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Standard treatment for localized non-metastatic renal cell carcinoma (RCC) is radical or partial nephrectomy. However, after radical surgery, patients with stage II-III have a substantial risk of relapse (around 35%). To date a unique standardized classification for the risk of disease recurrence still lack. Moreover, in the last years great attention has been focused in developing systemic therapies with the aim of improving the disease-free survival (DFS) of high-risk patients, with negative results from adjuvant VEGFR-TKIs. Therefore, there is still a need for developing effective treatments for radically resected RCC patients who are at intermediate/high risk of relapse. Recently, interesting results came from immune-checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, with a significant benefit in terms of disease-free survival from adjuvant pembrolizumab. However, the conflicting results of diverse clinical trials investigating different ICI-based regimens in the adjuvant setting, together with the still immature data on the overall survival advantage of immunotherapy, requires careful considerations. Furthermore, several questions remain unanswered, primarily regarding the selection of patients who could benefit the most from immunotherapy. In this review, we have summarized the main clinical trials investigating adjuvant therapy in RCC, with a particular focus on immunotherapy. Moreover, we have analyzed the crucial issue of patients' stratification according to the risk of disease recurrence, and we have described the possible future prospective and novel agents under evaluation for perioperative and adjuvant therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Recently, it was reported that the Bladder EpiCheck test is likely to represent a valid tool in the diagnostic process of patients who have suspected bladder carcinoma, with some controversial management decisions because of the technical limitations of cytology., Methods: Two hundred ninety patients with a diagnosis of nonmuscle-invasive bladder carcinoma who were admitted at the authors' department from March 2019 to December 2019 were treated and followed for 1 year. During follow-up, all patients were evaluated by voided urine cytology, white-light cystoscopy (according to European Association of Urology guidelines), and the Bladder EpiCheck test., Results: The cytologic diagnoses of high-grade urothelial carcinoma (HGUC) and suspicious for HGUC were histologically confirmed in 5 of 20 patients (25%) who had quantitative Bladder EpiCheck scores (EpiScores) from 60 to 69, in 23 of 36 patients (64%) who had EpiScores from 70 to 79, and in 42 of 56 patients (75%) and 57 of 63 patients (90%) who had EpiScores between 80 and 89 and EpiScores >90, respectively. Of 48 patients who had a cytologic diagnosis of HGUC or suspicious for HGUC with EpiScores ≥60 and negative histology, 20 (42%) had a recurrence of HGUC, which was cytologically and histologically confirmed, at 6-12 months during follow-up., Conclusions: To the best of the authors' knowledge, this is the first study in which patients at high risk for HGUC were stratified using the Bladder EpiCheck EpiScore. The results validate this methylation analysis tool as a useful method for predicting recurrent HGUC during the follow-up of patients with nonmuscle-invasive bladder carcinoma., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Argonautes (AGOs) are a highly conserved family of proteins found in most eukaryotes and involved in mechanisms of gene regulation, both at the transcriptional and post-transcriptional level. Among other functions, AGO proteins associate with microRNAs (miRNAs) to mediate the post-transcriptional repression of protein-coding genes. In this process, AGOs associate with members of the trinucleotide repeat containing 6 protein (TNRC6) family to form the core of the RNA-induced silencing complex (RISC), the effector machinery that mediates miRNA function. However, the description of the exact composition of the RISC has been a challenging task due to the fact the AGO's interactome is dynamically regulated in a cell type- and condition-specific manner. Here, we summarize some of the most significant studies that have identified AGO complexes in mammalian cells, as well as the approaches used to characterize them. Finally, we discuss possible opportunities to exploit what we have learned on the properties of the RISC to develop novel anti-cancer therapies. SIGNIFICANCE STATEMENT: The RNA-induced silencing complex (RISC) is the molecular machinery that mediates miRNA function in mammals. Studies over the past two decades have shed light on important biochemical and functional properties of this complex. However, many aspects of this complex await further elucidation, mostly due to technical limitations that have hindered full characterization. Here, we summarize some of the most significant studies on the mammalian RISC and discuss possible sources of biases in the approaches used to characterize it., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: To date, robotic surgery in urology is well established all over the world. The newest platform on the market is the HUGO™ RAS system, developed by Medtronic. In this paper we provide a brief description of the system and describe our system set-up and surgical approach with this new platform in our initial experience of robotic radical prostatectomy (RARP) series., Materials and Methods: After an official training, seven consecutive patients affected by localized prostate cancer underwent RARP with HUGO TM RAS system at our Institution. A description of our surgical approach and docking setup is provided. Docking and console times were reported for all precedures together with main suggestions to facilitate the use of this new system at the beginning of the experience., Results: Our operating room setup has shown to be safe, effective, and easy replicable. During our series, operative times appeared to be easy reproducible and comparable to those obtained with daVinci system. No major system faults and conflicts between robotic arms were observed after the first procedure., Conclusions: Our surgical approach and system configuration for performing RARP with the new HUGO™ RAS system appears to be safe, efficient and easy reproducible.

Background: Severe functional impairment is often considered a contraindication to intravesical therapy for nonmuscle-invasive bladder cancer (NMIBC). A tailored intravesical bacillus Calmette-Guérin (BCG) procedure was evaluated in high-risk (HR)-NMIBC patients with severe functional impairment., Materials and Methods: Patients with a Katz Index score of 2 or less and an initial diagnosis of HR-NMIBC with atraumatic insertion of a Foley-type indwelling catheter, bladder emptying, and BCG instillation were prospectively treated; after 2 hours, the bladder was emptied and the catheter was removed (group A).After propensity score matching, 52 patients in group A were compared with that of 52 consecutive patients in group B using a retrospective database, with similar baseline/oncological characteristics and treated with standard intermittent catheterization. Moreover, groups A and B were compared with that of 130 consecutive patients (group C) retrospectively evaluated, with similar oncological characteristics but with a Katz Index score of 3 or greater and treated with standard intermittent catheterization., Results: The discontinuation rates were 11.5%, 35%, and 9% in groups A, B, and C, respectively (A vs. B, log-rank score 42.52 [ p < 0.05]; B vs. C, 107.6 [ p < 0.05]; A vs. C, 3.45 [ p > 0.05]). The overall adverse event rates were 38.5%, 57.7%, and 39.2%, respectively (A vs. B, p = 0.04; B vs. C, 0.03; A vs. C, 0.92). The rates of severe adverse events were 1.9%, 1.9%, and 1.5%, respectively, without statistically significant differences. The cumulative HR disease-free survival rates were 63.4%, 48%, and 69.2%, respectively (A vs. B, log-rank score 154.9 [ p < 0.05]; B vs. C, 415 [ p < 0.05]; A vs. C, 244 [ p < 0.05])., Conclusions: A tailored intravesical instillation procedure may reduce BCG discontinuation and adverse effects., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Despite several efforts in the search for noninvasive biomarkers to provide prognostic information for noninvasive muscle bladder cancer, none have shown significant potential. In this context, standard urinalysis is still necessary to provide many data. This method is an inexpensive, simple, and easy-to-repeat tool to follow-up patients over time. Urinalysis does not fall within study protocols and allows evaluation of the immune activation/response (even if indirectly). As such, this method can certainly provide useful information for prognosis.

Introduction: EpiCheck is a new urinary test that analyses DNA methylation biomarkers in order to identify high-risk urothelial cancer MATERIALS AND METHODS: A prospective single centre study was performed. We analysed Epicheck results in a population of 231 patients in follow-up for non-muscle invasive bladder cancer. The primary endpoint was to evaluate sensitivity and specificity of Epicheck in detecting any type of bladder cancer recurrence. The secondary endpoint was to evaluate specificity and sensitivity of Epicheck in patients with high-risk recurrence and in patients recently treated with endovesical therapy (< 3 months)., Results: Negative predictive value (NPV) for cytology was 83 % while for bladder Epicheck it was 89 %, while positive predictive value (PPV) was 67 % and 73 % for cytology and Epicheck respectively. Considering only high grade non muscle invasive bladder cancer the sensitivity of Epicheck was 91 % and for cytology was 81 %, specificity was 85 % and 83 % and negative predictive value of Epicheck outreached 96 % compared to 92 % of cytology. Among patients with an ongoing or recent endovesical treatment it appears that sensitivity of Epicheck was 88% % compared to 73 % of cytology, specificity was 97 % and 85 % and NPV was 92 % compared to 82 % for cytology., Conclusion: The EpiCheck (test showed very high diagnostic values, higher than the currently, gold standard. The test might clinically improve the BCa management in terms of, reduced number of inconclusive/suspicious reports of cytology and endoscopy, reduced number of further examinations, reduced associated patient and economic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/aim: Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients., Patients and Methods: Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination., Results: We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate., Conclusion: The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The cement industry is intensive in energy and feedstock use. It includes three main phases: raw materials and energy supply, transport, and manufacturing. The sector is known for its considerable environmental impacts. The increase in energy efficiency and the use of non-fossil fuels and raw materials are considered mature technologies in cement industries. We evaluate different environmental impacts of the production of 1 t of cement in four Brazilian scenarios. We compare one business-as-usual reference scenario (case 1) to three alternative 2030 carbon mitigation sectoral plan scenarios (cases 2, 3a, and 3b) that assume mature technologies. We analyze all 18 impact categories within the ReCiPe 2016 Life Cycle Assessment methodology. Results show reductions in 17 impact categories, ranging from no change in ozone depletion (case 2) to 39% reduction in fossil resource scarcity (case 3b). The effects on climate change decreased 14% in case 2 and 33% in cases 3a and 3b. The clinkerization process is the greatest contributor to atmospheric impacts, while raw material consumption to toxicity impacts. In contrast, there is no single main process contributing to resource depletion impacts. The changes in cement production lead to carbon emission reductions above expected levels and to reductions in other environmental impact categories modeled in ReCiPe 2016 method., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium represents an unmissable event for oncologists who deal with renal cell carcinoma (RCC)., Aim and Results: This article describes the main acquisitions of RCC management, including the advent of a new combo (pembrolizumab+lenvatinib) as first-line therapy, the confirmation of an OS advantage of ICI plus VEGFR-TKI combinations over sunitinib at longer follow-up, the persistent benefit from these combinations in particular subgroups (clear cell mRCC tumors with sarcomatoid differentiation), and possible new approaches in subsequent lines of therapy (including the HIF-2α inhibitor belzutifan)., Conclusions: This 2021 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized management of mRCC.

Prostate cancer is the second most commonly diagnosed cancer in man. Since the first MRI was performed, enormous progress has been made in diagnosis, treatment, and follow up of PCa, mainly due to multiparametric prostatic MRI (mpMRI). Although mpMRI has become the best imaging tool for identifying PCa, some limitations still exist. Prostate imaging with mpMRI is, to date, the best way to locate suspicious lesions to trigger prostate biopsy, plan active surveillance, or definitive treatment. In case of relapse, mpMRI can help detect local disease and provide specific management. It is well known that there is a subset of patients in whom mpMRI fails to depict csPCa. These missed significant cancers demand great attention. Prostate mpMRI quality depends on several factors related to equipment (including equipment vendor, magnet field and gradient strength, coil set used, software and hardware levels, sequence parameter choices), patient (medications, body habitus, motion, metal implants, rectal gas), and most importantly the radiologic interpretation of images (learning curve effects, subjectivity of observations, interobserver variations, and reporting styles). Inter-reader variability represents a huge current limitation of this method. Therefore, mpMRI remains the best imaging tool available to detect PCa, guiding diagnosis, treatment, and follow up while inter-reader variability represents the best limitation. Radiomics can help identifying imaging biomarkers to help radiologist in detecting significant PCa, reducing examination times, and costs.

Background: Atypical small acinar proliferation (ASAP) occurs in approximately 5% of prostate biopsies. Approximately 30%-40% of these patients may develop prostate cancer (PCa) within a 5-year period, often not clinically significant. Current guidelines recommend a repeat biopsy within 3-6 months after the initial diagnosis, but it seem not to be the best strategy., Methods: Objectives -evaluating the natural history of ASAP, stratifying the risk of csPCa after ASAP, identifying predictive factors of PCa after atypical diagnosis. Materials and methods -retrospective single-institutional study on patients undergoing prostate biopsy for suspicious PCa (2005-2016). We evaluated the incidence of overall PCa, intermediate-high risk of PCa and csPCa in case of ASAP, according to D'Amico classification and Epstein modified criteria., Results: Out of 4.567 patients undergoing prostate biopsy, ASAP was detected in 2.6% of cases. All patients with ASAP underwent repeat saturation biopsy within 6 months and PCa was diagnosed in 34.5%. According to D'Amico classification, 26%, 5.9%, and 2.5% had low, intermediate, and high-risk disease, respectively. According modified Epstein criteria, the incidence of csPCa was 12.6%. LRT showed that the overall probability to develop PCa doubled when PSA density (PSAD) moved from values lower than 0.13 ng/ml/cc to class 0.13-0.30 ng/ml/cc, and it tripled when PSAD was higher than 0.30 ng/ml/cc., Conclusions: The rate of csPCa in patients with an initial diagnosis of ASAP who had repeat biopsy was 12.6%. The overall PCa rate was 34.5%. Among patient undergoing RP, an upgrading from ncsPCa to csPCa was reported in 35% of cases. PSAD is the only predictive factor directly associated to the risk of developing PCa on repeat biopsy. These findings suggest that immediate repeat biopsy remains the correct strategy in absence of novel predictor factors and non-invasive diagnostic evaluations.

Metanephric adenoma (MA) is an uncommon benign renal tumor whose histomorphological aspect resembles that of Wilms' tumor and papillary renal cell carcinoma. From a diagnostic and therapeutic perspective, recognition of this entity is important as it has a more favorable clinical outcome compared with Wilms' tumor and papillary renal cell carcinoma. MA should not be treated with nephrectomy if the tumor size is small, opting for a conservative treatment. However, the preoperative diagnosis of this disease is extremely challenging. The present study describes a case of this rare disease, showing an ambiguous radiological imaging and that only after a percutaneous biopsy, was defined as a MA and treated with partial nephrectomy. Moreover, the histological diagnosis of this case was partially complicated by the equivocal immunohistochemical analysis showing negativity for BRAF VE1 staining. Only the mutational analysis demonstrated the presence of the BRAF V600K mutation (for the first time described in a case of metanephric adenoma), highlighting the necessity of sequencing in case of MA with negativity for BRAF VE1 clone.

Huntington's disease (HD) is characterised by a triad of cognitive, behavioural, and motor symptoms which lead to functional decline and loss of independence. With potential disease-modifying therapies in development, there is interest in accurately measuring HD progression and characterising prognostic variables to improve efficiency of clinical trials. Using the large, prospective Enroll-HD cohort, we investigated the relative contribution and ranking of potential prognostic variables in patients with manifest HD. A random forest regression model was trained to predict change of clinical outcomes based on the variables, which were ranked based on their contribution to the prediction. The highest-ranked variables included novel predictors of progression-being accompanied at clinical visit, cognitive impairment, age at diagnosis and tetrabenazine or antipsychotics use-in addition to established predictors, cytosine adenine guanine (CAG) repeat length and CAG-age product. The novel prognostic variables improved the ability of the model to predict clinical outcomes and may be candidates for statistical control in HD clinical studies., Competing Interests: NG, RH, SS, and GP are employees of F. Hoffmann-La Roche Ltd. JL is a paid Advisory Board member for F. Hoffmann-La Roche Ltd and uniQure biopharma B.V, and a paid consultant for Vaccinex Inc, Wave Life Sciences USA Inc, Genentech Inc and Triplet Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from F. Hoffmann-La Roche Ltd. The funder was involved in the study design, analysis, interpretation of data and the decision to submit it for publication., (Copyright © 2021 Ghazaleh, Houghton, Palermo, Schobel, Wijeratne and Long.)

Background: A common limit of the widely used risk scores for preoperative assessment is the lack of information about aspects linked to frailty that may affect outcome, especially in the setting of elderly patients undergoing urological surgery. Frailty has recently been introduced as an additional characteristic to be assessed for better identifying patients at risk of negative outcomes., Objective: To examine the evidence for recent advances in preoperative assessment in patients undergoing urological surgery focussing on the detrimental effect of frailty on outcome, including major (mPCs) and total postoperative complications (tPCs), discharge to a facility, and mortality. The secondary aim was to establish which cut-off scores of the modified Frailty Index (mFI, 11 items) and/or simplified FI (sFI, five items) predicted PCs., Methods: We searched PubMed, the Excerpta Medica database (EMBASE), Cochrane Library and clinicaltrial.gov from inception to 31 May 2020. Studies reporting relationships between the investigated outcomes and patients' frailty were included. We estimated odds ratios (ORs) through a random effect model by using Revman 5.4., Results: Frailty, assessed by different tools, was associated with a significantly higher rate of 30-day (OR 1.73, 95% confidence interval [CI] 1.58-1.89) and 90-day (OR 2.09, 95% CI 1.14-3.82) mPCs and 30-day tPCs (OR 2.10, 95% CI 1.76-2.52). A mFI of ≥2 was associated with a higher rate of 30-day mPCs (OR 1.79, 95% CI 1.69-1.89) and greater 30-day mortality (OR 3.46, 95% CI 2.10-5.49). A pre-planned post hoc analysis also revealed that a sFI of ≥3 was predictive of mPCs (OR 3.30, 95% CI 2.12-5.12)., Conclusions: Frailty assessment may help to predict PCs and mortality in patients undergoing major urological surgery. Either a mFi of ≥2 or sFI of ≥3 should be considered potential 'red flags' for preoperative risk assessment and decision-making. There is not enough evidence to confirm the necessity to perform frailty assessment in minor urological surgery., (© 2020 The Authors BJU International © 2020 BJU International.)

Introduction: In cases of recurrent high-risk non-muscle-invasive bladder cancer, radical cystectomy (RC) is recommended. We compared oncologic and treatment-related outcomes of second-line conservative device-assisted therapy to RC., Patients and Methods: In a retrospective cohort study, we analyzed 209 consecutive patients with recurrent bacillus Calmette-Guérin-unresponsive high-risk non-muscle-invasive bladder cancer; 107 subjects refused RC and were offered electromotive drug administration (n = 44) or chemohyperthermia (n = 63) (group A), and 102 patients underwent RC (group B). In group A, patients who did not benefit from device-assisted treatment underwent RC. The endpoints were high-grade disease-free survival, progression-free survival, cancer-specific survival, overall survival, and treatment-related complications. Follow-up was based on international guideline recommendations. Analyses were performed with log-rank and Fisher exact tests., Results: The median follow-up was 59 months (SD ± 5.3). When comparing group A to B, overall survival rates were 91.6% and 90.2%, respectively (P > .05); cancer-specific survival was 94.4% and 96.1%, respectively (P > .05); high-grade disease-free survival was 43% and 74.5%, respectively (P < .05); and progression-free survival was 59.8% and 75.5%, respectively (P < .05). Patients with carcinoma-in-situ had worse oncologic outcomes compared to patients with papillary disease. In the multivariate analysis, multifocality, disease recurrence, and progression risk group were independently associated with device treatment failure. The 90-day RC-related overall complications rates were 63.9% in group A and 66.6% in group B (P = .63); grade 3 to 5 complications were 9.8% in group A and 9.8% in group B(P = .99). Complications within group A were comparable (P > .05)., Conclusion: Device-assisted treatment may a represent a valid second-line conservative tool in selected patients with recurrent high-risk non-muscle-invasive bladder cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To compare the efficacy of artificial urinary sphincter (AUS) vs retrourethral transobturator sling (RTS) in men with moderate post-prostatectomy urinary incontinence (PPI) using propensity score-matching analysis to enhance the validity of the comparison (Canadian Task Force classification II-2)., Patients and Methods: Consecutive men with moderate (3-5 pads/day) stress-prevalent PPI were included if implanted with a RTS (TiLOOP ® Male; pfm medical, Köln, Germany) or AUS (AMS800 ® ; Boston Scientific, Boston, MA, USA) since July 2011 to December 2017 and with ≥12 months of follow-up. Preoperative assessment included 24-h pad usage, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), urethrocystoscopy, and urodynamics if indicated. Propensity score-matching analysis was based on age, body mass index, Charlson Comorbidity Index, pad usage, previous radiotherapy, and urethrotomy. The primary outcome was at least 'much improved' response at 12-months according to the Patient Global Impression of Improvement questionnaire, without additional PPI surgery or prosthesis explantation., Results: Of 109 included patients, 70 patients were matched and the study groups were well balanced for the baseline matched variables. The median baseline 24-h pad usage was four in both groups (P = 0.10), and median follow-up was 51.2 months for AUS and 47.2 months (P = 0.5) for RTS patients. In the AUS and RTS cohorts, respectively, 33 (94.3%) and 24 (68.6%) patients achieved the primary outcome (P < 0.001), the 0-1 pad/day rates was 94.3% vs 68.6% (P = 0.012) at 12 months, and 91.4% vs 68.6% (P = 0.034) at last follow-up. At the last follow-up, the median 24-h leakage volumes, median ICIQ-SF scores and satisfaction rates were 0 vs 15 mL (P = 0.017), 4 vs 10 (P = 0.001), and 94.3% vs 68.6% (P = 0.012) in the AUS and RTS cohorts, respectively. There were no significant differences in overall rates of complications and re-interventions, although Clavien-Dindo Grade III complications (n = 3) occurred only in the AUS group. At sensitivity analysis, the study was reasonably robust to hidden bias., Conclusion: We found that AUS implantation significantly outperformed RTS in patients with moderate PPI for both subjective and objective outcomes., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Background: Circulating tumor cells (CTCs) represent a prerequisite for the formation of metastases. The aim of the study was to identify the role of CTCs as a biological marker of aggressiveness of prostate cancer and verify the expression of molecular markers predictive of response to different therapeutic approaches., Methods: Prospective, single-arm, non-randomized trial. Twenty-four patients with prostate cancer were enrolled into two groups: group 1 (N.=11) with localized prostate cancer treated with radical prostatectomy; group 2 (N.=13) with metastatic disease. We performed, dosage of blood PSA and testosterone, detection of EGFR, PSMA, PSA and Androgen Receptor (AR) expression on CTC during pre-treatment and follow-up at 1, 3, 9 and 18 months., Results: A total of 65 blood samples were evaluated. In group 1, pre-treatment sampling was negative for the expression of markers on CTC in 90% of the patients while group 2 pre-treatment sampling was positive for the expression of at least one biomarker in seven of 13 patients (54%). After treatment, four patients in group 2 experienced a reduced expression of the markers on CTC, however, in one case there was a new increase of PSA and PSMA at 3 months. One patient had a positivity of AR at 3 months., Conclusions: The expression of PSA, PSMA, EGFR and AR on CTCs appears to be absent in the pre-treatment samplings in cases of localized prostate cancer. The same markers are hyper-expressed before treatment mostly in metastatic prostate cancer and can relate with early biochemical relapse.

Background: Mitomycin C (MMC) is widely used, but the optimal dose and schedule have not been established., Objective: To evaluate the ablative power and patient safety of a short-term intensive schedule of intravesical MMC in patients with recurrent non-muscle-invasive bladder cancer (NMIBC)., Design, Setting, and Participants: This was a prospective, single-center, nonrandomized study that compared 47 patients (group 1) with a history of low- to intermediate-risk NMIBC with long free-recurrence intervals, recurrence of ≤1cm in maximum diameter, and negative cytology to 47 consecutive patients with the same baseline characteristics (group 2)., Intervention: Intravesical MMC three times per week for 2 wk for group 1. Transurethral resection of bladder tumor (TUR-BT) and early instillation and a weekly schedule of intravesical MMC for group 2. All cancer-free patients underwent monthly MMC maintenance. Follow-up included bladder mapping, voiding and washing urinary cytology, TUR of suspected area, TUR of previous tumor location, and ultrasound or computed tomography/magnetic resonance imaging., Outcome Measurement and Statistical Analysis: We used χ 2 and Student's t test for comparison of categorical and continuous variables, respectively. Kaplan-Meier curves were plotted to estimate cancer-free survival. The significance level was set to p<0.05., Results and Limitations: The complete response rate at 39 mo was 61.7% in group 1 and 70.2% in group 2 (p=0.38). Kaplan-Mayer analysis revealed no difference in cancer-free survival rates overall (log-rank <3.84), according to tumor size in each group (log-rank <3.84), or between the groups (log-rank <7.82). No cases of systemic toxicity were observed. Local toxicities did not differ between the groups (p=0.32) and resolved on treatment of symptoms, and no patient discontinued their treatment. Limitations include the small number of patients, selection bias because of the single tertiary center, and short follow-up., Conclusions: The proposed MMC schedule had good ablative power that can be explained by better concordance between the scheduled timing and the tumor cell duplication rate. The short-term intensive schedule could be considered as a therapeutic strategy to replace TUR-BT in selected NMIBC patients., Patient Summary: We report our experience of a tailored intravesical therapy schedule for bladder cancer. This schedule could be considered a therapeutic strategy to replace surgery for selected patients., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor for response of high risk non muscle invasive bladder cancer (HRNMIBC) treated with BCG therapy., Materials and Methods: Between March 2010 and February 2014 in a tertiary center 100 consecutive patients with newly diagnosed HRNMIBC were retrospectively analyzed. Patients were divided according to NLR value: 46 patients with NLR value less than 3 (NLR < 3 group), and 54 patients with NLR value more than 3 (NLR ≥ 3 group). At the end of follow-up 52 patients were high grade disease free (BCG-responder group) and 48 patients underwent radical cystectomy for high grade recurrence or progression to muscle invasive disease (BCG non-responder group). The average follow-up was 60 months., Intervention: analysis and correlation of preoperative NLR value with response to BCG in terms of recurrence and progression., Results: The optimal cut-off for NLR was ≥ 3 according to the receiver operating characteristics analysis (AUC 0.760, 95% CI, 0.669-0.850). Mean NLR value was 3.65 ± 1.16 in BCG non-responder group and 2.61 ± 0.77 in BCG responder group (p = 0.01). NLR correlated with recurrence (r = 0.55, p = 0.01) and progression risk scores (r = 0.49, p = 0.01). In multivariate analysis, NLR (p = 0.02) and EORTC recurrence risk groups (p = 0.01) were associated to the primary endpoint. The log-rank test showed statistically significant difference between NLR < 3 and NLR ≥ 3 curves (p < 0.05)., Conclusions: NLR value preoperatively evaluated could be a useful tool to predict BCG response of HRNMIBC. These results could lead to the development of prospective studies to assess the real prognostic value of NLR in HRNMIBC., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Objectives: To evaluate the efficacy and safety of a tailored endovesical immunotherapy protocol with biweekly BCG for elderly Patients with high risk non muscle invasive bladder cancer (HG-NMIBC)., Materials and Methods: We retrospectively evaluated data from 200 patients older than 80 years newly diagnosed with HG-NMIBC: 100 (group 1) with multiple comorbidities (WHO PS 2-3, ASA score ≥3, Charlson Comorbidity index ≥3, GFR<60 mL/min) were treated with BCG induction course administered biweekly; 100 (group 2) with statistically significant better conditions were treated with standard weekly BCG therapy. After the induction treatment disease-free patients underwent to at least one year of BCG maintenance therapy. Endpoints were: initial response to BCG, cancer-free survival and rate of progression at 2 years, rate of complications., Results: No statistically significant differences were found in terms of initial response to BCG (69% in Group 1 vs 71% in Group 2, P = 0.75), cancer free survival (57% vs 55% respectively, P = 0.77) and rate of progression (20% vs 14% respectively, P = 0.26) at 2 years. The difference in the rate of overall complications was statistically significant (15% in Group 1 vs 27% in Group 2, P = 0.03), in the rate of severe complications was not statistically significant (5% in Group 1 vs 7% in Group 2, P = 0.61)., Conclusion: A tailored regimen of BCG administration is possible and safe in frail elderly patients, limiting side effects and risk of undertreatment but maintaining oncological outcomes. Preliminary results in a small patients group are promising but larger randomized studies are needed to confirm our data., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects., Methods: This was a single-centre, randomized, double-blind, adaptive study of 37 subjects receiving single ascending oral doses of RG7342 (ranging from 0.06-1.2 mg, n = 27) or placebo (n = 10). A modified continual reassessment method, with control for the probability of overdosing based on the occurrence of dose-limiting events (DLEs), was applied to inform the subsequent dose decisions for RG7342., Results: DLEs consisted of dizziness, nausea and vomiting, and the incidence and severity of these adverse events increased in a concentration-dependent manner. RG7342 doses of 1.2 mg under fasting conditions, which reached a mean maximum plasma concentration (C max ) of 10.2 ng ml -1 , were not tolerated (four out of six subjects experienced DLEs). RG7342 showed dose-proportional pharmacokinetics, with rapid absorption and a biphasic decline, and a mean terminal half-life estimated to be >1000 h., Conclusions: Single oral doses of RG7342 were generally tolerated up to 0.6 mg under fasting and 0.9 mg under fed conditions in healthy subjects. Bayesian adaptive methods describing the probability of DLEs were applied effectively to support dose escalation. MTDs (fasting, fed) were associated with a C max of 6.5 ng ml -1 . The development of RG7342 was discontinued owing to the potential challenges associated with a long half-life in context of the observed adverse events., (© 2017 The British Pharmacological Society.)

Aims: To objectively assess and enhance the appropriateness of continence products provision to sufferers from urinary incontinence (UI) managed with containment strategies., Methods: Incontinent patients of five Italian continence care services were included in this industry-supported study from 01/2012 to 03/2016. All patients/carers have been invited to perform a 48-h home-based pad test and to fill in a diary. The primary outcome was the product appropriateness defined as the use of a pad with maximum absorbent capacity (MAC) from 30% to 50% higher than the individually measured urine load. Pads provision was corrected accordingly. Meaningful factors affecting products appropriateness and patient's satisfaction with the new products were also assessed., Results: The study included 14 493 subjects (mean age 78 years; 26% males, 74% females) using overall during the study days 98 362 pads. Sixty percent of the products were found to be not appropriate. In most of cases, (75%) products were inappropriate because too large. Age and pad weight gain, followed by gender, body weight, waist circumference, level of autonomy and mobility, pad wearing time, skin health status, and health district were independently associated to the propensity to inappropriateness. After correction of products prescription, a significant reduction (-31%) of the use of largest products was observed. At 6 months evaluation, 88% of evaluable participants were satisfied with the new prescription., Conclusions: Most of patients are provided with not appropriate containment products. The use of the 48-h pad test allows improving on an individual basis the appropriateness of products provision., (© 2017 Wiley Periodicals, Inc.)

Objective: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials., Methods: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up., Results: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy., Conclusions: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures., (© 2017 American Academy of Neurology.)

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer death in developed countries. Despite the primary treatments, 20-30% of patients experience a recurrence. The main objective of this study was to evaluate the clinical efficacy of salvage high intensity focused ultrasound (HIF U) after radical prostatectomy in terms of biochemical free survival rate (BFSR) and PSA nadir., Methods: Twenty two patients with local recurrence of Pca after radical prostatectomy underwent HIFU as first-line salvage therapy. Considering that in all HIFU experiences, PSA nadir and PSA failure are different and PSA definition of BFSR is unknown, we defined treatment success as a PSA nadir ≤0.4 ng/mL 3 months after treatment. All early and late medical and surgical complications were recorded., Results: Ten of the 22 patients (45.5%) were classified as "success" three months after HIFU, showing a nadir PSA≤0.4 ng/mL; 12/22 patients (54.5%) were classified as "failure" during follow-up (median follow-up: 48 months). Seventeen of 22 (77%) patients were continent (no-pad) before HIFU. A new diagnosis of stress urinary incontinence was made in 5 cases (early onset) after treatment. A case of vesicoureteral anastomotic stenosis was treated, endoscopically through cold urethrotomy. We did not observe cases of recto-urinary fistula or persistent lower urinary tract symptoms. Two sevenths of the patients complained about de novo erectile dysfunction after HIFU., Conclusions: The positive oncologic outcomes in the short term anyway obtained in selected patients, associated with documented mild side effects, represent the basis to start more organic, prospective, randomized and multicenter study protocols, that with a long term follow-up could confirm these promising preliminary results.

Primary hyperaldosteronism is a common cause of resistant hypertension. Aldosterone is produced in the adrenal by aldosterone synthase (AS, encoded by the gene CYP11B2). AS shares 93% homology to 11β-hydroxylase (encoded by the gene CYP11B1), responsible for cortisol production. This homology has hitherto impeded the development of a drug, which selectively suppresses aldosterone but not cortisol production, as a new treatment for primary hyperaldosteronism. We now report the development of RO6836191 as a potent (Ki 13 nmol/L) competitive inhibitor of AS, with in vitro selectivity >100-fold over 11β-hydroxylase. In cynomolgus monkeys challenged with synthetic adrenocorticotropic hormone, single doses of RO6836191 inhibited aldosterone synthesis without affecting the adrenocorticotropic hormone-induced rise in cortisol. In repeat-dose toxicity studies in monkeys, RO6836191 reproduced the adrenal changes of the AS - /- mouse: expansion of the zona glomerulosa; increased expression of AS (or disrupted green fluorescent protein gene in the AS -/- mouse); hypertrophy, proliferation, and apoptosis of zona glomerulosa cells. These changes in the monkey were partially reversible and partially preventable by electrolyte supplementation and treatment with an angiotensin-converting enzyme inhibitor. In healthy subjects, single doses of RO6836191, across a 360-fold dose range, reduced plasma and urine aldosterone levels with maximum suppression at a dose of 10 mg, but unchanged cortisol, on adrenocorticotropic hormone challenge, up to 360 mg, and increase in the precursors 11-deoxycorticosterone and 11-deoxycortisol only at or >90 mg. In conclusion, RO6836191 demonstrates that it is possible to suppress aldosterone production completely in humans without affecting cortisol production., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01995383., (© 2016 The Authors.)

Introduction: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death in industrialized countries. Even if the healing chances are very high after definitive treatment of localized disease, 20-30% of patients experience recurrence., Evidence Acquisition: A review of the literature on the management of local recurrent prostate cancer was conducted using the Medline and Embase electronic databases. Search terms included "biochemical relapse", "PSA recurrence", "prostate cancer", "prostate cancer recurrence", "prostate salvage therapy", "radiorecurrent prostate cancer", "Re-HIFU", "post HIFU", "post cryoablation", "postradiation", and "postprostatectomy salvage". The search was restricted to English-language articles. The websites of guidelines organizations (EAU, AUA, NICE) were consulted in order to identify evidence-based practice guidelines. The present role of salvage prostatectomy and radiation therapy was studied and today's outcomes and tomorrow perspectives of salvage focal therapies as cryoablation and HIFU have been analyzed., Evidence Synthesis: Although the treatment landscape for patients with biochemical recurrence prostate cancer remains challenging, new research is helping to identify patient populations suitable for specific therapies., Conclusions: Further evaluation in prospective clinical trials will hopefully confirm the role of therapeutic options in clinical practice and the impact on the long-term survival.

High-intensity focused ultrasound (HIFU) is a minimally invasive therapy applied for prostate cancer that capitalizes on the coagulation necrosis that occurs at temperatures greater than 60°C. Owing to a lack of long-term follow-up data the procedure is still considered experimental treatment. As primary therapy, HIFU is indicated in patients aged ≥70 years with clinical organ-confined disease, although it has also been used, with encouraging results, as first line salvage therapy after definitive treatment, and in locally advanced (T3-4) and non-metastatic hormone-resistant prostate cancer. Morbidity associated with this treatment method appears to be low and includes urinary retention (1-9%), urethral stricture (4-14%), incontinence (1-15%), erectile dysfunction (13-53%) and rectourethral fistulae (0-3%). The risk of complications increases with repeated treatments. A few studies have recently been published on HIFU as focal therapy. HIFU technology can be enhanced using means such as ultrasound microbubble contrast agents for assessment of therapy efficacy, magnetic resonance imaging to guide the enhancement of heat rate, and localized drug and gene delivery.

In chronic lymphocytic leukemia (CLL) patients, disruptions of the TP53 tumor suppressor pathway by 17p13 deletion (del17p), somatic TP53 mutations, or downregulation of microRNA-34a have been associated with a poor prognosis. So far, the impact of the various TP53 defects has not been evaluated in a large cohort of previously treated and relapsed CLL patients. Here, we present the results of TP53 gene sequencing and fluorescence in situ hybridization for del17p in a phase 3 clinical trial (REACH [Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia]). Of the 457 patients, 52 had TP53 mutations and 37 had del17p. In 24 (46%) of the TP53 mutated patients, no del17p was found and in 9 of the del17p patients, no TP53 mutation was identified. Based on a predicted proportion of TP53 disruption, a complete disruption of TP53 function, either by a combination of point mutations and/or del17p, was associated with a high risk for disease progression. Progression-free survival of patients with a heterozygous TP53 mutation was not significantly different from patients with a completely intact TP53 locus. In addition, only a complete loss of TP53 function correlated with low microRNA-34a expression levels. This trial was registered at www.clinicaltrials.gov as #NCT00090051.

Aim of this paper is to report a systematic review of the literature about the incidence and putative mechanisms of genital tract injuries following open and laparoscopic herniorraphy and their effects on sexual function and fertility and to point out the measures of prevention and of treatment. The most frequently described events have been intraoperative complications as bladder or spermatic cord structure damage, immediate postoperative complications as ischaemic orchitis, urinary retention, urinary tract infection, hydrocele or scrotal haematoma and bacterial orchitis, or long-term complications as chronic orchialgia, testis atrophy, sexual dysfunction and infertility. The evidence of literature shows that urological complication after hernioplasty are under-reported. Only a small number of studies to date have essentially dealt with sexual quality of life after inguinal hernia surgical repair. The sexual needs of patients with groin hernias are rarely discussed. Extensive laparoscopic procedures, due to the need of learning curve, have increased the risk of vas damage and infertility in young patients candidate to hernioplasty. Early diagnosis prevents urological complication as well as possible legal claims after hernia repair: it should be include careful history, objective and subjective symptoms and signs of uro-genital pathologies, lab data when necessary, immediate eco-color-Doppler imaging and urgent urological consultation. Despite the lack of prospective randomized trials, there is a growing evidence in literature about positive impact of hernioplasty on sexual function, encouraging future studies on this issue.

Urological diseases are becoming a major public health problem. In fact, they increasingly weigh on the economy of a country due to the high direct costs and the consequent significant loss of productivity. Prostate cancer represents 11% of the costs for the treatment of all cancers in the United States with $8 billion and a cost per-patient from diagnosis to death of $81,658. Instead bladder cancer has the higher costs per-patient in terms of medical care, from diagnosis until death (U.S. $ 96,553). In Italy, in a reference hospital, the average costs of non muscle-invasive forms treated with endoscopic resection (TURB) and infiltrating forms treated with radical cystectomy are approximately Euro 2242.20 and Euro 6860 respectively, but they increase due to the follow-up and the ancillary treatments. In the field of functional disease, in the U.S. the average annual expenditure per capita for incontinence, including inpatient and outpatient services is $1382. While for patients who had undergone surgery the average total spending rose to $3620. For overactive bladder the total cost in the United States is estimated at 12.02 billion U.S. dollars, with $9.17 billion allocated to the community costs and $ 2.85 billion for institutional costs. However, further pharmacoeconomic studies are required to better understand the net economic impact of any alternative strategies to those actually present. Stone disease is a highly prevalent and costly condition for which United States total health care expenditures, in the year 2000, were estimated to be almost $ 2.1 billion. Treatment of nephrolithiasis depends on stone size and location, but typically involves a surgical procedure such as extracorporeal shock wave lithotripsy (ESWL), ureteroscopic laser lithotripsy, percutaneous nephrostolithotomy (PCNL) or open stone surgery with an average expenditure per procedure of $2295, $1425, $3624, $2916 respectively.

The ideal method for treatment of varicocele is still controversial. The techniques of inguinal and sub-inguinal ligation, although less invasive than "high" abdominal ligations (Palomo, Ivanissevich), have been less popular than the former ones. Up to now most authors have considered as mandatory microsurgical techniques for the ligation of spermatic veins at inguinal or sub-inguinal level, or at least instruments of optical magnification in order to preserve testicular arterial supply of the spermatic and cremasteric artery at groin and to prevent testicular atrophia or gonadic ischemia. The aim of this study was to assess clinical outcomes of open surgical technique of varicocele repair compared to results derived from microsurgical series. A retrospective study included 45 patients of mean age 31 years (range 18-39) that underwent open surgical technique of inguinal ligation of spermatic veins in the period 2004-2009; clinical results of this series were compared with those obtained in five relevant studies derived from systematic review of the literature on microsurgical techniques. The pre-operatory evaluation in our series included a physical examination, a minimum of two semen analysis and scrotal color Doppler ultrasound. Post-operative pain, complication rates, days of hospitalization and time to return to work were considered as main outcomes. All patients were evaluated at 1 week, at 3 and 6 months after the operation by means of a physical examination, scrotal Doppler ultrasound and sperm analysis. Most patients (39/45) presented no pain in the first week, 6/45 mild to moderate pain (mean VAS score 2). None of the patients reported pain in the weeks thereafter The hospitalization (1.8 +/- 0.7 days) and the time for return to work (7.2 +/- 3.2 days) were not significantly different in microsurgical and open groups. During follow-up no complications like hydrocele or testicular atrophy were observed. Doppler ultrasound carried out 3 and 6 months after surgery, pointed out no reflux in testicular veins in 41/45 cases while in 4/45 it showed a persistence of reflux grade I, less than the grade before the treatment. Comparing pre-and post-operatory sperm analysis allowed us to observe a significant improvement either in spermatozoa concentration (22 +/- 4 40&#95;+/- 6 millions/ml, p < 0.01), either in motility (33 +/- 4% and 48 +/- 4%, p < 0.05), without significant changes in morphology. No significant differences were recorded comparing these data with those coming from microsurgical series. Our study reported positive clinical outcomes using the technique of sub-inguinal surgical ligature of varicocele without using microsurgical techniques or instruments of optical magnification. The operative time, complication and relapse rates, Doppler flow parameters and semen parameters were not significantly different from those reported in the literature of microsurgical techniques, with the advantage of such a simple surgical technique combined with cost savings and patient's comfort.

IGHV3-21-using chronic lymphocytic leukemia (CLL) is a distinct entity with restricted immunoglobulin gene features and poor prognosis and is more frequently encountered in Northern than Southern Europe. To further investigate this subset and its geographic distribution in the context of a country (Italy) with both continental and Mediterranean areas, 37 IGHV3-21 CLLs were collected out of 1076 cases enrolled by different institutions from Northern or Central Southern Italy. Of the 37 cases, 18 were identified as homologous (hom)HCDR3-IGHV3-21 CLLs and were found almost exclusively (16 of 18) in Northern Italy; in contrast, 19 nonhomHCDR3-IGHV3-21 cases were evenly distributed throughout Italy. Clinically, poor survivals were documented for IGHV3-21 CLLs as well as for subgroups of mutated and homHCDR3-IGHV3-21 CLLs. Negative prognosticators CD38, ZAP-70, CD49d, and CD79b were expressed at higher levels in homHCDR3 than nonhomHCDR3-IGHV3-21 cases. Differential gene expression profiling (GEP) of 13 IGHV3-21 versus 52 non-IGHV3-21 CLLs identified, among 122 best-correlated genes, TGFB2 and VIPR1 as down- and up-regulated in IGHV3-21 CLL cases, respectively. Moreover, GEP of 7 homHCDR3 versus 6 nonhomHCDR3-IGHV3-21 CLLs yielded 20 differentially expressed genes, with WNT-16 being that expressed at the highest levels in homHCDR3-IGHV3-21 CLLs. Altogether, IGHV3-21 CLLs, including those with homHCDR3, had a peculiar global phenotype in part explaining their worse clinical outcome.