Markus Graefen

University Medical Center Hamburg - Eppendorf, Hamburg, Hamburg, Germany

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Publications (604)2098.53 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To date, evidence on active surveillance (AS) is restricted to protocol-based studies and the current practice pattern outside medical centers is unknown.
    Der Urologe. Ausg. A. 11/2014;
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    ABSTRACT: BACKGROUND An increased tumor volume threshold (<2.5 ml) is suggested to define insignificant prostate cancer (iPCa). We hypothesize that an increasing tumor volume within iPCa patients increases the risk of biochemical recurrence (BCR) after radical prostatectomy (RP).METHODS We relied on RP patients treated between 1992 and 2008. Multivariable Cox regression analyses predicting BCR within patients harboring favorable pathological characteristics (≤pT2, pN0/Nx, Gleason 3 + 3). Kaplan–Meier analysis was performed for BCR-free survival within iPCa patients (≤pT2, pN0/Nx, Gleason 3 + 3, tumor volume: <0.5 vs. 0.5–2.49 ml).RESULTSFrom 1,829 patients, 141 (7.7%) and 310 (16.9%) harbored iPCa (tumor volume: <0.5 vs. 0.5–2.49 ml), respectively. Of those, 21 (14.9%) versus 31 (10.0%) had PSA >10 ng/ml. Tumor volume achieved independent predictor status for BCR. Specifically, iPCa patients with increasing tumor volume (0.5–2.49 ml) were at higher risk of BCR after RP than those with tumor volume <0.5 ml (HR: 8.8, 95% CI: 1.2–65.9, P = 0.04). Kaplan–Meier analysis recorded superior BCR-free survival in iPCa patients with lower tumor volume (<0.5 ml) (log-rank P = 0.009). The 10-year cancer-specific death rate was 0 versus 0.5%.CONCLUSIONS Contemporary iPCa definition incorporates intermediate and high-risk patients (PSA: 10–20 and >20 ng/ml). Despite most favorable pathological characteristics, iPCa patients are not devoid of BCR after RP. Moreover, iPCa patients were at higher risk of BCR, when increasing tumor volume up to 2.49 ml was at play. Taken together the contemporary concept of iPCa is suboptimal. Especially, an increased tumor volume threshold for defining iPCa cannot be recommended according to our data. Clinicians might take these considerations into account during decision-making process. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 10/2014; · 3.84 Impact Factor
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    ABSTRACT: Shear wave elastography (SWE) allows cancer detection by using focused ultrasound pulses for locally deforming tissue. These differences in tissue elasticity and stiffness are increasingly used in breast cancer imaging and also help detect potential tumor lesions within the prostate.
    The Journal of Urology 09/2014; · 3.75 Impact Factor
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    ABSTRACT: Open radical retropubic prostatectomy (RRP) in obese patients (BMI ≥30) is associated with increased perioperative morbidity. The aim of the study was to evaluate the possible benefit of DaVinci robotic-assisted laparoscopic prostatectomy (RARP) compared to RRP in obese patients.
    Der Urologe. Ausg. A. 09/2014;
  • European Urology Supplements 09/2014; 13(3):12–13. · 3.37 Impact Factor
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    ABSTRACT: Background:Pelvic lymph node dissection in patients undergoing radical prostatectomy for clinically localised prostate cancer is not without morbidity and its therapeutical benefit is still a matter of debate. The objective of this study was to develop a model that allows preoperative determination of the minimum number of lymph nodes needed to be removed at radical prostatectomy to ensure true nodal status.Methods:We analysed data from 4770 patients treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2011 from eight academic centres. For external validation of our model, we used data from a cohort of 3595 patients who underwent an anatomically defined extended pelvic lymph node dissection. We estimated the sensitivity of pathological nodal staging using a beta-binomial model and developed a novel clinical (preoperative) nodal staging score (cNSS), which represents the probability that a patient has lymph node metastasis as a function of the number of examined nodes.Results:In the development and validation cohorts, the probability of missing a positive lymph node decreases with increase in the number of nodes examined. A 90% cNSS can be achieved in the development and validation cohorts by examining 1-6 nodes in cT1 and 6-8 nodes in cT2 tumours. With 11 nodes examined, patients in the development and validation cohorts achieved a cNSS of 90% and 80% with cT3 tumours, respectively.Conclusions:Pelvic lymph node dissection is the only reliable technique to ensure accurate nodal staging in patients treated with radical prostatectomy for clinically localised prostate cancer. The minimum number of examined lymph nodes needed for accurate nodal staging may be predictable, being strongly dependent on prostate cancer characteristics at diagnosis.British Journal of Cancer advance online publication, 8 July 2014; doi:10.1038/bjc.2014.311
    European Urology Supplements 07/2014; · 3.37 Impact Factor
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    ABSTRACT: Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes-such as transmembrane protease, serine 2 (TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion-and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2-ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3+4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non-androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.
    European urology. 07/2014;
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    ABSTRACT: To assess the association between blood loss, blood transfusion (BT) and biochemical recurrence (BCR)-free, metastasis-free and overall survival after radical prostatectomy (RP) in a large single-center cohort of patients. Perioperative BT at oncologic surgery has been reported to be a potential risk factor for cancer recurrence and survival in several cancer entities. Current studies addressing the relationship between BT, blood loss and BCR-free survival in prostate cancer patients are controversial and include only series with fairly small patient cohorts.
    World Journal of Urology 07/2014; · 2.89 Impact Factor
  • K Lellig, B Beyer, M Graefen, D Zaak, C Stief
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    ABSTRACT: In Europe prostate cancer is one of the most common cancers among men. The diagnostics always include a control of the prostate-specific antigen (PSA) level and examination of a representative tissue sample from the prostate. With these findings it is possible to evaluate the degree of progression of the cancer and its prognosis. Several treatment options for localized prostate cancer are given by national and international guidelines including radical prostatectomy, percutaneous radiation therapy, or brachytherapy and surveillance of the cancer with optional treatment at a later stage. For the latter treatment option, known as active surveillance, strict criteria have to be met. The advantage of active surveillance is that only patients with progressive cancer are subjected to radical therapy. Patients with very slow or non-progressing cancer do not have to undergo therapy and thus do not have to suffer from the side effects. The basic idea behind active surveillance is that some cancers will not progress to a stage that requires treatment within the lifetime of the patient and therefore do not require treatment at all. Unfortunately the criteria for active surveillance are not definitive enough at the current time leading only to a delay in effective treatment for many patients. The surveillance strategy has without doubt a high significance among the treatment options for prostate cancer; however, at the current time it lacks reliable indicators for a certain prognosis. Therefore, patients must be informed in detail about the advantages and disadvantages of active surveillance.
    Der Urologe. Ausg. A. 06/2014;
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    ABSTRACT: The cytosolic factor Saccharomyces cerevisiae-like 1 (SEC14L1) is a regulator of lipid metabolism and signaling pathways that has been suggested to play a role in cancer. To learn more about its relevance for prostate cancer, SEC14L1 expression was analyzed on a tissue microarray containing samples from 11,152 prostate cancer patients. In benign prostate glands, SEC14L1 immunostaining was absent or weak. In prostate cancer, SEC14L1 positivity was found in 80% of 9,876 interpretable tumors including 9% with strong, 38% with moderate, and 32% with weak immunostaining. SEC14L1 expression was more frequent in TMPSSR2:ERGfusion-positive (89%) than in TMPSSR2:ERG-negative cancers (73%, p < 0.0001). Comparative analysis of SEC14L1 expression in TMPSSR2:ERG positive and negative cancers suggested a different role of SEC14L1 in the two subsets: In TMPSSR2:ERG-negative cancers, strong SEC14L1 expression was associated with early prostate specific antigen (PSA) recurrence (p = 0.0270), advanced tumor stage (p = 0.0042), high Gleason score (p < 0.0001), and high preoperative PSA levels (p = 0.0035). In TMPSSR2:ERG positive cancers, strong SEC14L1 staining was linked to a prolonged recurrence-free interval (p = 0.0023) and absence of lymph node metastases (p = 0.0002). Strong associations of high SEC14L1 levels with chromosomal deletions (5q, 6q, PTEN, 3p13; p < 0,0001) and a high Ki67 Labeling index (p < 0,0001) were seen in TMPSSR2:ERG negative but not TMPSSR2:ERG positive cancers. A direct or indirect role of SEC14L1 in maintenance of genomic integrity and regulating cell proliferation may thus exclusively exist in TMPSSR2:ERG negative cancers. In conclusion, our data suggest a markedly different role of SEC14L1 in TMPSSR2:ERG-negative and TMPSSR2:ERG -positive prostate cancers.
    Human pathology 06/2014; · 3.03 Impact Factor
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    ABSTRACT: To assess postoperative complication profiles and 30-day mortality (30 dM) in older patients undergoing either laparoscopic radical nephrectomy (LRN) compared with open partial nephrectomy (OPN) or laparoscopic partial nephrectomy (LPN) for early stage renal cell carcinoma.
    Urology 06/2014; 83(6):1285-93. · 2.42 Impact Factor
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    ABSTRACT: The role of HistoScanning™ (HS) in prostate biopsy is still indeterminate. Existing literature is sparse and controversial. To provide more evidence according to that important clinical topic, we analyzed institutional data from the Martini-Clinic, Prostate Cancer Center, Hamburg.
    World Journal of Urology 05/2014; · 2.89 Impact Factor
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    ABSTRACT: Prostate cancer (PCa) screening has been substantially influenced by the clinical implementation of serum prostate-specific antigen (PSA). In this context, improvement of early PCa detection and stage migration as well as reduced PCa mortality were achieved, and up-to-date PSA represents the gold standard biomarker of PCa diagnosis together with clinical findings. Nonetheless, PSA shows weakness in discriminating between malign and benign prostatic disease or indolent and aggressive cancers. As a result, the expansion of PSA screening is extensively debated with regard to overdetection and ultimately overtreatment, keeping in mind that PCa is still the third leading cause of cancer-specific mortality in the Western male population. Consequently, today's task is to increase the accuracy of PCa detection and furthermore to allow stratification for indolent PCa that might permit active surveillance and to filter out aggressive cancers necessitating treatment. Thus, novel biomarkers, especially in combination with approved clinical risk factors (e.g., age or family history of PCa), within multivariable prediction models carry the potential to improve many aspects of PCa diagnosis and to enable risk classification in clinical practice. Multivariable models lead to superior accuracy for PCa prediction instead of the use of a single risk factor. The aim of this article was to present an overview of known risk factors for PCa together with new promising blood- and urine-based biomarkers and their application within risk models that may allow risk stratification for PCa prior to prostate biopsy. Risk models may optimize PCa detection and classification with regard to improved PCa risk assessment and avoidance of unnecessary prostate biopsies.
    World Journal of Urology 05/2014; · 2.89 Impact Factor
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    ABSTRACT: To date, evidence on active surveillance (AS) is restricted to protocol-based studies. Conversely, practice patterns outside of such protocols are unknown. The aim of this study was to capture the current AS treatment patterns for localized prostate cancer in patients managed by office-based urologists compared to patients treated at a tertiary care center. Two prospective cohorts were investigated: 361 AS arm patients of the German Hormonal treatment, Active surveillance, Radiation therapy, OP, Watchful waiting (HAROW) study, an observational health service study and 387 protocol-based AS patients treated at the Department of Urology of the Kantonsspital Aarau, Switzerland were included. Observational non-protocol HAROW versus on-protocol Kantonsspital Aarau (KSA) was compared, and active-treatment-free survival represented the primary outcome. Study population of the observational HAROW versus tertiary care protocol-based KSA cohorts differed statistically significantly regarding age (p < 0.001) and proportion of patients meeting the Chism criteria (p < 0.001). In stratified analyses, AFTS at 1 and 2 years was, respectively, 87.7 % (95 % CI 84.0-91.7) and 75.0 % (95 % CI 69.7-80.8) in HAROW patients compared to 90.8 % (95 % CI 87.8-93.9) and 75.3 % (95 % CI 70.7-80.1) for patients in the KSA cohort (p = 0.97). We demonstrate significant differences in terms of AS inclusion, surveillance and discontinuation criteria between patients managed by office-based urologists compared to their tertiary care counterparts. Interestingly, the risk of deferred active therapy was equally moderate for both groups in the short-term follow-up.
    World Journal of Urology 05/2014; · 2.89 Impact Factor
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    ABSTRACT: NY-ESO-1 has been suggested as therapeutic cancer vaccine in prostate cancer. This study was undertaken to explore the relationship of NY-ESO-1 with tumor phenotype, biochemical recurrence, and molecular subgroups in hormone-naive prostate cancers. NY-ESO-1 immunohistochemistry was analyzed on a tissue microarray containing 11,152 prostate cancer samples. Results were compared to clinically follow-up data, ERG status, and deletions on PTEN, 3p13, 5q21, and 6q15. NY-ESO-1 expression was absent in benign prostate glands. In prostate cancer, NY-ESO-1 positivity was found 8.8% of our 8,761 interpretable tumors including 5.8% with weak, 2.5% with moderate, and 0.5% with strong expression. There was a threefold higher rate of NY-ESO-1 expression in ERG fusion positive tumors than in ERG negative cancers (P < 0.0001). There was a significant association with early PSA recurrence, which was largely limited to ERG positive cancers. Within the ERG positive subgroup, high NY-ESO-1 expression was associated with early biochemical recurrence (P = 0.0002) and high Gleason grade (P < 0.0001). In ERG negative cancers, NY-ESO-1 expression was also linked to PTEN (P = 0.0012) and 6q15 deletions (P = 0.0005). Our observations indicate a tight link of NY-ESO-1 expression to ERG activation and (to a lesser extent) PTEN- and 6q15-deletions in prostate cancer. The impact of these interactions on the likelihood of response to immunotherapy is unclear. The prognostic impact of NY-ESO-1 expression is little and not independent of histologic variables. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 05/2014; · 3.84 Impact Factor
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    ABSTRACT: We compare the complication rates and length of stay (LOS) of laser transurethral resection of the prostate (L-TURP) versus electrocautery transurethral resection of the prostate (E-TURP) in a population-based cohort. L-TURP has shown enhanced intraoperative safety and equivalent efficacy relative to E-TURP in several high volume centres.
    05/2014; 8(5-6):E419-24.
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    ABSTRACT: TMPRSS2:ERG fusions, in combination with deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, have been suggested to cooperatively drive tumor progression in prostate cancer. We utilized a novel heterogeneity tissue microarray containing samples from 10 different tumor blocks of 189 prostatectomy specimens to study heterogeneity of genomic PTEN alterations in individual foci. PTEN alterations were found in 48/123 (39%) analyzable individual tumor foci, including 40 foci with deletions, 7 with deletion and rearrangement, and 1 focus with rearrangement only. PTEN was homogeneously aberrant in only 4 (8%) and heterogeneously in 44 (92%) of the foci. We found a specific sequence of molecular events from PTEN breakage followed by deletion of DNA sequences flanking the breakpoint, resulting in homozygous deletion. The observation that 16 of 19 foci with homogeneous ERG positivity had focal PTEN alterations but none of 10 foci with PTEN alterations had focal ERG positivity (P<0.0001) suggests that PTEN alterations typically develop subsequent to ERG fusions. We demonstrate a high level of intratumoral heterogeneity of PTEN alterations with deletions and rearrangements that challenges potential PTEN routine diagnosis testing in biopsies. The observation that PTEN alterations develop subsequent to ERG fusion strongly suggests that ERG expression may directly drive development of PTEN aberrations.Modern Pathology advance online publication, 25 April 2014; doi:10.1038/modpathol.2014.70.
    Modern Pathology 04/2014; · 5.25 Impact Factor
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    ABSTRACT: The objectives of the study were to describe a novel score (safe-R), combining information on surgical margin status (SM) and extend of nerve-sparing (NS) applicable for all patients undergoing radical prostatectomy (RP), and to test the impact of our frozen-section navigated nerve-sparing approach (NeuroSAFE) on safe-R score. We retrospectively analyzed 9,635 RPs performed at our center between 2002 and 2011. Of these, 47 % were conducted with NeuroSAFE. Proportions of NS and SM status were assessed. Subsequently, a score for oncological safe NS (safe-R) was developed; Safe-R was categorized as 3 (for negative SM and bilateral NS), 2 (for negative SM and unilateral NS), 1 (for negative SM without NS), and 0 (for patients with positive SM), respectively. The impact of NeuroSAFE on safe-R was analyzed by chi-square test and confirmed by multinomial logistic regression, adjusting for preoperative risk factors. Applying NeuroSAFE resulted in enhanced safe-R score, indicating lower rates of positive SM and higher rates of NS, across all risk categories (all p < 0.001). For example in high-risk patients, NeuroSAFE resulted in lower proportions of safe-R 0 (27.6 vs. 33.6 %) and higher proportions of safe-R 3 (32.4 vs. 17.1 %, p < 0.001). Linkage between the NeuroSAFE approach and safe-R was confirmed after multinomial logistic adjustment for preoperative risk factors. All results were confirmed in a propensity-matched cohort (matched for preoperative risk factors and year of surgery, data not shown). Safe-R represents a novel tool to assess and report on oncological safe nerve-sparing in RP. NeuroSAFE is associated with enhanced safe-R scores.
    World Journal of Urology 03/2014; · 2.89 Impact Factor
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    ABSTRACT: Pretreatment tables for the prediction of pathologic stage have been published and validated for localized prostate cancer (PCa). No such tables are available for locally advanced (cT3a) PCa. To construct tables predicting pathologic outcome after radical prostatectomy (RP) for patients with cT3a PCa with the aim to help guide treatment decisions in clinical practice. This was a multicenter retrospective cohort study including 759 consecutive patients with cT3a PCa treated with RP between 1987 and 2010. Retropubic RP and pelvic lymphadenectomy. Patients were divided into pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (GS) subgroups. These parameters were used to construct tables predicting pathologic outcome and the presence of positive lymph nodes (LNs) after RP for cT3a PCa using ordinal logistic regression. In the model predicting pathologic outcome, the main effects of biopsy GS and pretreatment PSA were significant. A higher GS and/or higher PSA level was associated with a more unfavorable pathologic outcome. The validation procedure, using a repeated split-sample method, showed good predictive ability. Regression analysis also showed an increasing probability of positive LNs with increasing PSA levels and/or higher GS. Limitations of the study are the retrospective design and the long study period. These novel tables predict pathologic stage after RP for patients with cT3a PCa based on pretreatment PSA level and biopsy GS. They can be used to guide decision making in men with locally advanced PCa. Our study might provide physicians with a useful tool to predict pathologic stage in locally advanced prostate cancer that might help select patients who may need multimodal treatment.
    European Urology 03/2014; · 10.48 Impact Factor
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    ABSTRACT: To test the hypothesis that [-2]proPSA (p2PSA) and its derivates are more accurate than total-PSA (tPSA), free-PSA (fPSA) and percentage of fPSA to tPSA (%fPSA) in detecting prostate cancer (PCa) in men younger than 60 years. The analysis consisted of a nested case-control study from the PRO-psa Multicentric European Study (PROMEtheuS) project. The primary outcome was the measure of sensibility, specificity and accuracy of serum p2PSA, percentage of p2PSA to fPSA (%p2PSA) and Beckman Coulter PHI (Prostate Health Index) in men younger than 60 years of age who had undergone prostatic biopsy. The potential reduction of unnecessary biopsies and the characteristics of missing PCa were reported as secondary outcomes. Multivariate logistic regression models were complemented by predictive accuracy analysis and decision curve analysis. Over 1036 patients enrolled, 238 (22.9%) were younger than 60 years of age. Prostate cancer was found in 67 subjects (28.1%). p2PSA, %p2PSA and PHI values were significantly higher (p<0.0001) among these subjects; no differences were found for tPSA, fPSA and %fPSA values. At univariate analysis, %p2PSA (AUC: 0.704) and PHI (AUC: 0.7) were the most accurate predictors and significantly outperformed tPSA (AUC: 0.549), fPSA (AUC: 0.511) and %fPSA (AUC: 0.557) in the prediction of PCa at biopsy (p≤0.001). In multivariate logistic regression models, %p2PSA and PHI achieved independent predictor status and significantly increased the accuracy of multivariate models by 6.3% and 7.6%, respectively (p ≤0.05). PHI and %p2PSA are more accurate than the reference standard tests in predicting PCa in young men.
    BJU International 03/2014; · 3.05 Impact Factor

Publication Stats

8k Citations
2,098.53 Total Impact Points


  • 1998–2014
    • University Medical Center Hamburg - Eppendorf
      • Department of Urology
      Hamburg, Hamburg, Germany
  • 2013
    • European Molecular Biology Laboratory
      Heidelburg, Baden-Württemberg, Germany
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
    • Weill Cornell Medical College
      • Department of Urology
      New York City, New York, United States
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 2007–2013
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
  • 1997–2013
    • University of Hamburg
      • • Department of Urology
      • • Department of Pathology
      • • Institut für Ethnologie
      Hamburg, Hamburg, Germany
  • 2012
    • University of Wuerzburg
      • Department of Urology and Paediatric Urology
      Würzburg, Bavaria, Germany
    • University of Padova
      Padua, Veneto, Italy
  • 2011–2012
    • Henry Ford Health System
      Detroit, Michigan, United States
    • Institut Paoli Calmettes
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Michigan Institute of Urology
      Detroit, Michigan, United States
  • 2006–2012
    • Prostate Cancer Research Institute
      Los Angeles, California, United States
  • 2005–2012
    • Université de Montréal
      Montréal, Quebec, Canada
    • Universitätsklinikum Marienhospital Herne
      Herne, North Rhine-Westphalia, Germany
  • 2002–2012
    • Memorial Sloan-Kettering Cancer Center
      • Department of Surgery
      New York City, NY, United States
  • 2010–2011
    • Medical University of Graz
      Gratz, Styria, Austria
    • Krankenhaus Düren gem. GmbH
      Düren, North Rhine-Westphalia, Germany
    • Schön Klinik Hamburg
      Hamburg, Hamburg, Germany
    • CUNY Graduate Center
      New York City, New York, United States
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2009
    • Universitätsklinikum Freiburg
      • Institute of Pathology
      Freiburg, Lower Saxony, Germany
    • University Hospital Essen
      • Klinik für Urologie
      Essen, North Rhine-Westphalia, Germany
  • 2007–2009
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 2008
    • Charité Universitätsmedizin Berlin
      • Institute of Pathology
      Berlin, Land Berlin, Germany
  • 2003–2005
    • Karl-Franzens-Universität Graz
      Gratz, Styria, Austria