Berlin Institute for Urological Research

Berlin, Germany

Berlin Institute for Urological Research

Berlin, Germany
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Ecke T.H.,HELIOS Hospital Bad Saarow | Weiss S.,Charite University Hospital | Stephan C.,Charite University Hospital | Stephan C.,Berlin Institute for Urological Research | And 4 more authors.
Tumor Biology | Year: 2017

UBC® Rapid Test is a test that detects fragments of cytokeratins 8 and 18 in urine. We present results of a multicentre study measuring UBC® Rapid Test in bladder cancer patients and healthy controls with focus on carcinoma in situ (CIS) and high-grade bladder cancer. From our study with N = 452 patients, we made a stratified sub-analysis for carcinoma in situ of the urinary bladder. Clinical urine samples were used from 87 patients with tumours of the urinary bladder (23 carcinoma in situ, 23 non-muscle-invasive low-grade tumours, 21 non-muscle-invasive high-grade tumours and 20 muscle-invasive high-grade tumours) and from 22 healthy controls. The cut-off value was defined at 10.0 μg/L. Urine samples were analysed by the UBC® Rapid Test point-of-care system (concile Omega 100 POC reader). Pathological levels of UBC Rapid Test in urine are higher in patients with bladder cancer in comparison to the control group (p < 0.001). Sensitivity was calculated at 86.9% for carcinoma in situ, 30.4% for non-muscle-invasive low-grade bladder cancer, 71.4% for nonmuscle-invasive high grade bladder cancer and 60% for muscle-invasive high-grade bladder cancer, and specificity was 90.9%. The area under the curve of the quantitative UBC® Rapid Test using the optimal threshold obtained by receiveroperated curve analysis was 0.75. Pathological values of UBC® Rapid Test in urine are higher in patients with high-grade bladder cancer in comparison to low-grade tumours and the healthy control group. UBC® Rapid Test has potential to be more sensitive and specific urinary protein biomarker for accurate detection of highgrade patients and could be added especially in the diagnostics for carcinoma in situ and non-muscle-invasive high-grade tumours of urinary bladder cancer. © The Author(s) 2017.


Schaefer A.,Free University of Berlin | Stephan C.,University Hospital Charite | Busch J.,University Hospital Charite | Yousef G.M.,University of Toronto | Jung K.,Berlin Institute for Urological Research
Nature Reviews Urology | Year: 2010

MicroRNAs (miRNAs) are small, non-coding RNAs that have an important role in the regulation of carcinogenic pathways. The observations that miRNAs are differentially expressed in tumor versus corresponding normal tissue, and that they regulate important breakpoints during carcinogenesis, are of interest for urologic oncologists. As biomarkers, they might be helpful tools for diagnostic, prognostic and monitoring purposes. Furthermore, miRNAs might be potential targets for novel therapeutic strategies, especially in patients with tumor subtypes that do not respond to currently available therapies. In this Review, we will focus on the current proceedings of miRNA research in urologic tumors. In the past decade, the number of published articles related to miRNAs in urologic oncology has increased, highlighting the ongoing importance of miRNAs in this field. Current studies support the hypothesis that miRNA will gain influence in clinical practice. Here, therefore, we illustrate the current knowledge of miRNA function in urologic tumors and draw the attention of urologists to the future opportunities and challenges of this research field. © 2010 Macmillan Publishers Limited. All rights reserved.


Gummlich L.,Charité - Medical University of Berlin | Gummlich L.,Berlin Institute for Urological Research | Kahne T.,Otto Von Guericke University of Magdeburg | Naumann M.,Otto Von Guericke University of Magdeburg | And 4 more authors.
International Review of Cell and Molecular Biology | Year: 2016

Urological cancers are a very common type of cancer worldwide and have alarming high incidence and mortality rates, especially in kidney cancers, illustrate the urgent need for new therapeutic targets. Recent publications point to a deregulated COP9 signalosome (CSN)-cullin-RING ubiquitin-ligase (CRL) pathway which is here considered and investigated as potential target in urological cancers with strong focus on renal cell carcinomas (RCC). The CSN forms supercomplexes with CRLs in order to preserve protein homeostasis and was found deregulated in several cancer types. Examination of selected CSN-CRL pathway components in RCC patient samples and four RCC cell lines revealed an interesting deregulated p27Kip1-Skp2-CAND1 axis and two p27Kip1 point mutations in 786-O cells; p27Kip1V109G and p27Kip1I119T. The p27Kip1 mutants were detected in patients with RCC and appear to be responsible for an accelerated growth rate in 786-O cells. The occurrence of p27Kip1V109G and p27Kip1I119T in RCC makes the CSN-CRL pathway an attractive therapeutic target. © 2016 Elsevier Inc.


Busch J.,ChariteUniversity Medicine Berlin | Stephan C.,ChariteUniversity Medicine Berlin | Stephan C.,Berlin Institute for Urological Research | Herold A.,ChariteUniversity Medicine Berlin | And 9 more authors.
BJU International | Year: 2012

OBJECTIVE • To investigate biochemical recurrence (BCR) rates and data on postoperative incontinence in a large laparoscopic radical prostatectomy (LRP) cohort with extended follow-up. MATERIALS AND METHODS • BCR and independent predictors of BCR were identified using Kaplan-Meier and Cox regression analysis of 1845 patients who underwent LRP from 1999 to 2007. • Urinary incontinence was evaluated by pads per day and stratified as follows: 0-1 pad: no incontinence; 2-3 pads: mild incontinence; and ≥ 3 pads: severe incontinence. RESULTS • Organ-confined disease, extraprostatic extension, seminal vesicle invasion and lymph node metastasis were present in 71.3%, 20.5%, 6.7% and 3.2% of patients, respectively. The positive surgical margin rate was 29.2%. • Postoperatively, 74.9% of the patients were continent, while 9.2% had mild and 15.9% severe incontinence. • The mean follow-up was 5 years with a maximum follow-up of 11.3 years. • There were 51 overall deaths and six deaths from prostate cancer. The 5-year, 8-year and 10-year BCR-free survival rates were 83.9%, 78.6% and 75.6%, respectively. • On univariate analyses preoperative D'Amico risk classification, pathological tumour stage, postoperative Gleason sum and surgical margin status were predictors of BCR ( P < 0.001). • On multivariable analysis, D'Amico classification, Gleason sum ( P < 0.001), postoperative tumour stage ( P < 0.001), nodal status ( P < 0.001) and surgical margin status ( P =0.002) were independent predictors of BCR. CONCLUSIONS • LRP offers excellent long-term functional and oncological results with a low incidence of BCR for patients with localized disease. • These results could be used for patient counselling before robot-assisted laparascopic prostatectomy (RALP) until long-term follow-up data for RALP is available. © 2012 THE AUTHORS.


Wotschofsky Z.,University Hospital Charite | Wotschofsky Z.,Berlin Institute for Urological Research | Busch J.,University Hospital Charite | Jung M.,University Hospital Charite | And 10 more authors.
Clinica Chimica Acta | Year: 2013

Background: MicroRNAs are promising diagnostic and prognostic biomarkers in oncology. We aimed to evaluate the prognostic potential of selected microRNAs in primary clear cell renal cell carcinomas (ccRCC) as predictors of tumor recurrence after radical nephrectomy. Methods: miR-122, miR-141, miR-155, miR-184, miR-200c, miR-210, miR-224, and miR-514, validated as differentially expressed in a previous study, were measured by RT-PCR in matched malignant and non-malignant tumor samples after nephrectomy from 111 patients (89 without, 22 with metastases) and clinicopathological and outcome data were collected. Non-parametric statistical tests, receiver-operating characteristics, Kaplan-Meier-, and univariate as well as multivariate Cox regression analyses were performed. Results: Downregulation of miR-141/-184/-200c/-514 and upregulation of miR-122/-155/-210/-224 were not different between samples of non-metastatic and metastatic tumors except for miR-122 and miR-514. miR-514 was further downregulated in metastatic compared with non-metastatic tumors while the upregulation of miR-122 was significantly reduced in metastatic carcinomas. All miRNAs were suitable to discriminate malignant from non-malignant tissue. miR-122 and miR-514 were significantly related to the recurrence risk but only miR-514 provided independent prognostic information in the final model including relevant clinicopathological variables. Conclusions: MiR-122 and miR-514 play a role in tumor recurrence after nephrectomy. Expression of miR-514 was particularly downregulated in primary metastatic tumor and those that recur and might be a suitable adjunct marker for predicting tumor recurrence. © 2012 Elsevier B.V.


Ecke T.H.,HELIOS Hospital | Arndt C.,Lukaskrankenhaus Neuss | Stephan C.,Charite University Hospital | Stephan C.,Berlin Institute for Urological Research | And 6 more authors.
Anticancer Research | Year: 2015

Background/Aim: UBC Rapid is a test detecting fragments of cytokeratins 8 and 18 in urine. These are cytokeratins frequently overexpressed in tumor cells. We present the first results of a multi-centre study using UBC Rapid in patients with bladder cancer and healthy controls. Materials and Methods: Clinical urine samples from 92 patients with tumors of the urinary bladder (45 low-grade and 47 high-grade tumors) and from 33 healthy controls were used. Urine samples were analyzed by the UBC Rapid point-of-care (POC) system and evaluated both visually and quantitatively using a concile Omega 100 POC reader. For visual evaluation, different thresholds of band intensity for considering a test as positive were applied. Sensitivities and specificities were calculated by contingency analyses. Results: We found that pathological concentrations by UBC Rapid are detectable in urine of patients with bladder cancer. The calculated diagnostic sensitivity of UBC Rapid in urine was 68.1% for high-grade, but only 46.2% for low-grade tumors. The specificity was 90.9%. The area under the curve (AUC) after receiver-operated curve (ROC) analysis was 0.733. Pathological levels of UBC Rapid in urine are higher in patients with bladder cancer in comparison to the control group (p<0.0001). Conclusion: UBC rapid can differentiate between patients with bladder cancer and controls. Further studies with a greater number of patients will show how valuable these results are.


Jentzmik F.,University Hospital Charite | Stephan C.,University Hospital Charite | Miller K.,University Hospital Charite | Schrader M.,University Hospital Charite | And 6 more authors.
European Urology | Year: 2010

Background: Sarcosine in urine was recently suggested to be a promising tool in prostate cancer (PCa) diagnostics. Objective: To reevaluate sarcosine as a potential biomarker for early PCa detection and for prediction of tumour aggressiveness. Design, setting, and participants: Sarcosine was measured in urine samples from 106 PCa patients and 33 patients with no evidence of malignancy (NEM), confirmed by 8-12 core prostate biopsies, after standardised digital rectal examination, as well as from 12 healthy men and women. The results were related to the clinicopathologic data on prostate volume, tumour stage, Gleason score, and prostate specific antigen (PSA). Measurements: Sarcosine in urine was determined by gas chromatography-mass spectrometry using a commercial amino acid assay and was normalised to urine creatinine. Nonparametric statistical tests and receiver operating characteristics (ROC) analyses were performed to assess the diagnostic performance. Results and limitations: The median sarcosine-creatinine ratio in urine was 13% lower in PCa than in NEM patients. Sarcosine values were not associated with tumour stage (pT2 vs pT3) or grade (Gleason score <7 vs ≥7). ROC analyses proved that the discrimination between PCa and NEM patients was not improved by sarcosine in comparison with total PSA, but it was significantly worse than the percent free PSA. The higher proportion of PCa than NEM patients can be considered a limitation of this study. Conclusions: Sarcosine in urine after rectal digital examination cannot be considered as a suitable marker to differentiate between patients with and without PCa. © 2010 European Association of Urology.


Ecke T.H.,HELIOS Hospital | Bartel P.,HELIOS Hospital | Hallmann S.,HELIOS Hospital | Koch S.,HELIOS Hospital | And 7 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2012

Background: We evaluated the use of the artificial neural network (ANN) program "ProstataClass" of the Department of Urology and the Institute of Medical Informatics at the Charité-Universitätsmedizin Berlin in daily routine to increase prostate cancer (CaP) detection rate and to reduce unnecessary biopsies. Materials and methods: From May 2005 to April 2007, a total of 204 patients were included in the study. The Beckman Access PSA assay was used, and pretreatment prostate specific antigen (PSA) was measured prior to digital rectal examination (DRE) and 12 core systematic transrectal ultrasound (TRUS) guided biopsies. The individual ANN predictions were generated with the use of the ANN application for the Beckman Access PSA and free PSA assays, which relies on age, PSA, percent free prostate specific antigen (%fPSA), prostate volume, and DRE. Diagnostic validity of total prostate specific antigen (tPSA), %fPSA, and the ANN was evaluated by ROC curve analysis. Results: PSA and %fPSA ranged from 4.01 to 9.91 ng/ml (median: 6.65) and 5% to 48% (median: 15%), respectively. Of all men, 46 (22.5%) demonstrated suspicious DRE findings. Total prostate volume ranged from 7.1 to 119.2 cc (median: 35). Overall, 71 (34.8%) CaP were detected. Of men with suspicious DRE, 28 (60.9%) had CaP on initial biopsy. The ANN was 78% accurate in the original report. The AUC of ROC curve analysis was 0.51 for PSA, 0.66 for %PSA, and 0.72 for the ANN-Output, respectively. Conclusions: Our results in this independent cohort show that ANN is a very helpful parameter in daily routine to increase the CaP detection rate and reduce unnecessary biopsies. © 2012 Elsevier Inc..


Busch J.,Charité - Medical University of Berlin | Stephan C.,Berlin Institute for Urological Research | Klutzny A.,Charité - Medical University of Berlin | Hinz S.,Charité - Medical University of Berlin | And 7 more authors.
World Journal of Urology | Year: 2013

Purpose: The impact of positive surgical margins (PSM) on biochemical recurrence (BCR) has been heavily debated in laparoscopic radical prostatectomy (LRP). The aim of this study was to investigate the impact of PSM on BCR following LRP in patients with extended follow-up. Methods: Retrospective chart review of 1,845 patients who underwent LRP from 1999 to 2007. Predictors of PSM and BCR were identified utilizing univariate and multivariable logistic and Cox regression analyses, respectively. Results: Five hundred and thirty-seven patients (29. 1 %) had a PSM. Median postoperative follow-up was 56 months. 10-year BCR-free survival was 59. 2 and 82. 9 % for patients with and without PSM, respectively (p & 0. 0001). Clinical stage T2 (OR 1. 66; CI 1. 23-2. 25; p = 0. 001), a biopsy Gleason sum > 7 (OR 1. 84; CI 1. 06-3. 18; p = 0. 031) and preoperative prostate-specific antigen (PSA) levels of 10-20 ng/mL (OR 1. 58; CI 1. 12-2. 23; p = 0. 010) and >20 ng/mL (OR 6. 82; CI 3. 51-13. 27; p < 0. 0001) were independent predictors of PSM. Prostate size was inversely associated with PSM (OR 0. 99; CI 0. 98-1. 00; p = 0. 002). On multivariable analysis, LRP Gleason score of 7 (HR 2. 45; CI 1. 67-3. 40; p < 0. 0001) and >7 (HR 4. 76; CI 3. 15-7. 19; p < 0. 0001), PSM (HR 1. 49; CI 1. 14-2. 00; p = 0. 003), advanced pathological stages (p < 0. 001), and PSA 10-20 ng/mL (HR 1. 46; CI 1. 13-1. 89; p = 0. 004) were independent predictors of BCR. Conclusions: We demonstrated the independent predictive value of PSM for BCR in our LRP cohort with extended follow-up. Our results could potentially be transferred to robotic RP, in which long-term follow-up is lacking. © 2012 Springer-Verlag.


Gummlich L.,Charité - Medical University of Berlin | Gummlich L.,Berlin Institute for Urological Research | Rabien A.,Charité - Medical University of Berlin | Jung K.,Berlin Institute for Urological Research | And 2 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2013

The COP9 signalosome (CSN)-cullin-RING ubiquitin (Ub)-ligase (CRL) pathway is a prominent segment of the Ub proteasome system (UPS). It specifically ubiquitinates proteins and targets them for proteolytic elimination. As part of the UPS it maintains essential cellular processes including cell cycle progression, DNA repair, antigen processing and signal transduction. The CSN-CRL pathway consists of the CSN possessing eight subunits (CSN1-CSN8) and one CRL consisting of a cullin, a RING-domain protein and a substrate recognition subunit (SRS). In human cells approximately 250 CRLs exist each of which interacting with a specific set of substrates and the CSN. The CSN-CRL interplay determines the activity and specificity of CRL ubiquitination. The removal of the Ub-like protein Nedd8 from the CRL component cullin by the CSN (deneddylation) reduces the ubiquitinating activity and at the same time enables reassembly of CRLs in order to adapt to substrate specificity requirements. On the other hand, CRLs as well as substrates negatively influence the deneddylating activity of the CSN. In recent years evidence accumulated that deregulation of the CSN-CRL pathway can cause cancer. Here we review current knowledge on modifications of CSN and CRL components including CSN subunits, SRSs and cullins causing tumorigenesis with emphasis on urological neoplasia. The CSN-CRL pathway is a target of tumor-viruses as well as of a multitude of miRNAs. Recently evaluated miRNAs altered in urological cancers might have impact on the CSN-CRL pathway which has to be analyzed in future experiments. We propose that the pathway is a suitable target for future tumor therapy. © 2013 Elsevier Ltd.

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