André N Vis

VU University Medical Center, Amsterdamo, North Holland, Netherlands

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Publications (50)229.09 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno-histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.Modern Pathology advance online publication, 28 November 2014; doi:10.1038/modpathol.2014.154.
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    ABSTRACT: Objectives The traditional assumption of a linear relationship between serum testosterone and prostate cancer growth has been seriously challenged, as overwhelming evidence contradicts its basic principles. Luteinizing hormone–releasing hormone (LHRH) agonists are known to cause a peak in serum testosterone level in the initial weeks of treatment, and prevention of the clinical sequelae of testosterone flare by concomitant use of antiandrogens is recommended. Along the present biological concept that there appears to be a limit to the ability of androgens to stimulate prostate cancer growth, termed the saturation model, the use of antiandrogens to prevent this disease flare is questioned. The purpose of this review is to gain historical and modern evidence to provide an objective and up-to-date basis for clinical decision making. Methods and materials We performed a comprehensive research of the electronic databases PubMed and Embase until April 1, 2014. Studies with the subject of disease flare in men with prostate cancer on LHRH agonist therapy were included, as were studies that assessed the efficacy of antiandrogens to prevent this flare. Case reports were included as well. Results Overall, 25 studies considering disease flare were included: 9 randomized clinical trials with an LHRH agonist and an LHRH agonist/antiandrogen arm, 14 observational studies evaluating LHRH agonists only, and 2 case reports. The incidence of disease flare was reported between 0% and 83% owing to a wide set of clinical, biochemical, and radiological factors evaluated. In some of the randomized clinical trials, a statistically significant reduction of the incidence of disease flare by concomitant use of antiandrogens was reported. Most of these historical studies report on subjective worsening of disease symptoms as outcome measure. More objective outcome measures such as the prostate-specific antigen level did not seem to increase to higher than the baseline values. Conclusions At present, there is a lack of compelling data showing definite disease progression during the short period of testosterone flare after initiation of LHRH agonist therapy. Based on the saturation model, presence of disease flare and the need to prevent this flare by concomitant use of antiandrogens might well be a misconception.
    Urologic Oncology 08/2014; DOI:10.1016/j.urolonc.2014.04.016 · 3.36 Impact Factor
  • A.N. Vis
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    ABSTRACT: Gynaecomastie en pijn in de tepels (mastalgie) zijn frequent voorkomende bijwerkingen van bicalutamide 150 mg monotherapie. Profylactische tepelbestraling wordt in veel ziekenhuizen in Nederland toegepast. De door bicalutamide veroorzaakte gynaecomastie wordt vaak als mild ervaren en de mastalgie is meestal van voorbijgaande aard. Hoewel uit meerdere gerandomiseerde studies een statistisch significante afname van de frequentie van deze bijwerkingen blijkt, persisteert in de helft van de gevallen de gynaecomastie/mastalgie. Derhalve bestaat er twijfel over de effectiviteit en de klinische noodzaak tot profylactische tepelbestraling. Het anti-oestrogeen tamoxifen heeft een zeer hoge effectiviteit bij de preventie en behandeling van door bicalutamide veroorzaakte gynaecomastie/mastalgie. Bij patiënten die onder bicalutamide monotherapie uiteindelijk toch cosmetische bezwaren aangeven van hun gynaecomastie en/of bezwaarlijke mastalgie ervaren, kan gestart worden met het anti-oestrogeen tamoxifen. Momenteel zijn er geen aanwijzingen dat het medicament een negatieve invloed heeft op het oncologisch beloop van prostaatkanker. Abstract Profylactic radiotherapy of the nipple buds for bicalutamide use. Any Clinical value? Gynaecomasthia and breast pain (masthalgia) are frequently noticed side effects of bicalutamide 150 mg monotherapy. Prophylactic radiotherapy of the nipplebuds is applied in many hospitals in the Netherlands. Gynaecomasthia caused by bicalutamide is mostly experienced as mild, and the masthalghia is mostly self limiting. Despite the finding that several randomised clinical trials showed a statistically significant decrease in the relative amount of side effects, in half of the cases the gynaemasthia and/or masthalgia persists. Therefore, concerns exist over the effectivity and clinical need of prophylactic radiation of the nipple buds. The anti-estrogen drug tamoxifen has high effectivity in the prevention and treatment of gynaecomasthia/masthalgia caused by bicalutamide. In those patients on bicalutamide monotherapy who experience cosmetic complaints of their gynaecomasthia and/or suffer from masthalgia, tamoxifen may be prescibed. At present, there is no evidence that tamoxifen has a negative impact on the oncological outcome of prostate cancer.
    06/2014; 4(4):13-17. DOI:10.1007/s13629-014-0061-0
  • 05/2014; 4(3):74-74. DOI:10.1007/s13629-014-0029-0
  • European Urology Supplements 04/2014; 13(1):e734. DOI:10.1016/S1569-9056(14)60723-5 · 3.37 Impact Factor
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    ABSTRACT: OBJECTIVE: To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer. MATERIALS AND METHODS: A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m2), overweight (BMI 25-30 kg/m2), or obese (BMI >30 kg/m2). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated. RESULTS: The median serum testosterone concentration of the patients with a BMI <25 kg/m2 was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m2 had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m2 had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men. CONCLUSION: Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.
    Urology 02/2013; 81(5). DOI:10.1016/j.urology.2013.01.014 · 2.13 Impact Factor
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    ABSTRACT: PURPOSE: Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings. METHODS: In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily. RESULTS: Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth. CONCLUSIONS: Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.
    World Journal of Urology 10/2012; DOI:10.1007/s00345-012-0972-4 · 3.42 Impact Factor
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    ABSTRACT: Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over-treatment of non-progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head-to-head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub-stage according to a new system (micro-invasive [T1m] and extensive-invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub-group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub-stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision-making in T1 BC. •  To evaluate the prognostic significance of four molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette-Guérin. •  The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed. •  T1 sub-staging was done in two separate rounds, using a new system that identifies micro-invasive (T1m) and extensive-invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c). •  The EORTC risk scores for recurrence and progression were calculated. •  Uni- and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub-stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki-67, P53, P27 expression). •  The median follow-up was 6.5 years. Forty-two patients remained recurrence-free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients. •  In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub-stage (T1m/T1e) and carcinoma in situ (CIS) were significant. •  Molecular markers were significant in univariable and in multivariable analyses for recurrence. •  EORTC risk scores were not significant. •  CIS, female gender and sub-stage (T1m/T1e) were the most important variables for progression. •  The additional value of molecular markers was modest. •  Sub-stage (T1m/T1e) could potentially be incorporated in future tumour-node-metastasis classifications.
    BJU International 03/2012; 110(8):1169-76. DOI:10.1111/j.1464-410X.2012.10996.x · 3.13 Impact Factor
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    ABSTRACT: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range. Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone-releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined. All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group. Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined.
    The Journal of urology 03/2012; 187(5):1601-6. DOI:10.1016/j.juro.2011.12.063 · 3.75 Impact Factor
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    ABSTRACT: Owing to inconsistencies and methodological differences, the present peer-reviewed literature lacks conclusive data on the intraprostatic levels of androgens, in particular dihydrotestosterone (DHT), in untreated benign prostatic hyperplasia (BPH) and prostate cancer. To date, no difference has been shown between DHT concentrations in normal prostatic tissue and BPH, and nor has a difference been shown in DHT concentrations between the histologically distinct regions of the prostate. Recent literature has also failed to show a consistent difference in androgen level between BPH and prostate cancer. The role of intraprostatic DHT in the pathogenesis of BPH and in the initiation and progression of prostate cancer thus remains to be established. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels may lead to more optimized and more personalized forms of treatment, and probably new therapeutic targets as well.
    BJU International 01/2012; 109(2):176-82. DOI:10.1111/j.1464-410X.2011.10651.x · 3.13 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well.
    BJU International 01/2012; 109(2):183-8. DOI:10.1111/j.1464-410X.2011.10652.x · 3.13 Impact Factor
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    ABSTRACT: Stage pT1 bladder cancer comprises a heterogeneous group of tumors for which different management options are advocated. FGFR3 mutations are linked to favorable (low grade/stage) pTa bladder cancer while altered P53 is common in cases of high grade, muscle invasive (pT2 or greater) bladder cancer. We determined the frequency of FGFR3 mutations and P53 alterations in patients with pT1 bladder cancer and correlated these data to histopathological variables and clinical outcomes. We included 132 patients with primary pT1 bladder cancer from a total of 2 academic centers. A uropathologist reviewed the slides for grade and confirmed the pT1 diagnosis. FGFR3 mutation status was examined by SNaPshot® analysis and P53 expression was determined by standard immunohistochemistry. Kaplan-Meier and multivariate analyses were used to assess progression. FGFR3 mutations were detected in 37 of 132 pT1 bladder cancer cases (28%) and altered P53 was seen in 71 (54%). Only 8% of patients had the 2 molecular alterations (p = 0.001). FGFR3 mutation correlated with lower grade and altered P53 correlated with high grade pT1 bladder cancer. Median followup was 6.5 years. FGFR3 mutation status and carcinoma in situ were significant for predicting progression on univariate and multivariate analyses but P53 status was not. FGFR3 mutations selectively identify patients with pT1 bladder cancer who have favorable disease characteristics. Further study may confirm that FGFR3 identifies those who would benefit from a conservative approach to the disease.
    The Journal of urology 11/2011; 187(1):310-4. DOI:10.1016/j.juro.2011.09.008 · 3.75 Impact Factor
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    11/2011; 1(7). DOI:10.1007/s13629-011-0070-1
  • The Journal of Urology 04/2011; 185(4). DOI:10.1016/j.juro.2011.02.1687 · 3.75 Impact Factor
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    ABSTRACT: The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) [1]. To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG. In this multicenter study, we included 230 patients with primary non-muscle-invasive BCa (NMIBC). Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors. Median follow-up was 8.62 yr (interquartile range: 6.6-11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% (p<0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41-74%). We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores.
    European Urology 09/2010; 58(3):433-41. DOI:10.1016/j.eururo.2010.05.043 · 12.48 Impact Factor
  • European Urology Supplements 04/2010; 9(2):49-49. DOI:10.1016/S1569-9056(10)60059-0 · 3.37 Impact Factor
  • The Journal of Urology 04/2010; 183(4). DOI:10.1016/j.juro.2010.02.1183 · 3.75 Impact Factor
  • André N Vis, Fritz H Schröder
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    ABSTRACT: The inhibition of 5alpha-reductase (5AR) blocks the synthesis of the most powerful intracellular androgen, dihydrotestosterone (DHT). The prostate has two 5AR isoenzymes (5AR1 and 5AR2) that change in expression and cellular location during the development of prostate cancer and tumour progression. The objective of this review is to provide an understanding of the pharmacological properties and the potential clinical benefits of 5AR inhibition. We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies. 5AR1 expression increases with increasing aggressiveness and extension of malignant prostatic disease. Conversely, 5AR2 expression decreases from benign prostatic tissue to localized prostate cancer. The efficacy of 5AR2 monotherapy with finasteride alone or in combination with an androgen receptor antagonist on more final outcome measures seems to be limited. Combining an androgen receptor antagonist with a 5AR inhibitor in patients with asymptomatic, locally advanced or recurrent prostate cancer might be a reasonable first therapeutic hormonal approach. As plasma testosterone levels are maintained, beneficial effects on quality of life, potency and sexual function are expected. From studies on the dual 5AR inhibitor dutasteride, the drug produces a biochemical response in some men who progressed under androgen-deprivation therapy, and is generally well tolerated. Achieving more potent suppression of intracellular DHT synthesis by 5AR inhibition is expected to provide clinical benefit to patients. Previous studies have shown that 5AR inhibition, by dutasteride in particular, halts/delays the progression of disease, and might even cause regression of disease in patients with advanced prostate cancer.
    BJU International 08/2009; 104(9):1191-7. DOI:10.1111/j.1464-410X.2009.08743.x · 3.13 Impact Factor
  • André N Vis, Fritz H Schröder
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    ABSTRACT: Knowledge of the molecular and cellular changes that occur during the transition of hormone-naïve to castration-resistant prostate cancer (CRPC) is increasing rapidly. This might provide a window of opportunity for (future) drug development, and for treating patients with these potential devastating states of disease. The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen-deprived conditions. We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC. CRPC remains dependent on a functional androgen receptor (AR), AR-mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen-independent AR functioning, and have altered co-activator and co-repressor gene and protein expression. Furthermore, CRPCs might have the ability to synthesise androgens de novo from available precursors through a renewed and up-regulated synthesis of steroid-hormone converting enzymes. Blocking of enzymes key to de novo androgen synthesis could be an alternative means to treat patients with advanced and/or metastatic disease. In CRPC, prostate cancer cells still rely on intracellular androgens and on an active AR for growth and survival. CRPCs have gained mechanisms that enable them to use steroids from the circulation more efficiently through altered gene expression, and through a renewed and up-regulated synthesis of steroid hormone-converting enzymes. Additionally, CRPCs might synthesise AR isoforms that enable AR mediated processes independent from available androgens.
    BJU International 07/2009; 104(4):438-48. DOI:10.1111/j.1464-410X.2009.08695.x · 3.13 Impact Factor
  • The Journal of Urology 04/2008; 179(4):586-586. DOI:10.1016/S0022-5347(08)61719-X · 3.75 Impact Factor

Publication Stats

1k Citations
229.09 Total Impact Points

Institutions

  • 2009–2014
    • VU University Medical Center
      • Department of Urology
      Amsterdamo, North Holland, Netherlands
  • 2004–2014
    • Sint Franciscus Gasthuis Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2011–2013
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2005–2011
    • Erasmus MC
      • Department of Urology
      Rotterdam, South Holland, Netherlands
  • 2000–2007
    • Erasmus Universiteit Rotterdam
      • • Department of Urology
      • • Department of Pathology
      Rotterdam, South Holland, Netherlands