Non-muscle Invasive Bladder Cancer Risk Research Articles

Accurate Documentation Contributes to Guideline-concordant Surveillance of Nonmuscle Invasive Bladder Cancer: A Multisite Department of Veterans Affairs Study

To determine if accurate documentation of bladder cancer risk was associated with a clinician surveillance recommendation that is concordant with AUA guidelines among patients with nonmuscle invasive bladder cancer (NMIBC). We prospectively collected data from cystoscopy encounter notes from four Department of Veterans Affairs (VA) sites to ascertain whether they included accurate documentation of bladder cancer risk and a recommendation for a guideline-concordant surveillance interval. Accurate documentation was a clinician-recorded risk classification matching a gold standard assigned by the research team. Clinician recommendations were guideline-concordant if the clinician recorded a surveillance interval that was in line with the AUA guideline. Among 296 encounters, 75 were for low-, 98 for intermediate-, and 123 for high-risk NMIBC. 52% of encounters had accurate documentation of NMIBC risk. Accurate documentation of risk was less common among encounters for low-risk bladder cancer (36% vs 52% for intermediate- and 62% for high-risk, P<.05). Guideline-concordant surveillance recommendations were also less common in patients with low-risk bladder cancer (67% vs 89% for intermediate- and 94% for high-risk, P<.05). Accurate documentation was associated with a 29% and 15% increase in guideline-concordant surveillance recommendations for low- and intermediate-risk disease, respectively (P<.05). Accurate risk documentation was associated with more guideline-concordant surveillance recommendations among low- and intermediate-risk patients. Implementation strategies facilitating assessment and documentation of risk may be useful to reduce overuse of surveillance in this group and to prevent unnecessary cost, anxiety, and procedural harms.

How has the COVID-19 pandemic affected patients with primary bladder cancer?

The COVID-19-induced effects of primary bladder cancer (BC) patients have not yet been clarified. The aim of this study was to investigate the effects of the pandemic on the diagnosis, treatment, and follow-up of primary BC patients. A retrospective single-center analysis was made of all patients who underwent diagnostic and surgical procedures due to primary BC between November 2018 and July 2021. A total of 275 patients were identified and allocated to one of the groups: Pre-COVIDBC (BC diagnosed before the COVID-19 pandemic) or COVIDBC (during the pandemic). The BC patients diagnosed during the pandemic were mostly at higher stages (T2) (p = 0.04), the risk of non-muscle invasive BC (NMIBC) was higher (p = 0.02), and recurrence and progression scores were increased (p = 0.001) compared to patients diagnosed before the pandemic. The time to surgery from diagnosis (p = 0.001) and symptom duration (p = 0.04) were significantly prolonged during the pandemic and the rate of follow-up significantly decreased (p = 0.03). The study results highlight the significant increase in muscle invasive BC and the very high risk of NMIBC in patients presenting during the COVID-19 pandemic.

Time to event following bacillus Calmette-Guerin therapy initiation in Medicare beneficiaries with intermediate- to high-risk non-muscle invasive bladder cancer, 2010-2019.

473 Background: For patients with intermediate- to high-risk non-muscle invasive bladder cancer (NMIBC), standard of care includes transurethral resection (TURBT) followed by induction and maintenance intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). This study describes characteristics and clinical outcomes of Medicare beneficiaries newly diagnosed with NMIBC who initiated BCG therapy following TURBT. Methods: Retrospective cohort study using Centers for Medicare and Medicaid-sourced Medicare Fee-for-Service medical/pharmacy claims (100% sample). Patient selection criteria: ≥1 bladder cancer diagnosis 2010-2019, no prior radiotherapy, systemic therapy, cystectomy, or metastasis in 6 months post-diagnosis, continuously enrolled in Medicare ≥12 months pre- and post-index (or death). Index date = date of first BCG instillation. A literature-based definition for adequate maintenance BCG defined adequate (≥7 instillations of BCG within 274 days of BCG initiation) and inadequate (remainder) BCG therapy for patient stratification. Events: time to BCG discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis. Provider access to BCG (due to supply shortage), patient tolerability, and NMIBC risk status are not captured in claims data. Results: Of 46,052 BCG-treated patients eligible for analysis, 19,859 (43.1%) received adequate BCG therapy. The two cohorts had similar baseline characteristics (Table) and median duration of follow up (46 months). Median (interquartile range [IQR]) time from NMIBC diagnosis to BCG initiation was 2.8 (8.2) months for adequate, 3.7 (14.4) months for inadequate BCG. Time from BCG initiation to discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis are reported in the table. Conclusions: Between 2010 and 2019, 57% of Medicare patients initiating BCG following diagnosis of NMIBC and TURBT may not have received adequate BCG therapy. Patients with inadequate BCG therapy had numerically shorter time to radical cystectomy, systemic therapy, radiation, and metastasis than those with adequate BCG therapy. Characteristics &amp; Outcomes by Cohort. [Table: see text]

External validation of European Association of Urology NMIBC risk scores to predict progression after transurethral resection of bladder tumor in Korean patients with non-muscle-invasive bladder cancer.

PurposeThis study aimed to validate the newly proposed risk model in Korean patients diagnosed with non-muscle-invasive bladder cancer (NMIBC).Materials and MethodsA retrospective review was performed with 1,238 patients who underwent transurethral resection of bladder tumor from 2009 to 2020. We included 973 patients and categorized them into four risk groups according to the European Association of Urology (EAU) NMIBC risk stratification standards, which incorporate the World Health Organization 2004/2016 grading classification. Kaplan–Meyer survival analysis and multivariable analysis of time to progression were performed to calculate the probability of progression for all risk groups.ResultsA total of 973 patients were followed for 54.85 months. Patients were classified according to the risk factors proposed by the new NMIBC risk table and stratified into low, intermediate, high, and very high-risk groups based on the table. Cancer progression into muscle-invasive bladder cancer (MIBC) in each risk group was observed in 7 (4.4%), 24 (15.2%), 76 (48.1%), and 51 (32.3%) individuals, respectively. The progression rate was distinguishable between risk groups in the Kaplan–Meier progression-free survival analysis, and higher risk was associated with a higher rate of progression. The new NMIBC risk variables were demonstrated to have prognostic value in the multivariate analysis. The very high-risk group was associated with progression to muscle-invasive disease.ConclusionsThis study demonstrates that the new EAU NMIBC risk group categorization is feasible in predicting the progression of NMIBC into MIBC in the Korean population and thus should be applied to clinical practice in Korea.

Updated European Association of Urology (EAU) Prognostic Factor Risk Groups Overestimate the Risk of Progression in Patients with Non–muscle-invasive Bladder Cancer Treated with Bacillus Calmette-Guérin

BackgroundThe 2021 European Association of Urology (EAU) guidelines contain updated prognostic factor risk groups for non–muscle-invasive bladder cancer (NMIBC). These groups are based on the following predictors of progression: tumour stage, grade, number, and size; concomitant carcinoma in situ; and age. However, the groups were derived from datasets excluding patients treated with bacillus Calmette-Guérin (BCG). ObjectiveTo determine the validity of the updated EAU prognostic factor risk groups in patients with NMIBC treated with BCG. Design, setting, and participantsWe reviewed patients treated with BCG at our institution between 2000 and 2018. Patients were analysed according to the receipt of “at least induction” and “adequate” BCG (as defined by the US Food and Drug Administration). Risk groups were assigned according to the 2021 EAU NMIBC risk calculator (https://nmibc.net/). Outcome measurements and statistical analysisThe Kaplan-Meier method was used to estimate the risks of progression at 1 and 5 yr. Probabilities of progression obtained with the updated prognostic factor risk groups in our series were compared with those reported by the EAU. Discrimination was assessed using the concordance index (c-index). Results and limitationsA total of 529 patients received at least induction BCG with a median follow-up of 47.3 mo (interquartile range 25.3–86.9). Of these patients, 494 received adequate BCG. We found lower progression rates at 1 yr in the very-high-risk group patients receiving at least induction (6.9%) and adequate BCG (4.0%) versus 16.0% for the EAU predicted rates. Additionally, progression rates were also lower at 5 yr in the high-risk group—7.4% for at least induction and 5.3% for adequate BCG versus 9.6% for EAU predicted rates; the rates in the very-high-risk group were as follows: 16.7% for at least induction and 14.9% for adequate BCG versus 40.0% for EAU predicted rates. The c-index in our series was lower than that reported by the EAU (0.63 vs 0.80). Of interest, our multivariable analysis identified grade, stage, and age (p < 0.02) to be the predictors of progression after BCG therapy. ConclusionsWhile the 2021 EAU prognostic factor risk groups successfully stratified progression risks in our cohort, treatment with BCG reduced their discriminative ability. Furthermore, the groups overestimate progression risks in BCG-treated patients. These findings should be used in conjunction with the updated risk groups to counsel patients with higher-risk NMIBC about their risk of progression with and without BCG. Patient summaryAlthough the updated European Association of Urology prognostic factor risk groups are able to stratify patients with non–muscle-invasive bladder cancer according to their risk of progression to muscle-invasive bladder cancer, this risk is overestimated in patients treated with bacillus Calmette-Guérin (BCG).

&lt;i&gt;FGFR3, TERT, ТР53&lt;/i&gt; mutations and the &lt;i&gt;FGFR3&lt;/i&gt; gene expression in bladder cancer as prognostic markers

Background. Bladder cancer (BC) is a common urological cancer, 75 % of which are non-muscle invasive BC. After removal of the primary tumor, the adequate classification of malignancy and the defining of tumor progression risk remains an important issue, since it is associated with frequency of cystoscopy and choice of the BCG- or chemotherapy management.Objective: improve the algorithms of prognosis in intermediate-risk patients with non-muscle-invasive bladder cancer with the consideration of molecular characteristics of the primary tumor.Materials and methods. We studied 125 BC samples; mutations in the FGFR3, PIK3CA, TERT, and TP53 genes were determined by polymerase chain reaction and Sanger sequencing, as well as the expression of the FGFR3, EGFR, ERBB2, FOXA1, and GATA3 genes using realtime polymerase chain reaction.Results. Somatic mutations in the studied loci were detected in 65.6 % of the samples, five new mutations were identified. A decrease of the mutation frequency in the FGFR3 and TERT genes was shown, an increase — TP53 in order (Ta—T1/low G) &gt; (T1/high G) &gt; (&gt;T2/any G). The largest area under the ROC curve (0.807 ± 0.092, р = 0.004) was demonstratedfor the prognostic classifier with the independent variables: mutation in FGFR3 and/or TERT; mutation TP53; overexpression of the FGFR3 gene. The FGFR3, TERT mutations and/or FGFR3 overexpression in the absence of TP53 mutation indicates minimally invasive primary tumor. On the contrary, harboring TP53 mutation indicate the features of muscle-invasive BC at the genetic level. Using this algorithm, we reclassified 21 of T1G3 BC cases as having characteristics associated with non-invasive tumor in 43 %, and invasive BC in 57 % of patients.Conclusion. The aforementioned prognostic model could be used as additional laboratory test in assessing the malignancy and progression risk of non-muscle invasive BC.

Does Smoking Cessation at Primary Diagnosis Reduce the Recurrence Risk of Nonmuscle-Invasive Bladder Cancer? Results of a Prospective Study

Introduction: Evidence that smoking cessation at first diagnosis of nonmuscle-invasive bladder cancer (NMIBC) reduces the risk of recurrence is lacking. The aim of our prospective study was to analyze the association between patients’ changes in smoking habits after diagnosis and recurrence-free survival (RFS). Patients: After transurethral resection of primary NMIBC, patients were classified as “ex-smokers,” i.e., those definitively stopping, and as “active smokers,” i.e., those continuing or restarting to smoke. Smoking status was reassessed every 3 months during the first year and every 6 months thereafter. Data on patients’ demographics, smoking status, tumor characteristics, treatments, and follow-up were collected. Statistical analysis was performed adopting SPSS 15.0.1 and R3.4.2 software. Results: Out of 194 patients, 67 (34.5%) quit smoking after the diagnosis, while 127 (65.5%) did not. The clinical and pathological characteristics were homogeneously distributed. At a median follow-up of 38 months, 106 patients (54.6%) recurred, 33 (49.2%) ex- and 73 (60.3%) active smokers with a 3-year RFS of 42.3 and 50.7%, respectively (p = 0.55). No statistically significant association between recurrence, pathological features of the primary tumor, and patient smoking habits after diagnosis was detected. Results were not statistically influenced by the intensity (cigarette/day) and duration (years) of smoking. In multivariate analysis, cigarette smoking cessation at diagnosis did not significantly reduce tumor recurrence. Conclusion: In our prospective study, more than half of our patients recurred at 3 years. In multivariate analysis, smoking cessation did not significantly reduce tumor recurrence. However, the 8.4% reduction in favor of the ex-smokers suggests the need of larger studies with longer follow-ups. Surprisingly, only 35% of smokers definitively quit after diagnosis. The urologists should play a more active role to persuade the patients to stop smoking at first cancer diagnosis.

Involvement of haptoglobin phenotypes and genotypes in non-muscle invasive bladder cancer: A possible prognostic marker for risk stratification.

The association of haptoglobin (Hp) with various cancers has been reported and also it has been documented that the Hp phenotypes/genotypes have different functional ability. So, we examined phenotypes/genotypes of Hp in newly diagnosed, untreated non-muscle invasive bladder cancer (NMIBC) patients and investigated its prognostic value for risk stratification of the cancer. In eighty NMIBC patients and 80 healthy individuals the Hp genotypes and phenotypes were analyzed using polymerase chain reaction (PCR) and two-dimensional gel electrophoresis (2D-GE), respectively. Besides, the presence of the Hpα1, α2, and β chains in the sera was confirmed by Mass Spectrometry (MS). The frequencies of the 1-1 and 2-2 genotypes/phenotypes were respectively higher and lower in healthy subjects compared to the patients. Our results revealed that the 2-2 genotype/phenotype could increase the risk of NMIBC. There was a positive association between the 2-2 genotype/phenotype with the T category/grade of cancer (p<0.05). The present study implied a strong association between the Hp phenotypes and genotypes with NMIBC. It was found that the 2-2 genotype and phenotype could be a risk factor for NMIBC incidence, as well as, progression. This study introduced Hp genotyping as a possible cost-effective and precise method for prognosis of individuals at the risk of NMIBC.

Germline DNA copy number polymorphism to predict the efficacy of BCG therapy for non-muscle invasive bladder cancer.

431 Background: Bacillus Calmette-Guerin (BCG) intravesical instillation is the most effective immunotherapy for non-muscle-invasive bladder cancer (NMIBC), however there are few reliable markers to elucidate the efficacy of BCG therapy. Germline copy number polymorphisms (CNPs) are expected to affect various diseases including human malignancies, but the significance of CNPs in NMIBC treated with BCG therapy remains unclear. FAM81A located on 15q22.2 was reported as one of tumor-associated ETS shared target genes in prostate cancer. PCSK6 located on 15q26.3 was reported to regulate proliferation and tumor progression in several cancers. The purpose of this study is to determine the prognostic value of CNPs for NMIBC treated with BCG therapy. To our knowledge, this is the first report to confirm CNPs as a potential biomarker for assessing the efficacy of immunotherapy. Methods: Array comparative genomic hybridization (CGH) was performed to search for candidate whole genome-wide CNPs related to NMIBC susceptibility. Next, quantitative real-time polymerase chain reaction was carried out to evaluate the effect of BCG therapy for 57 Japanese patients with NMIBC treated with BCG intravesical instillation. Results: Eleven CNPs were associated with NMIBC risk in array CGH. FAM81A and PCSK6 copy number according to those CNPs examined showed significant relationship with disease progression in NMIBC treated with BCG. The means of the relative copy numbers of patients with CNP and those without it were 1.58 and 2.10 for FAM81A ( P &lt; 0.0001), and 1.06 and 1.80 for PCSK6 ( P &lt; 0.0001), respectively. Univariate Cox proportional hazards regression analysis showed that FAM81A ( P = 0.0022), and PCSK6 ( P = 0.0147) copy number had a significant effect on progression-free survival. In multivariate analyses, FAM81A copy number was an independent prognostic factor for progression-free survival ( P = 0.0419, RR = 7.59, 95% CI, 1.07–153.42). The combination of FAM81A or PCSK6 CNP was the most significant prognostic biomarker to predict the efficacy of BCG therapy for NMIBC ( P = 0.0002). Conclusions: Germline DNA CNPs may be a potential new biomarker for estimating the efficacy of BCG therapy in Japanese patients with NMIBC.

Use and Validation of the AUA/SUO Risk Grouping for Nonmuscle Invasive Bladder Cancer in a Contemporary Cohort.

We applied nonmuscle invasive bladder cancer AUA (American Urological Association)/SUO (Society of Urologic Oncology) guidelines for risk stratification and analyzed predictors of recurrence and progression. We retrospectively reviewed the records of 398 patients with nonmuscle invasive bladder cancer treated between 2001 and 2017. Descriptive statistics were used to compare AUA/SUO risk groups. Predictors of recurrence and progression were determined by multivariable regression. Kaplan-Meier analysis was done, a Cox proportional hazards regression model was created and time dependent AUCs were calculated to determine progression-free and recurrence-free survival by risk group. Median followup was 37 months (95% CI 35-42). Of the patients 92% underwent bacillus Calmette-Guérin induction and 46% received at least 1 course of maintenance treatment. Of the patients 11.5% were at low, 32.5% were at intermediate and 55.8% were at high risk. In patients at low, intermediate and high risk the 5-year progression-free survival rate was 93%, 74% and 54%, and the 5-year recurrence-free survival rate was 43%, 33% and 23%, respectively. Kaplan-Meier analysis was done to stratify high grade Ta 3 cm or less tumor recurrence-free and progression-free survival in the intermediate vs the high risk group. Relative to low risk, classification as intermediate and as high risk was an independent predictor of progression (HR 9.7, 95% CI 2.23-42.0, p <0.01, and HR 36, 95% CI 8.16-159, p <0.001, respectively). Recurrence was more likely in patients at high risk than in those at low risk (HR 2.03, 95% CI 1.11-3.71, p=0.022). For recurrence and progression the 1-year AUC was 0.60 (95% CI 0.546-0.656) and 0.68 (95% CI 0.622-0.732), respectively. The AUA/SUO nonmuscle invasive bladder cancer risk classification system appropriately stratifies patients based on the likelihood of recurrence and progression. It should be used at diagnosis to counsel patients and guide therapy.

American Urological Association Nonmuscle Invasive Bladder Cancer Risk Model Validation-Should Patient Age be Added to the Risk Model?

We evaluated the AUA (American Urological Association)/SUO (Society of Urologic Oncology) nonmuscle invasive bladder cancer risk model to predict nonmuscle invasive bladder cancer recurrence and progression prior to death. We performed a retrospective analysis using electronic medical records and cancer registry data of patients with nonmuscle invasive bladder cancer in a multicenter United States patient population. We evaluated recurrence-free and progression-free survival according to the AUA/SUO nonmuscle invasive bladder cancer risk model. We then assessed discriminative performance with the c-index and compared the cumulative incidence of recurrence, progression and death across 4 age groups. We identified 1,297 patients with nonmuscle invasive bladder cancer. Median followup in the cohort was 3.2 years. The c-index of the AUA/SUO recurrence model was 0.62 and for progression it was higher at 0.77. Patients younger than 60 years had a 40% greater probability of recurrent nonmuscle invasive bladder cancer vs death while patients 84 years old or older had a 12% greater probability of death prior to recurrence at 5 years. This study was limited by its retrospective design. The AUA/SUO nonmuscle invasive bladder cancer risk model provides predictive performance of recurrence and progression similar to that of previous similar risk models, such as the models of the European Organization for Research and Treatment of Cancer, the Club Urológico Español de Tratamiento Oncológico and the National Comprehensive Cancer Network®. This work illustrates the need to consider age in predictive tools for clinicians who treat patients with nonmuscle invasive bladder cancer.

Clinical Research on the Postoperative Recurrence of Non Muscle-Invasive Bladder Cancer

Background: Bladder cancer is a common malignant tumor in the urinary system, in which non muscle-invasive bladder cancer (NMIBC) is the most common. The recurrence rate of the patients after operation is high, which has a serious impact on the physical and mental health of the patients. Therefore, how to reduce the recurrence rate of NMIBC patients is the focus of clinical research.&#x0D; Objectives: To study the recurrent factor of NMIBC after surgery for promotion of therapeutic efficacy.&#x0D; Methods: Retrospective analysis of one hundred patients of carcinoma of urinary bladder were consecutively enrolled and data on gender, age, tumor stage, tumor grade, tumor size, tumor configuration, multiplicity, date of surgery, tumor histology, recurrence history, resident area, frequency of tumor recurrence, follow-up history as screening target to analyze by Cox proportional-risk model, and screen dependent factor which can be used to predict tumor recurrent risk after surgery.&#x0D; Results: Tumor size, tumor stage, tumor grade, frequency of tumor recurrence, multiplicity and history of regular follow-up are related to NMIBC recurrence after surgery.&#x0D; Conclusion: Aggregate analysis of these factors can evaluate recurrent risk of NMIBC and it is significant to the therapy of NMIBC.

Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG’s receptor ILT2 on peripheral CD8+ T cells

Background and ObjectiveRecurrence of non-muscle invasive bladder cancer (NMIBC) after initial management occurs in 60–70% of patients. Predictive criteria for recurrence remain only clinical and pathological. The aim of this study was to investigate the prognostic significance of the proportion of checkpoint HLA-G’s receptor ILT2-expressing peripheral CD8+ T cells.ResultsThe proportion of CD4+ILT2+and CD8+ILT2+ T cells was not increased in NMIBC compared to controls. However, a strong association was found between recurrence and CD8+ILT2+ T cell population levels (p = 0.0006). Two-year recurrence-free survival was 83% in patients with less than 18% CD8+ILT2+ T cells, 39% in the intermediary group, and 12% in patients with more than 46% CD8+ILT2+ T cells. Multivariate analyses demonstrated that the proportion of CD8+ILT2+ T cells was an independent predictive factor for recurrence. Adding CD8+ILT2+ T cells population level to clinical variables increased the predictive accuracy of the model by 4.5%.Materials and MethodsAll patients treated for NMIBC between 2012 and 2014 were included prospectively. Blood samples, tumor and clinico-pathological characteristics were collected. HLA-G expression was measured using IHC, and CD8+ILT2+ T cell levels using flow cytometry. Association between HLA-G and CD8+ILT2+ T cell population levels with NMIBC risk of recurrence was investigated using Cox regression analyses. Prediction was measured using the concordance index statistic.ConclusionsWe demonstrated a strong association between the proportion of circulating CD8+ILT2+ T cells and NMIBC risk of recurrence. Gain in prediction was substantial. If externally validated, such immunological marker could be integrated to predict NMIBC recurrence.

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

PurposeThe proto-oncogene forkhead box M1 (FOXM1) is associated with poor survival in many cancers. The impact of FOXM1 expression on progression-free survival (PFS) of non-muscle invasive bladder cancer (NMIBC) has not yet been investigated. The differential expression of FOXM1 between the different molecular NMIBC subtypes has further been assessed.MethodsTranscript levels of FOXM1 and MKI67 were determined in 460 NMIBC patients (UROMOL cohort) by RNA-Seq and validated in silico by the Chungbuk and Lund cohort (n = 277). FOXM1 and MKI67 cutoffs were identified by the minimal p value method. Variables were evaluated by multivariable Cox regression analyses in order to identify independent predictors.ResultsFOXM1 is an independent predictor for PFS superior to current histological, clinical and molecular staging methods. Patients with high FOXM1 expression have a 6- to 8-fold higher risk of progression in multivariable analysis (p < 0.03). Highest transcript levels were found in the Class 2 and genomically unstable molecular NMIBC subtype (p < 0.03). The proto-oncogene further positively correlated with tumor grade and stage. NMIBCs with high FOXM1 expression showed a PFS advantage when treated with intravesical BCG instillation.ConclusionFOXM1 is a highly prognostic marker for disease progression of NMIBC superior to current histological, clinical and molecular staging methods and MKI67. It is mainly expressed in the Class 2 and genomically unstable molecular bladder cancer subtypes. Its role in drug resistance development makes FOXM1 valuable biomarker for NMIBC risk stratification.

Exploring the roles of urinary HAI-1, EpCAM & EGFR in bladder cancer prognosis & risk stratification.

ObjectivesTo investigate whether elevated urinary HAI-1, EpCAM and EGFR are independent prognostic biomarkers within non-muscle-invasive bladder cancer (NMIBC) patients, and have utility for risk stratification to facilitate treatment decisions.ResultsAfter accounting for EAU risk group in NMIBC patients, the risk of BC-specific death was 2.14 times higher (95% CI: 1.08 to 4.24) if HAI-1 was elevated and 2.04 times higher (95% CI: 1.02 to 4.07) if EpCAM was elevated. The majority of events occurred in the high-risk NMIBC group and this is where the biggest difference is seen in the survival curves when plotted for EAU risk groups separately. In MIBC patients, being elevated for any of the three biomarkers was significantly associated with BC-specific mortality after accounting for other risk factors, HR = 4.30 (95% CI: 1.85 to 10.03).Patients and MethodsUrinary levels of HAI-1, EpCAM and EGFR were measured by ELISA in 683 and 175 patients with newly-diagnosed NMIBC and MIBC, respectively, recruited to the Bladder Cancer Prognosis Programme. Associations between biomarkers and progression, BC-specific mortality and all-cause mortality were evaluated using univariable and multivariable Cox regression models, adjusted for European Association of Urology (EAU) NMIBC risk groups. The upper 25% of values for each biomarker within NMIBC patients were considered as elevated. Exploratory analyses in urine from MIBC patients were also undertaken.ConclusionUrinary HAI-1 and EpCAM are prognostic biomarkers for NMIBC patients. These biomarkers have potential to guide treatment decisions for high-risk NMIBC patients. Further analyses are required to define the roles of HAI-1, EpCAM and EGFR in MIBC patients.

Serum microRNAs as predictors of risk for non-muscle invasive bladder cancer.

MicroRNAs (miRNAs) are implicated in the development of nearly all cancers and may function as promising biomarkers for early detection, diagnosis and prognosis. We sought to investigate the role of serum miRNAs as potential diagnostic biomarkers or biomarkers of risk for early-stage bladder cancer. First, we profiled global serum miRNAs in a pilot set of 10 non-muscle invasive bladder cancer (NMIBC) cases and 10 healthy controls matched on age, gender and smoking status. Eighty nine stably detectable miRNAs were selected for further testing and quantification by high-throughput Taqman analysis using the Fluidigm BioMark HD System to assess their association with NMIBC risk in both discovery and validation sets totaling 280 cases and 278 controls. We found miR-409-3p and six miRNAs expression ratios were significantly associated with risk of bladder cancer in both discovery and validation sets. Interestingly, we identified expression of miR-409-3p and miR-342-3p inversely correlated with age and age of onset of NMIBC. A risk score was generated based on the combination of three miRNA ratios (miR-29a-3p/miR-222-3p, miR-150-5p/miR-331-3p, miR-409-3p/miR-423-5p). In dichotomized analysis, we found individuals with high risk score showed increased risk of bladder cancer in the discovery, validation, and combined sets. Pathway enrichment analyses suggested altered miRNAs and cognate target genes are linked to the retinoid acid receptor (RAR) signaling pathway. Overall, these results suggested specific serum miRNA signatures may serve as noninvasive predictors of NMIBC risk. Biological insights underlying bladder cancer development based on the pathway enrichment analysis may reveal novel therapeutic targets for personalized medicine.

Spinal Anesthesia is Associated with Lower Recurrence Rates after Resection of Nonmuscle Invasive Bladder Cancer

We sought to determine whether anesthetic type (general vs spinal) would influence cancer recurrence following transurethral resection of bladder tumors. With institutional ethics board approval we examined the electronic medical records of all patients who underwent transurethral bladder tumor resection for nonmuscle invasive urothelial bladder cancer between 2011 and 2013 at a single tertiary care center. Followup information was gathered on all patients in December 2016. The time to first cancer recurrence and the incidence of cancer recurrence were the main outcome measures. A total of 231 patients underwent 1 or more transurethral bladder tumor resections between 2011 and 2013. Of the 231 patients 135 received spinal anesthesia and 96 received general anesthesia. On univariable analysis the 135 patients who received spinal anesthesia had a longer median time to recurrence than the 96 who received general anesthesia (42.1 vs 17.2 months, p = 0.014). As anticipated, adjuvant therapies and risk category were associated with recurrence rates (p = 0.003 and 0.042, respectively). On multivariable analyses incorporating a priori variables of nonmuscle invasive bladder cancer risk stratification and postoperative therapies the patients who received general anesthesia had a higher incidence of recurrence (OR 2.06, 95% CI 1.14-3.74, p = 0.017) and an earlier time to recurrence (HR 1.57, 95% CI 1.13-2.19, p = 0.008) than those who received spinal anesthesia. Anesthetic type was not associated with cancer progression or overall mortality. Patients who received spinal anesthesia had a lower incidence of recurrence and a delayed time to recurrence following transurethral bladder tumor resection for nonmuscle invasive bladder cancer. These findings should prompt large-scale prospective studies to confirm this association.

Germline DNA copy number variations as potential prognostic markers for non-muscle invasive bladder cancer progression

Accumulating evidence has suggested that germline DNA copy number variations (CNVs) affect various disorders, including human malignancies. However, the significance of CNVs in non-muscle invasive bladder cancer (NMIBC) remains unclear. The purpose of the present study was to identify the role of CNVs in NMIBC. Array comparative genomic hybridization (CGH) analysis was performed to search for candidate CNVs associated with NMIBC susceptibility. Quantitative polymerase chain reaction was carried out to evaluate CNVs associated with patient outcome in 189 NMIBC cases. In total, 11 CNVs were associated with NMIBC risk in array CGH analysis. Out of the 189 CNVs examined, family with sequence similarity 81 member A (FAM81A) and proprotein convertase subtilisin/kexin type 6 (PCSK6) CNVs exhibited a significant association with recurrence and disease progression in NMIBC. PCSK6 has been reported to regulate proliferation and tumor progression in breast and prostate malignancies. Notably, patients with pT1 stage had significantly lower PCSK6 relative copy number than those with pTa (P=0.0196). In multivariate analyses, PCSK6 copy number was an independent prognostic factor for progression-free survival (P=0.0456; risk ratio, 2.17; 95% confidence interval, 1.02-4.82). These data suggest that PCSK6 CNV is a potential new tumor marker for estimating disease progression in NMIBC.

MP44-09 GERMLINE COPY NUMBER POLYMORPHISM IDENTIFIED AS POTENTIAL PROGNOSTIC MARKER FOR PROGRESSION OF NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2017MP44-09 GERMLINE COPY NUMBER POLYMORPHISM IDENTIFIED AS POTENTIAL PROGNOSTIC MARKER FOR PROGRESSION OF NON-MUSCLE INVASIVE BLADDER CANCER Yoshiaki Yamamoto, Yutaka Suehiro, Yoshihisa Kawai, Ryo Inoue, Hiroaki Matsumoto, and Hideyasu Matsuyama Yoshiaki YamamotoYoshiaki Yamamoto More articles by this author , Yutaka SuehiroYutaka Suehiro More articles by this author , Yoshihisa KawaiYoshihisa Kawai More articles by this author , Ryo InoueRyo Inoue More articles by this author , Hiroaki MatsumotoHiroaki Matsumoto More articles by this author , and Hideyasu MatsuyamaHideyasu Matsuyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1340AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Germline copy number polymorphisms (CNPs) are expected to affect various diseases including human malignancies, but the significance of CNPs in non-muscle invasive bladder cancer (NMIBC) remains unclear. PCSK6 is reported to regulate proliferation and tumor progression in breast and prostate cancer, and affect sodium homeostasis. The purpose of this study is to determine the prognostic value of CNPs for NMIBC. To our knowledge, this is the first report to confirm CNPs as a potential biomarker for assessing the prognosis of NMIBC. METHODS Array comparative genomic hybridization (CGH) was performed to search for candidate CNPs related to NMIBC susceptibility. Next, quantitative real-time polymerase chain reaction was carried out to evaluate for CNPs related to patient's outcome in 190 NMIBC. RESULTS Eleven CNPs were associated with NMIBC risk in array CGH. FAM81A and PCSK6 copy number according to those CNPs examined showed significant relationship with recurrence and disease progression in NMIBC. Patients with pT1 stage had significantly lower PCSK6 copy number than those with pTa (P = 0.0258). Interestingly, patients with lower PCSK6 copy number had significantly higher sodium levels in the blood than those with higher PCSK6 copy number (P = 0.0144). Univariate Cox proportional hazards regression analysis showed that tumor grade (P = 0.0073), pT stage (P = 0.0086), Cytology (P = 0.0045), FAM81A (P = 0.0173), and PCSK6 (P = 0.0011) copy number had a significant effect on progression-free survival. In multivariate analyses, PCSK6 copy number was an independent prognostic factor for progression-free survival (P = 0.0380, risk ratio 2.25, 95% confidence interval 1.05-5.03). CONCLUSIONS These data suggest that PCSK6 CNP is potentially a new tumor marker for estimating the prognosis of NMIBC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e567 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Yoshiaki Yamamoto More articles by this author Yutaka Suehiro More articles by this author Yoshihisa Kawai More articles by this author Ryo Inoue More articles by this author Hiroaki Matsumoto More articles by this author Hideyasu Matsuyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Narrow band imaging-assisted transurethral resection reduces the recurrence risk of non-muscle invasive bladder cancer: A systematic review and meta-analysis.

ContextCompared with white light imaging (WLI) cystoscopy, narrow band imaging (NBI) cystoscopy could increase the visualization and detection of bladder cancer (BC) at the time of transurethral resection (TUR). NBI cystoscopy could increase the detection of BC, but it remains unclear whether narrow band imaging-assisted transurethral resection (NBI-TUR) could reduce the recurrence risk of non-muscle invasive bladder cancer (NMIBC). Several randomized clinical trials (RCTs) have recently tested the efficacy of NBI-TUR for NMIBC.ObjectiveTo perform a systematic review and meta-analysis of RCTs and evaluate the efficacy of NBI-TUR for NMIBC compared with white light imaging-assisted transurethral resection (WLI-TUR). The end point was recurrence risk.Evidence acquisition: A systematic review of PubMed, Medline, Ovid, Embase, Cochrane and Web of Science was performed in February 2016 and updated in July 2016.Evidence synthesis: Overall, six (n = 1084) of 278 trials were included. Three trials performed narrow band imaging-assisted electro-transurethral resection (NBI-ETUR), and two trials performed narrow band imaging-associated bipolar plasma vaporization (NBI-BPV). The last trial performed narrow band imaging-associated holmium laser resection (NBI-HLR). Statistical analysis was performed using Review Manager software (RevMan v.5.3; The Nordic Cochrane Center, Copenhagen, Denmark). The recurrence risk was compared by calculating risk ratios (RRs) with 95% confidence interval (CIs). Risk ratios with 95% CIs were calculated to compare 3-mo, 1-yr, and 2-yr survival rates. NBI-TUR was associated with improvements in the 3-mo recurrence risk (RR: 0.39; 95% CI, 0.26-0.60; p < 0.0001), 1-yr recurrence risk (RR: 0.52; 95% CI, 0.40-0.67; p < 0.00001) and 2-yr recurrence risk (RR: 0.60; 95% CI, 0.42-0.85; p = 0.004) compared with WLI-TUR.ConclusionsCompared with WLI-TUR, NBI-TUR can reduce the recurrence risk of NMIBC. The results of this review will facilitate the appropriate application of NBI in NMIBC.