(1) Background: Intravesical chemotherapy is the standard of care in intermediate-risk non-muscleinvasive bladder cancer (NMIBC). Different agents are used across the world based on availability, cost, and practice patterns. Epirubicin (EPI), one of these agents, has been used by many centers over many decades. However, its true differential efficacy compared to other agents and its tolerability are still poorly reported. We aimed to assess the differential efficacy and safety of intravesical EPI in NMIBC patients. (2) Methods: This study aimed to systematically review the efficacy and safety profile of Epirubicin (EPI) in the management of non-muscle invasive bladder cancer (NMIBC) compared to other adjuvant therapies. A systematic search of the PUBMED, Web of Science, clinicaltrials.gov, and Google Scholar databases was conducted on 31 December 2023, using relevant terms related to EPI, bladder cancer, and NMIBC. The inclusion criteria targeted studies that evaluated patients treated with EPI following the transurethral resection of bladder tumors (TURBT) for NMIBC and compared oncological outcomes such as recurrence and progression with other adjuvant therapies, including Mitomycin C (MMC), Gemcitabine (GEM), and Bacillus Calmette-Guérin (BCG). Additionally, studies investigating the safety profile of EPI administered intravesically at room temperature and under hyperthermia, as well as oncological outcomes associated with hyperthermic intravesical EPI administration, were included. (3) Results: Eleven studies reported adverse events after adjuvant intravesical instillations with EPI; the most frequently reported adverse events included cystitis (34%), dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%). Nine studies compared EPI to BCG in terms of recurrence and progression rates; BCG instillations showed a lower recurrence rate compared to EPI, with limited or non-significant differences in progression rates. Two studies found no significant differences between EPI and MMC regarding progression and recurrence rates. One study showed statistically significant lower recurrence and progression rates with GEM in high-risk NMIBC patients. Another study found no significant differences between EPI and GEM regarding recurrence and progression. (4) Conclusions: EPI exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC. Novel delivery mechanisms such as hyperthermia are interesting newcomers.

BACKGROUND: With the exception of the FDA-approved valrubicin and pembrolizumab, there are no standard second-line treaments for BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC).
OBJECTIVE: To provide a systematic review of the novel intravesically administered therapeutic agents for the salvage treatment of BCG-unresponsive NMIBC.
METHODS: Online search of the PubMed, EMBASE and Web of Science databases was performed. The endpoints of this review were to evaluate the efficacy of the agents in terms of complete response rates (CR) and durability of CR, overall survival, recurrence-free survival and cancer-specific survival and to report on their toxicity profile. A search on Clinicaltrials.gov was performed to identify ongoing clinical trials.
RESULTS: 14 studies were included in this review. The critical clinical need for the development of an effective, safe and durable intravesical drug for the salvage treatment of high-risk NMIBC seems to be met mainly by intravesical gene therapy; in fact, data support the FDA-approved nadofaragene firadenovec as a potentially important therapeutic advancement in this context. Promising results are also being obtained by the combination of N-803/BCG and by innovative drug delivery systems.
CONCLUSIONS: Considering the plethora of novel intravesical treatments that have completed phase II evaluation, one can reasonably expect that clinicians will soon have at their disposal new agents and treatment options for BCG-unresponsive NMIBC. In the near future, it will be up to the urologist to identify, for each specific patient, the right agent to use, based on safety, results and cost-effectiveness.

In non-muscle invasive bladder cancer, Bacillus Calmette-Guérin (BCG) responders benefit from strong Th1-type inflammatory and T cell responses mediating tumor rejection. However, the corresponding lack of anti-inflammatory Th2-type immunity impairs tissue repair in the bladder wall and facilitates the development of cystitis, causing urinary pain, urgency, incontinence, and frequency. Mechanistically, the leakage of the glycosaminoglycan (GAG) layer enables an influx of potassium ions, bacteria, and urine solutes towards the underlying bladder tissue, promoting chronic inflammation. Treatments directed towards re-establishing this mucopolysaccharide-based protective barrier are urgently needed. We discuss the pathomechanisms, as well as the therapeutic rationale of how chondroitin and hyaluronic acid instillations can reduce or prevent BCG-induced irritative bladder symptoms. Moreover, we present a case series of five patients with refractory BCG-induced cystitis successfully treated with combined chondroitin and hyaluronic acid instillations.

Bladder pain syndrome (BPS) is a complex syndrome, without a clearly defined etiology that encompasses different entities, such as interstitial cystitis. This leads to difficulties in establishing a precise definition, obtaining accurate prevalence data, and defining diagnostic criteria and standardized assessment methods. Moreover, there is no consensus regarding the treatment of BPS. Intravesical instillations with hyaluronic acid (HA) are an option, although no specific recommendations have been made yet.
To synthesize the scientific evidence on the therapeutic options available for BPS and to establish a work plan and recommendations for the use of intravesical instillations with HA. The Spanish Association of Urology, through the Functional, Female, and Urodynamic Urology Group, created a commission of experts. This commission was in charge of reviewing literature (evidence), agreeing on the work plan, and proposing recommendations.
There is great variability in literature on the treatment of BPS, without a standard regimen of intravesical instillation with HA (frequency and duration of initial and maintenance treatment).
Intravesical HA instillations (usual dose of 40 mg) are effective and safe. They can be combined with other options, with efficacy still to be determined in some cases. Treatment is divided into several initial weekly sessions, followed by maintenance treatment, usually monthly (unestablished duration of cycles). Recommendations on the management of BPS were agreed, with diagnostic criteria and guidelines for treatment with intravesical HA (initiation, reassessment, and follow-up).

BACKGROUND: Currently, no biomarkers of response to mitomycin C have been identified in non-muscle-invasive bladder cancer patients. Predictive biomarkers could improve the treatment outcome and eliminate adverse events from unnecessary treatment.
OBJECTIVE: To identify and validate predictive biomarkers of chemoresection with mitomycin C.
METHODS: The intervention group of a randomised controlled trial was identified for analyses. The study was conducted between January 2018 and June 2019 in two major urological departments in Denmark. Patients had a history of Ta low-grade/high-grade disease and were included upon recurrence. The intervention group (58 patients) received chemoresection with mitomycin C. Tumour and reference germline DNA from prior tumours were analysed by whole exome sequencing. Predictive biomarkers were validated in the context of Ta low-grade tumours from the UROMOL study.
METHODS: Response to chemotherapy (intervention group from the randomised controlled trial) and recurrence-free survival (UROMOL cohort) were measured. Groups were compared using Fisher\'s exact test and Wilcoxon rank sum test.
CONCLUSIONS: Chemoresponse was associated with the mutation status of SPTAN1, APC, and FGFR3, and the level of APOBEC signature contribution (p = 0.035, p = 0.034, p = 0.055, and p = 0.035, respectively). The main limitations include no biopsy for biomarker discovery immediately prior to chemoresection and the unmatched validation cohort.
CONCLUSIONS: Mutation status of APC, SPTAN1, and FGFR3 and the level of mutational contribution from APOBEC-related signatures were identified as potential predictive biomarkers for chemoresection with mitomycin C in non-muscle-invasive bladder cancer patients. A prospective validation study is however needed.
RESULTS: We investigated DNA from noninvasive bladder tumours in order to predict treatment response to chemotherapy. Four biomarkers showed promising results, which should be tested in future studies.

Penile granulomas has been rarely reported in the setting of BCG instillations. We present a 70 year-old male with multiple penile granulomas during BCG instillations due a high-grade urothelial bladder cancer. Histopathological study revealed granulomatous structures with central necrosis as seen after BCG therapy. Local treatment with cryotherapy has been shown to be effective. This case emphasizes the importance to suspect this adverse effect in patients under BCG treatment.

Little has been reported to date on the instillation of antimicrobials directly into the bladder in children. Children with complex urinary tract anomalies struggle frequently with recurrent urinary tract infections (UTI), with frequent emergence of antibiotic resistance. Gentamicin bladder instillation to treat and prevent UTI was described in children since 2006.
We adopted gentamicin bladder instillation in 2016 and evaluate herein our intermediate-term experience with it.
This study is a retrospective review of a prospectively initiated database and a clinical audit of our practice. The gentamicin bladder instillation was employed in 24 cases. A treatment regime was initiated for symptomatic documented UTI when resistance patterns precluded an oral alternative (14 cases), avoiding hospitalisation for parenteral antibiotics. A prophylaxis regime (19 cases-including 9 of the 14 who received an initial treatment regime) followed at least one breakthrough UTI while receiving oral prophylactic antibiotics. Two instillation volumes (8 mg gentamicin in 20 mL 0.9% NaCl or 20 mg gentamicin in 50 mL 0.9% NaCl) were used to suit different bladder capacities. The irrigation is given twice a day for 7 days in the treatment regime or once a day, every other day, in the prophylactic regime. Gentamicin serum levels (all cases) and audiology/audiometry testing (17/24 cases) were checked to assess the safety of this method.
The median age when either the treatment course or prophylaxis regime was started was 3.8 years. The treatment regime was 86% successful (12/14) to suppress an acute UTI. The mean duration of prophylaxis was 252 days (median: 256 days). The percentage of patients on the prophylactic regime who had no breakthrough UTI was 58%. No serum gentamicin was detectable secondary to the intravesical instillation. No attributable cases of sensorineural hearing loss were detected. Gentamicin resistance emerged in one case (4.16%).
Intravesical administration was feasible via various routes for a spectrum of complex lower urinary tract abnormalities (see Summary Figure). Concerns regarding systemic absorption, nephrotoxicity or ototoxicity were investigated and safety ensured. Limitations include being a small series of non-identical pathologies, albeit categorically similar and being a single-arm study, however, statistical significance was proven descriptively and analytically.
In selected cases and with the appropriate specialist support and logistics, intravesical gentamicin instillation is well-tolerated and safe to treat and/or prevent urinary tract infections in pateints with complex bladder conditions and lower urinary tract pathologies.

According to class M2.1 of the World Anti-Doping Agency (WADA) Prohibited List, the manipulation of doping control urine samples to alter their integrity and validity is prohibited both in- and out-of-competition. However, some paraplegic athletes with an overactive bladder need to be regularly treated with anti-cholinergic and anti-spasmodic drugs such as oxybutynin, which are often administered intravesically to reduce the substantial side effects observed after oral application. So far, it remains unclear whether such bladder instillations have a negative impact on analytical procedures and thus represent an anti-doping rule violation. Within this pilot study, urine samples were collected from five paraplegic athletes before and after an intravesical oxybutynin hydrochloride instillation. The samples were routinely tested for the presence of performance-enhancing drugs and afterwards fortified with 25 model compounds representing different classes of doping agents (anabolic agents, cannabinoids, diuretics, glucocorticoids, hormone and metabolic modulators, and stimulants) at low and medium concentrations. Additionally, the pH value and specific gravity were measured and the presence of oxybutynin was qualitatively determined by gas chromatography-mass spectrometry (GC-MS). In initial testing procedures, all samples were tested negative. Oxybutynin was present in most of the samples but found to have no significant effect on the detectability of the 25 model compounds subsequently added to each urine specimen. Therefore, it can be concluded that intravesical instillations with oxybutynin hydrochloride do not alter the integrity and validity of doping control urine samples.

OBJECTIVE: Evaluation of the intravesical instillation of doxorubicin for its effect on disease recurrence for patients with non-invasive bladder tumour.
METHODS: The study was performed at Al Assad University Hospital in Lattakia, Syria and included patients with non-invasive bladder tumours who were managed with transurethral resection and induction and maintenance therapy with intravesical doxorubicin. They were followed up by cystoscopy every 3 months for 2 years and every 6 months thereafter with special emphasis on recurrence rates.
RESULTS: The study included 85 patients with non-invasive bladder tumours: 23 with non-invasive papillary carcinoma (Stage Ta), 62 with tumour invading subepithelial connective tissue (Stage T1). Twelve patients had well differentiated tumours (Grade 1), 48 had moderately differentiated (Grade 2), 25 had poorly differentiated (Grade 3) tumours. The total recurrence rate was 23%. The rates of recurrence were 56% in Grade 3 and 0% in Grade 1. The recurrence rate was 41% in patients with large tumours versus 17% in those with small tumours; 44% in those with multiple tumours compared to 18% in those with solitary tumours; 30% of Stage Ta tumours recurred and 21% of Stage T1 tumours.
CONCLUSIONS: In short term follow-up, our rate of recurrence was 23%. Adjuvant intravesical doxorubicin was shown to reduce the recurrence of superficial bladder cancer. Tumour grade, size and number were shown to be prognostic factors for recurrence.