Concomitant Carcinoma In Situ Research Articles

Pattern and risk factors of intravesical recurrence after nephroureterectomy for upper tract urothelial carcinoma: A large Chinese center experience

There is currently no consensus about the pattern and risk factors of bladder recurrence after nephroureterectomy, especially in the Chinese population. We evaluated the pattern and risk factors based on data from a large Chinese center. The clinical and pathological data of 438 patients with upper tract urothelial carcinoma (UTUC), who underwent nephroureterectomy at Peking University First Hospital, Beijing, China between 2000 and 2010, was retrospectively analyzed. Univariate analysis by log-rank test and multivariate analysis by Cox proportional hazards regression model were used to determine the independent risk factors. A total of 135 patients (30.8%) developed intravesical recurrence within a median follow-up of 45 months (range: 12-144 months). The median interval of bladder recurrence was 15 months (range: 2.0-98.0 months), and the two peaks for recurrence were 4-6 months and 17-19 months. Lower tumor grade, tumor multifocality, concomitant carcinoma in situ (CIS) and tumors located in the lower ureter were significant risk factors by univariate and multivariate analysis. A risk-scoring system was developed and a significant difference was found between different risk evaluations. Patients with concomitant CIS tended to develop a late bladder recurrence. One hundred and eighteen patients (87.4%) received transurethral resection after bladder tumor recurrence. Lower tumor grade, tumor multifocality, concomitant CIS and tumors located in the lower ureter tend to be predictive for bladder recurrence after nephroureterectomy, although the underlying mechanism is not fully elucidated, and the scoring system could help risk stratification. Most recurrent tumors could be treated by transurethral resection and there were two peaks for recurrence, which is probably related to the mechanisms and may be unique to the Chinese population.

Ki-67 is an independent indicator in non–muscle invasive bladder cancer (NMIBC); Combination of EORTC risk scores and Ki-67 expression could improve the risk stratification of NMIBC

ObjectiveTo prove the predicting role of Ki-67 expression and to demonstrate that the combination of European Organization for Research and Treatment of Cancer (EORTC) risk scores and Ki-67 staining status could improve the risk stratification in a large series of patients with non–muscle invasive bladder cancer (NMIBC). Material and methodsFrom October 2002 to July 2010, in our cohort, 332 patients who were treated with transurethral resection of the bladder tumor were diagnosed with NMIBC by histopathologic analysis. Two experienced uropathologists rereviewed the slides. The EORTC risk scores for recurrence and progression were determined. Ki-67 expression was evaluated using immunohistochemical studies and scored for intensity and area of staining. We correlated Ki-67 expression scores with clinical and pathologic variables. We evaluated the prognosis role of EORTC risk scores, Ki-67 staining, and their combination on tumor recurrence-free survival and progression-free survival (PFS) by univariate analysis, multivariate analysis, and Kaplan-Meier survival curves. ResultsWith a median follow-up of 47 (range, 2–124) months, 119 patients (35.8%) had tumor recurrence and 40 patients (12%) had tumor progression. Ki-67 positivity (Ki-67>25%) was reported in 108 tumors (32.5%), and it was significantly associated with high EORTC risk scores for both tumor recurrence and progression. In univariate analysis, multifocality, tumor size, tumor stage, tumor grade, and Ki-67 staining correlated with recurrence-free survival, whereas tumor size, tumor stage, tumor grade, concomitant CIS, and Ki-67 staining correlated with PFS. In multivariable analysis, Ki-67 expression was an independent risk factor for predicting tumor recurrence (hazard ratio, 2.14; P<0.0001) and progression (hazard ratio: 2.97, P = 0.004). Kaplan-Meier curves showed that combining EORTC risk scores and Ki-67 staining led to more accurate prediction for tumor recurrence and progression (log-rank test; P<0.0001). ConclusionsKi-67 positivity is prognostic for predicting tumor recurrence and progression. Combination of EORTC risk scores with Ki-67 expression could improve the risk stratification for both recurrence and progression in NMIBC.

Impact of concomitant carcinoma in situ on upstaging and outcome following radical cystectomy for bladder cancer

To evaluate the impact of concomitant carcinoma in situ (CIS) on upstaging and outcome of patients treated with radical cystectomy with pelvic lymph node dissection. We collected and pooled a database of 1,968 patients who have undergone radical cystectomy between 1998 and 2008 in eight academic centers across Canada. Collected variables included patient's age, gender, tumor grade, histology and the presence of concomitant CIS with either cTa-1 or cT2 disease, dates of recurrence and death. In the presence of concomitant CIS, upstaging following radical cystectomy occurred in 48 and 55 % of patients with cTa-1 and cT2 disease, respectively. On univariate analysis, the presence of concomitant CIS with cT2 disease was associated with upstaging (p < 0.0001), and the presence of concomitant CIS with cTa-1 disease was also associated with upstaging but did not reach statistical significance (p = 0.0526). On multivariate analyses, the presence of concomitant CIS with either cTa-1 or cT2 tumors was independently prognostic of disease upstaging (p = 0.0001 and 0.0186, respectively). However, on multivariate analysis that incorporates pathologic stage, concomitant CIS was not significantly associated with worse overall, recurrence-free or disease-specific survival. These results demonstrate that while the presence of concomitant CIS on cystectomy specimens does not independently affect outcomes, its presence is significantly predictive of a higher rate of upstaging at radical cystectomy.

Frozen Section Analysis of Ureteral Margins in Patients Undergoing Radical Cystectomy for Bladder Cancer: Differential Impact of Carcinoma in situ in the Bladder on Reliability and Impact on Tumour Recurrence in the Upper Urinary Tract

Background: Patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) are at risk for upper urinary tract recurrence (UUTR), especially in case of carcinoma in situ (CIS). Data on the impact of CIS in the urinary bladder on ureteral tumour involvement or UUTR are conflicting. We presently evaluate the accuracy of intraoperative frozen section analysis (FSA) of the ureteral margin, the incidence of ureteral tumour involvement and their impact on UUTR in patients undergoing RC for UCB with versus without CIS of the bladder. Material and Methods: Between 2003 and 2007, 243 patients underwent RC in our department. 176 of these for UCB, either without CIS (n = 117, group I) or solitary/concomitant CIS (n = 59, group II). FSA was performed. Patients were followed up for UUTR. Results: Overall, 403 ureteral margins - including re-resections - were analysed (group I, n = 232; group II, n = 171). One patient (0.85%) in group I and 21 patients (35.6%) in group II had tumour involvement of the ureter (p < 0.0001) at the time of RC. The false-negative rate of FSA compared to final histopathology was 0.4% (1/232) for group I and 2.9% (5/171) for group II, respectively. Mean duration of follow-up was 26 months (1-72). In group II, 2 patients (1.1%) had UUTR in the follow-up; both had initially positive and subsequently false-negative FSA. Conclusions: Tumour involvement of the ureter is found significantly more often in solitary or concomitant CIS of the bladder. Intraoperative ureteral FSA is accurate and should be recommended in these patients. Ureteral tumour involvement predisposes to UUTR especially with initial positive margins mandating careful follow-up.

Facteurs pronostiques des tumeurs de la voie excrétrice urinaire supérieure

Upper urinary tract urothelial carcinoma (UTUC) is a rare disease. Thus, little evidence-based data are available to guide clinical decision-making. The aim of the study was to provide an overview of the currently available prognostic factors for UTUC. A systematic literature search was conducted using the PubMed databases to identify original articles regarding prognostic factors in patients with UTUC. We divided the prognostic factors for UTUC in four different categories: clinical factors, preoperative characteristics, intraoperative/surgical factors and postoperative/pathologic factors. Prognostic factors described in order of importance are: tumor stage and grade, lymph node involvement, a concomitant cis, age at the diagnostic, lymphovascular invasion, tumor architecture and necrosis, tumor location and multifocality, gender. The impact of obesity, smoking and other comorbidities (ECOG, ASA) on outcomes has been recently reported but needs to be validated. The endoscopic approach of distal ureter management during radical nephroureterectomy has been shown to be at higher risk of bladder recurrence. The incorporation of such prognosticators into clinical prediction models might help to guide decision-making with regard to timing of surveillance, type of treatment, performance of lymphadenectomy, and consideration of neoadjuvant or adjuvant systemic therapies.

394 CONCORDANCE IN MOLECULAR MARKER STATUS BETWEEN BLADDER TUMORS AT TIME OF TRANSURETHRAL RESECTION AND SUBSEQUENT RADICAL CYSTECTOMY: RESULTS OF A 5-YEAR PROSPECTIVE STUDY

You have accessJournal of UrologyUrothelial Cancer: Natural History, Markers & Pathophysiology1 Apr 2013394 CONCORDANCE IN MOLECULAR MARKER STATUS BETWEEN BLADDER TUMORS AT TIME OF TRANSURETHRAL RESECTION AND SUBSEQUENT RADICAL CYSTECTOMY: RESULTS OF A 5-YEAR PROSPECTIVE STUDY Yair Lotan, Aditya Bagrodia, Niccolo Passoni, Varun Rachakonda, Payal Kapur, Arthur Sagalowsky, and Shahrokh F. Shariat Yair LotanYair Lotan Dallas, TX More articles by this author , Aditya BagrodiaAditya Bagrodia Dallas, TX More articles by this author , Niccolo PassoniNiccolo Passoni Milan, Italy More articles by this author , Varun RachakondaVarun Rachakonda Dallas, TX More articles by this author , Payal KapurPayal Kapur Dallas, TX More articles by this author , Arthur SagalowskyArthur Sagalowsky Dallas, TX More articles by this author , and Shahrokh F. ShariatShahrokh F. Shariat New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1783AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Molecular alterations are common in patients with urothelial carcinoma of the bladder (UCB). In order to make appropriate decisions using molecular alterations, it is important to determine whether marker status at time of transurethral resection (TUR) is concordant with marker status at time of radical cystectomy (RC). This is particularly important to guide decisions regarding neoadjuvant therapies. We performed a 5 year prospective study to evaluate the role of molecular markers in patients with high grade UCB. The goal of the current study was to compare the concordance of molecular marker status of TUR and RC specimens from the same patient. METHODS We prospectively performed p53, p21, p27, Ki67, and cyclin E1 immunohistochemical staining on RC specimens from 243 patients treated with RC and bilateral lymphadenectomy. Of these, 96 patients had staining of the TUR specimen immediately preceding the RC available. RESULTS Median patient age was 70 yr with most being men (78, 81%). Time from TUR to RC was 2 months (IQR 3.5). Clinical stage was cTa/Tis/T1 (52, 54%), cT2 (37, 39%), cT3/T4 (2, 2%), and unknown (5, 5%). High-grade disease was present in 93% of the patients. Pathologic stage was pT0 (6, 6%), pT1 (40, 42%), pT2 (16, 17%), pT3 (27, 28%), and pT4 (7, 7%). Concomitant CIS was seen in 34 patients (35%) and lymphovascular invasion in 21 (22%). The median number of removed lymph nodes was 22 (IQR 16-31) and 20 patients (21%) had lymph node metastasis. Overall, 17 (18%) patients underwent neoadjuvant chemotherapy. The concordance of molecular biomarkers between TUR and RC was 89%, 80%, 88%, 86%, and 82% for cyclin E, p21, p27, p53 and Ki-67, respectively. The likelihood of concordance was not influenced by clinical or pathologic stage, grade, time from TUR to RC and use of neoadjuvant chemotherapy. CONCLUSIONS There is a high rate of concordance in the status of cell-cycle- and proliferation-related markers between the TUR preceding the RC and RC specimens itself. Clinical decision-making regarding neoadjuvant chemotherapy and RC could be guided by molecular marker status of the TUR specimen. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e160 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yair Lotan Dallas, TX More articles by this author Aditya Bagrodia Dallas, TX More articles by this author Niccolo Passoni Milan, Italy More articles by this author Varun Rachakonda Dallas, TX More articles by this author Payal Kapur Dallas, TX More articles by this author Arthur Sagalowsky Dallas, TX More articles by this author Shahrokh F. Shariat New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Female gender is associated with higher risk of disease recurrence in patients with primary T1 high-grade urothelial carcinoma of the bladder

An increasing body of evidence suggests gender differences in the presentation and prognosis of bladder cancer. We aimed to assess the impact of gender on outcomes in patients with primary T1 high-grade (HG) urothelial carcinoma of the bladder (UCB). We retrospectively analysed the data from 916 patients with primary T1HG UCB from 7 tertiary care centres. Patients were treated with transurethral resection of the bladder with or without intravesical instillation therapy (IVT). Univariable and multivariable Cox regression analyses assessed the effect of gender on outcomes. Within a median follow-up of 42.8 months, 365 (39.8 %) patients experienced disease recurrence, 104 (11.4 %) progression, 59 (6.4 %) cancer-specific mortality and 190 (20.7 %) mortality of any cause. Overall, 634 (69.2 %) patients received IVT of which 234 (25.5 %) received BCG therapy. Female gender (n = 190, 20.7 %) was associated with higher risk of disease recurrence (HR:1.359;1.071-1.724, p = 0.012) in all patients and in a subgroup of patients treated with BCG therapy (HR:1.717;1.101-2.677, p = 0.017). There was no difference between genders with regard to disease progression, cancer-specific mortality and any-cause mortality. In multivariable analyses that adjusted for the effects of concomitant carcinoma in situ (CIS), tumour size, number of tumours, and IVT, gender remained an independent predictor for disease recurrence (p = 0.026) when analysed in all patients, but not in the subgroup of BCG treated patients (p = 0.093). In patients with T1HG UCB, female gender is associated with higher risk of disease recurrence, but not with disease progression. This gender disparity may be due to differences in care and/or biology of UCB.

Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle–Invasive Bladder Cancer

Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have previously been included in gene expression signatures for outcome prediction in stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle-invasive bladder cancer (log-rank test; P < 0.001) in the Danish training cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P = 0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, Spain, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation of their clinical relevance.

Intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinomas: predictors and impact on subsequent oncological outcomes from a national multicenter study

To identify predictive factors and assess the impact on oncological outcomes of intravesical recurrence after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). Using a national multicentric retrospective dataset, we identified all patients with UTUC who underwent a RNU between 1995 and 2010 (n=482). Intravesical recurrence was tested as a prognostic factor for survival through univariable and multivariable Cox regression analysis. Overall, intravesical recurrence occurred in 169 patients (35%) with a median age of 69.2years (IQR: 60-76) and after a median follow-up of 39.5months (IQR: 25-60). Actuarial intravesical recurrence-free survival estimates at 2 and 5years after RNU were 72 and 45%, respectively. On univariable analyses, previous history of bladder tumor, tumor multifocality, laparoscopic approach, pathological T-stage, presence of concomitant CIS and lymphovascular invasion were all associated with intravesical recurrence. On multivariable analysis, previous history of bladder cancer, tumor multifocality and laparoscopic approach remained independent predictors of intravesical recurrence. Existence of intravesical recurrence was not correlated with worst oncological outcomes in terms of disease recurrence (p=0.075) and cancer-specific mortality (p=0.06). In the current study, intravesical recurrence occurred in 35% of patients with UTUC after RNU. Previous history of bladder cancer, tumor multifocality, concomitant CIS and laparoscopic approach were independent predictors of intravesical recurrence. These findings are in line with recent published data and should be considered carefully to provide a definitive surveillance protocol regarding management of urothelial carcinomas regardless of the location of urothelial carcinomas in the whole urinary tract.

Impact of Distal Ureter Management on Oncologic Outcomes Following Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

BackgroundThere is a lack of consensus regarding the optimal approach to the bladder cuff during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). ObjectivesTo compare the oncologic outcomes following RNU using three different methods of bladder cuff management. Design, setting, and participantsRetrospective analysis of 2681 patients treated with RNU for UTUC at 24 international institutions from 1987 to 2007. InterventionThree methods of bladder cuff excision were performed: transvesical, extravesical, and endoscopic. Outcome measurements and statistical analysisUnivariable and multivariable models tested the effect of distal ureter management on intravesical recurrence, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results and limitationsOf the 2681 patients, 1811 (67.5%) underwent the transvesical approach; 785 (29.3%), the extravesical approach; and 85 (3.2%), the endoscopic approach. There was no difference in terms of RFS, CSS, and OS among the three distal ureteral management approaches. Patients who underwent the endoscopic approach were at significantly higher risk of intravesical recurrence compared with those who underwent the transvesical (p=0.02) or extravesical approaches (p=0.02); the latter two groups did not differ from each other (p=0.40). Actuarial intravesical RFS estimates at 2 and 5 yr after RNU were 69% and 58%, 69% and 51%, and 61% and 42% for the transvesical, extravesical, and endoscopic approaches, respectively. In multivariate analyses, distal ureteral management (p=0.01), surgical technique (open vs laparoscopic; p=0.02), previous bladder cancer (p<0.001), higher tumor stage (trend; p=0.01), concomitant carcinoma in situ (CIS) (p<0.001), and lymph node involvement (trend; p<0.001) were all associated with intravesical recurrence. Excluding patients with history of previous bladder cancer, all variables remained independent predictors of intravesical recurrence. ConclusionsThe endoscopic approach was associated with higher intravesical recurrence rates. Interestingly, concomitant CIS in the upper tract is a strong predictor of intravesical recurrence after RNU. The association of laparoscopic RNU with intravesical recurrence needs to be further investigated.

Abstract 3656: Cathepsin E, Maspin, PLK1, and Survivin are promising prognostic protein markers for progression in non-muscle invasive bladder cancer

Abstract The majority of patients with bladder cancer are initially diagnosed with noninvasive or superficially invasive urothelial tumors. These tumors form a heterogeneous group, spanning from benign low grade Ta tumors that rarely progress to high grade T1 tumors with concomitant CIS that progress in up to 60% of cases. The histopathological parameters used in the clinic cannot precisely predict the individual disease course, and no molecular markers are currently in clinical use for predicting tumor recurrence or later progression. Previously, we have identified gene expression signatures for prediction of disease outcome for patients with non-muscle invasive bladder cancer. The aim of the present study was to validate key candidate markers from these signatures at the protein level. Four proteins were selected for investigation: Cathepsin E, Maspin, PLK1, and Survivin. We used three different tissue-microarrays with a total of 693 non-muscle invasive urothelial carcinomas from Danish, Swedish, and Spanish patient cohorts. The Danish patient cohort was used for optimizing IHC cutoff values and the Swedish-Spanish cohort was used as independent validation. Protein expression was measured by IHC and antibody specificity was validated by Western blotting. In the Danish patient cohort, we found the expression of Cathepsin E, Maspin, PLK1, and Survivin to be significantly associated with progression to stage T2-4 bladder cancer (for each marker: log-rank test; p&amp;lt;0.001). Multivariate Cox regression analysis identified Cathepsin E (p&amp;lt;0.001), Maspin (p=0.001), PLK1 (p=0.021), and Survivin (p=0.001) as independent prognostic markers. Furthermore, Cathepsin E, Maspin and Survivin expression significantly sub-grouped patients already stratified by EORTC risk scores. Survivin expression (log-rank test; p=0.004) and Maspin expression (log-rank test; p&amp;lt;0.001) significantly subgrouped the EORTC low risk patients. Cathepsin E expression subgrouped the EORTC high risk patients (log-rank test; p=0.001). Finally, we successfully validated the results in tumors from 410 patients from Sweden and Spain. Using univariate Cox regression analysis we identified Cathepsin E (p=0.002), Maspin (p&amp;lt;0.001), PLK1 (p=0.003), and Survivin (p=0.002) to show significant association with disease progression to muscle invasive bladder cancer in the Spanish-Swedish validation cohort. Furthermore, in multivariate analysis Cathepsin E (p=0.019) and Survivin (p=0.014) were significantly associated with disease progression when adjusting for other known clinical and histopathological risk factors. We conclude that all four protein markers may have prognostic value in non-muscle invasive bladder cancer for guiding optimal treatment of patients. Additional prospective studies are needed for further validation of the clinical relevance of the marker panel. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3656. doi:1538-7445.AM2012-3656

The lymphatic system in clinically localized urothelial carcinoma of the bladder: Morphologic characteristics and predictive value

ObjectiveTo assess the lymphatic vessel density (LVD) and lymphangiogenesis in urothelial carcinoma of the bladder (UCB) and to identify predictors of progression in patients treated by transurethral resection (TUR). Materials and methodsOne hundred eleven patients who underwent TUR for UCB were retrospectively included. Lymphatic endothelial cells were stained immunohistochemically [D2-40 (podoplanin) antibody in all samples; Prox-1, LYVE-1, and VEGFR-3 (Flt-4) in subgroups]. LVD was measured in representative intratumoral (ITLVD), peritumoral (PTLVD), and nontumoral (NTLVD) areas using standardized criteria. Double-immunostainings with D2-40/CD-34 were performed to distinguish between blood and lymphatic vessels, and D2-40/Ki-67 stainings were done to detect lymphangiogenesis. Lymph-specific parameters were correlated with pathologic and clinical characteristics. In patients with non-muscle-invasive UCB (n = 76) univariable and multivariable analyses were performed to identify predictors of progression. ResultsThe PTLVD was significantly higher than ITLVD and NTLVD (P < 0.001). Proliferating lymphatic vessels were observed in all specimens assessed with D2-40/Ki-67. Characteristic suburothelial D2-40 positivity was observed in noninvasive pTa tumors. LYVE-1-stainings revealed the existence of tumor-associated macrophages. The presence of intratumoral lymphatic vessels was significantly associated with higher tumor stage, high grade, and sessile growth (all P < 0.001). Muscle-invasive tumors (P = 0.020), higher grade (P = 0.026), the presence of lymphovascular invasion (P < 0.001), and concomitant carcinoma in situ (CIS) (P = 0.020), sessile growth (P = 0.004), and loss of suburothelial D2-40 positivity (P = 0.031) were associated with disease progression in univariable analysis. LVD values in any area were not significantly associated with progression despite detection of proliferating lymphatic vessels. The presence of concomitant CIS was identified as an independent predictor of progression on multivariable analysis (P = 0.041; hazard ratio 4.620). ConclusionsA high peritumoral LVD is present in clinically localized UCB. The presence of intratumoral lymphatic vessels correlates with characteristics of aggressive disease. Lymphangiogenesis occurs; however, the lymph-specific parameters tested in this study cannot be used to predict progression following TUR. The presence of concomitant CIS is an important risk factor for later disease progression in patients with non-muscle-invasive UCB. Our results contribute to the understanding of metastatic tumor spread in UCB.

1418 FROZEN SECTION OF THE DISTAL URETER AT THE TIME OF RADICAL CYSTECTOMY: INDICATIONS BASED ON CLINICAL PREDICTIVE FACTORS

You have accessJournal of UrologyBladder Cancer: Invasive I1 Apr 20121418 FROZEN SECTION OF THE DISTAL URETER AT THE TIME OF RADICAL CYSTECTOMY: INDICATIONS BASED ON CLINICAL PREDICTIVE FACTORS Oscar Rodríguez Faba, Juan Palou, Alberto Breda, Juan Antonio Peña, Lluís Gausa, Salvador Esquena, Juan Manuel López, and Humberto Villavicencio Oscar Rodríguez FabaOscar Rodríguez Faba Barcelona, Spain More articles by this author , Juan PalouJuan Palou Barcelona, Spain More articles by this author , Alberto BredaAlberto Breda Barcelona, Spain More articles by this author , Juan Antonio PeñaJuan Antonio Peña Barcelona, Spain More articles by this author , Lluís GausaLluís Gausa Barcelona, Spain More articles by this author , Salvador EsquenaSalvador Esquena Barcelona, Spain More articles by this author , Juan Manuel LópezJuan Manuel López Barcelona, Spain More articles by this author , and Humberto VillavicencioHumberto Villavicencio Barcelona, Spain More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1869AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The prevalence of CIS of the distal ureter below the common iliac vessels at the time of radical cystectomy (RC) has been reported to be 2-35% in many large series, being < 1% in the ureter above the iliac vessels. It is well known that up to 17% of the patients with distal ureteral CIS at time of RC will develop a recurrence in the upper tract within 5 years from surgery. In order to reduce the risk of recurrence many are speculating on the use of frozen sections at time of RC. Despite this the role of intra-operative FS remains controversial. The objective of our study was to identify the most relevant clinical predictive factors for distal ureter CIS involvement at the time of RC to determine which patients would possibly benefit the most from intraoperative FS. METHODS We retrospectively collected clinical-pathologic data on 1114 patients who underwent RC between August 1978 and June 2002,.Patients with concomitant distal ureter CIS on final pathology were identified and compared to those with a negative ureter. Univariate and multivariate analysis (ANOVA) were performed for patient's demographics, pathology of the primary tumour (multifocality, grade, concomitant CIS, CIS in the prostatic urethra, number of recurrences prior to RC, and progression from superficial to muscle invasive tumors) and previous BCG treatments. RESULTS 61 patients (5.47%) were found to have concomitant CIS of the distal ureter at the time of RC on final pathology. Mean age was 66 (47-85), and there were 55 (90.2%) males. Median follow up was 42.5 months. On univariate analysis bladder tumor multifocality (p<0.001), high grade (p<0.001), concomitant CIS (p<0.001), prostatic urethra involvement (p<0.001), ¡Ý2 recurrences prior to RC, and BCG treatment (p< 0.001) were found to be independent predictive factors for concomitant ureteral involvement. Tumor progression prior to RC did not reach statistical significance (p=0.44). On multivariate analysis (ANOVA) only, high grade (P<0.001), concomitant CIS (p=0.004), and BCG treatment prior to RC (p<0.001) were found to be independent clinical predictive factors for CIS in the distal ureter. CONCLUSIONS High grade bladder cancer, concomitant CIS and preoperative BCG treatment were found to be independent predictors of concomitant CIS of distal ureter in our series. Therefore we believe that patients presenting with these factors may benefit the most an intraoperative frozen section with the idea of performing a wider resection in case of positive results. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e575-e576 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Oscar Rodríguez Faba Barcelona, Spain More articles by this author Juan Palou Barcelona, Spain More articles by this author Alberto Breda Barcelona, Spain More articles by this author Juan Antonio Peña Barcelona, Spain More articles by this author Lluís Gausa Barcelona, Spain More articles by this author Salvador Esquena Barcelona, Spain More articles by this author Juan Manuel López Barcelona, Spain More articles by this author Humberto Villavicencio Barcelona, Spain More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1778 EXPRESSION OF INTEGRIN PROTEINS IN NON-MUSCLE INVASIVE BLADDER CANCER: SIGNIFICANCE OF INTRAVESICAL RECURRENCE FOLLOWING TRANSURETHRAL RESECTION

You have accessJournal of UrologyBladder Cancer: Superficial II1 Apr 20121778 EXPRESSION OF INTEGRIN PROTEINS IN NON-MUSCLE INVASIVE BLADDER CANCER: SIGNIFICANCE OF INTRAVESICAL RECURRENCE FOLLOWING TRANSURETHRAL RESECTION Hideaki Miyake, Hosny Behnsawy, and Masato Fujisawa Hideaki MiyakeHideaki Miyake Kobe, Japan More articles by this author , Hosny BehnsawyHosny Behnsawy Kobe, Japan More articles by this author , and Masato FujisawaMasato Fujisawa Kobe, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1795AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intravesical recurrence after transurethral resection (TUR) has been reported to occur in approximately 50% of patients with non-muscle invasive bladder cancer. Integrins are a family of transmembrane heterodimers, many of which function as receptors for extracellular matrix molecules. To date, a few studies have investigated the role of integrins in bladder cancer progression; therefore, it remains unknown whether intergrins have a significant impact on the prognosis of patients with bladder cancer, particularly that of those with non-muscle invasive disease. The objective of this study was to evaluate the expression levels of integrins in non-muscle invasive bladder cancer to clarify the significance of these proteins as predictors of intravesical recurrence in patients treated with TUR. METHODS This study included 161 patients with non-muscle invasive bladder cancer undergoing TUR between 2000 and 2007. Expression levels of α2, α3, α5, α6, β1 and β4 integrins in TUR specimens obtained from these patients were measured by immunohistochemical staining. RESULTS Of these 6 proteins, expression level of α2, α3, α6 and β4 integrins were significantly associated with several conventional predictive factors of intravesical recurrence. Univariate analysis identified expression level of α3, α6 and β4 integrins as significant predictors of intravesical recurrence, while tumor size, pathological T stage and concomitant carcinoma in situ (CIS) were also significant. Of these significant factors, β4 integrin expression level, pathological T stage and concomitant CIS appeared to be independently related to intravesical recurrence by multivariate analysis. Furthermore, there were significant differences in recurrence-free survival according to positive numbers of these three independent risk factors; that is, intravesical recurrence occurred in 10 of 49 patients who were negative for all risk factors (20.4%), 31 of 68 positive for a single risk factor (45.6%), and 30 of 44 positive for 2 or 3 risk factors (68.2%). CONCLUSIONS Consideration of expression levels of integrins in TUR specimens, in addition to conventional prognostic parameters, would contribute to accurate prediction of intravesical recurrence following TUR for non-muscle invasive bladder cancer. Moreover, combined evaluation of β4 integrin expression, pathological T stage and concomitant CIS would be particularly useful for further refinement of the system in predicting recurrence of non-muscle invasive bladder cancer following TUR. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e718 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hideaki Miyake Kobe, Japan More articles by this author Hosny Behnsawy Kobe, Japan More articles by this author Masato Fujisawa Kobe, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1268 SIGNIFICANCE OF RANDOM BLADDER BIOPSIES IN PATIENTS UNDERGOING TRANSURETHRAL RESECTION OF NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Detection and Screening1 Apr 20121268 SIGNIFICANCE OF RANDOM BLADDER BIOPSIES IN PATIENTS UNDERGOING TRANSURETHRAL RESECTION OF NON-MUSCLE INVASIVE BLADDER CANCER Masafumi Kumano, Hideaki Miyake, and Masato Fujisawa Masafumi KumanoMasafumi Kumano Kobe, Japan More articles by this author , Hideaki MiyakeHideaki Miyake Kobe, Japan More articles by this author , and Masato FujisawaMasato Fujisawa Kobe, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1600AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Random bladder biopsies, taken from normal areas of urothelium, are widely performed to detect concomitant carcinoma in situ (CIS) in patients undergoing transurethral resection (TUR) of non-muscle invasive bladder cancer. However, there are few reports investigating the outcomes of random bladder biopsies based on the data from large series; thus, the significance of random biopsies remains controversial. The objective of this study was to retrospectively review the clinical outcomes of random bladder biopsies in patients with non-muscle invasive bladder cancer to identify predictive factors significantly associated with the findings of random biopsies. METHODS This study included a total of 451 consecutive patients with histopathologically confirmed non-muscle invasive bladder cancer who underwent TUR and random bladder biopsies. The random biopsies were taken from the seven different sites of normal-appearing urothelium, including right wall, left wall, trigone, dome, posterior wall, anterior wall and prostatic urethra. RESULTS Random biopsies were positive in 72 patients (16.0%), of whom 66 (91.7%) and 6 (8.3%) were diagnosed as Tis and Ta, respectively. The incidence of positive random biopsies was significantly associated with past history of upper urinary tract cancer, urinary cytology before TUR, number of tumors, pathological stage, tumor grade and presence of concomitant CIS. Univariate analysis identified past history of upper urinary tract cancer, urinary cytology before TUR and number of tumors as significant predictors of positive random biopsies, among which only urinary cytology before TUR appeared to be independently associated with positive random bladder biopsies on multivariate analysis. Furthermore, consideration of the preoperative finding of urinary cytology could diagnose concomitant malignant disease by random biopsies with 59.4% sensitivity, 88.8% specificity, 50.0% positive predictive value and 92.0% negative predictive value. CONCLUSIONS These findings suggest that the outcome of urinary cytology before TUR could be a useful predictor of positive biopsies in patients with non-muscle invasive bladder cancer. Accordingly, it would be important to further discuss the indication of random bladder biopsies in patients who were preoperatively diagnosed as negative in urinary cytology in order to avoid unnecessary biopsies. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e513 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masafumi Kumano Kobe, Japan More articles by this author Hideaki Miyake Kobe, Japan More articles by this author Masato Fujisawa Kobe, Japan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

552 ANTI-IL10-R1 MONOCLONAL ANTIBODY WITH CONCOMITANT BACILLUS CALMETTE-GUERIN (BCG) PREVENTS METASTATIC BLADDER CANCER IN AN IN VIVO MOUSE MODEL

INTRODUCTION AND OBJECTIVES: Heat shock proteins (HSPs) are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. Furthermore, several HSPs are implicated with the prognosis of specific cancers. HSP60 and HSP90 have been proposed as prognostic factors for bladder cancer (BC). Since HSPs proteins are among the most immunogenic reported molecules and BCG therapy is immune dependent, the role of HSPs in patients with BC treated with BCG warrants investigation. Previously, our group showed that in primary T1 BC treated with BCG, FGRF3 mutation and protein overexpression were associated with a decreased risk of tumor progression. Here, we evaluated HSP70 expression levels and its relationship to pathological and clinical parameters in the same group of previously untreated primary T1 BC treated with BCG. We chose this patient specific BC population to minimize the influence of other factors such as previous treatments. METHODS: 69 patients diagnosed with primary T1 BC (confirmed by pathological review) treated at the University Health Network, Toronto were included in the study. Microarrays were built and HSP70 protein expression was determined by standard immunohistochemistry (HSP70 Antibody, StressMarq Biosciences Inc, Victoria, BC, Canada). Slides were co-reviewed with an experienced uro-pathologist with staining scores dependent on the expression and intensity of the marker. HSPs expression was correlated with pathological, clinical outcomes and with the expression of FGFR3. FGFR3 mutation status was examined by multiplex PCR-SNaPshot analysis. Kaplan-Meier method and multivariate Cox-regression analysis were used for data analysis. RESULTS: Mean age of patients was 71.1 years ( 8.5). HSP70 was found to be expressed in 29/53 (55%) high-grade tumors and in 9/14 (64%) low-grade tumors. Kaplan-Meier survival analysis demonstrated that the lack of HSP70 expression was a significant predictor for disease recurrence (p 0.05) but did not affect progression. In a multivariate model adjusting for grade, size and concomitant CIS, lack of HSP70 expression remained a significant predictor for recurrence (HR of 1.952, 95% CI 1.02-3.75; p 0.045). HSP70 was shown to correlate with FGFR3 expression and mutation (p 0.05). CONCLUSIONS: HSP70 is a promising marker in T1 BC treated with BCG. Both HSP70 and FGFR3 may play an important prognostic role in T1 BC identifying a group at lower risk of recurrence.

1762 REGIONAL DIFFERENCES IN PRACTICE PATTERNS AND OUTCOMES AFTER RADICAL CYSTECTOMY

You have accessJournal of UrologyBladder Cancer: Invasive III1 Apr 20121762 REGIONAL DIFFERENCES IN PRACTICE PATTERNS AND OUTCOMES AFTER RADICAL CYSTECTOMY Bassel G. Bachir, Faysal A. Yafi, Armen Aprikian, Joseph L. Chin, Jonathan Izawa, Yves Fradet, Louis Lacombe, Darrel Drachenberg, Eric Estey, Adrian Fairey, Ricardo Rendon, David Bell, Jean-Baptiste Lattouf, Ilias Cagiannos, and Wassim Kassouf Bassel G. BachirBassel G. Bachir Montreal, Canada More articles by this author , Faysal A. YafiFaysal A. Yafi Montreal, Canada More articles by this author , Armen AprikianArmen Aprikian Montreal, Canada More articles by this author , Joseph L. ChinJoseph L. Chin London, Canada More articles by this author , Jonathan IzawaJonathan Izawa London, Canada More articles by this author , Yves FradetYves Fradet Laval, Canada More articles by this author , Louis LacombeLouis Lacombe Laval, Canada More articles by this author , Darrel DrachenbergDarrel Drachenberg winnipeg, Canada More articles by this author , Eric EsteyEric Estey Edmonton, Canada More articles by this author , Adrian FaireyAdrian Fairey Edmonton, Canada More articles by this author , Ricardo RendonRicardo Rendon Halifax, Canada More articles by this author , David BellDavid Bell Halifax, Canada More articles by this author , Jean-Baptiste LattoufJean-Baptiste Lattouf Montreal, Canada More articles by this author , Ilias CagiannosIlias Cagiannos Ottowa, Canada More articles by this author , and Wassim KassoufWassim Kassouf Montreal, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1778AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To assess differences in practice patterns and outcomes across three separate regions in a universal health care system in patients who had undergone radical cystectomy. METHODS This multi-institutional series included 2287 patients who had undergone radical cystectomy at eight Canadian centers from 1998 until 2008. Collected variables included various clinical and pathological parameters, recurrence, and death stratified into three sets to account for the different regions (east, center, west). RESULTS Of 2287 patients, there were 1105 patients from eastern (group 1, 49%), 601 patients from central (group 2, 26%), and 581 from western Canada (group 3, 25%). The median follow-up of group 1, 2 and 3 was 22.1, 17.1, and 28.6 months respectively. There were no differences among the three geographical locations in terms of pathologic stage, rate of surgical margin positivity, adjuvant chemotherapy and smoking status. Rates of neoadjuvant chemotherapy were higher in group 2 compared with group 1 and 3 (p=0.07). There were statistically significant differences in clinicopathological parameters across the 3 groups, specifically gender distribution, performance of a lymphadenectomy, type of diversion and rates of concomitant cis, and lymphovascular invasion. The mean number of days to cystectomy from last TURBT was 50 vs. 79 vs. 69 days for groups 1, 2 and 3 respectively (p=0.0006). On Kaplan-Meier survival analysis, there was a statistically significant difference (p<0.0001) in overall survival (53.6% vs. 66.8% vs. 52.4% for groups 1, 2 and 3). CONCLUSIONS Significant variations in practice patterns were noted across different geographic regions in a universal health care system. The use of orthotopic bladder substitutes remains low across all 3 regions. Treatment delays are prolonged across Canada with significant regional variations. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e711 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bassel G. Bachir Montreal, Canada More articles by this author Faysal A. Yafi Montreal, Canada More articles by this author Armen Aprikian Montreal, Canada More articles by this author Joseph L. Chin London, Canada More articles by this author Jonathan Izawa London, Canada More articles by this author Yves Fradet Laval, Canada More articles by this author Louis Lacombe Laval, Canada More articles by this author Darrel Drachenberg winnipeg, Canada More articles by this author Eric Estey Edmonton, Canada More articles by this author Adrian Fairey Edmonton, Canada More articles by this author Ricardo Rendon Halifax, Canada More articles by this author David Bell Halifax, Canada More articles by this author Jean-Baptiste Lattouf Montreal, Canada More articles by this author Ilias Cagiannos Ottowa, Canada More articles by this author Wassim Kassouf Montreal, Canada More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Predicting clinical outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.

267 Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. Methods: Our study included 2,244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant CIS. The cohort was split for development (12 centers, n=1273) and external validation (11 centers, n=971). Results: At a median follow-up of 45 months, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p-for-trend &lt;0.001), lymph node metastasis (HR:1.98, p=0.002), lymphovascular invasion (HR:1.66, p&lt;0.001), sessile tumor architecture (HR:1.76, p&lt;0.001), and concomitant CIS (HR:1.33, p=0.035) were associated with disease recurrence. Similarly, T classification (p-for-trend &lt;0.001), lymph node metastasis (HR:2.23, p=0.001), lymphovascular invasion (HR:1.81, p&lt;0.001), and sessile tumor architecture (HR:1.72, p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be utilized for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

Prognostic value of SPINK1 expression in bladder cancer after radical cystectomy.

274 Background: Serine peptidase inhibitor Kazal type 1 (SPINK1) overexpression has been associated with poor outcomes. In one small study, loss of SPINK1 expression in urothelial carcinoma of the bladder (UCB) was associated with advanced tumor stage. We assessed the expression of SPINK1 in normal urothelium and UCB and analysed the association of SPINK1 with pathological features and clinical outcomes of patients treated with radical cystectomy (RC). Methods: The study used TMAs containing samples from 438 consecutive UCB patients treated with RC. 62 cases of normal urothelium were included as controls. A monoclonal antibody was used for immunohistochemical SPINK1 staining. SPINK1 expression of UCB was evaluated by two pathologists, blind to clinical outcome. Samples demonstrating less than 50% staining extent and 0 to 1 intensity (scale 0 to 3), were considered to have loss of expression. Results: SPINK1 expression was noted in umbrella cells of normal urothelium in 32/62 controls (52%). UCB of 254 patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with advanced pathological stage (p=0.002) and presence of lymph node (LN) metastasis (p=0.04). Within a median follow-up of 130 month (IQR 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (5-year RFS: 52±3 vs. 61±4 months; p=0.02) and cancer-specific mortality (5-year CSS: 59±3 vs. 68±3 months; p=0.03). In multivariable Cox regression analyses that adjusted for the effects of age, gender, tumor stage and grade, concomitant CIS, LN status and adjuvant chemotherapy, SPINK1 was not associated with disease recurrence (p=0.09) or cancer-specific death (p=0.12). Conclusions: While umbrella cells in normal urothelium commonly expresses SPINK1, more than half of UCB specimen exhibit loss of SPINK1 expression. Loss of SPINK1 expression is strongly correlated with local disease stage and LN metastasis. SPINK1 revealed no independent prognostic value for outcome prognostication, but it is a very promising marker for tumor staging which could be used for tailored follow-up protocols and possibly as a target for therapy as it has similarities with epidermal growth factor.

768 Concomitant CIS is a risk factor for the occurrence of progressive bladder cancer after nephroureterectomy in patients with upper urinary tract urothelial cancer

768 Concomitant CIS is a risk factor for the occurrence of progressive bladder cancer after nephroureterectomy in patients with upper urinary tract urothelial cancer