Implications for diagnosis and treatment strategies in non-muscle invasive bladder cancer with variant histology: a systematic review.

INTRODUCTION: The identification of variant histology (VH) has been recognized as a critical element in the diagnostic pathway of bladder cancer (BCa), both for prognostic and therapeutic implications. However, the current evidence on the oncological outcomes of patients harboring VH BCa mostly derives from studies including muscle-invasive disease. Consequently, the correct management of patients with non-muscle invasive bladder cancer (NMIBC) and VH is limited and conflicting, and the optimal therapeutic approach remains therefore controversial. EVIDENCE ACQUISITION: In this review, we aimed at reporting the current evidence on NMIBC with VH. EVIDENCE SYNTHESIS: Despite a constant increase in VH reporting at transurethral resection of bladder tumor (TURBT) specimens as compared to previous decades, we found that the incidence of VH is still sparse among studies. Furthermore, the agreement between TURBT and radical cystectomy (RC) specimens in VH identification is another matter of debate. Currently, most of the included studies report a poor overall concordance, especially for the micropapillary variant. Finally, while squamous and micropapillary variants are those associated with the worst survival outcomes, immediate RC is mostly considered for micropapillary tumors. Conversely, the survival benefit of immediate RC as compared to bladder-sparing approaches (i.e., BCG immunotherapy) for the other types of VH BCa is still an open question owing to the paucity of data available. CONCLUSIONS: Thus, in these patients, BCG treatment could be proposed considering the need for more intensive oncological surveillance.

Electromotive Drug Administration of Mitomycin C (EMDA/MMC) versus Intravesical Immunotherapy with Bacillus Calmette-Guérin (BCG) in Intermediate and High Risk Non Muscle Invasive Bladder Cancer.

BACKGROUND: Although TURB of tumor (TURBT) by itself can eradicate a non-muscle-invasive bladder cancer (NMIBC) completely, these tumors commonly recur and can progress to MIBC. It is, therefore, necessary to consider adjuvant therapy in most patients. The primary objective of the present study was to report our experience with EMDA/MMC and BCG, considering efficacy, progression, and recurrence, as adjuvant therapy in NMIBC patients; the secondary objective was to assess the efficacy of EMDA/MMC versus BCG as a comparative treatment. METHODS: Between April 2016 and February 2020, a series of 216 patients, with a diagnosis of intermediate- and high-risk NMIBC after TURBT, underwent adjuvant intravesical therapy. In 26 cases with a failure of the treatment, in patients unfit and unwilling for radical cystectomy, a repeated intravesical therapy was performed (2 had a twice repetition). Out of 244 adjuvant therapies, 140 EMDA/MMC and 104 BCG treatments were done. The following data were collected for each patient: baseline demographics and clinical data and perioperative and postoperative data. Overall patients' adjuvant intravesical therapies were included in a prospectively maintained institutional database, and a retrospective chart review was performed. We collected data on 2 main outcomes, recurrence-free survival (defined as a negative cystoscopy, cytology, and/or histology at the evaluation time point) and progression-free survival (defined as a negative cystoscopy or a nonprogressive tumor recurrence). RESULTS: The NMIBC progression rate was higher in BCG than EMDA/MMC but not statistically significant (respectively, 4.2% vs. 2.5%; p = 0.703). In the overall population, the risk of NMIBC recurrence was higher after BCG than EMDA/MMC (p = 0.025). In the subgroups of 59 paired patients with similar characteristics, no difference was observed between groups in NMIBC progression and recurrence. CONCLUSIONS: Our findings suggest that EMDA/MMC and BCG are safe and reproducible approaches as adjuvant treatment in NMIBC. EMDA/MMC permits to achieve a fine oncological management as adjuvant treatment in NMIBC, which is not less than that obtained with BCG.

Selecting the Best Candidates for Cisplatin-based Adjuvant Chemotherapy After Radical Cystectomy Among Patients with pN+ Bladder Cancer.

A trend towards greater benefit from adjuvant chemotherapy (ACT) in pN+ bladder cancer (BCa) has been observed in multiple randomized controlled trials. However, it is still unclear which patients might benefit the most from this approach. We retrospectively analyzed a multicenter cohort of 1381 patients with pTany pN1-3 cM0 R0 urothelial BCa treated with radical cystectomy (RC) with or without cisplatin-based ACT. The main endpoint was overall survival (OS) after RC. We performed 1:1 propensity score matching to adjust for baseline characteristics and conducted a classification and regression tree (CART) analysis to assess postoperative risk groups and Cox regression analyses to predict OS. Overall, 391 patients (28%) received cisplatin-based ACT. After matching, two cohorts of 281 patients with pN+ BCa were obtained. CART analysis stratified patients into three risk groups: favorable prognosis (≤pT2 and positive lymph node [PLN] count ≤2; odds ratio [OR] 0.43), intermediate prognosis (≥pT3 and PLN count ≤2; OR 0.92), and poor prognosis (pTany and PLN count ≥3; OR 1.36). Only patients with poor prognosis benefitted from ACT in terms of OS (HR 0.51; p < 0.001). We created the first algorithm that stratifies patients with pN+ BCa into prognostic classes and identified patients with pTany BCa with PLN ≥3 as the most suitable candidates for cisplatin-based ACT. PATIENT SUMMARY: We found that overall survival among patients with bladder cancer and evidence of lymph node involvement depends on cancer stage and the number of positive lymph nodes. Patients with more than three nodes affected by metastases seem to experience the greatest overall survival benefit from cisplatin-based chemotherapy after bladder removal. Our study suggests that patients with the highest risk should be prioritized for cisplatin-based chemotherapy after bladder removal.

Neoadjuvant chemotherapy does not increase peri-operative morbidity following radical cystectomy.

OBJECTIVE: To determine whether use of neoadjuvant chemotherapy (NAC) is associated with a higher risk of post-operative complications following radical cystectomy (RC) for bladder cancer (BCa). MATERIALS AND METHODS: We retrospectively reviewed records of patients undergoing RC for non-metastatic urothelial BCa at 13 tertiary care centres from 2007-2019. Patients who received NAC ('NAC + RC' group) were compared with those who underwent upfront RC ('RC alone' group) for intra-operative variables, incidence of post-operative complications as per the Clavien-Dindo classification (CDC) and rates of re-admission and re-intervention. Multivariable logistic regression analysis was performed to determine predictors of CDC overall and CDC major (grade III-V) complications. We also analysed the trend of NAC utilization over the study period. RESULTS: Of the 3113 patients included, 968 (31.1%) received NAC while the remaining 2145 (68.9%) underwent upfront RC for BCa. There was no significant difference between the NAC + RC and RC alone groups with regards to 30-day CDC overall (53.2% vs 54.6%, p = 0.4) and CDC major (15.5% vs 16.5%, p = 0.6) complications. The two groups were comparable for the rate of surgical re-intervention (14.6% in each group) and re-hospitalization (19.6% in NAC + RC vs 17.9% in RC alone, p = 0.2%) at 90 days. On multivariable regression analysis, NAC use was not found to be a significant predictor of 90-day CDC overall (OR 1.02, CI 0.87-1.19, p = 0.7) and CDC major (OR 1.05, CI 0.87-1.26, p = 0.6) complications. We also observed that the rate of NAC utilization increased significantly (p < 0.001) from 11.1% in 2007 to 41.2% in 2019, reaching a maximum of 48.3% in 2018. CONCLUSION: This large multicentre analysis with a substantial rate of NAC utilization showed that NAC use does not lead to an increased risk of post-operative complications following RC for BCa. This calls for increasing NAC use to allow patients to avail of its proven oncologic benefit.

Diagnostic accuracy of preoperative lymph node staging of bladder cancer according to different lymph node locations: A multicenter cohort from the European Association of Urology - Young Academic Urologists.

BACKGROUND: The preoperative lymph node (LN) staging of bladder cancer (BCa) addresses the subsequent therapeutic strategy and influences patient's prognosis. However, sparce evidence exists regarding the accuracy of conventional cross-sectional imaging, such as computed tomography or magnetic resonance imaging, in correctly detect LN status. We aimed to assess the diagnostic accuracy of conventional cross-sectional imaging in detecting preoperative LN involvement among BCa patients treated with radical cystectomy and pelvic lymph node dissection. METHODS: We retrospectively analyzed data of 1,104 patients who underwent preoperative LN staging with computed tomography or magnetic resonance imaging and subsequent radical cystectomy with pelvic lymph node dissection for BCa between 1997 and 2017 at three tertiary referral centers. Patients receiving neoadjuvant chemotherapy were excluded. We assessed the concordance between clinical (cN) and pathological LN (pN) status, defined as the accuracy of imaging in detecting LN involvement using pathological specimen as reference; concordance was expressed according to Cohen's kappa coefficient. Location-based sub-analyses were performed, distinguishing among external iliac, intern iliac, obturator, common iliac, presacral and paraaortic LNs. RESULTS: Among 870 cN0 patients, 68.9% were confirmed pN0 at pathological report; while among 234 cN+ patients, 50.5% were found with LN metastases at pathological specimen. Overall, conventional imaging showed slight concordance (64.9%) between cN and pN stages (sensitivity: 30%; specificity: 84%). At sub-analysis, no agreement between cN and pN status was found in each LN location, with the only exception of common iliac LNs with slight concordance (37.5%). Common iliac LNs achieved the highest sensitivity and positive likelihood ratio (15% and 2.4, respectively) compared to other LN locations. CONCLUSIONS: Overall, preoperative cross-sectional imaging exhibited a slight concordance between cN and pN status. Our location-based sub-analyses showed unsatisfactory results in each LN location- Thus, nomograms combining morphological patterns with serological and clinicopathological features are urgently required.

Variant histologies in bladder cancer: Does the centre have an impact in detection accuracy?

OBJECTIVE: To compare the accuracy in detecting variant histologies (VH) at transurethral resection of bladder (TURB) and radical cystectomy (RC) specimen among tertiary referral centres, in order to investigate potential reasons of discrepancies from the pathological point of view. PATIENTS AND METHODS: Clinical and histopathological data of TURB specimen and subsequent cystectomy specimen of 3,445 RC candidate patients have been retrospectively collected from 24 tertiary referral centres between 1980 and 2021. VH considered in the analysis were pure squamous cell carcinoma, urothelial carcinoma with squamous differentiation, pure adenocarcinoma, urothelial carcinoma with glandular differentiation, micropapillary bladder cancer (BCa), neuroendocrine BCa, and other variants. The degree of agreement between TURB and RC concerning the identification of VH was expressed as concordance, classified according to Cohen's kappa coefficient. RESULTS: A VH was reported in 17% of TURB specimens, 45% of which were not confirmed in RC. The lowest concordance rate was reported for micropapillary BCa with 11 out of 18 (61%) centres reporting no agreement, whereas neuroendocrine BCa achieved the highest concordance rate with only 3 centres (17%) reporting no agreement. Our results shows that even among centres with the advantage of a referent uropathologist the micropapillary variant is characterized by scarce accuracy between TURB and RC. Differences in TURB specimen acquisition by the urologist and in sampling methods among different centres are the main limitations of the study. CONCLUSIONS: Accuracy of TURB in detecting VH is poor for certain VH, in particular for micropapillary BCa, with evident variation among centres. Novel diagnostic tools are required to better identify these VH and drive patients toward a personalized treatment.

Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration.

PURPOSE: To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa). METHODS: We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36 months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy. RESULTS: Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively). CONCLUSION: BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.

The Role of Prior Bladder Cancer on Recurrence in Patients Treated with Radical Nephroureterectomy.

INTRODUCTION: The prognostic role of prior history of bladder cancer (BCa) among patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) is poorly addressed. We aimed to investigate the role of prior BCa on any recurrence, distant metastases, and bladder recurrence following RNU among low-grade (LG) and high-grade (HG) UTUC patients. PATIENTS AND METHODS: We retrospectively analyzed 1,580 UTUC patients treated with RNU at 8 tertiary referral centers between 1992 and 2016. Any recurrence was defined as recurrence in the urinary tract, in the resection bed, or distant metastases (defined as disease outside the urinary tract and regional lymph nodes). Time to recurrence was computed from RNU. Multivariable Cox models were generated to predict risk of any recurrence, distant metastases, and bladder recurrence according to prior BCa history, coded as no prior BCa, non-muscle-invasive (NMIBC), and muscle-invasive BCa (MIBC). RESULTS: Median follow-up for survivors was 4 years. Overall, 71%, 25%, and 4% of patients had no prior BCa, NMIBC and MIBC. 5-year any recurrence-free survival was 61%, 41%, and 19% in LG (P < .001) and 42%, 34%, and 30% in HG patients (P = .1) with no prior BCa, NMIBC, and MIBC. On multivariable models, LG patients with NMIBC and MIBC showed a significantly higher risk of any recurrence compared to no prior BCa (both p≤0.005); previous NMIBC was associated with any recurrence among HG patients (P = 0.04). 5-year distant metastases-free survival was 92%, 90%, and 87% in LG (P > .05) and 68%, 75%, and 45% in HG patients (P = .01) with no prior BCa, NMIBC, and MIBC. Previous NMIBC increased the risk of bladder recurrence among LG (P < .001) and HG (P = .003) patients. CONCLUSIONS: UTUC patients with prior history of BCa exhibit a higher risk of any recurrence after RNU. Our study provides important information which could address patient's counseling and decision-making process.

Carboplatin-based adjuvant chemotherapy versus observation after radical cystectomy in patients with pN1-3 urothelial bladder cancer.

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Survival Outcomes After Immediate Radical Cystectomy Versus Conservative Management with Bacillus Calmette-Guérin Among T1 High-grade Micropapillary Bladder Cancer Patients: Results from a Multicentre Collaboration.

BACKGROUND: Literature lacks clear evidence regarding the optimal treatment for non-muscle-invasive micropapillary bladder cancer (MPBC) due to its rarity and the presence of only small sample size and single-centre studies. OBJECTIVE: To assess cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and conservative management among T1 high-grade (HG) MPBC. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analysed a multicentre dataset including 119 T1 HG MPBC patients treated between 2005 and 2019 at 15 tertiary referral centres. The median follow-up time was 35 mo (interquartile range: 19-64). INTERVENTION: Patients underwent immediate RC versus conservative management with bacillus Calmette-Guérin. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes. Multivariable Cox analyses were performed to assess independent predictors of disease recurrence and disease progression after conservative management; covariates consisted of pure MPBC, concomitant lymphovascular invasion (LVI), and carcinoma in situ at initial diagnosis. RESULTS AND LIMITATIONS: Immediate RC and conservative management were performed in 27% and 73% of patients, respectively. CSM and OM did not differ significantly among patient treated with immediate RC versus conservative management (Pepe-Mori test p = 0.5 and log-rank test p = 0.9, respectively). Overall, 66.7% and 34.5% of patients experienced disease recurrence and disease progression after conservative management, respectively. At multivariable Cox analyses, concomitant LVI was an independent predictor of disease recurrence (p = 0.01) and progression (p = 0.03), while pure MPBC was independently associated with disease progression (p = 0.03). The absence of a centralised re-review and the retrospective design represent the main limitations of our study. CONCLUSIONS: Conservative management could achieve satisfactory results among T1 HG MPBC patients with neither pure MPBC nor LVI at initial diagnosis. PATIENT SUMMARY: Bacillus Calmette-Guérin seems to be an effective therapy for T1 micropapillary bladder cancer patients with neither pure micropapillary disease nor lymphovascular invasion at initial diagnosis.

Bladder perforation during transurethral resection of the bladder: a comprehensive algorithm for diagnosis, management and follow-up.

INTRODUCTION: Despite bladder perforation (BP) is a frequent complication during transurethral resection of bladder (TURB) for bladder cancer (BCa), literature lacks systematic reviews focusing on this issue. We aimed to investigate incidence, diagnosis, therapy, and prognosis after BP during TURB for BCa; therapy was distinguished between conservative (without the need for bladder repair) and surgical management (requiring bladder wall closure). EVIDENCE ACQUISITION: A systematic search was conducted up to April 2021 using PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science to identify articles focusing on incidence, detection, management, or survival outcomes after iatrogenic BP. The selection of articles followed the preferred reporting items for systematic review and meta-analyses process. EVIDENCE SYNTHESIS: We included 41 studies, involving 21,174 patients. Overall, 521 patients experienced BP during TURB for BCa, with a mean incidence of 2.4%, up to 58.3% when postoperative cystography is routinely performed after all TURB procedures. Risk factors were low body mass index (BMI) (P=0.01), resection depth (P=0.006 and P=0.03), and low surgical experience (P=0.006). Extraperitoneal BP (68.5%) were treated conservatively in 97.5% of patients; intraperitoneal BP were managed with surgical bladder closure in 56% of cases. Overall, three immediate BP-related deaths were recorded due to septic complications. Extravesical tumor seeding was observed after 6 intraperitoneal and 1 extraperitoneal BP (median time: 6.2 months). Intraperitoneal BP (P=0.0003) and bladder closure (P<0.001) were found as independent predictors of extravesical tumor recurrence. CONCLUSIONS: BP is more frequent than expected when proper diagnosis is routinely performed after all TURB procedures. Risk factors include low BMI, resection depth, and unexperienced surgeon. The risk of sepsis after BP suggests empirical antibiotic prophylaxis after BP.

The Impact of Primary Tumor Location on Long-Term Oncological Outcomes in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) accounts for up to 10% of all urothelial neoplasms. Currently, various tumor-related factors are proposed to be of importance in UTUC prognostic models; however, the association of the primary UTUC location with oncological outcomes remains controversial. Thus, we sought to perform a systematic review and meta-analysis of the latest available evidence and assess the impact of primary tumor location on long-term oncological outcomes in patients with UTUC undergoing radical nephroureterectomy. MATERIALS AND METHODS: A computerized systematic literature search was conducted in October 2021 through the PubMed, Web of Science, Scopus, and Cochrane Library databases. The primary endpoint was cancer-specific survival (CSS), and the secondary endpoints were overall survival (OS) and disease-free survival (DFS). Effect measures for the analyzed outcomes were reported hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among the total number of 16,836 UTUC in 17 included studies, 10,537 (62.6%) were renal pelvic tumors (RPTs), and 6299 (37.4%) were ureteral tumors (UTs). Pooled results indicated that patients with UT had significantly worse CSS (HR: 1.37, p < 0.001), OS (HR: 1.26, p = 0.003, and DFS (HR: 1.51, p < 0.001) compared to patients with RPT. Based on performed subgroup analyses, we identified different definitions of primary tumor location and geographical region as potential sources of heterogeneity. CONCLUSIONS: Ureteral location of UTUC is associated with significantly worse long-term oncological outcomes. Our results support the need for close follow-up and the consideration of perioperative chemotherapy in patients with UTUC located in the ureter. However, further prospective studies are needed to draw final conclusions.

Nephron sparing surgery for the treatment of renal masses: A single center experience.

BACKGROUND: Nowadays, the partial nephrectomy (PN) not only is considered oncological equivalent to radical nephrectomy as renal tumor's treatment, but has also give benefits in quality of life and overall survival of patients. OBJECTIVES: The primary objective of the present study was to report our single center experience with NSS, predominantly performed by a robot assisted access, in a high-volume center with large experience with minimally invasive surgery. METHODS: Between June 2018 and January 2020, a consecutive series of 109 patients (pts) with a renal mass suspicious of renal cell carcinoma, feasible of NSS, detected by ultrasound and abdominal computed tomography (CT), underwent NSS and they were included in a prospectively maintained institutional database. Baseline demographics and clinical characteristics, perioperative and postoperative parameters, pathological data were recorded. RESULTS: The mean clinical maximum CT tumor diameter was 37.3 ± 19.6 mm (median 31.5 mm; interquartile range 25-45 mm). PADUA risk was low in 54 pts (49.5%), intermediate in 48 pts (44.0%), high in seven pts (6.4%). The clinical T stage was mostly pT1a (70.6%). NSS was performed by open surgery in nine pts (8.3%), laparoscopy in one pts (0.9%) and was robot assisted in 99 pts (90.8%). A simple enucleation was performed in 67 pts (61.5%), an enucleoresection was performed in 37 pts (33.9%) and a partial nephrectomy was performed in five pts (4.6%). Warm ischemia was performed in 41 pts (37.6%), with a mean warm ischemia time of 5.1 ± 7.1 min. The mean pathological maximum tumor diameter was 35.5 ± 21.7 mm (median 30 mm; interquartile range 22-40 mm). Overall PSM rate was 11.9% (13 pts). In 78% of cases no complication was recorded. No major complications (grade III-IV-V) were noted. CONCLUSION: Our findings suggest that NSS is a safe, reproducible and minimally invasive approach as treatment of small renal masses. NSS permits to achieve a fine oncological management without any worsening of renal function.

Precision medicine in localized bladder cancer: Personalizing therapies to improve outcomes.

In the last decades, only few improvements have been made in the comprehension of bladder cancer tumor leading to few improvements in the development of new diagnostic and therapeutic approaches.However, in the last years several step forwards in the field of precision medicine have been made. In this review we focused on some of these elements such as the available biomarkers, the role of enhanced transurethral resection of the bladder and the role of the molecular classification in defining prognosis and therapeutic approaches in bladder cancer patients. Although several progresses have been made, at the time none of the existing biomarkers appear to be able to safely avoid the need of cystoscopy during the follow up of bladder cancer patients. However, these biomarkers representan important tool to follow up patients with a less invasive methods and in the near future might be able to substitute the need of cystoscopy. Enhanced transurethral resection technique can in some cases reduce the risk of recurrence during follow up, although its impact on survival outcomes is still under debate. Transurethral resection of the bladder represents a fundamental diagnostic and therapeutic step in the management of bladder cancer and these techniques can successfully improve its outcomes. Finally, the molecular classification of the bladder cancer represents one of the most exciting novelty in this field, improving consistently the knowledge of bladder cancer. Improvements regarding prognoses and therapeutics can be achieved although data stil need validation.

En las ultimas décadas, pocas mejoras se han hecho en la comprensión del cáncer de vejiga, llevándonos a tener muy poco desarrollo de nuevas técnicas diagnósticas y terapéuticas. En cambio, en los últimos años, varios pasos adelante se han realizado en este campo de la medicina de precisión. En este resumen nos centraremos en algunos elementos importantes como los biomarcadores, el papel de la resección transuretral de vejiga y el papel de las clasificaciones moleculares, en definir el pronóstico y nuevas terapias en pacientes con cáncer de vejiga. Algún progreso se ha conseguido, pero ninguno de los biomarcadore sexistentes parece ser capaz de evitar con seguridad la cistoscopia durante el seguimiento del cáncer de vejiga.A unque estos biomarcadores representan una herramienta importante en el seguimiento de pacientes con métodos menos invasivos y en un futuro no muy lejano podrán substituir a la cistoscopia. La técnica de resección transuretral mejorada en algunos casos reduce elriesgo de recurrencia durante el seguimiento, aunque el impacto en supervivencia aún está en debate. La resección transuretral de vejiga representa un paso fundamental para el diagnóstico y tratamiento en el manejo del cáncer de vejiga y estas técnicas pueden mejorar los resultados. Finalmente, la clasificación molecular del cáncer de vejiga representa una de las novedades mas interesantes en este campo, mejorando de forma consistente los conocimientos del cáncer de vejiga. Las mejoras en relación al pronóstico y tratamiento pueden ser conseguidas aunque los datos aún requieren validación.

Precision medicine in localized bladder cancer: Personalizing therapies to improve outcomes / Medicina de precisión en cáncer de vejiga localizado: terapias personalizadas para mejorar los resultados

In the last decades, only few improvements have been made in the comprehension of bladder cancer tumor leading to few improvements in the development of new diagnostic and therapeutic approaches. However, in the last years several step forwards in the field of precision medicine have been made. In this review we focused on some of these elements such as the available biomarkers, the role of enhanced transurethral resection of the bladder and the role of the molecular classification in defining prognosis and therapeutic approaches in bladder cancer patients. Although several progresses have been made, at the time none of the existing biomarkers appear to be able to safely avoid the need of cystoscopy during the follow up of bladder cancer patients. However, these biomarkers represent an important tool to follow up patients with a less invasive methods and in the near future might be able to substitute the need of cystoscopy. Enhanced transurethral resection technique can in some cases reduce the risk of recurrence during follow up, although its impact on survival outcomes is still under debate. Transurethral resection of the bladder represents a fundamental diagnostic and therapeutic step in the management of bladder cancer and these techniques can successfully improve its outcomes. Finally, the molecular classification of the bladder cancer represents one of the most exciting novelty in this field, improving consistently the knowledge of bladder cancer. Improvements regarding prognoses and therapeutics can be achieved although data still need validation

En las últimas décadas, pocas mejoras se han hecho en la comprensión del cáncer de vejiga, llevándonos a tener muy poco desarrollo de nuevas técnicas diagnósticas y terapéuticas. En cambio, en los últimos anos, varios pasos adelante se han realizado en este campo de la medicina de precisión. En este resumen nos centraremos en algunos elementos importantes como los biomarcadores, el papel de la resección transuretral de vejiga y el papel de las clasificaciones moleculares, en definir el pronóstico y nuevas terapias en pacientes con cáncer de vejiga. Algún progreso se ha conseguido, pero ninguno de los biomarcadores existentes parece ser capaz de evitar con seguridad la cistoscopia durante el seguimiento del cáncer de vejiga. Aunque estos biomarcadores representan una herramienta importante en el seguimiento de pacientes con métodos menos invasivos y en un futuro no muy lejano podrán substituir a la cistoscopia. La técnica de resección transuretral mejorada en algunos casos reduce el riesgo de recurrencia durante el seguimiento, aunque el impacto en supervivencia aún está en debate. La resección transuretral de vejiga representa un paso fundamental para el diagnóstico y tratamiento en el manejo del cáncer de vejiga y estas técnicas pueden mejorar los resultados. Finalmente, la clasificación molecular del cáncer de vejiga representa una de las novedades más interesantes en este campo, mejorando de forma consistente los conocimientos del cáncer de vejiga. Las mejoras en relación al pronóstico y tratamiento pueden ser conseguidas aunque los datos aun requieren validación

The effectiveness of multiparametric magnetic resonance imaging in bladder cancer (Vesical Imaging-Reporting and Data System): A systematic review.

OBJECTIVE: To evaluate the role of the Vesical Imaging-Reporting and Data System (VI-RADS) score in the diagnostic pathway of bladder cancer. METHODS: A systemic search of the contemporary literature was performed in December 2019 using the Medical Literature Analysis and Retrieval System Online (MEDLINE), the Excerpta Medica dataBASE (EMBASE), and Web of Science databases focussing on all available articles on VI-RADS. RESULTS: Overall, six of 15 articles were included. All the available articles evaluated the ability of radiologists to use the VI-RADS score for discriminating non-muscle-invasive bladder cancer (NMIBC) from muscle-invasive bladder cancer (MIBC). Considering a cut-off VI-RADS score of >2, the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were 78-91.9%, 85-91%.1, 69-78%, and 88-97.1%, respectively. Considering a VI-RADS score cut-off of >3, the sensitivity, specificity, PPV and NPV were 77-94.6%, 43.9-96.5%, 51.6-86%, and 63.7-93%, respectively. Good interobserver agreement was demonstrated in the evaluated studies with a κ score of 0.73-0.89. Only one study evaluated the utility of VI-RADS in determining the presence of MIBC in patients treated with transurethral resection of the bladder diagnosed with high-grade T1 before the second transurethral resection using a VI-RADS score cut-off of >2; the sensitivity, specificity, PPV and NPV were 85%, 93.6%, 74.5%, and 96.6%, respectively. CONCLUSION: The VI-RADS score, using multiparametric magnetic resonance imaging, showed excellent results in discriminating MIBC from NMIBC. Preliminary results have been reported for its use in patients with high-grade T1 bladder cancer. These results need to be validated in high-quality real-world settings. ABBREVIATIONS: DCE: dynamic contrast enhancement; DWI: diffusion-weighted imaging; (N)MIBC: (non-)muscle-invasive bladder cancer; mpMRI: multiparametric MRI; TURBT: transurethral resection of bladder tumour; (N)(P)PV: (negative) (positive) predictive value; SC: structural category; T2W: T2-weighted; VI-RADS: vesical imaging-reporting and data system.

Ureteral and urethral recurrence after radical cystectomy: a systematic review.

PURPOSE OF REVIEW: The clinical significance of ureteral and urethral recurrence in patients treated with radical cystectomy for bladder cancer is scarce and heterogeneous. The aim of the current review is to summarize the recent literature on incidence, diagnosis and oncologic outcomes of ureteral and urethral recurrences after radical cystectomy. RECENT FINDINGS: Frozen section analysis (FSA) of ureteral margin had a sensitivity and specificity of 69-77 and 83-96%, respectively. Considering the ureteral margin, the reported sensitivity and specificity were 33-93 and 99-100%, respectively. Transurethral biopsy of the prostatic urethra might help in counseling patients' treatment, although its accuracy and prognostic role is highly questionable. In patients treated with radical cystectomy, recurrence of the urethra or ureteral are rare, occurring approximately in 5% of patients. During the follow-up, urinary cytology and cross-sectional imaging improve the early detection of recurrence in asymptomatic patients, although the majority are diagnosed for symptomatic presentation. Their use should be tailored to the patient's risk of ureteral and/or urethral recurrence. Urethrectomy is indicated in case of singular urethral recurrence, whereas no clear data exists regarding the best management of ureteral recurrence, except surgical removal. SUMMARY: Intraoperative FSA of ureters and urethra share good specificity but poor sensitivity. Recurrence at urethra and upper tract are rare and discordant data exists regarding survival outcomes. Oncologic surveillance after radical cystectomy with the aim to detect these recurrences should be tailored to the individualized patient's risk.

Electro-mediated drug administration of mitomycin C in preventing non-muscle-invasive bladder cancer recurrence and progression after transurethral resection of the bladder tumour in intermediate- and high-risk patients.

OBJECTIVE: To evaluate the effectiveness of electro-mediated drug administration of mitomycin C (EMDA/MMC) after transurethral resection of the bladder tumour (TURBT) in preventing non-muscle-invasive bladder cancer (NMIBC) recurrence and progression and to explore clinical and demographic factors associated with treatment response. PATIENTS AND METHODS: Between April 2016 and August 2019, 112 patients diagnosed with intermediate- or high-risk NMIBC underwent a TURBT followed by an EMDA/MMC treatment. The percentage of treatment responders and progression-free survivors at 3 and 6 months were evaluated. RESULTS: Follow-up data were available for 101 patients (90%) at 3 months and 92 (82%) at 6 months. Response rates to EMDA/MMC treatment were 85% at 3 months and 75% at 6 months, and progression-free rates were 94% and 90%, respectively. No statistically significant differences were seen between intermediate- and high-risk patients. A higher risk of tumour recurrence and progression was associated with previous Bacillus Calmette-Guérin (BCG) failure. According to the Clavien-Dindo classification, only low-grade complications were observed. CONCLUSIONS: EMDA/MMC after TURBT was associated with high response and progression-free rates at 3 and 6 months, with only low-grade adverse events. These results confirm the efficacy and safety of EMDA/MMC as a therapeutic option for both intermediate- and high-risk patients. However, patients with BCG failure responded poorly to EMDA/MMC.Abbreviations: ACCI: age-adjusted Charlson Comorbidity Index; CHT: chemohyperthermia; CIS: carcinoma in situ; EMDA: electro-mediated drug administration; EORTC: European Organisation for Research and Treatment of Cancer; IQR: interquartile range; (N)MIBC: (non-)muscle-invasive bladder cancer; MMC: mitomycin C; OR, odds ratio; TURBT: transurethral resection of the bladder tumour.

Intravesical Treatment with Electro-Mediated Administration of Mytomicin C as Prophylaxis for Intermediate and High-Risk Nonmuscle-Invasive Bladder Cancer: A Retrospective Multicenter Study.

BACKGROUND: Topical therapy of nonmuscle-invasive bladder cancer (NMIBC) is based on immunotherapy with Bacillus Calmette-Guerin and chemotherapy administered by passive instillation, but an active drug administration achieves a better concentration of the drugs in the bladder. AIM: This study aimed to investigate the effectiveness of electromotive drug administration (EMDA) of mitomycin C (EMDA/MMC) in intermediate- and high-risk NMIBC patients 6 months after the end of induction treatment. MATERIALS AND METHODS: Sixty-five patients diagnosed with histologically confirmed NMIBC, with a complete transurethral resection of all visible tumors underwent EMDA/MMC. Primary endpoint was the proportion of responders at 3 or 6 months. RESULTS: Data on follow-up were available for 62 subjects at 3 months and 45 at 6 months. EMDA was effective in intermediate- and high-risk patients: because of the small number of cases no conclusions can be drawn on the efficacy in the low-risk group. No difference in the response to treatment between intermediate- (83.3%) and high-risk (84%) patients could be seen. CONCLUSIONS: EMDA/MMC is a useful technique for an effective and safe treatment of primary and recurrent NMIBC, and a valuable therapeutic option in intermediate- and high-risk NMIBC patients.

[Mitoxantrone chemoprophylaxis for multirecurrent multifocal superficial bladder tumours: results of a phase 2 controlled study]. / Mitoxantrone chemoprophyaxis for multirecurrent multifocal superficial bladder tumours: results of a phase 2 controlled study.

Twenty-three patients with multifocal superficial bladder cancer (stage Ta - T1) unresponsive to at least 3 different intravesical agents, were enrolled in a phase II study in order to evaluate the prophylactic effects of intravesical Mitoxantrone (20 mg) after complete endoscopic resection (TUR) of any papillary tumor. The median follow-up was 6 months; 19 patients (82%) experienced superficial tumor recurrence, 1 patient (4%) progression to muscle invasion and 3 (13%) were disease-free, respectively. Six patients (26%) experienced local side-effects. The progression rate is acceptable; the side effects are at least similar to those available in the literature, but in our experience, Mitoxantrone has no prophylactic effects against superficial bladder cancer unresponsive to previous treatment.