Practical aspects of planning, building, and interpreting tissue microarrays: the Cooperative Prostate Cancer Tissue Resource experience.

This is a review of several new approaches developed at or adopted by the Cooperative Prostate Cancer Tissue Resource (CPCTR) to resolve issues involved in tissue microarray (TMA) construction and use. CPCTR developed the first needle biopsy TMA, allowing researchers to obtain 200 or more consecutive cancer sections from a single biopsy core. Using radiographs of original paraffin blocks to measure tissue thickness we developed a method to produce TMAs with a larger number of usable sections. The modular approach to plan TMA construction is also a novel concept wherein TMAs of different types, such as tumor grade TMAs, metastasis TMA and hormone refractory tumors TMA can be combined to form an ensemble of TMAs with expanded research utility, such as support for tumor progression studies. We also implemented an open access TMA Data Exchange Specification that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. It ensures inter-laboratory reproducibility because it offers information describing the preparation of TMA blocks and slides. There are many important aspects that may be missed by both beginners and experienced investigators in areas of TMA experimental design, human subjects protection, population sample size, selection of tumor areas to sample, strategies for saving tissues, choice of antibodies for immunohistochemistry, and TMA data management.

Practice guidelines for autopsy pathology: autopsy reporting. Autopsy Committee of the College of American Pathologists.

The Autopsy Committee of the College of American Pathologists has prepared this revised guideline to reflect changes that have occurred in the reporting of autopsies since the original guideline was published in February 1995. It is intended to be an instrument to assist pathologists in the reporting of autopsies. The guideline is to be regarded as being primarily an educational tool. Application of these recommendations on autopsy reporting is to be made on the basis of the judgment of the pathologist engaged in a specific case.

U.S. Senate Bill 422: the Genetic Confidentiality and Nondiscrimination Act of 1997.

On March 11, 1997, Senator Pete Domenici introduced U.S. Senate Bill 422, the Genetic Confidentiality and Non-Discrimination Act of 1997. The bill specifies that "existing legal protections for genetic information are inadequate to ensure genetic privacy and to prevent genetic discrimination." The first stated purpose of the bill is "to define the circumstances under which DNA samples may be collected, stored, and analyzed and genetic information may be collected, stored, analyzed, and disclosed." The bill reinforces statutes already passed in 19 states that guarantee patients certain rights of control over their own personal genetic information (Congressional Record, S2141). This bill fundamentally changes the mechanism whereby molecular biologists acquire tissue, and defines new obligations between researchers and human subjects. Even if this bill is not passed in its present form, it appears inevitable that legislation with a similar intent will soon emerge. Any such legislation will carry the full weight and penalties of law. Because many current research practices may violate these proposed new regulations, researchers should understand the provisions of S. 422. Furthermore, it is crucial that researchers understand the bill now, before it becomes law, because this may be their last opportunity to lobby for any modifications of the bill.

Elevated prostate-specific antigen levels in black men and white men.

The usual ranges for prostate-specific antigen (PSA) are derived from a community-based population of White men but are used for screening on all men on the assumption that the differences between the PSA levels of different racial groups are small or have no clinical significance. Recently published reports, however, suggest that PSA levels in a specific racial population may vary directly with the relative risk of prostatic cancer within that population. PSA ranges were determined in Black and White men registered with the Veterans Affairs Maryland Health Care System, Baltimore, Maryland. The total patient census of 122,602 has near-equal numbers of Black and White men and maintains records of race designation for inpatients. Among the male patients with no known prostatic cancer, there were 10,808 men 40 years of age or older and 19,482 PSA test results. In this group, there were 3274 men identified as Black; 2993 identified as White, Not of Hispanic Origin, and 4541 identified as Other Race or Race Unknown. The 95th percentile PSA values in Black men and White men 40 through 49 years of age were 2.80 ng/mL and 2.01 ng/mL, respectively; 50 through 59 years old, 5.40 ng/mL and 4.19 ng/mL, respectively; 60 through 69 years old, 9.59 ng/mL and 7.00 ng/mL, respectively; 70 through 79 years old, 15.45 ng/mL and 9.40 ng/mL, respectively; and for men older than 80 years of age, the 95th PSA values were 21.05 ng/mL in Black men and 18.25 ng/mL in White men. In every age group, Black men had a higher range (for the 95th percentile) than did White men. The largest difference was found in men 70 through 79 years old; in this age group, the ratio of the upper limit of PSA for Black men compared with White men was 1.6 ng/mL.

SNOMED-encoded surgical pathology databases: a tool for epidemiologic investigation.

Pathology departments have invested considerable energy, sometimes extending over several decades, toward coding their anatomic pathology reports. As a result of these labors, there is now a vast amount of electronically coded data from surgical pathology reports, holding a wealth of information relevant to virtually every recognized pathologic entity. The original intent of the Systematized Nomenclature of Medicine (SNOMED) was to prepare population-based disease data from pathology reports, but no such studies have emerged in the medical literature. This is due in part to the nonuniform, idiosyncratic, and incomplete manner in which most SNOMED databases are constructed. Automatic (computer-driven) coding provides uniformity and completeness of SNOMED databases and offers the possibility of customized recoding for an entire collection of reports using any nomenclature and any set of coding algorithms. In prior investigations, we described a computer program that SNOMED-codes surgical pathology reports, and we provided an analysis of a large surgical pathology SNOMED database. In this report, we describe the importance of coded surgical pathology databases for research, teaching, hospital administration, and public health, and we explain the functional differences between coded databases and free-text collections of surgical pathology data. Surgical pathology departments and vendors of laboratory information systems can ensure that surgical report files can be automatically coded or recoded with any chosen nomenclature by adhering to simple guidelines.

A prototype Internet autopsy database. 1625 consecutive fetal and neonatal autopsy facesheets spanning 20 years.

OBJECTIVE: To demonstrate that cause-of-death statements can be generated by a computer algorithm from an autopsy database composed of diagnostic terms. DATA SOURCES: Over 49 000 autopsy facesheets contributed by over a dozen institutions were collected from a publicly accessible Internet autopsy database. This database is available at the following web site: http:@www.med.jhu.edu/pathology/iad.html STUDY SELECTION: To test the feasibility of creating and using a publicly available autopsy database, and to identify the technical and medicolegal problems that may arise with such a novel resource, a prototype study was designed by selecting autopsy facesheets from fetal and neonatal deaths. An algorithm was developed to determine the cause of death from the listing of anatomic diagnoses. DATA EXTRACTION: One thousand six hundred twenty-five fetal and neonatal autopsy facesheets were selected encompassing fetal and neonatal deaths occurring up to 28 days after birth. DATA SYNTHESIS: The algorithm determined causes of death from autopsy facesheet data in all cases. On review by an experienced pediatric pathologist, these automatically generated cause-of-death statements required no modification or only slight modification in over 90% of cases. CONCLUSIONS: A large multi-institutional autopsy database composed of demographic and diagnostic information has been deposited on the Internet. This information can be freely downloaded and used by any researcher without violating patient confidentiality. As a demonstration of one possible application of the database, fetal and neonatal autopsies generated cause-of-death statements using a computer algorithm. One can anticipate that the wealth of information contained in autopsy facesheets can be assembled into a database that will serve the public interest.

Maintaining patient confidentiality in the public domain Internet Autopsy Database (IAD).

The Internet provides the opportunity of permitting public access to large databases containing patient information that can be shared and utilized by epidemiologists, health planners, and medical researchers. Until now, large databases containing patient information have been held in strict confidence, with database access available only to approved researchers or to researchers with access limited to only specific portions of the database. The Internet Autopsy Database (IAD) consists of demographic and pathologic data from over 49,000 autopsies contributed by over a dozen academic medical institutions. Each autopsy record in the public database consists of a uniform set of demographics and SNOMED-compatible terms. To make the database publicly available, a strategy had to be devised that assured the privacy of every person included in the database. A key step involved translating the autopsy facesheets into a listing of SNOMED-compatible terms that effectively eliminated identifying terminology, replacing free text with a generic nomenclature that preserves diagnostic information. The entire database is available on the Internet at: http:@www.med.jhu.edu/pathology/iad.html

Impact of unfunded research in medicine, pathology, and surgery.

The impact of unfunded medical research (ie, research conducted with no visible means of support) has received scant attention. In this study, we counted research contributions from the 10 most-cited journals in the fields of internal medicine, pathology, and surgery. Ten consecutive articles, excluding case reports and review articles, for the years 1987, 1989, and 1991 were sampled from each of 10 journals for the three areas of medicine. Unfunded articles accounted for the majority of contributions (60% of pathology articles, 62% of internal medicine articles, and 74% of surgery articles). In 1987, funded research articles published received somewhat more citations (2,961) than unfunded research articles (2,368). Among articles supported by an NIH grant, the first author of the article was seldom the grant's principal investigator (38.6%, 26.9%, and 16.7% of funded articles by pathologists, internists, and surgeons, respectively). These results indicate that unfunded research plays a major role in medical research.

Prostate-specific antigen screening for prostate cancer: no reduction in Gleason scores.

Skepticism regarding prostate-specific antigen (PSA) screening arises from the possibility that screening procedures increase the yield of diagnosed prostate cancers occurring in an indolent form that does not require treatment. If PSA screening serves only to increase the yield of clinically trivial prostate cancer, one would expect a drop in the average Gleason score of prostate cancers detected with PSA screening compared with prostate cancers detected before the advent of PSA screening. In a 3-yr study of newly diagnosed prostate cancer, there was almost a 7-fold increase in PSA screening tests ordered between 1989 and 1992 and a greater than 2-fold increase in the number of newly diagnosed prostate cancers. In the same time period, the average Gleason scores of newly diagnosed prostate cancer increased slightly (from 6.2 to 6.5). In this study there was no prognostic difference (as predicted by Gleason score) between prostate cancers in populations whose cancers were diagnosed before and after the increased use of PSA as a screening tool.

Performance analysis of manual and automated systemized nomenclature of medicine (SNOMED) coding.

Many pathology departments rely on the accuracy of computer-generated diagnostic coding for surgical specimens. At present, there are no published guidelines to assure the quality of coding devices. To assess the performance of systemized nomenclature of medicine (SNOMED) coding software, manual coding was compared with automated coding in 9353 consecutive surgical pathology reports at the Baltimore Veterans Affairs Medical Center. Manual SNOMED coding produced 13,454 morphologic codes comprising 519 distinct codes; 209 were unique codes (assigned to only one report apiece). Automated coding obtained 23,744 morphologic codes comprising 498 distinct codes, of which 129 were unique codes. Only 44 (.5%) instances were found in which automated coding missed key diagnoses on surgical case reports. Thus, automated coding compared favorably with manual coding. To achieve the maximum performance, departments should monitor the output from automatic coders. Modifications in reporting style, code dictionaries, and coding algorithms can lead to improved coding performance.

Image analysis software for the detection of preneoplastic and early neoplastic lesions.

Preneoplastic lesions are usually small, and often appear as foci of atypical cells that blend into the surrounding normal tissue without producing a detectable tumor mass. Since these lesions seldom provide adequate tissue for biochemical studies, their detection often depends upon subtle distinctions in cytologic features. Image analysis permits pathologists to obtain quantitative measurements on cytologic and histologic preparations, so that visual impressions can be augmented by quantitative morphometry. Preneoplastic lesions have well-described morphometric features relating to nuclear area, texture, or shape. It is now feasible for every pathology department to capture images of pathologic material with equipment costing less than the price of a microscope. Captured image files can be analyzed using commercial software or software developed in several U.S. government agencies and made freely available to the public. Image analysis has been shown to improve the detection of preneoplastic cells. Recent improvements in the resolution of captured images, in the algorithms that measure preneoplastic descriptors, and in the ease and speed of transmission of images between laboratories, should increase our ability to detect and treat preneoplastic lesions.