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Division of Genitourinary Pathology

Email jepstein@jhmi.edu
Phone (410) 955-5043

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Division of Surgical Pathology

New Contemporary Prostate Cancer Grading System

Jonathan I. Epstein, M.D.

Director, Division of Genitourinary Pathology
Director, Division of Surgical Pathology
Primary Appointment in Pathology
Secondary Appointments in Oncology and Urology

Carcinoma of the prostate can vary from extremely indolent lesions such as those found incidentally at autopsy to aggressive tumors responsible for the second leading cause of cancer death in men. We have the largest number of completely studied radical prostatectomy specimens in the world and the largest anatomic pathology consult service of genitourinary specimens (>60/day). We are involved in multiple clinico-pathologic studies using a wide range of techniques on both biopsy and prostatectomy specimens to enhance our prognostic capabilities. Tissue microarrays are available for bladder and prostate cancer projects. The consult material also provides the unique opportunity to identify and describe new entities in genitourinary pathology.

Epstein JI, Walsh PC, CarMichael M, Brendler CB. Pathological and clinical findings to predict tumor extent of non-palpable (stage T1c) prostate cancer JAMA 271:368-374, 1994. Epstein JI, Allsbrook Jr. WC, Amin MB, Egevad LL & The ISUP grading committee. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 29: 1228-42, 2005.

Epstein JI, Amin MB, Reuter VR, Mostofi FK, and the Bladder Consensus Conference Committee. The World Health Organization/International Society of Urological Pathology Consensus Classification of Urothelial (Transitional Cell) Neoplasms of the Urinary Bladder. Am J Surg Pathol 22:1435-1448, 1998.

Pan C-C, Potter SR, Partin AW, Epstein, JI. The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the Gleason grading system Am J Surg Pathol 24:563-569, 2000.

Duffield A, Epstein JI. Detection of cancer in radical prostatectomy specimens with no residual carcinoma in the initial specimen. Am J Surg Pathol (January) 33:120-125,2009.

Email ljarend@jhu.edu
Phone (443) 287-0166
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Lois J. Arend, M.D., Ph.D.

Primary Appointment in Pathology

My laboratory studies the mechanisms of mammalian kidney development. Specifically, our studies involve various cell and molecular biology techniques to determine the role of the bioactive sphingolipid, sphingosine-1-phosphate (S1P), in organogenesis of the kidney. Our research indicates that S1P may be involved in development of conditions such as cystic kidney disease and Meckel syndrome. We also study the pathologic aspects of other kidney disease by various morphologic techniques, including light, immunofluorescence, and electron microscopy.

Arend LJ, Smart AM, and JP Briggs. Metanephric rat-mouse chimeras to study cell lineage of the nephron. Developmental Genetics 24(3/4):230-240, 1999

Arend LJ, Smart A, and JP Briggs. Mouse beta 6 integrin sequence, pattern of expression, and role in kidney development. J Am Soc Nephrol 11:2297-2305, 2000

Phillips CL, Arend LJ, Filson A, Kojetin D, Clendenon J, Fang S, and KW Dunn. Three dimensional imaging of embryonic mouse kidney by two-photon microscopy. Am J Pathol 158(1):49-55, 2001

Fu J, Jin Y, and LJ Arend. Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of XIAP. J Biol Chem Dec 26;278(52):52660-72, 2003

Lorenz, JN, L.J. Arend, R Robitz, RJ Paul, AJ MacLennan. Vascular dysfunction in S1P2 sphingosine-1-phosphate receptor knockout mice. American Journal of Physiology- Regulatory, Integrative and Comparative Physiol 292(1):R440-6, 2007

Kirby RJ, Jin Y, Fu J, Cubillos J, Swertfeger, D, Arend LJ. Dynamic regulation of sphingosine-1-phosphate homeostasis is critical for branching morphogenesis of the mouse metanephric kidney. Am J Physiol Renal Physiol 296:F634-F641, 2009

Kirby RJ, Swertfeger, D, Arend LJ. Crosstalk between GDNF/RET and S1P/S1PR signaling pathways regulates kidney epithelial cell migration. In Preparation.

Email sbagnas1@jhmi.edu
Phone (410) 502-0812
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Serena M. Bagnasco, M.D.

Primary Appointment in Pathology

Research interests currently include pathologic aspects and molecular markers of renal allograft dysfunction, and of native kidney disease. Studies are ongoing exploring new sources of potential biomarkers that can improve distinguishing among different types of injury in the transplanted kidney. Digital pathology of morphologic features of native kidney biopsies is being applied in correlation with clinical and molecular parameters for the analysis of proteinuric glomerular diseases in large multicenter, prospective, observational studies.

Pisitkun T, Gandolfo MT, Knepper M, Bagnasco SM. Application of system biology principles to protein biomarker discovery: urinary exosomal proteome in renal transplantation. Proteomics Clin. Appl. 2012;6(5-6):268-78.

Barisoni L, Nast CC, Jennette JC, Hodgin JB, Herzenberg AM, Lemley KV, Conway CM, Kopp JB, Kretzler M, Lienczewski C, Avila-Casado C, Bagnasco SM, Sethi S, Tomazewski J, Gasim AH, Hewitt SM. Digital pathology evaluation in the multicenter nephritic syndrome study network (NEPTUNE). Clin J Am Soc Nephrol. 2013;8:1449-59.

Bagnasco SM, Zachary AA, Racusen LC, Arend LJ, Carter-Monroe N, Alachkar N, Nazarian SM, Lonze BE, Montgomery RA, Kraus ES. Time Course of Pathologic Changes in Kidney Allografts of Positive Crossmatch HLA-Incompatible Transplant Recipients. Transplantation. 2014; 97:440-445.

Jackson AM, Sigdel TK, Delville M, Hsieh SC, Dai H, Bagnasco SM, Montgomery RA, Sarwal MM. Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol. 2015; 26:1161-71.

Sampson MG, Robertson CC, Martini S, Mariani L, Lemley K, Gillies CE, Otto EA, Kopp JB, Randolph A, Vega-Warner V, Eichinger F, Nair V, Gipson DS, Cattran D, Johnstone D, O’Toole J, Bagnasco S, Song P, Barisoni L, Troost J, Kretzler M, Sedor J, and the Nephrotic Syndrome Study Network: Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects. J Am Soc Nephrol 2015 (in press)

Bagnasco SM. Intimal arteritis in renal allografts: new takes on an old lesion. -Current Opinion in Transplantation, 2015 (in press).

Email ncarte13@jhmi.edu
Phone (410) 955-2386
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Naima Carter-Monroe, M.D.

Primary Appointment in Pathology

My research interests are in the fields of medical and transplant renal pathology, with a particular interest in the intersection between histopathologic parameters (the Banff Classification System) and socioeconomic and/or racial disparities and how the interaction of these factors effect graft survival. In addition, I am also interested in informatics applications with an emphasis on parsing the massive amounts of free-text data embedded in renal allograft pathology reports into discrete data elements to be incorporated into structured relational databases based on clinical utility and patient care needs.

Naqvi F, Matar D, Racusen L, Carter-Monroe N, Montgomery R, Alachkar N: Atypical Hemolytic Uremic Syndrome (aHUS) Recurrence Post Kidney Transplantation-A Single Center Experience. In: TRANSPLANTATION: 2014: LIPPINCOTT WILLIAMS & WILKINS 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA; 2014: 530-530.

Murakami CA, Attia D, Carter-Monroe N, Lucas GM, Estrella MM, Fine DM, Atta MG: The Clinical Characteristics and Pathological Patterns of Postinfectious Glomerulonephritis in HIV-Infected Patients. PloS one 2014, 9(10)

Lonze B, Zachary A, Magro C, Desai N, Orandi B, Dagher N, Singer A, Carter-Monroe N, Nazarian S, Segev D: Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. American Journal of Transplantation 2014, 14(2):459-465.

Bagnasco SM, Zachary AA, Racusen LC, Arend LJ, Carter-Monroe N, Alachkar N, Nazarian SM, Lonze BE, Montgomery RA, Kraus ES: Time Course of Pathologic Changes in Kidney Allografts of Positive Crossmatch HLA-Incompatible Transplant Recipients. Transplantation 2014, 97(4): 440-445.

Email ademarz@jhmi.edu
Phone (410) 614-5686

Related Websites
DeMarzo Laboratory

Tissue Microarray Core

Brady Urological Institute

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Angelo M. DeMarzo, M.D., Ph.D.

Primary Appointment in Pathology
Secondary Appointments in Oncology and Urology
Member; Graduate Program in Pathobiology

We study the molecular pathogenesis of prostate cancer development and progression including:

i) studies of etiological factors including the role of inflammation; and
ii) the molecular alterations responsible for driving the development of neoplastic precursors (prostatic intraepithelial neoplasia – PIN) as well as disease progression.

We study how MYC oncogene overexpression leads to PIN and prostate cancer and how MYC cooperates with PTEN loss in disease progression. We employ a number of molecular pathology techniques to human tissues as well mouse models, and, molecular techniques to cell culture systems.

We collaborate extensively with a number of other investigators as well as research team consisting of basic scientists/molecular biologists, epidemiologists, bioinformaticists, medical oncologists and urologists.


Nelson, W.G., De Marzo, A.M., and Isaacs, W.B. Mechanisms of disease. The molecular pathogenesis of prostate cancer: a new role for inflammation? New Eng. J. Med., 349:366-81, 2003.

De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256-69.

Koh CM, Gurel B, Sutcliffe S, Aryee MJ, Schultz D, Iwata T, Uemura M, Zeller KI, Anele U, Zheng Q, Hicks JL, Nelson WG, Dang CV, Yegnasubramanian S, De Marzo AM. Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. Am J Pathol. 2011 Apr;178(4):1824-34.

Xu J, Hicks JL, Park BH, Humphreys E, Partin AW, Han M, Netto GJ, Isaacs WB, De Marzo AM. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res. 2011; 17:6563-73.

Sfanos KS, Canene-Adams K, Hempel H, Yu SH, Simons BW, Schaeffer AJ, Schaeffer EM, Nelson WG, De Marzo AM. Bacterial Prostatitis Enhances 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine (PhIP)-Induced Cancer at Multiple Sites. Cancer Prev Res. 2015; 8:683-92.

Haffner MC, Weier C, Xu M, Vaghasia A, Gürel B, Gümüskaya B, Esopi DM, Fedor H, Tan HL, Kulac I, Hicks J, Isaacs WB, Lotan TL, Nelson WG, Yegnasubramanian S, De Marzo AM. Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol. 2015 Aug 31. doi: 10.1002/path.4628.

Hubbard GK, Mutton LN, Khalilia M, McMullin RP, Hicks JL, Bianchi-Frias D, Horn LA, Kulac I, Moubarek MS, Nelson PS, Yegnasubramanian S, De Marzo AM, and Bieberich CJ. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Can Res, 2015, In Press

Email cheaphy@jhmi.edu
Phone (443) 287-4730
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Christopher M. Heaphy, Ph.D.

Primary Appointment in Pathology

The overall research goal of my laboratory is to further understand the contribution of telomere biology in cancer development and progression. For a variety of human cancers (eg. prostate, breast, ovarian, brain, pancreas), new molecular biomarkers are urgently needed for improving risk assessment and for accurate prognostication of the disease to improve upon current prevention and treatment strategies. One molecular marker that may address these clinical problems is tissue-based telomere length measurements. Telomeres are nucleoprotein complexes that function to protect and stabilize the chromosomal ends by preventing chromosome fusions, masking inappropriate double strand DNA break damage signals, and inhibiting exonucleolytic degradation. In addition to assessing the translational potential of telomere length measurements, my laboratory also is working to elucidate the underlying mechanisms of tumor initiation and progression (e.g through telomere length alterations), as well as understanding how the interactions between the tumor and its' tissue microenvironment may facilitate this process.

Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Nagahashi Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK. Altered telomeres in tumors with ATRX and DAXX mutations. Science, 333:425, 2011.

Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E, Netto GJ, Epstein JI, Lotan TL, Westra WH, Shih IM, Iacobuzio-Donahue CA, Maitra A, Li QK, Eberhart CG, Taube JM, Rakheja D, Kurman RJ, Wu T, Roden RB, Argani P, De Marzo AM, Terracciano L, Torbenson M, Meeker AK. Prevalence of the Alternative Lengthening of Telomeres (ALT) telomere maintenance mechanism in human cancer subtypes. The American Journal of Pathology, 179:1608-1615, 2011.

Heaphy CM, Schreck KC, Raabe E, Mao X, Chu Q, An P, Poh W, Jiao Y, Rodriguez FJ, Odia Y, Meeker AK, Eberhart CG. A glioblastoma neurosphere line with alternative lengthening of telomeres. Acta Neuropathologica, 126:607-8, 2013.

Heaphy CM, Yoon GS, Peskoe SB, Joshu CE, Lee TK, Giovannucci E, Mucci LA, Kenfield SA, Stampfer MJ, Hicks JL, De Marzo AM, Platz EA, Meeker AK. Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death. Cancer Discovery, 3:1130-41, 2013.

Heaphy CM, Gaonkar G, Peskoe SB, Joshu CE, De Marzo AM, Lucia MS, Goodman PJ, Lippman SM, Thompson IM, Platz EA, Meeker AK. Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. The Prostate, 2015. doi: 10.1002/pros.22997.

Email tlotan1@jhmi.edu
Phone (410) 434-1003

Related Websites
Institute for Basic Biomedical Sciences

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Tamara Lotan, M.D.

Primary Appointment in Pathology; Secondary Appointment in Oncology

I am a urologic pathologist with a research laboratory focused on the role of PTEN/PI3K/mTOR signaling in epithelial development and tumorigenesis. My basic science lab works with a number of epithelial systems (prostate, breast, skin) and we are principally interested in understanding how these oncogenic signaling pathways regulate epithelial differentiation, apico-basal polarity and cell migration. Using transgenic mouse models combined with 3D culture and state-of-the-art live cell imaging techniques, our hope is that by understanding the role of this signal transduction network in epithelial embryonic development, we can help to elucidate the significance of these oncogenic signals during tumorigenesis and tumor progression.

The more translational arm of my laboratory effort is focused on validating PTEN as a potential predictive and prognostic biomarker in prostate cancer, and on defining alternative mechanisms of PTEN inactivation in prostate cancer. We also have an ongoing interest in the molecular phenotype of rare subtypes of prostate cancer, including small cell carcinoma, p63-positive prostatic carcinoma and intraductal prostatic carcinoma.


Lotan TL, Wang W,Gupta NS, Toubaji A, Haffner MC, Meeker AK, De Marzo AM, Epstein JI, and Netto GJ. ERG Gene Rearrangements are Common in Prostatic Small Cell Carcinoma. Modern Pathology. 2011; 24(6):820-8.

Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, Hicks JL, Park BH, Humphreys E, Partin AW, Han M, Netto GJ, Isaacs WB, De Marzo AM. PTEN Protein Loss by Immunostaining: Analytic Validation and Prognostic Indicator for a High Risk Surgical Cohort of Prostate Cancer Patients. Clinical Cancer Research. 2011; 17(20):6563-73.

Ghosh S, Lau H, Simons BW, Powell JD, Meyers DJ, De Marzo AM, Berman DM, Lotan TL. PI3K/mTOR Signaling Regulates Prostatic Branching Morphogenesis. Developmental Biology. 2011; 360(2):329-42.

Email ameeker@mail.jhmi.edu
Phone (410) 502-3398
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Alan K. Meeker, Ph.D.

Primary Appointment in Pathology; Secondary Appointment in Urology

Telomere Shortening in Cancer

The genesis and progression of cancer is thought to depend upon genetic instability. This is clearly seen at the chromosomal level in epithelial cancers, such as prostate and breast cancers, which show chromosomal instability as reflected by aberrations in both chromosomal number and structure, yet the molecular mechanisms responsible for chromosome destabilization during carcinogenesis and progression are largely unknown. Our lab is examining defective telomeres which appear to be an important route to chromosomal instability. Telomeres are specialized chromosomal structures consisting of terminal DNA tracts and associated binding proteins. Telomeres protect chromosome ends from fusing with other chromosome ends or other chromosomes containing DNA double strand breaks. In the absence of the telomere synthetic enzyme telomerase, telomeric DNA is subject to loss during cell division. Results from telomerase knockout mouse models indicate that telomere shortening can lead to an increased incidence of cancer in these animals, thus apparently playing a role in cancer initiation.

In close collaboration with Angelo De Marzo’s lab in the John Hopkins Pathology Department, we developed a novel quantitative fluorescence microscopy technique to measure telomere lengths directly in archival tissues, in order to find out if telomere shortening is playing a role in the initiation of human cancers. Making use of this technique in collaborative efforts with other faculty members in the Johns Hopkins Department of Pathology (Drs. Pedram Argani, Theresa Chan, Christine Iacobuzio-Donahue, Elizabeth Montgomery, Bridgette Ronnett and William Westra) we found that, indeed, telomeres are abnormally short in the vast majority of microscopic cancer precursor lesions in common epithelial cancers, including those of the bladder, breast, cervix, colon, esophagus, gall bladder, oral cavity and prostate.

Telomere length abnormalities appear to be one of the earliest and most prevalent molecular genetic alterations acquired in the multi-step process of tumorigenesis. These findings support a model whereby telomere dysfunction induces a mutator phenotype that acts at the chromosomal and sub-chromosomal levels to accelerate tumor development. We hypothesize that pre-malignant lesions displaying short telomeres are poised on the edge of genetic instability, and are therefore at risk of progressing on to fully invasive carcinomas.

Practically speaking, telomere shortening may have utility in cancer diagnosis, as well as an intermediate endpoint marker in chemoprevention studies. In addition, if telomere shortening is indeed playing a causal role in cancer initiation, then it represents a valid prevention target in its own right.

Telomere Shortening in Aging

Cells normally respond to short telomeres by halting their cell division activities or by committing cellular suicide (apoptosis). It is thought that these responses evolved in long-lived multicellular organisms to prevent the outgrowth of potentially cancerous cell populations. It has been postulated that a loss of division potential due to telomere shortening in proliferating tissues might contribute to certain age-related pathologies, such as the decreased wound healing seen in the elderly. This theory has been difficult to evaluate, as previous methods of telomere length measurement only gave information on the average telomere length of a large number of cells combined.

We believe that our telomere length assay, which features single cell resolution, can be used to test the hypothesized link between telomere shortening and human aging.


Meeker, A.K., Gage, W.R., Simon, I., Coffman, J.R., Platz, E.A., March, G., and DeMarzo, A.M. Telomere Length Assessment in Human Archival Tissues: Combined Telomere Fluorescent in Situ Hybridization and Immunostaining. American Journal of Pathology. 160:1259-1268, 2002.

Meeker, A.K., Hicks, J.L., Platz, E.A., March, G.E., Bennett, C.J., and De Marzo, A.M. Telomere Shortening is an Early Somatic DNA Alteration in Human Prostate Tumorigenesis. Cancer Research. 62:6405-6409, 2002.

Montgomery, E.A., Argani, P., Hicks, J.L., DeMarzo, A.M., and Meeker, A.K. Telomere Lengths of Translocation Associated and Non-Translocation Associated Sarcomas Differ Dramatically. American Journal of Pathology. 164:1523-1529, 2004.

Meeker, A.K., Hicks, J.L., Iacobuzio-Donahue, C.A., Montgomery, E.A., Westra, W.H., Chan, T.Y., Ronnett, B.M., and DeMarzo, A.M. Telomere Length Abnormalities Occur Early in the Initiation of Epithelial Carcinogenesis. Clinical Cancer Research. 10:3317-3326, 2004.

Meeker, A.K., Hicks, J.L., Gabrielson, E., Strauss, W.M., De Marzo, A.M., and Argani, P. Telomere Shortening Occurs in Subsets of Normal Breast Epithelium as well as In Situ and Invasive Carcinoma. American Journal of Pathology. 164:925-935, 2004.

Email hmiyamo1@jhmi.edu
Phone (410) 614-1442
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Hiroshi Miyamoto, M.D., Ph.D.

Primary Appointment in Pathology; Secondary Appointment in Urology

My research interests include molecular biology of steroid hormone receptors in genitourinary tumors. Specifically, we have been investigating the role of androgen receptor signals in the development and progression of bladder cancer. Epidemiological and clinical data indicate that men have a substantially higher risk of bladder cancer, whereas women tend to present with more aggressive tumors. The underlying mechanisms of how androgens regulate bladder tumorigenesis and tumor outgrowth will offer explanations for these gender-specific differences in cancer incidence and aggressiveness. We also assess the effects of new classes of androgen receptor antagonists on prostate cancer progression and characterize novel androgen receptor coregulators in prostate cancer cells.

Izumi K, Li Y, Ishiguro H, Zheng Y, Yao JL, Netto GJ, Miyamoto H. Expression of UDP-glucuronosyltransferase 1A in bladder cancer: Association with prognosis and regulation by estrogen. Mol Carcinogen 54(4): 314-324, 2014.

Li Y, Ishiguro H, Kawahara T, Kashiwagi, E, Izumi K, Miyamoto H. Loss of GATA3 in bladder cancer promotes cell migration and invasion. Cancer Biol Ther 15(4): 428-435, 2014.

Ishiguro H, Kawahara T, Zheng Y, Kashiwagi E, Li Y, Miyamoto H. Differential regulation of bladder cancer growth by various glucocorticoids: corticosterone and prednisone inhibit cell invasion without promoting cell proliferation or reducing cisplatin cytotoxicity. Cancer Chemother Pharmacol 74(2): 249-255, 2014.

Kawahara T, Kashiwagi E, Ide H, Li Y, Zheng Y, Miyamoto Y, Netto GJ, Ishiguro H, Miyamoto H. Cyclosporine A and tacrolimus inhibit bladder cancer growth through down-regulation of NFATc1. Oncotarget 6(3): 1582-1593, 2015.

Ishiguro H, Izumi K, Kashiwagi E, Zheng Y, Li Y, Kawahara T, Miyamoto H. Semenogelin I promotes prostate cancer cell growth via functioning as an androgen receptor coactivator and protecting against zinc cytotoxicity. Am J Cancer Res 5(2): 738-747, 2015.

Kawahara T, Shareef HK, Aljarah AK, Ide H, Li Y, Kashiwagi E, Netto GJ, Zheng Y, Miyamoto H. ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression. Oncotarget 2015 (in press).

Email gnetto1@jhmi.edu
Phone (410) 955-5082
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Georges J. Netto, M.D.

Primary Appointment in Pathology; Secondary Appointment in Urology and Oncology

My primary research interest and contributions have focused on the evaluation of molecular biomarkers that can serve as potential markers of detection, prognosticators and or therapeutic targets in the management of urologic malignancies.

1- TMPRSS2-ERG Fusion in Prostate Cancer: My initial work helped characterize the incidence and the role of TMPRSS2-ERG fusion as a prognostic biomarker in prostate adenocarcinoma including ductal adenocarcinoma, small cell carcinoma and “insignificant” prostate carcinoma in large cohorts of well annotated radical prostatectomy patients using tissue microarrays, Interphase cytogenetic FISH and immuno-histochemistry (IHC) Our group was among the earliest to establish the utility IHC as a surrogate for detecting the translocation and ERG overexpression. These contributions have facilitated the utilization of this biomarker in routine needle biopsy specimens together with PTEN (see below), as an adjunct to tumor grade and extent, in clinical management decision-making. 2- mTOR Pathway in Urologic Malignancies: Using high throughput tissue microarrays, my team helped elucidate the expression status of several key members of mTOR pathway in urologic malignancies. These included describing the role of PTEN loss of expression as a marker of early recurrence following radical prostatectomy. In addition, our work on muscle invasive and non muscle invasive bladder cancer and its variant histologies (eg. Plasmocytoid variant); clear cell and Chromophobe renal cell carcinomas ; and penile carcinoma have helped characterized the prognostic role of mTOR pathway members in these prevalent malignancies and the potential role of the pathway as a target of therapy 3- TERT promoter mutations in Bladder Cancer: Our group has been fortunate to make a very important discovery related to the high incidence of TERT gene promoter mutation in muscle invasive bladder cancer and upper tract urothelial carcinoma (over 70% of tumors). We then illustrated that TERT promoter mutation is the most common mutation to occur in all precursor lesions of invasive bladder cancer including PUNLMP, low and high grade non invasive papillary carcinoma and CIS. Most importantly, we were the first to show the utility of detecting this mutation in urine samples as an early marker of disease recurrence in patients under surveillance. We have since expanded our mutation panel and expanded the applicability of this biomarker to early detection/screening setting in addition to disease surveillance. Our work has promise to impact the way we clinically detect and follow up bladder cancer patients leading to significant decrease in in the need for repeated invasive and costly cystoscopy procedures.



Selected peer reviewed publications:

a) Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.Proc Natl Acad Sci U S A. 2013; PMCID: PMC3625331

b) Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg MP, Bivalacqua T, Allaf ME, Springer S, Wang Y, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N, Netto GJ. TERT Promoter Mutations Occur Early in Urothelial Neoplasia and are Biomarkers of Early Disease and Disease Recurrence in Urine. Cancer Res. 2013; PMCID: PMC3966102

c) Zheng X, Zhuge J, Bezerra SM, Faraj SF, Munari E, Fallon JT, Yang XJ, Argani P, Netto GJ, Zhong M. High Frequency of TERT mutations in Small Cell Carcinoma of Bladder. J Hematol Oncol. 2014 Jul 20;7:47.PMCID: PMC4223615.

d) Toubaji A, Albadine R, Meeker AK, Isaacs WB, Lotan T, Haffner MC, Chaux A, Epstein JI, Han M, Walsh PC, Partin AW, De Marzo AM, Platz EA, Netto GJ. Increased gene copy number of ERG on chromosome 21 but not TMPRSS2-ERG fusion predicts outcome in prostatic adenocarcinomas. Mod Pathol 2011; Nov;24(11):1511-20. PMCID: PMC3360950

e) Lotan TL, Toubaji A, Albadine R, Latour M, Herawi M, Meeker AK, DeMarzo AM, Platz EA, Epstein JI, Netto GJ. TMPRSS2-ERG gene fusions are infrequent in prostatic ductal adenocarcinomas. Mod Pathol 2009; 22(3):359-65. PMCID: PMC3484370

f) Albadine R, Latour M, Toubaji A, Haffner M, Isaacs WB, A Platz E, Meeker AK, Demarzo AM, Epstein JI, Netto GJ. TMPRSS2-ERG gene fusion status in minute (minimal) prostatic adenocarcinoma. Mod Pathol 2009; 22(11):1415-22 PMCID: PMC3354529

g) Chaux A, Albadine R, Toubaji A, Hicks J, Meeker A, Platz EA, De Marzo AM, Netto GJ. Immunohistochemistry for ERG expression as a surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. Am J Surg Pathol 2011; Jul;35(7):1014-20. PMCID: PMC3505676

Schultz L, Albadine R, Hicks J, Jadallah S, DeMarzo AM, Chen Y-B,Neilsen ME, Gonzalgo ML, Sidransky D, Schoenberg M, Netto GJ. Expression status and prognostic significance of mTOR pathway members in urothelial carcinoma of urinary bladder following cystectomy. Cancer 2010;116(23):5517-26. PMCID:PMC3568488

Schultz L, Chaux A, Albadine R, Hicks J, Kim JJ, De Marzo AM, Allaf ME, Carducci MA, Rodriguez R, Hammers H, Argani P, Reuter VE, Netto GJ. Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. Am J Surg Pathol 2011;35(10):1549-56. PMCID: PMC3505672

Chaux A, Peskoe SB, Gonzalez-Roibon N, Schultz L, Albadine R, Hicks J, De Marzo AM, Platz EA, Netto GJ. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod Pathol. 2012 Nov;25(11):1543-9. PMCID: PMC4380219

Chaux A, Munari E, Cubilla AL, Hicks J, Lecksell K, Burnett AL, Netto GJ. Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases.Histopathology. 2014;64(6):863-71.PubMed PMID: 24279699.

For a complete list of publications please refer to:

Email lracusen@jhmi.edu
Phone (410) 955-2386
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Lorraine C. Racusen, M.D.

Primary Appointment in Pathology

The focus of our research is on injury to the kidney. We are also studying morphologic aspects of native kidney and renal allograft injury and rejection, utilizing in-house biopsies and consultant cases, and computerized morphometric techniques. Current projects include pathologic correlates of antibody mediated rejection, assessment of chronic changes in renal allografts, and urinary molecule markers of renal allograft rejection. We are also collaborating with colleagues in nephrology to characterize animal models of acute and chronic renal injury.

Messias NC, Eustace J, Zachary AA, Tucker PC, Charney D, Racusen LC. Cohost study of the prognostic significance of acute transplant glomerulitisin acutely rejecting renal allografts. Transplantation 74: 655-60, 2001.

Solez K, Racusen LC. Role of renal biopsy in acute renal failure. Contrib. Nephrol. 132: 68-75, 2001.

Racusen LC, Solez K, Colvin R. Fibrosis and atrophy in the renal allograft - Interim report and new directions. Am J Transplan 2:203-6, 2002

Racusen LD, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - An addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 3:708-14, 2003

Email ksfanos@jhmi.edu
Phone (443) 287-4592

Related Websites
DeMarzo Laboratory

The Sfanos Lab

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Karen S. Sfanos, Ph.D.

Primary Appointment in Pathology

The Sfanos lab focuses on the study of human prostate cancer, with a particular emphasis on cancer prevention strategies as well as the etiological factors which may contribute to prostate cancer initiation and/or progression. We are specifically interested in agents that may lead to chronic prostatic inflammation, such as bacterial infections and prostatic concretions called corpora amylacea. Our work is based on the hypothesis that inflammation plays a key role in the development of the proposed “risk factor lesions” to human prostate cancer, i.e., proliferative inflammatory atrophy (PIA) and high grade prostatic intraepithelial neoplasia (PIN). Our previous studies have demonstrated the presence of multiple microbial species in the prostate of cancer patients and, importantly, many of the organisms identified are consistent with genera associated with inflammation-associated conditions including bacterial prostatitis and/or urinary tract infections. Dr. Sfanos works very closely with both genitourinary pathologists as well as epidemiologists in an effort to correlate discoveries in the laboratory with prostate cancer risk as well as disease pathology.


Sfanos K.S., Bruno T.C., Maris C.H., Xu L., Thoburn C.J., De Marzo A.M., Meeker A.K., Isaacs W.B., Drake C.G. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clinical Cancer Research, 14:3254-3261, 2008.

Sfanos K.S., Wilson B.A., De Marzo A.M., Isaacs W.B. Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer. Proceedings of the National Academy of Sciences (PNAS) U.S.A., 106:3443-3448, 2009.

Aloia A.L., Sfanos K.S.*, Isaacs W.B., Zheng Q., Maldarelli F., De Marzo A.M., Rein A. XMRV: A new virus in prostate cancer? Cancer Research, 70:10028-10033, 2010.

Shinohara D.B., Vaghasia A., Yu S-H., Mak T.N., Brüggemann H., Nelson W.G., De Marzo A.M., Yegnasubramanian S., Sfanos K.S. A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. Prostate, 73(9):1007-1015, 2013.

Sfanos K.S., Canene-Adams K., Hempel H., Yu S.-H., Simons B.W., Schaeffer A.J., Schaeffer E.M., Nelson W.G., De Marzo A.M. Bacterial prostatitis enhances 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced cancer at multiple sites. Cancer Prevention Research, Online AOP, 2015. doi: 10.1158/1940-6207

Yu S.-H., Zheng Q., Esopi D., Luo J., Macgregor-Das A., Antonarakis E.S., Vessella R., Morrissey C., De Marzo A.M., Sfanos K.S. A paracrine role for IL-6 in prostate cancer patients: Lack of production by primary or metastatic tumor cells. Cancer Immunology Research, Online AOP, 2015. doi: 10.1158/2326-6066


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