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).

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.

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.

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 ± 6.45), average single void volume (173.24 ± 36.48) mL, nighttime frequency of urination (2.43 ± 0.31), urgency episodes (3.12 ± 0.27), initial bladder capacity (149.82 ± 41.34) mL, and maximum bladder capacity (340.25 ± 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.

The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient\'s awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly affects MoCA testing when administered by the intravesical route. MoCA scores were lower with increasing age and higher in more formally educated individuals. Patients receiving BCG tended to maintain their MoCA scores, whereas almost half the control cases tended to show reduced scores. This benefit is supported by reduced pre-amyloid biomarkers in BCG-injected healthy volunteers and a favorable effect on neuronal dendritic development in animal models. Our results suggest that BCG has a beneficial impact on the cognitive status of older individuals.

BACKGROUND: Recent intravesical administration of adenoviral vectors, either as a single injection or in combination with immune checkpoint inhibitors, exemplified by cretostimogene grenadenorepvec and nadofaragene firadenovec, has demonstrated remarkable efficacy in clinical trials for non-muscle invasive bladder cancer. Despite their ability to induce an enhanced immune reaction within the lesion, the intracellular survival signaling of cancer cells has not been thoroughly addressed.
METHODS: An analysis of the prognostic data revealed a high probability of therapeutic efficacy with simultaneous inhibition of mTOR and STAT3. Considering the challenges of limited pharmaco-accessibility to the bladder due to its pathophysiological structure and the partially undruggable nature of target molecules, we designed a dual siRNA system targeting both mRNAs. Subsequently, this dual siRNA system was encoded into the adenovirus 5/3 (Ad 5/3) to enhance in vivo delivery efficiency.
RESULTS: Gene-targeting efficacy was assessed using cells isolated from xenografted tumors using a single-cell analysis system. Our strategy demonstrated a balanced downregulation of mTOR and STAT3 at the single-cell resolution, both in vitro and in vivo. This approach reduced tumor growth in bladder cancer xenograft and orthotopic animal experiments. In addition, increased infiltration of CD8+ T cells was observed in a humanized mouse model. We provided helpful and safe tissue distribution data for intravesical therapy of siRNAs coding adenoviruses.
CONCLUSIONS: The bi-specific siRNA strategy, encapsulated in an adenovirus, could be a promising tool to augment cancer treatment efficacy and overcome conventional therapy limitations associated with \"undruggability.\" Hence, we propose that dual targeting of mTOR and STAT3 is an advantageous strategy for intravesical therapy using adenoviruses.

Deep brain stimulation (DBS) is an advanced treatment in Parkinson\'s disease. We describe a 71-year-old patient in whom the DBS got infected with Mycobacterium bovis shortly after intravesical BCG instillations as an adjuvant treatment of bladder cancer. The DBS internal pulse generator and extension wires had to be replaced, and the patient was treated successfully with rifampicin, isoniazid, and ethambutol during three months. This case suggests that physicians need to be aware of the risk of this kind of infection and add a specific Mycobacterial test to the regular cultures.