Ex vivo Study of Partial Bladder Resection in a Porcine ModelEx vivo Study of Partial Bladder Resection in a Porcine Model.

INTRODUCTION: Partial cystectomy aims to preserve bladder function, yet its urodynamic impacts remain unclear. We investigate these effects using an ex-vivo porcine model, evaluating bladder volume, compliance, and wall thickness, alongside with thermal damage after bi- and monopolar resection. METHODS: Within an artificial human pelvis, we conducted partial bladder wall resections (5 cm2, 10 cm2). Urodynamic tests and sonography assessed volume, compliance, and thickness changes. Traction force for catheter retrieval and thermal collagen destruction were measured. RESULTS: Bladder compliance decreased by 1.12 and 1.5 after 5 cm2 and 10 cm2 resections respectively, with volume reductions of 3-6% and 10-18%. Wall thickness decreased by 20% and 30% post-resection. Comparable thermal damage was observed with mono- and bipolar resection methods. CONCLUSION: Our study outlines urodynamic impacts and technical considerations of partial cystectomy, affirming its endoscopic feasibility while highlighting potential bladder dysfunction risks.

Versatility and clinical effectiveness of a synthetic sealing hemostatic patch as alternative to parenchyma suturing in laparoscopic partial nephrectomy.

BACKGROUND: Improvements in laparoscopic partial nephrectomy (LPN) in order to minimize perioperative warm ischemia time (WIT), complications, and consequently patient outcome are desirable. Veriset™ is a ready-to-use hemostatic patch of absorbable oxidized cellulose and hydrogel components that has earlier been implemented in vascular and hepatic surgery. We report our experience using this device in LPN. METHODS: Patients with a solitary malignant renal mass suspicious for renal cancer underwent LPN with either the use of Veriset™ hemostatic patch (n = 40) or conventional suture technique (n = 40). Patient characteristics, operation time and WIT, postoperative course and complications were recorded retrospectively. Tumor complexity was calculated according to the R.E.N.A.L. score. Outcome was determined according to the "trifecta" criteria (negative surgical margin, WIT < 25 min, no complications within 30 days). RESULTS: No significant differences with regard to clinical parameters and median R.E.N.A.L. score (6) were observed between both groups. Operation time (mean 127.1 min vs. 162. 8 min; p = 0.001) and WIT were both lower in the Veriset™ group (14.6 min vs. 20.6 min; p = 0.01). No differences in surgical margins (p = 0.602) and overall complication rates at 30 (p = 0.599) and 90 days (p = 0.611) postoperatively were noticed. The surgical outcome according to "trifecta" was achieved in 65% of patients using Veriset™ and in 57.5% of patients by suture closure, respectively. CONCLUSION: The hemostatic Veriset™ patch can successfully be implemented in LPN. Handling and application appear favorable, thereby reducing operation time and WIT. The present results suggest that the device may represent an alternative to parenchyma suturing in LPN.

Stress urinary incontinence and regenerative medicine: is injecting functional cells into the urethra feasible based on current knowledge and future prospects?

PURPOSE OF REVIEW: Stress urinary incontinence (SUI) is one of the most prevalent disorders of the lower urinary tract. Actual standard conservative and surgical therapeutic modalities are offering a symptomatic relief without treating the underlying disorder. Therefore, advances in cell-based regenerative medicine have implemented the use of autologous cells with the aim to treat urinary incontinence. RECENT FINDINGS: Different types of cells have been investigated to regain the function of the rhabdosphincter muscle in the urethral closure complex: myogenic progenitor cells, adipose tissue-derived stromal cells and mesenchymal stromal cells were mostly applied. Many of the preclinical studies published success of cell therapies. However, most clinical studies included only a few patients and rather short periods of follow-up. Furthermore, different cell types as well as injection techniques were used. SUMMARY: The use of stem cells seems to be a feasible and safe technique with promising results in patients with SUI. However, as a result of heterogeneity of preclinical and clinical trials, the best approach to cell-based therapy in SUI is still under investigation. The definition of the optimal cell type applied for the regeneration of the sphincter, the development of surgical injection advices and adequate tools for the investigation of the muscle regeneration during the follow-up have to be investigated to improve the use of autologous cells in the therapy of SUI.

Determination of Free-PSA (fPSA) and fPSA/PSA-Ratio Using A Point-of-Care Device.

BACKGROUND: Prostate specific antigen (PSA) and free PSA (fPSA) are important tools for diagnosing prostate cancer (PC). Efforts are continuously undertaken to provide more patient-centered healthcare. The application of point-of-care (POC) systems for laboratory analyses represents a step in this direction. Previous investigations on total PSA measurements using a POC system (concile® Ω100 POC reader) showed good concordance with standard laboratory measurements. For the same POC reader a novel system for fPSA was developed. In the current study, we prospectively evaluated the quality of the POC system for fPSA. METHODS: Sixty-four patients undergoing PSA measurements in our outpatient clinic between 06/2015 and 09/2015 were enrolled in the study. We measured total PSA (tPSA) and fPSA with a POC reader system (concile® Ω100) and a standard laboratory system (Siemens Immulite 2000®) and compared the respective results using linear regression analyses for PSA, fPSA, and fPSA/tPSA ratio (%fPSA). RESULTS: The coefficients of determination (r²) for fPSA and %fPSA were 0.85 (p < 0.001) and 0.82 (p < 0.001) in the subgroup with total PSA between 4 and 10 ng/mL. In the subgroup with tPSA ≤ 4 ng/mL, r² for fPSA concile® was 0.55 (p < 0.001) and 0.10 (p = 0.088) for %fPSA. In the subgroup of tPSA > 10 ng/mL the r² for fPSA and %fPSA was 0.50 (p = 0.022) and 0.50 (p = 0.022), respectively. CONCLUSIONS: The POC fPSA values correlated well with the laboratory analyses, specifically in the clinically relevant diagnostic range of tPSA 4 - 10 ng/mL. These results complement the tPSA data obtained previously and indicate the reliability of the fPSA method and the resulting %fPSA score.

Collagen cell carriers seeded with human urothelial cells for urethral reconstructive surgery: first results in a xenograft minipig model.

PURPOSE: Urethral strictures are a common disease of the lower urinary tract in men. At present, the use of buccal mucosa is the method of choice for long or recurrent strictures. However, autologous tissue-engineered grafts are still under investigation for reconstructive urological surgery. The aim of this pilot study was to evaluate the use of human urothelial cells (HUC) seeded on bovine collagen type I-based cell carriers (CCC) in an animal model and to evaluate short-term outcome of the surgical procedure. METHODS: Four male Göttingen minipigs were used with immunosuppression (cyclosporine A) for this pilot xenograft study. HUC obtained from human benign ureteral tissue were stained by PKH26 and seeded on a collagen cell carrier (CCC). Seven weeks after urethral stricture induction and protective vesicostomy, cell-seeded CCC was implanted in the urethra with HUC luminal and antiluminal, respectively. After two weeks animals were euthanized, urethrography and histological assessment were performed. RESULTS: Surgery was technically feasible in all minipigs. Stricture was radiologically established 7 weeks after induction. CCC was visible after two weeks and showed good integration without signs of inflammation or rejection. In the final urethrography, no remaining stricture could be detected. Near porcine urothelium, PKH26-positive areas were found even if partially detached from CCC. Although diminished, immunofluorescence with pankeratin, CK20, E-cadherin and ZO-1 showed intact urothelium in several areas on and nearby CCC. CONCLUSION: Finally, this study demonstrates that the HUC-seeded CCC used as a xenograft in minipigs is technically feasible and shows promising results for further studies.

Return to Work and Normal Daily Life Activity after Open and Robot-Assisted Radical Prostatectomy--A Single Surgeon Analysis.

PURPOSE: To evaluate differences in health related quality of life and time to return to normal activities between patients treated with open radical prostatectomy (ORP) and robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Three hundred and two patients treated with RARP or ORP were prospectively enrolled. One year after surgery, patients received a questionnaire to evaluate social life, duration of being limited in daily and sexual life as well as satisfaction with the treatment. RESULTS: Both cohorts showed no differences in age, prostate specific-antigen-levels, Gleason score, prostate volume or T-stage (p > 0.05). Median blood loss was significant lower and the surgical time was significant higher in the RARP group. There were no significant differences regarding the duration of being limited in social or daily life or regarding the satisfaction with the treatment. The median time patients felt affected in their work was 2 months. There were no significant differences in terms of subjective global health status and HrQoL 3 months (p = 0.60 and p = 0.40) and 6 months (p = 0.30 and p = 0.20) after surgery. CONCLUSION: The present study confirms significant perioperative benefits for patients undergoing RARP compared to ORP. However, there is no difference in HrQoL as well as in the time to return to normal activities between patients treated with RARP and ORP.

Significance of apoptotic and non-apoptotic disseminated tumor cells in the bone marrow of patients with clinically localized prostate cancer.

BACKGROUND: Disseminated tumor cells (DTC) can be detected in a high proportion of patients with localized solid malignancies. In prostate cancer (PC), determination of DTCs is critically discussed as there are conflicting results on their prognostic value. The aim of the present study was to evaluate the presence and prognostic role of DTCs in PC patients with a high risk of disease recurrence. METHODS: 248 patients with clinically localized PC undergoing radical prostatectomy with features of increased risk of recurrence (PSA ≥10 ng/ml or Gleason score ≥ 4 + 3 = 7 or pT ≥3) were included. All patients underwent intraoperative bone marrow (BM) aspiration biopsy. BM cells were evaluated by immunocytochemistry for cytokeratines and the apoptosis marker caspase-cleaved cytokeratin 18 (M30). Results of immunocytochemistry were correlated with clinical and pathological parameters and clinical outcome of the patients. RESULTS: Of 248 patients, 47 (19.0%) had evidence of DTCs at time of radical prostatectomy. In 17 of these 47 patients (36.2%), DTCs expressed the apoptosis marker M30. We observed no correlation between the presence of DTCs and tumor stage, nodal stage, prostate-specific antigen, or Gleason score. After a median-follow-up of 58 months (23-76), no differences in rates of biochemical recurrence, development of metastases and cancer-specific death were observed between patients with and without DTCs while apoptosis markers had no role. CONCLUSIONS: In a single-centre cohort of patients with increased risk for disease recurrence, the presence of DTCs at the time of prostatectomy does not influence clinical outcome. For the first time in patients with PC, DTCs were evaluated for immunocytological features indicating apoptosis. Due to conflicting results of studies on DTCs, BM biopsies at time of radical prostatectomy cannot be recommended as a standard procedure in patients with clinically localized PC.

Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Quality of life outcomes after radical cystectomy: long-term standardized assessment of Studer Pouch versus I-Pouch.

PURPOSE: To investigate whether the ileal length used for the formation of two different orthotopic bladder substitutes [Studer (S)-Pouch vs. I-Pouch; 60 vs. 40 cm] impacts quality of life (QoL). MATERIALS AND METHODS: In this cross-sectional study, a total of 56 patients underwent radical cystectomy with ileal neobladder for bladder cancer [S-Pouch: 23 pat, 19 men, 4 women); I-Pouch: 33 pat (26 men, 7 women)]. They completed general (SF-36), cancer-specific (QLQ-C30) and bladder cancer-specific questionnaires (QLQ-BLM30) as well as a novel neobladder-specific questionnaire (TNQ). The questionnaire-based follow-up was 66 months (IQR 41-104; total range 9-161). RESULTS: I-Pouch patients reported better SF-36 physical health status (p = 0.026), QLQ-BLM30 continence scores (p < 0.001) and a more favorable QLQ-C30 total score compared to S-Pouch patients (p = 0.044). S-Pouch patients reported better QLQ-BLM30 general health status (p = 0.001). For the TNQ, no significant difference was found between both groups (p = 0.09). S-Pouch patients reported use of condom urinals more frequently (p = 0.026). S-Pouch patients tended to be on vitamin B12 substitution (p = 0.06). I-Pouch patients reported significantly higher micturition volumes (≥300 ml) compared to S-Pouch patients (30/33 vs. 16/23; p = 0.040). No differences were found with regard to bicarbonate supplementation and recurrent urinary tract infections. CONCLUSION: Non-neobladder-specific questionnaires show controversial results for QoL outcomes of patients with Studer and I-Pouch. The TNQ suggests that none of these two types of neobladder is superior to the other in terms of QoL. Hence, general questionnaires are not valid enough to adequately address QoL aspects in patients with different neobladders. Development and validation of neobladder-specific questionnaires are needed.

Robot-assisted radical cystectomy and intracorporeal neobladder formation: on the way to a standardized procedure.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Serum receptor activator of nuclear factor κB ligand (RANKL) levels predict biochemical recurrence in patients undergoing radical prostatectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is increasing evidence that the receptor activator of nuclear factor κB ligand (RANKL) pathway not only contributes to the development of bone metastases, but also influences tumour biology in earlier stages of cancer. The study shows that preoperative serum levels of RANKL and its inhibitor osteoprotegerin (OPG) have a prognostic impact in patients undergoing radical prostatectomy for clinically localized prostate cancer. Both high levels of RANKL and a higher RANKL/OPG ratio are independent predictors of early biochemical recurrence in these patients. OBJECTIVE: To assess the prognostic impact of proteins of the receptor activator of nuclear factor κB (RANKL) pathway in serum samples from patients undergoing radical prostatectomy. PATIENTS AND METHODS: We retrospectively determined soluble RANKL (sRANKL) and osteoprotegerin (OPG) by ELISA in serum samples of 178 patients undergoing radical prostatectomy between 2004 and 2006. Clinical and patient follow-up data were analysed using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS: Higher serum sRANKL levels (P = 0.01), lower serum OPG levels (P = 0.01) and a higher sRANKL/OPG ratio (P = 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis, adjusted for the common risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors. Neither sRANKL nor OPG showed a clear association with histopathological factors such as pT stage, pN Gleason score or resection margin status, nor were they associated with prostate-specific antigen level. CONCLUSIONS: Greater activity of the RANKL pathway in the serum of patients with prostate cancer undergoing radical prostatectomy is a risk factor for BCR. The RANKL pathway seems to contribute to the biological behaviour of prostate cancer even at the organ-confined stage of the disease.

Chemoprevention of prostate cancer by isoflavonoids.

In Europe, prostate cancer (PC) is the most common malignancy in males. There are three known risk factors strongly coherent to the development of PC: heredity, ethnical origin, and age. Migration studies have shown that environmental factors may influence the development of PC. In this context, specific nutritional components may exert an influence on the tumorigenesis of PC. Primary prevention of PC is still an important issue due to its high prevalence, treatment-associated morbidities, and long-term complications. Phytoestrogenes as flavonoids seem to play an essential role in the chemoprevention of PC which is possibly due to their hormonal function and antioxidative capability. Flavonoids and their subgroups are naturally existent in traditional asian and vegetarian nutrients as coverings of plants, fruits, and vegetables. Two of the most frequently investigated flavonoids are genistein and quercetin. These nutritional components may have therapeutic potential and may impact the development of PC. Even though these flavonoids show promising results in the chemoprevention of PC, the literature is almost experimental, epidemiological, and retrospective with a missing long-term follow-up. Therefore, randomized clinical trials are urgently needed to evaluate in depth its oncologic effects in PC.

Surgical removal of retroperitoneal tumors after chemotherapy treated testicular tumors.

In the era of chemotherapy, patients with advanced testicular tumor often presents with residual mass after completion of chemotherapy. Post chemotherapy RPLND is an important part of the multimodality treatment in these patients. According to current guidelines and recommendations, post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is recommended in NSGCT patients with all residual lesions and normalized tumor markers. In seminomas, surgery is considered in patients with residual tumor > 3 cm and a positive positron emission tomography (PET) scan. A conventional bilateral template should be performed for patients undergoing PC-RPLND. However, a modified template can be performed in select patients with low volume disease to reduce the long-term morbidities and peri-operative complications. Laparoscopic PC-RPLND is safe and feasible. The oncological outcome of PC-RPLND is excellent if all tumors are resected. PC-RPLND is a complex surgery and should be done in high volume tertiary centers.

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette-Guérin (BCG) Therapy.

In the expanding landscape of immune checkpoint inhibitors (CPI) in high-risk (HR) non-muscle-invasive bladder cancer (NMIBC), the role of programmed death ligand 1 (PD-L1) as prognostic and predictive is increasingly significant. However, data evaluating its variability and susceptibility to Bacillus Calmette-Guérin (BCG) therapy in HR NMIBC patients is scarce. This retrospective study analyzed 126 HR NMIBC tissue samples from 63 patients (38× BCG-treated, 25× BCG-naïve) at two time points to assess PD-L1 expression using the 'combined positivity score' (CPS) with the 22C3 DAKO antibody method and correlated it with clinicopathological parameters. A CPS > 10 defined PD-L1 positivity. The impact of initial PD-L1 status and its change over time on time-to-recurrence, progression-free survival, and overall survival (TTR, PFS, OS) was analyzed using Kaplan-Meier and Cox proportional hazard models. BCG treatment significantly increased PD-L1 expression (5.31 vs. 0.22, p = 0.0423), with PD-L1 positive cases rising post-treatment in the BCG group and remaining unchanged in BCG-naïve patients. Multivariate analysis including T-stage, CIS, grading, tumor size, multifocality, age, and sex revealed a significant correlation between PD-L1 status change to positivity and improved TTR (p = 0.03). Our findings demonstrate a potential modulation of the PD-L1 status by an intravesical BCG therapy. However, its prognostic value appears limited.

Porous Se@SiO2 nanocomposites play a potential inhibition role in hyperoxaluria associated kidney stone by exerting antioxidant effects.

Background: Nephrolithiasis seriously affects people's health with increasing prevalence and high recurrence rates. However, there is still a lack of effective interventions for the clinical prevention of kidney stones. Hyperoxaluria-induced renal tubular epithelial cell (TEC) injury is a known key factor in kidney stone formation. Thus, developing new drugs to inhibit the hyperoxaluria-induced TEC injury may be the best way. Methods: We synthesized the Se@SiO2 nanocomposites as described in Zhu's study. The size and morphology of the Se@SiO2 nanocomposites were captured by transmission electron microscopy. Cell viability was measured by a Cell Counting Kit-8 (CCK-8) assay. The mice were randomly divided into the following four groups: (I) the control group (n=6); (II) the Se@SiO2 group (n=6); (III) the glyoxylic acid monohydrate (GAM) group; and (IV) the GAM + Se@SiO2 group (n=6). The concentration of Se in the mice was quantified using inductively coupled plasma atomic emission spectroscopy. Results: The CCK-8 assays showed that Se@SiO2 nanocomposites had almost no obvious cytotoxicity on the Transformed C3H Mouse Kidney-1 (TCMK-1) cell. The mice kidney Se concentration levels in the Se@SiO2 groups (Se@SiO2 6.905±0.074 mg/kg; GAM + Se@SiO2 7.673±2.85 mg/kg) (n=6) were significantly higher than those in the control group (Control 0.727±0.072 mg/kg; GAM 0.747±0.074 mg/kg) (n=6). The Se@SiO2 nanocomposites reduced kidney injury, calcium oxalate crystal deposition, and the osteoblastic-associated proteins in the hyperoxaluria mice models. Conclusions: Se@SiO2 nanocomposites appear to protect renal TECs from hyperoxaluria by reducing reactive oxygen species production, suggesting the potential role of preventing kidney stone formation and recurrence.

Alterations of the RANKL pathway in blood and bone marrow samples of prostate cancer patients without bone metastases.

OBJECTIVES: The receptor activator of the NF-kB ligand (RANKL) pathway is a key mediator of prostate cancer (PC)-induced bone disease. However, little is known about this pathway in patients with non-metastatic PC. We aimed to investigate whether changes of RANKL, its inhibitor osteoprotegerin (OPG) and bone marrow-mesenchymal stromal cells (BM-MSCs) occur in PC patients without manifest bone metastases. PATIENTS AND METHODS: We determined OPG and soluble RANKL (sRANKL) in serum and corresponding bone marrow (BM) samples of 140 patients before radical prostatectomy by enzyme-linked immunosorbent assay (ELISA). As control serum samples of 50 patients with benign prostate hyperplasia were analyzed. BM mononuclear cells (BMNCs) of 16 PC patients were analyzed for expression of RANKL and CD271 (as marker for MSCs) by flow cytometry. RESULTS: PC patients had significantly lower serum levels of OPG compared to BPH patients (P = 0.007), whereas no differences were observed for serum sRANKL (P = 0.74). Both OPG and sRANKL concentrations of serum and corresponding BM samples correlated significantly (P < 0.0001 each). Interestingly, in PC patients, lower serum and BM OPG levels were associated with a higher proportion of BM-MSCs (P = 0.04 and 0.0016, respectively). No correlations were observed for sRANKL, OPG, BM-MSCs, and established risk parameters of PC. DISCUSSION: The results of the study indicate that localized PC is associated with early specific changes of the RANKL pathway in serum and bone marrow (BM). These changes might be part of the pre-metastatic niche of PC and implicate a potential benefit of RANKL inhibition in patients with localized PC.

Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?

BACKGROUND: Preclinical studies demonstrated effects of drugs inhibiting the mevalonate pathway including nitrogen-containing bisphosphonates (N-BPs) and statins on tumor growth and progression. The exact role of this pathway in prostate cancer (PC) has not been identified yet. Herein, we evaluate the expression of farnesyl pyrophosphate synthase (FPPS), the key enzyme of the mevalonate pathway, in PC. PATIENTS AND METHODS: Prostate cancer (PC) and benign prostate tissue of 114 men who underwent radical prostatectomy were constructed to a tissue microarray. Immunohistochemical staining of FPPS was quantified by the Remmele/Stegner immunoreactivity-score. Patients' clinical follow-up was assessed. IRS was correlated to pathological and clinical data. The impact of FPPS expression on clinical course was assessed univariate and multivariate. RESULTS: Mean IRS in PC and benign tissue was 5.7 (95% CI 5.0-6.5) and 2.6 (2.1-3.0, p < 0.0001). Mean IRS in PC tissue of patients with organ-confined and locally advanced disease (pT ≥ 3) was 5.09 (4.22-5.96) and 6.87 (5.57-8.17, p = 0.035). IRS of PC tissue significantly correlated with Gleason score (p = 0.03). Patients with PC tissue IRS >3 showed shorter recurrence-free survival compared to the remaining (p = 0.01). Increased FPPS expression is an independent risk factor for early biochemical recurrence (p = 0.032). CONCLUSIONS: This is the first study on FPPS in PC specimens. The association of FPPS with established histopathological risk parameters and biochemical recurrence implicates a contribution of the mevalonate pathway to PC progression. Further functional analysis is required to explore the role of this pathway in PC and to investigate whether FPPS expression affects the response of PC cells to N-BPs.

Gross Hematuria Associated with Anticoagulants and Antiplatelet Drugs: Analysis of Current Treatment Standards and Relevance of Co-medication and Pharmacological Interactions.

BACKGROUND: Anticoagulants and antiplatelet drugs are risk factors for gross hematuria (GH). Moreover, co-medication and drug-drug interactions (DDIs) may influence GH and its clinical course. OBJECTIVE: To investigate the relationship between GH and administration of oral anticoagulants and antiplatelet drugs. DESIGN, SETTING, AND PARTICIPANTS: Hospitalized patients with GH in an academic tertiary reference center were included. The use of individual compounds and DDIs were recorded and correlated to relevant clinical outcome factors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association between GH, DDIs, and clinical outcome parameters was analyzed using χ2 and Kruskal-Wallis tests. DDIs were systematically evaluated using a previously published calculator. RESULTS AND LIMITATIONS: A total of 189 patients with GH were eligible for the study. Of these, 76.2% took anticoagulants or antiplatelet drugs. The mean hospitalization duration was 4.7 d. The mean bladder irrigation duration was 3.1 d and the mean volume of irrigation fluid used was 22.8 l. Overall, 30.7% of patients had a pre-existing genitourinary malignancy. DDIs were observed in 31.9% of cases. The irrigation duration (p = 0.01) and volume of irrigation fluid (p = 0.05) were significantly associated with the use of anticoagulants or antiplatelet drugs. Specific DDI patterns were not predictive of clinical outcome. CONCLUSIONS: Medication with anticoagulants or antiplatelet drugs has a significant impact on GH and its clinical course. DDIs are a relevant issue and may lead to adverse clinical events or greater drug toxicity. Critical evaluation of medication and interdisciplinary counseling for patients with GH and urinary tract disease are recommended. PATIENT SUMMARY: Drugs taken to reduce the risk of blood clotting can increase the risk of blood in the urine (called hematuria) and medical expenses for treatment. Drug-drug interactions are a relevant issue, especially in elderly patients and those with other medical conditions who are taking several drugs. Thoughtful discussion of individual risk profiles for hematuria and medication is therefore recommended.

Influence of renal excretory function on the performance of urine based markers to detect bladder cancer.

PURPOSE: In hematuria cases urine based tests are used to detect bladder cancer, although the diagnostic yield remains insufficient due to influencing variables, including urinary tract infection. Many patients are elderly with renal insufficiency and have proteinuria as an additional influencing factor. To our knowledge no data are available on the accuracy of urine based bladder cancer tests in conjunction with renal function. MATERIALS AND METHODS: Urine samples of 449 patients with hematuria and histology were included in analysis. Cytology, fluorescence in situ hybridization, immunocytology and nuclear matrix protein 22 assay were done. Renal function was classified as normal, impaired or severely impaired based on serum creatinine, the glomerular filtration rate and proteinuria. False-positive rates were statistically compared in regard to renal function. RESULTS: A total of 382 patients did not have bladder cancer. There was an increased false-positive rate for creatinine and the glomerular filtration rate. The nuclear matrix protein 22 test showed a 22.0% and 46.7% false-positive rate in the normal and limited function cohorts, respectively (p = 0.05). Similar trends were noted for proteinuria. Indeterminate significance was detected, separating those with severely impaired function for immunocytology and those in the normal group for fluorescence in situ hybridization (p = 0.08 and 0.06, respectively). Proteinuria was a significant factor for urine cytology with increased false-positive results in the absence of urinary tract infection (p = 0.0017 and 0.05, respectively). CONCLUSIONS: To our knowledge this is the first study of renal function and the accuracy of urine based bladder cancer markers. Renal function influences the diagnostic yield. A decreased glomerular filtration rate was associated with increased false-positive nuclear matrix protein 22 results while proteinuria decreased urine cytology specificity. Renal function should be considered when urine based bladder cancer tests are interpreted.

XPA-210: a new proliferation marker determines locally advanced prostate cancer and is a predictor of biochemical recurrence.

PURPOSE: XPA-210 is a proliferation marker derived from Thymidine kinase-1. It is of clinical significance in kidney, breast, and bladder cancer. There are no data available for XPA-210 in prostate cancer (PC). Herein, we aim to determine the clinical usefulness of XPA-210 in PC. MATERIALS AND METHODS: In a retrospective study, cancer and benign tissue samples of 103 patients (median age 65 years, median PSA 9.04 ng/ml, median Gleason score 6) who underwent prostatectomy were constructed to a tissue micro array and stained for XPA-210. Semi-quantitative results were correlated with pathological and clinical data by Wilcoxon-Kruskall-Wallis and linear regression analysis. Expression levels in PC were correlated between the time of biochemical recurrence and the time to development of metastasis by the Kaplan-Meier method. Multivariate analysis was done to correlate those with the resection status. RESULTS: Mean staining score was 0.51-0.14 for tumor and benign tissue (P < 0.0001). Tumor staining score was significantly associated with Gleason score <6/≥6 (P < 0.0001) and T2/T >2 (P = 0.0007). When dividing the tumor score by the mean value, higher expression of XPA-210 was associated with a shorter time to biochemical recurrence (P = 0.003) and time to development of metastasis (P = 0.0061). Tumor staining (P = 0.0371) was an independent prognostic factor for biochemical relapse regardless of resection status. CONCLUSIONS: XPA-210 is a new tissue-based prognostic marker for prostate cancer histopathology. It reliably differentiates tumor and normal prostatic tissue predicting biochemical relapse and onset of metastatic disease. XPA-210 might be clinically useful for individual decision-making in PC-treatment.