Every year more than fourteen-thousand adults in the United States are diagnosed with glioma, the most common malignant tumor of the central nervous system. Gliomas arise from glue like glial cells and present with a range of grade and prognosis. Glioblastoma multiforme (GBM), a grade IV glioma, is the most common glioma subtype and carries dismal prognosis with fewer than one half of patients surviving one year after diagnosis. The standard treatment for GBM is resection followed by a cocktail of chemo and radiation therapy. Unfortunately, complete surgical resection is impossible for GBM, and intra-tumor heterogeneity, a GBM hallmark, negatively impacts chemo and radiation therapy efficacy. This thesis contains six chapters that evaluate advanced imaging and statistical methods that may be used to improve glioma management. Chapter one presents background information to establish the relationship of four subsequent studies with ranging topics on advanced imaging techniques, biopsy sampling, and radiomic analysis. In chapter two, a case report is presented that demonstrates the importance of advanced magnetic resonance imaging (MRI) such as arterial spin labeled (ASL) perfusion sequences. In this case, a patient with a benign cerebral lesion presents with receptive aphasia and of the imaging data acquired, only ASL showed decrease cerebral aphasia. Chapter three describes the impact biopsy selection has on correlation between prognostic and histologic features in 35 patients with GBM. Multiple biopsy selection methods were compared, resulting in a wide range in correlation significance. Chapter four presents different voxel-wise radiomic models in adult glioma patients. From one voxel-wise radiomic model, predicted disease compositions (PDC) were computed in 17 glioma patients and were able to significantly (α = 0.05) predict overall survival, tumor grade, and endothelial proliferation. Chapter five describes the feasibility and hardware constraints of simultaneous PET/MR imaging protocols. A dynamic infusion of fluorodeoxyglucose (FDG) was administered with simultaneous MR imaging including echo planar imaging (EPI) based sequences used for functional MRI (fMRI). Heat from the EPI sequences deposited in the PET detector hardware and resulted in significant hardware failure. Finally, chapter six provides outlook and application to glioma clinical management considering the methods and findings presented in each study.<br>

High-resolution computed tomography (HRCT) of the chest is commonly used in the diagnosis of a variety of lung diseases. Structural changes associated with clinical characteristics of disease may also define specific disease-associated physiologic states that may provide insights into disease pathophysiology. Gene expression profiling is potentially a useful adjunct to HRCT to identify molecular correlates of the observed structural changes. However, it is difficult to directly access diseased distal airway or lung parenchyma routinely for profiling studies. Previously, we have profiled bronchial airway in normal-appearing epithelial cells at the mainstem bronchus, detecting distinct gene expression alterations related to the clinical diagnosis of chronic obstructive pulmonary disease (COPD) and lung cancer. These gene expression alterations offer insights into the molecular events related to diseased tissue at more distal airways and in the parenchyma, which we hypothesize are due to a field-of-injury effect. Here, we expand this prior work by correlating airway gene expression to COPD and bronchiectasis phenotypes defined by HRCT to better understand the pathophysiology of these diseases. Additionally, we classified pulmonary nodules as malignant or benign by combining HRCT nodule imaging characteristics with gene expression profiling of the nasal airway. First, we collected brushing samples from the main-stem bronchus and assessed gene expression alterations associated with COPD phenotypes defined by K-means clustering of HRCT-based imaging features. We found three imaging clusters, which correlated with incremental severity of COPD: preserved, interstitial predominant, and emphysema predominant. 357 genes were differentially expressed between the normal and the emphysema predominant clusters. Functional analysis of the differentially expressed genes suggests a possible induction of inflammatory processes and repression of T-cell related biologic pathways, in the emphysema predominant cluster. We then discovered gene expression alterations associated with radiographic evidence of bronchiectasis (BE), an underdiagnosed obstructive pulmonary disease with unclear pathophysiology. We found 655 genes were differentially expressed in bronchial epithelium from individuals with radiographic evidence of BE despite none of the study participants having a clinical BE diagnosis. In addition to biological pathways that had been previously associated with BE, novel pathways that may play important roles in BE initiation were also discovered. Furthermore, we leveraged an independent single-cell RNA-sequencing dataset of the bronchial epithelium to explore whether the observed gene expression alterations might be cell-type dependent. We computationally detected an increased presence of ciliated and deuterosomal cells, as well as a decreased presence of basal cells in subjects with widespread radiographic BE, which may reflect a shift in the cellular landscape of the airway during BE initiation. Finally, we identified gene expression alterations within the nasal epithelium associated with the presence of malignant pulmonary nodules. A computational model was constructed for determining whether a nodule is malignant or benign that combines gene expression and imaging features extracted from HRCT. Leveraging data from single-cell RNA sequencing, we found genes increased in patients with lung cancer are expressed at higher levels within a novel cluster of nasal epithelial cells, termed keratinizing epithelial cells. In summary, we leveraged gene expression profiling of the proximal airway and discovered novel biological pathways that potentially drive the structural changes representative of physiologic states defined by chest HRCT in COPD and BE. This approach may also be combined with chest HRCT to detect weak signals related to malignant pulmonary nodules. / 2024-02-03T00:00:00Z

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Glioblastoma is a highly malignant tumor which mostly recurs locally around the resected contrast enhancement. However, it is difficult to identify tumor invasiveness pre-surgically, especially in non-enhancing areas. Thus, the aim of this thesis was to utilize multimodal MR technique to identify and characterize the peritumoral progression zone that eventually leads to tumor progression. Patients with newly diagnosed cerebral glioblastoma were included consecutively from our cohort between 2010 and2014. The presurgical MRI sequences included volumetric T1-weighted with contrast, FLAIR, T2-weighted, diffusion-weighted imaging, diffusion tensor and perfusion MR imaging. Postsurgical and follow-up MRI included structural and ADC images. Image deformation, caused by disease nature and surgical procedure, renders routine coregistration methods inadequate for MRIs comparison between different time points. Therefore, a two-staged non-linear semi-automatic coregistration method was developed from the modification of the linear FLIRT and non-linear FNIRT functions in FMRIB’s Software Library (FSL). Utilising the above mentioned coregistration method, a volumetric study was conducted to analyse the extent of resection based on different MR techniques, including T1 weighted with contrast, FLAIR and DTI measures of isotropy (DTI-p) and anisotropy (DTI-q). The results showed that patients can have a better clinical outcome with a larger resection of the abnormal DTI q areas. Further study of the imaging characteristics of abnormal peritumoural DTI-q areas, using MRS and DCS-MRI, showed a higher Choline/NAA ratio (p = 0.035), especially higher Choline (p = 0.022), in these areas when compared to normal DTI-q areas. This was indicative of tumour activity in the peritumoural abnormal DTI-q areas. The peritumoural progression areas were found to have distinct imaging characteristics. In these progression areas, compared to non-progression areas within a 10 mm border around the contrast enhancing lesion, there was higher signal intensity in FLAIR (p = 0.02), and T1C (p < 0.001), and there were lower intensity in ADC (p = 0.029) and DTI-p (p < 0.001). Further applying radiomics features showed that 35 first order features and 77 second order features were significantly different between progression and non-progression areas. By using supervised convolutional neural network, there was an overall accuracy of 92.4% in the training set (n = 37) and 78.5% in the validation set (n=14). In summary, multimodal MR imaging, particularly diffusion tensor imaging, can demonstrate distinct characteristics in areas of potential progression on preoperative MRI, which can be considered potential targets for treatment. Further application of radiomics and machine learning can be potentially useful when identifying the tumor invasive margin before the surgery.

Computed tomography (CT) imagery is an important weapon in the fight against lung cancer; various forms of lung cancer are routinely diagnosed from CT imagery. The growth of the suspect nodule is known to be a prognostic factor in the diagnosis of pulmonary cancer, but the change in other aspects of the nodule, such as its aspect ratio, density, spiculation, or other features usable for machine learning, may also provide prognostic information. We hypothesized that adding combined feature information from multiple CT image sets separated in time could provide a more accurate determination of nodule malignancy. To this end, we combined data from multiple CT images for individual patients taken from the National Lung Screening Trial. The resulting dataset was compared to equivalent datasets featuring single CT images for each patient. Feature reduction and normalization was performed as is standard. The highest accuracy achieved was 83.71% on a subset of features chosen by a combination of manual feature stability testing and the Correlation-based Feature Selection algorithm and classified by the Random Forests algorithm. The highest accuracy achieved with individual CT images was 81.00%, on a feature set consisting solely of the volume of the nodule in cubic centimeters.

Positron Emission Tomography (PET) is an imaging modality that has become increasingly beneficial in Radiotherapy by improving treatment planning (1). PET reveals tumor volumes that are not well visualized on computed tomography CT or MRI, recognizes metastatic disease, and assesses radiotherapy treatment (1). It also reveals areas of the tumor that are more radiosensitive allowing for dose painting - a non-homogenous dose treatment across the tumor (1). However, PET is not without limitations. The quantitative unit of PET images, the Standardized Uptake Value (SUV), is affected by many factors such as reconstruction algorithm, patient weight, and tracer uptake time (2). In fact, PET is so sensitive that a patient imaged twice in a single day on the same machine and same protocol will produce different SUV values. The objective of this research was to increase the capabilities of PET by exploring other quantitative PET/CT measures for Radiotherapy treatment applications. The technique of quantitative image feature analysis, nowadays known as radiomics, was applied to PET and CT images. Image features were then extracted from PET/CT images and how the features differed between conventional and respiratory-gated PET/CT images in lung cancer was analyzed. The influence of noise on image features was analyzed by applying uncorrelated, Gaussian noise to PET/CT images and measuring how significantly noise affected features. Quantitative PET/CT measures outside of image feature analysis were also investigated. The correlation of esophageal metabolic tumor volumes (tumor volume demonstrating high metabolic uptake) and endoscopically implanted fiducial markers was studied. It was found that certain image features differed greatly between conventional and respiratory-gated PET/CT. The differences were mainly due to the effect of respiratory motion including affine motion, rotational motion and tumor deformation. Also, certain feature groups were more affected by noise than others. For instance, contour-dependent shape features exhibited the least change with noise. Comparatively, GLSZM features exhibited the greatest change with added noise. Discordance was discovered between the inferior and superior tumor fiducial markers and metabolic tumor volume (MTV). This demonstrated a need for both fiducial markers and MTV to provide a comprehensive view of a tumor. These studies called attention to the differences in features caused by factors such as motion, acquisition parameters, and noise, etc. Investigators should be aware of these effects. PET/CT radiomic features are indeed highly affected by noise and motion. For accurate clinical use, these effects must be account by investigators and future clinical users. Further investigation is warranted towards the standardization of PET/CT radiomic feature acquisition and clinical application.

Over the years, cancer has increasingly become a global health problem [12]. For successful treatment, early detection and diagnosis is critical. Radiomics is the use of CT, PET, MRI or Ultrasound imaging as input data, extracting features from image-based data, and then using machine learning for quantitative analysis and disease prediction [23, 14, 19, 1]. Feature reduction is critical as most quantitative features can have unnecessary redundant characteristics. The objective of this research is to use machine learning techniques in reducing the number of dimensions, thereby rendering the data manageable. Radiomics steps include Imaging, segmentation, feature extraction, and analysis. For this research, a large-scale CT data for Lung cancer diagnosis collected by scholars from Medical University in China is used to illustrate the dimension reduction techniques via R, SAS, and Python softwares. The proposed reduction and analysis techniques were PCA, Clustering, and Manifold-based algorithms. The results indicated the texture-based features

Lung cancer has been a major cause of death among types of cancers in the world. In the early stages, lung nodules can be detected by the aid of imaging modalities such as Computed Tomography (CT). In this stage, radiologists look for irregular rounded-shaped nodules in the lung which are normally less than 3 centimeters in diameter. Recent advancements in image analysis have proven that images contain more information than regular parameters such as intensity, histogram and morphological details. Therefore, in this project we have focused on extracting quantitative, hand-crafted features from nearly 1400 lung CT images to train a variety of classifiers based on them. In the first experiment, in total 424 Radiomics features per image has been used to train classifiers such as: Random Forest (RF), Support Vector Machine (SVM), Decision Tree (DT), Naive Bayes (NB), Linear Discriminant Analysis (LDA) and Multi-Layer Perceptron (MLP). In the second experiment, we evaluate each feature category separately with our classifiers. The third experiment includes wrapper feature selection methods (Forward/Backward/Recursive) and filter-based feature selection methods (Fisher score, Gini Index and Mutual information). They have been implemented to find the most relevant feature set in model construction. Performance of each learning method has been evaluated by accuracy score, wherewe achieved the highest accuracy of 78% with Random Forest classifier (74% in 5-fold average) and 0.82 Area Under the Receiver Operating Characteristics (AUROC) curve. After RF, NB and MLP showed the best average accuracy of 71.4% and 71% respectively.

[pt] Gliomas estão entre os tumores cerebrais malignos mais comuns. Eles podem ser classificados entre gliomas de baixo e alto grau e sua identificação precoce é fundamental para o direcionamento do tratamento aplicado. Utilizando uma abordagem radiomics, o presente trabalho propõe o uso de índices de biodiversidade e de diversidade filogenética, definidos no campo da biologia, no problema de classificação de gliomas. O método proposto apresentou resultados promissores, com AUC-ROC (area under the ROC curve), acurácia, sensibilidade e especificidade de 0,951, 0,930, 0,967 e 0,827, respectivamente. / [en] Gliomas are among the most common malignant brain tumors. They can be classified into low-grade and high-grade gliomas and their early identification is crucial for treatment direction. Using a radiomics approach, the present work proposes the use of biodiversity and phylogenetic diversity biology indices to handle the glioma classification problem. The proposed method presented promising results, with AUC-ROC (area under the ROC curve), accuracy, sensitivity and specificity of 0,951, 0,930, 0,967 and 0,827, respectively.

L’imagerie multi-modale Tomographie par émission de positons (TEP)/ Tomodensitométrie(TDM) est la modalité d’imagerie la plus utilisée pour le diagnostic et le suivi des patients en oncologie. Les images obtenues par cette méthode offrent une cartographie à la fois de la densité des tissus (modalité TDM) mais également une information sur l’activité métabolique des lésions tumorales (modalité TEP). L’analyse plus approfondie de ces images acquises en routine clinique a permis d’extraire des informations supplémentaires quant à la survie du patient ou à la réponse au(x) traitement(s). Toutes ces nouvelles données permettent de décrire le phénotype d’une lésion de façon non invasive et sont regroupées sous le terme de Radiomics. Cependant, le nombre de paramètres caractérisant la forme ou la texture des lésions n’a cessé d’augmenter ces dernières années et ces données peuvent être sensibles à la méthode d’extraction ou encore à la modalité d’imagerie employée. Pour ces travaux de thèse, la variabilité de ces caractéristiques a donc été évaluée sur les images TDM et TEP à l’aide d’une cohorte test-retest : pour chaque patient, deux examens effectués dans les mêmes conditions, espacés d’un intervalle de l’ordre de quelques jours sont disponibles. Les métriques reconnues comme fiables à la suite de cette analyse sont exploitées pour l’étude de la survie des patients dans le cadre du cancer du poumon. La construction d’un modèle pronostique à l’aide de ces métriques a permis, dans un premier temps, d’étudier la complémentarité des informations fournies par les deux modalités. Ce nomogramme a cependant été généré par simple addition des facteurs de risque. Dans un second temps, les mêmes données ont été exploitées afin de construire un modèle pronostique à l’aide d’une méthode d’apprentissage reconnue comme robuste : les machines à vecteurs de support ou SVM (support vector machine). Les modèles ainsi générés ont ensuite été testés sur une cohorte prospective en cours de recrutement afin d’obtenir des résultats préliminaires sur la robustesse de ces nomogrammes. / Positron emission tomography (PET) / Computed tomography (CT) multi-modality imaging is the most commonly used imaging technique to diagnose and monitor patients in oncology. PET/CT images provide a global tissue density description (CT images) and a characterization of tumor metabolic activity (PET images). Further analysis of those images acquired in clinical routine supplied additional data as regards patient survival or treatment response. All those new data allow to describe the tumor phenotype and are generally grouped under the generic name of Radiomics. Nevertheless, the number of shape descriptors and texture features characterising tumors have significantly increased in recent years and those parameters can be sensitive to exctraction method or whether to imaging modality. During this thesis, parameters variability, computed on PET and CT images, was assessed thanks to a test-retest cohort : for each patient, two groups of PET/CT images, acquired under the same conditions but generated with an interval of few minutes, were available. Parameters classified as reliable after this analysis were exploited for survival analysis of patients in the context of non-small cell lug cancer (NSCLC).The construction of a prognostic model with those metrics permitted first to study the complementarity of PET and CT texture features. However, this nomogram has been generated by simply adding risk factors and not with a robust multi-parametric analysis method. In the second part, the same data were exploited to build a prognostic model using support vector machine (SVM) algorithm. The models thus generated were then tested on a prospective cohort currently being recruited to obtain preliminary results as regards the robustness of those nomograms.