Model-Based Approach for Diffuse Glioma Classification, Grading, and Patient Survival Prediction

The work in this dissertation proposes model-based approaches for molecular mutations classification of gliomas, grading based on radiomics features and genomics, and prediction of diffuse gliomas clinical outcome in overall patient survival. Diffuse gliomas are types of Central Nervous System (CNS) brain tumors that account for 25.5% of primary brain and CNS tumors and originate from the supportive glial cells. In the 2016 World Health Organization’s (WHO) criteria for CNS brain tumor, a major reclassification of the diffuse gliomas is presented based on gliomas molecular mutations and the growth behavior. Currently, the status of molecular mutations is determined by obtaining viable regions of tumor tissue samples. However, an increasing need to non-invasively analyze the clinical outcome of tumors requires careful modeling and co-analysis of radiomics (i.e., imaging features) and genomics (molecular and proteomics features). The variances in diffuse Lower-grade gliomas (LGG), which are demonstrated by their heterogeneity, can be exemplified by radiographic imaging features (i.e., radiomics). Therefore, radiomics may be suggested as a crucial non-invasive marker in the tumor diagnosis and prognosis. Consequently, we examine radiomics extracted from the multi-resolution fractal representations of the tumor in classifying the molecular mutations of diffuse LGG non-invasively. The proposed radiomics in the decision-tree-based ensemble machine learning molecular prediction model confirm the efficacy of these fractal features in glioma prediction. Furthermore, this dissertation proposes a novel non-invasive statistical model to classify and predict LGG molecular mutations based on radiomics and count-based genomics data. The performance results of the proposed statistical model indicate that fusing radiomics to count-based genomics improves the performance of mutations prediction. Furthermore, the radiomics-based glioblastoma survival prediction framework is proposed in this work. The survival prediction framework includes two survival prediction pipelines that combine different feature selection and regression approaches. The framework is evaluated using two recent widely used benchmark datasets from Brain Tumor Segmentation (BraTS) challenges in 2017 and 2018. The first survival prediction pipeline offered the best overall performance in the 2017 Challenge, and the second survival prediction pipeline offered the best performance using the validation dataset. In summary, in this work, we develop non-invasive computational and statistical models based on radiomics and genomics to investigate overall survival, tumor progression, and the molecular classification in diffuse gliomas. The methods discussed in our study are important steps towards a non-invasive approach to diffuse brain tumor classification, grading, and patient survival prediction that may be recommended prior to invasive tissue sampling in a clinical setting

Machine learning predicts histologic type and grade of canine gliomas based on MRI texture analysis.

Conventional MRI features of canine gliomas subtypes and grades significantly overlap. Texture analysis (TA) quantifies image texture based on spatial arrangement of pixel intensities. Machine learning (ML) models based on MRI-TA demonstrate high accuracy in predicting brain tumor types and grades in human medicine. The aim of this retrospective, diagnostic accuracy study was to investigate the accuracy of ML-based MRI-TA in predicting canine gliomas histologic types and grades. Dogs with histopathological diagnosis of intracranial glioma and available brain MRI were included. Tumors were manually segmented across their entire volume in enhancing part, non-enhancing part, and peri-tumoral vasogenic edema in T2-weighted (T2w), T1-weighted (T1w), FLAIR, and T1w postcontrast sequences. Texture features were extracted and fed into three ML classifiers. Classifiers' performance was assessed using a leave-one-out cross-validation approach. Multiclass and binary models were built to predict histologic types (oligodendroglioma vs. astrocytoma vs. oligoastrocytoma) and grades (high vs. low), respectively. Thirty-eight dogs with a total of 40 masses were included. Machine learning classifiers had an average accuracy of 77% for discriminating tumor types and of 75.6% for predicting high-grade gliomas. The support vector machine classifier had an accuracy of up to 94% for predicting tumor types and up to 87% for predicting high-grade gliomas. The most discriminative texture features of tumor types and grades appeared related to the peri-tumoral edema in T1w images and to the non-enhancing part of the tumor in T2w images, respectively. In conclusion, ML-based MRI-TA has the potential to discriminate intracranial canine gliomas types and grades

Classification of the glioma grading using radiomics analysis

Background Grading of gliomas is critical information related to prognosis and survival. We aimed to apply a radiomics approach using various machine learning classifiers to determine the glioma grading. Methods We considered 285 (high grade n = 210, low grade n = 75) cases obtained from the Brain Tumor Segmentation 2017 Challenge. Manual annotations of enhancing tumors, non-enhancing tumors, necrosis, and edema were provided by the database. Each case was multi-modal with T1-weighted, T1-contrast enhanced, T2-weighted, and FLAIR images. A five-fold cross validation was adopted to separate the training and test data. A total of 468 radiomics features were calculated for three types of regions of interest. The minimum redundancy maximum relevance algorithm was used to select features useful for classifying glioma grades in the training cohort. The selected features were used to build three classifier models of logistics, support vector machines, and random forest classifiers. The classification performance of the models was measured in the training cohort using accuracy, sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic curve. The trained classifier models were applied to the test cohort. Results Five significant features were selected for the machine learning classifiers and the three classifiers showed an average AUC of 0.9400 for training cohorts and 0.9030 (logistic regression 0.9010, support vector machine 0.8866, and random forest 0.9213) for test cohorts. Discussion Glioma grading could be accurately determined using machine learning and feature selection techniques in conjunction with a radiomics approach. The results of our study might contribute to high-throughput computer aided diagnosis system for gliomas

Forecasting Molecular Features in IDH-Wildtype Gliomas: The State of the Art of Radiomics Applied to Neurosurgery

Simple Summary The prognostic expectancies of patients affected by glioblastoma have remained almost unchanged during the last thirty years. Along with specific oncological research and surgical technical alternatives, corollary disciplines are requested to provide their contributions to improve patient management and outcomes. Technological improvements in radiology have led to the development of radiomics, a new discipline able to detect tumoral phenotypical features through the extraction and analysis of a large amount of data. Intuitively, the early foreseeing of glioma features may constitute a tremendous contribution to the management of patients. The present manuscript analyzes the pertinent literature regarding the current role of radiomics and its potentialities. Background: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, marks a step forward the future diagnostic approach to these neoplasms. Alongside this, radiomics has experienced rapid evolution over the last several years, allowing us to correlate tumor imaging heterogeneity with a wide range of tumor molecular and subcellular features. Radiomics is a translational field focused on decoding conventional imaging data to extrapolate the molecular and prognostic features of tumors such as gliomas. We herein analyze the state-of-the-art of radiomics applied to glioblastoma, with the goal to estimate its current clinical impact and potential perspectives in relation to well-rounded patient management, including the end-of-life stage. Methods: A literature review was performed on the PubMed, MEDLINE and Scopus databases using the following search items: "radiomics and glioma", "radiomics and glioblastoma", "radiomics and glioma and IDH", "radiomics and glioma and TERT promoter", "radiomics and glioma and EGFR", "radiomics and glioma and chromosome". Results: A total of 719 articles were screened. Further quantitative and qualitative analysis allowed us to finally include 11 papers. This analysis shows that radiomics is rapidly evolving towards a reliable tool. Conclusions: Further studies are necessary to adjust radiomics' potential to the newest molecular requirements pointed out by the 2021 WHO classification of CNS tumors. At a glance, its application in the clinical routine could be beneficial to achieve a timely diagnosis, especially for those patients not eligible for surgery and/or adjuvant therapies but still deserving palliative and supportive care

Radiomics analyses for outcome prediction in patients with locally advanced rectal cancer and glioblastoma multiforme using multimodal imaging data

Personalized treatment strategies for oncological patient management can improve outcomes of patient populations with heterogeneous treatment response. The implementation of such a concept requires the identification of biomarkers that can precisely predict treatment outcome. In the context of this thesis, we develop and validate biomarkers from multimodal imaging data for the outcome prediction after treatment in patients with locally advanced rectal cancer (LARC) and in patients with newly diagnosed glioblastoma multiforme (GBM), using conventional feature-based radiomics and deep-learning (DL) based radiomics. For LARC patients, we identify promising radiomics signatures combining computed tomography (CT) and T2-weighted (T2-w) magnetic resonance imaging (MRI) with clinical parameters to predict tumour response to neoadjuvant chemoradiotherapy (nCRT). Further, the analyses of externally available radiomics models for LARC reveal a lack of reproducibility and the need for standardization of the radiomics process. For patients with GBM, we use postoperative [11C] methionine positron emission tomography (MET-PET) and gadolinium-enhanced T1-w MRI for the detection of the residual tumour status and to prognosticate time-to-recurrence (TTR) and overall survival (OS). We show that DL models built on MET-PET have an improved diagnostic and prognostic value as compared to MRI

Context, intelligence and interactions for personalized systems

This special issue on Context, Intelligence and Interactions for Personalized Systems provides a snapshot of the latest research activities, results, and technologies and application developments focusing on the smart personalised systems in Ambient Intelligence and Humanized Computing. It is intended for researchers and practitioners from artificial intelligence (AI) with expertise in formal modeling, representation and inference on situations, activities and goals; researchers from ubiquitous computing and embedded systems with expertise in context-aware computing; and application developers or users with expertise and experience in user requirements, system implementation and evaluation. The special issue also serves to motivate application scenarios from various domains including smart homes and cities, localisation tracking, image analysis and environmental monitoring. For solution developers and providers of specific application domains, this special issue will provide an opportunity to convey needs and requirements, as well as obtain first-hand information on the latest technologies, prototypes, and application exemplars

Computational Modeling for Abnormal Brain Tissue Segmentation, Brain Tumor Tracking, and Grading

This dissertation proposes novel texture feature-based computational models for quantitative analysis of abnormal tissues in two neurological disorders: brain tumor and stroke. Brain tumors are the cells with uncontrolled growth in the brain tissues and one of the major causes of death due to cancer. On the other hand, brain strokes occur due to the sudden interruption of the blood supply which damages the normal brain tissues and frequently causes death or persistent disability. Clinical management of these brain tumors and stroke lesions critically depends on robust quantitative analysis using different imaging modalities including Magnetic Resonance (MR) and Digital Pathology (DP) images. Due to uncontrolled growth and infiltration into the surrounding tissues, the tumor regions appear with a significant texture variation in the static MRI volume and also in the longitudinal imaging study. Consequently, this study developed computational models using novel texture features to segment abnormal brain tissues (tumor, and stroke lesions), tracking the change of tumor volume in longitudinal images, and tumor grading in MR images. Manual delineation and analysis of these abnormal tissues in large scale is tedious, error-prone, and often suffers from inter-observer variability. Therefore, efficient computational models for robust segmentation of different abnormal tissues is required to support the diagnosis and analysis processes. In this study, brain tissues are characterized with novel computational modeling of multi-fractal texture features for multi-class brain tumor tissue segmentation (BTS) and extend the method for ischemic stroke lesions in MRI. The robustness of the proposed segmentation methods is evaluated using a huge amount of private and public domain clinical data that offers competitive performance when compared with that of the state-of-the-art methods. Further, I analyze the dynamic texture behavior of tumor volume in longitudinal imaging and develop post-processing frame-work using three-dimensional (3D) texture features. These post-processing methods are shown to reduce the false positives in the BTS results and improve the overall segmentation result in longitudinal imaging. Furthermore, using this improved segmentation results the change of tumor volume has been quantified in three types such as stable, progress, and shrinkage as observed by the volumetric changes of different tumor tissues in longitudinal images. This study also investigates a novel non-invasive glioma grading, for the first time in literature, that uses structural MRI only. Such non-invasive glioma grading may be useful before an invasive biopsy is recommended. This study further developed an automatic glioma grading scheme using the invasive cell nuclei morphology in DP images for cross-validation with the same patients. In summary, the texture-based computational models proposed in this study are expected to facilitate the clinical management of patients with the brain tumors and strokes by automating large scale imaging data analysis, reducing human error, inter-observer variability, and producing repeatable brain tumor quantitation and grading

Prediction of Molecular Mutations in Diffuse Low-Grade Gliomas Using MR Imaging Features

Diffuse low-grade gliomas (LGG) have been reclassified based on molecular mutations, which require invasive tumor tissue sampling. Tissue sampling by biopsy may be limited by sampling error, whereas non-invasive imaging can evaluate the entirety of a tumor. This study presents a non-invasive analysis of low-grade gliomas using imaging features based on the updated classification. We introduce molecular (MGMT methylation, IDH mutation, 1p/19q co-deletion, ATRX mutation, and TERT mutations) prediction methods of low-grade gliomas with imaging. Imaging features are extracted from magnetic resonance imaging data and include texture features, fractal and multi-resolution fractal texture features, and volumetric features. Training models include nested leave-one-out cross-validation to select features, train the model, and estimate model performance. The prediction models of MGMT methylation, IDH mutations, 1p/19q co-deletion, ATRX mutation, and TERT mutations achieve a test performance AUC of 0.83 ± 0.04, 0.84 ± 0.03, 0.80 ± 0.04, 0.70 ± 0.09, and 0.82 ±0.04, respectively. Furthermore, our analysis shows that the fractal features have a significant effect on the predictive performance of MGMT methylation IDH mutations, 1p/19q co-deletion, and ATRX mutations. The performance of our prediction methods indicates the potential of correlating computed imaging features with LGG molecular mutations types and identifies candidates that may be considered potential predictive biomarkers of LGG molecular classification

Imaging Based Prediction of Pathology in Adult Diffuse Glioma with Applications to Therapy and Prognosis

The overall aggressiveness of a glioma is measured by histologic and molecular analysis of tissue samples. However, the well-known spatial heterogeneity in gliomas limits the ability for clinicians to use that information to make spatially specific treatment decisions. Magnetic resonance imaging (MRI) visualizes and assesses the tumor. But, the exact degree to which MRI correlates with the actual underlying tissue characteristics is not known. In this work, we derive quantitative relationships between imaging and underlying pathology. These relations increase the value of MRI by allowing it to be a better surrogate for underlying pathology and they allow evaluation of the underlying biological heterogeneity via imaging. This provides an approach to answer questions about how tissue heterogeneity can affect prognosis. We estimated the local pathology within tumors using imaging data and stereotactically precise biopsy samples from an ongoing clinical imaging trial. From this data, we trained a random forest model to reliably predict tumor grade, proliferation, cellularity, and vascularity, representing tumor aggressiveness. We then made voxel-wise predictions to map the tumor heterogeneity and identify high-grade malignancy disease. Next, we used the previously trained models on a cohort of 1,850 glioma patients who previously underwent surgical resection. High contrast enhancement, proliferation, vascularity, and cellularity were associated with worse prognosis even after controlling for clinical factors. Patients that had substantial reduction in cellularity between preoperative and postoperative imaging (i.e. due to resection) also showed improved survival. We developed a clinically implementable model for predicting pathology and prognosis after surgery based on imaging. Results from imaging pathology correlations enhance our understanding of disease extent within glioma patients and the relationship between residual estimated pathology and outcome helps refine our knowledge of the interaction of tumor heterogeneity and prognosis

The Role of Arterial Spin Labelling (ASL) in Classification of Primary Adult Gliomas

Currently, the histological biopsy is the gold standard for classifying gliomas using the most recent histomolecular features. However, this process is both invasive and challenging, mainly when the lesion is in eloquent brain regions. Considering the complex interaction between the presence of the isocitrate dehydrogenase (IDH)-mutation, the upregulation of the hypoxia-induced factor (HIF), the neo-angiogenesis and the increased cellularity, perfusion MRI may be used indirectly for gliomas staging and further to predict the presence of key mutations, such as IDH. Recently, several studies have reported the subsidiary role of perfusion MRI in the prediction of gliomas histomolecular class. The three most common perfusion MRI methods are dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labelling (ASL). Both DSC and DCE use exogenous contrast agent (CA) while ASL uses magnetically labelled blood water as an inherently diffusible tracer. ASL has begun to feature more prominently in clinical settings, as this method eliminates the need for CA and facilitates quantification of absolute cerebral blood flow (CBF). As a non-invasive, CA-free test, it can also be performed repeatedly where necessary. This makes it ideal for vulnerable patients, e.g. post-treatment oncological patients, who have reduced tolerance for high rate contrast injections and those suffering from renal insufficiency. This thesis performed a systematic review and critical appraisal of the existing ASL techniques for brain perfusion estimation, followed by a further systematic review and meta-analysis of the published studies, which have quantitatively assessed the diagnostic performance of ASL for grading preoperative adult gliomas. The repeatability of absolute tumour blood flow (aTBF) and relative TBF (rTBF) ASL-derived measurements were estimated to investigate the reliability of these ASL biomarkers in the clinical routine. Finally, utilising the radiomics pipeline analysis, the added diagnostic performance of ASL compared with CA-based MRI perfusion techniques, including DSC and DCE, and diffusion-weighted imaging (DWI) was investigated for glioma class prediction according to the WHO-2016 classification