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A progressive subclass of early-stage non-muscle-invasive bladder cancer (NMIBC) frequently recurs and progress into invasive carcinoma, thus decreasing the overall survival rate of NMIBC. However, therapeutic development for progressive NMIBC has been challenging due to the lack of molecularly validated in vivo models and agents targeting its genetic vulnerability. We herein molecularly characterized an interventional model of progressive NMIBC and revealed the principal functions and therapeutic potential of microRNA-145 (miR-145) in early bladder tumorigenesis. N-butyl-N-(4-hydroxybutyl)nitrosamine-induced premalignant lesions (BiPLs) in rats exhibited downregulated expression of miR-145 as well as highly similar mutation/expression profiles to those of the human progressive NMIBC subclass with the worst prognosis. The expression patterns of miR-145 inversely correlated with those of BC-related oncogenes in BiPLs. We also demonstrated that miR-145 dominantly regulated interferon pathways and c-Myc expression, which play a crucial role in the pathogenesis of progressive NMIBC. Furthermore, we demonstrated that miR-145 replacement with a novel miR-145-based intravesical agent (miR-145S1) significantly inhibited the progression of BiPLs in vivo . These results provide insights into the essential role of miR-145 as the earliest-acting oncogenic driver of bladder tumorigenesis as well as a validated interventional model and novel miR-145-based nucleic acid therapeutic agent for progressive NMIBC., Competing Interests: Y.A. is the author of a patent for miR-145 assessed in this study. Y.A. has received grant support and LNP suspensions from Daiichi Sankyo Co., Ltd., (© 2023 The Author(s).)

Bladder cancer (BC) can be divided into two subgroups depending on invasion of the muscular layer: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Its aggressiveness is associated, inter alia, with genetic aberrations like losses of 1p, 6q, 9p, 9q and 13q; gain of 5p; or alterations in the p53 and p16 pathways. Moreover, there are reported metabolic disturbances connected with poor diagnosis-for example, enhanced aerobic glycolysis, gluconeogenesis or haem catabolism.Currently, the primary way of treatment method is transurethral resection of the bladder tumour (TURBT) with adjuvant Bacillus Calmette-Guérin (BCG) therapy for NMIBC or radical cystectomy for MIBC combined with chemotherapy or immunotherapy. However, intravesical BCG immunotherapy and immune checkpoint inhibitors are not efficient in every case, so appropriate biomarkers are needed in order to select the proper treatment options. It seems that the success of immunotherapy depends mainly on the tumour microenvironment (TME), which reflects the molecular disturbances in the tumour. TME consists of specific conditions like hypoxia or local acidosis and different populations of immune cells including tumour-infiltrating lymphocytes, natural killer cells, neutrophils and B lymphocytes, which are responsible for shaping the response against tumour neoantigens and crucial pathways like the PD-L1/PD-1 axis.In this review, we summarise holistically the impact of the immune system, genetic alterations and metabolic changes that are key factors in immunotherapy success. These findings should enable better understanding of the TME complexity in case of NMIBC and causes of failures of current therapies., (© 2023. The Author(s).)

At present, transurethral resection of bladder tumors (TURBT) is the main surgical method for treating non-muscle invasive bladder cancer (NMIBC), but its postoperative recurrence needs to be prevented. The aim of the present study was to investigate the efficacy of a 980-nm diode laser combined with preoperative intravesical instillation of pirarubicin (THP) for the prevention of NMIBC recurrence. The data of 120 patients with NMIBC who underwent transurethral resection between May 2021 and July 2022 were retrospectively collected, and these patients were followed up. The patients were divided into four groups based on the surgical method used and preoperative intravesical instillation of THP as follows: i) 980-nm diode laser with THP (LaT); ii) 980-nm diode laser alone (La); iii) TURBT with THP (TUT); and iv) TURBT alone (TU). Clinicopathological variables, postoperative complications and short-term outcomes among the aforementioned groups were analyzed. The blood loss volume and the incidence of perforation and delayed bleeding were significantly lower in the LaT and La groups compared with those in the TUT and TU groups. The days of bladder irrigation, catheter extubation and postoperative hospitalization were significantly shorter in the LaT and La groups compared with the TUT and TU groups. The detection rate of suspicious lesions was significantly higher in the THP irrigation groups (LaT and TUT) compared with that in the saline irrigation groups (La and TU). Tumor diameter and number, 980-nm laser and THP irrigation were shown to be independent risk factors in the Cox regression analysis. In addition, the recurrence-free survival (RFS) rate of the LaT group was significantly higher than that of the other three groups. In conclusion, a 980-nm diode laser can effectively reduce intraoperative blood loss and the incidence of perforation, and accelerate postoperative recovery. Preoperative intravesical instillation of THP is conducive to identifying suspicious lesions. The combination of a 980-nm laser with preoperative THP intravesical instillation can significantly prolong RFS time., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Tang et al.)

Background: Bladder cancer (BCa) is the most common malignancy of the urinary tract which can be divided into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), and their microbial differences are not fully understood. This study was conducted by performing 2bRAD sequencing for Microbiome (2bRAD-M) on NMIBC and MIBC tissue samples to investigate the microbiota differences between NMIBC and MIBC individuals., Methods: A total of 22 patients with BCa, including 7 NMIBC and 15 MIBC, were recruited. Tumor tissues were surgically removed as samples and DNA was extracted. Type IIB restriction endonucleases were used to enzymatically cleave the microbial genome for each microbe's tag and map it to species-specific 2bRAD markers to enable qualitative and quantitative studies of microbes between MIBC and NMIBC tissues., Results: A total of 527 species were detected. The microbial diversity of NMIBC tissues was significantly higher than that of MIBC tissues. Microbial composition of the two tumor tissues was similar, where Ralstonia_sp000620465 was the most dominant species. 4 species (Acinetobacter_guillouiae, Anoxybacillus_A_rupiensis, Brevibacillus_agri and Staphylococcus_lugdunensis) were enriched in NMIBC, while Ralstonia_mannitolilytica, Ralstonia_pickettii, and Ralstonia_sp000620465 were overrepresented in MIBC. 252 discriminatory character taxa were also revealed by linear discriminant analysis effect sizea (LEfSe). Species importance point plots identified Ralstonia_sp000620465, Cutibacterium_acnes and Ralstonia_pickettii as the three most important species between the two groups. Meanwhile, functional annotation analysis showed 3011 different COGs and 344 related signaling pathways between MIBC and NMIBC microbiome., Conclusion: This first 2bRAD-M microbiome study on MIBC and NMIBC tissues revealed significant differences in the microbial environment between the two groups, which implies a potential association between tumor microbial dysbiosis and BCa, and provides a possible target and basis for subsequent studies on the mechanisms of BCa development and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Xia, Zhong, Liu and Wang.)

Objective To report the oncological safety and the risk of progression for patients with non-muscle-invasive bladder cancer ( NMIBC) included in an active surveillance ( AS) programme after the diagnosis of recurrence. Patients and methods This is a prospective study enrolling patients with history of pathologically confirmed low grade pTa- pT1a NMIBC and diagnosed with a tumour recurrence. Inclusion criteria consisted of negative urine cytology, presence of ≤5 lesions with a diameter of ≤10 mm, absence of carcinoma in situ ( CIS) or persistent gross haematuria. The primary outcome of interest was adherence to AS. Need to proceed with treatment was defined as progression in number/dimension/positive cytology/symptoms (gross haematuria persistent) or any further intervention (resection or electro-fulguration). Finally, we assessed the up-grading and up-staging when transurethral resection of bladder tumour was performed. Results The study population consisted of 55 patients with a previous diagnosis of NMIBC (70 AS events) prospectively recruited since 2008. The mean patient age was 69.8 years. The median follow-up was 53 months. The median time patients remained under AS was 12.5 months. There was disease progression in 28 patients (51%). No patient progressed to muscle-invasive disease. In all, 15 patients (27.3%) had an increase in the number and/or size of the tumour, nine (16.4%) had haematuria, and four (7.3%) had a positive cytology. Only five (9%) patients in the whole series progressed to a high-grade tumour (Grade 3) or presented with associated CIS. The overall adherence to the follow-up schedule was 95%. Conclusion Our data show that an AS protocol for NMIBC could be a reasonable option in a select group of patients with small, recurrent cancers. [ABSTRACT FROM AUTHOR]

Pathological staging and grading are crucial for risk assessment in non-muscle-invasive bladder cancer (NMIBC). Molecular grading might support pathological evaluation and minimize interobserver variability. In this study, the well-established breast cancer markers ESR1, PGR, ERBB2, and MKI67 were evaluated as potential molecular markers to support grading and staging in NMIBC. We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with NMIBC. Messenger RNA (mRNA) expression of the aforementioned markers was measured by single-step reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) using RNA-specific TaqMan assays. Relative gene expression was determined by normalization to two reference genes (CALM2 and B2M) using the 40-ΔΔCT method and correlated to histopathological stage and grade. Pathological assessment was performed by an experienced uropathologist. Statistical analysis was performed using the SAS software JMP 9.0.0 version and GraphPad Prism 5.04. Of 381 cases of NMIBC, samples of 100 pTa and 255 pT1 cases were included in the final study. Spearman rank correlation revealed significant correlations between grade and expression of MKI67 (r = 0.52, p < 0.0001), ESR1 (r = 0.25, p < 0.0001), and ERBB2 (r = 0.18, p = 0.0008). In Mann-Whitney tests, MKI67 was significantly different between all grades (p < 0.0001), while ESR1 (p = 0.0006) and ERBB2 (p = 0.027) were significantly different between G2 and G3. Higher expression of MKI67 (r = 0.49; p < 0.0001), ERBB2 (r = 0.22; p < 0.0001), and ESR1 (r = 0.18; p = 0.0009) mRNA was positively correlated with higher stage. MKI67 (p < 0.0001), ERBB2 (p = 0.0058), and PGR (p = 0.0007) were significantly different between pTa and pT1. In NMIBC expression of ESR1, ERBB2 and MKI67 are significantly different between stage and grade. This potentially provides objective parameters for pathological evaluation. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to explore if the preoperative neutrophil-lymphocyte ratio (NLR) and fibrinogen level can help in distinguishing between muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Methods: We identified 669 patients who underwent surgery at our institution, and evaluated their preoperative NLRs and fibrinogen levels. Patients were divided into two groups, NMIBC (group-I) and MIBC (group-II), according to the postoperative pathology. For the intergroup comparison, data obtained from the two groups were evaluated using independent samples t-test. The cutoff value of the NLR, fibrinogen level, and integrated NLR and fibrinogen level was determined with receiver operating characteristic (ROC) curve. Results: The mean NLRs of group-I and group-II were found as 2.71±2.46 and 4.66±8.00, respectively (P<0.001). The fibrinogen levels of the two groups were ~3.13±0.70 g/L and 3.41±0.84 g/L, respectively (P=0.001). Whether the NLR, fibrinogen level, and integrated NLR and fibrinogen level can help in distinguishing between MIBC and NMIBC was evaluated with ROC curve. The cutoff value of NLR was estimated as 2.01 according to the Youden index. With this value, sensitivity was found as 67.1%, specificity was 52.7%, and area under receiver operating characteristic (ROC) curve (AUC) was 0.601 (P=0.031). The cutoff value of fibrinogen level was estimated as 3.17 g/L according to the Youden index. Accordingly, sensitivity was found as 58%, specificity was 58%, and AUC was 0.60 (P=0.001). The cutoff value of integrated NLR and fibrinogen level was found as 0.166; the sensitivity was found as 86%, specificity was 42%, and AUC was 0.801 (P=0.01). Conclusion: The data obtained in this study suggested that 67.1% of Ta-T1 tumors were likely to be invasive if the NLR was >2.01 and 58% were likely to be invasive if the fibrinogen level was >3.17 g/L. When we used both the NLR and fibrinogen level to distinguish between the MIBC and NMIBC, sensitivity was found to be 86%, and specificity was 42%. [ABSTRACT FROM AUTHOR]

Background At least half of the patients diagnosed with non–muscle-invasive bladder cancer (NMIBC) experience recurrence and approximately 15% will develop progression to muscle invasive or metastatic disease. Biomarkers for disease surveillance are urgently needed. Objective Development of assays for surveillance using genomic variants in cell-free tumour DNA from plasma and urine. Design, setting, and participants Retrospective pilot study of 377 samples from 12 patients with recurrent or progressive/metastatic disease. Three next-generation sequencing methods were applied and somatic variants in DNA from tumour, plasma, and urine were subsequently monitored by personalised assays using droplet digital polymerase chain reaction (ddPCR). Samples were collected from 1994 to 2015, with up to 20 yr of follow-up. Outcome measurements and statistical analysis Progression to muscle-invasive or metastatic bladder cancer; t test for ddPCR data. Results and limitations We developed from one to six personalised assays per patient. Patients with progressive disease showed significantly higher levels of tumour DNA in plasma and urine before disease progression, compared with patients with recurrent disease ( p = 0.032 and 1.3 × 10 −6 , respectively). Interestingly, tumour DNA was detected in plasma and urine in patients with noninvasive disease, being no longer detectable in disease-free patients. A significant level of heterogeneity was observed for each patient; this could be due to tumour heterogeneity or assay performance. Conclusions Cell-free tumour DNA can be detected in plasma and urine, even in patients with noninvasive disease, with high levels of tumour DNA detectable before progression, especially in urine samples. Personalised assays of genomic variants may be useful for disease monitoring. Patient summary Tumour DNA can be detected in blood and urine in early and advanced stages of bladder cancer. Measurement of these highly tumour-specific biomarkers may represent a novel diagnostic tool to indicate the presence of residual disease or to discover aggressive forms of bladder cancer early in the disease course. [ABSTRACT FROM AUTHOR]

Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the depth of transurethral resections of bladder tumour ( TURBT), residual cancer rates and up-staging rates in a contemporary Australian series. Materials and Methods Specimen reports from a single, major reporting pathology centre, servicing a group of urological oncologists in Sydney were obtained for TURBTs performed between October 2008 and February 2013. We examined the depth of TURBT, rates of repeat- TURBT (re- TUR) and residual cancer rates at the 3-6 month check cystoscopy. Results One thousand and two hundred and nine transurethral resection specimens retrieved during this period were analysed. There were 162 (13.4%) T1 specimens and 631 (52.2%) Ta specimens, 218 (34.5%) of which were high grade. Muscularis propria was present in 506 (41.9%) specimens in total and in 151 (39.7%) of 380 high-risk specimens (high grade Ta, T1). Of the 380 high-risk non-muscle-invasive tumours, 85 (22.4%) proceeded to re- TUR. Of the 48 T1 specimens and 37 Ta high grade specimens that proceeded to re- TUR, 7 (14.6%) and 1 (2.7%) respectively were upstaged to muscle-invasive disease. Rates of residual disease/early recurrence at 3-6 months was significantly better for those with re- TUR compared to those without 56.8% vs 82.5% ( P < 0.001) for Ta high grade and 39.6% vs 84% ( P = 0.028) for T1 tumours respectively. Conclusion Re- TUR rates in high-risk non-muscle-invasive bladder cancer are low. However in a contemporary series, the upstaging rates are low, but residual cancer rates high, supporting the need for re- TUR in this population. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the incremental cost‑effectiveness of hexaminolevulinate (Hexvix®) + Blue Light (H+BL) cystoscopy (compared to white light cystoscopy only) when used at initial transurethral resection of the bladder tumour (TURBT) for patients diagnosed with non‑muscle invasive bladder cancer (NMIBC) in Italy. METHODS: A cost‑effectiveness model has been developed to estimate the incremental cost‑effectiveness of introducing H+BL at initial TURBT for patients diagnosed with NMIBC in Italy. The model consists of two parts: 1) a short term decision tree which estimates the outcome of the initial diagnostic procedure, and 2) a Markov cohort model which is used to estimate long term outcomes through extrapolation based on data and assumptions about patient management, the natural history of the disease and the empirical efficacy of H+BL in improving diagnosis detection and reducing recurrence. Cost‑effectiveness results are expressed as incremental costs per QALY gained. Univariate and probabilistic sensitivity analyses are conducted to test the robustness of the model to changes in inputs and assumptions. RESULTS: Base case results suggest that Hexvix® is a dominant strategy when used in the resection of NMIBC. Hexvix® is expected to be associated with 0.070 incremental QALYs, with cost savings of € 435 per patient. Sensitivity analyses suggest that the cost of Hexvix® and the relative risk of recurrence in intermediate and low risk groups are key drivers in the model. Probabilistic analyses indicate that Hexvix® is expected to be cost‑effective in >99% of iterations, assuming a willingness to pay threshold of € 25,000 per QALY. CONCLUSION: In conclusion, Hexvix® is expected to be a cost‑effective strategy when used in the resection of NMIBC in Italy.

Background: Non-muscle invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence and progression, despite surgery and adjuvant therapies., Objective: To analyze the published results on the effectiveness of mitomycin C (MMC) applied with an electromotive drug administration device (EMDA) in the treatment of patients with non-muscle invasive bladder tumors., Method: A systematic review was conducted using the PubMed and Google Scholar search platforms. We selected the studies that included the recurrence and/or progression rates or complete response rate in patients diagnosed with NMIBC according to their treatment and included MMC applied with EMDA. The last search was performed in November 2021., Results: The search yielded 64 articles; 11 articles met the selection criteria. In two of the 11 selected articles, mitomycin C was applied with an EMDA device (MMC-EMDA) as an ablative treatment, avoiding surgery in 50% of the patients. In 1 of the 11 studies, the application of MMC-EMDA was used as an induction treatment using a single preoperative instillation with promising results. In the remaining 8 studies, adjuvant MMC was applied with the EMDA device; in 3 of these 8 cases, treatment with MMC-EMDA alone was applied initially. In another3 cases the same treatment was applied after nonresponse to bacillus Calmette Guerin (BCG), and in the last 2 studies, MMC-EMDA was applied in combination with the classic therapy (BCG). All the studies selected supported the efficacy and safety of MMC-EMDA in patients with intermediate and high- risk bladder cancer. In 3 studies, adjuvant therapy with MMC-EMDA was performed in nonresponders to BCG, finding that adjuvant therapy with MMC-EMDA applied to BCG nonresponders without CIS avoided or delayed surgery., Conclusions: The application of EMDA-enhanced MMC has been studied at different times of disease and with different administration protocols. It appears to delay bladder tumor recurrence and progression in certain populations. However, the methodological limitations of the published studies prevent definitive conclusions about its efficacy., Competing Interests: Conflict of interest All authors have no conflict of interest to report., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Biomarkers of different stages and grades of bladder cancer (BC) are important in clinical work. The objective of our study was to investigate new biomarkers of early-stage BC with liquid chromatography-high resolution mass spectrometry (LC-HRMS) using serum samples., Methods: A total of 215 cases were included in our study, including 109 healthy adults as the control group and 106 non-muscle invasive bladder cancer (NMIBC) patients as the NMIBC group. Serum samples were collected from BC patients in the early stage, called NMIBC, and healthy people before surgery. We used LC-HRMS to distinguish the NMIBC group from the control group and the low-grade NMIBC group from the control group., Results: An apparent difference between the NMIBC group and the control group was visualized by unsupervised principal component analysis (PCA). Metabolite panels for 16-hydroxy-10-oxohexadecanoic acid, PGF2a ethanolamide, sulfoglycolithocholate, and threoninyl-alanine were used to distinguish the two groups. The area under the curve (AUC) of the panels was 0.985, and the sensitivity and specificity were 98.63% and 98.59%, respectively. To distinguish the low-grade NMIBC group from the control group, serum metabolic profiling differences between the low-grade NMIBC group and control group samples were also analyzed. Metabolite panels of L-octanoylcarnitine, PGF2a ethanolamide, and threoninyl-alanine showed good discrimination performance. The AUC of the panels was 0.999, and the sensitivity and specificity were 97.8% and 100%, respectively., Conclusion: Metabolomics analysis of serum samples can distinguish the NMIBC group from the control group, particularly the early-stage low-grade NMIBC group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Sun, Ji, Liu and Qiao.)

Objective: To investigate the association of the preoperative systemic immune-inflammation index (SII) with recurrence-free survival (RFS) after transurethral resection of the bladder tumor (TURBT) of non-muscle-invasive bladder cancer (NMIBC) using propensity score matching (PSM) analysis., Methods: The clinicopathological characteristics and follow-up data of NMIBC patients were collected retrospectively from two tertiary medical centers. A 1:1 PSM analysis was carried out using the nearest-neighbor method (caliper size: 0.02). Cox regression analysis was used to identify the risk factors associated with RFS., Results: A total of 416 NMIBC patients were included in this study. Before and after matching, patients with increased SII had worse RFS (p < 0.0001 and p = 0.027, respectively). Multivariate Cox analysis identified SII as an independent predictor of RFS before (HR [95% CI]: 1.789 [1.232, 2.599], p = 0.002) and after matching (HR [95% CI]: 1.646 [1.077, 2.515], p = 0.021). In the matched subgroup analysis, an elevated SII had a significant association with postoperative worse RFS in the T1 stage (p = 0.025), primary status (p = 0.049), high-grade (p = 0.0015), and multiple lesions (p = 0.043) subgroups., Conclusion: SII could accurately stratify the prognosis of NMIBC patients before and after PSM analysis. An elevated SII was significantly associated with worse RFS in NMIBC patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

CIS of the bladder is associated with a high risk of progression. In the case of BCG failure, radical cystectomy should be performed. For patients who refuse or are ineligible, bladder-sparing alternatives are evaluated. This study aims to investigate the efficacy of Hyperthermic IntraVesical Chemotherapy (HIVEC) depending on the presence or absence of CIS. This retrospective, multicenter study was conducted between 2016 and 2021. Patients with non-muscle-invasive bladder cancer (NMIBC) with BCG failure received 6-8 adjuvant instillations of HIVEC. The co-primary endpoints were recurrence-free survival (RFS) and progression-free survival (PFS). A total of 116 consecutive patients met our inclusion criteria of whom 36 had concomitant CIS. The 2-year RFS rate was 19.9% and 43.7% in patients with and without CIS, respectively ( p = 0.52). Fifteen patients (12.9%) experienced progression to muscle-invasive bladder cancer with no significant difference between patients with and without CIS (2-year PFS rate = 71.8% vs. 88.8%, p = 0.32). In multivariate analysis, CIS was not a significant prognostic factor in terms of recurrence or progression. In conclusion, CIS may not be considered a contraindication to HIVEC, as there is no significant association between CIS and the risk of progression or recurrence after treatment., Competing Interests: The authors declare no conflict of interest.

Background: To evaluate the efficacy of intravesical chemotherapy replacement in patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), who underwent bacillus Calmette-Guérin (BCG) instillation but discontinued due to global shortages or toxicity of BCG., Methods: This retrospective study included patients with intermediate- and high-risk NMIBC who received BCG intravesical instillation. Those who discontinued the treatment were divided into the pure BCG group and chemotherapy replacement group. Comparisons between these groups were performed. The primary endpoint was bladder recurrence-free survival (RFS)., Results: A total of 480 patients were included. Baseline characteristics were similar between groups, but the total instillation times were higher in the chemotherapy replacement group than in the pure BCG group (n = 14.9 vs. 10.5). The chemotherapy replacement group had a better three-year RFS ( p = 0.022). On multivariate analysis, the pure BCG group had significantly increased all-time and 3-year recurrences (hazard ratio 2.015 and 2.148) compared to the chemotherapy replacement group., Conclusions: Chemotherapy replacement has a better three-year RFS than no instillation in patients with intermediate- and high-risk NMIBC who received BCG instillation but facing treatment stoppage.

Background: The Systemic Inflammatory Response Index (SIRI) is a novel prognostic biomarker based on peripheral blood counts of neutrophils, monocytes, and lymphocytes. Recent evidence suggests that it is associated with poor prognosis in various cancers. However, the predictive value of the SIRI in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) immunotherapy remains elusive. Therefore, this study aimed to evaluate the potential of SIRI as a prognostic factor in these patients., Methods: A total of 540 patients with NMIBC who underwent BCG immunotherapy following transurethral resection of bladder tumor (TURBT) were enrolled in this study. Using receiver operating characteristic (ROC) curves and the Youden index, patients were divided into high and low SIRI groups based on the cutoff values. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of BCG non-response. Thereafter, propensity score matching (PSM) was used to eliminate bias due to confounding factors between the low and high SIRI groups. Finally, the Kaplan-Meier method was used to compare recurrence-free survival (RFS) and progression-free survival (PFS) between the two groups., Results: Multivariable logistic regression analysis revealed that high SIRI (p = 0.001), high MLR (p = 0.015), and high tumor pathological T stage (p = 0.015) were significantly correlated with non-response to BCG therapy. In addition, both RFS and PFS were shorter in the high SIRI group than in the other group before and after PSM (both p < 0.05). Collectively, our results indicate that the combination of tumor pathological T staging and the SIRI can enhance the predictive power of BCG response., Conclusion: Pretreatment peripheral blood SIRI can be employed to predict the response to BCG immunotherapy and the prognosis of NMIBC patients. Taken together, the combination of T stage and SIRI demonstrated robust performance in predicting the response to BCG immunotherapy in NMIBC patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: The quality of the initial transurethral resection of bladder tumors (TURBT) plays a key role in accurate local staging thus affecting treatment decision-making and disease prognosis. TURBT is still the gold standard for non-muscle invasive bladder cancer (NMIBC). However, en bloc resection of bladder tumors (ERBT) gradually expanded as a promising alternative to TURBT, aiming to overcome certain inherent limitations of conventional resection. We hereby describe a step-by-step bipolar ERBT technique and briefly review the current trends surrounding the role of various en bloc techniques in the field., Case Presentation: We present the case of a 65-year old patient undergoing bipolar ERBT for a single, approximately 2 cm, papillary bladder mass. An experienced urologist completed the procedure within 17 min and without any intra- or postoperative complications. No conversion to TURBT was needed, and an adequate specimen for histological assessment was obtained. The patient made an uneventful recovery, and no recurrence was noted at 12-months., Conclusion: Our initial experience demonstrates that ERBT via bipolar current is relatively quick, safe, and reliable. Prospective comparative clinical trials will examine its efficacy, and long-term oncological superiority in managing NMIBC.

Objective To evaluate the efficacy and safety of low-dose (45 mg) intravesical bacille Calmette–Guérin (BCG) therapy in the treatment of patients with non-muscle-invasive bladder cancer (NMIBC), as intravesical BCG is the most acceptable adjuvant therapy for NMI transitional cell carcinoma of the bladder. However, in the standard regimen, undesirable effects are the main cause of treatment discontinuation. Patients and methods The present study included 37 men with primary NIMBC. All patients underwent complete TURB and 2 weeks later, a 6-week course of 45 mg BCG diluted in 50 mL isotonic saline was instilled into the bladder and retained for 2 h. Patients were evaluated for BCG efficacy (recurrence with or without progression) and safety by documentation of minor and/or major side-effects. Results There were no major or severe side-effects and no treatment discontinuations. Local adverse effects occurred in 20 patients, while systemic effects, in the form of fever, occurred in six patients (16.2%). There was recurrence in 14 patients (37.8%) after 18–34 months, with disease progression (muscle invasion) in four (10.8%) after 6–18 months. The recurrence index was 0.39/100 patients/month and the mean (range) tumour-free period was 30.97 (7–36) months. Conclusion Low-dose BCG intravesical therapy is an effective adjuvant treatment in NMIBC. However, this needs to be validated in future studies and in comparison with other proposed doses and/or regimens. [ABSTRACT FROM AUTHOR]

Current global economic crisis imposes healthcare system to reduce unnecessary investigations and increase early detection of tumors, to decrease the costs of an advanced disease. Several diagnostic pitfalls may occur dealing with bladder cancer (BC), particularly in nonmuscle-invasive (NMIBC) one. Hematuria, the commonest sign in NMIBC, is often underestimated. Urinary cytology is highly specific for high-grade tumors, but has a low sensitivity for low-grade BC, is operator dependent, and not always obtainable in clinical practice. Numerous urinary tests are available to ameliorate the accuracy of cytology, but none of them is routinly used in urological practice. Ultrasound could hardly detect a small bladder tumor, especially if located in the bladder neck or in the anterior wall. Computed tomography (CT) is widely adopted as an alternative to conventional urography, but its usefulness in patients with hematuria is still debated. MRI has a higher accuracy than CT for staging BC and evaluate the bladder-wall invasion. A negative cystoscopy cannot exclude Tis and should be accompanied by urinary cytology in patients with suspected Tis or high-risk NMIBC; however, new techniques such as narrow band imaging (NBI) and photodynamic (PDD) increase the detection rate of BC and flat lesions. Nearly half of all diagnostic resections present omission of muscle in the specimen or its mention in the pathology report, which is associated with an increased mortality. An adequate muscle sampling during endoscopic resection is mandatory, particularly in patients with high-grade disease. Recognition of pitfalls in diagnosis and management of BC represents the first step for a correct approach. [ABSTRACT FROM AUTHOR]

Objective: Snail, an inducer of the epithelial-to-mesenchymal transition, increases motility and invasiveness of cancer cells by repressing E-cadherin expression. We investigate the relationship between Snail expression and clinicopathological parameters and evaluate its prognostic significance in patients with non-muscle-invasive bladder cancer (NMIBC). Materials and methods: A total of 332 patients treated with transurethral resection of the bladder tumor between October 2002 and July 2010 were histopathologically confirmed to be NMIBC. Tumor recurrence and progression were followed up in all patients. Immunohistochemical staining of 332 slices was performed. The expression of Snail was evaluated by ICH and graded for intensity and area of staining. We correlated Snail scores with clinical and pathological variables, and association of Snail staining with tumor recurrence and progression was evaluated by univariate, multivariate analysis and Kaplan-Meier survival curves. Results: Of 332 patients with NMIBC, there was Snail positivity in 104 tumors (31.3 %), and Snail expression correlated with age, multifocality, carcinoma in situ, tumor stage and tumor grade (each p < 0.05, respectively). A multivariate Cox regression model revealed that Snail expression was an independent predictor of tumor recurrence [hazard ratio (HR) 1.95, p = 0.001] and progression (HR 2.34, p = 0.014) in patients with NMIBC. Kaplan-Meier estimates showed that Snail expression was significantly associated with recurrence and progression (log-rank test, p < 0.0001, respectively). Conclusions: Analysis of Snail expression in 332 NMIBC tissue specimens revealed its potential usefulness as a biomarker to predict the NMIBC prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) have been widely proposed to have predictive value for the patient prognosis of many malignancies, including bladder cancer. However, the predictive value of their combination in non-muscle-invasive bladder cancer (NMIBC) is unclear., Methods: Cases of NMIBC patients who underwent transurethral resection of the bladder tumor were recruited from two tertiary public medical centers. A systemic inflammatory marker (SIM) score was calculated based on comprehensive consideration of NLR, PLR, and LMR. Recurrence-free survival (RFS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. The Log rank test was used to compare differences between the groups. Cox regression was used to screen risk factors affecting RFS and PFS. Nomogram models were established and validated, and patients were stratified based on the model scores., Results: The study dataset was grouped according to a 7:3 randomization, with the training cohort consisting of 292 cases and the validation cohort consisting of 124 cases. Cox regression analysis showed that SIM score is an independent predictor of RFS and PFS in NMIBC patients. The novel models were established based on the SIM score and other statistically significant clinicopathological features. The area under the curve (AUC) for predicting 1-, 2-, and 3-year RFS was 0.667, 0.689, and 0.713, respectively. The AUC for predicting 1-, 2-, and 3-year PFS was 0.807, 0.775, and 0.862, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. The established models were applied to the patient evaluation of the validation cohort, which proved the great performance of the novel models., Conclusion: The novel models based on the SIM score and clinicopathological characteristics can accurately predict the survival prognosis of NMIBC patients, and the models can be used by clinicians for individualized patient assessment and to assist in clinical decision-making., Competing Interests: The authors declare that they have no competing interests for this work., (© 2023 Ding et al.)

Objectives: To be the first to apply a novel 450 nm blue diode laser in transurethral resection of bladder tumor (TURBt) to treat patients with non-muscle invasive bladder cancer (NMIBC) and evaluate its efficacy and safety during the preoperative period compared to the conventional plasmakinetic electrocautery., Materials and Methods: Randomized controlled trial (RCT) in five medical centers was designed as a non-inferiority study and conducted from October 2018 to December 2019. Patients with NMIBC were randomized to the blue laser or plasmakinetic electrocautery group for TURBt. As the first study to evaluate this novel blue laser device, the primary outcome was the effective resection rate of bladder tumors, including effective dissection and hemostasis. The secondary outcomes were the perioperative records, including surgical time, postoperative indwelling catheter time, hospital stay length, blood loss, reoperation rate, wound healing and adverse events., Results: A total of 174 patients were randomized to either the blue laser group (85 patients) or plasmakinetic electrocautery group (89 patients). There was no statistical significance in the clinical features of bladder tumors, including tumor site, number and maximum lesion size. Both the blue laser and plasmakinetic electrocautery could effectively dissect all visible bladder tumors. The surgical time for patients in the blue laser group was longer (p=0.001), but their blood loss was less than that of patients in the control group (p=0.003). There were no differences in the postoperative indwelling catheter time, hospital stay length, reoperation rate or other adverse events. However, the patients undergoing TURBt with the blue laser showed a faster wound healing at 3 months after operation., Conclusion: The novel blue laser could be effectively and safely used for TURBt in patients with NMIBC, and this method was not inferior to plasmakinetic electrocautery during the perioperative period. However, TURBt with the blue laser may provide the benefit to reduce preoperative blood loss and accelerate postoperative wound healing. Moreover, longer follow-up to confirm recurrence-free survival benefit was required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Jiang, Zhang, Jiang, Lin, Luo, Fan, Yang, Chen, Zhang, Wang, Wei, Guo, Huang and He.)

Objective: To assess the oncologic outcomes and the safety profile of a reduced-dose versus full-dose BCG regimen in patients with non-muscle-invasive bladder cancer (NMIBC)., Material and Methods: We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The PubMed, Embase, and Web of Science databases were searched in January 2022 for studies that analyzed oncological outcomes and compared between reduced- and full-dose BCG regimens., Results: Seventeen studies including 3757 patients met our inclusion criteria. Patients who received reduced-dose BCG had significantly higher recurrence rates (OR 1.19; 95%CI, 1.03-1.36; p = 0.02). The risks of progression to muscle-invasive BC (OR 1.04; 95%CI, 0.83-1.32; p = 0.71), metastasis (OR 0.82; 95%CI, 0.55-1.22; p = 0.32), death from BC (OR 0.80; 95%CI, 0.57-1.14; p = 0.22), and all-cause death (OR 0.82; 95%CI, 0.53-1.27; p = 0.37) were not statistically different. When restricting the analyses to randomized controlled trials, we found similar results. In subgroup analysis, reduced dose was associated with a higher rate of BC recurrence in studies that used only an induction regimen (OR 1.70; 95%CI, 1.19-2.42; p = 0.004), but not when a maintenance regimen was used (OR 1.07; 95%CI, 0.96-1.29; p = 0.17). Regarding side effects, the reduced-dose BCG regimen was associated with fewer episodes of fever (p = 0.003), and therapy discontinuation (p = 0.03)., Conclusion: This review found no association between BCG dose and BC progression, metastasis, and mortality. There was an association between reduced dose and BC recurrence, which was no longer significant when a maintenance regimen was used. In times of BCG shortage, reduced-dose regimens could be offered to BC patients., (Copyright © 2022 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Non-muscle invasive bladder cancer (NMIBC) has a high recurrence rate, which places a significant burden on both patients and the healthcare system. Hence, it holds significant importance to predict the recurrence risk following treatment for individuals diagnosed with non-muscle invasive bladder cancer (NMIBC). As new generation technologies continue to emerge, an increasing number of recurrence risk prediction tools are being developed and discovered. This article provides an overview of the primary recurrence risk prediction tools currently available, including the liquid biopsy, tissue biopsy, and risk prediction tables. Each of these tools is described in detail and illustrated with relevant examples. Furthermore, we conduct an analysis of the advantages and disadvantages of these tools. This article aims to enhance the reader's understanding of the current progress in recurrence prediction tools and encourage their practical utilization in the fields of precision medicine and public health.

Introduction & Objectives: The standard bladder cancer management was often marked by unsatisfactory outcomes. This prospective, single-center study compared the diagnostic accuracy specific for narrow band imaging (NBI) and respectively white light cystoscopy (WLC) among non-muscular invasive bladder cancer (NMIBC) patients. Materials & Methods: 81 consecutive NMIBC suspected cases were included based on the presence of hematuria and/or on ultrasound suspicious aspect. All patients were evaluated by both WLC and NBI cys-toscopy. WL-visible lesions were removed by classical transurethral resection of bladder tumors (TURBT), while NBI resection was exclusively applied in tumors solely detected by this particular visualization method. Results: Subsequent to NBI cystoscopy, substantially improved CIS and overall NMIBC patients' detection rates were determined. A significant proportion of additional lesions was identified in NBI regardless of the bladder cancer stage. Improved tumor detection rates were established for NBI when compared to white light concerning all NMIBC categories of patients. The more numerous false-positive results affected the NBI-TURBT related specificity compared to the standard investigation protocol. Conclusions: NBI cystoscopy and TURBT were outlined as providing an efficient modality of significantly improving NMIBC detection, thus optimizing tumor ablation. The solely NBI diagnosed NMIBC cases and tumors largely supported this conclusion. [ABSTRACT FROM AUTHOR]

Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB) were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher's test p = 0.023). Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p = 0.041). Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients. [ABSTRACT FROM AUTHOR]

Background: Transurethral resection of the bladder tumor with or without adjuvant intravesical instillation (IVI) has been the standard treatment for non-muscle-invasive bladder cancer (NMIBC), whereas a high percentage of patients still experience local tumor recurrence and disease progression after receiving the standard treatment modalities. Unfortunately, current relevant prediction models for determining the recurrent and progression risk of NMIBC patients are far from impeccable., Methods: Clinicopathological characteristics and follow-up information were retrospectively collected from two tertiary medical centers between October 2018 and June 2021. The least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were used to screen potential risk factors affecting recurrence-free survival (RFS) of patients. A nomogram model was established, and the patients were risk-stratified based on the model scores. Both internal and external validation were performed by sampling the model with 1,000 bootstrap resamples., Results: The study included 299 patient data obtained from the Affiliated Hospital of Xuzhou Medical University and 117 patient data obtained from the First Affiliated Hospital of Guangxi Medical University. Univariate regression analysis suggested that urine red blood cell count and different tumor invasion locations might be potential predictors of RFS. LASSO-Cox regression confirmed that prior recurrence status, times of IVI, and systemic immune-inflammation index (SII) were independent factors for predicting RFS. The area under the curve for predicting 1-, 2-, and 3-year RFS was 0.835, 0.833, and 0.871, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. A user-friendly risk calculator based on the model is deposited at https://dl0710.shinyapps.io/nmibc&#95;rfs/., Conclusion: Internal and external validation analyses showed that our model had excellent predictive discriminatory ability and stability. The risk calculator can be used for individualized assessment of survival risk in NMIBC patients and can assist in guiding clinical decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ding, Deng, Xia, Wang, Zhang, Zhang, Shao and Wang.)

Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8 + T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Liu, Yuan, Zhu, Hu, Hu, Wang, Wang, Huang and Xing.)