Comparison of standard vs. palliative management for bladder cancer in patients older than 85 years: multicenter study of 317 de novo tumors

BackgroundThe peak incidence of bladder cancer (BCa) occurs at 85 years but data on treatment and outcome are sparse in this age group. We aimed to compare the outcomes of high-grade nonmuscle invasive BCa (HG NMIBC) and muscle invasive BCa (MIBC) treated with standard therapies vs. palliative management in patients >85 years.MethodsRetrospective multicenter study of 317 patients >85 years who underwent transurethral resection (TURB) for de novo BCa between 2014 and 2016. Standard management consisted in following EAU-guidelines and palliative in monitoring patients without applying oncological treatments after TURB. Low-grade tumors were not compared because all of them were considered to have followed a standard management.ResultsMedian age was 87 years (85–97). ASA-score was as follows: II, 34.7%; III, 52.1%; IV, 13.2%. Pathological examination showed: 86 Low-grade NMIBC (27.1%), 156 HG NMIBC (49.2%), and 75 MIBC (23.7%). Median follow-up of the series was 21 months (3–61) and median overall survival (OS) 29 (24–33). Among HG NMIBC, 77 patients (49.4%) received standard treatments (BCG, restaging TURB) and 79 (50.6%) palliative management. Among MIBC, 24 (32%) received standard management (cystectomy, radiotherapy, chemotherapy) and 51 (68%) palliative. Applying standard management in HG NMIBC was an independent prognostic factor of OS (44 months vs. 24, HR 1.95; P = 0.013) and decreased the emergency visit rate (33% vs. 43%). In MIBC, the type of management was not a related to OS (P = 0.439) and did not decrease the emergency visit rate (33% vs. 33%). ASA and Charlson-score were not predictors of OS in HG NMIBC (P = 0.368, P = 0.386) and MIBC (P = 0.511, P = 0.665).ConclusionsChronological age should not be a contraindication for applying standard therapies in NMIBC. In MIBC the survival is low regardless of the type of management. The lack of correlation between OS and ASA or Charlson-score raises the necessity of a geriatric assessment for selecting the best treatment strategy.     

STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer

ObjectiveImprovements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC.Materials and MethodsSTAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models.ResultsSTAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC.ConclusionsSTAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted.     

Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review

Context

Some studies report that tumour progression in patients with non-muscle-invasive bladder cancer (NMIBC) is associated with a poor prognosis. However, no systematic evidence is available.

Objective

The aim of the study was to systematically review literature to determine the long-term cancer-specific survival in patients with high-risk NMIBC (T1G3, multifocal, highly recurrent, or carcinoma in situ) having tumour progression.

Evidence acquisition

A systematic review was conducted by searching PubMed and the Cochrane library for studies published between 2006 and 2011. Additional studies were identified by scanning reference lists of relevant papers. We attempted to retrieve missing data by contacting the corresponding author. Keywords used included bladder cancer, high-risk, high grade, carcinoma in situ, non-muscle invasive bladder cancer, progression, and survival. Studies were included when they met the following criteria: inclusion of at least 75 patients having high-risk NMIBC, patients were initially treated conservatively with transurethral resection of the bladder tumour and intravesical instillations, a median follow-up of at least 48 mo, and reporting data on progression to muscle-invasive bladder cancer (MIBC) and death resulting from bladder cancer (BCa).

Evidence synthesis

Literature was systematically reviewed, and 19 trials were included, producing a total of 3088 patients, of which 659 (21%) showed progression to MIBC and 428 (14%) died as a result of BCa after a median follow-up of 48-123 mo. Survival after progression from high-risk NMIBC to MIBC was 35%. Progression to MIBC and BCa-related death in high-risk NMIBC were found to be relatively early events, occurring mainly within 48 mo. Finally, even in cases of early cystectomy in patients with high-risk NMIBC, a relevant proportion of these patients appear not be cured of their disease.

Conclusions

This study provides systematically gathered evidence showing a poor prognosis for patients with high-risk NMIBC and tumour progression.     

Analysis of hOGG1 genotype as a prognostic marker for muscle invasive bladder cancer: a novel approach using peptide nucleic acid-mediated, real-time PCR clamping

ObjectiveDNA damage repair mechanisms are a source of genetic mutation and are believed to play an important role in human cancer. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is involved in the recognition and repair of DNA damage. The value of the hOGG1 genotype as a prognostic indicator for bladder cancer (BC) was assessed using a novel technological approach.Materials and methodsThe association between genetic polymorphisms of hOGG1 codon 326 and clinicopathologic characteristics of 337 patients with BC was analyzed using peptide nucleic acid (PNA)-mediated real-time PCR clamping.ResultsTumor grade and size were significantly associated with the hOGG1 codon 326 genotype in non-muscle-invasive bladder cancer (NMIBC). The Cys326Cys polymorphism was significantly associated with progression and cancer specific survival in patients with muscle-invasive bladder cancer (MIBC). Multivariate Cox regression analysis indicated that the hOGG1 Cys326Cys polymorphism is associated with a protective effect on progression and a more dominant survival benefit than the Ser326Ser polymorphism in MIBC (hazard ratio 0.284 and 0.305, respectively).ConclusionsAnalysis of genotypes and clinical data for 337 BC patients indicates that the hOGG1 genotype may be a useful prognostic genetic marker for MIBC.     

The prognostic roles of CYP19A1 expression in bladder cancer patients of different genders

BackgroundThe incidence of bladder cancer (BCa) in male is approximately three to four times higher than in female, but the oncological outcomes in female patients with BCa are significantly worse than in male patients. Although many biomarkers have been identified in recent decades to predict the prognosis of BCa patients, few of them are able to distinguish the prognosis of BCa patients with gender difference. Aromatase encoded by the CYP19A1 gene catalyzes the conversion of androgens to estrogens. In this study, we investigate the prognosis significance of CYP19A1 expression considering the gender difference in BCa patients from four available public databases.MethodsFour available public databases of BCa, including {"type":"entrez-geo","attrs":{"text":"GSE13507","term_id":"13507"}}GSE13507, TCGA-BLCA, E-MTAB-4321, and E-MTAB-1803, were utilized in this analysis. The overall survival (OS) and progression-free survival (PFS) in different stages and genders were evaluated using the Kaplan-Meier analysis based on the optimal cut-off values of CYP19A1 expression. Then, Gene Set Enrichment Analysis (GSEA) were further performed to explore the potential biologic pathways by altering CYP19A1 expression in BCa patients.ResultsThe results showed that patients with high CYP19A1 expression had a poorer outcome compared with those with low expression in both BCa cohorts in general. Higher CYP19A1 expression in male patients were significantly associated with shorter survival for either non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC). However, female NMIBC patients with high CYP19A1 expression were identified to have a better prognosis, whereas high CYP19A1 expression in female MIBC patients were significantly associated with poorer survival. The result of the GSEA showed that different outcomes in female and male patients with NMIBC were related to the interaction of CYP19A1 and the cell-cycle-related pathways.ConclusionsThese findings demonstrated that CYP19A1 expression might have a potential role in distinguishing the prognosis of female BCa patients dependent on tumor stage. Our results provide new insights for aromatase-mediated BCa therapy.     

Value of multiparametric magnetic resonance imaging for local staging of invasive urinary bladder tumours.

BackgroundInitial tumour staging in bladder cancer mainly relies on the histo-pathological outcome of the transurethral bladder tumour resection (TURBT) and imaging by means of a CT-scan (CT-intravenous urography; CT-IVU). The reported risk of understaging varies from 24-50%. To further improve the the evaluation of depth of invasion of the bladder tumour the application of magnetic resonance imaging (MRI) may be useful. To substantiate the additional value of this imaging modality the present observational study was designed.Study designThis is a prospective observational study to analyse bladder tumour staging with multiparametric magnetic resonance imaging (mpMRI) in patients with a known bladder tumour, who are planned for radical cystectomy.Study populationPatients with an invasive bladder cancer who are planned for radical cystectomy.InterventionPatients were accrued during their visit to the outpatient department of urology. They underwent routine cystoscopy, laboratory tests (including serum Creatinin) and CT-IVU investigations and subsequently a mpMRI.Main study parameters/endpointsTo demonstrate the value of mpMRI in the initial staging of bladder tumours using radiological bladder tumour stage (T-stage) based on mpMRI and pathological bladder tumour stage based on ‘whole-mount’ histo-pathology after radical cystectomy.ResultsThirty-seven participants with known bladder tumours underwent mpMRI and subsequent cystectomy. After mpMRI 10 participants were diagnosed with non-muscle-invasive bladder cancer (NMIBC) and 27 participants with muscle-invasive bladder cancer (MIBC). In the ‘whole-mount’ pathology results 12 participants had NMIBC and 25 participants had MIBC. We found a sensitivity and specificity of 0.88 en 0.58 respectively, for the evaluation of MIBC. The positive and negative predictive value were 81% and 70% respectively. The diagnostic accuracy of mpMRI to differentiate between NMIBC and MIBC was 78%.ConclusionsWe found a sensitivity of 88% and a specificity of 58% for mpMRI to discriminate NMIBC from MIBC.     

Comparison of the prognosis of primary vs. progressive muscle invasive bladder cancer after radical cystectomy: Results from a large multicenter study

PurposeTo assess whether progressive and primary muscle invasive bladder cancer (MIBC) have different prognosis after radical cystectomy or not. To date only a few data are available on this topic with conflicting results. Further studies on large cohort are needed to clarify these outcomes that may influence bladder cancer management for these patients.Material and methodsA multicentre retrospective study was conducted on patient treated for MIBC at 5 centres between 2005 and 2015 by radical cystectomy. Patients’ outcomes were compared between patients with primary MIBC vs. progressive MIBC subsequent to a history of non-muscle invasive bladder cancer (NMIBC).ResultsA total of 1197 patients were included. Median (IQ) age was 65 (58–72) years and median follow-up was 65 months. Baseline characteristics were similar between the groups as well as the Tumour pT stage, N status and positive surgical margins. Patients with progressive MIBC had worse overall survival (OS) (hazard ratio [HR] 1.36, [95%CI 1.10–1.76]; P = 0.004), cancer specific survival (CSS) (HR 1.41 [1.13–1.78]; P = 0.002), and recurrence-free survival (RFS) (HR 1.21 [1.01–1.49]; P = 0.05). Pathological stage ≥pT3, positive surgical margins, and positive lymph nodes status (pN+) were also found as predictors of OS, CSS, and RFS.ConclusionsOur results suggest that patient having a progressive BC have a worse prognosis in terms of OS, PFS, and CSS than patient with primary disease. These 2 groups may require different management and patients with high risk NMIBC should be assessed properly to avoid progression and be offered early cystectomy.     

Prospective Assessment of Vesical Imaging Reporting and Data System (VI-RADS) and Its Clinical Impact on the Management of High-risk Non–muscle-invasive Bladder Cancer Patients Candidate for Repeated Transurethral Resection

BackgroundVesical Imaging Reporting and Data System (VI-RADS) score is adopted to provide preoperative bladder cancer (BCa) staging. Repeated transurethral resection of bladder tumor (Re-TURBT) is recommended in most of high-risk non–muscle-invasive bladder cancers (HR-NMIBCs) due to possibility of persistent/understaged disease after initial TURBT. No diagnostic tools able to improve patient’s stratification for such recommendation exist.ObjectiveTo (1) prospectively validate VI-RADS for discriminating between NMIBC and muscle-invasive bladder cancer (MIBC) at TURBT, and (2) evaluate the accuracy of VI-RADS for identifying HR-NMIBC patients who could avoid Re-TURBT and detecting those at higher risk for understaging after TURBT.Design, setting, and participantsPatients with BCa suspicion were offered multiparametric magnetic resonance imaging (mpMRI) before TURBT. According to VI-RADS, a cutoff of ≥3 to define MIBC was assumed. TURBT reports were compared with preoperative VI-RADS scores to assess accuracy of mpMRI for discriminating between NMIBC and MIBC. HR-NMIBC Re-TURBT reports were compared with preoperatively recorded VI-RADS scores to assess mpMRI accuracy in predicting Re-TURBT outcomes.InterventionMultiparametric MRI of the bladder before TURBT.Outcome measurements and statistical analysisSensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated for mpMRI performance in patients undergoing TURBT and for HR-NMIBC patients candidate for Re-TURBT. Performance of mpMRI was assessed by receiver operating characteristic curve analysis. Ƙ statistics was used to estimate inter- and intrareader variability.Results and limitationsA total of 231 patients were enrolled. Multiparametric MRI showed sensitivity, specificity, PPV, and NPV for discriminating NMIBC from MIBC at initial TURBT of 91.9% (95% confidence interval [CI]: 82.2–97.3), 91.1% (95% CI: 85.8–94.9), 77.5% (95% CI: 65.8–86.7), and 97.1% (95% CI: 93.3–99.1), respectively. The area under the curve (AUC) was 0.94 (95% CI: 0.91–0.97). Among HR-NMIBC patients (n = 114), mpMRI before TURBT showed sensitivity, specificity, PPV, and NPV of 85% (95% CI: 62.1–96.8), 93.6% (95% CI: 86.6–97.6), 74.5% (95% CI: 52.4–90.1), and 96.6% (95% CI: 90.5–99.3) respectively, to identify patients with MIBC at Re-TURBT. The AUC was 0.93 (95% CI: 0.87–0.97).ConclusionsVI-RADS is accurate for discriminating between NMIBC and MIBC. Within HR-NMIBC cases, VI-RADS could, in future, improve the selection of patients who are candidate for Re-TURBT.Patient summaryWe investigated the accuracy of Vesical Imaging Reporting and Data System (VI-RADS) score to asses bladder cancer staging before transurethral resection of bladder tumors, and we explored the performance of VI-RADS score as a future preoperative predictive tool for the selection of high-risk non–muscle-invasive bladder cancer patients who are candidate for undergoing early repeated transurethral resection of the primary tumor site.     

Circulating microRNAs in serum: novel biomarkers for patients with bladder cancer?

Purpose

Recent studies indicate that circulating microRNAs in serum/plasma are a novel class of non-invasive biomarkers with diagnostic and prognostic information. So far, circulating microRNAs have not been analyzed in patients with bladder cancer.

Methods

We collected serum from patients with non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and non-malignant urological disease. Total RNA was isolated from 400 μl of serum using the mirVana PARIS Kit; the artificial cel-miR-39 was spiked-in prior to RNA isolation to control different RNA isolation efficiencies. Quantitative real-time PCR was applied to measure the levels of 22 microRNAs upregulated in BCA tissue (miR-15a, miR-18a, miR-21, miR-93, miR-96, miR-103, miR-130b, miR-135b, miR-141, miR-182, miR-183, miR-190, miR-191, miR-200b, miR-422b, miR-425, miR-449b, miR-601, miR-639, miR-644, miR-649 and miR-1233) in the marker identification cohort (NMIBC, n = 11, MIBC, n = 10; controls, n = 10). The most promising serum microRNAs were tested in a validation cohort (NMIBC, n = 65, MIBC, n = 61; controls, n = 105).

Results

The RNA recovery was similar in patients with NMIBC, MIBC and control subjects. The analysis of serum microRNA levels in the marker identification cohort indicated that serum miR-141 and miR-639 levels were increased in bladder cancer patients compared to CTRL. The analysis of these miR-141 and miR-639 in the validation cohort demonstrated that microRNA levels were similar in bladder cancer patients and control subjects. Furthermore, microRNA levels were not correlated with clinicopathological parameters (pT-stage, metastasis, grading).

Conclusions

The analysis of serum miR-141 and miR-639 levels does not seem to be helpful in the diagnosis or prognosis of BCA.     

The role of urine markers,white light cystoscopy and fluorescence cystoscopy in recurrence,progression and follow-up of non-muscle invasive bladder cancer

Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 70 % of all bladder cancer cases and represents a heterogeneous pathological entity, characterized by a variable natural history and oncological outcome. The combination of cystoscopy and urine cytology is considered the gold standard in the initial diagnosis of bladder cancer, despite the limited sensitivity. The first step in NMIBC management is transurethral resection of the bladder tumour (TURBT). This procedure is marked by a significant risk of leaving residual disease. The primary landmark in NMIBC is the high recurrence rate. Fluorescence cystoscopy improves the bladder cancer detection rate, especially for flat lesions, and improves the recurrence-free survival by decreasing residual tumour. Progression to muscle invasive tumours constitutes the second important landmark in NMIBC evolution. Stage, grade, associated CIS and female gender are the major prognostic factors in this regard. The evolution to MIBC has a major negative impact upon the survival rate and quality of life of these patients. Fluorescence cystoscopy improves the detection rate of bladder cancer but does not improve the progression-free survival. Urine markers such as ImmunoCyt and Uro Vysion (FISH) have also limited additional value in diagnosis and prognosis of NMIBC patients. Major drawbacks are the requirement of a specialized laboratory and the additional costs. In this review, the risks of recurrence and progression are analysed and discussed. The impact of white light cystoscopy, fluorescence cystoscopy and urine markers is reviewed. Finally, the means and recommendations regarding follow-up are discussed.     

Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature

ContextFollow-up of patients treated for bladder cancer (BCa) is of great importance for both non–muscle-invasive BCa (NMIBC) and muscle-invasive BCa (MIBC) because of the high incidence of recurrence and progression. The schedule and methods of follow-up should reflect the individual clinical situation.ObjectiveTo evaluate the existing evidence for intensity and duration of follow-up recommendations in patients after surgical treatment of BCa.Evidence acquisitionWe searched the Medline, Embase, and Cochrane databases for published data on the follow-up of patients with NMIBC and MIBC after radical cystectomy (RC).Evidence synthesisFollow-up in patients with NMIBC is necessary because of the high probability of tumour recurrence and the risk of progression. Cystoscopy plus cytology are the standard methods for follow-up. Cystoscopy should be done 3 mo after the transurethral resection in every patient, and the frequency after that depends on the individual recurrence/progression risk. Cytology should be used as an adjunctive method to cystoscopy in intermediate- and high-risk patients. None of the currently available urinary markers or imaging methods can substitute for cystoscopy-based follow-up. High-risk NMIBC patients require regular lifelong upper urinary tract monitoring. Follow-up in MIBC is based on the fact that early detection of recurrence after RC allows for timely treatment with the aim of improving outcomes. Patients with extravesical and lymph node–positive disease should have the most intensive follow-up because of the highest recurrence risk. Routine upper urinary tract imaging is advisable for all patients and should continue in the long term. Follow-up also allows for early detection of urinary diversion–related complications, the rate of which increases with time.ConclusionsFollow-up in BCa is necessary for diagnosing recurrence and progression, as well as for evaluating complications after radical treatment. Since randomised studies investigating the most appropriate follow-up schedule are lacking, most recommendations are based on only the retrospective experience. Nonetheless, reasonable recommendations can be made until further prospective randomised studies testing different follow-up schedules have been performed.     

Molecular Characterization of Bladder Cancer

Purpose of Review

Bladder cancer (BCa) management had remained unchanged for 20+ years with clinicians, in contrast to many other cancer types, rarely relying on molecular characteristics to guide management. The past 5 years have yielded significant advances in our knowledge of the molecular basis of BCa and concurrent advances in systemic therapy. We aim to highlight the key developments and potential future direction of BCa management.

Recent Findings

Next-generation sequencing (NGS) has drastically altered the understanding of muscle-invasive BCa (MIBC) and non-muscle invasive BCa (NMIBC). MIBC molecular subtyping efforts from several groups worldwide grouped into an international consortium into five classes, broadly grouped into basal and luminal subtypes, have attempted to improve prediction of clinical outcomes and treatment response, either chemotherapy or immunotherapy. NMIBC molecular subtyping is yielding similar disease stratification, superior to histopathology alone. Additionally, with new actionable targets being identified for patients non-responsive to traditional therapy, ongoing and upcoming clinical trials are increasingly emphasizing the importance of the molecular testing.

Summary

The molecular characterization of bladder cancer is rapidly progressing and will likely alter treatment paradigms in the near future.

     

Serum IL-6 level is associated with clinical outcome of intravesical gemcitabine therapy in T1 non-muscle–invasive bladder cancer

PurposeSerum biomarkers are valuable tools to predict the prognosis of anticancer therapies. This study aimed to evaluate the impact of serum interleukin-6 (IL-6) level on the clinical outcome of intravesical gemcitabine (GEM) therapy in non-muscle–invasive bladder cancer (NMIBC).MethodsThis retrospective study enrolled 71 patients initially diagnosed with T1 NMIBC who underwent intravesical GEM therapy between 2017 and 2019. The expression of IL-6 gene was examined by real-time PCR. Serum IL-6 level was determined by enzyme-linked immunosorbent assay (ELISA). The cell viability after gemcitabine treatment was measured by CCK-8 assay. The optimal serum IL-6 cutoff values for recurrence prediction were calculated using receiver-operating characteristic curve analysis with reference to cancer recurrence. Recurrence-free survival was compared by the log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify the prognostic factors influencing recurrence-free survival after treatment with intravesical GEM.ResultsIncreased expression and secretion of IL-6 were observed in GEM-resistant sublines compared with parental bladder cancer cell lines. Serum IL-6 level rendered a sensitivity of 82.6% and a specificity of 77.1% to correlate with the cancer recurrence after intravesical GEM. Patients with a high serum IL-6 level exhibited shorter recurrence-free survival after intravesical GEM. Moreover, serum IL-6 level in our NMIBC cohort was significantly associated with clinicopathological characteristics, such as tumor diameter, multifocality, concomitant CIS, and grade. Serum IL-6 level was an independent prognostic factor for recurrence-free survival in NMIBC patients treated with intravesical GEM.ConclusionGiven that it was significantly associated with clinical outcome of intravesical GEM therapy, serum IL-6 level might be used as a potential prognostic biomarker for intravesical GEM in T1 NMIBC.     

Investigating the association between the urinary microbiome and bladder cancer: An exploratory study

IntroductionWe sought to investigate the association between the urinary microbiome and bladder cancer, including the difference between nonmuscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer, and Bacillus Calmette Guerin (BCG) responsive vs. BCG-refractory NMIBC.MethodsUrine specimens were collected from consecutive patients with bladder cancer and healthy volunteers. Urine samples were analyzed using 16S rRNA sequencing to identify and compare any present bacteria. Alteration in the urinary microbiome was described in terms of alpha (diversity of populations within a sample) and beta diversities (differences between populations among different samples). Analyses were corrected for age, sex, method of sample preservation, and method of collection (mid-stream catch vs. catheterized urine).ResultsFifty-three samples (43 patients with bladder cancer, and 10 controls) were included. For bladder cancer patients, mean age was 70 years, 7 (16%) were females; and 29 (67%) had NMIBC. Among patients with NMIBC, 11 (38%) patients received BCG, 6 of which had recurrence or progression after a median follow up of 13 months. Comparing the microbiome of bladder cancer patients vs. healthy controls, beta-diversity was significantly different, with Actinomyces, Achromobacter, Brevibacterium, and Brucella significantly more abundant in urine samples of bladder cancer patients. Comparing NMIBC and MIBC, Hemophilus and Veillonella were significantly more abundant in urine of MIBC patients, while Cupriavidus was significantly more abundant in NMIBC patients. Among NMIBC patients, Serratia and Brochothrix, Negativicoccus, Escherichia-Shigella, and Pseudomonas were significantly more abundant in patients who responded to BCG in comparison to those who did not.ConclusionUrinary microbiome varied between patients with bladder cancer and healthy controls. Moreover, urinary microbial profiles differed among patient with NMIBC vs. MIBC, and among BCG responsive vs. BCG refractory NMIBC.     

Intermediate-term survival of robot-assisted versus open radical cystectomy for muscle-invasive and high-risk non-muscle invasive bladder cancer in The Netherlands

BackgroundRadical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited.ObjectiveTo assess the intermediate-term overall survival (OS) and recurrence-free survival (RFS) of patients with MIBC and high-risk non-MIBC (NMIBC) who underwent ORC versus RARC in clinical practice.Methods and materialsA nationwide retrospective study in 19 Dutch hospitals including patients with MIBC and high-risk NMIBC treated by ORC (n = 1086) or RARC (n = 386) between January 1, 2012 and December 31, 2015. Primary and secondary outcome measures were median OS and RFS, respectively. Survival outcomes were estimated using Kaplan-Meier curves. A multivariable Cox regression model was developed to adjust for possible confounders and to assess prognostic factors for survival including clinical variables, clinical and pathological disease stage, neoadjuvant therapy and surgical margin status.ResultsThe median follow-up was 5.1 years (95% confidence interval ([95%CI] 5.0–5.2). The median OS after ORC was 5.0 years (95%CI 4.3–5.6) versus 5.8 years after RARC (95%CI 5.1–6.5). The median RFS was 3.8 years (95%CI 3.1–4.5) after ORC versus 5.0 years after RARC (95%CI 3.9–6.0). After multivariable adjustment, the hazard ratio for OS was 1.00 (95%CI 0.84–1.20) and for RFS 1.08 (95%CI 0.91–1.27) of ORC versus RARC. Patients who underwent ORC were older, had higher preoperative serum creatinine levels and more advanced clinical and pathological disease stage.ConclusionORC and RARC resulted in similar intermediate-term OS and RFS in a cohort of almost 1500 MIBC and high-risk NMIBC.     

Impact of substratification on predicting oncological outcomes in patients with primary high-risk non-muscle-invasive bladder cancer who underwent transurethral resection of bladder tumor

ObjectivesTo validate the substratification of high-risk in the European Association of Urology (EAU) guidelines and to develop the simplified substratification to improve usefulness and predictive accuracy on oncological outcomes in patients with primary high-risk nonmuscle-invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumor (TURBT).Materials and methodsWe retrospectively evaluated 428 patients with primary high-risk NMIBC who underwent TURBT from November 1993 to April 2019. First, the efficacy of the EAU highest-risk on intravesical recurrence-free survival (RFS) and muscle-invasive bladder cancer (MIBC)-free survival was evaluated with univariate analyses. Second, we developed our simplified substratification based on multivariate analysis for intravesical RFS (lower- and higher-risk). We compared predictive accuracy on oncological outcomes using the receiver operating characteristic curve between the EAU and the simplified substratifications.ResultsMedian age and median follow-up periods were 72 years and 51 months, respectively. The EAU highest-risk was not associated with shorter intravesical RFS and MIBC-free survival (P = 0.054 and P = 0.350, respectively). In multivariate analysis, tumor size, grade 3, and chronic kidney disease were significantly associated with shorter intravesical RFS, and we developed the simplified substratification including those 3 factors. Of 428 patients, 89 (21%) were substratified into the simplified higher-risk. The predictive accuracy of the simplified substratification on intravesical recurrence, MIBC and metastasis progression, and cancer-specific mortality was significantly superior to the EAU substratification.ConclusionOur simplified substratification might contribute to improving predictive accuracy on intravesical recurrence, MIBC and metastasis progression, and cancer-specific mortality in patients with primary high-risk NMIBC who underwent TURBT.     

PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer

ObjectivesPFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) is induced by hypoxia and is strongly associated with glycolysis. Previously, we reported that PFKFB4 expression level may serve as a predictor of progression in non-muscle-invasive bladder cancer (NMIBC). Here, the role of PFKFB4 in NMIBC and the relationship between PFKFB4 expression and biological behavior in bladder cancer was investigated.MethodsOne hundred ninety-three primary NMIBC tissue specimens were analyzed by real-time PCR. Immunohistochemical staining was performed on 77 subsets of tumor samples. The results were compared with clinicopathologic parameters, and the Kaplan-Meier method and a multivariate Cox regression model were used to identify the prognostic value of PFKFB4 for recurrence and progression.ResultsThe mRNA expression levels of PFKFB4 were significantly higher in patients with high stage carcinoma and multiple tumors as compared to low stage and single tumors (P < 0.05 for each). Kaplan-Meier estimates revealed significant differences in time to recurrence and progression between low- and high-mRNA expression groups (log-rank test, P = 0.015 and 0.003, respectively). Multivariate Cox regression analysis revealed that the level of PFKFB4 expression is an independent predictor of bladder tumor progression (HR, 2.026; 95% CI, 1.177–3.488; P = 0.011). Immunohistochemical findings were generally concordant with mRNA expression levels.ConclusionsPFKFB4 has an important role in the progression of NMIBC, and may serve as a useful prognostic indicator for bladder cancer progression.     

Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study

Transurethral resection of bladder tumour (TURBT) is central to the diagnosis of muscle-invasive bladder cancer (MIBC). With the oncological safety of TURBT unknown, staging inaccuracies commonplace, and correct treatment of MIBC potentially delayed, multiparametric magnetic resonance imaging (mpMRI) may offer rapid, accurate, and noninvasive diagnosis of MIBC. BladderPath is a randomised trial comparing risk-stratified (5-point Likert scale) image-directed care with TURBT for patients with newly diagnosed BC. To date, we have screened 279 patients and randomised 113. Here we report on the first 100 participants to complete staging: 48 in pathway 1 (TURBT) and 52 in pathway 2 (mpMRI for possible MIBC, Likert 3–5). Fifty of 52 participants designated Likert 1–2 (probable NMIBC) from both pathways were confirmed as having NMIBC (96%). Ten of 11 cases diagnosed as NMIBC by mpMRI have been pathologically confirmed as NMIBC, and 10/15 cases diagnosed as MIBC by mpMRI have been treated as MIBC (5 participants underwent TURBT). The specificity of mpMRI for identification of MIBC remains a limitation. These initial experiences indicate that it is feasible to direct possible MIBC patients to mpMRI for staging instead of TURBT. Furthermore, a 5-point Likert scale accurately identifies patients with low risk of MIBC (Likert 1–2), and flexible cystoscopy biopsies appear sufficient for diagnosing BC.Patient summaryWe are conducting a clinical trial to assess whether some bladder tumour surgery can be replaced by magnetic resonance imaging scans to determine the stage of the cancer in patients whose tumours appear to be invasive. Our early data suggest that this approach is feasible. The data also show that using a visual score ('Likert scale') can help to identify bladder tumours that are very unlikely to be invasive, and that taking a biopsy in the outpatient clinic when first inspecting the bladder via a camera (diagnostic flexible cystoscopy) is useful for confirming bladder cancer.     

Association of smoking status and recurrence of non-muscle invasive bladder cancer among patients managed with blue light cystoscopy

PurposeSmoking has a strong causal association with bladder cancer but the relationship with recurrence is not well established. We sought to assess the association of smoking status on recurrence of non-muscle invasive bladder cancer (NMIBC) in a contemporary cohort of patients with predominantly high-risk, recurrent NMIBC managed with photodynamic enhanced cystoscopy.Materials and methodsWe performed a retrospective study of patients with NMIBC included in a multi-institutional registry. Our primary exposure of interest was smoking status. Our primary outcome was first recurrence of NMIBC. Kaplan-Meier analysis was used to calculate recurrence free probabilities and Cox proportional hazards regression was used to evaluate the impact of smoking status on recurrence free survival.ResultsOur analytic cohort included 723 adults with bladder cancer, 11.5% with primary NMIBC and 88.5% with recurrent NMIBC. The majority of patients were white, male, and had high-risk NMIBC (72.6%). 52.6% of included patients were former smokers and 12.7% were current smokers. During the three-year study period, there was a NMIBC recurrence in 259 of the 723 patients (35.8%). The 1- and 3-year probability of recurrence was 19% and 44%, respectively. The grade and stage of recurrences were 28.9% LG Ta, 34.4% HG Ta, 15.8% pure CIS, 0.3% LG T1, 15.4% HG T1, and 5.4% unknown. After adjustment for a priori clinical and demographic factors, smoking status had no significant association with recurrence.ConclusionSmoking status was not significantly association with recurrence in a study of patients with predominantly high-risk recurrent NMIBC managed with photodynamic enhanced cystoscopy.     

Increased BCL2L12 expression predicts the short-term relapse of patients with TaT1 bladder cancer following transurethral resection of bladder tumors

ObjectivesMore than half of the diagnosed patients with bladder cancer (BCa) recur at least once following their initial treatment. Thus, patients' monitoring and prognosis is of utmost importance. However, the need for intensive surveillance of BCa significantly burdens patients' health-related quality of life. The aim of the present study is the expression analysis of BCL2L12, a recently identified member of the BCL2 apoptosis-related gene family, in BCa and the evaluation of BCL2L12 prognostic significance for the survival outcome of the patients.Methods and materialsOur study included 115 patients with BCa, and tissue specimens were obtained from the tumor area as well as from adjacent normal bladder wall. BCL2L12 expression was determined using quantitative real-time polymerase chain reaction assay, and was further correlated with patients' clinicopathological features and follow-up survival data.ResultsUp-regulated BCL2L12 expression levels were detected in malignant bladder specimens compared with normal ones. The higher BCL2L12 expression was further associated with shorter disease-free survival of the patients with BCa. Focusing on patients with TaT1 non–muscle invasive BCa, BCL2L12 expression levels were correlated with higher recurrence rate at the first follow-up cystoscopy and were unveiled to be an independent unfavorable predictor of patients' short-term recurrence following transurethral resection. Finally, BCL2L12 expression levels were also associated with poor disease-free survival of the high-grade TaT1 patients.ConclusionsOur data highlight the unfavorable prognostic value of BCL2L12 for patients with BCa and support its potential clinical use for the assessment of TaT1 patients' recurrence risk.