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.     

A prognostic immune predictor,HLA-DRA,plays diverse roles in non-muscle invasive and muscle invasive bladder cancer

BackgroundThere is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).Materials and MethodsTissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa.ResultsPatients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers.ConclusionsHigh expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology.     

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.     

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.     

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.     

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.     

The effect of tumor grade heterogeneity on recurrence in non-muscle invasive bladder cancer

ObjectiveTo investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance.MethodsWe identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy.ResultsTwo hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence.ConclusionsThe prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.     

Expression patterns and prognostic role of transketolase-like 1 in muscle-invasive bladder cancer

Purpose

The pentose phosphate pathway (PPP) has been shown to play an important role in the metabolism of cancer cells. The transketolase-like 1 gene (TKTL1) encodes an enzyme representing an essential component of this pathway. Its expression has been demonstrated to correlate with stage and outcome in various tumors. The aim of the present study was to assess expression patterns and the prognostic role of TKTL1 in muscle-invasive bladder cancer (MIBC).

Patients and methods

The expression of TKTL1 was assessed in a tissue microarray consisting of histopathologically benign and malign tissue of 112 patients who underwent radical cystectomy due to MIBC. Cytoplasmatic and nuclear expression were assessed by immunohistochemistry and compared separately with clinicopathologic parameters and outcome.

Results

Cytoplasmatic expression of TKTL1 was exclusively present in tumor tissue. In contrast, the proportion of nuclei positive for TKTL1 was higher in histopathologically benign tissue compared with malign tissue. No correlation was observed between cytoplasmatic or nuclear TKTL1 expression and tumor stage, grade or the presence of metastases. Patients with lymph node involvement showed a decreased frequency of cytoplasmatic expression compared with node-negative patients (p = 0.01). However, no further correlation was observed between the expression of TKTL1 and clinical outcome of patients.

Conclusions

The present study shows that the cytoplasmatic expression of TKTL1 is specific for MIBC tissue compared with histopathologically benign urothelium. This specific expression is present in a subgroup of MIBC potentially identifying patients with activated PPP suitable for a targeted inhibition of sugar metabolism. In contrast to other malignancies, TKTL1 shows no prognostic significance in MIBC.

     

Is a restaging TURBT necessary in high-risk NMIBC if the initial TURBT was performed with blue light?

ObjectivesTo evaluate whether a restaging transurethral resection of bladder tumor (TURBT) is necessary in high-risk nonmuscle invasive bladder cancer (NMIBC) if the initial TURBT was performed using blue light (BL) technology.Methods and materialsUsing the multi-institutional Cysview registry between 2014 and 2021, all consecutive adult patients with known NMIBC (Ta and T1 disease) who underwent TURBT followed by a restaging TURBT within 8 weeks were reviewed. Patients were stratified according to their initial TURBT, BL vs. white light (WL), and compared to determine rates of residual disease and upstaging. Univariate analysis was performed using Mann-Whitney U and chi-square tests, with P < 0.05 considered significant.ResultsOverall, 115 patients had TURBT for NMIBC followed by a restaging TURBT within 8 weeks and were included in the analysis. Patients who underwent BL compared to WL for their initial TURBT had higher rates of benign pathology on restaging TURBT, although this was not statistically significant (47% vs. 30%; P = 0.08). Of patients with residual tumors on restaging TURBT, there were no differences in rates of Ta (22% vs. 26.5%; P = 0.62), T1 (22% vs. 26.5%; P = 0.62), or CIS (5.5% vs. 13%; P = 0.49) when the initial TURBT was done using BL compared to WL. Rates of upstaging to muscle invasive disease were also not different when initial TURBT was performed using BL compared to WL (3% vs. 4%; P = 0.78).ConclusionsTURBT using BL does not reduce rates of residual disease or risk of upstaging on restaging TURBT in Ta or T1 disease. Thus, a restaging TURBT is still necessary even if initial TURBT was performed using BL.     

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.     

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.     

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.     

Endoscopic surveillance for bladder cancer: a systematic review of contemporary worldwide practices

BackgroundThe aim of this systematic review was to identify the current endoscopic surveillance strategies in use across the world and to determine whether these were sufficient or if any recommendations for changes in the guidelines could be made. This review focused on the cystoscopic follow-up of non-muscle invasive bladder cancer (NMIBC) patients and muscle invasive bladder cancer (MIBC) patients who had undergone bladder sparing treatments.MethodsA literature search was carried out on Medline and Embase using OVID gateway according to a pre-defined protocol. Systematic screening of the identified studies was carried out by two authors. Quality assessment was performed using the Joanna Briggs critical appraisal tools. Data was extracted on various aspects including the follow-up regime utilised, patients included, outcomes investigated and a summary of the results. The studies were compared in a narrative nature.ResultsA total of 2,604 studies were identified from the search strategy, of which 14 were deemed suitable for inclusion following the screening process. The studies identified were from nine countries and were mainly observational or qualitative. There was a huge variation in the follow-up regimes utilised within the studies with no clear consensus as to which regime was the most suitable. However, all studies utilised an initial cystoscopy at three months post-TURBT. No studies were identified which investigated the endoscopic follow-up strategies for MIBC patients who opted for bladder conservation with chemoradiation.ConclusionsThere is no universally accepted protocol for endoscopic follow-up of patients with NMIBC bladder cancer. Guidance on cystoscopic monitoring of bladder in patients who have undergone chemoradiation for MIBC is also lacking.     

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.     

Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3)

Objectives  To review understaging and survival of patients who underwent early versus deferred radical cystectomy (RCX) for high-risk non-muscle invasive bladder cancer (NMIBC; T1 G3). Methods  The results of 1,521 RCXs including 1,420 for bladder cancer were reviewed: (1) A total of 114 patients with high-risk NMIBC underwent a single TUR-BT followed by immediate RCX to estimate the understaging rate. (2) As much as 260 patients with NMIBC had long-term follow-up before RCX to determine the upgrading and upstaging over time. (3) We compared survival in patients with initial T1 G3 bladder cancer (BC) treated with early RCX (n = 175) versus deferred RCX (n = 99) for recurrent T1 G3. Results  (1) Our understaging rate was 20.2%. (2) Allowing NMIBC to upgrade portents a 19% survival disadvantage. (3) The 10 years cancer-specific survival rate was 78.7% in early and 64.5% in deferred RCX. Conclusions  Early, as compared to deferred RCX, has a distinct survival advantage for high-risk NMIBC. Patients should be counselled accordingly.     

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.     

Adverse upgrading and/or upstaging in contemporary low-risk prostate cancer patients

Background

Upgrading and/or upstaging in low-risk prostate cancer (PCa) patients may represent an indication for active treatment instead of active surveillance (AS). We addressed contemporary upgrading and/or upstaging rates in a large population based-cohort of low-risk PCa patients.

Materials and methods

Whitin the SEER database (2010–2015), NCCN low-risk PCa patients were identified across management modalities: radical prostatectomy (RP), radiotherapy (RT) and non-local treatment (NLT). In RP patients, upgrading and/or upstaging rates were assessed in logistic regression models.

Results

Overall, of 27,901 low-risk PCa patients, 38% underwent RP vs 28% RT vs 34% NLT. RP patients were the youngest and harbored the highest percentage of positive cores and a higher rate of cT2a than NLT. At RP, 46.2% were upgraded to GGG?≥?2, 6.0% to GGG?≥?3 and 10.5% harbored nonorgan-confined stage (NOC, pT3-4 or pN1). Of NOC patients, 1.6% harbored GGG?≥?3, 6.3% harbored GGG2 and 2.6% harbored GGG1. Of pT2 patients, 4.4% harbored GGG?≥?3, 33.9% harbored GGG2 and 51.3% harbored GGG1. Age, PSA, percentage of positive cores and number of positive cores independently predicted the presence of NOC and/or GGG?≥?3, but with low accuracy (63.9%).

Conclusions

In low-risk PCa, critical changes between tumor grade and stage at biopsy vs RP may be expected in very few patients: NOC with GGG?≥?3 in 1.6% and NOC with GGG2 in 6.3%. Other patients with upgrading and/or upstaging combinations will invariably harbor either pT2 or GGG1 that far less critically affect PCa prognosis.

     

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.     

Multiple Tissue Biomarkers Independently and Additively Predict Prostate Cancer Pathology Outcomes

BackgroundDistinguishing indolent from aggressive prostate cancer remains a key challenge for decision making regarding prostate cancer management. A growing number of biomarkers are now available to help address this need, but these have rarely been examined together in the same patients to determine their potentially additive value.ObjectiveTo determine whether two previously validated plasma markers (transforming growth factor β1 [TGFβ1] and interleukin-6 soluble receptor [IL6-SR]) and two validated tissue scores (the Genomic Evaluators of Metastatic Prostate Cancer [GEMCaP] and cell cycle progression [CCP] scores) can improve on clinical parameters in predicting adverse pathology after prostatectomy, and how much they vary within tumors with heterogeneous Gleason grade.Design, setting, and participantsA case-control study was conducted among men with low-risk cancers defined by biopsy grade group (GG) 1, prostate-specific antigen (PSA) ≤10 ng/mL, and clinical stage ≤ T2 who underwent immediate prostatectomy. We collected paraffin-fixed prostatectomy tissue and presurgical plasma samples from 381 cases from the University of California, San Francisco, and 260 cases from the University of Washington.Outcome measurements and statistical analysisPathologic outcomes were minor upgrading/upstaging (GG 2 or pT3a) or major upgrading/upstaging (GG ≥ 3 or ≥ pT3b), and multinomial regression was performed to determine putative markers’ ability to predict these outcomes, controlling for PSA, percent of positive biopsy cores, age, and clinical site. For upgraded tumors, a secondary analysis of the GEMCaP and CCP scores from the higher-grade tumor was also performed to evaluate for heterogeneity.Results and limitationsOverall, 357 men had no upgrading/upstaging event at prostatectomy, 236 had a minor event, and 67 had a major event. Neither TGFβ1 nor IL6-SR was statistically significantly associated with any upgrading/upstaging. On the contrary, both the CCP and the GEMCaP score obtained from Gleason pattern 3 tissue were directly associated with minor and major upgrading/upstaging on univariate analysis. The two scores correlated with each other, but weakly. On multinomial analysis including both scores in the model, the CCP score predicted minor upgrading/upstaging (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.05–2.49) and major upgrading/upstaging (OR 2.26, 95% CI 1.05–4.90), p = 0.04), and the GEMCaP score also predicted minor upgrading/upstaging (OR 1.05, 95% CI 1.03–1.08) and major upgrading/upstaging (OR 1.07, 95% CI 1.04–1.11), p < 0.01). The other clinical parameters were not significant in this model. Among upgraded tumors including both Gleason patterns 3 and 4, both the GEMCaP and the CCP score tended to be higher from the higher-grade tumor. The main limitation was the use of virtual biopsies from prostatectomy tissue as surrogates for prostate biopsies.ConclusionsBiomarker signatures based on analyses of both DNA and RNA significantly and independently predict adverse pathology among men with clinically low-risk prostate cancer undergoing prostatectomy.Patient summaryValidated biomarker scores derived from both prostate cancer DNA and prostate cancer RNA can add independent information to help predict outcomes after prostatectomy.