Co-administration of tyrosine kinase inhibitors with rottlerin in metastatic prostate cancer cells.

After prostatectomy due to prostate carcinoma, patients often develop metastases. Although prostate cancer is susceptible to hormonal manipulation, many patients become castration-resistant. Therefore, new therapies are the focus of investigations. We analyzed the effect of the tyrosine kinase inhibitors (TKIs), sorafenib and sunitinib, in combination with rottlerin, a PKCδ inhibitor, on metastatic mechanisms in prostate carcinoma cells. LNCaP and PC-3 prostate carcinoma cells were treated with sorafenib or sunitinib alone at various concentrations (1-20 µM) or in combination with rottlerin (10 µM) for 24 h. Then, cell toxicity (MTT test) and cell proliferation (BrdU incorporation assay) were quantified. The study demonstrated a dose-dependent inhibitory effect of sorafenib and sunitinib on PC-3 and LNCaP cell activity and proliferation. Both agents showed significantly stronger cytotoxic effects in LNCaP cells. At the highest concentrations, sorafenib and sunitinib inhibited the viability of LNCaP cells up to 2 % and 31 %, respectively, and the viability of PC-3 cell line up to 20 % and 43 %, respectively. The proliferation of both cell lines was significantly stronger inhibited by sorafenib than by sunitinib. In LNCaP cells, sorafenib and sunitinib at the highest concentrations inhibited cell proliferation up to 46 % and 49 %, respectively, and the proliferation of PC-3 line up to 40 % and 47 %, respectively. Rottlerin reduced the viability and proliferation of PC3 cells to 81 % and 42 %, whereas the viability and proliferation of LNCaP cells were reduced to 25 % and 57 %, respectively. Sorafenib and sunitinib at low concentrations partly neutralized the inhibitory effect of rottlerin on cell viability and proliferation. On the other hand, in PC-3 cells, rottlerin reduced the inhibitory effects of sorafenib and sunitinib at the highest concentrations on cell viability from 20 % to 30 % and from 43 % to 61 %, respectively. An additive effect on cell activity was observed after treating LNCaP cells with both sunitinib at high concentrations and rottlerin. This combination increased the cytotoxic effect from 31 % to 13 % at the highest sunitinib concentration. Our results showed that monotherapy with sorafenib was the most efficient in both PCa cell lines. A marginally additive effect of rottlerin was only observed in LNCaP cells treated with sunitinib at a high concentration. Sorafenib and sunitinib reduced cell migration in PC-3 cells to 10 % and 32 % of untreated cells, respectively. Co-treatment with sorafenib/sunitinib and rottlerin did not result in a significantly stronger anti-migratory effect than the treatment with each TKI alone. Given the strong cytotoxic effect of TKIs, especially sorafenib, on LNCaP cells, the results of the migration assay in this line were severely biased and not considered in the analysis. Unlike in other malignancies, combination therapy with TKI and rottlerin seems not beneficial in prostate cancer. More promising seems to be monotherapy with rottlerin, but further studies are needed to confirm this observation.

Orthotopic MAINZ pouch bladder substitution - long-term follow-up.

INTRODUCTION: After radical cystectomy, orthotopic neobladder is one surgical strategy for urinary diversion. To assess the usefulness of an operation, long-term data are essential. We examined long-term complications and continence rates of orthotopic ileocecal (MAINZ pouch) bladder substitution. MATERIAL AND METHODS: Between 1986 and 2011, 193 patients underwent orthotopic MAINZ pouch bladder substitution. Until July 2000, ureter implantation was performed into the ascending colon through a submucosal tunnel technique (Goodwin-Hohenfellner). After July 2000, ureters were implanted into the terminal Ileum using the ileocecal valve to prevent reflux: the left spatulated ureter by an end-to-end (Wallace) and the right ureter by an end-to side technique (Nesbit). Surgical and medical follow-up reports were evaluated and a recent follow-up was obtained by a questionnaire. RESULTS: Median follow-up in 183 patients was 72 months (1-336). A total of 74 patients (38%) died during the follow-up. A surgical intervention was required in 26 out of 193 patients with early complications while 45 out of 183 patients had late and 17 patients had both, early and late complications. Ureteral stenosis was found in 13% of submucosal implanted ureters, 13% with the Wallace technique, and 3.6% with the Nesbit technique. In total, 66 patients responded to the questions concerning long-term continence (minimal follow-up >2 years). Overall, 84.8% were completely continent, 1.6%, reported grade I and 9.8% grade II stress incontinence. CONCLUSIONS: The long-term continence and complication rates are comparable to those of other types of orthotopic bladder substitution. Orthotopic MAINZ pouch procedure can be considered as one of the options for orthoptic diversion, which stands the test of time.

Risk-adjusted proposal for >60 months follow up after surgical treatment of organ-confined renal cell carcinoma according to life expectancy.

OBJECTIVES: To determine the long-term oncological outcome of organ-confined (

Interrupted versus Continuous Suturing for Vesicourethral Anastomosis During Radical Prostatectomy: A Systematic Review and Meta-analysis.

CONTEXT: Vesicourethral anastomosis (VUA) is a crucial step during radical prostatectomy (RP). Generally, either a continuous (CS) or an interrupted suture (IS) is used. However, there is no clear evidence if one technique is superior to the other. OBJECTIVE: This study aimed to provide a systematic overview and comparison between IS and CS for the VUA during RP. EVIDENCE ACQUISITION: The study was conducting according to the PRISMA guidelines. A systematic data base search (Pubmed, Embase, and Central) was performed. Outcomes included catheterization time, extravasation, anastomotic time, length of hospital stay, continence, and development of strictures. EVIDENCE SYNTHESIS: A total of 2021 studies were retrieved, of which nine studies (1475 patients) were included in analysis. Results showed a shorter catheterization time (2.06 d; 95% confidence interval [CI]: 0.56-3.57; p=0.007), anastomotic time (6.39min; 95% CI: 3.68-9.10; p<0.001), and a lower rate of extravasation (odds ratio [OR]: 2.36; 95% CI: 1.26-4.43; p<0.007) in favor of CS. There were no differences between groups concerning length of hospital stay (0.40 d; 95% CI: -1.41-2.20; p=0.670) or continence at 3 mo (OR: 1.09; 95% CI: 0.83-1.44; p=0.540), 6 mo (OR: 1.04; 95% CI: 0.67-1.61; p=0.870) or 12 mo (OR: 1.43; 95% CI: 0.92-2.24; p=0.110), respectively. The incidence of urethral strictures was not different between the techniques (OR: 1.00; 95% CI: 0.42-2.40; p=1.000). The quality of evidence according to Grading of Recommendations Assessment, Development and Evaluation tool was rated as low. CONCLUSIONS: This meta-analysis showed advantages of CS for catheterization time, anastomotic time, and rate of extravasation without compromising other parameters. Although CS seems to offer favorable results, its technical challenge in open RP and the generally low quality of data makes a clear recommendation impossible. PATIENT SUMMARY: Continuous and interrupted suturing are safe suture techniques for the vesicourethral anastomosis during radical prostatectomy. The choice of the suture technique should be based on surgeon's experience and technical approach. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42017076126.

In renal cell carcinoma the PTEN splice variant PTEN-Δ shows similar function as the tumor suppressor PTEN itself.

BACKGROUND: Loss of PTEN is involved in tumor progression of several tumor entities including renal cell carcinoma (RCC). During the translation process PTEN generates a number of splice variants, including PTEN-Δ. We analyzed the impact of PTEN-Δ in RCC progression. METHODS: In specimens of RCC patients the expression of PTEN-Δ and PTEN was quantified. The PTEN expressing RCC cell line A498 and the PTEN deficient 786-O cell line were stably transfected with the PTEN-Δ or PTEN transcript. In Caki-1 cells that highly express PTEN-Δ, this isoform was knocked down by siRNA. Cell migration, adhesion, apoptosis and signaling pathways activities were consequently analyzed in vitro. RESULTS: Patients with a higher PTEN-Δ expression had a longer lymph node metastasis free and overall survival. In RCC specimens, the PTEN-Δ expression correlated with the PTEN expression. PTEN-Δ as well as PTEN induced a reduced migration when using extracellular matrix (ECM) compounds as chemotaxins. This effect was confirmed by knockdown of PTEN-Δ, inducing an enhanced migration. Likewise a decreased adhesion on these ECM components could be shown in PTEN-Δ and PTEN transfected cells. The apoptosis rate was slightly increased by PTEN-Δ. In a phospho-kinase array and Western blot analyses a consequently reduced activity of AKT, p38 and JNK could be shown. CONCLUSIONS: We could show that the PTEN splice variant PTEN-Δ acts similar to PTEN in a tumor suppressive manner, suggesting synergistic effects of the two isoforms. The impact of PTEN-Δ in context of tumor progression should thus be taken into account when generating new therapeutic options targeting PTEN signaling in RCC.

Calcium-sensing receptor (CaSR) promotes development of bone metastasis in renal cell carcinoma.

Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo. The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR-transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR-transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.

Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade.

Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo. 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis. Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment.

Pregnancy After Urinary Diversion at Young Ages-Risks and Outcome.

OBJECTIVE: To assess the urologic and obstetric outcomes during and after pregnancy following urinary diversion (UD) performed during childhood or adolescence. MATERIALS AND METHODS: From our UD database, we identified 25 women who became pregnant between 1981 and 2013. Reasons for UD were neurogenic bladder, exstrophy, trauma, sinus urogenitalis, and interstitial cystitis. Seventeen had continent cutaneous diversion, 4 had continent anal diversion, and 4 had colonic conduit. RESULTS: The average age at delivery was 27.8 (18-39) years. Thirty-seven pregnancies occurred; 1 patient decided for an induced abortion. Thirty-two healthy children were born. Five patients had a spontaneous abortion before the 12th week. Main urologic complications were urinary tract infections in 11 of 32 successful pregnancies. Twelve patients presented with dilatation of the upper urinary tract; 3 of them required a temporary nephrostomy tube. Four of 25 patients required an indwelling catheter because of difficulties of clean intermittent catheterization. One small bowel injury occurred during cesarean section. One patient with exstrophy developed uterine prolapse; 1 nipple prolapse was surgically repaired in the same anesthesia after the cesarean section. Two patients had 3 vaginal deliveries, whereas 28 had a cesarean section. All children were healthy, without malformation, and with mean Apgar scores of 7.8, 8.9, and 9.7 for the 1st, 5th, and 10th minutes of life, respectively. No persistent urologic complications were observed. CONCLUSION: After UD, pregnancy is possible without major complications. Because of an increased risk of pyelonephritis and dilatation of the upper urinary tract requiring intervention, these pregnancies should be considered high-risk pregnancies. Delivery should be carried out in a center of expertise with urologic standby.

Continent Anal Urinary Diversion in Classic Bladder Exstrophy: 45-Year Experience.

OBJECTIVE: To evaluate the long-term outcomes in patients with classic bladder exstrophy and continent anal urinary diversion (CAD) for continence, upper urinary tract status, secondary malignancies, and sexual function. PATIENTS AND METHODS: The medical records of 82 exstrophy patients having undergone CAD in our department between 1970 and 2015 were reviewed. Patients were invited for follow-up examinations and asked to complete validated questionnaires relating to sexual function. RESULTS: Thirty-two of 57 eligible patients with a median follow-up of 23.9 years were included in the study. Ninety-seven percent of patients were fully continent during daytime. Upper urinary tract and renal function remained stable in 75% and 87%, respectively. Five patients developed secondary malignancies originating from the rectal reservoir. Forty-one percent received prophylactic alkaline substitution. Sexual function as measured by the Female Sexual Function Index and the International Index on Erectile Function was negatively affected in all domains in both genders. Eighty-six percent of patients had a stable relationship and 35% were married. Five women conceived a total of 6 healthy children. Paternity rate was 40%. CONCLUSION: CAD constitutes an effective treatment option with acceptable long-term outcomes in exstrophy patients in whom all attempts at restoring the lower urinary tract have failed. Long-term follow-up of the upper urinary tract, assessment of acid-base balance, and endoscopy of the rectosigmoid reservoir are paramount for the safety of this type of management. Evaluation of sexual dysfunction should be an active part of follow-up.

Integrin α5 triggers the metastatic potential in renal cell carcinoma.

The therapy of advanced renal cell carcinoma (RCC) is still a major challenge. To intervene therapeutically a deeper comprehension of the particular steps of metastasis is necessary. In this context membrane bound receptors like integrins play a decisive role. We analyzed the integrin α5 expression in 141 clear cell RCC patients by Western blot. Patients with RCC expressed a significant higher level of integrin α5 in tumor than in normal tissue. The integrin α5 expression correlated with tumor grade, the development of distant metastases within five years after tumor nephrectomy and reduced survival. The RCC cell lines Caki-1 and CCF-RC1, which highly express integrin α5, were treated with fibronectin in combination with or without an inhibiting anti-integrin α5 antibody. Afterwards the migration, adhesion, viability and prominent signaling molecules were analyzed. Both cell lines showed a significant reduced migration potential as well as a decreased adhesion potential to fibronectin after treatment with an integrin α5 blocking antibody. A contribution of the AKT and ERK1/2 signaling pathways could be demonstrated. The results indicate integrin α5 as a potent marker to discriminate patients' tumor prognosis. Consequently the integrin subunit α5 can be considered as a target for individual therapy of advanced RCC.

Long-term outcome after urinary diversion using the ileocecal segment in children and adolescents: Complications of the efferent segment.

INTRODUCTION: Long-term outcomes are of special concern in children after urinary diversion. In a single institution study we evaluated retrospectively the long-term outcomes of urinary diversion in children, in whom the ileocecal segment had been used, in respect to complications of the efferent segment. METHODS: The Mainz pouch was used in 107 children for continent urinary diversion. Indications were neurogenic bladder (53%, 57/107), exstrophy-epispadias complex (25%, 27/107), malignancy (13%, 14/107), and others (9%, 9/107). Continent cutaneous diversion was performed in 95 patients, and 12 patients received bladder augmentation/substitution with a continent cutaneous stoma. As efferent segment, we used the in situ submucosally embedded appendix in 55/107, and an intussuscepted ileal nipple valve in 45/107 patients, other in seven patients. Complication rates and degree of satisfaction with urinary diversion were evaluated by assessing medical records and using follow-up questionnaires. RESULTS AND DISCUSSION: The median follow-up time was 15.9 years (0.4-27.6 years). There was a significant difference between the stenosis rates of appendical stoma and the intussuscepted ileal nipple valve. In general, 38% of patients (41/107) with a continent cutaneous stoma developed a stoma stenosis at the skin level, with 41% (17/41) of those having recurrent stenoses (2-6×). Of the patients with an appendix stoma, 49% (27/55) developed a stenosis, compared with 20% (9/45) of those with an intussuscepted ileal nipple valve (p < 0.001). In an attempt to reduce the incidence of stenosis, we implemented use of the ACE stopper during the last 2 years, but whether this is successful is subject to further investigations. For surgical treatment of stoma stenosis, reanastomosis of the efferent segment to the skin (n = 37, re-stenosis rate 37%, [14/37]) was superior to endoscopic scar incision (n = 44, re-stenosis rate 59% [26/44], OR 2.4). The overall continence rate was 85% (91/107). At the latest follow-up, 89% (49/55) of patients with an appendix stoma and 82% (37/45) of those with an intussuscepted ileal nipple valve were completely continent. CONCLUSION: The in situ submucosally embedded appendix and the intussuscepted ileal nipple valve are reliable continence mechanisms in the long-term median follow-up of nearly 16 years. The stomal stenosis rate is approximately double for the submucosal appendix, likely because of its smaller diameter in comparison with the ileal valve. Although we encountered a high overall rate of complications, the satisfaction rate with the diversion was high (99% [88/89] satisfied or very satisfied patients).

Incidence of Cardiovascular Events after Nephrectomy - A Single Centre, Matched Pair Analysis between Donor and Tumour Nephrectomy in a Long Term Follow-Up.

INTRODUCTION: The study aimed to compare the incidence of cardiovascular events (CVEs) after donor nephrectomy (DN) and radical tumor nephrectomy (RN), according to an estimated glomerular filtration rate (eGFR), were evaluated over time. MATERIALS AND METHODS: Follow-up was collected for DN who underwent surgery from 1998 to 2007 for CVE and renal function. All DN were matched for age to patients treated by RN or adenoma enucleation (control group), who were eligible for DN. eGFR was estimated using the Cockgroft-Gould formula. Patients with preoperative comorbidities were excluded. RESULTS: Thirty DN (median age 48.9 years) were included with a median follow-up of 138.5 months (interquartile range 119-159). No significant differences in patients' characteristics were found preoperatively (p > 0.5). Four out of 30 DN developed a CVE (3 myocardial infarctions (MI), 1 stroke), 2 of 30 patients in the control group (both MI) and 8 of 30 RN patients (6 MI, 2 strokes, p > 0.05). Arterial hypertension developed in 14 DN (46.7%), in 12 (40%) after RN and in 15 controls. The CVE occurred after a median time of 68 months (5-231) and were related to a drop of ∼30% in the eGFR irrespective of the group. CONCLUSION: Decline of renal function after nephrectomy is the main risk factor for CVE. Close monitoring of renal function and new onset hypertension is warranted.

Differences in Overall and Cancer-specific Survival of Patients Presenting With Chromophobe Versus Clear Cell Renal Cell Carcinoma: A Propensity Score Matched Analysis.

OBJECTIVES: To investigate prognostic parameters for the oncological outcome of patients treated for chromophobe renal cell carcinoma (chRCC) in comparison with patients treated for clear cell RCC (ccRCC) using propensity score matching for survival analysis. METHODS: From 1969 to 2009, we identified 1010 from 3567 patients with RCC. Survival was analyzed using Kaplan-Meier estimate for histological subtypes including 109 chRCC and 901 ccRCC. Uni- and multivariate Cox regression was used to analyze prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Propensity score matching was performed to adjust for differences in patient characteristics among histological subgroups. RESULTS: The median follow-up was 61 months (range 0-289). chRCC showed longer OS (5 year, 90.1%; 10 year, 74.2%; 15 year, 61.4%) and CSS (94.2%, 89.7%, 89.7%) compared with ccRCC (OS 75.7%, 54.9%, 46.1% and CSS 84.7%, 75.4%, 72.2%; P = .002). Multivariate Cox regression revealed histology as a significant prognostic factor. Propensity score matching showed a difference in 72.4% (OS) and 87.2% (CSS) of matching attempts confirming the significant impact of histology. Univariate Cox regression showed nephron sparing surgery, no metastasis and no symptoms at presentation, age <65, eosinophilic features, low American Society of Anesthesiologists score, and Charlson Comorbidity Index to be beneficial for CSS. Only age at surgery, metastasis at presentation, and American Society of Anesthesiologists and Charlson Comorbidity Index scores were significant factors for OS in chRCC patients. CONCLUSION: ChRCC appears to have a favorable outcome compared with ccRCC. Even after adjustment for differences in characteristics known to have an influence on survival by propensity score matching, histology remains a significant prognostic factor.

Treatment of cT1a Renal Tumours in Germany: A Nationwide Survey.

OBJECTIVE: To identify clinical parameters influencing German urologists treating cT1a renal tumours, we performed a nationwide survey among members of the German urological associations (DGU and BDU). MATERIAL AND METHODS: In spring 2012, DGU and BDU members were invited to complete our survey. For 8 cases and 3 index patients, participants were asked about their preferred treatment. Multivariate analyses were used to identify significant parameters leading the responders to favour radical nephrectomy (RN) over nephron sparing surgery (NSS) as well as active surveillance (AS) over invasive treatment. RESULTS: Three hundred six (7.4%) forms were included in our analysis. In patients with larger tumours (4 vs. 2 cm, OR 3.16), endophytic growth (endophytic vs. exophytic, OR 2.70), hilar tumour location (perihilar vs. polar, OR 14.37), normal renal function (normal vs. decreased, OR 1.92) and elderly patients (elderly vs. young, OR 2.14) RN was preferred. Based on decreased renal function (decreased vs. normal, OR 12.74), elderly (elderly vs. young, OR 14.31) and hilar tumour location (perihilar vs. polar, OR 2.14), 77.2% of respondents recommended AS for selected patients. Treating physician factors had no influence on the treatment preference. CONCLUSIONS: Elderly patients with small tumours and impaired renal function were candidates for AS. Younger patients mainly underwent NSS. However, when the tumours' location was endophytic or hilar, RN was recommended.

Sexual Function and Fertility of Women with Classic Bladder Exstrophy and Continent Urinary Diversion.

PURPOSE: We evaluated the outcome in female patients with classic bladder exstrophy and continent urinary diversion for sexual function and fertility. MATERIALS AND METHODS: We reviewed the medical records of female exstrophy patients who underwent continent urinary diversion in our department between 1969 and 2014. Patients were invited for followup examination and asked to complete questionnaires relating to sexual function, social integration and maternity. RESULTS: Of 38 eligible patients 29 (response rate 76%) with a followup of 22.3 years were included in study. Primary continent urinary diversion was done in 62% of patients and 38% underwent secondary continent urinary diversion after failed reconstruction of the exstrophic bladder. Sexual function as measured by the Female Sexual Function Index was only little affected in all domains except desire. Mean total Female Sexual Function Index score was 28.4 of a possible 36. Of the women 31% were classified as at risk for sexual dysfunction, 72% had a stable relationship, 41% were married and 31% had completed higher education. The incidence of pelvic organ prolapse requiring surgical repair was 38%. A total of 16 healthy children were conceived by 12 patients. The pregnancy rate after primary continent urinary diversion was higher than after secondary diversion. CONCLUSIONS: The sexuality and fertility of female patients with exstrophy after continent urinary diversion appears to be comparable with those in previously reported series of patients in whom the bladder was preserved. Management of sexual function, gynecologic pathologies and fertility should be an active part of long-term followup.

Bone scintigraphy predicts bisphosphonate-induced osteonecrosis of the jaw (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC).

OBJECTIVES: The aim of this study was to evaluate the role of bone scintigraphy (BS) in early prediction of clinically asymptomatic bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIAL AND METHODS: BS of mCRPC patients treated with BP was evaluated for pathologic tracer uptake of the jaws in BS suspicious for BRONJ. Results were compared to development of clinically evident BRONJ. Sensitivity, specificity and predictive values of BS for the detection of BRONJ as well as time from beginning of BP therapy to pathologic tracer uptake in BS and time from pathologic tracer uptake in BS to clinically evident BRONJ were determined. RESULTS: Thirty BP-treated patients were included. Nine patients (30%) had pathologic BS lesions of the jaws. Six patients (20%) developed BRONJ. Sensitivity and specificity of BS for BRONJ prediction were 67 and 79%. Median time from the start of BP treatment to pathologic tracer uptake in BS was 28 months (range 10-33) and from pathologic tracer uptake in BS to clinically evident BRONJ 6.5 months (range 2-19). Pathologic tracer uptake in BS was significantly more often observed in patients who developed BRONJ compared to patients who did not (p = 0.049; OR 7.6). CONCLUSIONS: Patients with pathologic tracer uptake in the jaws in BS significantly more often develop BRONJ. An unsuspicious BS is predictive for absence of BRONJ in the future. CLINICAL RELEVANCE: We conclude that when BS has been performed, it should not only be used to assess tumour stage and treatment response but also to check for pathologic tracer uptake in the jaws in BS to detect BRONJ at an early stage in mCRPC patients receiving bisphosphonates.

Sexual Function, Social Integration and Paternity of Males with Classic Bladder Exstrophy following Urinary Diversion.

PURPOSE: We evaluated patients with classic bladder exstrophy and a history of urinary diversion for sexual function, social integration and paternity. MATERIALS AND METHODS: We reviewed the medical records of males older than 18 years with exstrophy who had undergone urinary diversion at our department between 1969 and 2014. Patients were invited for structured followup examinations and were asked to complete questionnaires relating to sexual function, social integration and paternity. RESULTS: Of 79 eligible patients 39 (49%) with a mean followup of 23.8 years (range 2 to 45) were included in the study. Of the patients 41% had undergone primary urinary diversion and 59% had undergone secondary urinary diversion after failed reconstruction of the exstrophic bladder. Sexual function as measured by the International Index of Erectile Function was negatively affected in all domains, with mild to moderate dysfunction in 90% of patients. Of the patients 73% had a stable relationship and 32% were married. A high level of education had been achieved by 77% of patients. Sperm quality was poor (oligoasthenoteratozoospermia) in 71% of patients. Among the patients 11 had fathered a total of 16 healthy children. CONCLUSIONS: Despite multiple reconstructive procedures of the genitourinary tract, including removal of the exstrophic bladder and subsequent urinary diversion, sexuality and paternity in this subset of patients was comparable to reported series of men in whom the bladder had been preserved. Evaluation of sexual function and fertility should be part of long-term followup, and treatment should be offered if indicated. Currently staged concepts of exstrophy repair should be applied to improve the cosmetic and functional outcomes of the genitourinary tract in patients with exstrophy.

Concomitant Gleason Score ≥ 7 prostate cancer is an independent prognosticator for poor survival in nonmetastatic bladder cancer patients undergoing radical cystoprostatectomy.

PURPOSE: In bladder cancer (BCa) patients undergoing radical cystoprostatectomy (RCPx), concomitant prostate cancer (PCa) is a common finding. Up to now there is no clear evidence to suggest that concomitant PCa is a predictor of outcome in these patients. Aim of this study was to assess incidence and clinicopathologic characteristics of concomitant PCa in RCPx specimen and correlate it to survival parameters from a single-centre material over two decades. METHODS: All men who had undergone RCPx for BCa at our institution between 1994 and 2013 were included in this study. Clinicopathologic parameters for BCa and PCa were evaluated and correlated with outcome parameters. Survival analysis was performed for the subgroup of nonmetastatic organ-confined BCa to evaluate the role of concomitant Gleason Score (GS) ≥7 PCa. RESULTS: Of 945 men who had undergone RCPx for BCa, concomitant PCa was present in 237 patients (25.1 %). There was a significant increase in PCa incidence from 18.9 to 32.3 % between 1994 and 2013 (p = 0.009). Concomitant PCa represented a more aggressive phenotype at the end of the study (p = 0.037). In nonmetastatic organ-confined BCa, concomitant GS ≥7 PCa (HR 3.09; p = 0.0001) and age > 68 (HR 1.80; p = 0.0004) were independent negative predictors for overall survival. CONCLUSIONS: Concomitant PCa in RCPx specimen of BCa patients is a common finding. The incidence of concomitant PCa has significantly increased within 2 decades, presenting a more aggressive phenotype. Age and in particular concomitant GS ≥7 PCa are independent prognosticators for poor survival in patients with nonmetastatic organ-confined BCa.

Pancreatic Fistulae after Urologic Surgery - A Single Centre Experience.

INTRODUCTION: To evaluate incidence, symptoms and management of postoperative pancreatic fistula (POPF) after urologic surgery based on our experience. MATERIAL AND METHODS: Database was searched for clinically evident POPF after urologic surgery between 1998 and 2014. Fistulae were graded using the POPF classification. Clinical course of every POPF patient was evaluated. RESULTS: During this time, 3,200 surgeries for renal, adrenal and retroperitoneal pathologies were performed. Twelve POPF occurred postoperatively in this series. Eight fistulae were POPF grade A, 3 POPF grade B and one POPF grade C. POPF became clinically evident after a median of 3 days (IQR 2-3). In all POPF grade A/B patients, secretion from the pancreatic fistula completely subsided under conservative therapy. In one POPF grade C patient with positive surgical margins of urothelial cancer, conservative treatment failed and the patient died due to POPF-related sepsis. CONCLUSIONS: POPF is a rare complication after urologic surgery. Conservative therapy is the first choice of treatment and will be successful in the majority of cases. Pancreatic fistula after surgery of recurrent malignancy may have a poor outcome.

Intermittent hyperammonemic encephalopathy after ureterosigmoidostomy: spontaneous onset in the absence of hepatic failure.

Intermittent hyperammonemic encephalopathy after ureterosigmoidostomy is a rare, but if unrecognized, potentially lethal condition. Ureterosigmoidostomy was performed in a male patient with bladder extrophy. After 35 years, he developed hyperammonemic encephalopathy. Diagnostic procedures did not reveal hepatic nor metabolic disorders. Despite administration of preventive medical treatment, several episodes recurred. A durable prevention was finally achieved by conversion into an ileal conduit. Intermittent hyperammonemic encephalopathy can occur decades after ureterosigmoidostomy. In the case of absence of metabolic disorders and resistance to medical treatment, conversion into a urinary diversion using an ileal segment constitutes an effective ultima ratio.