Quantitative Assessment of Cancer Vascular Architecture by Skeletonization of High-resolution 3-D Contrast-enhanced Ultrasound Images: Role of Liposomes and Microbubbles.

The accurate characterization and description of the vascular network of a cancer lesion is of paramount importance in clinical practice and cancer research in order to improve diagnostic accuracy or to assess the effectiveness of a treatment. The aim of this study was to show the effectiveness of liposomes as an ultrasound contrast agent to describe the 3-D vascular architecture of a tumor. Eight C57BL/6 mice grafted with syngeneic B16-F10 murine melanoma cells were injected with a bolus of 1,2-Distearoyl-sn-glycero-3-phosphocoline (DSPC)-based non-targeted liposomes and with a bolus of microbubbles. 3-D contrast-enhanced images of the tumor lesions were acquired in three conditions: pre-contrast, after the injection of micro bubbles, and after the injection of liposomes. By using a previously developed reconstruction and characterization image processing technique, we obtained the 3-D representation of the vascular architecture in these three conditions. Six descriptive parameters of these networks were also computed: the number of vascular trees (NT), the vascular density (VD), the number of branches, the 2-D curvature measure, the number of vascular flexes of the vessels, and the 3-D curvature. Results showed that all the vascular descriptors obtained by liposome-based images were statistically equal to those obtained by using microbubbles, except the VD which was found to be lower for liposome images. All the six descriptors computed in pre-contrast conditions had values that were statistically lower than those computed in presence of contrast, both for liposomes and microbubbles. Liposomes have already been used in cancer therapy for the selective ultrasound-mediated delivery of drugs. This work demonstrated their effectiveness also as vascular diagnostic contrast agents, therefore proving that liposomes can be used as efficient “theranostic” (i.e. therapeutic 1 diagnostic) ultrasound probes

GyneScan: An Improved Online Paradigm for Screening of Ovarian Cancer via Tissue Characterization

Ovarian cancer is the fifth highest cause of cancer in women and the leading cause of death from gynecological cancers. Accurate diagnosis of ovarian cancer from acquired images is dependent on the expertise and experience of ultrasonographers or physicians, and is therefore, associated with inter observer variabilities. Computer Aided Diagnostic (CAD) techniques use a number of different data mining techniques to automatically predict the presence or absence of cancer, and therefore, are more reliable and accurate. A review of published literature in the field of CAD based ovarian cancer detection indicates that many studies use ultrasound images as the base for analysis. The key objective of this work is to propose an effective adjunct CAD technique called GyneScan for ovarian tumor detection in ultrasound images. In our proposed data mining framework, we extract several texture features based on first order statistics, Gray Level Co-occurrence Matrix and run length matrix. The significant features selected using t-test are then used to train and test several supervised learning based classifiers such as Probabilistic Neural Networks (PNN), Support Vector Machine (SVM), Decision Tree (DT), k-Nearest Neighbor (KNN), and Naïve Bayes (NB). We evaluated the developed framework using 1300 benign and 1300 malignant images. Using 11 significant features in KNN/PNN classifiers, we were able to achieve 100% classification accuracy, sensitivity, specificity, and positive predictive value in detecting ovarian tumor. Even though more validation using larger databases would better establish the robustness of our technique, the preliminary results are promising. This technique could be used as a reliable adjunct method to existing imaging modalities to provide a more confident second opinion on the presence/absence of ovarian tumor

past present and future ultrasonographic techniques for analyzing ovarian masses

Ultrasonography is today the method of choice for distinguishing between benign and malignant adnexal pathologies. Using pattern recognition several types of tumors can be recognized according to their characteristic appearance on gray-scale imaging. Color Doppler imaging should be used only to perform a semiquantitative color score or evaluate the flow location. International Ovarian Tumor Analysis group had standardized definitions characterizing adnexal masses and suggested the use of 'simple rules' in premenopausal women. Recently, the use of 3D vascular indices has been proposed but its potential use in clinical practice is debated. Also computerized aided diagnosis algorithms showed encouraging results to be confirmed in the future

Feature Space Modeling for Accurate and Efficient Learning From Non-Stationary Data

A non-stationary dataset is one whose statistical properties such as the mean, variance, correlation, probability distribution, etc. change over a specific interval of time. On the contrary, a stationary dataset is one whose statistical properties remain constant over time. Apart from the volatile statistical properties, non-stationary data poses other challenges such as time and memory management due to the limitation of computational resources mostly caused by the recent advancements in data collection technologies which generate a variety of data at an alarming pace and volume. Additionally, when the collected data is complex, managing data complexity, emerging from its dimensionality and heterogeneity, can pose another challenge for effective computational learning. The problem is to enable accurate and efficient learning from non-stationary data in a continuous fashion over time while facing and managing the critical challenges of time, memory, concept change, and complexity simultaneously. Feature space modeling is one of the most effective solutions to address this problem. For non-stationary data, selecting relevant features is even more critical than stationary data due to the reduction of feature dimension which can ensure the best use a computational resource to produce higher accuracy and efficiency by data mining algorithms. In this dissertation, we investigated a variety of feature space modeling techniques to improve the overall performance of data mining algorithms. In particular, we built Relief based feature sub selection method in combination with data complexity iv analysis to improve the classification performance using ovarian cancer image data collected in a non-stationary batch mode. We also collected time series health sensor data in a streaming environment and deployed feature space transformation using Singular Value Decomposition (SVD). This led to reduced dimensionality of feature space resulting in better accuracy and efficiency produced by Density Ration Estimation Method in identifying potential change points in data over time. We have also built an unsupervised feature space modeling using matrix factorization and Lasso Regression which was successfully deployed in conjugate with Relative Density Ratio Estimation to address the botnet attacks in a non-stationary environment. Relief based feature model improved 16% accuracy of Fuzzy Forest classifier. For change detection framework, we observed 9% improvement in accuracy for PCA feature transformation. Due to the unsupervised feature selection model, for 2% and 5% malicious traffic ratio, the proposed botnet detection framework exhibited average 20% better accuracy than One Class Support Vector Machine (OSVM) and average 25% better accuracy than Autoencoder. All these results successfully demonstrate the effectives of these feature space models. The fundamental theme that repeats itself in this dissertation is about modeling efficient feature space to improve both accuracy and efficiency of selected data mining models. Every contribution in this dissertation has been subsequently and successfully employed to capitalize on those advantages to solve real-world problems. Our work bridges the concepts from multiple disciplines ineffective and surprising ways, leading to new insights, new frameworks, and ultimately to a cross-production of diverse fields like mathematics, statistics, and data mining

Automated Strategies in Multimodal and Multidimensional Ultrasound Image-based Diagnosis

Medical ultrasonography is an effective technique in traditional anatomical and functional diagnosis. However, it requires the visual examination by experienced clinicians, which is a laborious, time consuming and highly subjective procedure. Computer-aided diagnosis (CADx) have been extensively used in clinical practice to support the interpretation of images; nevertheless, current ultrasound CADx still entails a substantial user-dependency and are unable to extract image data for prediction modelling. The aim of this thesis is to propose a set of fully automated strategies to overcome the limitations of ultrasound CADx. These strategies are addressed to multiple modalities (B-Mode, Contrast-Enhanced Ultrasound-CEUS, Power Doppler-PDUS and Acoustic Angiography-AA) and dimensions (2-D and 3-D imaging). The enabling techniques presented in this work are designed, developed and quantitively validated to efficiently improve the overall patients’ diagnosis. This work is subdivided in 2 macro-sections: in the first part, two fully automated algorithms for the reliable quantification of 2-D B-Mode ultrasound skeletal muscle architecture and morphology are proposed. In the second part, two fully automated algorithms for the objective assessment and characterization of tumors’ vasculature in 3-D CEUS and PDUS thyroid tumors and preclinical AA cancer growth are presented. In the first part, the MUSA (Muscle UltraSound Analysis) algorithm is designed to measure the muscle thickness, the fascicles length and the pennation angle; the TRAMA (TRAnsversal Muscle Analysis) algorithm is proposed to extract and analyze the Visible Cross-Sectional Area (VCSA). MUSA and TRAMA algorithms have been validated on two datasets of 200 images; automatic measurements have been compared with expert operators’ manual measurements. A preliminary statistical analysis was performed to prove the ability of texture analysis on automatic VCSA in the distinction between healthy and pathological muscles. In the second part, quantitative assessment on tumor vasculature is proposed in two automated algorithms for the objective characterization of 3-D CEUS/Power Doppler thyroid nodules and the evolution study of fibrosarcoma invasion in preclinical 3-D AA imaging. Vasculature analysis relies on the quantification of architecture and vessels tortuosity. Vascular features obtained from CEUS and PDUS images of 20 thyroid nodules (10 benign, 10 malignant) have been used in a multivariate statistical analysis supported by histopathological results. Vasculature parametric maps of implanted fibrosarcoma are extracted from 8 rats investigated with 3-D AA along four time points (TPs), in control and tumors areas; results have been compared with manual previous findings in a longitudinal tumor growth study. Performance of MUSA and TRAMA algorithms results in 100% segmentation success rate. Absolute difference between manual and automatic measurements is below 2% for the muscle thickness and 4% for the VCSA (values between 5-10% are acceptable in clinical practice), suggesting that automatic and manual measurements can be used interchangeably. The texture features extraction on the automatic VCSAs reveals that texture descriptors can distinguish healthy from pathological muscles with a 100% success rate for all the four muscles. Vascular features extracted of 20 thyroid nodules in 3-D CEUS and PDUS volumes can be used to distinguish benign from malignant tumors with 100% success rate for both ultrasound techniques. Malignant tumors present higher values of architecture and tortuosity descriptors; 3-D CEUS and PDUS imaging present the same accuracy in the differentiation between benign and malignant nodules. Vascular parametric maps extracted from the 8 rats along the 4 TPs in 3-D AA imaging show that parameters extracted from the control area are statistically different compared to the ones within the tumor volume. Tumor angiogenetic vessels present a smaller diameter and higher tortuosity. Tumor evolution is characterized by the significant vascular trees growth and a constant value of vessel diameter along the four TPs, confirming the previous findings. In conclusion, the proposed automated strategies are highly performant in segmentation, features extraction, muscle disease detection and tumor vascular characterization. These techniques can be extended in the investigation of other organs, diseases and embedded in ultrasound CADx, providing a user-independent reliable diagnosis

Biochemical markers and combination testing for the diagnosis of ovarian cancer in women with symptoms or signs suspicious of ovarian cancer

Ovarian cancer (OC) has the highest mortality of all gynaecological cancers. A significant contributing factor to the high mortality in OC is delayed diagnosis. Currently, there is no consensus regarding the best test for early diagnosis. A review of existing systematic reviews about symptoms, biochemical markers and US test used alone or in combination for the diagnosis of OC in symptomatic women demonstrated that existing reviews were variable in quality, applicability and limited by poor reporting. I attempted to address these deficiencies in two reviews on the accuracy of biomarkers alone and symptoms, biomarkers or US in combination for the diagnosis of OC in symptomatic women in generalist settings in pre and postmenopausal women separately. My thesis finds key methodological issues, e.g., literature is not applicable to generalist settings as studies included women typical of tertiary healthcare settings, some studies excluded borderline tumours which inflates estimates of sensitivity, important differences exist in test performance between pre and postmenopausal women. Main results are 1) reviews not applicable to primary care settings – more research is needed. 2) for biomarkers i) HE4 at the threshold of 60-80pMol/L and 130-150pMol/L is recommended in pre and postmenopausal women for low prevalence settings ii) ROMA or LR2 in premenopausal women to replace RMI in secondary/tertiary setting; continue with RMI for postmenopausal women as it shows comparable accuracy to ROMA and LR2

Ovarian Tumor Characterization and Classification Using Ultrasound-A New Online Paradigm

Among gynecological malignancies, ovarian cancer is the most frequent cause of death. Image mining algorithms have been predominantly used to give the physicians a more objective, fast, and accurate second opinion on the initial diagnosis made from medical images. The objective of this work is to develop an adjunct computer-aided diagnostic technique that uses 3D ultrasound images of the ovary to accurately characterize and classify benign and malignant ovarian tumors. In this algorithm, we first extract features based on the textural changes and higher-order spectra information. The significant features are then selected and used to train and evaluate the decision tree (DT) classifier. The proposed technique was validated using 1,000 benign and 1,000 malignant images, obtained from ten patients with benign and ten with malignant disease, respectively. On evaluating the classifier with tenfold stratified cross validation, the DT classifier presented a high accuracy of 97 %, sensitivity of 94.3 %, and specificity of 99.7 %. This high accuracy was achieved because of the use of the novel combination of the four features which adequately quantify the subtle changes and the nonlinearities in the pixel intensity variations. The rules output by the DT classifier are comprehensible to the end-user and, hence, allow the physicians to more confidently accept the results. The preliminary results show that the features are discriminative enough to yield good accuracy. Moreover, the proposed technique is completely automated, accurate, and can be easily written as a software application for use in any compute

Ovarian Tumor Characterization and Classification Using Ultrasound-A New Online Paradigm.

Among gynecological malignancies, ovarian cancer is the most frequent cause of death. Image mining algorithms have been predominantly used to give the physicians a more objective, fast, and accurate second opinion on the initial diagnosis made from medical images. The objective of this work is to develop an adjunct computer-aided diagnostic technique that uses 3D ultrasound images of the ovary to accurately characterize and classify benign and malignant ovarian tumors. In this algorithm, we first extract features based on the textural changes and higher-order spectra information. The significant features are then selected and used to train and evaluate the decision tree (DT) classifier. The proposed technique was validated using 1,000 benign and 1,000 malignant images, obtained from ten patients with benign and ten with malignant disease, respectively. On evaluating the classifier with tenfold stratified cross validation, the DT classifier presented a high accuracy of 97 %, sensitivity of 94.3 %, and specificity of 99.7 %. This high accuracy was achieved because of the use of the novel combination of the four features which adequately quantify the subtle changes and the nonlinearities in the pixel intensity variations. The rules output by the DT classifier are comprehensible to the end-user and, hence, allow the physicians to more confidently accept the results. The preliminary results show that the features are discriminative enough to yield good accuracy. Moreover, the proposed technique is completely automated, accurate, and can be easily written as a software application for use in any computer