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Background Aim of this study was to evaluate and compare perioperative outcomes of transperitoneal (TP) and retroperitoneal (TR) approaches in a multi-institutional cohort of minimally invasive partial nephrectomy (MI-PN). Material and methods All consecutive patients undergone MI-PN for clinical T1 renal tumors at 26 Italian centers (RECORd2 project) between 01/2013 and 12/2016 were evaluated, collecting the pre-, intra-, and postoperative data. The patients were then stratified according to the surgical approach, TP or RP. A 1:1 propensity score (PS) matching was performed to obtain homogeneous cohorts, considering the age, gender, baseline eGFR, surgical indication, clinical diameter, and PADUA score. Results 1669 patients treated with MI-PN were included in the study, 1256 and 413 undergoing TP and RP, respectively. After 1:1 PS matching according to the surgical access, 413 patients were selected from TP group to be compared with the 413 RP patients. Concerning intraoperative variables, no differences were found between the two groups in terms of surgical approach (lap/robot), extirpative technique (enucleation vs standard PN), hilar clamping, and ischemia time. Conversely, the TP group recorded a shorter median operative time in comparison with the RP group (115 vs 150 min), with a higher occurrence of intraoperative overall, 21 (5.0%) vs 9 (2.1%); p = 0.03, and surgical complications, 18 (4.3%) vs 7 (1.7%); p = 0.04. Concerning postoperative variables, the two groups resulted comparable in terms of complications, positive surgical margins and renal function, even if the RP group recorded a shorter median drainage duration and hospital length of stay (3 vs 2 for both variables), p Conclusions The results of this study suggest that both TP and RP are feasible approaches when performing MI-PN, irrespectively from tumor location or surgical complexity. Notwithstanding longer operative times, RP seems to have a slighter intraoperative complication rate with earlier postoperative recovery when compared with TP.

Background and Objectives: The incidence of urothelial cancer in males is higher than in females; however, females have a higher risk of recurrence and progression. The aim of our study was to report the effect of gender on the oncological outcome in advanced urothelial cancer. Materials and Methods: In our retrospective study, all patients had undergone primary surgical treatment for urothelial cancer and were affected by stage IV disease at the time of chemotherapy. Response to therapy and toxicity were evaluated. Subgroups were analyzed for tumour presentation, first- and second-line treatment response, progression-free survival (PFS) and overall survival (OS). Results. Seventy-five patients, 18 (24%) females and 57 (76%) males, were considered. Investigation into the distribution of individual characteristics according to gender revealed a significant difference only for smoking, with a prevalence of smokers in women (p = 0.029). At the end of follow-up, OS was higher in females (27.5% vs. 17.4%; p = 0.047). Smoking did not significantly influence OS (p = 0.055), while univariate Cox regression analysis confirmed that males had a higher risk of death (HR = 2.28, 95% CI 0.99–129 5.25), with borderline statistical significance (p = 0.053). Men showed higher PFS than women both after first-line (p = 0.051) and second-line chemotherapy (p = 0.018), with a lower risk of progression (HR = 0.29, 95% CI 0.10–0.86; p = 0.026). No differences were found between genders with regard to toxicity. Conclusions. In our series, PFS rates following first- and second-line therapies for advanced urothelial carcinoma confirmed that females have a greater risk of progression than males.

Background: To investigate the perioperative and morbidity outcomes after partial nephrectomy (PN) in patients with short life expectancy (SLE) (≥95% 10-year expected mortality (10y-EM)), to assess the main predictors of outcomes in this population and to compare these results with those of a group at the opposite upper range with long LE (LLE, ≤5% 10y-EM) relying on a multicenter Italian prospective registry of kidney surgery (the RECORD 2 project). Methods: Clinical data of 4,325 patients undergone kidney surgery were collected at 26 urological Italian Centers from 2013 to 2016. SLE was defined as a ≥95% 10y-EM (assessed using the age-adjusted Charlson comorbidity index [CCI]). A multivariable logistic regression for overall postoperative complications, acute kidney injury (AKI), positive surgical margins (SM) and ∆ estimated glomerular filtration rate (eGFR) ≥25% at 2 years from surgery was performed in patients with SLE including clinically relevant variables. Adjusted outcomes reported as mean (SD) of the 2 groups were generated using separate multivariable logistic regression models and compared. Results: Overall, 559 patients with SLE were selected. Patients had an ASA score ≥3 in 58.4% of cases. A clinical T1a, T1b, and T2 stage was found in 412 (74.5%), 124 (22.4%), and 17 (3.1%) patients. The median PADUA score was 7 (6–8). Surgical and medical postoperative complication rates were registered in 14.8% and 6% cases. Postoperative AKI was reported in 27.3% cases, positive surgical margins (PSM) in 9.3% cases. In this subgroup of patients, ASA score, cerebrovascular disease, surgery in low volume centers, and open surgery were independent predictors of overall complications. ASA and PADUA scores, renal clamping, resection technique and lower eGFR at baseline were independent predictors of AKI. PADUA score, open approach and resection technique were independent predictors of PSM. Cardiovascular disease, hilar clamping, and resection technique were independent predictors of eGFR decrease >25% at 2 years from surgery. Patients with SLE were compared with those with LLE (n = 302). All analyzed parameters at baseline were significantly different among the groups with the exception of cancer laterality. After adjusting for several clinical variables, the SLE group had a significantly higher risk rate of adjusted overall postoperative complication rate compared to the LLE group (20.6% ± 0.36 vs. 9.9% ± 0.65, P < 0.0001), while the overall intraoperative complications (4.1% ±0.13 vs. 2.3% ± 0.23), overall postoperative major complications (3.8% ± 0.09 vs. 1.9% ± 0.14) adjusted AKI (24.2% ± 0.37 vs. 22.6% ± 0.92), positive surgical margins (8% ± 0.22 vs. 6.4% ± 0.49), and 2-year RF loss (13.4% ± 0.17 vs. 12.4% ± 0.74). Conclusion: In selected patients with SLE, PN is feasible with an acceptable safety profile that is overall comparable to patients with no LE limitations. While a robotic approach and surgery performed in high volume centers could reduce the risk of complications, an off-clamp approach and a SE surgical technique may decrease the risk of postoperative AKI and of longer term eGFR decrease.

Visceral metastasis is widely considered a prognostic factor for overall survival of men with metastatic castration-sensitive prostate cancer (mCSPC) and has been historically managed with androgen deprivation therapy (ADT). More recently, this therapeutic scenario has been enriched by the possibility to integrate ADT with chemotherapy or novel androgen-signaling-targeted inhibitors. In order to define the effect of chemotherapy/androgen-signaling-targeted inhibitors plus ADT, we performed a pooled analysis on patients with mCSPC and visceral metastases, revealing that survival was significantly improved in patients without visceral metastasis (hazard ratio, 0.64; 95% confidence interval, 0.56-0.74; P .01) compared to men with visceral metastases (hazard ratio, 0.68; 95% confidence interval, 0.51-0.91; P .01). Although several limitations do not allow us to draw definitive conclusions, our analysis confirms the efficacy of chemotherapy/androgen-signaling-targeted inhibitors in combination with ADT in mCSPC with visceral metastases as well. In the absence of specific randomized controlled trials, symptoms, toxicity, cost, patient preference, and clinical experience should guide the decision to add chemotherapy or androgen receptor-targeted therapy to ADT in patients with visceral metastases from mCSPC.

Patients diagnosed with non-clear renal cell carcinoma have often been excluded from clinical trials due to the shortage of treatments available, the low incidence of tumours with non-clear histology, and the corresponding diversity of intrinsic molecular features. This approach led to a knowledge gap in finding the optimal treatment for patients diagnosed with non-clear cell renal carcinoma. Cabozantinib, a potent multiple tyrosine kinase receptor inhibitor, has been recently investigated in patients with non-clear cell histologies of renal cell cancer. In this review, we have summarized available data on the use of cabozantinib in non-clear renal cell carcinoma.

PURPOSE: to evaluate clinical predictors of positive surgical margins (PSMs) in a large multicenter prospective observational study and to develop a clinic nomogram to predict the likelihood of PSMs after partial nephrectomy (PN). MATERIALS AND METHODS: We prospectively evaluated 4308 patients who had surgical treatment for renal tumors between January 2013 and December 2016 at 26 urological Italian Centers (RECORd 2 project). Two multivariable logistic models were evaluated to predict the likelihood of PSMs. Center caseload was dichotomized using a visual assessment adjusted for several predictors of PSMs. A nomogram predicting PSMs was developed. RESULTS: Overall, 2076 patients treated with PN were evaluated. pT1a, pT1b, pT2 and pT3a were recorded in 68.7%, 22.6%, 2.1% and 6.6% of the patients, respectively. PSMs were recorded in 342 (16.5%) patients. From a null multivariable model against number of PN/year, 60 PN/year were identified as the best cut-off to define a high-volume centre. At multivariable analysis, clinical stage (cT1a vs. cT2 [OR 1.94]; p = 0.03), volume centre (≤60 PN/year) (OR 2.22; p

Introduction: Microchimerism (MC) is the presence of a small amount of foreign cells or DNA within a person’s circulation or tissues. It has been identified also in recipients of solid organ transplants where it seems to be critical for the development and maintenance of immunological tolerance. Nevertheless, natural and/or iatrogenic MC can be acquired prior to transplantation, through pregnancy and/or blood transfusion. Objective: The aim of this study was to detect the presence of MC in women after renal transplantation from male cadaveric donors and its relationship with graft outcomes. Methods: We studied by qPCR the presence of the DYS14 gene sequence of the Y chromosome in 12 females who received a kidney graft from a male donor before transplantation (T0), after 15 days (T1) and 1 year of transplantation (T2). We found the sequence in all recipients after renal transplantation. Results: All the women were negative for this sequence prior to transplantation (T0). Mean (SD) Y-related DNA quantity was 0.80 (0.69) ng/mL plasma and 0.15 (0.26) ng/mL plasma at T1 and T2, respectively. No acute rejection was observed, and mean (SD) estimated Cr clearance was 68.8 (16.9) mL/min within 1 year from transplantation. Conclusions: Presence of MC was associated with good kidney graft outcomes after 1 year of transplantation, but further studies will be needed to investigate the relationship between clinical outcomes and the development of MC in renal transplant recipient.

OBJECTIVE To investigate the correlation of a history of lower urinary tract symptomatology during childhood with lower urinary tract dysfunction in young adult women. SUBJECTS AND METHODS This was a multicentre, prospective, case-control study conducted between April 2013 and November 2015. A total of 300 women, aged 18-40 years, participated. The case group comprised women attending urogynaecology clinics for various lower urinary tract complaints and the control group was recruited from a healthy population. Exclusion criteria were designed to avoid common causes of lower urinary tract dysfunction and symptoms and included diabetes mellitus, neurological disease and pelvic inflammatory disease. All women completed a self-administered 77-item questionnaire, exploring childhood urological and bowel history, as well as current urological, bowel and sexual symptoms. Statistical analysis was performed using chi-squared and Fisher's exact tests to compare categorical variables. Multivariate logistic regression models were fit for the prediction of the adult outcomes, incorporating as explanatory variables all those that showed a significant P value in bivariate analysis. P values < 0.05 were considered statistically significant. RESULTS Women with childhood urinary voiding and storage symptoms had a higher prevalence of these symptoms in adult life compared with women without such history. Women with urinary tract infections (UTIs) during childhood had a higher incidence of adult UTIs compared with women without this problem in childhood. CONCLUSIONS Lower urinary tract dysfunction in childhood seems to 'persist' in young adult life but the implications of this finding in clinical practice need to be defined in future studies.

Objectives To present our experience with a sigmoid orthotopic neobladder. Methods We retrospectively evaluated the functional and oncological outcomes of 160 patients who underwent orthotopic neobladder reconstruction using a detubularized 20–25-cm sigmoid segment at our institution. Each patient was evaluated every 3 months the first year, every 6 months for the next 4 years and annually thereafter. Urodynamic studies of all consenting patients were carried out after 6 months, and 2, 5 and 10 years. We carried out the log–rank test, and used Cox regression models and Kaplan–Meier survival analysis. The anova test was used to compare urodynamic findings over time. Results Mean follow up was 6.8 years (range 0.65–21.7 years). Overall survival was 58.1% at 5 years, and 47.1% at 10 years. Early complications occurred in 36 patients (22.6%); late complications in 40 (25%). Stage V chronic kidney disease developed in two patients (1.3%). Complete (daytime and night-time) continence, defined as no need for pads or condom devices, was achieved by 45% of patients at 5 years, daytime continence was achieved by just 36% of patients; both were unchanged at 10 years. A significant difference emerged in maximal neobladder capacity and post-void residual values between 6 months and 2 years, and between 2 and 5 years (P < 0.01 and P = 0.03, respectively). Conclusions Sigmoid neobladder continence and capacity significantly improve over the first 5 years, and they remain stable over the long term. Upper urinary tract function is not affected by endoluminal pressure, and the rate of metabolic imbalance is negligible.

Objectives To evaluate outcomes and quality of life in patients operated transvaginally with an original mesh shape for uterus-sparing prolapse surgery and to demonstrate the safety and efficacy of the technique. Study design We prospectively evaluated 66 postmenopausal patients (POP-Q Stage III: 32, IV: 34) operated between May 2008 and December 2013. We used wide weave polypropylene monofilament mesh that functions as a hammock anchored posteriorly to sacrospinous ligaments, its anterior wings exit the pelvis through the obturatory membrane. Follow-up was scheduled at 3-, 12- months and in May 2016. Prolapse-Quality of Life Questionnaire (P-QoL) was administered preoperatively, at 12 months and in May 2016. The chi square and Wilcoxon test were used for statistical analysis. Results Mean follow-up was 5.6 (SD: 1.6, Range: 1.1–8.1) years. The overall success rate (POP-Q ≤ 2) was 92.5% at 12 months and 84.4% at May 2016, these data remained stable over time (p > 0.05). Early complications occurred in 2 (3%) patients, late in 5 (7.8%) of which mesh extrusion in 4 (6.3%). Data from P-QoL showed significant improvement between preoperative and postoperative data (P 0.05). De-novo dyspareunia was 17.6% at 12 months and 10.3% at May 2016. Conclusions The low rate and grade of complications demonstrates the safety of the procedure, which offers stable anatomical correction with significant improvement in QoL.

Introduction Coital urinary incontinence (CUI) is not much explored during clinical history, and this could lead to an underestimation of the problem. Aim To evaluate the prevalence and clinical risk factors of CUI in women with urinary incontinence (UI), and to measure the impact of CUI on women’s sexuality and quality of life. Methods This was a multicenter international study, conducted in Italy, Greece, the United States, and Egypt. Inclusion criteria were: sexually active women with UI and in a stable relationship for at least 6 months. Exclusion criteria were: age Main Outcome Measures To evaluate the CUI and its impact on sexual life we used the open questions on CUI as well as the International Consultation on Incontinence questionnaire and Patient Perception of Bladder Condition questionnaire. Results In this study 1,041 women (age 52.4 ± 10.7 years) were included. In all, 53.8% of women had CUI: 8% at penetration, 35% during intercourse, 9% at orgasm, and 48% during a combination of these. Women with CUI at penetration had a higher prevalence of SUI, women with CUI during intercourse had higher prevalence of MUI with predominant SUI, and women with CUI at orgasm had higher prevalence of UUI and MUI with predominant UUI component. Previous hysterectomy was a risk factor for CUI during any phase, while cesarean delivery was a protective factor. Previous failed anti-UI surgery was a risk factor for CUI during penetration and intercourse, and body mass index >25 kg/m2 was a risk factor for CUI at intercourse. According to International Consultation on Incontinence questionnaire scores, increased severity of UI positively correlated with CUI, and had a negative impact on the quality and frequency of sexual activity. Clinical Implications This study should encourage physicians to evaluate the CUI; in fact, it is an underestimated clinical problem, but with a negative impact on quality of life. Strengths & Limitations The strength of this study is the large number of women enrolled, while the limitation is its observational design. Conclusion CUI is a symptom that can affect sexual life and should be investigated during counseling in all patients who are referred to urogynecological centers.

There is evidence that an inflammatory microenvironment is associated with the development and progression of prostate cancer (PCa), although the determinants of intrinsic inflammation in PCa cells are not completely understood. Here we investigated whether expression of intrinsic microsomal PGE synthase-1 (mPGES-1) enhanced aggressiveness of PCa cells and might be critical for epidermal growth factor receptor (EGFR)-mediated tumour progression. In PCa, overexpression of EGFR promotes metastatic invasion and correlates with a high Gleason score, while prostaglandin E2 (PGE2) has been reported to modulate oncogenic EGFR-driven oncogenicity. Immunohistochemical studies revealed that mPGES-1 in human prostate tissues is correlated with EGFR expression in advanced tumours. In DU145 and PC-3 cell lines expressing mPGES-1 (mPGES-1SC cells), we demonstrate that silencing or ‘knock down’ of mPGES-1 (mPGES-1KD) or pharmacological inhibition by MF63 strongly attenuates overall oncogenic drive. Indeed, mPGES-1SC cells express stem-cell-like features (high CD44, β1-integrin, Nanog and Oct4 and low CD24 and α6-integrin) as well as mesenchymal transition markers (high vimentin, high fibronectin, low E-cadherin). They also show increased capacity to survive irrespective of anchorage condition, and overexpress EGFR compared to mPGES-1KD cells. mPGES-1 expression correlates with increased in vivo tumour growth and metastasis. Although EGFR inhibition reduces mPGES-1SC and mPGES-1KD cell xenograft tumour growth, we show that mPGES-1/PGE2 signalling sensitizes tumour cells to EGFR inhibitors. We propose mPGES-1 as a possible new marker of tumour aggressiveness in PCa.

IntroductionSolitary fibrous tumor (SFT) of the kidney represents a rare neoplasm, and its malignant potential seems to be scarce. Classically, a radical nephrectomy is regarded as the treatment of choice for this condition.Case ReportWe present the case of a 37-year-old male patient who underwent left robotic clampless partial nephrectomy of an SFT of the kidney. Our patient has been followed-up carefully, and at 15-month examination, he is free of recurrence. This is the second case of an SFT managed through a conservative approach.ConclusionsIn our opinion, according to tumor's dimensions, partial nephrectomy may be considered for treating small SFTs.

Serous borderline tumors are rare neoplasms. Herein we report our conservative approach, whose rationale is neoplasm low-malignant potential. Tumor was removed under general anesthesia, and frozen section ruled out a germinal malignancy or a stromal tumor such as rhabdomyosarcoma. Ultrasound evaluation was initially performed every 3 months during the first 2 years, every 6 months during the next 3 years, and annually thereafter. After 8 years, the patient has not experienced any relapse, either clinical or ultrasonographical. In our opinion, conservative approach, whose final decision relies on intraoperative frozen section, represents the best option and does not jeopardize long-term oncological outcome.

Objective: Prevention may improve the quality of life and sexual and reproductive health. To improve prevention require a comprehensive research approach that examines the frequency and risk factors for urologic conditions. In June 2016 the Italian Urologic Society coordinated a preventive initiative : the 1st Week of Male Urologic Prevention ”#Controllati”. Material and methods: During the 1st Week of Male Urologic Prevention “#Controllati”, men aged 18 years or more were invited to attend participating urologic centers for a free of charge visit for counseling about urologic or andrologic conditions. Each participating man underwent a physical examination. Further he was asked about his a medical history and about his urologic symptoms, sexual activity and possible related problems. Results: Data were collected in 81 centers: 2380 men answered the questionnaire. A total of 1226 subjects participating in the study reported one or more urinary symptom [51.5% (IC 95% 48.9%-54.5%)]. The risk of any urinary symptoms increased with age: in comparison with men aged < = 30 years or less the risk of any urinary symptoms was 2.31, 2.92, 5.12, 7.82 and 17.02 respectively in the class age 31-40, 41-50, 51-60, 61-70 and > = 71. Overweight/obese men were at increased risk of any urinary symptoms [OR1.35 (95% CI 1.12-1.64)]. 27.2% (IC 95% overall 25.2% -29.3%) of the subjects had at least a sexual disorder (erectile dysfunction, premature ejaculation, hypoactive sexual desire). The erectile dysfunction and hypoactive sexual desire increased with age, but premature ejaculation tended to be higher among younger aged men aged 40 years or more. Current any urinary symptoms [OR 1.85 (CI 1.40-2.43)], hypertension [OR 1.66 (95% CI 1.21-2.26) and diabetes (OR 2.37 (95% CI 1.45-3.88)] increased the risk of erectile dysfunction. Conclusions: This large survey gives a picture of the burden of the more frequent urologic conditions offering useful information in order to focus preventive campaign.

After radical cystectomy or pathologies affecting the ureter(s), bowel segments can be employed to restore the natural urine flow or to create an external urinary diversion. Nevertheless, the interposition of bowel segments in the urinary tract is not devoid of complications. In fact, bowel's microstructure differs from the urothelium; specifically its mucosa is aimed at reabsorption, rather than storage. The aim of this paper is to revise the pathophysiology of complications related to bowel's mucosal properties. Those are: metabolic imbalance, malabsorption of vitamins, cholelitiasis, nephrolitiasis and infections. Their entity varies according to the segment used and to its length, which reflects the surface in contact with urine. Mostly, they occur on the long-term, but metabolic imbalances might occur soon after surgery as well.

Introduction Although several new measurements for female sexual dysfunction (FSD) have recently been developed, the Female Sexual Function Index (FSFI) remains the gold standard for screening and one of the most widely used questionnaires. The Italian translation of the FSFI has been used in several studies conducted in Italy, but a linguistic validation of the Italian version does not exist. Aim The aim of this study was to perform a linguistic validation of the Italian version of the FSFI. Methods A multicenter cross‐sectional study conducted in 14 urological and gynecological clinics, uniformly distributed over Italian territory. We performed all steps necessary to determine the reliability and the test–retest reliability of the Italian version of the FSFI. The study population was a convenience sample of 409 Italian women. Main Outcome Measures The reliability of the questionnaire was calculated using Cronbach's alpha, which was considered weak, moderate, or high if its value was found less than 0.6, between 0.6 and 0.8, or equal to or greater than 0.8, respectively. The test–retest reliability was assessed for all women in the sample by calculating Pearson's concordance correlation coefficient for each domain and for the total score, both at baseline and after 15 days (r range between −1.00 to +1.00, where +1.00 indicates the strongest positive association). Results Cronbach's alpha coefficents for total and domain score were sufficiently high, ranging from 0.92 to 0.97 for the total sample. The test–retest procedure revealed that the concordance correlation coefficient was very high both for FSFI‐I total score (Pearson's P = 0.93) and for each domain (Pearson's P always >0.92). Conclusion For the first time in the literature, our study has produced a validated and reliable Italian version of the FSFI questionnaire. Consequently, the Italian FSFI can be used as a reliable tool for preliminary screening for female sexual dysfunction for Italian women. Filocamo MT, Serati M, Li Marzi V, Costantini E, Milanesi M, Pietropaolo A, Polledro P, Gentile B, Maruccia S, Fornia S, Lauri I, Alei R, Arcangeli P, Sighinolfi MC, Manassero F, Andretta E, Palazzetti A, Bertelli E, Del Popolo G, and Villari D. The Female Sexual Function Index (FSFI): Linguistic validation of the Italian version. J Sex Med 2014;11:447–453.

We report a case of a 30 years old male affected by synchronous bilateral germ cell tumor with a history of unilateral cryptorchidism; the patient underwent surgical treatment followed by adjuvant radiotherapy on paraaortic and iliac lymphnodes. Patients with synchronous tumors usually present with a higher stage disease in contrast to those with unilateral testicular carcinoma, yet the prognosis remains equally favorable.

The purpose of this study was to evaluate the potential usefulness of [18F]-Choline PET/CT in the restaging of prostate cancer patients, who presented a rising PSA.We evaluated 170 prostate cancer patients, previously radically treated, that were referred for restaging with [18F]-Choline PET/CT.A total of 129 patients (median PSA 4.29 ng/ml at relapse) showed one or more areas of high uptake on PET/CT scan, while 41 patients with a median PSA of 1.07 ng/ml at relapse showed negative PET/CT scans. No false negative was found, while 31 patients were identified as false positive. Specificity of Choline PET/CT in our series was 56.9 %, while sensibility was 100 %. At the time of restaging, a PSA value superior or equal to 1 ng/ml was found to be a statistically significant predictive factor of PET positivity, either at the univariate (p0.0001) and at the multivariate analysis (p0.0001).Based on our findings, [18F]-Choline PET/CT is confirmed as a useful diagnostic tool to detect early recurrence, in patients with increasing PSA after primary treatment. However, in case of a mild increase in PSA, positive results must be validated with other techniques, as specificity and positive predictive value of [18F]-Choline PET/CT decrease with the lower values of PSA.

// Erika Terzuoli 1, * , Sandra Donnini 1, 2, * , Federica Finetti 1 , Gabriella Nesi 3 , Donata Villari 4 , Hiromi Hanaka 5 , Olof Radmark 5 , Antonio Giachetti 1 , Marina Ziche 1, 2 1 Department of Life Sciences, University of Siena, 53100, Siena, Italy 2 Istituto Toscano Tumori (ITT), 50136, Florence, Italy 3 Department of Surgery and Translational Medicine, University of Florence, 50136, Florence, Italy 4 Department of Clinical and Experimental Medicine, University of Florence, 50136, Florence, Italy 5 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden * These authors contributed equally to this work Correspondence to: Marina Ziche, email: marina.ziche@unisi.it Keywords: miR-186, mPGES-1/PGE-2, VEGF, prostate cancer, tumor angiogenesis Received: January 12, 2016 Accepted: June 01, 2016 Published: June 14, 2016 ABSTRACT Prostaglandin E-2 (PGE-2) promotes tumor angiogenesis via paracrine secretion of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF). Since miRNAs regulate several cell processes, including angiogenesis, we sought to determine whether they would influence PGE-2-induced VEGF. We compared DU145 and PC3 prostate cancer cells bearing the mPGES-1 enzyme (mPGES-1 +/+ ) and producing PGE-2, with those in which the enzyme was silenced or deleted (mPGES-1 -/- ). We demonstrated that mPGES-1/PGE-2 signaling decreased Dicer expression and miRNA biogenesis. Genome-wide sequencing of miRNAs revealed that miR-15a and miR-186, associated with expression of VEGF and hypoxia inducible factor-1α (HIF-1α), were down-regulated in mPGES-1 +/+ cells. As a consequence, mPGES-1 +/+ tumor cells expressed high levels of VEGF and HIF-1α, induced endothelial cells activation and formed highly vascularized tumors. Mir-186 mimic inhibited VEGF expression in mPGES-1 +/+ tumor xenografts and reduced tumor growth. In human prostate cancer specimens, mPGES-1 was over-expressed in tumors with high Gleason score, elevated expression of VEGF and HIF-1α, high microvessel density and decreased expression of Dicer, miR15a and miR-186. Thus, clear evidence for regulating miRNA processing and VEGF output by intrinsic PGE-2 production provides a means to distinguish between aggressive and indolent prostate tumors and suggests a potential target for controlling tumor progression.

Background To identify molecular biomarkers for tumor diagnosis and monitoring of disease progression, several noninvasive tests on liquid biopsy have been proposed for different cancers including those of urogenital origin. Among biomarkers, carbonic anhydrase IX (CAIX) has gained attention as it regulates extracellular pH and induces cytoplasmic alkalization contributing to malignant progression and poor treatment outcome. Works on tissues suggested the potential use of CAIX as a tumor biomarker for urogenital malignancies, but only few studies have been performed on its detection in urine. Scope The aim of the present study is the measurement of CAIX messenger RNA (mRNA) in urine sediments of patients affected by kidney, prostate, and bladder cancers to evaluate the clinical sensitivity and specificity of the test. Procedures The quantification of the total CAIX mRNA concentration and of its full-length isoform (CAIX FL) have been performed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) on RNA extracted from urine sediments of patients affected by urogenital cancers. Results Urinary total CAIX mRNA expression resulted to be lower in patients with kidney and prostate cancer in comparison with the control group, but no statistically significant difference could be evidenced for bladder cancer. The evaluation of the relative percentage of FL isoform mRNA (FL%) showed a significant increase of FL% in urine from patients with cancer (median = 70.8%) in comparison with the healthy subjects (median = 2.6%) and this finding was confirmed for each cancer type separately. The comparison among receiver operating characteristic curves for total CAIX mRNA, CAIX FL mRNA, and FL% indicated that FL% shows the best diagnostic performance with 90% sensitivity and 72% specificity. Comparison of the results obtained in urine with those found in the corresponding tissues indicated 80% concordance. Conclusions The CAIX mRNA expression in urine sediments can be considered a surrogate marker of CAIX expression in tumor tissues of urogenital origin. In particular, the analysis of FL% possesses the best characteristics to be a suitable noninvasive biomarker for urogenital cancer diagnosis.

In men with adverse pathology after radical prostatectomy, the most appropriate timing to administer radiotherapy (RT) remains a topic of debate. We analyzed in terms of efficacy, prognostic factors and toxicity the two therapeutic strategies: immediate postoperative radiotherapy (PORT) and salvage radiotherapy (SART). Between January 1995 and November 2010, 307 patients underwent adjuvant or salvage radiotherapy, after prostatectomy. In the PORT group, 42 patients (20.7 %) had biochemical failure, with a median time to biochemical failure of 1.8 years; two parameters (age at diagnosis and PSA pre-RT) resulted to be significant at the survival analysis for overall survival (p = 0.003 and p = 0.046, respectively). In the SART group, 33 patients (31.7 %) had biochemical relapse; sixteen patients died of prostate cancer; postoperative hormones therapy, conformal radiotherapy and level of PSA pre-RT >1.0 ng/ml resulted to be significant at the survival analysis, p = 0.009, p = 0.039 and p = 0.002, respectively. Our study is limited by its retrospective and nonrandomized design. As such, decisions to treat with adjuvant or salvage radiotherapy and the time to initiate therapy were based on patient preference and physician counseling. Our recommendation is to suggest adjuvant radiotherapy for all patients with adverse prognostic factors and to reserve salvage radiotherapy for low-risk patients, when the biochemical recurrence occurs.

In human cancers, carbonic anhydrase IX (CAIX) influences cell proliferation and tumor progression, maintaining intracellular and extracellular pH under hypoxic conditions. An alternative CAIX isoform, lacking of exons 8-9 (AS) and independent from the levels of hypoxia, was recently demonstrated in cancer cells. AS-CAIX competes with the full-length (FL) isoform in the regulation of the extracellular pH, mainly in a mild hypoxic status. In the present study, we evaluated mRNA expression of the 2 CAIX isoforms and their clinical relevance in bladder cancers and urine sediments.We measured mRNA expression of FL- and AS-CAIX isoforms in tumor tissues and benign mucosa from 45 patients with bladder transitional cell carcinoma. The expression of the 2 isoforms was also measured in urine sediment of 81 bladder cancer patients and 93 control subjects.Expression of FL-CAIX mRNA was lower than AS-CAIX in benign mucosa (P = 0.006) whereas in paired bladder cancers FL-CAIX mRNA was higher (P = 0.007). Consequently, the percentage of FL-CAIX in bladder cancers [median: 62.6%] was significantly higher than in benign mucosa [15.0%] (P0.0001). In the urinary sediments of bladder cancer patients FL-CAIX mRNA was significantly higher in comparison with normal controls (P = 0.003). FL-CAIX percentage appeared dramatically higher in urine sediments of bladder cancer patients [64.5%] in comparison with controls [7.5%] (P0.0001). In addition, FL-CAIX% was significantly different in sediments from pTa-pT1 and ≥ pT2 patients [51.5% and 91.7%, respectively] (P = 0.016). Stratification according tumor grade indicated that FL-CAIX% was significantly lower in G1 bladder cancers [33.3%] in comparison with G2-G3 [88.6%] (P = 0.005) The clinical sensitivity for FL-CAIX% in urine sediments was 0.93, with a 0.76 specificity. Using the same cut-off positive predictive value (PPV) was 0.78, whereas negative predictive value (NPV) was 0.93.Our results seem to indicate that in bladder cancers and related urine sediments, FL-CAIX is the prevalent and is the most accurate clinically relevant variant surrogate of hypoxic stress.

Objectives Urinary hypermethylation of BCL2, hTERT, and DAPK promoters has been previously demonstrated as an accurate biomarker for the detection of urothelial carcinoma of the bladder (UCB) in patients undergoing radical cystectomy. In the present study, we investigated with a validation intent the frequency and levels of methylation of the same 3 genes in tumor tissue and urine sediment of patients undergoing transurethral resection (TUR) for non-muscle-invasive (NMI) UCB. Materials and methods A total of 108 consecutive patients with NMI UCB and 105 controls with no genitourinary malignancies were enrolled in this prospective study conducted in 2 tertiary referral academic urological departments with an advanced molecular laboratory. The frequency and levels of methylated BCL2, hTERT, and DAPK promoters were evaluated with quantitative methylation-specific real-time polymerase chain reaction in DNA extracted from tumor tissue and paired normal bladder mucosa retrieved at the time of TUR in patients, and from urine in patients and controls. Results In tumor tissue, at least 1 gene was hypermethylated in 91% patients (BCL2 in 62%, hTERT in 53%, DAPK in 48%). Methylation of hTERT was significantly correlated with tumor grade ( P = 0.026). In urine sediment sensitivity and specificity were 76% and 98%, respectively, using BCL2 and hTERT. The number of methylated genes was highly correlated with tumor grade ( P = 0.005). Methylated BCL2 and hTERT in urine sediment were highly correlated with those of the corresponding bladder tumor qualitatively ( P P = 0.005). Methylation levels of BCL2 and hTERT were variably associated with tumor grade and stage, but were significantly correlated with patient age ( P = 0.004 and P = 0.027, respectively). Conclusions These findings suggest that quantitative methylation analysis of BCL2 and hTERT, but not DAPK, in urine sediment may be a useful tool in the diagnosis of NMI UCB, deserving future applicability studies.

The aim of this study was to review the treatment, toxicity, and outcomes in patients with stage I seminoma after orchidectomy.A retrospective chart review of all patients with stage I seminoma referred for initial treatment during the last 49 years was performed. Initial treatment approaches, toxicity, and outcomes were analyzed.A total of 320 patients were seen between 1960 and 2009. Median age at diagnosis was 37 years (range: 20-72), with a median follow-up of 22.7 years (range: 1-48). All patients but 12 were treated with adjuvant radiotherapy. Acute toxicity was mainly gastrointestinal, with 7.6% classified as grade 2. The 10-year disease-specific survival and relapse-free survival were 97.7 and 97.6%, respectively. 8 patients (2.7%) developed a relapse and were managed with chemotherapy. 10 patients died, 6 of the disease and 4 from other causes (disease-free at time of death).In the management of stage I seminoma, 3 treatment options are available; currently in the European Consensus, surveillance is the first choice, considering the overall comparable outcome and the low acute and late toxicity. Adjuvant radiotherapy and adjuvant chemotherapy should be considered as alternative options only if the patient declines the surveillance strategy.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To report the oncological outcome of 106 patients who had locally advanced prostate cancer with microscopic bladder neck invasion, identified in a series of 1129 patients surgically treated with retropubic radical prostatectomy over a 12-year period. PATIENTS AND METHODS All specimens were reviewed. Microscopic bladder neck invasion was defined as the presence of neoplastic cells within the smooth muscle bundles of the bladder neck, with no accompanying prostatic glandular tissue on the corresponding slide. Survival was analysed for different subgroups in relation to several variables. RESULTS The follow-up (median 7.2 years, mean 6.68, range 0.3–14) was available for 106 patients with microscopic bladder neck invasion. Seminal vesicle invasion was present in 69.8% of the cases, lymph node involvement in 29.2%, apex infiltration in 31.8%, and positive surgical margins in 23.6%. Biochemical progression occurred in 61 (57.5%) patients, and 25 of them died from cancer. The mean (sd) biochemical progression-free survival was 0.68 (0.05), 0.59 (0.05), 0.40 (0.05) and 0.38 (0.05) at 1, 2, 5 and 10 years, respectively. Age, Gleason score and lymph node invasion were independent prognostic factors on multivariate analysis. Overall and cancer-specific survival rates were 0.75 (0.04) and 0.80 (0.04) at 5 years and 0.57 (0.04) and 0.75 (0.04) at 10 years, respectively. Univariate analysis showed that seminal vesicle invasion, lymph node involvement and surgical Gleason score ≥8 significantly increased the risk of death. On multivariate analysis only the surgical Gleason score had an independent prognostic role with regard to overall survival (P = 0.01; odds ratio 2.82, 95% confidence interval 1.2–6.4) and cancer-specific survival (P

Background Life expectancy after transplantation has improved, and cancer may soon be the leading cause of late death after transplantation. The guidelines of the American and European societies of nephrology and urology have not yet established the optimal frequency for screening for renal cell carcinoma (RCC) of native kidneys in patients who have undergone renal transplantation. Objective To evaluate the prevalence, prognosis, and risk factors of RCC in a series of patients followed up for 16 years in our transplantation unit. Materials and Methods Our study is a follow-up observational cohort study conducted in 694 consecutive renal transplant recipients admitted to our institution from July 1991 through July 2007. At our institution, ultrasound studies of the native kidneys were performed every 6 months after renal transplantation. Results In the patient cohort studied, 10 patients developed a renal tumor (1.6% incidence). Three patients died of causes other than recurrence of RCC. Seven patients are alive with no evidence of RCC recurrence or metastatic disease after a mean (range) follow-up of 41 (12–96) months. Acquired cystic kidney disease and dialysis duration were positively associated with development of RCC. Conclusions The incidence of RCC in the literature varies between 0.3% and 4.8%. The variability depends on the timing of follow-up, with a higher incidence in prospective studies with strict follow-up. We advise ultrasound studies performed by specialized physicians every 6 months after transplantation. More detailed guidelines designed by the major international transplantation societies are necessary.

Laser-assisted microdissection has mainly been used in cancer studies to excise pure cell populations from heterogeneous tissues. Cancer and normal cells selected by laser-assisted microdissection have frequently been used for mRNA expression studies usually by reverse transcriptase-quantitative polymerase chain reaction (qPCR). Recently, real time immuno-qPCR was developed as a new tool for highly sensitive measurements of proteins. Using reverse transcriptase-qPCR and immuno-qPCR, we measured the amounts of prostate-specific antigen mRNA and its corresponding protein in homogeneous and comparable cell populations, collected from normal and cancer prostates by laser-assisted microdissection. With these techniques, prostate-specific antigen mRNA and protein were quantified over a wide range of concentrations with a sensitivity sufficient to analyze single prostate cells (LNCaP). We did not find significant differences in prostate-specific antigen protein and mRNA between normal and cancer cells. The expression of prostate-specific antigen protein and mRNA was highly correlated in both normal and pathological cells. In microdissected peritubular stromal areas of prostate cancers, the concentration of prostate-specific antigen protein was about 100 times higher than in normal prostate, indicating an increased transit of secreted prostate-specific antigen. In the same samples, prostate-specific antigen mRNA was not detectable. Our data demonstrate, for the first time, the feasibility of simultaneous application of reverse transcriptase-qPCR and immuno-qPCR in studies of homogeneous cell populations, collected by laser-assisted microdissection. The approach is expected to become a very powerful tool for expression studies in human cancers at both mRNA and protein levels.

Human prostate is now considered a target for vitamin D receptor (VDR) ligands, such as BXL-628. Because BXL-628 inhibited prostate growth without interfering with androgen signaling, it represents a new option for benign prostate hyperplasia (BPH) therapy. However, BPH symptoms are related not only to prostate size, but also to compensatory bladder hypertrophy and eventual overactivity. We now report that human bladder expresses VDR (determined by real-time PCR immunohistochemistry and Western blot) and responds to VDR agonists, such as the natural ligand, calcitriol, and its synthetic and less hypercalcemic derivative, BXL-628. Experiments were conducted with stromal cells derived from human bladder neck obtained at surgery from BPH patients. BXL-628 counteracted keratinocyte growth factor (KGF) and androgen-induced cell proliferation and stimulated apoptosis with a parallel reduced expression of the survival oncoprotein Bcl-2. Prolonged serum starvation time-dependently pushed bladder stromal cells to express activated myofibroblast markers, such as desmin and smoothelin, without changing other contractile-related proteins and intermediate filaments, such as vimentin. Chronic exposure to BXL-628 prevented starvation-induced cell phenotype modification. Because hypertrophy and starvation-induced bladder remodeling are supposed to underlie bladder overactivity, it is possible that BXL-628 might be helpful in reducing not only cumbersome symptoms related to prostate overgrowth, but also those related to bladder irritation.

The efficacy of weekly paclitaxel in androgen-independent prostate cancer and its addictive cytotoxicity with anthracycline derivatives led us to determine the safety and efficacy of a weekly schedule of paclitaxel and epirubicin. Between October 2000 and November 2002, 32 patients were enrolled in this study. Patients characteristics included a median age of 72 years (range 68-77), adequate hepatic, cardiac, renal and bone marrow functions, ECOG performance status of 1-2, and no prior chemotherapy. All patients had received hormonal manipulation and seven patients (22%) had received prior palliative radiation therapy. The regimen consisted of paclitaxel 70 mg/m2 i.v. infusion for 2 h and epirubicin 30 mg/m2 in bolus every week. Treatment was continued for 3 months or until disease progression or unacceptable toxicity were observed. During the study, prostate-specific antigen (PSA) was monitored and response was defined as a 50% reduction in PSA levels, to be confirmed 4 weeks later. Thirty-one patients were evaluable for toxicity and 21 for objective response. Seventeen patients (57%) had a decline above 50% in PSA level that lasted more than 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 5.5 months. Ten of the 21 patients with measurable disease (47%) had a confirmed objective response (one complete response and 20 partial responses). Thirteen of 25 symptomatic patients (56 %) had improvement in pain. The median time to disease progression was 7.6 months and the median survival was 12.9. The most prominent grade 3 toxicities were reversible myelosuppression and fatigue. Nausea, vomiting, diarrhea and peripheral edema were minimal. No evidence of cardiac toxicity was recorded. Alopecia was frequent, but reversible, in all patients. We conclude that despite the small sample size, this study demonstrates that the combination of weekly paclitaxel and epirubicin is a well-tolerated regimen for androgen-independent prostate cancer. The results imply that a combination of these agents in a weekly schedule may have clinical potential in prostate cancer treatment.

A vesico-vaginal fistula (VVF) is a fistulous tract that connects bladder and vagina, causing urine leakage via the vagina. In the developed world, iatrogenic postoperative VVF is the most common case. Classically, when treating a VVF via the abdominal route, an abdominal flap is mobilized and interposed between the bladder and the vagina.In our video, we describe a robotic VVF repair technique with no omental flap interpositioning for a vaginal vault-located fistula.Duration of surgery was 95 min, estimated blood loss was50 ml. The postoperative course was uneventful. At the 6-month follow-up, which included clinical and cystographic examinations, the patient had not experienced any recurrence.In our opinion, a two-layered suturing technique using two semi-continuous sutures for vaginal closure and perpendicular interrupted stitches for bladder closure does not require omental flap mobilization, reducing operating time and possible complications related to accidental peritoneal injuries.

Prostate growth and differentiation is under the control of androgens not only during fetal life and childhood but also in adulthood, and it has been proposed that increased prostatic concentration of androgens, or increased androgen responsiveness, causes benign prostatic hyperplasia (BPH). However, different androgen ablation strategies such as treatment with GnRH agonists and finasteride resulted in a modest decrease of the hyperplastic prostate volume. In the last few years it became evident that both androgen-dependent and androgen-independent growth factors promote prostate enlargement by inducing cell proliferation or reducing apoptosis. Therefore, new therapeutic strategies, aimed at reducing intraprostatic growth factor signaling, are under investigation. In this study, we report further evidence that a non hypercalcemic-analogue of vitamin D3, analogue (V) decreases growth factor-induced human BPH cell proliferation and survival. We found that Des (1-3) insulin-like growth factor [Des (1-3) IGF-I], an IGF-I analogue, which does not bind to IGF-binding proteins, is a potent mitogen for BPH stromal cells via a dual mechanism: stimulation of cell growth and inhibition of apoptosis. Similar results were previously reported for another growth factor for BPH cells, keratinocyte growth factor (KGF). Accordingly, we speculate that both KGF and IGF might be involved in the pathogenesis of BPH. We also found analogue (V) not only inhibits the mitogenic activity of growth factors on BPH cells, but even decreased the basal expression of bcl-2, and induced apoptosis. Therefore, vitamin D3 analogues might be considered for the medical treatment of BPH.

The etiology and progression of renal carcinomas (RCC) is still poorly understood. RCC have been classified into several pathological entities. The most frequent type, clear cell carcinoma, accounts for about 80% of sporadic RCC and shows several chromosome abnormalities documented both by conventional cytogenetics, loss of eterozygosity (LOH) and replication error (RER) studies. In 10 clear cell type sporadic RCC we evaluated LOH and RER using a set of 10 micro satellite markers covering the chromosome 3p region, which has been suggested for interstitial deletions. Electrophoresis was performed by automated sequencer ABI Prism 377 and data were analyzed with Genescan and Genotyper 2.5 softwares. We revealed allelic loss in 48,7% of informative microsatellites and a single case of RER. We found the highest LOH frequency in 3p25-26 region where maps Von Hippel-Lindau (VHL) oncosuppressor gene. In addition, DNA hypermethylation, an alternative mechanism of VHL gene silencing, was evaluated by methylation-specific PCR. However hypermethylation status was not detected in any of our tumor samples.

Angiogenesis is a tightly controlled process which depends on the balance between stimulating and inhibiting factors. When this balance is disrupted, angiogenesis acquires a pathological meaning. The list of molecules able to induce angiogenesis is heterogeneous with respect to their chemical characteristics and biological properties. Quantitative measurement of tumor angiogenesis is necessary for the choice of therapeutic strategies and as an endpoint for antiangiogenic therapy. We are developing a quantitative RT-PCR which measures the expression of specific factors in real time. With the use of this rapid technique, measurement of the expression of the angiogenic factors and inhibitors is also possible in specimens as small as biopsies.

Renal transplant recipients are a population usually considered at a higher risk of malignancies, mostly skin cancer and lymphoproliferative disorder. In recent years, prostate cancer in renal transplant recipients has been becoming more frequent. This is probably due to the growing age and the longer survival of the transplanted patients. We report the case of a 50-year-old man with prostate cancer and renal allograft, who received radiotherapy after prostatectomy at the Institute of Radiotherapy of the University of Florence. Radiotherapy is part of the standard treatment for many cases of prostate cancer. According to the few series reported in the literature and also to our experience, radiation therapy is feasible also in renal transplant recipients with accurate treatment planning.

Actinomycosis of the urinary bladder is rare, mostly subsequent to abdomino-pelvic infection, and usually affects women with long-term use of an intrauterine device. We describe a case of vesical actinomycosis mimicking a papillary bladder tumour in a 56-year-old woman with primary manifestation of the disease in the genital tract, subjected to two transurethral resections after relapse of a polypoid mass in the bladder. Urological procedures are necessary to differentiate actinomycosis from bladder cancer and the diagnosis is often made histologically.

Androgen-independent prostate carcinoma (AICP) is one of the tumors that continue to respond poorly to chemotherapy. Recently, protocols based on the use of docetaxel have significantly improved survival for patients in this disease. In other types of neoplastic disease, combined therapy with taxanes and anthracycline derivatives has been shown to produce additive effects in terms of growth inhibition, and superior tolerability when associated with weekly administration schedules. These findings prompted us to examine the tolerability and efficacy of weekly treatment of AICP with docetaxel (DOX) plus epirubicin (EPI). We enrolled 35 chemotherapy-naive men with AICP (mean age 72 years, range 68-77) and normal hepatic, renal, and cardiac function. The chemotherapy protocol provided for the IV administration of DOX (30 mg/m 2 ) and EPI (30 mg/m 2 ) on days 1, 8, and 15 every 28 days. Treatment was continued for 6 months or until disease progression and/or unacceptable toxicity was observed. Serum levels of prostate-specific antigen (PSA) were monitored in all patients, and reductions from baseline values of >50% were considered indicative of positive responses to treatment. Thirty-four patients were included in the analysis of toxicity, and objective responses to treatment were assessed in the 28 patients with measurable lesions. Nineteen patients (56%) experienced PSA reductions of >50% that persisted for more than 4 weeks. The response to therapy was classified as complete in 1 of the 28 patients (4%) with measurable disease (at the lymph node level). Thirteen others (13/28, 46%) had partial responses, in nine (32%) the disease remained unchanged, and progression was observed in the remaining five (18%); overall response rate was 50% (CR + PR). Of the 27 patients with pain at the time of enrollment, 16 (59%) experienced pain reduction during treatment. The median time to disease progression was 11.7 months (95% CI: 7.7-15.7) while the median survival time was 18.7 months (95% CI: 12.3-25.1). During the study, four patients developed grade 3 anemia and leukopenia, which was reversible in all cases. Lower grades of asthenia, nausea, vomiting, diarrhea, and peripheral edema were also observed. There were no cases of cardiotoxic effects. Alopecia was frequent but reversible in all cases. The results of this preliminary study indicate that the combined administration of DOX and EPI for treatment of AIPC is effective and well tolerated. The weekly administration of the drug combination appears to be a promising approach to the treatment of these tumors.

The enzyme tankyrase-1 (TNKS-1), a member of the growing family of poly(ADP-ribose) polymerases (PARPs), was identified as a component of the human telomeric complex. PARPs catalyze the formation of long chains of poly(ADP-ribose) onto protein acceptors using NAD(+) as a substrate. TNKS-1 interacts with the telomeric DNA-binding protein TTAGGG repeat-binding factor 1 (TRF1), which is a negative regulator of telomere length. TNKS-1 is a positive regulator of telomere elongation and its activity appears to be upregulated in some human cancers.We evaluated for the first time TNKS-1 mRNA expression by real time RT-PCR in tumor tissue, paired normal mucosa and urine sediment in patients with transitional cell carcinoma (TCC) of the bladder. Samples were collected from 41 consecutive patients, 20 with non-muscle-invasive (pTa-pT1) and 21 with muscle-invasive (/=pT2) bladder TCC. Results obtained in urine sediment were compared with those from 40 healthy subjects matched for age and sex.In pTa-pT1 tumor tissues, TNKS-1 mRNA levels were significantly higher than in/=pT2 patients (p0.0001). In urine sediment from TCC patients, independent of tumor stage, TNKS-1 mRNA levels were significantly higher than in healthy controls, with maximal levels in/=pT2 patients. In particular, TNKS-1 mRNA levels in urine were elevated in 31/41 patients with a sensitivity of 81% in/=pT2 tumors and 65% in pTa-pT1 TCC. Of patients with pTa-pT1 tumors, 11 had a recurrence within 18 months after initial transurethral resection. In these patients, urine levels of TNKS-1 mRNA were higher than in non-relapsing patients (p=0.038).In this preliminary study, TNKS-1 mRNA in urine sediment from patients with bladder TCC correlated with tumor stage, and higher preoperative levels were associated with increased risk of early recurrence.

OBJECTIVE To determine, in a multicentre prospective study, the accuracy of the tissue‐resonance interaction method (TRIMprob, new technology developed for the noninvasive analysis of electromagnetic anisotropy in biological tissues) in the diagnosis of prostate cancer. PATIENTS AND METHODS Two hundred patients (mean age 67.4 years) scheduled to have prostatic biopsies (because of a prostate‐specific, PSA, antigen level of ≥4 ng/mL or a suspicious digital rectal examination, DRE) were preliminarily examined while unaware of their clinical details using TRIMprob in five different centres. The final diagnosis obtained with TRIMprob was compared with the final histological diagnosis after extended biopsies. RESULTS Of the 188 evaluable patients (mean PSA level 9.3 ng/mL, sd 8.8; mean prostate volume 62.0 mL, sd 32.4), 61 (32.4%) had a positive biopsy for adenocarcinoma of the prostate. The overall sensitivity, specificity, positive predictive value, negative predictive value (NPV) and accuracy of TRIMprob were 80%, 51%, 44%, 84% and 60%, respectively. The prostate cancer detection rate after biopsy was significantly higher in patients with a positive examination (49/111, 44%) than in patients with a negative TRIMprob (12/77, 15%; P

Objectives The aim of this study was to assess efficacy and safety of association of duloxetine and rehabilitation compared with rehabilitation alone in men with SUI after radical retropubic prostatectomy (RRP), and to compare continence rate even after planned duloxetine suspension. Methods After catheter removal, 112 patients were randomized to receive rehabilitation and duloxetine (group A) or rehabilitation alone (group B), for 16 wk. Inclusion criteria: postprostatectomy SUI with daily incontinent episodes frequency (IEF) of four or greater. After 16 wk both groups suspended duloxetine/placebo and continued rehabilitation. All patients completed incontinence quality of life (I-QoL) questionnaire and bladder diary. Wilcoxon test was used to analyse changes in IEF and in I-QoL score; Fisher exact test was used to compare continent patients between the groups. Results Adverse events for duloxetine was 15.2%. 102 men completed the study. There was a significant decrease in pad use in group A. After 16 wk, 39 patients versus 27 were dry ( p =0.007). At 20 wk, 4 wk after planned interruption of duloxetine, we observed a U-turn, 23 patients were completely dry in group A versus 38 in group B ( p =0.008). Whereas, after 24 wk, 31 in group A versus 41 in group B were dry ( p =0.08). The decrease in IEF and improvements in I-QoL scores were significantly greater in group A for the first 16 wk. Conclusions The data suggest that combination therapy might provide another treatment option for SUI in men that might increase the percentage of early postsurgery continence.

Introduction. The incidence of urological complications after kidney transplantation varies from 3% to 14%, with a probable loss of the graft in 10% to 15% of cases and a mortality rate of up to 15%, despite improvements in prevention, diagnosis, and treatment as well as the use of new immunosuppressive therapies. Urinous fistulae, which are considered early complications of transplantation, are due to ischemic damage or necrosis generally occurring in the distal third of the ureter. Preservation of accessory arteries to the lower portion of the kidney is important, as they may constitute the blood supply of this segment of the collecting system or ureter. Their ligation may lead to necrosis and urinary fistulae. Ureteral stenosis, as late complication, is related to a pathology of the ureter itself, to infections, to abscesses, to fibrosis, and to ischemia. An early endoscopic approach permits resolution in 70% of cases. The aim of this retrospective study was to determine incidence and treatment of these complications. Materials and methods. From 1991 to 2004 we performed 453 kidney transplantations both from cadaveric and living donors. In 199 patients we performed a transvesical ureteroneocystostomy (UNCS), and in 260, an extravesical UNCS. Results. The nine patients who showed fistulae (1.9%) underwent surgical treatment. In eight we used a direct ureteral reimplantation, and in one, a Boari flap technique. Nephrectomy was necessary in four patients, including two who died of septic complications. In all 26 cases of ureteral stenosis (5.6%), we used an endourological approach (anterograde or retrograde), with surgical treatment afterward in 11 patients (42%) nine direct reimplants, one anastomosis to the native ureter (transplantation from a living donor), and in one case a Boari flap technique four patients who underwent surgical treatment showed progressive damage to graft function. Conclusions. In all patients who showed fistulae we suggest surgical review: for patients with ureteral stenosis, we suggest first an endourological approach and only when it is not successful do we consider surgical treatment.

Objective: The study presents an original uterus sparing technique for transvaginal repair of total genitourinary prolapse. The technique employs a synthetic mesh of mixed polypropylene and 910 polyglactin fibers. Methods: The prosthesis creates a support for the cystocele, the cervix and the enterocele. It has four anchoring sites: two at the rear in the sacrospinous ligaments and two at the front in the arcus tendineous of the levator ani muscle. Between February 2001 and December 2004, 24 patients (mean age 66.9 years), presenting symptoms of uterine prolapse, cystocele and enterocele (POP-Q stage III-IV Aa associated to II-III-IV C), were treated with our procedure. Pre- and postoperative parameters were evaluated statistically. Results: No patient had any serious complications. The mean follow-up was 31.1 months (range 6–52). 19 patients (79.1%) have shown excellent results and have been completely cured. In 5 other cases (20.8%), the cystocele was completely cured and there was a significant improvement in the hysterocele and the enterocele. One patient required surgical treatment for postoperative stress incontinence. Statistical analysis of data regarding the pre- and postoperative prolapse stage demonstrated a high degree of objective cure rates (p < 0.0001). Conclusions: While hysterectomy remains the habitual treatment for severe uterine prolapse, our technique provides a promising alternative solution. It is also significant that there were no complications of erosion or infection associated with the prosthesis.

OBJECTIVE: Calcitriol analogues might represent an interesting new therapy for benign prostate hyperplasia (BPH). We here report the preclinical characterization of BXL-628, an analogue selected for an ongoing double-blind, randomized, placebo-controlled phase II trial in BPH. DESIGN: Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats. METHODS: BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis. RESULTS: BXL-628 inhibited human BPH cell proliferation and induced apoptosis even in the presence of androgens or growth factors. It also decreased prostate growth to an extent similar to finasteride, inducing DNA fragmentation and apoptosis, both in intact and in testosterone-supplemented castrated rats. Accordingly, BXL-628, like finasteride, increased the expression of clusterin, a prostatic atrophy marker. However, BXL-628 did not inhibit 5 alpha-reductase 1 and 2, did not bind to the androgen receptor (AR) in BPH homogenates and did not affect AR-coupled luciferase activity. In addition, BXL-628 did not affect rat pituitary and testis activity or calcemia. CONCLUSIONS: BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH.

We have recently found that analog V (BXL-353, a calcitriol analog) inhibits growth factor (GF)-stimulated human benign prostate hyperplasia (BPH) cell proliferation by disrupting signal transduction, reducing Bcl-2 expression, and inducing apoptosis. We now report that BXL-353 blocks in vitro and in vivo testosterone (T) activity. BPH cells responded to T and dihydrotestosterone (DHT) with dose-dependent growth and reduced apoptosis. Exposure of BPH cells to BXL-353 significantly antagonized both T- and DHT-induced proliferation and induced apoptosis, even in the presence of T. To verify whether BXL-353 reduced prostate growth in vivo, we administered it orally to either intact or castrated rats, supplemented with T enanthate. Nonhypercalcemic doses of BXL-353 time- and dose-dependently reduced the androgen effect on ventral prostate weight, similarly to finasteride. Comparable results were obtained after chronic administration of BXL-353 to intact rats. Clusterin (an atrophy marker) gene and protein were up-regulated by BXL-353 in rat prostate, and nuclear fragmentation was widely present. The antiandrogenic properties of BXL-353 did not interfere with pituitary and testis function, as assessed by serum determination of rat LH and T. BXL-353 did not compete for androgen binding to BPH homogenates and failed to inhibit 5α-reductase type 1 and type 2 activities. In conclusion, BXL-353 blocks in vitro and in vivo androgen-stimulated prostate cell growth, probably acting downstream from the androgen receptor, without affecting calcemia or sex hormone secretion. BXL-353 and other vitamin D3 analogs might thus represent an interesting class of compounds for treating patients with BPH.