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Gastric cancer is the fourth most common malignancy in the world, and mortality due to gastric cancer is second only to that from lung cancer. 'Transcriptome dissection' is a detailed analysis of the entire expressed transcripts from a cancer, for the purpose of understanding the precise molecular mechanism of pathogenesis. Serial analysis of gene expression (SAGE) is a suitable technique for performing transcriptome dissection. Gastric cancers of different stages and histology were analyzed on SAGE, and one of the largest gastric cancer SAGE libraries in the world was created (GEO accession number GSE 545). Through SAGE, many candidate genes have been identified as potential diagnostic and therapeutic targets for the treatment of gastric cancer. Regenerating islet-derived family, member 4 (Reg IV) participated in 5-fluorouracil (5-FU) resistance and peritoneal metastasis, and its expression was associated with an intestinal phenotype of gastric cancer and with endocrine differentiation. GW112 expression correlated with advanced tumor stage. Measurement of Reg IV and GW112 levels in sera indicated a sensitivity of 57% for detection of cancer. SPC18 participated in tumor growth and invasion through transforming tumor growth factor-alpha upregulation. Palate, lung, and nasal epithelium carcinoma-associated protein (PLUNC) was a useful marker for gastric hepatoid adenocarcinoma. Expression of SOX9, HOXA10, CDH17, and loss of claudin-18 expression were associated with an intestinal phenotype of gastric cancer. Information obtained from transcriptome dissection greatly contributes to diagnosis and treatment of gastric cancer.

This article is a review of the history of the clinicopathologic conference, a teaching method used for and by physicians in medical schools and hospitals throughout the United States since the beginning of the 20th century.

Clinicians and pathologists do their work, of course, in quite different ways. Because both groups are trained as physicians, however, this training commonality makes all involved seem basically to be on the same "medical team." There are, nevertheless, some fundamental differences between the 2 groups that can on occasion cause significant difficulties in mutual understanding; there are reasons to believe that such differences are becoming more pronounced. Although the differences in viewpoints are often subtle and, therefore, seemingly not very important, these differences have very profound causes and can be profound in their effects. This narrative examines the underlying broad historical-sociological-philosophical bases for these differences with the aim of illuminating their importance to medicine and their prospective importance to pathology in particular.

In September, 2007, the Japanese Ministry of Health, Labor and Welfare legislated that clinical laboratory doctors can advocate the clinical laboratory in hospitals and clinical offices. The decision was monumentous, and we, clinical laboratory physicians, can see patients from April, 2008. Although our roles and/or details have not officially been determined, we must definite the contribution of clinical laboratory doctors. One of our plans is to set up a conference room in the Division of Clinical Laboratory to explain their medical tests to patients. Laboratory data are not always explained in detail by doctors, since they are busy and do not have enough time to see patients. Subsequently, clinical laboratory physicians will be able to comply with patients' wishes for medical testing. In addition, to prevent the development of lifestyle-related diseases and their related metabolic syndrome in Japanese people, a new specified health checkup system has recently been established by the Japanese Ministry of Health, Labor and Welfare, and the system will start from April, 2008. Since more than 20 million people from 40 to 74 years old are estimated to undergo this health checkup, total quality assurance in the clinical laboratory is required to provide accurate and precise test values by the government. Therefore, our clinical laboratory physicians should play a central role to guarantee the specified health checkup system.

Coupling anatomic pathology work cells with a macrosystem construct creates a decision-making perspective that can improve service quality, reduce risk, and enhance patient safety. The authors examine recent changes that have had an impact on anatomic pathology macrosystems, the evolving macrosystem tactics to ensure maintenance of patient safety, and macrosystem change theory. They explore the usefulness of high reliability organization theory and normal accident theory. They conclude with an analysis of the potential for enhanced patient safety through macrosystem consolidation, standardization, and communication in a best care algorithm based on outcome analysis.

There is an international shortage of veterinary clinical pathologists in the workplace. Current trainees in veterinary clinical pathology may choose to pursue careers in academe, diagnostic laboratories, government health services, biopharmaceutical companies, or private practice. Academic training programs attempt to provide trainees with an exposure to several career choices. However, due to the proprietary nature of much of the work in the biopharmaceutical industry, trainees may not be fully informed regarding the nature of work for veterinary clinical pathologists and the myriad opportunities that await employment in the biopharmaceutical industry. The goals of this report are to provide trainees in veterinary clinical pathology and other laboratory personnel with an overview of the work-life of veterinary clinical pathologists employed in the biopharmaceutical industry, and to raise the profile of this career choice for those seeking to enter the workforce. Biographical sketches, job descriptions, and motivation for 3 successful veterinary clinical pathologists employed in the biopharmaceutical industry are provided. Current and past statistics for veterinary clinical pathologists employed in the biopharmaceutical industry are reviewed. An overview of the drug development process and involvement of veterinary clinical pathologists in the areas of discovery, lead optimization, and candidate evaluation are discussed. Additional duties for veterinary clinical pathologists employed in the biopharmaceutical industry include development of biomarkers and new technologies, service as scientific resources, diagnostic support services, and laboratory management responsibilities. There are numerous opportunities available for trainees in veterinary clinical pathology to pursue employment in the biopharmaceutical industry and enjoy challenging and rewarding careers.

Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in oncology. Most GISTs are KIT-expressing and KIT signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light on the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; activating KIT mutations have been identified in tumors affecting most of these cell lineages. This review will include a summary of the biology behind the specific targeted therapies, emphasizing the central role of KIT and PDGFRA oncogenic mutations in GISTs and their clinical and pathologic correlates. The role of KIT immunohistochemistry vs mutation testing will be discussed, with an insight into the indications for KIT/PDGFRA genotyping in GIST. The morphologic and molecular changes that appear with imatinib treatment, such as response and acquired imatinib resistance, are being discussed. The success GIST story based on targeted molecular paradigm may be applied in other imatinib-responsive sarcoma, such as dermatofibrosarcoma protuberans.

The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

Background: Changes in blood banking and transfusion medicine (BB/TM) in the past 15 years may have made BB/TM a less attractive career choice than previously for physicians., Study Design and Methods: To evaluate this, we developed a survey of professional activities and sent it to all physicians who took the BB/TM specialty examination offered by the American Board of Pathology (ABP) between 1995 and 2004., Results: The examination was taken by 390 physicians (range, 25-68/year). Responses to the survey were received by 151 (39%). The number of candidates did not appear to be declining during the 10 years. All physicians who responded had practiced BB/TM and 94 percent were still doing so. Forty-three percent were engaged in BB/TM full-time and another 10 percent for at least 75 percent of the time. Most of the remaining time was devoted to pathology. Forty-three percent practiced in a university hospital, 22 percent in a community hospital, and 21 percent in a blood center. Examples of practice activities included transfusion service (85%), therapeutic apheresis (63%), stem cell collection (46%), stem cell laboratory (32%), and coagulation laboratory (29%). Sixty-six percent are involved in research., Discussion: Interest in BB/TM careers is not decreasing as evidenced by the number of physicians taking the ABP specialty examination. Most currently practice BB/TM, many in an academic environment. Their activities are diverse. Many are involved in research and have presented abstracts at professional meetings. Approximately 60 percent combine the practice of BB/TM with pathology, but only a few (6%) practice hematology.

Molecular assays have now become essential to the pathologist and clinician alike in diagnosing and managing disease. This article highlights the techniques and molecular targets no longer ancillary to basic research. Ripe for discussion are the likely future impact of genetics on clinical care, the potential models for service provision, and the broader ethical, legal, and social issues related to the use of genetic information for nonmedical purposes. Molecular methods are forecasted to increase in assisting in the diagnosis of human diseases. The author's mission is to embrace this discipline and use these technologies in clinical practice.

In the recent years, two trends emerged in the clinical laboratory: the miniaturisation of equipments to provide point-of-care testing (POCT) and a concentration of laboratories through mergers and acquisitions. New technology has expanded both opportunities. POCT provides the benefit of a convenient test where it is needed, i.e. near the patient. For companies, it is easier and cheaper to develop such tests, since technical requirements are somewhat less stringent, being an interesting area for start-ups. Nanotechnology is one of the most fascinating technical advances, with some advocating a US$1 trillion market-size for it by 2015. Laboratory tests and biomaterials will probably be greatly influenced by it, with new approaches for molecular diagnosis, with tests that can target both DNA and proteins in a process that eliminates PCR and allows multiplex analysis. On the other hand, there is a strong trend towards the globalisation of clinical laboratories and that occurs in four areas: a) Consumption of health services abroad; b) Movement of Health Personnel; c) Cross-Border delivery of trade; and d) Commercial presence. Each of these areas presents new challenges and opportunities for clinical laboratories, what will certainly shape the way we work today and in the future.

Several current forces have set anticipated future changes in health care in motion, or, at least, have set the stage for change. End-consumer demand increasingly drives the market; as a result, entire businesses are transforming or emerging anew to meet these demands. In general, consumers demand high quality at reasonable cost, to be delivered as fast as possible with minimal inconvenience. The health care consumer takes this expectation further, to include the desire for all helpful information regarding one's health to be made readily available for him/her to make the best decision and minimize morbidity, mortality, misdiagnosis, and inconvenience. This article addresses the impact upon the laboratory by considering four key interrelated dynamics that affect these trends: market, medicine, technology, and information systems.

Pathology informatics involves management and analysis of large complex data sets derived from various tests performed in clinical and anatomic pathology laboratories, annotated biorepositories, image analysis, telepathology, and large scale experiments, including gene expression analysis, proteomics, and tissue array studies. It facilitates intelligent use of computing technologies to improve patient care and understand the natural history of disease. Herein, we describe the various bioinformatics tools used to support translational research at the University of Pittsburgh Medical Center.

Purpose: To evaluate the clinical impact of pathology review before prostate brachytherapy., Methods and Materials: Original and reviewing pathologists' reports were retrospectively collected from 1323 men treated with prostate brachytherapy between July 1998 and October 2005 at one institution. Statistical analysis was performed pre- and post-January 2002. The clinical impact of pathology review was evaluated., Results: Gleason Score (GS) change (GS(Delta)) occurred in 25.2% (334) of cases; GS increased in 21.6%, decreased in 2.4%, and diagnosed malignancy in 1.2% of cases. Post-2002, concordance in attributed GS improved, with GS(Delta) of 31.9-20.6%, respectively (p<0.001), and a reduction in the average GS(Delta) (p<0.001). The clinical impact was substantial with management changing in 14.8% of cases., Conclusion: Concordance between the original and reviewing pathologists' GS has improved during the study period. Nevertheless, discordance persists in one of five cases. Pathology review remains essential, if treatment decisions hinge on GS.

There have been increasing numbers of applications using oral fluids, saliva in particular, as the target substrate for performing clinical diagnostic tests. These have focused primarily on point-of-care (POC) testing. These POC testing approaches range from, for example, currently available, highly specialized screening tests for the presence of antibodies recognizing HIV to the potential development of "lab-on-a-chip" platforms. Broad claims have been made that the latter will revolutionize clinical laboratory testing. From the perspective of large centralized clinical laboratories, multiple issues must be considered before implementing individual tests using saliva as the target fluid in a POC format or using saliva as a universal test fluid for measuring multiple analytes in a centralized laboratory format. The current scope of laboratory testing is large and comprehensive, involving both POC and centralized testing. Current academic laboratory programs have the ability to qualitatively identify and/or quantitatively measure several thousand analytes in various target matrices including blood, plasma, serum, urine, joint fluid, pleural fluid, peritoneal fluid, cerebrospinal fluid, and tissue. These tests fall into multiple clinical pathology disciplines, including clinical chemistry, hematology, coagulation, transfusion medicine, microbiology, cytogenetics, molecular diagnosis, and immunology. In addition, before implementing a given test, multiple issues need to be evaluated to ensure the validity of the reported result; these include considerations involving the three major phases of testing: preanalytical (e.g., patient identification and specimen collection, stability, and transport), analytical (e.g., sensitivity, specificity, accuracy, and precision), and postanalytical (e.g., reporting results, quality improvement, and turn-around-time).

The transcription factors (TFs) that controls the intricate machinery of multistep differentiation and activation programs of the lymphoid system, represent a complex array of proteins, whose identification and function has only in part been completed. TFs are usually expressed during specific differentiation or activation cellular programs, making them interesting tools in diagnostic immunohistochemistry. In fact, the specificity of some of these TFs for lineage or activation/differentiation passages or their abnormal expression in specific disease entity, represents a feature that has been exploited in diagnostic/prognostic immunohistochemistry. Bcl-6 was the prototype of this class of markers. Currently, the expanding knowledge of the TFs involved in the differentiation programs and in the activation processes of T-lymphocyte and B-lymphocyte in normal and neoplastic conditions and the availability of antibodies able to efficiently recognize these TFs in histologic material, represent a powerful tool in diagnostic hematopathology. In this review we will consider the basic biologic aspects and the applications in hematopathology of some of the lymphocyte-related TFs, including Pax5/BSAB, MUM1/IRF4, BOB1, Oct-2, T-bet, and FOXP3. This field is rapidly evolving, as witnessed by the ongoing growing number of novel TFs with possible diagnostic applications appearing in the literature.

Array-based comparative genomic hybridization (array CGH) genome scanning is a powerful method for the global detection of gains and losses of genetic material in both congenital and neoplastic disorders. When used as a clinical diagnostic test, array CGH combines the whole genome perspective of traditional G-banded cytogenetics with the targeted identification of cryptic chromosomal abnormalities characteristic of fluorescence in situ hybridization (FISH). However, the presence of structural variants in the human genome can complicate analysis of patient samples, and array CGH does not provide morphologic information about chromosome structure, balanced translocations, or the actual chromosomal location of segmental duplications. Identification of such anomalies has significant diagnostic and prognostic implications for the patient. We therefore propose that array CGH should be used as a guide to the presence of genomic structural rearrangements in germline and tumor genomes that can then be further characterized by FISH or G-banding, depending on the clinical scenario. In this article, we share some of our experiences with diagnostic array CGH and discuss recent progress and challenges involved with the integration of array CGH into clinical laboratory medicine.

Inflammatory skin disease is a diagnostic challenge for both dermatologists and pathologists. Unlike the diagnosis of cutaneous neoplasms, biopsies of inflammatory disorders generally present a differential diagnosis for the pathologist. Similarly, the dermatologist is also presented with a clinical differential diagnosis prompting the biopsy. Assimilating all of the information is challenging yet rewarding when an accurate diagnosis is made. In this review we present several "newer" inflammatory diseases of the skin and discuss the differential diagnosis. Many of these entities are associated with underlying systemic disease, making early recognition and diagnosis critical. Pathologists should be familiar with these histopathologic findings to assist with the optimal clinical-pathological diagnosis.

'Evidence based medicine' is a paradigm introduced in the 1990s in which collection of clinical data in a reproducible and unbiased way is intended to guide clinical decision-making. This paradigm has been promulgated across the spectrum of medicine, but with more limited critical analysis in the realm of pathology. The 'evidence base' in support of our practices in Anatomic Pathology is a critical issue, given the key role that such diagnoses play in patient management decisions. The question is, 'On what basis are diagnostic opinions rendered in Anatomic Pathology?' The operative question becomes, 'What is the published literature that supports our anatomic pathology interpretations?' This second question was applied to the published literature in Hepatopathology, by identifying the 'citation classics' of this discipline. Specifically, the top 150 most-cited liver pathology articles were analyzed for: authorship; journal of publication; type of publication; and year of publication. Results are as follows. First, it is indeed true that the preeminent hepatopathologists of the age are the most cited authors in the 'top 150'. Second, the most cited articles in hepatopathology are not published in the pathology literature, but are instead published in much higher impact clinical journals. Third, the pathology of viral hepatitis is demonstrated to be extraordinarily well-grounded in 'evidence based medicine'. Much of the remainder of the hepatopathology literature falls into a 'narrative based' paradigm, which is the rigorous reporting of case experience without statistical clinical outcomes validation. Finally, the years of publication reflect, on the one hand, a vigorous recent literature in the pharmaceutical treatment of viral hepatitis, and on the other, a broadly distributed set of 'narrative' articles from the 1960s, 1970s, 1980s, and 1990s. In conclusion, the discipline of hepatopathology appears to be well-grounded in 'evidence based medicine' in the realm of viral hepatitis. The remainder of our discipline rests predominantly upon the time-honored identification of disease process through the publication of narrative case series.

We started outpatient consultation by clinical laboratory physicians in Gunma University Hospital in June, 2002. Three days a week, five clinical laboratory physicians examine outpatients or answer questions concerning laboratory tests in an outpatient consulting room. The number of outpatients referred has gradually increased since we started this consultation. Among the wide rage of cases examined, there have been many preoperative patients with eye disorders from the Department of Ophthalmology. There are some advantages of our outpatient consultation. For example, we are able to give patients a detailed and unrushed explanation of their laboratory data, and close cooperation with clinical laboratory technicians enables physicians to perform quick and smooth echo-guided fine needle aspiration cytology of thyroid nodules. We hope that our consulting work by clinical laboratory physicians will become widely known to patients and doctors.

As there is a lack of hard data in the literature about many of the issues relating to diagnosing and reporting prostate cancer, we sought to survey current practices. A questionnaire was sent to 93 genitourinary pathologists with a response rate of 69%. Almost all respondents (95%) used formalin as fixative for needle biopsies. Unstained intervening sections were retained by 47%. Three levels of needle biopsies were used routinely by 63%. For verification of a diagnosis of cancer, high-molecular-weight cytokeratin was still the most commonly used immunohistochemical marker (91%), followed by p63 (58%) and alpha-methylacyl-CoA-racemase (50%). Features considered pathognomonic for cancer were glomeruloid bodies (58%), collagenous micronodules (64%), circumferential perineural invasion (84%), and growth in fat (36%). With none of these present, 39% required a minimum of 2 to 10 glands (median, 3) to diagnose cancer, whereas the others had no lower limit. A Gleason score was always given to even minute cancer foci by 86% and typically a Gleason score 6 was assigned (77%). Perineural invasion was mentioned by 86%. The extent of cancer on needle biopsies was quantified by all respondents with number of involved cores (80%) being the most commonly used measure. Linear extent was estimated by almost all, either as a percentage (80%) or millimeters of cancer length (41%) or both (22%). Measuring cancer from end to end or subtracting intervening benign tissue were almost equally common. For those general pathologists who would like to be in the mainstream of most urological pathologists, our survey data provide a guideline on how to diagnose and report prostate cancer.

The criteria for diagnosing prostatic intraepithelial neoplasia (PIN) and lesions suspicious for cancer are described in the literature. However, it is unknown how these are applied in practice by experts in genitourinary (GU) pathology. A questionnaire was sent to 93 GU pathologists in countries around the world with the purpose of surveying current practices. The response rate was 69% including 40 North American pathologists and 24 from other continents. For preneoplastic lesions, the term PIN was universally endorsed by the respondents. PIN was graded by 83%, usually as low/high-grade PIN (LGPIN/HGPIN) or as HGPIN only. Most respondents would usually not report lesions that may qualify for LGPIN. A majority (81%) did not specify architectural patterns of PIN. With both HGPIN and invasive cancer present, 69% would still mention HGPIN. Among the diagnostic criteria for HGPIN were any nucleoli visible (52%), or nucleoli seen in at least 10% of cells (33%). However, 56% would diagnose HGPIN in the absence of prominent nucleoli, most commonly based on prominent pleomorphism, marked hyperchromasia or mitotic figures. The number of cores involved with HGPIN was specified by 50%. Lesions suspicious for but not diagnostic of carcinoma were reported by 45% as atypia, atypical glands or suspicious for cancer and by 42% as atypical small acinar proliferation. The degree of suspicion was further defined by 41%. Our survey data may serve as a guideline to general pathologists on how to diagnose and report atypia and PIN in prostate biopsies.

After a short historical review covering the past 150 years, different aspects of training and practice are considered. Prominent institutes, men and women who have made significant contributions to neuropathology are considered although those still living are not included. There are those countries with neuropathology as a speciality, countries with subspecialty and those countries without neuropathology as a speciality or subspeciality. In order to harmonize teaching, training, examinations and regulations, EURO-CNS (European Confederation of Neuropathological Societies) was founded in 1993. This allowed the recognition of the training charter of neuropathology by the Board of Pathology (1998), the organization of European courses and European congresses, and the achievement of concerted actions simultaneously, recognition of the subspecialty of Neuropathology by the UEMS (Union Européenne des Médecins Spécialistes) Council was obtained in 1997. Data relating to the current position of neuropathology are included and the future of education and the challenges facing neuropathology are discussed.