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Follicular lymphoma (FL) is one of the most common lymphoid malignancies in the western world. FL has a variable clinical course, and important clinical treatment decisions for FL patients are based on histological grading, which is done by manually counting the large malignant cells called centroblasts (CB) in ten standard microscopic high-power fields from H&E-stained tissue sections. This method is tedious and subjective; as a result, suffers from considerable inter and intrareader variability even when used by expert pathologists. In this paper, we present a computer-aided detection system for automated identification of CB cells from H&E-stained FL tissue samples. The proposed system uses a unitone conversion to obtain a single-channel image that has the highest contrast. From the resulting image, which has a bimodal distribution due to the H&E stain, a cell-likelihood image is generated. Finally, a two-step CB detection procedure is applied. In the first step, we identify evident nonCB cells based on size and shape. In the second step, the CB detection is further refined by learning and utilizing the texture distribution of nonCB cells. We evaluated the proposed approach on 100 region-of-interest images extracted from ten distinct tissue samples and obtained a promising 80.7% detection accuracy.

The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.

Clinical data that may be used in a secondary capacity to support research activities are regularly stored in three significantly different formats: (1) structured, codified data elements; (2) semi-structured or unstructured narrative text; and (3) multi-modal images. In this manuscript, we will describe the design of a computational system that is intended to support the ontology-anchored query and integration of such data types from multiple source systems. Additional features of the described system include (1) the use of Grid services-based electronic data interchange models to enable the use of our system in multi-site settings and (2) the use of a software framework intended to address both potential security and patient confidentiality concerns that arise when transmitting or otherwise manipulating potentially privileged personal health information. We will frame our discussion within the specific experimental context of the concept-oriented query and integration of correlated structured data, narrative text, and images for cancer research.

Neuroblastoma is one of the most common childhood cancers. We are developing an image analysis system to assist pathologists in their prognosis. Since this system operates on relatively large-scale images and requires sophisticated algorithms, computerised analysis takes a long time to execute. In this paper, we propose a novel approach to benefit from high memory bandwidth and strong floating-point capabilities of graphics processing units. The proposed approach achieves a promising classification accuracy of 99.4% and an execution performance with a gain factor up to 45 times compared to hand-optimised C++ code running on the CPU.

In this paper, a comparison is made between a global and a local approach for computer-aided classification of virtual slides from breast tumor sections. The first approach classifies the images according to both color and texture information from the whole tissue, whereas the second one classifies them only on shape and texture from epithelial compartment. The originality of this study is that only low resolution virtual slides are used. As the cytological details are not visible at low resolution, the classification is only based on architectural aspect of each lesion. Experimental results on images from breast tumor sections show that some information is already present in low resolution virtual slides, allowing the classification in benign lesions versus malignant carcinomas.

In this paper we develop a fully automated method for the segmentation of the femur in axial MR images and its use in the analysis of imaging biomarkers for osteoarthritis (OA). The proposed method is based on anatomical constraints implemented using morphological operations to extract the femur medulla and a level set evolution to extract the femur cortex. The average agreement of the automated segmentation algorithm with ground truth manual segmentations was 0.94 +/- 0.03 calculated using the Zijdenbos similarity index (ZSI). A pooled variance t-test analysis found significant associations between the KL grade, a clinical measure of OA severity, and both the cross-sectional area (CSA) of the femur medulla (p = 0.02) and the ratio of the femur medulla CSA to the femur cortex CSA (p = 0.04) for women. No significant association between femur measurements and KL grade was found for men.

In this paper we explore a method of segmentation of muscle interstitial adipose tissue (IAT) in MR images of the thigh. The objective is to apply the method towards research into biomarkers of osteoarthritis (OA). T1-weighted images of the thigh are intensity standardized through bias field correction and intensity normalization. IAT within the thigh muscles is then segmented using a threshold combined with morphological constraints applied on connected regions in the thresholded image. The morphological constraints can be adjusted to allow for highly sensitive or highly specific IAT segmentation. The use of the morphological constraints improved the specificity of IAT segmentation over a threshold segmentation method from 0.54 to 0.67, while retaining a nearly equivalent sensitivity of 0.82 compared to 0.84. We then present a preliminary statistical analysis to demonstrate the application of the automated IAT segmentation. Finally, we specify a protocol for further exploration of IAT by leveraging the massive imaging dataset of the Osteoarthritis Initiative (OAI).

Cystic Fibrosis (CF) is the most common lethal genetic disorder in the Caucasian population, affecting about 30,000 people in the United States. It results in inflammation, hence thickening of airway (AW) walls. It has been demonstrated that AW inflammation begins early in life producing structural AW damage. Because this damage can be present in patients who are relatively asymptomatic, lung disease can progress insidiously. High-resolution computed tomographic imaging has also shown that the AWs of infants and young children with CF have thicker walls and are more dilated than those of normal children. The purpose of this study was to develop computerized methods which allow rapid, efficient and accurate assessment of computed tomographic AW and vessel (V) dimensions from axial CT lung images. For this purpose, a full-width-half-max based automatic AW and V size measurement method was developed. The only user input required is approximate center marking of AW and V by an expert. The method was evaluated on a patient population of 4 infants and 4 children with different stages of mild CF related lung disease. This new automated method for assessing early AW disease in infants and children with CF represents a potentially useful outcome measure for future intervention trials.

Histopathological examination is one of the most important steps in evaluating prognosis of patients with neuroblastoma (NB). NB is a pediatric tumor of sympathetic nervous system and current evaluation of NB tumor histology is done according to the International Neuroblastoma Pathology Classification. The number of cells undergoing either mitosis or karyorrhexis (MK) plays an important role in this classification system. However, manual counting of such cells is tedious and subject to considerable inter- and intra-reader variations. A computer-assisted system may allow more precise results leading to more accurate prognosis in clinical practice. In this study, we propose an image analysis approach that operates on digitized NB histology samples. Based on the likelihood functions estimated from the samples of manually marked regions, we compute the probability map that indicates how likely a pixel belongs to an MK cell. Component-wise 2-step thresholding of the generated probability map provides promising results in detecting MK cells with an average sensitivity of 81.1% and 12.2 false positive detections on average.

Follicular lymphoma (FL) is the second most common non-Hodgkins lymphoma in the United States. While the current diagnosis depends heavily on the review of H&E-stained tissues, additional sources of information such as IHC are occasionally needed. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) can be used to generate protein profiles from localized tissue regions, thus making it possible to relate changes in tissue histology to the changes in the protein signature of the tissue. It may be possible to determine potential biomarkers that can indicate disease state and prognosis based on the protein profile. This research aims to combine two different but related types of data in order to develop a unique diagnosis methodology that can potentially improve the accuracy of diagnosis. Preliminary analysis has shown promising results for distinguishing intrafollicle regions from the mantle and follicle zones in normal tissue.

Over the past decade, dramatic increases in computational power and improvement in image analysis algorithms have allowed the development of powerful computer-assisted analytical approaches to radiological data. With the recent advent of whole slide digital scanners, tissue histopathology slides can now be digitized and stored in digital image form. Consequently, digitized tissue histopathology has now become amenable to the application of computerized image analysis and machine learning techniques. Analogous to the role of computer-assisted diagnosis (CAD) algorithms in medical imaging to complement the opinion of a radiologist, CAD algorithms have begun to be developed for disease detection, diagnosis, and prognosis prediction to complement the opinion of the pathologist. In this paper, we review the recent state of the art CAD technology for digitized histopathology. This paper also briefly describes the development and application of novel image analysis technology for a few specific histopathology related problems being pursued in the United States and Europe.

We present a pathological image analysis system for the computer-aided prognosis of neuroblastoma, a childhood cancer. The image analysis system automatically classifies Schwannian stromal development of pathological tissues and determines the grade of differentiation. Due to the demanding computational cost of processing large digitized slides, the system was implemented on a cluster of computers with automated load balancing within a multi-resolution framework. In our experiments, the overall accuracies for stromal classification and the grade of differentiation were 96.6% and 95.3%, respectively. Additionally, the multi-resolution framework reduced the run time of the single resolution approach by 53% and 34% on average for stromal classification and grade of differentiation, respectively. For these two cases, parallelization on a 16-node cluster reduced the sequential run time by 92% and 88% on average. Accuracy and efficiency of these techniques are promising for the development a computer-assisted neuroblastoma prognosis system.

This paper describes a Grid-aware image reviewing system (GridIMAGE) that allows practitioners to (a) select images from multiple geographically distributed digital imaging and communication in medicine (DICOM) servers, (b) send those images to a specified group of human readers and computer-assisted detection (CAD) algorithms, and (c) obtain and compare interpretations from human readers and CAD algorithms. The currently implemented system was developed using the National Cancer Institute caGrid infrastructure and is designed to support the identification of lung nodules on thoracic computed tomography. However, the infrastructure is general and can support any type of distributed review. caGrid data and analytical services are used to link DICOM image databases and CAD systems and to interact with human readers. Moreover, the service-oriented and distributed structure of the GridIMAGE framework enables a flexible system, which can be deployed in an institution (linking multiple DICOM servers and CAD algorithms) and in a Grid environment (linking the resources of collaborating research groups). GridIMAGE provides a framework that allows practitioners to obtain interpretations from one or more human readers or CAD algorithms. It also provides a mechanism to allow cooperative imaging groups to systematically perform image interpretation tasks associated with research protocols.

Grid computing-the use of a distributed network of electronic resources to cooperatively perform subsets of computationally intensive tasks-may help improve the speed and accuracy of radiologic image interpretation by enabling collaborative computer-based and human readings. GridCAD, a software application developed by using the National Cancer Institute Cancer Biomedical Informatics Grid architecture, implements the fundamental elements of grid computing and demonstrates the potential benefits of grid technology for medical imaging. It allows users to query local and remote image databases, view images, and simultaneously run multiple computer-assisted detection (CAD) algorithms on the images selected. The prototype CAD systems that are incorporated in the software application are designed for the detection of lung nodules on thoracic computed tomographic images. GridCAD displays the original full-resolution images with an overlay of nodule candidates detected by the CAD algorithms, by human observers, or by a combination of both types of readers. With an underlying framework that is computer platform independent and scalable to the task, the software application can support local and long-distance collaboration in both research and clinical practice through the efficient, secure, and reliable sharing of resources for image data mining, analysis, and archiving., ((c) RSNA, 2007.)

Neuroblastoma is a childhood cancer of the nervous system. Current prognostic classification of this disease partly relies on morphological characteristics of the cells from H&E-stained images. In this work, an automated cell nuclei segmentation method is developed. This method employs morphological top-hat by reconstruction algorithm coupled with hysteresis thresholding to both detect and segment the cell nuclei. Accuracy of the automated cell nuclei segmentation algorithm is measured by comparing its outputs to manual segmentation. The average segmentation accuracy is 90.24+/-5.14%

We are developing a computer-aided diagnosis (CAD) system for lung nodule detection on thoracic helical computed tomography (CT) images. In the first stage of this CAD system, lung regions are identified by a k-means clustering technique. Each lung slice is classified as belonging to the upper, middle, or the lower part of the lung volume. Within each lung region, structures are segmented again using weighted k-means clustering. These structures may include true lung nodules and normal structures consisting mainly of blood vessels. Rule-based classifiers are designed to distinguish nodules and normal structures using 2D and 3D features. After rule-based classification, linear discriminant analysis (LDA) is used to further reduce the number of false positive (FP) objects. We performed a preliminary study using 1454 CT slices from 34 patients with 63 lung nodules. When only LDA classification was applied to the segmented objects, the sensitivity was 84% (53/63) with 5.48 (7961/1454) FP objects per slice. When rule-based classification was used before LDA, the free response receiver operating characteristic (FROC) curve improved over the entire sensitivity and specificity ranges of interest. In particular, the FP rate decreased to 1.74 (2530/1454) objects per slice at the same sensitivity. Thus, compared to FP reduction with LDA alone, the inclusion of rule-based classification lead to an improvement in detection accuracy for the CAD system. These preliminary results demonstrate the feasibility of our approach to lung nodule detection and FP reduction on CT images.

Rationale and Objectives: The authors evaluated the effect of optimal neural network architecture selection on the performance of a computer-aided diagnostic system designed to detect microcalcification clusters on digitized mammograms., Materials and Methods: The authors developed a computer program to detect microcalcification clusters automatically on digitized mammograms. Previously, they found that a properly selected and trained convolution neural network (CNN) could reduce false-positive (FP) findings and therefore improve the accuracy of microcalcification detection. In the current study, they evaluated the effectiveness of the CNN optimized with an automated optimization technique in improving the accuracy of the microcalcification detection program, comparing it with the manually selected CNN. An independent test data set was used, which included 472 mammograms selected from the University of South Florida public database and contained 253 biopsy-proved malignant clusters., Results: At an FP rate of 0.7 cluster per image, the film-based sensitivity was 84.6% for the optimized CNN, compared with 77.2% for the manually selected CNN. For clusters imaged on both craniocaudal and mediolateral oblique views, a cluster could be considered detected when it was detected on one or both views. For this case-based approach, at an FP rate of 0.7 per image, the sensitivity was 93.3% for the optimized and 87.0% for the manually selected CNN., Conclusion: The classification of true and false signals is an important step in the microcalcification detection program. An optimized CNN can effectively reduce FP findings and improve the accuracy of the computer-aided detection system.