Medicine (St Vincent's) - Theses
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ItemClinical, Immunological and Radiological Features of Endocrine Immune Related Adverse Events( 2020)Immune checkpoint blockade is a cancer treatment aimed at restoring and enhancing the ability of the immune system to combat a tumour. A recognised side effect is “collateral” immune damage to healthy tissue, or immune related adverse events (irAEs). Immune toxicity to endocrine glands can be rapid and irreversible and may result in the need for lifelong hormone replacement. A major challenge is identifying which patients will develop endocrine irAEs when treated with checkpoint inhibitors. The role of predictive biomarkers such as HLA type or autoantibodies has not been prospectively evaluated. The possibility of detecting pre-clinical endocrine dysfunction using MRI and PET imaging is described in small case series only. This project aims to 1. Define the clinical and immunological features of checkpoint inhibitor related diabetes, hypophysitis and thyroiditis in contrast to spontaneously occuring endocrine autoimminuty and 2. Explore ways to predict and detect endocrine toxicity early with biomarkers and imaging. First, I define the phenotype and immune mechanisms underlying checkpoint inhibitor related autoimmune diabetes. It was then relevant to discuss atypical or alternate phenotypes of diabetes and pancreatitis which have emerged over the past 2 years. This chapter concludes with a discussion of potential treatments aiming to reverse islet cell destruction, with a letter to the editor published in response to a case report. The next focus is the diagnostic evaluation of checkpoint inhibitor related hypophysitis. After hypothesising that the true incidence may be underappreciated, this chapter reviews the clinical, biochemical and radiological features in a cohort of patients monitored closely for this irAE. The third component of the thesis reviews the incidence and natural history of checkpoint inhibitor related thyroiditis. Defining the natural history provided important information guiding management of the hyperthyroid and hypothyroid phases respectively. This chapter includes a diagnostic accuracy study evaluating the role of FDG-PET/CT as a novel tool in the diagnosis of this irAE. In defining the natural history and diagnostic features of these three endocrine immune related adverse events, important recommendations about biochemical screening and the complementary role of routine cancer immaging are made. Importantly, treatment considerations relevant to oncologists and endocrinologists alike are outlined.
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ItemPerioperative cardiovascular complications: incidence in patients undergoing cancer surgery and preoperative risk prediction using 18F-fluorodeoxyglucose cardiac positron emission tomography imaging( 2018)Background: Major perioperative cardiac complications affect over 10 million patients annually worldwide. Cancer is associated with multiple shared cardiovascular risk factors, but the incidence of cardiovascular complications after cancer surgery is unknown. Furthermore, cardiovascular risk prediction remains challenging. Cardiopulmonary exercise testing (CPET) objectively assesses exercise capacity and can predict overall perioperative morbidity and mortality and guide prehabilitation strategies, but cardiac imaging is required to determine the location and severity of coronary artery disease preoperatively. Currently available stress tests rely on surrogate markers for ischaemia and the evidence supporting these investigations perioperatively is weak. Cardiac positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) can image myocardial metabolism directly. Myocardial ischaemia appears as a ‘hot spot’ due to uptake of radiolabelled glucose in ischaemic myocytes undergoing anaerobic metabolism. Performing cardiac PET imaging after CPET may improve cardiac-specific perioperative risk prediction. However, accurate imaging requires preparation with a high-fat low-carbohydrate (HF-LC) diet, and the feasibility of incorporating cardiac PET imaging into existing preoperative CPET clinics is unknown. This thesis explores the incidence of cardiovascular complications in a cancer surgery population, and the feasibility of post-exercise cardiac PET imaging for preoperative risk assessment prior to major cancer surgery, within the setting of a CPET clinic. Methods: Cardiovascular complications within 30 days of cancer surgery were retrospectively investigated during a 12-month period at a single cancer institution (Peter MacCallum Cancer Centre, Melbourne, Australia). Screening identified patients via positive troponin results, ICD-10 diagnosis, and a manual search of intensive care unit discharge summaries. Standardized diagnostic criteria then identified the primary outcome—the incidence of myocardial injury after noncardiac surgery (MINS) or perioperative myocardial infarction (MI). Secondary outcomes included arrhythmias, cardiac failure, pulmonary oedema/fluid overload, pulmonary embolism, stroke, and cardiac death. A prospective pilot study investigating the feasibility of cardiac PET imaging after CPET was conducted. Feasibility endpoints included compliance with preoperative HF-LC diet and fasting; the ability to inject the FDG tracer within 15 minutes of peak exercise, the ability to complete cardiac PET imaging within 120 minutes, and the ability to suppress FDG uptake in background normal myocardium. Postoperative follow-up included cardiac complications and mortality within 30 days of surgery. Results: Over a 12-month period, 4,743 patients underwent cancer surgery. Seventy patients experienced 95 cardiovascular complications within 30 days postoperatively (overall incidence 1.5%). Amongst patients undergoing intermediate/high-risk surgery, the incidence was 8.4%. Perioperative MI/MINS occurred in 13 patients (0.27%). The 30-day all-cause mortality in those with cardiovascular complications after cancer surgery was 10% (n=7), and 42% (n=3) had a documented cardiac cause of death. Twenty-six patients undergoing intermediate to high-risk cancer surgery were enrolled in the cardiac PET pilot study over an eighteen-month period (July 2014-January 2016). Overall protocol feasibility was achieved in 81% (95% CI 62% to 91%). Of the 24 patients who completed exercise testing, FDG was injected within 15 minutes (mean 9.8 minutes) of peak exercise in all patients, and cardiac PET imaging completed within 120 minutes (mean 84.2 minutes) in 96% of patients. Twenty-one patients proceeded to surgery; three patients experienced postoperative myocardial injury or infarction, of which two had positive or equivocal cardiac PET imaging (and negative sestamibi myocardial perfusion imaging). One patient with normal CPET and cardiac PET results suffered MINS following bleeding requiring massive transfusion. Conclusions: Overall, there is a low incidence of perioperative acute myocardial infarction following cancer surgery. However, the retrospective study design and lack of routine postoperative troponin monitoring may have underestimated the true incidence. Patients undergoing intermediate/high risk cancer surgery are at greater risk, and the 30-day all-cause mortality in those with cardiovascular complications is significant.
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ItemDevelopment of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis( 2018)Objective: Systemic Sclerosis (SSc) is a multi-organ connective tissue disease resulting in fibrosis of the skin and internal organs. We sought to develop the first damage index (DI) in systemic sclerosis (SSc). Methods: Following systematic review of the literature focusing on methodology used to develop damage indices in other rheumatological conditions, the following methods were used to develop the SCTC-DI. The conceptual definition of organ damage in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic review of the literature and consultation with three experienced patient partners and 7 non-rheumatologist experts produced a list of potential items for inclusion in the DI. The following steps were used to reduce the items; (1) Expert members of the SCTC (n=331) were invited by email to rate the appropriateness of each item for inclusion in the DI using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1,568 patients followed for a mean of 4.8 years, the univariable relationships between the remaining items and the end points of mortality and morbidity (physical component summary score of the Short Form 36) were analysed, and items with p value < 0.10 were retained; (3) using multivariable regression analysis against the above endpoints, coefficients were used to determine a weighted score for each item; (4) internal and external retrospective validation was performed to demonstrate construct and criterion validity. Results: Ninety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items. One further item was forced into the multivariable model by experts, due to clinical importance, to create a 23-item weighted SCTC Damage Index (SCTC-DI). Conclusions: Through the combined use of consensus and data driven methods, a 23-item SCTC-DI was developed. Future prospective validation is planned.
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ItemQuantifying organ damage in systemic sclerosis: rationale, methodology and item generation( 2018)Purpose: The overall purpose of this thesis is to form a rationale for the development of a disease damage index in systemic sclerosis and to inform item generation for inclusion in this index through: (1) appraisal of existing measures of disease status in systemic sclerosis (SSc); and (2) quantifying the accrual of organ damage in patients with early SSc using ad hoc criteria. Methods: (1) A systematic review of Medline (1966–2015), EMBASE (1974–2015), and Cochrane Library (inception–2015) was undertaken to identify indices of disease status in SSc. The study focused on objective measures and excluded non-English articles. Measures were reviewed for content, whether they measured activity, damage and/or severity and if they were validated according to the OMERACT filter; (2) Patients in the Australian Scleroderma Cohort Study enrolled within two years of onset of the first non-Raynaud’s SSc symptom were included. Organ damage was defined by a group of six experts as substantial and permanent loss of organ function due to SSc. Results: (1) Of the 4558 articles retrieved through the search, 58 articles were identified for review. A further 44 articles were found through a search of the bibliography of relevant articles. The systematic review identified the following 10 “composite” (multi-organ) indices: two disease activity indices, six disease severity scales, and two combined response indices. There was no disease ‘damage index’ for SSc. The Valentini disease activity index has face validity, partial validity for content and criterion validity, and sensitivity to change, but not for reliability. The Medsger disease severity scale has face, content and criterion validity but not construct validity, sensitivity to change and reliability. (2) The study identified 278 patients with early SSc. Among these, 38% had diffuse SSc. Damage was more common in the diffuse than in the limited disease subtype in the kin/musculoskeletal (75% vs. 25.2%, p<0.001) and lung (31.4% vs. 19.9%, p = 0.035) domains at year seven of follow-up. The rates of damage accrual were highest in the kin/musculoskeletal, gastrointestinal and respiratory systems at year two (29.1%, 18.7%, 14.4%), increasing at year five (41.4%, 30.6%, 21.2%) and declining thereafter to year seven (43.9%, 32.7%, 23.0%). In particular, there was early accrual of damage due to joint contracture (22.3%), gastrointestinal dysmotility (11.5%) and pulmonary fibrosis with forced vital capacity <70% predicted (9.7%) at year two. The highest accrual rate of organ-specific damage from years two to seven was seen in faecal incontinence followed by proximal muscle weakness and pulmonary fibrosis. Conclusions: (1) The study identified a number of composite and organ-specific indices in SSc, incorporating mostly objective measures, developed to quantify disease activity, severity, and response in clinical trials. However, none of the indices was developed to exclusively quantify organ damage. Most of the existing indices require further validation according to the OMERACT filter; (2) Substantial accrual of organ damage occurs early in the course of disease, particularly in diffuse SSc. This provides a strong rationale for the development and validation of a SSc damage index.
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ItemThe relationship between occupational sunlight exposure and non-melanoma skin cancer( 2015)Aims and Background: Australia has the highest incidence of skin cancer in the world and ultraviolet (UV) radiation exposure is the dominant environmental determinant of all major forms of skin cancer. Two recent systematic reviews and meta-analysis of the available epidemiological evidence clearly indicate that occupational ultraviolet radiation (UVR) exposure is a substantial risk factor for the development of non- melanoma skin cancer. This study is an initial attempt to investigate the role of occupational sunlight exposure in the development of non-melanoma skin cancer in men in Australia. Methods: A case-control study was conducted. One hundred cases were recruited from the Skin and Cancer Foundation Inc. Controls included 14 age- and gender-matched subjects nominated by the cases. A questionnaire was administered through face-to- face interviews to collect information on pigmentary and genetic characteristics, occupational and recreational exposure assessment, and time of first diagnosis of non- melanoma skin cancer, confirmed with histopathological diagnosis. Conditional logistic regression models were implemented. Subsequently, a one-way analysis of variance (ANOVA) was used to investigate the relationship of each risk factor with occupational sun exposure. Results: There was insufficient evidence to conclude that there was a relationship between occupational sun exposure and non-melanoma skin cancer, because of the small sample size of matched case-control pairs. As the results for the small sample size of the matched case-control group were not statistically significant, a one-way analysis of variance (ANOVA) was performed to compare the risk factors. Fitzpatrick Skin Type was the only risk factor that showed a statistically significantly different occupational exposure profile (with a P-value of 0.035) but even then the differences were minor and only between skin phototype 2 and 3. There were no significant relationships between occupation exposure and the other risk factors. Conclusion: Unfortunately, analysis of the small number of matched case-control pairs was not statistically significant and it was not possible to draw any conclusions regarding the role of occupational sunlight exposure in the development of non- melanoma skin cancer. We experienced unexpectedly high levels of reluctance from case subjects to propose control subjects to participate in the study, which impacted on data collection and subsequently the study results. It has been well established that solar UVR is a risk factor for skin cancer. Outdoor workers are potentially exposed to high levels of UVR. More epidemiological studies are needed to improve our understanding and awareness of skin cancer as well as aid the development of prevention strategies at workplaces to reduce outdoor workers’ exposure to UVR.
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Item“A tale of two cities”: Studies on host control of chronic hepatitis B infection & Comparative evaluation of methods for quantifying cytokine production( 2016)Globally, an estimated 240 million people are living with chronic hepatitis B (CHB) [1], and the number is approximately 218000 in Australia [2]. Inactive hepatitis B e antigen (HBeAg)-negative patients are the most prevalent group, who are defined by with sustained virological response (SVR). This state is associated with favorable prognosis and low risk of liver complications. Through monitoring the serological markers and immune markers by flow cytometry, as well as advanced techniques such as transcriptome mapping, progress has been made on unveiling the mechanism of host immunological control of the CHB infection. Furthermore, it is of great clinical significance to accurately identify relapse of patients (Chapter 1). Few studies have focused on effectively identifying the treatment-naïve inactive carriers (IC), and we are particularly interested in predicting sustained inactivation through monitoring the serum HBV DNA level and HBsAg titer. Based on a retrospective/longitudinal study, we report that HBV DNA is a better predictor over HBsAg, and it is not beneficial to add HBsAg into the prediction model. The cutoff value of HBV DNA>2.5log IU/mL is effective for identifying IC with the NPV 93.6% for 12 months and 92.3% for 24 months. In another words, IC with baseline HBV DNA load<2.5 log IU/mL is likely to maintain the sustained inactivation for another 1 and 2 years, with a probability over 90% (Chapter 2). We also developed a protocol for effectively selecting peripheral blood mononuclear cells (PBMCs) subpopulations- including monocytes, Natural Killer (NK) cells, and rest of the PBMCs from inactive HBeAg negative patients undergoing clinical relapse after NA therapy cessation. Corresponding selection kits (from Miltenyi Biotec or Stemcell Technologies) were compared, and sample quality and the purification of the sample was analysed. Extracted mRNA samples will undergo expression profiling in the future, expected to pinpoint the biomarkers and unveil the mechanism of the carrier relapse (Chapter 3). For host immunity studies, accurate assessment of cytokine profile is an important perspective. We performed the comparative evaluation of two most commonly used methods for quantifying cytokines, flow cytometry and ELISA, based on the model of TLR stimulated human monocytes. Fundamentally different biological patterns were ascertained regarding cytokines from the two assays, and were mainly evidenced by the more comprehensive information that was available by flow cytometry (Chapter 4). For applying this optimized methodology, which is presenting results from flow cytometry and ELISA in parallel, to CHB studies, we adopted a human hepatocyte cell line, HepG2 (Chapter 5).
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ItemNo Preview AvailableBioimaging in colorectal cancer - prediction of response to neoadjuvant treatment( 2015)Over the last decade the management of colorectal cancer has changed significantly with the benefits of neoadjuvant therapies and new adjuvant treatments becoming apparent. Surgical strategies have also evolved with initial evidence that some patients can be successfully managed with local excision or omission of any surgery at all, resulting in a shift towards the individualisation of cancer management. The management of rectal cancer is based on primary staging assessment which relies on imaging techniques such as CT, MRI and ERUS. Recent advances in technology have improved the accuracy and widened the applications of these techniques. With the progress in medical and surgical treatments for rectal cancer, the optimal management of rectal cancer has become more complex. The evolving ability to tailor optimal treatment to the individual has created new roles for imaging such as prediction of response to treatment, restaging with assessment of response to treatment and prediction of prognosis. Consequently, prediction of response will become an important component of modern pre-operative assessment of rectal cancer to optimise individualisation of medical and surgical treatment. Beyond the established role of primary staging of malignancies, the role of conventional imaging techniques in re-staging following neoadjuvant treatment may be of increasing importance. Novel functional imaging techniques such as FDG-PET, DW (diffusion weighted) MRI are also emerging, the roles of which are yet to be determined. This thesis will examine the current status of bio-imaging and explore new imaging techniques in rectal cancer. At the Peter MacCallum Cancer Centre, we have been routinely performing staging and restaging imaging with CT, MRI and PET for the last 5 years which has resulted in a cohort of patients in whom these imaging techniques can be evaluated. This thesis also aims to evaluate a recent and evolving functional imaging technique- DW-MRI, in the prediction of response of rectal cancer to chemo-radiation.
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ItemIncreasing the hair inductive potential of human dermal papilla cells: stimulating and characterising cell aggregation( 2015)Dermal papilla cells (DPCs) are able to induce hair follicles. DPC tend to aggregate both in vitro and in vivo. This tendency is associated with their ability to induce hair growth. The use of DPCs to treat alopecia is limited because human DPCs lose their hair-inducing activity in culture, whereas ovine DPC do not. The aims of this study were to characterise the molecular phenotype of ovine DPC aggregates, and to determine whether aggregating ovine DPCs secrete factors affecting the aggregative behaviour or inductive potential of human DPCs. Expression of papilla markers in cultured ovine DPCs was characterised. The effects of ovine factors, different culture substrates and medium compositions on aggregative behaviour of human DPCs were determined. Co-cultures of ovine and human papilla cells, separated by a permeable membrane were observed to determine whether the ovine cells secrete soluble factors that affect human cell aggregation. Ovine DPC aggregates expressed 16 papilla markers, showing they have a similar phenotype to papillae in vivo. In co-culture experiments, well-formed aggregates were produced in human:ovine DPC mixtures. In contrast, unmixed human DPCs remained in a monolayer state, indicating that ovine cells are required to initiate aggregation but the human cells are then able to incorporate into aggregates. Both human and ovine DPCs had a higher tendency to aggregate in medium containing 20% (v/v) lamb serum compared to 10% (v/v) foetal calf serum. The effect of co-culturing human with ovine DPCs separated by a permeable membrane gave positive additional effects to human aggregation. In summary, ovine biomolecules show potential for increasing the aggregative behaviour of human DPCs in culture. These biomolecules might eventually be used to treat androgenetic alopecia.
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ItemExamining non-melanoma skin cancer trends in Australia using data from Medicare Australia( 2014)Background: Non-melanoma skin cancers (NMSC) are the most common cancer in Australia, costing the Australian Government $511 million in 2010. NMSC incidence studies have typically utilised face-to-face interview methods that rely on self-reporting of skin cancers. Studies overseas have employed national medical system billing data to examine trends in NMSC. The work in this thesis has adopted this novel approach for evaluating skin cancer trends. Objectives: 1. Determine the completeness of Medicare Australia (MA) in capturing skin cancer cases. 2. Examine the up-to-date incidence rates of NMSC to 2012. 3. Examine rates of recurrent and incompletely excised (residual) NMSC in Australia. Methods: Data from MA, Medicare Benefits Online and Victorian Cancer Registry (VCR) from 2004-2008 were extracted for use in this thesis. MA and VCR melanoma cases were compared. Regression and a paired-samples t-test was performed. NMSC incidence was estimated by determining the number of separate patients treated for a NMSC. The proportion of recurrences and residuals were calculated. Results: Medicare Australia data were found to correlate with the VCR data set. Incidence rates for NMSC were 856 per 105 people in 2012. This incidence was forecast to increase to 1636 per 105 in 2015. 1.54% of NMSC required treatment for a recurrence and 1.26% of NMSC required retreatment for incomplete excision. Conclusion: This thesis has contributed the following: 1. Demonstration of a correlation between MA and VCR melanoma data, suggesting that MA could potentially be used for examining trends in other skin cancers including NMSC. 2. An up-to-date incidence of NMSC in Australia to 2012. 3. Proportion of NMSC that required treatment for residual lesions. 4. Proportion of NMSC that required treatment for recurrent lesions.
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ItemBreast cancer stem cell properties in the PMC42 breast cancer cell line system( 2010)Epithelial to mesenchymal transition, EMT, is a developmental process that may be adopted by tumour cells to facilitate metastasis. EMT changes resulting in a more mesenchymal phenotype have been associated with a “migrating stem cell” pattern in breast and other carcinoma cells. PMC42 human breast cancer cells can be induced by epidermal growth factor (EGF) to a more mesenchymal state and adopt cancer stem cell characteristics. This study investigated the cancer stem cell properties in EGF-induced EMT in the PMC42 system, which consists of the predominantly mesenchymal PMC42-ET cell line and its epithelial-like subline, PMC42-LA. Quantitative reverse transcriptase polymerase chain reaction, qRT-PCR, was used to measure relative gene expression levels following EGF-induced EMT ofPMC42 cells in two- and three-dimensional cell cultures. Stem cell properties were evaluated through immunocytochemistry and two-channel fluorescence-activated cell sorting (FACS). CD44+/CD24- expression, a marker of breast cancer stem cells (BCSC), was measured after EGF-induced EMT. Ten ng/mL EGF treatment increased the number of cells expressing CD44+/CD24- in PMC42-ET but not in PMC42-LA cells as shown by FACS analysis. A mammosphere formation assay, which measures the ability of cells to form complex structures, was used to assess the functionality of the stem like properties exhibited by the different cell populations. This evidence of stemness was found in the BCSC-like population (CD44+/CD24-) of PMC42-ET cells. Expression of embryonic stem cell markers such as ABCG2 and ITGA6, EMT-BCSC related genes generated from EMT and BCSC bioinformatic comparison, and CD24-correlated genes (SerpinE1, EMP1, EMP3, AXL and VIM) were examined in the PMC42 system. EGF-induced EMT increased those gene expressions in the PMC42 system. PLP2 and VIL2, components of the Invasiveness Gene Signature derived from BCSC (Liu et al., 2007), showed no change in expression during EGF-induced EMT of PMC42. In conclusion, transcriptional changes demonstrating an increased stem-like or BCSC-like characteristic was observed in the PMC42 system following an EGF induced EMT. These results suggest the existence of a subpopulation of PMC42 cells which inherently resemble BCSC and provide new insights into the potential role of these subpopulations in EMT-associated metastasis.