Douglas P. Clark, M.D.	Dorothy L. Rosenthal, M.D.	Yener S. Erozan, M.D.
Syed Z. Ali, M.D.	Brigitte M. Ronnett, M.D.	Karen Gustafson, M.D., Ph.D.
Soner Altiok, M.D., Ph.D.

 

Douglas P. Clark, M.D. | 410-955-1180 | dclark@jhmi.edu My laboratory is interested in the molecular characterization of cellular damage. The translational arm of my research characterizes molecular alterations in cytologic samples of human tumors. My laboratory believes that in the future, diagnostic cytopathologists will be called upon to provide a complete molecular characterization of human tumors in addition to a morphologic assessment. That the end, my laboratory has expanded its translational research projects that are aimed at the molecular characterization of human tumor cells from cytologic samples, particularly fine needle aspiration biopsies (FNAs). Our goal is to develop a technological infrastructure through which FNA samples can be assayed for molecules with therapeutic or prognostic significance. Current projects in the laboratory include the examination of DNA methylation profiles in human tumors as well as gene expression in thyroid neoplasms. Yang B, Guo M, Herman JG, and Clark DP: Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 163(3):1101-1107, 2003. Cohen Y, Rosenbaum E, Clark DP, Zeiger MA, Umbricht CB, Tufano RP, Sidransky D, Westra WH: Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid: A potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res 10(8):2761-2765, 2004. Gustafson KS, Furth EE, Heitjan DF, Fansler ZB and Clark DP. DNA methylation profiling of cervical squamous intraepithelial lesions using liquid-based cytology specimens: An approach that utilizes receiver-operating characteristics analysis. Cancer (Cancer Cytopathol) 102:259-268, 2004. Umbricht CB, Conrad GT, Clark DP, Westra WH, Smith DC, Zahurak M, Saji M, Smallridge RC, Goodman S, Zeiger MA: Human telomerase reverse transcriptase (TERT) gene expression and the surgical management of suspicious thyroid tumors. Clin Cancer Res 10:5762-5768, 2004. Yang B, House MG, Mingzhou G, Herman JG, and Clark DP: Methylation-profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma. Mod Pathol. 2005 Mar;18(3):412-20. Wang XF, Qian DZ, Ren M, Kato Y, Wei Y, Zhang L, Fansler Z, Clark DP, Nakanishi Q, Pili R: Epigenetic modulation of retinoic acid receptor beta 2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. Clin Can Res 2005 May 1; 11(9):3535-3542. Zhang J, Martins CR, Fansler ZB, Roemer KL, Kincaid EA, Gustafson KS, Heitjan DF, Clark DP: DNA methylation in anal intraepithelial lesions and anal squamous cell carcinoma. (In Press) Clin Cancer Res 2005.

Dorothy L. Rosenthal, M.D. | | drosenthal@jhmi.edu As a clinically oriented cytopathologist, my research efforts are directed at answering diagnostic questions which are difficult or impossible when relying solely on morphologic features. Determination of molecular changes, such as telomerase activity in neoplasms of the thyroid and breast, utilizing routinely acquired cell samples, is a promising augmentation to the visual impression. Justifying the worth of cytologic techniques, especially on-site assessment of radiologically guided Fine Needle Aspirates, is important to demonstrate. Using evidence based methods, we are analyzing resource utilization and patient outcomes. Rosenthal, DL: Computerized Scanning Devices for Pap Smear Screening: Current Status and Critical Review, (invited review) Clinics in Lab Med 17:263-284, 1997. Rosenthal, DL: Automation and the Endangered Future of the Pap Test (invited commentary), JNCI 90:738-749, 1998. Apple SK, Jahomi S, Nieberg RK, Hecht Jr., Rosenthal DL, and Grody WW: Polymerase Chain Reaction-Based K-ras Mutation Detection of Cholangiocarcinoma in Routine Cytologic Smears. Acta Cytol 42:459, 1998. Nicol TL, Silberman M, RosenthalDL, and Borowitz MJ. The Accuracy of Combined Cytopathologic and Flow Cytometric Analysis in the Diagnosis of Fine Needle Aspirates of Lymph Nodes. Am J Clin Pathol , 114:18-28, 2000. Vlahos NP, Dragisic KG, Wallach EE, Burroughs FH, Fluck S, Rosenthal DL. Clinical Significance of the Qualification of Atypical Squamous Cells of Undetermined Significance: An Analysis on the basis of Histologic Diagnoses. Am J Obstet Gynecol 4:885-90, 2000. Briscoe D, Adair CF, Thompson LD, Tellado MV, Buckner SB, Rosenthal DL, O’Leary TJ. Telecytologic Diagnosis of Breast Fine Needle Aspiration Biopsies. Intraobserver Concordance. Acta Cytol 2:175-80, 2000. Diette G, White P, Terry P, Jenckes M, Rosenthal DL, Rubin HR. Utility of On-Site Cytopathology Assessment for Bronchoscopic Evaluation of Lung Masses and Adenopathy. Chest 4:1186-90, 2000.

Yener S. Erozan, M.D. | 410-955-1180 | yerozan@jhmi.edu My special areas of interest are pulmonary and gastro-intestinal cytopathology. In addition to studying the morphology and evaluation of various specimen collection and preparation techniques, I am interested in correlating the light microscopy findings of cellular material with data obtained by other techniques (e.g., immunocytochemistry, molecular/genetic markers) and in the application of the latter in diagnostic cytopathology. I have been collaborating with Dr. Melvyn Tockman in the investigation of cytopathologic, morphometric and antigenic characteristics of lung cancer during the developing stages. Tockman MS, Qiao Y, Li L, Zhao GA, Sharma R, Cavenaugh LL, Erozan YS. Safe separation of sputum cells from mucoid glycoprotein. Acta Cytol 39:1128-1136, 1995. Tockman MS, Mulshine JL, Piantadosi S, Erozan YS, Gupta PK, Ruckdeschel JC, Taylor PR, Zhukov T, Zhou WH, Qiao YL, Yao S. For the Lung Cancer Early Detection Work Group Investigators and the Yunnan Tin Coporation Investigators: Prospective detection of preclinical lung cancer results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression. Clin Can Res 3:2237-2246, 1997. Qiao YL, Tockman MS, Li L, Erozan YS, Yao SX, Barrett MJ, Zhou WH, Giffen CA, Luo XC, Taylor PR. A case-cohort study of an early biomarker of lung cancer in a screening cohort of Yunnan Tin Miners in China. Can Epidemiology, Biomarkers and Prevention 6:893-900, 1997. Ali SZ and Erozan YS. Thymoma: Cytopathologic features and differential diagnosis of fine needle aspiration. Acta Cytol 42:845-854, 1998.

Syed Z. Ali, M.D. | 410-955-1180 | sali@jhmi.edu Fine needle aspiration (FNA) has a widely recognized and established role as the initial diagnostic modality in most neoplastic and inflammatory disorders of the viscera and soft tissues. My major interest is focused on clinico-morphologic studies primarily based on FNA of brain, breast, and soft tissues with integration of clinico-radiologic data and ancillary techniques such as immuno-cytochemistry, electron microscopy, and molecular genetics. These latter techniques not only augment our morphologic diagnoses in difficult cases, but often also provide important pathogenetic and prognostic information about these lesions. Digital photo imaging and telepathology is rapidly emerging as a major tool, not only in education and research, but also in diagnostic pathology. By utilizing state-of-the-art imaging equipment, I am involved in several on-going projects in this exciting new field ranging from web-based tutorials to sophisticated virtual photomicroscopy. Ali SZ, Zakowski MF, Reuter V: Small cell neuroendocrine carcinoma of urinary bladder. A cytopathologic study of 23 cases. Cancer 79:356-361, 1997. Ali SZ, Hoon V, Hoda SA, Heelan R, Zakowski MF: Solitary fibrous tumor: A cytologic-histologic study with clinical, radiologic and immunohistochemical correlations. Cancer Cytopathol 81:116-121, 1997. Green I, Ali SZ, Allen EA, Zakowski MF: Spectrum of cytopathologic variations in medullary thyroid carcinoma. Fine needle aspiration findings in 19 cases. Cancer Cytopathol 81:40-44, 1997. Ali SZ, Erozan YS: Thymoma: Cytopathologic features and differential diagnoses on fine needle aspiration. Acta Cytol 42:845-854, 1998. Guiter GE, Manon A, Ali SZ, Allen EA, Zakowski MF: Cytopathology of insular carcinoma of the thyroid. Cancer Cytopathol 87:196-202, 1999. Allen EA, Ali SZ, Mathew S: Lymphoid lesions of the parotid. Diagn Cytopathol 21:170-173, 1999.

Brigitte M. Ronnett, M.D. | 410-614-2971 | bronnett@jhmi.edu My research interests are focused on clinicopathologic studies in gynecologic pathology. Recent and ongoing studies are aimed at investigating primary and metastatic mucinous neoplasms involving the ovaries utilizing both traditional clinicopathologic methods and immunohistochemical and molecular techniques. We have re-defined pseudomyxoma peritonei as a pathologic entity and as it relates to mucinous ovarian neoplasms and have re-evaluated the diagnostic categorization of all mucinous ovarian tumors. Other areas of interest include gynecologic cytopathology and diagnostic immunohistochemistry. Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM: Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis: A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to pseudomyxoma peritonei. Am J Surg Pathol 1995; 19:1390-1408. Ronnett BM, Shmookler BM, Diener-West M, Sugarbaker PH, Kurman RJ: Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol 1997; 16:1-9. Ropel MA, Ronnett BM, Kurman RJ: Diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: Borderline, microinvasive, invasive, and metastatic. Am J Surg Pathol 1999; 23:617-635. Szych C, Staebler A, Connolly DC, Wu R, Cho KR, Ronnett BM: Molecular genetic evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Am J Pathol 1999; 154:1849-1855.

Soner Altiok, MD, PhD | 443-287-4638 | saltiok1@jhmi.edu My research interests include the analyses of signal transduction pathways in fine needle aspiration samples to develop molecular parameters for assessing the efficacy of chemotherapy in vivo and to identify potential targets for rational therapy. We are also investigating the application of various proteomics techniques such as surface-enhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry for tumor profiling to identify the primary site of metastatic tumors of unknown origins. S. Altiok (2003). Molecular markers in cervical cytology. Clinics in Laboratory Medicine 23:709-728. S. Altiok, A Papputsky, D. Batt, T. Roberts, J. Downwards and H. Avraham (1999). Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-kinase/AKT in breast cancer cells. Journal of Biological Chemistry 274:32274-32278. S. Altiok and B. Groner (1998). Regulation of gene expression in mammary epithelial cells by cellular confluence and sequence specific DNA binding factors. Biochemical Society Symposium. 63. Mammary gland and differentiation, Chapter 10, 115-131. S. Altiok, M. Xu and B.M. Spiegelman (1997). PPAR-gamma induces cell cycle withdrawal: Inhibition of E2F/DP DNA binding activity via downregulation of PP2A. Genes&Development 11:1987-1999.

Karen Gustafson, MD, PhD | 410-502-1985 | kgustaf1@jhmi.edu My current research interests are in the area of gynecologic cytopathology, with a focus on translational research to identify novel molecular biomarkers with diagnostic and prognostic utility for cervical carcinoma and its precursor lesions. Recently, we have examined DNA methylation alterations in cervical carcinogenesis and their potential use as biomarkers for high-grade squamous intraepithelial lesions in cervical cytology specimens. In addition, I am also interested in understanding the biological role of DNA methylation in the pathogenesis of cervical carcinoma. Gustafson KS, Furth EE, Heitjan DF, Fansler ZB, Clark DP. DNA methylation profiling of cervical squamous intraepithelial lesions using liquid-based cytology specimens: An approach that utilizes receiver-operating characteristic analysis. Cancer Cytopathol. 102: 259-268, 2004 Barrett DM, Gustafson KS, Wang J, Wang SZ, Ginder GD. A GATA factor mediates cell type-restricted induction of HLA-E gene transcription by gamma interferon. Mol. Cell. Biol. 24: 6194-6204, 2004 Gustafson KS, LiVolsi VA, Furth EE, Pasha TL, Putt ME, Baloch ZW. Peroxisome proliferator-activated receptor-gamma expression in follicular-patterned lesions of the thyroid: Caveats for the use of immunohistochemical studies. Am. J. Clin. Pathol. 120: 175-181, 2003 Yu GH, Gustafson KS, Sturgis CD. Fine needle aspiration. In: Sciarra J.J., ed. Gynecology & Obstetrics. Philadelphia, Lippincott-Raven Publishers, 2002