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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]

Bladder cancer (BC) is the most common malignancy of the urinary tract. About 75% of all BC patients present with non-muscle-invasive BC (NMIBC), of which up to 70% will recur, and 15% will progress in stage and grade. As the recurrence and progression rates of NMIBC are strongly associated with some clinical and pathological factors, several risk stratification models have been developed to individually predict the short- and long-term risks of disease recurrence and progression. The NMIBC patients are stratified into four risk groups as low-, intermediate-, high-risk, and very high-risk by the European Association of Urology (EAU). Significant heterogeneity in terms of oncological outcomes and prognosis has been observed among NMIBC patients within the same EAU risk group, which has been partly attributed to the intrinsic heterogeneity of BC at the molecular level. Currently, we have a poor understanding of how to distinguish intermediate- and (very-)high-risk NMIBC with poor outcomes from those with a more benign disease course and lack predictive/prognostic tools that can specifically stratify them according to their pathologic and molecular properties. There is an unmet need for developing a more accurate scoring system that considers the treatment they receive after TURBT to enable their better stratification for further follow-up regimens and treatment selection, based also on a better response prediction to the treatment. Based on these facts, by employing a multi-layered - omics (namely, genomics, epigenetics, transcriptomics, proteomics, lipidomics, metabolomics) and immunohistopathology approach, we hypothesize to decipher molecular heterogeneity of intermediate- and (very-)high-risk NMIBC and to better stratify the patients with this disease. A combination of different -omics will provide a more detailed and multi-dimensional characterization of the tumor and represent the broad spectrum of NMIBC phenotypes, which will help to decipher the molecular heterogeneity of intermediate- and (very-)high-risk NMIBC. We think that this combinatorial multi-omics approach has the potential to improve the prediction of recurrence and progression with higher precision and to develop a molecular feature-based algorithm for stratifying the patients properly and guiding their therapeutic interventions in a personalized manner. [ABSTRACT FROM AUTHOR]

Background: The predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette–Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy. Methods: For this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Seven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34–5.32, P < 0.001) and progression (HR = 1.72, 95% CI = 1.13–2.60, P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy. Conclusion: This meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT. Systematic review registration: https://inplasy.com/inplasy-2024-7-0058/ , identifier 202470058. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is still the most common cancer of the bladder tract and the ninth most common cancer in the world. Most people who get bladder cancer have nonmuscle invasive bladder cancer (NMIBC), which has a much lower death rate than muscle invasive bladder cancer. Urologists are now more interested in enbloc removal of bladder tumor (ERBT), but there are only a few small studies that look at hydrodissemination during ERBT. ERBT gives a lot of detrusor muscle samples (more than 95%) and good samples for figuring out what's wrong. So far, it hasn't been looked into whether second resections can be avoided. All energy tools, like lasers and electric cautery, have been used to do ERBT with the same positive effects on the patient and the cancer. Conclusions: The numbers show that there isn't a big difference between normal and perioperative morbidity transurethral resection of bladder tumors, but only a few of the papers used a structured way to group them. There are no conclusions that can be made about how ERBT affects recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: Follow-up protocols for non-muscle-invasive bladder cancer (NMIBC) include mainly cystoscopy and urinary cytology. However, the role of urine cytology during follow-up for low-grade (LG) NMIBC is not entirely known, and studies assessing adherence to guideline recommendations have revealed an overuse of urinary cytology. Our aim with this study was to evaluate the impact of urine cytology as a complementary method to cystoscopy during follow-up for LG NMIBC. We found that performing urine cytology during follow-up for primary LG non-muscle-invasive bladder cancer is only useful to detect recurrences when suspicious lesions are seen during cystoscopic evaluation. Nevertheless, a positive cytology alerts to the risk of progression to high-grade disease during surveillance. Background and Objective: The role of urine cytology during follow-up for low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is not well established, although cytology has low sensitivity in detecting LG recurrences. Our study aims to evaluate the impact of urine cytology as a complementary method to cystoscopy during follow-up for LG NMIBC. Methods: Patients diagnosed with primary LG TaT1 bladder cancer (BC) between 2010 and 2020 were included. Patients were stratified according to the EAU NMIBC scoring model. Urine cytology was performed during follow-up cystoscopy. The outcomes of the study were BC recurrence and upgrading to high-grade (HG). Cytology utility was established by assessing whether its result led to management change. Results: We included 337 patients with LG TaT1 BC. EAU risk group distribution was low in 262 (77.7%), intermediate in 57 (16.9%), and high-risk in 18 (5.3%) cases. With a median follow-up of 5 years, 166 (49.3%) patients experienced recurrence. Cystoscopy was positive in 154 (92.8%) and suspicious in 12 (7.2%) cases. Urine cytology was positive in 33 (19.9%) cases but only changed management in 3 (0.89%), all with suspicious cystoscopy. Positive cytology at first recurrence was associated with higher risk of upgrading during follow-up (HR 2.781, p = 0.006) and lower upgrading-free survival (p = 0.001). Conclusions: The role of urine cytology to detect first recurrences during follow-up for primary LG TaT1 NMIBC might be limited to patients with non-conclusive lesions in the cystoscopy. A positive cytology at first recurrence is associated with a higher risk of upgrading to HG BC during follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer is the ninth most commonly diagnosed form of cancer in both sexes worldwide and the fifth in Europe. The most common form, non-muscle-invasive bladder cancer, is highly prevalent with high recurrence rates and has wide range of outcomes that is partially due to the variability in the treatment delivered. Therefore, some recommendations have been done by the European Association of Urology to standardize their management. Several quality control indicators have been proposed to monitor the adherence of urologists and hospitals to these recommendations. A quality control indicator program has been initiated in the hospitals that are a part of the Flemish Hospital Network in June 2013 using a specific prospective registry. We have recently published the first analysis of these quality control indicators, which showed significant differences between the hospitals. Before publishing the second analysis with more patients and additional quality control indicators, we aimed to describe the characteristics of the cohort in this study. Purpose: Bladder cancer (BC) is a heterogeneous disease with varying outcomes, influenced by disease heterogeneity and variability in treatment and follow-up. Risk groups have been established for non–muscle-invasive BC (NMIBC) to standardize therapy, and several quality control indicators (QCIs) monitor adherence to these risk group-based guidelines. However, controversial results had been obtained regarding the oncological benefits of these QCIs until recent high-quality studies from large registries showed their usefulness. To improve adherence to the European Association of Urology (EAU) Guidelines and benchmark current care in Flemish hospitals within Vlaams Ziekenhuisnetwerk–KU Leuven (VZNKUL), a QCI program for NMIBC was initiated in 2013. This study aims to describe the demographic, clinical, and treatment data of patients enrolled in this program. Participants: The VZNKUL–NMIBC Quality Indicators Program Registry is a prospective cohort including patients treated and followed up with at seven academic and non-academic Flemish hospitals since June 2013. Data collection includes patient characteristics, tumor data, treatment, and oncological outcomes. Findings to date: From June 2013 to December 2020, 4744 transurethral resections of bladder tumors (TURBTs) from 2237 unique patients were analyzed. Most patients (80%) were men with a median age of 73. The median time from diagnosis to TURBT was 19 days. A single tumor was detected in 37% of TURBTs. Tumors larger than 3 cm were found in 20.8% of cases. In 46% of TURBTs, a reTURBT was scheduled according to guidelines. The complication rates were 7.5% and 2.4% for bladder perforation and bleeding, respectively. Postoperative single intravesical instillation of chemotherapy (SIVIC) was administered to 56.9% of 1533 indicated patients with a median time to administration of 4.7 h. Among the cohort, 60.4% had NMIBC, and 9.3% had muscle-invasive BC. Of 972 high-risk patients, 60.7% received adequate BCG induction, while 39.4% received adequate maintenance. After BCG induction ± maintenance, 39.7% were tumor-free, with 17.7% recurrence and 4% progression to muscle-invasive BC. BCG treatment was terminated early for 17% of patients due to intolerance. Early cystectomy was performed for 2.4% of the BCG-naïve patients, and 27.7% of patients with BCG failure underwent a BCG rechallenge. For intermediate-risk patients, 2.1% received adequate BCG, and 23% received intravesical chemotherapy. The median follow-up was 57 months. Five-year recurrence-free, progression-free, cancer-free, overall, and cancer-specific survival rates were 53%, 91.6%, 89%, 70.6%, and 95.6%, respectively, for the NMIBC patients. Of 400 non-metastatic MIBC patients, 217 (54.3%) underwent radical cystectomy (RC), of whom 46% received neoadjuvant chemotherapy, while 18 (4.5%) refused RC, and 74 (18.5%) were considered unfit for the surgery. Future plans: The VZNKUL–NMIBC Quality Indicators Program Registry will continue collecting data to evaluate QCIs and monitor treatment quality, enabling hospitals to benchmark their performance and improve patient care. Additionally, the registry's real-world data can support research and international collaboration. Trial registration: The study was registered on ClinicalTrials.gov (NCT04167332). [ABSTRACT FROM AUTHOR]

To investigate the cadence of recurrence in patients with low grade intermediate-risk non-muscle invasive bladder cancer (LG IR-NMIBC) based on clinical determinants. We aim to describe patterns in rates of recurrence to better inform surveillance regimens for this chronic, burdensome, and costly disease. Using baseline and follow-up data from participants in the West Midlands' (United Kingdom, UK) Bladder Cancer Prognosis Programme (BCPP), we assessed overall recurrence rate and recurrence-free intervals throughout the follow-up period for IR-NMIBC participants. Recurrence-free intervals were calculated using the Kaplan-Meier method. We identified 379 patients with G1/G2 pTa tumors classified as intermediate risk. Median age was 70 and 284/379 (75%) were male. The median follow-up time was 4.2 years (95% CI: 3.9-4.8). After 5 years of follow-up, 53% of patients had at least one recurrence. One-year recurrence-free survival (RFS) was 75% and 4-year RFS was 50%. The median time to or between 1st, 2nd, 3rd, 4th, and 5th sequential recurrences was 49, 19, 12, 14, and 10 months, respectively. Over half of patients with IR-NMIBC are destined to recur. Our data suggest that a subset of patients experience acceleration of recurrence over time and that this acceleration may serve as a potential kinetic biomarker for these individuals that could inform surveillance intervals and future treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: The incomplete resection of non-muscle invasive bladder cancer (NMIBC) augments the risk of disease recurrence. Imaging-guided surgery by molecular probes represents a pivotal strategy for mitigating postoperative recurrence. Traditional optical molecular probes, primarily composed of antibodies/peptides targeting tumour cells and fluorescent groups, are challenged by the high heterogeneity of NMIBC cells, leading to inadequate probe sensitivity. We have developed a collagen-adhesive probe (CA-P) to target the collagen within the tumour microenvironment, aiming to address the issue of insufficient imaging sensitivity. Methods: The distribution characteristics of collagen in animal bladder cancer models and human bladder cancer tissues were explored. The synthesis and properties of CA-P were validated. In animal models, the imaging performance of CA-P was tested and compared with our previously reported near-infrared probe PLSWT7-DMI. The clinical translational potential of CA-P was assessed using human ex vivo bladder tissues. Results: The distribution of collagen on the surface of tumour cells is distinct from its expression in normal urothelium. In vitro studies have demonstrated the ability of the CA-P to undergo a "sol-gel" transition upon interaction with collagen. In animal models and human ex vivo bladder specimens, CA-P exhibits superior imaging performance compared to PLSWT7-DMI. The sensitivity of this probe is 94.1%, with a specificity of 81%. Conclusion: CA-P demonstrates the capability to overcome tumour cell heterogeneity and enhance imaging sensitivity, exhibiting favorable imaging outcomes in preclinical models. These findings provide a theoretical basis for the application of CA-P in intraoperative navigation for NMIBC. [ABSTRACT FROM AUTHOR]

Purpose: To compare the oncological outcomes between standard radical cystectomy (SRC) and organ-sparing cystectomy (OSC) in male patients diagnosed with bladder cancer. Methods: Patients with stage Ta-T3 bladder cancer who underwent OSC or SRC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The association between preoperative factors and the implementation of OSC was analyzed using logistic regression. Propensity score matching (PSM) was employed to balance baseline characteristics between the two groups. Patients' overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan–Meier method. Subgroup analyses based on the T stage were also conducted. Results: A total of 7264 patients were included, with 96.8% (7033 patients) receiving SRC and 3.2% (231 patients) receiving OSC. Patients with higher T stages and high-grade tumors were less likely to undergo OSC. After PSM, OSC was associated with significantly worse OS and CSS than SRC. Subgroup analysis revealed that OSC did not lead to worse OS and CSS in non-muscle invasive bladder cancer and T2 stage patients, but it resulted in significantly worse outcomes in T3 stage patients. Conclusion: Our study indicates that OSC is associated with poorer oncological outcomes compared to SRC, particularly in patients with advanced-stage tumors. These findings suggest the need for stringent selection criteria for OSC in bladder cancer patients. Given the negative impact on prognosis, stage T3 should potentially be considered a contraindication for OSC. Further evidence is required to confirm these assertions. [ABSTRACT FROM AUTHOR]

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]

The grading of non-muscle invasive bladder cancer (NMIBC) continues to face challenges due to subjective interpretations, which affect the assessment of its severity. To address this challenge, we are developing an innovative artificial intelligence (AI) system aimed at objectively grading NMIBC. This system uses a novel convolutional neural network (CNN) architecture called the multi-scale pyramidal pretrained CNN to analyze both local and global pathology markers extracted from digital pathology images. The proposed CNN structure takes as input three levels of patches, ranging from small patches (e.g., 128 × 128 ) to the largest size patches ( 512 × 512 ). These levels are then fused by random forest (RF) to estimate the severity grade of NMIBC. The optimal patch sizes and other model hyperparameters are determined using a grid search algorithm. For each patch size, the proposed system has been trained on 32K patches (comprising 16K low-grade and 16K high-grade samples) and subsequently tested on 8K patches (consisting of 4K low-grade and 4K high-grade samples), all annotated by two pathologists. Incorporating light and efficient processing, defining new benchmarks in the application of AI to histopathology, the ShuffleNet-based AI system achieved notable metrics on the testing data, including 94.25% ± 0.70% accuracy, 94.47% ± 0.93% sensitivity, 94.03% ± 0.95% specificity, and a 94.29% ± 0.70% F1-score. These results highlight its superior performance over traditional models like ResNet-18. The proposed system's robustness in accurately grading pathology demonstrates its potential as an advanced AI tool for diagnosing human diseases in the domain of digital pathology. [ABSTRACT FROM AUTHOR]

Non-muscle invasive bladder cancer (NMIBC) is currently mainly treated with the approach of transurethral resection of bladder tumor (TURBT) followed by pathology investigation of the obtained specimens. However, this approach—TURBT—has a few drawbacks, owing to the inherent technical defect—"piecemeal" resection. With development of medical science and surgical techniques, a new kind of surgical operation—"en bloc" resection of bladder tumor (ERBT)—emerged, hoping to completely remove bladder tumor with surrounding normal tissue. The detrusor muscle layer beneath the tumor is removed, and the surgical quality of bladder tumor is enhanced, with a better pathological outcome, reduced intraoperative complications and lower recurrence rate eventually. This paper reviews current literature concerning a brief history of ERBT developing, surgical steps, its indications, advantages on surgical margin, recurrence during follow-up, pathological performance—presence of detrusor muscle, residual tumor and upstage, as well as such issue as "is reTURBT necessary after ERBT?" and the guiding significance of ERBT in substaging of T1 bladder cancer. [ABSTRACT FROM AUTHOR]

Recent studies have identified a urinary microbiome, dispelling the myth of urine sterility. Intravesical bacillus Calmette–Guérin (BCG) therapy is the preferred treatment for intermediate to high-risk non-muscle-invasive bladder cancer (BCa), although resistance occurs in 30–50% of cases. Progression to muscle-invasive cancer necessitates radical cystectomy. Our research uses 16S rRNA gene sequencing to investigate how the urinary microbiome influences BCa and its response to BCG therapy. Urine samples were collected via urethral catheterization from patients with benign conditions and non-muscle-invasive BCa, all of whom underwent BCG therapy. We utilized 16S rRNA gene sequencing to analyze the bacterial profiles and metabolic pathways in these samples. These pathways were validated using a real metabolite dataset, and we developed predictive models for malignancy and BCG response. In this study, 87 patients participated, including 29 with benign diseases and 58 with BCa. We noted distinct bacterial compositions between benign and malignant samples, indicating the potential role of the toluene degradation pathway in mitigating BCa development. Responders to BCG had differing microbial compositions and higher quinolone synthesis than non-responders, with two Bifidobacterium species being prevalent among responders, associated with prolonged recurrence-free survival. Additionally, we developed highly accurate predictive models for malignancy and BCG response. Our study delved into the mechanisms behind malignancy and BCG responses by focusing on the urinary microbiome and metabolic pathways. We pinpointed specific beneficial microbes and developed clinical models to predict malignancy and BCG therapy outcomes. These models can track recurrence and facilitate early predictions of treatment responses. [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]

Background: Urothelial carcinoma presents as non-muscle-invasive bladder cancer (NMIBC) in ~75% of primary cases. Addressing the limitations of the TNM and WHO04/16 classification systems, this study investigates genetic alterations, the mitotic activity index (MAI), and immunohistochemistry (IHC) markers CK20, p53, and CD25 as better prognostic biomarkers in NMIBC. Methods: Using the Oncomine™ Focus Assay for targeted next-generation sequencing (NGS), 409 single-nucleotide variations (SNVs) and 193 copy number variations (CNVs) were identified across 287 patients with TaT1 tumors. Results: FGFR3 and PIK3CA alterations were significantly more prevalent in Ta tumors, while T1 tumors had significant ERBB2 alterations. Low-grade (LG) tumors were enriched with FGFR3 alterations, while high-grade (HG) tumors were significantly associated with ERBB2 alterations, as well as FGFR1 and CCND1 amplifications. FGFR3 alterations were linked to shorter recurrence-free survival (RFS; p = 0.033) but improved progression-free survival (PFS; p < 0.001). Conversely, ERBB2 alterations (p < 0.001), ERBB3 mutations (p = 0.044), and both MYC (p < 0.001) and MYCN (p = 0.011) amplifications were associated with shorter PFS. Survival analysis of gene sets revealed inverse associations between PIK3CA and ERBB2 (p = 0.003), as well as PIK3CA and MYC (p = 0.005), with PFS. Conclusions: In multivariate Cox regression, MAI was the strongest predictor for PFS. Integrating genetic alterations and histopathological features may improve risk stratification in NMIBC. [ABSTRACT FROM AUTHOR]

To assess if receiving sequential intravesical chemotherapy (Gemcitabine-Docetaxel, Gem-Doce) therapy was associated with similar oncologic efficacy to bacillus Calmette-Guérin (BCG) in patients with treatment-naïve, high-risk non-muscle invasive bladder cancer (HR-NMIBC). Single-center, retrospective cohort study of 80 patients with HR-NMIBC initiating first-line Gem-Doce or BCG between August 2020 and August 2023. Surveillance was conducted with cystoscopy, urine cytology, and cross-sectional imaging. The primary oncologic outcome was high-grade bladder tumor recurrence during surveillance. Kaplan-Meier method was applied to determine 12- and 24-month recurrence-free survival (RFS) after initiation of therapy. Tolerance of each intravesical therapies was assessed. About 53/80 (66%) received Gem-Doce and 27/80 (34%) received BCG with overall 18-month median follow-up. There were 10 recurrences after Gem-Doce and 7 after BCG. The RFS at 12- and 24-months for Gem-Doce (12-months: 87%, 24-months: 75%) was not significantly different than BCG (12-months: 85%, 24-months: 81%). Lastly, Gem-Doce had significantly fewer patients with AEs compared to BCG (40% vs 74%). Limitations include retrospective design, small cohort size, and intermediate oncologic follow-up. Our data suggest that sequential intravesical Gem-Doce is an oncologically efficacious and, potentially better tolerated, alternative to BCG for treatment-naïve HR-NMIBC. [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]

The study aimed to examine the impact of diabetes mellitus type 2 (DMII) on the oncological outcomes of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) using comprehensive real-world data. We performed an analysis of data on NMIBC patients treated with BCG from the United States (US) National Phase II BCG/Interferon (IFN) trial database (125 centers) and pooled databases from three tertiary care institutions: France (FR), Lebanon (LB) (2000–2021), and the US (University of Iowa) (2011–2021). There were 867 patients from the Phase II trial, 1232 from the FR/LB cohort, and 233 from the US (Iowa) cohort (n = 2332). DM II was reported in 13% of the Phase II trial cohort, 14.4% of the FR/LB cohort, and 33.5% of the US (Iowa) cohort. The median follow-up was 24 months in the Phase II trial cohort, 25 months in the FR/LB cohort, and 48 months in the US (Iowa) cohort. In multivariable Cox regression analyses, DMII was not significantly associated with recurrence or progression of the tumor in any of the cohorts included in this study. DMII may not be a clinical prognostic factor for NMIBC patients treated with BCG. Prospective evaluation is needed. [ABSTRACT FROM AUTHOR]

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette–Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. [ABSTRACT FROM AUTHOR]

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Background/Objectives: Bladder cancer is a very important issue in contemporary urology. The aim of this pilot study was to assess for the first time the clinical utility of semaphorin 3C (sema3C) and 4A (sema4A) in patients with non-muscle-invasive bladder cancer (NMIBC). Methods: The experiment involved 15 patients with NMIBC and 5 patients without malignancies as the control group. Plasma and urinary concentrations of sema3C and sema4A were assessed by using an enzyme-linked immunosorbent assay (ELISA). Urinary sema4A concentration was below the detection level. Results: There was no statistically significant difference between patients and controls in terms of plasma sema4A and sema3C or urinary sema3C concentrations (p > 0.05). There was a significantly higher sema3C plasma concentration in patients with low-grade tumors (p = 0.0132) and an upward trend in sema4A plasma concentration for the subjects with Ta-stage tumors. Urinary sema3C concentration positively correlated with tumor size (R = 0.57, p = 0.03). Plasma sema3C concentration correlated negatively with tumor grade (R = −0.62, p = 0.01). Conclusions: Urinary sema4A concentration, which is below the detection threshold, is unlikely to be useful as a marker of NMIBC. Plasma sema4A concentration and sema3C concentration in plasma and urine cannot be used as stand-alone markers of NMIBC at this point. The plasma concentration of sema3C can potentially be considered in the future as a marker for tumors of lower grades. Plasma sema4A concentration could potentially be considered in the future as a marker for tumors of earlier stages. All of these observations are preliminary, so they have to be assessed in larger cohorts to make reliable recommendations. Nevertheless, our study lays the groundwork for further research to develop potential tests that could be used in daily practice to monitor and predict the course of cancer. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) prognosis varies significantly due to the biological and clinical heterogeneity. High-risk stage T1-G3, comprising 15–20% of NMIBCs, involves the lamina propria and is associated with higher rates of recurrence, progression, and cancer-specific mortality. In the present study, we have evaluated the enumeration of tumour-derived extracellular vesicles (tdEVs) and circulating tumour cells (CTCs) in high-risk NMIBC patients and their correlation with survival outcomes such as time to progression (TTP), and cancer-specific survival (CSS). Eighty-three high-risk T1-G3 NMIBC patients treated between September 2010 and January 2013 were included. Blood samples were collected before a transurethral resection of the bladder (TURB) and analysed using the CellSearch® system. The presence of at least one CTC was associated with a shorter TTP and CSS. Extending follow-up to 120 months and incorporating automated tdEV evaluation using ACCEPT software demonstrated that tdEV count may additionally stratify patient risk. Combining tdEVs and CTCs improves risk stratification for NMIBC progression, suggesting that tdEVs could be valuable biomarkers for prognosis and disease monitoring. Further research is needed to confirm these findings and establish the clinical significance of tdEVs in early-stage cancers. [ABSTRACT FROM AUTHOR]

Introduction: Bladder cancer is a common malignant tumor with significant heterogeneity, making personalized risk stratification crucial for optimizing treatment and prognosis. This study aimed to develop a prognostic model based on oxidative stress-related genes to guide risk assessment in bladder cancer. Methods: Differentially expressed oxidative stress-related genes were identified using the GEO database. Functional enrichment and survival analyses were performed on these genes. A risk-scoring model was built and tested for prognostic value and therapeutic response prediction. Expression of key genes was validated by qRT-PCR in samples from two muscle-invasive and two non-muscle-invasive bladder cancer patients. Results: Several oxidative stress-related genes were identified as significantly associated with survival. The risk-scoring model stratified patients into high- and low-risk groups, accurately predicting prognosis and therapeutic responses. qRT-PCR confirmed the differential expression of key genes in patient samples. Discussion: The study provides a concise risk stratification model based on oxidative stress-related genes, offering a practical tool for improving personalized treatment in bladder cancer. Further validation is required for broader clinical application. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of ageing on survival outcomes in Bacillus Calmette–Guérin (BCG) treated non-muscle invasive bladder cancer (NMIBC) patients and its synergy with adequate BCG treatment. Method: Patients with NMIBC who received BCG treatment from 2001 to 2020 were divided into group 1 (< = 70 years) and group 2 (> 70 years). Overall Survival (OS), Cancer-Specific Survival (CSS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS) were analyzed using the Kaplan–Meier method. Multivariable Cox regression analysis was used to adjust potential confounding factors and to estimate Hazard Ratio (HR) and 95% Confidence Interval (CI). Subgroup analysis was performed according to adequate versus inadequate BCG treatment. Results: Overall, 2602 NMIBC patients were included: 1051 (40.4%) and 1551 (59.6%) in groups 1 and 2, respectively. At median follow-up of 11.0 years, group 1 (< = 70 years) was associated with better OS, CSS, and RFS, but not PFS as compared to group 2 (> 70 years). At subgroup analysis, patients in group 1 treated with adequate BCG showed better OS, CSS, RFS, and PFS as compared with inadequate BCG treatment in group 2, while patients in group 2 receiving adequate BCG treatment had 41% less progression than those treated with inadequate BCG from the same group. Conclusions: Being younger (< = 70 years) was associated with better OS, CSS, and RFS, but not PFS. Older patients (> 70 years) who received adequate BCG treatment had similar PFS as those younger with adequate BCG treatment. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer continues to be a significant health issue, leading to ongoing research into novel biomarkers and treatment strategies. This study aims to evaluate the potential of serum fibronectin levels and fibronectin gene polymorphisms as biomarkers for predicting the recurrence and treatment response in patients with NMIBC undergoing intravesical BCG therapy. Methods: Between June 2022 and December 2022, data of 73 patients who applied to the Mersin University Urology Clinic due to NMIBC and were followed and treated in our clinic, receiving intravesical BCG treatment, when necessary, as well as 56 individuals without any malignancy, were prospectively examined. Serum fibronectin levels were measured using the enzyme-linked immunosorbent assay method. PCR testing was applied for the fibronectin gene RS10202709 and RS 35,343,655 gene polymorphisms by using Real-Time PCR. Results: The mean serum fibronectin level in the patient group was 76.794 ± 66.998ng/ml. Simultaneously, it was 50.486 ± 25.156ng/ml in the control group, and these differences in serum fibronectin levels were statistically significant(p = 0.003). Out of the 73 patients included in the study, recurrence of bladder cancer was observed in 53 of them. They were divided into two groups based on the recurrence times: early recurrence and late recurrence. The mean fibronectin level in the early recurrence group was 102 ± 86.1 ng/ml, while it was 44.7 ± 11.8 ng/ml in the late recurrence group. Emphasize the significance of the higher fibronectin levels in the early recurrence group by stating, patients with early recurrence exhibited significantly higher serum fibronectin levels compared to those with late recurrence (p < 0.001), suggesting a potential role for fibronectin as a prognostic biomarker. Conclusions: The statistically higher concentrations of serum fibronectin levels in patients with bladder cancer observed in our study are a noteworthy finding. These findings suggest that serum fibronectin levels could serve as a valuable prognostic biomarker for early recurrence in NMIBC patients, although their predictive value for BCG treatment response remains limited. [ABSTRACT FROM AUTHOR]

Background: Glutathione, along with its related enzymes, constitutes a key antioxidant defense mechanism against oxidative stress and cancer formation in the body. Among urological malignancies, bladder cancer ranks second following prostate cancer. Oxidative stress has significant involvement in the development and prognosis of bladder cancer. This investigation aimed to examine the impact of glutathione on prognosis in patients with non-muscle-invasive bladder cancer. Methods: This study included 98 patients with high grade non-muscle-invasive bladder cancer who had undergone intravesical Bacillus Calmette–Guérin therapy and 30 healthy controls with no history of uroepithelial carcinoma of the bladder. The patients with bladder cancer were evaluated in three subgroups. Group 1 consisted of 41 patients who did not experience recurrence during follow-up, Group 2 included 28 patients who had recurrent tumors, and Group 3 consisted of 29 patients who progressed to muscle-invasive stages. Blood samples were collected from all participants. Blood levels of reduced, oxidized, and total glutathione were measured spectrophotometrically. Results: Reduced glutathione levels significantly differed among the groups (p < 0.001), attributed to the control group exhibiting higher reduced glutathione levels compared with Groups 1, 2, and 3 (p < 0.001). There were no significant differences in reduced glutathione levels between Groups 1 and 2, Groups 1 and 3, or Groups 2 and 3 (p > 0.05). Total glutathione levels varied significantly among the groups (p < 0.001), with the control group having higher levels than Groups 1, 2, and 3 (p < 0.001). No significant differences were detected between any of the paired patient groups in terms of total glutathione levels (p > 0.05). Regarding oxidized glutathione levels, the difference was statistically significant (p < 0.001), with the control group showing lower levels than the remaining three groups (p < 0.001). Paired comparisons revealed no significant differences in oxidized glutathione levels (p > 0.05). Conclusions: This study revealed that glutathione had an effect on the emergence of bladder cancer but did not affect its prognosis. Nevertheless, we recommend that future studies with larger bladder cancer patient cohorts should be conducted to comprehensively determine the impact of glutathione on the prognosis of this cancer. [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]

Residual nonvisible bladder cancer after proper treatment caused by technological and therapeutic limitations is responsible for tumor relapse and progression. This study aimed to demonstrate the feasibility of a solution for simultaneous detection and treatment of bladder cancer lesions smaller than one millimeter. The α5β1 integrin was identified as a specific marker in 81% of human high-grade nonmuscle invasive bladder cancers and used as a target for the delivery of targeted gold nanorods (GNRs). In a preclinical model of orthotopic bladder cancer expressing the α5β1 integrin, the photoacoustic imaging of targeted GNRs visualized lesions smaller than one millimeter, and their irradiation with continuous laser was used to induce GNR-assisted hyperthermia. Necrosis of the tumor mass, improved survival, and computational modeling were applied to demonstrate the efficacy and safety of this solution. Our study highlights the potential of the GNR-assisted theranostic strategy as a complementary solution in clinical practice to reduce the risk of nonvisible residual bladder cancer after current treatment. Further validation through clinical studies will support the findings of the present study. [ABSTRACT FROM AUTHOR]

Purpose: To report the oncological outcomes and the tolerance between 6 instillations and more than 6 cycles of hyperthermic intravesical chemotherapy(HIVEC) in patients with non-muscle invasive bladder cancer(NMIBC). Methods: This is a multicenter retrospective study from a national database including 9 expert centers. All patients treated with HIVEC between 2016 and 2023 for NMIBC were included. Patients were classified into two groups according to the total number of HIVEC instillations, including induction plus maintenance. Kaplan-Meier curves were computed to present survival outcomes. Results: 261 patients with a median follow-up of 25.5 months were included. 199(76.2%) and 62(23.8%) were treated by 6 and more than 6 cycles of HIVEC, respectively. The 2-years RFS(40.2% vs. 34.4%,p = 0.3) and the 2-years PFS(86% vs. 87%,p = 0.85) were similar between group treated with 6 and more than 6 instillations. 2-years CSS and OS were also similar between both groups. Univariate Cox regression showed no association between the number of bladder instillation and RFS (HR = 1.2 95%CI[0.8–1.84], p = 0.3) or PFS (HR = 0.8 95%CI[0.29–2.02], p = 0.2). In the group treated with more than 6 cycles, 2-years RFS and 2-years PFS were similar between patients who received induction plus maintenance compared to those treated with induction only. Finally, hematuria and urinary burning were significantly higher in the group treated by more than 6 cycles (21% vs. 8.5%(p < 0.01),and 29% vs. 17% (p = 0.03), respectively). Serious side effects(grade ≥ 3) are rare(3.1%) and similar in both groups. Conclusions: Results show no significant difference in two years RFS, PFS, CSS and OS according to number of instillations received, while toxicity profile seems better in the group receiving six instillations only. [ABSTRACT FROM AUTHOR]

Bladder cancer (BCa) is the fourth most common cancer in men and one of the most common urinary tract cancers, especially in developed countries. The aim of this paper is to comprehensively analyze the biology of bladder cancer, including its epidemiology, etiology, histological types, risk factors, clinical symptoms, and diagnostic methods. The paper presents the dominant histological types of bladder cancer, such as transitional cell carcinoma (TCC), which accounts for 90–95% of cases, squamous cell carcinoma (SCC), and adenocarcinoma, which is much rarer. Risk factors, such as smoking, occupational exposure to chemicals, schistosomiasis, and genetic factors, which significantly affect the pathogenesis of bladder cancer, are also discussed. The paper focuses on modern diagnostic methods, including blue light cystoscopy (BLC) and computed tomography urography (CTU), which show increased sensitivity and specificity in detecting early neoplastic changes. The importance of TNM classification and the role of neoadjuvant chemotherapy in improving patient prognosis are also discussed. Based on a review of the scientific literature, the paper emphasizes the need for early diagnosis and an individualized therapeutic approach, which may contribute to improving the survival and quality of life of patients with bladder cancer. The potential for prevention, including quitting smoking and limiting exposure to harmful chemicals, has also been demonstrated to significantly reduce the risk of disease. Patient education and monitoring high-risk groups are key to reducing the incidence of bladder cancer. [ABSTRACT FROM AUTHOR]

High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics—Keytruda, Adstiladrin, and Anktiva—have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC. [ABSTRACT FROM AUTHOR]

Objective: To study the relationship between serum irisin (Irisin), mitogen-dependent oncogene (DJ-1) and recurrence after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC). Methods: 180 NMIBC patients who underwent TURBT in our hospital from January 2020 to January 2022 were selected as the study subjects. All patients were treated with TURBT, and the levels of serum Irisin and DJ-1 were detected and compared between two groups before operation. The clinical data of NMIBC patients were collected, and the influencing factors of recurrence after TURBT in NMIBC patients were analyzed by established multivariate Logistic regression model. The predictive value of serum Irisin and DJ-1 for recurrence after TURBT in NMIBC patients was evaluated by receiver operating characteristic (ROC) curve. Results: Among the 180 patients, 42 cases recurred, accounting for 23.33%, and were included in recurrence group. There were 138 cases of non-recurrence, accounting for 76.67%, which were included in non-recurrence group. The serum Irisin level in recurrence group was lower than that in non-recurrence group, while the DJ-1 level was higher than that in non-recurrence group (P<0.05). The proportion of patients with clinical TNM stage T1, organizational classification into poorly differentiated and multiple tumors in recurrence group was higher than that in non-recurrence group (P<0.05). Multivariate Logistic regression analysis showed that, clinical TNM stage was T1 stage, organizational classification was poorly differentiated, the number of tumors was multiple, serum Irisin decreased and DJ-1 increased were risk factors for postoperative recurrence. The results of ROC analysis showed that, the combined detection of serum Irisin and DJ-1 had the highest predictive value for recurrence after TURBT in NMIBC patients. The area under the curve (AUC) of the combined detection was 0.858, the sensitivity was 94.32%, and the specificity was 79.34%, which was higher than that of each index alone. Conclusion: The decrease of serum Irisin and the increase of DJ-1 are relate to the recurrence of NMIBC patients after TURBT, and the combine detection of the two has a high predictive value for the recurrence after TURBT. [ABSTRACT FROM AUTHOR]

Background: The tumoricidal complex alpha1‐oleate targets bladder cancer cells, triggering rapid, apoptosis‐like tumor cell death. Clinical effects of alpha1‐oleate were recently observed in patients with non‐muscle invasive bladder cancer (NMIBC), using a randomized, placebo‐controlled study protocol. Aims: To investigate if there are dose‐dependent effects of alpha1‐oleate. Materials and Methods: Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1‐oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. Results: Strong, dose‐dependent anti‐tumor effects were detected in alpha1‐oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1‐oleate. Uptake of alpha1‐oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis‐like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug‐related side effects were not recorded, except for local irritation at the site of instillation. Discussion and Conclusions: These dose‐dependent anti‐tumor effects of alpha1‐oleate are promising and support the potential of alpha1‐oleate treatment in patients with NMIBC. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Neoadjuvant cisplatin-based combination chemotherapy (NAC) followed by radical cystectomy is the standard of care for cisplatin-fit patients harboring muscleinvasive bladder cancer (MIBC). Prediction of response to NAC is essential for clinical decision-making regarding alternatives in case of non-response, and bladder-sparing in case of complete response. This research aimed to assess the performance of machine learning in predicting therapeutic response following NAC treatment in patients with MIBC. METHODS: A systematic review adhering to the PRISMA guidelines was conducted until July 2023. The study integrated articles relating to artificial intelligence and NAC response in MIBC from various databases. The quality of articles was evaluated using the Quality Assessment Tool for Diagnostic Accuracy Studies 2 (QUADAS-2). A meta-analysis was subsequently performed on selected studies to determine the sensitivity and specificity of machine learning algorithms in predicting NAC response. RESULTS: Of 655 articles identified, 12 studies comprising 1523 patients were included, and four studies were eligible for meta-analysis. The sensitivity and specificity of the studies were 0.62 (95% confidence interval [CI] 0.50–0.72) and 0.82 (95% CI 0.72–0.89), respectively, with a heterogeneity score (I²) of 38.5%. The machine learning algorithms used computed tomography, genetic, and anatomopathologic data as input and exhibited promising potential for predicting NAC response. [ABSTRACT FROM AUTHOR]

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

Purpose: In high-risk non-muscle-invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy post-transurethral resection of bladder tumor (TURBT). Intravesical gemcitabine, used as an alternative or second-line therapy amid BCG shortages, lacks outcome studies in the Korean population. Materials and Methods: Patients who received weekly intravesical gemcitabine for 6 weeks after TURBT from 2019 to 2022 were retrospectively investigated. Based on the American Urological Association risk classification, patients with high- or very high-risk NMIBC who refused cystectomy were included. Maintenance treatment was performed depending on their risk. Recurrence was defined as histologic confirmation on subsequent cystoscopic biopsies or TURBT. Disease free survival (DFS) was evaluated by the Kaplan-Meier method. Results: The study included 60 patients, comprising 45 high-risk (group 1) patients with a median age of 76 years and 15 very high-risk (group 2) patients with a median age of 68 years. Among them, 28 patients had previously received intravesical BCG. Over a median follow-up of 22 months, recurrence occurred in 31 patients in group 1 and 11 in group 2. The DFS rates of the highrisk group and the very high-risk group were 57.8% versus 40% at 1 year, 20.7% versus 21.3% at 2 years and 20.7% versus 21.3% at 3 years, respectively (p=0.831). Tis stage (p=0.042) and prostatic urethra invasion (p=0.028) were significant predictors of DFS. Cancer-specific mortality rates were 2.2% in group 1 and 6.7% in group 2 (p=0.441). Conclusions: Similar DFS outcome between high-risk and very high-risk patients were observed based on short-term results in Korea. This finding is crucial for clinical practice; however, studies analyzing more patients and long-term outcomes are needed. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background/Objectives: Bladder cancer is a prevalent urinary system malignancy and urinary cytology is widely used for its screening and follow-up. A novel diagnostic tool called Bladder Epicheck® (BE) is increasingly being used for monitoring the recurrence of non-muscle-invasive bladder cancer (NMIBC). The simultaneous use of BE and urinary cytology can increase the diagnostic performances in the follow-up of bladder neoplasms. Methods: In this multicenter study, we retrospectively evaluated the data of 322 patients in follow-up for a high-grade bladder carcinoma over a six-year period (from January 2018 to March 2024). The diagnostic performances of both cytology and BE and their combination were calculated using histology as gold standard. Results: Recurrences were diagnosed as high-grade urothelial carcinoma NMIBC in 18 cases, low-grade papillary NMIBC in 8 cases, and carcinoma in situ (CIS) in 4 cases. Cytological analysis correctly identified 26 out of 30 carcinomas, while 286 were correctly diagnosed as negative results. BE correctly identified 25 out of 30 carcinomas, 285 were correctly diagnosed as negative results. The combination of BE and urinary cytology correctly identified 29 out of 30 carcinomas, while 289 were correctly diagnosed as negative results. Conclusions: The combination of BE and cytology could be the most effective approach for follow-up diagnosis in patients with high-grade NMIBC, reducing unnecessary invasive procedures. [ABSTRACT FROM AUTHOR]

Abstract No pan‐India‐specific guidelines exist for the management of urological cancers. Although western guidelines are useful for informing management strategies, they do not account for the nuances of management in the Indian context. A modified Delphi method was used to provide a framework for the systematic development of India‐centric guidelines for the management of three uro‐oncology disease states: small renal masses, non‐muscle invasive bladder cancer and high‐risk/locally advanced prostate cancer.

Abstract Background Detecting carcinoma prostate (CaP) after intravesical Bacillus Calmette Guerin (BCG) immunotherapy for non‐muscle invasive bladder cancer (NMIBC) poses diagnostic challenges. Granulomatous prostatitis (GP) has an incidence of 0.8%–3.3% in post‐intravesical BCG patients and 6% incidence in a PIRADS 5 lesion on multiparametric MRI (mpMRI). Patients with GP after intravesical BCG may have clinical, biochemical, and radiological features similar to CaP. In our study, we evaluate the reliability of mpMRI in diagnosing CaP after intravesical BCG therapy. Materials and Methods We reviewed the NMIBC patients treated with intravesical BCG therapy between 2017 and 2023 and investigated those who underwent mpMRI and MR fusion biopsy in suspicion of CaP. A total of 120 patients had intravesical BCG immunotherapy, and 10 patients met our selection criteria. We performed a descriptive analysis of these patients and assessed the sensitivity and specificity of mpMRI in diagnosing CaP. Results The sensitivity of mpMRI in detecting CaP was 100%, and the specificity was 28.6%. Similarly, the negative predictive value for detecting CaP was 100%, and the positive predictive value was 37.5%. Among patients evaluated with mpMRI, a PIRADS 4 or 5 lesion was seen in 8 (80%) patients, and there was no lesion in 2 (20%) patients. The mpMRI detected 1 lesion in 6 patients (60%) and 2 (20%) in 2 patients. The lesions had a PIRADS score of 4 and 5 in 6 (60%) and 2 (20%) patients, respectively. Among these lesions, 8 (80%) were in the peripheral zone and 2 (20%) in the transition zone. In the MR fusion biopsy of these 10 patients, 7 (70%) had granulomatous prostatitis, and 3 (30%) had CaP. Conclusion In our study on evaluating the reliability of mpMRI in diagnosing CaP among post‐intravesical BCG patients, we noted that although PIRADS in mpMRI had high sensitivity in identifying prostate lesions, its specificity for detecting CaP is limited.

Introduction Distant recurrence of non‐muscle invasive bladder cancer is a rare condition that is poorly understood and difficult to detect in follow‐up protocols. Case presentation A 73‐year‐old female with a history of T1N0M0 bladder cancer 8 years ago suffered from a left axillary tumor, a left lung tumor, left mediastinal lymph node swelling, and bilateral adrenal gland tumors. Initially, she was diagnosed with metastatic left breast cancer of the left accessory mamma by needle biopsy of an axillary tumor. Subsequent bronchoscopic biopsy of the mediastinal lymph node revealed metastatic urothelial carcinoma, although no recurrence was detected in the urinary tract. She underwent systemic therapy, and all regions shrank without reprogression. Conclusion Non‐muscle invasive bladder cancer should be managed considering distant metastasis. If the origin of the metastatic lesions is unknown, this disease should be considered as a possible origin, even in the absence of urinary tract recurrence.

BACKGROUND: Bladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy. METHODS: The CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication. DISCUSSION: The CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03933826. Registered on May 1, 2019.

The Vesical Imaging-Reporting and Data System (VI-RADS) is a standard magnetic resonance imaging (MRI) and diagnostic method for muscle-invasive bladder cancer that was published in 2018. Several studies have demonstrated that VI-RADS has high diagnostic power and reproducibility. However, reading VI-RADS requires a certain amount of expertise, and radiologists need to be aware of the various pitfalls. MRI of the bladder includes T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCEI). T2WI is excellent for understanding anatomy. DWI and DCEI show high contrast between the tumor and normal anatomical structures and are suitable for staging local tumors. Bladder tumors are classified into five categories according to their size and morphology and their positional relationship to the bladder wall based on the VI-RADS diagnostic criteria. If the T2WI, DWI, and DCEI categories are the same, the category is the VI-RADS category. If the categories do not match, the DWI category is the VI-RADS category. If image quality of DWI is not evaluable, the DCEI category is the final category. In many cases, DWI is dominant, but this does not mean that T2WI and DCEI can be omitted from the reading of the bladder. In this educational review, typical and atypical teaching cases are demonstrated, and how to resolve misdiagnosis and the limitations of VI-RADS are discussed. The most important aspect of VI-RADS reading is to practice multiparametric reading with a solid understanding of the characteristics and role of each sequence and an awareness of the various pitfalls. [ABSTRACT FROM AUTHOR]

Abstract Objective This study aims to investigate the impact of risk group classification, restaging transurethral resection (re‐TURBT), and adjuvant treatment intensity on recurrence and progression risks in high‐grade Ta tumours in patients with non‐muscle invasive bladder cancer (NMIBC). Materials and methods Data from a comprehensive bladder cancer database were utilized for this study. Patients with primary high‐grade Ta tumours were included. Risk groups were classified according to AUA/SUO criteria. Tumour characteristics and patient demographics were analysed using descriptive statistics. Cox proportional hazard regression models were used to assess the effect of re‐TURBT and other clinical/treatment‐related predictors on recurrence‐ and progression‐free survivals. The survivals by selected predictors were estimated using Kaplan–Meier method, and groups were compared by the log‐rank test. Results Among 218 patients with high‐grade Ta bladder cancer, those who underwent re‐TURBT had significantly better 5‐year recurrence‐free survival (71.1% vs. 26.8%, p = 0.0009) and progression‐free survival (98.6% vs. 73%, p = 0.0018) compared with those with initial TURBT alone. Full BCG treatment (induction and maintenance) showed lower recurrence risk, especially in high‐risk patients. However, residual disease at re‐TURBT did not significantly affect recurrence risk. Conclusions This study highlights the significance of risk group classification, the role of re‐TURBT, and the intensity of adjuvant treatment in the management of high‐grade Ta tumours. A risk‐adapted model is crucial to reduce the burden of unnecessary intravesical treatment and endoscopic procedures.

Abstract Background A few studies regarding the epidemiology and risk factors of Non-muscle Invasive Bladder Cancer (NMIBC) are reported from Sub-Saharan African countries (SSA), including Somalia, and the African literature is scant on the management of NMIBC. The present study aims to evaluate the clinical-histopathological characteristics and factors associated with the survival rate of patients with NMIBC. Method This six-year cohort study included 196 patients with NMIBC. It reviewed the clinical and histopathological characteristics and factors predicting cancer-specific survival for these patients. Results The mean patient age was 59.01 ± 11.50 years, with a male-to-female ratio of 2.8:1. Urothelial carcinoma (UC) constituted the most common pathological type, accounting for 90.8%; Ta LG and T1HG were the most common histopathological tumour stage and grade (n = 90, 45.9%, vs. n = 56, 28.6%), respectively. The mean tumour size was 4.72 ± 2.81 cm. The cancer-specific mortality(CSM) was 13.3%. Age [2.252(2.310–2.943], p

Introduction. There is evidence of a connection between infectious and inflammatory lesions of the lower urinary tract and bladder cancer (BCa). However, there is virtually no data on the urine microbiota of middle-aged and elderly men with suspected BCa. This knowledge is extremely important from the point of view of studying the role of the infectious-inflammatory hypothesis in the genesis of BCa.Objective. To conduct a comparative assessment of the microbiota of bladder urine obtained during natural urination and bladder catheterization through standard and extended cultural studies in men with a presumptive diagnosis of non-muscle-invasive bladder cancer (NMIBC).Materials & methods. The prospective comparative study with consecutive patient recruitment included 23 men older than 45 years with suspected NMIBC based on clinical, laboratory and sonographic data, as well as with no history of infectious and inflammatory diseases of the kidneys and urinary tract, including sexually transmitted infections and recurrent infections of other organs and systems. A midstream urine samples and catheter-drained urine immediately before urethrocystoscopy were subjected to bacteriological analysis. Urine culture study was carried out using a standard set of nutrient media under aerobic cultivation conditions and an expanded set of nutrient media under aerobic and anaerobic cultivation conditions.Results. An anaerobic spectrum of microorganisms was predominantly detected in the urine of patients with suspected NMIBC. Moreover, Peptococcus spp. was more often found among anaerobic taxa. (70%), Eubacterium spp., Propionibacterium spp. (45% each, respectively), among representatives of the aerobes — Corynebacterium spp. (60%), S. lentus (up to 45%), S. haemolyticus (35%) and E. faecalis (30%). Data from a comparative analysis of the detection frequencies of microorganisms depending on the method of collecting material and the set of media for cultivation showed that more isolates are isolated in the midstream urine samples than in the study of catheter urine (2.9- and 1.9-fold with the standard and extended sets of media, respectively). In addition, when performing an extended bacteriological study compared to the standard method, the detection of microorganisms is 3.5-fold higher when examining an average portion of urine and 5.1-fold higher when examining catheter urine. The average number of microorganisms per one patient is also higher when using the extended method (midstream portion — 4.7 ± 1.9; catheterised urine — 2.3 ± 1.0) in comparison with the standard one (midstream portion — 1.3 ± 0.9; catheterised urine — 0.3 ± 0.5).Conclusion. Middle-aged and older men with NMIBC are characterized by asymptomatic bacteriuria in the form of a wide range of aerobic and anaerobic microorganisms. The urine pattern obtained with a urethral catheter contains a significantly narrower range of bacteria compared to the sample obtained through natural urination. It is advisable to carry out an extended cultural urine examination to study the characteristics of the microbiota / microbiome of the urine of the bladder immediately before the urethrocystoscopy procedure by collecting urine with a urethral catheter.

Background: Pelvic organ-preserving radical cystectomy (POPRC) has been reported to result in a better postoperative quality of life in female with bladder cancer compared to standard radical cystectomy (SRC). However, its oncological outcomes remain a concern. Patients and methods: Female patients with bladder cancer who underwent POPRC or SRC were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was used to identify predictors of POPRC usage. To avoid the potential impact of baseline differences between groups on survival, a 1:2 propensity score matching (PSM) was implemented. After that, Kaplan-Meier curves and Log-rank tests were used to determine the significance of overall survival (OS) differences between patients in the SRC group and POPRC group. Finally, subgroup analysis based on predetermined indicators was performed. Results: A total of 2193 patients were included with a median follow-up of 53 months, of whom 233 (10.6%) received POPRC and 1960 (89.4%) received SRC. No definitive predictors of POPRC were identified. Before PSM, POPRC resulted in comparable OS to SRC (HR = 1.09, p = 0.309), while after PSM, POPRC was associated with significantly worse OS (HR = 1.23, p = 0.038). In subgroup analyses, POPRC led to non-inferior OS (HR = 1.18, 95%CI 0.71–1.95, p = 0.531) in patients with non-muscle invasive bladder cancer (NMIBC) and T2 patients (HR = 1.07, p = 0.669), but significantly worse OS in T3 patients (HR = 1.41, p = 0.02). Conclusion: Currently, patients undergoing POPRC have not undergone strict screening, and candidates for POPRC should have more stringent criteria in the future to achieve satisfactory oncological outcomes. However, flaws in the study make more evidence needed to support our findings. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is a prevalent malignant tumor with high heterogeneity. Current treatments, such as transurethral resection of bladder tumor (TURBT) and intravesical Bacillus Calmette-Guérin (BCG) therapy, still have limitations, with approximately 30% of non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC), and a substantial number of MIBC patients experiencing recurrence after surgery. Immunotherapy has shown potential benefits, but accurate prediction of its prognostic effects remains challenging. Methods: We analyzed bladder cancer RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and used various machine learning algorithms to screen for feature RNAs related to tumor-infiltrating immune cells (TIICs) from single-cell data. Based on these RNAs, we established a TIIC signature score and evaluated its relationship with overall survival (OS) and immunotherapy response in bladder cancer patients. Results: The study identified 171 TIIC-RNAs and selected 11 TIIC-RNAs with prognostic value through survival analysis. The TIIC signature score established using a machine learning fusion method was significantly associated with OS and showed good predictive performance in different datasets. Additionally, the signature score was negatively correlated with immunotherapy response, with patients with low TIIC feature scores showing better survival outcomes after immunotherapy. Further biological functional analysis revealed a close association between the TIIC signature score and immune regulation processes, cellular metabolism, and genetic variations. Conclusion: This study successfully constructed and validated an RNA signature scoring system based on tumor-infiltrating immune cell (TIIC) features, which can effectively predict OS and the effectiveness of immunotherapy in bladder cancer patients. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the prognostic utility of Activity-dependent neuroprotective protein (ADNP) expression in Circulating Tumor Cells (CTCs) inpatients with Non-muscle-invasive Bladder Cancer (NMIBC) undergoing Transurethral Resection of Bladder Tumor (TURBT). A prospective cohort of 74 bladder cancer patients and 22 non-cancer controls were enrolled. The expression of ADNP mRNA was detected by immunomagnetic beads-droplet digital PCR. The ADNP mRNA expression was evaluated in patients with high-risk NMIBC and those with indeterminate invasion depth post 2nd TURBT. Primary cultured bladder cancer cells and PBMCs from healthy donors were immunofluorescence stained. Our findings suggest that baseline ADNP mRNA level in CTCs shows potential as a prognostic marker for NMIBC with a sensitivity of 83.33% and a specificity of 73.58%. In comparison to baseline, ADNP mRNA expression increased post 2nd TURBT in 5 patients, where 2 experienced recurrence. Meanwhile, among the 12 patients with decreased levels, only one patient relapsed. A considerable limitation of this study entails the small sample size. The Immuno-magnetic beads-ddPCR technique provided a viable method for ADNP mRNA detection in CTCs from bladder cancer patients. The preoperative ADNP mRNA level in CTCs was identified as a prognostic indicator for NMIBC. Longitudinal monitoring of ADNP mRNA in CTCs of bladder cancer patients shows promise in evaluating treatment responses and predicting prognosis. [ABSTRACT FROM AUTHOR]