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1.  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.
doi:10.1158/1541-7786.MCR-12-0300
PMCID: PMC3579011  PMID: 23204394
CLT1; fibronectin; bladder cancer; integrin α5β1; chloride intracellular channel 3
2.  Mapping stain distribution in pathology slides using whole slide imaging 
Background:
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.
Results:
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.
Conclusions:
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.
doi:10.4103/2153-3539.126140
PMCID: PMC3952401  PMID: 24672736
Stain distribution image; stain recognition; whole slide imaging
3.  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.
doi:10.1371/journal.pone.0083120
PMCID: PMC3869779  PMID: 24376648
4.  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.
doi:10.1371/journal.pone.0079542
PMCID: PMC3832612  PMID: 24260246
5.  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.
doi:10.1002/ijc.27317
PMCID: PMC3291748  PMID: 22025313
clear cell; papillary serous; prognostic biomarkers; chemokines; metastasis
6.  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.
doi:10.4103/2153-3539.108542
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
7.  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.
doi:10.4103/2153-3539.112689
PMCID: PMC3714902  PMID: 23869286
History; pathology informatics; clinical informatics; electronic medical record; laboratory information systems; pathology education
8.  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.
doi:10.4103/2153-3539.116866
PMCID: PMC3779393  PMID: 24083056
Digital; magnification; pathology; resolution; whole slide image
9.  Needs and workflow assessment prior to implementation of a digital pathology infrastructure for the US Air Force Medical Service 
Background:
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.
Aim:
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.
Results:
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.
Conclusions:
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.
doi:10.4103/2153-3539.122388
PMCID: PMC3869953  PMID: 24392246
Air force; anatomic pathology; consultation; contextual inquiry; digital pathology; informatics; workflow; workload distribution
10.  Primary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: a persisting diagnostic challenge 
Diagnostic Pathology  2012;7:151.
Aim
This study attempted to distinguish primary bladder adenocarcinoma (PBA) from metastatic colonic adenocarcinomas (MCA), which is a difficult diagnostic and clinical problem.
Methods
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.
Results
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.
Conclusion
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: http://www.diagnosticpathology.diagnomx.eu/vs/1393156268152357
doi:10.1186/1746-1596-7-151
PMCID: PMC3502416  PMID: 23121893
Bladder; Adenocarcinoma; Primary; Metastatic; Colorectal; Beta-catenin; E-cadherin
11.  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.
doi:10.1155/2012/498324
PMCID: PMC3474240  PMID: 23094187
12.  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.
doi:10.1016/j.jsbmb.2010.10.002
PMCID: PMC3010457  PMID: 20955794
Vitamin D receptor; Non-small cell lung cancer; Biomarker; Survival; Prognosis
13.  Integration of digital gross pathology images for enterprise-wide access 
Background:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.4103/2153-3539.93892
PMCID: PMC3327039  PMID: 22530178
DICOM; digital image; LIS; PACS; pathology; wrapper
14.  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.
doi:10.4103/2153-3539.96751
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
15.  Use of contextual inquiry to understand anatomic pathology workflow: Implications for digital pathology adoption 
Background:
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.
Objective:
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.
Results:
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.
Conclusions:
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.
doi:10.4103/2153-3539.101794
PMCID: PMC3519008  PMID: 23243553
Anatomic pathology; contextual inquiry; workflow; digital pathology
16.  Experience with multimodality telepathology at the University of Pittsburgh Medical Center 
Several modes of telepathology exist including static (store-and-forward), dynamic (live video streaming or robotic microscopy), and hybrid technology involving whole slide imaging (WSI). Telepathology has been employed at the University of Pittsburgh Medical Center (UPMC) for over a decade at local, national, and international sites. All modes of telepathology have been successfully utilized to exploit our institutions subspecialty expertise and to compete for pathology services. This article discusses the experience garnered at UPMC with each of these teleconsultation methods. Static and WSI telepathology systems have been utilized for many years in transplant pathology using a private network and client-server architecture. Only minor clinically significant differences of opinion were documented. In hematopathology, the CellaVision® system is used to transmit, via email, static images of blood cells in peripheral blood smears for remote interpretation. While live video streaming has remained the mode of choice for providing immediate adequacy assessment of cytology specimens by telecytology, other methods such as robotic microscopy have been validated and shown to be effective. Robotic telepathology has been extensively used to remotely interpret intra-operative neuropathology consultations (frozen sections). Adoption of newer technology and increased pathologist experience has improved accuracy and deferral rates in teleneuropathology. A digital pathology consultation portal (https://pathconsult.upmc.com/) was recently created at our institution to facilitate digital pathology second opinion consults, especially for WSI. The success of this web-based tool is the ability to handle vendor agnostic, large image files of digitized slides, and ongoing user-friendly customization for clients and teleconsultants. It is evident that the practice of telepathology at our institution has evolved in concert with advances in technology and user experience. Early and continued adoption of telepathology has promoted additional digital pathology resources that are now being leveraged for other clinical, educational, and research purposes.
doi:10.4103/2153-3539.104907
PMCID: PMC3551511  PMID: 23372986
Digital imaging; robotic; static; teleconsultation; telemicroscopy; telepathology; video microscopy; whole slide imaging
17.  Testicular touch preparation cytology in the evaluation of male infertility 
CytoJournal  2011;8:24.
Background:
Male infertility is traditionally evaluated by tissue core biopsies of the testes. Touch preparations (TP) of these biopsies have been infrequently used. The aim of this study is to report our experience with using testicular biopsy TP for the evaluation of male infertility.
Materials and Methods:
A retrospective search was performed for cases of testes biopsies with concurrent TP. These cases were evaluated for clinical information, specimen adequacy, and cytological–histological correlation.
Results:
A total of 39 cases were identified from men with a mean age of 34 years (range 23 to 50 years). TP slides were satisfactory for evaluation in 31 (89%) cases, and less than optimal in four due to low cellularity, obscuring blood or air drying artifact. Cytopathology showed concordance with the biopsy in almost all cases. In one discordant case where the biopsies showed no active spermatogenesis, a rare sperm were identified on the TP.
Conclusions:
TP of the testis is a helpful adjunct to biopsy because of its ability to clearly evaluate all stages of spermatogenesis. These data demonstrate that TP cytopathology of the testes in our experience has an excellent correlation with both normal testicular biopsies and those showing pathological spermatogenesis, and in rare cases may provide added benefit in evaluating the presence of spermatogenesis for male infertility. Albeit uncommon, cytopathologists may be required to identify and evaluate spermatogenic elements in cytology specimens being submitted from men with infertility.
doi:10.4103/1742-6413.91244
PMCID: PMC3263021  PMID: 22279493
Cytology; infertility; spermatogenesis; testis; touch preparation
18.  Immunohistochemical Staining of Slit2 in Primary and Metastatic Prostatic Adenocarcinoma1 
Translational Oncology  2011;4(5):314-320.
BACKGROUND: Conflicting roles for Slit2, a protein involved in mediating the processes of cell migration and chemotactic response, have been previously described in prostate cancer. Here we use immunohistochemistry to evaluate the expression of Slit2 in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). METHODS: Tissue microarrays were immunostained for Slit2. The staining intensities were quantified using automated image analysis software. The data was statistically analyzed using one-way analysis of variance with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Eleven cases of NDP, 35 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 106 cases of PCa, and 37 cases of Mets were analyzed. RESULTS: Specimens of PCa and HGPIN had the highest absolute staining for Slit2. Significant differences were seen between PCa and NDP (P < .05), PCa and NAC (P < .05), HGPIN and NDP (P < .05), and HGPIN and NAC (P < .05). Whereas the average Mets staining was not significantly different from NDP or NAC, several individual Mets cases featured intense staining. CONCLUSIONS: To our knowledge, this represents the first study comparing the immunohistochemical profiles of Slit2 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC. These findings suggest that Slit2 expression can be increased in HGPIN, PCa, and Mets, making it a potentially important biomarker for prostate cancer.
PMCID: PMC3162306  PMID: 21966548
19.  Prostatic Adenocarcinoma Metastatic to Pleomorphic Liposarcoma, a “Collision Phenomenon”: Report of a Case with Review of Pelvic Collision Tumors 
“Collision tumor” is an uncommon phenomenon characterized by coexistence of two completely distinct and independent tumors at the same site. Collision tumors have been reported in different sites in the body; however, these are particularly uncommon in the pelvic cavity. A 70-year-old man, with prior history of urothelial and prostate cancer, presented with a large pelvic mass detected on imaging studies. Pathological examination revealed a large liposarcoma with prostatic carcinoma embedded in it. Immunohistochemistry and florescence in situ hybridization studies were performed to reach to a conclusive diagnosis. To the best of our knowledge, this is the second case reported till date. We present the challenges encountered in the diagnosis of this case and review of pelvic collision tumors.
doi:10.4061/2011/173541
PMCID: PMC3166762  PMID: 21904691
20.  Diagnostic utility of p63/P501S double sequential immunohistochemical staining in differentiating urothelial carcinoma from prostate carcinoma 
Diagnostic Pathology  2011;6:67.
Background
Distinguishing urothelial carcinoma (UC) from prostate carcinoma (PC) is important due to potential therapeutic and prognostic implications. However, this can be a diagnostic challenge when there is limited tissue and in poorly differentiated tumors. We evaluated the diagnostic utility of a dual immunohistochemical stain comprising p63 and P501S (prostein), applied sequentially on a single slide and visualized by double chromogen reaction, in differentiating these two cancers. Thus far, there have been no previous studies assessing the diagnostic utility of p63 and P501S combined together as a dual immunostain in distinguishing between these two cancers.
Methods
p63/P501S dual-color sequential immunohistochemical staining was performed on archival material from 132 patients with high-grade UC and 23 patients with PC, and evaluated for p63 (brown nuclear) and P501S (red cytoplasmic) expression. Both the staining intensity and percentage of positive tumor cells were assessed.
Results
p63 was positive in 119/132 of UC and negative in PC. P501S was positive in 22/23 of PC and negative in UC. The p63+/P501S- immunoprofile had 90% sensitivity and 100% specificity for UC. The p63-/P501S+ immunoprofile had 96% sensitivity and 100% specificity for PC.
Conclusion
Our results indicate that double sequential immunohistochemical staining with p63 and P501S is highly specific and can be a useful tool in distinguishing UC from PC especially when there is limited diagnostic tissue as it can be performed on a single slide.
doi:10.1186/1746-1596-6-67
PMCID: PMC3163513  PMID: 21777423
21.  Digital Imaging in Cytopathology 
Rapid advances are occurring in the field of cytopathology, particularly in the field of digital imaging. Today, digital images are used in a variety of settings including education (E-education), as a substitute to multiheaded sessions, multisite conferences, publications, cytopathology web pages, cytology proficiency testing, telecytology, consultation through telecytology, and automated screening of Pap test slides. The accessibility provided by digital imaging in cytopathology can improve the quality and efficiency of cytopathology services, primarily by getting the expert cytopathologist to remotely look at the slide. This improved accessibility saves time and alleviates the need to ship slides, wait for glass slides, or transport pathologists. Whole slide imaging (WSI) is a digital imaging modality that uses computerized technology to scan and convert pathology and cytology glass slides into digital images (digital slides) that can be viewed remotely on a workstation using viewing software. In spite of the many advances, challenges remain such as the expensive initial set-up costs, workflow interruption, length of time to scan whole slides, large storage size for WSI, bandwidth restrictions, undefined legal implications, professional reluctance, and lack of standardization in the imaging process.
doi:10.4061/2011/264683
PMCID: PMC3140195  PMID: 21785680
22.  Immunohistochemical analysis of ezrin-radixin-moesin-binding phosphoprotein 50 in prostatic adenocarcinoma 
BMC Urology  2011;11:12.
Background
Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is an adapter protein which has been shown to play an active role in a wide variety of cellular processes, including interactions with proteins related to both tumor suppression and oncogenesis. Here we use immunohistochemistry to evaluate EBP50's expression in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets).
Methods
Tissue microarrays were immunohistochemically stained for EBP50, with the staining intensities quantified using automated image analysis software. The data were statistically analyzed using one-way ANOVA with subsequent Tukey tests for multiple comparisons. Eleven cases of NDP, 37 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 103 cases of PCa, and 36 cases of Mets were analyzed in the microarrays.
Results
Specimens of PCa and Mets had the lowest absolute staining for EBP50. Mets staining was significantly lower than NDP (p = 0.027), BPH (p = 0.012), NAC (p < 0.001), HGPIN (p < 0.001), and PCa (p = 0.006). Additionally, HGPIN staining was significantly higher than NAC (p < 0.009) and PCa (p < 0.001).
Conclusions
To our knowledge, this represents the first study comparing the immunohistochemical profiles of EBP50 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC and suggests that EBP50 expression is decreased in Mets. Given that PCa also had significantly higher expression than Mets, future studies are warranted to assess EBP50's potential as a prognostic biomarker for prostate cancer.
doi:10.1186/1471-2490-11-12
PMCID: PMC3132203  PMID: 21672215
23.  Immunohistochemical profiles of claudin-3 in primary and metastatic prostatic adenocarcinoma 
Diagnostic Pathology  2011;6:12.
Background
Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets).
Methods
Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays.
Results
PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p < 0.05 in both cases) and NAC (p < 0.05 in both cases). PIN had a lower, but non-significant, staining score than PCa and Mets, but a statistically higher score than both BPH and NAC (p < 0.05 for both cases). No significant differences were observed between PCa, Mets, and PIN.
Conclusions
To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis.
doi:10.1186/1746-1596-6-12
PMCID: PMC3033791  PMID: 21255442
24.  Immunohistochemical staining of radixin and moesin in prostatic adenocarcinoma 
Background
Some members of the Protein 4.1 superfamily are believed to be involved in cell proliferation and growth, or in the regulation of these processes. While the expression levels of two members of this family, radixin and moesin, have been studied in many tumor types, to our knowledge they have not been investigated in prostate cancer.
Methods
Tissue microarrays were immunohistochemically stained for either radixin or moesin, with the staining intensities subsequently quantified and statistically analyzed using One-Way ANOVA or nonparametric equivalent with subsequent Student-Newman-Keuls tests for multiple comparisons. There were 11 cases of normal donor prostates (NDP), 14 cases of benign prostatic hyperplasia (BPH), 23 cases of high-grade prostatic intraepithelial neoplasia (HGPIN), 88 cases of prostatic adenocarcinoma (PCa), and 25 cases of normal tissue adjacent to adenocarcinoma (NAC) analyzed in the microarrays.
Results
NDP, BPH, and HGPIN had higher absolute staining scores for radixin than PCa and NAC, but with a significant difference observed between only HGPIN and PCa (p = < 0.001) and HGPIN and NAC (p = 0.001). In the moesin-stained specimens, PCa, NAC, HGPIN, and BPH all received absolute higher staining scores than NDP, but the differences were not significant. Stage 4 moesin-stained PCa had a significantly reduced staining intensity compared to Stage 2 (p = 0.003).
Conclusions
To our knowledge, these studies represent the first reports on the expression profiles of radixin and moesin in prostatic adenocarcinoma. The current study has shown that there were statistically significant differences observed between HGPIN and PCa and HGPIN and NAC in terms of radixin expression. The differences in the moesin profiles by tissue type were not statistically significant. Additional larger studies with these markers may further elucidate their potential roles in prostatic neoplasia progression.
doi:10.1186/1472-6890-11-1
PMCID: PMC3029218  PMID: 21235778
25.  Contemporary issues in transfusion medicine informatics 
The Transfusion Medicine Service (TMS) covers diverse clinical and laboratory-based services that must be delivered with accuracy, efficiency and reliability. TMS oversight is shared by multiple regulatory agencies that cover product manufacturing and validation standards geared toward patient safety. These demands present significant informatics challenges. Over the past few decades, TMS information systems have improved to better handle blood product manufacturing, inventory, delivery, tracking and documentation. Audit trails and access to electronic databases have greatly facilitated product traceability and biovigilance efforts. Modern blood bank computing has enabled novel applications such as the electronic crossmatch, kiosk-based blood product delivery systems, and self-administered computerized blood donor interview and eligibility determination. With increasing use of barcoding technology, there has been a marked improvement in patient and specimen identification. Moreover, the emergence of national and international labeling standards such as ISBT 128 have facilitated the availability, movement and tracking of blood products across national and international boundaries. TMS has only recently begun to leverage the electronic medical record to address quality issues in transfusion practice and promote standardized documentation within institutions. With improved technology, future growth is expected in blood bank automation and product labeling with applications such as radio frequency identification devices. This article reviews several of these key informatics issues relevant to the contemporary practice of TMS.
doi:10.4103/2153-3539.74961
PMCID: PMC3046378  PMID: 21383927
Blood bank; barcode; computer; donor; electronic crossmatch; FDA; informatics; transfusion medicine; virtual

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