Markus A Kuczyk

Hannover Medical School, Hanover, Lower Saxony, Germany

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Publications (198)625.8 Total impact

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    ABSTRACT: GATA-binding proteins 1 (GATA1) and 2 (GATA2) are zinc-finger transcription factors and belong to the GATA family proteins 1-6. GATA1 interacts with the TP53 tumor suppressor gene, and both GATAs have been shown to be involved in cell growth, apoptosis, and tumorigenesis of several solid tumors. GATA1 and GATA2 expression alterations are associated with poor survival and adverse clinicopathology in prostate and colorectal cancer, while the significance and prognostic value in clear cell renal cell carcinoma (ccRCC) has not been investigated as yet. We investigated relative messenger RNA (mRNA) expression levels of GATA1 and GATA2 in 77 ccRCC and 58 paired adjacent noncancerous renal tissues by quantitative real-time reverse-transcribed PCR. Relative mRNA expression levels were determined using the ΔΔCt method. GATA1 and GATA2 expression levels were significantly decreased in tumor tissues compared with normal tissues (p < 0.001, paired t test). In univariate logistic regression analysis, decreased GATA1 and GATA2 expression levels were associated with advanced tumor disease (p = 0.005 and 0.008), positive distant metastasis (p = 0.03 and 0.001), and lymph node metastasis status (p = 0.011 and 0.038). Reduced expression levels of GATA1 and GATA2 were associated with an increased risk of disease recurrence (p = 0.005 and 0.006; hazard ratio = 0.05 and 0.21). Pairwise bivariate analysis after adjusting for clinicopathological parameters revealed relative mRNA expression of GATA1, but not GATA2, as an independent candidate prognosticator for ccRCC. Our results support that GATA1 and GATA2 are involved in ccRCC tumor biology possibly affecting tumor development and aggressiveness.
    Targeted Oncology 09/2014; · 3.46 Impact Factor
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    ABSTRACT: Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of RCC, after clear cell (ccRCC) and papillary RCC. Its lower incidence and frequent exclusion from clinical trials might be why chRCC characteristics have not been extensively studied. The aim of our study was to examine tumor characteristics and long-term prognosis of chRCC compared to ccRCC. We collected 4,210 evaluable patients subjected to surgery for chRCC (n = 176) or ccRCC (n = 4,034) at five centers in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm, and Marburg) between 1990 and 2010. Patients with chRCC were significantly younger (mean, 60.1 vs. 62.1 years) and tended to be more frequently female (43.8 vs. 36.5 %). Although Fuhrman grade and median tumor diameter were not significantly different, significantly fewer patients with chRCC than with ccRCC presented with high tumor stage or metastasis at diagnosis (18.5 vs. 43.8 %). Moreover, significantly more chRCC patients were treated with partial nephrectomy (41.5 vs. 26.2 %). Accordingly, 5-year cancer-specific survival (CSS) rates were 83.2 % for chRCC against 75.8 % for ccRCC patients (p = 0.014, log rank). However, in multivariate analysis, chromophobe subtype was not confirmed as a significant positive prognostic factor for RCC (HR 0.88, 95 % CI 0.63-1.24; p = 0.48 Cox regression). This is one of the largest studies to date showing that chRCC is associated with a significantly lower risk of locally invasive tumor growth and metastatic disease than ccRCC. We conclude that the clinical behavior of chRCC is less aggressive than that of ccRCC, independent of Fuhrman grade or tumor size.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 09/2014; · 2.68 Impact Factor
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    ABSTRACT: The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequently displays nuclear and nucleolar pleomorphism. The present study reevaluates this grading system in a series of patients with nonsarcomatoid chRCC. We identified 176 (3.6%) patients with nonsarcomatoid chRCC in a total of 4897 patients who underwent surgery for RCC at five centers in Germany between 1990 and 2010. The mean follow-up was 51.1 months. The three groups (G1 vs. G2 vs. G3/4) were comparable in terms of age, sex, tumor diameter and lymphnode metastasis. They only differed significantly in tumor stage (p = 0.01) and the incidence of synchronous visceral metastasis (p = 0.04). The 5-year cancer-specific-survival (CSS) rates were 84.4% for G1 (n = 32), 84.3% for G2 (n = 108), and 74.1% for G3/4 tumors (n = 33) (p = 0.58). Accordingly, multivariate analysis including age, sex, tumor stage and metastatic disease did not identify Fuhrman grading as an independent predictor of CSS in patients with chRCC (p = 0.4). We were able to demonstrate in a large multicenter cohort that the Fuhrman grading system does not qualify as a prognostic tool in patients with chRCC.
    Human pathology 08/2014; · 3.03 Impact Factor
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    ABSTRACT: Experimental and clinical studies have suggested a role for phosphodiesterase (PDE) isoenzymes in the control of the human lower urinary tract. This study aimed to investigate the expression of PDE isoenzymes and the effects of PDE inhibitors (PDE-Is) in isolated human urethral smooth muscle (USM). The expression of messenger ribonucleic acid (mRNA) specifically encoding for PDE isoenzymes and isoforms (1A, 1B, 1C, 2A, 4A, 4B, 4C, 4D, 5A and 11A) was analysed by means of reverse transcriptase polymerase chain reaction (RT-PCR). Using the tissue bath technique, the effects of vinpocetine (PDE1-I), erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA-HCl=MEP1) (PDE2-I), rolipram (PDE4-I), sildenafil, vardenafil and tadalafil (PDE5-Is) (0.01µM - 10µM) on the tension of USM induced by norepinephrine were investigated. The production of cyclic guanosine monophosphate (cyclic GMP) and cyclic adenosine monophosphate (cyclic AMP) was measured by means of radioimmunoassays. RT-PCR analysis revealed the expression of PDE1B, PDE1C, PDE4A, PDE4C, PDE4D, PDE5A and PDE11A. The tension induced by norepinephrine (NE) was reversed by the PDE inhibitors with the following rank order of efficacy: rolipram (mean: -39%)≥sildenafil (-35%)>vardenafil (-26%)>tadalafil (-20%)>vinpocetine (-16%)>MEP1 (-2%). The relaxing effects of the drugs were paralleled by an elevation in tissue levels of cyclic AMP and cyclic GMP. Selective inhibitors of PDE4 and PDE5 can antagonize the tension induced by alpha-adrenergic stimulation of USM. PDE inhibition might represent an interesting option to facilitate the relaxation of the human outflow region.
    European journal of pharmacology. 08/2014;
  • Yuri Tolkach, Markus Kuczyk, Florian Imkamp
    European Urology 08/2014; · 10.48 Impact Factor
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    ABSTRACT: Introduction: Over the last 20 years, basic and clinical research activities studying the male and female sexual responses have led to several pharmacological options to treat male erectile dysfunction (ED) and female arousal and orgasmic disorders. While some strategies exclusively focus on peripheral mechanisms - such as nitric oxide/cyclic GMP signaling, which is known to play a role in the control of genital vascular and nonvascular smooth muscle - others have considered the central pathways involved in mediating arousal and orgasmic functions in females as well as the induction of penile erection in males. Aside from dopaminergic agonists, drugs known to target the central melanocortin system have also been assumed to have a promising potential in the treatment of female and male sexual dysfunctions. Areas covered: The present review summarizes the achievements that have been made in the clinical development of melanocortin receptor (MCR) agonists (melanotan I, melanotan II, bremelanotide) for the treatment of symptoms of sexual arousal and orgasmic disorders in adult females and ED in males. Expert opinion: The data available at present have facilitated our understanding of how the melanocortin pathway regulates both the male and female sexual functions. Indeed the data warrant further investigation to demonstrate the impact of the activation of MCRs by specific agonists on penile erection and female arousal and orgasm function.
    Expert Opinion on Investigational Drugs 08/2014; · 4.74 Impact Factor
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    ABSTRACT: Bladder cancer (BC) represents a growing health care problem worldwide. In times of tight budgets and an aging society, new strategies for the transurethral treatment of BC are needed. Laser devices used for tumor vaporization and/or en bloc resection provide an alternative to parvenu strategies.
    World Journal of Urology 06/2014; · 2.89 Impact Factor
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    ABSTRACT: Partial nephrectomy (PN) preserves renal function and has become the standard approach for T1a renal cell carcinoma (RCC). However, there is still an ongoing debate as to which patients will actually derive greater benefit from partial than from radical nephrectomy (RN). The aim of this study was to retrospectively evaluate the impact of the type of surgery on overall survival (OS) in patients with localized RCC.
    BMC Cancer 05/2014; 14(1):372. · 3.33 Impact Factor
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    ABSTRACT: Nephron sparing surgery for renal tumors has evolved as the standard of care for resectable renal tumors. Laparoscopic partial nephrectomy (PN) has gained recognition after technical refinements were able to match the well-established criteria for open partial nephrectomy. Laparoendoscopic surgery (LESS) is one of the approaches to further minimize invasiveness of laparoscopic surgery.
    World Journal of Urology 05/2014; · 2.89 Impact Factor
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    ABSTRACT: In 2006, the German Testicular Cancer Study Group initiated an extensive evidence-based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project's effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson's χ2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second-opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice.
    Oncology Reports 04/2014; · 2.30 Impact Factor
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    ABSTRACT: Galectins are known to regulate cell differentiation and growth as well as cell adhesion and apoptosis. Galectins have been discussed as possible prognosticators for survival in renal cell cancer (RCC) and other urological tumors. They might also play an emerging role as possible new marker-proteins for RCC. In this study, we analyzed the expression of galectin-1 and galectin-3 mRNA in order to further investigate their clinical significance in RCC. Tissue samples were obtained from 106 patients undergoing surgery for RCC. The expression of galectin-1 and galectin-3 mRNA in normal kidney and corresponding cancer tissue was analyzed using quantitative real time PCR. Differences in expression levels of paired tissue samples were assessed using paired two-sample tests. Associations of relative mRNA expression levels in tumor tissues with clinical findings were analyzed using univariate logistic regression. The expression of galectin-1 (p < 0.001) and -3 (p < 0.001) mRNA were significantly higher in RCC when compared to the adjacent normal kidney tissue. For clear cell RCC, an association of male gender with higher galectin-1 and galectin-3 mRNA expression (p = 0.054, p = 0.034) was detected. For all RCCs, galectin-1 mRNA expression failed to show a significant association with advanced disease as well as a higher rate of lymph node metastases (p = 0.058, p = 0.059). The mRNA expression of galectin-1 and galectin-3 is significantly increased in RCC cancer tissue. The higher mRNA expression in tumor tissue of male patients raises the question of a functional connection between galectins and the higher prevalence of RCC in men. Associations with advanced disease might lead to new ways of identifying patients at higher risk of recurrent disease and might even facilitate early metastasectomy with curative intent.
    BMC Clinical Pathology 04/2014; 14(1):15.
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    ABSTRACT: The anti-androgen withdrawal syndrome (AAWS) can be seen in one-third of patients after discontinuation of first-generation non-steroidal anti-androgen therapy. With the introduction of new agents for anti-androgen therapy as well as alternate mechanisms of action, new therapeutic options before and after docetaxel chemotherapy have arisen (Ohlmann et al. in World J Urol 30(4):495-503, 2012). The question regarding the occurrence of an enzalutamide withdrawal syndrome (EWS) has not been evaluated yet. In this study, we assess prostate-specific antigen (PSA) response after discontinuation of enzalutamide. In total 31 patients with metastatic castration-resistant prostate cancer (mCRPC) underwent an enzalutamide withdrawal and were evaluated. Data were gathered from 6 centres in Germany. Patients with continuous oral administration of enzalutamide with rising serum PSA levels were evaluated, starting from enzalutamide withdrawal until subsequent therapy was initiated, follow-up ended or death of the patient occurred. Statistical evaluation was performed applying one-sided binomial testing using R-statistical software, version 3.0.1. Mean withdrawal follow-up was 6.5 weeks (range 1-26.1 weeks). None of the 31 patients showed a PSA decline. Mean relative PSA rise over all patients was 73.9 % (range 0.5-440.7 %) with a median of 44.9 %. If existent, an AAWS is at least very rare for enzalutamide in patients with mCRPC after taxane-based chemotherapy and does not play a clinical role in this setting. This may be attributed to the different pharmacodynamics of enzalutamide. Longer duration of therapy or a longer withdrawal interval may reveal a rare EWS in the future.
    World Journal of Urology 04/2014; · 2.89 Impact Factor
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    ABSTRACT: Transcriptional inactivation and CpG island (CGI) methylation of GATA transcription factor family members GATA3 and GATA5 have been reported for a few types of human cancer. Whether high-density CGI methylation of GATA3 or GATA5 is associated with the clinical course of patients with renal cell cancer (RCC) has not been clarified. Quantitative methylation-specific PCR assays were carried out to analyze 25 tumor cell lines including 6 RCC lines and 119 RCC and 87 adjacent normal tissues for the presence of densely methylated sequences. Methylation values were statistically compared with clinicopathological and recurrence-free survival (RFS) data for patients. Comparison of GATA3 and GATA5 methylation in different tumor cell lines revealed a marker-specific methylation characteristic with high and frequent signals for both methylation marks in RCC lines. GATA3 and GATA5 CGI relative methylation levels were found to be strongly associated with the state of metastasis (P=0.003 and P<0.001, respectively) and advanced disease (P=0.024 and P<0.001, respectively). Moreover, an independent decrease in RFS in Cox proportional hazard analysis was found for tumors exhibiting high GATA5 methylation (P<0.001, hazard ratio, 19.3; 95% confidence interval, 4.58-81.6). Epigenetic alterations in GATA family members may be associated with aggressive tumor phenotypes in RCC, and in the case of GATA5, may serve as a new independent molecular marker for aggressiveness and disease progression.
    Oncology Reports 02/2014; · 2.30 Impact Factor
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    ABSTRACT: GATA-5, a zinc-finger transcription factor and member of the GATA family proteins 1-6, is known to be involved in cellular differentiation. We recently found that tumor-specific hypermethylation of the GATA5 CpG island (CGI) occurs in renal cell carcinoma (RCC) and is associated with an adverse clinical outcome. In this study, we investigated whether epigenetic GATA5 alterations may result in changes in GATA5 mRNA expression levels and correlate with the observed prognostic impact of epigenetic changes in GATA5 in RCC. Quantitative real-time reverse-transcribed polymerase chain reaction was applied to measure relative GATA5 mRNA expression levels in 135 kidney tissue samples, including 77 clear cell RCC (ccRCC) tissues and 58 paired adjacent normal renal tissue samples. Relative GATA5 expression levels were determined using the DeltaDeltaCt method and detection of three endogenous control genes then compared to previously measured values of relative methylation. The mean relative GATA5 mRNA expression level exhibited an approximately 31-fold reduction in tumor specimens compared with corresponding normal tissues (p < 0.001, paired t-test). Decreased GATA5 mRNA expression was inversely correlated with increased GATA5 CGI methylation (p < 0.001) and was associated with shortened recurrence-free survival in ccRCC patients (p = 0.023, hazard ratio = 0.25). GATA5 mRNA expression is decreased in ccRCC, likely due to gene silencing by methylation of the GATA5 CGI. Moreover, reduced GATA5 mRNA levels were associated with a poor clinical outcome, indicating a possible role of GATA5 for the development of aggressive ccRCC phenotypes.
    BMC Cancer 02/2014; 14(1):101. · 3.33 Impact Factor
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    ABSTRACT: Laparoscopy introduction has dramatically changed urology. Novel techniques, such as laparoendoscopic single-site surgery (LESS) and natural orifice translumenal endoscopic surgery (NOTES), might also have substantial influence. This 2012 survey evaluated present laparoscopy use, its appraisal among urologic surgeons, laparoscopy training, and use of new techniques. Results were compared to the previous surveys, demonstrating the 10-year development of laparoscopy. A detailed questionnaire regarding demographic data, laparoscopy use, attitudes concerning laparoscopy, and novel techniques was send to 424 departments in Germany, Austria, and Switzerland. Procedures performed in 25 indications were quantitatively evaluated. The response rate was 63 % (269). Eighty-six percent of the respondents reported performing laparoscopy, compared to 54 % in 2002. Only 16 % expected economic advantages with laparoscopy, whereas 67 % expected shorter hospitalization. Seventy percent of responders anticipated comparable functional and oncological results between laparoscopic procedures and open surgery. Slow learning curves (81 %) and insufficient training facilities (32 %) were reported to impair laparoscopic surgery. On average, laparoscopic and non-laparoscopic surgical teams consisted of 2.5 and 3.5 members, respectively. LESS procedures were performed at 15 % of institutions. Twenty-two percent of respondents considered NOTES techniques valuable for future urology. Few indications (laparoscopic prostatectomies or nephrectomies) were performed frequently in specialized centers, and the rapidly increasing procedure numbers observed between 2002 and 2007 had dropped to a mild accretion. The results demonstrate broad acceptance of laparoscopy in German urologic surgery, depict the need for structured training facilities, and indicate limited impact of novel techniques (LESS and NOTES). The survey demonstrates the 10-year development of urologic laparoscopy and the broad acceptance of laparoscopic techniques.
    World Journal of Urology 02/2014; · 2.89 Impact Factor
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    ABSTRACT: Neurofilament Heavy polypeptid (NEFH) belongs to the group of type IV intermediate filament proteins. DNA methylation of the NEFH promoter and loss of expression have previously been shown to activate the AKT/β-catenin pathway in tumor cells. When identifying hypermethylation of the NEFH CpG island (CGI) in renal cell cancer (RCC) we asked whether methylation could provide clinical or prognostic information for RCC and/or predict therapy response in patients with metastatic RCC (mRCC) undergoing antiangiogenic therapy. Relative methylation of the NEFH CGI was analyzed in 132 RCC samples and 83 paired normal tissues using quantitative methylation-specific PCR. Results were statistically compared with tumor histology, clinicopathological parameters, progression-free survival (PFS) as well as with overall survival (OS) in a subset of 18 mRCC patients following antiangiogenic therapy regimens. The NEFH CGI methylation demonstrated a tumor-specific increase (P < 0.001), association with advanced disease (P < 0.001), and distant metastasis (P = 0.005). Higher relative methylation was also significantly associated with a poor PFS (HR = 8.6, P < 0.001) independent from the covariates age, gender, diameter of tumors, state of advanced disease, and local and distant metastasis. Median OS following targeted therapy was 29.8 months for patients with low methylation versus 9.8 months for the group with high methylation (P = 0.028). We identified NEFH methylation as a candidate epigenetic marker for prognosis of RCC patients as well as prediction of anti-vascular endothelial growth factor-based therapy response.
    Cancer Medicine 01/2014;
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    ABSTRACT: Abstract Introduction:Despite today's standard procedure for staging and treating non-muscle-invasive bladder cancer by transurethral resection via a wire loop (TURBT), several other publications have dealt with a different concept of en bloc resection of bladder tumors using different energy sources. Material and methods: MEDLINE and the Cochrane central register were searched for the following terms: en bloc, mucosectomy, laser, resection, ablation, Neodym, Holmium, Thulium, transitional cell carcinoma. Results:Fourteen research articles dealing with en bloc resection of non-muscle-invasive bladder cancer could be identified (modified resection loops: six, laser: six, waterjet hydrodissection: two). Conclusion: En bloc resection of bladder tumors >1 cm can be performed safely with very low complication rates independent of the power source. By using laser, complication rates might even be decreased, based on their good hemostatic effect and by avoiding the obturator nerve reflex. A further advantage seems to be accurate pathologic staging of en bloc tumors. Randomized controlled trials are still needed to support the assumed advantages of en bloc resection over the standard TURBT with regard to primary targets: First-time clearance of disease, accurate staging and recurrence rates.
    Minimally invasive therapy & allied technologies: MITAT: official journal of the Society for Minimally Invasive Therapy 01/2014; · 1.33 Impact Factor
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    ABSTRACT: Enzalutamide is a novel antiandrogen which is approved for the treatment of metastatic, castration-resistant prostate cancer (mCRPC) after taxane-based chemotherapy. The efficacy of enzalutamide after the sequence docetaxel and abiraterone is not proven. Thirty-five mCRPC patients in the German compassionate use program, who received enzalutamide after progression with taxane-based chemotherapy and abiraterone were prospectively evaluated. The endpoints of the study were overall survival, radiologic progression-free survival and safety. The median treatment duration on enzalutamide was 2.8 months. The median overall survival was 7.5 months [95% confidence interval (CI) 4.7-10.3] while median progression-free survival assessed by imaging was 3.1 months (95% CI 1.4-4.8). The most common toxicities of all grades were anemia and weight loss. Although the results are limited by a small patient number, the consecutive use of enzalutamide and abiraterone after taxane-based chemotherapy shows a modest clinical activity. Thus, sequence therapy alternating between chemotherapy and antihormonal drugs might be a more promising approach in mCRPC treatment.
    Advances in Therapy 01/2014; · 2.44 Impact Factor
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    ABSTRACT: VEGF-targeted therapy increases both the progression-free (PFS) and overall survival (OS) of patients with metastasized renal cell cancer (mRCC). Identification of molecular phenotypes of RCC could improve risk-stratification and the prediction of the clinical disease course. We investigated whether gene-specific DNA hypermethylation can predict PFS and OS among patients undergoing anti-VEGF-based therapy. Primary tumor tissues from 18 patients receiving targeted therapy were examined retrospectively using quantitative methylation-specific PCR analysis of CST6, LAD1, hsa-miR-124-3, and hsa-miR-9-1 CpG islands. PFS and OS were analyzed for first-line and sequential antiangiogenic therapies using the log rank statistics. Sensitivity and specificity were determined for predicting first-line therapy failure. Hypermethylation of CST6 and LAD1 was associated with both a shortened PFS (log rank p = 0.009 and p = 0.004) and OS (p = 0.011 and p = 0.043). The median PFS observed for the high and low methylation groups of CST6 and LAD1 was 2.0 vs.11.4 months. LAD1 methylation had a specificity of 1.0 (95% CI 0.65-1.0) and a sensitivity of 0.73 (95% CI 0.43-0.90) for the prediction of first-line therapy. CST6 and LAD1 methylation are candidate epigenetic biomarkers showing unprecedented association with PFS and OS as well as specificity for the prediction of the response to therapy. DNA methylation markers should be considered for the prospective evaluation of larger patient cohorts in future studies.
    PLoS ONE 01/2014; 9(3):e91440. · 3.53 Impact Factor

Publication Stats

3k Citations
625.80 Total Impact Points

Institutions

  • 1996–2014
    • Hannover Medical School
      • • Department of Nuclear Medicine
      • • Clinic for Urology
      • • Institute for Clinical Pharmacology
      Hanover, Lower Saxony, Germany
  • 2009–2013
    • cipto mangunkusumo hospital
      Batavia, Jakarta Raya, Indonesia
  • 2004–2010
    • University of Tuebingen
      • Department of Urology
      Tübingen, Baden-Wuerttemberg, Germany
  • 2008
    • Maria Hilf Hospital, Daun
      Daun, Rheinland-Pfalz, Germany
  • 2005–2006
    • Universitätsklinikum Tübingen
      • Department of Urology
      Tübingen, Baden-Württemberg, Germany
    • Albertinen Krankenhaus
      Hamburg, Hamburg, Germany
  • 2001
    • Osaka University
      • Division of Urology
      Ōsaka-shi, Osaka-fu, Japan