Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3 , cause Cowden syndrome (CS) , which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas , the frequency of loss of flanking markers around PTEN is approximately 30 to 40% , and the somatic intragenic PTEN mutation frequency is <5%. In this study , we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples , 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium , the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, decreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study. (Am J Pathol 1999, 155:1253-1260)

describe histopathological prostate in¯ammation will prove useful in evaluating prostate disease. Keywords prostatitis, chronic nonbacterial prostatitis, prostatodynia, chronic pelvic pain syndrome, histopathology, in¯ammation IntroductionThe histological term prostatitis implies the presence of pathological in®ltration of the prostate by in¯ammatory cells, but the relationship of these ®ndings with the clinical syndrome of prostatitis and other prostate diseases is only just emerging. A renewed interest in the pathogenesis, diagnosis and treatment of the chronic prostatitis syndromes emerged over the latter half of the 1990s. This trend in urological research is the result of pressure from patient advocacy groups, interest from industrial and government funding sources, and a recent awareness of the epidemiological scope of the problem. As the 20th century closed, much research activity was instigated, including new epidemiological studies [1,2], the development of a new consensus-based disease de®nition and classi®cation system [3], establishment of proposed outcome measures [4], development of research guidelines for clinical studies for chronic prostatitis [5] and initiation of randomized controlled trials. However, the causes involved in these syndromes continue to evade sporadic research efforts. The roles of white blood cells, microorganisms, immunological mediators and their relationship with histopathological patterns and clinical scenarios remains poorly understood perhaps partly because of a lack of descriptive standardization of these variables. The objective of the present programme was to develop a standardized histopathological classi®cation system for chronic prostatitis based on a literature review, extensive prospective evaluations in two recognized prostatitis research centres with revision based on the consensus of international urological centres identi®ed as having major expertise or interest in chronic prostatitis. Methods Literature reviewArticles were included for review if they evaluated histological evidence of in¯ammation in the prostate found in prostatitis syndromes, BPH, prostate cancer, infertility and other conditions (including incidental pathological ®ndings in men with no lower urinary tract disease) that may be associated with prostatic in¯ammation (`human studies' and`English language' literature). Articles were identi®ed through Medline from 1979 to 1999, using the following exploded MeSH headings; prostatitis, chronic nonbacterial prostatitis, chronic abacterial prostatitis, chronic pelvic pain syndrome (CPPS), and prostatodynia combined with pathology' and`histology; prostate' combined with in¯ammation'. The Medline search was undertaken for this study by the Cochrane Review Group in Prostate Diseases and Urologic Malignancies. Additional studies were identi®ed by reviewing abstracts of the AUA (1989±99) and International Prostatitis Collaborative Network (IPCN) Meetings (1998±99) and cross-checking bibliographies of retrieved studies, reviews and book chapters. Study i...

In this paper we present a high-throughput system for detecting regions of carcinoma of the prostate (CaP) in HSs from radical prostatectomies (RPs) using probabilistic pairwise Markov models (PPMMs), a novel type of Markov random field (MRF). At diagnostic resolution a digitized HS can contain 80K×70K pixels -far too many for current automated Gleason grading algorithms to process. However, grading can be separated into two distinct steps: 1) detecting cancerous regions and 2) then grading these regions. The detection step does not require diagnostic resolution and can be performed much more quickly. Thus, we introduce a CaP detection system capable of analyzing an entire digitized whole-mount HS (2×1.75 cm 2 ) in under three minutes (on a desktop computer) while achieving a CaP detection sensitivity and specificity of 0.87 and 0.90, respectively. We obtain this high-throughput by tailoring the system to analyze the HSs at low resolution (8 µm per pixel). This motivates the following algorithm:Step 1) glands are segmented, Step 2) the segmented glands are classified as malignant or benign, and Step 3) the malignant glands are consolidated into continuous regions. The classification of individual glands leverages two features: gland size and the tendency for proximate glands to share the same class. The latter feature describes a spatial dependency which we model using a Markov prior. Typically, Markov priors are expressed as the product of potential functions. Unfortunately, potential functions are mathematical abstractions, and constructing priors through their selection becomes an ad hoc procedure, resulting in simplistic models such as the Potts. Addressing this problem, we introduce PPMMs which formulate priors in terms of probability density functions, allowing the creation of more sophisticated models. To demonstrate the efficacy of our CaP detection system and assess the advantages of using a PPMM prior instead of the Potts, we alternately incorporate both priors into our algorithm and rigorously evaluate system performance, extracting statistics from over 6000 simulations run across 40 RP specimens. Perhaps the most indicative result is as © 2010 Elsevier B.V. All rights reserved. * Corresponding authors jpmonaco@rci.rutgers.edu (James P. Monaco), anantm@rci.rutgers.edu (Anant Madabhushi).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMed Image Anal. Author manuscript; available in PMC 2011 August 1.

Deletions involving chromosome 10q23 occur frequently in prostatic carcinomas. Recently, a novel tumour suppressor gene, PTEN, mapping to this interval, has been identi®ed. Mutation or deletion of PTEN has been observed in a proportion of prostate cancer cell lines; however, primary prostate carcinomas have not been studied. We have investigated the involvement of PTEN in primary prostatic adenocarcinomas using a panel of 51 matched normal and prostate tumour DNAs. We ®rst determined the proportion of tumours with allele loss at loci in 10q23 which span the region containing the PTEN gene. Our results show that LOH involving 10q23 is common in primary prostate carcinomas. Twenty-®ve of 51 (49%) tumours showed loss of heterozygosity (LOH) over the region spanning the PTEN locus. We next directly analysed the PTEN gene for mutations of the coding region using single strand conformation polymorphism (SSCP) and sequence analyses. Of those tumours with LOH, only a single tumour was found to carry a missense mutation in PTEN. No mutations in PTEN were identi®ed in tumours without LOH. Our results suggest either that mutation of PTEN is a late event in prostate tumorigenesis, or that another tumour suppressor gene important in prostate cancer may lie close to PTEN in 10q23.

North American women have a one in eight lifetime risk of developing breast cancer, and approximately one in three women with breast cancer will die of metastases. We, and others, have recently shown that high levels of expression of hepatocyte growth factor (HGF) and its receptor Met are associated with invasive human breast cancer and may be causally linked to metastasis. This high level of HGF and Met expression has been considered as a possible indicator of earlier recurrence and shortened survival in breast cancer patients. In contrast, HGF expression (but not Met) is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention in the treatment of breast cancer. We have recently demonstrated that sustained activation or hyper-activation of c-Src and Stat3, which occurs in invasive breast cancer, can stimulate strong expression of HGF in carcinoma cells. In contrast, transient induction of Stat3 occurs in normal epithelium and promotes mammary tubulogenesis. We hypothesize that increased autocrine HGF-Met signaling is a critical downstream function of c-Src-Stat3 activation in mammary tumorigenesis. Future studies will identify novel Stat3 consensus sites that regulate HGF promoter activity and HGF expression preferentially in carcinoma cells and could lead to novel therapeutic drugs that specifically block HGF expression in mammary carcinoma cells, and which could be used in combined treatments to abrogate metastasis.

SummaryWe examined a panel of sporadic breast carcinomas for loss of heterozygosity (LOH) in a 10-cM interval on chromosome 10 known to encompass the PTEN gene. We detected allele loss in 27 of 70 breast tumour DNAs. Fifteen of these showed loss limited to a subregion of the area studied. The most commonly deleted region was flanked by D10S215 and D10S541 and encompasses the PTEN locus. We used a combination of denaturing gradient gel electrophoresis and single-strand conformation polymorphism analyses to investigate the presence of PTEN mutations in tumours with LOH in this region. We did not detect mutations of PTEN in any of these tumours. Our data show that, in sporadic breast carcinoma, loss of heterozygosity of the PTEN locus is frequent, but mutation of PTEN is not. These results are consistent with loss of another unidentified tumour suppressor in this region in sporadic breast carcinoma.

We propose a novel and accurate method based on ultrasound RF time series analysis and an extended version of support vector machine classification for generating probabilistic cancer maps that can augment ultrasound images of prostate and enhance the biopsy process. To form the RF time series, we record sequential ultrasound RF echoes backscattered from tissue while the imaging probe and the tissue are stationary in position. We show that RF time series acquired from agar-gelatin-based tissue mimicking phantoms, with difference only in the size of cell-mimicking microscopic glass beads, are distinguishable with statistically reliable accuracies up to 80.5%. This fact indicates that the differences in tissue microstructures affect the ultrasound RF time series features. Based on this phenomenon, in an ex vivo study involving 35 prostate specimens, we show that the features extracted from RF time series are significantly more accurate and sensitive compared to two other established categories of ultrasound-based tissue typing methods. We report an area under receiver operating characteristic curve of 0.95 in tenfold cross validation and 0.82 in leave-one-patient-out cross validation for detection of prostate cancer.

Flocking is a widely used industrial process in which short lengths of synthetic fibers are applied to backing fabric to produce plush material. In response to an apparent outbreak of interstitial lung disease in flock workers, the Centers for Disease Control hosted a clinical-pathological workshop to identify the defining characteristics of the disease and possible etiologic agents. Six pathologists reviewed 15 biopsies of 15 cases (out of a clinical caseload of 20 patients) and assessed the pattern, extent and degree of pulmonary inflammation, fibrosis, and other changes. A consensus clinical-pathologic diagnosis was reached for each patient and correlated with clinical and radiologic findings. Four of eight open lung biopsies and one of seven closed (transbronchial) lung biopsies demonstrated a characteristic pattern to which the descriptive terminology lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was applied. The other biopsies showed nonspecific inflammatory changes, airspace organization, and diffuse alveolar damage. One open lung biopsy demonstrated respiratory bronchiolitis with lymphoid hyperplasia. None of the lung biopsies showed more than mild interstitial fibrosis and no granulomas were identified. The consensus of the workshop was that lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was a characteristic and distinctive pattern of injury in the flock workers' lung biopsies. Although the etiology of this disease remains undefined at present, the injury pattern and environmental studies suggest a chronic immunologic response to inhaled material.