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1.  Carnegie Mellon University bioimaging day 2014: Challenges and opportunities in digital pathology 
Recent advances in digital imaging is impacting the practice of pathology. One of the key enabling technologies that is leading the way towards this transformation is the use of whole slide imaging (WSI) which allows glass slides to be converted into large image files that can be shared, stored, and analyzed rapidly. Many applications around this novel technology have evolved in the last decade including education, research and clinical applications. This publication highlights a collection of abstracts, each corresponding to a talk given at Carnegie Mellon University's (CMU) Bioimaging Day 2014 co-sponsored by the Biomedical Engineering and Lane Center for Computational Biology Departments at CMU. Topics related specifically to digital pathology are presented in this collection of abstracts. These include topics related to digital workflow implementation, imaging and artifacts, storage demands, and automated image analysis algorithms.
PMCID: PMC4168545  PMID: 25250190
Challenges; digital pathology; image analysis; opportunities
2.  MicroRNA-940 suppresses prostate cancer migration and invasion by regulating MIEN1 
Molecular Cancer  2014;13(1):250.
MicroRNAs (miRNAs) are crucial molecules that regulate gene expression and hence pathways that are key to prostate cancer progression. These non-coding RNAs are highly deregulated in prostate cancer thus facilitating progression of the disease. Among the many genes that have gained importance in this disease, Migration and invasion enhancer 1 (MIEN1), a novel gene located next to HER2/neu in the 17q12 amplicon of the human chromosome, has been shown to enhance prostate cancer cell migration and invasion, two key processes in cancer progression. MIEN1 is differentially expressed between normal and cancer cells and tissues. Understanding the regulation of MIEN1 by microRNA may enable development of better targeting strategies.
The miRNAs that could target MIEN1 were predicted by in silico algorithms and microarray analysis. The validation for miRNA expression was performed by qPCR and northern blotting in cells and by in situ hybridization in tissues. MIEN1 and levels of other molecules upon miRNA regulation was determined by Western blotting, qPCR, and immunofluorescence. The functional effects of miRNA on cells were determined by wound healing cell migration, Boyden chamber cell invasion, clonal and colony formation assays. For knockdown or overexpression of the miRNA or overexpression of MIEN1 3′UTR, cells were transfected with the oligomiRs and plasmids, respectively.
A novel miRNA, hsa-miR-940 (miR-940), identified and validated to be highly expressed in immortalized normal cells compared to cancer cells, is a regulator of MIEN1. Analysis of human prostate tumors and their matched normal tissues confirmed that miR-940 is highly expressed in the normal tissues compared to its low to negligible expression in the tumors. While MIEN1 is a direct target of miR-940, miR-940 alters MIEN1 RNA, in a quantity as well as cell dependent context, along with altering its downstream effectors. The miR-940 inhibited migratory and invasive potential of cells, attenuated their anchorage-independent growth ability, and increased E-cadherin expression, implicating its role in mesenchymal-to-epithelial transition (MET).
These results, for the first time, implicate miR-940, a regulator of MIEN1, as a promising novel diagnostic and prognostic tool for prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-250) contains supplementary material, which is available to authorized users.
PMCID: PMC4246551  PMID: 25406943
Migration; Invasion; Post-transcription regulation; Prostate cancer; MicroRNA; MIEN1; miRNA-940
3.  CLT1 Targets Bladder Cancer through Integrin α5β1 and CLIC3 
Molecular cancer research : MCR  2012;11(2):194-203.
High grade non-muscle invasive bladder cancer is commonly treated with Bacillus Calmette-Guérin, an immunotherapeutic that depends on fibronectin and tumor cell integrin α5β1 for internalization into bladder cancer cells. We previously demonstrated that the anti-angiogenic peptide CLT1 forms cytotoxic complexes with fibronectin that are cooperatively internalized into proliferating endothelium through ligation of integrins and chloride intracellular channel 1. While CLT1 has no effect on mature, differentiated cells, we show here that CLT1 is highly cytotoxic for a panel of bladder tumor cell lines as well as a variety of cell lines derived from kidney, lung, breast and prostate cancer. Paralleling our previous results, we found CLT1-induced tumor cell death to be increased in the presence of fibronectin, which mediated CLT1 internalization and subsequent autophagic cell death in a mechanism that depends on tumor cell integrin α5β1 and chloride intracellular channel 3 (CLIC3). This mechanistic link was further supported by our results showing upregulation of α5β1 and CLIC3 in CLT1-responsive tumor cell lines and co-localization with CLT1 in tumor tissues. Incubating tumor tissue from bladder cancer patients with fluorescein-conjugated CLT1 resulted in a strong and specific fluorescence while normal bladder tissue remained negative. Based on its affinity for bladder tumor tissue and strong anti-tumor effects, we propose that CLT1 could be useful for targeting bladder cancer.
PMCID: PMC3579011  PMID: 23204394
CLT1; fibronectin; bladder cancer; integrin α5β1; chloride intracellular channel 3
4.  Mapping stain distribution in pathology slides using whole slide imaging 
Whole slide imaging (WSI) offers a novel approach to digitize and review pathology slides, but the voluminous data generated by this technology demand new computational methods for image analysis.
Materials and Methods:
In this study, we report a method that recognizes stains in WSI data and uses kernel density estimator to calculate the stain density across the digitized pathology slides. The validation study was conducted using a rat model of acute cardiac allograft rejection and another rat model of heart ischemia/reperfusion injury. Immunohistochemistry (IHC) was conducted to label ED1+ macrophages in the tissue sections and the stained slides were digitized by a whole slide scanner. The whole slide images were tessellated to enable parallel processing. Pixel-wise stain classification was conducted to classify the IHC stains from those of the background and the density distribution of the identified IHC stains was then calculated by the kernel density estimator.
The regression analysis showed a correlation coefficient of 0.8961 between the number of IHC stains counted by our stain recognition algorithm and that by the manual counting, suggesting that our stain recognition algorithm was in good agreement with the manual counting. The density distribution of the IHC stains showed a consistent pattern with those of the cellular magnetic resonance (MR) images that detected macrophages labeled by ultrasmall superparamagnetic iron-oxide or micron-sized iron-oxide particles.
Our method provides a new imaging modality to facilitate clinical diagnosis. It also provides a way to validate/correlate cellular MRI data used for tracking immune-cell infiltration in cardiac transplant rejection and cardiac ischemic injury.
PMCID: PMC3952401  PMID: 24672736
Stain distribution image; stain recognition; whole slide imaging
5.  Pocket pathologist: A mobile application for rapid diagnostic surgical pathology consultation 
Telepathology allows the digital transmission of images for rapid access to pathology experts. Recent technologic advances in smartphones have allowed them to be used to acquire and transmit digital images of the glass slide, representing cost savings and efficiency gains over traditional forms of telepathology. We report our experience with developing an iPhone application (App - Pocket Pathologist) to facilitate rapid diagnostic pathology teleconsultation utilizing a smartphone.
Materials and Methods:
A secure, web-based portal ( was created to facilitate remote transmission of digital images for teleconsultation. The App augments functionality of the web-based portal and allows the user to quickly and easily upload digital images for teleconsultation. Image quality of smartphone cameras was evaluated by capturing images using different adapters that directly attach phones to a microscope ocular lens.
The App was launched in August 2013. The App facilitated easy submission of cases for teleconsultation by limiting the number of data entry fields for users and enabling uploading of images from their smartphone's gallery wirelessly. Smartphone cameras properly attached to a microscope create static digital images of similar quality to a commercial digital microscope camera.
Smartphones have great potential to support telepathology because they are portable, provide ubiquitous internet connectivity, contain excellent digital cameras, and can be easily attached to a microscope. The Pocket Pathologist App represents a significant reduction in the cost of creating digital images and submitting them for teleconsultation. The iPhone App provides an easy solution for global users to submit digital pathology images to pathology experts for consultation.
PMCID: PMC4023036  PMID: 24843822
Application; cell phone; consultation; digital pathology; iPhone; smartphone; telepathology
6.  Digital pathology: A systematic evaluation of the patent landscape 
Digital pathology is a relatively new field. Inventors of technology in this field typically file for patents to protect their intellectual property. An understanding of the patent landscape is crucial for companies wishing to secure patent protection and market dominance for their products. To our knowledge, there has been no prior systematic review of patents related to digital pathology. Therefore, the aim of this study was to systematically identify and evaluate United States patents and patent applications related to digital pathology.
Materials and Methods:
Issued patents and patent applications related to digital pathology published in the United States Patent and Trademark Office (USPTO) database ( (through January 2014) were searched using the Google Patents search engine (Google Inc., Mountain View, California, USA). Keywords and phrases related to digital pathology, whole-slide imaging (WSI), image analysis, and telepathology were used to query the USPTO database. Data were downloaded and analyzed using the Papers application (Mekentosj BV, Aalsmeer, Netherlands).
A total of 588 United States patents that pertain to digital pathology were identified. In addition, 228 patent applications were identified, including 155 that were pending, 65 abandoned, and eight rejected. Of the 588 patents granted, 348 (59.18%) were specific to pathology, while 240 (40.82%) included more general patents also usable outside of pathology. There were 70 (21.12%) patents specific to pathology and 57 (23.75%) more general patents that had expired. Over 120 unique entities (individual inventors, academic institutions, and private companies) applied for pathology specific patents. Patents dealt largely with telepathology and image analysis. WSI related patents addressed image acquisition (scanning and focus), quality (z-stacks), management (storage, retrieval, and transmission of WSI files), and viewing (graphical user interface (GUI), workflow, slide navigation and remote control). An increasing number of recent patents focused on computer-aided diagnosis (CAD) and digital consultation networks.
In the last 2 decades, there have been an increasing number of patents granted and patent applications filed related to digital pathology. The number of these patents quadrupled during the last decade, and this trend is predicted to intensify based on the number of patent applications already published by the USPTO.
PMCID: PMC4060404  PMID: 25057430
Digital pathology; image analysis; intellectual property; legal; patent; telepathology; whole-slide imaging
7.  Smartphone adapters for digital photomicrography 
Photomicrographs in Anatomic Pathology provide a means of quickly sharing information from a glass slide for consultation, education, documentation and publication. While static image acquisition historically involved the use of a permanently mounted camera unit on a microscope, such cameras may be expensive, need to be connected to a computer, and often require proprietary software to acquire and process images. Another novel approach for capturing digital microscopic images is to use smartphones coupled with the eyepiece of a microscope. Recently, several smartphone adapters have emerged that allow users to attach mobile phones to the microscope. The aim of this study was to test the utility of these various smartphone adapters.
Materials and Methods:
We surveyed the market for adapters to attach smartphones to the ocular lens of a conventional light microscope. Three adapters (Magnifi, Skylight and Snapzoom) were tested. We assessed the designs of these adapters and their effectiveness at acquiring static microscopic digital images.
All adapters facilitated the acquisition of digital microscopic images with a smartphone. The optimal adapter was dependent on the type of phone used. The Magnifi adapters for iPhone were incompatible when using a protective case. The Snapzoom adapter was easiest to use with iPhones and other smartphones even with protective cases.
Smartphone adapters are inexpensive and easy to use for acquiring digital microscopic images. However, they require some adjustment by the user in order to optimize focus and obtain good quality images. Smartphone microscope adapters provide an economically feasible method of acquiring and sharing digital pathology photomicrographs.
PMCID: PMC4141421  PMID: 25191623
Digital pathology; digital photomicrography; smartphone microscope adapters
8.  Automated grading of renal cell carcinoma using whole slide imaging 
Recent technology developments have demonstrated the benefit of using whole slide imaging (WSI) in computer-aided diagnosis. In this paper, we explore the feasibility of using automatic WSI analysis to assist grading of clear cell renal cell carcinoma (RCC), which is a manual task traditionally performed by pathologists.
Materials and Methods:
Automatic WSI analysis was applied to 39 hematoxylin and eosin-stained digitized slides of clear cell RCC with varying grades. Kernel regression was used to estimate the spatial distribution of nuclear size across the entire slides. The analysis results were correlated with Fuhrman nuclear grades determined by pathologists.
The spatial distribution of nuclear size provided a panoramic view of the tissue sections. The distribution images facilitated locating regions of interest, such as high-grade regions and areas with necrosis. The statistical analysis showed that the maximum nuclear size was significantly different (P < 0.001) between low-grade (Grades I and II) and high-grade tumors (Grades III and IV). The receiver operating characteristics analysis showed that the maximum nuclear size distinguished high-grade and low-grade tumors with a false positive rate of 0.2 and a true positive rate of 1.0. The area under the curve is 0.97.
The automatic WSI analysis allows pathologists to see the spatial distribution of nuclei size inside the tumors. The maximum nuclear size can also be used to differentiate low-grade and high-grade clear cell RCC with good sensitivity and specificity. These data suggest that automatic WSI analysis may facilitate pathologic grading of renal tumors and reduce variability encountered with manual grading.
PMCID: PMC4141422  PMID: 25191622
Computer-aided diagnosis; Fuhrman nuclear grade; nuclear size distribution imaging; renal cell carcinoma; whole slide imaging
9.  Journal of Pathology Informatics thanks its reviewers 
PMCID: PMC4168641  PMID: 25250189
10.  Can Digital Pathology Result In Cost Savings? A Financial Projection For Digital Pathology Implementation At A Large Integrated Health Care Organization 
Digital pathology offers potential improvements in workflow and interpretive accuracy. Although currently digital pathology is commonly used for research and education, its clinical use has been limited to niche applications such as frozen sections and remote second opinion consultations. This is mainly due to regulatory hurdles, but also to a dearth of data supporting a positive economic cost-benefit. Large scale adoption of digital pathology and the integration of digital slides into the routine anatomic/surgical pathology “slide less” clinical workflow will occur only if digital pathology will offer a quantifiable benefit, which could come in the form of more efficient and/or higher quality care.
As a large academic-based health care organization expecting to adopt digital pathology for primary diagnosis upon its regulatory approval, our institution estimated potential operational cost savings offered by the implementation of an enterprise-wide digital pathology system (DPS).
Projected cost savings were calculated for the first 5 years following implementation of a DPS based on operational data collected from the pathology department. Projected savings were based on two factors: (1) Productivity and lab consolidation savings; and (2) avoided treatment costs due to improvements in the accuracy of cancer diagnoses among nonsubspecialty pathologists. Detailed analyses of incremental treatment costs due to interpretive errors, resulting in either a false positive or false negative diagnosis, was performed for melanoma and breast cancer and extrapolated to 10 other common cancers.
When phased in over 5-years, total cost savings based on anticipated improvements in pathology productivity and histology lab consolidation were estimated at $12.4 million for an institution with 219,000 annual accessions. The main contributing factors to these savings were gains in pathologist clinical full-time equivalent capacity impacted by improved pathologist productivity and workload distribution. Expanding the current localized specialty sign-out model to an enterprise-wide shared general/subspecialist sign-out model could potentially reduce costs of incorrect treatment by $5.4 million. These calculations were based on annual over and under treatment costs for breast cancer and melanoma estimated to be approximately $26,000 and $11,000/case, respectively, and extrapolated to $21,500/case for other cancer types.
The projected 5-year total cost savings for our large academic-based health care organization upon fully implementing a DPS was approximately $18 million. If the costs of digital pathology acquisition and implementation do not exceed this value, the return on investment becomes attractive to hospital administrators. Furthermore, improved patient outcome enabled by this technology strengthens the argument supporting adoption of an enterprise-wide DPS.
PMCID: PMC4168664  PMID: 25250191
Anatomic pathology; cost; cost analysis; digital pathology; productivity; whole slide imaging
13.  Cartilage Oligomeric Matrix Protein in Idiopathic Pulmonary Fibrosis 
PLoS ONE  2013;8(12):e83120.
Idiopathic pulmonary fibrosis (IPF) is a progressive and life threatening disease with median survival of 2.5–3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein (COMP), a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes (Fold change 13, p-value <0.05) in IPF lungs. This finding was confirmed at the mRNA level by nCounter® expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-β1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-β1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity (FVC). Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-β1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-β1 signaling should be persuaded.
PMCID: PMC3869779  PMID: 24376648
14.  Development of a Reactive Stroma Associated with Prostatic Intraepithelial Neoplasia in EAF2 Deficient Mice 
PLoS ONE  2013;8(11):e79542.
ELL-associated factor 2 (EAF2) is an androgen-responsive tumor suppressor frequently deleted in advanced prostate cancer that functions as a transcription elongation factor of RNA Pol II through interaction with the ELL family proteins. EAF2 knockout mice on a 129P2/OLA-C57BL/6J background developed late-onset lung adenocarcinoma, hepatocellular carcinoma, B-cell lymphoma and high-grade prostatic intraepithelial neoplasia. In order to further characterize the role of EAF2 in the development of prostatic defects, the effects of EAF2 loss were compared in different murine strains. In the current study, aged EAF2−/− mice on both the C57BL/6J and FVB/NJ backgrounds exhibited mPIN lesions as previously reported on a 129P2/OLA-C57BL/6J background. In contrast to the 129P2/OLA-C57BL/6J mixed genetic background, the mPIN lesions in C57BL/6J and FVB/NJ EAF2−/− mice were associated with stromal defects characteristic of a reactive stroma and a statistically significant increase in prostate microvessel density. Stromal inflammation and increased microvessel density was evident in EAF2-deficient mice on a pure C57BL/6J background at an early age and preceded the development of the histologic epithelial hyperplasia and neoplasia found in the prostates of older EAF2−/− animals. Mice deficient in EAF2 had an increased recovery rate and a decreased overall response to the effects of androgen deprivation. EAF2 expression in human cancer was significantly down-regulated and microvessel density was significantly increased compared to matched normal prostate tissue; furthermore EAF2 expression was negatively correlated with microvessel density. These results suggest that the EAF2 knockout mouse on the C57BL/6J and FVB/NJ genetic backgrounds provides a model of PIN lesions associated with an altered prostate microvasculature and reactive stromal compartment corresponding to that reported in human prostate tumors.
PMCID: PMC3832612  PMID: 24260246
15.  Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression 
CXCL12 is a chemotactic cytokine that has pro-metastatic functions in several malignancies through interactions with its receptor, CXCR4. CXCL12 is an estrogen-regulated gene, and notably, estrogen is a major risk factor for endometrial cancer (EC) development. As few studies examine concurrent CXCL12, CXCR4, and estrogen receptor (ER) expression in EC patients, we examined this pathway in 199 EC patients with data from the University of Pittsburgh Medical Center Cancer Registry. Immunohistochemistry (IHC) was used to detect CXCR4, CXCL12, and ER protein expression. As CXCR4 expression was positive in all cases, this investigation focused on associations between CXCL12 and ER expression, clinicopathologic factors, and survival outcomes using chi-square tests, Kaplan-Meier graphs, and log-rank tests. CXCL12 expression was negative in 63 cases (32%) and positive in 136 cases (68%). Negative CXCL12 expression was borderline significantly associated with metastasis (χ2 p=0.07). ER expression was negative in 75 cases (38%) and positive in 124 cases (62%). Positive ER expression was significantly associated with low grade and early stage tumors (χ2 p<0.001). CXCL12 and ER were not significantly associated (χ2 p=0.11). Positive CXCL12 expression was associated with longer overall survival (OS) (log-rank p=0.006) and longer recurrence-free survival (RFS) (log-rank p=0.01) in ER negative patients, but not in ER positive patients. We identified a unique molecular signature associated with better OS and RFS in EC patients. In addition to pathological characteristics of the tumor, expression of CXCL12 and ER may be clinically useful for assigning adjuvant treatment to EC cases.
PMCID: PMC3291748  PMID: 22025313
clear cell; papillary serous; prognostic biomarkers; chemokines; metastasis
16.  Privacy and security of patient data in the pathology laboratory 
Data protection and security are critical components of routine pathology practice because laboratories are legally required to securely store and transmit electronic patient data. With increasing connectivity of information systems, laboratory work-stations, and instruments themselves to the Internet, the demand to continuously protect and secure laboratory information can become a daunting task. This review addresses informatics security issues in the pathology laboratory related to passwords, biometric devices, data encryption, internet security, virtual private networks, firewalls, anti-viral software, and emergency security situations, as well as the potential impact that newer technologies such as mobile devices have on the privacy and security of electronic protected health information (ePHI). In the United States, the Health Insurance Portability and Accountability Act (HIPAA) govern the privacy and protection of medical information and health records. The HIPAA security standards final rule mandate administrative, physical, and technical safeguards to ensure the confidentiality, integrity, and security of ePHI. Importantly, security failures often lead to privacy breaches, invoking the HIPAA privacy rule as well. Therefore, this review also highlights key aspects of HIPAA and its impact on the pathology laboratory in the United States.
PMCID: PMC3624703  PMID: 23599904
Antivirus; audit; biometrics; data backup; data integrity; encryption; firewall; health insurance portability and accountability act; internet; password; privacy; security; spyware; virtual private networks
17.  The history of pathology informatics: A global perspective 
Pathology informatics has evolved to varying levels around the world. The history of pathology informatics in different countries is a tale with many dimensions. At first glance, it is the familiar story of individuals solving problems that arise in their clinical practice to enhance efficiency, better manage (e.g., digitize) laboratory information, as well as exploit emerging information technologies. Under the surface, however, lie powerful resource, regulatory, and societal forces that helped shape our discipline into what it is today. In this monograph, for the first time in the history of our discipline, we collectively perform a global review of the field of pathology informatics. In doing so, we illustrate how general far-reaching trends such as the advent of computers, the Internet and digital imaging have affected pathology informatics in the world at large. Major drivers in the field included the need for pathologists to comply with national standards for health information technology and telepathology applications to meet the scarcity of pathology services and trained people in certain countries. Following trials by a multitude of investigators, not all of them successful, it is apparent that innovation alone did not assure the success of many informatics tools and solutions. Common, ongoing barriers to the widespread adoption of informatics devices include poor information technology infrastructure in undeveloped areas, the cost of technology, and regulatory issues. This review offers a deeper understanding of how pathology informatics historically developed and provides insights into what the promising future might hold.
PMCID: PMC3714902  PMID: 23869286
History; pathology informatics; clinical informatics; electronic medical record; laboratory information systems; pathology education
18.  Relationship between magnification and resolution in digital pathology systems 
Many pathology laboratories are implementing digital pathology systems. The image resolution and scanning (digitization) magnification can vary greatly between these digital pathology systems. In addition, when digital images are compared with viewing images using a microscope, the cellular features can vary in size. This article highlights differences in magnification and resolution between the conventional microscopes and the digital pathology systems. As more pathologists adopt digital pathology, it is important that they understand these differences and how they ultimately translate into what the pathologist can see and how this may impact their overall viewing experience.
PMCID: PMC3779393  PMID: 24083056
Digital; magnification; pathology; resolution; whole slide image
19.  Needs and workflow assessment prior to implementation of a digital pathology infrastructure for the US Air Force Medical Service 
Advances in digital pathology are accelerating integration of this technology into anatomic pathology (AP). To optimize implementation and adoption of digital pathology systems within a large healthcare organization, initial assessment of both end user (pathologist) needs and organizational infrastructure are required. Contextual inquiry is a qualitative, user-centered tool for collecting, interpreting, and aggregating such detailed data about work practices that can be employed to help identify specific needs and requirements.
Using contextual inquiry, the objective of this study was to identify the unique work practices and requirements in AP for the United States (US) Air Force Medical Service (AFMS) that had to be targeted in order to support their transition to digital pathology.
Subjects and Methods:
A pathology-centered observer team conducted 1.5 h interviews with a total of 24 AFMS pathologists and histology lab personnel at three large regional centers and one smaller peripheral AFMS pathology center using contextual inquiry guidelines. Findings were documented as notes and arranged into a hierarchal organization of common themes based on user-provided data, defined as an affinity diagram. These data were also organized into consolidated graphic models that characterized AFMS pathology work practices, structure, and requirements.
Over 1,200 recorded notes were grouped into an affinity diagram composed of 27 third-level, 10 second-level, and five main-level (workflow and workload distribution, quality, communication, military culture, and technology) categories. When combined with workflow and cultural models, the findings revealed that AFMS pathologists had needs that were unique to their military setting, when compared to civilian pathologists. These unique needs included having to serve a globally distributed patient population, transient staff, but a uniform information technology (IT) structure.
The contextual inquiry method helped reveal similarities and key differences with civilian pathologists. Such an analysis helped identify specific instances that would benefit from implementing digital pathology in a military environment. Employing digital pathology to facilitate workload distribution, secondary consultations, and quality assurance (over-reads) could help the AFMS deliver more accurate, efficient, and timely AP services at a global level.
PMCID: PMC3869953  PMID: 24392246
Air force; anatomic pathology; consultation; contextual inquiry; digital pathology; informatics; workflow; workload distribution
20.  Primary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: a persisting diagnostic challenge 
Diagnostic Pathology  2012;7:151.
This study attempted to distinguish primary bladder adenocarcinoma (PBA) from metastatic colonic adenocarcinomas (MCA), which is a difficult diagnostic and clinical problem.
Twenty-four cases of bladder adenocarcinomas (12 primary & 12 metastatic colorectal) were included in the study with urothelial carcinoma (UC) and colonic adenocarcinoma (CA) as controls. A panel of immunohistochemical (IHC) stains along with fluorescence in-situ hybridization (FISH), using the UroVysion probe set, was performed.
The majority of the PBAs presented with advanced disease. Enteric histologic subtype was the most common morphological variant. Strong nuclear with cytoplasmic-membranous staining of β-catenin was seen in 75% of MCA and only 16.7% PBA (<10% staining cells). Although abnormal nuclear staining with E-cadherin was seen in both PBA and MCA, it was more frequent in former. CK-7, CK-20, villin and CDX-2 stains were not helpful in distinguishing the two entities. FISH did not reveal any unique differences in chromosomal abnormality between the two groups.
Although there was a statistically significant difference in β-catenin and E-cadherin staining between two groups, we did not find any IHC or FISH marker that was specific for PBA. Distinction between PBA and MCA remains a diagnostic problem and clinical correlation is vital before rendering a diagnosis.
Virtual slides
The virtual slides for this article can be found here:
PMCID: PMC3502416  PMID: 23121893
Bladder; Adenocarcinoma; Primary; Metastatic; Colorectal; Beta-catenin; E-cadherin
21.  Epidermal Inclusion Cyst Presenting as a Palpable Scrotal Mass 
Case Reports in Urology  2012;2012:498324.
We report a scrotal epidermal inclusion cyst located outside the median raphe which a rare entity in the absence of trauma and few cases have been reported. 47 year old male presents with a complaint of right sided testicular swelling and discomfort. On examination a 3 cm mass was palpated between the scrotum and the medial thigh on the subcutaneous tissue with a positive slip sign. Complete surgical excision of the cyst was performed. Histopathology confirmed epidermal inclusion cyst with no evidence of malignancy.
PMCID: PMC3474240  PMID: 23094187
22.  Nuclear Vitamin D Receptor Expression is Associated with Improved Survival in Non-Small Cell Lung Cancer 
Vitamin D has been shown to have anti-proliferative effects in a wide variety of cancers including lung cancer. The anticancer effects of Vitamin D are mediated primarily by its active metabolite, 1,25-dihydroxyvitamin D (calcitriol), through vitamin D receptor (VDR) signaling. However, thus far there have been no studies evaluating the association between VDR expression and survival outcome in lung cancer. Using immunohistochemical analysis, we evaluated VDR expression, separately in the nucleus and cytoplasm, in lung cancer samples from 73 non-small cell lung carcinoma (NSCLC) patients with no prior therapy, and investigated the association between VDR expression and overall survival (OS). Cox proportional hazard models were used for our primary analyses. There were 44 deaths during a median follow-up of 51 months (range 13-93 months). High nuclear VDR expression was associated with improved OS after adjusting for age, gender, stage, smoking status, and histology (adjusted hazard ratio, 0.36; 95% confidence interval, 0.17-0.79). There was no association between cytoplasmic VDR expression and OS. Our results suggest that nuclear VDR status may be a prognostic marker in NSCLC. Future large studies to replicate our findings and to assess the impact of VDR gene polymorphisms on VDR expression are required as therapies targeting the vitamin D signaling pathway may be influenced by VDR status in the target lung cancer tissue.
PMCID: PMC3010457  PMID: 20955794
Vitamin D receptor; Non-small cell lung cancer; Biomarker; Survival; Prognosis
23.  Integration of digital gross pathology images for enterprise-wide access 
Sharing digital pathology images for enterprise- wide use into a picture archiving and communication system (PACS) is not yet widely adopted. We share our solution and 3-year experience of transmitting such images to an enterprise image server (EIS).
Gross pathology images acquired by prosectors were integrated with clinical cases into the laboratory information system's image management module, and stored in JPEG2000 format on a networked image server. Automated daily searches for cases with gross images were used to compile an ASCII text file that was forwarded to a separate institutional Enterprise Digital Imaging and Communications in Medicine (DICOM) Wrapper (EDW) server. Concurrently, an HL7-based image order for these cases was generated, containing the locations of images and patient data, and forwarded to the EDW, which combined data in these locations to generate images with patient data, as required by DICOM standards. The image and data were then “wrapped” according to DICOM standards, transferred to the PACS servers, and made accessible on an institution-wide basis.
In total, 26,966 gross images from 9,733 cases were transmitted over the 3-year period from the laboratory information system to the EIS. The average process time for cases with successful automatic uploads (n=9,688) to the EIS was 98 seconds. Only 45 cases (0.5%) failed requiring manual intervention. Uploaded images were immediately available to institution- wide PACS users. Since inception, user feedback has been positive.
Enterprise- wide PACS- based sharing of pathology images is feasible, provides useful services to clinical staff, and utilizes existing information system and telecommunications infrastructure. PACS-shared pathology images, however, require a “DICOM wrapper” for multisystem compatibility.
PMCID: PMC3327039  PMID: 22530178
DICOM; digital image; LIS; PACS; pathology; wrapper
24.  Review of advanced imaging techniques 
Pathology informatics encompasses digital imaging and related applications. Several specialized microscopy techniques have emerged which permit the acquisition of digital images (“optical biopsies”) at high resolution. Coupled with fiber-optic and micro-optic components, some of these imaging techniques (e.g., optical coherence tomography) are now integrated with a wide range of imaging devices such as endoscopes, laparoscopes, catheters, and needles that enable imaging inside the body. These advanced imaging modalities have exciting diagnostic potential and introduce new opportunities in pathology. Therefore, it is important that pathology informaticists understand these advanced imaging techniques and the impact they have on pathology. This paper reviews several recently developed microscopic techniques, including diffraction-limited methods (e.g., confocal microscopy, 2-photon microscopy, 4Pi microscopy, and spatially modulated illumination microscopy) and subdiffraction techniques (e.g., photoactivated localization microscopy, stochastic optical reconstruction microscopy, and stimulated emission depletion microscopy). This article serves as a primer for pathology informaticists, highlighting the fundamentals and applications of advanced optical imaging techniques.
PMCID: PMC3385156  PMID: 22754737
2-photon microscopy; 4Pi microscopy; advanced imaging; confocal microscopy; digital; microscopy; optical coherence tomography; optics; photoactivated localization microscopy; spatially modulated illumination microscopy; stimulated emission depletion microscopy
25.  Use of contextual inquiry to understand anatomic pathology workflow: Implications for digital pathology adoption 
For decades anatomic pathology (AP) workflow have been a highly manual process based on the use of an optical microscope and glass slides. Recent innovations in scanning and digitizing of entire glass slides are accelerating a move toward widespread adoption and implementation of a workflow based on digital slides and their supporting information management software. To support the design of digital pathology systems and ensure their adoption into pathology practice, the needs of the main users within the AP workflow, the pathologists, should be identified. Contextual inquiry is a qualitative, user-centered, social method designed to identify and understand users’ needs and is utilized for collecting, interpreting, and aggregating in-detail aspects of work.
Contextual inquiry was utilized to document current AP workflow, identify processes that may benefit from the introduction of digital pathology systems, and establish design requirements for digital pathology systems that will meet pathologists’ needs.
Materials and Methods:
Pathologists were observed and interviewed at a large academic medical center according to contextual inquiry guidelines established by Holtzblatt et al. 1998. Notes representing user-provided data were documented during observation sessions. An affinity diagram, a hierarchal organization of the notes based on common themes in the data, was created. Five graphical models were developed to help visualize the data including sequence, flow, artifact, physical, and cultural models.
A total of six pathologists were observed by a team of two researchers. A total of 254 affinity notes were documented and organized using a system based on topical hierarchy, including 75 third-level, 24 second-level, and five main-level categories, including technology, communication, synthesis/preparation, organization, and workflow. Current AP workflow was labor intensive and lacked scalability. A large number of processes that may possibly improve following the introduction of digital pathology systems were identified. These work processes included case management, case examination and review, and final case reporting. Furthermore, a digital slide system should integrate with the anatomic pathologic laboratory information system.
To our knowledge, this is the first study that utilized the contextual inquiry method to document AP workflow. Findings were used to establish key requirements for the design of digital pathology systems.
PMCID: PMC3519008  PMID: 23243553
Anatomic pathology; contextual inquiry; workflow; digital pathology

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