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

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

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

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

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

Background: The number of studies suggesting that en bloc resection of bladder tumor (ERBT) is superior to transurethral resection of bladder tumor (TURBT) for non-muscle-invasive bladder cancer (NMIBC) management is growing. The aim of this review is to discuss the features of these procedures and to determine the prospects of en bloc in NMIBC management. Materials and methods: We conducted a literature search using two databases (Medline and Scopus) and included any research which reported ERBT outcomes. Results: The lasers with minimal tissue penetration depth are becoming the main tool for ERBT. Unfortunately, most of the systematic reviews continue to be characterized by high heterogeneity. However, recent studies indicate that ERBT may have the edge when it comes to the detrusor muscle rate and the quality of the histological specimen. ERBT may favor in terms of in-field relapse, but its rate in the studies varies greatly. As for out-field relapse-free survival, the data are still lacking. The strongest evidence supports that ERBT is superior to TURBT in complications rate (bladder perforation). ERBT is feasible irrespective to tumor size and location. Conclusions: ERBT has gained in momentum with the increasingly widespread use of this kind of laser surgery. The introduction of novel sources (TFL and Thulium:YAG pulsed laser) will definitely affect how the field develops and will result in further improvements in safety and precision. The latest trials make us more certain in our belief that ERBT will be beneficial in terms of histological specimen quality, relapse rate and complications rate. [ABSTRACT FROM AUTHOR]

Purpose: To learn about the history and development of en bloc resection of bladder tumour (ERBT), and to discuss its future directions in managing bladder cancer. Methods: In this narrative review, we summarised the history and early development of ERBT, previous attempts in overcoming the tumour size limitation, consolidative effort in standardising the ERBT procedure, emerging evidence in ERBT, evolving concepts in treating large bladder tumours, and the future directions of ERBT. Results: Since the first report on ERBT in 1980, there has been tremendous advancement in terms of its technique, energy modalities and tumour retrieval methods. In 2020, the international consensus statement on ERBT has been developed and it serves as a standard reference for urologists to practise ERBT. Recently, high-quality evidence on ERBT has been emerging. Of note, the EB-StaR study showed that ERBT led to a reduction in 1-year recurrence rate from 38.1 to 28.5%. An individual patient data meta-analysis is currently underway, and it will be instrumental in defining the true value of ERBT in treating non-muscle-invasive bladder cancer. For large bladder tumours, modified approaches of ERBT should be accepted, as the quality of resection is more important than a mere removal of tumour in one piece. The global ERBT registry has been launched to study the value of ERBT in a real-world setting. Conclusion: ERBT is a promising surgical technique in treating bladder cancer and it has gained increasing interest globally. It is about time for us to embrace this technique in our clinical practice. [ABSTRACT FROM AUTHOR]

Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for urothelial bladder tumors is the Tumor, Node, Metastasis classification, which reflects differences between non-muscle-invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma (MIBC) and it depends on the extent to which tumor has infiltrated the bladder wall and other tissues and organs. NMIBC and MIBC exhibit great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. In recent years, studies based on mRNA expression profiling revealed the existence of biologically relevant molecular subtypes of UC, which show variant molecular features that can provide more precise stratification of UC patients. Here, we present a complex classification of UC based on mRNA expression studies and molecular subtypes of NMIBC and MIBC in detail with regard to different mRNA expression profiles, mutational signatures, and infiltration by non-tumor cells. The possible impact of molecular subtyping on treatment decisions and patients' outcomes is outlined, too. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Detection of non-muscle invasive bladder cancer (NMIBC) is crucial to facilitate complete tumor resection, thus improving the survival rate as well as reducing the recurrence frequency and treatment expense. Fluorescence imaging cystoscopy is an effective method for the detection of NMIBC. However, its application is limited as the commonly applied fluorescent agents such as dyes and photosensitizers usually lack specific tumor accumulation and are vulnerable to photobleaching. Furthermore, the broad emission band of conventional fluorescent agents limits their imaging and detection efficacy. To overcome these limitations, upconversion nanoparticles (UCNPs) have been selected as the fluorescent agent, due to their resistance to photobleaching, less background auto-fluorescence, and narrow emission bands. In order to achieve active tumor targeting, the UCNPs are coated with a glycosylated phospholipid layer. The glycosylated phospholipid-coated UCNPs exhibited high selective accumulation in cancer cells over normal cells and enhanced the upconversion luminescence (UCL) (at 540 nm and 660 nm) from bladder cancer cells under 980 nm laser irradiation. Glycosylated phospholipid coating that promotes uptake of UCNPs by cancer cells, and UCL emitted from UCNPs under NIR (980 nm) laser irradiation for cancer cell imaging. [ABSTRACT FROM AUTHOR]

High-grade non-muscle-invasive bladder cancer (HG NMIBC) patients are at high risk (HR) of progression to muscle-invasion. Bladder-preserving therapies for this patient subgroup are limited, and additional treatments are desirable. Recently, enfortumab vedotin, targeting cancer-associated NECTIN4, has been approved for the treatment of advanced urothelial carcinoma. However, data on the expression of NECTIN4 and its therapeutic potential for HR NMIBC are scarce. Here, NECTIN4 was immunohistochemically analyzed in urothelial HG NMIBC by studying cohorts of carcinoma in situ (CIS)/T1HG (N = 182 samples), HG papillary tumors from mixed-grade lesions (mixed TaHG) (N = 87) and papillary HG tumors without a history of low-grade disease (pure TaHG/T1HG) (N = 98) from overall 225 patients. Moreover, inter-lesional NECTIN4 heterogeneity in multifocal HG NMIBC tumors was determined. A high prevalence of NECTIN4 positivity was noted across HG NMIBC subgroups (91%, N = 367 samples), with 77% of samples showing moderate/strong expression. Heterogenous NECTIN4 levels were observed between HG NMIBC subgroups: non-invasive areas of CIS/T1HG and pure TaHG/T1HG samples showed NECTIN4 positivity in 96% and 99%, with 88% and 83% moderate/strong expressing specimens, respectively, whereas significantly lower NECTIN4 levels were detected in mixed TaHG lesions (72% positivity, 48% of samples with moderate/strong NECTIN4 expression). Moreover, higher NECTIN4 heterogeneity was observed in patients with multifocal mixed TaHG tumors (22% of patients) compared to patients with multifocal CIS/T1HG and pure TaHG/T1HG tumors (9% and 5%). Taken together, NECTIN4-directed antibody–drug conjugates might be promising for the treatment of HR NMIBC patients, especially for those exhibiting CIS/T1HG and pure TaHG/T1HG tumors without a history of low-grade disease. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) represents a significant global therapeutic challenge, particularly in the era of Bacillus Calmette–Guérin (BCG) shortage. High-risk NMIBC can progress to muscle invasive or metastatic disease in 25% of patients. Optimal treatment selection, according to risk stratification, is imperative. International guidelines slightly differ in their categorisation of low, intermediate and high-risk NMIBC. Nonetheless, a single post-operative instillation of chemotherapy with Mitomycin C (MMC) or Gemcitabine improves relapse-free survival (RFS) in low-risk NMIBC. Induction and maintenance intravesical BCG remains the historical gold standard for patients with intermediate or high-risk NMIBC. However, clinicians may be forced to consider alternatives given the current BCG shortage. Both intravesical MMC and Gemcitabine have been associated with similar efficacy to BCG, albeit in smaller studies. MMC may also be manipulated using a variety of methods to potentiate its effects. BCG treatment delivery may also be modified without affecting efficacy through dose reduction and abbreviation or omission of maintenance therapy. Preliminary data also highlight that directly proceeding to radical cystectomy may not adversely affect long-term quality of life measures. Access to new systemic and intravesical therapies must be prioritised for patients with BCG recurrent or unresponsive disease. When used in conjunction with molecularly defined biomarkers, these agents herald the potential for improved survival outcomes and alleviation of the current BCG shortage. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the prognostic value of systemic immune-inflammation index (SII) to refine risk stratification of the heterogeneous spectrum of patients with non-muscle-invasive bladder cancer (NMIBC) Methods: In this multi-institutional cohort, preoperative blood-based SII was retrospectively assessed in 1117 patients with NMIBC who underwent transurethral resection of bladder (TURB) between 1996 and 2007. The optimal cut-off value of SII was determined as 580 using the best Youden index. Cox regression analyses were performed. The concordance index (C-index) and decision curve analysis (DCA) were used to assess the discrimination of the predictive models. Results: Overall, 309 (28%) patients had high SII. On multivariable analyses, high SII was significantly associated with worse PFS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.23–2.77; P = 0.003) and CSS (HR 2.53; 95% CI 1.42–4.48; P = 0.001). Subgroup analyses, according to the European Association of Urology guidelines, demonstrated the main prognostic impact of high SII, with regards to PFS (HR 3.39; 95%CI 1.57–7.31; P = 0.002) and CSS (HR 4.93; 95% CI 1.70–14.3; P = 0.005), in patients with intermediate-risk group; addition of SII to the standard predictive model improved its discrimination ability both on C-index (6% and 12%, respectively) and DCA. In exploratory intergroup analyses of patients with intermediate-risk, the improved discrimination ability was retained the prediction of PFS and CSS. Conclusion: Preoperative SII seems to identify NMIBC patients who have a worse disease and prognosis. Such easily available and cheap standard biomarkers may help refine the decision-making process regarding adjuvant treatment in patients with intermediate-risk NMIBC. [ABSTRACT FROM AUTHOR]

Purpose: Bacille Calmette-Guérin (BCG) is a well-established treatment for preventing or delaying tumour recurrence following high-grade nonmuscle invasive bladder cancer (NMIBC) resection. However, many patients will experience recurrence or progression during or following BCG. This scenario has been one of the most challenging in urologic oncology for several decades since BCG implementation. Finally, significant progress has occurred lately. The aim of this review was to summarize for the practising urologist the current treatment options available in 2020 or expected to be ready for routine use in the near future for patients with high-risk NMIBC who experience BCG failure. Methods: Narrative review using data through the end of 2020. Results: First, the definition of BCG unresponsive disease which is critical in counseling and managing patients has finally reached a consensus. Second, some promising options other than radical cystectomy are finally available and many other should be in a near future. The options can be categorized as chemotherapy, device-assisted therapy, check-point inhibitors, new intravesical and systemic agents and sequential combinations of these newer modalities with conventional therapy. Conclusions: Considering the options that are currently under scrutiny, many of which in phase III trials, clinicians should have at their disposal several new treatment options in the next five years. [ABSTRACT FROM AUTHOR]

Reliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213-231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation. [ABSTRACT FROM AUTHOR]

Purpose: The De Ritis ratio (aspartate aminotransferase/alanine aminotransferase, DRR) has been linked to oncological outcomes in several cancers. We aimed to assess the association of DRR with recurrence-free survival (RFS) and progression-free survival (PFS) in patients with non-muscle-invasive bladder cancer (NMIBC). Methods: We conducted a retrospective analysis of 1117 patients diagnosed with NMIBC originating from an established multicenter database. To define the optimal pretreatment DRR cut‐off value, we determined a value of 1.2 as having a maximum Youden index value. The overall population was therefore divided into two De Ritis ratio groups using this cut‐off (lower, < 1.2 vs. higher, ≥ 1.2). Univariable and multivariable Cox regression analyses were used to investigate the association of DRR with RFS and PFS. The discrimination of the model was evaluated with the Harrel's concordance index (C-index). Results: Overall, 405 (36%) patients had a DRR ≥ 1.2. On univariable Cox regression analysis, DRR was significantly associated with RFS (HR: 1.23, 95% CI 1.02–1.47, p = 0.03), but not with PFS (HR: 0.96, 95% CI 0.65–1.44, p = 0.9). On multivariable Cox regression analysis, which adjusted for the effect of established clinicopathologic features, DRR ≥ 1.2 remained significantly associated with worse RFS (HR:1.21, 95% CI 1.00–1.46, p = 0.04). The addition of DRR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index = 0.683 vs. C-index = 0.681). On DCA the inclusion of DRR did not improve the net-benefit of the prognostic model. Conclusion: Despite the statistically significant association of the DRR with RFS in patients with NMIBC, it does not seem to add any prognostic or clinical benefit beyond that of currently available clinical factors. [ABSTRACT FROM AUTHOR]

Introduction: After transurethral resection of a bladder tumor, patients frequently have a recurrence of the disease, thereby requiring adjuvant therapy. Purpose: The study aimed to determine the prognostic value of expression levels of p53, Ki-67, and survivin, and to develop a new prognostic model for patients with non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of a bladder tumor. Methods: The study group consisted of 101 patients with primary NMIBC. Univariate followed by multivariate Cox proportional hazard regression analysis was performed to obtain a model including the smallest possible number of descriptive variables with the highest statistical significance and impact on risk. Results: The RECINT model (RECurrence In Not Treated) including factors independently associated with cancer recurrence (tumor size [HR 1.148; p = 0.034], intensity of the color reaction for p53 [HR 1.716; p = 0.008], Ki-67 [HR 3.001; p = 0.022], and survivin [HR 1.461; p = 0.021]) adequately stratified recurrence free-survival (R2 = 0.341, p < 0.001) in patients with primary NMIBC. Patients with the lowest RECINT score (0–6) had the lowest probability of cancer recurrence (1- and 5-year recurrence of 16%) in comparison with other groups (p < 0.001). Conclusions: The RECINT model may be useful for stratifying the risk of recurrence in patients with non-muscle-invasive bladder cancer and may allow for identification of those who may benefit the most from adjuvant BCG immunotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The objectives of this study were to determine the prognostic value of expression levels of selected biomarkers and their statistical analysis in relation to survival and standard histopathologic examination and other clinicopathologic variables in non-muscle invasive bladder cancer (NMIBC). BACKGROUND: Worldwide, bladder cancer is a frequent malignant disease with rising incidence. Characteristic invasiveness and high recurrence rates call for more diagnostic methods to obtain more accurate information. Prognosis is affected by a significant interpersonal variability of the disease. For this reason, constant search for alternative and better diagnostic methods is essential. METHODS: We analysed cancer tissue from patients with Ta and T1 bladder cancer. E-cadherin and Ki-67 expression levels were analysed using immunohistochemical staining. The expression levels quantified to a percentual amount were statistically analysed in relation to survival and their frequency distribution in the study group. RESULTS: E-cadherin and Ki-67 expression levels show high association with tumor stage and grade (p<0.001), in contrast, the association with recurrence has proven insignificant. Patients with non-aberrant biomarker expression levels have much higher survival rates than the cases with aberrant expression. CONCLUSION: Low expression levels of Ki-67 and high expression levels of E-cadherin positively affect survival of patients, whereas aberrant expressions pose poorer prognosis (Tab. 2, Fig. 2, Ref. 33). Text in PDF www.elis.sk. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of en bloc re-resection (EBRS) in patients who had undergone previous en bloc resection for high-risk non-muscle-invasive bladder cancer (NMIBC). Methods: An international, multicenter, observational retrospective analysis of prospectively collected data. Patients with a high-risk NMIBC who had previously undergone en bloc resection were scheduled for EBRS of the resected area after 40 days. The primary outcome was the presence of residual tumor or recurrence-free survival. Results: Overall, 78 patients underwent EBRS. Only five (6.41%) residual cancers were found: one patient had a pTa G3 (1.28%) cancer and four (5.13%) had a pTis. The detrusor muscle was preserved in all samples. Only one patient had a positive margin on EBRS. No procedure called for a conversion to traditional re-TURBT. No patient experienced bladder perforation or other intra-operative complications. The recurrence rate at the first follow-up cystoscopy (RRFF-C at 3 months) was 3.85% (three patients). The median follow-up period was 30.8 months (range 6.9–76.0 months). In univariate analysis, the only predictor of recurrence was grade. Overall we observed 11 recurrences. Only one tumor progressed to T2 MIBC. Conclusions: The low rates of residual tumor, recurrence, and progression seem to raise doubts about the efficacy of EBRS in patients who have previously undergone en bloc resection. EBRS appears to be a feasible and safe procedure with a low rate of complications. However, further data will be needed before EBRS can be used in clinical trials or recommended as a treatment modality. [ABSTRACT FROM AUTHOR]

Introduction: There is an urgent need to identify patients with bladder cancer (BC) who are at high risk of recurrence or progression. Calgranulin A is a strong marker for muscle-invasive or advanced BC and recent studies have shown its potential for identifying patients at risk even in non-muscle-invasive bladder cancer (NMIBC). The present study examines risks of recurrence and progression dependent on immunostaining with calgranulin A in NMIBC.Methods: Calgranulin A protein expression was evaluated through the immunohistochemistry of 158 randomly selected, transurethrally resected BC specimens of separate patients (pTa 89, pT1 69) using tissue microarrays. Kaplan-Meier survival analysis and Cox regression were performed to determine whether calgranulin A expression is associated with recurrence-free survival (RFS), progression-free survival (PFS), or cancer-specific survival (CSS).Results: Calgranulin A expression is significantly different between pTa and pT1 tumors (p = 0.000, Mann-Whitney U test) and between tumor grades (p = 0.015, Kruskal-Wallis test). Kaplan-Meier estimates produced significant results for low and high calgranulin A expression concerning RFS [5y-RFS 70.4 ± 4.0% vs. 35.9 ± 12.5%, median RFS not reached (NR) vs. 12.0 ± 4.4 month, p = 0.029, log-rank test], PFS (5y-PFS 90.3 ± 2.7% vs. 51.5 ± 14.0%, median PFS NR in both groups, p = 0.000, log-rank test), and CSS (5y-CSS 92.9 ± 2.6% vs. 70.7 ± 12.4%, median CSS NR in both groups, p = 0.005, log-rank test). Calgranulin A remained an independent factor for RFS (p = 0.024, HR 2.43) and PFS (p = 0.002, HR 5.92) according to the multivariate Cox regression model.Conclusions: Calgranulin A expression in NMIBC, detected through immunohistochemistry, is a promising marker for the identification of NMIBC patients at high risk of recurrence and progression. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Checkpoint inhibition has emerged as new therapeutic option in muscle-invasive bladder cancer. The objective of the present study was to evaluate the prognostic role of PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification.Materials and methods: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survival (CSS).Results: We have analyzed 334 patients with NMIBC at stage pT1 for mRNA analysis. Data from 296 patients (79% male, median age: 72 years) could be used. Spearman correlation revealed significant associations between mRNA expressions of PD1/PDL1 (ρ: 0.6024, p < 0.0001), CD3/PDL1 (ρ: 0.5728, p < 0.0001) and CD3/PD1 (ρ: 0.7005, p < 0.0001). Kaplan–Meier analysis revealed that high PDL1 mRNA expression (≥ 33.83) is a favorable prognostic factor with regard to better RFS (p = 0.0018), PFS (p = 0.021) and CSS (p = 0.012). Multivariate Cox-regression analysis proved PDL1 expression to be an independent prognosticator for RFS [HR 0.48 (0.31–0.72), p = 0.0005], PFS [HR 0.45 (0.24–0.80), p = 0.0059] and CSS [HR 0.31 (0.13–0.67), p = 0.0021].Conclusion: High mRNA expression of PDL1 predicts improved RFS, PFS and CSS of pT1 NMIBC. Following prospective validation, this objective measurement of PD-L1 might help stratify patients with NMIBC for immunotherapy and identify patients who might benefit from early cystectomy. [ABSTRACT FROM AUTHOR]

Background: Detailed information is not currently available on the incidence, natural course, and management of asymptomatic abnormal prostate findings incidentally detected by radiologic evaluations after BCG therapy for non-muscle-invasive bladder cancer patients. Methods: We identified 38 patients who were evaluated by contrast-enhanced CT scans before TUR-BT and after BCG therapy between 2006 and 2012. We evaluated the clinical courses of patients with abnormal radiologic findings of the prostate gland after BCG therapy. Results: Abnormal findings on CT scans were found in the prostate glands of 11 of the 38 patients examined (28.9%), none of whom exhibited any sign or symptom associated with prostatitis. Abnormal findings included a low attenuation area ( n = 6, 15.8%), contrast enhancement ( n = 3, 7.9%), and a low attenuation area and contrast enhancement in the prostate gland ( n = 2, 5.3%). During the follow-up, abnormal prostate findings disappeared spontaneously in most cases without any anti-bacterial or anti-tuberculous drug treatments. No significant differences were observed in patient clinical backgrounds, with the exception of post-BCG prostate volumes, between patients with and without abnormal CT findings. Furthermore, no significant differences were noted in the incidence of the adverse effects of BCG therapy, tumor recurrence rates, or progression rates between patients with and without abnormal CT findings of the prostate gland after BCG therapy. Conclusions: Asymptomatic abnormal prostate findings incidentally detected by CT after BCG therapy are not rare, and these disappear over time during the follow-up period without any treatment. [ABSTRACT FROM AUTHOR]

CD44 is involved in cancer-cell growth, invasion, proliferation and metastasis and is also a causal factor for acquisition of resistance to apoptosis. Therefore we evaluated different SNPs of CD44 gene viz. CD44rs187116 A/G, CD44rs4755392 A/T, CD44rs187115 C/T, CD44rs13347 C/T and CD44 rs353639 G/T for bladder cancer risk in North Indian population. 240 bladder cancer patients and 270 cancer free controls were recruited in this study. Genotyping was done by PCR-RFLP for CD44rs187116 A/G. However, CD44rs4755392 A/T, CD44rs187115 C/T, CD44rs13347 C/T and CD44 rs353639 G/T were genotyped by allelic discrimination Taqman assay. Statistical analysis was done by SPSS. In-silico analysis was done using F-SNP. We found reduced risk in variant genotype, TT of rs4755392 ( p = 0.011) as well as in variant allele, T ( p = 0.045). No risk was seen in rs13347, heterozygous genotype, CT ( p = 0.023) and variant allele, T ( p = 0.007). The dominant model, CT + TT also revealed reduced risk ( p = 0.009). A marginal risk was seen in dominant model, GT + TT of rs353639 ( p = 0.044) and reduced risk in variant allele T ( p = 0.040). A significant manifold risk was seen in smokers carrying variant genotype, TT of CD44rs353639 G/T ( p = 0.038, OR 1.960). Haplotypic analysis revealed significant association in 4 sets viz. TCCGG p = 0.005, TTCGA p = 0.039, ACTGG p = 0.008 and TCTGA p = 0.006. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs187115, rs13347 and rs353639. Our study suggests that rs353639 shows a marginal risk for bladder cancer susceptibility, whereas rs4755392 and rs13347 have reduced risk of bladder cancer and rs187115 and rs187116 had no effect on bladder cancer susceptibility in North Indians. [ABSTRACT FROM AUTHOR]

Differential expression of cytokeratins (CK) is a characteristic feature of chemoresistant luminal (KRT20) and chemosensitive intrinsic aggressive basal (KRT5) subtypes in muscle-invasive bladder cancer (MIBC). We investigated mRNA expression of KRT5 and KRT20 and its predictive value in stage pT1 bladder cancer. In retrospective analysis of clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder, a single-step RT-qPCR was used to measure mRNA expression. Furthermore, immunohistochemical (IHC) staining of CK20, panCK, and MIB1 was performed. Valid measurements were obtained from 231 samples out of a series of 284 patients. Spearman correlation revealed significant associations between mRNA and protein expression of KRT20/CK20 (ρ 0.6096, p < 0.0001) and MKI67/MIB1 (ρ 0.5467, p < 0.0001). A positive correlation was found between MKI67 and KRT20 expression (ρ 0.3492, p < 0.0001), while MKI67 and KRT5 were negatively correlated (ρ -0.1693, p = 0.01). High KRT20 expression (≥40.26) was significantly associated with worse recurrence free survival (RFS) (p = 0.001), progression-free survival (PFS) (p = 0.0003), and cancer specific survival (CSS) (p = 0.0414). The combination of high KRT20 expression and low KRT5 expression (<36.83) was associated with unfavorable RFS (p = 0.0038) and PFS (p = 0.0003) and proved to be the only independent predictor for RFS (p = 0.0055) and PFS (p = 0.0023) in multivariate analysis. KRT20 mRNA determination was superior to CK20 protein estimation with regard to RFS and PFS prediction. KRT20 and KRT5 mRNA quantification can predict recurrence and progression of stage pT1 NMIBC reflecting basal and luminal subtypes of MIBC and is superior to CK20 protein expression determined by IHC. [ABSTRACT FROM AUTHOR]

Background and Objectives: The adjuvant treatment of non-muscle-invasive bladder cancer (NMIBC) is based on the individual risk profile (RP) and its sufficient transfer from the clinic to the doctor's office. The objectives of our study were to verify the importance and degree of transfer of RP and recommendation for risk-adapted adjuvant treatment (RAAT) in patients with NMIBC as well as to develop appropriate tools for this purpose, if necessary.Materials and Methods: An email-based survey distributed to urologists in Brandenburg, Berlin, Bavaria and Lower Saxony explored the questions mentioned above. In addition, a tool for risk stratification and information transfer for patients with NMIBC was developed and validated.Results: From a total of 134 questionnaires analyzed, 55 were from clinic urologists (CUs) and 79 were from ambulant urologists (AUs). Although 9 out of 10 urologists considered the RP of importance, only 29 % of CUs and 24 % of AUs (p = 0.553) confirmed that the RP was always mentioned in medical reports. The recommendation for RAAT was confirmed from 62 % of CUs and 20 % of AUs (p < 0.001). A recommendation for RAAT in the medical report was requested by 86 % of AUs. The risk calculator presented here - to our knowledge the first with integration of the 2004 WHO grading - is delivered in all mathematically possible constellations a RP, according to guideline recommendations.Conclusion: Urologists in the clinic and doctor's office both attach considerable importance to the determination and transfer of RP and the recommendation for RAAT. There was evidence to suggest an overestimation of the quality of medical reports by the CU. The risk calculator provides an easy and cost-neutral option to improve risk stratification and information transfer from the clinic to the doctor's office. [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]

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]

Authors of this have concluded that the "bipolar transurethral resection of bladder tumor (TURBT) has no significant advantages in efficacy and safety for treatment of NMIBC compared to monopolar TURBT". Keywords: Meta-analysis; NMIBC; MIBC; TURBT; Bipolar; Monopolar EN Meta-analysis NMIBC MIBC TURBT Bipolar Monopolar 3691 3692 2 10/14/21 20210901 NES 210901 This comment refers to the article available online at https://doi.org/10.1007/s00345-020-03271-3. [Extracted from the article]

Non-muscle-invasive bladder cancer is characterized by frequent recurrences requiring repeated transurethral resections and carries a risk of progression to muscle-invasive disease. The routinely used, passive diffusion irrigation of the bladder with mitomycin C has achieved limited success in avoiding these events. We review two methods that may improve penetration of mitomycin C into the bladder wall, thus leading to better results in terms of recurrence rate and bladder preservation. [ABSTRACT FROM AUTHOR]

Background: The management of stage T1 poorly differentiated G3 bladder cancer invading the lamina propria continues to be debated. These tumours are associated with a high risk of recurrence and progression; concomitant carcinoma in situ and/or multifocality are negative prognostic factors. Choosing between a preserving approach such as trans-urethral resection of the bladder (TURB) followed by maintenance bacillus Calmette-Guerin (BCG) and an invasive approach like cystectomy is critical. Patients and methods: Overall, 80 patients underwent TURB and RE-TURB followed by intra-vesical induction treatment with BCG plus maintenance (Group A) while 72 patients underwent immediate radical cystectomy with extended lymphadenectomy (Group B). Patients were divided into 3 subgroups: uni-focal tumours, multi-focal tumours and carcinoma in situ associated lesions. In Group A, time to first recurrence and time to progression were analysed. A comparison was made between Group A and Group B regarding progression-free survival, cancer-specific survival and overall survival with a median follow-up time of 8.3 years. Results: As far as concerns Group A patients, 42 recurrences (52.5%) were reported in a median time of 10.4 months (range 3-26) and 25 progressions (31.2%) in a median time of 25 months (range 3-68). As far as concerns time to first recurrence and time to progression, both the Kaplan-Meier survival curves obtained are significant and P values are, respectively, 0.0263 and 0.0011. Comparing Groups A and B patients, 25 progressions (31.2%) in a median time of 25 months (range 3-68) and 18 progressions (25%) in a median time of 25.9 months (range 4-72), respectively, were recorded. Regarding overall survival, at 10 years, 24 deaths (42.5%) occurred in a median time of 55.4 months (range 12-94) in Group A and 42 deaths (58.3%) in a median time of 54.9 months (10-100) in Group B. Cancer-specific survival was evaluated in Group A with a total of 18 deaths (22.5%) in a median time of 47.5 months (range 16-78), and in Group B with a total of 16 deaths (22.2%) in a median time of 45.7 months (range 16-88). The progression-free survival Kaplan-Meier curve is not significant, the P value being 0.3801; the overall survival curve is significant with a P value of 0.0487 while the cancer-specific survival curve is not significant with a P value of 0.9762. Discussion: In Group A, considering 'time to first recurrence', the difference is greater between unifocal lesions and multifocal or Cis-associated lesions. Conversely, for 'time to progression', there is a greater difference between unifocal and multifocal tumours and Cis-associated tumours. Looking at 'progression-free survival' in Group A and Group B patients, there is no statistically significant difference, like in cancer-specific survival. A statistically significant difference was observed in overall survival being in favour of conservative treatment thus reflecting that conservative treatment is not burdened by all the surgical and post-operative complications of cystectomy. Conclusions: Although NMIBC invading the lamina propria, stage G3, with or without Cis-associated lesions are burdened both by a high volume of recurrences and progressions, cystectomy could be considered an aggressive approach. New biological markers are now needed which are able to predict the behaviour of the cancer and to guide the decision-making process between conservative or aggressive treatment. [ABSTRACT FROM AUTHOR]