A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. MATERIALS AND METHODS: This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. RESULTS: Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. CONCLUSIONS: In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

Long-term outcomes of bladder-sparing therapy vs radical cystectomy in BCG-unresponsive non-muscle-invasive bladder cancer.

OBJECTIVE: To quantify the oncological risks of bladder-sparing therapy (BST) in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) compared to upfront radical cystectomy (RC). PATIENTS AND METHODS: Pre-specified data elements were collected from retrospective cohorts of patients with BCG-unresponsive NMIBC from 10 international sites. After Institutional Review Board approval, patients were included if they had BCG-unresponsive NMIBC meeting United States Food and Drug Administration criteria. Oncological outcomes were collected following upfront RC or BST. BST regimens included re-resection or surveillance only, repeat BCG, intravesical chemotherapy, systemic immunotherapy, and clinical trials. RESULTS: Among 578 patients, 28% underwent upfront RC and 72% received BST. The median (interquartile range) follow-up was 50 (20-69) months. There were no statistically significant differences in metastasis-free survival, cancer-specific survival, or overall survival between treatment groups. In the BST group, high-grade recurrence rates were 37% and 52% at 12 and 24 months and progression to MIBC was observed in 7% and 13% at 12 and 24 months, respectively. RC was performed in 31.7% in the BST group and nodal disease was found in 13% compared with 4% in upfront RC (P = 0.030). CONCLUSION: In a selected cohort of patients, initial BST offers comparable survival outcomes to upfront RC in the intermediate term. Rates of recurrence and progression increase over time especially in patients treated with additional lines of BST.

Amniotic bladder therapy: six-month follow up treating interstitial cystitis/bladder pain syndrome.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by chronic pelvic pain and usually accompanies lower urinary tract symptoms. We have previously reported that amniotic bladder therapy (ABT) provides symptomatic improvement in refractory IC/BPS patients for up to 3 months. Herein, we evaluated the durability of ABT up to 6 months. MATERIALS AND METHODS: Consecutive IC/BPS patients received intra-detrusor injections of 100 mg micronized amniotic membrane. Clinical evaluation and patient-reported outcome measurements including Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) and Overactive Bladder Assessment Tool (OAB) were assessed. RESULTS: Twenty-five consecutive recalcitrant IC/BPS patients were included in the study with an average age of 47.4 ± 14.4 years (29-67 years). After ABT, the IC/BPS symptoms improved gradually up to 3 months in all patients with an average improvement in ICSI, ICPI, BPIC-SS and OAB score of 72.8%, 71.9%, and 66.6%, (p < 0.001) respectively, at 3 months. At 4 months after ABT, 7 patients experienced a rebound in symptoms and requested another injection which resulted in a significant improvement in IC/BPS symptoms after 2, 4, and 8 weeks (p < 0.01). For the 18 patients who received only one injection, the IC/BPS symptoms were still significantly lower at 5 and 6 months compared to baseline (p < 0.01), suggesting a possible durable effect based on the ICSI, ICPI, BPIC-SS, and OAB questionnaire scores. CONCLUSIONS: ABT provided an improvement in pain and lower urinary tract symptoms up to 6 months post-treatment in some refractory IC/BPS patients.

Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model.

OBJECTIVES: To test if intravesical instillation of both an anti-programmed cell death protein 1 (PD-1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non-muscle-invasive bladder cancer that is refractory to intravesical bacillus Calmette-Guérin can be treated by systemic anti-PD-1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once-weekly instillations of intravesical anti-PD-1 in a murine model. MATERIALS AND METHODS: Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or intravesical reovirus + anti-PD-1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long-term immunity and tumour-immune profile. RESULTS: With a median follow-up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9-32.6; P < 0.001), anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001), and reovirus + anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001). Monotherapy with anti-PD-1 or reovirus demonstrated no significant differences in survival (P = 0.067). Mass cytometry showed that reovirus + anti-PD-1 treatment enriched monocytes and decreased myeloid-derived suppressor cells, generating an immuno-responsive tumour microenvironment. Depletion of CD8+ T cells eliminated the survival advantage provided by the intravesical treatment. CONCLUSIONS: Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti-PD-1 antibody, or the combination confers superior survival compared to controls. Tumour-immune microenvironment differences indicated myeloid-derived suppressor cells and CD8+ T cells mediate the treatment response.

A preliminary report assessing the feasibility and effectiveness of amniotic bladder therapy in patients with chronic radiation cystitis.

INTRODUCTION: Chronic radiation cystitis (CRC) can develop between 6 months and 20 years after radiation therapy that presents with symptoms of urinary frequency, urgency, bladder pain, and nocturia. Amniotic membrane (AM) is known to contain pro-regenerative properties and could thereby be a potential therapeutic modality for radiation-induced tissue injury of the bladder. MATERIALS AND METHODS: CRC patients recalcitrant to previous treatments received amniotic bladder therapy (ABT) comprised of intra-detrusor injections of 100 mg micronized AM (Clarix Flo) diluted in 10 mL 0.9% preservative-free sodium chloride. Clinical evaluation and questionnaires (Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS), Overactive Bladder (OAB) Assessment Tool, and SF-12 Health Survey) were repeated at preop and 2, 4, 8 and 12 weeks post-injection. RESULTS: Five consecutive female patients aged 64.4 ± 20.1 years with a median CRC disease duration of 10 years were included. After ABT, BPIC-SS scores improved from baseline to 12 weeks (36.6 ± 1.1 to 12.6 ± 3.1) and this was associated with an improvement in ICSI, ICPI, OAB, and SF-12 scores. One patient had an acute urinary tract infection at 2 weeks but was successfully treated with oral antibiotics. No other adverse events related to micronized AM injections were observed. Uroflow assessments showed increases in voided volume for all five patients. CONCLUSIONS: This data provides additional evidence for the potential benefit of ABT in patients with chronic inflammatory conditions of bladder such as CRC.

Intravesical mitomycin C (MMC) and MMC + cytosine arabinoside for non-muscle-invasive bladder cancer: a randomised clinical trial.

OBJECTIVES: To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara-C) therapy. PATIENTS AND METHODS: A total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara-C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups. RESULTS: A total of 81 and 87 patients were randomised into the MMC and MMC + Ara-C groups, respectively. Overall, the RFS in the MMC + Ara-C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate-risk NMIBC, but not in those with high-risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara-C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P < 0.001), and the frequency of a urinary pH of >7.0 in the MMC and MMC + Ara-C groups was 6.3% and 26.7%, respectively (P < 0.001). Multivariate analysis models including clinicopathological features and second transurethral resection demonstrated that increased urinary pH was associated with better outcomes (hazard ratio 0.18, 95% confidential interval 0.18-0.038; P < 0.001). In all, there were 14 and 10 adverse events in the MMC and MMC + Ara-C groups, respectively, without a significant difference (P = 0.113). CONCLUSIONS: Our randomised clinical trial suggested that intravesical therapy with MMC and Ara-C is useful and safe for patients with intermediate-risk NMIBC. Increase in urinary pH with Ara-C is speculated as a mechanism for increased anti-cancer effects.

Non-maintenance intravesical Bacillus Calmette-Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study.

BACKGROUND: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). METHODS: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. RESULTS: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts. CONCLUSIONS: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

Time interval from transurethral resection of bladder tumour to bacille Calmette-Guérin induction does not impact therapeutic response.

OBJECTIVES: To investigate bacille Calmette-Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan-Meier and log-rank tests analysed differences in recurrence-free (RFS) and progression-free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. RESULTS: A total of 518 patients received adequate BCG at a median (range) of 26 (6-188) days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7-33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P = 0.966), RFS (P = 0.632) or PFS (P = 0.789). On both uni- and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99-1.00, P = 0.449; and for PFS was 0.99, 95% CI 0.98-1.00, P = 0.074). CONCLUSION: The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response.

Approaches to Non-Muscle-Invasive Bladder Cancer.

PURPOSE OF REVIEW: Non-muscle-invasive bladder cancer (NMIBC) is a heterogenous malignancy with high recurrence and progression rates, which necessitate uniform recommendations for diagnosis and management. Herein, we review the literature, with an emphasis on guidelines and contemporary diagnostic techniques and interventions. RECENT FINDINGS: Guidelines around the world have adopted a schema which risk-stratify cases at diagnosis, to offer evidence-based treatment and surveillance recommendations. Enhanced endoscopic technologies can improve detection of NMIBC and reduce recurrence. The present Bacillus Calmette-Guerin (BCG) shortage in the USA has led to new strategies to prioritize the most high-risk cases. The entity of BCG-unresponsive high-risk NMIBC remains a challenge to manage, with multiple novel treatments under investigation; fortunately, new therapies have been approved, such as immune checkpoint inhibitors, and others are showing tremendous promise. The standardization of NMIBC management, with evolving detection techniques and therapeutics, offers great potential to improve patient outcomes and survivorship.

Guideline adherence for radical cystectomy significantly affects survival outcomes in non-muscle-invasive bladder cancer patients.

BACKGROUND: The relationship between guideline adherence for radical cystectomy of non-muscle-invasive bladder cancer and patient prognoses currently remains unclear. We investigated whether guideline adherence at the time of non-muscle-invasive bladder cancer affects the oncological outcomes of bladder cancer patients who underwent radical cystectomy. METHODS: Among 267 cTa-4N0-2M0 bladder cancer patients, 70 who underwent radical cystectomy under the non-muscle-invasive bladder cancer or muscle-invasive bladder cancer status that progressed from non-muscle-invasive bladder cancer were identified. Patients who followed the guidelines from initial transurethral resection of bladder tumors to radical cystectomy were defined as the guideline adherent group (n = 52), while those who did not were the guideline non-adherent group (n = 18). RESULTS: In the guideline non-adherent group, 8 (44.4%) out of 18 were diagnosed with highest risk non-muscle-invasive bladder cancer for Bacillus Calmette Guérin-naïve patients and 7 (38.9%) had a Bacillus Calmette Guérin unresponsive tumor status. Five-year recurrence-free survival and cancer-specific survival rates for the guideline non-adherent group vs guideline adherent group were 38.9% vs 69.8% (P = 0.018) and 52.7% vs 80.1% (P = 0.006), respectively. A multivariate analysis identified guideline non-adherence as one of independent indicators for disease recurrence (hazard ratio = 2.81, P = 0.008) and cancer-specific death (hazard ratio = 4.04, P = 0.003). In a subgroup analysis of 49 patients with cT1 or less non-muscle-invasive bladder cancer at the time of radical cystectomy, guideline non-adherence remained an independent prognostic factor for cancer-specific survival (hazard ratio = 3.46, P = 0.027). CONCLUSIONS: Guideline adherence during the time course of the non-muscle-invasive bladder cancer stage may result in a favorable prognosis of patients who receive radical cystectomy. Even under non-muscle-invasive bladder cancer status, radical cystectomy needs to be performed with adequate timing under guideline recommendations.

[Expert consensus on intravesical therapy for non-muscle invasive bladder cancer (2021 edition)].

Bladder cancer is one of the common malignant tumors in China, with 75% of bladder cancer being non-muscle invasion with a high recurrence rate after surgery. Intravesical therapy is an useful methods to either directly kill tumor cells by infusing cytotoxic drugs into the bladder or directly or indirectly induce local immune responses of the body through infusing immune agents, such as bacillus calmette guerin, and thus reduce the risk of tumor recurrence and progression. In 2019, the Urological Chinese Oncology Group issued the "Expert consensus on intravesical therapy on non-muscle invasive bladder cancer" . Recently, great progress in the clinical diagnosis and treatment of non-muscle invasive bladder cancer has been achieved domestically and abroad, including the risk assessment of non-muscle invasive bladder cancer, the therapeutic choice of intravesical drugs, the adverse reactions and treatment experience of intravesical therapy, and clinical research on new types of intravesical drugs. This consensus is made according to domestic and overseas evidence-based medicine in combination with current clinical practice and experience of intravesical therapy for non-muscle invasive bladder cancer in China. It is an update of the 2019 expert consensus, with the wish to provide a guidance for domestic clinical standardized intravesical therapy for non-muscle invasive bladder cancer.

Factors affecting guideline adherence in the initial treatment of non-muscle invasive bladder cancer: Retrospective study in a French peripheral hospital.

OBJECTIVES: To assess whether the initial treatment of non-muscle invasive bladder cancer (NMIBC) was performed according to the guidelines, and to determine the reasons why initial treatment was not provided in nonadherence cases. MATERIALS AND METHODS: We retrospectively reviewed all patients with NMIBC who underwent their first transurethral resection of bladder tumor (TURBT) at a peripheral hospital, between 2007 and 2016. The treatment offered to the patient was compared to the European Association of Urology guidelines according to risk stratification. For each patient who did not receive the treatment according to the guidelines, one of the following reasons was identified: poor patient compliance, poor patient general health status, urologist's decision, lack of resources. RESULTS: One hundred fifty-nine patients were included with a mean age of 72.2 years at the time of NMIBC diagnosis. The low-risk patients were strictly treated according to the guidelines. Among the intermediate-risk patients, 14% received mitomycin C. Among the high-risk patients, 39% received intravesical Bacillus Calmette-Guerin. In the nonadherence cases (61%), the reasons were related to the patient in 44% of cases (poor compliance, 21%; poor patient general health status, 23%), urologist's decision in 54% of cases, and lack of resources in 2% of cases. Thirty-seven percent of the high-risk patients underwent re-resection. CONCLUSIONS: Overall, adherence to NMIBC guidelines was low in all treatment types (intravesical therapy, re-resection, or cystectomy for very high-risk patients), but this finding was similar to that in previous studies. Reasons were mainly related to the urologist's decision or to the patient condition (poor compliance or poor general health status). LEVEL OF EVIDENCE: 3.

Updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and what.

INTRODUCTION: Intravesical therapy has been an important aspect of the management of non-muscle invasive bladder cancer (NMIBC) for 40 years. Bacillus Calmette-Guerin (BCG) is considered standard of care for intermediate and high-grade non-invasive disease, yet understanding the nuances of subsequent intravesical therapy is important for any provider managing bladder cancer. Herein, we review the literature and describe optimal use of intravesical therapies for NMIBC. METHODS: A comprehensive search of the medical literature was performed and highlighted in this review of intravesical therapy for NMIBC. RESULTS: Post-resection intravesical Mitomycin C therapy for low-risk disease remains an important component of care, and gemcitabine now has level-one evidence demonstrating efficacy in this setting but is not yet a guideline recommendation. BCG intravesical therapy remains the most effective therapy preventing recurrence and progression of intermediate and high-risk NMIBC. Adequately characterizing BCG-failure is critical in determining the next step in management which includes radical cystectomy, additional intravesical immunotherapy, chemotherapy with intravesical gemcitabine ± docetaxel and clinical trials. CONCLUSIONS: Intravesical therapy remains the mainstay of treatment for NMIBC and bladder preservation. Intravesical induction BCG followed by maintenance therapy remains standard of care for intermediate and high-risk patients. Detailing the timing and characteristics of recurrence after intravesical therapy is crucial in determining subsequent treatment recommendations. Current clinical trials focus on systemic immunotherapy and enhancing the intravesical immune response by augmenting the delivery mechanism.

Comparison of gemcitabine and anthracycline antibiotics in prevention of superficial bladder cancer recurrence.

BACKGROUND: Because of the failure, shortage and related toxicities of Bacillus Calmette-Guérin (BCG), the other intravesical chemotherapy drugs are also widely used in clinical application. Gemcitabine and anthracycline antibiotics (epirubicin and pirarubicin) are widely used as first-line or salvage therapy, but which drug is better is less discussed. METHODS: A total of 124 primary NMIBC patients administered intravesical therapy after transurethral resection of bladder tumor (TURBT) at Nanjing Drum Tower hospital from January 1996 to July 2018. After TURBT, all patients accepted standard intravesical chemotherapy. Recurrence was defined as the occurrence of a new tumor in the bladder. Progression was defined as confirmed tumor invading muscular layer. Treatment failure was defined as need for radical cystectomy (RC), systemic chemotherapy and radiation therapy. RESULTS: Of the 124 patients who underwent intravesical chemotherapy, 84 patients were given gemcitabine, 40 patients were given epirubicin or pirarubicin, with mean follow-up times (mean ± SD) of (34.8 ± 17.9) and (35.9 ± 22.1) months respectively. The clinical and pathological features of patients show no difference between two groups. Recurrence rate of patients given gemcitabine was 8.33% (7 out of 84), the recurrence rate was 45% (18 out of 40) for epirubicin or pirarubicin (P < 0.0001). The progression rates of gemcitabine, anthracycline antibiotics groups were 2.38% (2 out of 84) and 20% (8 out of 40), respectively (P < 0.001). The rate of treatment failure is 8.33% (7 out of 84) and 25% (10 out of 40), respectively (P = 0.012). Gemcitabine intravesical chemotherapy group was significantly related to a lower rate of recurrence (HR = 0.165, 95% CI 0.069-0.397, P = 0.000), progression (HR = 0.160, 95% CI 0.032-0.799, P = 0.026) and treatment failure (HR = 0.260, 95% CI 0.078-0.867, P = 0.028). CONCLUSION: In conclusion, gemcitabine intravesical chemotherapy group was significantly related to a lower rate of recurrence, progression and treatment failure. Gemcitabine could be considered as a choice for these patients who are not suitable for BCG.

Intravesical tacrolimus in treatment of intractable interstitial cystitis/bladder pain syndrome - A pilot study.

AIMS: Interstitial cystitis/Bladder pain syndrome (IC/BPS) is a chronic condition with limited effectiveness of current treatments without any cure. Cyclosporine A is effective in intractable cases of BPS/IC. Tacrolimus has same mechanism of action. The purpose of this pilot study was to find if tacrolimus instilled in bladder is effective in treating BPS/IC without side effects. METHODS: From February 2013 till Dec. 2017 tacrolimus dissolved in DMSO/sterile water was instilled in bladder of 24 patients of intractable BPS/IC. Patients received one to six cycles of therapy at interval of 14 days. Base line complete blood count, blood glucose, renal and liver function test were done and repeated after every three instillations. Serum tacrolimus level was also measured in 10 patients. Primary study endpoint was Global Response Assessment (GRA) score. RESULTS: 13 out of 24 patients showed improvement in a follow up extending from 6 to 63 month. Except for post- instillation flare in symptoms no side effects were observed in the patients during follow-up. Blood levels of tacrolimus reach same safe level irrespective of using either DMSO or water for preparing the solution. CONCLUSIONS: Intravesical tacrolimus dissolved in DMSO/water has been found effective in 54% patients of intractable BPS/IC without significant side effects in this pilot study. For the first time we have discovered that though tacrolimus is believed to be insoluble in water it gets absorbed by bladder urothelium when a solution of tacrolimus in water is instilled in urinary bladder. It should be offered to the patients before offering surgery.

Low-dose Bacillus Calmette-Guerin versus full-dose for intermediate and high-risk of non-muscle invasive bladder cancer: a Markov model.

BACKGROUND: To compare the efficacy of low dose (27 mg) Bacillus Calmette-Guérin (BCG) and a full dose (81 mg) BCG immunotherapy for patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after a typical transurethral bladder resection. METHODS: We constructed a Markov model for a 20-year simulation of the disease to compare the overall survival of patients with intermediate and high-risk of NMIBC between the full-dose therapy (FD group) and the low-dose therapy (LD group). Base case analysis, one-way and two-way sensitivity analysis and a second-order Monte Carlo analysis were performed based on data from 15 published articles. RESULTS: The expected overall survivals were 9.56 (9.55-9.57) years for FD group and 9.63 (9.61-9.64) years for LD group(P < 0.001). The estimated mortality in the FD group at 5, 10, and 20 years were 34.23%, 57.51% and 83.14%, respectively. The corresponding values in the LD group were 34.11%, 57.17%, 82.16%, respectively. Age-specific mortality and metastatic rate after undergoing radical cystectomy (RC) were the most two sensitive parameters in both groups. The rate of disease recurrence with disease worsening is the determining factor when choosing the optimal dose of BCG treatment. CONCLUSIONS: A low-dose BCG treatment may act slightly better than a full-dose BCG treatment for patients with intermediate and high-risk of NMIBC. This finding will require further high-quality studies to validate.

Current Therapeutic Strategies in Clinical Urology.

The field of urology encompasses all benign and malignant disorders of the urinary tract and the male genital tract. Urological disorders convey a huge economic and patient quality-of-life burden. Hospital acquired urinary tract infections, in particular, are under scrutiny as a measure of hospital quality. Given the prevalence of these pathologies, there is much progress still to be made in available therapeutic options in order to minimize side effects and provide effective care. Current drug delivery mechanisms in urological malignancy and the benign urological conditions of overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), and urinary tract infection (UTI) will be reviewed herein. Both systemic and local therapies will be discussed including sustained release formulations, nanocarriers, hydrogels and other reservoir systems, as well as gene and immunotherapy. The primary focus of this review is on agents which have passed the preclinical stages of development.

Management of High-grade T1 Urothelial Carcinoma.

PURPOSE OF REVIEW: The optimal management of high-grade T1 (HGT1) urothelial carcinoma (UC) is complex given its high rate of recurrence, progression, and cancer-specific mortality as well as its clinical variability. Our current treatment paradigm has been supplemented by recent data describing the expanding options for salvage intravesical therapy, bladder preservation, and the promising role of molecular epidemiology. In the current review, we attempt to summarize and critically analyze these studies. RECENT FINDINGS: Evidence describing new intravesical therapies has demonstrated an adequate safety profile and some efficacy in BCG-unresponsive patients who desire bladder preservation. However, response rates are still poor in this high-risk patient population, and it is important to keep these data in perspective when counseling patients. Concomitantly, the continued molecular characterization of non-muscle-invasive bladder cancer may suggest potential therapeutic targets as well as predictors of treatment response in the future. The integration of new intravesical therapies and molecular data into the current treatment paradigm for HGT1 urothelial carcinoma will be critical to improving oncologic outcomes in this particularly high-risk population.

Anti-inflammatory use may not negatively impact oncologic outcomes following intravesical BCG for high-grade non-muscle-invasive bladder cancer.

PURPOSE: To evaluate whether anti-inflammatory agents affect outcomes in patients receiving intravesical BCG therapy for high-grade (HG) non-muscle-invasive bladder cancer (NMIBC). METHODS: We reviewed the records of 203 patients in a prospective database of HG NMIBC from 2006 to 2012 at a single institution. Patients who had muscle-invasive disease (n = 32), low-grade pathology (n = 4), underwent early cystectomy within 3 months (n = 25), had <3 months of follow-up (n = 11), or did not receive an induction course of intravesical BCG (n = 32) were excluded. Clinicopathologic data were tabulated including demographics, comorbidities, pathologic stage and grades, intravesical therapy, and concomitant use of aspirin, NSAIDs, COX inhibitors, and statins. Multivariate Cox regression analysis explored predictive factors for recurrence, progression (stage progression or progression to cystectomy), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Ninety-nine patients with HG NMIBC who received at least one induction course of intravesical BCG were identified, with median follow-up of 31.4 months. There were 20 (20.2 %) deaths, including 6 (6.1 %) patients with bladder cancer-related mortality. 13 % patients experienced tumor progression and 27 % underwent cystectomy following failure of intravesical therapy. Anti-inflammatory use included statins (65 %), aspirin (63 %), or non-aspirin NSAIDs/COX inhibitors (26 %). Anti-inflammatory use was not significantly predictive of recurrence, progression, or mortality outcomes on Cox regression. CIS stage was associated with higher progression, while age, BMI, and Charlson score were independent predictors of overall mortality. CONCLUSION: Despite speculation of inhibitory effects on BCG immunomodulation there was no evidence that anti-inflammatory agents impacted oncologic outcomes in patients receiving BCG for HG NMIBC.

High-Risk Non-Muscle-Invasive Bladder Cancer-Therapy Options During Intravesical BCG Shortage.

Bladder cancer is the second commonest urinary tract malignancy with 70-80 % being non-muscle invasive (NMIBC) at diagnosis. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression. Intravesical Bacilli Calmette-Guerin (BCG) is commonly used as first line therapy in this patient group but there is a current worldwide shortage. BCG has been shown to reduce recurrence in high-risk NMIBC and is more effective that other intravesical agents including mitomycin C, epirubicin, interferon-alpha and gemcitabine. Primary cystectomy offers a high change of cure in this cohort (80-90 %) and is a more radical treatment option which patients need to be counselled carefully about. Bladder thermotherapy and electromotive drug administration with mitomycin C are alternative therapies with promising short-term results although long-term follow-up data are lacking.