Prognosis Of Non-muscle Invasive Bladder Cancer Research Articles

Comparison of thulium and holmium lasers with conventional transurethral bladder resection for non-muscle invasive bladder cancer

Introduction. The gold standard of treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) is transurethral resection of the bladder (TURB) in combination with intravesical therapy. However, this procedure may cause serious complications. At the same time, studies of various lasers for the treatment of NMIBC have demonstrated their safety and efficacy. Despite this, the topic has not yet been fully explored and is not widely practiced in clinical oncology, making further research necessary.Objective. To compare thulium and holmium lasers with conventional TURB for management of non-muscle-invasive bladder cancer (NMIBC).Materials & methods. In our study, depending on the treatment approach, 84 NMIBC-patients were divided into three groups. Group 1 included 27 patients (34.14%), who underwent laser thulium bladder resection; group 2 included 25 patients (29.76%), who underwent laser holmium bladder resection, and group 3 included 32 patients (38.1%), who underwent standard TURB. Prior to surgery, all patients received a standard set of preoperative general clinical and instrumental examinations for bladder cancer, and the choice of surgical approach was based on informed patient consent, taking into account the benefits and risks of the three treatment options. All surgeries were performed in accordance with established protocols.Results. In the TURB group, the surgery time was the longest and totalled in 20.5 ± 7.4 min. Laser technologies reduce the surgery time to 16.3 ± 5.3 min for a holmium laser and to 14.7 ± 5.2 min for a thulium laser. Also, in groups 1 and 2, a shorter duration of postoperative bladder irrigation was noted (4.4 ± 1.8 and 4.7 ± 1.6 hours) and shorter periods of postoperative bladder catheterisation (1.5 ± 0.08 and 1.6 ± 0.08 days) compared to group 3, where these indicators were 16.4 ± 2.5 hours and 2.5 ± 0.13 days, respectively. Among patients undergoing either holmium or thulium surgery, a higher rate of disease-free survival has been noted. Independent prognostic factors that influence the prognosis of NMIBC in all groups include the type of surgery, history of bladder tumors, and pathological stage.Conclusion. The use of laser technology, such as thulium and holmium laser, in bladder wall resection for NMIBC shows promising results and provides a good clinical outcome that is comparable to (and in some cases, superior to) standard TURB.

Comparison of thulium and holmium lasers with conventional transurethral bladder resection for non-muscle invasive bladder cancer

Introduction. The gold standard of treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) is transurethral resection of the bladder (TURB) in combination with intravesical therapy. However, this procedure may cause serious complications. At the same time, studies of various lasers for the treatment of NMIBC have demonstrated their safety and efficacy. Despite this, the topic has not yet been fully explored and is not widely practiced in clinical oncology, making further research necessary.Objective. To compare thulium and holmium lasers with conventional TURB for management of non-muscle-invasive bladder cancer (NMIBC).Materials & methods. In our study, depending on the treatment approach, 84 NMIBC-patients were divided into three groups. Group 1 included 27 patients (34.14%), who underwent laser thulium bladder resection; group 2 included 25 patients (29.76%), who underwent laser holmium bladder resection, and group 3 included 32 patients (38.1%), who underwent standard TURB. Prior to surgery, all patients received a standard set of preoperative general clinical and instrumental examinations for bladder cancer, and the choice of surgical approach was based on informed patient consent, taking into account the benefits and risks of the three treatment options. All surgeries were performed in accordance with established protocols.Results. In the TURB group, the surgery time was the longest and totalled in 20.5 ± 7.4 min. Laser technologies reduce the surgery time to 16.3 ± 5.3 min for a holmium laser and to 14.7 ± 5.2 min for a thulium laser. Also, in groups 1 and 2, a shorter duration of postoperative bladder irrigation was noted (4.4 ± 1.8 and 4.7 ± 1.6 hours) and shorter periods of postoperative bladder catheterisation (1.5 ± 0.08 and 1.6 ± 0.08 days) compared to group 3, where these indicators were 16.4 ± 2.5 hours and 2.5 ± 0.13 days, respectively. Among patients undergoing either holmium or thulium surgery, a higher rate of disease-free survival has been noted. Independent prognostic factors that influence the prognosis of NMIBC in all groups include the type of surgery, history of bladder tumors, and pathological stage.Conclusion. The use of laser technology, such as thulium and holmium laser, in bladder wall resection for NMIBC shows promising results and provides a good clinical outcome that is comparable to (and in some cases, superior to) standard TURB.

Modifying Effects of Genetic Variations on the Association Between Dietary Isothiocyanate Exposure and Non-muscle Invasive Bladder Cancer Prognosis in the Be-Well Study.

Dietary isothiocyanate (ITC) exposure from cruciferous vegetable (CV) intake may improve non-muscle invasive bladder cancer (NMIBC) prognosis. This study aims to investigate whether genetic variations in key ITC-metabolizing/functioning genes modify the associations between dietary ITC exposure and NMIBC prognosis outcomes. In the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study), a prospective cohort of 1472 incident NMIBC patients, dietary ITC exposure is assessed by self-reported CV intake and measured in plasma ITC-albumin adducts. Using Cox proportional hazards regression models, stratified by single nucleotide polymorphisms (SNPs) in nine key ITC-metabolizing/functioning genes, it is calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression. The rs15561 in N-acetyltransferase 1 (NAT1) is alter the association between CV intake and progression risk. Multiple SNPs in nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappa B (NFκB) are modify the associations between plasma ITC-albumin adduct level and progression risk (pint < 0.05). No significant association is observed with recurrence risk. Overall, >80% study participants are present with at least one protective genotype per gene, showing an average 65% reduction in progression risk with high dietary ITC exposure. Despite that genetic variations in ITC-metabolizing/functioning genes may modify the effect of dietary ITCs on NMIBC prognosis, dietary recommendation of CV consumption may help improve NMIBC survivorship.

Recurrent Bacteriuria as a Prognosis Marker in the Adjuvant Treatment of Non-Muscle Invasive Bladder Cancer

PurposeBacteriuria may affect the response to adjuvant therapy in non-muscle invasive bladder cancer (NMIBC). The main aim of this study was to examine the effect of recurrent bacteriuria (RB) on the prognosis of NMIBC in women receiving intravesical therapy. Materials and MethodsWe designed a prospective observational study from 2012 to 2019. We included women with bladder cancer treated with transurethral resection of the bladder (TURB) and adjuvant intravesical treatment. Significant bacteriuria was defined as a presence in urine cultures at or above 100,000 colony-forming units per millilitre. The recurrent bacteriuria group included patients with significant bacteriuria in at least two determinations in 6 months or in 3 or more determinations in a year. The institutional board approved the study. ResultsOne hundred thirty-six patients diagnosed with NMIBC participate in the study, of whom 100 met the inclusion criteria. During follow-up, 48 were categorized in the RB group and 52 formed the non-bacteriuria group (NB). RB Group Had a Better OutcomeEight patients (16.67%) experiencing a recurrence of the same grade, with no progression to a higher-grade tumor or muscle-invasive tumor. In the NB group, 18 (34.6%) patients presented a recurrence (P = .001) and 22 (42.3%) progressed to a higher-grade tumor or muscular invasion (P = .001). The presence of RB was identified as a predictor of good response in multivariate regression with a relative risk of 0.13 (P = .018) ConclusionsFemale patients with RB had a better response to adjuvant treatment for NMIBC. The RB group showed lower rates of tumor recurrences and progression.

Effect of regional versus general anesthesia on recurrence of non-muscle invasive bladder cancer: a systematic review and meta-analysis of eight retrospective cohort studies

BackgroundRegional anesthesia appears to reduce cancer recurrence, but the optimal anesthesia modality for non-muscle invasive bladder cancer (NMIBC) were still under debate. Therefore, we sought to assess the effect of regional and GA only upon the recurrence and long-term prognosis of NMIBC through this meta-analysis.MethodsWe performed an extensive literature search of PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (up to October 30, 2022) to identify eligible articles on the possible impact of different anesthetic modalities for the recurrence rate of NMIBC.ResultsEight studies comprising 3764 participants, including 2117 subjects with RA and 1647 with GA, were finally enrolled. Cancer recurrence rate was significantly lower in subjects with RA than those with GA (RR 0.84, 95%CI 0.72–0.98, P = 0.03). We didn’t detect the differences between GA and RA in the time of recurrence (SMD 2.07, 95% CI -0.49–4.63, P = 0.11) and cancer progression (RR 1.14, 95%CI 0.71–1.84, P = 0.59). Results from subgroup analysis demonstrated that spinal anesthesia could significantly decrease the incidence of cancer recurrence in comparison with general anesthesia (RR 0.80, 95%CI 0.72–0.88, P < 0.001) and high-risk NMIBC patients who received RA tended to have less recurrence (HR 0.55, 95%CI 0.39–0.79, P = 0.001) than those receiving GA.ConclusionsRA, especially spinal anesthesia, may be effective in reducing the recurrence rate after transurethral resection of NMIBC. More prospective experimental and clinical studies are needed to validate our findings.Trial registrationINPLASY registration INPLASY2022110097.

A Pilot Intervention Designed to Increase Cruciferous Vegetable Intake to Reduce Bladder Cancer Recurrence and Progression

Study Purpose: Bladder cancer is one of the top 10 most common cancers in the US and is the most expensive cancer to treat. The majority of bladder cancers (70–80%) are diagnosed at early stages as non-muscle invasive bladder cancer (NMIBC), which can be removed surgically. However, 50–80% of NMIBC recurs within 5 years, and 15–30% progresses with poor survival. Current treatment is limited. Preclinical and epidemiologic evidence suggests that dietary isothiocyanates (ITCs) in cruciferous vegetables could be a non-invasive and cost-effective strategy to improve NMIBC prognosis. Thus, the purpose of our study was to develop and pilot test a cruciferous vegetable intervention designed to increase ITC exposure in NMIBC survivors. Methods: We used a blinded 2-arm randomized controlled trial (RCT) to test the preliminary efficacy of a 6-month cruciferous vegetable intervention for NMIBC survivors. The intervention consisted of mailed materials, a live phone-call to review the materials, and 11 Interactive Voice Responses calls. Three-day urine samples, 3-day dietary recalls, and survey data were collected at baseline and 6-months. Two-sided Wilcoxon rank-sum tests were used for between-group comparisons. Results: Forty-nine NMIBC patients diagnosed in 2018–2019 were randomized and 42 (22 treatment, 20 control) were retained for 6-month follow-up. Participants were mostly male (71.4%) and White (90.5%), with an average age of 67.4 years. Compared to the control, the treatment group reported 35.0 g (95% CI: −14.9, 85.0; P = 0.014) higher Cruciferae intake (treatment = 58.6 ± 54.5 g vs. control = 23.6 ± 96.1g) and increased urinary ITC levels by 11.1 μmol/g creatinine (treatment = 14.2 ± 24.5 vs. control = 3.1 ± 13.9, P = 0.027) at 6-month follow-up. Conclusion: Our behavioral cruciferous vegetable intervention is the first to significantly increase cruciferous vegetable intake and ITC levels in NMIBC survivors. Our evidence-based dietary intervention has the potential to offer an affordable, scalable option for NMIBC survivors to reduce their risk of recurrence and improve outcomes.

Associations of dietary isothiocyanate exposure from cruciferous vegetable consumption with recurrence and progression of non–muscle-invasive bladder cancer: findings from the Be-Well Study

BackgroundHigh recurrence and progression rates are major clinical challenges for non–muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. ObjectivesThis study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. MethodsThe study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015–2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC–albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. ResultsOver a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC–albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). ConclusionsOur findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

PD13-06 UTILITY OF A MOLECULAR SIGNATURE FOR PREDICTING RECURRENCE AND PROGRESSION IN NON-MUSCLE-INVASIVE BLADDER CANCER PATIENTS: COMPARISON WITH THE EORTC, CUETO AND 2021 EAU RISK GROUPS

You have accessJournal of UrologyCME1 Apr 2023PD13-06 UTILITY OF A MOLECULAR SIGNATURE FOR PREDICTING RECURRENCE AND PROGRESSION IN NON-MUSCLE-INVASIVE BLADDER CANCER PATIENTS: COMPARISON WITH THE EORTC, CUETO AND 2021 EAU RISK GROUPS Xuan-Mei Piao, Yun-Sok Ha, Jae Hoon Kang, Seon-Kyu Kim, Seong-Hwan Park, Kyungchan Min, Hansoo Park, Kyeong Kim, Ho Won Kang, Sun Jin Song, Won Tae Kim, and Seok Joong Yun Xuan-Mei PiaoXuan-Mei Piao More articles by this author , Yun-Sok HaYun-Sok Ha More articles by this author , Jae Hoon KangJae Hoon Kang More articles by this author , Seon-Kyu KimSeon-Kyu Kim More articles by this author , Seong-Hwan ParkSeong-Hwan Park More articles by this author , Kyungchan MinKyungchan Min More articles by this author , Hansoo ParkHansoo Park More articles by this author , Kyeong KimKyeong Kim More articles by this author , Ho Won KangHo Won Kang More articles by this author , Sun Jin SongSun Jin Song More articles by this author , Won Tae KimWon Tae Kim More articles by this author , and Seok Joong YunSeok Joong Yun More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003260.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The utility of the clinicopathological risk estimators such as European Organization for Research and Treatment of Cancer (EORTC), Spanish Urology Association for Oncological Treatment (CUETO) models and EAU risk groups for predicting prognosis of non-muscle-invasive bladder cancer (NMIBC) is controversial. The aim of this study was to compare the utility of a molecular signature-based subtype predictor (MSP888) with the EORTC, CUETO risk tables and 2021 EAU risk groups in NMIBC patients. METHODS: A total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the MSP888, EORTC, CUETO and 2021 EAU risk scores was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing for transcriptomic profiling, and their MSP888 subtype was evaluated according to previously developed molecular classifiers. The ability of the EORTC score, MSP888, Lund and UROMOL molecular subtypes to predict progression of 460 NMIBC patients from the UROMOL project was assessed. RESULTS: Cox regression analyses showed that the MSP888 subtype was an independent predictor of NMIBC progression in the CBNUH cohort (p<0.05). Particularly in patients not treated with BCG, MSP888 significantly linked with risk of disease recurrence and progression (both p<0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis in the CBNUH cohort. The MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict progression of NMIBC patients in the UROMOL cohort (all p<0.05). CONCLUSIONS: The molecular clustering predictor MSP888 is favorable for stratifying NMIBC patients to facilitate optimal treatment. Source of Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (grant numbers- 2020R1I1A3062508 and 2021R1I1A1A01050891); and NRF funded by the Ministry of Science and ICT (MIST) (grant number- 2020R1F1A1068488); and NRF funded by the Korean government (grant numbers- 2014M3C9A306855425, 2021M3H9A209695312, and 2022R1A2C200848011); and by a grant from the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (grant number- KGM5192221); and by a grant of the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e407 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Xuan-Mei Piao More articles by this author Yun-Sok Ha More articles by this author Jae Hoon Kang More articles by this author Seon-Kyu Kim More articles by this author Seong-Hwan Park More articles by this author Kyungchan Min More articles by this author Hansoo Park More articles by this author Kyeong Kim More articles by this author Ho Won Kang More articles by this author Sun Jin Song More articles by this author Won Tae Kim More articles by this author Seok Joong Yun More articles by this author Expand All Advertisement PDF downloadLoading ...

Utility of a Molecular Signature for Predicting Recurrence and Progression in Non-Muscle-Invasive Bladder Cancer Patients: Comparison with the EORTC, CUETO and 2021 EAU Risk Groups.

To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p &lt; 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p &lt; 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment.

Modified immunoscore improves the prediction of progression-free survival in patients with non-muscle-invasive bladder cancer: A digital pathology study.

Tumour-infiltrating lymphocytes (TIL), known to be of prognostic value in various solid tumours, have been in the focus of research in the last years. TIL are often quantified via IMMUNOSCORE ® (IS), a scoring system based on TIL cell densities. Recent studies were able to replicate these findings for muscle-invasive bladder cancer (MIBC), however data regarding non-muscle-invasive bladder cancer (NMIBC) are scarce. This study aimed to evaluate the value of a modified Immunoscore (mIS) as a predictive marker for NMIBC prognosis using tissue-micro-arrays (TMAs). We analysed two TMAs containing 316 samples from 158 patients with NMIBC, stained for CD3, CD8, CD45RO and FOXP3. Stained TIL were captured by digital pathology, cumulated, averaged, and reported as density (stained cells per mm²). The mIS was then constructed based on density of all four immune-cell types. Clinical, pathological and follow-up data were collected retrospectively. Univariable and multivariable cox regression analysis was performed to assess the potential value of mIS as a predictor for progression free survival (PFS) and recurrence-free-survival (RFS). Patients within “European Organisation for Research and Treatment of Cancer” (EORTC) risk groups were further substratified in high mIS and low mIS subgroups. Finally log-rank test was used to compare the different survival curves. The median age in our cohort was 68 years (Interquartile Range (IQR): 60 - 76), and 117 (74%) patients were male. A total of 26 patients (16.5%) were classified as EORTC low risk, 45 (28.5%) as intermediate risk and 87 (55.1%) as high risk. Patients in the EORTC high risk group with low mIS showed a shorter PFS in comparison to high mIS (HR 2.9, CI 0.79 – 11.0, p=0.082). In contrast, no predictive potential regarding PFS was observed in intermediate or low risk groups. Furthermore, mIS was not able to predict RFS in any EORTC risk group. mIS could be utilized to predict prognosis more accurately in high-risk patients with NMIBC by identifying those with higher or lower risk of progression. Therefore, mIS could be used to allocate these highrisk patients to more streamlined follow-up or more aggressive treatment strategies.

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.

Prognostic Value of BUB1 for Predicting Non-Muscle-Invasive Bladder Cancer Progression.

Non-muscle-invasive bladder cancer (NMIBC) is a common disease with a high recurrence rate requiring lifetime surveillance. Although NMIBC is not life-threatening, it can progress to muscle-invasive bladder cancer (MIBC), a lethal form of the disease. The management of the two diseases differs, and patients with MIBC require aggressive treatments such as chemotherapy and radical cystectomy. NMIBC patients at a high risk of progression benefit from early immediate cystectomy. Thus, identifying concordant markers for accurate risk stratification is critical to predict the prognosis of NMIBC. Candidate genetic biomarkers associated with NMIBC prognosis were screened by RNA-sequencing of 24 tissue samples, including 16 NMIBC and eight normal controls, and by microarray analysis (GSE13507). Lastly, we selected and investigated a mitotic checkpoint serine/threonine kinase, BUB1, that regulates chromosome segregation during the cell cycle. BUB1 gene expression was tested in 86 NMIBC samples and 15 controls by real-time qPCR. The performance of BUB1 as a prognostic biomarker for NMIBC was validated in the internal Chungbuk cohort (GSE13507) and the external UROMOL cohort (E-MTAB-4321). BUB1 expression was higher in NMIBC patients than in normal controls (p < 0.05), and the overexpression of BUB1 was correlated with NMIBC progression (log-rank test, p = 0.007). In in vitro analyses, BUB1 promoted the proliferation of bladder cancer cells by accelerating the G2/M transition of the cell cycle. Conclusively, BUB1 modulates the G2/M transition to promote the proliferation of bladder cancer cells, suggesting that it could serve as a prognostic marker in NMIBC.

The diagnostic applicability of A-type Lamin in non-muscle invasive bladder cancer

PurposeLamin A is a major component of the nuclear lamina maintaining nuclear integrity, regulation of gene expression, cell proliferation, and apoptosis. Its deregulation in cancer has been recently reported to be associated with its prognosis. However, its clinical significance in non-muscle invasive bladder cancer (NMIBC) remains to be defined. Material/methodsImmunohistochemical staining and RT-qPCR were performed to screen the expression patterns of Lamin A/C protein and Lamin A mRNA respectively in 58 high and low grade NMIBC specimens. ResultsLamin A/C protein was expressed only in the nucleus and less exhibited in NMIBC tissues compared to non-tumoral ones. On the other side, Lamin A mRNA was up-regulated in NMIBC compared to controls. Nevertheless, both expression patterns (protein and mRNA) were not correlated to clinical prognosis factors and were not able to predict the overall survival of patients with high-grade NMIBC. ConclusionsThe deregulation of A-type Lamin is not associated with the prognosis of NMIBC, but it could serve as a diagnostic biomarker distinguishing NMIBC patients from healthy subjects suggesting its involvement as an initiator event of tumorigenesis in our cohort.

Genome-wide Meta-analysis Identifies Novel Genes Associated with Recurrence and Progression in Non–muscle-invasive Bladder Cancer

BackgroundNon–muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed. ObjectiveTo identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC. Design, setting, and participantsWe analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation. Outcome measurements and statistical analysisCohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort. Results and limitationsThis meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33–1.82, p = 4.0 × 10–8), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59–0.84, pFDR = 0.003). Twelve other loci were suggestively associated with RFS (p < 10–5), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature. ConclusionsIn this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression. Patient summaryIn this study, we searched for inherited DNA changes that affect the outcome of non–muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.

RNA-seq analysis of non-muscular invasive bladder cancer to reveal different gene expression profiles between smoking and non-smoking patients.

478 Background: Bladder cancer is the ninth most common malignancy in the world, approximately 75% of patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). Smoking has been established to be a carcinogenic risk factor of bladder cancer. Nevertheless, the detailed relationship between smoking and progression of NMIBC are poorly understood. In this study, we revealed high expressed genes in smoking patients were significantly related to tumor progression in NMIBC patients. Methods: A total of 54 NMIBC patients including 19 never smokers and 35 smokers (current smokers and previous smokers) were enrolled in this study.The gene expression profiles were obtained by RNA-seq and the differentially expressed genes between smoking and non-smoking patients were identified using DESeq2 .The further analysis of the association between genes expression and patient survival in NMIBC cohorts(Jakob et al., 2016)and IMvigor 210 cohorts(Jonathan et al., 2016)by Kaplan-Meier survival estimate. Results: We identified 46 differentially expressed genes (p&lt;0.05) in smoking and non-somking NMIBC patients. IDO1 and KRT14 gene, which related to bladder cancer progression and poor prognosis, was identified significantly higher expressed in somking group compared with non-smoking and they have a logFC of 2.6,3.9 with FDR 1.83E-5,3.40E-5 respectively. The expression of other genes, including KRT6A, CASP14, SERPINA1, MYO3A and IL20RB, were significantly higher in smoking patients compared to non-somking. Notably, survival data analysis from 476 NMIBC cohorts showed that IL20RB had a significant relationship with poor PFS(p = 0.021) and in the Mvigor 210 Cohort including 310 advanced or metastatic urothelial carcinoma patients treated with atezolizumab, we found that the high expression of IL20RB was significantly related to poor OS(p = 0.002). Conclusions: We identified 14 genes related to tumor progression were significantly higher in smoking NMIBC patients than in non-smoking. Among these genes, the expression of IL20RB was related to the poor prognosis of NMIBC, and it may correlates with reduced clinical benefit of immunotherapeutic in patients with urothelial carcinoma.

A Molecular Signature Determines the Prognostic and Therapeutic Subtype of Non-Muscle-Invasive Bladder Cancer Responsive to Intravesical Bacillus Calmette-Guérin Therapy.

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each p = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools.

Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer

BackgroundIntermediate-risk non–muscle-invasive bladder cancer (NMIBC) involves heterogeneous patients, resulting in uncertainty regarding its prognosis and the indication of adjuvant therapy. Previous studies suggested a correlation between tumor location, especially bladder neck involvement (BNI), and patient prognosis of NMIBC. ObjectiveWe investigated the role of BNI in risk substratification of intermediate-risk NMIBC patients. Design, setting, and participantsThis single-institutional study included 436 primary or recurrent intermediate-risk NMIBC patients based on risk stratification in the European Association of Urology guidelines. InterventionAll patients underwent transurethral resection of the bladder tumor. Outcome measurements and statistical analysisThe primary and secondary endpoints were progression and recurrence, respectively. The associations of BNI with the endpoints were examined using the Kaplan-Meier method and the Cox proportional hazards model. Results and limitationsOverall, 205 (47%) patients had multiple tumors and 276 (63%) underwent intravesical therapy. BNI was observed in 53 (12%) patients. During the median follow-up of 42 mo, 12 (3%) and 211 (48%) patients experienced progression and recurrence, respectively. Multivariate analysis showed that BNI was an independent predictor for both progression (hazard ratio 10.98, p < 0.001) and recurrence (hazard ratio 2.12, p < 0.001). The progression rate was significantly higher in patients with BNI compared with those without BNI (13% vs 1% at 3 yr and 20% vs 1% at 6 yr; p < 0.001). Analogous findings were observed for recurrence. The progression rate was more remarkably stratified by BNI in 103 recurrent cases (17% vs 3% at 3 yr and 34% vs 3% at 6 yr in patients with vs without BNI; p < 0.001). A limitation of this study was its retrospective nature. ConclusionsBNI substratified intermediate-risk NMIBC patients well regarding their risks of progression and recurrence, which could help determine follow-up and therapeutic strategies for these patients. Patient summaryThe associations of bladder neck involvement with progression and recurrence were evaluated in patients with intermediate-risk non–muscle-invasive bladder cancer. We found that bladder neck involvement was a good factor for substratifying patients based on their risks of progression and recurrence. Bladder neck involvement can be useful in determining follow-up and therapeutic strategies for intermediate-risk non–muscle-invasive bladder cancer.

MicroRNA Dysregulation and Non-Muscle-Invasive Bladder Cancer Prognosis.

The high rate of non-muscle-invasive bladder cancer recurrence is a major challenge in patient management. miRNAs functionally regulate tumor cell proliferation and invasion, and have strong potential as biomarkers because they are robust to degradation. The objective of this project was to identify reproducible prognostic miRNAs in resected non-muscle-invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype. We utilized patients diagnosed with primary non-muscle-invasive bladder cancer in three independent cohorts for a biomarker discovery/validation approach. Baseline tumor tissue from patients with the clinically challenging, non-muscle-invasive primary low stage (Ta), high grade, and T1 tumors (tumors extending into the lamina propria) comprised the discovery cohort (n = 38). We isolated the tumor tissue RNA and assessed a panel of approximately 800 miRNAs. miR-26b-5p was the top-ranking prognostic tumor tissue miRNA, with a time-to-recurrence HR 0.043 for levels above versus below median, (P adj = 0.0003). miR-26b-5p was related to a dose-response reduction in tumor recurrence, and levels above the median were also associated with reduced time-to-progression (P adj = 0.02). We used two independent longitudinal cohorts that included both low-grade and high-grade Ta and T1 tumors for validation and found a consistent relationship between miR-26b-5p and recurrence and progression. Our results suggest that miR-26b-5p levels may be prognostic for non-muscle-invasive bladder cancer recurrence, and can feasibly be assessed in baseline tumor tissue from a wide variety of clinical settings. Early identification of those non-muscle-invasive bladder tumor patients with refractory phenotypes would enable individualized treatment and surveillance.

Unraveling UCA1 lncRNA prognostic utility in urothelial bladder cancer.

In the era of precision oncology, bladder cancer (BlCa) is characterized by generic patient management and lack of personalized prognosis and surveillance. Herein, we have studied the clinical significance of urothelial cancer associated 1 (UCA1) lncRNA in improving patients' risk stratification and prognosis. A screening cohort of 176 BlCa patients was used for UCA1 quantification. The Hedegaard et al. (n = 476) and The Cancer Genome Atlas (TCGA) provisional (n = 413) were analyzed as validation cohorts for non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), respectively. Patients' survival outcome was assessed using recurrence and progression for NMIBC or death for MIBC as clinical endpoint events. Bootstrap analysis was performed for internal validation of Cox regression analysis, whereas the clinical benefit of disease prognosis was assessed by decision curve analysis. UCA1 was significantly overexpressed in bladder tumors compared with normal urothelium, which was confirmed only in the case of NMIBC. Interestingly, reduced expression of UCA1 was correlated with muscle-invasive disease as well as with tumors of higher stage and grade. UCA1 loss was strongly associated with higher risk of short-term relapse [hazard ratio (HR) = 1.974; P = 0.032] and progression to invasive stages (HR = 3.476; P = 0.023) in NMIBC. In this regard, Hedegaard et al. and TCGA validation cohorts confirmed the unfavorable prognostic nature of UCA1 loss in BlCa. Finally, prognosis prediction models integrating UCA1 underexpression and established clinical disease markers contributed to improved stratification specificity and superior clinical benefit for NMIBC prognosis. Underexpression of UCA1 correlates with worse disease outcome in NMIBC and contributes to superior prediction of disease early relapse and progression as well as improved patient stratification specificity.

Abstract 4343: Molecular identification of bladder cancer gene expression subtypes

Abstract Bladder urothelial carcinoma (BLCA) comprises two main types: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). To discovery the subtype of BLCA, we used gene expression data from 165 patient cohort (102 NMIBC, 63 MIBC). Three other gene expression data sets including the Sweden 1 cohort (97 NMIBC, 45 MIBC), the Sweden 2 cohort (213 NMIBC, 93 MIBC), and 408 MIBC sample from The Cancer Genome Atlas (TCGA) and 476 sample (460 NMIBC, 16 MIBC, the multicenter European UROMOL consortium). For selection of subtype-specific gene set, we used significance analysis of microarrays (SAM). Then, subtype-specific genes were trained by prediction analysis for microarrays (PAM) to build a classifier. Clustering analyses were applied to gene expression data of training set identified four molecular subtypes with different clinical outcomes. The majority of patients with class 1 were the low-grade NMIBC and associated with the prognosis of NMIBC, for cancer-specific survival (P =0.003, log-rank test). Class 2 patients, characterized by FGFR3 overexpression and downregulated immune pathways, showed the intermediate prognosis. Class 3 tumors showed high expression of cell-cycle genes and downregulated notch signaling pathway. Furthermore, high-grade NMIBC were predominantly found in class 3, indicating that NMIBC patients classified as class 3 would be more likely to progress to MIBC. Class 4 tumors, mainly composed of MIBC, were characterized by high expression of immune-related genes which is positively associated with potential response to immunotherapy. We further validated the BLCA subtypes in four independent data sets (n = 1,471), including the RNA-seq data set, by applying the 786-gene classifier onto the data sets. As expected, the progression rate of NMIBC patients classified as class 3 was significantly increased compared with other three classes in the RNA-seq data set (P &amp;lt; 0.001, log-rank test). Citation Format: In-Sun Chu, Bic-Na Song, Sun-Hee Leem. Molecular identification of bladder cancer gene expression subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4343.