High-grade Urothelial Carcinoma Of Bladder Research Articles

Survival nomogram for high-grade bladder cancer patients after surgery based on the SEER database and external validation cohort.

The aim of this study was to develop a comprehensive and effective nomogram for predicting overall survival (OS) rates in postoperative patients with high-grade bladder urothelial carcinoma. Patients diagnosed with high-grade urothelial carcinoma of the bladder after radical cystectomy (RC) between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. We randomly split (7:3) these patients into the primary cohort and the internal validation cohort. Two hundred eighteen patients from the First Affiliated Hospital of Nanchang University were collected as the external validation cohort. Univariate and multivariate Cox regression analyses were carried out to seek prognostic factors of postoperative patients with high-grade bladder cancer (HGBC). According to these significant prognostic factors, a simple-to-use nomogram was established for predicting OS. Their performances were evaluated using the concordance index (C-index), the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study included 4,541 patients. Multivariate Cox regression analysis demonstrated that T stage, positive lymph nodes (PLNs), age, chemotherapy, regional lymph nodes examined (RLNE), and tumor size were correlated with OS. The C-index of the nomogram in the training cohort, internal validation cohort, and external validation cohort were 0.700, 0.717, and 0.681, respectively. In the training, internal validation, and external validation cohorts, the ROC curves showed that the 1-, 3-, and 5-year areas under the curve (AUCs) were higher than0.700, indicating that the nomogram had good reliability and accuracy. Theresults of calibration and DCA showed good concordance and clinical applicability. A nomogram was developed for the first time to predict personalized 1-, 3-, and 5-year OS in HGBC patients after RC. The internal and external validation confirmed the excellent discrimination and calibration ability of the nomogram. The nomogram can help clinicians design personalized treatment strategies and assist with clinical decisions.

UBC®Rapid Is Sensitive in Detecting High-Grade Bladder Urothelial Carcinoma and Carcinoma in situ in Asian Population

Objectives: Bladder cancer is a common type of malignancy. UBC®Rapid is a novel immunoassay detecting urine cytokeratin 8/18 protein. Studies have shown good accuracy of UBC®Rapid in detecting bladder cancer. UBC®Rapid has however to date not been evaluated in Asian patients. We evaluated UBC®Rapid in detecting Asian bladder cancer, together with urine cytology. Methods: In total, 112 patients were recruited from National University Hospital Singapore and 103 patients were included in this study, comprising 49 patients with bladder urothelial carcinoma (UC), 21 patients with bladder benign lesions, and 33 patients with normal bladder. All the bladder cancer and benign lesions were confirmed by histology. Voided urine was collected for UBC®Rapid test. The results were compared with urine cytology. Results: The bladder UC group had remarkably higher UBC®Rapid value than the control groups. The sensitivity, specificity, positive, and negative predictive value of UBC®Rapid in detecting bladder UC were 53%, 85.5%, 76.5%, and 66.8%, respectively. Those of urine cytology were 40.8%, 96.3%, 90.9%, and 64.2%, respectively. Adding UBC®Rapid to urine cytology increased sensitivity to 57.1% but decreased specificity to 81.8%. UBC®Rapid was sensitive in detecting high-grade bladder UC (61.1%) and carcinoma in situ (CIS) (72.7%), as compared to urine cytology for bladder UC (55.6%) and CIS (54.5%), respectively. Conclusion: UBC®Rapid is sensitive in detecting high-grade bladder UC and CIS in Asian population. It may be useful as an adjunct test to achieve better detection of bladder cancer.

1771P Genomic characteristics and clinical outcomes of HRAS-mutated urothelial bladder cancer

HRAS gene encodes the GTPase HRAS protein, a member of the RAS superfamily, which is enriched in high-grade urothelial bladder carcinoma (UBC). We aimed to characterize genomic and clinical outcomes of patients with HRAS mutations (HRASmt) as a possible prognostic and therapeutic biomarker. A total of 3,426 UBC tissue samples underwent molecular profiling at Caris Life Sciences utilizing NGS of DNA. MAP kinase pathway activation and the likelihood of a tumor’s response to anti-PD(L)1 therapy were measured via MPAS and IFN signature, respectively. Wilcoxon, Fisher’s exact were used for statistical significance. Overall survival (OS) was calculated from the date of tissue collection or the start of treatment until the last contact from insurance claims. All comparisons were conducted between HRAS mutated tumors and the entire UBC general cohort (GC). HRASmt were detected in 107 patients with metastatic UBC (3.12%). Of those, 70% were detected in primary and 30% from metastatic sites. HRASmt were associated with lower TMB (5 vs 8 mut/Mb, q<0.01) and higher PD-L1 expression (55.3% vs 39.1%, q<0.01). HRASmt tumors harbored less TP53 (25.5% vs 60.1%, q<0.05), RB1 (5.3% vs 22.1%, q<0.05), FGFR3 (1.9% vs 13.9%, q<0.05), and KMT2D (14.0% vs 25.4%, q<0.05), but more BRAF mutations (14.0% vs 2.1%, q<0.05). The most frequent HRAS point mutation involved Q61 (47.6%). HRAS-Q61 mutant tumors showed higher MPAS scores (2.21 vs 0.6, q<0.001), enrichment in pathways (all q<0.05) such as EMT (0.86 vs 0.83), TGFb (0.91 vs 0.89), angiogenesis (0.78 vs 0.75) and notch signaling (0.82 vs 0.81). Patients with HRAS-Q61 point mutations experienced worse OS and prognosis compared to HRASwt tumors when treated with checkpoint inhibitors (HR 1.45, 95% 1.01-2.10; p <0.05). HRAS-Q61 point mutations represent a clinically relevant mutation in UBC, as evidenced by its association with worse clinical outcomes compared to HRASwt tumors. Our transcriptomic analysis suggests HRAS-Q61 mutations were associated with lower response to immunotherapy and leads to MAPK activation, as well as modulation of important TME pathways, possibly indicating a distinct biological and clinical phenotype. Our study provides rationale for therapeutic HRAS targeting in UBC.

Downregulation of PTCD1 in Bladder Urothelial Carcinoma Predicts Poor Prognosis and Levels of Immune Infiltration.

Pentatricopeptide repeat domain 1 (PTCD1) was reported to regulate mitochondrial metabolism and oxidative phosphorylation. However, the effect and mechanism of PTCD1 in the development of bladder urothelial carcinoma (BLCA) remain unclear. The databases from The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were used to analyze the expression changes, clinical features, and prognostic values of PTCD1. A nomogram was built to predict the prognostic outcomes of BLCA cases. The potential genes interacting with PTCD1 were explored by Weighted Gene Coexpression Network Analysis (WGCNA). The estimation of associations between PTCD1 and tumor mutations, tumor immunities, and m6A methylations was performed. The study found that the gradual decrease of PTCD1 expression was observed with the increase of stage and grade. Low PTCD1 expression was greatly correlated with higher pathological stage, N stage, and poor prognosis in TCGA cohorts; interestingly, low-grade BLCA cases all exhibited high expression of PTCD1. HPA database analysis implied that the expression of PTCD1 protein in BLCA was lower than that in normal bladder tissue, and the protein expression of PTCD1 in high-grade BLCA was lower than that in low-grade BLCA. Multivariate Cox regression analysis indicated that PTCD1 may serve as an independent factor influencing prognosis of BLCA. Mechanistically, PTCD1 played a regulatory role in BLCA progression through multiple tumor-related pathways containing PI3K-Akt signaling, ECM-receptor interaction, oxidative phosphorylation, and extracellular matrix organization. WGCNA reported that PTCD1 had a strong positive correlation with POLR2J, ZNHT1, ATP5MF, PDAP1, BUD31, and COPS6. Besides, the mRNA expression of PTCD1 was negatively associated with immune cells' infiltrations, immune functions, and checkpoints, especially with some m6A methylation regulators in BLCA. In sum, downregulation of PTCD1 expression may be involved in the development of BLCA and remarkably correlated with poor prognosis. Meantime, it showed an influence in immune cell infiltration and may serve as an agreeable prognostic indicator in BLCA.

FTIR Spectroscopic Imaging Supports Urine Cytology for Classification of Low- and High-Grade Bladder Carcinoma.

Bladder urothelial carcinoma (BC) is a common, recurrent, life-threatening, and unpredictable disease which is difficult to diagnose. These features make it one of the costliest malignancies. Although many possible diagnostic methods are available, molecular heterogeneity and difficulties in cytological or histological examination induce an urgent need to improve diagnostic techniques. Herein, we applied Fourier transform infrared spectroscopy in imaging mode (FTIR) to investigate patients' cytology samples assigned to normal (N), low-grade (LG) and high-grade (HG) BC. With unsupervised hierarchical cluster analysis (UHCA) and hematoxylin-eosin (HE) staining, we observed a correlation between N cell types and morphology. High-glycogen superficial (umbrella) and low-glycogen piriform urothelial cells, both with normal morphology, were observed. Based on the spectra derived from UHCA, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were performed, indicating a variation of protein content between the patient groups. Moreover, BC spectral cytology identified a low number of high-glycogen cells for which a shift of the carbohydrate/phosphate bands was also observed. Despite high cellular heterogeneity, PLS-DA was able to classify the spectra obtained. The voided urine FTIR cytology is one of the options that might be helpful in BC diagnosis, as high sensitivity and specificity up to 97% were determined.

Effects of Concurrent Chemoradiotherapy on the Metastasis and the Mesenchymal Transition of Bladder Urothelial Carcinoma Cells.

Cancer stem cells (CSCs) have been suggested playing a crucial role in the tumorigenesis and tumor progression. Clinically, concurrent chemoradiotherapy (CCRT) after transurethral resection of the bladder is the widely accepted treatment option for high-grade bladder urothelial carcinoma (UC); however, a proportion of bladder UC patients still suffer from recurrence and metastasis. In the present study, we investigated the stemness properties of bladder UC cells with respect to various disease stages. The metastatic capability and epithelial-mesenchymal transition (EMT) of the parental cells and the CSC cells of bladder UC, after chemotherapy with cisplatin alone or CCRT were also studied, respectively. The aldehyde dehydrogenase (ALDH)-positive cells were analyzed by a flow cytometer. The inhibitory effects of radiation in combination with cisplatin on the cell viability, migration, invasion and EMT characteristics were also examined. We found that the proportion of ALDH+-CSCs of bladder UC cells and the disease grading were independent. Furthermore, cisplatin alone significantly (p<0.05) enhanced the migration of both grade-III T24 cells and advanced-stage HT1197 cells, while CCRT treatment significantly (p<0.05) inhibited the T24 cell migration capability, compared to the cisplatin alone group. Interestingly, we found that the cell invasion capability was obviously increased upon the treatment with CCRT in both T24 and HT1197 CSCs. Furthermore, cisplatin played a promoting role in EMT whether in the presence or absence of irradiation. CSCs as well as EMT signaling might contribute to the resistance and metastasis of one-shot CCRT in malignant bladder cancer.

Evaluation of a fractional-order calculus diffusion model and bi-parametric VI-RADS for staging and grading bladder urothelial carcinoma.

To evaluate the feasibility of high b-value diffusion-weighted imaging (DWI) for distinguishing non-muscle-invasive bladder cancer (NMIBC) from muscle-invasive bladder cancer (MIBC) and low- from high-grade bladder urothelial carcinoma using a fractional-order calculus (FROC) model as well as a combination of FROC DWI andbi-parametric Vesical Imaging-Reporting and Data System (VI-RADS). Fifty-eight participants with bladder urothelial carcinoma were included in this IRB-approved prospective study. Diffusion-weighted images, acquired with 16 b-values (0-3600 s/mm2), were analyzed using the FROC model. Three FROC parameters, D, β, and μ, were used for delineating NMIBC from MIBC and fortumor grading. A receiver operating characteristic (ROC) analysis was performed based on the individual FROC parameters and their combinations, followed by comparisons with apparent diffusion coefficient (ADC) and bi-parametric VI-RADS based on T2-weighted images and DWI. D and μ were significantly lower in the MIBC group than in the NMIBC group (p = 0.001 for each), and D, β, and μ all exhibited significantly lower values in the high- than in the low-grade tumors (p ≤ 0.011). The combination of D, β, and μ produced the highest specificity (85%), accuracy (78%), and the area under the ROC curve (AUC, 0.782) for distinguishing NMIBC and MIBC, and the best sensitivity (89%), specificity (86%), accuracy (88%), and AUC (0.892) for tumor grading, all of which outperformed the ADC. The combination of FROC parameters with bi-parametric VI-RADS improved the AUC from 0.859 to 0.931. High b-value DWI with a FROC model is useful in distinguishing NMIBC from MIBC and grading bladder tumors. • Diffusion parameters derived from a FROC diffusion model may differentiate NMIBC from MIBC and low- from high-grade bladder urothelial carcinomas. • Under the condition of a moderate sample size, higher AUCs were achieved by the FROC parameters D (0.842) and μ (0.857) than ADC (0.804) for bladder tumor grading with p ≤ 0.046. • The combination of the three diffusion parameters from the FROC model can improve the specificity over ADC (85% versus 67%, p = 0.031) for distinguishing NMIBC and MIBC and enhance the performance of bi-parametric VI-RADS.

P53 Expression analysis in Low Grade and High Grade Urothelial Bladder Carcinoma and the Association with Tumor Stages

BackgroundUrothelial carcinoma is the most common bladder malignancy in men. Risk factors include smoking, chemicals exposure, radiation,schistosoma hematobium infection. P53 mutation is the most common mutation in urothelial bladder carcinoma that cause p53 proteinaccumulation which are detected through immunohistochemical examination. The aim of this study is to analyze the differencesbetween p53 expression in low and high grade urothelial and the carcinomas association of p53 expression with tumor stage.MethodsThis was a cross sectional study with 47 cases (22 cases of low grade and 25 cases of high grade) urothelial carcinoma in AnatomicalPathology Department Faculty Medicine of Universitas Indonesia/Cipto Mangunkusumo Hospital (FKUI/RSCM) in 2009-2017. Allcases stained with p53 antibody with immunohistochemical methods with positive cut off ≥20%.ResultsP53 positive expression are found in 33 samples, 20 cases of high grade and 13 cases in low grade; 22 cases of Nonmuscle invasivebladder cancer and 11 cases of Muscle invasive bladder cancer.ConclusionThe expression of p53 in low grade and high grade urotelial carcinoma of the bladder and its association with tumor stage showed nosignificant difference.

Methodology for triage of urologic surgical cases in the setting of a pandemic

BackgroundThe first wave of the COVID-19 pandemic in March 2020 forced our healthcare system in the Bronx, New York to cancel nearly all scheduled surgeries. We developed a framework for prioritizing postponed urologic surgeries that was utilized once cases were permitted to be rescheduled. As many parts of our country experience first and second waves of this pandemic, our framework may serve as a resource for other centers experiencing restrictions on the scheduling of elective urologic surgeries.MethodsAs the COVID-19 pandemic started and peaked in New York, almost all of our scheduled urologic surgeries were cancelled. Each Urologist was asked to rank his/her cancelled surgeries by priority (Level 1—least urgent; Level 2—moderately urgent; Level 3—most urgent). A committee of Urologists assigned a subclass to Level 3 and 2 cases (3a—least urgent; 3b—moderately urgent; 3c—most urgent; 2a—lower priority; 2b—higher priority). The committee then reviewed cases by urgency to derive a final priority ranking.ResultsA total of 478 total urologic surgeries were canceled and categorized: 250 Level 1, 130 Level 2, 98 Level 3 (73 adult, 25 pediatric). Level 3c involved renal cell carcinoma ≥ T2b, high-grade bladder urothelial carcinoma, adrenal mass/cancer > 6 cm, testicular cancer requiring radical orchiectomy, and penile cancer. Level 3b involved T2a renal masses requiring nephrectomy, while high-risk prostate cancer and symptomatic nephrolithiasis were classified as 3a. Level 2 included testicular cancer requiring retroperitoneal lymph node dissection and complicated benign prostatic hyperplasia. Surgeries for urologic reconstruction, non-complicated nephrolithiasis, erectile dysfunction, and urinary incontinence were considered Level 1.ConclusionsOur disease-specific approach to surgical rescheduling offers appropriate guidance for triaging urologic surgeries. Our system can provide guidance to other institutions as COVID-19 cases surge in different regions and with the growing second wave.

Molecular subtyping and immune-gene signatures identify a subset of clinical T1 high-grade (cT1 HG) and cT2 bladder urothelial carcinoma (UC) as candidates for single-agent immune checkpoint inhibition (ICI)

We aimed to determine whether a similar ICI-based approach could be used by considering selected cT1 HG and cT2 bladder UC as optimal candidates for single-agent ICI. Data from transurethral resection of the bladder tumor (TURBT) specimens from 2 studies was evaluated. The MOL cohort included 206 patients (pts) with HG cT1N0M0 (N=87) or cT2N0M0 (N=119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (N=102), was used as ICI-treated UC reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher® assay). Immune-signatures scores (ISS) and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of the outcomes in relation to the molecular signatures and ISS. In the MOL cohort, luminal tumors (LT) were less frequently upstaged at RC vs non-LT (p=0.02). However, organ-confined (OC; pT£2; N=75) LT and non-OC (NOC; pT³3; N=24) LT at RC had statistically similar ISS, assessed with immune190 (0.09 vs 0.09), IFN-a (0.003 vs 0.26), IFN-g (-0.19 vs -0.17) and inflammation score (-0.1 vs -0.1). The remaining OC (N=57) and NOC (N=49) tumors were classified as basal (26/25), luminal infiltrated (19/11), claudin-low (11/8) and neuroendocrine-like (NE-like; 1/5). Except for the NE-like cases, the remaining OC and NOC non-LT showed higher ISS, with particularly high-scores for the claudin-low tumors. Progression-free survival outcomes for LT vs non-LT were favorable, but non-significant (p=0.2). In the MOL cohort, overall survival was inferior for Immune190-high vs low tumors (median split, p=0.042). In further analyzing the MOL cohort we identified a population of cT1-T2N0M0 tumors which shared molecular features with tumors included in PURE-01. These profiles were consistent regardless of whether the tumor was ultimately identified as OC or NOC, suggesting that treatment with ICI could be proposed to more selected cT1 HG. Clinical trials will be required to confirm the clinical utility of these observations.

756P Molecular subtyping and immune-gene signatures identify a subset of clinical T1 high-grade (cT1 HG) and cT2 bladder urothelial carcinoma (UC) as candidates for single-agent immune checkpoint inhibition (ICI)

756P Molecular subtyping and immune-gene signatures identify a subset of clinical T1 high-grade (cT1 HG) and cT2 bladder urothelial carcinoma (UC) as candidates for single-agent immune checkpoint inhibition (ICI)

Shear Wave Elasticity Differentiation Between Low- and High-Grade Bladder Urothelial Carcinoma and Correlation With Collagen Fiber Content.

To investigate the differences in the shear wave elasticity and collagen fiber content between low- and high-grade bladder urothelial carcinoma and study the relationship between elasticity and the content of collagen fiber. A total of 66 patients with bladder tumors who were referred to our hospital underwent transrectal or transvaginal conventional ultrasound and shear wave elasticity examinations. After bladder urothelial carcinoma was pathologically confirmed, 34 cases of low-grade and 32 cases of high-grade carcinoma were enrolled. The specimens underwent Masson trichrome staining, and image-processing software was used to quantitatively analyze the area of collagen fiber. Based on conventional ultrasound, the low- and high-grade groups were similar in the number, location, interior echoes, basal portion, size, and vascularity (P > .05); nevertheless, the difference in the surface condition (smooth or rough) was statistically significant (P = .03). The high-grade group had significantly higher maximum and mean elasticity than the low-grade group (P < .01). The percentage of the collagen fiber area in the high-grade group was significantly higher than that in the low-grade group (mean ± SD, 11.45% ± 1.66% versus 7.64% ± 0.70%; P = .01). There was a positive correlation between maximum elasticity, mean elasticity, and the percentage of the collagen fiber area (r = 0.75 and 0.52, respectively; P < .01). Shear wave elasticity can be used to differentiate between low- and high-grade bladder urothelial carcinoma. The elasticity of lesions has a close correlation with the content of collagen fiber, which may have an important impact on tissue stiffness and the development of bladder cancer.

Predicting residual tumor for T1 high-grade bladder urothelial carcinoma before second transurethral resection specimens.

e17018 Background: Second transurethral resection (TUR), which is now recommended for all T1 high-grade bladder urothelial carcinoma, may not be necessary for patients with minimal tumor burden at the first TUR. T1 microstaging by the recognition of the muscularis mucosae or vascular plexus may be one promising method for evaluating tumor burden, but is sometimes technically difficult to assess. The number of TUR chips with tumor invading into lamina propria (T1chips) is easy to assess and can be available for all patients with T1 bladder urothelial carcinoma. Our aim was to determine clinicopathological factors which can predict the existence of residual tumor on the second TUR specimens for T1 high-grade bladder urothelial carcinoma. Methods: A total of 50 patients were diagnosed with T1 high-grade bladder urothelial carcinoma after the first TUR. We performed second TUR for the 50 patients. The median interval from the first and the second TUR was 6 week (range, 2-10). Voided urine cytology was taken in all patients between the first and the second TUR, at least 1 week after the first TUR. The existence of proper muscle tissue was confirmed in all specimens for the first and the second TUR. Tumor size, the number of tumor, the presence of carcinoma in situ (CIS), the number of TUR chips containing lamina propria invasion (T1chips) were recorded for the first TUR specimens. Results: A total of 20 (40%) patients had residual tumor on the second TUR. The second TUR stage was: T0 30 (60%); Ta/is 7 (14%); T1 9 (18%); and T2 4 (8%), respectively. In univariate analysis, positive urine cytology before the first TUR (48% vs 0% in negative), positive urine cytology between the first and second TUR (76% vs 21% in negative), and multiple T1 chips on the first TUR specimens (58% vs 6% in one T1 chip) were associated with residual tumor on the second TUR. In addition, in multivariate analysis, the number of T1 chips on the first TUR and urine cytology between the first and the second TUR were the significant predictors for residual tumor on the second TUR. Of 15 patients with multiple T1 chips and positive urine cytology between the first and the second TUR, 13 (87%) had residual tumor on the second TUR, compared to 0% (0/15) in those with one T1 chip and negative urine cytology between the first and the second TUR. Conclusions: Second TUR may not be necessary for all patients with T1 high-grade bladder urothelial carcinoma. The number of T1 chips on the first TUR and urine cytology between the first and the second TUR are useful factors for predicting second TUR stage.

MP72-04 T1 SUBSTAGE IN NON-MUSCLE INVASIVE BLADDER UROTHELIAL CARCINOMA CAN PREDICT PROGRESSION FREE SURVIVAL

You have accessJournal of UrologyBladder Cancer: Non-invasive III (MP72)1 Apr 2020MP72-04 T1 SUBSTAGE IN NON-MUSCLE INVASIVE BLADDER UROTHELIAL CARCINOMA CAN PREDICT PROGRESSION FREE SURVIVAL Yu-kuang Chen*, Tzu-Ping Lin, Yen-Hwa Chang, Junne-Yih Kuo, Hsiao-Jen Chung, Howard Hung-Hao Wu, Eric Yi-Hsiu Huang, Chih-Chieh Lin, Yu-Hua Fan, I-shen Huang, Shih-Yen Lu, Alex T.L. Lin, and William J. Huang Yu-kuang Chen*Yu-kuang Chen* More articles by this author , Tzu-Ping LinTzu-Ping Lin More articles by this author , Yen-Hwa ChangYen-Hwa Chang More articles by this author , Junne-Yih KuoJunne-Yih Kuo More articles by this author , Hsiao-Jen ChungHsiao-Jen Chung More articles by this author , Howard Hung-Hao WuHoward Hung-Hao Wu More articles by this author , Eric Yi-Hsiu HuangEric Yi-Hsiu Huang More articles by this author , Chih-Chieh LinChih-Chieh Lin More articles by this author , Yu-Hua FanYu-Hua Fan More articles by this author , I-shen HuangI-shen Huang More articles by this author , Shih-Yen LuShih-Yen Lu More articles by this author , Alex T.L. LinAlex T.L. Lin More articles by this author , and William J. HuangWilliam J. Huang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000952.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: For urothelial bladder cancer, the depth of tumor invasion and tumor grade affect prognosis significantly. Among non-muscle invasive bladder urothelial carcinomas (UC) of the urinary bladder, T1 stage have much variable clinical presentation and course. 2016 World Health Organization (WHO) classification recommended the use of substaging, but there is no consensus in optimal system. We analyzed the outcomes of focal and extensive T1 substaging according to the depth of lamina propria invasion (1.0 mm as cut off value) in our institute. METHODS: From 2007 to 2015, patients with pathology report of focal (≤ 1.0 mm) and extensive (>1.0 mm) T1 high grade bladder urothelial carcinoma (UC) were enrolled retrospectively. Patients with history of (pure) CIS, muscle invasive or upper tract UC were excluded. The pathological grading and staging were reported by two pathologists with consensus. The definition of recurrence was reappearance of UC in the bladder, and progression was advancing in stage, metastasis or death caused by UC. Outcomes including recurrence free survival (RFS), progression free survival (PFS), cancer specific (CSS) and overall survival (OS) were analyzed with Kaplan-Meier method. RESULTS: A total of 363 patients were in the cohort, with 55-month follow-up in average. The mean age was 74 (±12.0) years old. One hundred and thirty-eight (38%) patient were classified as T1 focal substage, and 225 patients were T1 extensive. There were no significant differences in the demographic variables including sex, age, smoking or medical comorbidity between the two groups. With Kaplan-Meier survival analysis, PFS was significant shorter (p=0.024, log-rank test, figure) in T1 extensive group, but we were unable to demonstrate a difference in RFS (p=0.168), CSS (p=0.102) or OS (p=0.515) between two groups. After multivariate adjustment with concurrent CIS, tumor size, focality and recurrent status, extensive T1 also showed a poor PFS (HR=1.95, p=0.007), but still no significant difference in RFS (HR=1.35, p=0.061), CSS (HR=1.49, p=0.242) or OS (HR=0.74, p=0.12). CONCLUSIONS: In our single institute cohort, using 1.0 mm as a cut-off value of lamina propria invasion, extensive T1 predicted shorter progression free survival as compared with focal T1. Source of Funding: n/a © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1074-e1075 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yu-kuang Chen* More articles by this author Tzu-Ping Lin More articles by this author Yen-Hwa Chang More articles by this author Junne-Yih Kuo More articles by this author Hsiao-Jen Chung More articles by this author Howard Hung-Hao Wu More articles by this author Eric Yi-Hsiu Huang More articles by this author Chih-Chieh Lin More articles by this author Yu-Hua Fan More articles by this author I-shen Huang More articles by this author Shih-Yen Lu More articles by this author Alex T.L. Lin More articles by this author William J. Huang More articles by this author Expand All Advertisement PDF downloadLoading ...

Gene Expression Profiles Identified Novel Urine Biomarkers for Diagnosis and Prognosis of High-Grade Bladder Urothelial Carcinoma.

Bladder urothelial carcinoma (BC) has been identified as one of the most common malignant neoplasm worldwide. High-grade bladder urothelial carcinoma (HGBC) is aggressive with a high risk of recurrence, progression, metastasis, and poor prognosis. Therefore, HGBC clinical management is still a challenge. We performed the present study to seek new urine biomarkers for HGBC and investigate how they promote HGBC progression and thus affect the prognosis based on large-scale sequencing data. We identified the overlapped differentially expressed genes (DEGs) by combining GSE68020 and The Cancer Genome Atlas (TCGA) datasets. Subsequent receiver operating characteristic (ROC) curves, Kaplan-Meier (KM) curves, and Cox regression were conducted to test the diagnostic and prognostic role of the hub genes. Chi-square test and logistic regression were carried out to analyze the associations between clinicopathologic characteristics and the hub genes. Ultimately, we performed gene set enrichment analysis (GSEA), protein-protein interaction (PPI) networks, and Bayesian networks (BNs) to explore the underlying mechanisms by which ECM1, CRYAB, CGNL1, and GPX3 are involved in tumor progression. Immunohistochemistry based on The Human Protein Atlas and quantitative real-time polymerase chain reaction based on urine samples confirmed the downregulation and diagnostic values of the hub genes in HGBC. In conclusion, our study indicated that CRYAB, CGNL1, ECM1, and GPX3 are potential urine biomarkers of HGBC. These four novel urine biomarkers will have attractive applications to provide new diagnostic methods, prognostic predictors and treatment targets for HGBC, which could improve the prognosis of HGBC patients, if validated by further experiments and larger prospective clinical trials.

Enhanced CDR1as Promotes the Development of Bladder Urothelial Carcinoma.

The current study aimed to evaluate the expression of circular RNA (circRNA) CDR1as in bladder urothelial carcinoma and adjacent normal tissues, thereby laying the foundation for the research of bladder urothelial carcinoma. The level of CDR1as was evaluated in the tissues of bladder urothelial carcinoma patients. ROC analysis was carried out to explore the possible diagnostic value of CDR1as. In the current study, we showed novel data that the expression of CDR1as in bladder urothelial carcinoma tissues was significantly higher than that in adjacent tissues. Furthermore, the expression of CDR1as was significantly higher in non-muscle invasive bladder cancer (NMIBC) and high-grade cancer tissues than in muscle invasive bladder cancer (MIBC) and low-grade cancer tissues. In patients with lymph node metastasis, the expres-sion of CDR1as was also significantly higher. Moreover, the expression of CDR1as was higher in high-stage, high-grade bladder urothelial carcinoma than in low-stage and low-grade cancer tissues. Real time PCR analysis showed that there was no difference in the expression of CDR1as among the patients according to the grouping of gender (male vs. female), age (≤ 65 years vs. > 65 years), tumor size (≤ 3 cm vs. > 3 cm), and lymphatic invasion (LVI). The current study for the first time showed upregulation of CDR1as may be involved in the development and progression of bladder urothelial carcinoma.

Treatment Strategy for Newly Diagnosed T1 High-grade Bladder Urothelial Carcinoma: New Insights and Updated Recommendations

ContextHigh-grade T1 (T1HG) bladder cancer (BCa) has a very high likelihood of disease recurrence and progression to muscle invasion. Radical cystectomy is considered the best chance at cure, albeit with a high risk of morbidity, and is overtreatment for some patients. Treatment with bacillus Calmette-Guerin (BCG) allows bladder preservation but may risk disease progression. ObjectiveTo systematically review the current literature on the management of T1HG BCa and provide updated treatment recommendations. Evidence acquisitionMedline, EMBASE, and Epub Ahead of Print databases were searched in November 2017 to identify observational cohort studies and controlled trials, between 1946 and 2017, associated with diagnosis, treatment, and prognosis of T1HG BCa. Evidence synthesisClinical understaging and/or persistence of disease is not uncommon at initial transurethral resection (TUR); thus, a second re-TUR is recommended for cases with T1HG BCa. Patients electing a bladder preservation approach should undergo induction BCG therapy followed by a maintenance schedule, while patients with several high-risk features should consider immediate cystectomy and those with BCG-refractory or BCG-unresponsive disease should be considered for early cystectomy. Current phase I/II clinical trials for T1HG patients may offer future bladder preservation therapy approaches. ConclusionsT1HG tumours are heterogeneous in nature and challenging to treat. Bladder preservation with BCG induction and maintenance, or radical cystectomy is the current standard treatment modality of choice for these tumours. Promising therapies for BCG-unresponsive disease are currently under investigation. Patient summaryPatients with high-grade T1 bladder cancer are at a high risk of tumour recurrence and progression, requiring more aggressive treatment such as bladder removal. Bladder preservation therapies are available (and new therapies are being tested in clinical trials); however, patients should be aware that currently bladder removal is considered the best opportunity for cancer cure.

Contrast-Enhanced Ultrasound Differentiation Between Low- and High- Grade Bladder Urothelial Carcinoma and Correlation With Tumor Microvessel Density.

Time-intensity curves (TICs) of contrast-enhanced ultrasound (CEUS) were analyzed retrospectively to differentiate between low-grade and high-grade bladder urothelial carcinoma, and to investigate correlation with tumor microvessel density (MVD). The data of 105 patients with pathologically confirmed bladder urothelial carcinoma (55 low-grade and 50 high-grade) were reviewed. Lesions were examined before surgery using conventional ultrasound and CEUS with TIC analysis. The TIC parameters time from peak to one-half the signal intensity (TPH) and the corresponding descending slope (DS) of the low-grade and high-grade groups were compared, and receiver operating characteristic curves constructed. The MVDs of the resectioned tissue specimens were quantified via immunohistochemistry for CD34. Based on conventional ultrasound, the low-grade and high-grade groups were similar in tumor shape, number, topography, internal echo, height, width, and vascularity. The TPH of the high-grade group was significantly longer than that of the low-grade group, and the DS was lower. The cutoff points of TPH and DS for differentiating low-grade and high-grade bladder urothelial carcinoma were 48.06 seconds and 0.15 dB/seconds, respectively (area under the receiver operating characteristic curve = 0.79 for both). The mean MVDs per high-power field of the low-grade and high-grade groups were 41.39 16.65 and 51.03 20.16, respectively (P = .009). The TPH correlated linearly with MVD (P < .01), as did the DS (P < .01). Contrast-enhanced ultrasound can be used to differentiate low from high-grade bladder urothelial carcinoma. The TIC parameters of CEUS reflect the MVD of bladder urothelial tumors and may be helpful for evaluating tumor angiogenesis, with implications for clinical diagnosis, treatment, and prognosis.

The prognostic value of preoperative serum albumin-globulin ratio for high-grade bladder urothelial carcinoma treated with radical cystectomy: A propensity score-matched analysis.

Albumin-globulin ratio (AGR) has been reported as an independent risk factor for survival outcomes of a variety of malignancies. We aimed to further examine the prognostic value of AGR for urothelial carcinoma of bladder (UCB) using a propensity score-matched (PSM) analysis. The medical data of 189 high-grade UCB patients undergoing radical cystectomy were retrospectively reviewed. AGR was defined as the ratio of serum albumin to nonalbumins (serum total protein-albumin). The association of preoperative AGR with clinicopathologic characteristics and prognosis were assessed. Multivariate analyses using Cox regression models were applied to evaluate the independent prognostic factors. The receiver operating curve analysis indicated 1.55 as the optimal cutoff value to define low or high AGR. In prematched cohorts, Kaplan-Meier analysis indicated that AGR lower than 1.55 was associated with poorer overall survival (OS), progression-free survival (PFS), and tumor-specific survival (TSS) (P < 0.001 for all). Multivariable cox analyses also showed that AGR lower than 1.55 were an independent risk factor for survival outcomes, including OS, PFS, and TSS (P < 0.01 for all). In particular, AGR lower than 1.55 remained its prognostic value after PSM analysis. Low AGR was a significant unfavorable factor for UCB patients treated with radical cystectomy. This viable parameter should be enrolled in the pretreatment risk stratification for UCB.

Elevated preoperative plasma fibrinogen level is an independent predictor of malignancy and advanced stage disease in patients with bladder urothelial tumors

PurposeTo investigate the association between preoperative plasma fibrinogen levels and clinicopathological features in patients with bladder urothelial tumors. MethodsIn this retrospective single-center study, we evaluated preoperative plasma fibrinogen levels in 503 patients newly diagnosed with bladder urothelial tumors between January 2009 and October 2014. All patients received surgical intervention as the primary treatment method. Associations between preoperative plasma fibrinogen levels and clinicopathological parameters were analyzed. Univariate and multivariate logistic regression analyses were performed to identify independent associations. ResultsThe mean preoperative fibrinogen level in patients with bladder urothelial carcinoma (BUC) was significantly higher than that in patients with papilloma or papillary urothelial neoplasm of low malignant potential (PUNLMP) (P = 0.004). Additionally, patients with BUC with advanced-stage disease showed elevated plasma fibrinogen levels compared to patients with early-stage disease (high-grade BUC vs. low-grade BUC: P = 0.002; muscle-invasive BUC vs. non-muscle-invasive BUC: P = 0.010). In a multivariate regression model, a plasma fibrinogen level >3.04 g/L was identified to be independently associated with the presence of BUC (hazard ratio [HR] = 1.653, P = 0.047), high-grade BUC (HR = 1.869, P = 0.004), and muscle-invasive BUC (HR = 1.870, P = 0.044). ConclusionsElevated preoperative plasma fibrinogen level is an independent predictor of malignancy as well as advanced-stage carcinoma in patients with bladder urothelial tumors, suggesting that plasma fibrinogen may be a promising diagnostic and prognostic biomarker for bladder tumors.