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Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 70–75% of all bladder cancer cases. The standard treatment for high-risk NMIBC involves transurethral tumour resection followed by intravesical Bacillus Calmette–Guerin (BCG) immunotherapy. While BCG immunotherapy is both safe and effective, it frequently leads to the development of lower urinary tract symptoms (LUTS) such as urinary urgency, frequency, dysuria, and pelvic discomfort. These symptoms can significantly diminish patients' quality of life and may result in the discontinuation of BCG treatment, adversely affecting oncological outcomes. Despite the considerable clinical impact of BCG-induced LUTS, the underlying mechanisms remain unclear, hindering the implementation or development of effective treatments. This review provides novel insights into the potential mechanisms underlying BCG-induced LUTS, focusing on the integrated roles of afferent and efferent nerves in both normal and pathological bladder sensation and function. Specifically, this review examines how the body's response to BCG—through the development of inflammation, increased urothelial permeability, and altered urothelial signalling—might contribute to LUTS development. Drawing from known mechanisms in other common urological disorders and data from successful clinical trials involving NMIBC patients, this review summarises evidence supporting the likely changes in both sensory nerve signalling and bladder muscle function in the development of BCG-induced LUTS. However, further research is required to understand the intricate mechanisms underlying the development of BCG-induced LUTS and identify why some patients are more likely to experience BCG intolerance. Addressing these knowledge gaps could have profound implications for patients' quality of life, treatment adherence, and overall outcomes in NMIBC care. [ABSTRACT FROM AUTHOR]

What is this summary about? This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC). One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive). What happened in the studies? In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 μg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 μg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 μg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row. What were the key takeaways? N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years. As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events. Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease. Clinical Trial Registration:NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study) Tweetable Abstract Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder [ABSTRACT FROM AUTHOR]

It has been 30 years since Photofrin‐PDT was approved for the treatment of bladder cancer in Canada. However, Photofrin‐PDT failed to gain popularity due to bladder complications. The PDT with red light and IV‐administered Photofrin could permanently damage the bladder muscle. We have been developing a new combination strategy of PpIX‐PDT with singlet oxygen‐cleavable prodrugs for NMIBC with minimal side effects, avoiding damage to the bladder muscle layer. PpIX can be excited by either green (532 nm) or red (635 nm) light. Red light could be more efficacious in vivo due to its deeper tissue penetration than green light. Since HAL preferentially produces PpIX in tumors, we hypothesized that illuminating PpIX with red light might spare the muscle layer. PpIX‐PDT was used to compare green and red laser efficacy in vitro and in vivo. The IC50 of in vitro PpIX‐PDT was 18 mW/cm2 with the red laser and 22 mW/cm2 with the green laser. The in vivo efficacy of the red laser with 50, 75, and 100 mW total dose was similar to the same dose of green laser in reducing tumor volume. Combining PpIX‐PDT with prodrugs methyl‐linked mitomycin C (Mt‐L‐MMC) and rhodamine‐linked SN‐38 (Rh‐L‐SN‐38) significantly improved efficacy (tumor volume comparison). PpIX‐PDT or PpIX‐PDT + prodrug combination did not cause muscle damage in histological analysis. Overall, a combination of PpIX‐PDT and prodrug with 635 nm laser is promising for non‐muscle invasive bladder cancer treatment. [ABSTRACT FROM AUTHOR]

Mitochondria play an essential role in cancer treatment by providing apoptotic signals. Hexyl aminolevulinate, an FDA‐approved diagnosis for non‐muscle invasive bladder cancer, induces the production of protoporphyrin IX (PpIX) preferentially by mitochondria in cancer cells. Photosensitizer PpIX upon illumination can release active chemotherapy drugs from singlet oxygen‐activatable prodrugs. Prodrugs placed close enough to PpIX formed in mitochondria can improve the antitumor efficiency of PpIX‐PDT. The preferred uptake of prodrugs by cancer cells and tumors can further enhance the selective damage of cancer cells over non‐cancer cells and surrounding normal tissues. Mitochondriotropic prodrugs of anticancer drugs, such as paclitaxel and SN‐38, were synthesized using rhodamine, a mitochondrial‐targeting moiety. In vitro, the mitochondrial targeting helped achieve preferential cellular uptake in cancer cells. In RT112 cells (human bladder cancer cells), intracellular prodrug concentrations were 2–3 times higher than the intracellular prodrug concentrations in BdEC cells (human bladder epithelial cells), after 2 h incubation. In an orthotopic rat bladder tumor model, mitochondria‐targeted prodrugs achieved as much as 34 times higher prodrug diffusion in the tumor area compared to the nontumor bladder area. Overall, mitochondria targeting made prodrugs more effective in targeting cancer cells and tumors over non‐tumor areas, thereby reducing nonspecific toxicity. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) initially employed red light, which caused some patients to experience permanent bladder contractions. PDT using the FDA‐approved drug hexaminolevulinate (HAL), which produces protoporphyrin IX (PpIX) in the tumor, showed some promise but has low efficacy in treating non‐muscle‐invasive bladder cancer (NMIBC). We developed singlet oxygen‐activatable prodrugs of two anticancer drugs, paclitaxel and mitomycin C, to enhance the antitumor effect of PpIX‐PDT without producing systemic side effects, by promoting only local release of the active chemotherapeutic agent. Orthotopic NMIBC model was used to compare the efficacy of prodrugs only, PpIX‐PDT, and prodrugs + PpIX‐PDT. 532 nm laser with a total power of 50 mW for 20 min (60 J, single treatment) was used with HAL and prodrugs. Histology and microscopic methods with image analysis were used to evaluate the tumor staging, antitumor efficacy, and local toxicity. Prodrug + PpIX‐PDT produced superior antitumor efficacy than PpIX‐PDT alone with statistical significance. Both PpIX‐PDT alone and combination therapy resulted in mild damage to the bladder epithelium in the normal bladder area with no apparent damage to the muscle layer. Overall, SO‐cleavable prodrugs improved the antitumor efficacy of PpIX‐PDT without causing severe and permanent damage to the bladder muscle layer. [ABSTRACT FROM AUTHOR]

Objective: To investigate and compare the performance of urinary cytology and the Xpert BC Monitor test in the detection of bladder cancer in various clinically significant patient cohorts, including patients with carcinoma in situ (CIS), in a prospective multicentre setting, aiming to identify potential applications in clinical practice. Patients and Methods: A total of 756 patients scheduled for transurethral resection of bladder tumour (TURBT) were prospectively screened between July 2018 and December 2020 at six German University Centres. Central urinary cytology and Xpert BC Monitor tests were performed prior to TURBT. The diagnostic performance of urinary cytology and the Xpert BC Monitor was evaluated according to sensitivity (SN), specificity (SC), negative predictive value (NPV) and positive predictive value (PPV). Statistical comparison of urinary cytology and the Xpert BC Monitor was conducted using the McNemar test. Results: Of 756 screened patients, 733 (568 male [78%]; median [interquartile range] age 72 [62–79] years) were included. Bladder cancer was present in 482 patients (65.8%) with 258 (53.5%) high‐grade tumours. Overall SN, SC, NPV and PPV were 39%, 93%, 44% and 92% for urinary cytology, and 75%, 69%, 59% and 82% for the Xpert BC Monitor. In patients with CIS (concomitant or solitary), SN, SC, NPV and PPV were 59%, 93%, 87% and 50% for urinary cytology, and 90%, 69%, 95% and 50% for the Xpert BC Monitor. The Xpert BC Monitor missed four tumours (NPV = 98%) in patients with solitary CIS, while potentially avoiding 63.3% of TURBTs in inconclusive or negative cystoscopy and a negative Xpert result. Conclusion: Positive urinary cytology may indicate bladder cancer and should be taken seriously. The Xpert BC Monitor may represent a useful diagnostic tool for correctly identifying patients with solitary CIS and unsuspicious or inconclusive cystoscopy. [ABSTRACT FROM AUTHOR]

Abstract Purpose The advantages of en bloc resection of bladder tumors (ERBT) over transurethral resection of bladder tumors (TURBT) in terms of patient prognosis are not yet clear, and there are some technical limitations. We aimed to compare the tumor recurrence in non-muscle invasive bladder cancer (NMIBC) patients with tumor diameter ≥ 3 cm undergoing either TURBT or thulium laser ERBT. Methods The patients included were those diagnosed with NMIBC based on pathological confirmation and underwent TURBT or modified thulium laser ERBT in the Department of Urology at Tongji Hospital from 2019 to 2024. The patients’ medical records were meticulously collected and postoperative follow-up was diligently conducted by trained personnel. Recurrence-free survival curves were generated utilizing the Kaplan–Meier method, and group comparisons were performed using the log-rank trend test. To minimize biases, we employed stratified survival analysis, alongside univariate and multivariate Cox regression analysis. Results This study included a total of 396 patients with NMIBC, with 214 undergoing TURBT and 182 undergoing ERBT. For all patients, there was no significant difference (P = 0.180) in RFS between the TURBT and ERBT groups. For patients with tumor diameter ≥ 3 cm, stratified analysis revealed that the RFS of the ERBT group was significantly better than that of the TURBT group (P = 0.033). However, in patients with tumor diameter

Introduction: To evaluate the efficacy and side effects of re-circulant hyperthermic intravesical chemotherapy versus conventional treatments for intermediate risk non-muscle invasive bladder cancer (NMIBC). Methods: A randomized 3-arm, parallel group trial was conducted at a single tertiary care centre. 135 patients with low-grade intermediate-risk cancer, having undergone complete resection of bladder tumor were included. Patients were assigned 1:1:1, to receive intra-vesical chemo-hyperthermia (C-HT), mitomycin-C (MMC) or BCG therapy. There was no treatment crossover. Patients were followed up with check cystoscopy every 3 months for histopathological recurrence. Results: The three arms were comparable in terms of age, gender, tumor size, number of tumors and clinical stage or grade of tumors. Mean tumor size was 2.58 (± 0.88) cm and the mean number of tumors resected was 2.04 (± 1.02) (Range 1–5). There was no significant difference between the various groups for tumor recurrence (χ2 = 1.96, p = 0.375) or time to recurrence (13.6 vs. 10.8 vs. 9.8 months, p = 0.844) though incidence of non-healing necrotic area was higher with C-HT (22.2% vs. 11.1% and 4.8%, χ2 = 6.093, p = 0.048). Median (IQR) follow up period was 26 (12–52) months. Treatment discontinuation or drug intolerance was significantly higher in BCG arm (p = 0.03). Conclusions: Intravesical C-HT with MMC, conventional MMC and BCG are equally effective and comparable alternatives for intravesical therapy in low-grade intermediate-risk NMIBC. Higher incidence of non-healing resection site with C-HT and higher local symptoms with BCG are a concern. [ABSTRACT FROM AUTHOR]

Purpose: The advantages of en bloc resection of bladder tumors (ERBT) over transurethral resection of bladder tumors (TURBT) in terms of patient prognosis are not yet clear, and there are some technical limitations. We aimed to compare the tumor recurrence in non-muscle invasive bladder cancer (NMIBC) patients with tumor diameter ≥ 3 cm undergoing either TURBT or thulium laser ERBT. Methods: The patients included were those diagnosed with NMIBC based on pathological confirmation and underwent TURBT or modified thulium laser ERBT in the Department of Urology at Tongji Hospital from 2019 to 2024. The patients' medical records were meticulously collected and postoperative follow-up was diligently conducted by trained personnel. Recurrence-free survival curves were generated utilizing the Kaplan–Meier method, and group comparisons were performed using the log-rank trend test. To minimize biases, we employed stratified survival analysis, alongside univariate and multivariate Cox regression analysis. Results: This study included a total of 396 patients with NMIBC, with 214 undergoing TURBT and 182 undergoing ERBT. For all patients, there was no significant difference (P = 0.180) in RFS between the TURBT and ERBT groups. For patients with tumor diameter ≥ 3 cm, stratified analysis revealed that the RFS of the ERBT group was significantly better than that of the TURBT group (P = 0.033). However, in patients with tumor diameter < 3 cm, there was no significant difference (P = 0.150) between the two groups. Univariate (HR: 0.52, 95% CI 0.28–0.96, P = 0.036) and multivariate (HR: 0.49, 95% CI 0.25–0.93, P = 0.031) Cox analyses revealed that ERBT was an independent protective factor for recurrence in NMIBC patients with tumor diameter ≥3cm. Conclusion: This study found that thulium laser ERBT may offer advantages in managing NMIBC patients with tumor diameters ≥ 3 cm. This could potentially drive the clinical application of thulium laser ERBT. Trial registration: Protocol was registered at Chinese Clinical Trial Register (ChiCTR) with number ChiCTR2000035407 on 12 August 2020. [ABSTRACT FROM AUTHOR]

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. Patients and 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Non-muscle invasive bladder cancer (NMIBC) is characterised by high rates of recurrence and progression, requiring substantial healthcare resources. In Latin America, the incidence of NMIBC is set to increase due to an aging population and lifestyle changes. To better understand the current challenges for NMIBC treaters and patients, a mixedmethods approach was leveraged combining secondary research with qualitative interviews from healthcare providers in Brazil, Colombia, Mexico and Argentina. Our analysis found that significant challenges persist across the region, particularly due to Bacillus Calmette-Guérin shortages, inconsistent adherence to clinical guidelines and significant socioeconomic disparities for patients accessing healthcare services. Addressing these challenges requires improved patient advocacy, strategic use of clinical trials and better resource distribution to enhance NMIBC management across Latin America. [ABSTRACT FROM AUTHOR]

Background: Multiple clinical studies have demonstrated the numerous advantages of urine methylation test over cytology for monitoring patients with non-muscle invasive bladder cancer (NMIBC) following surgery. This research aims to provide a systematic review and meta-analysis to evaluate the efficacy and limits of urine methylation test in the clinical management of NMIBC. Methods: This research was carried out by conducting a comprehensive search of clinical trials comparing cytology and urine methylation test for NMIBC followup using databases such as PubMed, Embase, Web of Science, and the Cochrane Library up until May 2023, including references from relevant articles. The study is registered on PROSPERO with ID CRD42023398969. Result: This study comprised six studies with a total of 1676 patients. The analysis revealed that the AUC of urine methylation test had a greater AUC than that of the cytology examination (0.89 vs 0.71). In post-operative follow-up of patients with NMIBC, the urine methylation test demonstrated a significant sensitivity (0.69 vs 0.52), but with lower specificity (0.87 vs 0.93) than cytology examination. Conclusion: The urine methylation test and cytology examination have both shown strong diagnostic performance in screening for NMIBC patients. However, urine methylation test outperforms cytology examination in terms of accuracy and sensitivity. Systematic review registration: PROSPERO, identifier CRD42023398969. [ABSTRACT FROM AUTHOR]

Le traitement standard des tumeurs de la vessie non infiltrant le muscle (TVNIM) de haut risque ou de risque intermédiaire reste la résection transurétrale de vessie, suivie d'instillations intravésicales de BCG. Cependant, le BCG présente d'importantes limites, avec notamment une réponse non durable chez près de la moitié des patients et des effets indésirables significatifs. Cette revue présente les alternatives thérapeutiques au BCG. Parmi elles, des immunothérapies ciblant la voie PD1, administrées par voie systémique, montrent des résultats prometteurs en combinaison avec le BCG. Les traitements administrés par voie intravésicale incluent les instillations de gemcitabine seule ou en association avec du docétaxel, la thermo-chimiothérapie et les dispositifs intravésicaux à libération continue de gemcitabine ou d'erdafitinib. La connaissance et la maîtrise de ces alternatives par l'urologue sont nécessaires pour améliorer la prise en charge des patients suivis pour TVNIM. The standard treatment for high-risk or intermediate-risk non-muscle-invasive bladder tumors (NMIBC) remains transurethral resection of the bladder followed by intravesical BCG instillations. However, BCG has significant limitations, including a non-durable response in nearly half of the patients and considerable adverse effects. This review examines alternative therapies to BCG. Among them, systemic immune checkpoint inhibitors show promising results in combination with BCG. Intravesical therapies include instillations of gemcitabine alone or combined with docetaxel, thermo-chemotherapy, and continuous-release intravesical devices delivering gemcitabine or erdafitinib. Urologists have to be aware of these alternatives to BCG to improve the management of NMIBC patients. [ABSTRACT FROM AUTHOR]

Purpose: To assess prognostic significance of residual tumor at repeat transurethral resection (reTUR) in contemporary non-muscle-invasive bladder cancer (NMIBC) patients. Methods: Patients were identified retrospectively from eight referral centers in France, Italy and Spain. The cohort included consecutive patients with high or very-high risk NMIBC who underwent reTUR and subsequent adjuvant BCG therapy. Results: A total of 440 high-risk NMIBC patients were screened, 29 (6%) were upstaged ≥ T2 at reTUR and 411 were analyzed (T1 stage: n = 275, 67%). Residual tumor was found in 191 cases (46%). In patients with T1 tumor on initial TURBT, persistent T1 tumor was found in 18% of reTUR (n = 49/275). In patients with high-grade Ta tumor on initial TURBT, T1 tumor was found in 6% of reTUR (n = 9/136). In multivariable logistic regression analysis, we found no statistical association between the use of photodynamic diagnosis (PDD, p = 0.4) or type of resection (conventional vs. en bloc, p = 0.6) and the risk of residual tumor. The estimated 5-yr recurrence and progression-free survival were 56% and 94%, respectively. Residual tumor was significantly associated with a higher risk of recurrence (p < 0.001) but not progression (p = 0.11). Only residual T1 tumor was associated with a higher risk of progression (p < 0.001) with an estimated 5-yr progression-free survival rate of 76%. Conclusions: ReTUR should remain a standard for T1 tumors, irrespective of the use of en bloc resection or PDD and could be safely omitted in high-grade Ta tumors. Persistent T1 tumor at reTUR should not exclude these patients from conservative management, and further studies are needed to explore the benefit of a third resection in this subgroup. [ABSTRACT FROM AUTHOR]

Objective: To develop a prognostically relevant scoring system for stage pT1 non‐muscle‐invasive bladder cancer (NMIBC) incorporating tumour budding, growth pattern and invasion pattern because the World Health Organisation grading system shows limited prognostic value in such patients. Patients and Methods: The tissue specimens and clinical data of 113 patients with stage pT1 NMIBC who underwent transurethral resection of bladder tumour were retrospectively investigated. Tumour budding, and growth and invasion patterns were evaluated and categorised into two grade groups (GGs). GGs and other clinical and histopathological variables were investigated regarding recurrence‐free survival (RFS), progression‐free survival (PFS), cancer‐specific survival (CSS) and overall survival (OS) using univariable and multivariable Cox regression analyses. Results: The integration of two tumour budding groups, two growth patterns, and two invasion patterns yielded an unfavourable GG (n = 28; 24.7%) that had a high impact on oncological outcomes. The unfavourable GG was identified as an independent RFS and OS predictor (P = 0.004 and P = 0.046, respectively) and linked to worse PFS (P = 0.001) and CSS (P = 0.001), irrespective of the European Association of Urology risk group. The unfavourable GG was associated with higher rates of BCG‐unresponsive tumours (P = 0.006). Study limitations include the retrospective, single‐centre design, diverse therapies and small cohort. Conclusions: We present a morphology‐based grading system for stage pT1 NMIBC that correlates with disease aggressiveness and oncological patient outcomes. It therefore identifies a highest risk group of stage pT1 NMIBC patients, who should be followed up more intensively or receive immediate radical cystectomy. The grading incorporates objective variables assessable on haematoxylin and eosin slides and immunohistochemistry, enabling an easy‐to‐use low‐cost approach that is applicable in daily routine. Further studies are needed to validate and confirm these results. [ABSTRACT FROM AUTHOR]

Introduction: Previously, in a randomised trial we demonstrated bipolar transurethral resection of bladder tumor (TURBT) could achieve a higher detrusor sampling rate than monopolar TURBT. We hereby report the long-term oncological outcomes following study intervention. Methods: This is a post-hoc analysis of a randomized phase III trial comparing monopolar and bipolar TURBT. Only patients with pathology of non-muscle invasive bladder cancer (NMIBC) were included in the analysis. Per-patient analysis was performed. Primary outcome was recurrence-free survival (RFS). Secondary outcomes included progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: From the initial trial, 160 cases were randomised to receive monopolar or bipolar TURBT. 24 cases of non-urothelial carcinoma, 22 cases of muscle-invasive bladder cancer, and 9 cases of recurrences were excluded. A total of 97 patients were included in the analysis, with 46 in the monopolar and 51 in the bipolar group. The median follow-up was 97.1 months. Loss-to-follow-up rate was 7.2%. Regarding the primary outcome of RFS, there was no significant difference (HR = 0.731; 95%CI = 0.433–1.236; P = 0.242) between the two groups. PFS (HR = 1.014; 95%CI = 0.511–2.012; P = 0.969), CSS (HR = 0.718; 95%CI = 0.219–2.352; P = 0.584) and OS (HR = 1.135; 95%CI = 0.564–2.283; P = 0.722) were also similar between the two groups. Multifocal tumours were the only factor that was associated with worse RFS. Conclusion: Despite the superiority in detrusor sampling rate, bipolar TURBT was unable to confer long-term oncological benefits over monopolar TURBT. [ABSTRACT FROM AUTHOR]

Background: To advance the use of recent discoveries in clinical setting, it is crucial to establish a consensus regarding the molecular classification of bladder cancer (BC). BC remains a significant global public health issue. It ranks as the 10th most frequently diagnosed cancer and the 13th leading cause of cancerrelated deaths globally. Efforts are underway to develop classification systems for non-muscle invasion bladder cancer (NMIBC) and muscle invasion bladder cancer (MIBC) due to the significant differences in treatment approaches. Conclusions: We conducted a search through various scientific websites, including original papers and clinical trials, to explore the classification journey of bladder cancer and the rationale for each subtype. Most of the molecular classifications are highlighted in the following manuscript aiming to be of significant value in near future in treatment strategies to improve the outcome. Further clinical trials focusing on the impact of molecular classification are urgently needed to advance the understanding and treatment of BC. [ABSTRACT FROM AUTHOR]

BackgroundNon-muscle-invasive Bladder Cancer (NMIBC) is notorious for its high recurrence rate of 70-80%, imposing a significant human burden and making it one of the costliest cancers to manage. Current prediction tools for NMIBC recurrence rely on scoring systems that often overestimate risk and lack accuracy. Machine learning (ML) and artificial intelligence (AI) are transforming oncological urology by leveraging molecular and clinical data to enhance predictive precision.MethodsThis comprehensive review critically examines ML-based frameworks for predicting NMIBC recurrence. A systematic literature search was conducted, focusing on the statistical robustness and algorithmic efficacy of studies. These were categorised by data modalities (e.g., radiomics, clinical, histopathological, genomic) and types of ML models, such as neural networks, deep learning, and random forests. Each study was analysed for strengths, weaknesses, performance metrics, and limitations, with emphasis on generalisability, interpretability, and cost-effectiveness. ResultsML algorithms demonstrate significant potential, with neural networks achieving accuracies of 65–97.5%, particularly with multi-modal datasets, and support vector machines averaging around 75%. Models combining multiple data types consistently outperformed single-modality approaches. However, challenges include limited generalisability due to small datasets and the "black-box" nature of advanced models. Efforts to enhance explainability, such as SHapley Additive ExPlanations (SHAP), show promise but require refinement for clinical use.ConclusionThis review illuminates the nuances, complexities and contexts that influence the real-world advancement and adoption of these AI-driven techniques in precision oncology. It equips researchers with a deeper understanding of the intricacies of the ML algorithms employed. Actionable insights are provided for refining algorithms, optimising multimodal data utilisation, and bridging the gap between predictive accuracy and clinical utility. This rigorous analysis serves as a roadmap to advance real-world AI applications in oncological care, highlighting the collaborative efforts and robust datasets necessary to translate these advancements into tangible benefits for patient management.

ABSTRACT Background Metastatic disease of a urinary bladder cancer localized in the upper abdomen is very rare. This case report describes the first patient with a urinary bladder cancer progression, initially presenting as a gastric outlet obstruction due to peritoneal carcinomatosis. Case We present the case of a 78‐years‐old male patient who was admitted to Hospital St. Josef Braunau in Austria with persistent vomiting. In the medical history, the most prominent finding was a diagnosed high‐risk NMIBC. At the time, patient was between 2. and 3. BCG maintenance instillation cycle, following two transurethral resections. Routine follow‐up cystoscopy 1 month before admission to our department showed no evidence of disease recurrence. Due to the therapy resistant vomiting, gastroscopy was performed, revealing duodenal stenosis without mucosal changes. Subsequently performed abdominal CT‐scan showed homogenous swelling of the mesenteric fat tissue around duodenum, spreading retroperitoneal to both kidneys. In the absence of the typical peritoneal carcinomatosis features, the finding was firstly described as an inflammation of mesenteric fat or panniculitis mesenterialis. Further deterioration of patient's condition and later occurred bilateral hydronephrosis raised a suspicion of peritoneal carcinomatosis. Consequently, conducted laparoscopic exploration confirmed the suspicion describing the tissue conglomerate typical for peritoneal carcinomatosis surrounding the duodenum. Pathohistological analysis of taken samples proved urothelial cancer cells, confirming the diagnosis of metastatic bladder cancer disease. Conclusion This case report presents a very unusual presentation of metastatic urinary bladder cancer that could help clinicians to consider this diagnosis when encountering similar clinical features.

BackgroundBladder carcinoma is a type of urological tumor with high risks of recurrence and progression. The triglyceride-glucose (TyG) index has demonstrated significant promise as a prognostic marker for metabolic health in different types of cancer. Further research is needed to explore the relationships among non-muscle-invasive bladder cancer (NMIBC), the TyG index, and its prognostic importance. Purpose of this preliminary research is to assess the predictive significance of the TyG index for recurrence and progression risk in NMIBC patients.MethodsData from patients admitted between October 2018 and July 2021 were reviewed, and there are 198 patients in total were included. The experimental data were supplied by medical records. In addition, patient prognoses were followed up via telephone. Furthermore, patients were separated into two groups: the high and low TyG groups, using X-tile software. Apart from recurrence-free survival (RFS), progression-free survival (PFS) was the main outcome. According to the TyG index, nomograms were also established.ResultsThe cohort consisted of 93 patients in the high TyG group and 105 patients in the low TyG group. The TyG index was a key prognostic factor for postoperative RFS (HR = 2.726, 95% CI = 1.474–5.041, p = 0.001) and PFS (HR = 2.846, 95% CI = 1.359–5.957, p = 0.006) among patients with NMIBC. The log-rank test revealed a notable disparity between the low and high TyG groups regarding RFS (p = 0.0025) and PFS (p = 0.0110). Moreover, it was strongly connected to well-known NMIBC risk factors. Because the TyG index exhibited good predictive value, the nomogram models were formulated.ConclusionThe TyG index serves as an isolated predictor of both RFS and PFS among patients with NMIBC, revealing new insights into disease treatment mechanisms. Indeed, the TyG index serves as a credible indicator of risk classification while facilitating early intervention among patients with NMIBC.

Objective This study aimed to evaluate the combined efficacy of hyperthermia and chemotherapy using a bladder cancer organoid model and to explore hyperthermia-related molecular pathways.Method Tumor organoids were generated by embedding RT4 bladder cancer cells into Matrigel. The resulting organoids were treated with pirarubicin or gemcitabine at 37 °C or 42 °C. Proliferation was determined by Ki67 immunofluorescence staining, and apoptosis was assessed using a TdT-mediated dUTP nick end labeling (TUNEL) assay. RNA sequencing was used to identify the differentially expressed genes.Results Bladder cancer organoids were successfully established and exhibited robust proliferative abilities. Treatment with gemcitabine or pirarubicin under hyperthermic conditions caused pronounced structural damage to the organoids and increased cell death compared to that in the normothermically treated group. Furthermore, Ki67 labeling and TUNEL assays showed that the hyperthermia chemotherapy group showed a significantly reduced proliferation rate and high level of apoptosis. Finally, RNA sequencing revealed the IFN-γ signaling pathway to be associated with hyperthermia.Conclusion Overall, hyperthermia combined with chemotherapy exerted better therapeutic effects than those of normothermic chemotherapy in grade 1-2 non-muscle-invasive bladder cancer, potentially through activation of the IFN-γ-JAK-STAT pathway.

Background Doxorubicin is an anthracycline antibiotic widely used as a chemotherapeutic agent to treat solid tumors and hematologic malignancies. Bladder cancer is the second most common genitourinary malignancy and can be classified into muscle-invasive bladder cancer and non-muscle-invasive bladder cancer (NMIBC). In Indonesia, NMIBC is treated by doxorubicin instillation. Several risk factors have been suggested to be associated with doxorubicin-induced cardiomyopathy, but on their quantitative effects no consensus has as yet been reached. This study aimed to determine the risk factors of doxorubicin-induced cardiomyopathy in NMIBC patients with intravesical doxorubicin instillation. Methods A cross-sectional study was conducted involving 74 NMIBC patients who received local treatment by doxorubicin instillation after transurethral resection of bladder tumor (TURBT). Data were collected on the risk factors that may be favorable to doxorubicin-induced cardiomyopathy, namely age, sex, hypertension, type 2 diabetes mellitus, smoking, and NMIBC risk classification. The dependent variable was cardiomyopathy with decreasing left ventricular ejection fraction (LVEF) below 50 %. Multiple logistic regression was used to analyze the data. Results The prevalence of cardiomyopathy was 6.75% (5/74). Type 2 diabetes mellitus was a significant risk factor for doxorubicin-induced cardiomyopathy among our subjects (aOR=34.30;95% C.I.:1.36-865-86;p=0.032). In contrast, age, sex, risk classification, hypertension, and smoking were nonsignificant predictors for doxorubicin-induced cardiomyopathy (p>0.05). Conclusion This study demonstrated that type 2 diabetes mellitus increased the risk of cardiomyopathy in doxorubicin users among patients with NMIBC. More research is necessary regarding the mechanisms underlying type 2 diabetes mellitus as a risk factor for doxorubicin-induced cardiomyopathy.

Introduction: 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. Areas covered: 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). Expert opinion: 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. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants. Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. Most people have surgery to remove the cancer cells while leaving the rest of the bladder intact. This is called transurethral resection of a bladder tumor (TURBT). For people with high-risk NMIBC, a medicine called Bacillus Calmette-Guérin (BCG) is placed directly inside the bladder after TURBT. A 'high risk' classification means that the cancer is more likely to spread or come back after treatment. Some people's cancer does not respond to BCG or returns after BCG treatment. Researchers are currently looking at whether BCG combined with other immunotherapies may prevent cancer growth more than BCG on its own. Immunotherapy helps the immune system recognize and kill cancer cells. Sasanlimab is an immunotherapy medicine that is not yet approved to treat people with NMIBC. It is given as an injection under the skin. In this CREST study, researchers are looking at how safe and effective sasanlimab plus BCG is for people with high-risk NMIBC. Around 1000 people are taking part in CREST. They must have had TURBT 12 weeks or less before joining the study. Researchers want to know how long people live without certain events occurring, such as bladder cancer cells returning. A plain language summary of this article can be found as Supplementary Material. Clinical Trial Registration:NCT04165317; 2019-003375-19 (EudraCT) (ClinicalTrials.gov) CREST is a phase III study evaluating the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG versus current standard-of-care BCG monotherapy for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is the tenth most common cause of cancer worldwide and is the thirteenth leading cause of cancer mortality. The non-muscle invasive (NMI) variant represents 75% of cases and has a mortality rate of less than 1%; however, it has a high recurrence rate. The gold standard of management is transurethral resection in the case of new lesions. However, this is associated with significant morbidity and costs, so the reduction of these procedures would contribute to reducing complications, morbidity, and the burden to the health system associated with therapy. In this clinical scenario, strategies such as active surveillance have emerged that propose to manage low-risk BC with follow-up; however, due to the low evidence available, this is a strategy that is underutilized by clinicians. On the other hand, in the era of biomarkers, it is increasingly known how to use them as a tool in BC. Therefore, the aim of this review is to provide to clinical practitioners the evidence available to date on AS and the potential role of biomarkers in this therapeutic strategy in patients with low-grade/risk NMIBC. This is the first review linking use of biomarkers and active surveillance, including 29 articles.

Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 70–75% of all bladder cancer cases. The standard treatment for high-risk NMIBC involves transurethral tumour resection followed by intravesical Bacillus Calmette–Guerin (BCG) immunotherapy. While BCG immunotherapy is both safe and effective, it frequently leads to the development of lower urinary tract symptoms (LUTS) such as urinary urgency, frequency, dysuria, and pelvic discomfort. These symptoms can significantly diminish patients’ quality of life and may result in the discontinuation of BCG treatment, adversely affecting oncological outcomes. Despite the considerable clinical impact of BCG-induced LUTS, the underlying mechanisms remain unclear, hindering the implementation or development of effective treatments. This review provides novel insights into the potential mechanisms underlying BCG-induced LUTS, focusing on the integrated roles of afferent and efferent nerves in both normal and pathological bladder sensation and function. Specifically, this review examines how the body’s response to BCG—through the development of inflammation, increased urothelial permeability, and altered urothelial signalling—might contribute to LUTS development. Drawing from known mechanisms in other common urological disorders and data from successful clinical trials involving NMIBC patients, this review summarises evidence supporting the likely changes in both sensory nerve signalling and bladder muscle function in the development of BCG-induced LUTS. However, further research is required to understand the intricate mechanisms underlying the development of BCG-induced LUTS and identify why some patients are more likely to experience BCG intolerance. Addressing these knowledge gaps could have profound implications for patients’ quality of life, treatment adherence, and overall outcomes in NMIBC care.

Bladder cancer (BC) is one of the most prevalent cancers worldwide. Non-muscle invasive bladder cancer (NMIBC), comprising the majority of initial BC presentations, requires accurate risk stratification for optimal management. This review explores the evolving role of programmed cell death ligand 1 (PD-L1) as a prognostic biomarker in NMIBC, with a particular focus on its implications in the context of Bacillus Calmette-Guérin (BCG) immunotherapy. The literature suggests a potential association between elevated PD-L1 status and adverse outcomes, resistance to BCG treatment, and disease progression. However, conflicting findings and methodological issues highlight the heterogeneity of PD-L1 assessment in NMIBC, probably due to the complex biological mechanisms that regulate the interaction between PD-L1 and the tumor microenvironment. The identification of PD-L1 as a prognostic biomarker provides ground for tailored therapeutic interventions, including immune checkpoint inhibitors (ICIs). Nevertheless, challenges such as intratumoral heterogeneity and technical issues underscore the need for standardized protocols and larger, homogeneous trials. This review contributes to the ongoing debate on the personalized management of NMIBC patients, focusing on the advances and perspectives of incorporating PD-L1 as a biomarker in this setting. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is the tenth most common cause of cancer worldwide and is the thirteenth leading cause of cancer mortality. The non-muscle invasive (NMI) variant represents 75% of cases and has a mortality rate of less than 1%; however, it has a high recurrence rate. The gold standard of management is transurethral resection in the case of new lesions. However, this is associated with significant morbidity and costs, so the reduction of these procedures would contribute to reducing complications, morbidity, and the burden to the health system associated with therapy. In this clinical scenario, strategies such as active surveillance have emerged that propose to manage low-risk BC with follow-up; however, due to the low evidence available, this is a strategy that is underutilized by clinicians. On the other hand, in the era of biomarkers, it is increasingly known how to use them as a tool in BC. Therefore, the aim of this review is to provide to clinical practitioners the evidence available to date on AS and the potential role of biomarkers in this therapeutic strategy in patients with low-grade/risk NMIBC. This is the first review linking use of biomarkers and active surveillance, including 29 articles. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer is a common disease in urological patients. The approach to treatment depends on the severity of the tumor; in this article, we focus on tumors that do not invade the muscle layer of the bladder. Those tumors are resected during an endoscopic procedure (TURBT), but often reoccur. Treating bladder cancer with drugs instead of surgical removal of the bladder (radical cystectomy) is paramount for patients quality of life and overall well-being. The aim of this paper is to review methods of conservative treatment of tumors unresponsive to the typical treatment of choice (BCG instillations). Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of BCG-unresponsive tumors is scarce and usually leads to Radical Cystectomy. In this paper, we review recent advancements in conservative treatment of BCG-unresponsive tumors. The main focus of the paper is FDA-approved medications: Pembrolizumab and Nadofaragene Firadenovec (Adstiladrin). Other, less researched therapeutic possibilities are also included, namely: N-803 immunotherapy, TAR-200 and TAR-210 intravesical delivery systems and combined Cabazitaxel, Gemcitabine and Cisplatin chemotherapy. Conservative treatment and delaying radical cystectomy would greatly benefit patients' quality of life; it is undoubtedly the future of BCG-unresponsive NMIBC. [ABSTRACT FROM AUTHOR]

L'objectif de cette mise au point était de rappeler les critères permettant de définir un patient non répondeur au BCG mais aussi de décrire les traitements disponibles et en cours de développement dans cette phase de la maladie. Un schéma d'administration de BCG optimal est respecté lorsque le patient a reçu : au moins 5/6 instillations pendant le traitement d'induction et au moins 2/3 instillations durant le 1er cycle d'entretien (un 2e cycle d'induction étant possible). Un patient est considéré comme non répondeur au BCG si la récidive est de haut grade. Ainsi un patient est qualifié de non répondeur au BCG lorsqu'il présente : une récidive papillaire de haut grade dans les 6 mois suivant la dernière instillation de BCG, ou une récidive sous la forme de CIS dans les 12 mois suivant la dernière instillation de BCG. Le traitement de référence pour la prise en charge des patients non répondeurs au BCG est la cystectomie totale. Néanmoins il existe des alternatives à la cystectomie par l'utilisation de traitements systémiques ou endovésicaux. Les traitements systémiques par inhibiteurs du check-point immunitaire. Les traitements endovésicaux, sous les formes d'immunothérapie, de chimiothérapie, de thérapie génique et virale et de thérapie ciblée. Notre rôle auprès des patients est de proposer l'inclusion dans les essais cliniques évaluant ces alternatives thérapeutiques dans cette indication. The objective of this update was to recall the criteria for defining a patient who is non-responsive to BCG but also to describe the treatments available and under development in this phase of the disease. An optimal BCG administration schedule is respected when the patient has received: at least 5/6 instillations during the induction treatment and at least 2/3 instillations during the 1st maintenance cycle (a 2nd induction cycle being possible). A patient is considered non-responsive to BCG if the recurrence is high grade. Thus a patient is qualified as non-responder to BCG when he presents: a high-grade papillary recurrence within 6 months following the last instillation of BCG, or a recurrence in the form of CIS within 12 months following the last instillation of BCG. The standard treatment for the management of patients who do not respond to BCG is total cystectomy. However, there are alternatives to cystectomy through the use of systemic or endovesical treatments. Systemic treatments with immune checkpoint inhibitors. Endovesical treatments, in the forms of immunotherapy, chemotherapy, gene and viral therapy and targeted therapy. Our role with patients is to propose inclusion in clinical trials evaluating these therapeutic alternatives in this indication. [ABSTRACT FROM AUTHOR]

Introduction: Local therapies for high risk non-muscle-invasive bladder cancer (NMIBC) such as intravesical chemotherapy (IVC) have shown a high rate of progression and recurrence (1). Intravesical Bacillus Calmette-Guérin (BCG) for local therapies has been shown to reduce progression and recurrence in patient with NMIBC. However, its potential role is limited in high burden countries for tuberculosis (TB) due to its low specificity that can cause wrong diagnosis or false positive in patients with clinically diagnosed tuberculosis. BCG vaccine that has to be given for most people in tuberculosis endemic countries will induce trained immunity that could reduce the effectivity of intravesical BCG for NMIBC Moreover, intravesical BCG is contraindicated in patient with or previous tuberculosis. The potential clinical benefit of intraarterial chemotherapy (IAC) in delaying the recurrence and progression of high-risk NMIBC have been investigated with promising results (2, 3). We aimed to conduct a meta-analysis to evaluate the potential anti-tumor effect of IAC in NMIBC. Methods: We conducted a comprehensive search of published articles in Cochrane Library, Pubmed, and Science-Direct to identify relevant randomized controlled trials (RCTs) and observational studies comparing IAC alone or combined with IVC versus IVC/BCG alone in NMIBC. The protocol of preferred reporting items for systematic review and meta-analysis (PRISMA) was applied to this study. Results: Four RCTs and 4 cohort observational studies were eligible in this study and 5 studies were included in meta-analysis. The risk ratio of tumor recurrence was reduced by 35% (RR = 0.65; 95% CI 0.49-0.87; p = 0.004) in IAC plus IVC, while recurrence-free survival (RFS) was prolonged by 45% (HR: 0.55; 95% CI, 0.44-0.69; p < 0.001). The risk of tumor progression was reduced by 45% (RR = 0.55; 95% CI 0.41-0.75; p = 0.002) and tumor progression-free survival (PFS) was also prolonged by 53% (HR: 0.47; 95% CI, 0.34-0.65; p < 0.001). Some RCT's had high or unclear risk of bias, meanwhile 4 included cohort studies had overall low risk of bias, therefore the pooled results need to be interpreted cautiously. Subgroup analysis revealed that the heterogeneity outcome of tumour recurrence might be attributed to the difference in NMIBC stages and grades. Conclusions: The IAC alone or combined with IVC following bladder tumor resection may lower the risk of tumor recurrence and progression. These findings highlight the importance of further multi institutional randomized controlled trials with bigger sample size using a standardized IAC protocol to validate the current results. [ABSTRACT FROM AUTHOR]

Background: The most prevalent cancer of the urinary system and the fourth most frequent cancer in men is bladder cancer. Up to 45% of non-muscle-invasive bladder cancers (NMIBC), may develop into muscle-invasive disease within 5 years after initial diagnosis, depending on the risk profile. The neutrophil to lymphocyte ratio (NLR), which is an emerging marker of host inflammation and can be easily calculated from routine complete blood counts (CBCs) with differentials, has shown to be an independent prognostic factor for a variety of solid malignancies, including urinary tract cancer. Pyuria is a well-documented prognostic factor in urinary tract carcinomas, according to several research. The relationship between preoperative pyuria and recurrence in patients with NMIBC is unclear, even though some studies found that pyuria was a strong predictor of poor prognosis in patients with NMIBC. Our study's objective was to compare the prognostic effect of pre-treatment pyuria and NLR on the likelihood of progression and recurrence in individuals with primary NMIBC. Materials and methodology: Data obtained from 100 bladder cancer patients who underwent transurethral resection of bladder tumor (TURBT) from June 2021 to January 2023 were evaluated prospectively. Inclusion criteria: Age more than 18 years, having tumor size less than 3 × 3 cm, single tumor, no H/O TURBT. Exclusion criteria: Age less than 18 years, size more than 3 × 3 cm, multiple tumors, H/O TURBT. Results: We demonstrated in the current study that, compared to NLR, preoperative pyuria was more substantially linked with intravesical recurrence, higher T stage and disease progression following TURBT for NMIBC. [ABSTRACT FROM AUTHOR]

Objective To evaluate the presence and subtypes of tertiary lymphatic structures (TLSs) in urothelial carcinoma of the bladder (UCB) and to analyze their associated clinicopathological characteristics and prognostic significance. Methods The study enrolled 580 patients with surgically treated UCB, including 313 non-muscle invasive bladder cancer (NMIBC) and 267 muscle-invasive bladder cancer (MIBC). The presence and subtypes of TLSs were identified by immunohistochemistry (CD20, CD3, Bcl-6, and CD21). TLSs were classified into non-GC (nGC) TLS and GC TLS subtypes based on germinal center (GC) formation. Disease-free survival (DFS) was used as an endpoint outcome to evaluate the prognostic significance of TLS and its subtypes in UCB. Results TLSs were more common in MIBC than in NMIBC (67.8% vs 48.2%, P  < .001), and the tumor-infiltrating lymphocyte (TIL) mean density was significantly higher in MIBC than in NMIBC (24.0% vs 17.5%, P  < .001). Moreover, a positive correlation was found between TLS presence and GC structure formation and TIL infiltration in UCB. Endpoint events occurred in 191 patients. Compared to patients with endpoint events, patients without disease progression exhibited higher TIL density and more TLSs (P <.05). Kaplan–Meier curves showed that TLS was associated with better DFS in NMIBC (P  = .041) and MIBC (P  = .049). However, the Cox multivariate analysis did not demonstrate the prognostic significance of TLS. Conclusions TLS is heterogeneous in UCB, and that TLS and GC structures are related to TIL density and prognostic events. However, TLS as a prognostic indicator remains unclear, warranting further investigation. [ABSTRACT FROM AUTHOR]

Abstract Background Bladder cancer is the most common tumor of the genitourinary tract. Transitional cell carcinoma is divided into two categories: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). In spite of the high recurrence rate, NMIBC has good prognosis, while MIBC has poor prognosis due to local organ invasion and metastases. Mp-MRI shows better tumor detection and staging. The aim of this study is to validate VI-RADS in detecting MIBC and assessing interobserver agreement and impact of reader's experience. Results At cutoff value of VI-RADS score ≥ 3, the VI-RADS showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 96.8%,83.3%, 93.8%, 90.9%, and 93%, respectively, for reader 1, 93.5%, 91.7%, 84.6%, and 93% for reader 2, and 96.8%,83.3%, 93.8%, 90.9%, and 93% for reader 3. The interobserver agreement between individual readers was excellent among the three readers. Conclusions Vesical imaging-reporting and data system (VI-RADS) is a good method showing satisfactory sensitivity, specificity, and diagnostic value for detecting detrusor muscle invasion.

Abstract Background The primary objective of the research was to develop a method using radiomics-based computed tomography (CT) to predict muscle invasion in bladder cancer (BCa) before surgery. Methods A total of 269 patients with bladder cancer were divided into two groups; training group (n = 188 cases) and validation group (n = 81 cases). Radiomics characteristics were determined by analyzing the CT images of each patient. The least absolute shrinkage and selection operator (LASSO) technique was used for developing a radiomics signature. Furthermore, logistic regression (LR), the support vector machine (SVM), decision tree (DT), and Artificial Neural Network (ANN) models were applied to differentiate between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Their performance was determined using the area under the receiver operating characteristic curve (AUC-ROC). In addition, accuracy, specificity, and sensitivity evaluations were also conducted. Results The radiomics signature was found to be successful in its prediction. A total of 1036 radiomics features were found in the 269 patients, and out of those, 16 were selected as the best predictors of radiomics features. The results revealed that the ANN classifier had the best performance, with a validation set accuracy of 0.950. Conclusions The current work used machine learning and radiomics techniques to successfully construct a prediction model for muscle invasion in bladder cancer. The ANN model produced significant outcomes that may be used in clinical diagnosis or therapy.

To the Editor, Bladder cancer is one of the most common cancers in humans, representing the 7th and 17th type of neoplasm in both genders. Its incidence and mortality are quite heterogeneous in different countries and are due to different risk factors, quality and prevalence of healthcare and the possibility of early diagnosis and treatment of the tumor and its potential recurrences. [...]

Introduction: Local therapies for high risk non-muscle-invasive bladder cancer (NMIBC) such as intravesical chemotherapy (IVC) have shown a high rate of progression and recurrence (1). Intravesical Bacillus Calmette-Guérin (BCG) for local therapies has been shown to reduce progression and recurrence in patient with NMIBC. However, its potential role is limited in high burden countries for tuberculosis (TB) due to its low specificity that can cause wrong diagnosis or false positive in patients with clinically diagnosed tuberculosis. BCG vaccine that has to be given for most people in tuberculosis endemic countries will induce trained immunity that could reduce the effectivity of intravesical BCG for NMIBC Moreover, intravesical BCG is contraindicated in patient with or previous tuberculosis. The potential clinical benefit of intraarterial chemotherapy (IAC) in delaying the recurrence and progression of high-risk NMIBC have been investigated with promising results (2, 3). We aimed to conduct a meta-analysis to evaluate the potential anti-tumor effect of IAC in NMIBC. Methods: We conducted a comprehensive search of published articles in Cochrane Library, Pubmed, and Science-Direct to identify relevant randomized controlled trials (RCTs) and observational studies comparing IAC alone or combined with IVC versus IVC/BCG alone in NMIBC. The protocol of preferred reporting items for systematic review and meta-analysis (PRISMA) was applied to this study. Results: Four RCTs and 4 cohort observational studies were eligible in this study and 5 studies were included in meta-analysis. The risk ratio of tumor recurrence was reduced by 35% (RR = 0.65; 95% CI 0.49-0.87; p = 0.004) in IAC plus IVC, while recurrence-free survival (RFS) was prolonged by 45% (HR: 0.55; 95% CI, 0.44-0.69; p < 0.001). The risk of tumor progression was reduced by 45% (RR = 0.55; 95% CI 0.41-0.75; p = 0.002) and tumor progression-free survival (PFS) was also prolonged by 53% (HR: 0.47; 95% CI, 0.34-0.65; p < 0.001). Some RCT’s had high or unclear risk of bias, meanwhile 4 included cohort studies had overall low risk of bias, therefore the pooled results need to be interpreted cautiously. Subgroup analysis revealed that the heterogeneity outcome of tumour recurrence might be attributed to the difference in NMIBC stages and grades. Conclusions: The IAC alone or combined with IVC following bladder tumor resection may lower the risk of tumor recurrence A systematic review and meta-analysis of intraarterial chemotherapy for non muscle invasive bladder cancer: Promising alternative therapy in high tuberculosis burden countries Zakaria Aulia Rahman 1, 2, Furqan Hidayatullah 1, 2, Jasmine Lim3, Lukman Hakim1, 4 1 Department of Urology, Faculty of Medicine, Universitas Airlangga; 2 Dr. Soetomo General-Academic Hospital, Surabaya, East Java, Indonesia; 3 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 4 Universitas Airlangga Teaching Hospital, Surabaya, East Java, Indonesia. DOI: 10.4081/aiua.2024.12154 Summary and progression. These findings highlight the importance of further multi institutional randomized controlled trials with bigger sample size using a standardized IAC protocol to validate the current results.

IntroductionInduction intravesical Bacillus Calmette-Guerin (BCG) followed by maintenance after transurethral resection of bladder tumor, is the standard adjuvant therapy for high-risk non-muscle invasive bladder cancer (NMIBC). There is sparse evidence on the practice of intravesical BCG in Australia. Our aim was to determine the outcomes of intravesical BCG therapy in NMIBC in Southwestern Sydney.MethodsThis was a multi-center retrospective audit of NMIBC patients who received intravesical BCG between January 2008 and June 2020. Data was collected across six tertiary hospitals in South Western Sydney. Primary outcome was disease-free survival (DFS). Secondary outcomes were overall survival (OS), BCG induction and maintenance rates.ResultsOf the 200 eligible patients over 12.5 years, median age was 77 years and 83% were male. Of these, 55%, 4.5%, 35% and 5% were Tis, Ta, T1 and unknown stage, respectively. All patients received induction BCG and 56% received maintenance BCG (range 3-36 months). Completion rate of induction BCG was 91%. Only 9% ceased treatment due to intolerance. The median duration of cystoscopy follow-up was 17 months. After a median follow-up time of 37 months, 55% developed recurrence (29% non-muscle invasive, 32% muscle-invasive disease, 8% distant metastasis). The 1-year and 5-year DFS rates were 72% and 41% (median DFS: 39 months). The 1-year and 5-year OS rates were 98% and 87% (median OS: not reached).ConclusionThe DFS and OS rates were comparable to previous literature. This provides real-world data to assist future clinical trials in NMIBC.

Non-muscle invasive bladder cancer (NMIBC) accounts for ~70-75% of total bladder cancer tumors and requires effective early intervention to avert progression. The cornerstone of high-risk NMIBC treatment involves trans-urethral resection of the tumor followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. However, BCG therapy is commonly accompanied by significant lower urinary tract symptoms (LUTS) including urinary urgency, urinary frequency, dysuria, and pelvic pain which can undermine treatment adherence and clinical outcomes. Despite this burden, the mechanisms underlying the development of BCG-induced LUTS have yet to be characterized. This review provides a unique perspective on the mechanisms thought to be responsible for the development of BCG-induced LUTS by focussing on the sensory nerves responsible for bladder sensory transduction. This review focuses on how the physiological response to BCG, including inflammation, urothelial permeability, and direct interactions between BCG and sensory nerves could drive bladder afferent sensitization leading to the development of LUTS. Additionally, this review provides an up-to-date summary of the latest clinical data exploring interventions to relieve BCG-induced LUTS, including therapeutic targeting of bladder contractions, inflammation, increased bladder permeability, and direct inhibition of bladder sensory signaling. Addressing the clinical burden of BCG-induced LUTS holds significant potential to enhance patient quality of life, treatment compliance, and overall outcomes in NMIBC management. However, the lack of knowledge on the pathophysiological mechanisms that drive BCG-induced LUTS has limited the development of novel and efficacious therapeutic options. Further research is urgently required to unravel the mechanisms that drive BCG-induced LUTS. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the combined efficacy of hyperthermia and chemotherapy using a bladder cancer organoid model and to explore hyperthermia-related molecular pathways. Method: Tumor organoids were generated by embedding RT4 bladder cancer cells into Matrigel. The resulting organoids were treated with pirarubicin or gemcitabine at 37 °C or 42 °C. Proliferation was determined by Ki67 immunofluorescence staining, and apoptosis was assessed using a TdT-mediated dUTP nick end labeling (TUNEL) assay. RNA sequencing was used to identify the differentially expressed genes. Results: Bladder cancer organoids were successfully established and exhibited robust proliferative abilities. Treatment with gemcitabine or pirarubicin under hyperthermic conditions caused pronounced structural damage to the organoids and increased cell death compared to that in the normothermically treated group. Furthermore, Ki67 labeling and TUNEL assays showed that the hyperthermia chemotherapy group showed a significantly reduced proliferation rate and high level of apoptosis. Finally, RNA sequencing revealed the IFN-γ signaling pathway to be associated with hyperthermia. Conclusion: Overall, hyperthermia combined with chemotherapy exerted better therapeutic effects than those of normothermic chemotherapy in grade 1-2 non-muscle-invasive bladder cancer, potentially through activation of the IFN-γ-JAK-STAT pathway. [ABSTRACT FROM AUTHOR]

Objectives: Multiple clinical practice guidelines, conflicting evidence, and physician perceptions result in variations in risk stratification among patients with non‐muscle‐invasive bladder cancer (NMIBC). This study aims to describe the extent of this variation and its impact on management approaches in the Asia‐Pacific region. Methods: We conducted a cross‐sectional survey involving 32 urologists and seven medical oncologists with ≥8 years of experience managing early‐stage bladder cancer patients across Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. The physicians completed an anonymous questionnaire that assessed their risk stratification and respective management approaches, based on 19 NMIBC characteristics. For each NMIBC characteristic, they were required to select one risk group, and their most preferred management approach. Results: Our results demonstrated a higher consensus on risk classification versus management approaches. More than 50% of the respondents agreed on the risk classification of all NMIBC characteristics, but 42% or fewer chose the same treatment option as their preferred choice for all but two characteristics—existence of variant histology (55%) and persistent high‐grade T1 disease on repeat resection (52%). Across territories, there was the greatest variation in preferred treatment options (i.e., no treatment, intravesical chemotherapy, or Bacillus Calmette‐Guérin [BCG] treatment) for intermediate‐risk patients and the highest consensus on the treatment of very high‐risk patients, namely radical cystectomy. Conclusions: Our study revealed considerable variation in risk stratification and management of NMIBC in the region. It is critical to develop practical algorithms to facilitate the recognition of NMIBC and standardize the treatment of NMIBC patients. [ABSTRACT FROM AUTHOR]

Background Transurethral resection of the bladder tumor (TURBT) is the treatment of choice and gold standard for the treatment of clinical non-muscle invasive bladder cancer. Incomplete resection, tumor cell re-implantation, presence of subclinical tumors lead to recur rence of bladder cancer. According to guideline recommendations, restage TURBT is indicated 2-6 weeks after the initial TURBT in high-risk patients. The objective of the present study was undertaken to evaluate role of restage TURBT in high risk nonmuscle invasive bladder cancer (NMIBC). Objective To identify the category of patients with high risk non-muscle invasive bladder cancer who may benefit from a routine restage TURBT procedure. Materials and Methods In this prospective observational study, biopsy proven NMIBC patients with gross total painless hematuria secondary to urinary bladder mass from October 2017 to June 2019 were enrolled. Patients with high risk disease on primary TURBT underwent re-TURBT within 2-6 weeks of primary procedure. Residual/recurrent disease and tumor upstaging were recorded. Logistic regression analysis were used to explore risk factors associated with residual/recurrent disease and tumor upstaging during re-TURBT. Results A total of 250 patients (deep muscle involvement, n=237 and no muscle involvement, n=13) with histopathologically confirmed high risk disease following re-TURBT were included in the final analysis. During re-TURBT, 18% patients had residua or recurrent tumor. Presence of upper tract changes, presence of perivesical fat stranding and tumor size > 3cm, high grade histopathology and positive urine for malignant cytology were significantly associated with risk of residual or recurrent disease. Absence of muscle in primary TURBT specimen, presence of recurrent/residual growth in re-TURBT specimen, bladder tumor antigen increased the risk of upstaging. Conclusion Despite the low recurrence rate of tumor in re-TURBT, reTURBT within 2-6 weeks of primary TURBT is an essential step for the accurate diagnosis among NMIBC patients. This further aids in deciding the subsequent treatment step in patients with upstaging and recurrent/residual tumor. [ABSTRACT FROM AUTHOR]

Simple Summary: For certain malignancies, comorbidities are associated with an increased risk of cancer recurrence. However, it is unknown if this is also true for localized, non-muscle-invasive bladder cancer. The Charlson–Deyo comorbidity score is a commonly used tool for comorbidity-associated survival. We relied on this tool to stratify patients into low vs. high comorbidity burden groups and tested whether the comorbidity burden affected the risk of recurrence. Our data suggest that patients who harbor a high comorbidity burden have an increased risk of tumor recurrence. Purpose: To test the association between the Charlson–Deyo Comorbidity Index (CCI) and the recurrence of non-muscle-invasive bladder cancer (NMIBC). Methods: NMIBC (Ta, T1, TIS) patients who underwent transurethral resection of bladder tumor (TURB) between 2010 and 2018 were identified within a retrospective data repository of a large university hospital. Kaplan–Meier estimates and uni- and multivariable Cox regression models tested for differences in risk of recurrence according to low vs. high comorbidity burden (CCI ≤ 4 vs. >4) and continuously coded CCI. Results: A total of 1072 NMIBC patients were identified. The median follow-up time of the study population was 55 months (IQR 29.6–79.0). Of all 1072 NMIBC patients, 423 (39%) harbored a low comorbidity burden vs. 649 (61%) with a high comorbidity burden. Overall, the rate of recurrence was 10% at the 12-month follow-up vs. 22% at the 72-month follow-up. In low vs. high comorbidity burden groups, rates of recurrence were 6 vs. 12% at 12 months and 18 vs. 25% at 72 months of follow-up (p = 0.02). After multivariable adjustment, a high comorbidity burden (CCI > 4) independently predicted a higher risk of recurrence (HR 1.42, 95% confidence interval (CI) 1.06–1.92, p = 0.018). After multivariable adjustment, the hazard of recurrence increased by 5% per each one-unit increase on the CCI scale (HR 1.05, 95% CI 1.00–1.10, p = 0.04). Conclusions: Comorbidities in NMIBC patients are common. Our data suggest that patients with higher CCI have an increased risk of BC recurrence. As a consequence, patients with a high comorbidity burden should be particularly encouraged to adhere to NMIBC guidelines and conform to follow-up protocols. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is the most common tumor of the genitourinary tract. Transitional cell carcinoma is divided into two categories: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). In spite of the high recurrence rate, NMIBC has good prognosis, while MIBC has poor prognosis due to local organ invasion and metastases. Mp-MRI shows better tumor detection and staging. The aim of this study is to validate VI-RADS in detecting MIBC and assessing interobserver agreement and impact of reader's experience. Results: At cutoff value of VI-RADS score ≥ 3, the VI-RADS showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 96.8%,83.3%, 93.8%, 90.9%, and 93%, respectively, for reader 1, 93.5%, 91.7%, 84.6%, and 93% for reader 2, and 96.8%,83.3%, 93.8%, 90.9%, and 93% for reader 3. The interobserver agreement between individual readers was excellent among the three readers. Conclusions: Vesical imaging-reporting and data system (VI-RADS) is a good method showing satisfactory sensitivity, specificity, and diagnostic value for detecting detrusor muscle invasion. [ABSTRACT FROM AUTHOR]

Objective: To investigate how well the Sysmex automated urine-analyzer’s atypical-cell parameter can predict oncological outcomes when compared to cytology and pathology data in the follow-up of NMIBC patients. Material and Methods: We prospectively collected clinical data from 273 patients who underwent cystoscopic examination due to benign and malign reasons in our center between June 2020 and March 2021. Patients were divided into 2 groups. (Group-1: Patients with no previous diagnosis of bladder cancer(BC), Group-2: Patients with previously diagnosed NMIBC). The a typical-cell parameter was determined by studying the urine sample given by the patient for urinalysis. The atypical-cell parameter’s sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were assessed. Results: A total of 76(41.1%) patients underwent diagnostic procedures (Group-1) and remaining 109(58.9%) patients were NMIBC patients (Group-2) who subjected to control cystoscopy on follow-up. BC was detected in 70 patients, 28 of whom were newly diagnosed (Group-1). Remaining 42 patients had recurrence during their follow-up (Group-2). Atypical cell values of 70 patients with BC were determined to be statistically significantly higher than those without malignancy. In Group-2, median atypical-cell values for those with no malignancy, those with low-grade BC reccurrence, and those with high-grade BC recurrence were 0.00(IQR:0.00–0.80), 0.25(IQR:0.10℃1.10) and 1.20(IQR:0.70–2.15), respectively (p<0.001). For a cut-off of 0.1 atypical cells/µL, sensitivity and specificity were measured as 83.33% and 53.73%, respectivel (AUC:0.727;p-value<0.001). Conclusion: Atypical-cell parameter of the Sysmex-UF-5000 automated urine-analyzer is a newly introduced research parameter. The results of this study are promising. Based on our results, we presume that the atypical-cell parameter may be used in surveillance of the NMIBC patients. Multi-center studies with larger patient populations are required to prove its efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: BCG immunotherapy plays an important role in bladder cancer treatment. Unfortunately, we do not know how exactly the tumor microenvironment influences cancer cells and which cells have the most important impact on the outcome. The aim of the study was to assess how the components of the microenvironment affect tumor recurrence. We show that patients with intense CD4+ cell infiltration (>4.6%) or weak CD20+ cell infiltration (<10%), as well as patients with high PD-L1 expression on tumor cells (≥1%), could be characterized by a higher risk of recurrence. Our results provide data with potential clinical utility and may be essential for the assessment of tumor immunological status, which would be taken into account when selecting a follow-up and treatment strategy. Introduction: A tumor microenvironment plays an important role in bladder cancer development and in treatment response. Purpose: The aim of the study was to assess how the components of the microenvironment affect tumor recurrence and to find the potential biomarkers for immunotherapy in NMIBC. Methods: The study group consisted of 55 patients with primary NMIBC. Immunohistochemistry was performed on sections of primary papillary urothelial carcinoma of the bladder. Cox proportional hazard multiple regression analysis was performed to characterize tumors with the highest probability of an unfavorable outcome. Results: Multivariate analysis confirmed that the CD4 (p = 0.001), CD20 (p = 0.008) and PD-L1 expressed on tumor cells (p = 0.01) were independently associated with the risk of recurrence of bladder cancer. Patients with weak CD4+ cell infiltration (<4.6%) and severe CD20+ infiltration (>10%) belong to the group with a lower risk of recurrence. The cancer in this group also frequently recurs after 12 months (p = 0.0005). Conclusions: The evaluation of CD4+ and CD20+ cells in the tumor microenvironment, in addition to PD-L1 on tumor cells, facilitates the determination of a group of patients with a low risk of recurrence. [ABSTRACT FROM AUTHOR]

Bladder cancer has a significant impact on patients, in terms of both morbidity and financial burden. This is especially true for patients with nonmuscle-invasive bladder cancer, who undergo long-term surveillance via cystoscopy and imaging, resulting in significant costs and risks. To address this issue, urinary tumor DNA analysis, or “urinary liquid biopsy,” has emerged as a potential solution to reduce the testing burden and mitigate many of the costs and risks. Over time, urinary tumor DNA analysis has undergone several refinements. However, existing FDA-approved urinary biomarker assays currently lack the sensitivity and specificity to significantly impact clinical decision-making. Subsequent iterations of these technologies have attempted to bridge this gap by improving their diagnostic accuracy, and ultimately, clinical utility. Here, we discuss the current role as well as future directions of urinary tumor DNA analysis for the detection and long-term surveillance of nonmuscle-invasive bladder cancer.

Non-muscle invasive bladder cancer (NMIBC) accounts for ~70–75% of total bladder cancer tumors and requires effective early intervention to avert progression. The cornerstone of high-risk NMIBC treatment involves trans-urethral resection of the tumor followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. However, BCG therapy is commonly accompanied by significant lower urinary tract symptoms (LUTS) including urinary urgency, urinary frequency, dysuria, and pelvic pain which can undermine treatment adherence and clinical outcomes. Despite this burden, the mechanisms underlying the development of BCG-induced LUTS have yet to be characterized. This review provides a unique perspective on the mechanisms thought to be responsible for the development of BCG-induced LUTS by focussing on the sensory nerves responsible for bladder sensory transduction. This review focuses on how the physiological response to BCG, including inflammation, urothelial permeability, and direct interactions between BCG and sensory nerves could drive bladder afferent sensitization leading to the development of LUTS. Additionally, this review provides an up-to-date summary of the latest clinical data exploring interventions to relieve BCG-induced LUTS, including therapeutic targeting of bladder contractions, inflammation, increased bladder permeability, and direct inhibition of bladder sensory signaling. Addressing the clinical burden of BCG-induced LUTS holds significant potential to enhance patient quality of life, treatment compliance, and overall outcomes in NMIBC management. However, the lack of knowledge on the pathophysiological mechanisms that drive BCG-induced LUTS has limited the development of novel and efficacious therapeutic options. Further research is urgently required to unravel the mechanisms that drive BCG-induced LUTS.