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In our multi-institutional cohort study, 24% of patients with clear cell renal cell carcinoma (RCC) met the KEYNOTE-564 trial inclusion criteria. According to the Stuart-Merrill risk-adapted model, the proportion of these patients “not eligible” for adjuvant pembrolizumab because of higher probability of other-cause mortality than of RCC recurrence would be 81%, 66%, 43%, and 29% at “recommended” follow-up of ≤2.0, ≤5, ≤10, and ≤20 yr, respectively.

Our novel and straightforward risk classification integrates currently available preoperative risk tools and can help in identifying patients with miN1 disease in whom radical prostatectomy may achieve the best oncological outcomes in the context of a multimodal approach. Therefore, it can assist physicians in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography.

The interrelationship between male sexual desire and erectile dysfunction (ED) has been scantly investigated. Thus, we aimed at investigating the prevalence of and the predictors of unrecognised low sexual desire/interest (uLSD/I) in a cohort of men with new onset ED. Complete data from 1587 men seeking for first medical help for ED between 2010 and 2021 were analysed. Comorbidities were scored with the Charlson Comorbidity Index (CCI). At entrance, all patients were asked to self-report low sexual desire/interest and completed the International Index of Erectile Function (IIEF) and the Beck Depression Inventory (BDI) (depressive symptoms scored as BDI ≥ 11). The IIEF-erectile function (IIEF-EF) domain was categorised according to Cappelleri’s criteria. The median value of the IIEF-sexual desire domain (IIEF-SD) was used to dichotomise men with uLSD/I along with ED (IIEF-SD < 7) vs. ED-only (IIEF-SD ≥ 7). Circulating hormones were measured in every patient. Hypogonadism was defined as total testosterone (tT) <3.0 ng/mL. Descriptive statistics and logistic regression models tested the association between clinical variables and uLSD/I. Of 1197 patients not self-reporting LSD/I, 369 (30.8%) had IIEF-SD < 7. Patients with ED + uLSD/I were older [median (IQR) 54(41–63) vs. 49(36–59) years], had lower IIEF-EF [10.5(5–22) vs. 22(11–28)] but higher BDI [6(3–12) vs. 4(1–8)] and lower tT [4.3(3.2–5.7) vs. 4.8(3.2–6.3) ng/mL] compared to ED-only men (all p< 0.05). Overall, ED + uLSD/I men had higher rate of severe ED (49.9% vs. 23.9%), and of BDI ≥ 11 (30.6% vs. 18.2%) (all p< 0.05). At multivariable logistic regression analysis, lower tT (OR: 0.82), lower IIEF-EF scores (OR:0.95) and BDI ≥ 11 (OR:2.51) were independently associated with ED + uLSD/I, after accounting for age (all p< 0.05). Almost 30% of men seeking first medical help for ED-only had also uLSD/I. Men with both conditions were older, had higher rates of severe ED and more depressive symptoms. A detailed investigation of sexual desire should be always included in men self-complaining only of ED.

Introduction: It is unknown whether race/ethnicity affects access and/or survival after neoadjuvant (NAC) or adjuvant chemotherapy (ADJ) at radical cystectomy (RC). We addressed these knowledge gaps. Material and Methods: Within the Surveillance, Epidemiology, and End Results database (2007–2020), we identified NAC candidates (T2-T4N0M0) and ADJ candidates (T3-T4 and/or N1-3). We focused on the four most prevalent race/ethnicities: Caucasians, Hispanics, African American (AA), and Asian/Pacific Islanders (API). Multivariable logistic regression models (MLR) tested access to NAC and ADJ. Subsequently, within NAC-exposed patients, survival analyses consisting of Kaplan–Meier plots and multivariable Cox regression models addressed CSM according to race/ethnicity were fitted. We repeated the same methodology in ADJ-exposed patients. Results: In 6418 NAC candidates, NAC was administered in 1011 (19.0%) Caucasians, 88 (21.0%) Hispanics, 65 (17.0%) AA, and 53 (18.0%) API. In MLR, AA exhibited lower access rates to NAC (OR 0.83, p= 0.04). In NAC-exposed patients, AA independently predicted higher CSM (HR 1.3, p&lt; 0.001) and API independently predicted lower CSM (HR 0.83, p= 0.03). Similarly, in 5195 ADJ candidates, ADJ was administered to 1387 (33.0%) Caucasians, 100 (28.0%) Hispanics, 105 (29.0%) AA, and 90 (37.0%) API. In MLR, AA (OR 68, p= 0.003) and Hispanics (OR 0.69, p= 0.004) exhibited lower access rates to ADJ. In ADJ-exposed patients, AA independently predicted lower CSM (HR 1.32, p&lt; 0.001), while API showed better CSM (HR 0.82, p= 0.01). Conclusion: Relative to Caucasians, AA are less likely to receive either NAC or ADJ. Moreover, relative to Caucasians, AA exhibit higher CSM even when treated with either NAC or ADJ.

Introduction: Trimodal therapy (TMT) is the most validated bladder-sparing treatment for organ-confined urothelial carcinoma of the urinary bladder (OC UCUB, namely cT2N0M0). However, it is unknown if barriers to the use of TMT or cancer-specific mortality (CSM) differences exist according to race/ethnicity. We addressed this knowledge gap. Material and methods: Within the Surveillance, Epidemiology, and End Results database (2004–2020), we identified OC UCUB patients aged from 18 to 85 treated with radical cystectomy (RC) or TMT. Temporal trends described TMT versus RC use over time. Subsequently, in the subgroup of TMT-treated patients, survival analyses consisting of Kaplan–Meier plots and multivariable Cox regression (MCR) models addressed CSM according to race/ethnicity. Results: Among 19,501 assessable patients, 15,336 (79%) underwent RC versus 4165 TMT (21%). Overall, of all races/ethnicities, 16,245 (83.3%) were White Americans, 1215 (6.3%) Hispanics, 1160 (5.9%) African Americans, and 881 (4.5%) Asian/Pacific Islanders. Among TMT-treated patients, 3460 (83.1%) were White Americans, 298 (7.1%) African Americans, 218 (5.3%) Hispanics, and 189 (4.5%) Asian/Pacific Islanders. The lowest rate of TMT use relative to RC and TMT patients was recorded in Hispanics (17.9%). Over time, TMT use increased in White Americans (EAPC: + 4.5%, p= 0.001) and Asians/Pacific Islanders (EAPC: + 5.2%, p= 0.003), but not in others. Kaplan–Meier analyses showed median CSM of 49 months, 41 months, and 34 months and not reached in White Americans, Hispanics, African Americans, and Asian/Pacific Islanders, respectively (p= 0.02). In MCR models, two race/ethnicity subgroups independently predicted either worse (African Americans, HR: 1.20, p= 0.02) or better CSM (Asian/Pacific Islanders, HR: 0.75, p= 0.02). Conclusion: Race/ethnicity affects both access to TMT (lower access in Hispanics) as well as survival after TMT (better in Asians/Pacific Islanders and worse in African Americans).

Current tools for predicting lymph node invasion (LNI) in prostate cancer have suboptimal performance in miN0M0 disease on prostate-specific membrane antigen positron emission tomography imaging and are associated with a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel model should be used to identify patients with miN0M0 disease who should be considered for ePLND to reduce the risk of unnecessary procedures without missing LNI cases.

The developments of the open-source OpenMolcaschemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcascan address, while showing that OpenMolcasis an attractive platform for state-of-the-art atomistic computer simulations.

BACKGROUND: The influence of age and comorbidities during decision-making for patients with renal cell carcinoma remains controversial.OBJECTIVE: To comprehensively review the available evidence regarding the impacts of age and comorbidities on the decision to perform partial nephrectomy (PN).EVIDENCE ACQUISITION: A systematic review was conducted in accordance with PRISMA and registered with PROSPERO (CRD42022344759). Only randomized control trials, prospective cohort studies, registry-based studies, or single/multi-institutional retrospective cohort studies comparing PN to other therapeutic options for cT1N0M0 renal masses were considered. The primary outcome was to assess differences in patients’ baseline characteristics between different treatments in order to investigate how those aspects have influenced clinical decision-making. Finally, perioperative outcomes were compared across the different options.EVIDENCE SYNTHESIS: Overall, patients who underwent PN were 3 to 11 years younger than those who underwent other treatments. Baseline renal function was slightly better in patients who underwent PN than in those who underwent radical nephrectomy (RN), active surveillance (AS), or tumor ablation. Patients undergoing PN had an average pre-treatment eGFR 4 to 6 points (mL/min/1.73 m2) higher than patients undergoing RN or tumor ablation. Likewise, the proportion of baseline chronic kidney disease (CKD) before treatment was higher in patients undergoing other treatments, with a rate of CKD between 6% and 56% higher compared with that for PN. A slightly higher proportion of baseline diabetes mellitus (DM) and cardiovascular comorbidities (CVD) were found in patients who underwent PN than in those who underwent RN (20% vs. 21% for DM and 37% vs. 41% for CVD). On average, patients who underwent AS and tumor ablation had more comorbidities, in terms of Charlson comorbidity index (CCI), DM, and CVD (50% vs. 38% for CCI =2; 25% vs. 20% for DM; and 43% vs. 37% for CVD). In terms of Eastern Cooperative Oncology Group (ECOG) Performance Status and American Society of Anesthesiologists (ASA) classification, no major differences were found between PN and other treatments, but a trend emerged whereby more fit patients underwent PN compared with RN (16% of ECOG >1 for PN vs. 18% for RN and 15% of ASA grade =3 for PN vs. 26% for RN). Again, tumor ablation was preferred for less fit patients (31% of ASA grade =3). No study included in our systematic review reported the baseline frailty status of patients treated for cT1 renal masses. The rates of perioperative complications and length of hospital stay (LOS) were similar between different techniques.CONCLUSIONS: Patients who underwent PN tended to be younger and fitter than those who underwent other available treatments for cT1 renal masses. Since this technique aims at reducing renal function impairment after surgery, a greater effort should be made to optimize patient selection to include more comorbid patients for whom PN might be useful.

ABSTRACTIntroductionErectile dysfunction (ED) affects between 12.9% and 28.1% of men worldwide, presenting a strong aged-correlated prevalence. Several pharmacological treatments are currently available for ED, which can be classified into oral, injection, and topical/intraurethral therapies.Areas coveredExtensive research on PubMed/MEDLINE until February 2023 was performed. For each of the aforementioned drug classes, available molecules, and formulations, their efficacy and most common adverse events as well as general guidelines on prescription were investigated and extensively described. A glimpse into future directions regarding ED pharmacotherapy is also present.Expert opinionIn recent years, there have been significant developments in pharmacological treatments for ED. It is essential for physicians to identify the best treatment option for patients based on their preferences and sexual habits. The treatment approach for ED has shifted from a sequential to a parallel paradigm, where all treatment options are available as first-line therapies. While there are promising regenerative therapies for ED, such as shockwaves and platelet-rich plasma injections, pharmacological treatment is still the most effective option for most patients.

We investigated the relationship between biochemical recurrence after robot-assisted radical prostatectomy and surgeon’s experience. As opposed to open and laparoscopic radical prostatectomy, surgeons starting with robot-assisted radical prostatectomy had similar outcomes to those of more experienced surgeons, and we hypothesized that surgical education in robotics might be an important determinant of such a finding.

Background: Combination systemic therapies have become the standard for metastatic hormone-sensitive prostate cancer (mHSPC). However, the effect of age on oncologic outcomes remains unknown. Our aim was to perform a systematic review, meta-analysis, and network meta-analysis (NMA) on the effect of chronological age on overall survival (OS) in patients treated with combination therapies for mHSPC. Methods: We searched the PubMed®, Web of ScienceTM, and Scopus®databases to identify randomized controlled trials (RCTs) that analyzed the efficacy of combination systemic therapies using ADT plus docetaxel and/or androgen receptor signaling inhibitor (ARSI) in patients with mHSPC. We included studies, which provided separate hazard ratios (HRs) for younger vs. older patients. The selected age cut-off was 70 years (±5 years). Our outcome of interest was OS. Results: We included nine RCTs with a total of 9183 patients. Younger and older men constituted 51% and 49% of included patients, respectively. Docetaxel plus ADT significantly improved OS among both older (HR 0.79, 95% CI 0.63–0.99, p= 0.04) and younger patients (HR 0.79, 95% CI 0.69–0.90, p&lt; 0.001) with no differences according to age. ARSI plus ADT improved OS in older (HR 0.72, 95% CI 0.64–0.80, p&lt; 0.001) and younger (HR 0.58, 95% CI 0.51–0.66, p&lt; 0.001) patients; younger patients did benefit more (p= 0.02). On NMA treatment ranking, triplet therapy showed the highest probability of OS benefit irrespective of age group; in older patients, the benefit of triplet therapy compared to doublet was less expressed. Conclusions: Patients with mHSPC benefit from combination systemic therapies irrespective of age; the effect is, however, more evident in younger patients. Chronological age alone seems not to be a selection criteria for the administration of combination systemic therapies.

A range of drugs have a direct role in triggering ischaemic priapism. We aimed at identifying: a) which medications are associated with most priapism-reports; and, b) within these medications, comparing their potential to elicit priapism through a disproportionality analysis. The FDA Adverse Event Reporting System (FAERS) database was queried to identify those drugs associated the most with priapism reports over the last 5 years. Only those drugs being associated with a minimum of 30 priapism reports were considered. The Proportional Reporting Ratios (PRRs), and their 95% confidence intervals were computed. Out of the whole 2015–2020 database, 1233 priapism reports were identified, 933 of which (75.7%) were associated with 11 medications with a minimum of 30 priapism-reports each. Trazodone, olanzapine and tadalafil showed levels of disproportionate reporting, with a PRR of 9.04 (CI95%: 7.73–10.58), 1.55 (CI95%: 1.27–1.89), and 1.42 (CI95%: 1.10–1.43), respectively. Most (57.5%) of the reports associated with the phosphodiesterase type 5 inhibitors (PDE5Is) were related with concomitant priapism-eliciting drugs taken at the same time and/or inappropriate intake/excessive dosage. Patients taking trazodone and/or antipsychotics need to be aware of the priapism-risk; awareness among prescribers would help in reducing priapism-related detrimental sequelae; PDE5I-intake is not responsible for priapism by itself, when appropriate medical supervision is provided.

To investigate pathological stage at radical prostatectomy (RP) using the “Partin tables” approach in NCCN high-risk (HR) prostate cancer (PCa) patients.

Objective: To test whether body mass index (BMI) amongst patients with metastatic castration-resistant prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific survival. Methods: Individual patient data from 1577 men with mCRPC treated with docetaxel and prednisone from the control arms of ASCENT2, VENICE, and MAINSAIL were considered. The role of BMI on survival outcomes was investigated both as a continuous and categorical variable (≤24.9 vs. 25–29.9 vs. ≥30 km/m2). BMI ≥ 30 kg/m2was considered obese. Analyses were adjusted for age, PSA, ECOG performance status, number of metastases and prior treatment. The Cox semi-proportional hazard model was used to predict OS, whereas competing risks regression was used for predicting cancer-specific mortality (CSM). To exclude any possible effect attributable to higher doses of chemotherapy (titrated according to body-surface area), we checked for eventual interactions between BMI and chemotherapy dose (both as continuous-continuous and categorical-continuous interactions). Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25–31) kg/m2. Median follow-up for survivors was 12 months. Of the 1577 patients included, 655 were deceased by the end of the studies. Regarding OS, BMI emerged as a protective factor both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p= 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p= 0.027, relatively to normal weight). The protective effect of high BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p= 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p= 0.018). No interaction was detected between the BMI categories and the docetaxel dose at any level in our analyses (all p» 0.05). Conclusions: Obese patients with mCRPC had better cancer-specific and overall survival as compared to overweight and normal weight patients. The protective effect of BMI was not related to receiving higher chemotherapy doses. Further studies aimed at elucidating the biological mechanism behind this effect are warranted.

Several small single-center studies have reported a prognostic role for Ki-67 labeling index in advanced urothelial carcinoma of the urinary bladder. To investigate whether Ki-67 was a useful biomarker of oncological outcome after radical cystectomy for urothelial carcinoma, we assessed its expression in tumor tissue from 713 patients treated with radical cystectomy and bilateral lymphadenectomy at six centers. A high Ki-67 labeling index was independently associated with established features of aggressive urothelial carcinoma, disease recurrence, and cancer-specific survival. Addition of Ki-67 labeling index improved the accuracy of standard multivariate outcome prediction models, as measured by Harrell concordance index, by 2.9% for disease recurrence and 2.4% for bladder cancer-specific survival (P < .001, two-sided Mantel--Haenszel)--a statistically and potentially clinically significant margin. In conclusion, routine assessment of Ki-67 expression status along with assessment of other established predictors of urothelial carcinoma outcome has the potential to improve identification of patients who are at increased risk for disease progression after radical cystectomy and thus may benefit from perioperative systemic chemotherapy.

•To date, the prognostic role of prior bladder cancer (BCa) among patients with upper tract urothelial carcinoma (UTUC) is still poorly addressed.•We aimed to investigate the role of prior BCa on any recurrence (aR), distant metastasis (DM), and bladder recurrence following RNU among low-grade (LG) and high-grade (HG) UTUC patients.•We retrospectively analyzed a multicenter cohort of 1,580 patients treated with radical nephroureterectomy (RNU) for UTUC. Median follow-up was 4 years.•The Kaplan-Meier curves were applied to assess aR, DM, and bladder recurrence, computed from the time of RNU. Multivariable Cox models were generated to predict the risk of aR, DM, and bladder recurrence. All analyses were stratified by tumor grade (LG and HG), site of recurrence (aR, DM, and bladder recurrence), and prior history of BCa (no prior BCa, non-muscle-invasive [NMIBC], and muscle-invasive bladder cancer [MIBC]).•Both LG and HG UTUC patients with prior BCa had a significantly increased risk of aR and bladder recurrence on multivariable Cox models, compared to individuals with no prior BCa.•The main strength of our paper is represented by the fact that this is the first study in which analyses were stratified according to both UTUC grade and muscle-invasiveness of prior BCa history. Additionally, our cohort represent the largest cohort available in literature that evaluates the role of prior BCa on aR after RNU for UTUC.•The present study is limited by its retrospective design and the lack of some information on prior BCa, such as multifocality or previous intravesical therapy.

Novel immune checkpoint inhibitors hold promise for non–muscle-invasive bladder cancer. Cooperation between urologists and other multidisciplinary bladder cancer specialists can surmount the challenges involved in using these agents in bladder-sparing approaches. This strategy could deliver a new era of comprehensive evaluation and multimodal treatment for this patient population.

Studies comparing radical prostatectomy (RP) to radiation therapy (RT) have consistently shown that patients undergoing RT have a higher risk of other-cause mortality (OCM) compared to RP, signifying poor health status of the former patients. We aimed to evaluate the impact of RP versus RT on cancer-specific mortality (CSM) over a cohort with equivalent OCM risk.

OBJECTIVE--Aims of this study were 1) to assess sexual function and endocrine profile among fertile type 1 diabetic women during the follicular and luteal phases of the menstrual cycle, 2) [...]

Objective: Erectile dysfunction and depression are highly associated. Previous studies have shown benefits of phosphodiesterase-5 inhibitor treatment for erectile dysfunction associated with antidepressant therapy or subsyndromal depression. The present study assessed the safety and efficacy of vardenafil in men with erectile dysfunction and untreated mild depression. Method: In this 12-week, multicenter, randomized, flexible-dose, parallel-group, double-blind study, 280 men with erectile dysfunction for at least 6 months and untreated mild major depression received placebo or vardenafil, 10 mg/day, for 4 weeks, with the option to titrate to 5 mg/ day or 20 mg/day after each of two consecutive 4-week intervals. Endpoints included International Index of Erectile Function erectile function domain and 17item Hamilton Depression Rating Scale (HAM-D) scores. Results: Vardenafil produced statistically significant and clinically meaningful improvement in all erectile function parameters. The International Index of Erectile Function erectile function domain score was 22.9 with vardenafil compared to 14.9 with placebo. The HAM-D score was lower in the vardenafil group (7.9) than in the placebo group (10.1). Treatment with vardenafil was the most important predictor for return to normal erectile function. Improvement in International Index of Erectile Function erectile function domain score was the most important predictor of remission in depressive symptoms. Conclusions: Vardenafil was well tolerated and highly efficacious in men with erectile dysfunction and untreated mild major depression. Significant improvements in erectile function and depression were observed in patients treated with vardenafil versus placebo. Erectile dysfunction treatment should be considered a component of therapy for men with depression and erectile dysfunction.

OBJECTIVE -- In the 5-10% of diabetic men with type 1 diabetes, erectile dysfunction (ED) may be a particularly common and unwanted complication. This is the first study focusing exclusively [...]

We theoretically monitor the photoinduced ππ* → nπ* internal conversion process in 4-thiouracil (4TU), triggered by an optical pump. The element-sensitive spectroscopic signatures are recorded by a resonant X-ray probe tuned to the sulfur, oxygen, or nitrogen K-edge. We employ high-level electronic structure methods optimized for core-excited electronic structure calculation combined with quantum nuclear wavepacket dynamics computed on two relevant nuclear modes, fully accounting for their quantum nature of nuclear motions. We critically discuss the capabilities and limitations of the resonant technique. For sulfur and nitrogen, we document a pre-edge spectral window free from ground-state background and rich with ππ* and nπ* absorption features. The lowest sulfur K-edge shows strong absorption for both ππ* and nπ*. In the lowest nitrogen K-edge window, we resolve a state-specific fingerprint of the ππ* and an approximate timing of the conical intersection via its depletion. A spectral signature of the nπ* transition, not accessible by UV–vis spectroscopy, is identified. The oxygen K-edge is not sensitive to molecular deformations and gives steady transient absorption features without spectral dynamics. The ππ*/nπ* coherence information is masked by more intense contributions from populations. Altogether, element-specific time-resolved resonant X-ray spectroscopy provides a detailed picture of the electronic excited-state dynamics and therefore a sensitive window into the photophysics of thiobases.

The term scrotoplasty embraces several techniques which aim to restore a normal scrotal appearance and function. We provide here a quick reference tool to allow the urologist to select the appropriate surgical strategy among the several available options. A comprehensive research was carried out on MEDLINE/PubMed to identify relevant studies concerning this topic, including a range of key words, e.g., scrotoplasty, ventral phalloplasty, scrotal reconstruction, scrotomegaly, penoscrotal web, scrotal lifting, scrotal reduction, scrotectomy, scrotal lymphoedema. Scrotal skin defects may be related with Fournier’s gangrene, traumatic events, and surgery for genital cancers or peno-scrotal lymphoedema. The reconstructive management of these conditions is relatively reproducible in the hands of experienced urologists, if aware of the basics of scrotal surgery. Primary tension-free wound closure and local pedicled flaps typically allow optimal surgical outcomes for repairing most of these scrotal defects, with split-thickness skin grafts (STSGs) and/or distant flaps being required only when dealing with extensive skin losses. The demand for genitals’ aesthetic surgery among adults is on the increase recently. Although the scientific evidence regarding this topic is scarce, reduction scrotoplasty and peno-scrotal webbing correction techniques are easy, safe and effective solutions to improve genital cosmesis, being carried out in isolation or in combination with penile prosthesis implantation. More robust scientific evidence is needed to achieve a uniformed consensus regarding the optimal surgical management in this broad field, and surgical innovation should continue to refine current reconstructive techniques.

Multireference methods are known for their ability to accurately treat states of very different nature in many molecular systems, facilitating high-quality simulations of a large variety of spectroscopic techniques. Here, we couple the multiconfigurational restricted active space self-consistent field RASSCF/RASPT2 method (of the CASSCF/CASPT2 methods family) to the displaced harmonic oscillator (DHO) model, to simulate soft X-ray spectroscopy. We applied such an RASSCF/RASPT2+DHO approach at the K-edges of various second-row elements for a set of small organic molecules that have been recently investigated at other levels of theory. X-ray absorption near-edge structure (XANES) and X-ray photoelectron spectroscopy (XPS) are simulated with a sub-eV accuracy and a correct description of the spectral line shapes. The method is extremely sensitive to the observed spectral shifts on a series of differently fluorinated ethylene systems, provides spectral fingerprints to distinguish between stable conformers of the glycine molecule, and accurately captures the vibrationally resolved carbon K-edge spectrum of formaldehyde. Differences with other theoretical methods are demonstrated, which show the advantages of employing a multireference/multiconfigurational approach. A protocol to systematically increase the number of core-excited states considered while maintaining a contained computational cost is presented. Insight is eventually provided for the effects caused by removing core–electrons from a given atom in terms of bond rearrangement and influence on the resulting spectral shapes within a unitary orbital-based framework for both XPS and XANES spectra.

Background: The most recent overall survival (OS) and adverse event (AE) data have not been compared for the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treatment alternatives. Methods: We performed a systematic review and network meta-analysis focusing on OS and AE according to the most recent apalutamide, enzalutamide, and darolutamide reports. We systematically examined and compared apalutamide vs. enzalutamide vs. darolutamide efficacy and toxicity, relative to ADT according to PRISMA. We relied on PubMed search for most recent reports addressing prospective randomized trials with proven predefined OS benefit, relative to ADT: SPARTAN, PROSPER, and ARAMIS. OS represented the primary outcome and AEs represented secondary outcomes. Results: Overall, data originated from 4117 observations made within the three trials that were analyzed. Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order. In the subgroup of PSA-doubling time (PSA-DT) ≤ 6 months patients, enzalutamide ranked first, followed by darolutamide and apalutamide in that order. Conversely, in the subgroup of PSA-DT 6–10 months patients, darolutamide ranked first, followed by apalutamide and enzalutamide, in that order. Regarding grade 3+ AEs, darolutamide was most favorable, followed by enzalutamide and apalutamide, in that order. Conclusion: The current network meta-analysis suggests the highest OS efficacy and lowest grade 3+ toxicity for darolutamide. However, in the PSA-DT ≤ 6 months subgroup, the highest efficacy was recorded for enzalutamide. It is noteworthy that study design, study population, and follow-up duration represent some of the potentially critical differences that distinguish between the three studies and remained statistically unaccounted for using the network meta-analysis methodology. Those differences should be strongly considered in the interpretation of the current and any network meta-analyses.

Concomitant sexual disorders have progressively shown increased prevalence in men at first outpatient presentation. We sought to i) estimate the prevalence of unreported premature ejaculation (PE) in a homogenous cohort of 1258 men seeking first medical help for erectile dysfunction (ED) as their primary compliant; ii) compare the baseline sociodemographic and clinical characteristics of men with only ED(ED-only) compared to those with ED and PE(ED + PE); and, iii) investigate the likelihood of detecting PE among men self-reporting only ED over a 16-year period at a single tertiary-referral centre. Descriptive statistics compared sociodemographic and clinical characteristics between ED-only patients and those with unreported concomitant primary/secondary PE(ED + PE). Logistic regression models predicted the risk of having ED + PE at baseline. Local polynomial regression models graphically explored the probability of reporting PE among ED men with ≤40 vs. 41–60 vs. >60 years over the analysed timeframe. Of all, 932 (74.1%) were ED-only and 326 (25.9%) ED + PE patients, respectively. ED + PE patients were younger, presented with fewer comorbidities, and lower rates of severe ED (all p≤ 0.04). At multivariable logistic regression analysis, younger age (OR:0.98) and low sexual desire/interest (OR:1.54) were independently associated with ED + PE at first clinical assessment (all p= 0.03). The likelihood of detecting unreported concomitant primary/secondary PE among patients complaining of only ED at first presentation worrisomely increased among younger and middle-aged men over the last 16 years.

A limited number of studies have described patients on finasteride showing findings which were consistent with Peyronie’s disease (PD). We aimed to detect a pharmacovigilance signal of possible association between finasteride and PD-related clinical features. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the ten drugs which were associated the most with the adverse drug reactions (ADRs) recorded as “penile curvature” and/or “Peyronie’s disease”. A similar analysis, including the same drugs, was carried out for the EMA (European Medicines Agency) EudraVigilance (EV) database. Descriptive data have been analyzed, and Proportional Reporting Ratios (PRRs) have been computed against the other nine drugs of the database. Overall, 860 reports of “penile curvature” and/or “Peyronie’s disease”, were identified in the FAERS database, 214 of which (24.9%) were associated with finasteride. Most reports (56.9%) were submitted by healthcare professionals. Where a treatment-indication was stated, the vast majority of reports (176/210; 83.8%) were associated with androgenetic alopecia. The outcome of most ADRs was “serious” (82.2%), with 96 ADRs resulting in levels of permanent disability. For 97/214 individual cases, penile curvature/PD reports were not part of a syndromic cluster suggestive of post-finasteride syndrome (PFS). The PRR resulted 6.6 (95% CI: 5.6–7.8) and 11.8 (95% CI: 9.08–15.33), respectively, in the FAERS and in the EV databases. Notwithstanding the related limitations and biasing factors of pharmacovigilance studies based on spontaneous reporting, the PRR values here identified should be interpreted as strong signals of disproportionality. These findings, per se, are however not useful to confirm any causal association. Clinical studies are needed to investigate on the possible role for finasteride in causing PD-related clinical features, an hypothesis which remains highly speculative due to the very questionable quality of present data.

We aimed to evaluate the relationship between serum testosterone (T) levels and penile curvature in a cohort of men presenting for chronic phase Peyronie’s disease (PD). Clinical data from 149 patients assessed for chronic phase PD between 2016 and 2019 at a single academic center were analyzed. Deformity assessment was conducted during an intracavernosal injection-induced rigid erection. Both total T (tT) and calculated free T (cFT) were assessed in every patient and considered as continuous variables or according to quartiles of the normal range. Hypogonadism was defined for tT < 10.4 nmol/L. Descriptive statistics and linear regression models tested the association between Tvalues and the severity of penile curvature. Overall, median tT value was 15.9 (11.4–20.8) nmol/L in the whole cohort; median curvature magnitude and plaque size were 45 (30–60) degrees and 1.5 (0.8–2.0) cm, respectively. Penile curvature (40.0 vs. 45.0 degree; p= 0.7) and plaque size (1.5 vs. 1.3 cm; p= 0.4) were similar between eugonadal and hypogonadal patients. The magnitude of penile curvature did not differ across tT quartiles (p= 0.31). Both at univariable (β1.32; p< 0.01) and multivariable (β1.34; p< 0.01) linear regression model, only duration of PD was associated with the severity of penile curvature magnitude. The results of this cross-sectional study confirmed that there is no association between serum Tvalues and the severity of penile curvature in patients with chronic phase PD. Only PD duration is associated with penile deformity severity.

A 41-yr-old, otherwise healthy, premenopausal woman presented at our uro-oncology clinic with a diagnosis of muscle-invasive bladder cancer following a transurethral resection of the bladder performed at another center. After a thorough discussion with the patient, she was enrolled in the phase II PURE-01 trial (NCT02736266), testing three cycles of neoadjuvant pembrolizumab (200mg) every 3 wk before radical cystectomy. Before treatment, imaging studies were obtained as per the protocol using computed tomography (CT), [18F]fluorodeoxyglucose positron emission tomography/CT, and multiparametric magnetic resonance imaging of the bladder, defining a clinically localized T2N0M0 stage. As per the protocol, potential biomarkers were assessed, including PD-L1 expression (84% combined positive score), tumor mutational burden (16.67 mut/Mb), and genomic profiling (FoundationONE assay; somatic mutation in TP53, EZH2, APC, TERT, CDKN1A, CDKN1B, and ARID1Agenes, and truncation in BRCA2gene). After immunotherapy, the patient underwent a robot-assisted radical cystectomy with extended pelvic lymph node dissection. The final pathology report revealed absence of residual disease (ie, pathological complete response, ypT0ypN0). During follow-up, the only relevant and permanent immune-mediated adverse event was hypothyroidism secondary to an autoimmune thyroiditis. It appeared 2 mo after radical cystectomy and it was managed successfully with hormonal replacement therapy. Two years after treatment, the patient is asymptomatic and free from disease recurrence.

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher’s exact test, and logistic regression analyses to analyze the associations between the various FGFR3alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3GAs or high FGFR3signature scores, or had lncRNA-FGFR3–active tumors. Despite an association of high FGFR3gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time.

Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node–involved penile squamous-cell carcinoma (PSCC) are lacking.