Alon Z Weizer

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

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Publications (174)632.4 Total impact

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    ABSTRACT: Metanephric adenoma (MA) is a rare benign renal tumor comprised of a neoplastic proliferation of primitive metanephric tubular cells. A previous study identified BRAF V600E mutations in approximately 90% of MA and found that similar BRAF exon 15 mutations are exceedingly rare in other common renal tumors, including renal cell carcinoma and oncocytoma. A recent follow-up study has validated mutation-specific immunohistochemistry (IHC) for detection of BRAF V600E mutations in a small cohort of MA. Here, we extend these findings to a larger, independent cohort of MA, demonstrating an overall 88% sensitivity and 100% specificity for BRAF V600E IHC. In addition, we report 2 cases of MA with novel BRAF exon 15 mutations, including a V600D missense mutation and a compound V600D and K601L missense mutation. Finally, we evaluate BRAF V600E IHC in a large tissue microarray cohort of common renal tumors and find no significant expression in several renal cell carcinoma subtypes. These data support a role for BRAF V600E IHC in diagnostically challenging cases of MA and expand the spectrum of BRAF exon 15 mutations in this uncommon but unique renal neoplasm.
    The American journal of surgical pathology. 01/2015;
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    ABSTRACT: Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next-generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high-grade papillary urothelial carcinomas (UCs), with one tumor harboring an underlying invasive component. NGS of 409 cancer-related genes was performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) blocks representing each papillary tumor (n = 5), the invasive component of one tumor, and matched normal tissue. We identified nine unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity. Copy number and loss of heterogeneity (LOH) profiles were similar in all six carcinomas; however, the invasive carcinoma component uniquely showed focal CDKN2A loss and chromosome 9 LOH and did not harbor gains of chromosomes 5p or X that were present in the other tumor samples. Phylogenetic analysis supported the invasive component arising from a shared progenitor prior to the outgrowth of cells in the non-invasive tumors. Results were extended to three additional cases of upper tract UC with paired non-invasive/invasive components, which identified driving alterations exclusive to both non-invasive and invasive components. Lastly, we performed targeted RNA sequencing (RNAseq) using a custom bladder cancer panel, which confirmed gene expression signature differences between paired non-invasive/invasive components. The results and approaches presented here may be useful in understanding the clonal relationships in multifocal cancers or paired non-invasive/invasive components from routine FFPE specimens.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2014; · 2.56 Impact Factor
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    ABSTRACT: The significance of a positive UroVysion FISH assay is uncertain in patients with normal cystoscopy. This multicenter study evaluates the clinical significance of a positive FISH assay in patients with no visible tumor and excluding those with a positive cytology. A multi-institutional, retrospective study of patients with a history of urothelial carcinoma of the bladder identified 664 patients with a FISH assay after excluding those with cystoscopic evidence of a tumor and/or positive cytology. Our primary end point was cancer recurrence, defined by biopsy. Progression was defined as recurrence with a tumor stage ≥T2. Statistical analyses were performed using Fisher's exact test as a one-tailed test and Chi-square test with significance at 0.05, using SPSS(®) version 19.0 (SPSS Inc., Chicago, IL, USA). Of the 664 patients in this study, tumor stage was Ta (363, 55 %), T1 (183, 28 %), and CIS (109, 16 %) and most were high grade (440 pts, 66 %). The median follow-up was 26 months (3-104 months), and 277 (41.7 %) patients were recurred. In patients who were FISH positive, mean time to recurrence was 12.6 months, compared to 17.9 months if FISH negative (p = 0.03). In univariate analysis, atypical cytology, positive FISH, cystoscopic findings (atypical vs. normal), and previous intravesical therapy were associated with recurrence (p < 0.05). On multivariate analysis, pathologic stage, cystoscopic findings, and cytology were independently associated with recurrence (p < 0.05). Progression to ≥T2 disease occurred in 34 (5.1 %) patients in this cohort. On multivariate analysis, only initial T stage and FISH result were found to be independent predictors of progression (p < 0.05). Patients with a positive FISH and atypical cytology are more likely to recur even in the absence of visible tumor. FISH positivity may portend a higher risk for progression. These findings require prospective validation.
    World Journal of Urology 11/2014; · 3.42 Impact Factor
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    ABSTRACT: To validate the independent predictive value of Ki-67 in patients with high-grade upper tract urothelial carcinoma (UTUC). 475 patients from the international UTUC collaboration who underwent extirpative surgery for high-grade UTUC were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray (TMA) formed from this patient cohort. Ki-67 expression was assessed in a semi-quantitative fashion and considered overexpressed at a cut-off of 20%. Multivariate analyses (MVA) were performed to assess independent predictors of oncological outcomes and Harrell's C indices (HCI) were calculated for predictive models. Median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was overexpressed in 25.9% of patients. Ki-67 overexpression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ (CIS), and regional lymph node metastases. In Kaplan-Meier analyses, overexpressed Ki-67 was associated with worse recurrence-free (RFS) (HR 12.6, p<0.001) and cancer-specific survival (CSS) (HR 15.8, p<0.001). In MVA, Ki-67 was an independent predictor of RFS (HR 1.6, 95% CI 1.07-2.30, p=0.021) and CSS (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved HCI from 0.66 to 0.70 (p<0.0001) for both RFS and CSS in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for RFS and 0.81 to 0.83 (p=0.005) for CSS in our post-operative model. Ki-67 was validated as an independent prognostic predictor of RFS and CSS in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of Urology 11/2014; · 3.75 Impact Factor
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    ABSTRACT: To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC). We performed a multi-institutional review of clinical and pathologic information on patients receiving extirpative surgery for UTUC from 1990 to 2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, phosphorylated-4EBP1, phosphorylated-AKT, PTEN, HIF-1a, raptor, and cyclin D was performed on tissue microarrays from radical nephroureterectomy (RNU) specimens. Prognostic markers were identified and the significance of altered markers was assessed with the Kaplan-Meier analysis and the Cox regression analysis. Six hundred twenty patients were included. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariate analysis, PI3K (odds ratio, 1.28; P = .001) and cyclin D (odds ratio, 3.45; P = .05) were significant predictors of clinical outcomes. Cumulative marker score was defined as low risk (no altered markers or 1 altered marker) or high risk (cyclin D and PI3K altered). Patients with high-risk marker score had a significantly higher proportion of high-grade disease (91% vs 71%; P <.001), non-organ-confined disease (61% vs 33%; P <.001), and lymphovascular invasion (35% vs 20%; P = .001). The Kaplan-Meier analysis demonstrated a significant difference in cancer-specific mortality (CSM) based on the risk groups. On Cox regression multivariate analysis for CSM incorporating non-organ-confined disease, grade, lymphovascular invasion, tumor architecture, and marker score, high-risk biomarker score was an independent predictor of CSM (hazard ratio, 1.5; 95% confidence interval, 1.04-2.3; P = .03). Alterations in mTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of mTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens. Copyright © 2014 Elsevier Inc. All rights reserved.
    Urology 11/2014; 84(5):1134-40. · 2.13 Impact Factor
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    ABSTRACT: Inverted urothelial papilloma (IUP) is an uncommon neoplasm of the urinary bladder with distinct morphological features. Studies regarding the role of human papillomavirus (HPV) in the etiology of IUP have provided conflicting evidence of HPV infection. Additionally, little is known regarding the molecular alterations present in IUP or other urothelial neoplasms which might demonstrate inverted growth pattern like low-grade or high-grade urothelial carcinoma. Here, we evaluated for the presence of common driving somatic mutations and HPV within a cohort of inverted urothelial papillomas, (n = 7) noninvasive low-grade papillary urothelial carcinomas with inverted growth pattern (n = 5,) and noninvasive high-grade papillary urothelial carcinomas with inverted growth pattern (n = 8). HPV was not detected in any case of inverted urothelial papilloma or inverted urothelial carcinoma by either ISH or by PCR. Next generation sequencing identified recurrent mutations in HRAS (Q61R) in 3 of 5 inverted urothelial papillomas, described for the first time in this neoplasm. Additional mutations of Ras pathway members were detected including HRAS, KRAS, and BRAF. The presence of Ras pathway member mutations at a relatively high rate suggests this pathway may contribute to pathogenesis of inverted urothelial neoplasms. Additionally, we did not find any evidence supporting a role for HPV in the etiology of inverted urothelial papilloma.
    Human pathology 09/2014; · 2.81 Impact Factor
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    ABSTRACT: Purpose To assess the relationship between healthcare system performance on nationally endorsed prostate cancer quality of care measures and prostate cancer treatment outcomes. Methods This is a retrospective cohort study including 48,050 men from Surveillance Epidemiology and End Results – Medicare linked data who were diagnosed with localized prostate cancer between 2004 and 2009 and followed through 2010. Based on a composite quality measure, we categorized the healthcare systems in which these men were treated into 1-star (bottom 20%), 2-star (middle 60%), and 3-star (top 20%) systems. We then examined the association of healthcare system-level quality of care with outcomes using multivariable logistic and Cox regression. Results Patients who underwent prostatectomy in 3-star versus 1-star healthcare systems had a lower risk of perioperative complications (odds ratio 0.80, 95% confidence interval [CI] 0.64-1.00). However, these patients were more likely to undergo a procedure addressing treatment-related morbidity (e.g., 11.3% vs. 7.8% treated for sexual morbidity, p=0.043). Among patients undergoing radiotherapy, star-ranking was not associated with treatment-related morbidity. Among all patients, star-ranking was not significantly associated with all-cause mortality (Hazard Ratio [HR] 0.99, 95% CI 0.84-1.15) or secondary cancer therapy (HR 1.04, 95% CI 0.91-1.20). Conclusion We found no consistent associations between healthcare system quality and outcomes, which questions how meaningful these measures ultimately are for patients. Thus, future studies should focus on the development of more discriminative quality measures.
    The Journal of urology 09/2014; · 3.75 Impact Factor
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    ABSTRACT: Prostate capsule sparing and nerve sparing cystectomies are alternative procedures for bladder cancer that may reduce morbidity while achieving cancer control. However, the comparative effectiveness of these approaches has not been established. We sought to evaluate the functional and oncologic outcomes of patients undergoing these two procedures.
    The Journal of Urology 07/2014; · 3.75 Impact Factor
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    ABSTRACT: Robot-assisted radical cystectomy (RARC) is an emerging operative alternative to open surgery for the management of invasive bladder cancer. Studies from single institutions provide limited data due to the small number of patients. In order to better understand the related outcomes, a world-wide consortium was established in 2006 of patients undergoing RARC, called the International Robotic Cystectomy Consortium (IRCC). Thus far, the IRCC has reported its findings on various areas of operative interest and continues to expand its capacity to include other operative modalities and transform it into the International Radical Cystectomy Consortium. This article summarizes the findings of the IRCC and highlights the future direction of the consortium.
    Indian journal of urology : IJU : journal of the Urological Society of India. 07/2014; 30(3):314-7.
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    ABSTRACT: To determine the relationship between prostate gland and tumor volume in men undergoing radical prostatectomy (RP) for prostate cancer. We hypothesized that larger tumors within smaller prostate glands are associated with more aggressive disease characteristics.
    Urology 06/2014; · 2.13 Impact Factor
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    ABSTRACT: Papillary renal cell carcinoma (P-RCC) is the second most common type of malignant renal epithelial tumor, and can be subclassified into type 1, which demonstrates simple cuboidal low-grade epithelium, and type 2, which demonstrates pseudostratified high grade epithelium with abundant eosinophilic cytoplasm. Despite this clinically useful subclassification, P-RCCs exhibit considerable histomorphologic diversity, with many cases having features differing from classically described type 1 and type 2 tumors. To our knowledge, there has been no recent study which has methodically evaluated the histomorphologic features of a series of P-RCCs. To address this, we evaluated a cohort of P-RCCs diagnosed between 1997 and 2004 with long term clinical follow-up data (n = 56). Histomorphologic features previously described in the spectrum of type 1 and type 2 P-RCCs were recorded for each tumor, including nuclear grade, complete tumor capsule, and cytoplasmic eosinophilia, as well as several other features. The current TNM staging (AJCC 7th edition) was assigned to all cases. Histomorphologic features were diverse, demonstrating classic type 1 P-RCC and classic type 2 P-RCC morphology, and several tumors with non-classical features. Four patients in this cohort had distant metastasis. The primary tumor was equally divided between type 1 (2 cases) and type 2 (2 cases) morphology in the cases with metastasis. All P-RCC cases with metastases demonstrated presence of high nuclear grade and high tumor stage in the primary tumor. Cluster analysis using staging parameters and histomorphologic features divided tumors into two primary clusters. All primary tumors associated with metastasis were in the same cluster.
    Human pathology 06/2014; · 2.81 Impact Factor
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    ABSTRACT: Robot-assisted retroperitoneoscopic partial nephrectomy (RARPN) may be used for posterior renal masses or with prior abdominal surgery; however, there is relatively less familiarity with RARPN.
    European Urology 05/2014; · 12.48 Impact Factor
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    ABSTRACT: Preservation of renal function is the major benefit of partial over radical nephrectomy. We evaluated patients undergoing minimally invasive partial nephrectomy (MIPN) to better understand factors predicting long-term renal function.
    The Journal of Urology 05/2014; · 3.75 Impact Factor
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    ABSTRACT: To evaluate health-related quality of life (HRQL) using validated bladder-specific Bladder Cancer Index (BCI) and European Organization for Research and Treatment of Cancer Body Image scale (BIS) between open radical cystectomy (ORC) and robot-assisted radical cystectomy (RARC). This was a retrospective case series of all patients who underwent radical cystectomy. Patients were grouped based on surgical approach (open vs robot assisted) and diversion technique (extracorporeal vs intracorporeal). Patients completed BCI and BIS preoperatively and at standardized postoperative intervals (at least 2). The primary exposure variable was surgical approach. The primary outcome measure was difference in interval and baseline BCI and BIS scores in each group. The Fisher exact, Wilcoxon rank-sum, and Kruskal-Wallis tests were used for comparisons. Eighty-two and 100 patients underwent RARC and ORC, respectively. Compared with RARC, more patients undergoing ORC had an American Society of Anesthesiology score ≥3 (66% vs 45.1% RARC; P = .007) and shorter median operative time (350 vs 380 minutes; P = .009). Baseline urinary, bowel, sexual function, and body image were not different between both the groups (P = 1.0). Longitudinal postoperative analysis revealed better sexual function in ORC group (P = .047), with no significant differences between both the groups in the other 3 domains (P = .11, .58, and .93). Comparisons regarding diversion techniques showed similar findings in baseline and postoperative HRQL data, with no significant differences in the HRQL and body image domains. RARC has comparable HRQL outcomes to ORC using validated BCI and BIS. The diversion technique used does not seem to affect patients' quality of life.
    Urology 04/2014; 83(6). · 2.13 Impact Factor
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    ABSTRACT: To present the benefits and utility of tumor enucleation as an alternative technique to sharp excision during minimally invasive partial nephrectomy (MIPN). We retrospectively compared enucleation and sharp excision during MIPN, with the aim of determining benefits and limitations of enucleation in this setting. Among 602 patients undergoing MIPN at our institution, 86 and 516 underwent enucleation and sharp excision, respectively, as determined by the surgeon. The nephrometry score was greater in the enucleation vs sharp excision group (mean, 6.7 vs 6.3), but all other preoperative parameters were similar. The mean ischemia and operative times were 4 and 32 minutes shorter in the enucleation group, respectively, likely owing to less frequent entry into renal sinus (21% vs 41%) and need for tumor bed suturing (41% vs 62%), compared with those in the sharp excision group. There was no association with blood loss, positive margins, urine leak, blood transfusion, major complications, renal function, recurrence, or survival. Enucleation appears to provide the benefits of reduced surgical entry into the renal sinus, less need for tumor bed suturing, and shorter operative time, without any impact on functional or oncologic outcomes. Given favorable preoperative radiography and intraoperative findings, enucleation is a useful technique for patients undergoing MIPN.
    Urology 04/2014; · 2.13 Impact Factor
  • European Urology Supplements 04/2014; 13(1):e17–e17a. · 3.37 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e694. · 3.75 Impact Factor
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    ABSTRACT: Objectives The purpose of the RAZOR study is to compare open versus robotic radical cystectomy, pelvic lymph node dissection and urinary diversion regarding oncologic outcomes, complications and quality of life measures with a primary endpoint of 2-year progression free survival. Patients and MethodsRAZOR is a multi-institutional, randomized, non-inferior, phase 3 trial that will enroll at least 320 patients with T1-T4, N0-1, M0 bladder cancer with approximately 160 patients in both robotic and open arms at a total of 15 participating institutions.Data will be collected prospectively at each institution regarding cancer outcomes, complications from surgery and quality of life measures and then submitted to trial data management services, Cancer Research and Biostatistics (CRAB) for final analyses. Results306 patients have been randomized to date and accrual to the RAZOR trial is expected to conclude in 2014.In this study, we report RAZOR trial experimental design, objectives, data safety and monitoring and accrual update. Conclusions The RAZOR trial is a landmark study in urological oncology, randomizing T1-T4, N0-N1, M0 bladder cancer patients to open versus robotic radical cystectomy, pelvic lymph node dissection and urinary diversion.RAZOR is a multi-institutional, non-inferiority trial evaluating cancer outcomes, surgical complications and quality of life measures of open versus robotic cystectomy with a primary endpoint of 2-year progression free survival.Full data from the RAZOR trial are not expected until 2016—2017.
    BJU International 02/2014; · 3.13 Impact Factor
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    ABSTRACT: Readmissions after radical cystectomy are common, burdensome, and poorly understood. For these reasons, the authors conducted a population-based study that focused on the causes of and time to readmission after radical cystectomy. Using Surveillance, Epidemiology, and End Results-Medicare data, at total of 1782 patients who underwent radical cystectomy from 2003 through 2009 were identified. A piecewise exponential model was used to examine reasons for readmission as well as patient and clinical factors associated with the timing of readmission. One in 4 patients (25.5%) were readmitted within 30 days of discharge after radical cystectomy. Compared with patients without readmission, those readmitted were similar with regard to age, sex, and race. Readmitted patients had more complications (33.8% vs 13.9%; P < .001) and were more likely to have been discharged to skilled nursing facilities from their index admission (P < .001). The average time to readmission and subsequent length of stay were 11.5 days and 6.7 days, respectively. The majority of readmissions (67.4%) occurred within 2 weeks of discharge, 66.8% had emergency department charges, and 25.9% involved intensive care unit use. Although the spectrum of reasons for readmission varied over the 4 weeks after discharge, the most common included infection (51.4%), failure to thrive (36.3%), and urinary (33.2%) and gastrointestinal (23.1%) etiologies; 95.8% of patients had ≥ 1 of these diagnosis groups present at the time of readmission. Readmissions after radical cystectomy are common and time-dependent. Interventions to prevent and reduce the readmission burden after cystectomy likely need to focus on the first 2 weeks after discharge, take into consideration the spectrum of reasons for readmission, and target high-risk individuals. Cancer 2014. © 2014 American Cancer Society.
    Cancer 01/2014; · 5.20 Impact Factor
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    ABSTRACT: Objective: To report the long-term oncologic outcomes and survival estimates associated with MIPN, and to determine factors associated with those outcomes and survival estimates. Methods: A single-institution, retrospective review was performed on all patients undergoing MIPN for renal cell carcinoma between 1998 and 2011 with minimum 1-year follow-up. Bivariate and multivariate analyses were performed to assess associations between demographic, perioperative, and tumor factors with recurrence and survival. Survival was estimated utilizing the Kaplan-Meier method. Results: Of 417 patients undergoing MIPN, median overall and oncologic follow-up were 3.3 and 2.9 years, respectively. The mean patient age was 63 years (SD: +/- 13.4). The mean tumor size was 2.9 cm (SD: +/- 1.48). Only 6.7% of patients had a pathologic stage T2 or greater. There was only 1 cancer-related death. Estimates for overall survival at 2, 5 years and 10 years were 95.6%, 89.1% and 70.7%, respectively. Estimates for recurrence-free survival (any recurrence) at 2, 5 years and 10 years were 98.2%, 93.5% and 88.3%, respectively. On multivariate analysis, only tumor stage was associated with recurrence, and only patient age and ASA score were associated with overall survival. Technical aspects of the procedure, such as positive margins or use of enucleation, did not influence recurrence or survival. Conclusions: Cancer recurrence after MIPN, in a cohort of mostly pT1 tumors, is rare. Recurrence and overall survival are associated with non-modifiable factors rather than technical ones.
    Journal of endourology / Endourological Society 01/2014; · 1.75 Impact Factor

Publication Stats

2k Citations
632.40 Total Impact Points

Institutions

  • 2008–2014
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of Texas at Dallas
      Richardson, Texas, United States
    • Medical University of Vienna
      • Department of Urology
      Wien, Vienna, Austria
    • Keio University
      • Department of Urology
      Edo, Tōkyō, Japan
  • 1970–2014
    • University of Michigan
      • Department of Urology
      Ann Arbor, Michigan, United States
  • 2012–2013
    • Weill Cornell Medical College
      • Department of Urology
      New York City, New York, United States
  • 2011
    • Kitasato University
      • Department of Urology
      Edo, Tōkyō, Japan
  • 2009–2011
    • University of Texas Southwestern Medical Center
      • Department of Urology
      Dallas, TX, United States
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • New York Presbyterian Hospital
      New York City, New York, United States
  • 2002–2003
    • Duke University Medical Center
      • Division of Urology
      Durham, NC, United States