Urothelial Carcinoma Group Research Articles

Changes in Urinary Exosomal Nuclear Matrix Protein-22 in Dogs With Urothelial Carcinoma: A Pilot Study.

Nuclear matrix protein-22 (NMP-22) is widely used in human medicine as a prognostic and diagnostic tool for urothelial carcinoma (UC). In addition, the use of urinary exosomes as a liquid biopsy tool is emerging for the diagnosis of certain types of cancer in human medicine. This study aimed to investigate the change in urinary exosomal NMP-22 for the diagnosis of UC in dogs. Among canine patients who visited the veterinary hospital, urine was collected from those whose owners provided consent. A total of 23 dogs (UC group, n=6; control group, n=17) were included in the analysis. After exosomes were isolated from the urine, NMP-22 was measured using enzyme-linked immunosorbent assay. In the UC group, the expression of NMP-22 in urinary exosomes was significantly higher than that in non-UC groups (p<0.0001). NMP-22 is significantly increased in exosomes in the urine of dogs diagnosed with UC, suggesting that urinary exosome NMP-22 can be considered as one of the liquid biopsy tools for diagnosing UC in dogs.

UriFind assay and association with whole course management of urothelial carcinoma in a large multicentric, prospective China cohort.

e16588 Background: The gold standard to diagnose and monitor urothelial carcinoma is cystoscopy, which is invasive and painful. The currently available non-invasive methods to detect urothelial carcinoma are either of unsatisfying sensitivity or limited specificity in China. Previously, a DNA methylation assay, termed UriFind, was developed, and showed a compelling sensitivity and specificity in a retrospective cohort. This study aimed to further validate its performance in a large multicentric, prospective China cohort. Methods: Patients involved in the whole course of UC management were recruited in this cohort. The cohort contained 931 patients diagnosed with urothelial carcinoma (UC), and 994 controls with benign diseases and 78 healthy participants from 12 hospitals across China. Urine samples were collected before the therapy, and analyzed with quantitative PCR of ONECUT2 and VIM methylation (UriFind), FISH and urinary cytology. Sensitivity, specificity, accuracy, PPV and NPV of these assays were evaluated as compared to the diagnostic gold standard of cystoscopy, histology results or clinical diagnosis. Results: The UC group of the cohort consisted of 683 non-muscle invasive UC (73.4%), 203 muscle invasive UC (21.8%) and 45 unavailable stage (4.8%). The patients of low, high-grade UC and unavailable grade were 244(26.2%), 651(69.9%) and 36 (3.9%), respectively. Overall sensitivity, specificity, accuracy, PPV and NPV of UriFind was 82.3%, 91.2%, 87.3%, 88.1% and 86.7%, respectively. The specificity of healthy participants was 100%. The overall sensitivity and accuracy of UriFind were significantly higher than urine cytology (40% and 55.7%) and FISH (68.2% and 73.6%), while the specificity was similar to cytology (93.9%) and FISH (87.3%). Importantly, UriFind achieved a great improvement of sensitivity in whole course management, including low grade tumor (56.1%), small and single tumor (63.3%), residual tumor after therapy (71.4%) and recurrent tumor (84.3%). Conclusions: The performance of UriFind is well validated with significantly higher sensitivity and accuracy than urine cytology and FISH in UC detection in this cohort with 2003 cases. This assay facilitates whole course management of urothelial carcinoma, which may reduce the burden of cystoscopy and unnecessary second TURBT. Clinical trial information: NCT04314245 .

MP63-18 UriFIND ASSAY FACILITATES WHOLE COURSE MANAGEMENT OF UROTHELIAL CARCINOMA IN A LARGE MULTICENTRIC, PROSPECTIVE CHINA COHORT

MP63-18 UriFIND ASSAY FACILITATES WHOLE COURSE MANAGEMENT OF UROTHELIAL CARCINOMA IN A LARGE MULTICENTRIC, PROSPECTIVE CHINA COHORT

Preoperative accuracy of diagnostic evaluation of urachal carcinoma.

We analyzed the clinical data of patients with urachal carcinoma (UrC) in order to strengthen urologists' understanding of UrC and improve preoperative diagnosis. The clinical data of 37 patients with UrC admitted to our hospital from October 2005 to April 2022 were retrospectively analyzed, and 40 patients with urothelial carcinoma (UCa) of bladder were enrolled as the control group. We compared and analyzed the imaging, cystoscopy and immunohistochemistry, serum tumor markers, fluorescence in situ hybridization (FISH) of UrC and bladder UCa for early diagnosis and evaluation of diagnostic accuracy. A total of 37 patients with UrC were enrolled in this study, including 30 males and seven females, with a median age of 52.00 (44.50-63.50) years. Imaging and cystoscopy suggest that UrC grows primarily outside the bladder cavity and is found in the middle line of the dome or anterior wall of the bladder. There was a significant difference in tumor location between the UrC group and the UCa group (10.13 mm vs. -7.06 mm, p < 0.001). Immunohistochemistry revealed that CK20 and CDX-2 were both diffusely and strongly positive. β-catenin was strongly positive in cytoplasm and membrane, but negative in nuclear staining. Carcinoembryonic antigen (CEA) and carbohydrate antigen 72-4 (CA724) expression levels were significantly higher in the UrC group than in the UCa group (p < 0.05). In the diagnosis of UrC, the area under the curve (AUC) of CEA combined with CA724 was the greatest. FISH's sensitivity in diagnosing UrC (5/7, 71.43%) was not significantly different from that of UCa (71.43% vs. 77.50%, p=0.659). Imaging examination has the highest sensitivity and specificity among the accuracy evaluation of different diagnostic methods. Imaging and cystoscopy are the powerful diagnostic methods for UrC. Serum tumor markers may assist in diagnosis, prognosis, and monitoring. Positive urine FISH can easily misdiagnose UrC as UCa.

Combination of hyperthermia and intravesical chemotherapy for the treatment of pT1 stage bladder cancer: A retrospectively clinical study.

To evaluate the efficiency and safety of combined local bladder hyperthermia and intravesical chemotherapy (IVC) for the treatment of patients with pT1 stage bladder cancer. A total of 189 patients with pT1 who underwent transurethral resection of bladder cancer (TURBT) were retrospectively reviewed. After TURBT, the patients with low-grade urothelial carcinoma (UC) were treated with either an IVC with pirarubicin (THP) protocol or chemo-thermotherapy (CHT) with THP protocol, whereas patients with high-grade UC were treated with either an intravesical immunotherapy (IVI) with bacillus Calmette-Guerin (BCG) protocol or CHT protocol, patients' characteristics, tumor biological features, and follow-up data were analyzed and compared between CHT and IVC group in low-grade UC, CHT, and IVI group in high-grade UC, respectively. The median follow-up time was 24 months. In patients with low-grade UC, the median recurrence free survival (RFS) interval and costs of treatment in CHT group were significantly higher than those in IVC group (p=.01, p<.001, respectively), CHT was associated with higher RFS compared with IVC by Kaplan-Meier analysis, and three patients in IVC group upgraded to high grade when tumor recurred, whereas no cases were found upgraded in CHT group, p=.38. In patients with high-grade UC, tumor recurrence rates at 12 (p=.004) and 24 months (p=.004) after TURBT, rate of complications (p=.04)-especially for hematuresis (p=.03) and irritation symptoms (p=.04)-the median costs of treatment (p<.001) in CHT group were significantly lower than those in IVI group, RFS interval, health-related quality of life) at 12 and 24 months after TURBT in CHT group was significantly higher than those in IVI group (p<.001, p=.002, and p<.001, respectively), and CHT was associated with higher RFS compared with IVI by Kaplan-Meier analysis. The rate of patients upstaged to pT2 in CHT group seemed lower than that in IVI group, but there was no significantly statistical difference (14.3% vs. 24%, p=.58). CHT has a beneficial prophylactic effect in patients with pT1 bladder cancer, especially in patients with high-grade UC, which is much more effective and safer than BCG, meanwhile it costs less compared with BCG.

Histological variants and lymphovascular invasion in upper tract urothelial carcinoma can stratify prognosis after radical nephroureterectomy.

Patients with histological variants (HV) of bladder cancer have more advanced disease and poorer survival rates than those with pure urothelial carcinoma (UC). Moreover, lymphovascular invasion (LVI) is an important biomarker after RNU in systematic reviews and meta-analyses. Thus, here we investigated the clinical and prognostic impact of HV and LVI in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Data from 223 UTUC patients treated with RNU without neoadjuvant chemotherapy were retrospectively evaluated. We analyzed differences in clinicopathological features and survival rates between patients with pure UC and those with HV. Conditional survival (CS) analysis was performed to obtain prognostic information over time. A total of 32 patients (14.3%) had HV, with the most common variant being squamous differentiation, followed by glandular differentiation. UTUC with HV was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and LVI, compared to pure UC (all P < 0.01). Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were all significantly worse in the HV group compared to the pure UC group (all, P < 0.001). In multivariable analysis, HV and LVI were independent predictors of CSS and OS. We classified the patients into three groups using these two predictors: low-risk (neither HV nor LVI), intermediate-risk (either HV or LVI), and high-risk (both HV and LVI). Significant differences in PFS, CSS, and OS rates were found among the 3 groups. In CS analysis, the conditional PFS, CSS, and OS rates at 1, 2, 3, 4, and 5 years improved with increased duration of event-free survival. CS analysis revealed that most progression events occurred within 2 years after RNU, and patients with risk factors had worse PFS at all time points. A risk model using HV and LVI can stratify PFS, CSS, and OS of patients treated with RNU. In addition, CS analysis revealed that HV and LVI were poor prognostic factors over time after RNU.

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.

Response to neoadjuvant chemotherapy in histologic variants of bladder cancer.

458 Background: Localized muscle invasive bladder carcinoma is mostly treated with neoadjuvant chemotherapy (NAC) before surgery in order to improve the outcome. Urothelial carcinoma (UC) is the most frequent histological type. Histological variants (pure or mixed) occur in 10% of bladder carcinoma. There is a lack of data on NAC efficacy for these histological subtypes. In this study, we evaluated the histologic response to NAC in the variant population of bladder cancer. Methods: Patients from 2 french hospitals (CHU de Nantes and ICM) treated with NAC for bladder cancer from 2010 to August 2021 were included in this retrospective study. We compared response to NAC between UC and histologic variants (pure or mixed) on cystectomy piece. The histological response was defined by the tumor downstaging after NAC (≤pT1Nx). We also collected the pathological complete response (pCR), which was defined by no residual tumor on the cystectomy piece. Results: 87 patients were included. 31 patients harbored a variant pattern: 7 squamous component, 3 adenocarcinoma component, 5 micropapillary component, 2 sarcomatoid component, 4 neuroendocrine carcinoma, 4 nest, 1 lymphoepithelial carcinoma, 2 giant cell, 1 undifferentiated, 1 micropapilallary and adenocarcinoma component and 1 adenosquamous component; 56 were conventional UC. NAC was MVAC in 77% of patient in the variant group, and 82% in the UC group. Others chemotherapy drugs were used as gemzar cisplatine, and platine etoposide. Downstaging was observed in 55% of patients in the variant group (17/31) and in 59% in the UC group (33/56). The difference was not statistically significant (p &lt;0,44). pCR was observed in 39% of patients in the variant group (12/31) and 43% in the UC group (24/56), the difference was not significant (p&lt; 0.44). Conclusions: NAC can be effective in the histologic variant population of bladder carcinoma, nevertheless these data could be confirmed in a larger cohort.

Five-year survival comparison of different treatment modalities for muscle invasive urothelial carcinoma, squamous cell carcinoma and adenocarcinoma of the bladder: An analysis of the National Cancer Database.

575 Background: Localized muscle invasive bladder cancer carries a significant recurrence and mortality rate. The purpose of this study was to compare 5-year overall survival (OS) of neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), RC alone, bladder preserving chemoradiotherapy (BPCRT) and radiation alone (RT) on selected histologies. Methods: We sampled the National Cancer Database (NCDB) for bladder cancer patients diagnosed with AJCC 7th Stage 2 and 3 for urothelial carcinoma (UC) including variant histologies, squamous cell carcinoma (SCC) and adenocarcinoma (AC) from 2004-2018 with definitive intent treatment. 5-year Kaplan-Meier survival plots were utilized to assess survival differences amongst treatment modalities and stratified by selected histologies. Multivariate cox regression models were used to compare hazard ratios and logistic regression analysis was performed for covariate analysis. A p-value &lt;0.05 was considered statistically significant. Results: A total of 20,629 patients met inclusion criteria. The average age was 69.51 + 11.02 years, 68% were male. UC represented 94.1% of selected histologies, followed by 4.6% SCC and 1.3% AC. For all combined histologies, 5-year OS for patients with NAC followed by RC was 58%, 48% for RC alone, 33% for BPCRT and 10% for RT alone. RC alone provided a longer OS in the SCC and AC groups, 48% and 47% respectively (p&lt;0.001). NAC followed by RC showed superior OS in the UC group (58%, p&lt;0.001), with OS decreasing to 43% in SCC and 44% in AC. BPCRT showed lower 5-year OS in all selected histologies when compared to NAC followed by RC and RC alone (33% in UC, 27% in SCC and 24% in AC group). In all selected histologies, RT showed the lowest 5-year OS (10% in UC, 8% in SCC and 17% in AC group; p&lt;0.001). Furthermore, covariables associated with lower 5-year survival were male sex (p&lt;0.001) and TNM Stage 3 (p&lt;0.001). Conclusions: NAC followed by RC showed improved 5-year OS for UC. The benefit of NAC was marginal for SCC and AC histology. RC is better than BPCRT for all histologies. RT alone showed inferior 5-year OS for all histologies.[Table: see text]

Pembrolizumab for treating advanced urothelial carcinoma in patients with impaired performance status: Analysis of a Japanese nationwide cohort.

BackgroundThe benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum‐refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug.MethodsThis retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0–1, 2, and 3–4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2.ResultsThe numbers of patients with PS 0–1, 2, and 3–4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil–lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors.ConclusionsPS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR <3.5 and no liver metastasis may most greatly benefit from pembrolizumab therapy.

Discovery of Novel Protein Biomarkers in Urine for Diagnosis of Urothelial Cancer Using iTRAQ Proteomics

Urothelial carcinoma (UC) is the ninth most prevalent malignancy worldwide. Noninvasive and efficient biomarkers with high accuracy are imperative for the surveillance and diagnosis of UC. CKD patients were enrolled as a control group in this study for the discovery of highly specific urinary protein markers of UC. An iTRAQ-labeled quantitative proteomic approach was used to discover novel potential markers. These markers were further validated with 501 samples by ELISA assay, and their diagnostic accuracies were compared to those of other reported UC markers. BRDT, CYBP, GARS, and HDGF were identified as novel urinary UC biomarkers with a high discrimination ability in a population comprising CKD and healthy subjects. The diagnostic values of the four novel UC markers were better than that of a panel of well-known or FDA-approved urinary protein markers CYFR21.1, Midkine, and NUMA1. Three of our discovered markers (BRDT, HDGF, GARS) and one well-known marker (CYFR21.1) were finally selected and combined as a marker panel having AUC values of 0.962 (95% CI, 0.94-0.98) and 0.860 (95% CI, 0.83-0.89) for the discrimination between UC and normal groups and UC and control (healthy + CKD) groups, respectively.

Relationships among cigarette smoking, urinary biomarkers, and urothelial carcinoma risk: a case-control study.

Cigarette smoke is a known risk factor for urothelial carcinoma (UC). However, there is limited information about the distributions and effects of volatile organic compounds (VOCs) on smoking-related UC risk. With this hospital-based case-control study, we explored the associations between urinary levels of cotinine and VOC metabolites (acrylamide, 1,3-butadiene, and benzene) and the risk of UC. Urological examinations and pathological verifications were used to confirm the diagnoses of UC. All study participants provided smoking-related information via questionnaires and face-to-face interviews; they also provided urine samples for the measurement of VOC metabolites, cotinine, and 8-hydroxydeoxyguanosine (8-OHdG), which was used as an indicator of oxidative stress. We applied multiple logistic regression analysis to estimate the risk of UC, and we found that levels of urinary cotinine and 8-OHdG were higher in the UC group than in the control group. Furthermore, urinary levels of VOC metabolites, including N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine, N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine-3, trans,trans-muconic acid (t,t-MA), and S-phenylmercapturic acid (SPMA), increased with increasing levels of urinary cotinine. After adjusting for potential risk factors, dose-response relationships were observed between UC risk and urinary levels of AAMA, t,t-MA, SPMA, and 8-OHdG. Participants with high urinary levels of cotinine, AAMA, t,t-MA, SPMA, and 8-OHdG had risks of UC that were 3.5- to 6-fold higher than those of participants with lower levels. Future, large-scale investigations of the risks of UC should be explored, and repeated measurement of VOC metabolites should be assessed.

Prognostic significance of non-urothelial carcinoma of bladder: analysis of nationwide hospital-based cancer registry data in Japan.

To identify the prognosis of pure non-urothelial carcinoma (non-UC) of bladder and to compare them with those of pure urothelial carcinoma (UC). We used Japan's nationwide hospital-based cancer registry data to extract histologically confirmed pure non-UC and UC cases of bladder diagnosed in 2008-2009. We estimated the 5-year overall survival (OS) by a Kaplan-Meier analysis. A total of 8094 patients with confirmed histological subtypes of bladder cancer were identified. The most common pure non-UC was squamous cell carcinoma (SQ, n=192, 2.4%) followed by adenocarcinoma (AC, n=138, 1.7%) and small cell neuroendocrine carcinoma (SmC, n=54, 0.7%). The proportion of female patients (48%) was significantly higher in the SQ group compared with the pure UC group (P<0.001). The 5-year OS rate of the non-UC patients was significantly worse than that of the UC patients (40 vs. 61%, P<0.001). According to stages, the 5-year OS rates of the stage I and III non-UC patients were significantly worse than those of the UC patients (P=0.001). Considering histologic subtypes and stages, the 5-year OS rates of the stage I SQ patients were worse than those of the AC and SmC patients (46, 68 and 64%, respectively). The prognosis of pure non-UC was worse than that of pure UC, especially in the stage I and III non-UC patients. To improve these patients' oncologic outcomes, a more aggressive surgical approach may be necessary in stage I patients with non-UC, especially in pure SQ.

Signet-Ring Cell Carcinoma as an Independent Prognostic Factor for Patients With Urinary Bladder Cancer: A Population-Based Study

Background: Primary signet-ring cell carcinoma (SRCC) is a rare variation of adenocarcinoma. Although SRCC of the urinary bladder is highly malignant, it is often neglected due to its rarity.Materials and Methods: We used the national Surveillance, Epidemiology, and End Results (SEER) database (2004–2016) to compare SRCC with urothelial carcinoma (UC) and investigated the prognostic values of the clinicopathological characteristics and survival outcomes in SRCC of the urinary bladder. Multivariable Cox proportional hazard model, subgroup analyses, and propensity score matching (PSM) were used.Results: In all, 318 patients with SRCC and 57,444 patients with UC were enrolled. Compared with those with UC, patients with SRCC were younger at diagnosis (P < 0.001) and had higher rates of muscle invasive disease (P < 0.001), lymph node metastasis (P < 0.001), and distal metastasis (P < 0.001), as well as higher-grade tumors (P = 0.004). A Cox proportional hazard regression analysis showed that the SRCC group was associated with significantly higher risks of overall mortality (OM) compared with the UC group [hazard ratios (HR) = 1.44, 95% confidence intervals (95% CI) = 1.26–1.63, P < 0.0001]. Patients with SRCC also had a higher risk of cancer-specific mortality (CSM; HR = 1.40, 95% CI = 1.18–1.65, P < 0.0001). After PSM, the SRCC group also experienced higher risks of OM (HR = 1.45, 95% CI = 1.24–1.68, P < 0.0001) and CSM (HR = 1.47, 95% CI = 1.20–1.79, P = 0.0001) compared with the UC group. In the subgroup analyses, no significant interactions were observed in sex, age, N stage, M stage, and lymph nodes removed in terms of both OM and CSM.Conclusion: The prognosis of SRCC is poorer than that of UC, even after adjustment for baseline demographic and clinicopathological characteristic as well as cancer treatment. SRCC is an independent prognostic factor for patients with urinary bladder cancer.

The impact of histologic variants of urothelial carcinoma on clinical outcomes following trimodal bladder-preserving therapy.

421 Background: The current guidelines for muscle-invasive bladder cancer recommend the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, a trimodal approach involving the combination of maximal transurethral resection (TUR) and combined chemoradiotherapy is an alternative in selected patients. Clinical outcomes of patients with histologic variants have not well been known. Methods: From 1990 to 2015, 148 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal TUR of the bladder tumor, intra-arterial chemotherapy and radiotherapy at our institution. We compared complete response rate (CRR) of bladder preservation, 5-yr cause-specific survival (CSS), and 5-yr overall survival (OS) for the patients with pure urothelial carcinoma (UC) or variant UC. OS and CSS were analyzed by using the Kaplan-Meier method and log-rank test. Results: The median follow-up was 38.3 months. All patients were T2-T3N0M0 (T2, n = 90; T3, n = 58). There were no significant differences in clinical characteristics between pure and variant UC groups. Eleven (7%) of the 148 patients had variant UC; 7 (64%) had UC with squamous and/or glandular differentiation, and 4 (36%) had other forms, including sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), and clear cell variants (n = 1). There was no significant difference between pure UC and variant UC for CRR of bladder preservation (85% vs 82%, p = 0.66), the 5-yr CSS (88% vs 75%, p = 0.86) and the 5-yr OS (81% vs 75%, p = 0.66). Conclusions: Our findings indicate that trimodal bladder-preserving therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients with variant UC.

Clinical Significance of Squamous Differentiation in Urothelial Carcinoma of the Bladder.

The prognostic value of squamous differentiation (SD) in urothelial carcinoma (UC) of the bladder is unclear. The aim of this study was to identify the clinical significance of SD in UC in terms of oncological outcomes in patients undergoing radical cystectomy (RC). We evaluated consecutive patients with muscle-invasive bladder cancer (MIBC; clinical T2-4aN0M0) treated with RC at our institution from March 2003 to March 2017. We enrolled 20 and 81 patients with UC with SD (UCSD) and pure UC, respectively. Postoperative survival outcomes were compared between the patients with UCSD and pure UC using the Kaplan-Meier method. Pre- and postcystectomy factors that influenced the overall survival (OS) and recurrence-free survival (RFS) were investigated in these patients. Multivariate Cox regression models were used to identify the predictors of OS and RFS. With a median follow-up time of 31 months, the 5-year OS rate of the UCSD and pure UC groups was 41.1% and 69.7% (P = .002) and the 5-year RFS rate was 51.8% and 59.5% (P = .027), respectively. The shape of the Kaplan-Meier curves for UCSD suggested a more rapid course of the disease within the first 2 years than observed in pure UC. Multivariate analyses suggested that SD in UC was significantly associated with OS (hazard ratio [HR]: 4.22; 95% confidence interval [CI]: 1.20-14.8; P = .024) and close to significance for a lower RFS (HR: 2.13, 95% CI: 0.74-6.15, P = .064). Our results indicate that SD may be an independent predictor of OS and RFS in UC of MIBC in patients undergoing RC.

The Impact of Plasmacytoid Variant Histology on the Survival of Patients with Urothelial Carcinoma of Bladder after Radical Cystectomy

BackgroundThe clinical significance of the plasmacytoid variant (PCV) in urothelial carcinoma (UC) is currently lacking. ObjectiveTo compare clinical outcomes of patients with any PCV with that of patients with pure UC treated with radical cystectomy (RC). Design, setting, and participantsWe identified 98 patients who had pathologically confirmed PCV UC and 1312 patients with pure UC and no variant history who underwent RC at our institution between 1995 and 2014. Outcome measurements and statistical analysisUnivariable and multivariable Cox regression and Cox proportional hazards regression to determine if PCV was associated with overall survival (OS). Results and limitationsPatients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group (21% vs 4.1%, respectively, p<0.0001). Median OS for the pure UC versus the PCV patients were 8 yr and 3.8 yr, respectively. On univariable analysis, PCV was associated with an increased risk of overall mortality (hazard ratio=1.34, 95% confidence interval: 1.02–1.78, p=0.039). However, on multivariable analysis adjusted for age, sex, neoadjuvant chemotherapy received, lymph node status, pathologic stage, and soft margin status, the association between PCV and OS was no longer significant (hazard ratio=1.06, 95% confidence interval: 0.78, 1.43, p=0.7). This retrospective study is limited by the lack of pathological reanalysis, and the impact of other concurrent mixed histology cannot be determined in this study. ConclusionsPatients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor. Patient summaryPlasmacytoid urothelial carcinoma is a rare and aggressive form of bladder cancer. Patients with plasmacytoid urothelial carcinoma had worse adverse pathologic features, but this was not associated with worse overall mortality when compared with patients with pure urothelial carcinoma.

MP44-04 SIGNIFICANCE OF SERUM N-GLYCAN PROFILING AS A DIAGNOSTIC BIOMARKER IN UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2017MP44-04 SIGNIFICANCE OF SERUM N-GLYCAN PROFILING AS A DIAGNOSTIC BIOMARKER IN UROTHELIAL CARCINOMA Masaaki Oikawa, Shingo Hatakeyama, Tohru Yoneyma, Yuki Tobisawa, Takuma Narita, Hayato Yamamoto, Yasuhiro Hashimoto, Takuya Koie, Shintaro Narita, Atsushi Sasaki, Norihiko Tsuchiya, Tomonori Habuchi, Ippei Takahashi, Shigeyuki Nakaji, and Chikara Ohyama Masaaki OikawaMasaaki Oikawa More articles by this author , Shingo HatakeyamaShingo Hatakeyama More articles by this author , Tohru YoneymaTohru Yoneyma More articles by this author , Yuki TobisawaYuki Tobisawa More articles by this author , Takuma NaritaTakuma Narita More articles by this author , Hayato YamamotoHayato Yamamoto More articles by this author , Yasuhiro HashimotoYasuhiro Hashimoto More articles by this author , Takuya KoieTakuya Koie More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Atsushi SasakiAtsushi Sasaki More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Tomonori HabuchiTomonori Habuchi More articles by this author , Ippei TakahashiIppei Takahashi More articles by this author , Shigeyuki NakajiShigeyuki Nakaji More articles by this author , and Chikara OhyamaChikara Ohyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1335AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The clinical diagnosis of urothelial carcinoma (UC) relies on invasive methods in patients with hematuria. Although more sensitive and noninvasive screening methods are required, a specific serum biomarker for UC is lacking.To examine whether the serum glycan-based biomarkers can be applied to detecting UC. METHODS Between April 1994 and June 2016, serum N-glycan concentrations were retrospectively measured in 212 patients with UC before treatment (UC group) and 212 pair-matched controls (VLT group) using glycoblotting and mass spectrometry.N-glycan levels were compared between the groups using receiver operating characteristic (ROC) curves to select candidate N-glycans. We created an N-glycan score based on the combination of candidate N-glycans. The specificity and sensitivity of the candidate N-glycan score were evaluated using ROC curves. RESULTS The N-glycan score was calculated using six N-glycans (m/z 1566, 1687, 1769, 1871, 2011, 2337) that were significantly associated with UC. The median N-glycan score was significantly higher in the UC group than in the VLT group (5.0 vs. 1.0, P < 0.001). The predictive value of the N-glycan score for UC detection was significant, with a sensitivity, specificity, and area under the curve of 93%, 81%, and 0.95%, respectively. CONCLUSIONS Serum N-glycan content has the potential to be a specific and sensitive novel serum biomarker that may improve the accuracy of detection for UC and reduce unnecessary invasive screening. Validation of this test in a large-scale prospective study is needed. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e564-e565 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Masaaki Oikawa More articles by this author Shingo Hatakeyama More articles by this author Tohru Yoneyma More articles by this author Yuki Tobisawa More articles by this author Takuma Narita More articles by this author Hayato Yamamoto More articles by this author Yasuhiro Hashimoto More articles by this author Takuya Koie More articles by this author Shintaro Narita More articles by this author Atsushi Sasaki More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Ippei Takahashi More articles by this author Shigeyuki Nakaji More articles by this author Chikara Ohyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Significance of Serum N-glycan Profiling as a Diagnostic Biomarker in Urothelial Carcinoma

BackgroundThe clinical diagnosis of urothelial carcinoma (UC) relies on invasive methods in patients with hematuria. Although more sensitive and noninvasive screening methods are required, a specific serum biomarker for UC is lacking. ObjectiveTo examine whether serum glycan-based biomarkers can be applied to UC detection. Design, setting, and participantsBetween April 1994 and June 2016, serum N-glycan concentrations were retrospectively measured in 212 patients with UC before treatment (UC group) and 212 pair-matched controls using glycoblotting and mass spectrometry. Outcome measurements and statistical analysisN-glycan levels were compared between the groups using receiver operating characteristic curves to select candidate N-glycans. We created an N-glycan score based on the combination of candidate N-glycans. The specificity and sensitivity of the candidate N-glycan score were evaluated using receiver operating characteristic curves. Results and limitationsThe N-glycan score was calculated using six N-glycans (m/z 1566, m/z 1687, m/z 1769, m/z 1871, m/z 2011, and m/z 2337) that were significantly associated with UC. The median N-glycan score was significantly higher in the UC group than in the pair-matched control group (5.0 vs 1.0, p<0.001). The N-glycan score correctly classified UC patients with a sensitivity, specificity, and area under the curve of 93%, 81%, and 0.95, respectively. The limitations of our study included its retrospective nature and nonclinical setting. ConclusionsSerum N-glycan content has the potential to be a specific and sensitive novel serum biomarker that may improve the accuracy of the detection for UC and reduce unnecessary invasive screening. Validation of this test in a large-scale prospective study is needed. Patient summaryCombination of serum N-glycan (N-glycan score) is a novel serum marker for urothelial carcinoma that is expressed by 93% of patients and thus is far more sensitive than classic urine cytology. Validation in a large patient cohort is needed.

MCM10 overexpression implicates adverse prognosis in urothelial carcinoma.

Urothelial carcinoma (UC) occurs in the upper urinary tract (UTUC) and the urinary bladder (UBUC). The molecular pathogenesis of UC has not been fully elucidated. Through data mining of a published transcriptome of UBUC (GSE31684), we identified Minichromosome Maintenance Complex Component 2 (MCM2) and MCM10 as the two most significantly upregulated genes in UC progression among the MCM gene family, the key factors for the initiation of DNA replication. To validate the clinical significance of MCM2 and MCM10, immunohistochemistry, evaluated by H-score, was used in a pilot study of 50 UTUC and 50 UBUC samples. Only a high expression level of MCM10 predicted worse disease-specific survival (DSS) and inferior metastasis-free survival (MeFS) for both UTUC and UBUC. Correspondingly, evaluation of MCM10 mRNA expression in 36 UTUCs and 30 UBUCs showed significantly upregulated levels in high stage UC, suggesting its role in tumor progression. Evaluation of 340 UTUC and 296 UBUC tissue samples, respectively, demonstrated that high MCM10 immunoexpression was significantly associated with advanced primary tumors, nodal status, and the presence of vascular invasion in both groups of UCs. In multivariate Cox regression analyses, adjusted for standard clinicopathological features, MCM10 overexpression was independently associated with DSS (UTUC hazard ratio [HR]=2.401, P = 0.013; UBUC HR=4.323, P=0.001) and with MeFS (UTUC HR=3.294, P<0.001; UBUC HR=1.972, P=0.015). In vitro, knockdown of MCM10 gene significantly suppressed cell proliferation in both J82 and TCCSUP cells. In conclusion, MCM10 overexpression was associated with unfavorable clinicopathological characteristics and independent negative prognostic effects, justifying its potential theranostic value in UC.