Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers.

BACKGROUND: The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. METHODS: A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. RESULTS: Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. CONCLUSION: Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. IMPLICATIONS FOR PRACTICE: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.

Content-based histopathology image retrieval using CometCloud.

BACKGROUND: The development of digital imaging technology is creating extraordinary levels of accuracy that provide support for improved reliability in different aspects of the image analysis, such as content-based image retrieval, image segmentation, and classification. This has dramatically increased the volume and rate at which data are generated. Together these facts make querying and sharing non-trivial and render centralized solutions unfeasible. Moreover, in many cases this data is often distributed and must be shared across multiple institutions requiring decentralized solutions. In this context, a new generation of data/information driven applications must be developed to take advantage of the national advanced cyber-infrastructure (ACI) which enable investigators to seamlessly and securely interact with information/data which is distributed across geographically disparate resources. This paper presents the development and evaluation of a novel content-based image retrieval (CBIR) framework. The methods were tested extensively using both peripheral blood smears and renal glomeruli specimens. The datasets and performance were evaluated by two pathologists to determine the concordance. RESULTS: The CBIR algorithms that were developed can reliably retrieve the candidate image patches exhibiting intensity and morphological characteristics that are most similar to a given query image. The methods described in this paper are able to reliably discriminate among subtle staining differences and spatial pattern distributions. By integrating a newly developed dual-similarity relevance feedback module into the CBIR framework, the CBIR results were improved substantially. By aggregating the computational power of high performance computing (HPC) and cloud resources, we demonstrated that the method can be successfully executed in minutes on the Cloud compared to weeks using standard computers. CONCLUSIONS: In this paper, we present a set of newly developed CBIR algorithms and validate them using two different pathology applications, which are regularly evaluated in the practice of pathology. Comparative experimental results demonstrate excellent performance throughout the course of a set of systematic studies. Additionally, we present and evaluate a framework to enable the execution of these algorithms across distributed resources. We show how parallel searching of content-wise similar images in the dataset significantly reduces the overall computational time to ensure the practical utility of the proposed CBIR algorithms.

A Semi-Automated Positioning System for contact-mode Atomic Force Microscopy (AFM).

Contact mode Atomic Force Microscopy (CM-AFM) is popularly used by the biophysics community to study mechanical properties of cells cultured in petri dishes, or tissue sections fixed on microscope slides. While cells are fairly easy to locate, sampling in spatially heterogeneous tissue specimens is laborious and time-consuming at higher magnifications. Furthermore, tissue registration across multiple magnifications for AFM-based experiments is a challenging problem, suggesting the need to automate the process of AFM indentation on tissue. In this work, we have developed an image-guided micropositioning system to align the AFM probe and human breast-tissue cores in an automated manner across multiple magnifications. Our setup improves efficiency of the AFM indentation experiments considerably. Note to Practitioners: Human breast tissue is by nature heterogeneous, and in the samples we studied, epithelial tissue is formed by groups of functional breast epithelial cells that are surrounded by stromal tissue in a complex intertwined way. Therefore sampling a specific cell type on an unstained specimen is very difficult. To aid us, we use digital stained images of the same tissue annotated by a certified pathologist to identify the region of interest (ROI) at a coarse magnification and an image-guided positioning system to place the unstained tissue near the AFM probe tip. Using our setup, we could considerably reduce AFM operating time and we believe that our setup is a viable supplement to commercial AFM stages with limited X-Y range.

Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways.

BACKGROUND: There is increasing evidence that stromal cell interactions are required for the survival and drug resistance of several types of B-cell malignancies. There is relatively little information regarding the role of the bone marrow/lymphoid microenvironment in the pathogenesis of mantle cell lymphoma. In this study we investigated the interaction of primary mantle cell lymphoma cells with stromal cells in an ex vivo co-culture system. DESIGN AND METHODS: The murine stromal cell line MS-5 and human bone marrow mesenchymal stromal cells were each co-cultured with primary mantle cell lymphoma cells for up to 7 months. Mantle cell lymphoma cultures alone or combined with human stromal cells were analyzed for cell number, cell migration, nuclear factor-κB activation and drug resistance. RESULTS: Co-culture of mantle cell lymphoma cells and human stromal cells results in the survival and proliferation of primary mantle cell lymphoma cells for at least 7 months compared to mantle cell lymphoma cells cultured alone. Mantle cell lymphoma-human stromal cell interactions resulted in activation of the B-cell activating factor/nuclear factor-κB signaling axis resulting in reduced apoptosis, increased mantle cell lymphoma migration and increased drug resistance. CONCLUSIONS: Direct mantle cell lymphoma-human stromal cell interactions support long-term expansion and increase the drug-resistance of primary mantle cell lymphoma cells. This is due in part to activation of the canonical and non-canonical nuclear factor κB pathways. We also demonstrated the ability of B-cell activating factor to augment CXCL12- and CXCL13-induced cell migration. Collectively, these findings demonstrate that human stromal cell-mantle cell lymphoma interactions play a pivotal role in the pathogenesis of mantle cell lymphoma and that analysis of mantle cell lymphoma-human stromal cell interactions may help in the identification of novel targets for therapeutic use.

Nuclear factor-kappaB modulation in patients undergoing induction chemotherapy for acute myelogenous leukemia.

PURPOSE: Nuclear factor-kappaB (NF-kappaB) is constitutively expressed in many acute myelogenous leukemia (AML) cells and AML stem cells. Ex vivo treatment of AML cells with inhibitors of NF-kappaB results in diminished AML cell survival and enhances the cytotoxic effects of chemotherapeutic agents. The purpose of this study was to determine if standard anti-inflammatory agents modulate AML cell nuclear NF-kappaB when administered in conjunction with induction chemotherapy. EXPERIMENTAL DESIGN: Patients with newly diagnosed AML were treated with dexamethasone, choline magnesium trisalicylate, or both for 24 hours prior to and 24 hours following initiation of standard induction chemotherapy. AML cell nuclear NF-kappaB was measured at baseline, 24, and 48 hours. RESULTS: Choline magnesium trisalicylate +/- dexamethasone decreased nuclear NF-kappaB, whereas dexamethasone alone was associated with an increase in nuclear NF-kappaB in AML cells. CONCLUSIONS: These results show the feasibility of NF-kappaB modulation in conjunction with induction chemotherapy for patients with AML using inexpensive readily available medications. A follow-up study to determine the effects of NF-kappaB modulation on clinical end points is warranted.

Roadmap to a Comprehensive Clinical Data Warehouse for Precision Medicine Applications in Oncology.

Leading institutions throughout the country have established Precision Medicine programs to support personalized treatment of patients. A cornerstone for these programs is the establishment of enterprise-wide Clinical Data Warehouses. Working shoulder-to-shoulder, a team of physicians, systems biologists, engineers, and scientists at Rutgers Cancer Institute of New Jersey have designed, developed, and implemented the Warehouse with information originating from data sources, including Electronic Medical Records, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology and Pathology archives, and Next Generation Sequencing services. Innovative solutions were implemented to detect and extract unstructured clinical information that was embedded in paper/text documents, including synoptic pathology reports. Supporting important precision medicine use cases, the growing Warehouse enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information of patient tumors individually or as part of large cohorts to identify changes and patterns that may influence treatment decisions and potential outcomes.

A phase I clinical trial of 12- O-tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies.

Phorbol esters activate protein kinase C and modulate a variety of downstream cell signaling pathways. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that induces differentiation or apoptosis in a variety of cell lines at low concentrations. A phase I dose escalation trial of TPA was undertaken for patients with relapsed or refractory malignancies. The starting dose was 0.063 mg/m2 and most patients were treated with an intravenous infusion of TPA on days 1-5 and 8-12 followed by a 2-week rest period prior to retreatment. Thirty-five patients were treated. A biological assay was used to monitor levels of TPA-like activity in the blood after treatment. Serious adverse events included individual episodes of gross hematuria, a grand mal seizure, syncope, and hypotension. Many patients had transient fatigue, mild dyspnea, fever, rigors, and muscular aches shortly after the infusion. Dose-limiting toxicities included syncope and hypotension at a dose of 0.188 mg/m2. Only a single patient had evidence of tumor response. These studies establish 0.125 mg/m2 as the maximally tolerated dose when TPA is administered on this schedule.

Adenovirus infection and cytotoxicity of primary mantle cell lymphoma cells.

Mantle cell lymphoma (MCL) is a distinct form of non-Hodgkin's lymphoma (NHL) derived from CD5+ B cells. MCL cells overexpress cyclin D1 as a consequence of translocation of the gene into the immunoglobulin heavy-chain gene locus. MCL is an aggressive form of NHL with frequent relapses after standard-dose chemotherapy. In this context, a variety of novel therapies for patients with MCL have been investigated. In this study, we use an expanded panel of attenuated adenoviruses to study adenovirus-mediated cytotoxicity of MCL cells. Our results demonstrate: 1) adenovirus infection of MCL cells despite the absence of receptor/coreceptor molecules known to be important for adenovirus infection of other cells types; 2) cytotoxicity of MCL cells after infection with specific adenovirus mutants; 3) a high degree of cytotoxicity after infection of some patient samples with viruses lacking the E1B 19k "antiapoptotic" gene; and 4) cytotoxicity after infection with viruses containing mutations in E1A pRb or p300 binding. The extent of cytotoxicity with the panel of viruses demonstrated interpatient variability, but 100% cytotoxicity, as determined by molecular analysis, was detected in some samples. These studies provide the foundation for: 1) the development of adenoviruses as cytotoxic agents for MCL and 2) analyses of key regulatory pathways operative in MCL cells.

Toward a Portable Cancer Diagnostic Tool Using a Disposable MEMS-Based Biochip.

GOAL: The objective of this study is to design and develop a portable tool consisting of a disposable biochip for measuring electrothermomechanical (ETM) properties of breast tissue. METHODS: A biochip integrated with a microheater, force sensors, and electrical sensors is fabricated using microtechnology. The sensor covers the area of 2 mm and the biochip is 10 mm in diameter. A portable tool capable of holding tissue and biochip is fabricated using 3-D printing. Invasive ductal carcinoma and normal tissue blocks are selected from cancer tissue bank in Biospecimen Repository Service at Rutgers Cancer Institute of New Jersey. The ETM properties of the normal and cancerous breast tissues (3-mm thickness and 2-mm diameter) are measured by indenting the tissue placed on the biochip integrated inside the 3-D printed tool. RESULTS: Integrating microengineered biochip and 3-D printing, we have developed a portable cancer diagnosis device. Using this device, we have shown a statistically significant difference between cancerous and normal breast tissues in mechanical stiffness, electrical resistivity, and thermal conductivity. CONCLUSION: The developed cancer diagnosis device is capable of simultaneous ETM measurements of breast tissue specimens and can be a potential candidate for delineating normal and cancerous breast tissue cores. SIGNIFICANCE: The portable cancer diagnosis tool could potentially provide a deterministic and quantitative information about the breast tissue characteristics, as well as the onset and disease progression of the tissues. The tool can be potentially used for other tissue-related cancers.

12-O-tetradecanoylphorbol-13-acetate (TPA)-induced dual-specificity phosphatase expression and AML cell survival.

12-O-Tetradecanoylphorbol-13-acetate (TPA) is being developed as a therapeutic agent by virtue of its being a potent modulator of signal transduction in pre-clinical models of AML [Strair RK, Schaar D, Goodell L, Aisner J, Chin KV, Eid J, et al. Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate. Clin Cancer Res 2002;8:2512-8]. In this report, we identify a subset of primary AML samples that undergoes apoptosis after exposure to TPA and demonstrate that TPA-induced cytotoxicity is associated with modulation of the ERK signaling pathway. Analysis of mitogen-activated protein kinase (MAPK) dual-specificity phosphatases (DUSP), as potential regulators of AML cell signaling, indicates that these genes are coordinately regulated and rapidly induced by TPA in primary AML cells. Therefore, TPA-induced primary AML cytotoxicity is associated with modulation of ERK signaling which may be partially mediated by regulation of phosphatase expression.

Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate.

PURPOSE: Phorbol esters are capable of inducing a broad range of cellular effects,including the maturation/differentiation of hematopoietic cell lines (E. Huberman and M. F. Callaham, Proc. Natl. Acad. Sci. USA, 76: 1293-1297, 1979; J. Lotem and L. Sachs, Proc. Natl. Acad. Sci. USA, 76: 5158-5162, 1979; G. Rovera et al., Proc. Natl. Acad. Sci. USA, 76: 2779-2783, 1979; H. P. Koeffler, J. Clin. Investig., 66: 1101-1108, 1980). The ability to induce this differentiation at very low concentrations stimulated investigators to administer a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), to patients with myeloid leukemias in the People's Republic of China (Z. T. Han et al., Proc. Natl. Acad. Sci. USA, 95: 5357-5361, 1998). The tolerability of this therapy in China prompted Phase I studies of TPA in the United States. The purpose of this report is to demonstrate the tolerance of TPA at doses that result in detectable biological activity in blood and malignant cells. EXPERIMENTAL DESIGN: TPA was administered to patients with relapsed/refractory hematological malignancies. RESULTS: Phenotypic effects were detected in malignant cells and TPA-associated biological activity was present in blood for up to several hours after the infusion. CONCLUSIONS: These studies confirm the feasibility of TPA administration to humans and establish the foundation for the development of phorbol esters as therapy for patients with a variety of malignant and nonmalignant disorders.

Image mining for investigative pathology using optimized feature extraction and data fusion.

In many subspecialties of pathology, the intrinsic complexity of rendering accurate diagnostic decisions is compounded by a lack of definitive criteria for detecting and characterizing diseases and their corresponding histological features. In some cases, there exists a striking disparity between the diagnoses rendered by recognized authorities and those provided by non-experts. We previously reported the development of an Image Guided Decision Support (IGDS) system, which was shown to reliably discriminate among malignant lymphomas and leukemia that are sometimes confused with one another during routine microscopic evaluation. As an extension of those efforts, we report here a web-based intelligent archiving subsystem that can automatically detect, image, and index new cells into distributed ground-truth databases. Systematic experiments showed that through the use of robust texture descriptors and density estimation based fusion the reliability and performance of the governing classifications of the system were improved significantly while simultaneously reducing the dimensionality of the feature space.

Adenovirus infection of primary malignant lymphoid cells.

Adenovirus infection represents a cellular stress that induces host cell pro-apoptotic responses. To overcome this barrier to productive infection, viral polypeptides modulate a variety of host cell pathways. The interface of these early viral gene products with key cellular regulatory proteins has provided considerable information concerning basic cellular mechanisms operative in cell cycle regulation, transcriptional control and apoptosis. The overlap of these mechanisms with those impacted during oncogenesis provides the opportunity to use adenoviruses and adenovirus mutants to characterize the state of key regulatory pathways in specific malignant cells. For example, adenoviruses mediate cytotoxicity after infection of chronic lymphocytic leukemia (CLL) cells, mantle cell lymphoma (MCL) cells and multiple myeloma cell lines. Specific adenovirus mutants demonstrate enhanced cytotoxicity and, in many cases, apoptosis is not the primary mechanism of cell death. Analysis of these infections with respect to both the features of the primary malignant cell and the mechanisms of adenovirus-mediated cytotoxicity holds the prospect of providing novel insights into the status of key regulatory pathways in individual patient malignant cells. These studies also hold the prospect of supporting the development of specific attenuated adenoviruses as therapeutic agents with selective cytotoxicity for specific primary lymphoid malignancies.

Mechanical phenotyping of breast cancer using MEMS: a method to demarcate benign and cancerous breast tissues.

The mechanical properties of tissue change significantly during the progression from healthy to malignant. Quantifying the mechanical properties of breast tissue within the tumor microenvironment can help to delineate benign from cancerous stages. In this work, we study high-grade invasive ductal carcinoma in comparison with their matched tumor adjacent areas, which exhibit benign morphology. Such paired tissue cores obtained from eight patients were indented using a MEMS-based piezoresistive microcantilever, which was positioned within pre-designated epithelial and stromal areas of the specimen. Field emission scanning electron microscopy studies on breast tissue cores were performed to understand the microstructural changes from benign to malignant. The normal epithelial tissues appeared compact and organized. The appearance of cancer regions, in comparison, not only revealed increased cellularity but also showed disorganization and increased fenestration. Using this technique, reliable discrimination between epithelial and stromal regions throughout both benign and cancerous breast tissue cores was obtained. The mechanical profiling generated using this method has the potential to be an objective, reproducible, and quantitative indicator for detecting and characterizing breast cancer.

Probabilistic estimation of mechanical properties of biomaterials using atomic force microscopy.

Nanoindentation using contact-mode atomic force microscopy (AFM) has emerged as a powerful tool for effective material characterization of a wide variety of biomaterials across multiple length scales. However, the interpretation of force-indentation experimental data from AFM is subject to some debate. Uncertainties in AFM data analysis stems from two primary sources: The exact point of contact between the AFM probe and the biological specimen and the variability in the spring constant of the AFM probe. While a lot of attention has been directed toward addressing the contact-point uncertainty, the effect of variability in the probe spring constant has not received sufficient attention. In this paper, we report on an error-in-variables-based Bayesian change-point approach to quantify the elastic modulus of human breast tissue samples after accounting for variability in both contact point and the probe spring constant. We also discuss the efficacy of our approach to a wide range of hyperparameter values using a sensitivity analysis.

Cobblestone-area forming cells derived from patients with mantle cell lymphoma are enriched for CD133+ tumor-initiating cells.

Mantle cell lymphoma (MCL) is associated with a significant risk of therapeutic failure and disease relapse, but the biological origin of relapse is poorly understood. Here, we prospectively identify subpopulations of primary MCL cells with different biologic and immunophenotypic features. Using a simple culture system, we demonstrate that a subset of primary MCL cells co-cultured with either primary human mesenchymal stromal cells (hMSC) or murine MS-5 cells form in cobblestone-areas consisting of cells with a primitive immunophenotype (CD19-CD133+) containing the chromosomal translocation t (11;14)(q13;q32) characteristic of MCL. Limiting dilution serial transplantation experiments utilizing immunodeficient mice revealed that primary MCL engraftment was only observed when either unsorted or CD19-CD133+ cells were utilized. No engraftment was seen using the CD19+CD133- subpopulation. Our results establish that primary CD19-CD133+ MCL cells are a functionally distinct subpopulation of primary MCL cells enriched for MCL-initiating activity in immunodeficient mice. This rare subpopulation of MCL-initiating cells may play an important role in the pathogenesis of MCL.

Fluorescence microscopy is superior to polarized microscopy for detecting amyloid deposits in Congo red-stained trephine bone marrow biopsy specimens.

The classic gold standard for detecting amyloid deposits is Congo red-stained bright field and polarized microscopy (CRPM). A prior study showed that Congo red fluorescence (CRF) microscopy had increased sensitivity compared with traditional CRPM when analyzing fat pad specimens. The purpose of the current study was to determine the sensitivity of CRF for evaluating Congo red-stained bone marrow biopsy specimens, and to compare these results with those of CRPM. We compared the CRPM and the CRF analyses of 33 trephine bone marrow biopsy specimens with clinical or morphologic suspicion of amyloid deposits. These results were verified against immunohistochemical staining with anti-amyloid P antibody. CRF achieved 100% sensitivity, and CRPM achieved 75% sensitivity. Both groups showed 100% specificity compared with amyloid P immunohistochemical staining. The results show that CRF is a sensitive method to analyze trephine bone marrow biopsy specimens for amyloid deposits.

Lack of expression of MTAP in uncommon T-cell lymphomas.

UNLABELLED: The majority of peripheral T-cell lymphomas were found to lack methylthioadenosine phosphorylase, an enzyme that is essential for the salvage of adenine from methylthioadenosine, a product of polyamine synthesis. Importantly, tumors that lack this enzyme have been shown to be more sensitive to inhibitors of de novo purine synthesis (6-thioguanine, methotrexate). BACKGROUND: T-cell lymphomas, in particular peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), have only limited and noncurative treatment options. PATIENTS AND METHODS: We report here that a high percentage of PTCL, AITL, and ALCL lack the enzyme methylthioadenosine phosphorylase (MTAP), as do T-cell leukemia and T-cell lymphoblastic leukemia. MTAP-deficient cells cannot cleave endogenous methylthioadenosine to adenine and 5-methylthioribose-1-phosphate, a precursor of methionine, and as a result have enhanced sensitivity to inhibitors of de novo purine biosynthesis. A recently introduced antifolate, pralatrexate, which has been shown to inhibit de novo purine biosynthesis, has been approved for treatment of PTCL and may have an increasing role in therapy. An alternative strategy involving coadministration of methylthioadenosine and high-dose 6-thioguanine has been proposed and may prove to be selectively toxic to MTAP-deficient uncommon lymphomas. CONCLUSION: Thus the consequences of MTAP deficiency suggest that new therapeutic interventions for T-cell lymphoma may be feasible.

ImageMiner: a software system for comparative analysis of tissue microarrays using content-based image retrieval, high-performance computing, and grid technology.

OBJECTIVE AND DESIGN: The design and implementation of ImageMiner, a software platform for performing comparative analysis of expression patterns in imaged microscopy specimens such as tissue microarrays (TMAs), is described. ImageMiner is a federated system of services that provides a reliable set of analytical and data management capabilities for investigative research applications in pathology. It provides a library of image processing methods, including automated registration, segmentation, feature extraction, and classification, all of which have been tailored, in these studies, to support TMA analysis. The system is designed to leverage high-performance computing machines so that investigators can rapidly analyze large ensembles of imaged TMA specimens. To support deployment in collaborative, multi-institutional projects, ImageMiner features grid-enabled, service-based components so that multiple instances of ImageMiner can be accessed remotely and federated. RESULTS: The experimental evaluation shows that: (1) ImageMiner is able to support reliable detection and feature extraction of tumor regions within imaged tissues; (2) images and analysis results managed in ImageMiner can be searched for and retrieved on the basis of image-based features, classification information, and any correlated clinical data, including any metadata that have been generated to describe the specified tissue and TMA; and (3) the system is able to reduce computation time of analyses by exploiting computing clusters, which facilitates analysis of larger sets of tissue samples.

PathMiner: a Web-based tool for computer-assisted diagnostics in pathology.

Large-scale, multisite collaboration has become indispensable for a wide range of research and clinical activities that rely on the capacity of individuals to dynamically acquire, share, and assess images and correlated data. In this paper, we report the development of a Web-based system, PathMiner , for interactive telemedicine, intelligent archiving, and automated decision support in pathology. The PathMiner system supports network-based submission of queries and can automatically locate and retrieve digitized pathology specimens along with correlated molecular studies of cases from "ground-truth" databases that exhibit spectral and spatial profiles consistent with a given query image. The statistically most probable diagnosis is provided to the individual who is seeking decision support. To test the system under real-case scenarios, a pipeline infrastructure was developed and a network-based test laboratory was established at strategic sites at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Robert Wood Johnson University Hospital, the University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, The Cancer Institute of New Jersey, and Rutgers University. The average five-class classification accuracy of the system was 93.18% based on a tenfold cross validation on a close dataset containing 3691 imaged specimens. We also conducted prospective performance studies with the PathMiner system in real applications in which the specimens exhibited large variations in staining characters compared with the training data. The average five-class classification accuracy in this open-set experiment was 87.22%. We also provide the comparative results with the previous literature and the PathMiner system shows superior performance.