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1.  Robot-assisted radical cystectomy and intracorporeal neobladder formation: on the way to a standardized procedure 
Robot-assisted radical cystectomy (RARC) with intracorporeal diversion has been shown to be feasible in a few centers of excellence worldwide, with promising functional and oncologic outcomes. However, it remains unknown whether the complexity of the procedure allows its duplication in other non-pioneer centers. We attempt to address this issue by presenting our cumulative experience with RARC and intracorporeal neobladder formation.
We retrospectively identified 62 RARCs in 50 men and 12 women (mean age 63.6 years) in two tertiary centers. Intracorporeal Studer neobladders were created, duplicating the steps of standard open surgery. Perioperative and postoperative variables and complications were analyzed using standardized tools. Functional and oncological results were assessed.
The mean operative time was 476.9 min (range, 310 to 690) and blood loss was 385 ml (200 to 800). The mean hospital stay was 16.7 (12 to 62) days with no open conversion. Perioperative complications were grade II in 15, grade III in 11, and grade IV in 5 patients. The mean nodal yield was 22.9 (8 to 46). Positive margins were found in in 6.4%. The 90- and 180-day mortality rates were 0% and 3.3%. The average follow-up was 37.3 months (3 to 52). Continence was achieved in 88% of patients. The cancer-specific survival rate and overall survival rate were 84% and 71%, respectively.
A RARC with intracorporeal neobladder creation is safe and reproducible in ‘non-pioneer’ tertiary centers with robotic expertise with acceptable operative time and complications. Further standardization of RARC with intracorporeal diversion is a prerequisite for its widespread use.
PMCID: PMC4326337  PMID: 25560783
intracorporeal diversion; laparoscopy; neobladder; radical cystectomy; robot-assisted
2.  Stepwise Application of Urine Markers to Detect Tumor Recurrence in Patients Undergoing Surveillance for Non-Muscle-Invasive Bladder Cancer 
Disease Markers  2014;2014:973406.
Background. The optimal use of urine markers in the surveillance of non-muscle-invasive bladder cancer (NMIBC) remains unclear. Aim of the present study was to investigate the combined and stepwise use of the four most broadly available urine markers to detect tumor recurrence in patients undergoing surveillance of NMIBC. Patients and Methods. 483 patients with history of NMIBC were included. Cytology, UroVysion, fluorescence in situ hybridization (FISH), immunocytology (uCyt+), and NMP22 ELISA were performed before surveillance cystoscopy. Characteristics of single tests and combinations were assessed by contingency analysis. Results. 128 (26.5%) patients had evidence of tumor recurrence. Sensitivities and negative predictive values (NPVs) of the single tests ranged between 66.4–74.3 and 82.3–88.2%. Two-marker combinations showed sensitivities and NPVs of 80.5–89.8 and 89.5–91.2%. A stepwise application of the two-test combinations with highest accuracy (cytology and FISH; cytology and uCyt+; uCyt+ and FISH) showed NPVs for high-risk recurrences (G3/Cis/pT1) of 98.8, 98.8, and 99.1%, respectively. Conclusions. Combinations of cytology, FISH, immunocytology, and NMP22 show remarkable detection rates for recurrent NMIBC. Stepwise two-test combinations of cytology, FISH, and immunocytology have a low probability of missing a high-risk tumor. The high sensitivities may justify the use of these combinations in prospective studies assessing the use of urine markers to individualize intervals between cystoscopies during follow-up.
PMCID: PMC4284969  PMID: 25587206
3.  Chromosomal alterations in exfoliated urothelial cells from bladder cancer cases and healthy men: a prospective screening study 
BMC Cancer  2014;14(1):854.
Chromosomal instability in exfoliated urothelial cells has been associated with the development of bladder cancer. Here, we analyzed the accumulation of copy number variations (CNVs) using fluorescence in situ hybridization in cancer cases and explored factors associated with the detection of CNVs in tumor-free men.
The prospective UroScreen study was designed to investigate the performance of UroVysion™ and other tumor tests for the early detection of bladder cancer in chemical workers from 2003–2010. We analyzed a database compiling CNVs of chromosomes 3, 7, and 17 and at 9p21 that were detected in 191,434 exfoliated urothelial cells from 1,595 men. We assessed the accumulation of CNVs in 1,400 cells isolated from serial samples that were collected from 18 cancer cases up to the time of diagnosis. A generalized estimating equation model was applied to evaluate the influence of age, smoking, and urine status on CNVs in cells from tumor-free men.
Tetrasomy of chromosomes 3, 7 and 17, and DNA loss at 9p21 were the most frequently observed forms of CNV. In bladder cancer cases, we observed an accumulation of CNVs that started approximately three years before diagnosis. During the year prior to diagnosis, cells from men with high-grade bladder cancer accumulated more CNVs than those obtained from cases with low-grade cancer (CNV < 2: 7.5% vs. 1.1%, CNV > 2: 16-17% vs. 9-11%). About 1% of cells from tumor-free men showed polysomy of chromosomes 3, 7, or 17 or DNA loss at 9p21. Men aged ≥50 years had 1.3-fold more cells with CNVs than younger men; however, we observed no further age-related accumulation of CNVs in tumor-free men. Significantly more cells with CNVs were detected in samples with low creatinine concentrations.
We found an accumulation of CNVs during the development of bladder cancer starting three years before diagnosis, with more altered cells identified in high-grade tumors. Also, a small fraction of cells with CNVs were exfoliated into urine of tumor-free men, mainly exhibiting tetraploidy or DNA loss at 9p21. Whether these cells are preferentially cleared from the urothelium or are artifacts needs further exploration.
PMCID: PMC4247705  PMID: 25412927
Aneuploidy; Bladder cancer; Chromosomal instability; Copy number variation; DNA gain; DNA loss; Fluorescence in situ hybridization; Tetrasomy
4.  Accurate Risk Assessment of Patients with Asymptomatic Hematuria for the Presence of Bladder Cancer 
World journal of urology  2012;30(6):847-852.
Bladder cancer is frequently diagnosed during a workup for hematuria. However, most patients with microscopic hematuria and many with gross hematuria are not appropriately referred to urologists. We hypothesized that in patients presenting with asymptomatic hematuria, the risk of having bladder cancer can be predicted with high accuracy. Towards this end, we analyzed risk factors in patients with asymptomatic hematuria and developed a nomogram for the prediction of bladder cancer presence.
Data from 1,182 consecutive subjects without a history of bladder cancer undergoing initial evaluation for asymptomatic hematuria were collected at three centers. Clinical risk factors including age, gender, smoking status, and degree of hematuria were recorded. All subjects underwent standard workup including voided cytology, upper tract imaging, and cystourethroscopy. Factors associated with the presence of bladder cancer were evaluated by univariable and multivariable logistic regression analyses. The multivariable analysis was used to construct a nomogram. Internal validation was performed using 200 bootstrap samples.
Of the 1,182 subjects who presented with asymptomatic hematuria, 245 (20.7%) had bladder cancer. Increasing age (OR=1.03, p<0.0001), smoking history (OR=3.72, p<0.0001), gross hematuria (OR=1.71, p=0.002), and positive cytology (OR=14.71, p<0.0001) were independent predictors of bladder cancer presence. The multivariable model achieved 83.1% accuracy for predicting the presence of bladder cancer.
Bladder cancer presence can be predicted with high accuracy in patients who present with asymptomatic hematuria. We developed a nomogram to help optimize referral patterns (i.e., timing and prioritization) of patients with asymptomatic hematuria.
PMCID: PMC4004026  PMID: 23124847
urinary bladder neoplasms; hematuria; nomograms; early detection of cancer; carcinoma
5.  Prospective evaluation of fluorescence-guided cystoscopy to detect bladder cancer in a high-risk population: results from the UroScreen-Study 
SpringerPlus  2014;3:24.
To prospectively evaluate the role of fluorescence-guided cystoscopy in a high-risk bladder cancer population undergoing screening based on a multi-marker panel of urine-tests (UroScreen-study).
Patients and methods
UroScreen was conducted as a validation study for tumor markers within the frame of a health surveillance program of workers with occupational exposure to aromatic amines. Voluntary annual screens were done in 1,609 men. Cytology, quantitative NMP22® assay, and UroVysion (FISH) were applied to 7091 urine samples. Subjects with at least one positive urine-based tumor marker and/or persisting microscopic hematuria were offered fluorescence-guided (PDD) instead of white light cystoscopy. In case of suspicious findings histopathological evaluation by transurethral biopsy was performed. Data were statistically summarized and compared to tumors found by the standard algorithm of the screening study.
Twenty-two subjects with a mean age of 58 years (39–72) underwent PDD cystoscopy. Of those 3 had positive NMP22 tests, 14 positive FISH tests and 9 suspicious cytologies. Two had persisting microscopic hematuria only. PDD cystoscopy revealed enhanced unifocal fluorescence in 14. All had subsequent transurethral biopsy or resection. In total, 1 urothelial carcinoma (pTaG1, low grade) was diagnosed. In the other participants urothelial cancer of the bladder was ruled out. Chronic cystitis was revealed in 8 of 14 biopsies. No higher detection rate was found using PDD than with the standard algorithm of the UroScreen study in which 17 tumors were detected by white light cystoscopy.
The use of PDD does not lead to a higher cancer detection rate in a high-risk screening population. Larger sample sizes may be needed to ultimately asses the value of PDD for bladder cancer screening.
PMCID: PMC3905106  PMID: 24478941
Urothelial cancer of the bladder; Urine based tumor marker; Bladder cancer screening; NMP22; UroVysion; UroScreen; Cytology; Photodynamic diagnostics; Cystoscopy
7.  Intracorporeal ileal ureter replacement using laparoscopy and robotics 
Ileal ureter is a suitable treatment option for patients with long ureteric strictures. Minimally invasive techniques have been shown to be as safe as open techniques but superior in terms of post–operative recovery. We report our experience using minimally invasive techniques for total intracorporeal ureteral replacement.
Material and methods
A chart review revealed five patients who underwent intracorporeal ileal ureter using minimally invasive techniques in the preceding 5 years. 4 patients underwent conventional laparoscopic surgery and 1 patient underwent robotic–assisted surgery. Patient's characteristics, perioperative data and functional outcomes as well as a detailed description of surgical technique are reported. In all 5 of these patients, the ileal ureter was performed completely intracorporeally.
The median age of our patients is 61 (range 42–73). The median operative time was 250 minutes (range 150–320) and median blood loss was 100 ml (range 50–200). The median hospital stay was 8 days (range 6–10) and there were no major perioperative complications reported. At median follow up of 22 months (range 4–38), there were no recurrences of strictures or any other complications.
We have demonstrated the safety and feasibility of minimally invasive intracorporeal ileal ureter. Numbers are still small but its application is likely to grow further.
PMCID: PMC4310887  PMID: 25667767
ileal ureter; ileal interposition; minimally invasive; laparoscopy; intracorporeal; ureteric strictures; robotics
8.  Bladder cancer discussed on the internet: a systematic analysis of gender differences of initial posters on an online discussion board 
SpringerPlus  2013;2:445.
To evaluate gender differences of initial posters in threads dealing with bladder cancer on an online discussion board.
529 threads opened between 09/2005 and 03/2012 were screened on the largest German speaking bladder cancer online discussion board. 366 threads fulfilled the requirements for this study. Gender, age, number, status of concern and oncological situation of initiating posters as well as their motives and language style were analyzed following a standardized protocol.
Threads were initiated in 45% (164/366) by men and in 55% (202/366) by women. Mean age of male initiating posters was 50 years and of female posters 44 years (p < 0.001). Of males 80% (132/164) were concerned patients and 20% (32/164) relatives or friends. Of females they were 39% (78/202) and 61% (124/202), respectively (p < 0.001). In general motives for initial posting were focused on medical information and did not differ between both genders. 81% of the posters asked for medical information or therapeutic recommendations regarding diagnosis, treatment and prognosis. However, women significantly more often expressed their wish for emotional support (p = 0.034) and in tendency wanted to share their experiences with others (p = 0.057). Language analysis revealed that women significantly more often used a tentative language style than men (p = 0.003).
Even though women are less often affected by bladder cancer, they are more active –especially for their concerned family members - on the evaluated discussion board than men. Whereas both genders equally often ask for medical information, women more often want to share their experiences and look for emotional support.
PMCID: PMC3790904  PMID: 24102040
9.  Immunocytology Is Strong Predictor of Bladder Cancer Presence in Patients With Painless Hematuria: A Multicentre Study 
European urology  2011;61(1):185-192.
Although the performance of immunocytology has been established in the surveillance of patients with urothelial carcinoma of the bladder (UCB), its value in the initial detection of UCB in patients with painless hematuria remains unclear.
To determine whether immunocytology improves our ability to predict the likelihood of UCB in patients with painless hematuria. Further, to test the clinical benefit of immunocytology in this setting using decision curve analysis.
Design, setting, and participants
The subjects were 1182 consecutive patients without a history of UCB presenting with painless hematuria and were enrolled at three centres.
All patients underwent upper-tract imaging, cystourethroscopy, voided urine cytology, and immunocytology analysis. Bladder tumors were biopsied and histologically confirmed as UCB.
Multivariable regression models were developed. Area under the curve was measured and compared using the DeLong test. A nomogram was constructed from the full multivariable model. Decision curve analysis was performed to evaluate the clinical benefit associated with use of the multivariable models including immunocytology.
Results and limitations
Immunocytology had the largest contribution to a multivariable model for the prediction of UCB (odds ratio: 18.3; p < 0.0001), which achieved a 90.8% predictive accuracy. Decision curve analysis revealed that models incorporating immunocytology achieved the highest net benefit at all threshold probabilities.
Immunocytology is a strong predictor of the presence of UCB in patients who present with painless hematuria. Incorporation of immunocytology into predictive models improves diagnostic accuracy by a statistically and clinically significant margin. The use of immunocytology in the diagnostic workup of patients with hematuria appears promising and should be further evaluated.
PMCID: PMC3628750  PMID: 21924544
Cystoscopy; Decision curve analysis; Early detection of cancer; Hematuria; Immunocytology; Nomograms; Urinary bladder neoplasms
10.  Insulin Receptor Isoforms A and B as well as Insulin Receptor Substrates-1 and -2 Are Differentially Expressed in Prostate Cancer 
PLoS ONE  2012;7(12):e50953.
In different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation.
We studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27Kip1 was quantified by real-time RT-PCR and immunohistochemistry.
Insulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27Kip1 content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019).
We found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.
PMCID: PMC3519512  PMID: 23251408
11.  Severe paraneoplastic hypereosinophilia in metastatic renal cell carcinoma 
BMC Urology  2012;12:7.
Renal cell carcinoma can cause various paraneoplastic syndromes including metabolic and hematologic disturbances. Paraneoplastic hypereosinophilia has been reported in a variety of hematologic and solid tumors. We present the first case in the literature of severe paraneoplastic hypereosinophilia in a patient with renal cell carcinoma.
Case presentation
A 46 year-old patient patient with a history of significant weight loss, reduced general state of health and coughing underwent radical nephrectomy for metastasized renal cell carcinoma. Three weeks after surgery, the patient presented with excessive peripheral hypereosinophilia leading to profound neurological symptoms due to cerebral microinfarction. Systemic treatment with prednisolone, hydroxyurea, vincristine, cytarabine, temsirolimus and sunitinib led to reduction of peripheral eosinophils but could not prevent rapid disease progression of the patient. At time of severe leukocytosis, a considerable increase of cytokines associated with hypereosinophilia was measurable.
Paraneoplastic hypereosinophilia in patients with renal cell carcinoma might indicate poor prognosis and rapid disease progression. Myelosuppressive therapy is required in symptomatic patients.
PMCID: PMC3348004  PMID: 22436420
Paraneoplastic; Hypereosinophilia; Leukocytosis; Renal cell carcinoma; Leukemoid reaction; Encephalopathy
12.  Point-of-Care Tests for Bladder Cancer: The Influencing Role of Hematuria 
Advances in Urology  2011;2011:937561.
Introduction. Several point-of-care tests (POCT) are available for the diagnosis of bladder cancer (BC). We evaluate the impact of HU (hematuria) on performance of POCTs. Materials and Methods. Urine from 10 donors was diluted with blood from 0.5 to 0.00625%. BladderCheckR, BTAstatR, BCMR, and BTAR tests were applied. Tests were additionally conducted in 54 patients with HU. HU was stratified according to the amount of erythrocytes (RBC)/μL using two systems: (1) no HU; mild microscopic HU; severe microscopic HU; gross HU; (2) I <25 RBCs; <250 II; ≥250 III. Results were compared to HU status and histopathology. Results. Gross HU became evident between 2090 RBCs/μL and 1065/μL. Addition of blood led to default tests in all 4: BladderCheckR 0.25%; BCM 0.025%, BioNexia 0.00625%, and BTAstat <0.00625%. Rates of false positives for BladderCheck, BTAstat, BCM, and BioNexia were 5.9, 11.8, 0, and 1.8% without HU and 0, 66.7, 44.4, and 66.7% with HU. BTAstat, BCM, and BioNexia were independently influenced by HU (P < 0.0002). Conclusions. NMP22-BladderCheck was most resistant to blood. The diagnostic yield of all others was significantly influenced by HU. A well-defined HU grading helps to define limits of HU for a reliable interpretation of BC-POCTs.
PMCID: PMC3227231  PMID: 22162681
13.  Long-term results after endoscopic VUR-treatment using dextranomer / hyaluronic acid copolymer – 5-year experience in a single-center 
A number of bulking agents have been used for the endoscopic correction of vesicoureteral reflux in children. We present our long-term results of endoscopic use of dextranomer/hyaluronic acid copolymer (Deflux®) for VUR treatment in children.
Patients and methods
Between 2004 and 2008, 21 children underwent endoscopic subureteral injection of Deflux® in 30 ureters as an outpatient procedure. Twelve children had unilateral reflux (2 duplicated systems) and nine had bilateral reflux. Median age was 5-years (6-months to 14.9-years). Six weeks postoperatively, a voiding cystourethrogram was performed. This study examined the disappearance of VUR and urinary tract infection (UTI) in the long-term follow-up as well as QoL (questionnaire of the parents).
No intra- or postoperative complications had been noticed. In 25 ureters (83%), VCUG showed no VUR 6-weeks postoperatively. Three children received a 2nd injection (two successful). After a median follow-up of 2.5 years, 27 ureters in 17 children (90%) had no urinary tract infection and VUR. The questionnaire results in regard to quality of life (QoL) were very good in the successfully treated children and the parents would choose the same treatment option again.
Subureteral injection of Deflux® for children with VUR is an effective treatment option with a low complication rate.
PMCID: PMC3921717  PMID: 24578870
vesicoureteral reflux; minimally invasive therapy; dextranomer/hyaluronic acid; health-related quality of life; subureteral injection
14.  Embryology and anatomy of the vesicoureteric junction with special reference to the etiology of vesicoureteral reflux 
Therapeutic Advances in Urology  2009;1(5):243-250.
Concerning the ureterovesical junction – the region most important for the anti-reflux mechanism – there is still a lot of misunderstanding and misinterpretation with regard to normal fetal development. Data are scarce on possible causes of primary vesicoureteral reflux and on involved mechanisms of the so-called maturation process of refluxing ureteral endings. The ratio of the intravesical ureteral length to the ureteral diameter is obviously lower than assumed so far, as clearly revealed by some studies. Therefore it can be doubted that the length and course of the intravesical ureter is of sole importance in the prevention of reflux. Additionally refluxing intravesical ureteral endings present with dysplasia, atrophy, and architectural derangement of smooth muscle fibers. Besides, a pathologically increased matrix remodeling combined with deprivation of the intramural nerve supply has been confirmed. Consequently, symmetrical narrowing of the very distal ureteral smooth muscle coat creating the active valve mechanism to defend reflux is not achievable. It is apparent that primary congenital vesicoureteral reflux seems to be the result of an abnormality within the ureterovesical junction with an insufficient muscular wrap. Nature is believed to establish much more sophisticated mechanisms than the so-called passive anti-reflux mechanism. Remodeling processes within the ureterovesical junction of refluxing ureteral endings support that maturation itself is nothing else than wound or defect healing and not a restitution of a morphological normal ureterovesical junction. Lacking the nerve supply a restoration of any muscular structure can not be achieved.
PMCID: PMC3126077  PMID: 21789071
human fetal development; ureterovesical junction; vesicoureteral reflux; children; extracellular matrix; nerve supply

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