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Mohamad Moussa,1 Athanasios Papatsoris,2 Mohamed Abou Chakra,1 Athanasios Dellis2,3 1Department of Urology, Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon; 2 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece; 3Department of Surgery, School of Medicine, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, GreeceCorrespondence: Athanasios Papatsoris 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, GreeceFax +302132058605Email agpapatsoris@yahoo.grAbstract: Nowadays the therapeutic landscape for advanced and metastatic urothelial carcinoma continues to evolve. The recent regulatory approval of enfortumab vedotin (EV) for the treatment of advanced urothelial cancer confirms the evolving role of antibody-drug conjugates. EV demonstrates a favorable profile in heavily pretreated patients with locally advanced or metastatic urothelial carcinoma. Early survival reports demonstrate a significant antitumor effectiveness along with a rather acceptable safety profile in a difficult-to-treat population.Keywords: enfortumab vedotin, bladder cancer, metastasis, urothelial cancer

Background: Guidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce., Methods: A secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method., Results: Median follow-up (f/u) for all patients was 23 months (IQR 13-34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months)., Conclusions: Gem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results., Competing Interests: Declaration of competing interest I affirm that none of the authors have a conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

While more than four decades have elapsed since intravesical Bacillus Calmette-Guérin (BCG) was first used to manage non-muscle invasive bladder cancer (NMIBC), its precise mechanism of anti-tumor action remains incompletely understood. Besides the classic theory that BCG induces local (within the bladder) innate and adaptive immunity through interaction with multiple immune cells, three new concepts have emerged in the past few years that help explain the variable response to BCG therapy between patients. First, BCG has been found to directly interact and become internalized within cancer cells, inducing them to act as antigen-presenting cells (APCs) for T-cells while releasing multiple cytokines. Second, BCG has a direct cytotoxic effect on cancer cells by inducing apoptosis through caspase-dependent pathways, causing cell cycle arrest, releasing proteases from mitochondria, and inducing reactive oxygen species-mediated cell injury. Third, BCG can increase the expression of programmed death ligand 1 (PD-L1) on both cancer and infiltrating inflammatory cells to impair the cell-mediated immune response. Current data has shown that high-grade recurrence after BCG therapy is related to CD8 + T-cell anergy or 'exhaustion'. High-field cancerization and subsequently higher neoantigen presentation to T-cells are also associated with this anergy. This may explain why BCG therapy stops working after a certain time in many patients. This review summarizes the detailed immunologic reactions associated with BCG therapy and the role of immune cell subsets in this process. Moreover, this improved mechanistic understanding suggests new strategies for enhancing the anti-tumor efficacy of BCG for future clinical benefit., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Growing evidence suggests that many patients with high-risk non-muscle invasive urothelial carcinoma (NMIUC) can undergo bladder-sparing management with salvage intravesical therapies. However, inherent or developed disease resistance, particularly after multiple lines of prior salvage therapy, implores the continued pursuit of new treatment combinations. Herein, we describe the outcomes of 26 patients (31 treated units; 24 lower tract, 7 upper tract) with high-risk NMIUC treated with sequential intravesical gemcitabine and cabazitaxel with concomitant intravenous pembrolizumab (GCP) at the University of Iowa from August 2020 to February 2023. Median (IQR) follow-up was 30 (IQR: 17-35) months. Treated units had a history of high-risk NMIUC with a median of four prior endoluminal inductions. Overall, 87% of units presented with CIS or positive urine cytology. The 1- and 2-year recurrence-free survival was 77% (CI: 58-88%) and 52% (CI: 30-70%), respectively. The 2-year progression-free and cancer-specific survival was 70% (CI: 44-85%) and 96% (CI: 75-99%), respectively. In total, 22/26 (85%) patients reported any adverse event and 5/26 (19%) reported a grade ≥3 adverse event; however, all patients tolerated a full induction course. These results suggest that GCP is an effective and tolerable treatment option for patients with recurrent high-risk NMIUC.

Introduction: Intravesical sequential doublet chemotherapy (SDC) is being used increasingly as a rescue treatment for nonmuscle-invasive bladder cancer failing bacillus Calmette-Guérin (BCG), as single-agent chemotherapies are less effective, especially for carcinoma in situ. Considering the current BCG shortage, intravesical SDC also provides an efficacious alternative to BCG. Our aim is to detail the implementation to assist with establishing an efficient and practical intravesical SDC clinic for urologic practice., Methods: We searched PubMed for published studies with the Medical Subject Heading of "intravesical chemotherapy" and "non-muscle invasive bladder cancer." The search was limited to English-language journals and full papers only. The initial search resulted in 260 articles, of which 20 relevant studies were selected., Results: Five important processes were identified in the successful and efficient administration of intravesical SDC: (1) patient preparation, (2) medication procurement, (3) medication administration, (4) medication immediate aftermath, and (5) patient instruction and education. Safety precautions should be taken when handling each chemotherapy drug. A clinical pharmacist may be required for drug preparation. An important step in providing intravesical SDC is to use a closed system for the instillation of the chemo-solution. A special protocol should be adopted for every drug with its proper dwell time. The induction course consists of weekly instillation for 6 weeks. If an initial response is noted, maintenance therapy is recommended, typically monthly for 24 months., Conclusions: Successful intravesical SDC clinics necessitate appropriate patient selection, standardized workflow procedures, patient education, and good communication between the urologist, clinical pharmacists, and oncology nurses.

Introduction: Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade lesions that frequently recur and rarely metastasize. There are currently no guidelines on the management of bladder IMTs. This systematic review aims to describe the clinical presentation and compare the management options for bladder IMTs., Methods: A PubMed/Medline search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the following Mesh terms: ("inflammatory myofibroblastic") AND ("tumor") OR ("tumor") AND ("bladder") AND ("case report"). A total of 75 case reports were included in the analysis., Results: The mean age of the patients was 36 years. 65% of the cases initially presented with hematuria. 68% of the tumors stained positive for anaplastic lymphoma kinase, and 20% invaded the muscularis. Patients underwent either transurethral resection of the bladder tumor (TURBT) only (34%), TURBT followed by complementary partial cystectomy (16%), or TURBT followed by radical cystectomy (4%). 36% and 9% of the cases underwent partial and radical cystectomy after the initial diagnosis, respectively. Cystectomies were performed using an open (74%), laparoscopic (14%), robotic-assisted (10%), or unknown (2%) approach. At a mean follow-up of 14 months, the recurrence and metastasis rates were about 9% and 4%, respectively. In addition, we present the case of a 49-year-old woman with a bladder IMT who underwent TURBT followed by laparoscopic partial cystectomy. The patient remains tumor free postoperatively (follow-up period of 12 months)., Conclusion: A complete surgical excision of the bladder IMT is crucial for the optimal management of these cases. Proper differentiation of this tumor from sarcoma or leiomyosarcoma leads to the best outcomes., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Urology.)

Purpose: To understand the treatment plans suggested for BCG-unresponsive non-muscle invasive disease (NMIBC) patients in the Arab countries and therapeutic decisions applied for BCG-naive patients during BCG shortage time., Methods: A 10-minute online survey was distributed through the Arab Association of Urology (AAU) office to urologists in the Arab countries who treat patients with NMIBC., Results: One hundred six urologists responded to the survey. The majority of urologists had treated, in the past 6 months, > 10 patients with NMIBC who were considered BCG-unresponsive (55% of respondents). Radical cystectomy (RC) was the most popular treatment option (recommended by 50%) for these patients. This was followed by intravesical chemotherapy (30%), repeat BCG therapy (12%), resection with ongoing surveillance (8%). Clinical trials and intravenous checkpoint inhibitors were never selected. The most preferred intravesical chemotherapy was by ranking: 60% gemcitabine, 19% mitomycin C, 8% docetaxel, 8% gemcitabine/docetaxel, 4% sequential gemcitabine/mitomycin C, and 1% valrubicin. The use of intravesical chemotherapy appears limited by Arab urologists due to concerns regarding clinical efficacy (fear of progression) and the lack of clear recommendations by urology societies. Given the BCG shortage, which may vary per Arab country, Arab urologists have adjusted by prioritizing BCG for T1 and carcinoma in situ (CIS) patients over Ta, adapting intravesical chemotherapy, and reducing the dose/strength of BCG administered. Most physicians report an eagerness to utilize novel therapies to address the BCG deficit, especially to try intravesical chemotherapy., Conclusions: Even though Arab urologists are in the majority of cases selecting RC for BCG-unresponsive cases, one-third of them are most recently initiating intravesical chemotherapy as an alternative option. To further assist Arab urologists in the appropriate selection of BCG unresponsive high risk NMIBC patient treatments, enhanced education and pathway protocols are needed.

Introduction: The combination of intravesical gemcitabine (Gem) with docetaxel (Doce) or with mitomycin C (MMC) has been used in the primary setting as an alternative to Bacillus Calmette-Guerin (BCG) to treat high-risk (HR) and intermediate-risk (IR) non-muscle invasive bladder cancer (NMIBC), as well in the rescue setting for patients in whom BCG has failed., Area Covered: Efficacy and safety of Gem/Doce and Gem/MMC to treat NMIBC in BCG-naive and failure settings., Expert Opinion: In the BCG-naive setting, Gem/Doce was the primary alternative combination therapy reported, with a weighted mean of 12- and 24-month recurrence-free survival (RFS) of 79% and 77% for HR disease and 84% and 76% for IR disease, respectively. In the HR BCG-failure setting, the weighted mean of 12- and 24-month RFS was 60% and 42% for Gem/Doce and 63% and 40% for Gem/MMC. While patients without BCG exposure and papillary disease only benefit the most from Gem/Doce, there is also reasonable efficacy in BCG refractory disease and CIS. Combination therapy is well tolerated, with grade III toxicity reported in less than 1% of patients. Unlike single-agent chemotherapy, intravesical Gem/Doce is considered effective and safe regardless of risk-stratification.

Background: To evaluate the impact of having first-degree relatives (FDR) with bladder cancer (BC) among non-muscle invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette - Guérin (BCG) on their oncological outcomes., Methods: The National Phase II BCG/Interferon (IFN) trial database from 125 sites in the U.S.A. (1999-2001) and multi-institutional databases from France (FR) and Lebanon (LB) (2000-2021) were queried for NMIBC patients treated with BCG. Cox regression models were used to evaluate the effect of BC family history on tumor recurrence and progression in their relatives., Results: There were 867 patients in the U.S.A. cohort and 1232 patients in the FR/LB cohort. Almost 8% of patients in both cohorts had FDR with BC. Patients in the FR/LB cohort were more likely to have carcinoma in situ tumors (CIS) (41% vs. 24%, p  < 0.01). Having FDR with BC was not significantly associated with tumor recurrence or progression in the U.S.A. cohort. Conversely, on multivariable analysis FDR history was significantly associated with a 2.10 times increased risk of recurrence ( p  < 0.01) and a 3.01 times increased risk of progression ( p  < 0.01) in the FR/LB cohort., Conclusion: A family history of BC could have an important impact on the response to BCG.

The study aimed to examine the impact of diabetes mellitus type 2 (DMII) on the oncological outcomes of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) using comprehensive real-world data. We performed an analysis of data on NMIBC patients treated with BCG from the United States (US) National Phase II BCG/Interferon (IFN) trial database (125 centers) and pooled databases from three tertiary care institutions: France (FR), Lebanon (LB) (2000-2021), and the US (University of Iowa) (2011-2021). There were 867 patients from the Phase II trial, 1232 from the FR/LB cohort, and 233 from the US (Iowa) cohort ( n  = 2332). DM II was reported in 13% of the Phase II trial cohort, 14.4% of the FR/LB cohort, and 33.5% of the US (Iowa) cohort. The median follow-up was 24 months in the Phase II trial cohort, 25 months in the FR/LB cohort, and 48 months in the US (Iowa) cohort. In multivariable Cox regression analyses, DMII was not significantly associated with recurrence or progression of the tumor in any of the cohorts included in this study. DMII may not be a clinical prognostic factor for NMIBC patients treated with BCG. Prospective evaluation is needed.

Introduction: The goal of this survey was to evaluate the treatment and practice pattern of patients with high-grade papillary Ta, T1 nonmuscle-invasive bladder cancer (NMIBC), and carcinoma in situ (CIS) in bacillus Calmette-Guérin (BCG)-unresponsive (with adequate BCG exposure = adequate BCG) and those with less than adequate BCG exposure (BCG-exposed)., Methods: An internet-based survey with a target duration of 5 minutes was sent to US urologists who manage patients with NMIBC. Respondents were recruited from the Sesen Bio target list based upon BCG utilization., Results: In 2022, 100 urologists who manage patients with papillary tumors and 159 urologists who manage patients with CIS tumors filled out the survey. Most (78%) were community-based urologists. Study respondents managed an average of 33 (range: 6-158) CIS patients and 44 (range: 10-200) high-grade patients with papillary disease (without CIS) over the past 6 months. Approximately 70% of physicians identified either gemcitabine (∼40%) or mitomycin C (∼30%) as the most often used intravesical chemotherapies for BCG unresponsive and BCG exposed groups. Most physicians reported the use of gemcitabine 2 g or mitomycin C 40 mg in a specific regimen for induction (once a week × 6 weeks) and maintenance (once a month × 12 months). Responses were consistent across groups of BCG therapy (adequate vs BCG-exposed). Physicians were slightly more likely to use a maintenance regimen for the adequate BCG patient., Conclusions: The most common treatments received by patients with BCG-unresponsive and BCG-exposed NMIBC were intravesical chemotherapy (single-agent gemcitabine or mitomycin C), regardless of whether CIS or papillary disease was present.

Introduction: Failure, intolerance, or shortage of bacillus Calmette-Guerin (BCG) treatment for patients with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) leave many facing the prospect of radical cystectomy (RC). However, despite the lack of large-scale randomized controlled studies with single-agent intravesical gemcitabine (Gem), it has emerged as a popular salvage agent after BCG failure or even a treatment alternative to BCG., Areas Covered: 1. Characterization of treatment regimen details pertaining to single-agent intravesical adjuvant Gem use among disease states of NMIBC characterized by risk and BCG exposure. 2. Comparison of safety and efficacy of Gem according to risk category, type of tumor (papillary vs. carcinoma in situ (CIS)), and tumor grades., Expert Opinion: Two randomized studies in early BCG failure disease demonstrate that single-agent Gem has superior efficacy versus repeated BCG therapy or mitomycin C. Studies enrolling patients with predominantly papillary disease without CIS, intermediate-risk (IR) disease, and less BCG exposure appear to derive the highest benefits from adjuvant Gem in terms of recurrence and progression. However, studies with cohorts enriched for a predominance of CIS, HR disease and/or more extensive BCG failure have poorer 2-year recurrence free survival and a somewhat higher risk of progression and RC.

Introduction: Liquid biopsies are used for the detection of tumor-specific elements in body fluid. Their application in prognosis and diagnosis of muscle/non-muscle invasive bladder cancer (MIBC/NMIBC) or upper tract urothelial cancer (UTUC) remains poorly known and rarely mentioned in clinical guidelines., Areas Covered: Herein, we provide an overview of current data regarding the use of liquid biopsies in urothelial tumors., Expert Opinion: Studies that were included analyzed liquid biopsies using the detection of circulating tumor cells (CTCs), deoxyribonucleic acid (DNA), ribonucleic acid (RNA), exosomes, or metabolomics. The sensitivity of blood CTC detection in patients with localized cancer was 35% and raised to 50% in patients with metastatic cancer. In NMIBC patients, blood CTC was associated with poor prognosis, whereas discrepancies were seen in MIBC patients. Circulating plasma DNA presented a superior sensitivity to urine and was a good indicator for diagnosis, follow-up, and oncological outcome. In urine, specific bladder cancer (BC) microRNA had an overall sensitivity of 85% and a specificity of 86% in the diagnosis of urothelial cancer. These results are in favor of the use of liquid biopsies as biomarkers for in urothelial cancer management.

Introduction: To investigate the safety, oncologic, surgical, and functional outcomes of RPP and RRP for localized prostate cancer (Pca), especially focusing on RPP., Materials and Methods: From March 2005 to January 2021, we retrospectively reviewed the records of 685 patients undergoing RPP ( n  = 320) or RRP ( n  = 365) for localized Pca. Surgical and functional outcomes, and complications were compared. Oncological outcomes were also compared using Kaplan-Meier survival analysis., Results: A higher biochemical recurrence rate were noted in RRP than in RPP group (28.8% vs 21.6%, respectively; p  = 0.03). A local recurrence was detected in a few numbers of patients (4.4%) with no statistically significant differences by surgical groups ( p  = 0.71). No significant differences were observed in the cancer-specific survival and the overall survival according to the surgical approach. Positive surgical margins were similar in the two techniques.In comparison to RRP, patients undergoing RPP have less postoperative pain, decreased transfusion rate, and less catheterization time. Complete continence was achieved in 96.9% of the RPP group at 18 and 24 months versus 91.8% and 92.3% in the RRP group at 18 and 24 months, respectively ( p  = 0.005 and p  = 0.01, respectively). At 18 months of follow-up, the nerve-sparing technique was performed equally between the two groups, the mean of erectile function domain improved more in RPP than RRP (12.71 vs 10.42 respectively, p  < 0.001). Medical and surgical complication rates were higher for RRP than RPP., Conclusions: RPP showed acceptable oncologic outcomes and excellent functional outcomes when compared to RRP.

Scrotal calcinosis is a rare disorder characterized by multiple papules or nodules of calcification in the scrotal skin. The pathogenesis of this disease is poorly understood. The condition presents as several brown to yellowish asymptomatic nodules on the scrotum. Excision followed by scrotal reconstruction is the treatment of choice. It leaves a good cosmetic result with low chances of recurrence. Newer treatments, such as ablative lasers, have been proposed with very good results. We describe the case of a 28-year-old patient with a history of severe acne treated with oral isotretinoin that presented for scrotal nodules. On laboratory examination, hypercalcemia was found with normal phosphorus, parathyroid hormone, and vitamin D hormone levels. Hypercalcemia was linked to his isotretinoin therapy. Serum calcium concentrations normalized after cessation of isotretinoin and hydration. Because the patient refused surgery, a biopsy of the lesion confirmed the diagnosis of scrotal calcinosis. Then the patient was referred to a cosmetic laser center to treat his condition.

Priapism is a persistent penile erection lasting longer than 4 hours, that needs emergency management. This disorder can induce irreversible erectile dysfunction. There are three subtypes of priapism: ischemic, non-ischemic, and stuttering priapism. If the patient has ischemic priapism (IP) of less than 24-hours (h) duration, the initial management should be a corporal blood aspiration followed by instillation of phenylephrine into the corpus cavernosum. If sympathomimetic fails or the patient has IP from 24 to 48h, surgical shunts should be performed. It is recommended that distal shunts should be attempted first. If distal shunt failed, proximal, venous shunt, or T-shunt with tunneling could be performed. If the patient had IP for 48 to 72h, proximal and venous shunt or T-shunt with tunneling is indicated, if those therapies failed, a penile prosthesis should be inserted. Non-ischemic priapism (NIP) is not a medical emergency and many patients will recover spontaneously. If the NIP does not resolve spontaneously within six months or the patient requests therapy, selective arterial embolization is indicated. The goal of the management of a patient with stuttering priapism (SP) is the prevention of future episodes. Phosphodiesterase type 5 (PDE5) inhibitor therapy is considered an effective tool to prevent stuttering episodes but it is not validated yet. The management of priapism should follow the guidelines as the future erectile function is dependent on its quick resolution. This review briefly discusses the types, pathophysiology, and diagnosis of priapism. It will discuss an updated approach to treat each type of priapism.

Ureteroarterial fistula (UAF) is a rare but life-threatening condition because of massive hemorrhage. Risk factors include degenerative vascular diseases, previous vascular surgery, pelvic radiation, chemotherapy, pelvic surgery, and prolonged ureteral stenting. The most common presentation of UAF is massive hematuria with hemorrhagic shock. The diagnosis is always difficult even with angiography. Endovascular repair with stenting and/or coiling is effective and safe. The surgical treatment should be used in recurrent UAF cases. We reported a rare case describing rapid management of a UAF in a patient who presented with hematuria even when we had no diagnosis on the initial CT scan. The patient was in shock. Deployment of a stent graft within the common iliac artery bypassing the UAF was performed. The patient improved rapidly.

Parkinson's disease (PD) is recognized as the most common neurodegenerative disorder after Alzheimer's disease. Lower urinary tract symptoms are common in patients with PD, either storage symptoms (overactive bladder symptoms or OAB) or voiding symptoms. The most important diagnostic clues for urinary disturbances are provided by the patient's medical history. Urodynamic evaluation allows the determination of the underlying bladder disorder and may help in the treatment selection. Pharmacologic interventions especially anticholinergic medications are the first-line option for treating OAB in patients with PD. However, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects. Intra-detrusor Botulinum toxin injections, electrical stimulation were also used to treat OAB in those patients with variable efficacy. Mirabegron is a β3-agonist that can also be used for OAB with superior tolerability to anticholinergics. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Deep brain stimulation (DBS) surgery is effective in improving urinary functions in PD patients. Sexual dysfunction is also common in PD. Phosphodiesterase type 5 inhibitors are first-line therapies for PD-associated erectile dysfunction (ED). Treatment with apomorphine sublingually is another therapeutic option for PD patients with ED. Pathologic hypersexuality has occasionally been reported in patients with PD, linked to dopaminergic agonists. The first step of treatment of hypersexuality consists of reducing the dose of dopaminergic medication. This review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic test, and management of PD. Lastly, the urologic outcomes and therapies are reviewed.

Cell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long gene transcripts, which are partially transcribed in short cycles. Using mathematical simulations of cell proliferation, we identify an emergent property that this filter can act as a tuning knob to control gene transcript expression, cell diversity, and the number and proportion of different cell types in a tissue. Our predictions are supported by comparison to single-cell RNA-seq data captured over embryonic development. Additionally, evolutionary genome analysis shows that fast-developing organisms have a narrow genomic distribution of gene lengths while slower developers have an expanded number of long genes. Our results support the idea that cell cycle dynamics may be important across multicellular animals for controlling gene transcript expression and cell fate., Competing Interests: MA, RI, TT, GB No competing interests declared, (© 2021, Abou Chakra et al.)

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Lower urinary tract dysfunction due to MS includes a dysfunction of the storage phase or dysfunction of the voiding phase or a detrusor-sphincter dyssynergia. Baseline evaluation includes a voiding chart, an ultrasound scan of the urinary tract, urine culture, and an urodynamic study. For storage symptoms, antimuscarinics are the first-line treatment, and clean intermittent catheterization (CIC) is indicated if there is concomitant incomplete bladder emptying. Intradetrusor injections with botulinum toxin A (BTX-A), are recommended for refractory cases. Urinary diversion is rarely indicated. For patients with voiding symptoms, CIC and alpha-blockers are usually offered. Sexual dysfunction in patients with MS is multifactorial. Phosphodiesterase type 5 inhibitors are first-line therapies for MS-associated erectile dysfunction in both male and female patients. This review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic tests, and management of MS. Lastly, the urologic outcomes and therapies are reviewed., Competing Interests: The authors have no conflicts of interest to disclose., (2021, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Objectives: No clinical studies testing erectile function (EF) post radical cystectomy (RC) were done. Our objective was to assess the effect of early pharmacologic therapy after RC using intracorporeal injection (ICI), phosphodiesterase inhibitor (PDE5i) and PDE5i+ICI., Materials and Methods: In our randomized, double-blinded study, we prospectively enrolled 160 potent male patients with invasive bladder cancer. Patients were operated by RC using the nerve-sparing (NS) or non-nerve sparing (NNS) technique. They were treated since 1 month postoperatively by different regimens (PDE5i vs. ICI vs. ICI+PDE5i). Patients were evaluated using the international index of erectile function questionnaire and were followed up regularly at 1, 3, 6, and 12 months using the same parameters., Results: One month after therapy, the mean of EF domain improved in both NS and NNS group. In the NNS group, in patients treated with ICI alone and ICI+PDE5i, the EF domain at 12 months moved to the moderate and to the mild category respectively. In patients treated by the NS approach, the mean value remained in the mild category with or without therapy., Conclusions: Early pharmacotherapy since one-month post RC using ICI and a combination of ICI+PDE5i can improve the erectile function of patients operated with a NNS approach.

Introduction : Currently, in prostate cancer, an increasing number of novel drugs are being used to delay its advancement to metastatic castration-resistant prostate cancer (mCRPC). Apalutamide, enzalutamide, and most recently, darolutamide (novel androgen receptor antagonists) have been approved for nonmetastatic castration-resistant prostate cancer (nmCRPC). Areas covered : The authors have evaluated darolutamide, covering all aspects of the clinical development, competence, and safety profile of the drug. Expert opinion : The unique structure of darolutamide is characterized by a high affinity for androgen receptors and detainment of antagonist activity in mutant isoforms of androgen receptors. In clinical practice, this is the main reason that makes darolutamide exceptional in terms of safety and efficacy compared to other drugs in this category. Darolutamide is considered to have the lowest probability for adverse events (AEs) compared to apalutamide and enzalutamide. Future studies, along with real-world clinical data are warranted to improve personalized treatment strategies as well as sequencing treatment between approved novel drugs.

Neurogenic erectile dysfunction (NED) can be defined as the inability to achieve or maintain an erection due to central or peripheral neurologic disease. Neurologic diseases can also affect the physical ability and psychological status of the patient. All these factors may lead to a primary or secondary NED. Medication history plays an important role since there are many drugs commonly used in neurologic patients that can lead to ED. The assessment of NED in these patients is generally evolving with the application of evoked potentials technology in the test of somatic and autonomic nerves, and functional magnetic resonance imaging. With the electrophysiological examinations, neurogenic causes can be determined. These tools allow to categorize neurologic lesion and assess the patient prognosis. The first-line treatment for NED is phosphodiesterase inhibitors. Second-line treatments include intracavernous and intraurethral vasoactive injections. Third-line treatments are penile prostheses. The efficacy and safety of each treatment modality depend on the specific neurologic condition. This review discusses the physiology, pathophysiology, diagnosis, and treatment of ED in multiple peripheral and central neurologic conditions, as well as for future research.

Introduction: Treatment of recurrent Urinary tract infections (UTIs) has become challenging because of the dramatic increase in the rates of recurrent infection andof multidrug-resistant (MDR) infections., Areas Covered: The authors review recurrent UTIs(rUTI) management in women., Expert Opinion: Continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment has all been demonstrated to be effective in managing rUTIs in women. Intravaginal estrogen therapy , shows potential toward preventing rUTI. Oral vaccine Uro-Vaxom seems to reduce the number of UTIs. There is evidence that other therapies (e.g. cranberry, Methenamine hippurate, oral D-mannose) may decrease the number of symptomatic UTIs. The treatment of CRE-UTIs is focused on a colistin backbone. Carbapenems are considered first-line agents for UTIs caused by ESBL, but their use is associated with increased MDR. The usage of non-carbapenem for the treatment of ESBL UTIs is necessary. Cefepime, Piperacillin-Tazobactam, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam are justified options. Oral therapy with Pivmecillinam, Fosfomycin, and Nitrofurantoin can be used against uncomplicated UTIs due to ESBL infection.

Introduction: Many patients with non-muscle-invasive bladder cancer (NMIBC) failed intravesical BCG therapy. Currently, radical cystectomy is the recommended standard of care for those patients. There is unfortunately no effective other second-line therapy recommended., Areas Covered: In this review, we present the topics of BCG unresponsive NMIBC; definition, prognosis, and further treatment options: immunotherapy, intravesical chemotherapy, gene therapy, and targeted individualized therapy., Expert Opinion: There are major challenges of the management of NMIBC who failed BCG therapy as many patients refuse or are unfit for radical cystectomy. Multiple new modalities currently under investigation in ongoing clinical trials to better treat this category of patients. Immunotherapy, especially PD-1/PD-L1 inhibitors, offers exciting and potentially effective strategies for the treatment of BCG unresponsive NMIBC. As the data expands, it is sure that soon there will be established new guidelines for NMIBC.

Introduction: Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC., Areas Covered: In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression., Expert Opinion: Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.

Cystine stones are relatively uncommon compared with other stone compositions, constituting just 1% to 2% of adult urinary tract stone diseases, and accounting for up to 10% of pediatric stone diseases. Two responsible genes of cystinuria have been identified, the SLC3A1 and the SLC7A9. Cystinuria is diagnosed by family history, stone analysis, or by measurement of urine cystine excretion. Current treatments for cystinuria include increased fluid intake to increase cystine solubility by maintaining daily urine volume of greater than 3 Liter (L). Limiting sodium and protein intake can decrease cystine excretion. When conservative therapy fails, then pharmacologic therapy may be effective. Alkaline urine pH in the 7.0-7.5 range will reduce cystine solubility and can be achieved by the addition of alkali therapy. If these measures fail, cystine-binding thiol drugs such as tiopronin and D-penicillamine are considered. These compounds bind cysteine and prevent the formation of less soluble cystine. These drugs, however, have poor patient compliance due to adverse effects. Captopril can be useful in the treatment of cystine stones but the drug has not been tested in rigorous clinical trials. Novel potential therapies such as alpha-lipoic acid and crystal growth inhibitors (L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME)) were developed and tested in animals. Those therapies showed promising results. Compliance with treatment was associated with a lower rate of cystine stone formation., (2020, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Peyronie's disease (PD) is a connective tissue disorder of the penis characterized by fibrosis and plaque formation within the tunica albuginea. PD is characterized by painful penile curvature that impairs sexual intercourse. Stem cell therapy is one of the recent non-invasive treatment options for patients with PD and it has promising results. Stem cells are undifferentiated cells that are capable of self-renewal and differentiation, promoting the repair of tissues via their immunomodulatory and anti-inflammatory action. Adipose-derived stem cells (ADSC) are used most widely due to their abundant tissue source and ease of isolation. Multiple studies have indicated the efficacy of stem cell therapy as a potential treatment for fibrotic diseases. Clearly, ADSCs may represent a way to treat and prevent PD in both rat and human models. Further clinical studies are needed to confirm the efficacy of stem cell therapy for PD in humans., (2020, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Introduction : Urolithiasis is a common, highly recurrent disease with increasing prevalence worldwide. There are many dietary and pharmacological measures to prevent kidney stones. Areas covered : Herein, the authors explore medical expulsive therapy as well as pharmacological therapies to prevent/treat urolithiasis. Expert opinion : All stone formers should be advised to increase their fluid intake sufficiently to achieve a urine volume of at least 2.5 L/day. In the case of hypercalciuria, a thiazide diuretic should be prescribed while in cases of hypocitraturia, potassium citrate should be given. In the case of hyperoxaluria, the treatment depends on the type of hyperoxaluria. Pyridoxine or calcium supplements with a meal can be offered. For uric acid stone formers, alkali therapy is the standard of care whereas allopurinol can be beneficial in hyperuricosuric stone formers. For cystine stone formers, increased fluid intake, restriction of sodium and animal protein ingestion, and urinary alkalinization are the standard therapies used. Cystine binding thiol drugs such as tiopronin and D-penicillamine are reserved for patients where a conservative approach fails. For struvite stone formers, optimal management is the complete stone removal. Acetohydroxamic acid may be offered only after surgical options have been exhausted, for patients with residual stones but it has many side effects.

Background: No known data in the literature assessing practice of kidney stone prevention in the emergency department (ED) is available., Objectives: Assess patient perception and compliance to kidney stone prevention given within the emergency department. It also indirectly detects the attitude and practice patterns of primary care providers in kidney stone prevention., Materials and Methods: This is a qualitative study done in a single institution from January 2018 to January 2019 that includes 99 patients that were diagnosed with kidney or ureteral stone in ED and were discharged home, all of them where stone formers. They were asked to fill a self- administered questionnaire when they are able to read, or interviewed by the resident within the ED when they are unable to read., Results: The majority of patients (68%) did not receive any instructions about kidney stones prevention within the ED. Most of patients who follow instructions if it was given were educated (90%), had an insurance coverage (85%), and had an income higher than $1000 per month (76%), (p < 0.05). Seventy one percents of patients believe in the effectiveness of stone prevention if it was provided and most of them are interested in learning about these preventive strategies (82%). Reasons for not following the instructions about kidney stones prevention measures were the cost (53.1%) following by the lack of explanation by ED physicians (18.8%). The majority of patients (62.6%) prefer to receive kidney stones prevention measures from urologists., Conclusion: Most of patients in our institute did not receive kidney stones prevention measures in ED despite that they declared their interest in following these measures. Most of the time they did not adhere to those measures due to socioeconomic factors and lack of clarifications. If these instructions were given within the ED, it could lead to an acceptable compliance rate.