Supratrigonal cystectomy and augmentation cystoplasty with ileum or ileocecum in the treatment of ulcerative interstitial cystitis/bladder pain syndrome: a 14-year follow-up.

INTRODUCTION AND HYPOTHESIS: This study analyzes the long-term results of supratrigonal cystectomy and augmentation cystoplasty in patients with severe ulcerative interstitial cystitis/bladder pain syndrome (IC/BPS) and reduced bladder capacity. METHODS: Outcome data were retrospectively and prospectively collected and analyzed in women who underwent supratrigonal cystectomy and augmentation cystoplasty for ulcerative IC/BPS at Muenster University Hospital between 1991 and 2006. We used cross-tabulation and Pearson's Chi-squared test to examine how outcome is influenced by age, preoperative functional bladder volume, and choice of augmentation material. RESULTS: After a median 171-month follow-up, analysis could be done in 26 of 27 patients. Persistent pain necessitated early revision in 2 patients (7.7%). Mean postoperative O'Leary Sant IC Score was 12.7 in the prospectively questioned patients. Responses to Patient Global Impression of Improvement (PGI-I) were: "very much better" in 15 cases (65.2%) and "much better" in 7 (30.4%). Twelve patients (52.2%) emptied their augmented bladder voluntarily, whereas 7 (32%) needed intermittent self-catheterization (ISC). The rate of patients requiring ISC tended to be lower when detubularized ileocecal bowel was used. All 5 patients (19.2%) with late relapse of ulcerative IC/BPS needed ISC. CONCLUSIONS: Severe ulcerative IC/BPS can be curatively treated in some patients by supratrigonal cystectomy and augmentation, which is associated with a high satisfaction rate and few long-term complications even over a very long follow-up. In our analysis, the need for ISC is a risk factor for late relapse, although ileocecal augmentation could increase the proportion of patients with sufficient voluntary micturition.

High/low-volume center experience predicts outcome of AMS 800 in male stress incontinence: Results of a large middle European multicenter case series.

AIM: To analyze the influence of implantation volume of artificial sphincters (AMS 800) on outcome in a large central European multicenter cohort study. METHODS: As part of the DOMINO (Debates on Male Incontinence) project, the surgical procedures and outcomes were retrospectively analyzed in a total of 473 patients who received an artificial sphincter (AMS 800) between 2010 and 2012. Clinics that implanted at least 10 AMS 800 per year were defined as high-volume centers. RESULTS: Sixteen centers had a mean rate of 9.54 AMS 800/y of which five clinics were identified as high-volume centers. They implanted significantly more double cuffs (55% vs 12.1%; P < .001), used the perineal approach significantly more often (78% vs 67.7%; P = .003) and chose larger mean cuff sizes (4.63 cm vs 4.42 cm; P = .002). With a mean follow-up of 18 months, the revision rate was significantly higher at low-volume centers (38.5% vs 26.7%; P = .037), urethral erosion being the main reason for revision. Social continence (0-1 pads/24 h) was achieved significantly more often in high-volume centers (45.5% vs 24.2%; P = .002). CONCLUSIONS: Our study showed significantly better continence results and lower revision rates at high-volume centers, confirming earlier results that are still true in this decade. We, therefore, recommend surgery for male incontinence at qualified centers.

The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells.

Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 µM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis.

The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma.

BACKGROUND: Up to 50% of penile squamous cell carcinomas (pSCC) develop in the context of high-risk human papillomavirus (HR-HPV) infection. Most of these tumours have been reported to show basaloid differentiation and overexpression of tumour suppressor protein p16(INK4a). Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour aggressiveness, however, is still subject to research. METHODS: In tissue specimens from 58 patients with surgically treated pSCC between 1995 and 2012, we performed p16(INK4a) immunohistochemistry and DNA extraction followed by HPV subtyping using a PCR-based approach. The results were correlated with histopathological and clinical parameters. RESULTS: 90.4% of tumours were of conventional (keratinizing) subtype. HR-HPV DNA was detected in 29.3%, and a variety of p16(INK4a) staining patterns was observed in 58.6% of samples regardless of histologic subtype. Sensitivity of basaloid subtype to predict HR-HPV positivity was poor (11.8%). In contrast, sensitivity and specificity of p16(INK4a) staining to predict presence of HR-HPV DNA was 100% and 57%, respectively. By focussing on those samples with intense nuclear staining pattern for p16(INK4a), specificity could be improved to 83%. Both expression of p16(INK4a) and presence of HR-HPV DNA, but not histologic grade, were inversely associated with pSCC tumour invasion (p = 0.01, p = 0.03, and p = 0.71). However, none of these correlated with nodal involvement or distant metastasis. In contrast to pathological tumour stage, the HR-HPV status, histologic grade, and p16(INK4a) positivity failed to predict cancer-specific survival. CONCLUSIONS: Our results confirm intense nuclear positivity for p16(INK4a), rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in pSCC. HR-HPV / p16(INK4a) positivity, independent of histological tumour grade, indicates a less aggressive local behaviour; however, its value as an independent prognostic indicator remains to be determined. Since local invasion can be judged without p16(INK4a)/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of pSCC.

Serum 17ß-estradiol fails as a marker in identification of aggressive tumour disease in patients with localized prostate cancer.

BACKGROUND: There is evidence that obesity is associated with an aggressive prostate cancer (PC). Furthermore, preclinical studies suggest that oestrogens may play a pivotal role in this context. The biological processes underlying these observations are not fully understood. We prospectively evaluated whether obesity and/or preoperative estradiol levels are associated with high-grade cancer in patients with clinically localized PC at the time they underwent radical retropubic prostatectomy (RRP). METHODS: Preoperative sex hormone serum 17ß-estradiol (E2) as well as body mass index (BMI) and waist circumference (WC) were assessed in a cohort of 746 consecutive men treated with RP from February 2011 to October 2014. The data were correlated with patient-specific and clinicopathologic variables. RESULTS: A total of 746 patients underwent RRP. Median age was 68.0 years. Median E2 serum level was 18.3 ng/l (IQR 12.9-24.2 ng/l). Median BMI was 26.6 kg/m(2) (IQR 24.6-29.1 kg/m(2)), and the median WC was 103 cm (IQR 96-110 cm). Serum E2 below or above the normal range was not found more frequently in obese patients (high BMI: p = 0.62; large WC: p = 0.83). E2 was not associated with BMI in our cohort of patients (r = 0.07, p = 0.10) or WC (r = 0.07, p = 0.10). There was no association between preoperative serum E2 levels and tumour stage (p = 0.86, Fisher's exact), tumour grade (p = 0.37), lymph node involvement (p = 0.59) or Gleason score (p = 0.44). However, obesity correlated with tumour stage and grade (p = 0.036, Fisher's exact) and nodal metastasis (p = 0.039, Fishers' exact). CONCLUSION: Pretreatment serum 17ß-estradiol (E2) cannot be considered as a suitable marker for aggressive tumour disease in patients with localized prostate cancer.

Survival advantage of partial over radical nephrectomy in patients presenting with localized renal cell carcinoma.

BACKGROUND: Partial nephrectomy (PN) preserves renal function and has become the standard approach for T1a renal cell carcinoma (RCC). However, there is still an ongoing debate as to which patients will actually derive greater benefit from partial than from radical nephrectomy (RN). The aim of this study was to retrospectively evaluate the impact of the type of surgery on overall survival (OS) in patients with localized RCC. METHODS: Renal surgery was performed in 4326 patients with localized RCC (pT ≤ 3a N/M0) at six German tertiary care centers from 1980 to 2010: RN in 2955 cases (68.3%), elective (ePN) in 1108 (25.6%), and imperative partial nephrectomy (iPN) in 263 (6.1%) cases. The median follow-up for all patients was 63 months. Kaplan-Meier and Cox regression analyses were carried out to identify prognosticators for OS. RESULTS: PN was performed significantly more often than RN in patients presenting with lower tumor stages, higher RCC differentiation, and non-clear cell histology. Accordingly, the calculated 5 (10)-year OS rates were 90.0 (74.6)% for ePN, 83.9 (57.5)% for iPN, and 81.2 (64.7)% for RN (p < 0.001). However, multivariate analysis including age, sex, tumor diameter and differentiation, histological subtype, and the year of surgery showed that ePN compared to RN still qualified as an independent factor for improved OS (HR 0.79, 95% CI 0.66-0.94, p = 0.008). CONCLUSION: Even allowing for the weaknesses of this retrospective analysis, our multicenter study indicates that in patients with localized RCC, PN appears to be associated with better OS than RN irrespective of age or tumor size.

Corpulence is the crucial factor: association of testosterone and/or obesity with prostate cancer stage.

OBJECTIVES: To evaluate whether low testosterone levels or obesity, or both, are directly associated with tumor stage/grade in patients with clinically localized prostate cancer. METHODS: Preoperative androgen serum levels (total and free testosterone), sex hormone-binding globulin, body mass index and waist circumference were assessed in 510 consecutive European Caucasian men treated with radical prostatectomy. Hormone levels and body mass index/waist circumference were correlated with patient- and tumor-specific characteristics using multivariable logistic regression analysis. RESULTS: Even though we confirmed an inverse correlation between bodyweight and testosterone levels, only overweight - but not low testosterone - was associated with advanced disease and poor differentiation of prostate cancer. Using multivariate analyses, both body mass index ≥30 kg/m(2) and waist circumference >110 cm were associated with high-grade disease (Gleason score ≥8). A waist circumference >110 cm also correlated significantly with lymph node metastasis. CONCLUSIONS: This is the first study showing that obesity, but not low serum testosterone levels, is significantly associated with high grade and metastatic disease in men diagnosed with clinically localized prostate cancer. The present findings suggest that low androgen levels at diagnosis, which used to be held responsible for the development of aggressive prostate cancer, is only an epiphenomenon of obesity rather than the cause of prostate cancer development and/or progression.

High CRP values predict poor survival in patients with penile cancer.

BACKGROUND: High levels of circulating C-reactive protein (CRP) have recently been linked to poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP level in patients with squamous cell carcinoma (SCC) of the penis. METHODS: This retrospective analysis included 79 penile cancer patients with information about their serum CRP value prior to surgery who underwent either radical or partial penectomy at two German high-volume centers (Ulm University Medical Center and Hannover Medical School) between 1990 and 2010. They had a median (mean) follow-up of 23 (32) months. RESULTS: A significantly elevated CRP level (>15 vs. ≤ 15 mg/l) was found more often in patients with an advanced tumor stage (≥pT2) (38.9 vs. 11.6%, p=0.007) and in those with nodal disease at diagnosis (50.0 vs. 14.6%, p=0.007). However, high CRP levels were not associated with tumor differentiation (p=0.53). The Kaplan-Meier 5-year cancer-specific survival (CSS) rate was 38.9% for patients with preoperative CRP levels above 15 mg/l and 84.3% for those with lower levels (p=0.001). Applying multivariate analysis and focusing on the subgroup of patients without metastasis at the time of penile surgery, both advanced local tumor stage (≥pT2; HR 8.8, p=0.041) and an elevated CRP value (>15 mg/l; HR 3.3, p=0.043) were identified as independent predictors of poor clinical outcome in patients with penile cancer. CONCLUSIONS: A high preoperative serum CRP level was associated with poor survival in patients with penile cancer. If larger patient populations confirm its prognostic value, its routine use could enable better risk stratification and risk-adjusted follow-up of patients with SCC of the penis.

Circulating free testosterone is an independent predictor of advanced disease in patients with clinically localized prostate cancer.

PURPOSE: To evaluate the clinical value of the pre-treatment calculated free testosterone (fT), total testosterone (tT), sexual hormone-binding globulin (SHBG) and estradiol (E2) levels as potential predictors of pathological stage and grade in patients with clinically localized prostate cancer. METHODS: Preoperative sex hormone serum levels were prospectively measured in 137 patients who underwent radical prostatectomy at the University Hospital Ulm from February 2011 to February 2012. We related sex hormone levels to clinicopathologic data including tumour stage, Gleason score and prostate specific antigen (PSA). (Non)parametric statistical tests and receiver operating characteristics (ROC) analyses were performed. RESULTS: Preoperative serum fT levels were significantly associated with advanced disease (pT3-4 and/or pN+; p = 0.047) and lymph node involvement (pN+) (p = 0.027). Patients with low (<0.047 µg/l) vs. normal fT values (≥0.047 µg/l) were associated with higher tumour stage (p = 0.049), positive lymph node status (pN+ , p = 0.038) and advance disease (p = 0.016). Moreover, low tT values (≤0.193 µg/l; p = 0.018) and elevated SHBG levels (>48.4 nmol/l, p = 0.043) correlated with a higher Gleason score. Conversely, E2 levels were not associated with tumour stage or grade. Applying multivariate analysis, unlike tT, SHBG, and E2 levels, low fT levels were a significant independent predictor of advanced disease (relative hazard ratio 3.05, p = 0.028). CONCLUSIONS: Low pre-treatment fT levels were significantly associated with tumour stage and extraprostatic tumour spread and might-in addition or combination with PSA-serve as a useful prognostic parameter for prostate cancer patients prior to radical prostatectomy.

Elevated C-reactive protein values predict nodal metastasis in patients with penile cancer.

BACKGROUND: The nodal status is a strong predictor for cancer specific death in patients with penile carcinoma, and the C-reactive protein (CRP) level at diagnosis has recently been shown to be associated with poor clinical outcome in various solid malignancies. Therefore, this retrospective study was performed to evaluate the association between preoperative CRP levels and the incidence of nodal metastasis in patients with squamous cell carcinoma (SCC) of the penis. METHODS: The analysis included 51 penile cancer patients who underwent either radical or partial penectomy for pT1-4 penile cancer between 1990 and 2010. The nodal status was correlated with patient and tumor specific characteristics. RESULTS: Sixteen (31%) patients had lymph node metastasis at the time of penile cancer surgery. Nodal status was associated with tumor stage but did not correlate significantly with tumor grade. In contrast, high presurgical CRP levels were significantly associated with the diagnosis of nodal involvement (p = 0.04). The optimal CRP cut-off value to predict lymph node metastasis was set at 20 mg/l based on ROC analysis. CONCLUSIONS: Since a high preoperative serum CRP level was closely correlated with nodal disease, it could be used as an additional marker to help identify patients with penile cancer who may benefit from inguinal lymph node dissection.

Does overweight influence the prognosis of renal cell carcinoma? Results of a multicenter study.

OBJECTIVES: To assess the impact of overweight on prognosis of renal cell carcinoma patients. PATIENTS AND METHODS: A total of 2030 patients who underwent surgery for renal cell carcinoma from 1990 to 2011 in three University Medical Centers were included in this retrospective analysis. For all patients, height and weight measurements at the time of diagnosis were available for review. The median (mean) follow up was 56.6 months (66.0 months). RESULTS: A low body mass index was significantly associated with poor tumor differentiation, histology, microscopic vascular invasion and metastatic disease at the time of diagnosis. A lower-than-average body surface area - stratified according to the European average for men (1.98 m(2)) and women (1.74 m(2)) - was significantly related to older age, poor tumor differentiation, the histological subtype and microscopic vascular invasion. In addition, a low visceral fat area calculated in a subgroup of 133 evaluable patients was associated with a higher risk of advanced disease (pT3-4 and/or N/M+) at diagnosis. The tumor-specific 5-year survival rate was 71.3, 78.7 and 80.1%, for patients with a body mass index of, <25, 25-30 and ≥30. Multivariate analysis confirmed body mass index as an independent prognostic factor. CONCLUSION: Our findings suggest that overweight represents an independent prognostic factor in renal cell carcinoma patients. Further research should address the question of why obese people have a higher incidence of renal cell carcinoma, but at the same time a significantly better prognosis than other patients, particularly in the case of localized disease.

A New Proximal Adjustable Sling ATOMS SSP® Implantation Technique with Focus on the Urethral Bulb: Lessons Learned from Revision Surgery.

BACKGROUND: Adjustable sling ATOMS-SSP results in ventral compression of the urethra with favorable results in the treatment of men with mild to moderate stress incontinence. However, with transobturator tunneling and mesh fixation, the surgeon has a range of options, which leads to different results and sometimes unfavorable positioning of the silicone cushion. Using retrograde urethrography (RUG), we identified ATOMS patients with considerable misplacement. We then modified the implantation technique when we performed the revision, and now present here our first experiences with this new surgical technique. METHODS: Patients after ATOMS-SSP implantation at our clinic were systematically subjected to a RUG if incontinence persisted after adjustments. In case of unfavorable positioning, a revision was performed with the aim of achieving an idealized urethroproximal position of the silicone pad. During follow-up, a repeat RUG was performed, and both subjective and objective outcome parameters were recorded. RESULTS: Four men met the above criteria and underwent revision with reimplantation using our new technique. All patients postoperatively experienced significantly improved continence. RUGs demonstrated an ideal ATOMS position immediately below the proximal bulbar urethra. CONCLUSIONS: Our proximal implantation technique, presented here for the first time, allows optimal positioning of the ATOMS SSP, which is reflected in the objective parameters and RUG. Its use in primary implantation should also be considered and an expansion to the indication of severe stress incontinence seems possible, but this should only be done in studies.

Is the Standard Artificial Urinary Sphincter AMS 800 Still a Treatment Option for the Irradiated Male Patient Presenting with a Devastated Bladder Outlet?

BACKGROUND: Circular urethral compression with an artificial sphincter allows control of voiding, even in patients with severe stress urinary incontinence, but it heightens the risk of urethral atrophy and erosion. This study of one of the largest populations of patients treated with radiotherapy investigates the additive effect of the post-radiogenic stricture of the membranous urethra/bladder neck on AMS 800 artificial urinary sphincter outcomes. METHODS: In a retrospective multicenter cohort study, we analyzed patients fitted with an AMS 800, comparing those who had received radiotherapy with patients presenting a devastated bladder outlet (stricture of the membranous urethra/bladder neck). We determined the correlation between these groups of patients using both univariate and stepwise adjusted multivariate regression. The revision-free interval was estimated by a Kaplan-Meier plot and compared by applying the log-rank test. A p value below 0.05 was considered statistically significant. RESULTS: Of the 123 irradiated patients we identified, 62 (50.4%) had undergone at least one prior desobstruction for bladder-neck/urethra stenosis. After a mean follow-up of 21 months, the latter tended to achieve social continence less frequently (25.7% vs. 35%; p = 0.08). Revision was required significantly more often for this group (43.1% vs. 26.3%; p = 0.05) due to urethral erosion in 18 of 25 cases. A stenosis recurred in five cases; desobstruction was performed in two cases, leading to erosion in both. Multivariate analysis revealed a significantly higher risk of revision when recurrent stenosis necessitated at least two prior desobstructions (HR 2.8; p = 0.003). CONCLUSIONS: A devastated bladder outlet is associated with a lower proportion of men with social continence and a significantly higher need for revision compared with irradiated patients without a history of urethral stenosis. Alternative surgical procedures should be discussed beforehand, especially in cases of recurrent urethral stenosis.

Validation of CRP as prognostic marker for renal cell carcinoma in a large series of patients.

BACKGROUND: To evaluate the prognostic significance of the pre-operative C-reactive protein (CRP) serum level in patients with renal cell cancer (RCC). METHODS: We evaluated 1,161 RCC patients with complete patient and tumour specific characteristics as well as information about their pre-operative CRP-level, who had undergone either radical nephrectomy or nephron-sparing surgery at two German high-volume centres (University Hospitals of Hannover and Ulm). The mean follow-up was 54 months. RESULTS: The CRP-level, stratified to three subgroups (CRP ≤ 4, 4-10, and >10 mg/l), correlated significantly with tumour stage (p < 0.001), the risk of presenting nodal disease (2.1, 3.1, and 16.4%) and distant metastasis (2.9, 8.6, and 30.0%; p < 0.001). The Kaplan-Meier 5-year cancer specific survival (CSS) rates were 89.4, 77.9, and 49.5%, respectively (p < 0.001). Multivariate analysis identified CRP as an independent prognosticator for CSS as well as overall survival (p < 0.001). Patients with a CRP of 4-10 and >10 mg/l had a 1.67 and 2.48 fold higher risk of dying due to their RCC compared to those with a pre-operative CRP ≤4 mg/l, respectively. CONCLUSIONS: A high preoperative serum CRP level is an independent predictor of poor survival in patients with RCC. Its routine use could allow better risk stratification and risk-adjusted follow-up of RCC patients.

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells.

BACKGROUND: Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC). METHODS: Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay. RESULTS: The NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway. CONCLUSIONS: Our results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.

The ileal neobladder in female patients with bladder cancer: long-term clinical, functional, and oncological outcome.

PURPOSE: To assess long-term clinical and oncological outcome in women undergoing radical cystectomy and ileal neobladder reconstruction for invasive bladder cancer. METHODS: From 1995 to 2010, a total of 121 women with clinically organ-confined urothelial carcinoma underwent radical cystectomy with an orthotopic ileal neobladder. Median follow-up was 56 months. Clinical course, functional, pathological, and oncological outcome of these women were analyzed. RESULTS: Seventy-six patients (62.8%) experienced a complication of some type within 90 days of the procedure. 56 patients (46.3%) experienced minor complications, whereas 20 patients (16.5%) experienced major complications. Pathological subgroups included 70 patients (57.9%) with organ confined, lymph node-negative tumors, 24 (19.8%) with extravesical, lymph node-negative disease and 27 (22.3%) patients with lymph node-positive disease. The 5-year overall survival rate in patients with organ-confined (≤pT2, pN0), locally advanced (≥pT3, pN0), and metastatic disease was 80.2%, 81.9%, and 45.1%, respectively. 4 women (3.3%) experienced a local (pelvic) recurrence. One patient presented with a urethral recurrence (0.8%). Daytime and nighttime urinary continence (0-1 pad) was reported by 82.4 and 76.5%, respectively. Clean intermittent self-catheterization was required by 58.0%. The retrospective study design was the major limitation of the study. CONCLUSIONS: Despite a considerable complication rate, radical cystectomy with orthotopic diversion in female patients with bladder cancer may be considered a standard therapeutic option for selected patients with excellent oncological outcome including a low incidence of local and urethral recurrence.

AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells.

PURPOSE: A recently identified mechanism allowing prostate cancer (PCa) cells to grow in the absence of androgens is the expression of constitutively active, C-terminally truncated androgen receptor (AR) variants lacking vast parts of the ligand-binding domain. These AR variants termed ARΔLBD are either products of alternative splicing, point mutations leading to premature stop codons or proteolytic cleavage of the AR. Some controversies exist about the requirement of additional full-length AR for the full transcriptional activity of the ARΔLBD. On basis of a mutated, C-terminally truncated AR termed Q640X, we developed an experimental model for the study of ARΔLBD in PCa cells. METHODS: Activation of AR-dependent promoters was analyzed by reporter gene assays. Dimerization studies were conducted using a mammalian two-hybrid system. RESULTS: Although Q640X/Q640X homodimers were able to induce the expression of certain AR target genes, Q640X/AR heterodimers were necessary to activate the full panel of androgen-dependent genes under androgen-deprived conditions. CONCLUSIONS: The following study supports the hypothesis that castration-resistant prostate cancer (CRPC) cells are able to activate specific androgen-dependent genes by selective modulation of the ratio between ARΔLBD and their putative dimerization partners like the full-length AR or other ARΔLBD in the absence of androgens. The present data suggest that AR-mutant Q640X is a powerful experimental tool for the functional analysis of ARΔLBD in CRPC.

Neoadjuvant therapy of renal cell carcinoma: a novel treatment option in the era of targeted therapy?

The study was carried out to evaluate the effectiveness, toxicity and optimal duration of neoadjuvant therapy for patients with organ-confined or locally advanced renal cell carcinoma in the era of targeted agents. A literature review was carried out using Medline/Pubmed articles, as well as congress reports from the last five American Society of Clinical Oncology, American Urological Association and European Association of Urology Annual Meetings. Neoadjuvant targeted therapy is feasible and shows toxicity similar to that seen in a palliative setting. Most studies recommend an application for 2-4 months. The current data situation is best for sunitinib. Surgery can apparently be carried out the day right after discontinuing the drug. However, even sunitinib leads to only a mean 10% decrease in primary tumor size, and one-quarter to one-fifth of all patients show local tumor progression during treatment. Few patients (approximately 12%) with a vena cava tumor thrombus achieve a significant decrease in its level under neoadjuvant therapy; here too, progression is observed in a significant number of cases. Even the new targeted agents show limited effectiveness in achieving relevant remissions of the primary tumor. Furthermore, tumor progression is seen in a significant percentage of patients during neoadjuvant therapy. Thus, even today in the era of targeted agents, a neoadjuvant approach should only be made in patients with localized or locally advanced renal cell carcinoma, which primarily seem to be absolutely inaccessible by (partial) nephrectomy.