<H3>Overview</H3>

   <P>The Laboratory of Pathology of the National Cancer Institute offers a multifaceted
    four-year training program for residents in anatomical
    pathology. The philosophy and underlying guiding principle of this
    training program is to provide a broad and in-depth exposure to the
    subject matter of anatomic pathology with an emphasis on clinical
    correlation, relationships to disease mechanisms, and exposure to
    investigational opportunities in both basic and applied research.
    Residents become fully grounded in the laboratory techniques,
    observational and descriptive analysis procedures, and communication
    skills required to gain the maximum information prior to rendering a
    diagnosis. Each case under study is approached within the context of the individual
    patient\''s clinical course, strong collaborative interactions among the clinicians
    caring for the patient, and disease pathophysiology and investigational questions.
    Training occurs mostly within the Laboratory of Pathology and through our affiliations
    with the Armed Forces Institute of Pathology and George Washington University.</P>
   <P>The research activities of the staff are substantial and
    diversified, incorporating the most modern techniques available in
    biomedical research and based upon a firm foundation of an intricate
    knowledge of the biology of the disease state. The laboratory also
    offers subspecialty fellowships in surgical pathology, cytopathology and hematopathology
    that integrate advanced diagnostic pathology with
    opportunities for laboratory research and instruction in sophisticated
    laboratory techniques.</P>
   <H3>Structure of the Clinical Training Program</H3>
   <P>Clinical training in the Anatomic Pathology Program includes three years of
    rotations and subspecialty training. The first year provides for an intense experience
    in postmortem, surgical pathology, and cytopathology diagnosis. Separate one month
    subspecialty rotations inforensic pathology (Armed Forces Institute of Pathology
    and District of Columbia Medical Examiner affiliations), surgical pathology/OB
    GYN pathology (George Washington University affiliation), and pediatric pathology
    (Children\''s National Medical Center) broaden the training offered at the NIH.
    Integrated rotations in dermatopathology, neuropathology, pediatric pathology,
    hematopathology, flow cytometry, immunopathology, electron microscopy, and cytogenetics
    are provided during all three years. Residents in the third year gain more authority
    in making diagnostic decisions and supervising other residents in both surgical
    and postmortem pathology. There are also further opportunities for clinical and
    research electives at this time.</P>
   <P>Instruction in anatomic pathology starts with the examination of
    fresh tissue, microscopic slides prepared from representative sections, laboratory
    data, radiographs, and special studies including flow cytometry, immunohistochemistry,
    electron microscopy, and molecular genetic analysis. The primary route for the
    resident to acquire knowledge and gain feedback on performance is direct one-on-one
    interactions with the staff. The formal aspects of the educational experience
    include systematic staff instruction in the categorical topics of anatomic pathology,
    supplementation of case material by study sets, lectures by consultants, and full
    pathology training courses provided within and outside the department. Numerous
    conferences, seminars, rounds, and meetings provide exchange of information and
    points of view with patient care physicians. In addition to gaining knowledge
    and improving diagnostic skills, residents develop maturity of judgment and the
    ability to work with peers, subordinates, supervisors, and clinicians in other
    disciplines in order to maximize the accuracy and quality of clinical care. Finally,
    residents learn to use and appreciate the new molecular diagnostic techniques
    (with a full understanding of their limitations) that will play an ever-increasing
    role in the future.</P>
   <H3>Structure of the Research Training Program</H3>
   <P>The Laboratory of Pathology offers extensive training in experimental pathology.
    The research experience is rich and tailored to the background and interests of
    the resident. During the interview process the candidate meets with the clinical
    and basic science investigators in the department. After entering the program,
    the resident consults with the scientific staff and chooses a research project
    and advisor. At this time, laboratory bench space and access to all equipment
    and resources necessary to support the project are provided.</P>
   <P>Some of the areas of investigation in which the trainees may
    participate include the following:</P>
   <UL>
    <LI>Cancer invasion and metastasis, genetic and biochemical mechanisms.
     </LI>
    <LI>Carbohydrate and protein receptors mediating cell adhesion and
     motility.
     </LI>
    <LI>Extracellular matrix remodelling.
     </LI>
    <LI>Oncogene transcriptional regulation.
     </LI>
    <LI>Hematopathology, basic and applied molecular genetics research.
     </LI>
    <LI>Pediatric tumor biology.
     </LI>
    <LI>Applied surgical pathology studies in breast cancer, lung disease,
     drug resistance, gene product  expression, and molecular markers of
     progression.
     </LI>
    <LI>Basic molecular biology.
     </LI>
   </UL>
   <H3>Program Faculty and Research Interests</H3>
   <H4>Surgical Pathology Section</H4>
   <UL>
    <LI>Dr. Maria Merino, in collaboration with other members of the Surgical Pathology
     staff, is investigating the role of different tumor markers (e.g., Ki 67, collagenases
     and GCDFP-15) as prognostic tools in the diagnosis of breast, ovarian and thyroid
     cancer, as well as soft tissue sarcomas. The section is also investigating the
     use of antibodies against P-glycoprotein, which has been associated with a multidrug-resistant
     phenotype.
     </LI>
    <LI>Dr. Irina Lubensky is studying the loss of heterozygosity of
     chromosome 3p in premalignant and malignant renal tumors, both
     spontaneous and associated with von Hippel-Lindau Syndrome. She is also examining
     the anatomic distribution of primary gastrinomas and
     metastases in patients with Zollinger-Ellison syndrome.
     </LI>
   </UL>
   <H4>Postmortem Pathology Section</H4>
   <UL>
    <LI>Dr. David Kleiner is studying the biochemical interactions between the human
     gelatinase A and TIMP-2. He is also working with the Liver Disease section of
     the NIDDK characterizing the hepatic pathologic changes in viral hepatitis and
     primary biliary cirrhosis. The Postmortem Pathology Section serves as a source
     of research material for the study of diseases under protocol at the NIH Clinical
     Center.
     </LI>
   </UL>
   <H4>Cytopathology Section</H4>
   <UL>
    <LI>Dr. Diane Solomon researches the application of immunocytochemistry in diagnostic
     cytopathology. Lymphoid markers have been utilized to differentiate reactive processes
     from lymphoma, as well as to subtype lymphomas when possible. Several monoclonal
     antibodies have been evaluated for specificity and sensitivity to carcinoma cells
     versus reactive mesothelial cells in the diagnosis of metastatic carcinoma in
     cavity fluids. Currently under investigation is the use of in situ hybridization
     as an ancillary diagnostic technique for cytology. Through a national consensus
     conference, this section has established the "Bethesda" system for standardizing
     the classification and reporting of PAP smears.
     </LI>
    <LI>Dr. Andrea Abati\''s research interests include the morphologic effects of
     photodynamic therapy in body fluids and respiratory cytology in chronic granulomatous
     disease of childhood. Over the past two years she has been evaluating microembolic
     phenomenon and is currently evaluating new antibodies for specificity and sensitivity
     in mesothelioma. She hopes to incorporate image analysis and fluorescence in situ
     hybridization with these diagnostic and research efforts.
     </LI>
   </UL>
   <H4>Ultrastructural Pathology Section</H4>
   <UL>
    <LI>Dr. Maria Tsokos has focused on two major areas of research: 1) the identification
     of markers and employment of techniques that help in the diagnosis and histogenetic
     characterization of Ewing\''s sarcoma, primitive neuroectodermal tumors (PNET),
     and rhabdomyosarcoma; and 2) the definition of histologic, biologic and other
     factors to predict the biologic aggressiveness of tumors.
     </LI>
    <LI>Dr. Yasmine Hijazi\''s research interests in the Ultrastructural
     Pathology section deal with pediatric round-cell tumors particularly
     Ewing\''s sarcoma/PNET and rhabdomyosarcomas. In addition she is involved in collaborative
     studies using the electron microscope as an ancillary diagnostic technique. Dr.
     Hijazi\''s cytopathology research interests include urinary tract and lymph node
     cytology, as well as
     immunocytochemistry and its application to cytologic diagnosis.
     </LI>
   </UL>
   <H4>Extracellular Matrix Pathology Section</H4>
   <UL>
    <LI>Dr. William G. Stetler-Stevenson\''s laboratory is studying the role of matrix
     metalloproteinases in cell invasion. In addition, the laboratory is interested
     in the biological activities of the tissue inhibitors of metalloproteinases. Recent
     work has demonstrated that in addition to inhibiting matrix metalloproteinases
     these agents also affect the growth of a variety of cell types. Specifically,
     TIMP-2 inhibits the bFGF-induced growth of human microvascular endothelial cells.
     This appears to be mediated by a receptor-dependent mechanism that is currently
     under investigation.
     </LI>
   </UL>
   <H4>Biochemical Pathology Section</H4>
   <UL>
    <LI>Dr. David Roberts is conducting research on the function of complex carbohydrates
     in tumor-cell adhesion and host-pathogen interactions, and the role of the adhesive
     glycoproteins laminin, thrombospondin and the thrombospondin receptor in tumor
     growth and metastasis.
     </LI>
   </UL>
   <H4>Tumor Invasion and Metastases Section</H4>
   <UL>
    <LI>Dr. Lance Liotta is studying invasion and metastasis as a culmination of a
     series of progressive steps resulting in genetic changes over and above those
     required for uncontrolled proliferation. Expression of the metastatic phenotype
     depends on a balance between positive and negative regulatory gene products. Understanding
     the action of these gene products has led to new strategies for prognosis and
     therapy.
     </LI>
    <LI>Dr. Elise Kohn has identified a new signal transduction inhibitor that blocks
     tumor cell cytokine-stimulated growth and motility. The
     inhibitor, termed CAI, is a substituted imidazole that constitutes a new approach
     to cancer therapy. In animal models using a variety of human tumors, including
     melanoma, CAI has produced primary tumor and
     metastasis regression following oral administration. CAI clinical phase I trials
     have begun.
     </LI>
   </UL>
   <H4>Molecular Pathology Section</H4>
   <UL>
    <LI>Dr. Mark Sobel is studying laminin receptors and their role in tumor cell
     metastasis. He has found a strong correlation between laminin receptor mRNA and
     protein levels and metastatic outcome for colon and breast cancer.
     </LI>
   </UL>
   <H4>Women\''s Cancer Section</H4>
   <UL>
    <LI>Dr. Pat Steeg has obtained the full-length cDNA for Nm23, a novel gene for
     which RNA levels are reduced in high metastatic potential murine melanoma cell
     lines and human tumor cells. Loss of Nm23 expression in breast cancer is associated
     with highly significant reduction in survival. Transfection of Nm23 cDNA leading
     to augmented Nm23 protein production abrogates metastasis by a non-immunologic
     mechanism in rodent melanoma models. Recent studies indicate that the Nm23 protein
     is an NDP kinase.
     </LI>
   </UL>
   <H4>Hematopathology Section</H4>
   <UL>
    <LI>Dr. Elaine Jaffe conducts a major program in diagnostic and
     experimental hematopathology. While the emphasis is on clinical
     protocols based at NCI, collaborations exist with physicians in other
     categorical institutes. Dr. Jaffe supervises an internationally
     recognized consultation service that receives over 1600 cases per year
     in consultation from the general medical community. The Hematopathology Section
     continues its active research program on the molecular and immunological characterization
     of malignant lymphomas. Areas of emphasis include the interrelationship of Hodgkin\''s
     disease and the non-Hodgkin\''s lymphomas, angiocentric lymphomas, and the role
     of Epstein-Barr virus in lymphoproliferative disorders.
     </LI>
    <LI>Dr. Maryalice Stetler-Stevenson is studying factors that are
     associated with a more aggressive clinical behavior in lymphomas.
     Current studies have identified a pattern of gene expression associated with a
     more aggressive behavior in Burkitt\''s lymphoma. She is investigating the action
     these genes may have in B-cell neoplasia. Dr. Stetler-Stevenson is also studying
     aneuploidy and cell-cycle fractions in benign and malignant tumors, both hematopoietic
     and solid, to determine the prognostic and diagnostic importance of these clinical
     laboratory determinations.
     </LI>
    <LI>Dr. Mark Raffeld\''s investigations are concerned with the molecular
     abnormalities associated with different types of malignant lymphomas,
     and their application to clinical diagnosis. His current research
     interests include the molecular basis of indolent lymphoma progression
     and the functional effects of MYC gene coding-region mutations that are frequent
     in Burkitt\''s lymphomas.
     </LI>
   </UL>
   <H4>Gene Regulation Section</H4>
   <UL>
    <LI>Dr. David Levens studies the biochemical mechanisms employed during the transcription,
     processing and translation of RNA in order to identify pathology resulting from
     aberrant regulation. Currently, the section has two main areas of research: 1)
     the transcriptional
     regulation of c-myc; and 2) the trans-activation of the gibbon ape
     leukemia virus by a set of factors binding to AP1 sites from T cells.
     </LI>
   </UL>
   <H4>Molecular Immune Activation Section</H4>
   <UL>
    <LI>Dr. Kathleen Kelly is investigating the consequences of mitogen-
     mediated signals to T cells. She has isolated over sixty novel cDNA
     clones that represent mRNA species induced by PHA and PMA in human
     peripheral blood T cells. Primary sequence analyses on five clones have been completed
     and have revealed two functional classes of proteins encoded by these genes: lymphokines
     and DNA-binding
     proteins/transcription factors. The functional activities of the three
     putative lymphokines are currently being tested using recombinant
     proteins.
     </LI>
   </UL>
   <H4>Office of the Chief</H4>
   <UL>
    <LI>Dr. Susan Mackem is interested in elucidating the molecular mechanisms by
     which pattern formation is regulated during embryonic development. Using limb
     morphogenesis, a model system for pattern formation that is readily amenable to
     various experimental manipulations, Dr. Mackem is employing subtractive hybridization
     approaches to isolate cDNA clones for genes that are induced during pattern formation
     in the embryonic limb, and that play potential roles in determining limb-type
     identity.
     </LI>
   </UL>
   <H3>Examples of Papers Authored by Program Faculty</H3>
   <UL>
    <LI>Jaffe ES, Raffeld M, Medeiros MJ. Histopathologic subtypes of indolent lymphomas:
     caricatures of the mature B-cell system. Semin Oncol 1993;20:3-30.
     </LI>
    <LI>Kleiner DE Jr, Stetler-Stevenson WG. Structural biochemistry and
     activation of matrix metalloproteinases. Curr Opin Cell Biol 1993;5:891-897.
     </LI>
    <LI>MacDonald NJ, De La Rosa A, Benedict MA, Freije JMP, Krutzsch H, Steeg PS.
     A serine phosphorylation of Nm23, and not its nucleoside diphosphate kinase activity,
     correlates with suppression of tumor metastatic potential. J Biol Chem 1993;268:25780-25789.
     </LI>
    <LI>Merino MJ, Jaffe G. Age contrast in ovarian pathology. Cancer
     1993;71:537-544.  Rohan PJ, Davis P, Moskaluk C, Kearns M, Krutszch H, Siebenlist
     U, Kelly K. Pac-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science
     1993;259:1763-1766.
     </LI>
    <LI>Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell
     interactions with the extracellular matrix during invasion and
     metastasis. Annu Rev Cell Biol 1993;9:541-573.
     </LI>
    <LI>Takimoto M, Tomonaga T, Matunis M, Avigan M, Krutzsch H, Dreyfuss G, Levens
     D. Specific binding of heterogeneous ribonucleoprotien particle protein K to the
     human c-myc promoter, in vitro. J Biol Chem
     1993;268:18249-18258.
     </LI>
   </UL>
   <H3>Program Graduates</H3>
   <P>A list of former residents of the Laboratory of Pathology of the NCI who are
    currently serving as departmental chairpersons is provided:</P>
   <UL>
    <LI>Dr. Costan W. Berard. St. Jude\''s Children\''s Research Hospital,
     Memphis, Tennessee.
     </LI>
    <LI>Dr. L. Maximillian Buja. University of Texas, Houston, Texas.
     </LI>
    <LI>Dr. Jeffrey Cossman. Georgetown University School of Medicine,
     Washington, District of Columbia.
     </LI>
    <LI>Dr. Robert M. Friedman. Uniformed Services University of the Health Sciences,
     Bethesda, Maryland.
     </LI>
    <LI>Dr. A. Julian Garvin. Medical University of South Carolina,
     Charleston, South Carolina.
     </LI>
    <LI>Dr. Peter M. Howley. Department of Pathology, Harvard University
     School of Medicine, Cambridge, Massachusetts.
     </LI>
    <LI>Dr. Gerhard Krueger. University of Cologne, Cologne, Germany.
     </LI>
    <LI>Dr. Lance A. Liotta. Laboratory of Pathology, National Cancer
     Institute, Bethesda, Maryland.
     </LI>
    <LI>Dr. Timothy J. O\''Leary. Department of Cellular Pathology, Armed Forces Institute
     of Pathology, Washington, D.C.
     </LI>
    <LI>Dr. Deborah Powell. University of Kentucky College of Medicine,
     Lexington, Kentucky.
     </LI>
    <LI>Dr. Timothy J. Triche. Department of Laboratories, Children\''s Hospital of
     Los Angeles, Los Angeles, California.
     </LI>
    <LI>Dr. Peter Banks. Director, Anatomic Pathology, Health Science Center, San
     Antonio, Texas.
     </LI>
   </UL>
   <H3>Application Information</H3>
   <P>The Anatomic Pathology Program at NIH is fully accredited by the
    Accreditation Council for Graduate Medical Education. Upon completion of the four
    year program, residents are fully eligible to sit for boards in anatomic pathology.
    Qualified candidates must have completed at least an MD degree. Many candidates
    also have a PhD degree, and some have completed a general or subspecialty residency.
    There are three to four positions available per year, and candidates should apply
    from nine months to a year in advance. Residents usually stay in the program for
    three to four years.</P>
   <P>For further information, the applicant should contact:</P>
   <BLOCKQUOTE>
    Dr. William G. Stetler-Stevenson<BR>
    Assistant Director<BR>
    Anatomic Pathology Residency Training Program<BR>
    National Cancer Institute<BR>
    National Institutes of Health<BR>
    Building 10, Room 2A33<BR>
    10 CENTER DR MSC 1500<BR>
    BETHESDA MD 20892-1500<BR>
    (301) 496-3185<BR>
    FAX: 301-402-0043
    </BLOCKQUOTE>
   <H3>Electronic Application</H3>
   <P>The quickest and easiest way to find out more about this training program or
    to apply for consideration is to do it electronically. Press the appropriate button
    below to request further information or apply for consideration.</P>