pT1 Non-muscle-invasive Bladder Cancer Research Articles

A novel grading approach predicts worse outcomes in stage pT1 non-muscle-invasive bladder cancer.

To develop a prognostically relevant scoring system for stage pT1 non-muscle-invasive bladder cancer (NMIBC) incorporating tumour budding, growth pattern and invasion pattern because the World Health Organisation grading system shows limited prognostic value in such patients. The tissue specimens and clinical data of 113 patients with stage pT1 NMIBC who underwent transurethral resection of bladder tumour were retrospectively investigated. Tumour budding, and growth and invasion patterns were evaluated and categorised into two grade groups (GGs). GGs and other clinical and histopathological variables were investigated regarding recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) using univariable and multivariable Cox regression analyses. The integration of two tumour budding groups, two growth patterns, and two invasion patterns yielded an unfavourable GG (n = 28; 24.7%) that had a high impact on oncological outcomes. The unfavourable GG was identified as an independent RFS and OS predictor (P = 0.004 and P = 0.046, respectively) and linked to worse PFS (P = 0.001) and CSS (P = 0.001), irrespective of the European Association of Urology risk group. The unfavourable GG was associated with higher rates of BCG-unresponsive tumours (P = 0.006). Study limitations include the retrospective, single-centre design, diverse therapies and small cohort. We present a morphology-based grading system for stage pT1 NMIBC that correlates with disease aggressiveness and oncological patient outcomes. It therefore identifies a highest risk group of stage pT1 NMIBC patients, who should be followed up more intensively or receive immediate radical cystectomy. The grading incorporates objective variables assessable on haematoxylin and eosin slides and immunohistochemistry, enabling an easy-to-use low-cost approach that is applicable in daily routine. Further studies are needed to validate and confirm these results.

The impact of variant histologies in patients with pT1 non-muscle invasive bladder cancer undergoing re-staging transurethral resection of bladder tumor

The impact of variant histologies in patients with pT1 non-muscle invasive bladder cancer undergoing re-staging transurethral resection of bladder tumor

The prognostic impact of tumor necrosis in non-muscle invasive bladder cancer.

We aimed to investigate the impact of tumor necrosis in non-muscle invasive bladder cancer on patients' recurrence and progression rates and survival outcomes. This study was conducted retrospectively in a single tertiary center in Turkey. Medical records of patients who underwent transurethral resection of the bladder tumor between January 2016 and January 2021 were reviewed. Patients with pTa and pT1 non-muscle invasive bladder cancer who had undergone complete resection were included in our study. All pathological specimens were reevaluated for the presence of tumor necrosis. A total of 287 patients (244 males and 43 females) were included in our study. Of them, 33 (11.5%) patients had tumor necrosis. The rates of multiple and large tumors (>3 cm) were higher in patients with tumor necrosis (p=0.002 and p<0.001, respectively). Tumor necrosis was associated with higher rates of pT1 diseases (p<0.001), high-grade tumors (p<0.001), and the presence of lymphovascular invasion (p=0.007). The mean recurrence-free survival of patients with tumor necrosis was 42.3 (4.6) months, and the recurrence-free survival of patients without tumor necrosis was 43.5 (1.8) months (p=0.720). The mean progression-free survival of patients with tumor necrosis was 43.1 (4.6) months, and the progression-free survival of patients without tumor necrosis was 58.4 (0.9) months. In log-rank analysis, there was a statistically significant difference between patients with and without tumor necrosis in terms of progression-free survival (p<0.001). In this study, we demonstrated that patients with non-muscle invasive bladder cancer and tumor necrosis in pathological specimens have shorter progression-free survival and more adverse pathological features.

Prognostic and Predictive Value of Fibroblast Growth Factor Receptor Alterations in High-grade Non–muscle-invasive Bladder Cancer Treated with and Without Bacillus Calmette-Guérin Immunotherapy

BackgroundLimited data are available on the prognostic and predictive value of fibroblast growth factor receptor alterations (FGFRa) relative to clinical outcomes in patients with non–muscle-invasive bladder cancer (NMIBC). ObjectiveTo determine whether FGFRa may be clinically useful in stratifying for treatment response in a real-world cohort of patients with pT1 NMIBC treated and untreated with bacillus Calmette-Guérin (BCG) instillation therapy. Design, setting, and participantsA pooled dataset of matched clinical and genomic data (1992–2015) for pT1 NMIBC patients was assessed by the Bladder Cancer Research Initiative for Drug Targets in Germany consortium. Outcome measurements and statistical analysisKey efficacy outcomes were recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS), which were estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model. Results and limitationsIn this retrospective study of 263 patients with high-grade NMIBC, at a median follow-up of 63 mo, 32% showed recurrence and 15% progressed to muscle-invasive bladder cancer. FGFRa were found in 43% of patients, including 39% mutations and 5.7% fusions. FGFRa were associated with lower rates of concomitant carcinoma in situ. Among patients with or without FGFRa, there was no significant difference in PFS, RFS, and DSS in those who were BCG treated or BCG naive, or in the overall population. Limitations include the retrospective design from a single-center setting. ConclusionsIn patients with high-risk NMIBC, FGFRa were frequently observed. Patients with FGFRa who often exhibit recurrence/relapse after BCG treatment have a high unmet need. Patient summaryOur retrospective study suggests that fibroblast growth factor receptor alterations (FGFRa) occur frequently in non–muscle-invasive bladder cancer (NMIBC). Outcomes were similar with or without FGFRa in patients with NMIBC, both overall and for standard bacillus Calmette-Guérin (BCG) treatment.

La probabilidad de detección de tumor residual en la segunda resección transuretral del cáncer de vejiga urotelial PT1 según los factores de riesgo

ObjectiveTo analyze the predictive factors for residual tumors in the second resection after the initial transurethral resection of bladder tumor (TUR-BT) in patients with pT1 tumors and to develop a simple method to predict the probability of residual tumor detection. Material and methodsPatients with pT1 bladder cancer who underwent a second resection within 2 to 6 weeks after the initial transurethral resection of bladder tumor were included in our retrospective study. The patients’ demographics and the tumor characteristics of the initial and second resections were recorded. ResultsA total of 144 patients were included in our analysis with a 53-month follow-up. In the univariate logistic regression analysis, tumor grade, concomitant carcinoma in situ, macroscopic appearance of the tumor (solid vs papillary), and presence of a variant histology, were significant risk factors for residual tumor. In the multivariate analysis, tumor grade was the only independent predictor of residual tumor at second transurethral resection (OR: 5.62, 95% CI: 1.228–25.708, p=0.026). According to our findings, the patients with the highest risk have a 90.9% residual tumor detection probability at the second resection, and the patients with the lowest risk have 25.4% ConclusionsTumor grade, macroscopic appearance of the tumor (solid vs papillary), and concomitant carcinoma in situ, were important predictors of residual tumors at second resection of primary pT1 non-muscle invasive bladder cancer patients. We were able to calculate the probability of residual tumor which helped us determine risk adapted strategies according to these probabilities.

Tumor budding correlates with tumor invasiveness and predicts worse survival in pT1 non-muscle-invasive bladder cancer

Tumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (p = 0.003), discontinuous invasion pattern (p = 0.039), discohesive growth pattern (p < 0.001) and extensive lamina propria invasion (p < 0.001). In Kaplan–Meier analysis, tumor budding was associated with significantly worse RFS (p = 0.005), PFS (p = 0.017) and CSS (p = 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (p = 0.012), PFS (p = 0.011) and CSS (p = 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.

P100 - Time to cystectomy affects survival in initial pT1 non-muscle invasive bladder cancer

P100 - Time to cystectomy affects survival in initial pT1 non-muscle invasive bladder cancer

942 - Nomogram to predict Bacillus Calmette Guerin (BCG) instillation response in pT1 non-muscle invasive bladder cancer

942 - Nomogram to predict Bacillus Calmette Guerin (BCG) instillation response in pT1 non-muscle invasive bladder cancer

Smoke load prognostic impact on bacillus Calmette-Guérin (BCG) treated non-muscle invasive bladder cancer.

Smoking habit is the major risk factor for bladder cancer (BC), related to about 50% of these tumors; however, the tobacco dose-effect impact on BC immune treatment is underexplored. This study evaluates the impact of smoke load on non-muscle invasive bladder cancer (NMIBC) prognosis after intravesical BCG. Smoke load, recurrence, progression and disease-specific survival were evaluated in a retrospective study including NMIBC patients treated with intravesical BCG between 2006 and 2015. Multivariate Cox regression, ROC and Kaplan-Meier curves were utilized. 132 pT1 NMIBC patients were included: 95 (72%) males, mean age 69.6 ± 10.5years and mean smoking pack-years 22.0 ± 20.8. Recurrence, progression and disease-specific death occurred in 69 (52.3%, mean 20.55 ± 20.44months), 22 (16.7%, mean 31.39 ± 20.19months) and 11 (8.3%, mean 37.23 ± 18.34months), respectively. Smoke load significantly impacted recurrence, HR = 1.019 (95% CI 1.008-1.030, p = 0.0004), and progression, HR = 1.034 (95% CI 1.016-1.052, p = 0.0002), but not survival. For every 1-year increment in pack-years, the risk of relapse and progression increases by 1.9% and 3.4%, respectively. Over 20 pack-year showed the best predictive prognostic power. The smoke load has a potential prognostic role in terms of recurrence and progression in the BCG treated NMIBC. Future studies should explore the smoking impact on the immune system, mainly beyond 20 pack-year.

Prognostic Role of mRNA-Expression of Aquaporins (AQP) 3, 4, 7 and 9 in Stage pT1 Non-Muscle-Invasive Bladder Cancer.

AQP proteins show a variety of functions in human cell metabolism. The role of different AQP subtypes in tumor metabolism and prognosis are subject of ongoing research. To investigate the mRNA expression of Aquaporin (AQP) 3, 4, 7 and 9 in pT1 non-muscle-invasive bladder cancer (NMIBC) and its prognostic value in therapeutic decision making. Formalin-fixed-paraffin-embedded (FFPE) tissues from transurethral resection of the bladder (TURB) from 112 patients with initial diagnosis of stage pT1 NMIBC were analyzed retrospectively together with clinical data and therapeutic approaches. mRNA expression of AQP3, 4, 7 and 9 was measured and quantified using RT-qPCR. Of the 112 patients (83.9%male, median age 72 years), 40 had a recurrence (35.7%), 16 a progression (14.3%) and 14 patients (12.5%) died tumor-related. mRNA expression for AQP3 was detected in 99.1%, AQP4 in 46.4%, AQP7 in 86.6%and AQP9 in 97.3%. Spearman analysis revealed statistically significant correlations between AQP3, AQP7 and AQP9 mRNA expression with adverse clinical and histopathological parameters (WHO1973 grade 3, concomitant Cis or multifocality). High AQP9 mRNA expression was associated with worse PFS in the total cohort (p = 0.034) and in Grade 3 tumors (p = 0.003) in Kaplan-Meier analysis. In patients with bladder sparing approach, high AQP3 mRNA expression was significantly associated with worse CSS in patients receiving BCG therapy (p = 0.029). mRNA expression of AQP3, 7 and 9 correlates with adverse clinical and pathological parameters. AQP3 and 9 may help to identify a subgroup of highest risk patients who may be considered for early cystectomy.

The prognostic value of routine second transurethral resection in patients with newly diagnosed stage pT1 non-muscle-invasive bladder cancer: results from randomized 10-year extension trial.

To evaluate the impact of routine second TUR on the long-term outcome of patients with newly diagnosed stage pT1 non-muscle-invasive bladder cancer (NMIBC) MATERIAL AND METHODS: A total of 210 patients (mean age 62.1years, 89.5% were males) with stage pT1 NMIBC who underwent first TUR were prospectively randomized into two groups including second TUR (n = 105) and no second TUR (n = 105) groups. Data on recurrence, disease progression, 7-year and 10-year recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) were recorded. The median follow-up time was 119months (IQR 65-168). Per-protocol (PP) analysis revealed that compared to patients without second TUR, patients with second TUR had significantly higher 5-year, 7-year and 10-year rates for RFS (59.4%, 57.9% and 54.8% vs. 36.3%, 31.7% and 26.8%, respectively, p < 0.001) and PFS (93.3%, 91.9% and 90.4% vs. 74.0%, 71.4% and 68.5%, respectively, p < 0.001). According to PP and intention-to-treat (ITT) analyses, the 10-year OS rate was significantly higher in patients with second TUR (59.1 vs. 40.8%, p = 0.004). Multivariate analysis revealed that undergoing second TUR (OR 1.661, 95% CI 1.156-2.385, p = 0.006) was an independent determinant of prolonged OS. In conclusion, these findings indicate the prognostic value of second TUR in stage pT1 NMIBC patients, not only for RFS and PFS advantages but also for the long-term OS advantage. Therefore, second TUR should be routinely performed in all stage pT1 NMIBC patients with life expectancy of at least 10years, given the positive contribution to all oncological outcomes.

Stromal lymphocyte infiltration is associated with tumour invasion depth but is not prognostic in high-grade T1 bladder cancer

IntroductionAssessment of tumour-infiltrating lymphocytes (TILs) can provide important prognostic information in various cancers and may be of value in predicting response to immunotherapy. The objective of the present study was to investigate the association of stromal lymphocytic infiltration with clinicopathological parameters and their correlation with outcomes in patients with high-grade pT1 non–muscle-invasive bladder cancer (NMIBC). Materials and methodsWe retrospectively analysed clinical data and formalin-fixed paraffin-embedded (FFPE) tissues of 147 patients with primary high-grade pT1 NMIBC who underwent transurethral resection of the bladder. The stromal TIL density was scored as percentage of the stromal area infiltrated by mononuclear inflammatory cells over the total intratumoural stromal area. The main end-point was correlation with cancer-specific survival (CSS). ResultsMedian follow-up was 8.2 years (6.1–9.5). Induction Bacillus Calmette–Guérin therapy was undergone by 126 patients (86%). Stromal TILs were high (≥10%) in 82 tumours (56%) and were positively associated with the tumour invasion depth (p = 0.01) and cancers with variant histology (p = 0.01). For the CSS analysis, high (≥10%) versus. low (<10%) stromal TIL hazard ratio (95% confidence interval) was 1.70 (0.7–3.9, p = 0.2). ConclusionsA higher density of stromal TILs was associated with the tumour invasion depth in pT1 NMIBC. The level of TILs was not associated with survival outcomes. These data suggest that tumour aggressiveness is associated with an increased adaptive immune response in pT1 NMIBC. Characterisation of T-cell subtypes along with B-cells may be critical to enhance our knowledge of the host immune response in patients with high-risk NMIBC.

BOXIT—A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004)

BackgroundNon–muscle-invasive bladder cancer (NMIBC) has a significant risk of recurrence despite adjuvant intravesical therapy. ObjectiveTo determine whether celecoxib, a cyclo-oxygenase 2 inhibitor, reduces the risk of recurrence in NMIBC patients receiving standard treatment. Design, setting, and participantsBOXIT (CRUK/07/004, ISRCTN84681538) is a double-blinded, phase III, randomised controlled trial. Patients aged ≥18 yr with intermediate- or high-risk NMIBC were accrued across 51 UK centres between 1 November 2007 and 23 July 2012. InterventionPatients were randomised (1:1) to celecoxib 200mg twice daily or placebo for 2 yr. Patients with intermediate-risk NMIBC were recommended to receive six weekly mitomycin C instillations; high-risk NMIBC cases received six weekly bacillus Calmette-Guérin and maintenance therapy. Outcome measurements and statistical analysisThe primary endpoint was time to disease recurrence. Analysis was by intention to treat. Results and limitationsA total of 472 patients were randomised (236:236). With median follow-up of 44 mo (interquartile range: 36–57), 3-yr recurrence-free rate (95% confidence interval) was as follows: celecoxib 68% (61–74%) versus placebo 64% (57–70%; hazard ratio [HR] 0.82 [0.60–1.12], p=0.2). There was no difference in high-risk (HR 0.77 [0.52–1.15], p=0.2) or intermediate-risk (HR 0.90 [0.55–1.48], p=0.7) NMIBC. Subgroup analysis suggested that time to recurrence was longer in pT1 NMIBC patients treated with celecoxib compared with those receiving placebo (HR 0.53 [0.30–0.94], interaction test p=0.04). The 3-yr progression rates in high-risk patients were low: 10% (6.5–17%) and 9.7% (6.0–15%) in celecoxib and placebo arms, respectively. Incidence of serious cardiovascular events was higher in celecoxib (5.2%) than in placebo (1.7%) group (difference +3.4% [–0.3% to 7.2%], p=0.07). ConclusionsBOXIT did not show that celecoxib reduces the risk of recurrence in intermediate- or high-risk NMIBC, although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib. Patient summaryCelecoxib was not shown to reduce the risk of recurrence in intermediate- or high-risk non–muscle-invasive bladder cancer (NMIBC), although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib.

FOXM1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT1 non-muscle-invasive bladder cancer.

To investigate the role of forkhead box protein M1 (FOXM1) mRNA expression and its prognostic value in stage pT1 non-muscle-invasive bladder cancer (NMIBC). Clinical data and formalin-fixed paraffin-embedded tissues from transurethral resection of the bladder from patients with stage pT1 NMIBC, treated with an organ-preserving approach, were analysed retrospectively. Total RNA was isolated using commercial RNA extraction kits, and mRNA expression of FOXM1, MKI67, KRT20 and KRT5 was measured by single-step quantitative RT-PCR using RNA-specific TaqMan Assays. Statistical analysis was performed using Spearman's Rho, Wilcoxon or Kruskal-Wallis tests, Kaplan-Meier estimates of recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS) and Cox regression analysis. Data from 296 patients (79.4% men, median age 72 years) were available for the final evaluation. Spearman correlation analysis showed that mRNA expression of FOXM1 was significantly correlated with MKI67 (ρ: 0.6530, P < 0.001) and with the luminal subtype, reflected by the positive correlation with KRT20 (ρ: 0.2113, P < 0.001). Furthermore, there was also a strong correlation of FOXM1 expression with adverse clinical and pathological variables, such as concomitant carcinoma in situ (P = 0.05), multifocal tumours (P = 0.005) and World Health Organization 1973 grade 3 disease (P < 0.001). Kaplan-Meier analysis showed overexpression of FOMX1 to be associated with worse PFS (P = 0.028) and worse CSS (P = 0.015). FOXM1 overexpression was also shown to be a predictive risk factor for CSS (hazard ratio 1.61 [1.13-2.34], L-R chi-squared: 7.19, P = 0.007). FOXM1 overexpression identified a subgroup of patients within the luminal subtype with worse RFS (P = 0.017), PFS (P < 0.001) and CSS (P = 0.015). Patients with low FOXM1 expression had better outcomes, irrespective of instillation therapy, whereas patients with high FOXM1 expression benefitted from intravesical chemotherapy with mitomycin C. High FOXM1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT1 NMIBC.

High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients.

Checkpoint inhibition has emerged as new therapeutic option in muscle-invasive bladder cancer. The objective of the present study was to evaluate the prognostic role of PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification. We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survival (CSS). We have analyzed 334 patients with NMIBC at stage pT1 for mRNA analysis. Data from 296 patients (79% male, median age: 72years) could be used. Spearman correlation revealed significant associations between mRNA expressions of PD1/PDL1 (ρ: 0.6024, p<0.0001), CD3/PDL1 (ρ: 0.5728, p<0.0001) and CD3/PD1 (ρ: 0.7005, p<0.0001). Kaplan-Meier analysis revealed that high PDL1 mRNA expression (≥33.83) is a favorable prognostic factor with regard to better RFS (p=0.0018), PFS (p=0.021) and CSS (p=0.012). Multivariate Cox-regression analysis proved PDL1 expression to be an independent prognosticator for RFS [HR 0.48 (0.31-0.72), p=0.0005], PFS [HR 0.45 (0.24-0.80), p=0.0059] and CSS [HR 0.31 (0.13-0.67), p=0.0021]. High mRNA expression of PDL1 predicts improved RFS, PFS and CSS of pT1 NMIBC. Following prospective validation, this objective measurement of PD-L1 might help stratify patients with NMIBC for immunotherapy and identify patients who might benefit from early cystectomy.

Is restaging transurethral resection necessary in patients with non-muscle invasive bladder cancer and limited lamina propria invasion?

ObjectivesTo evaluate the influence of lamina propria invasion type at initial transurethral resection (TUR) on restaging pathology. Materials and methodsWe reviewed prospectively maintained records of all patients with a high-grade pT1 nonmuscle invasive bladder cancer who underwent both initial and restaging TUR within 6 weeks at our center between 2001 and 2016. The pathology of second TUR specimens was analyzed with regard to the characteristics of lamina propria invasion found at initial resection. ResultsWe included 198 patients, with a median age of 70 years (interquartile range: 63–79). Muscle was present in the initial TUR specimen in 107 patients (54%). Pathology restaging was pT0 in 73 patients (37%), pTis in 44 (22%), pTa in 27 (14%), pT1 in 50 (25%), and pT2 in 4 (2%). Eighty-seven patients (44%) had tumors with minimal lamina propria invasion at initial TUR: 53 specimens (27%) had focal invasion (few malignant cells in the lamina propria); 15 specimens (7.6%) had superficial invasion (invasion of the lamina propria to the level of the muscularis mucosae [T1a]); and 19 specimens (10%) had multifocal superficial invasion (multiple areas of T1a). Of the patients with minimal lamina propria invasion, residual disease was found in 54 patients (62%). However, none of those patients had T2 disease. ConclusionsA significant number of patients with T1 tumors have residual disease at restaging TUR as do patients with minimal lamina propria invasion. The extent of T1 invasion does not eliminate the need for repeat TUR.

High Androgen Receptor mRNA Expression Is Independently Associated with Prolonged Cancer-Specific and Recurrence-Free Survival in Stage T1 Bladder Cancer

INTRODUCTION: High-risk non–muscle-invasive bladder cancer (NMIBC) remains challenging given the high probability of progression. Given that the androgen receptor (AR) has been discussed as a possible factor in the development and progression of bladder cancer, we investigated the predictive value of AR in stage pT1 NMIBC. MATERIALS AND METHODS: We retrospectively analyzed the clinical data and AR mRNA expression in 296 patients with stage pT1 NMIBC who underwent a transurethral resection of the bladder. The mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured by reverse transcription quantitative real-time polymerase chain reaction. AR expression was also correlated to KRT5 and KRT20 mRNA expression. RESULTS: Kaplan-Meier analysis indicated that high AR1 mRNA expression ≥35.47 is associated with statistically significant better recurrence-free survival (RFS) (P=.0007), progression-free survival (PFS) (P=.0420), and cancer-specific survival (CSS) (P=.0050). Multivariate Cox regression analysis revealed that high AR1 mRNA expression is an independent prognostic marker for RFS (P=.0029) and CSS (P=.0119). Spearman rank correlation revealed a significant positive association between mRNA expression of AR1 and KRT5 (rs: 0.3171, P<.0001) as well as a negative association with multifocal tumors (rs: 0.1478, P<.0109). No association was noted between AR1 expression and tumor grade, concomitant CIS, gender, tumor size, and KRT20 in patients with stage T1 NMIBC. CONCLUSIONS: AR mRNA expression can predict RFS and CSS in patients with stage T1 NMIBC. Further studies are necessary to refine the relevance of AR mRNA expression compared with immunohistochemically detectable AR expression.

In stage pT1 non-muscle-invasive bladder cancer (NMIBC), high KRT20 and low KRT5 mRNA expression identify the luminal subtype and predict recurrence and survival.

Differential expression of cytokeratins (CK) is a characteristic feature of chemoresistant luminal (KRT20) and chemosensitive intrinsic aggressive basal (KRT5) subtypes in muscle-invasive bladder cancer (MIBC). We investigated mRNA expression of KRT5 and KRT20 and its predictive value in stage pT1 bladder cancer. In retrospective analysis of clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder, a single-step RT-qPCR was used to measure mRNA expression. Furthermore, immunohistochemical (IHC) staining of CK20, panCK, and MIB1 was performed. Valid measurements were obtained from 231 samples out of a series of 284 patients. Spearman correlation revealed significant associations between mRNA and protein expression of KRT20/CK20 (ρ 0.6096, p<0.0001) and MKI67/MIB1 (ρ 0.5467, p<0.0001). A positive correlation was found between MKI67 and KRT20 expression (ρ 0.3492, p<0.0001), while MKI67 and KRT5 were negatively correlated (ρ -0.1693, p=0.01). High KRT20 expression (≥40.26) was significantly associated with worse recurrence free survival (RFS) (p=0.001), progression-free survival (PFS) (p=0.0003), and cancer specific survival (CSS) (p=0.0414). The combination of high KRT20 expression and low KRT5 expression (<36.83) was associated with unfavorable RFS (p=0.0038) and PFS (p=0.0003) and proved to be the only independent predictor for RFS (p=0.0055) and PFS (p=0.0023) in multivariate analysis. KRT20 mRNA determination was superior to CK20 protein estimation with regard to RFS and PFS prediction. KRT20 and KRT5 mRNA quantification can predict recurrence and progression of stage pT1 NMIBC reflecting basal and luminal subtypes of MIBC and is superior to CK20 protein expression determined by IHC.

ERBB2 Expression as Potential Risk-Stratification for Early Cystectomy in Patients with pT1 Bladder Cancer and Concomitant Carcinoma in situ

Background/Aims/Objectives: It is difficult to identify patients with a non-muscle-invasive bladder cancer (NMIBC) at stage pT1 with concomitant carcinoma in situ (Cis) who will benefit from an early cystectomy. Methods: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues of patients with NMIBC. Messenger ribonucleic acid (mRNA) expression of progesterone receptor (PGR), estrogen receptor (ESR1), ERBB2, and marker of proliferation Ki-67 (MKI67) was measured by single-step reverse transcription quantitative real-time polymerase chain reaction using RNA-specific TaqMan assays. Relative gene expression was determined by the normalization of 2 reference genes (CALM2, B2M) using the 40 ΔΔCT method and relative gene expression was correlated to the histopathological stage and oncological outcome. Results: Of 302 patients with pT1 NMIBC in the initial transurethral resection of the bladder, 65 had a concomitant Cis. Elevated ERBB2 expression (>40.1) significantly correlated with progress in patients with and without concomitant Cis (p = 0.020 and p = 0.049, respectively). For the subgroup of pT1 with concomitant Cis, elevated ERBB2 expression significantly discriminated between a high-risk group of 55% progression-free survival (PFS) and a low-risk group of 90% PFS after a 5-year follow-up (p = 0.020). Cox-regression analysis revealed ERBB2 expression as the only independent prognostic factor for PFS (p = 0.0037). Conclusions: High mRNA expression of ERBB2 can identify patients with pT1 NMIBC with concomitant Cis, who have a high risk of progression and might benefit from an early cystectomy.

Risk Factors Predictive of Recurrence and Progression for Patients Who Suffered Initial Recurrence After Transurethral Resection of Stage pT1 Bladder Tumor in Chinese Population

Bladder cancer is one of the most common malignancies worldwide and the stage pT1nonmuscle invasive bladder cancer (NMIBC) has a high probability of recurrence after initial diagnosis and treatment. However, risk factors predictive of repeated recurrence and progression of pT1 bladder tumors after primary relapse have not been uncovered. Thus, we conducted the retrospective study.A total of 418 patients who suffered initial recurrence after transurethral resection (TUR) of pT1 bladder tumor were selected for the analyses. Clinic information of the patients was retrieved from their medical records. Recurrence-free survival (RFS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. The probability of recurrence and progression by multivariate analyses was used as a surrogate marker to construct receiver operating curve (ROC).Results showed that variables including time to prior recurrence time, prior treatment, number of tumor, tumor size, tumor grade, and time of instillation after surgery were associated with the repeated recurrence of pT1 bladder tumor (P < 0.05). The variables including time to prior recurrence time, tumor size, tumor grade, carcinoma in situ (CIS), and time of instillation after surgery were associated with progression of pT1 bladder tumor (P < 0.05). In the present study, the multivariate model showed an area under ROC (AUC) value of 0.754 and 0.798 for tumor recurrence and progression, respectively, which was more effective in prediction than a single risk factor.In conclusion, we have identified several risk factors relevant to RFS and PFS for patients who have had a history of recurrence of pT1 bladder tumor after TUR. These predictive factors may help urologists to stratify patients into distinct risk groups of recurrence and progression, which probably contributes to the individualized treatment for patients.