A mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery.

Intravesical therapy (IT) is widely used to tackle various urological diseases. However, its clinical efficacy is decreased by the impermeability of various barriers presented on the bladder luminal surface, including the urinary mucus layer and the densely packed tissue barrier. In this study, we report a mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery. Upon intravesical instillation, its poloxamer 407 (PLX) hydrogel gelated and adhered to the urothelium to prolong its intravesical retention. The urea afterwards diffused into the hydrogel, thus generating a concentration gradient. Urease-powered membrane nanomotors (UMN) without asymmetric surface engineering could catalyze the urea and migrate down this concentration gradient to deeply and unidirectionally penetrate the urothelial barrier. Moreover, the intravesical hybrid system-delivered gemcitabine could effectively inhibit the bladder tumor growth without inducing any side effect. Therefore, our mucoadhesive-to-penetrating nanomotors-in-hydrogel system could serve as an alternative to IT to meet the clinical need for more efficacious therapeutics for urological diseases.

Short-term outcomes of intravesical gemcitabine for non-muscle-invasive bladder cancer after recent approval for use in Korea.

PURPOSE: In high-risk non-muscle-invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy post-transurethral resection of bladder tumor (TURBT). Intravesical gemcitabine, used as an alternative or second-line therapy amid BCG shortages, lacks outcome studies in the Korean population. MATERIALS AND METHODS: Patients who received weekly intravesical gemcitabine for 6 weeks after TURBT from 2019 to 2022 were retrospectively investigated. Based on the American Urological Association risk classification, patients with high- or very high-risk NMIBC who refused cystectomy were included. Maintenance treatment was performed depending on their risk. Recurrence was defined as histologic confirmation on subsequent cystoscopic biopsies or TURBT. Disease free survival (DFS) was evaluated by the Kaplan-Meier method. RESULTS: The study included 60 patients, comprising 45 high-risk (group 1) patients with a median age of 76 years and 15 very high-risk (group 2) patients with a median age of 68 years. Among them, 28 patients had previously received intravesical BCG. Over a median follow-up of 22 months, recurrence occurred in 31 patients in group 1 and 11 in group 2. The DFS rates of the high-risk group and the very high-risk group were 57.8% versus 40% at 1 year, 20.7% versus 21.3% at 2 years and 20.7% versus 21.3% at 3 years, respectively (p=0.831). Tis stage (p=0.042) and prostatic urethra invasion (p=0.028) were significant predictors of DFS. Cancer-specific mortality rates were 2.2% in group 1 and 6.7% in group 2 (p=0.441). CONCLUSIONS: Similar DFS outcome between high-risk and very high-risk patients were observed based on short-term results in Korea. This finding is crucial for clinical practice; however, studies analyzing more patients and long-term outcomes are needed.

Clinical and molecular response to alpha1-oleate treatment in patients with bladder cancer.

BACKGROUND: The tumoricidal complex alpha1-oleate targets bladder cancer cells, triggering rapid, apoptosis-like tumor cell death. Clinical effects of alpha1-oleate were recently observed in patients with non-muscle invasive bladder cancer (NMIBC), using a randomized, placebo-controlled study protocol. AIMS: To investigate if there are dose-dependent effects of alpha1-oleate. MATERIALS AND METHODS: Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1-oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. RESULTS: Strong, dose-dependent anti-tumor effects were detected in alpha1-oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1-oleate. Uptake of alpha1-oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis-like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug-related side effects were not recorded, except for local irritation at the site of instillation. DISCUSSION AND CONCLUSIONS: These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.

Adjunctive intravesical EDTA-tromethamine treatment of a biofilm-associated recurrent Escherichia coli cystitis in a dog.

A 15-month-old spayed female greater Swiss mountain dog was brought to our clinic because of relapsing episodes of urinary tract infection, present since her adoption at 2 mo of age. A diagnosis of chronic bacterial cystitis associated with an invasive, biofilm-forming uropathogenic Escherichia coli was made with bladder-wall histology and fluorescent in situ hybridization analysis. Local treatment with EDTA-tromethamine (EDTA-Tris) infusions along with parenteral cefquinome and prophylactic measures (Type-A proanthocyanidins and probiotics) coincided with clinical and bacterial remission. The dog has been free of clinical signs of urinary tract infection for >4 y. Biofilm-forming uropathogenic E. coli can cause chronic, recurrent cystitis due to low antibiotic efficacy and should be considered in cases of recurrent cystitis in dogs, especially in the absence of identified predisposing factors. This case report describes the diagnostic and therapeutic options that were used to manage a case of this type. Key clinical message: Fluorescent in situ hybridization analysis may be considered in the diagnosis of chronic bacterial cystitis in dogs, and intravesical instillations of EDTA-Tris may be helpful in managing such cases.

Traitement adjuvant intravésical avec de l'EDTA-trométhamine chez un chien présentant une cystite récurrente à Escherichia coli formant des biofilmsUne chienne grand bouvier suisse stérilisée de 15 mois nous a été présentée pour des épisodes d'infection du tractus urinaire récidivants depuis son adoption à l'âge de 2 mois. Une cystite bactérienne chronique associée à un Escherichia coli uropathogène formant des biofilms a été identifiée par l'examen histologique de la paroi vésicale et par hybridation in situ fluorescente. Des instillations intravésicales d'EDTA et trométhamine (EDTA-Tris) en complément d'une antibiothérapie parentérale de courte durée (cefquinome) et de mesures prophylactiques (proanthocyanidines de type A et probiotiques) ont permis une guérison clinique et bactériologique de la cystite pendant plus de 4 ans. Les infections par Escherichia coli formant des biofilms peuvent causer des cystites chroniques récurrentes dues à une faible efficacité des antibiotiques et doivent être incluses dans le diagnostic différentiel des cystites récurrentes chez le chien, particulièrement en l'absence d'autre facteur prédisposant. Ce rapport propose des stratégies diagnostiques et thérapeutiques ayant permis la prise en charge d'un de ces cas.Message clinique clé :L'analyse par hybridation in situ fluorescente peut être envisagé dans le diagnostic de cystite bactérienne chronique chez les chiens, et l'instillation intravésicale d'EDTA-Tris peut être utile dans la gestion de tels cas.(Traduit par les auteurs).

Efficacy and tolerance of hyperthermic intravesical chemotherapy (HIVEC) according to the number of instillations administered.

PURPOSE: To report the oncological outcomes and the tolerance between 6 instillations and more than 6 cycles of hyperthermic intravesical chemotherapy(HIVEC) in patients with non-muscle invasive bladder cancer(NMIBC). METHODS: This is a multicenter retrospective study from a national database including 9 expert centers. All patients treated with HIVEC between 2016 and 2023 for NMIBC were included. Patients were classified into two groups according to the total number of HIVEC instillations, including induction plus maintenance. Kaplan-Meier curves were computed to present survival outcomes. RESULTS: 261 patients with a median follow-up of 25.5 months were included. 199(76.2%) and 62(23.8%) were treated by 6 and more than 6 cycles of HIVEC, respectively. The 2-years RFS(40.2% vs. 34.4%,p = 0.3) and the 2-years PFS(86% vs. 87%,p = 0.85) were similar between group treated with 6 and more than 6 instillations. 2-years CSS and OS were also similar between both groups. Univariate Cox regression showed no association between the number of bladder instillation and RFS (HR = 1.2 95%CI[0.8-1.84], p = 0.3) or PFS (HR = 0.8 95%CI[0.29-2.02], p = 0.2). In the group treated with more than 6 cycles, 2-years RFS and 2-years PFS were similar between patients who received induction plus maintenance compared to those treated with induction only. Finally, hematuria and urinary burning were significantly higher in the group treated by more than 6 cycles (21% vs. 8.5%(p < 0.01),and 29% vs. 17% (p = 0.03), respectively). Serious side effects(grade ≥ 3) are rare(3.1%) and similar in both groups. CONCLUSIONS: Results show no significant difference in two years RFS, PFS, CSS and OS according to number of instillations received, while toxicity profile seems better in the group receiving six instillations only.

Adverse Effects of Intravesical OnabotulinumtoxinA Injection in Patients with Idiopathic Overactive Bladder or Neurogenic Detrusor Overactivity: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

Despite the efficacy of onabotulinumtoxinA, its safety profile remains a concern. This meta-analysis reviewed the major adverse events (AEs) associated with intravesical onabotulinumtoxinA treatment in patients with neurogenic detrusor overactivity (NDO) and idiopathic overactive bladder (iOAB). Randomized controlled trials (RCTs) conducted between January 2000 and December 2022 were searched for adult patients administered different onabotulinumtoxinA dosages or onabotulinumtoxinA vs. placebo. Quality assessment was performed using the Cochrane Collaboration tool, and statistical analysis was performed using Review Manager version 5.3. A total of 26 RCTs were included in the analysis, including 8 on NDO and 18 on iOAB. OnabotulinumtoxinA vs. placebo significantly increased the urinary tract infection (UTI) incidence in patients with NDO (relative risk, or RR, 1.54) and iOAB (RR, 2.53). No difference in the RR with different onabotulinumtoxinA dosages was noted. Urinary retention was frequent with onabotulinumtoxinA use in the NDO (RR, 6.56) and iOAB (RR, 7.32) groups. Similar observations were made regarding the risks of de novo clean intermittent catheterization (CIC). The risk of voiding difficulty increased with onabotulinumtoxinA use in patients with iOAB. Systemic AEs of onabotulinumtoxinA, including muscle weakness (RR, 2.79) and nausea (RR, 3.15), were noted in patients with NDO; most systemic AEs had a low incidence and were sporadic.

Efficacy, Satisfaction, and Compliance: Insights from 15 Years of Botulinum Toxin Use for Female Urgency Urinary Incontinence.

Urgency urinary incontinence (UUI) refractory to medical treatment poses significant challenges despite advancements. This study evaluates the efficacy of intravesical botulinum toxin for UUI and identifies factors influencing treatment outcomes. Among 368 women receiving botulinum toxin injections, 74.5% achieved a complete discontinuation of pad usage. Predictors of efficacy included lower pre-treatment pad usage and the absence of prior sling placement. Patients often required repeat injections (60.3%), with younger age and satisfaction correlating with treatment repetition. The interval between injections averaged 18 months, influenced by logistical challenges and patient preferences. Despite concerns about diminishing efficacy, subjective perceptions did not align with objective findings. Limitations include retrospective analysis and heterogeneous clinical records. In conclusion, intravesical botulinum toxin is effective for UUI, with pre-treatment pad usage and sling placement history influencing outcomes and patient characteristics influencing treatment repetition.

Intravesical Botulin Toxin-A Injections for Neurogenic Bladder Dysfunction in Children: Summary Update on Last 10 Years of Research.

Neurogenic bladder dysfunction (NB) represents a challenge in pediatric urology. Intravesical botulin toxin-A (BTX-A) bladder injection is part of the armamentarium for the treatment of this condition, usually after failed first-line medical strategies and before the escalation to more invasive options such as neuromodulation or augmented cystoplasty in severe cases. However, there is still a lack of consensus about the appropriate treatment modality for the pediatric population. A review of the last 10 years' research was performed on the PubMed database by two authors. Articles doubly selected and meeting the inclusion criteria were collected and analyzed for their study type, demographics, neurological disease(s) at diagnosis, BTX-A treatment modality and duration, previous treatment, clinical and urodynamic parameters, adverse events, outcomes, and follow-ups. A total of 285 studies were initially selected, 16 of which matched the inclusion criteria. A cohort of 630 patients was treated with BTX-A at a median age of 9.7 years, 40% of which had a diagnosis of myelomeningocele. The results of the selected publications show the overall efficacy and safety of BTX-A injections in children and confirmed BTX-A as a valuable strategy for NB treatment in pediatric population. Nevertheless, up to now, the literature on this topic offers scarce uniformity among the published series and poor protocol standardization.

Developments in conservative treatment for BCG-unresponsive non-muscle invasive bladder cancer.

INTRODUCTION: To reduce the risk of disease recurrence and progression of intermediate and high-risk Non-Muscle Invasive Bladder Cancers (NMIBCs), intravesical adjuvant treatment with Bacillus Calmette-Guerin (BCG) represents the standard of care, although up to 50% of patients will eventually recur and up to 20% of them will progress to Muscle Invasive Bladder Cancer (MIBC). Radical Cystectomy (RC) is the treatment of choice in this setting; however, this represents a major and morbid surgery, thus meaning that not all NMIBCs patient could undergo or may refuse this procedure or may refuse. The search for effective bladder sparing strategies in NMIBCs BCG-unresponsive patients is a hot topic in the urologic field. AREAS COVERED: We aimed to review the most important bladder-preserving strategies for BCG unresponsive disease, from those used in the past, even though rarely used nowadays (intravesical chemotherapy with single agents), to current available therapies (e.g. intravesical instillation with Gemcitabine-Docetaxel), and to future upcoming treatments (Oportuzumab Monatox). EXPERT OPINION: At present, bladder-preserving treatments in BCG-unresponsive patients are represented by the use of intravesical instillations, systemic immunotherapies, both with good short-term and modest mid-term efficacy, and numerous clinical trials ongoing, with encouraging initial results, in which patients could be recruited.

Synergistic intravesical instillation for bladder cancer: CRISPR-Cas13a and fenbendazole combination therapy.

BACKGROUND: CRISPR-Cas13a is renowned for its precise and potent RNA editing capabilities in cancer therapy. While various material systems have demonstrated efficacy in supporting CRISPR-Cas13a to execute cellular functions in vitro efficiently and specifically, the development of CRISPR-Cas13a-based therapeutic agents for intravesical instillation in bladder cancer (BCa) remains unexplored. METHODS: In this study, we introduce a CRISPR-Cas13a nanoplatform, which effectively inhibits PDL1 expression following intravesical instillation. This system utilizes a fusion protein CAST, created through the genetic fusion of CRISPR-Cas13 and the transmembrane peptide TAT. CAST acts as a potent transmembrane RNA editor and is assembled with the transepithelial delivery carrier fluorinated chitosan (FCS). Upon intravesical administration into the bladder, the CAST-crRNAa/FCS nanoparticles (NPs) exhibit remarkable transepithelial capabilities, significantly suppressing PDL1 expression in tumor tissues.To augment immune activation within the tumor microenvironment, we integrated a fenbendazole (FBZ) intravesical system (FBZ@BSA/FCS NPs). This system is formulated through BSA encapsulation followed by FCS coating, positioning FBZ as a powerful chemo-immunological agent. RESULTS: In an orthotropic BCa model, the FBZ@BSA/FCS NPs demonstrated pronounced tumor cell apoptosis, synergistically reduced PDL1 expression, and restructured the immune microenvironment. This culminated in an enhanced synergistic intravesical instillation approach for BCa. Consequently, our study unveils a novel RNA editor nanoagent formulation and proposes a potential synergistic therapeutic strategy. This approach significantly bolsters therapeutic efficacy, holding promise for the clinical translation of CRISPR-Cas13-based cancer perfusion treatments.

Update on the Mechanism of Action of Intravesical BCG Therapy to Treat Non-Muscle-Invasive Bladder Cancer.

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.

Comparative analysis of adverse events among intravesical drugs in bladder cancer: a real-world study on FAERS database.

BACKGROUND: Intravesical therapy is a commonly utilized treatment for non-muscle invasive bladder cancer (NMIBC). This study focuses on summarizing the signals of all intravesical drugs and aims to highlight the comprehensive differences in adverse events (AEs) between these drugs. RESEARCH DESIGN AND METHODS: We conducted pharmacovigilance data analysis based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. RESULTS: We elucidated all signals compared with the overall FAERS database or other administration routes for Bacillus Calmette-Guerin (BCG), mitomycin, gemcitabine, valrubicin, and epirubicin. Notably, the distribution of reported AEs associated with intravesical therapy exhibited a noticeable inclination toward male patients. Furthermore, all five drugs demonstrated a disproportionate distribution in local AEs, particularly in renal and urinary disorders. Additionally, specific signals and findings were summarized for each individual drug. Finally, we highlighted the AEs that resulted in serious outcomes for each drug. CONCLUSION: We have compiled an overview of the AEs tied to intravesical drugs whilst considering their individual distinctions. These insightful findings serve to enrich our comprehension of the safety profiles and potential risks linked to intravesical therapy.

How Intravesical Platelet-Rich Plasma Can Help Patients with Interstitial Cystitis/Bladder Pain Syndrome: A Comprehensive Scoping Review.

INTRODUCTION AND HYPOTHESIS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition characterized by chronic inflammation that affects the bladder. The study was aimed at evaluating the effectiveness of intravesical platelet-rich plasma (PRP) injections in patients with IC/BPS. METHODS: We conducted a comprehensive search strategy to involve studies that investigate the efficacy of intravesical PRP injections or instillations over different time intervals. Various outcome measures were assessed, including pain scores, functional outcomes, urodynamic parameters, and surface expressions on the urothelium. RESULTS: Our search strategy revealed 1,125 studies. After screening, ten articles met the inclusion criteria. Intravesical PRP significantly reduced the visual analog scale (VAS) compared with baseline scores. Several clinical trials reported significant improvements in the global response rate (GRA), O'Leary-Sant Symptom (OSS) questionnaire, Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Urodynamic parameters such as maximum flow rate (Qmax) and post-voiding residual (PVR) showed significant improvements in some studies. CONCLUSION: The study concluded that intravesical PRP injections could be a promising effective treatment option for IC/BPS patients by their significant ability to reduce pain. However, improvement of urodynamic and functional outcomes is still not clear. Further large comparative trials are still warranted to assess the efficacy of PRP instillation.

Preliminary evidence for therapeutic impact of intravesical glucosamine on protamine sulfate and potassium chloride-induced bladder overactivity in rat model.

PURPOSE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB). METHODS: Ninety-two female Sprague-Dawley (SD) rats were divided into 4 groups i.e. protamine sulfate (PS), N-acetylcysteine (NAC), and glucosamine-treated PS (GPS), and normal saline control (NC) were used. We induced hyperactivity in rats via intravesical infusion of PS and potassium chloride (KCl), whereas the NC group underwent a sustained intravesical saline infusion for 1 h. N-acetylcysteine (NAC), a potential antioxidant as well as anti-inflammatory agent was employed as positive control. Cystometrography (CMG) was then conducted to determine urodynamic parameters, i.e., leak point pressure (LPP, n = 48) and inter-contractile interval, the duration between two voids (ICI, n = 32). RESULTS: LPP was significantly elevated in the GPS group (mean ± SD: 110.9 ± 6.2 mmHg) compared to the NC (81.0 ± 32.5 mmHg), PS (40.3 ± 10.9 mmHg), and NAC group (70.3 ± 19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3 ± 40.2 s) compared to the NC group (216.0 ± 41.7 s), PS group (128.8 ± 23.6 s), and NAC group (193.8 ± 28.3 s). CONCLUSION: This preliminary study implies the ameliorative impact of GPS treatment on OAB in terms of improved urodynamic parameters, including LPP and ICI.

Strategies for Safe Transurethral Injections of Botulinum Toxin into the Bladder Wall.

Introduction: Transurethral injections into the bladder wall with botulinum toxin are an established treatment for refractory overactive bladder or detrusor overactivity. With the current injection technique, an average of approx. 18% and up to 40% of botulinum toxin is injected next to the bladder wall, potentially causing reduced efficacy or non-response. The article aims to evaluate the reasons for incorrect injections and propose strategies for complete delivery of the entire botulinum toxin fluid into the bladder wall. Material and Methods: Unstructured literature search and narrative review of the literature. Results: Incorrect injection of botulinum toxin fluid next to the bladder wall is caused by pushing the injection needle too deep and through the bladder wall. Bladder wall thickness decreases with increasing bladder filling and has a thickness of less than 2 mm beyond 100 mL in healthy individuals. Ultrasound imaging of the bladder wall before botulinum toxin injection can verify bladder wall thickness in individual patients. Patient movements during the injection therapy increase the chance of incorrect placement of the needle tip. Conclusions: Based on the literature search, it is helpful and recommended to (1) perform pretreatment ultrasound imaging of the bladder to estimate bladder wall thickness and to adjust the injection depth accordingly, (2) fill the bladder as low as possible, ideally below 100 mL, (3) use short needles, ideally 2 mm, and (4) provide sufficient anesthesia and pain management to avoid patient movements during the injection therapy.

Clinical efficacy and safety analysis of type A botulinum toxin in the treatment of adolescents with refractory overactive bladder.

The objective of this study was to assess the clinical effectiveness and safety of type A botulinum toxin in the treatment of refractory overactive bladder in adolescents. We conducted a retrospective analysis of 37 adolescent patients with refractory overactive bladder who were treated at the Urology Department of Hangzhou Third People's Hospital between January 2018 and August 2023. These patients received intravesical injections of type A botulinum toxin at a concentration of 10 U/mL, with an average of 20 injection points. We recorded changes in urination diaries and urodynamic parameters both before and 1 month after treatment. After 1 month of treatment, significant improvements were observed in several parameters, when compared to the pretreatment values. These included daytime frequency of urination (11.13 ±â€…6.45), average single void volume (173.24 ±â€…36.48) mL, nighttime frequency of urination (2.43 ±â€…0.31), urgency episodes (3.12 ±â€…0.27), initial bladder capacity (149.82 ±â€…41.34) mL, and maximum bladder capacity (340.25 ±â€…57.12) mL (all P < .001). After the first treatment, 5 patients had mild hematuria, 4 patients had urinary tract infection, and 1 patient had urinary retention, which was relieved after catheterization. No serious complications or adverse reactions were observed in other patients. The follow-up period ranged from 6 to 18 months, and the duration of efficacy varied from 2 to 8 months. Eight patients who initially had treatment failure achieved symptom relief after reinjection. In adolescents with refractory overactive bladder who do not respond well to conventional drug therapy, type A botulinum toxin can be administered safely and effectively. It significantly improves lower urinary tract symptoms and enhances the quality of life for these patients.