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.