Urothelial Carcinoma Of The Upper Urinary Tract Research Articles

Diagnostic and Therapeutic Challenges of Rare Urogenital Cancers: Urothelial Carcinoma of the Renal Pelvis, Ureters and Urethra.

Urothelial carcinoma (UC) is a neoplastic growth that affects the lining of the urinary tract from the renal pelvis to the distal urethra. Urothelial cancer occurs less commonly along the upper urinary tract (renal pelvis and ureter) accounting for 5-10% and even rarer along the urethra approximately less than 1%. The incidence of UC of the upper urinary tract and urethra has been reported in the United States and Europe by the Surveillance, Epidemiology, and End Results Program and the Rare Cancers in Europe project, respectively. Considering the rarity of upper tract urothelial carcinoma (UTUC) and primary urethral cancer (PUC), there is a paucity of data from Sub-Saharan Africa. Both the European Association of Urology guideline and the National Comprehensive Cancer Network guideline have provided some clinical updates on the management of UTUC and PUC. However, UTUC and PUC present mostly at a more advanced stage than UC of bladder. A high index of suspicion is necessary for diagnosis even more for UTUC. Organ-sparing surgery is possible for both localized UTUC and PUC but stringent follow-up with urine cytology, endoscopy and imaging is mandated for early detection of recurrence.

UroVysion® predicts intravesical recurrence after radical nephroureterectomy for urothelial carcinoma of the upper urinary tract: a prospective study.

Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for urothelial carcinoma of the upper urinary tract (UCUUT) is common. One of the mechanisms driving this is the implantation of cancer cells from the UCUUT at the RNUs. Therefore, their detection after RNU can assist in predicting IVR. This study aimed to examine the utility of UroVysion® as a tool for predicting bladder recurrence after RNU for UCUUT. We prospectively enrolled 65 patients who received RNU for high-grade UCUUT between October 2013 and April 2017. Of the 65 patients, 54 (83.1%) who had both bladder urine samples available immediately after RNU (0 postoperative days: POD) and 5days after RNU (5POD) were selected. We performed UroVysion® and cytology. Twenty-two patients showed IVR with 32 foci. UroVysion® results at 0POD (26 patients, 48.1%) and/or 5POD (31 patients, 57.4%) were positive in 42 (77.8%) patients. The sensitivity, specificity, positive predictive value, and negative predictive value of UroVysion® for included cases were measured for both 0POD and 5POD samples; they were determined to be 95.5% (21/22), 34.4% (11/32), 50.0% (21/42), and 91.7% (11/12), respectively. For cytology, these values were 75.0% (15/20), 52.9% (18/34), 48.4% (15/31), and 78.3% (18/23), respectively. Forty-two (64.6%) patients who were UroVysion®-positive demonstrated IVR. The IVR rate between the group positive for either 0POD or 5POD and that negative for both significantly differed for both UroVysion® (p = 0.019) and cytology (p = 0.046). Multiple urine tests using UroVysion® after RNU could be a useful predictor for IVR.

PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations.

TPS5095 Background: Radical surgery ± cisplatin‐based (neo)adjuvant chemotherapy (NAC) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients are unable to receive NAC due to cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a FGFR1–3 selective oral tyrosine kinase inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in patients with high-risk invasive urothelial carcinoma and susceptible FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 patients. Adults with high-risk invasive UTUC or UBC with susceptible FGFR3 genetic alterations (i.e. activating mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for or refusing cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin-based NAC are eligible. Those who received non cisplatin-based NAC are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Patients receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include quality of life, pharmacokinetics, cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. The study was initiated in late 2019 and is expected to end in 2024. Clinical trial information: NCT04197986 .

Contemporary conditional cancer-specific survival after radical nephroureterectomy in patients with nonmetastatic urothelial carcinoma of upper urinary tract.

To examine the effect of conditional survival on 5-year cancer-specific survival (CSS) probability after radical nephroureterectomy (RNU) in a contemporary cohort of patients with non-metastatic urothelial carcinoma of the upper urinary tract (UTUC). Within the Surveillance, Epidemiology and End Results database (2004-2015), 6826 patients were identified. Conditional 5-year CSS estimates were assessed after event-free follow-up duration. Multivariable Cox regression (MCR) models predicted cancer-specific mortality (CSM) according to event-free follow-up length. Overall, 956 (14.0%) were T1 low grade(LG)N0 , 1305 (19.1%) T1 high grade(HG)N0 , 1215 (17.8%) T2 N0 , 2249 (32.9%) T3 N0 and 1101 (16.1%) T4 N0 /Tany N1-3 . From baseline, 93.4% to 94.2% in T1 LGN0 provided 5-year CSS and, respectively, 86.2% to 95.3% in T1 HGN0 , 77.5% to 87.8% in T2 N0 , 63.0% to 91.1% in T3 N0 , and 38.8% to 88.2% in T4 N0 /Tany N1-3 . In MCR models, relative to T1 LGN0 , T1 HGN0 (Hazard ratio [HR] 1.7), T2 N0 (HR 3.0), T3 N0 (HR: 5.2), and T4 N0 /Tany N1-3 (HR 11.9) were independent predictors of higher CSM. Conditional HRs decreased to levels equivalent to T1 LGN0 at 3 years vs 5 years of event-free survival for T1 HGN0 and all other groups, respectively. A direct relationship exists between event-free follow-up and survival probability after RNU. From a clinical perspective, such survival estimates may have particular importance during preoperative counseling.

PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations.

TPS600 Background: Radical surgery ± cisplatin‐based (neo)adjuvant therapy (NAT) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients (pts) are unable to receive NAT because of cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC, and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a selective FGFR1–3 inhibitor, has shown promising clinical activity and tolerability in pts with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in pts with high-risk invasive urothelial carcinoma and FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 pts. Adults with high-risk invasive UTUC or UBC with FGFR3 genetic alterations (i.e. mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin- based NAT are eligible. Those who received non cisplatin-based NAT are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Pts receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include: quality of life; pharmacokinetics; cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. Enrollment is expected to begin in January 2020. Trial registration: EudraCT 2019-003248-63. Clinical trial information: EudraCT 2019-003248-63.

Special Issue on Molecular Research Efforts in Urothelial Carcinoma: Summary of Included Topics

This Special Issue of International Journal of Molecular Sciences (IJMS) covers one of the most intriguing and emerging fields in terms of molecular oncology and uro-oncologic research efforts over the recent years, namely urothelial carcinoma of the bladder (UCB), as well as urothelial carcinoma of the upper urinary tract (UTUC). A total of 8 articles published in this Special Issue highlight the current progress in molecular oncology and cancer genetics in UCB, including a wide range of research topics, such as FGFR-inhibitors, sarcopenia in UCB, molecular predictors of response following neoadjuvant chemotherapy, exercise cardiac training impacts in the murine UCB model, Obatoclax, tropomyosins as potential biomarkers, immunotherapeutic approaches, as well as a transcriptional analysis of immunohistochemically defined UCB-subgroups. Find a brief summary of the respective articles below.

5-Fluorouracil-based adjuvant chemotherapy improves the clinical outcomes of patients with lymphovascular invasion of upper urinary tract cancer and low expression of dihydropyrimidine dehydrogenase.

Lymphovascular invasion (LVI) by urothelial carcinoma of the upper urinary tract (UC-UUT) is associated with an unfavorable prognosis. However, a high proportion of patients with UC-UUT are unable to receive the recommended doses of cisplatin-based adjuvant chemotherapy due to advanced age or renal dysfunction resulting from nephroureterectomy. Tegafur-uracil is an oral form of 5-fluorouracil whose efficacy is influenced by the activities of enzymes associated with its metabolism, such as dihydropyrimidine dehydrogenase (DPD), orotatephosphoribosyltransferase (OPRT) and thymidylate synthase (TS). The aim of the present study was to investigate the efficacy of adjuvant 5-fluorouracil chemotherapy for UC-UUT with LVI, and to assess the expression of enzymes associated with 5-fluorouracil metabolism as promising biomarkers of therapy efficacy. The present study retrospectively investigated 52 cases of UC-UUT. Following nephroureterectomy, tegafur-uracil was administered to 15 out of 30 patients with LVI who were not eligible for cisplatin-based adjuvant chemotherapy. Levels of DPD, OPRT and TS expression in tumor specimens were determined by reverse transcription-quantitative polymerase chain reaction, and their associations with the efficacy of adjuvant 5-fluorouracil chemotherapy were analyzed. The levels of DPD, OPRT and TS expression were not associated with pathological factors or outcome, although a higher expression of TS was associated with a poorer outcome. Adjuvant 5-fluorouracil chemotherapy significantly improved the outcome of patients with lower DPD expression. However, the levels of OPRT and TS expression did not influence therapeutic efficacy. Adjuvant 5-fluorouracil chemotherapy appears to be effective for lymphovascular-invasive UC-UUT in patients with lower DPD expression.

Value of imaging in upper urinary tract tumors

Staging of bladder cancer, hematuria as well as the evaluation of unclear findings of the kidneys and ureters are the most frequent indications for imaging of the upper urinary tract (UUT). Endourological assessment of the UUT is much more invasive compared to imaging of the bladder, raising the question of the optimal imaging technique. Several technical improvements regarding computed tomography (CT) as well as magnetic resonance imaging (MRI) were implemented in recent years. To compare the efficacy and limitations of the most important imaging techniques regarding the UUT. Systematic review of the literature and current German, European, and American guidelines regarding bladder cancer, urothelial carcinoma of the UUT and hematuria. The CT-based urography has superseded excretory urography and is the first choice for imaging of the UUT. In case of contraindications, MRI is afeasible alternative. In all cases, aurography phase is indispensable. Imaging of the UUT has to be used in areasonable combination together with endourological methods and cytology. Optical coherence tomography, confocal laser endomicroscopy and scientific innovations such as radiomics might improve UUT imaging and differential diagnosis of UUT lesions in the future.

Molecular subtype classification of urothelial carcinoma in Lynch syndrome.

Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome‐associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome‐associated UC. Thus, Lynch syndrome‐associated UCs of the upper urinary tract and the urinary bladder were identified in the Danish hereditary nonpolyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole‐genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from patients with Lynch syndrome were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data were analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome‐associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome‐associated UC as urothelial‐like tumors with only 20% being genomically unstable, basal/SCC‐like, or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger datasets revealed that Lynch syndrome‐associated UC shares molecular similarities with sporadic UC. In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the urothelial‐like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch‐repair defective subset.

Adjuvant Radiation Therapy for High Stage Urothelial Carcinoma of the Upper Urinary Tract

The role of adjuvant radiation therapy after curative surgery to high stage urothelial carcinoma (transitional cell carcinoma) of the renal pelvis and ureter has not been proved in large randomized controlled trials and is controversial in clinical practice because of its rarity. Furthermore, the NCCN guideline has mentioned about the role of adjuvant chemotherapy (CT) but not adjuvant radiotherapy (RT) in such patents. The aim of this study is to define the benefit of adjuvant RT following curative surgery of high stage urothelial carcinoma of the upper urinary tract (UTUC) by determining the clinical outcomes. Between 2006 and 2015, patients with pathologic T3/4 and/or N+ UTUC who underwent nephroureterectomy with bladder cuff resection (NUR+BCR) were retrospectively examined at our institution. The administration of adjuvant RT or CT was at physician’s discretion. The Kaplan-Meier method was used to estimate cancer-specific survival (CSS), locoregional recurrence-free survival (LRFS), bladder recurrence-free survival (BRFS) and distant metastasis-free survival (DMFS). Differences in risk-adjusted outcomes between RT and non-RT groups were assessed using a multivariate Cox proportional Hazards model. A total of 106 patients had pT3-4 and/or N+ UTUC. Postoperative RT was administered in 20 (18.9%) of patients. Median dose of RT was 50.4 Gy (range, 45.0 to 64.8 Gy). With a median follow-up of 29.3 months, 3-year CSS were 84.4% vs. 73.1% (p=0.320), 3-year LRFS were 81.5% vs. 60.9% (p=0.102), 3-year BRFS were 92.3% vs. 77.4% (p=0.306) and 3-year DMFS were 73.1% vs. 59.1% (p=0.386) in the RT vs. non-RT groups, respectively. On multivariate analysis, patients with the administration of adjuvant RT had a better LRFS (HR, 0.04; 95% CI 0.002 to 0.591; p=0.02) and better trend in CSS (HR, 0.12; 95% CI, 0.01 to 1.12; p=0.06). However, no statistically significant difference in BRFS and DMFS between RT and non-RT groups could be demonstrated. Adjuvant RT following curative surgery may improve locoregional control and potentially improve survival in patients with high stage UTUC. Beyond the NCCN guideline suggestion other than adjuvant CT for such patients, adjuvant RT may be another considerable modality for such patients, especially as an alternative treatment for patient who is not suitable to receive CT.

Clinical and demographic characteristics among patients with urothelial carcinomas of the upper urinary tract and bladder in Taiwan

BackgroundUrothelial carcinoma (UC) is derived from the urothelium of the urinary tract, and includes cancers of the bladder, renal pelvis and ureter. The aim of this study was to investigate the clinical and demographic features among patients with bladder cancer and urothelial carcinoma of the upper urinary tract (UTUC) in Taiwan. MethodsThe present study recruited a total of 736 histopathologically confirmed UC cases, which consisted of 470 bladder cancer and 266 UTUC between September 1998 and December 2009. Clinical and demographic features were collected by an interview utilizing a structured questionnaire, and supplemented by medical chart review. This study was approved by institutional review boards of the collaborating hospitals. The multivariate Cox proportional hazards model was performed to investigate prognostic factors for disease-free survival (DFS) and overall survival (OS). All statistical analyses were performed using the Statistical Analysis Software for Windows, version 9.1 (SAS Institute, Cary, NC, USA). ResultsUTUC patients had higher proportions of advanced clinical stage (T2–4) and poor cell differentiation (G3). Bladder cancer patients with advanced clinical stages (T2–3 and T4) had increased risks of poorer OS (hazard ratio, HR = 1.7 and 3.9, respectively). UTUC patients with the advanced clinical stage (T4) had a significantly greater risk of poorer OS (HR = 8.7). Bladder cancer patients with a high grade (G2–3) had a significantly increased risk of poorer OS (HR = 3.8). ConclusionBased on the limited parameters and heterogeneous data, the present study merely observed that bladder cancer and UTUC patients with the higher tumor stage have a significant increased risk of poor overall survival. Therefore, the causal mechanisms of UC prognosis remained to be further explored in a larger population.

Association between lymph node yield and survival among patients undergoing radical nephroureterectomy for urothelial carcinoma of the upper tract.

Prior studies examining the value of lymph node (LN) dissection (LND) in patients with urothelial carcinoma of the upper urinary tract (UTUC) have produced conflicting results. The objective of the current study was to assess the relationship between LN yield and survival among patients undergoing radical nephroureterectomy (RNU). The National Cancer Data Base was used to identify patients with non-metastatic UTUC who were treated with RNU between 2004 and 2012. The association between LN yield and overall survival (OS) was assessed using Cox proportional hazards regression, with adjustment for patient, tumor, and facility characteristics. Of the 14,472 patients, 2926 (20%) underwent LND. The median yield was 2 LNs (interquartile range 1-6 LNs). Among the entire cohort and the LN-negative (pN0) subgroup, a higher LN yield was associated with lower all-cause mortality (multivariable hazard ratio [HR] 0.94 per 5 LNs removed, 95% confidence interval [95% CI] 0.89-1.00 [P = .034] for the entire cohort and HR 0.86, 95% CI 0.79-0.94 [P = .001] for the pN0 subgroup). Among patients with positive LNs (pN+), there was no association noted between LN yield and OS; however, positive and negative LN counts were found to be independent predictors of OS (HR 1.27 per 5 positive LNs, 95% CI 1.16-1.39 [P<.001] and HR 0.90 per 5 negative LNs, 95% CI 0.82-1.00 [P = .049]). In this large, contemporary cohort of patients with UTUC, LND was found to be used infrequently despite evidence that a higher LN yield is associated with lower all-cause mortality. Cancer 2017;123:1741-1750. © 2017 American Cancer Society.

Prognostic Role of Neutrophil-to-lymphocyte Ratio-based Markers During Pre- and Postadjuvant Chemotherapy in Patients With Advanced Urothelial Carcinoma of Upper Urinary Tract.

The aim of the present study was to assess the prognostic significance of neutrophil-to-lymphocyte ratio (NLR)-based markers before and after adjuvant chemotherapy (ACH) in patients with urothelial carcinoma of the upper urinary tract (UTUC) undergoing radical nephroureterectomy (RNU) and ACH. The data from 112 patients with advanced UTUC who had undergone first-line ACH after RNU from 1994 to 2012 were reviewed. After excluding 22 patients, the clinicopathologic data for 90 patients were analyzed, in particular, the NLR and derived NLR (dNLR) preoperatively and before and after ACH. Cancer-specific survival (CSS) and overall survival (OS) outcomes were measured using Kaplan-Meier analysis. To identify the predictors for the oncologic outcomes, a multivariate Cox regression model was used. Patients with a higher preoperative NLR, pre-ACH dNLR, and post-ACH dNLR had poorer CSS and OS than their counterparts with lower values. After adjustment of various clinicopathologic factors, age at surgery (≥ 65 years; hazard ratio [HR], 3.13) and higher post-ACH dNLR (HR, 3.06) remained significant predictors for CSS. Similarly, age (≥ 65 years; HR, 2.90) and elevated post-ACH dNLR (≥ 2.3; HR, 2.89) were also identified as predictors of OS on multivariate analysis. A higher post-ACH dNLR was independently predictive of poor CSS and OS in patients with advanced UTUC receiving systemic ACH after RNU. From the obtained data, we propose that the NLR-based marker could be a readily available and valuable biomarker for predicting oncologic outcomes after chemotherapy.

Sarcopenia predicts survival outcomes among patients with urothelial carcinoma of the upper urinary tract undergoing radical nephroureterectomy: a retrospective multi-institution study.

We aimed to evaluate the effect of sarcopenia, a condition of low muscle mass, on the survival among patients who were undergoing radical nephroureterectomy (RNU) for urothelial carcinoma of the upper urinary tract (UCUT). We retrospectively reviewed consecutive patients with UCUT (cT[any]N0M0) who underwent RNU between 2003 and 2013 at our department and its affiliated institutions. Preoperative computed tomography images were used to calculate each patient's skeletal muscle index, an indicator of whole-body muscle mass. Sarcopenia was defined according to the sex-specific consensus definitions, based on the patient's skeletal muscle and body mass indexes. We analyzed the relapse-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) after RNU to identify factors that predicted patient survival. A total of 137 patients were included, and 90 patients (65.7%) were diagnosed with sarcopenia. Compared to the non-sarcopenic patients, the sarcopenic patients had a significant inferior 5-year RFS (48.8 vs. 79.6%, p=0.0002), CSS (57.1 vs. 92.6%, p<0.0001), and OS (48.2 vs. 90.6%, p<0.0001). Multivariate analyses revealed that sarcopenia was an independent predictor of shorter RFS, CSS, and OS (all, p<0.0001). Sarcopenia was an independent predictor of survival among patients with UCUT who were undergoing RNU.

Preoperative pyuria predicts advanced pathologic tumor stage and worse survival in patients with urothelial carcinoma of the upper urinary tract treated by radical nephroureterectomy

ObjectivesTo investigate the association of preoperative pyuria with pathologic features and oncologic outcomes in patients with urothelial carcinoma of the upper urinary tract (UTUC) treated by radical nephroureterectomy (RNU). Material and methodsA cohort of 176 patients treated with RNU from January 2001 to December 2014 were retrospectively reviewed. Logistic regression and survival analysis methodology was used to investigate the association of preoperative pyuria with clinicopathologic outcomes. ResultsAmong this cohort, 36 (20.5%) presented with preoperative pyuria. Logistic regression revealed that pyuria was significantly associated with advanced pT stage (P = 0.001). During a median follow-up of 41 months (interquartile range: 22–60), 65 (37%) patients died, including 54 (31%) from UTUC. Overall survival rates at 3 year and 5 years in patients with pyuria were significantly lower than those in patients without pyuria (62.3% and 36.1% vs. 78.4% and 65.3%, respectively; P = 0.004). Also, cancer-specific survival rates at 3 year and 5 years in patients with pyuria were significantly lower than in patients without pyuria (65.7% and 50% vs. 80% and 67.6%, respectively; P = 0.016). Furthermore, in the multivariate analysis, after incorporating only preoperative factors, pyuria was found to be an independent predictor of overall survival and cancer-specific survival (P = 0.005 and P = 0.028, respectively). ConclusionsPreoperative pyuria among UTUC patients underwent RNU was significantly associated with advanced pathologic tumor stage and worse survival. Our data suggested that pyuria as a prognostic predictor could be valuable in preoperative risk stratification and guiding better therapeutic approaches, but further validation in a larger population is needed.

Analysis of prostate cancer foci in patients with transrectal 10-core systemic random biopsy—Can we predict pathological stage of prostate cancer through trus biopsy?

Analysis of prostate cancer foci in patients with transrectal 10-core systemic random biopsy—Can we predict pathological stage of prostate cancer through trus biopsy?

Subcellular localisation of anillin is associated with different survival outcomes in upper urinary tract urothelial carcinoma

BackgroundThe protein anillin (ANLN) has important roles in cell cytokinesis. Until now, no studies have evaluated the role of ANLN expression in a large cohort of patients with urothelial carcinoma...

MP7-14 EXPRESSION OF STEROID HORMONE RECEPTORS AND ITS PROGNOSTIC SIGNIFICANCE IN UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (UCUUT)

You have accessJournal of UrologyBladder Cancer: Upper Tract TCC II1 Apr 2015MP7-14 EXPRESSION OF STEROID HORMONE RECEPTORS AND ITS PROGNOSTIC SIGNIFICANCE IN UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (UCUUT) Eiji Kashiwagi, Kazutoshi Fujita, Seiji Yamaguchi, Hiroaki Fushimi, Leonardo Reis, George Netto, Norio Nonomura, and Hiroshi Miyamoto Eiji KashiwagiEiji Kashiwagi More articles by this author , Kazutoshi FujitaKazutoshi Fujita More articles by this author , Seiji YamaguchiSeiji Yamaguchi More articles by this author , Hiroaki FushimiHiroaki Fushimi More articles by this author , Leonardo ReisLeonardo Reis More articles by this author , George NettoGeorge Netto More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.221AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Emerging evidence suggests that the steroid hormone receptor signaling pathways play an important role in the outgrowth of urothelial carcinoma. Although recent studies have assessed the expression of androgen receptor (AR), estrogen receptors (ERs), glucocorticoid receptor (GR), and/or progesterone receptor (PR) in bladder tumor specimens, their status in UCUUT remains largely unknown. METHODS We immunohistochemically stained for AR, ERα, ERβ, GR, and PR in the tissue microarrays consisting of 99 UCUUT samples and paired non-neoplastic urothelium from each case. We then analyzed the associations between their expression and clinicopathologic features available for our patient cohort. RESULTS AR/ERα/ERβ/GR/PR was positive in 20%/18%/63%/63%/16% of tumors, which was significantly lower (except PR) than in benign urothelial tissues [58% (P<0.001)/41% (P<0.001)/85% (P<0.001)/84% (P=0.001)/13% (P=0.529)]. AR expression (11% vs. 28%; P=0.045) and ERβ expression (51% vs. 68%; P=0.056) were significantly and marginally, respectively, down-regulated in renal pelvic tumors, compared with ureteral tumors, whereas ERα expression (22% vs. 12%; P=0.2723), GR expression (58% vs. 68%; P=0.395), and PR expression (9% vs. 20%; P=0.155) were similar between the two groups. AR/PR expression also tended to be higher (P=0.072)/lower (P=0.052) in male tumors (27%/10%) than in female tumors (10%/26%), while no significant difference in the positivity of ERα (17% vs. 21%; P=0.790), ERβ (58% vs. 69%; P=0.296), or GR (67% vs. 56%; P=0.395) between genders was seen. In addition, there were no significant associations between expression pattern of each receptor and tumor grade or stage (pT/pN). Kaplan-Meier and log-rank tests further revealed no significant prognostic value of AR, ERα, ERβ, GR, or PR expression in these 99 patients. However, ERα (P=0.040) or PR (P=0.040) positivity in 54 patients with pT3 or pT4 tumor was strongly associated with disease-specific mortality. CONCLUSIONS In accordance with previous observations in bladder specimens, significant decreases in the expression of AR, ERα, ERβ, or GR in UCUUT were observed, compared with non-neoplastic urothelium. In contrast, no strong correlations of each receptor expression with tumor grade or stage were found. Nonetheless, our results further support the involvement of AR/ERα/ERβ/GR/PR signals in the development and progression of UCUUT. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e69 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eiji Kashiwagi More articles by this author Kazutoshi Fujita More articles by this author Seiji Yamaguchi More articles by this author Hiroaki Fushimi More articles by this author Leonardo Reis More articles by this author George Netto More articles by this author Norio Nonomura More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Comparison of the clonality of urothelial carcinoma developing in the upper urinary tract and those developing in the bladder

PurposeTo identify the origin of synchronous and metachronous urothelial carcinoma (UC) of the bladder and upper urinary tract to get a better understanding of the basic mechanism behind the multifocality of UC, which may provide a sound bases for the future development of new strategies for detection, prevention and therapy.MethodsSix patients with UC of the bladder and synchronous or metachronous UC of the upper urinary tract were studied. Genetic analysis involving the study of loss of heterozygosity (LOH) has been evaluated on their tumours using well characterised and new markers of UC (D9S171, D9S177, D9S303 and TP53).ResultsFive of the six patients demonstrated informative results. Four of five (80%) of patients had synchronous or metacharonous UC tumour and showed patterns of LOH consistent with tumorigenesis from monoclonal tumour origin. One of five (20%) patients exhibited a LOH consistent with oligoclonal tumorigenesis.ConclusionThese findings suggest that both the monoclonal and field cancerization theory of tumorigenesis may play a role in tumors of the urothelial tract. However, more data is needed.

Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing.

In humans, exposure to aristolochic acid (AA) is associated with urothelial carcinoma of the upper urinary tract (UTUC). Exome sequencing of UTUCs from 19 individuals with documented exposure to AA revealed a remarkably large number of somatic mutations and an unusual mutational signature attributable to AA. Most of the mutations (72%) in these tumors were A:T-to-T:A transversions, located predominantly on the nontranscribed strand, with a strong preference for deoxyadenosine in a consensus sequence (T/CAG). This trinucleotide motif overlaps the canonical splice acceptor site, possibly accounting for the excess of splice site mutations observed in these tumors. The AA mutational fingerprint was found frequently in oncogenes and tumor suppressor genes in AA-associated UTUC. The AA mutational signature was observed in one patient's tumor from a UTUC cohort without previous indication of AA exposure. Together, these results directly link an established environmental mutagen to cancer through genome-wide sequencing and highlight its power to reveal individual exposure to carcinogens.