Measuring and modelling lung microstructure with hyperpolarised gas MRI

This thesis is concerned with the development of new techniques for measuring and modelling lung microstructure with hyperpolarised gas magnetic resonance imaging (MRI). This aim was pursued in the following five chapters: Development of a framework for lobar comparison of lung microstructure measurements derived from computed tomography (CT) and 3He diffusion-weighted MRI evaluated in an asthmatic cohort. Statistically significant linear correlations were obtained between 3He diffusion-weighted MRI and CT lung microstructure metrics in all lobar regions. Implementation of compressed sensing (CS) to facilitate the acquisition of 3D multiple b-value 3He diffusion-weighted MRI in a single breath-hold for whole lung morphometry mapping. Good agreement between CS-derived and fully-sampled whole lung morphometry maps demonstrates that CS undersampled 3He diffusion-weighted MRI is suitable for clinical lung imaging studies. Acquisition of whole lung morphometry maps with 129Xe diffusion-weighted MRI and CS. An empirically-optimised 129Xe diffusion time (8.5 ms) was derived and 129Xe lung morphometry values demonstrated strong agreement with 3He equivalent measurements. This indicates that 129Xe diffusion-weighted MRI is a viable alternative to 3He for whole lung morphometry mapping. Implementation of an in vivo comparison of the stretched exponential and cylinder theoretical gas diffusion models with both 3He and 129Xe diffusion-weighted MRI. Stretched exponential model diffusive length scale was related to cylinder model mean chord length in a non-linear power relationship; while the cylinder model mean alveolar diameter demonstrated excellent agreement with diffusive length scale. Investigation of clinical and physiological changes in lung microstructure with 3He and 129Xe diffusion-weighted MRI. Longitudinal studies with 3He and 129Xe diffusion-weighted MRI were used investigate changes in lung microstructure in cystic fibrosis and idiopathic pulmonary fibrosis. Lung inflation mechanisms at the acinar level were also investigated with 3He and 129Xe diffusion-weighted MRI acquired at two different lung volumes

Semi-quantitative immunohistochemical exploration of lung tissue remodelling in idiopathic pulmonary fibrosis

Aim: This thesis explores the complex cellular and biological interrelationships involved in Idiopathic Pulmonary Fibrosis (IPF) lung tissue remodelling using immunohistochemical analysis. Methods and results: 21 IPF and 19 control lung tissues were examined for expression and localisation of key pathogenic markers implicated in Epithelial Mesenchymal Transition (EMT), proliferation, and cell cycle within alveolar type II cells (ATII cells) and fibroblastic foci. E-cadherin was expressed in IPF and control ATII cells (mean expression score >75%). In IPF, mean expression of N-cadherin was scanty (mean expression score <10%): however 4 cases demonstrated augmented expression in ATII cells correlating to histological disease status (as reflected by number of fibroblastic foci) (Pearson correlation score 0.557). Transforming growth factor-ß (TGF-ß) protein expression was significantly increased in IPF ATII cells with variable expression within fibroblastic foci. The proliferation marker Ki-67 was observed within hyperplastic ATII cells but not in cells overlying foci. IPF ATII cells demonstrated variable Surfactant protein-C (SP-C). Hyperplastic ATII cells overlying fibroblastic foci expressed Cyclin D1, p53, p21WAF1, SOCS3 and p16INK4A. Conclusions: There is inconclusive evidence to support the role of EMT in the pathogenesis of IPF. Histological analysis suggests TGF-ß-stimulated myofibroblasts initiate a contractile response within established fibroblastic foci leading to mechanical stress on the surrounding alveolar epithelium. My data provides evidence of potential TGF-ß-mediated contact inhibition of ATII cells overlying fibroblastic foci, leading to prolonged cell stasis and subsequent senescence. This ATII cell senescence may lead to a reduction in the lung tissue remodelling capacity of IPF epithelium within the micro-niche areas surrounding fibroblastic foci. Information derived from this study may be used to develop targeted interventions aimed at reducing the number of fibroblastic foci and therefore improving ATII cell regeneration of the alveolar epithelium. Marker expression correlation with histological disease activity may emerge as future prognostic indicators for IPF

Hyperpolarized Xenon-129 Magnetic Resonance Imaging of Functional Lung Microstructure

Hyperpolarized 129Xe (HXe) is a non-invasive contrast agent for lung magnetic resonance imaging (MRI), which upon inhalation follows the functional pathway of oxygen in the lung by dissolving into lung tissue structures and entering the blood stream. HXe MRI therefore provides unique opportunities for functional lung imaging of gas exchange which occurs from alveolar air spaces across the air-blood boundary into parenchymal tissue. However challenges in acquisition speed and signal-to-noise ratio have limited the development of a HXe imaging biomarker to diagnose lung disease. This thesis addresses these challenges by introducing parallel imaging to HXe MRI. Parallel imaging requires dedicated hardware. This work describes design, implementation, and characterization of a 32-channel phased-array chest receive coil with an integrated asymmetric birdcage transmit coil tuned to the HXe resonance on a 3 Tesla MRI system. Using the newly developed human chest coil, a functional HXe imaging method, multiple exchange time xenon magnetization transfer contrast (MXTC) is implemented. MXTC dynamically encodes HXe gas exchange into the image contrast. This permits two parameters to be derived regionally which are related to gas-exchange functionality by characterizing tissue-to-alveolar-volume ratio and alveolar wall thickness in the lung parenchyma. Initial results in healthy subjects demonstrate the sensitivity of MXTC by quantifying the subtle changes in lung microstructure in response to orientation and lung inflation. Our results in subjects with lung disease show that the MXTC-derived functional tissue density parameter exhibits excellent agreement with established imaging techniques. The newly developed dynamic parameter, which characterizes the alveolar wall, was elevated in subjects with lung disease, most likely indicating parenchymal inflammation. In light of these observations we believe that MXTC has potential as a biomarker for the regional quantification of 1) emphysematous tissue destruction in chronic obstructive pulmonary disease (using the tissue density parameter) and 2) parenchymal inflammation or thickening (using the wall thickness parameter). By simultaneously quantifying two lung function parameters, MXTC provides a more comprehensive picture of lung microstructure than existing lung imaging techniques and could become an important non-invasive and quantitative tool to characterize pulmonary disease

Chronic obstructive pulmonary disease and risk of lung cancer

Abstract Background: Lung cancer is a main cause of death in patients suffering from COPD and smokers with COPD have an increased risk of lung cancer compared to healthy smokers. COPD comprises a broad range of features, including emphysema, chronic bronchitis, asthmatic features, and acute exacerbations in COPD (AECOPD). We hypothesized that some of these features of COPD represent a higher risk of lung cancer and non-pulmonary cancer. Aims: 1. To explore if emphysema and airway wall thickness assessed quantitatively on CT increase the risk of lung cancer and non-pulmonary cancer. 2. To investigate if acute exacerbations in COPD are associated with the risk of lung cancer, and to see whether this association differs based on coexisting asthma. 3. To examine and compare two lung cancer screening scores in our population of patients with COPD. Materials and Methods: Participants included in the analyses of all three papers were from the GenKOLS study in Bergen, Norway, conducted between January 2003 and January 2005. Participants were 40-85 years of age and had a smoking history of at least 2.5 pack-years at baseline. GenKOLS was conducted as a case-control study. COPD was diagnosed when post-bronchodilator FEV1/FVC was <0.70 and FEV1<80% predicted. Baseline examinations included a detailed questionnaire on smoking habits, respiratory symptoms, and disease history, as well as pulmonary function tests. Approximately half of all the participants had a chest CT scan. Baseline data were linked to incident cancer data from the Cancer Registry of Norway throughout the year 2013. All subjects with a cancer diagnosis before inclusion were excluded from the analyses. In Paper III, the subjects were divided into high and low risk according to the National Lung Cancer Screening Trial (NLST) inclusion criteria, and the COPD-Lung Cancer Screening Score (COPD-LUCSS). Cox proportional hazards regression were used to examine the hazard ratios (HR) for the effect of the predictor variables on the risk of cancer. Results: 1. After adjustment for age, sex, pack-years, age of onset of smoking, smoking status at baseline, and FEV1, the baseline amount of emphysema remained a significant predictor of the incidence of non-pulmonary cancer and lung cancer. Airway wall thickness did not predict cancer independently. 2. AECOPD was significantly associated with lung cancer during ten years of follow-up only in COPD patients without asthma. The analysis was adjusted for sex, age, smoking variables, FEV1, and BMI. 3. The NLST selection criteria, and the COPD-LUCSS were both significantly associated with the risk of lung cancer. The area under the curve values showed that both models have poor discriminatory abilities in our cohort. There was no significant difference in the discriminatory ability between the scores. Conclusions: Some features of COPD were significantly associated with the risk of lung cancer, and even non-pulmonary cancer. Emphysema was significantly associated with lung cancer risk and risk of non-pulmonary cancer, whereas airway wall thickness was not. AECOPD was associated with an increased risk of lung cancer only in COPD patients without asthma. Some of these features of COPD might be of use in evaluating those who could benefit from lung cancer screening. Although both the NLST selection criteria and the COPD-LUCSS, were associated with an increased risk of lung cancer, both scores had poor discriminatory abilities in our cohort of COPD patients. More studies are needed to find better models to target those at higher risk of lung cancer.Doktorgradsavhandlin

Post-TB lung damage amongst Malawian adults

INTRODUCTION: Pulmonary tuberculosis (PTB) remains an important risk factor for chronic lung disease (CLD) in sub-Saharan Africa (sSA), but our understanding of the nature of post-TB lung damage, its evolution over time, and the associated morbidity remains limited. This information is needed to inform clinical care and health system approaches to the management of those surviving PTB disease. METHODS: A general review of the literature on CLDs in sSA, TB disease and epidemiology, and post-TB lung damage and its associated morbidity were completed, followed by a systematic review of the prevalence and pattern of post-TB structural lung pathology. Primary data presented in this thesis were drawn from two studies based in urban Blantyre, Malawi. The first was a cross-sectional survey of respiratory abnormalities amongst adults in the community which was completed as part of the Burden of Obstructive Lung Disease (BOLD) initiative. The second was a prospective cohort study of HIV-positive and negative adults completing treatment for PTB which aimed to describe a) the prevalence of respiratory pathology at TB treatment completion using symptoms, quality of life scores, spirometry and high-resolution CT imaging, and b) the relationships between post-TB lung damage at treatment completion and adverse outcomes over 1-year of followup. RESULTS: The systematic review identified 39 studies of variable quality describing post-TB structural lung damage. A lack of prospective data, and data from sSA and HIV-positive groups was noted. Few studies related structural damage to symptoms, spirometry, or morbidity. The BOLD data estimated a high burden of respiratory symptoms and abnormal spirometry amongst adults aged ≥18 years in urban Blantyre: 11.8% reported ≥1 symptom, and 4.8% had airway obstruction. The prevalence of the low-FVC pattern of abnormal spirometry varied according to the reference range used for standardisation, from 9.0% (local reference range) to 38.6% (NHANES III reference range). A considerable burden of residual lung pathology was seen amongst 405 adults completing treatment for PTB in Blantyre: 60.7% had ongoing weekly/monthly respiratory symptoms, and 34.2% of participants had abnormal spirometry at PTB treatment completion. Participants had a median of 1.4 lobes of abnormal parenchyma on CT imaging. Moderate-severe bronchiectasis was seen in 44%, and 9.6% had ≥1 ‘destroyed’ lobe. The burden of pathology was lower in HIV-positive vs. HIV-negative adults, but patterns of abnormality were similar. The odds of ongoing respiratory symptoms or an impaired quality of life at 1-year were over three-fold higher amongst those with both extensive structural damage and abnormal spirometry at PTB treatment completion. CONCLUSION: Post-TB lung damage is a common but neglected form of CLD amongst both HIV-positive and negative adults in Malawi, and occurs against a high background prevalence of respiratory symptoms and abnormal spirometry in the community. Severe forms are associated with considerable ongoing morbidity including persistent symptoms and reduced quality of life. Further work is required to understand the range of patterns of post-TB lung damage, and their relationship with long-term outcomes such as respiratory exacerbations and mortality. However, this is a neglected population and interventions to maximise their health following PTB treatment completion are required

Characterization of alar ligament on 3.0T MRI: a cross-sectional study in IIUM Medical Centre, Kuantan

INTRODUCTION: The main purpose of the study is to compare the normal anatomy of alar ligament on MRI between male and female. The specific objectives are to assess the prevalence of alar ligament visualized on MRI, to describe its characteristics in term of its course, shape and signal homogeneity and to find differences in alar ligament signal intensity between male and female. This study also aims to determine the association between the heights of respondents with alar ligament signal intensity and dimensions. MATERIALS & METHODS: 50 healthy volunteers were studied on 3.0T MR scanner Siemens Magnetom Spectra using 2-mm proton density, T2 and fat-suppression sequences. Alar ligament is depicted in 3 planes and the visualization and variability of the ligament courses, shapes and signal intensity characteristics were determined. The alar ligament dimensions were also measured. RESULTS: Alar ligament was best depicted in coronal plane, followed by sagittal and axial planes. The orientations were laterally ascending in most of the subjects (60%), predominantly oval in shaped (54%) and 67% showed inhomogenous signal. No significant difference of alar ligament signal intensity between male and female respondents. No significant association was found between the heights of the respondents with alar ligament signal intensity and dimensions. CONCLUSION: Employing a 3.0T MR scanner, the alar ligament is best portrayed on coronal plane, followed by sagittal and axial planes. However, tremendous variability of alar ligament as depicted in our data shows that caution needs to be exercised when evaluating alar ligament, especially during circumstances of injury

A graph-based approach for the retrieval of multi-modality medical images

Medical imaging has revolutionised modern medicine and is now an integral aspect of diagnosis and patient monitoring. The development of new imaging devices for a wide variety of clinical cases has spurred an increase in the data volume acquired in hospitals. These large data collections offer opportunities for search-based applications in evidence-based diagnosis, education, and biomedical research. However, conventional search methods that operate upon manual annotations are not feasible for this data volume. Content-based image retrieval (CBIR) is an image search technique that uses automatically derived visual features as search criteria and has demonstrable clinical benefits. However, very few studies have investigated the CBIR of multi-modality medical images, which are making a monumental impact in healthcare, e.g., combined positron emission tomography and computed tomography (PET-CT) for cancer diagnosis. In this thesis, we propose a new graph-based method for the CBIR of multi-modality medical images. We derive a graph representation that emphasises the spatial relationships between modalities by structurally constraining the graph based on image features, e.g., spatial proximity of tumours and organs. We also introduce a graph similarity calculation algorithm that prioritises the relationships between tumours and related organs. To enable effective human interpretation of retrieved multi-modality images, we also present a user interface that displays graph abstractions alongside complex multi-modality images. Our results demonstrated that our method achieved a high precision when retrieving images on the basis of tumour location within organs. The evaluation of our proposed UI design by user surveys revealed that it improved the ability of users to interpret and understand the similarity between retrieved PET-CT images. The work in this thesis advances the state-of-the-art by enabling a novel approach for the retrieval of multi-modality medical images

Case series of breast fillers and how things may go wrong: radiology point of view

INTRODUCTION: Breast augmentation is a procedure opted by women to overcome sagging breast due to breastfeeding or aging as well as small breast size. Recent years have shown the emergence of a variety of injectable materials on market as breast fillers. These injectable breast fillers have swiftly gained popularity among women, considering the minimal invasiveness of the procedure, nullifying the need for terrifying surgery. Little do they know that the procedure may pose detrimental complications, while visualization of breast parenchyma infiltrated by these fillers is also deemed substandard; posing diagnostic challenges. We present a case series of three patients with prior history of hyaluronic acid and collagen breast injections. REPORT: The first patient is a 37-year-old lady who presented to casualty with worsening shortness of breath, non-productive cough, central chest pain; associated with fever and chills for 2-weeks duration. The second patient is a 34-year-old lady who complained of cough, fever and haemoptysis; associated with shortness of breath for 1-week duration. CT in these cases revealed non thrombotic wedge-shaped peripheral air-space densities. The third patient is a 37‐year‐old female with right breast pain, swelling and redness for 2- weeks duration. Previous collagen breast injection performed 1 year ago had impeded sonographic visualization of the breast parenchyma. MRI breasts showed multiple non- enhancing round and oval shaped lesions exhibiting fat intensity. CONCLUSION: Radiologists should be familiar with the potential risks and hazards as well as limitations of imaging posed by breast fillers such that MRI is required as problem-solving tool