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Background: Docetaxel plus prednisone is a standard treatment for castration-resistant prostate cancer. Cyclophosphamide may be an effective combination partner. Methods: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. Results: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered to be cancer related. Conclusions: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways in cancer. We investigated the expression of PDK-1 and DJ-1/PARK7 in RCC and their prognostic relevance. Methods: RCC tumor tissue and corresponding normal parenchyma samples were obtained from 91 patients with clear cell RCC. Expression of PDK-1 and DJ-1/PARK7 was determined on the mRNA and protein levels using quantitative RT-PCR and immunohistochemistry. Expression ratios tumor/normal were analyzed for associations with pathological stage and grade (Kruskal-Wallis ANOVA, chi-square test). Potential associations with progression-free and overall survival were analyzed using Cox regression models. Results: PDK-1 mRNA expression was up-regulated as compared to normal tissue ( p < 0.001). Differences were observed by tumor stage ( p < 0.05) with a trend toward lower expression with increasing stage ( p > 0.01). Expression ratio tumor/normal also showed differences by tumor stage with the lowest ratio observed in advanced (pT3) disease. MRNA expression data were confirmed on the protein level with the lowest protein expression in pT3 tumors. PDK-1 expression ratio tumor/normal was inversely associated with outcome after adjustment for stage and grade (HR, 0.54; 95 % CI, 0.31-0.94). No associations observed for DJ-1/PARK7 expression. Conclusions: PDK is up-regulated in RCC, but down-regulation may be associated with progression toward a metastasizing behavior. Given the role of PDK-1 in the control of glucose metabolism, aerobic glycolysis via up-regulation of PDK-1 may be an early event in RCC development, but less relevant for the progression toward an aggressive phenotype. [ABSTRACT FROM AUTHOR]

Objective: The risk of local recurrence after radical prostatectomy (RP) is considerably dependent on local tumor stage. To improve local staging, the aim of this study was to assess the feasibility of quantitative methylation-specific PCR (Q-MSP) for the identification of promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1) to detect occult prostate cancer (PCa) cells in the prostatic fossa after RP. Methods: A total of 39 consecutive patients with clinically organ-confined PCa underwent RP. After gland excision, biopsies were obtained from eight defined areas of the prostatic fossa and bisected for both histopathological and molecular analyses. Results were related to clinicopathological data including tumor stage, Gleason score, prostate-specific antigen (PSA), and biochemical recurrence. Results: Of 39 patients, 11 with PCa had at least one positive molecular margin status indicated by GSTP1 methylation. These included 5 of 17 (29.4%) with organ-confined and 6 of 22 (27.3%) with advanced (≥pT3 and/or pN+) PCa. GSTP1 methylation in surgical margins strongly correlated with histopathological R-status ( P = 0.022) and preoperative PSA ( P = 0.01) whereas no association with tumor stage (pT2 vs pT3), grade (Gleason score <7 vs ≥7), and lymph node status was found. No patient experienced biochemical relapse. Conclusions: GSTP1 hypermethylation detected by Q-MSP in prostatic fossa biopsies after RP is well suited for the detection of occult tumor cells in surgical margins. However, the limited number of patients and the short-term follow-up does not allow definite conclusions on the prognostic value of GSTP1 in surgical margins. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Treatment recommendations such as interdisciplinary guidelines are always based on scientific publications. However, high-quality studies are very often focused on single-centre series of selected cases. Health care research has failed to provide comprehensive information that describes the clinical reality of prostate cancer management even in smaller centres. This is a health care research study with 17 participating centres. Any prostate cancer centre can use the internet-based database , at no additional cost, to collect and analyze data for quality management, to conduct consecutive follow-up assessments, and to compare their data with the averages recorded by all other centres. The database also enables time trend analysis of certain quality parameters in an annual comparison. OBJECTIVES • To report our experience with an Internet-based multicentre database that enables tumour documentation, as well as the collection of quality-related parameters and follow-up data, in surgically treated patients with prostate cancer. • The system was used to assess the quality of prostate cancer surgery and to analyze possible time-dependent trends in the quality of care. PATIENTS AND METHODS • An Internet-based database system enabled a standardized collection of treatment data and clinical findings from the participating urological centres for the years 2005-2009. • An analysis was performed aiming to evaluate relevant patient characteristics (age, pathological tumour stage, preoperative International Index of Erectile Function-5 score), intra-operative parameters (operating time, percentage of nerve-sparing operations, complication rate, transfusion rate, number of resected lymph nodes) and postoperative parameters (hospitalization time, re-operation rate, catheter indwelling time). • Mean values were calculated and compared for each annual cohort from 2005 to 2008. The overall survival rate was also calculated for a subgroup of the Berlin patients. RESULTS • A total of 914, 1120, 1434 and 1750 patients submitted to radical prostatectomy in 2005, 2006, 2007 and 2008 were documented in the database. • The mean age at the time of surgery remained constant (66 years) during the study period. • More than half the patients already had erectile dysfunction before surgery (median International Index of Erectile Function-5 score of 19-20). • During the observation period, there was a decrease in the percentage of pT2 tumours (1% in 2005; 64% in 2008) and a slight increase in the percentage of patients with lymph node metastases (8% in 2005; 10% in 2008). No time trend was found for the operating time (142-155 min) or the percentage of nerve-sparing operations (72-78% in patients without erectile dysfunction). • A decreasing frequency was observed for the parameters: blood transfusions (1.9% in 2005; 0.5% in 2008), postoperative bleeding (2.6%; 1.2%) and re-operations (4.5%; 2.8%). The mean hospitalization time decreased accordingly (10 days in 2005; 8 days in 2008). The examined subcohort had an overall mortality of 1.5% (median follow-up of 3 years). CONCLUSIONS • An Internet-based database system for tumour documentation in patients with prostate cancer enables the collection and assessment of important parameters for the quality of care and outcomes. • The participating centres show an improvement in the quality of surgical management, including a reduction of the complication rate. [ABSTRACT FROM AUTHOR]

Transperitoneal radical cystectomy with intraperitoneal ileal neobladder is the standard surgical treatment for muscle-invasive bladder cancer. To reduce morbidity, we established in 2002 an extraperitoneal approach including extraperitonealization of the ileal neobladder. This retrospective study compares the results of the two procedures with a focus on the peri- and postoperative course. Ninety-five male patients with invasive urothelial cancer who underwent radical cystectomy with ileal neobladder at our hospital from January 1998 to May 2007 were analyzed. Forty-seven patients underwent transperitoneal radical cystectomy with intraperitoneal ileal neobladder. The remaining 48 were submitted to the extraperitoneal technique with extraperitonealization of the neobladder. We compared both methods regarding operating time, intraoperative blood loss, complications and oncological outcome. The incidence of postoperative ileus was significantly lower after the extraperitoneal than after the transperitoneal approach (2/48 vs. 10/47 cases; p = 0.012). However, pelvic lymphoceles were more frequent (6 vs. 0 cases; p = 0.014). The two techniques did not differ with regard to the other major and minor complications, the operating time (mean 377.4 vs. 405.4 min) or the intraoperative blood loss (mean 363 vs. 412 ml). Oncological outcome disclosed no difference between both techniques. The extraperitoneal technique with extraperitonealization of the ileal neobladder is comparable in safety and reliability to the transperitoneal surgical approach and yields good peri- and postoperative results with regard to the parameters we examined. Noteworthy are the significant reduction of postoperative ileus and the higher incidence of lymphoceles. Both may be caused by the separate extraperitoneal regional healing processes. [ABSTRACT FROM AUTHOR]

Germ cell tumors are the most common malignancies in men under 50 years and also the most common cause of death from solid tumors in this age group. The past few decades have seen no change in the fact that 40% of such tumors have already metastasized by the time of initial diagnosis. In contrast to the majority of metastasized solid tumors, germ cell tumors can be effectively treated by cisplatin-based polychemotherapy. They only rarely show resistance mechanisms. Resistance to chemotherapeutics has been extensively examined in urological and nonurological tumors. Various mechanisms enabling malignant tumor cells to avoid the cytotoxic effect of chemotherapeutics have been discovered in the past few years. On the other hand, the reasons for the excellent responsiveness of germ cell tumors to chemotherapy have remained unclear. Theoretical models for the high cure rates of germ cell tumors after cisplatin-based polychemotherapy consider, on the one hand, molecular-biological aspects of malignant germ cell tumor cells per se and, on the other hand, the immunological and nonimmunological response mechanisms of the patients. This review article summarizes theoretical models for the high chemotherapy sensitivity of germ cell tumors and points out new therapeutic prospects. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Numerous molecular parameters are thought to be implicated in renal cell carcinoma (RCC) tumor biology and may therefore reflect the malignant potential of individual tumors. Their investigation may thus help to improve the postoperative management of RCC patients. This study characterized the mRNA expression levels and evaluated the prognostic effect of the mitochondrial inhibitor of apoptosis antagonists Smac/DIABLO and Omi/HtrA2 in tumor tissue from clear-cell RCC patients. The relative gene expression (RGE) was analyzed by real-time RT-PCR in tumor tissue obtained from 85 patients (median follow-up: 47 months) following surgical treatment. Expression data was correlated to clinico-pathological variables and outcome. The RGE of Smac/DIABLO was lowest in patients with primary metastases, intermediate in those who progressed to metastatic disease, and highest in those who did not develop metastases during follow-up ( P = 0.006). Expression levels of Smac/DIABLO and Omi/HtrA2 were strongly correlated with each other (Pearson coefficient 0.90). Recurrence-free and tumor-specific survival was shorter in patients with low Smac/DIABLO levels ( P = 0.019 and P = 0.001) as well as in those with low Omi/HtrA2 tumor expression ( P = 0.033 and P = 0.032). Contrary to Omi/HtrA2, low Smac/DIABLO levels were still predictive of a reduced time to recurrence (hazard rate 5.31; 95% CI: 1.16–24.21) and tumor-specific survival (hazard rate 4.24; 95% CI: 1.22–14.77) in explorative multivariate analysis. The mRNA expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 are strongly inter-correlated, but do not relate to tumor stage or grade of RCC. Our data suggest that expression of Smac/DIABLO, but not Omi/HtrA2, is inversely associated with outcome of RCC patients. [ABSTRACT FROM AUTHOR]

The polycomb group protein Enhancer of Zeste Homolg 2 (EZH2), a repressor of gene transcription, has been linked to the progression of various malignancies. This study was done to examine a potential correlation of EZH2 mRNA expression with clinicopathological parameters and outcome in patients with urothelial carcinoma (UC) of the bladder. We determined the relative EZH2 gene expression by quantitative RT-PCR in tumor specimens from a cohort of 100 patients with UC (mean follow-up 44.2 months). EZH2 expression levels were correlated to pathological tumor features and outcome. Enhancer of Zeste Homolg 2 was expressed in 90% of the tumor samples. Expression levels increased in parallel with tumor stage ( P = 0.002). High grade UC displayed significantly elevated EZH2 levels compared to low grade disease ( P < 0.0001). High EZH2 expression was related to an abbreviated time to recurrence in muscle invasive carcinomas (pT ≥ 2) ( P = 0.028). No such correlation was detected in the group of superficial tumors (pT ≤ 1) ( P = 0.191). High EZH2 expression levels were associated with an increased risk of tumor related death in the univariate analysis (relative risk, 3.1; P = 0.029). This association became non-significant when the prognostic effect of tumor stage was considered in a multivariate model. Enhancer of Zeste Homolg 2 expression is related to an aggressive tumor behavior but due to its strong association with pathological features, EZH2 levels do not provide independent prognostic information. [ABSTRACT FROM AUTHOR]

The functional relationship between promoter hypermethylation and gene inactivation has been demonstrated for few genes only. We examined the promoter methylation status of two important tumor suppressor genes APAF-1 and DAPK-1 in bladder cancer as well as the mRNA expression pattern of these two genes for possible correlation between promoter hypermethylation and transcriptional repression. The methylation status and mRNA expression levels were related to clinicopathological features in 34 patients with transitional cell carcinoma (TCC) of the bladder with a median clinical follow-up of more than 45 months. Tissue from ten patients with nonmalignant disease served as a control group. Quantitative real-time PCR-based detection methods were used for determination of the normalized index of methylation (NIM) as well as the mRNA expression level. APAF-1 and DAPK-1 methylation and mRNA expression was observed in all tumor and normal control samples investigated. Methylation (NIM) levels were significantly higher in tumor tissue for APAF-1 and DAPK-1, but median mRNA expression levels did not differ significantly comparing tumorous and non tumorous tissue. No correlation between expression levels of APAF-1 and DAPK-1 mRNA and tumor stage or grade was observed. However, in superficial TCC a strong correlation between higher NIM levels and lower mRNA expression of the APAF-1 gene was observed ( P = 0.014). Our results, although preliminary, provide first time in vivo expression analysis of the APAF-1 gene in bladder cancer specimen, suggesting expression control by promoter methylation in early stage tumor disease of the bladder. [ABSTRACT FROM AUTHOR]

The expression of the inhibitor of apoptosis (IAP) family members cIAP1 and cIAP2 have been shown to be altered in various cancer entities. This study was done to characterize the tumor-related expression profile of cIAP1 and cIAP2 in patients with renal cell carcinomas (RCC) and to evaluate its potential predictive value after curative resection. Expression of cIAP1 and cIAP2 was analyzed by real-time RT-PCR in RCC and corresponding normal tissue samples obtained from a cohort of 127 RCC patients (median follow-up: 48 months) undergoing surgical treatment. Expression data was correlated to histopathological variables and outcome. Overexpression of cIAP1 and cIAP2 occurred in most RCC specimens ( p < 0.001), but 20% of the patients had lower cIAP levels in malignant than in normal tissue. The cIAP1 expression correlated with the tumor stage, levels being higher in pT1 tumors than in advanced pathological stages ( p = 0.002). Decreased cIAP1 expression in RCC relative to paired normal samples predicted an abbreviated time to recurrence (hazard rate 2.96; 95% CI: 1.23-7.09) and tumor-specific survival (hazard rate 2.78; 95% CI: 1.22-6.38) irrespective of the tumor stage and grade. The prognostic effect of cIAP1 was most pronounced in patients with pT3 disease (log rank test p = 0.001). The results of uni- and multivariate analysis suggest a prognostic value of cIAP1 expression for RCC patients, downregulation indicating an aggressive, potentially lethal phenotype. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Purpose: Blunt abdominopelvic trauma frequently results in injuries to the urinary organs, especially in polytrauma. The urotrauma is rarely an acute life-threatening event; however, it may lead to severe complications. Methods: This review addresses the under-representation of urological trauma management in interdisciplinary medical training and its impact on patient outcomes. It compiles evidence-based recommendations and guidelines from multiple specialties, focusing on common challenges in managing these injuries. The resource is tailored for primary care physicians in radiology, trauma surgery, internal medicine, urology, and nephrology. Results: Urinary tract injuries can occur even if the patient's condition initially appears normal. An exclusion diagnosis is obligatory by contrast medium tomography of the entire urinary tract and, if suspected, an additional uroendoscopic examination. Interventional therapy by catheterisation of the urinary tract is often required. Urosurgical treatment is not commonly needed, but when there is a demand, it must be administered via an interdisciplinary approach with visceral and trauma surgery. Over 90% of life-threatening kidney injuries (usually up to grade 4–5 AAST) are presently treated by interventional radiologists. Acute kidney injury (AKI) as a complication in trauma patients may complicate clinical management and often worsens the outcome. The incidence of trauma-associated AKI in patients admitted to an intensive care unit is high. Conclusions: Patients suffering from blunt abdominopelvic trauma should ideally be referred to certified trauma centres with subspecialised or fully specialised care provided by visceral/vascular surgery, trauma surgery, interventional radiology, urology, and nephrology. This recommendation is based on the complex nature of most damage patterns. [ABSTRACT FROM AUTHOR]

Background: For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called "functional autoantibodies" bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods: Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56–78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48–82 years, median 64) with urinary stone disorders (controls). Results: Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007. Conclusions: We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Treatment for localized prostate cancer (PCa) can cause long-term changes in erectile functioning. However, data on the importance of sexuality and possible consequences of altered erectile functioning on self-esteem in men with localized PCa are lacking.Methods: Self-report questionnaires were completed by 292 men with PCa, initially managed with active surveillance (AS) or radical prostatectomy (RP). Independent t-tests were conducted to evaluate group differences. A sequential multiple regression model was fitted to analyze the associations between the importance of sexuality, changes in erectile functioning and impairment of self-esteem. Interaction effects were tested using simple slope analyses.Results: Participants were 70 ± 7.2 years old and 66.5% rated sex as being "rather/very important". The two groups differed markedly in changes in erectile functioning, importance of sexuality and impairment of self-esteem (p < .001), with higher values in RP patients. Regression analysis showed that after adjustment for control variables and importance of sexuality, changes in erectile functioning were still associated with impairment of self-esteem (B = .668, SE = .069, p < .001). The interaction of changes in erectile functioning and importance of sexuality reached significance (B = .318, SE = .062, p < .001).Conclusions: RP patients report more changes in erectile functioning than AS patients. Moreover, in men with localized PCa, erectile functioning and self-esteem are closely related. Sexuality seems to be important for the majority of these men. Physicians should address the possibility of erectile dysfunction and its potential effects on psychological well-being before the treatment decision. [ABSTRACT FROM AUTHOR]

To demonstrate the added benefit of multiparametric (mp)MRI risk stratification during active surveillance. This prospective, single-arm, nonrandomized study included 82 men with low-risk prostate cancer (PCa). We compared two biopsy strategies in parallel. The first biopsy strategy was an in-bore and transrectal ultrasound (TRUS) biopsy in men with suspicious mpMRI findings. The second was a TRUS biopsy in all 82 men, blinded to the results of the previously performed mpMRI. We identified 27/82 men with suspicious mpMRI. Of those 27 men, we detected 8/27 with csPCa on biopsy, and we identified two men with in-bore biopsy exclusively, three men with TRUS biopsy exclusively, and three men with both biopsy strategies. Of the 55/82 men with nonsuspicious mpMRI (who only received TRUS biopsies), two men had csPCa. TRUS biopsy of the entire cohort of 82 men would have led to the correct diagnosis of 80% men with csPCa, requiring all 82 men to receive biopsies (csPCa in 10% of the 82 biopsies). Conducting in-bore biopsies plus TRUS biopsies in men with suspicious mpMRI would have also led to the detection of 80% of men with csPCa, requiring only 27 men to receive biopsies (csPCa in 30% of the 27 biopsies). The combination of TRUS and in-bore biopsies, limited to men with suspicious mpMRI, resulted in a similar detection rate of csPCa compared to TRUS biopsies of all men but required only one-third of men to undergo biopsy. Our results indicate that in-bore and TRUS biopsies continue to complement each other. [ABSTRACT FROM AUTHOR]