Combinatorial optimisation for arterial image segmentation.

Cardiovascular disease is one of the leading causes of the mortality in the western world. Many imaging modalities have been used to diagnose cardiovascular diseases. However, each has different forms of noise and artifacts that make the medical image analysis field important and challenging. This thesis is concerned with developing fully automatic segmentation methods for cross-sectional coronary arterial imaging in particular, intra-vascular ultrasound and optical coherence tomography, by incorporating prior and tracking information without any user intervention, to effectively overcome various image artifacts and occlusions. Combinatorial optimisation methods are proposed to solve the segmentation problem in polynomial time. A node-weighted directed graph is constructed so that the vessel border delineation is considered as computing a minimum closed set. A set of complementary edge and texture features is extracted. Single and double interface segmentation methods are introduced. Novel optimisation of the boundary energy function is proposed based on a supervised classification method. Shape prior model is incorporated into the segmentation framework based on global and local information through the energy function design and graph construction. A combination of cross-sectional segmentation and longitudinal tracking is proposed using the Kalman filter and the hidden Markov model. The border is parameterised using the radial basis functions. The Kalman filter is used to adapt the inter-frame constraints between every two consecutive frames to obtain coherent temporal segmentation. An HMM-based border tracking method is also proposed in which the emission probability is derived from both the classification-based cost function and the shape prior model. The optimal sequence of the hidden states is computed using the Viterbi algorithm. Both qualitative and quantitative results on thousands of images show superior performance of the proposed methods compared to a number of state-of-the-art segmentation methods

Coronary Angiography

In the intervening 10 years tremendous advances in the field of cardiac computed tomography have occurred. We now can legitimately claim that computed tomography angiography (CTA) of the coronary arteries is available. In the evaluation of patients with suspected coronary artery disease (CAD), many guidelines today consider CTA an alternative to stress testing. The use of CTA in primary prevention patients is more controversial in considering diagnostic test interpretation in populations with a low prevalence to disease. However the nuclear technique most frequently used by cardiologists is myocardial perfusion imaging (MPI). The combination of a nuclear camera with CTA allows for the attainment of coronary anatomic, cardiac function and MPI from one piece of equipment. PET/SPECT cameras can now assess perfusion, function, and metabolism. Assessing cardiac viability is now fairly routine with these enhancements to cardiac imaging. This issue is full of important information that every cardiologist needs to now

Improving stroke risk prediction and individualised treatment in carotid atherosclerosis

Background: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. Currently, this risk estimation is based on measurements of stenosis and neurological symptoms, which determines the therapy of either medical treatment with or without carotid endarterectomy. The efficacy of this therapy is low and higher accuracy of diagnosis and therapy is warranted. Imaging of carotid plaque morphology using software for visualisation of plaque components may improve assessment of plaque phenotype and stroke risk. These studies aimed firstly to investigate if, and if yes, how, the carotid plaque morphology with image analysis of CTA associated with on-going biology in the corresponding specimen. Secondly, if risk stratification in clinical risk scores can be linked to the aforementioned associations. Finally, if the on-going biological processes can be specifically predicted out of the CTA imaging analysis. Methods: Plaque features were analysed in pre-operative CTA with dedicated software. In study I and II, the plaques were stratified according to quantified high and low of each feature, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry was performed to evaluate the findings in plaques. In study III, patient phenotype, according to clinical stroke risk scores of CAR and ABCD2 stratified the cohorts of high vs low scores which were subsequently profiled with microarrays, followed by bioinformatic analyses and correlation analyses of plaque morphology in CTA. In study IV, the microarray transcriptomes were individually coupled to morphological data from the CTA analysis, developing models with machine intelligence to predict the gene expression from a CTA image. The models were then tested in unseen patients. Results: In study I, stabilising markers and processes related to SMCs and ECM organisation were associated with highly calcified plaques, while inflammatory and lipid related processes were repressed. PRG4, a novel marker for atherosclerosis, was identified as the most up-regulated gene in highly calcified plaques. Study II showed that carotid lesions with large lipid rich necrotic core, intraplaque haemorrhage or plaque burden were characterized by molecular signatures coupled with inflammation and extracellular matrix degradation, typically linked with instability. Symptomatology associated with large lipid rich necrotic core and plaque burden. Cross-validated prediction model for symptoms, showed that plaque morphology by CTA alone was superior to stenosis degree. Study III revealed that a high clinical risk score in CAR and ABCD2, reflect a plaque phenotype linked to immune response and coagulation, where the novel ABCB5, was one of the most up-regulated genes. The high risk scores correlated with the plaque components matrix and calcification but no positive association with stenosis degree. Study IV resulted in 414 robustly predicted transcripts from the CTA image analysis, of which pathway analysis showed biological processes associated with typical pathophysiology of atherosclerosis and plaque instability. The model testing demonstrated a good correlation between predicted and observed transcript expression levels and pathway analysis revealed a unique dominant mechanism for each individual. Conclusions: Biological processes in carotid plaques associated to vulnerability, can be linked to plaque morphology analysed with CTA image analysis. Patient phenotype classified with clinical risk scores associates to plaque phenotype and morphology in CTA. The biological processes in the atherosclerotic plaque can be predicted with plaque morphology CTA analysis in this small pilot study, providing a possibility to precision medicine after validation in larger scale studie

Cluster analysis of the signal curves in perfusion DCE-MRI datasets

Pathological studies show that tumors consist of different sub-regions with more homogeneous vascular properties during their growth. In addition, destroying tumor's blood supply is the target of most cancer therapies. Finding the sub-regions in the tissue of interest with similar perfusion patterns provides us with valuable information about tissue structure and angiogenesis. This information on cancer therapy, for example, can be used in monitoring the response of the cancer treatment to the drug. Cluster analysis of perfusion curves assays to find sub-regions with a similar perfusion pattern. The present work focuses on the cluster analysis of perfusion curves, measured by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The study, besides searching for the proper clustering method, follows two other major topics, the choice of an appropriate similarity measure, and determining the number of clusters. These three subjects are connected to each other in such a way that success in one direction will help solving the other problems. This work introduces a new similarity measure, parallelism measure (PM), for comparing the parallelism in the washout phase of the signal curves. Most of the previous works used the Euclidean distance as the measure of dissimilarity. However, the Euclidean distance does not take the patterns of the signal curves into account and therefore for comparing the signal curves is not sufficient. To combine the advantages of both measures a two-steps clustering is developed. The two-steps clustering uses two different similarity measures, the introduced PM measure and Euclidean distance in two consecutive steps. The results of two-steps clustering are compared with the results of other clustering methods. The two-steps clustering besides good performance has some other advantages. The granularity and the number of clusters are controlled by thresholds defined by considering the noise in signal curves. The method is easy to implement and is robust against noise. The focus of the work is mainly the cluster analysis of breast tumors in DCE-MRI datasets. The possibility to adopt the method for liver datasets is studied as well

Multimodality Imaging of Anatomy and Function in Coronary Artery Disease

Various modalities are available in the diagnostic and prognostic evaluation of patients presenting with known or suspected coronary artery disease (CAD). A rapidly expanding technique is noninvasive coronary angiography with Multi-Slice Computed Tomography (MSCT), which allows accurate detection of significant stenoses. The main value of the technique lies in the noninvasive exclusion of CAD in patients with intermediate pre-test likelihood. Although imaging in populations such as patients with previous stent placement appears to be more challenging, promising results have been obtained in these populations as well. However, it remains important to realize that the presence of coronary atherosclerosis with luminal obstruction does not invariably imply the presence of ischemia. Accordingly, a noninvasive angiographic imaging technique as MSCT cannot be used to predict the hemodynamical importance of lesions. In patients with borderline stenosis, therefore, functional testing (which can be performed by nuclear imaging, stress echocardiography or MRI) will remain necessary to determine management. Nonetheless, detection of CAD at a far earlier stage than functional imaging is an important advantage of MSCT. Initial investigations suggest that MSCT may distinguish different plaque characteristics between various presentations. Potentially, this information could be useful for risk stratification. Finally, additional non-coronary information can be derived as well. LV function can be evaluated with high accuracy while also information on the cardiac venous system can be obtained.LEI Universiteit LeidenNederlandse Hartstichting, ICIN Toshiba Medical Systems BV, Vital Images BV, Biotronik BV, Stichting EMEX, Foundation Imago, J.E. Jurriaanse Stichting, Medtronic BV, Astellas Pharma BV, St Jude Medical BV, Tyco Healthcare BV, Amgen BV (Breda), Boehringer Ingelheim BV, GE Healthcare Medical Diagnostics (Eindhoven), Pfizer BV, Siemens BV, Bristol-Myers Squibb, Boston Scientific Benelux BV, Merck Sharp & Dohme BV.Vasculaire biologie en interventi

Navigation system based in motion tracking sensor for percutaneous renal access

Tese de Doutoramento em Engenharia BiomédicaMinimally-invasive kidney interventions are daily performed to diagnose and treat several renal diseases. Percutaneous renal access (PRA) is an essential but challenging stage for most of these procedures, since its outcome is directly linked to the physician’s ability to precisely visualize and reach the anatomical target. Nowadays, PRA is always guided with medical imaging assistance, most frequently using X-ray based imaging (e.g. fluoroscopy). Thus, radiation on the surgical theater represents a major risk to the medical team, where its exclusion from PRA has a direct impact diminishing the dose exposure on both patients and physicians. To solve the referred problems this thesis aims to develop a new hardware/software framework to intuitively and safely guide the surgeon during PRA planning and puncturing. In terms of surgical planning, a set of methodologies were developed to increase the certainty of reaching a specific target inside the kidney. The most relevant abdominal structures for PRA were automatically clustered into different 3D volumes. For that, primitive volumes were merged as a local optimization problem using the minimum description length principle and image statistical properties. A multi-volume Ray Cast method was then used to highlight each segmented volume. Results show that it is possible to detect all abdominal structures surrounding the kidney, with the ability to correctly estimate a virtual trajectory. Concerning the percutaneous puncturing stage, either an electromagnetic or optical solution were developed and tested in multiple in vitro, in vivo and ex vivo trials. The optical tracking solution aids in establishing the desired puncture site and choosing the best virtual puncture trajectory. However, this system required a line of sight to different optical markers placed at the needle base, limiting the accuracy when tracking inside the human body. Results show that the needle tip can deflect from its initial straight line trajectory with an error higher than 3 mm. Moreover, a complex registration procedure and initial setup is needed. On the other hand, a real-time electromagnetic tracking was developed. Hereto, a catheter was inserted trans-urethrally towards the renal target. This catheter has a position and orientation electromagnetic sensor on its tip that function as a real-time target locator. Then, a needle integrating a similar sensor is used. From the data provided by both sensors, one computes a virtual puncture trajectory, which is displayed in a 3D visualization software. In vivo tests showed a median renal and ureteral puncture times of 19 and 51 seconds, respectively (range 14 to 45 and 45 to 67 seconds). Such results represent a puncture time improvement between 75% and 85% when comparing to state of the art methods. 3D sound and vibrotactile feedback were also developed to provide additional information about the needle orientation. By using these kind of feedback, it was verified that the surgeon tends to follow a virtual puncture trajectory with a reduced amount of deviations from the ideal trajectory, being able to anticipate any movement even without looking to a monitor. Best results show that 3D sound sources were correctly identified 79.2 ± 8.1% of times with an average angulation error of 10.4º degrees. Vibration sources were accurately identified 91.1 ± 3.6% of times with an average angulation error of 8.0º degrees. Additionally to the EMT framework, three circular ultrasound transducers were built with a needle working channel. One explored different manufacture fabrication setups in terms of the piezoelectric materials, transducer construction, single vs. multi array configurations, backing and matching material design. The A-scan signals retrieved from each transducer were filtered and processed to automatically detect reflected echoes and to alert the surgeon when undesirable anatomical structures are in between the puncture path. The transducers were mapped in a water tank and tested in a study involving 45 phantoms. Results showed that the beam cross-sectional area oscillates around the ceramics radius and it was possible to automatically detect echo signals in phantoms with length higher than 80 mm. Hereupon, it is expected that the introduction of the proposed system on the PRA procedure, will allow to guide the surgeon through the optimal path towards the precise kidney target, increasing surgeon’s confidence and reducing complications (e.g. organ perforation) during PRA. Moreover, the developed framework has the potential to make the PRA free of radiation for both patient and surgeon and to broad the use of PRA to less specialized surgeons.Intervenções renais minimamente invasivas são realizadas diariamente para o tratamento e diagnóstico de várias doenças renais. O acesso renal percutâneo (ARP) é uma etapa essencial e desafiante na maior parte destes procedimentos. O seu resultado encontra-se diretamente relacionado com a capacidade do cirurgião visualizar e atingir com precisão o alvo anatómico. Hoje em dia, o ARP é sempre guiado com recurso a sistemas imagiológicos, na maior parte das vezes baseados em raios-X (p.e. a fluoroscopia). A radiação destes sistemas nas salas cirúrgicas representa um grande risco para a equipa médica, aonde a sua remoção levará a um impacto direto na diminuição da dose exposta aos pacientes e cirurgiões. De modo a resolver os problemas existentes, esta tese tem como objetivo o desenvolvimento de uma framework de hardware/software que permita, de forma intuitiva e segura, guiar o cirurgião durante o planeamento e punção do ARP. Em termos de planeamento, foi desenvolvido um conjunto de metodologias de modo a aumentar a eficácia com que o alvo anatómico é alcançado. As estruturas abdominais mais relevantes para o procedimento de ARP, foram automaticamente agrupadas em volumes 3D, através de um problema de optimização global com base no princípio de “minimum description length” e propriedades estatísticas da imagem. Por fim, um procedimento de Ray Cast, com múltiplas funções de transferência, foi utilizado para enfatizar as estruturas segmentadas. Os resultados mostram que é possível detetar todas as estruturas abdominais envolventes ao rim, com a capacidade para estimar corretamente uma trajetória virtual. No que diz respeito à fase de punção percutânea, foram testadas duas soluções de deteção de movimento (ótica e eletromagnética) em múltiplos ensaios in vitro, in vivo e ex vivo. A solução baseada em sensores óticos ajudou no cálculo do melhor ponto de punção e na definição da melhor trajetória a seguir. Contudo, este sistema necessita de uma linha de visão com diferentes marcadores óticos acoplados à base da agulha, limitando a precisão com que a agulha é detetada no interior do corpo humano. Os resultados indicam que a agulha pode sofrer deflexões à medida que vai sendo inserida, com erros superiores a 3 mm. Por outro lado, foi desenvolvida e testada uma solução com base em sensores eletromagnéticos. Para tal, um cateter que integra um sensor de posição e orientação na sua ponta, foi colocado por via trans-uretral junto do alvo renal. De seguida, uma agulha, integrando um sensor semelhante, é utilizada para a punção percutânea. A partir da diferença espacial de ambos os sensores, é possível gerar uma trajetória de punção virtual. A mediana do tempo necessário para puncionar o rim e ureter, segundo esta trajetória, foi de 19 e 51 segundos, respetivamente (variações de 14 a 45 e 45 a 67 segundos). Estes resultados representam uma melhoria do tempo de punção entre 75% e 85%, quando comparados com o estado da arte dos métodos atuais. Além do feedback visual, som 3D e feedback vibratório foram explorados de modo a fornecer informações complementares da posição da agulha. Verificou-se que com este tipo de feedback, o cirurgião tende a seguir uma trajetória de punção com desvios mínimos, sendo igualmente capaz de antecipar qualquer movimento, mesmo sem olhar para o monitor. Fontes de som e vibração podem ser corretamente detetadas em 79,2 ± 8,1% e 91,1 ± 3,6%, com erros médios de angulação de 10.4º e 8.0 graus, respetivamente. Adicionalmente ao sistema de navegação, foram também produzidos três transdutores de ultrassom circulares com um canal de trabalho para a agulha. Para tal, foram exploradas diferentes configurações de fabricação em termos de materiais piezoelétricos, transdutores multi-array ou singulares e espessura/material de layers de suporte. Os sinais originados em cada transdutor foram filtrados e processados de modo a detetar de forma automática os ecos refletidos, e assim, alertar o cirurgião quando existem variações anatómicas ao longo do caminho de punção. Os transdutores foram mapeados num tanque de água e testados em 45 phantoms. Os resultados mostraram que o feixe de área em corte transversal oscila em torno do raio de cerâmica, e que os ecos refletidos são detetados em phantoms com comprimentos superiores a 80 mm. Desta forma, é expectável que a introdução deste novo sistema a nível do ARP permitirá conduzir o cirurgião ao longo do caminho de punção ideal, aumentado a confiança do cirurgião e reduzindo possíveis complicações (p.e. a perfuração dos órgãos). Além disso, de realçar que este sistema apresenta o potencial de tornar o ARP livre de radiação e alarga-lo a cirurgiões menos especializados.The present work was only possible thanks to the support by the Portuguese Science and Technology Foundation through the PhD grant with reference SFRH/BD/74276/2010 funded by FCT/MEC (PIDDAC) and by Fundo Europeu de Desenvolvimento Regional (FEDER), Programa COMPETE - Programa Operacional Factores de Competitividade (POFC) do QREN

Imaging of Tumour Microenvironment for the Planning of Oncological Therapies Using Positron Emission Tomography

Tumour cells differ from normal tissue cells in several important ways. These differences, like for example changed energy metabolism, result in altered microenvironment of malignant tumours. Non-invasive imaging of tumour microenvironment has been at the centre of intense research recently due to the important role that this changed environement plays in the development of malignant tumours and due to the role it plays in the treatment of these tumours. In this respect, perhaps the most important characteristics of the tumour microenvironment from this point of view are the lack of oxygen or hypoxia and changes in blood flow (BF). The purpose of this thesis was to investigate the processes of energy metabolism, BF and oxygenation in head and neck cancer and pancreatic tumours and to explore the possibilities of improving the methods for their quantification using positron emission tomography (PET). To this end [18F]EF5, a new PET tracer for detection of tumour hypoxia was investigated. Favourable uptake properties of the tracer were observed. In addition, it was established that the uptake of this tracer does not correlate with the uptake of existing tracers for the imaging of energy metabolism and BF, so the information about the presence of tissue hypoxia cannot therefore be obtained using tracers such as [18F]FDG or [15O]H2O. These results were complemented by the results of the follow-up study in which it was shown that the uptake of [18F]EF5 in head and neck tumours prior to treatment is also associated with the overall survival of the patients, indicating that tumour hypoxia is a negative prognostic factor and might be associated with therapeutic resistance. The influences of energy metabolism and BF on the survival of patients with pancreatic cancer were investigated in the second study. The results indicate that the best predictor of survival of patients with pancreatic cancer is the relationship between energy metabolism and BF. These results suggest that the cells with high metabolic activity in a hypoperfused tissue have the most aggressive phenotype.Siirretty Doriast