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Out of 52 immune-related parameters in muscle-invasive bladder cancer, 39 were significant, and of these, 16 were independent prognostic parameters. The strongest prognostic factor was the density of intraepithelial CD8+ T cells, representing the terminal end route of tumor cell killing. Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data. The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. Quantification of intraepithelial CD8+ T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology. [ABSTRACT FROM AUTHOR]

Abstract: Background: The advantage of photodynamic diagnosis in detecting urothelial cell carcinoma (UCC) of the bladder has been demonstrated clearly, but it comes at the price of a higher false-positive rate. Optical coherence tomography (OCT) is a noninvasive, real-time, microstructural imaging modality that uses near-infrared light for a point analysis of the bladder-wall microstructure. Objective: To evaluate whether adding targeted OCT analysis of lesions that are suspicious at white-light (WL) and hexaminolevulinate (HAL) fluorescence cystoscopy improves diagnostic accuracy in the detection of UCC. Design, setting, and participants: In this prospective single-center study with same-patient comparison, patients with suspected UCC first received an intravesical instillation of HAL. Cystoscopy was performed in WL, followed by blue-light inspection and OCT scanning. Intervention: Suspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied. Measurements: We measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT. Results and limitations: In 66 patients studied, 232 lesions were detected, were scanned by OCT, and were subsequently resected or biopsied. Additionally, 132 areas of normal-appearing urothelium were investigated by all three methods and biopsied. On a per-lesion basis, sensitivity and specificity were respectively 69.3% and 83.7% for WL, 97.5% and 78.6% for HAL, and 97.5% and 97.9% for HAL combined with OCT. Overall, UCC was diagnosed in 58 patients (87.9%), with a per-patient sensitivity of 89.7% for WL and 100% for both HAL alone and HAL with targeted OCT. Per-patient specificity for HAL alone and targeted HAL was 62.5% and 87.5%, respectively. The limitation of OCT results from poor visualization of flat lesions in WL, making scanning a time-consuming procedure. Conclusions: Combining fluorescence cystoscopy with targeted OCT increases the specificity of fluorescence cystoscopy significantly, with no added morbidity, and reduces the need for unnecessary (false-positive) biopsies. [Copyright &y& Elsevier]

The aim of the present study was to identify and test a urine marker panel of genes involved in DNA methylation and histone modification for the detection of urothelial carcinoma of the bladder (UCB). RNA samples obtained from the voided urine of 227 patients with asymptomatic microscopic haematuria (AMH) were analysed. Gene array analysis was performed on 18 randomly selected cDNA samples, which revealed that histone deacetylase 9 (HDAC9), HDAC3, tRNA (cytosine-5-)-methyltransferase1 and DNA methyltransferase 1 were differentially expressed between patients with UCB and control subjects. Subsequently, reverse transcription-quantitative polymerase chain reaction analysis was employed to test the performance of the identified four-gene panel on the remaining 209 cDNA samples. In this targeted discovery cohort, all four genes were significantly associated with UCB on univariable analyses [each odds ratio (OR) >2, P<0.05], but only HDAC3 was significant following multivariable analysis (OR=2.8, P=0.011). The addition of HDAC3 to a base risk factor model improved its accuracy by 1.4%. These data suggest that urinary HDAC3 is associated with the presence of UCB in patients with AMH; however, HDAC3 improved the accuracy of the established risk factors only to a marginal extent. [ABSTRACT FROM AUTHOR]

Purpose: We hypothesized sarcopenia as predictive factor as a response to upfront chemotherapy of muscle-invasive urothelial bladder cancer (MIBC). Methods: We retrospectively studied 30 patients who received upfront cisplatin-based chemotherapy for MIBC (pT2–4 N0/+ M0) before planned radical cystectomy. Skeletal muscle index (SMI) was calculated by CT at study baseline and following completion of chemotherapy. Patients were stratified according to the presence of sarcopenia. Endpoints included clinical and pathological response. Results: Sixteen of the 30 patients (53.3%) had sarcopenia at baseline. The median SMI was 51.2 cm2/m2 (IQR 45.6–57.9). Throughout the course of chemotherapy, 22 patients (73.3%) experienced a decline in SMI, which ranged from 1 to 20% (median decline 3%, p < 0.01). All 16 patients with baseline sarcopenia persisted, while 5 of 14 patients (35.7%) without baseline sarcopenia became sarcopenic (p = 0.06). None of the clinical variables were predictive of clinical or pathological response, including SMI (p = 0.78 and p = 0.59), sarcopenia (p = 0.65 and p = 0.16) and SMI kinetics (p = 0.54 and p = 0.77). Conclusion: Sarcopenia is present in a considerable proportion of patients with MIBC undergoing upfront cisplatin-based chemotherapy before planned RC. SMI decreases during treatment, but neither baseline SMI nor its kinetics is associated with response to chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Guidelines support the use of neoadjuvant (NAC) and adjuvant (AC) chemotherapy in muscle-invasive bladder cancer. However, data from North America reported the underutilization of NAC in favor of AC despite the lower level of scientific evidence supporting AC. We aimed to assess current practice patterns of NAC and AC in ­Germany. Methods: A 15-question online survey was developed and sent via email newsletters to members of the ­German Association of Urology and of the German Society of Residents in Urology in October 2016 to analyze current practice patterns. Results: The survey yielded 141 individual responses from 61 different German urology departments. Eighty-nine (69.0%) and 119 (93.0%) participants were stated to regularly use NAC and AC respectively. The number of participants who were stated to use NAC and AC regularly was not associated with the type of institution (academic vs. nonacademic), number of hospital beds, and number of cystectomies performed annually. Gemcitabine/cisplatin combination chemotherapy was named as the primarily used NAC regimen by 80 (95%) respondents. The median number of administered cycles was 3 for NAC and 4 for AC. In the case of cisplatin ineligibility, combination chemotherapy with gemcitabine/carboplatin was the most common regimen. Respondents stated that chemotherapy was generally administered by urologists (81% for NAC and 85% for AC). Conclusions: Our survey of current practice shows a high acceptance rate of NAC in Germany, which was independent of the type of institution. Although the scientific level of evidence for AC is lower, it still seems to be more widely accepted than NAC. NAC and AC were generally administered by urologists. [ABSTRACT FROM AUTHOR]

Objective: To investigate the characteristics and outcomes of late recurrence (LR) in patients with bladder cancer (BCa) treated with radical cystectomy (RC) and to identify clinicopathologic predictors of LR and postrecurrence survival.Materials and Methods: This multicenter study included 1652 BCa patients. LR was defined as occurring more than 5 years after RC. Differences in postrecurrence overall survival according to the timing of disease recurrence and the location of recurrence were calculated using the log-rank test. A logistic regression model was used to identify predictors of LR, and Cox regression models were used to evaluate variables associated with postrecurrence overall survival (OS).Results: Overall, 548 patients experienced disease recurrence. Of these, 67 patients (12.2%) experienced LR, with a median time to recurrence of 86 months (interquartile range 70.5-107.2). LR was more likely to be located in the urothelium (P = .005). On multivariable analysis, younger age (P = .008) and non-organ confined disease (P = .03) were found to be predictors of LR. Postrecurrence 5-year OS was worse in patients who experienced early recurrence compared with those with LR (12% vs 25%, P = .02) and in those with nonurothelial recurrence compared to those with disease recurrence in the remaining urothelium (12% vs 51%, P < .001). Older age (P < .001), non-organ confined disease at RC (P = .02), and nonurothelial recurrence site (P = .002) were independently associated with postrecurrence OS.Conclusion: LR after RC is an uncommon but non-negligible event that harbors unique characteristics. LR is associated with better OS compared to early recurrence. Our findings reinforce the need for lifelong follow-up of BCa patients after RC. [ABSTRACT FROM AUTHOR]

Purpose: Overexpression of Caveolin-1 has been associated with cancer growth, migration, and metastases in several malignancies, but only few data are available on its role in bladder cancer (BCa). The aim of this study is to validate Caveolin-1 as a prognosticator of recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) in a large cohort of patients treated with radical cystectomy (RC) for BCa.Methods: Caveolin-1 expression was evaluated by immunochemistry on a tissue microarray from 424 patients treated with RC for UCB at a single institution. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positively. Univariable and multivariable Cox proportional hazards regression models were used to assess the association of Caveolin-1 expression with RFS, OS, and CSS.Results: Overexpression of Caveolin-1 was observed in 116 (27.4%) patients and was associated with lymph node metastasis (P = 0.003). Median follow-up for patients alive at last follow-up was 129 months (interquartile range [IQR]: 82-178). Patients with overexpression of Caveolin-1 had significant worse RFS, OS, and CSS compared to those with normal expression (log-rank test, P = 0.008, P = 0.001, and P = 0.005, respectively). At multivariable analyses that adjusted for the effects of standard clinicopathologic features, Caveolin-1 remained associated with OS (hazard ratio = 1.47, P = 0.002) and CSS (hazard ratio = 1.42, P = 0.03). Conversely, no association with RFS was found (P = 0.1). Addition of Caveolin-1 in a model for prediction of survival did not improve the accuracy of the prognostic model. Actually, C-index did not differ among models with or without Caveolin-1 (0.72 for a model predicting RFS, 0.65 for OS, and 0.71 for CSS).Conclusions: Caveolin-1 is overexpressed in one-third of patients with BCa treated with RC. Overexpression of Caveolin-1 is significantly associated with OS and CSS, but not with RFS, in patients with BCa treated with RC. However, it is not clinically useful as it does not improve upon the predictive accuracy of survival achieved by pathologic variables alone. [ABSTRACT FROM AUTHOR]

Introduction: We sought to describe incidence of histological variants after radical cystectomy (RC) due to bladder cancer (BCa). Moreover, we investigated survival outcomes accounting for this parameter.Methods: We retrospectively evaluated data from 1,067 patients with BCa treated with RC between 1990 and 2013 at a single tertiary care referral center. All specimen were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the effect of different histopathological variant on recurrence, cancer-specific mortality (CSM), and overall mortality (OM) after accounting for all available confounders.Results: Of 1,067 patients, 729 (68.3%) harbored pure urothelial BCa while 338 (31.7%) were found to have a variant. Considering uncommon variants, 21 (2.0%) were sarcomatoid, 10 (0.9%) lymphoepitelial, 19 (1.8%) small cell, 109 (10.2%) squamous, 89 (8.3%) micropapillary, 23 (2.2%) glandular, 34 (3.2%) mixed variants, and 33 (3.1%) were found with other types of variants. With a median follow-up of 6.2 years, 343 recurrence, 365 CSM, and 451 OM were recorded, respectively. At multivariable Cox regression analyses, the presence of small cell variant was associated with higher recurrence (hazard ratio [HR] = 3.47, P<0.001), CSM (HR = 3.30, P<0.04), and OM (HR = 2.97, P<0.003) as compared with pure urothelial cancer. Conversely, no survival differences were recorded considering other histological variants (all P> 0.1).Conclusion: Our study confirms that histological variant is not an infrequent event at RC specimen. However, in our single-center series, only patients found with small cell variant were associated with a negative effect on survival after RC. [ABSTRACT FROM AUTHOR]

Objective: To develop a preoperative multivariable decision-making tool to predict nonorgan-confined urothelial carcinoma of the bladder (NOC-UCB) using standard clinical and pathological factors as well as biomarkers of systemic inflammatory response.Materials and Methods: We retrospectively analyzed a prospectively maintained single-institutional database comprising 310 patients with clinically N0 M0 UCB who underwent radical cystectomy (RC) with pelvic lymph node dissection without neoadjuvant cisplatin-based chemotherapy (NAC). NOC-UCB was defined as pT3-4/Nany or pTany/N + disease. A predictive nomogram was built based on significant variables in a bootstrap-corrected multivariable logistic regression model. The accuracy was measured by the area under the curve. Decision-curve analysis was used to evaluate the clinical net benefit.Results: NOC-UCB was found in 147 (47%) of the 310 patients. On multivariable analysis, T stage at transurethral resection of the bladder, lymphovascular invasion, abnormal imaging, and Glasgow prognostic score (GPS) were all independent predictors of NOC-UCB and formed the basis of the nomogram. By adding the GPS, the accuracy of the nomogram improved by 4.7% to 81.7%. The decision curve analysis showed a net benefit of this model compared with the Green model and the strategies of treating all patients or no patient with NAC. Limitations include the retrospective design and the lack of a validation cohort.Conclusion: NOC-UCB at radical cystectomy can be accurately predicted. The accuracy of preoperative models can be improved by adding biomarkers of systemic inflammatory response, such as the GPS. The use of this nomogram may help physicians to accurately identify patients with NOC-UCB who may benefit from NAC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate urinary Aurora A Kinase ( AURKA) mRNA expression as a diagnostic biomarker for urothelial bladder cancer (UBC). Methods: One hundred and eighty-eight urine samples from patients with UBC ( n = 122) and controls with hematuria ( n = 66) were investigated. AURKA expression was quantified using real-time PCR and compared with voided urinary cytology. Associations with stage and grade were assessed. The area under curve was used to quantify the predictive accuracy (PA). Results: The sensitivity and the specificity of AURKA for UBC were 83.6 and 65.2 %, respectively (PA = 74.4 %). Among those with detectable AURKA, the quantity of expression was similar in cases and controls. Compared with Ta, tumors staged T1 and T2 showed a 9.31-fold and 4.78-fold increased AURKA expression ( p = 0.034), respectively. Further, high-grade tumors showed 5.33-fold higher expression levels than low-grade tumors ( p = 0.031). AURKA and urinary cytology showed similar overall PA for UBC detection (74.4 vs. 72.1 %, p = 0.588). For low-grade tumors, AURKA was more accurate (72.5 vs. 59.0 %, p = 0.004), while cytology was more accurate for high-grade lesions (76.8 vs. 89.1 %, p = 0.011). Conclusions: In patients with hematuria, AURKA is associated with the presence and grade of UBC, suggesting a role as diagnostic and prognostic biomarker. As AURKA is more accurate in low-grade tumors but less accurate in high-grade tumors than urinary cytology, both could be complementary in detecting UBC. [ABSTRACT FROM AUTHOR]

Background: Standard survival statistics do not take into consideration the changes in the weight of individual variables at subsequent times after the diagnosis and initial treatment of bladder cancer. Objective: To assess the changes in 5-yr conditional survival (CS) rates after radical cystectomy for bladder cancer and to determine how well-established prognostic factors evolve over time. Design, setting, and participants: We analyzed data from 8141 patients treated with radical cystectomy at 15 international academic centers between 1979 and 2012. Interventions: Radical cystectomy and pelvic lymph node dissection. Outcome measurements and statistical analysis: Conditional cancer-specific survival (CSS) and overall survival (OS) estimates were calculated using the Kaplan-Meier method. The multivariable Cox regression model was used to calculate proportional hazard ratios for the prediction of mortality after stratification by clinical characteristics (age, perioperative chemotherapy status) and pathologic characteristics (pT stage, grade, lymphovascular invasion, pN stage, number of nodes removed, margin status). The median follow-up was 32 mo. Results and limitations: The 5-yr CSS and OS rates were 67.7% and 57.5%, respectively. Given a 1-, 2-, 3-, 5- and 10-yr survivorship, the 5-yr conditional OS rates improved by +5.6 (60.7%), +8.4 (65.8%), +7.6 (70.8%), +3.0 (72.9%), and +1.9% (74.3%), respectively. The 5-yr conditional CSS rates improved by +5.6 (71.5%), +9.8 (78.5%), +7.9 (84.7%), +7.2 (90.8%), and 5.6% (95.9%), respectively. The 5- and 10-yr CS improvement was primarily noted among surviving patients with advanced stage disease. The impact of pathologic parameters on CS estimates decreased over time for both CSS and OS. Findings were confirmed on multivariable analyses. The main limitation was the retrospective design. Conclusions: CS analysis demonstrates that the patient risk profile changes over time. The risk of mortality decreases with increasing survivorship. The CS rates improve mainly in the case of advanced stage disease. The impact of prognostic pathologic features decreases over time and can disappear for long-term CS. Take Home Message: The period elapsed after radical cystectomy is predictive for cancer-specific and overall survival. The risk of mortality decreases with increasing survivorship, mainly for surviving patients with adverse pathologic factors. [ABSTRACT FROM AUTHOR]

Urinary biomarkers are needed to improve the management and reduce the cost of urothelial bladder cancer (UBC); however, none have been recommended yet for clinical practice. This study evaluated carbonic anhydrase IX (CAIX) as a diagnostic urinary biomarker for UBC. CAIX was analyzed by quantitative polymerase chain reaction in urine samples of 196 patients with UBC and 123 controls with hematuria. Paired samples from urine and tumor tissue were evaluated in 16 cases. Data were validated in 155 independent samples. The sensitivity and specificity of CAIX for UBC detection were 86.2% and 95.1%, respectively (area under the curve [AUC]: 90.5%). There was a significant association of CAIX expression between the paired urine and tumor specimens ( p = 0.002). CAIX showed a significantly higher predictive accuracy than urinary cytology (90.5% vs 71.7%), specifically in low-grade tumors (90.0% vs 61.8%). CAIX expression decreased with increasing tumor stage and grade. Analyses in an independent validation cohort confirmed the high accuracy of CAIX for diagnosing UBC (AUC: 88.3%). Patient summary We evaluated carbonic anhydrase IX (CAIX) as a urinary marker for bladder cancer (BCa) using a large series of patients from a single hospital. We found that urinary CAIX has a high sensitivity and specificity for diagnosing BCa. [ABSTRACT FROM AUTHOR]

Introduction: Bladder cancer (BC) is diagnosed by cystoscopy, which is invasive, costly and causes considerable patient discomfort. MicroRNAs (miR) are dysregulated in BC and may serve as non-invasive urine markers for primary diagnostics and monitoring. The purpose of this study was to identify a urinary miR signature that predicts the presence of BC.Methods: For the detection of potential urinary miR markers, expression of 384 different miRs was analyzed in 16 urine samples from BC patients and controls using a Taqman™ Human MicroRNA Array (training set). The identified candidate gene signature was subsequently validated in an independent cohort of 202 urine samples of patients with BC and controls with microscopic hematuria. The final miR signature was developed from a multivariable logistic regression model.Results: Analysis of the training set identified 14 candidate miRs for further analysis within the validation set. Using backward stepwise elimination, we identified a subset of 6 miRs (let-7c, miR-135a, miR-135b, miR-148a, miR-204, miR-345) that distinguished BC from controls with an area under the curve of 88.3%. The signature was most accurate in diagnosing high-grade non-muscle invasive BC (area under the curve = 92.9%), but was capable to identify both low-grade and high-grade disease as well as non-muscle and muscle-invasive BC with high accuracies.Conclusions: We identified a 6-gene miR signature that can accurately predict the presence of BC from urine samples, independent of stage and grade. This signature represents a simple urine assay that may help reducing costs and morbidity associated with invasive diagnostics. [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the incidence of carcinoma in situ (CIS) in patients treated with radical cystectomy (RC) due to bladder cancer and to assess its effect on recurrence and survival rates.Methods: The study focused on 1,128 consecutive nonmetastatic patients with bladder cancer treated with RC at a single tertiary care referral center from 1994 to 2014. The Kaplan-Meier method was used to compare recurrence, cancer-specific mortality (CSM), and overall mortality-free rates in the overall population and in pT0-pT2 and pT3-pT4 patients after stratifying according to the presence of CIS. Multivariable (MVA) Cox regression analyses tested the effect of the presence of CIS on survival outcomes. MVA competing risk analyses were performed to assess the effect of CIS on urothelial recurrence.Results: The presence of CIS was reported in 277 (24.6%) patients. During a median follow-up of 6 years, 355 recurrences, 377 CSM, and 468 overall mortality were reported. At MVA Cox regression analyses, the presence of concomitant CIS was not associated with any survival effect when the overall population was considered (all P≥0.3). At MVA Cox regression analyses, there was no effect of CIS on survival outcomes in pT3-pT4 patients (all P>0.2); on the contrary, the presence of CIS was associated with worse CSM in pT0-pT2 patients only (hazard ratio [HR] = 1.82; CI: 1.01-3.29; P = 0.04). At MVA competing risk analyses predicting urothelial recurrence only, the presence of CIS was associated to an increased risk of urothelial recurrence in pT0-pT2 patients (HR = 2.99; CI: 1.05-8.53; P = 0.04), pT3-pT4 patients (HR = 10.29; CI: 1.40-75.75; P = 0.02), and in the overall population (HR = 4.47; CI: 1.81-11.07; P = 0.001).Conclusion: An increased risk of developing urothelial recurrence only was recorded in patients diagnosed with CIS at RC. Physicians should consider this aspect ensuring a more severe follow-up schemes in patients who harbored this pathological feature. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the overexpression of human epidermal growth factor receptor 2 (HER2) in patients with bladder cancer (BCa) and to assess its association with oncological outcomes.Methods: This retrospective single-center study included 354 patients with BCa treated with radical cystectomy (RC). HER2 status was assessed with immunohistochemistry and scored according to HercepTest. Conditional survival and competing risk regression were performed to assess the association between HER2 expression and survival outcomes.Results: HER2 was overexpressed in 36% of patients. HER2 overexpression was associated with features of tumor aggressiveness such as lymph-node metastases (P = 0.002). At a median follow-up of 123 months (interquartile range: 79-180), 160 patients (45%) experienced disease recurrence, 263 patients (74%) died and 157 (44%) died of cancer. On multivariable analyses, HER2 overexpression was not significantly associated with any oncological outcomes. Adding HER2 status to a model for the prediction of survival outcomes did not change the accuracy of the model for any of the outcomes. Interestingly, HER2 status significantly affected late disease recurrence (P = 0.05 for conditional survival at 24 months).Conclusions: More than one third of RC patients overexpress HER2 in their tumors. HER2 overexpression was associated with features of biological and clinical aggressiveness. HER2 did not add prognostic significance to the standard established predictors of survival outcomes after RC. However, due to the high overexpression rate, it could represent a target for therapy in select advanced BCa tumors. [ABSTRACT FROM AUTHOR]

Background: The neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein (CRP) are markers of systemic inflammatory response, which have been associated with the prognosis of multiple malignancies, but their relationships with oncologic outcomes of non-muscle-invasive bladder cancer (NMIBC) have not been well studied yet.Patients and Methods: We retrospectively reviewed the medical records of 1,117 patients with NMIBC who underwent a transurethral resection of the bladder. Univariable and multivariable competing risk regression models were used to assess the association of preoperative NLR and CRP with disease recurrence and progression to muscle-invasive disease. The median follow-up was 64 months.Results: In total, 360 patients (32.2%) had a high NLR (≥2.5) and 145 (13.0%) had a high CRP (≥5mg/l). On multivariable analyses, a high NLR was associated with both disease recurrence (subhazard ratio [SHR] = 1.27, P = 0.013) and progression (SHR = 1.72, P = 0.007), and high CRP was associated with disease progression (SHR = 1.72, P = 0.031). Adding NLR and CRP to the multivariable model predicting disease progression lead to a relevant change in discrimination (+2.0%). In a subgroup analysis of 300 patients treated with bacillus Calmette-Guerin, both high NLR and high CRP were associated with disease progression (SHR = 2.80, P = 0.026 and SHR = 3.51, P = 0.021, respectively), and NLR was associated with disease recurrence (SHR = 1.46, P = 0.046). There was also an increase in the discrimination of the model predicting progression after bacillus Calmette-Guerin following the inclusion of both markers (+2.4%).Conclusion: In patients with NMIBC, markers of systemic inflammation response are associated with disease recurrence and progression. The inclusion of such markers in prognostic models does enhance their accuracy. [ABSTRACT FROM AUTHOR]