Douglas P. Clark, M.D.	Dorothy L. Rosenthal, M.D.	Yener S. Erozan, M.D.
Syed Z. Ali, M.D.	Karen Gustafson, M.D., Ph.D.	Qing Kay Li, 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. Jimeno A, Kulesza P, Kincaid E, Bouaroud N, Chan A, Forastiere A, Brahmer J, Clark DP, Hidalgo M: C-fos assessment as a marker of anti-epidermal growth factor receptor effect. Cancer Res 2006 66(4):2385-2390. Moff SL, Clark DP, Maitra A, Pandey A, and Thuluvath PJ. Utility of bile duct brushings in the detection of cholangiocarcinoma in patients with primary sclerosing cholangitis. J Clin Gastroent, 2006 40(4):336-341. Pu RT, Laitala LE, Clark DP: Methylation profiling of urothelial carcinoma in urine cytopathology. Acta Cytol 2006 Sep-Oct;50(5):499-506. Lee JL, Kelly D, Gravitt PE, Fansler Z, Maksem JA, Clark DP: Validation of a low-cost, liquid-based screening method for cervical intraepithelial neoplasia. Am J Obstet Gynecol 2006 Oct;195(4):965-70. Kelly D, Kincaid E, Fansler Z, Rosenthal, Clark DP: Detection of cervical high-grade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProExTM C). Cancer (Cancer Cytopathol) 2006;108:494-500. Jimeno A, Kulesza P, Wheelhouse J, Chan A, Zhang X, Kincaid E, Chen R, Clark DP, Forastiere A, Hidalgo M: Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Bri J Cancer 2007; 96: 952-959. Pu RT, Sheng Z-M, Michael CW, Rhode MG, Clark DP, O’Leary TJ: Methylation profiling of mesothelioma using real-time methylation-specific PCR. Diagn Cytopathol 2007; 35: 498-502. Chen F, Clark DP, Hawkins AL, Morsberger LA, Griffin CA: A break-apart FISH assay for detecting RET translocations in papillary thyroid carcinoma. Cancer Genet Cytogenet, 2007; 178(2):128-134. Murphy KM, Chen F, Clark DP: Identification of immunohistochemical biomarkers for papillary thyroid carcinoma using gene expression profiling. Human Pathol, 2008; 39(3): 420-426. Baloch ZW, Cibas ES, Clark DP, Layfield LJ, Ljung B-M, Pitman MB, Abati, A: The National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference: A Summation. Cytojournal 2008; 5(1):6. Prasad NB, Somervell H, Tufano RP, Dackiw APB, Marohn MR, Califano JA, Wang Y, Westra WH, Clark DP, Umbricht CB, Libutti SK, Zeiger MA: Identification of genes differentiallly expressed in benign versus malignant thyroid tumors. Clin Cancer Res 2008, 14(11):3327-3337. Filie AC, Asa S, Geisenger KR, Logani S, Merino M, Nikiforov YE, Clark DP: Utilization of Ancillary Studies in Thyroid Fine Needle Aspirates: A Synopsis of the National Cancer Institute* Thyroid Fine Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008; 36(6):438-441.

Dorothy L. Rosenthal, M.D. | | drosenthal@jhmi.edu For over half a century the field of Cytopathology has expanded and achieved a recognized place among medical disciplines. The discipline has relied on morphologic features to distinguish benign from malignant lesions and to sub classify them to a significant degree. However, recognizing that disease begins at a molecular level, only to be reflected by the morphology of the cells, I firmly believe that we must now design tests that will define the molecular changes that have taken place within the diseased cells. The Pap test for cervical cancer screening has been an undisputed success in detecting precursor lesions of the uterine cervix and dramatically reducing the number of women dying from that disease. My research efforts are now dedicated to an “improved” Pap test, one that capitalizes on well established morphologic changes and also reflects the molecular injury that has taken place as a result of a viral infection. Predictably, once this test is proven to be reliable, the same principles may be applied to other diseases, such as cancers of the lung, head & neck, breast and colon. These are exciting times in which to capitalize on a host of technical and intellectual innovations. I am looking forward to exploring some of these great possibilities. Rosenthal, DL: Computerized Scanning Devices for Pap Smear Screening: Current Status and Critical Review, (invited review) Clinics in Lab Med 17:263-284, 1997. Levi AW, Kelly DP, Rosenthal DL, Ronnett BM. Atypical Squamous Cells of Undetermined Significance (ASC-US) in Liquid-Based Cytologic Specimens: Results of Reflex HPV Testing and Histologic Follow-up in Routine Practice with Comparison of Interpretive and Probabilistic Reporting Methods. Cancer Cytopath 2003;99:191-7. Rosenthal DL: Cervical disease screening and detection: emerging techniques in molecular diagnostic assays. MLO Med Lab Obs. 2004; 36:10-11. Zuna RE, Wang SS, Rosenthal DL, Jeronimo J, Schiffman M, Solomon D, for ASCUS/LSIL Triage Study (ALTS) Group. Determinants of human papillomavirus (HPV) negative low-grade squamous intraepithelial lesions (LSIL) in the ASCUS/LSIL Triage Study (ALTS). Cancer Cytopathology 2005 105:253-62. Kelly D, Kincaid E, Fansler Z, Rosenthal DL, Clark DP. Detection of cervical high-grade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProExTM C) Cancer Cytopathology. 2006;108:494-500. Diaz-Montes TP, Farinola MA, Zahurak ML, Bristow RE, Rosenthal DL. Clinical utility of atypical glandular cells (AGC) classification: Cytohistologic comparison and relationship to HPV results. Gynecologic Oncology. 2007;104:366-71. 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. Kulesza P, Torbenson M, Sheth S, Erozan YS, Ali SZ: Cytopathologic grading of hepatocellular carcinoma on fine needle aspiration. Cancer Cytopathol 2004; 102(4):247-258 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.

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 2004; 102: 259-268. Owens CL, Rojas DN, Burroughs FH, Gustafson KS. "Low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion" is a distinct cytologic category: histologic outcomes and HPV prevalence. Am. J. Clin. Pathol. 2007; 128: 398-403. Gustafson KS. Locked nucleic acids can enhance the analytical performance of quantitative methylation-specific PCR. J. Mol. Diagn. 2008; 10: 33-42. Kahn SL, Ronnett BM, Gravitt PE, Gustafson KS. Quantitative methylation-specific PCR for the detection of aberrant DNA methylation in liquid-based Pap tests. Cancer 2008; 114(1): 57-64. Gustafson KS, Clark DP. Molecular cytopathology. 2008. In: Tubbs R. and Stoler M., eds. Cell and Tissue Based Molecular Pathology. Elsevier Science Publishers.

Qing Kay Li, MD., PhD. | 410-955-1180 | Qli23@jhmi.edu My areas of interest are pulmonary and effusion cytology. In addition to the study of the morphology of various diseases, my main research interest is to apply the advanced technology of cellular and molecular biology to the field of cytology, particularly in the area of early detection of lung cancer. Identification and utilization of the molecular markers not only augment our morphological diagnostic skills in difficult cases, but also provide important prognostic and therapeutic information on lung cancers. Currently, my research is focused on: (1) detection of circulating tumor cells in non-small cell lung cancer patients; (2) identification of molecular markers and intracellular signaling pathways that are involved in the progression of lung cancer, and (3) discovering novel molecular biomarkers with early diagnostic and prognostic significance. Miao H., Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, Rhim JS, Sedor JR, Burnett E, and Wang B. Activation of EphA receptor tyrosine kinase inhibits the Ras/MARK pathway. Nature (Cell Biol) 2001; 3:527-530. Bey EA, Xu B, Bhattacharjee A, Oldfield CM, Zhao X, Li Q, Subbulakshmi V, Feldman GM, Wientjes FB and Cathcart MK. Protein Kinase C delta is required for p47phox phosphorylation and translocation in activated human monocytes. J. Immunol. 2004; 173:5730-5738. Li Q, Murphy M, Ross JS, Sheehan CE and Carlson JA. Skp2 and p27 kip1 expression in melanocytic nevi and melanoma: an inverse relationship. J. Cutan. Pathol. 2004; 31:633-642. Li Q, Bavikatty N, and Michael CW. The role of Immunohistochemistry in the distinguishing squamous cell carcinoma from mesothelioma and adenocarcinoma in pleural effusion. Semin Diagn Pathol. 2006; 23:15-19. Li Q, Subbulakshmi V, Oldfield C, Amir R, Weyman CM, Wolfman A and Cathcart MK. Protein kinase C alpha regulates phosphorylation and enzymatic activity of cytosolic phospholipase A2 in vitro and in activated human monocytes. Cell Signal 2007; 19:359-366. Li QK, Geddes S, Burroughs FH, Ali SZ. 2008. Low-grade Neuroendocrine neoplasm of the lung on fine needle aspiration. 2008 Mod. Pathol. 21(supplement):78A. Li QK, Tully E, Askin, FB, Clark DP, Gabrielson E. Overexpression of NRF2 is correlated with KAEP1 gene mutation in pulmonary papillary adenocarcinoma. 2008 Cancer Cytopathol. 114(supplement):411.