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.
OBJECTIVE: To investigate if there are dose-dependent effects of alpha1-oleate.
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.
CONCLUSIONS: These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.

OBJECTIVE: 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.
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.

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).

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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.

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.

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.

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.

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.

UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.