells as Zn2+ ions rescue HIF1α protein expression and are implicated in the normoxic stabilisation of the HIF1α protein by competing with Fe2+ ions at the PHD binding sites. Therefore zinc dysregulation in CRPC cells is an important factor in the development of resistance, as well as potentially progression to metastatic disease and poor prognosis in PCa.
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ItemCharacterisation of tumour-infiltrating lymphocytes in benign and malignant prostate tissues( 2018)Over the past decade, we have seen a significant advancement in the treatment of metastatic castrate-resistant prostate cancer (PC). Cancer immunotherapy is now a reality, but the information on tumour infiltrating lymphocytes (TILs) in human prostate tissues is still limited. This project aims to evaluate and compare T cell characteristics in blood and tissues from patients with benign and malignant prostate conditions using flow-cytometry. Patients with benign prostatic hyperplasia (BPH) and normal prostate (NP) were used as controls and compared with patients with PC. We also examined the effects of androgen deprivation therapy (ADT) on systemic immune responses and immune regulation in patients with advanced/metastatic PC. The T cell characteristics evaluated were: (1) The proportion of regulatory T cell (Treg) and CD8/Treg ratio; (2) The percentage of activated cytotoxic lymphocytes (CTLs); and (3) The T cell maturation status. We found that the proportion of Treg in PC tissue was 5.6%, consistent with other studies. We did not find any differences in the proportion of Treg or CD8/Treg ratio in tissues for the three patient groups. When evaluating PC involved vs PC non-involved tissues, as an internal control comparison, PC involved tissues were found to have a higher percentage of Treg (6.89% vs 4.15%, p-value of 0.045) and a lower CD8+/Treg ratio (54 vs 119, p-value of 0.0032) than PC non-involved tissues. Despite a small number of 6 cases, the differences were statistically significant. These findings support the hypothesis of local immunosuppression in PC-involved tissues, and that such immunosuppression might be compartmentalised even to the level of specific lobes of the prostate. In this compartmentalised environment, PC cells can evade and survive the immune system’s defences. This study did not find any correlation between Gleason scores and the percentage of Treg in the CD4+ T cell subset or the CD8/Treg ratio either in PBMC or PC tissue. In the PC group, the same percentages of CD8+ T cells were found in both tissues and peripheral blood for majority of the patients. This showed that CD8+ T cells were not expelled or excluded from the tumour micro-environments, therefore the PC tissues were of the T-inflamed phenotype. When comparing tissue with PBMC, the levels of Treg are two times higher in tissues (both benign and malignant) than in peripheral blood. This could be a phenomenon across all tissue types and not exclusive to the prostate. Their role presumably is to maintain peripheral tolerance. We also found that the percentage of activated CD8+ T cells was ~20 times higher in tissues than in blood, regardless of the tissue type. Again, it is possible that this is not exclusive to the prostate. Profiling the immune infiltrates of other tissue types will help to clarify this. Using PCR, we have assessed the cytokine profiles in benign and malignant prostate tissues, and there were no significant differences in the levels of IFNγ, TNFα, TGFβ and IL-10 expressions. Our assays did not detect IL-4, IL-5 and IL-13 in any sample. To assess the impact of ADT on T cells, we evaluated the T cell characteristics in peripheral blood of 15 patients before ADT, at 3 months and then at 9-12 months after ADT. There was a significant reduction in the percentage of Treg by 15% after 3 months of ADT. This suggested there was an initial reduction in immune suppression during the first year of ADT. There was a significant decreased in the proportion of naïve T after 9-12 months of ADT. This suggested naïve T cells might have developed into other more mature T cell subsets after ADT.
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Item18F-fluorodeoxyglucose positron emission tomography as a biomarker for colorectal cancer liver metastases( 2017)Background: Colorectal cancer is the second most common cause of cancer-related death in Australia. The majority of patients with colorectal cancer develop liver metastases but only those amenable for surgical resection have a possibility of long term survival. Recent advances in achieving macroscopic resectability of colorectal liver metastases needs to be balanced urgently, by an ability to assess systemic micrometastatic disease. Tumour staging by 18F-fluorodeoxyglucose positron emission tomography (PET) is a non-invasive tool already in routine use. Aim: To explore metabolic characteristics assessed by PET as biomarkers for colorectal cancer liver metastases. Methods / Results: Four studies were performed, each addressing separate aspects regarding the utility of tumour metabolic assessment. The first three studies were performed on retrospective cohorts while the fourth study was a prospective study. The studies and main novel findings are summarized below: 1) The Prognostic Impact of Tumour Metabolism an a Single PET Scan after Preoperative Chemotherapy Various parameters that characterize and quantify tumour metabolism were assessed for their prognostic ability. These parameters were compared to clinical and pathological features as well as previously verified prognostic scoring systems. The metabolic parameters corresponding to metabolic tumour burden were found to be most prognostic on a single PET scan following preoperative chemotherapy. 2) The Prognostic Impact of Tumour Metabolic Response to Preoperative Chemotherapy The prognostic ability of metabolic response to preoperative chemotherapy was assessed using the serial assessment of various metabolic parameters. In comparison, tumour size shrinkage on computed tomography and pathological response, the current gold standards of chemotherapy response evaluation, were assessed. Metabolic response to preoperative chemotherapy was shown to be the best prognostic indicator. 3) Metabolic Response Correlated to Biological Mechanisms The biological mechanisms underlying the prognostic impact of metabolic response was explored. Immunohistochemical analysis of six tumour biomarkers showed an inverse correlation between metabolic response and the expression of Ki-67, a marker of cellular proliferation; and a direct correlation between metabolic response and the expression of p16, a tumour suppressor. 4) Early Metabolic Response Assessment The use of early tumour metabolic response after only the first cycle of preoperative chemotherapy was assessed for the ability to predict eventual metabolic response. Early tumour metabolic response after one cycle of chemotherapy did not predict eventual metabolic response or clinical outcome. Conclusion: This thesis showed tumour metabolism to be a powerful prognostic indicator for patients with colorectal cancer liver metastases. In particular, it reveals the burden of disease as well as the sensitivity of the metastases to systemic chemotherapy. PET assessment of tumour metabolic response to chemotherapy should be routinely performed, particularly in patients undergoing complex liver surgery.
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ItemRole of p21-activated kinases in pancreatic cancer( 2016)Pancreatic cancer remains one of the most lethal of all solid tumours with an overall 5-year survival rate of 7%. Management has not improved significantly over the last thirty years and based on current trends, is expected to become the second leading cause of cancer-related mortality by 2030. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care as a single agent. Furthermore, the presence of the dense stroma, characteristic of pancreatic cancer, contributes to therapeutic resistance and poor therapeutic response. Thus, a better understanding of the underlying genetic and molecular mechanisms is urgently required to find targeted and effective therapies. There is growing evidence that p21-activated kinases (PAKs) are involved in pancreatic carcinogenesis. The PAK family consist of six isoforms, two of which, PAK1 and PAK4, are upregulated and/or hyper-activated in pancreatic cancer. PAK1 can mediate many different cellular processes including the regulation of cytoskeletal dynamics and cell adhesion, the evasion of apoptosis, the promotion of cell survival, proliferation, migration and invasion, the fibrosis that constitutes the stroma, and the interplay between cancer cells and the stroma. PAK1’s role has not been fully elucidated in pancreatic cancer and has not been evaluated as a target for therapeutic intervention. The work presented in this thesis investigates the role of PAK1 in pancreatic cancer and the effect of PAK1 inhibitors, alone and in combination with gemcitabine, on pancreatic cancer growth, metastasis, stroma, and survival. First, we investigated the effect of glaucarubinone, a known inhibitor that reduces the activity of PAK1 and PAK4, on pancreatic cancer growth, migration and murine survival. Using 4 human and 2 murine pancreatic cancer cell lines, PAK1 and PAK4 was expressed in all pancreatic cancer cell lines tested and proliferation and migration/invasion inhibited by treatment of glaucarubinone with reduction in PAK1 and PAK4 activity in vitro. Synergistic inhibition was observed when combined with gemcitabine with decrease in pancreatic cancer proliferation in vitro, decrease in pancreatic cancer growth in human xenograft tumours in vivo, and increase in murine survival in an orthotopic immunocompetent model in vivo. This was one of the first studies that showed clinical benefit of targeting and reducing PAK1 in pancreatic cancer. Using more direct methods of reducing PAK1 activity, shRNA knockdown systems, and a PAK1 selective inhibitor, FRAX597, were utilised. shRNA knockdown of PAK1 resulted in a reduction in pancreatic cancer cell proliferation and survival and sensitised cells to gemcitabine in vitro. PAK1 was also found to be key regulator of signalling pathways such as PI3K and HIF1α. FRAX597 treatment decreased pancreatic cancer cell proliferation and migration/invasion and synergised with gemcitabine to decrease cell proliferation in vitro. FRAX597, combined with gemcitabine, reduced pancreatic tumour volume and increased murine survival in preclinical orthotopic immunocompetent murine models in vivo. Although, further clinical validation is required, it illustrates the clinical potential of a PAK1 inhibitor, FRAX597, combined with gemcitabine to improve pancreatic cancer patient outcomes. PAK1’s role was investigated in pancreatic stellate cells (PSCs), which are primarily responsible for the fibrosis that constitutes the pancreatic cancer stroma. This was the first study to show the presence of PAK1 activity in isolated human PSCs. The treatment of the selective PAK1 inhibitor, FRAX597, on PSCs resulted in a reduction in their activation, proliferation, and increase in apoptosis in vitro. PAK1 knockout mice tumours had decreased expression and activity of PAK1, associated with increased murine survival, showing the effect of depleting host PAK1 in an orthotopic immunocompetent murine model in vivo. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis and targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer. Together, these results illustrate the importance of PAK1 signalling in pancreatic cancer and the possible therapeutic benefit of targeting PAK1 with gemcitabine on pancreatic cancer growth and the stroma to increase the survival of pancreatic cancer patients.
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ItemSelection and management of men for active surveillance in low risk prostate cancer( 2016)Aims: To investigate: 1. Selection of men for active surveillance of prostate cancer a. Validation of risk calculators b. Suitability for inclusion of Gleason 3+4 disease. 2. Performance of prostate biopsy during AS a. Differences in quality of diagnostic biopsy between academic and referral centres. b. Optimization of biopsy templates c. Examination of prognostic indicators for disease progression Methods: Data were obtained from several difference sources: • Men suitable for AS on prostate biopsy but undergoing upfront radical prostatectomy were pooled from 3 international academic institutions in Cambridge (UK), Toronto (Canada) and Melbourne (Australia). • Prospectively maintained AS prostate cancer database at Princess Margaret Cancer Centre (PMCC) (1997-2012). Analyses performed: • Four risk calculators were assessed for their ability to predict different definitions of insignificant prostate cancer by area under the curve (AUC) of receiver operating characteristic curves and Brier scores for discrimination, calibration curves and decision curve analysis. • Men with biopsy Gleason 3+4 disease, suitable according to modified Royal Marsden, Sunnybrook Toronto and PRIAS selection criteria, were assessed for presence of adverse pathology at upfront radical prostatectomy. • Patients on AS at a tertiary referral centre (PMCC) were dichotomized depending on where their diagnostic biopsy was performed (interval versus external). Multivariate logistic regression was performed to examine for predictors of re-classification at the second, or confirmatory, biopsy. • Mapping of all patients with pathological progression at PMCC for location of disease progression enabled comparison of hypothetical biopsy templates (sextant and standard extended) to the institutional template used. • Men on AS at PMCC were evaluated for presence of disease progression at serial biopsy in the prostate transition zone (TZ). Multivariate Cox proportional hazards regression evaluated predictors of TZ progression. • At PMCC, men were dichotomized based on presence of cancer at their confirmatory biopsy. Pathological progression was investigated using a Cox proportional hazards regression model. Results: • All 4 models predicting presence of insignificant prostate cancer had weak discrimination at best (AUC 0.618-0.664). • Presence of Gleason 3+4 at biopsy, compared to 3+3 disease, increases risk of adverse pathology at radical prostatectomy if modified Sunnybrook Toronto criteria are used (19% versus 33%, p≤0.001). Using a stricter protocol such as PRIAS, there was no statistical difference between the groups. • External biopsy predicted both grade related re-classification (OR 4.14, C.I. 2.01-8.54, p<0.001) and volume related re-classification (OR 3.43, C.I. 1.87-6.25, p<0.001). • Sextant and standard extended biopsy templates were inferior to the institutional biopsy template in detecting presence of cancer (84% and 99% versus 100%), and pathological progression (47.9% and 81.9% versus 100%). • At each subsequent biopsy during AS, 2.7-6.7% of men had disease progression only in the TZ which would not have been detected if TZ biopsy was not performed. Predictors of TZ progression were maximum % single core (HR 1.99, C.I. 1.30-3.04, p=0.002), and MRI reporting cancer (HR 3.19, C.I. 1.23-8.27, p=0.02). • Men with no cancer at confirmatory biopsy were less likely to have pathological progression (HR 0.47, CI 0.29-0.77, p=0.003). Sub-analysis showed this was predictive of volume-related progression (HR=0.36, CI 0.20-0.62, p=0.0006) and not grade-related progression. Conclusions: • Utilization of models predicting suitability for AS should be used with caution as external validation in our cohort was weak. • If considering biopsy Gleason 3+4 disease for AS, a stricter protocol such as PRIAS must be utilized. • At PMCC, patients who had their initial diagnostic prostate biopsy for AS done externally, were more likely to have worse pathological features and re-classify on the second biopsy. • For men on AS, sextant and standard extended biopsy are less likely to detect prostate cancer or disease progression than the template used at PMCC. • TZ biopsy should be considered for all men having serial biopsy on AS, in particular those with high % core involvement or positive MRI findings. • Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression.
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ItemThe role of hypoxia inducible factor 1 alpha (HIF1α) in prostate cancer( 2016)Prostate cancer (PC) is one of the most prevalent cancers in men. Although many PCs are indolent, a significant proportion will metastasize and develop resistance to therapy. Contemporary screening tests lack the finesse to accurately differentiate aggressive PCs from indolent tumours, potentially leading to over-diagnosis and over-treatment. While cellular hypoxia often plays an integral role in carcinogenesis and tumour progression, this connection has been difficult to demonstrate in PC. However, a downstream marker of hypoxia, Hypoxia inducible factor 1α (HIF1α), which is a transcription factor that protects cells against noxious stimuli, is frequently over expressed in PC. Therefore, the role of HIF1α in PC was investigated in this thesis. The Castrate resistant PC (CRPC)-like human PC cell lines PC3 and DU145 were found to over-express HIF1α protein compared to an androgen-sensitive cell line LNCaP under normoxic conditions. Using HIF1α 5’UTR-luciferase constructs in PC3 cells, further experiments revealed that increased translation of HIF1α mRNA regulated by a 70bp GC-rich, secondary structure in the 5’UTR of the HIF1α promoter may be responsible for normoxic HIF1α overexpression. Cell proliferation assays revealed that PC3 cells over-expressing HIF1α were more resistant to destruction by cytotoxic agents (H2O2 and 5-fluorouracil) than androgen-dependent LNCaP cells. Reduction of HIF1α expression in PC3 cells using RNA interference decreased both the resistance towards cytotoxic agents and cell migration. Conversely, in the androgen-dependent LNCaP cells overexpression of HIF1α increased the resistance to cytotoxic agents. One hundred prostate tumours were then immune-stained for HIF1α and outcomes measured. On multivariate analysis HIF1α was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen-deprivation therapy (ADT). Notably the tumours that did not express HIF1α did not metastasise or develop CRPC. Next, the effects of non-specific HIF1α inhibitors (digoxin, metformin and angiotensin-2 receptor blockers) were investigated in ninety-eight patients who had continuous ADT as first line therapy and developed CRPC. The median CRPC-free survival was longer in men using HIF1α inhibitors compared to those not on inhibitors (6.7 yrs vs. 2.7yrs, p=0.01) and there was a 71% reduction in the risk of developing CRPC (p=0.02) and an 81% reduction in the risk of developing metastases (p=0.02) after adjustment for Gleason score, age and PSA. Finally, the effects of metformin were investigated in 2055 men treated for PC with external beam radiotherapy. Surprisingly, metformin did not result in any improvement in time to biochemical failure, time to metastases or overall survival in men undergoing radiotherapy, but there was an 1.5 fold increase in PC-specific deaths (p<0.05) in men on metformin who received ADT when adjusted for cancer risk and co-morbidities. In conclusion, the results presented in this thesis indicate that HIF1α is a promising marker in PC, which may be used for early identification of cancers that potentially will progress to metastases and develop resistance to ADT. HIF1α is likely to contribute to metastasis and chemo-resistance of CRPC, targeted reduction of HIF1α may improve outcomes of aggressive PC.
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ItemThromboembolism and neoadjuvant chemoradiation for rectal cancer( 2015)Thromboembolism (TE) is one of the leading causes of morbidity and mortality in cancer, is an independent predictor of reduced survival, and the overall rate of TE in cancer patients is increasing. Assessing the TE risk of an individual patient at a given time point and the benefit of thromboprophylaxis (TP) can be complex, involving widely variable TE rates according to tumour related factors (such as cancer subtype and disease stage), as well as patient and treatment related factors. Some, such as surgery and hospitalisation are well recognised and appropriately targeted with mechanical and pharmacological thromboprophylaxis (TP) strategies backed by Level I evidence. There is evidence that TP after hospital discharge following surgery (extended TP) is also beneficial. Recently, subgroups such as those with metastases receiving palliative chemotherapy have been shown to be at equally high risk, and also benefit from primary TP. Both chemotherapy and central venous access devices (CVAD) have been shown to be independently associated with development of TE. In addition, early studies examining neoadjuvant radiotherapy (nRT) in rectal cancer reported higher rates of TE however this finding was not repeated in subsequent studies using modern radiotherapy techniques. Extrapolating these findings raises the question of TE risk and the potential benefit of TP during neoadjuvant radiotherapy (nRT) or chemoradiotherapy (nCRT) for rectal cancer. This thesis explores the current evidence and contemporary guidelines concerning TE risk during nCRT, demonstrating considerable uncertainty and a lack of robust data. Randomised trials examining nCRT in rectal cancer are systematically reviewed to determine rates of TE, demonstrating a failure to capture TE events due to inadequate complication reporting frameworks. Existing attitudes and prescribing practices of specialist rectal cancer surgeons are surveyed, as well as barriers to TP prescribing. Issues of equipoise, ownership and logistical problems with outpatient TP prescribing were identified. The historical TE rate and epidemiology over a prolonged follow-up period in rectal cancer patients, as well as the relationship to nCRT is examined at both Peter MacCallum Cancer Centre in Australia and the Cleveland Clinic in the United States. These studies demonstrated that most TE events occurred in patients with metastatic disease receiving ambulatory palliative chemotherapy, and that the overall rate of TE in patients treated with nCRT was not elevated over those patients who had surgery alone. Finally, a prospective study of thrombogenic biomarkers in patients with rectal cancer was undertaken demonstrating significant coagulation abnormalities in colorectal cancer patients at baseline, but no major alteration during neoadjuvant chemoradiation. Marked and prolonged procoagluant abnormalities were demonstrated in the post-operative phase. Thus the current literature, attitudes of treating clinicians, historical rates, as well as candidate biomarkers for prospective TE risk were examined in nCRT for rectal cancer for the first time, identifying future potential research questions aimed at reducing this common complication of cancer care.
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ItemConsiderations for surgical intervention in metastatic cancer to the spine: evaluation of risk factors for pathologic fracture and spinal cord compression, and analysis of pre-operative scoring systems for the prognostication and treatment of patients with spinal metastases( 2014)The spine has structural load bearing and neural-protective functions, and tumour growth and bony destruction caused by spinal metastases results in pathologic fracture and cord compression, causing pain, neurological deficit, impaired function and quality of life. Surgery is the only method to immediately stabilise the spine and decompress the spinal cord. Survival prognosis is one of the key factors in selecting patients for surgery, and there are a number of scoring systems aimed at prognostication and treatment decision making for patients with spinal metastases, however these differ in the parameters assessed and prognostic value. The ability to predict those patients with spinal metastases most likely to progress to pathological fracture or develop spinal cord compression may simplify the surgical decision-making process and enable earlier surgical intervention, with the potential to prevent permanent neurological deficit and disability and maintain function and quality of life for the remainder of the patient's life. This thesis considers the complexities of treatment decision making for patients with spinal metastases, with two major aims: 1) An evaluation of patient risk factors and radiological parameters associated with pathological fracture and metastatic epidural spinal cord compression, and 2) Validation of survival prognostication of current pre-operative prognostic scoring systems, in order to optimise the treatment decision-making process. The methodology involved retrospective assessment of clinical and radiological parameters of 72 patients with spinal metastases who had undergone decompressive and/or stabilisation surgery for pathological fracture and/or metastatic epidural spinal cord compression or nerve root compression. The items assessed for association with pathological fracture or metastatic epidural spinal cord compression were: tumour size, location, type and lesion morphology, disease burden, pain and function. Pre-operative scores were calculated for each patient, and the prognostic value of each scoring system evaluated by comparison of predicted and actual survival. The results showed that tumour size within the vertebral body, vertebral endplate and three-column involvement, tumour growth rate, multiple vertebral metastases, and pain were associated with increased risk for pathological fracture. Vertebral posterior element and costovertebral joint involvement by tumour, primary tumour growth rate and presence of visceral metastases were associated with metastatic epidural spinal cord or nerve root compression. All patients with pathological fracture had at least one of three risk factors – pain; >25% tumour occupancy of vertebral body; and endplate or 3-column involvement – and incidence of pathological fracture increased with higher number of risk factors. The Revised Tokuhashi, Bauer, Modified Bauer, and Tomita scoring systems were the most reliable for survival prediction. It is concluded that these risk factors should be considered in the decision-making process for surgery for spinal metastases. Patients with spinal metastases causing pain, greater than 25% occupancy of the vertebral body and involving the vertebral endplate or all three columns should be considered for prophylactic or therapeutic decompressive and stabilization surgery. As a component of comprehensive treatment planning, we recommend the use of Revised Tokuhashi, Modified Bauer, and Tomita scoring systems due to their favourable survival prognostic accuracy and clearly outline of treatment strategy according to prognostic group.
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ItemThe Effect of Co-stimulation Blockade on Survival of Xenogeneic Pancreatic Beta-cells( 2014)Diabetes mellitus is a chronic disease affecting millions of people worldwide. Currently, the only potential cure is through pancreatic transplantation, either as whole organ or with pancreatic islet cells. However, the morbidity associated with immunosuppression and the scarcity of donor organs do not support the common practice of pancreatic transplantation. Both these factors can potentially be addressed by xenotransplantation of genetically modified cells that are capable of attenuating the immune system. The costimulation pathway of the immune system was the focus of this project, in particular blockade of the ICOS (inducible costimulation molecule) and CTLA-4 (cytotoxic T lymphocyte associated antigen 4) pathways to prolong xenograft survival. To address the problem of diabetes as well as investigate the efficacy of costimulation blockade on xenograft survival, rat insulinoma (beta) cell lines (INS-1E) stably expressing either ICOS-Ig or CTLA4-Ig were generated. The secreted proteins were demonstrated to be biologically active in xenogeneic mixed lymphocyte reactions by their ability to inhibit lymphocyte proliferation. Unfortunately, the in vivo effect of these transgenic INS-1E cells on xenograft survival was unable to be determined because of their failure to establish as tumours due to the slow growth rate of these cells following subcutaneous injection into BALB/c mice. The aim of the second part of this project was to assess the effect of rationally mutated ICOS-Ig on xenograft survival. PIEC (pig iliac endothelial cells) stably expressing ICOS-Ig with single (K52/S and S76/E) and combined (K52/S + S76/E) amino acid mutations were generated. In vitro, compared to wild type ICOS-Ig, the mutants with single amino acid substitutions showed stronger binding avidity to ICOS ligand. This increase in binding avidity however did not translate into superior inhibition of lymphocyte proliferation compared to wild type ICOS-Ig in xenogeneic mixed lymphocyte reactions. Similarly in vivo, the PIECs secreting mutated forms of ICOS-Ig did not prolong xenograft survival after subcutaneous injection of these cells into BALB/c mice. These data suggest that despite their higher avidity, the ICOS-Ig mutants are not biologically more superior than wild type ICOS-Ig both in vitro and in vivo.