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1 Departments of Pathology, 2 Biochemistry, 3 Environmental Medicine, and 4 Urology, New York University School of Medicine, New York, New York; 5 Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin; 6 Department of Pathology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania; 7 Department of Pathology, George Washington University, Washington DC; 8 Department of Pathology, Howard University, Washington DC; 9 Department of Pathology, University of Illinois, Chicago, Illinois; and 10 National Cancer Institute, Bethesda, Maryland
ABSTRACT
Purpose: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a National Cancer Institute-supported tissue bank that provides large numbers of clinically annotated prostate cancer specimens to investigators. This communication describes the CPCTR to investigators interested in obtaining prostate cancer tissue samples.
Experimental Design: The CPCTR, through its four participating institutions, has collected specimens and clinical data for prostate cancer cases diagnosed from 1989 onward. These specimens include paraffin blocks and frozen tissue from radical prostatectomy specimens and paraffin blocks from prostate needle biopsies. Standardized histopathological characterization and clinical data extraction are performed for all cases. Information on histopathology, demography (including ethnicity), laboratory data (prostate-specific antigen values), and clinical outcome related to prostate cancer are entered into the CPCTR database for all cases. Materials in the CPCTR are available in multiple tissue formats, including tissue microarray sections, paraffin-embedded tissue sections, serum, and frozen tissue specimens. These are available for research purposes following an application process that is described on the CPCTR web site (www.prostatetissues.org).
Results: The CPCTR currently (as of October 2003) contains 5135 prostate cancer cases including 4723 radical prostatectomy cases. Frozen tissues, in some instances including patient serum samples, are available for 1226 cases. Biochemical recurrence data allow identification of cases with residual disease, cases with recurrence, and recurrence-free cases.
Conclusions: The CPCTR offers large numbers of highly characterized prostate cancer tissue specimens, including tissue microarrays, with associated clinical data for biomarker studies. Interested investigators are encouraged to apply for use of this material (www.prostatetissues.org).
INTRODUCTION
Prostate cancer research has been hampered by the limited access to large numbers of prostate tissue samples with associated clinical and outcome data. Several different reasons account for the difficulty in accessing human prostate tissue specimens. First, most academic institutions lack the infrastructure required for adequate tissue banking. The few existing resources with prostate cancer specimens are primarily intended for use at the institution level or in limited consortia of institutions and have not been made available to the wider research community. Second, prostate cancer requires significant pathology assistance for the identification, procurement, and characterization of normal and tumor tissues. Such pathology assistance is often limited in most diagnostic services, where pathologists are frequently overtaxed. Third, outcome-related research requires human tissue specimens in sufficiently large numbers and with long follow-up times to allow statistically valid analyses. Most current studies are limited by small sample sizes, single institution selection bias, and limited follow-up data. Accurate long-term follow-up presents a major challenge for prostate cancer because patients often continue their care through their local physicians and thus can be lost to follow-up. In addition, patients who consider their cancer cured after initial therapy may not have their serum levels of prostate-specific antigen (PSA) or other clinical hallmarks adequately monitored.
Collection of samples and data on an adequately large number of prostate cancer cases is typically beyond the scope of any single medical center. In 1999, the National Cancer Institute (NCI), recognizing the need for a multicenter effort in prostate cancer tissue banking, issued an RFA for a consortium effort to accomplish this.11 In April 2000, four academic institutions were funded to form a national prostate cancer tissue resource, the Cooperative Prostate Cancer Tissue Resource (CPCTR). The resource is entirely funded by an individual Cooperative Agreement Grant from the NCI to each of the four participating sites. The resource functions as a consortium with all four participating sites working jointly with the NCI. The group is organized in the form of a "virtual tissue bank" with a central database but specimens located at each site. The goal of the CPCTR is to collect large numbers of prostate cancer specimens with accurate quality-controlled and standardized pathological review of specimens and detailed, quality-controlled outcome data for use in biomarker validation studies and to make this collection available to the research community.
MATERIALS AND METHODS
Participating Institutions.
The CPCTR comprises four academic institutions: George Washington University Medical Center (Washington DC); Medical College of Wisconsin (Milwaukee, WI); New York University School of Medicine (New York, NY); and the University of Pittsburgh (Pittsburgh, PA). The following hospitals are associated with these institutions.
(a) George Washington University Medical Center: The George Washington University Medical Center; Howard University Hospital (Washington DC); The Virginia Urology Center (Richmond, VA); and the University of Pennsylvania (Philadelphia, PA).
(b) Medical College of Wisconsin: Froedtert Hospital (Milwaukee, WI); Milwaukee Veterans Administration Medical Center (Milwaukee, WI); Community Memorial Hospital (Menomonee Falls, WI); and University of Illinois at Chicago (Chicago, IL).
(c) New York University School of Medicine: New York University School of Medicine Medical Center (Tisch Hospital) (New York, NY); Bellevue Hospital (New York, NY); and the New York Harbor Veterans Administration Medical Center (New York, NY).
(d) University of Pittsburgh: University of Pittsburgh Medical Center-Presbyterian Shadyside Hospital(s) (Pittsburgh, PA).
The CPCTR has access to cases from a variety of medical care settings that include university medical centers as well as private, public, and Veterans Administration hospitals. The participating hospitals are distributed across six states in the Northeastern and Midwestern regions of the United States. This varied access to cases allows accrual of cases that reflect a wide diversity of patients undergoing prostate cancer management in the United States.
Organization of the CPCTR.
The cooperative group has developed a system of operations to enable standardized governance, administration, and networking among the four sites as well as standardized daily operations. The details of the organization are described in the Resource Manual of Operations, located at one of the CPCTR web sites.12
Operations of the CPCTR.
At each site, cases are identified from pathology records; tissue blocks are retrieved; a specimen inventory is maintained; pathology material is characterized by CPCTR-designated pathologists; clinical data are extracted from urologists’ charts and electronic databases, including hospital information systems and tumor registry databases; and all data are entered into a comprehensive database. The data at each site are exported to a central database after de-identification. The specimens, however, physically remain at each site. The virtual tissue bank model has been successfully used by another NCI-supported cooperative resource focused on breast cancer, the Cooperative Breast Cancer Tissue Resource (1)
, and has been adopted by the CPCTR with various modifications.
Types of Specimens.
At each institution, archival radical prostatectomy specimens from 1989 to 1998 were identified from the pathology records. At the time of compilation of this communication (October 2003), there were 4723 radical prostatectomy cases in the CPCTR. Of these, 3047 are cases with archival paraffin blocks from surgical patients predominantly treated between 1990 and 1998. The remaining 1226 cases are recent cases (accrued from 2001 onward) with prospectively banked tissue (both frozen and paraffin-embedded tissue). At some of the sites of the CPCTR, blood, serum, and urine samples have also been collected before or at the time of surgery from prospectively banked radical prostatectomy patients. The CPCTR has also accrued diagnostic needle biopsy specimens from 1080 of the radical prostatectomy patients and from 862 prostate cancer patients who did not undergo a radical prostatectomy. The latter samples represent patients who were not eligible for prostatectomy and received radiation or hormonal therapy, underwent watchful waiting, or have died from other causes including other cancers.
Pathological Characterization.
A CPCTR pathologist performs a full independent review of each case including a pathological characterization of the histological features of each case and of individual paraffin tissue blocks retained by the tissue banks at each site. Standardization of the pathology review has been achieved by expanding on the basic criteria outlined elsewhere (2)
. These pathology criteria and their enhancement from the primary pathology literature are described in a CPCTR histology manual.13
To ensure intra- and inter-institutional uniformity in pathological interpretation, CPCTR pathologists also participate every 6 months in quality assurance exercises (such as tutorials, independent reevaluation of randomly selected specimens by pathologists at each site, and joint examination of both randomly selected and problem cases).
Procurement of Fresh Tissue from Radical Prostatectomy Specimens.
In 2001, the CPCTR started prospective collection of fresh tissue from radical prostatectomy specimens. Protocol-based tissue sampling techniques are used to procure tissue as soon as possible after removal from the patient (<20 min from time of removal at surgery to tissue freezing) while adequately preserving the specimen for pathological characterization (assessment of pathological stage, margin status, and grade). The technique of sectioning the radical prostatectomy specimen used at most of the sites is a modification of the technique described by Bova et al. (3)
. Briefly, the surface of the gland is marked with India ink, and then the capsule is stripped from the gland. This procedure permits procurement of tissue from the gland for banking while allowing for diagnostic evaluation of the entire prostate capsule tissue for surgical margin status and stage. Alternate whole 0.5-cm-thick slices of the radical prostatectomy specimen are routinely procured for the CPCTR and are flash frozen and stored at –150°C in vapor phase liquid nitrogen freezers. Each slice is typically quartered (approximately 2 x 2 cm) before freezing. The tissue storage containers and wrapping used ensure specimen stability without package rupture and avoidance of cross-contamination between samples. Initial characterization of the frozen tissue is achieved through histopathological evaluation of the permanent sections made from tissue slices adjacent to the frozen tissue slices. Before disbursement to investigators, the frozen tissue is characterized for the presence and extent of tumor by analyzing frozen sections to deliver characterized tissues containing verified lesions for research. To date, quality assurance examination has demonstrated that tumor can be identified and isolated from frozen tissues in approximately 70% of the cases. Quality assurance studies are also performed on an ongoing basis on small subsets of samples for mRNA and protein integrity in the cryopreserved tissue.
Tissue Microarrays (TMAs).
The CPCTR has constructed TMAs using material from radical prostatectomy patients with adequate clinical follow-up information to support outcome-related studies. In an initial TMA, pathological material derived from a series of 299 chronologically consecutive radical prostatectomy patients has been arrayed over four blocks with a single focus of tumor from each patient tumor represented in quadruplicate. Nontumor prostate tissue cores from suprapubic prostatectomy specimens of patients with benign prostatic hypertrophy and from normal prostates harvested from organ donors are included as normal tissue controls. "Positive" control samples include cell pellets from the metastasis-derived PC3 and LNCaP prostate cancer cell lines (4
, 5)
. Clinical, pathological, and follow-up data on these patients (see Table 1
) are available in an XML (extensible markup language) file format (6
, 7)
. The XML file and details of the layout of the TMA are available on the CPCTR web site.14
Additional types of TMAs are being developed.
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PSA data, which are critical for postsurgical prostate cancer follow-up, are not routinely collected by cancer registries, and each institution has therefore developed alternate methods for obtaining PSA data such as extraction from patient charts or from laboratory databases in a manner consistent with human subject regulations. Interpretation of PSA data is performed in a uniform manner at the central data center through an algorithmic assessment and categorization of cases into biochemical recurrence cases, nonrecurrence cases, cases with postsurgical residual elevated PSA, or cases whose category "cannot be determined." The algorithm’s PSA thresholds have been determined through a review of the literature and consultation with prostate cancer experts, and they were validated at each site through a comprehensive analysis of clinical features of a series of individual cases. The details of this algorithm will be reported elsewhere.
Common Data Elements.
The CPCTR database consists of a set of over 130 common data elements collected for each patient, which capture the clinical, pathological, and tissue sample inventory data. The document detailing these common data elements can be found at the CPCTR web site.15
The common data elements comprise the following general categories: demographic information; clinical history; clinical pathology (PSA) values; Gleason grading and pathology characteristics for individual blocks retained in the CPCTR (so-called matrix blocks, five of which are collected for each case); overall histological characteristics of the radical prostatectomy; lymph node status and lymph node block characteristics; clinical stage and progression information; vital status; and information about types of adjuvant therapy. The dataset for the biopsy cases contains slight variations on individual block descriptors. The CPCTR captures the pathology characteristics of the tissue specimens at the level of individual paraffin tissue blocks and frozen tissue slices for each case. From each case, paraffin blocks of cancer are selected for inclusion in the CPCTR collection, with annotation for each block of histological tumor type, size of tumor focus, Gleason grade, presence of high-grade prostatic intraepithelial neoplasia, and presence of perineural, seminal vesicle, or lymphovascular invasion. A detailed annotation is also used for a lymph node matrix block of cases in which metastatic tumor was identified in lymph nodes removed at the time of radical prostatectomy. The two other types of matrix blocks annotated by the CPCTR are blocks containing prostatic intraepithelial neoplasia (but no cancer) and benign prostate tissue blocks that may be used as control tissue. The data elements that are routinely provided to investigators [in Health Insurance Portability and Accountability Act (HIPAA)-compliant fashion] include the following elements: year of birth; year of diagnosis; year of prostatectomy; histological type of cancer; Gleason score (including primary and secondary grade); lymph nodes examined; lymph nodes positive for cancer; pathological tumor-node-metastases (TNM) stage; vital status; PSA recurrence; year of PSA recurrence; and PSA recurrence-free year. Other data elements (120 additional data elements are captured) can be provided on request (for a complete list of common data elements, see the CPCTR web site15
).
Human Subject Protection: Regulations and Informed Consent.
The specimens and information collected by the CPCTR are de-identified before being provided to researchers, and the CPCTR and its participating institutions comply with all applicable federal, state, and local laws and regulations as well as site-specific regulations, including institutional HIPAA policies. Whereas all specimens and clinical data are de-identified before they are entered into the central database, a link to the participant/subject is maintained for the essential purpose of continuing follow-up. Therefore, the local sites have all been required to obtain full board approval from local institutional review boards to collect information with these links and for their protocols for handling of CPCTR materials and information. Each of the sites maintains its own database of specimens and clinical and follow-up information in a secure manner, thus assuring local control over patient confidentiality. Patient identifiers are removed from the data that are provided to the central database, ensuring that only de-identified data associated with the specimens are provided to investigators. The de-identification process differs slightly among each of the four sites. In the case of prospectively collected specimens and data, all sites obtain written informed consent before collecting patient specimens and data for the CPCTR. Researchers using the CPCTR still need to obtain institutional review board approval at their own institutions for each project that uses CPCTR material. Because the data provided are de-identified, most projects will require only an expedited institutional review board review. Local sites have all achieved compliance with their institutional HIPAA policies. This required institution of new mechanisms for obtaining informed consent because different routes of access to patients had to be established, and collaboration was necessary with private physicians to access patient clinical data while abiding by different institutional HIPAA policies among the members of local consortia. The CPCTR was also required to modify the data provided to investigators to ensure that HIPAA’s proscribed set of 18 data elements are omitted from sample records [the so-called safe harbor approach to HIPAA compliance (8)
]. These issues will be the subject of a separate publication.
Application for Use of Material.
Instructions on how to apply for specimens are available from the CPCTR web site.14
Investigators are requested to first submit a letter of intent (LOI) indicating their proposed study and tissue requirements. The LOI is reviewed by a research evaluation panel (REP) consisting of an independent group of experts in prostate cancer convened by the NCI. Because the REP includes two pathologists, a urologist, and a biostatistician, who are all investigators, the REP is well rounded and up to date in the field of prostate cancer research. The REP reviews the LOIs and full applications strictly on the basis of scientific merit. The REP takes into consideration the aims/objectives, significance, and methodology of the proposed research, as well as the competence of the investigator. The REP also reviews the statistical strength of the proposal and the utilization of clinical data. The REP does not primarily consider the request based on the availability of specimens, but the REP may comment on this. The REP provides recommendations to the CPCTR principal investigators for approving the LOI or proposed study. Once approval of the LOI is obtained, the investigator is asked to submit a full application with additional detailed information describing the research project. The CPCTR principal investigators approve requests based on the recommendation of the REP and the availability of specimens. Once the full application has been approved, personnel at the data center coordinate identification and procurement of samples for the request by individual sites. At the time that these tissue requests are filled, the clinical information for the selected cases (including vital and cancer status) is updated at each site so that the up-to-date clinical information is provided to the investigator.
Application for TMAs.
The application process for TMA slides only requires completion of a LOI that is reviewed by the REP, resulting in an expedited review. The investigator is not typically required to submit additional information. Together with the TMA test slides, additional TMA slides are provided for optimizing test conditions. The investigator using the TMA slides is asked to provide feedback to the CPCTR on technical aspects of the staining as a quality assurance measure for the slides provided by the CPCTR. Alternatively, the investigator may send the raw data to the CPCTR for use in quality assurance assessment.
Cost.
The fee schedule for provision of material is available from the CPCTR web site.14
These charges are intended to partially defray the costs of tissue preparation and shipping. The CPCTR coordinating committee will consider reducing or eliminating charges for an investigator with a scientifically meritorious application but without adequate resources. This will require the investigator to justify such a request and to assure sufficient resources exist to complete the study.
Information about the CPCTR.
The CPCTR web site14
contains additional details about the CPCTR, including a frequently asked questions section. Investigators are encouraged to post any additional questions to the listserver of the CPCTR (ASK-CPCTR-L{at}NCI.NIH.GOV), which will be responded to by one of the principal investigators.
RESULTS
The CPCTR currently has accrued over 5100 prostate cancer cases, consisting of both archival paraffin tissues and prospectively banked frozen and paraffin tissues. The largest number of specimens in the CPCTR’s collection comprises radical prostatectomy cases, of which approximately 4200 cases have been accrued. The vast majority of these cases are prostatic adenocarcinoma, whereas a small number of cases represent different histological subtypes including 14 ductal, 13 mucinous, and 2 signet ring carcinomas and 1 neuroendcrine carcinoma (Table 1)
. African-American cases account for 15% of all cases in the CPCTR (Table 1)
, which represents one of the largest collections of African-American radical prostatectomy tissues generally available for research to date.
The demographic data of the CPCTR radical prostatectomy cases from the contemporary era (2000–2003) and the 1990–1998 period indicate a mean age at diagnosis that is similar to that of other published large series of radical prostatectomy cases (9, 10, 11, 12, 13, 14)
, with the exception of the Johns Hopkins series (Ref. 15
; see Table 2
). The mean age at radical prostatectomy, a factor that is determined by surgical selection criteria, was similar among the CPCTR series and other published series covering the same time periods. This suggests that the samples in the CPCTR collection are representative of other patient populations that have been studied in the United States.
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. These pathological findings may reflect the experience of the early prostatectomy era (1989–1998), when presurgical screening was imprecise and did not readily exclude candidates with more advanced prostate cancer. These data are likely to represent the actual status of prostate cancer treatment in the United States during the 1990s because they include patients who were treated at multiple institutions across the country (as opposed to patients referred to and selected for treatment at a single institution).
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. The mean follow-up of these patients was 75 months (range, 0–167 months). Of these patients, 914 underwent PSA nadir (82%). Of these 914 patients, 155 (17%) developed PSA recurrence with an average time to biochemical recurrence of 35 months (range, 8–130 months), and 759 (83%) are currently without evidence of PSA recurrence with a mean follow-up period of 52 months (range, 8–167 months). Of the cohort of 1108 radical prostatectomy patients, 194 (18%) had persistent elevated PSA values after prostatectomy and failed to reach nadir, as defined by a decrease of serum PSA to <0.2 within 6 months of prostatectomy. These men probably are patients in whom the tumor mass was not completely resected by surgery or who had metastatic disease or men in whom sufficient residual prostate tissue remained after surgery to result in elevated serum PSA levels. These patients are being followed over time to determine their rate of subsequent PSA rise as well as any clinical evidence of prostate cancer. Of the 1108 patients analyzed, 15 (1%) currently (as of October 2003) have clinical evidence of recurrence, and 89 (8%) have died.
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The "biopsy-only" cases include 508 prostate needle biopsy cases in which a nonsurgical intervention was implemented (25% radiation, 15% hormonal therapy, 16% radiation and hormonal therapy, 1% watchful waiting, 1% alternative/experimental treatment) and 354 cases who did not receive any documented intervention.
DISCUSSION
In its 3.5 years of existence, the CPCTR has collected high-quality, well-characterized tissue samples from over 5000 prostate cancer cases, most with associated clinical follow-up information. At the current rate of accrual, approximately 1300 additional cases will be added per year. The clinical data are continuously updated, and the quality of the pathological and clinical data is regularly scrutinized as part of routine quality assurance measures. The CPCTR collection of consecutive prostate specimen samples at four separate institutions representing 13 hospitals across the country provides investigators with specimens that are representative of the status of prostate cancer biology and treatment in the United States. Importantly, this collection lacks the selection bias that is typical of single institution collections, which improves the likelihood that results obtained from studies using CPCTR samples will be more directly representative and applicable to prostate cancer patients in the United States. Although a CPCTR of this size across multiple institutions has the advantage of diversity of medical care settings and populations, it poses challenges in the collection of clinical follow-up data, especially postoperative PSA information. However, the CPCTR is able to collect high-quality follow-up and outcome data associated with the CPCTR tissue samples. Because the CPCTR continuously updates follow-up and outcome information, studies performed using CPCTR tissues can also be updated in future years as new follow-up data become available.
Evaluation of patient outcome after radical prostatectomy has been described for multiple large cohorts (9, 10, 11
, 15
, 18) . In these published series, the focus has been on the biochemical recurrence rate after radical prostatectomy as determined by a rise in PSA after an initial drop to undetectable levels (PSA nadir). Most of these studies represent single institution-based radical prostatectomy series, often conducted under the direction of a single urologist, in conjunction with a single pathologist and using a selected patient population. Although some of these studies are multi-institutional, they differ from the CPCTR in that they do not have a uniform pathology review of the cases, often relying on results extracted from pathology reports (19)
. The wider patient diversity present in the CPCTR-associated hospitals may account for some of the differences observed between the characteristics of the CPCTR and those of other large single institution series (see Table 3
). Other factors, such as variation in the pathology review, may also contribute to these differences.
The incidence of patients who fail to undergo PSA nadir after radical prostatectomy (nadir rate) is not well established in the literature. The CPCTR results indicate that a large number of patients fail to undergo PSA nadir when standardized criteria are applied across cases and that these patients are more likely to have died or to be living with clinical evidence of disease than cases that did reach nadir. Of note, a similarly high incidence of postprostatectomy elevated PSA values has been suggested in a previous small study (20) . The presence of cases with postprostatectomy elevated PSA values may reflect the heterogeneous population of patients undergoing radical prostatectomy in the CPCTR collection, including patients who would not have been considered for radical prostatectomy based on currently used surgical criteria. Current efforts within the CPCTR are focusing on examination of initial diagnostic biopsy, clinical stage, and pre-prostatectomy PSA values in an effort to define criteria that identify patients who fail to achieve postsurgical PSA nadir and are not appropriate candidates for surgery.
One of the limitations of other existing collections of prostate tumor tissue and, for that matter, other tumor tissues has been the scarcity of samples from patients representing the extreme ends of the diagnostic and pathological spectrum. Most prostate cancer tissue samples in repositories are from radical prostatectomy specimens and therefore overrepresent moderately differentiated cancers (Gleason score of 6 and 7) and organ-confined tumors. Samples from patients with advanced aggressive disease or from tumors that are likely to be "clinically insignificant" are underrepresented in these other prostate tissue repositories. Patients with advanced aggressive disease are most often represented only by their diagnostic prostate needle biopsy. The small amount of needle biopsy tissue remaining after a clinical diagnosis can sustain only a very limited number of research studies. One of the innovations of the CPCTR has been to develop a method by which these needle biopsy samples can be incorporated into TMAs. The details of this method will be reported elsewhere (21) . Using such biopsy TMAs, each needle biopsy case can provide up to 100 consecutive sections, substantially increasing the potential for their use in biomarker validation studies. The CPCTR plans to incorporate biopsy material into its production of TMAs, thereby maximizing the utility of this highly valuable material. As the CPCTR is evolving, it is expanding the types of specimens accrued based on the identification of additional needs in the prostate cancer research community. These unique collections include normal prostate tissue from organ donors, as well as metastatic tissue samples harvested from consented patients within 1 h after death ("warm autopsies"). These tissues are banked as high-quality frozen tissues and as formalin-fixed paraffin tissue blocks, and they are available through the CPCTR and the University of Pittsburgh.
After 3 years of initial accrual of cases, the CPCTR has recently moved into its next phase to begin disbursement of samples and data to investigators. An early example of use of the CPCTR by an investigator is an ongoing study for the validation of a novel biomarker for the prediction of patient outcome using needle biopsy and paired prostatectomy material.
In summary, the CPCTR represents a large, richly diverse, and highly annotated repository of prostate cancer tissues with associated quality-controlled clinical follow-up information that lacks selection bias in many respects and is available to investigators to support tissue-based prostate cancer research. The continued activities of this group will lead to accrual of even greater numbers of tissue specimens, enhancement of clinical data, and construction of various prostate cancer TMAs to expand the variety of tissue samples available for researchers. The success of the CPCTR will be measured by the ability of the investigators it supports to conduct meaningful studies on prognostication and treatment of prostate cancer and by the impact of their research results.
ACKNOWLEDGMENTS
We acknowledge all of the following contributors to the development of the CPCTR.
(a) George Washington University: John Bayerl, Eugenie Estime, Farrell Hartigan, Judith Horn, Charmaine Mckenzie, and Deana McRae.
(b) Medical College of Wisconsin: Trisha St. Laurence-Urbaniak, Pat Recely, Martha See, William See, Peter Langenstroer, Robert Donnel, Hongyung Choi, Jeanne Hryciuk, Douglas Chausow, Michael Whittaker, Mary Fernandez, Lawrence Clowry, Rueben Eisenstein, Andrea Samaniego, Tracey Brodzeller, Andrea Kahler, Sharon Fuller, Sushma Kaul, and Kuei-Fang Tai.
(c) New York University: Richard Buchsbaum, Soraya Kernizan, Xiangtian Kong, Kyle Kuhn, Payal Patel, Joanne Schmoll, Lindsay Stanton, and Hiroko Watanabe.
(d) University of Pittsburgh: Marie Acquafondata, Sheldon Bastacky, Michelle Bisceglia, Vicky Chu, Dilip Gupta, Drazen Jukic, Marianne Notaro, Jennifer Steudler, and Susan Urda and Tracy Wagner (funded members). We also specially recognize the unfunded members of the Pitt team including John Gilbertson, Wendy Hilliard, and Alena Sikorova.
(e) National Cancer Institute: Roger Aamodt, Barbara Conley, Kevin Dobbin, Michael Radmacher, Sheila Taube, and James Tricoli.
(f) Information Management Services: Sherrill Long and Winnie Ricker.
FOOTNOTES
Grant support: National Cancer Institute Grants UO1-CA86743, UO1-CA86735, UO1-CA86772, and UO1-CA86739.
Requests for reprints: Jonathan Melamed, New York University Medical Center, TH-461, 560 First Avenue, New York, NY 10016.
11 http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99–012.html. 
12 http://www.pathology.pitt.edu/pdf/cpctr/cpctr-moo-110403jo.pdf.
13 http://www.pathology.pitt.edu/pdf/cpctr/histomanual25.pdf.
14 http://www.prostatetissues.org.
15 http://www.pathology.pitt.edu/pdf/cpctr/cpctr-cde-v22.pdf.
Received 2/ 5/04; revised 4/ 1/04; accepted 4/ 8/04.
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