BACKGROUND: Intravesical administration of interleukin 12 (IL-12) co-formulated with the biopolymer, chitosan (CS/IL-12), has demonstrated remarkable antitumor activity against preclinical models of bladder cancer. However, given historical concerns regarding severe toxicities associated with systemic IL-12 administration in clinical trials, it is important to evaluate the safety of intravesical CS/IL-12 prior to clinical translation.
OBJECTIVE: To evaluate the pharmacokinetics as well as the local and systemic toxicities of intravesical CS/IL-12 immunotherapy in laboratory mice.
METHODS: Local inflammatory responses in mouse bladders treated with intravesical IL-12 or CS/IL-12 were assessed via histopathology. Serum cytokine levels following intravesical and subcutaneous (s.c.) administrations of IL-12 or CS/IL-12 in laboratory mice were compared. Systemic toxicities were evaluated via body weight and liver enzyme levels.
RESULTS: Intravesical IL-12 and CS/IL-12 treatments did not induce significant local or systemic toxicity. IL-12 dissemination and exposure from intravesical administration was significantly lower compared to s.c. injections. Weekly intravesical CS/IL-12 treatments were well-tolerated and did not result in blunted immune responses.
CONCLUSIONS: Intravesical CS/IL-12 is safe and well-tolerated in mice. In particular, the lack of cystitis and acute inflammation justifies continued investigation of intravesical CS/IL-12 immunotherapy in larger animals and patients with bladder cancer.

BACKGROUND: Devices that increase the penetrance of intravesical chemotherapeutics are emerging as alternatives to classical Bacillus Calmette Guérin (BCG) treatment.
OBJECTIVE: To compare the efficacy of mitomycin C applied with the electromotive drug delivery device (MMC-EMDA) versus BCG in patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) without carcinoma in situ (CIS).
METHODS: Prospective non-randomized study in which 47 patients received MMC-EMDA (40 mg of MMC diluted in 50 mg of distilled water at 20 mA for 30 min. Regimen of 6 weekly and then 6 monthly instillations) and 48 patients received BCG (50 mg of OncoCITE® diluted in 50 ml of normal saline for 60 min. Regimen of 6 weekly instillations and then 3 weekly instillations at months 3, 6 and 12). The primary endpoint was the recurrence-free rate (RFR) at 24 months. Secondary endpoints were time to recurrence and progression-free rate (PFR) at 24 months follow-up.
RESULTS: Baseline patient assessment and mean follow-up time were similar in both groups (MMC-EMDA group: 26.4 months; BCG group: 28.4 months (p = 0.44)). The RFR at 24 months was 80.9% for the MMC-EMDA group and 77.1% for the BCG group (p = 0.969). The mean time to recurrence was 12.5 months in the MMC-EMDA group and 14 months in the BCG group (p = 0.681). At 24 months, PFR was 97.9% in the MMC-EMDA group and 93.8% in the BCG group (p = 0.419).
CONCLUSIONS: No differences were found between MMC-EMDA and BCG treatments in patients with high-risk and intermediate-risk NMIBC without CIS.

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.

BACKGROUND: Intravesical treatment for non-muscle invasive bladder cancer (NMIBC) aims to reduce recurrences and stop progression. Hyperthermia-enhanced chemotherapy with devices like COMBAT BRS, Unithermia, and BR-TRG-I is a promising alternative to conventional Bacillus de Calmette Guerin (BCG) therapy.
OBJECTIVE: To systematically review the efficacy of hyperthermia generated by conduction devices in the treatment of NMIBC.
METHODS: The review followed the preferred reporting items for systematic reviews and meta-analyses guidelines. A search was performed in the PubMed, Cochrane Library, Scopus, and ClinicalTrials.gov databases. Two reviewers independently assessed the eligibility of candidate studies and abstracted data from studies that met the inclusion criteria. The primary endpoint was assessment of recurrence. Secondary objectives included evaluation of treatment progression and safety.
RESULTS: Thirty studies meeting inclusion criteria underwent data extraction. In intermediate-risk NMIBC patients, COMBAT versus mitomycin C (MMC) in normothermia revealed no superiority in reducing recurrence or progression. High-risk NMIBC patients using COMBAT achieved similar or superior outcomes to BCG. BR-TRG-I demonstrated superior results over normothermia in intermediate- and high-risk NMIBC patients. Unithermia proved less effective than BCG in high-risk NMIBC. Progression outcomes were promising with COMBAT and BR-TRG-I, but comprehensive analysis was limited due to inconsistent assessment across studies. Adverse events were primarily mild-moderate, with some device-specific differences.
CONCLUSIONS: Studies on conduction hyperthermia present great variability, which do not allow us to determine the superiority of 1 device over another in terms of recurrence, progression, and/or adverse effects. Further research with consistent administration protocols is crucial for definitive conclusions.

BACKGROUND: Despite the publication of several meta-analyses regarding the efficacy of certain therapies in helping individuals with interstitial cystitis (IC) / bladder pain syndrome (BPS), these have not provided a comprehensive review of therapeutic strategies. The study aimed to determine the efficacy of various therapies for IC/BPS and identify potential moderating factors using randomized controlled trials (RCTs).
METHODS: We queried the PubMed, Cochrane, and Embase databases to identify prospective RCTs using inclusion criteria: 1) patients diagnosed with IC, 2) interventions included relevant treatments, 3) comparisons were a specified control or placebo, 4) outcomes were mean differences for individual symptoms and structured questionnaires. The pairwise meta-analysis and network meta-analysis (NMA) were performed to compare the treatments used in IC/BPS. Hedges\' g standardized mean differences (SMDs) were used for improvement in all outcomes using random-effects models. Efficacy outcomes included individual symptoms such as pain, frequency, urgency, and nocturia, as well as structured questionnaires measuring IC/BPS symptoms.
RESULTS: A comprehensive literature search was conducted which identified 70 RCTs with 3,651 patients. The analysis revealed that certain treatments, such as instillation and intravesical injection, showed statistically significant improvements in pain and urgency compared to control or placebo groups in traditional pairwise meta-analysis. However, no specific treatment demonstrated significant improvement in all outcomes measured in the NMA. The results of moderator analyses to explore influential variables indicated that increasing age was associated with increased nocturia, while longer follow-up periods were associated with decreased frequency.
CONCLUSIONS: This systematic review and meta-analysis provide insights into the efficacy of various treatments for IC. Current research suggests that a combination of therapies may have a positive clinical outcome for patients with IC, despite the fact that treatment for this condition is not straightforward.
BACKGROUND: PROSPERO CRD42022384024.

OBJECTIVE: To evaluate the impact of adjuvant therapy on oncological outcomes in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC), as due to the poorly-defined and overlapping diagnostic criteria optimal decision-making remains challenging in these patients.
METHODS: In this multicentre study, patients treated with transurethral resection of bladder tumour for Ta disease were retrospectively analysed. All patients with low- or high-risk NMIBC were excluded from the analysis. Associations between adjuvant therapy administration with recurrence-free survival (RFS) and progression-free survival (PFS) rates were assessed in Cox regression models.
RESULTS: A total of 2206 patients with intermediate-risk NMIBC were included in the analysis. Among them, 1427 patients underwent adjuvant therapy, such as bacille Calmette-Guérin (n = 168), or chemotherapeutic agents, such as mitomycin C or epirubicin (n = 1259), in different regimens up to 1 year. The median (interquartile range) follow-up was 73.3 (38.4-106.9) months. The RFS at 1 and 5 years in patients treated with adjuvant therapy and those without were 72.6% vs 69.5% and 50.8% vs 41.3%, respectively. Adjuvant therapy was associated with better RFS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.89, P < 0.001), but not with PFS (P = 0.09). In the subgroup of patients aged ≤70 years with primary, single Ta Grade 2 <3 cm tumours (n = 328), adjuvant therapy was not associated with RFS (HR 0.71, 95% CI 0.50-1.02, P = 0.06). While in the subgroup of patients with at least one risk factor including patient age >70 years, tumour multiplicity, recurrent tumour and tumour size ≥3 cm (n = 1878), adjuvant intravesical therapy was associated with improved RFS (HR 0.78, 95% CI 0.68-0.88, P < 0.001).
CONCLUSIONS: In our study, patients with intermediate-risk NMIBC benefit from adjuvant intravesical therapy in terms of RFS. However, in patients without risk factors, adjuvant intravesical therapy did not result in a clear reduction in the recurrence rate.

Urothelial carcinoma of the bladder remains a challenging disease to treat. Intravesical instillation of BCG has demonstrated tremendous efficacy in preventing recurrence. BCG related necrotizing granulomatous epididymo-orchitis is rare and has not been previously linked to brachytherapy for adenocarcinoma of the prostate. We hypothesize that prior brachytherapy has a deleterious effect on the verumontanum that can result in retrograde transmission of BCG particles leading to granulomatous epididymo-orchitis. This is the first case report of necrotizing granulomatous epididymo-orchitis related to BCG in a patient status post brachytherapy for adenocarcinoma of the prostate.

Bladder Pain Syndrome (BPS) is a puzzling and complicated disorder. 12 such patients, with a mean age 48.3 years, were treated with weekly intravesical instillation of admixture of alkalinized lidocaine, bupivacaine, heparin and steroids for six weeks. Evaluating the benefits of this therapy, patients experienced 82.2% & 90.9% relief at 3rd & 6th week of instillation. After completion of six cycles of therapy, patients experienced 68.7% & 65.3% relief at 3rd & 6th month follow up, concluding the early and long term relief of BPS.

OBJECTIVE: Non-muscle-invasive bladder cancer (NMIBC) can recur, partly due to seeding of free tumour cells after transurethral resection of bladder tumour (TURBT). Intravesical chemotherapy post-TURBT can reduce the risk but is used infrequently and inconsistently due to cost, complexity and side effects. The objective of this study was to prospectively assess continuous bladder irrigation using water, which may be a safer and easier alternative with comparable effectiveness.
METHODS: WATIP was a prospective, single-arm phase 2 study of water irrigation during and for at least 3 h after TURBT for bladder tumours noted on imaging or flexible cystoscopy. Participants were assessed clinically for adverse effects and with blood tests within 24 h for sodium, haemoglobin and lactate dehydrogenase. The primary endpoints were safety (defined as < 10% adverse events of CTCAE grade ≥ 3), and feasibility (defined as the intervention being delivered as planned in > 90% of cases) and secondary endpoint was recurrence-free rates (RFR).
RESULTS: Water irrigation was delivered as planned in 29 (97%) of 30 participants (median age 67 years, 25 (83%) males). The only adverse event (grade 2) was clot retention in one (3.3%) participant. Water irrigation significantly reduced urothelial cell counts in catheter effluent over time, unlike saline irrigation which did not. RFR was 56.2% (9/16 participants with low-risk NMIBC) at first cystoscopy (median interval 108 days) and 62.5% (5/8 evaluable low-risk NMIBC) at 12 months.
CONCLUSIONS: Water irrigation during and after TURBT is feasible and safe. Prospective assessment of its effect on NMIBC recurrence compared to post-TURBT intravesical chemotherapy is needed before recommending its use in routine clinical practice. Trial registration ANZCTR registration ID ACTRN12619000517178 on 1 April 2019.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: A family history of BC could have an important impact on the response to BCG.