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1.  Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer 
BMC Cancer  2015;15:155.
The role of urine markers in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC) is discussed extensively. In case of negative cystoscopy the additional prognostic value of these markers has not been clearly defined yet. The present study is the first systematic approach to directly compare the ability of a urine marker panel to predict the risk of recurrence and progression in bladder cancer (BC) patients with no evidence of relapse during surveillance for NMIBC.
One hundred fourteen patients who underwent urine marker testing during surveillance for NMIBC and who had no evidence of BC recurrence were included. For all patients cytology, Fluorescence-in-situ-hybridization (FISH), immunocytology (uCyt+) and Nuclear matrix protein 22 enzyme-linked immunosorbent assay (NMP22) were performed. All patients completed at least 24 months of endoscopic and clinical follow-up of after inclusion.
Within 24 months of follow-up, 38 (33.0%) patients experienced disease recurrence and 11 (9.8%) progression. Recurrence rates in patients with positive vs. negative cytology, FISH, uCyt+ and NMP22 were 52.6% vs. 21.9% (HR = 3.9; 95% CI 1.75-9.2; p < 0.001), 47.6% vs. 25.0% (HR 2.7; 1.2-6.2; p = 0.01), 43.8% vs. 22.4% (HR 3.3; 1.5-7.6; p = 0.003) and 43.8% vs. 16.7% (HR 4.2; 1.7-10.8; p = 0.001). In patients with negative cytology, a positive NMP22 test was associated with a shorter time to recurrence (p = 0.01), whereas FISH or uCyt+ were not predictive of recurrence in these patients. In the group of patients with negative cytology and negative NMP22, only 13.5% and 5.4% developed recurrence and progression after 24 months.
Patients with positive urine markers at time of negative cystoscopy are at increased risk of recurrence and progression. In patients with negative cytology, only NMP22 is predictive for recurrence. Patients with negative marker combinations including NMP22 harbour a low risk of recurrence. Therefore, the endoscopic follow-up regimen may be attenuated in this group of patients.
PMCID: PMC4374530  PMID: 25884545
Urine markers; Prediction; Recurrence; Risk; Surveillance; Anticipatory positive
2.  Targeting Bone Metabolism in Patients with Advanced Prostate Cancer: Current Options and Controversies 
Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC) who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL), antiresorptive agents have been shown to improve bone mineral density (BMD) and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs) in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy.
PMCID: PMC4329828  PMID: 25802521
3.  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
4.  Robot–assisted radical cystectomy and intracorporeal urinary diversion – safe and reproducible? 
Robot–assisted radical cystectomy (RARC) plus intracorporeal urinary diversion is feasible. Few centers worldwide demonstrated comparable functional and oncologic outcomes. We reported a large series of RARC and intracorporeal diversion to assess its feasibility and reproducibility.
Material and methods
We identified 101 RARCs in 82 men and 19 women (mean age 68.3 years) from October 2009 to October 2014. The patients underwent RARC and pelvic lymphadenectomy followed by intracorporeal urinary diversion (ileal conduit/ neobladder). Out of the 101 patients, 28 (27.7%) received intracorporeal ileal conduits and 73 (72.3%) intracorporeal neobladders. Studer pouch was performed in all the patients who underwent intracorporeal neobladder formation. Perioperative, functional and oncologic results including CSS and OS are reported.
Mean operative time was 402.3 minutes (205–690) and blood loss was 345.3 ml (50–1000). The mean hospital stay was 17.1 days (5–62). All the surgeries were completed with no open conversion. Minor complications (Grade I and II) were reported in 27.7% of patients while major complications (grade III and above) were reported in 36.6% of patients. The mean nodal yield was 20.6 (0–46). Positive ureteric margins were found in 8.9% of patients. The average follow–up was 27.5 months (1–52). Daytime continence could be achieved in 89.2% of patients who underwent intracorporeal neobladder. The 3–year cancer specific survival (CSS) and overall survival (OS) was 80.2% and 69.8% respectively.
RARC with intracorporeal diversion is safe and reproducible in ‘non–pioneer’ tertiary centers with robotic expertise having acceptable operative time and complications as well as comparable functional and oncologic outcomes.
PMCID: PMC4408389  PMID: 25914833
radical cystectomy; neobladder; ileal conduit; intracorporeal diversion; robot–assisted laparoscopy
5.  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
6.  High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients 
BMC Cancer  2014;14:649.
The Wnt inhibitor Dickkopf-1 (DKK-1) has been linked to the progression of malignant bone disease by impairing osteoblast activity. In addition, there is increasing data to suggest direct tumor promoting effects of DKK-1. The prognostic role of DKK-1 expression in prostate cancer remains unclear.
A prostate cancer tissue microarray (n = 400) was stained for DKK-1 and DKK-1 serum levels were measured in 80 patients with prostate cancer. The independent prognostic value of DKK-1 expression was assessed using multivariate analyses.
DKK-1 tissue expression was significantly increased in prostate cancer compared to benign disease, but was not correlated with survival. However, high DKK-1 serum levels at the time of the diagnosis were associated with a significantly shorter overall and disease-specific survival. Multivariate analyses defined high serum levels of DKK-1 as an independent prognostic marker in prostate cancer (HR 3.73; 95%CI 1.44-9.66, p = 0.007).
High DKK-1 serum levels are associated with a poor survival in patients with prostate cancer. In light of current clinical trials evaluating the efficacy of anti-DKK-1 antibody therapies in multiple myeloma and solid malignancies, the measurement of DKK-1 in prostate cancer may gain clinical relevance.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-649) contains supplementary material, which is available to authorized users.
PMCID: PMC4167148  PMID: 25182503
DKK-1; Prostate cancer; Prognosis
7.  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
9.  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
10.  Circulating Fibronectin Controls Tumor Growth12 
Neoplasia (New York, N.Y.)  2013;15(8):925-938.
Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.
PMCID: PMC3730044  PMID: 23908593
11.  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
12.  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
13.  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
14.  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

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