Edward M Schaeffer

Johns Hopkins Medicine, Baltimore, Maryland, United States

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Publications (158)767.09 Total impact

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    ABSTRACT: Purpose: There is a clear need to improve risk stratification and identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets. Experimental design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4y). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score. Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell cycle progression (CCP) signature, and CAPRA-S). Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes.
    No preview · Article · Dec 2015 · Clinical Cancer Research
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    ABSTRACT: Objectives: To evaluate the association between the Prostate Health Index (PHI) and adverse pathology in a cohort of African-American (AA) men undergoing radical prostatectomy (RP). Methods: Eighty consecutive AA men with PSA of 2-10 ng/ml underwent measurement of PSA, free PSA (fPSA), and p2PSA prior to RP. PHI was calculated as [(p2PSA/fPSA) x (PSA)(½)]. Biomarker association with pT3 disease was assessed using logistic regression, and covariates were added to a baseline multivariable model including digital rectal examination (DRE). Biomarker ability to predict pT3 disease was measured using the area under the ROC curve (AUC). Results: Sixteen men (20%) demonstrated pT3 disease on final pathology. Mean age, PSA, and %fPSA were similar in men with and without pT3 disease (all p > 0.05), while PHI was significantly greater in men with pT3 disease (mean 57.2 vs. 46.6, p=0.04). Addition of PHI to the baseline multivariable model improved discriminative ability by 12.9% (p=0.04) and yielded greater diagnostic accuracy than models including other individual biomarkers. Conclusions: In African-American men with PSA of 2-10 ng/ml, PHI was predictive of pT3 prostate cancer and may help to identify men at increased risk of adverse pathology. Additional studies are needed to substantiate these findings and identify appropriate thresholds for clinical use.
    No preview · Article · Dec 2015 · Urology
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    ABSTRACT: Background: It remains unclear whether men selecting active surveillance (AS) are at increased risk of unfavorable longer term outcomes as compared with men who undergo immediate treatment. Objective: To compare adverse pathologic outcomes in men with favorable-risk prostate cancer who underwent delayed prostatectomy after surveillance (DPAS) to those who elected immediate prostatectomy (IRP). Design, setting, and participants: We conducted a retrospective analysis of a prospective AS registry from 2004 to 2014. From the Johns Hopkins AS program (n=1298), we identified a subset of men who underwent DPAS (n=89) and was representative of the entire cohort, not just those that were reclassified to higher risk. These men were compared with men who underwent IRP (n =3788). Outcome measurements and statistical analysis: We measured adverse pathologic features (primary Gleason pattern ≥4, seminal vesicle invasion [SVI], or lymph node [LN] positivity). Multivariable models were adjusted for age, prostate-specific antigen density, and baseline risk classification. Results and limitations: Delayed prostatectomy occurred at a median of 2.0 yr (range: 0.6-9.0) after diagnosis. The DPAS and IRP cohorts demonstrated similar proportions of men with primary Gleason pattern ≥4 (17% vs 20%; p=0.11), SVI (3.3% vs 3.2%; p=0.53), LN positivity (2.3% vs 1.2%; p=0.37), and overall adverse pathologic features (21.3% vs 17.0%; p=0.32). The adjusted odds ratio of adverse pathology was 1.33 (95% confidence interval, 0.82-2.79; p=0.13) for DPAS as compared with IRP. Limitations include a modest cohort size and a limited number of events. Conclusions: In men with favorable-risk cancer, the decision to undergo AS is not independently associated with adverse pathologic outcomes. Patient summary: This report compares men with favorable-risk prostate cancer who elected active surveillance with those who underwent immediate surgery accounting for evidence that approximately one-third of men who choose surveillance will eventually undergo treatment. Our findings suggest that men who are closely followed with surveillance may have similar outcomes to men who elect immediate surgery, but additional research is needed.
    No preview · Article · Oct 2015 · European Urology
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    ABSTRACT: Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental design: Germline ASPN D-repeat-length was retrospectively analyzed in 1600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 non-cancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 (HR=1.72, 95%CI=1.05-2.81, P=0.032) and heterozygosity for ASPN D13/14 (HR=1.86, 95%CI=1.03-3.35, P=0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR=0.44, 95%CI=0.21-0.94, P=0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression.
    No preview · Article · Oct 2015 · Clinical Cancer Research
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    ABSTRACT: Patient summary: This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships.
    No preview · Article · Oct 2015 · European Urology
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    ABSTRACT: Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1-/- mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby, SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic-invasion of prostate cancer. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: To investigate the rate of premature instrument exchange during robot assisted laparoscopic radical prostatectomy (RALRP) and robot assisted partial nephrectomy (RAPN). The majority of robotic instruments have a predetermined lifespan of 10 uses, however, it is unknown if instruments are routinely exchanged prior to 10 uses in clinical practice. We retrospectively reviewed instrument use in consecutive RALRP and RAPN cases performed by high-volume robotic surgeons at one tertiary care center between January 2011 and October 2014. The number of instruments used per case was evaluated and instances of additional instrument utilization were noted. Exchange number was compared between the first and second half of cases performed. Operative times were compared between cases with and without exchange. Student's t-test and Pearson's χ2 test were used to determine statistical significance. 3 surgeons performed 1579 RALRP procedures and 2 surgeons performed 313 RAPN procedures. During RALRP, monopolar curved scissors required exchange in 12.4% cases. Other instruments were exchanged in less than 2% of cases. Exchange rates were similar for RAPN. Only exchange of Prograsp forceps decreased with increasing surgeon experience (p=.02) and instrument exchange did not lengthen operative times (p > 0.05 for all instruments). During RALRP and RAPN, monopolar curved scissors required exchange in approximately 10% of cases, while other instruments were rarely exchanged. Robotic instrument lifetime may not uniformly be 10 uses. The pre-set lifetime of robotic instruments and/or pricing should be reevaluated. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Urology
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    ABSTRACT: Small cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small cell carcinoma from adenocarcinoma. We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small cell carcinoma and adenocarcinoma specimens. Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small cell carcinoma from prostatic adenocarcinoma in patient specimens (n=13 and 9, respectively). At the protein level cyclin D1, but not p16, was useful to distinguish small cell carcinoma from adenocarcinoma. Overall, 88% (36/41) of small cell carcinomas showed cyclin D1 loss by immunostaining compared to 2% (2/94) of Gleason score 7-10 primary adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9-10 primary adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death. Cyclin D1 loss identifies prostate tumors with small cell differentiation and may identify a small subset of adenocarcinomas with poor prognosis. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Aug 2015 · Clinical Cancer Research
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    ABSTRACT: Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer-specific mortality (p<0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p<0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    No preview · Article · Jun 2015 · European Urology
  • Debasish Sundi · Edward M. Schaeffer

    No preview · Article · May 2015 · European Urology
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    ABSTRACT: Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets. The high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (age<65) versus older (age⩾65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated age-specific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients. Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.Prostate Cancer and Prostatic Disease advance online publication, 19 May 2015; doi:10.1038/pcan.2015.22.
    No preview · Article · May 2015 · Prostate cancer and prostatic diseases
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    ABSTRACT: Dietary carcinogens, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and chronic inflammation have each been implicated as etiological agents in prostate cancer. We hypothesized that bacterial prostatitis would accelerate PhIP-induced pre-invasive lesions in the rat prostate. Male Fischer 344 rats were assigned into 4 groups: Control (untreated), PhIP (200 ppm in the diet for 20 weeks), E. coli (prostatic inoculation in week 10), or PhIP+E. coli. Study animals were monitored for a total of 52 weeks and were euthanized as necessary based on strict criteria for health status and tumor burden. Animals treated with E. coli initially developed acute and chronic inflammation in all lobes of the prostate, whereas inflammation was observed predominantly in the ventral lobe at time of death. PhIP+E. coli-treated animals exhibited a marked decrease in survival compared to PhIP-alone treated animals as a result of an increase in the number of invasive cancers that developed at multiple sites including the skin, small intestine, and Zymbal's gland. Despite their earlier mortality, PhIP+E. coli-treated animals developed an increased average number of precancerous lesions within the prostate compared to PhIP-treated animals, with a significantly increased Ki-67 index. Multiplexed serum cytokine analysis indicated an increase in the level of circulating IL-6 and IL-12 in PhIP+E. coli-treated animals. Elevated serum IL-6 levels correlated with the development of precancerous lesions within the prostate. These results suggest that bacterial infections and dietary carcinogens - two conceivably preventable cancer risk factors - may synergistically promote tumorigenesis. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · May 2015 · Cancer Prevention Research
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    ABSTRACT: Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests. To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping. We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS(+)) or SPINK1 overexpression (SPINK1(+)). Associations with clinical features and outcomes by multivariate logistic regression analysis and receiver operating curves. The m-ERG classifier showed 95% accuracy in an independent validation subset (155 samples). Across cohorts, 45% of PCas were classified as m-ERG(+), 9% as m-ETS(+), 8% as m-SPINK1(+), and 38% as triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Gene expression profiling supports three underlying molecularly defined groups: m-ERG(+), m-ETS(+), and m-SPINK1(+)/triple negative. On multivariate analysis, m-ERG(+) tumors were associated with lower preoperative serum prostate-specific antigen and Gleason scores, but greater extraprostatic extension (p<0.001). m-ETS(+) tumors were associated with seminal vesicle invasion (p=0.01), while m-SPINK1(+)/triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients (p<0.001). Clinical outcomes were not significantly different among subtypes. A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathologic differences were found among subtypes based on global expression patterns. Molecular subtyping of prostate cancer can be achieved using extra data generated from a clinical-grade, genome-wide expression-profiling prognostic assay (Decipher). Transcriptomic and clinical analysis support three distinct molecular subtypes: (1) m-ERG(+), (2) m-ETS(+), and (3) m-SPINK1(+)/triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Incorporation of subtyping into a clinically available assay may facilitate additional applications beyond routine prognosis. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    No preview · Article · May 2015 · European Urology
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    Full-text · Article · Apr 2015 · The Journal of Urology
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    ABSTRACT: Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at-risk men treated only with RP until the time of metastasis. To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making. Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified (n=3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins. Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration. Overall, 43% of the cohort (n=1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72-0.97) and 0.78 (95% CI, 0.67-0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50-0.66] and 0.70 [95% CI, 0.63-0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP). Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR. Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Apr 2015 · European Urology
  • Debasish Sundi · Edward M. Schaeffer · Ashley E. Ross

    No preview · Article · Apr 2015 · European Urology
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    Preview · Article · Apr 2015 · The Journal of Urology
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    Preview · Article · Apr 2015 · The Journal of Urology
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    Preview · Article · Apr 2015 · European Urology Supplements
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    Wesley Ludwig · Michael Gorin · Mark Ball · Edward Schaeffer · Misop Han · Mohamad Allaf

    Full-text · Article · Apr 2015 · The Journal of Urology

Publication Stats

2k Citations
767.09 Total Impact Points

Institutions

  • 2003-2015
    • Johns Hopkins Medicine
      • • Department of Pathology
      • • Department of Urology
      Baltimore, Maryland, United States
  • 2014
    • Detroit Medical Center
      Detroit, Michigan, United States
    • University of Washington Seattle
      Seattle, Washington, United States
    • Hofstra North Shore-LIJ School of Medicine
      New York, New York, United States
  • 2007-2014
    • George Washington University
      • School of Medicine and Health Sciences
      Washington, Washington, D.C., United States
  • 2005-2014
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2013
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
    • Northwestern University
      • Department of Urology
      Evanston, Illinois, United States
    • University of Alabama at Birmingham
      • Department of Surgery
      Birmingham, Alabama, United States
  • 2012
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of Miami
      • Department of Medicine
      كورال غيبلز، فلوريدا, Florida, United States
    • Case Western Reserve University
      Cleveland, Ohio, United States