Medicine (St Vincent's) - Theses
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ItemAdenocarcinoma of the lung: an exploration of the relationships between histopathology, molecular pathology and inflammatory markers and their relationship to patient outcomes( 2017)Lung cancer remains the most common cause of cancer related death worldwide, with nearly 1.4 million deaths in 2008 globally. Adenocarcinoma is the most common type of lung cancer, and its frequency compared to other histologic subtypes is increasing. The simplicity of the label “adenocarcinoma” hides its significant pathologic and clinical heterogeneity. This thesis explores a number of clinicopathologic correlates in lung adenocarcinoma specimens obtained from patients treated at St Vincent’s Hospital in Melbourne, Australia. In 2011 the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) proposed a new classification system for pulmonary adenocarcinoma. This was subsequently adopted in the 2015 edition of the World Health Organisation Classification of Tumours of the Lung, Pleura, Thymus and Heart. Multiple groups demonstrated that the new classification had prognostic significance following resection of pulmonary adenocarcinoma independent of stage. The impact of the classification in metastatic disease was not known. This thesis found that it was possible to identify the adenocarcinoma patterns of solid with mucin, papillary, micropapillary and acinar in each specimen taken from a metastatic site and semi-quantitatively assess each component. Further, the identification of a major pattern was not prognostic, but did predict for differences in survival time for patients treated with systemic therapy. The worst outcomes were observed for patients with tumours with a major solid pattern. The major solid pattern was also found to have infrequent occurrence of activating epidermal growth factor receptor (EGFR) mutations. As this is the first time that this novel finding has been reported. Validation from other groups is required. The presence of the IASLC/ATS/ERS classification as a robust new tool with clinical relevance has led to further research to define other clinicopathologic correlates. Oncogene driver mutations in genes such as EGFR and Kirsten RAS (KRAS) are critical in selection of therapy in advanced disease. This thesis examined relationships between adenocarcinoma subtype and mutation status for patients who had resected lung adenocarcinoma. Patients with solid predominant adenocarcinoma were significantly less likely to have EGFR mutations, while KRAS mutation was a frequent event in invasive mucinous adenocarcinoma. No other significant associations were found. The findings were consistent with those recently reported by other groups from centres located in predominantly Caucasian countries. EGFR inhibition and the discovery of EGFR mutations was the starting point for a major change in the approach to treatment of advanced lung adenocarcinoma, however resistant to treatment occurs. It had been suggested that upregulation of phosphorylated STAT3 (pSTAT3) via interleukin 6 (IL6) and Janus Kinase (JAK) may be linked to EGFR mutation status in the absence of treatment with EGFR tyrosine kinase inhibitors and therefore may offer a rational target to delay resistance to such therapies. In the patient cohort studied the presence of EGFR or KRAS mutation status did not enrich for activation of IL6, JAK1 or pSTAT3 as determined by immunohistochemistry. Further, there was no clinicopathologic or prognostic correlates of note found by the IL6, JAK1 or pSTAT3 activation state. The assessment of IL6, JAK1 and pSTAT3 in the same samples and by two methods to assess positivity was a unique feature of this study. In conclusion this contributes new knowledge on the relevance of pathologic subtyping in advanced lung adenocarcinoma. It confirms and consolidates recent reports oncogene mutation status and adenocarcinoma subtype following surgical resection. It examines the IL6 / JAK1 / pSTAT3 pathway in detail in resected pulmonary adenocarcinoma. Translational research that explores why adenocarcinoma subtypes have different outcomes by treatment may allow clinicians to direct therapies differently or unlock new pathways for targeting lung adenocarcinoma with therapeutic effect.
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ItemA health and economic impact analysis of robotic surgery for the treatment of localised prostate cancer in the Victorian public health system( 2017)Background: The rising prevalence of prostate cancer in Australia will increasingly contribute significant morbidity, mortality and economic burden on society. Radical prostatectomy is the mainstay of treatment for localised prostate cancer, and robotic prostatectomy the dominant surgical approach to management in the United States and Europe. Large systematic reviews have demonstrated some perioperative and functional benefits of robotic over open and laparoscopic approaches, however no differences in oncological outcomes have been demonstrated to date. The cost of the robot is undoubtedly greater than open and laparoscopic approaches however studies have shown a significant cost offset due to reduced length of stay and other improved clinical outcomes. We aim to perform a comprehensive health and economic impact analysis of robotic surgery for the treatment of localised prostate cancer in the Victorian public health system since the introduction of the da Vinci surgical robot to Peter MacCallum Cancer Centre (Peter Mac) in July 2010. Methods: To compare patterns of care and perioperative outcomes of robotic prostatectomy to other approaches, we utilised a large dataset from the Victorian Admitted Episodes Dataset (VAED) including all prostatectomy patients performed in the Victorian public sector since the installation of the da Vinci robot. Additionally the RARP series of perioperative, complication, oncological, functional and quality of life (QOL) outcomes at Peter Mac was compared to local, national and international literature. We then created an economic model to evaluate the incremental cost of robotic-assisted radical prostatectomy (RARP) versus open radical prostatectomy (ORP) and laparoscopic radical prostatectomy (LRP), incorporating the cost-offset from differences in length of stay and blood transfusion rate. The economic model constructs estimates of the diagnosis-related group (DRG) costs of ORP and LRP, adds the gross cost of the surgical robot (capital, consumables, maintenance and repairs), and manipulates these DRG costs to obtain a DRG cost per day, which can be used to estimate the cost-offset associated with RARP in comparison with ORP and LRP. Economic modelling was performed around a base-case scenario assuming a 7-year robot lifespan and 124 RARPs performed per financial year. One and two-way sensitivity analyses were performed for the four-arm da Vinci S HD, Si and Si dual console surgical systems. Results: The robotic surgical approach has become the dominant technique to radical prostatectomy for localised prostate cancer in the Victorian health system over ORP and LRP. The introduction of a surgical robot to the Victorian public system has resulted in centralisation of prostatectomy to Peter Mac with huge institutional growth since its instillation. Length of hospital stay and blood transfusion rates are significantly improved with the robotic approach. Positive surgical margin rates with RARP are improved compared to prior Victorian data consisting of primarily an ORP cohort. Complication and oncological outcomes of RARP are comparable between surgical approaches and to large international RARP series. Definitive comparison of RARP functional and QOL outcomes between approaches was difficult without a comparative cohort however compared favourably with previous literature. Improvements in length of stay and blood transfusion rates offset most of the additional cost of the robot in the base case scenario where 124 robotic cases are performed per year. RARP can become cost-equivalent with ORP where ~140 cases are performed in the base-case scenario. Increasing the surgical volume, lifespan of the robot and reducing the cost of the consumables can ameliorate cost. Conclusions: The da Vinci surgical robot has been safely introduced into the Victorian public health system at Peter Mac. The addition of the robot has significantly altered the way we treat patients with localised prostate cancer in Victoria. The robotic approach confers some clinical advantages compared to laparoscopic and open prostatectomy consistent with international literature, and the reduction in length of stay offsets much of the increased cost of the robotic procedure.
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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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ItemAdvanced characterisation of pulmonary hypertension: Assessment of right ventricular diastolic function and pulmonary artery wave reflection( 2016)Pulmonary hypertension is the net haemodynamic consequence of a wide variety of underlying pathologies. As disease progresses, right ventricular systolic dysfunction may develop. However, by the time this occurs, prognosis is poor. Like the situation in the left ventricle, chronically increased right ventricular afterload first leads to right ventricular hypertrophy and hypothetically, diastolic dysfunction. Although there is some evidence from animal models for this, human data is limited. Theoretically, the identification of right ventricular diastolic dysfunction may assist in the earlier diagnosis of pulmonary hypertension. This thesis provides evidence that right ventricular diastolic dysfunction does exist in the setting of pulmonary hypertension, that it occurs earlier than systolic dysfunction, and that it can be identified by invasive pressure measurement in the right ventricular cavity. Although echocardiography provides a useful way to assess left ventricular diastolic function, data presented here will show that currently available echocardiographic measurement of right ventricular diastolic function may not be sensitive enough to detect abnormal function. The secondary hypothesis tested is that a pressure/time analysis of pulmonary wave reflection can provide additional information in the assessment of patients with pulmonary hypertension. Data suggests that a metric of wave reflection, the pulmonary augmentation index, is closely associated with standard measures of right ventricular afterload, and therefore may not add value. However, the time to wave reflection is related to the site of obstruction in the pulmonary circulation and could theoretically assist in identifying disease aetiology.
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ItemBreast cancer risk assessment and risk management:: Development of a personalised, web- based, decision support tool (iPrevent®)( 2016)Breast cancer risk is a complex interaction of environmental factors, inheritance and genetics. Awareness of her personal breast cancer risk can allow a woman to make informed decisions regarding the management of her risk, through screening or risk reduction measures such as surgery or medication. The effect of risk factors, both inherited and modifiable, on breast cancer risk is complex but mathematical models exist to estimate an individual’s risk. These models use epidemiological data to quantify the risk for an individual, based on a range of their risk factors. As these models were developed primarily for research purposes, they are not designed for ease-of-use by a range of clinicians, nor designed to be used by those unfamiliar with estimating breast cancer risk. Once estimated, a woman’s breast cancer risk must then be explained in a way that is comprehensible to the woman, together with ways to manage that risk in a similar format. If this were achieved for all women, it may allow them to make informed choices and potentially even prevent breast cancer or reduce its impact greatly. The ultimate aim of this research was to develop a user-friendly computerised, web-based breast cancer risk assessment and risk management support tool. This tool, called iPrevent©, uses the existing mathematical models to estimate individualised breast cancer risk, but using a user friendly interface. It then goes further, and provides Cancer Australia guideline-based recommendations, based on that risk, for each individual woman. It presents the risks and befits of each evidence-based intervention in a similar manner to the risk so that women can make an informed choice regarding their breast cancer prevention strategy. Before developing iPrevent©, I first examined the other possible effects of being a carrier of a mutation in breast cancer predisposition genes, as it was hypothesised that other factors such as fertility effects, could have a large bearing on any future decisions women may make, including risk reducing surgery. I then explored current behaviours to reduce risk among women at highest risk, in an attempt to understand the magnitude of the possible benefits of iPrevent© in this highest risk group. Through focus group studies, I examined the information needs of clinicians to facilitate breast cancer risk discussions. Understanding the needs of end-user clinicians of iPrevent© ensures it could meet their needs. This usability may increase uptake and use, of both the tool and breast cancer risk management strategies where appropriate. This tool, iPrevent©, is currently undergoing clinical validation studies, outside the scope of this thesis, but will shortly become freely available with the aim of increasing individual awareness of each woman’s own breast cancer risk, enabling her to manage that risk according to the evidence, Cancer Australia guidelines and her own preferences.
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ItemCoronary microcirculatory function in patients with ischaemic heart disease: a focus on novel assessment, management and outcomes of coronary microcirculatory function( 2015)Although there have been improvements in pharmacotherapy and percutaneous coronary intervention, patients with ischaemic heart disease, still pose a significant health burden. It has become increasingly evident that cardiovascular outcomes are impacted upon by dysfunction of the coronary microvasculature. Novel direct invasive measures, such as the index of microcirculatory resistance (IMR), have recently been developed. This index of microvascular function has been shown to have significant clinical utility in patients with ischaemic heart disease. However, to date, the body of knowledge on the state of the microcirculation as assessed by IMR in subsets of patients, such as thrombolysed ST-segment elevation myocardial infarction (STEMI) and Non-ST segment elevation myocardial infarction (NSTEMI), is lacking. Furthermore, in patients with NSTEMI, the effect of targeted therapies on IMR and hence microvascular function, is unknown. Finally, no test is perfect and the development of supplementary invasive measures of microvascular function may improve the management of patients with ischaemic heart disease and further enhance our understanding of microvascular dysfunction. The aim of this thesis was to examine microvascular function in patients with ischaemic heart disease. Specifically, I will examine and compare microvascular function, as assessed in particular by IMR, in patients presenting with thrombolysed ST-segment elevation myocardial infarction undergoing a pharmacoinvasive strategy and non-ST segment elevation myocardial infarction. I will examine the relationship between measures of microvascular function, including the IMR, and left ventricular recovery in patients presenting with ST-segment elevation myocardial infarction and undergoing a pharmacoinvasive strategy. I will also examine microvascular function, as assessed by IMR, and the role of the antiplatelet agent, abciximab, in patients presenting with Non-ST segment elevation myocardial infarction. Finally, I will examine and evaluate a novel measure of microvascular function, the coronary artery augmentation index, in patients with stable angina undergoing percutaneous coronary intervention. A full representation of patients with ischaemic heart disease undergoing percutaneous coronary intervention (PCI) were studied; 31 patients with STEMI, 36 patients with NSTEMI and 40 patients with stable angina. Invasive coronary physiological measurements in the culprit vessel were taken during the index procedure at varying times depending on the study protocol. Left ventricular function was assessed by either transthoracic echocardiography or cardiac MRI and compared with measures of microvascular function. Cardiac biomarker levels were taken pre-procedure, at the time of procedure and post procedure for up to 24 hours post intervention. In summary, the main findings of this thesis are: • Invasive measures of microvascular function, such as IMR, are significantly higher in a pharmacoinvasive STEMI population than in a clinically stable NSTEMI population. • In a STEMI population undergoing a pharmacoinvasive strategy, in contrast to other traditional markers of microvascular dysfunction, post PCI IMR correlates with left ventricular function and has the potential to predict left ventricular recovery at three months post STEMI. • In patients with NSTEMI undergoing PCI, a bolus dose of intracoronary abciximab improves coronary microvascular function as assessed by IMR. • Coronary augmentation index is a valid and reproducible measure of microvascular function in patients with stable angina undergoing PCI. • Coronary augmentation index is a predictor of periprocedural myocardial injury and may be able to identify those patients who are at greater risk of such injury following intervention. The findings of this Doctor of Medical Science are novel and have important clinical implications for the clinician. The work in this thesis supports the notion that it is important to consider microvascular dysfunction in patients with ischaemic heart disease undergoing PCI. With accurate assessment and appropriate management clinical outcomes may be improved. The work presented does warrant further investigation in larger multicentre trials. I anticipate that these will support the findings of this thesis and by measuring microvascular function will can aid risk-stratification and enable a more intensive therapeutic strategy not only within the catheterisation laboratory, but post procedure in the short and medium term.
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ItemChronic hepatitis B in an Australian tertiary hospital cohort: natural history of disease and the association of viral markers with histological and serological outcomes( 2015)Chronic Hepatitis B (CHB) is a major worldwide public health problem with an estimated 240 million people chronically infected and at risk of the complications of liver cirrhosis and hepatocellular carcinoma. There are recognized phases of disease in CHB which are usually defined using a combination of HBeAg status, HBV DNA level and ALT level. These can provide a useful framework to conceptualise a patient’s risk of fibrosis and need for treatment. Using the large CHB cohort at our tertiary hospital in Melbourne, we described our patient group in terms of their phase of disease in a cross-sectional analysis in chapter 3. This analysis highlighted some of the limitations of tests used, eg the insensitivity of older generation HBV DNA. Histological liver injury due to hepatitis B virus (HBV) was also able to be examined in a large proportion of our cohort with liver biopsies and in chapter 4 we evaluated the effect of HBV DNA on liver fibrosis. We found that increasing HBV DNA was associated with increasing prevalence of significant fibrosis in HBeAg negative patients, however in HBeAg positive patients, the reverse was true. This once again leads back to the concept of phase of disease in which HBeAg positive patients in the immune tolerant phase have normal ALT and minimal fibrosis despite very high HBV DNA levels. Longitudinal analysis of untreated HBeAg negative patients in chapter 5 brought to light some of the weaknesses of current classification systems for phase of disease, since we showed that low level fluxes in viral load in HBeAg negative patients were common and strict thresholds for HBV DNA to define the immune control phase were often crossed. The effects of HBV genotype and viral variants (precore and basal core promoter) on liver histology were examined in chapter 6. No significant associations were found although there was a trend towards higher prevalence of significant fibrosis in patients with HBV genotype C. Furthermore we explored the role of the novel markers of quantitative HBeAg and HBsAg (qHBeAg and qHBsAg) for classification of patients into phases in the natural history of CHB and found significant differences in qHBsAg levels in patients in different phases of disease in chapter 7. Finally we evaluated the role of qHBeAg and qHBsAg in the setting of Nucleos(t)ide analogue treatment by comparing 2 groups of HBeAg positive patients, one of which was known to lose HBeAg during the 18 months of followup and the other group which did not. Differences in both baseline and on treatment levels of qHBeAg were found between the 2 groups, however no significant differences in qHBsAg levels were noted. Management of CHB frequently involves monitoring patients to decide on the need and optimal time for therapy. A better understanding of the tools used in evaluating patients and the performance of these in different phases of disease and on therapy helps to enhance the clinical care of CHB patients.
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ItemDetermining standards of care in the context of medical negligence, professional practice and informed consent in Victoria( 2014)The proposed Doctor of Medical Science by compilation seeks to describe recent medicolegal issues, with a focus on determination of standards of care with respect to clinical practice in Victoria in the context of professional negligence and informed consent. In the course of medical care, professional negligence can occur at any point during a doctor/patient relationship including assessment, diagnosis, advice and/or treatment. Integral to professional standards and negligence, and during any of these steps, lies the concept of informed consent and how information is communicated to patients in order to not only promote patient autonomy and beneficial outcomes, but also to protect medical practitioners from potential litigation. The proposed doctorate is comprised of 12 manuscripts and explores the question of by whom and how reasonable standards of care in clinical practice are determined in the context of professional negligence, and by virtue of this, who and how informed consent in clinical practice is determined. Causation, although a fundamental element in the tort of negligence, is excluded from this thesis. The doctorate commences with a general discussion around two of the fundamental elements in the tort of negligence in common law jurisdictions, the identification of a relationship which implies a duty of care, and the fundamental breach of that duty. Written for a medical audience, the doctorate discusses case law and legislation specific to medical professionals, and manuscripts will refer to practical and emerging issues for a medical readership such as interpretation of diagnostic tests, misdiagnosis, informed consent for procedures, standards of privacy and consent in the communication of information, the use of protocols to minimise breach of standards of care, refusal to treat and end-of-life decision making. In so doing, the doctorate explores specific clinical examples and situations which explore by whom and how professional negligence and informed consent are determined, whether it be by the medical practitioner, the courts or the patients themselves.
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ItemThe clinical utility of serum tumour markers prostate specific antigen and carcinoembryonic antigen in evaluating the effectiveness of chemotherapy for advanced prostate and colorectal cancers( 2014)Palliative chemotherapy for the treatment of metastatic castrate resistant prostate cancer (mCRPC) and metastatic colorectal cancer (mCRC) should only continue if the patient is deriving some benefit. Clinicians assess benefit using a variety of methods. The tumour markers, prostate specific antigen (PSA) and carcinoembryonic antigen (CEA) can be used as part of this assessment. I explored the clinical utility of using PSA and CEA to guide decisions on palliative chemotherapy for mCRPC and mCRC patients. I evaluated if falling levels of PSA predicted for a palliative response (decreasing pain and/or pain medication), and improved survival in 161 patients with mCRPC treated with mitoxantrone and prednisone in a randomised clinical trial. I also performed a phase IV analysis of 133 patients treated at Princess Margaret Hospital, Toronto, Canada to see how they compared with the clinical trial. Also, a retrospective cohort of 142 patients with mCRC treated with oxaliplatin-based chemotherapy at St Vincent’s Hospital Melbourne were evaluated to see if falling levels of CEA predicted survival and shrinkage of secondaries. A PSA response of 50% occurred in 34% of patients in the mitoxantrone and prednisone arm of the study and in 28% of the post trial cohort (P=0.36) A PSA response of 50% is predictive of a palliative response, although the strength of the association was relatively weak (phi coefficient =0.28, P = 0.001). The positive predictive value of a PSA response for a palliative response was 53%. Using a landmark analysis, PSA responders lived longer (P=0.0004). A CEA response of 50% occurred in 74% of the mCRC patients. Using a landmark analysis, CEA responders lived longer (P<0.0001). CEA response did correlate with radiological responses. Seventy per cent of the CEA responders had a complete or partial response on computed tomography (CT) scanning, but 42% of the CEA responders also had stable disease, and 36% of the CEA non-responders had a partial response. Both PSA and CEA responses yield useful adjunctive clinical information and should be part of the clinical assessment of the palliative benefit from chemotherapy for mCRPC and mCRC.
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ItemNovel biomarkers in the early detection of pulmonary arterial hypertension in systemic sclerosis( 2013)Systemic sclerosis (SSc) is a complex disease characterised by extensive fibrosis, vascular abnormalities and autoantibodies. Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in SSc, and the early detection of PAH has emerged as an essential component of disease management. The hypothesis for this thesis is that biomarkers, either alone or in combination with other non-invasive screening investigations, may improve screening in patients with SSc-PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. To begin, I present a comprehensive review of SSc-PAH focusing on the rationale and methods used to facilitate the early detection of SSc-PAH. Next, I present a systematic review highlighting some of the limitations in current screening practices, demonstrating the clinical need to further evaluate and refine current screening before making recommendations regarding the nature and frequency of screening. I then evaluate the screening utility of N-terminal-pro brain natriuretic peptide (NT-proBNP) in SSc-PAH, first proposing, and later validating a novel screening strategy combining NT-proBNP with pulmonary function tests (PFT) in a high-risk group of patients for SSc-PAH. Using this strategy, only patients who screen ‘positive’ to the proposed screening algorithm undergo echocardiography and further confirmatory testing for PAH. I show that asymmetric dimethylarginine, a novel biomarker of endothelial dysfunction involved in nitric oxide metabolism, may be an important screening and diagnostic biomarker for SSc-PAH, especially when combined with NT-proBNP. I also evaluate various other cytokines, chemokines and growth factors, previously suggested to play a role in SSc-PAH, and show in a well-characterised population of SSc-PAH patients that serum levels of interleukin-6 (IL-6), interleukin-13 (IL-13), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), fractalkine (FKN), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are not specific biomarkers of SSc-PAH. However, VEGF and ICAM-1 levels appeared to correlate with markers of PAH severity and deserve further study. I showed the wide variability of measured levels of these cytokines, chemokines and growth factors in SSc patients, possibly reflecting the heterogeneity of this complex disease. Overall, I demonstrate that biomarkers, particularly when combined with other non-invasive screening investigations such as PFT, may identify patients with SSc-PAH.