Non-muscle Invasive Bladder Cancer Patients Research Articles

Real-world treatment patterns among patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin (BCG).

404 Background: Intravesical BCG is a common treatment in high-risk NMIBC patients; however supply constraints and regimen demands for patients have been reported and may impact long term patient outcomes. This study examined treatment patterns in NMIBC patients receiving intravesical BCG. Methods: Adults with NMIBC treated with intravesical BCG during any line of therapy (LOT) on or after the index date (first date for transurethral resection of the bladder tumor [TURBT] or initiation of intravesical therapy) were selected from de-identified IBM MarketScan Commercial and Medicare Supplemental Databases (1/1/2010-2/28/2021) and Multi-State Medicaid Database (1/1/2010-12/31/2019). Classification of NMIBC on the index date required that patients have no prior systemic antineoplastic therapy, radiotherapy, or cystectomy. Treatment patterns were evaluated from the index date until the end of the NMIBC phase (earliest of initiation of systemic antineoplastic therapy, cystectomy, radiotherapy, diagnosis for metastatic cancer, end of insurance eligibility, or end of data availability). Discontinuation of a LOT was defined as having a treatment gap > 180 days for BCG (90 days for other agents) or switching to a new LOT. During each LOT, adequate BCG treatment was defined as having ≥5 claims during induction (first 42 days of treatment) and ≥2 claims during maintenance (beyond the first 42 days). Results: There were 5,410 NMIBC patients treated with BCG over a mean (median) follow up of 25.5 (18.9) months. The population was 79% male; mean age was 67 years. The majority of patients only received a single LOT (76%; TABLE). The predominant first LOT was BCG (93.1% of NMIBC patients); however, the majority (69.8%) did not receive adequate BCG induction/maintenance in first LOT. Nearly half (46.4%) of first LOT patients had reassessment for disease progression by TURBT. BCG retreatment after a six-month lapse was observed as the predominant second LOT, with > 90% receiving inadequate BCG induction/maintenance. Conclusions: While intravesical BCG remains the most common therapy for NMIBC, less than a third of patients receive adequate BCG treatment in the first LOT; with this percentage further decreasing in the few patients who receive a subsequent LOT. In light of supply and demand constraints, results of this study further emphasize a need for additional treatment options that are effective, safe, and tolerable for patients with NMIBC.[Table: see text]

Number of transurethral procedures after non-muscle-invasive bladder cancer and survival in causes other than bladder cancer.

Previous research has associated repeated transurethral procedures after a diagnosis of non-muscle invasive bladder cancer (NMIBC) with increased risk of death of causes other than bladder cancer. We investigated the overall and disease-specific risk of death in patients with NMIBC compared to a background population sample. We utilized the database BladderBaSe 2.0 containing tumor-specific, health-related and socio-demographic information for 38,547 patients with NMIBC not primarily treated with radical cystectomy and 192,733 individuals in a comparison cohort, matched on age, gender, and county of residence. The cohorts were compared using Kaplan-Meier curves and Hazard ratios (HR) from a Cox regression models. In the NMIBC cohort, we analyzed the association between number of transurethral procedures and death conditioned on surviving two or five years. Overall survival and survival from causes other than bladder cancer estimated with Kaplan-Meier curves was 9.3% (95% confidence interval (CI) (8.6%-10.0%)) and 1.4% (95% CI 0.7%-2.1%) lower respectively for the NMIBC cohort compared to the comparison cohort at ten years. In a Cox model adjusted for prognostic group, educational level and comorbidity, the HR was 1.03 (95% CI 1.01-1.05) for death from causes other than bladder cancer comparing the NMIBC cohort to the comparison cohort. Among the NMIBC patients, there was no discernible association between number of transurethral procedures and deaths of causes other than bladder cancer after adjustment. The number of procedures were, however, associated with risk of dying from bladder cancer HR 3.56 (95% CI 3.43-3.68) for four or more resections versus one within two years of follow-up. The results indicate that repeated diagnostic or therapeutic transurethral procedures under follow-up do not increase of risk dying from causes other than bladder cancer. The modestly raised risk for NMIBC patients dying from causes other than bladder cancer is likely explained by residual confounding.

Addition of Chromosome 17 Polysomy and HER2 Amplification Status Improves the Accuracy of Clinicopathological Factor-Based Progression Risk Stratification and Tumor Grading of Non-Muscle-Invasive Bladder Cancer.

Simple SummaryThe addition of chromosome 17 polysomy/HER2 amplification status to the updated EAU and AUA scores improves their accuracy, allowing molecular reclassification of EAU high-risk NMIBCs and G2 tumors. Based on this, we propose to reclassify the non-HER2 amplified, non-polysomic EAU 3–4 (high- and very high-risk) cases to the EAU 2 (intermediate) risk group to prevent unnecessarily strict follow-up and treatment for these patients. Furthermore, to classify Chr17 polysomic and/or HER2 amplified G2 tumors as high-grade (HG) and non-HER2 amplified, non-polysomic G2 tumors as low-grade (LG) NMIBCs (G1 and G3 tumors remain graded as low- and high-grade, respectively). Thus, the implementation of Chr17 polysomy/HER2 amplification testing would provide an immediate and simple solution to further refine the prognostic risk assessment of NMIBCs in the uro-oncology practice.Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) significantly worsens life expectancy. Its risk can be assessed by clinicopathological factors according to international guidelines. However, additional molecular markers are needed to refine and improve the prediction. Therefore, in the present study, we aimed to predict the progression of NMIBCs to MIBC by assessing p53 expression, polysomy of chromosome 17 (Chr17) and HER2 status in the tissue specimens of the tumors of 90 NMIBC patients. Median follow-up was 77 months (range 2–158). Patients with Chr17 polysomy or HER2 gene amplification had a higher rate of disease progression (hazard ratio: 7.44; p < 0.001 and 4.04; p = 0.033, respectively; univariate Cox regression). Multivariable Cox regression models demonstrated that the addition of either Chr17 polysomy or HER2 gene amplification status to the European Association of Urology (EAU) progression risk score increases the c-index (from 0.741/EAU/ to 0.793 and 0.755, respectively), indicating that Chr17 polysomy/HER2 amplification status information improves the accuracy of the EAU risk table in predicting disease progression. HER2/Chr17 in situ hybridization can be used to select non-progressive cases not requiring strict follow-up, by reclassifying non-HER2-amplified, non-polysomic NMIBCs from the high- and very high-risk groups of EAU to the intermediate-risk group.

Can a reresection be avoided after initial en bloc resection for high-risk nonmuscle invasive bladder cancer? A systematic review and meta-analysis.

BackgroundThis study aims to evaluate the effectiveness of en bloc resection for patients with nonmuscle invasive bladder cancer (NMIBC) and explore whether a reresection can be avoided after initial en bloc resection.Material and methodsWe conducted research in PubMed, EMBASE, Cochrane Library, and Web of Science up to October 12, 2021, to identify studies on the second resection after initial en bloc resection of bladder tumor (ERBT). R software and the double arcsine method were used for data conversion and combined calculation of the incidence rate.ResultsA total of 8 studies involving 414 participants were included. The rate of detrusor muscle in the ERBT specimens was 100% (95%CI: 100%–100%), the rate of tumor residual in reresection specimens was 3.2% (95%CI: 1.4%–5.5%), and the rate of tumor upstaging was 0.3% (95%CI: 0%–1.5%). Two articles compared the prognostic data of the reresection and non-reresection groups after the initial ERBT. We found no significant difference in the 1-year recurrence-free survival (RFS) rate (OR = 1.44, 95%CI: 0.67–3.09, P = 0.35) between the two groups nor in the rate of tumor recurrence (OR = 0.72, 95%CI: 0.44–1.18, P = 0.2) or progression (OR = 0.98, 95%CI: 0.33–2.89, P = 0.97) at the final follow-up.ConclusionsERBT can almost completely remove the detrusor muscle of the tumor bed with a very low postoperative tumor residue and upstaging rate. For high-risk NMIBC patients, an attempt to appropriately reduce the use of reresection after ERBT seems to be possible.

Immediate post-operative intravesical instillation of a single dose chemotherapy is not superior to continuous saline irrigation

Introduction and objectivesTo evaluate whether there is any difference between immediate postoperative instillation of intravesical chemotherapy (IPOIC) and continuous saline bladder irrigation (CSBI) in terms of bladder cancer (BC) recurrence in patients with primary low- or intermediate-risk non-muscle-invasive BC (NMIBC). Materials and methodsMedical records of 1482 patients who underwent transurethral resection of bladder tumor between March 1994 and August 2020 were reviewed retrospectively. Patients were divided into two groups according to IPOIC and/or CSBI administration status [Group-1 = CSBI alone; Group-2 = CSBI following IPOIC]. Low- and intermediate-risk NMIBC patients were also divided into subgroups according to IPOIC and/or CSBI administration status. ResultsA total of 594 patients with primary NMIBC were included. Of the patients, 86 (14.5%) were female and 508 (85.5%) were male with a median age of 69 (60–78) years. The frequency of patients in Group-1 and Group-2 were 361 (60.8%) and 233 (39.2%), respectively. Recurrent disease was observed in 213 (35.9%) patients. There was no difference between the groups when they were compared for recurrent disease frequency, median time to first recurrence and frequency of recurrence within first 12 months (P = .064, P = .671, and P = .145, respectively). Disease recurrence rates in low-risk NMIBC patients was lower when they were treated with “CSBI following IPOIC” when compared to “CSBI alone” (P = .042). However, no difference was observed in low-risk NMIBC subgroups when they were compared for pathological features of recurrent tumors such as number, size, grade, stage, and presence of carcinoma in situ (P > .05, for each). Conclusions“CSBI following IPOIC” combination was not superior to “CSBI alone” for preventing adverse pathological outcomes in recurrent low- and intermediate-risk NMIBC.

Efficacy of compound aluminum sulfate injection as a monotherapeutic regimen in non-muscle invasive bladder cancer patients: a retrospective single-arm cohort study.

BackgroundCompound aluminum sulfate injection (CASI) originated from a Chinese traditional medicine, “Kuzhiye”, and has been used in treating non-muscle invasive bladder cancer (NMIBC). Previous studies suggested that CASI was a potential monotherapeutic drug for NMIBC. However, the efficacy and safety of CASI in the treatment of NMIBC, as well as the long-term recurrence after treatment, need to be further evaluated.MethodsA multicenter retrospective single-arm cohort study was conducted. From 2006 to 2009, 101 patients (74 men and 27 women, aged 58.9±11.9 years) with T1 or benign NMIBC were enrolled. Each patient was directly injected with CASI through catheter needle into the root of NMIBC. Vital signs, electrocardiography, blood count, blood biochemistry, and urine analysis were re-examined on day 2 and day 14 after CASI injection, together with a cystoscopic examination 4 weeks after CASI treatment was performed for all patients to assess the clinical activity and safety of CASI. To study long-term efficacy, patients in center 2 were followed up for recurrence with a median follow-up time of 13.8 years.ResultsFor the 101 patients enrolled in this study, demographic characteristics in the 3 centers showed no significant differences. After CASI, 2 patients showed administration site-dependent, but not dose-dependent, increase in their aluminum concentration in 24 hours without obvious abnormality in blood biochemistry. The overall effective rate was 97.03%, including complete tumor necrosis in 94 patients. Treatment-related adverse events occurred in 20 patients (19.80%), including 9 drug-related and 11 cystoscopy-related adverse events (AEs). All AEs were endurable and disappeared within 2 weeks without any treatment. The maximum tolerated single dose of CASI was 21 mL. Among the 43 patients at center 2, 3 patients were excluded because they changed to other treatment regimen. As of April 2022, of the 40 patients enrolled, 22 had no recurrence and 7 relapsed. The follow-up time was 2–16.2 years. The other 11 patients were lost to follow up.ConclusionsCASI may be an effective and safe option for the treatment of NMIBC and is expected to be a potential monotherapy regimen for NMIBC.

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

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

How to reduce bacillus Calmette-Guérin discontinuation in patients with severe functional impairment.

BackgroundSevere functional impairment is often considered a contraindication to intravesical therapy for nonmuscle-invasive bladder cancer (NMIBC). A tailored intravesical bacillus Calmette-Guérin (BCG) procedure was evaluated in high-risk (HR)-NMIBC patients with severe functional impairment.Materials and methodsPatients with a Katz Index score of 2 or less and an initial diagnosis of HR-NMIBC with atraumatic insertion of a Foley-type indwelling catheter, bladder emptying, and BCG instillation were prospectively treated; after 2 hours, the bladder was emptied and the catheter was removed (group A).After propensity score matching, 52 patients in group A were compared with that of 52 consecutive patients in group B using a retrospective database, with similar baseline/oncological characteristics and treated with standard intermittent catheterization. Moreover, groups A and B were compared with that of 130 consecutive patients (group C) retrospectively evaluated, with similar oncological characteristics but with a Katz Index score of 3 or greater and treated with standard intermittent catheterization.ResultsThe discontinuation rates were 11.5%, 35%, and 9% in groups A, B, and C, respectively (A vs. B, log-rank score 42.52 [p < 0.05]; B vs. C, 107.6 [p < 0.05]; A vs. C, 3.45 [p > 0.05]). The overall adverse event rates were 38.5%, 57.7%, and 39.2%, respectively (A vs. B, p = 0.04; B vs. C, 0.03; A vs. C, 0.92). The rates of severe adverse events were 1.9%, 1.9%, and 1.5%, respectively, without statistically significant differences. The cumulative HR disease-free survival rates were 63.4%, 48%, and 69.2%, respectively (A vs. B, log-rank score 154.9 [p < 0.05]; B vs. C, 415 [p < 0.05]; A vs. C, 244 [p < 0.05]).ConclusionsA tailored intravesical instillation procedure may reduce BCG discontinuation and adverse effects.

The Role of Fluorescence In Situ Hybridization in the Surveillance of Non-Muscle Invasive Bladder Cancer: An Updated Systematic Review and Meta-Analysis.

Background: Fluorescence in situ hybridization (FISH) has become a popular biomarker for subsequent monitoring the recurrence of non-muscle invasive bladder cancer (NMIBC), several studies have investigated the ability of FISH to detect recurrence in the surveillance of NMIBC. However, the results were inconsistent. Methods: We conducted a systematic literature search extensively on authenticated databases including PubMed/Medline, Embase, Web of Science, Ovid, and Cochrane Library. Meta-analysis was performed to find out the sensitivity and specificity of FISH in predicting recurrence of NMIBC. Results: 15 studies were ultimately included in this meta-analysis, a total of 2941 FISH evaluations from 2385 NMIBC patients were available. The pooled sensitivity of FISH was 68% (95% CI: 0.58–0.76), and the pooled specificity was 64% (95% CI: 0.53–0.74). Subgroup analyses were performed in 7 studies without Bacillus Calmette–Guerin (BCG) treatment, the pooled sensitivity was 82% (95% CI: 0.68–0.90), and the pooled specificity was 63% (95% CI: 0.37–0.82). And in 9 studies using “UroVysion standard” to define positive FISH results showed a pooled sensitivity of 60% (95% CI: 0.50–0.70) and specificity of 70% (95% CI: 0.61–0.78). Conclusions: The findings of this study indicate that FISH has a satisfactory sensitivity (68%) and specificity (64%) and could be a potential biomarker in the surveillance of NMIBC. Moreover, BCG treatment and different FISH methods may have an impact on the sensitivity and specificity, these factors should be taken into account when making clinical strategy.

Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition)

Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued “Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline”. Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette–Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

Identification of Long Non-Coding RNA MIR4435-2HG as a Prognostic Biomarker in Bladder Cancer.

The abnormal expression of long non-coding RNAs(lncRNAs) is closely related to the prognosis of patients. This finding may indicate a new target for the treatment of malignant tumors. Non-muscle invasive bladder cancer (NMIBC) is the most common subtype of bladder cancer, and BCG intravesical therapy is the first-line treatment for NMIBC, but about half of NMIBC patients relapse within two years after BCG treatment. Therefore, it is necessary to screen out lncRNAs related to the prognosis and treatment of BGC-resistant patients. Here, we performed differential expression analysis of lncRNAs in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and screened MIR4435-2HG as the only BCG-response-related lncRNA. Then, the prognosis value of MIR4435-2HG was validated in several publicly available cohorts, and confirmed its prognostic value in bladder cancer of different stages. In addition, we also analyzed its genetic alterations, clinical relevance, function enrichment, and association with other biomarkers. Further validation of the expression of MIR4435-2HG might be helpful to instruct NMIBC prognosis and treatment.

Contemporary use trends and effect on survival of pelvic lymph node dissection for non-muscle-invasive bladder cancer.

BackgroundPatients diagnosed with non-muscle-invasive bladder cancer (NMIBC) who are at a very high risk of disease progression and failure of Bacillus Calmette-Guerin treatment are recommended to undergo immediate radical cystectomy (RC). The role and optimal degree of pelvic lymph node dissection (PLND) during RC for NMIBC patients, however, have not been well investigated.Patients and methodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients. Overall survival (OS) was assessed with the Kaplan–Meier technique. Multivariable Cox regression analysis was conducted to determine independent factors of OS.ResultsA total of 1,701 patients were identified in the SEER database from 2004 to 2015. Any level of PLND (>0 lymph nodes examined) was performed in 1,092 patients (64.2%). The median number of lymph nodes examined was 8 (interquartile range, 0–20) in T1, 0 (interquartile range, 0–11) in Ta, and 0 (interquartile range, 0–14) in Tia patients. Compared with non-PLND, any level of PLND improved OS in T1 but not in Ta or Tis patients. Compared to limited (1–9 lymph nodes examined) and non-PLND, extensive PLND (lymph nodes examined ≥10) resulted in better OS only in T1 patients (all p < 0.001, adjusted significance level = 0.017). PLND was identified as a independent protective factor for OS.ConclusionBased on the SEER database, we found that PLND during RC led to better OS and extensive PLND was associated with better OS in T1 but not in Ta or Tis patients. The implementation of PLND was insufficient both in population proportions and scope.

Prognostic value of preoperative platelet-related parameters and plasma fibrinogen in patients with non-muscle invasive bladder cancer after transurethral resection of bladder tumor.

Aim: To investigate the prognostic value of preoperative mean platelet volume (MPV), MPV/lymphocyte ratio (MPVLR), MPV/platelet count ratio and plasma fibrinogen in patients with non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). Methods: A total of371 patients who underwent TURBT were enrolled. The main end points were disease-free survival (DFS) and overall survival (OS). Results: MPVLR, tumor size, tumor number and pathological grade were independent risk factors for postoperative DFS. Age and pathological grade were independent risk factors for postoperative OS. Conclusion: MPVLR is an independent risk factor for DFS in NMIBC patients andcould be used as a parameter to predict postoperative tumor recurrence in patients after TURBT.

Lymphocyte-to-Monocyte Ratio (LMR) During Induction Is a Better Predictor Than Preoperative LMR in Patients Receiving Intravesical Bacillus Calmette -Guerin for Non-Muscle-Invasive Bladder Cancer.

The prognostic value of the lymphocyte-to-monocyte ratio during induction (ILMR) remains unclear in non-muscle-invasive bladder cancer (NMIBC) patients receiving Bacillus Calmette-Guérin (BCG). We aimed to determine and compare the prognostic value of the ILMR, preoperative lymphocyte-to-monocyte ratio (PLMR) and their dynamic changes (PILMR). This study collected the data from NMIBC patients receiving BCG treatment in our institution. The prognostic value of the PLMR, ILMR and PILMR was analyzed by the Kaplan−Meier method and Cox proportional hazard regression models. The concordance index and receiver operating characteristic curve analysis were employed to compare the prognostic value of these three factors. Our study enrolled 197 patients. These patients included 170 male patients, and the mean age was 64.17 years. During the follow-up time, 85 patients experienced recurrence, and 55 patients experienced progression. According to the results of COX multivariable analysis, PLMR (P=0.011) and ILMR (P<0.001) could independently predict the recurrence of NMIBC patients receiving BCG. Meanwhile, ILMR (P=0.001) and PILMR (P=0.036) were also the independent prognostic factors of progression. Compared with PLMR and PILMR, ILMR was associated with better accuracy for NMIBC patients receiving BCG. This study first found that the ILMR could independently predict the prognosis of NMIBC patients receiving BCG. Furthermore, we also identified that ILMR was associated with higher prognostic value than PLMR and PILMR, which might help to select an optimal treatment schedule for patients with NMIBC.

Prediction of the postoperative prognosis in patients with non-muscle-invasive bladder cancer based on preoperative serum surface-enhanced Raman spectroscopy

Non-muscle-invasive bladder cancer (NMIBC) is a common urinary tumor and has a high recurrence rate due to improper or inadequate conservative treatment. The early and accurate prediction of its recurrence can be helpful to implement timely and rational treatment. In this study, we explored a preoperative serum surface-enhanced Raman spectroscopy based prognostic protocol to predict the postoperative prognosis for NMIBC patients at the time even before treatment. The biochemical analysis results suggested that biomolecules related to DNA/RNA, protein substances, trehalose and collagen are expected to be potential prognostic markers, which further compared with several routine clinically used immunohistochemistry expressions with prognostic values. In addition, high prognostic accuracies of 87.01% and 89.47% were achieved by using the proposed prognostic models to predict the future postoperative recurrence and recurrent type, respectively. Therefore, we believe that the proposed method has great potential in the early and accurate prediction of postoperative prognosis in patients with NMIBC, which is with important clinical significance to guide the treatment and further improve the recurrence rate and survival time.

The Prognostic Value of the Circulating Tumor Cell-Based Four mRNA Scoring System: A New Non-Invasive Setting for the Management of Bladder Cancer.

Simple SummaryBladder cancer with similar diagnosis based on traditional classification exhibits different behaviors and therapeutic outcomes. Thus, circulating tumor cells (CTCs) represent a more accurate approach to investigate bladder cancer features. Our results demonstrate that risk score based on EGFR, TRPM4, TWIST1, and ZEB1 four-gene signature in CTCs is markedly and undoubtedly associated with recurrence, suggesting an innovative and non-invasive strategy to manage both non muscle invasive and muscle invasive bladder cancer progression without the necessity of repetitive and onerous cystoscopies.Bladder cancer (BC) is one of the most expensive lifetime cancers to treat because of the high recurrence rate, repeated surgeries, and long-term cystoscopy monitoring and treatment. The lack of an accurate classification system predicting the risk of recurrence or progression leads to the search for new biomarkers and strategies. Our pilot study aimed to identify a prognostic gene signature in circulating tumor cells (CTCs) isolated by ScreenCell devices from muscle invasive and non-muscle invasive BC patients. Through the PubMed database and Cancer Genome Atlas dataset, a panel of 15 genes modulated in BC with respect to normal tissues was selected. Their expression was evaluated in CTCs and thanks to the univariate and multivariate Cox regression analysis, EGFR, TRPM4, TWIST1, and ZEB1 were recognized as prognostic biomarkers. Thereafter, by using the risk score model, we demonstrated that this 4-gene signature significantly grouped patients into high- and low-risk in terms of recurrence free survival (HR = 2.704, 95% CI = 1.010–7.313, Log-rank p < 0.050). Overall, we identified a new prognostic signature that directly impacted the prediction of recurrence, improving the choice of the best treatment for BC patients.

Abstract 517: Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence

Abstract INTRODUCTION AND OBJECTIVE: High recurrence rates found in non-muscle invasive bladder cancer (NMIBC) pose a financial and psychological burden for patients. We demonstrated that bladder cancer (BC) cells release protein disulfide isomerase (PDI), a redox-regulated ER-resident protein, via extracellular vesicles (EVs) when experiencing high levels of ER stress for their own survival. Chronic exposure to PDI-enriched BC EVs induced malignant transformation in recipient non-transformed cells. We hypothesized that the dynamic redox state in BC cells determines PDI cellular localization and tumors with elevated PDI preferentially incorporate PDI into EVs for removal. Furthermore, PDI expression levels and subcellular localization in tumors from NMIBC patients may predict NMIBC recurrence. METHODS: Retrospective chart review identified 122 patients with newly diagnosed low-grade NMIBC classified into 2 groups: recurrent (N=55) and non-recurrent (N=67) during follow-up period. Formalin fixed paraffin embedded tumor specimens from index transurethral resection of bladder tumor (TURBT) were obtained and a tissue microarray (TMA) was constructed. Immunofluorescent staining of TMA sections was conducted using antibodies against PDI and BiP, an ER stress marker. Stained tissues were photographed and tumor regions in each field were manually masked and confirmed by a genitourinary pathologist. Within each tumor region, total antibody labeling was determined by measuring the mean pixel intensity values with NIH ImageJ/Fiji. Manders coefficient was used to assess the colocalization of epitopes using JACoP plugin in ImageJ. RESULTS: Tumor tissues from patients that recurred expressed significantly higher levels of PDI and BiP. Moreover, high PDI and BiP expression predicted worse recurrence-free survival. These data suggest that tissues under higher levels of ER stress—as indicated by higher levels of PDI and BiP expression—have a higher risk of recurrence. Significantly higher levels of PDI were detected in non-ER cytosol in recurrent cohort tumors. CONCLUSIONS: This study provides a novel mechanism for BC recurrence and valuable clinical predictive biomarkers for NMIBC recurrence and progression. Future clinical applications targeting this pathway may be an avenue to prevent NMIBC recurrence. Citation Format: Kit L. Yuen, Chia-Hao Wu, Christopher R. Silvers, Alexis R. Steinmetz, Hiroshi Miyamoto, Edward M. Messing, Yi-Fen Lee. Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 517.

Abstract 5831: Urinary exosome analysis as a marker of treatment response in bladder cancer patients

Abstract Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, BCG treatment failure will lead to recurrence and tumor progression. In this study, urinary exosomes content (miRNA profile) was evaluated as a possible marker of BCG treatment response in NMIBC patients. Methods: Urine samples from patients with bladder cancer were collected at the time of surgery and during patient follow up to 1 year. Urine from healthy volunteers were also included. Clinical and pathological information such as tumor grade (High Grade (HG), Low Grade (LG)), depth of invasion (Ta, T1, CIS), and response to BCG treatment was also obtained. Exosome Isolation and total RNA extraction including microRNAs from cell-free urine after centrifugation were obtained. Library preparation for miRNA expression was done (QIAseq® miRNA Library) for Next-Generation Sequencing (NGS) analysis in a NextSeq 2000 single read platform, 75 bp with 15-20 million reads per sample. Reads were then queried against miRDeep2 software for identification. Only miRNAs having at least 20 counts considering all samples were included. After normalization, significantly and deferentially expressed microRNAs (&amp;gt;2-Fold) were selected for analysis. Bioinformatic analysis including sequence alignment was performed under the STAR-based approach. Identified microRNAs were then used to classify/predict the response to treatment and its relationship with other clinicopathologic variables. Results: A total of 56 urine samples from 13 patients were available/used for analysis including 10 High Grade Ta and 3 High Grade T1 patients. Urine from normal healthy donors (N=3) was also included. Clinicopathological features were patients with HGTa=10, HGT1=3 and 3 control samples. Regarding treatment response 9 patients were BCG responders and 4 BCG unresponsive. When compared to BCG unresponsive patients, BCG responders showed 45 differentially expressed miRNAs. Statistically significant differentially expressed miRNAs (Fold-change &amp;gt;2, p value &amp;lt;0.05) were 12 miRNAs, upregulated were miR132-3p (p=0.042); miR-187-3p (p=0.021); miR-409-3p (p=0.043) and miR1301-3p (p=0.048). Downregulated miRNAs were miR-let7-5p (p=0.007), miR-3605-3p (p=0.047), miR-140-5p (p=0.031), miR-500a-5p (p=0.051), miR-629-5p (p=0.039), miR-454-3p (p=0.05), miR-2110 (p=0.049) and miR-30c-5p (p=0.03). Interestingly, miRPathDABv2.0 analysis predicted those microRNAs be related to cancer, including bladder cancer. They showed targeting important pathways as PI3K.Akt, Wnt/B catenin and P53 signaling related with disease progression and treatment response. Conclusion: Our study supports the value of urinary exosomal microRNAs as non-invasive biomarkers to predict BCG treatment response in nonmuscle-invasive bladder cancer. Citation Format: Vladimir Valera, Beatriz Walter, Maria J. Merino. Urinary exosome analysis as a marker of treatment response in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5831.

La dosis única de instilación intravesical postoperatoria inmediata de quimioterapia no es superior al lavado continuo con suero

Introduction and objectivesTo evaluate whether there is any difference between immediate postoperative instillation of intravesical chemotherapy (IPOIC) and continuous saline bladder irrigation(CSBI) in terms of bladder cancer(BC) recurrence in patients with primary low- or intermediate-risk non-muscle-invasive BC (NMIBC). Materials and methodsMedical records of 1482 patients who underwent transurethral resection of bladder tumor between March 1994 and August 2020 were reviewed retrospectively. Patients were divided into two groups according to IPOIC and/or CSBI administration status (Group 1: CSBI alone; Group 2: CSBI following IPOIC). Low- and intermediate-risk NMIBC patients were also divided into subgroups according to IPOIC and/or CSBI administration status. ResultsA total of 594 patients with primary NMIBC were included. Of the patients, 86 (14.5%) were female and 508 (85.5%) were male with a median age of 69 (60-78) years. The frequency of patients in group 1 and group 2 were 361 (60.8%) and 233 (39.2%), respectively. Recurrent disease was observed in 213 (35.9%) patients. There was no difference between the groups when they were compared for recurrent disease frequency, median time to first recurrence and frequency of recurrence within first 12 months (P=.064, P=.671, and P=.145, respectively). Disease recurrence rates in low-risk NMIBC patients was lower when they were treated with “CSBI following IPOIC” when compared to “CSBI alone” (P=.042). However, no difference was observed in low-risk NMIBC subgroups when they were compared for pathological features of recurrent tumors such as number, size, grade, stage, and presence of carcinoma in situ (P>.05, for each). Conclusions“CSBI following IPOIC” combination was not superior to “CSBI alone” for preventing adverse pathological outcomes in recurrent low- and intermediate-risk NMIBC.

A Robust Immuno-Prognostic Model of Non-Muscle-Invasive Bladder Cancer Indicates Dynamic Interaction in Tumor Immune Microenvironment Contributes to Cancer Progression.

Non-muscle-invasive bladder cancer (NMIBC) accounts for more than 70% of urothelial cancer. More than half of NMIBC patients experience recurrence, progression, or metastasis, which essentially reduces life quality and survival time. Identifying the high-risk patients prone to progression remains the primary concern of risk management of NMIBC. In this study, we included 1370 NMIBC transcripts data from nine public datasets, identified nine tumor-infiltrating marker cells highly related to the survival of NMIBC, quantified the cells’ proportion by self-defined differentially expressed signature genes, and established a robust immuno-prognostic model dividing NMIBC patients into low-risk versus high-risk progression groups. Our model implies that the loss of crosstalk between tumor cells and adjacent normal epithelium, along with enriched cell proliferation signals, may facilitate tumor progression. Thus, evaluating tumor progression should consider various components in the tumor immune microenvironment instead of the single marker in a single dimension. Moreover, we also appeal to the necessity of using appropriate meta-analysis methods to integrate the evidence from multiple sources in the feature selection step from large-scale heterogeneous omics data such as our study.