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IntroductionImmunotherapy is changing the way we think about and treat urothelial carcinoma (UC). The PD-1/PD-L1 pathway inhibition has shown robust efficacy, associated with an acceptable toxicity profile, in patients with locally advanced and metastatic unresectable disease, addressing a high decades-old unmet medical need. Material and methodsUsing the Pubmed database, we conducted a literature review for English written published articles up to June 2020. The highest available evidence for the immunotherapy treatment of UC with ICIs were evaluated. The leading phase one, two and three clinical trials were considered for inclusion (n = 12). Patient’s data were extracted from studies depicting the UTUC subpopulation.ResultsTwo monoclonal antibodies targeting PD-1 (pembrolizumab and nivolumab) and three to its ligand PD-L1 (atezolizumab, avelumab, and durvalumab) have obtained US FDA and EMA approval for the second-line treatment of platinum-pretreated patients, between 2016 and 2019. Atezolizumab and Pembrolizumab are even currently approved in the first-line setting for cisplatin ineligible patients, with PD-L1- positive tumor. The neoadjuvant scenario in localized high-risk disease is still evolving, with the first data available to date limited to the muscle-invasive bladder carcinoma. The management of patients with upper tract urothelial carcinoma (UTUC: renal pelvis and ureters) is complicated by the lack of specific high-level evidence, due to the rarity of the disease. No published studies addressing immunotherapy in UTUC patients only are available. The largest clinical trials aimed at UC patients, regardless of the upper or lower location of the primary tumor, have enrolled a minority of patients with UTUC, providing the data on which our current knowledge is based. However, targeted scientific efforts are needed to improve our level of care.ConclusionsThis review summarizes the main currently available evidence on the use of the PD-1/PD-L1 pathway inhibition with reference to patients presenting with UTUC.

Sexual disorders following retroperitoneal pelvic lymph node dissection (RPLND) for testis tumor can affect the quality of life of patients. The aim of the current study was to investigate several different andrological outcomes, which may be influenced by robot-assisted (RA) RPLND. From January 2012 to March 2020, 32 patients underwent RA-RPLND for stage I nonseminomatous testis cancer or postchemotherapy (PC) residual mass. Modified unilateral RPLND nerve-sparing template was always used. Major variables of interest were erectile dysfunction (ED), premature ejaculation (PE), dry ejaculation (DE), or orgasm alteration. Finally, fertility as well as the fecundation process (sexual intercourse or medically assisted procreation [MAP]) was investigated. Ten patients (31.3%) presented an andrological disorder of any type after RA-RPLND. Hypospermia was present in 4 (12.5%) patients, DE (International Index of Erectile Function-5 [IIEF-5] <25) in 3 (9.4%) patients, and ED in 3 (9.4%) patients. No PE or orgasmic alterations were described. Similar median age at surgery, body mass index (BMI), number of nodes removed, scholar status, and preoperative risk factor rates were identified between groups. Of all these 10 patients, 6 (60.0%) were treated at the beginning of our robotic experience (2012-2016). Of all 32 patients, 5 (15.6%) attempted to have a child after RA-RPLND. All of these 5 patients have successfully fathered children, but 2 (40.0%) required a MAP. In conclusion, a nonnegligible number of andrological complications occurred after RA-RPLND, mainly represented by ejaculation disorders, but ED occurrence and overall sexual satisfaction deficit should be definitely considered. No negative impact on fertility was described after RA-RPLND.

Low-intensity extracorporeal shockwave therapy (LiESWT) represents a promising treatment for patients with erectile dysfunction (ED). We investigated the efficacy of LiESWT combined with tadalafil 5 mg once daily in men with type 2 diabetes mellitus (T2DM) and ED and compared LiESWT protocols administering different number of shockwaves. We performed a retrospective matched-pair comparison using data from a prospectively maintained database. Seventy-eight patients who received tadalafil 5 mg once daily for 12 weeks + LiESWT performed with an electrohydraulic source for 3 weeks (Group A) were matched 1:1 to patients who received tadalafil 5 mg once daily alone for 12 weeks (Group B). A subgroup analysis was performed according to the number of shockwaves delivered during each session (1500, 1800, and 2400 in subgroup A1, A2, and A3, respectively). The mean International Index of Erectile Function-5 (IIEF-5) score variations with respect to baseline recorded at 4, 12, and 24 weeks after the end of the treatment were investigated as treatment outcomes. The mean IIEF-5 scores significantly improved in all groups and subgroups at 4-week follow-up without intergroup differences. At 12- and 24-week follow-up, the mean IIEF-5 improvement was significantly higher among patients in the A3 subgroup (+5.0 ± 2.1 [P < 0.001] and +4.7 ± 2.3 [P < 0.001], respectively). The combined approach with tadalafil 5 mg once daily and LiESWT with a protocol involving 2400 shockwaves provides significant advantages in terms of IIEF-5 improvement and durability compared to tadalafil 5 mg once daily alone in patients with T2DM and ED.

PurposeTo evaluate the efficacy of Lactobacillus paracasei CNCM I-1572 (L. casei DG®) in both prevention of symptomatic recurrences and improvement of quality of life in patients with chronic bacterial prostatitis (CBP).MethodsPatients with CBP attending a single Urological Institution were enrolled in this phase IV study. At enrollment, all patients were treated with antibiotics in agreement with EAU guidelines and then were treated with L. casei DG® (2 capsules/day for 3 months). Clinical and microbiological analyses were carried out before (enrollment, T0) and 6 months (T2) after the treatment. Both safety and adherence to the treatment were evaluated 3 months (T1) after the enrollment. NIH Chronic Prostatitis Symptom Index (CPSI), International Prostate Symptom Score (IPSS) and Quality of Well-Being (QoL) questionnaires were used. The outcome measures were the rate of symptomatic recurrence, changes in questionnaire symptom scores and the reduction of antibiotic use.ResultsEighty-four patients were included. At T2, 61 patients (72.6%) reported a clinical improvement of symptoms with a return to their clinical status before symptoms. A time dependent improvement in clinical symptoms with significant changes in NIH-CPSI, IPSS and QoL (mean difference T2 vs T0: 16.5 ± 3.58; − 11.0 ± 4.32; + 0.3 ± 0.09; p < 0.001), was reported. We recorded that L. casei DG® treatment induced a statistically significant decrease in both (p < 0.001) symptomatic recurrence [1.9/3 months vs 0.5/3 months] and antibiotic use [− 7938 UDD]. No clinically relevant adverse effects were reported.ConclusionsL. casei DG® prevents symptomatic recurrences and improves the quality of life in patients with CBP, reducing the antibiotic use.

PurposeTo perform a cumulative analysis of the current evidence on the surgical and functional outcomes of bipolar endoscopic enucleation of the prostate (b-EEP) versus bipolar transurethral resection of the prostate (b-TURP).MethodsA systematic review of the literature was performed on PubMed, Ovid®, and Scopus® according to Preferred Reporting Items for Systematic Review and Meta-analysis Statement (PRISMA Statement). The meta-analysis was conducted using the Review Manager 5.3 software. Parameters of interest were surgical and functional outcomes. Weighted mean difference, and odds ratio with 95% confidence interval were calculated for continuous and binary variables, respectively. Pooled estimates were calculated using the random-effect model.ResultsFourteen comparative studies were included. No statistically significant difference in terms of overall baseline characteristics was found. b-EEP had higher amount of resected tissue (p < 0.0001), shorter catheter time (p = 0.006), lower Hb drop (p = 0.03), and shorter length of stay (p < 0.0001). Equally, overall post-operative complications were lower (p = 0.01) as well as short (p = 0.04), and long-term complication rate (p = 0.04). There was higher re-intervention rate in the b-TURP group (p = 0.02) whereas b-EEP group had smaller residual prostate volume (p = 0.03), and lower post-operative PSA values (p < 0.00001). At long term, b-EEP presented lower IPSS (p = 0.04), higher Qmax (p = 0.002), and lower PVR (p < 0.00001).Conclusionsb-EEP is an effective and safe surgical treatment for BPO. This procedure might offer several advantages over standard b-TURP, including the resection of a larger amount of tissue within the same operative time, shorter hospitalization, lower risk of complications, and lower re-intervention rate.This was submitted to PROSPERO registry: CRD42019126748.

BackgroundWe hypothesized that the residency status (rural area [RA] vs urban clusters [UC] vs urban areas [UA]) affects stage and cancer-specific mortality (CSM) in contemporary newly diagnosed prostate cancer (PCa) patients of all stages, regardless of treatment.MethodsNewly diagnosed PCa patients with available residency status were abstracted from the Surveillance, Epidemiology, and End Results database (2004–2016). Propensity-score (PS) matching, cumulative incidence plots, multivariate competing-risks regression (CRR) models were used.ResultsOf 531,468 PCa patients of all stages, 6653 (1.3%) resided in RA, 50,932 (9.6%) in UC and 473,883 (89.2%) in UA. No statistically significant or clinically meaningful differences in stage at presentation or CSM were recorded. Conversely, 10-year other cause-mortality (OCM) rates were 27.2% vs 23.7% vs 18.9% (p < 0.001) in RA vs UC vs UA patients, respectively. In CRR models, RA (subhazard ratio [SHR] 1.38; p < 0.001) and UC (SHR 1.18; p < 0.001) were independent predictors for higher OCM relative to UA. These differences remained statistically significant in fully PS-adjusted multivariate CRR models.ConclusionRA, and to a lesser extent UC, PCa patients are at higher risk of OCM than UA patients. Higher OCM may indicate shorter life expectancy and should be considered in treatment decision making.

Hydrogen sulfide (H₂S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). L-Cysteine (L-Cys) acts as a natural substrate for the synthesis of H₂S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert L-Cys to H₂S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H₂S [sodium hydrogen sulfide (NaHS)] or L-Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum. L-Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and L-Cys promote penile erection, and the response to L-Cys is blocked by PAG. Our data demonstrate that the L-Cys/H₂S pathway mediates human corpus cavernosum smooth-muscle relaxation.

AimsThe European Association of Urology guideline for upper tract urothelial carcinoma (UTUC) relies on two grading system: 1973 World Health Organization (WHO) and 2004/2016 WHO. No consensus has been made which classification should supersede the other and both are recommended in clinical practice. We hypothesized that one may be superior to the other.MethodsNewly diagnosed non-metastatic UTUC patients treated with radical nephroureterectomy were abstracted from the Surveillance, Epidemiology, and End Results database (2010–2016). Kaplan–Meier plots and multivariable Cox regression models (CRMs) tested cancer-specific mortality (CSM), according to 1973 WHO (G1 vs. G2 vs. G3) or to 2004/2016 WHO (low-grade vs. high-grade) grading systems. Haegerty’s C-index quantified accuracy.ResultsOf 4271 patients, according to 1973 WHO grading system, 134 (3.1%) were G1, 436 (10.2%) were G2 and 3701 (86.7%) were G3; while according to 2004/2016 WHO grading system, 508 (11.9%) were low grade vs 3763 (88.1%) high grade. In multivariable CRMs, high grade predicted higher CSM (Hazard ratio: 1.70, p < 0.001). Conversely, neither G2 (p = 0.8) nor G3 (p = 0.1) were independent predictors of worse survival. The multivariable models without consideration of either grading system were 74% accurate in predicting 5-year CSM. Accuracy increased to 76% after either addition of the 1973 WHO or 2004/2016 WHO grade.ConclusionsFrom a statistical standpoint, either 1973 WHO or 2004/2016 WHO grading system improves the accuracy of CSM prediction to the same extent. In consequence, other considerations such as intra- and interobserver variability may represent additional metrics to consider in deciding which grading system is better.

Background and Objectives: Despite advancements in the diagnosis and treatment of testicular germ cell tumours (TGTCs), challenges persist in identifying reliable biomarkers for early detection and precise disease management. This narrative review addresses the role of microRNAs (miRNAs) as potential diagnostic tools and therapeutic targets in the treatment of TGCTs. Materials and Methods: Three databases (PubMed®, Web of Science™, and Scopus®) were queried for studies investigating the utility of miRNA as diagnostic tools, assessing their prognostic significance, and evaluating their potential to guide TGCT treatment. Different combinations of the following keywords were used, according to a free-text protocol: “miRNA”, “non-coding RNA”, “small RNA”, “Testicular Cancer”, “seminomatous testicular germ cell”, “non-seminomatous testicular germ cell”. Results: The potential of miRNAs as possible biomarkers for a non-invasive diagnosis of TGCT is appealing. Their integration into the diagnostic pathway for TGCT patients holds the potential to enhance the discriminative power of conventional serum tumour markers (STMs) and could expedite early diagnosis, given that miRNA overexpression was observed in 50% of GCNIS cases. Among miRNAs, miR-371a-3p stands out with the most promising evidence, suggesting its relevance in the primary diagnosis of TGCT, particularly when conventional STMs offer limited value. Indeed, it demonstrated high specificity (90–99%) and sensitivity (84–89%), with good positive predictive value (97.2%) and negative predictive value (82.7%). Furthermore, a direct relationship between miRNA concentration, disease burden, and treatment response exists, regardless of disease stages. The initial evidence of miRNA decrease in response to surgical treatment and systemic chemotherapy has been further supported by more recent results suggesting the potential utility of this tool not only in evaluating treatment response but also in monitoring residual disease and predicting disease relapse. Conclusions: MiRNAs could represent a reliable tool for accurate diagnosis and disease monitoring in the treatment of TGCT, providing more precise tools for early detection and treatment stratification. Nevertheless, well-designed clinical trials and comprehensive long-term data are needed to ensure their translation into effective clinical tools.

BackgroundRace/ethnicity may predispose to less favorable prostate cancer characteristics in intermediate risk prostate cancer (IR PCa) patients. We tested this hypothesis in a subgroup of IR PCa patients treated with radical prostatectomy (RP).MethodsWe relied on the Surveillance, Epidemiology and End Results 2004–2016. The effect of race/ethnicity was tested in univariable and multivariable logistic regression analyses predicting upstaging (pT3+/pN1) and/or upgrading (Gleason Grade Group [GGG] 4–5) at RP.ResultsOf 20,391 IR PCa patients, 15,050 (73.8%) were Caucasian, 2857 (14.0%) African-American, 1632 (8.0%) Hispanic/Latino and 852 (4.2%) Asian. Asian patients exhibited highest age (64 year), highest PSA (6.8 ng/ml) and highest rate of GGG3 (31.9%). African-Americans exhibited the highest percentage of positive cores at biopsy (41.7%) and the highest proportion of NCCN unfavorable risk group membership (54.6%). Conversely, Caucasians exhibited the highest proportion of cT2 stage (35.6%). In univariable analyses, Hispanic/Latinos exhibited the highest rates of upstaging/upgrading among all race/ethnicities, in both favorable and unfavorable groups, followed by Asians, Caucasians and African-Americans in that order. In multivariable analyses, Hispanic/Latino race/ethnicity represented an independent predictor of higher upstaging and/or upgrading in favorable IR PCa (odds ratio [OR] 1.27, p < 0.01), while African-American race/ethnicity represented an independent predictor of lower upstaging and/or upgrading in unfavorable IR PCa (OR 0.79, p < 0.001).ConclusionRace/ethnicity predisposes to differences in clinical, as well as in pathological characteristics in IR PCa patients. Specifically, even after full statistical adjustment, Hispanic/Latinos are at higher and African-Americans are at lower risk of upstaging and/or upgrading.