The effects of AURKA overexpression associated with poor clinical outcomes have been attributed to increased cell cycle progression and the development of genomic instability with aneuploidy. We used RNA interference to examine the effects of AURKA overexpression in human bladder cancer cells. Knockdown had minimal effects on cell proliferation but blocked tumor cell invasion. Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target that was repressed by AURKA. Chromatin immunoprecipitation and NNMT promoter luciferase assays revealed that AURKA's effects on NNMT were caused by PAX3-mediated transcriptional repression and overexpression of NNMT blocked tumor cell invasion in vitro. Overexpression of AURKA and activation of its downstream pathway was enriched in the basal subtype in primary human tumors and was associated with poor clinical outcomes. We also show that the FISH test for the AURKA gene copy number in urine yielded a specificity of 79.7% (95% confidence interval [CI] = 74.2% to 84.1%), and a sensitivity of 79.6% (95% CI = 74.2% to 84.1%) with an AUC of 0.901 (95% CI = 0.872 to 0.928; P < 0.001). These results implicate AURKA as an effective biomarker for bladder cancer detection as well as therapeutic target especially for its basal type.

INTRODUCTION AND OBJECTIVES: Muscle-invasive urothelial carcinoma of the urinary bladder (UCUB) is an aggressive disease. The standard treatment of care is radical cystectomy (RC). Trimodal bladder-preserving treatment (BPT), including transurethral resection of the bladder tumor, radiation, and chemotherapy has gained considerable interest. We sought to perform a comparative effectiveness assessment of RC vs. BPT in a stage-for-stage analysis. METHODS: We performed a retrospective cohort study of Medicare beneficiaries with non-metastatic muscle-invasive (T2eT4a, N0) UCUB treated with RC or BPT from 1991 to 2009. Following instrumental variable analysis that accounts for both measured and unmeasured confounders, multivariable Coxand competing-risks regression two-stage residual inclusions models were fitted. All analyses were stratified according to disease stage (organ-confined vs. non-organ confined). Our primary outcomes were overall survival (OS) and cancer-specific mortality (CSM). RESULTS: Overall 4168 patients with muscle-invasive UCUB were identified, where 3488 (84%) underwent RC and 680 (16%) received BPT, respectively. During the entire study span, the 5-year OS rates for RC and BPT were 42.9% (95% confidence interval [CI]1⁄441 to 45%) and 21.8% (95% CI1⁄419 to 26%), respectively. Five-year CSM rates were 34.0% (95% CI1⁄432 to 36) and 47.6% (95% CI1⁄444 to 52) for the same groups, respectively. In patients with organ-confined UCUB (T2N0), BPTtreated individuals had significantly increased risks of mortality (hazard ratio [HR]: 1.49, 95% CI1⁄41.04e2.13, P1⁄40.031) and CSM (HR: 1.66, 95% CI1⁄41.03e2.67, P1⁄40.036) compared to RC patients. Among those with non-organ confinedUCUB ( T3N0), no differencewas noted with respect to OS (HR: 1.22, 95%CI1⁄40.62e2.40, P1⁄40.571) and CSM (HR: 1.13, 95% CI1⁄40.48e2.64, P1⁄40.780) between the two groups. CONCLUSIONS: RC was associated with improved cancer control outcomes compared to BPT in organ-confined UCUB. However, no difference between the two treatment modalities was observed with respect to survival amongst patients with more advanced disease stage.

At present, radical cystectomy is a mainstay in the management of all bladder cancers , whether of conventional urothelial histology or variant. However, in the case of some variants, it is clearly not enough and multimodal therapy is an imperative. In other cases, systemic therapy might be ineffective or even detrimental if it leads to delay in surgery (ie, squamous cell carcinoma). Thus, identification of variant histology is a critical part of bladder cancer staging because such histology may require appropriately tailored therapy.

302 Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carcinoma. We have previously published clinical risk stratification groups for patients with conventional urothelial carcinoma and sought to identify if these were valid in patients with this variant histology. Methods: An IRB approved review of 1910 patients in our radical cystectomy database revealed 106 patients with preoperative diagnosis of ≤cT4aN0M0 MPBC between December 1992 and January 2012 who underwent upfront radical cystectomy (RC, n = 74) or neoadjuvant chemotherapy (NAC) followed by RC (n = 32). To determine whether patients with MPBC can be risk stratified using traditional risk factors, a recursive partitioning analysis (RPA) was performed. Results: In multivariate analyses, hydronephrosis (HR=3.1; p=0.01), and extent of MPBC at transurethral resection (TUR) (HR=1.9; p=0.04) were associated with shortened OS. In the reduced model, clinical stage also achieved significance (HR=2.8; p=0.03). Results were similar for DSS: hydronephrosis (HR=2.4, p=0.03), extent of MPBC (HR=2.1, p=0.03) and clinical stage (HR=4.7, p=0.02). Using the RPA analysis, following risk groups were identified according to OS or DSS: 1) cT1 disease with no hydronephrosis; 2) cT2 or higher with no hydronephrosis; or 3) hydronephrosis (with any cT stage). These groups corresponded to a low, intermediate and high-risk groups with 5-year OS and DSS rates of 85% and 91%, 50% and 57% and 16% and 17%, (p<0.001), respectively. We found these risk groups to hold true in those treated with NAC or upfront RC; those who received NAC trended towards better outcomes. Conclusions: In patients with MPBC, preoperative risk factors can help stratify patients into different risk groups similar to what is seen in patients with conventional UC. Presence of hydronephrosis is an especially ominous sign.

PURPOSE OF REVIEW:The true clinical significance of variant histology is controversial and diagnosis is challenging, especially in the setting of nonmuscle invasive (NMI) disease. If the presence of variant architecture in NMI identifies a high-risk population with a worse prognosis and better suited for early aggressive intervention (i.e., radical cystectomy), then treatment recommendations should reflect this notion. This review outlines the current evidence and determines whether histologic variants should change management of patients with nonmuscle invasive bladder cancer.RECENT FINDINGS:Patients with high-risk NMI tumors and variant histology should be offered early cystectomy, especially if harboring pure squamous, adenocarcinoma, sarcomatoid, plasmacytoid, or micropapillary disease. In patients with small cell disease, systemic primary chemotherapy is the ideal option followed by local therapy for primary tumor control. For squamous/glandular differentiation, nested variant, and other rare variants, intravesical therapy is an option based on standard risk stratification in patients with NMI disease. Diligence is needed in the presence of variant histology to minimize the risk of understaging as well as close surveillance to not compromise the opportunity of cure.SUMMARY:The management of nonmuscle invasive bladder cancer with variant histology is challenging, largely in part to the high risk of understaging and the background of already existing controversy regarding the management of high-risk NMI disease for standard urothelial cell carcinoma (early cystectomy vs. intravesical therapy). Future studies should be focused identifying if variant architecture confers different tumor biology than that of pure urothelial carcinoma, and if this difference translates into innovations in bladder sparing therapies.

Bladder cancer stem cell research is rapidly expanding based on the knowledge of cancer stem cells from various cancer types and normal stem cells as models. In various cancer types, cancer stem cells have been implicated in therapeutic resistance and relapse after initial therapy. Understanding how cancer stem cells differ from bulk cancer cells and how cancer stem cells contribute to relapse and resistance are essential to develop novel therapeutics to target cancer stem cells effectively. Here we review the latest information on bladder cancer stem cells, their biological characteristics, including their response to treatment, recurrence, immune context and technical problems encountered in bladder cancer stem cell research.

You have accessJournal of UrologyBladder Cancer: Invasive II1 Apr 2014MP55-20 OUTCOME OF PATIENTS WITH CLINICALLY NODE-POSITIVE BLADDER CANCER WHO UNDERGO CONSOLIDATIVE SURGERY AFTER PRE-OPERATIVE CHEMOTHERAPY: MD ANDERSON CANCER CENTER EXPERIENCE Philip Ho, Daniel Willis, Jeevitha Patil, Karen Tart, Sahil Parikh, Jay Shah, Scott Delacroix, Arlene Siefker-Radtke, Colin Dinney, Louis Pisters, and Ashish Kamat Philip HoPhilip Ho More articles by this author , Daniel WillisDaniel Willis More articles by this author , Jeevitha PatilJeevitha Patil More articles by this author , Karen TartKaren Tart More articles by this author , Sahil ParikhSahil Parikh More articles by this author , Jay ShahJay Shah More articles by this author , Scott DelacroixScott Delacroix More articles by this author , Arlene Siefker-RadtkeArlene Siefker-Radtke More articles by this author , Colin DinneyColin Dinney More articles by this author , Louis PistersLouis Pisters More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1568AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives We previously reported results of our phase II study in patients with retroperitoneal lymph node (RPLN) metastasis from bladder cancer (BC) undergoing consolidative surgery after pre-operative chemotherapy. Here we present an expanded cohort of patients who underwent consolidative surgery after chemotherapy for clinically node-positive BC. Methods We reviewed results of patients from our IRB approved protocol including those with clinical evidence of nodal metastasis in the pelvis or retroperitoneum (M1), without visceral metastasis, from 1995-2010. The endpoint of the study was cancer-specific survival (CSS) calculated from time of surgical consolidation. Results A total of 55 patients with either clinical pelvic lymph node (PLN) metastasis (n=29) or PLN and RPLN metastasis (n=26) were identified. Median CSS was 19 months for all patients; 21 for PLN alone and 16 for PLN and RPLN disease. Kaplan-Meier estimate of 5-year CSS was 31% for the entire group with no difference between PLN alone and PLN with RPLN disease. According to AJCC 2010 criteria, clinical nodal stage was N1: 16, N2: 5, N3: 8, and M1 (RPLN): 26. Majority (94%) of patients received cisplatinum-based chemotherapy. At cystectomy, all patients underwent a PLN dissection (PLND) with 12 patients (all clinical M1 RPLN) undergoing concurrent RPLN dissection (RPLND) to the renal hilum. In all, 30 of 55 (55%) patients were pN0 at the time of surgical extirpation while 26% (5 of 19) were pN+ despite radiologic complete response after chemotherapy. 5-year CSS was 57% for pN0 disease and 9% for pN+ disease (p<0.0001). Median survival in patients with residual tumor in PLN (n=17) was 10.5 months vs. 7 months for RPLN (n=8) (median survival was not reached in pN0 patients, p<0.001). 17 patients who developed recurrences outside the surgical field did so after a median of 8 months. While no recurrences occurred within the lymphadenectomy template, 2 of 14 (14%) patients with clinical M1 RPLN disease who did not undergo RPLND had recurrences in RPLN basin; both died within 6 months despite salvage chemotherapy. Conclusions Post-chemotherapy consolidative surgical resection may result in 5-year disease-free survival in patients with clinical evidence of node-positive disease, including those with RPLN positive disease, who have major response to chemotherapy. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e563 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Philip Ho More articles by this author Daniel Willis More articles by this author Jeevitha Patil More articles by this author Karen Tart More articles by this author Sahil Parikh More articles by this author Jay Shah More articles by this author Scott Delacroix More articles by this author Arlene Siefker-Radtke More articles by this author Colin Dinney More articles by this author Louis Pisters More articles by this author Ashish Kamat More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2014MP34-07 DIFFERENTIAL GENE EXPRESSION IN RESPONSIVE VERSUS RECURRENT NON-MUSCLE INVASIVE HIGH-GRADE UROTHELIAL CARCINOMAS AFTER INDUCTION BCG Philip Ho, Daniel Willis, Saad Aldousari, Charles Guo, Colin Dinney, Xifeng Wu, and Ashish Kamat Philip HoPhilip Ho More articles by this author , Daniel WillisDaniel Willis More articles by this author , Saad AldousariSaad Aldousari More articles by this author , Charles GuoCharles Guo More articles by this author , Colin DinneyColin Dinney More articles by this author , Xifeng WuXifeng Wu More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1020AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although BCG remains the intravesical therapy of choice after TURBT for high-grade non-muscle invasive bladder carcinomas (NMIBC), a recurrence and progression rate of up to 40% occurs after induction treatment. BCG failure likely can be attributed, at least partially, to inherent tumoral characteristics. In this study, our goal was to seek out differences in gene expression profile between tumors that recurred and those free from recurrence after induction BCG. METHODS Primary bladder tumors from TURBT specimens were obtained from patients enrolled in a prospective study evaluating predictive markers for response to BCG. The analysis was restricted to high-grade Ta and T1 lesions. Tumors were arrayed using the Illumina Platform – DASL v3 to profile tumors for mRNA differential expression after tumor tissues were identified by a dedicated GU pathologist. RESULTS mRNA expression profiles of 12 primary tumors that responded to BCG with no subsequent recurrences were compared to 5 primary tumors that recurred after BCG. Demographic and tumor stage distribution between the two groups were not statistically different. Median time to recurrence after TURBT was 7 months (range: 4-11 months). Median follow-up for all patients was 50 months. Using Ingenuity Pathway Analysis, we found a significant increase in expression of genes within specific functional pathways by tumors that developed recurrence after BCG: cell cycle progression (p=9.2e-5), cell death (p=6.8e-4), necrosis (p=4.54e-4), apoptosis (p=7.4e-3), cell proliferation (p=4.9e-3), migration of antigen presenting cells (p=0.044), and immunological diseases (p=0.015). Highly overexpressed genes include chemokine receptors CXCR2 (fold change (FC) 2.969, p=7.75e-6) and CXCR4 (FC 2.337, p=0.022), nuclear receptor NR4A1 (FC 3.776, p=4.4e-4), and transcription factor SOX2 (FC 2.48, p=1.02e-3). CONCLUSIONS Compared to BCG-responsive tumors, high-grade NMIBC that recur after BCG treatment have increased expression of genes implicated in bladder cancer growth and survival, invasion, response to therapy, and metastasis. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e364 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Philip Ho More articles by this author Daniel Willis More articles by this author Saad Aldousari More articles by this author Charles Guo More articles by this author Colin Dinney More articles by this author Xifeng Wu More articles by this author Ashish Kamat More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

You have accessJournal of UrologyBladder Cancer: Invasive IV1 Apr 2014MP61-07 IDENTIFICATION OF DISTINCT BASAL AND LUMINAL SUBSETS OF HUMAN BLADDER CANCERS WITH DIFFERENT SENSITIVITIES TO FRONTLINE CHEMOTHERAPY Woonyoung Choi, Sima Porten, Seungchan Kim, Beat Roth, Teiwei Chang, Daniel Willis, Mai Tran, I-Ling Lee, Jonathan Melquist, Jolanta Bondaruk, Tadeusz Majewski, Shizhen Zhang, Shanna Pretzsch, Keith Baggerly, Elizabeth Plimack, Jean Hoffman-Censits, Arlene Siefker-Radtke, Bogdan Czerniak, Colin Dinney, and David McConkey Woonyoung ChoiWoonyoung Choi More articles by this author , Sima PortenSima Porten More articles by this author , Seungchan KimSeungchan Kim More articles by this author , Beat RothBeat Roth More articles by this author , Teiwei ChangTeiwei Chang More articles by this author , Daniel WillisDaniel Willis More articles by this author , Mai TranMai Tran More articles by this author , I-Ling LeeI-Ling Lee More articles by this author , Jonathan MelquistJonathan Melquist More articles by this author , Jolanta BondarukJolanta Bondaruk More articles by this author , Tadeusz MajewskiTadeusz Majewski More articles by this author , Shizhen ZhangShizhen Zhang More articles by this author , Shanna PretzschShanna Pretzsch More articles by this author , Keith BaggerlyKeith Baggerly More articles by this author , Elizabeth PlimackElizabeth Plimack More articles by this author , Jean Hoffman-CensitsJean Hoffman-Censits More articles by this author , Arlene Siefker-RadtkeArlene Siefker-Radtke More articles by this author , Bogdan CzerniakBogdan Czerniak More articles by this author , Colin DinneyColin Dinney More articles by this author , and David McConkeyDavid McConkey More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1884AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Muscle-invasive bladder cancers (MIBCs) are a heterogeneous group of tumors that display widely variable clinical outcomes and responses to conventional chemotherapy. METHODS We used whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 flash frozen primary tumors to identify 3 distinct subsets of muscle-invasive bladder cancer (MIBC). We confirmed the existence of these 3 subsets in a second cohort of 57 formalin-fixed, paraffin-embedded (FFPE) MIBCs and in 2 other public datasets. RESULTS The first “basal” subset of MIBCs shared biomarkers with basal/triple negative breast cancers, expressed EMT markers, an active "basal" EGFR-STAT3-p63 transcriptional network, and displayed squamous differentiation. These basal cancers presented at a later stage and were associated with poor clinical outcomes. A third “luminal” subset expressed estrogen receptor and PPARγ gene signatures, luminal breast differentiation markers, and activating FGFR3 mutations. Luminal BC cell lines were sensitive to FGFR3 inhibition. The second subset was characterized by active p53 pathway activation. p53-like MIBCs also contained luminal biomarkers, were infiltrated with stromal cells, and were resistant to neoadjuvant cisplatin-based chemotherapy. CONCLUSIONS Molecular subtyping of MIBCs can be used to identify lethal cancers.The observation that bladder and breast cancers share significant features has implications for prognostication and the development of targeted therapies. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e685 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Woonyoung Choi More articles by this author Sima Porten More articles by this author Seungchan Kim More articles by this author Beat Roth More articles by this author Teiwei Chang More articles by this author Daniel Willis More articles by this author Mai Tran More articles by this author I-Ling Lee More articles by this author Jonathan Melquist More articles by this author Jolanta Bondaruk More articles by this author Tadeusz Majewski More articles by this author Shizhen Zhang More articles by this author Shanna Pretzsch More articles by this author Keith Baggerly More articles by this author Elizabeth Plimack More articles by this author Jean Hoffman-Censits More articles by this author Arlene Siefker-Radtke More articles by this author Bogdan Czerniak More articles by this author Colin Dinney More articles by this author David McConkey More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyUrothelial Cancer: Medical & Surgical Therapy1 Apr 2013526 PROGNOSTIC SIGNIFICANCE OF P0 STAGE IN PATIENTS WITH MICROPAPILLARY BLADDER CANCER UNDERGOING RADICAL CYSTECTOMY Mario Fernandez, Daniel Willis, Rebecca Slack, Rian Dickstein, Sahil Parikh, Arlene Siefker-Radtke, Charles Guo, Bogdan Czerniak, Jay Shah, Louis Pisters, H. Barton Grossman, Colin Dinney, and Ashish Kamat Mario FernandezMario Fernandez Houston, TX More articles by this author , Daniel WillisDaniel Willis Houston, TX More articles by this author , Rebecca SlackRebecca Slack Houston, TX More articles by this author , Rian DicksteinRian Dickstein Houston, TX More articles by this author , Sahil ParikhSahil Parikh Houston, TX More articles by this author , Arlene Siefker-RadtkeArlene Siefker-Radtke Houston, TX More articles by this author , Charles GuoCharles Guo Houston, TX More articles by this author , Bogdan CzerniakBogdan Czerniak Houston, TX More articles by this author , Jay ShahJay Shah Houston, TX More articles by this author , Louis PistersLouis Pisters Houston, TX More articles by this author , H. Barton GrossmanH. Barton Grossman Houston, TX More articles by this author , Colin DinneyColin Dinney Houston, TX More articles by this author , and Ashish KamatAshish Kamat Houston, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1920AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The absence of detectable disease in the pathologic specimen (P0) after radical cystectomy (RC) confers an excellent prognosis for patients with conventional urothelial carcinoma. However, there are mixed reports concerning the durability of a P0 finding in patients with micropapillary bladder cancer (MPBC). Here we evaluated and report the prognostic significance of P0 stage in a contemporary series of patients with MPBC treated with RC. METHODS An IRB approved review of 1910 patients in our RC database revealed the presence of 172 patients with preoperative diagnosis of MPBC. Of these, 29 (16.9%) were pT0N0M0 in the surgical specimen. Survival was assessed by the Kaplan-Meier method and compared by means of the log-rank test. Various pre-operative variables were assessed for prognostic significance. RESULTS For patient who achieve P0 status at RC, the 5-yr estimates of overall (OS), disease-specific (DSS) and recurrence-free survival (RFS) were 76%, 87% and 85% respectively; which are not dissimilar to what we have previously reported for conventional urothelial carcinoma (5-yr estimates of OS, DSS, and RFS being 84%, 88%, and 84%, respectively). Clinical stages were cT1cN0: 11 patients (38%); cT2cN0: 12 (42%); cT2cN3: 2 (7%); cT3cN0: 1 (3%); cT3N1: 2 (7%); cT4bN0: 1 (3%). Twenty-five patients (86%) received pre-surgical chemotherapy, mostly cisplatin-based (76%). After a median follow-up of 54 months, 4 patients developed recurrences; 3 died of disease. The median time to recurrence was not reached at the time of last follow-up. Within the limitation of small numbers in this rare subtype of bladder cancer, clinical T - and N stage and LVI on TUR specimen were significantly associated with reduced DSS (p=0.020, p=0.0003 & p=0.027, respectively) on univariate analysis. Survival rates were similar in those with and without preoperative chemotherapy. CONCLUSIONS MPBC patients who are P0 at cystectomy have a good prognosis but not all can be considered cured of their disease. As with conventional urothelial carcinoma, the favorable prognosis conferred by a P0 state appears to be independent of whether this is achieved by administration of chemotherapy or by thorough pre-cystectomy transurethral resection. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e215-e216 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Metrics Author Information Mario Fernandez Houston, TX More articles by this author Daniel Willis Houston, TX More articles by this author Rebecca Slack Houston, TX More articles by this author Rian Dickstein Houston, TX More articles by this author Sahil Parikh Houston, TX More articles by this author Arlene Siefker-Radtke Houston, TX More articles by this author Charles Guo Houston, TX More articles by this author Bogdan Czerniak Houston, TX More articles by this author Jay Shah Houston, TX More articles by this author Louis Pisters Houston, TX More articles by this author H. Barton Grossman Houston, TX More articles by this author Colin Dinney Houston, TX More articles by this author Ashish Kamat Houston, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

308 Background: We have previously reported that intravesical BCG is ineffective as therapy for micropapillary variant of bladder cancer. Since then, smaller reports have emerged with differing conclusions. Here we report our updated experience and expanded number of patients with micropapillary bladder cancer (MPBC), with emphasis on cT1 MPBC. Methods: An IRB approved institutional review of our bladder cancer database identified 255 patients presenting with MPBC with 72 patients staged as cT1N0M0 at the time of initial diagnosis. Statistical and descriptive analysis was performed using IBM SPSS Statistics version 20 and survival analysis was performed using the Kaplan-Meier estimator and compared using the log-rank test. Results: Of the 72 patients with cT1 MPBC, intravesical BCG was used in 38 patients (53%), while 32 (44%) proceeded directly to radical cystectomy. This included 15 (20%) who received neoadjuvant chemotherapy for lymphovascular invasion (LVI). Kaplan-Meier estimates of overall survival (OS) and disease specific survival (DSS) at 5 and 10 years were 66% and 45%, and 70% and 61%, respectively. Among those receiving BCG, 28 (74%) recurred at a median of 7 mo., and 17 (45%) progressed, including 8 (30%) who developed metastatic disease. Among the 10 post BCG patients who underwent cystectomy after progression, median DSS was 43 mo. (mean=53 mo.) and 5 year DSS was 33%, whereas among those proceeding directly to cystectomy, median DSS was not reached (mean=152 mo.) and the 5 year DSS rate was 92% (p<0.001). For OS, upfront cystectomy conferred a median survival of 170 mo. versus 92 mo. for those receiving BCG as initial therapy (p=0.05). There was no association of OS with the presence of CIS, repeat transurethral resection (TUR), or history of intravesical therapy prior to the diagnosis of MPBC. Interestingly, the extent of micropapillary component in the initial TUR specimen did have prognostic value for those treated with BCG as patients with focal MPBC were 2.3 times less likely to progress (p=0.02). Conclusions: Our updated findings support the use of upfront radical cystectomy prior to progression of disease in patients with cT1 MPBC. BCG therapy should be attempted only in select patients as there is a high risk of disease progression during BCG treatment.

4538 Background: Muscle-invasive bladder cancers (MIBCs) are a heterogeneous group of tumors that display widely variable clinical outcomes and responses to conventional chemotherapy. Methods: We used whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 flash frozen primary tumors to identify 3 distinct subsets of muscle-invasive bladder cancer (MIBC). We confirmed the existence of these 3 subsets in a second cohort of 57 formalin-fixed, paraffin-embedded (FFPE) MIBCs and in 2 other public datasets. Analysis of primary tumors and mechanistic studies in human bladder cancer cell lines identified tumors that respond to FGFR inhibitors or chemotherapy. Results: The first subset was driven by an active "basal" EGFR-STAT3-p63 transcriptional network, and was associated with poor clinical outcomes. High miR-200c expression stratified the survival of these basal tumors. The second subset was characterized by active p53 pathway activation, and tumors and cell lines with these features were resistant to cis-platinum based chemotherapy. The third subset expressed "luminal" markers and active estrogen receptor (ER) and PPARγ signaling, and luminal cell lines were sensitive to fibroblast growth factor receptor (FGFR) inhibition. Conclusions: Molecular subtyping of MIBCs can be used to identify lethal cancers and enrich for tumors that will respond to FGFR inhibitors or conventional chemotherapy.

OBJECTIVE:To review a multi-institutional series of robot-assisted nephroureterectomy (RANU) for management of upper urinary tract urothelial carcinoma (UUTUC) with respect to technique and perioperative outcomes.PATIENTS AND METHODS:Between May 2007 and July 2011, 43 RANU were performed at three institutions for UUTUC with review of perioperative outcomes. A three- or four-armed robotic technique was used in all cases based on surgeon preference and the entirety of all procedures was performed using the robot-assisted technique. Single and two robot-docking techniques are described.RESULTS:The mean (range) operating time was 247 (128-390) min, blood loss was 131 (10-500) mL and the median (range) length of stay was 3 (2-87) days. Pathology was pTa in nine patients, pT1 in 14 patients, pT2 in three patients, pT3 in 15 patients and pT4 in two patients. Lymph node dissection was performed in 22 patients (51%) with a mean (range) lymph node count of 11 (4-23). There were six postoperative complications: bleeding requiring a blood transfusion (grade II), splenic bleeding (grade IV), two cases of pneumonia (grade II) and two cases of rhabdomyolysis (grades II and IV). Nine recurrences (six bladder, two within the retroperitoneum and one in the contralateral collecting system) have been found to date on routine surveillance with a mean follow-up of 9 months.CONCLUSIONS:RANU is a feasible alternative to laparoscopic and open techniques. Particular steps of the operation including sutured closure of the cystotomy and regional lymphadenectomy are facilitated with the use of robot-assisted surgery. Long-term outcomes are necessary to assess the relative efficacy of these approaches to more established techniques; however, early perioperative outcomes appear promising.

You have accessJournal of UrologyBladder Cancer: Metastatic Disease + Staging1 Apr 20131883 DOES THE EXTENT OF MICROPAPILLARY COMPONENT IMPACT CLINICAL OUTCOME? Daniel Willis, Mario Fernandez, Charles Guo, Bogdan Czerniak, Rian Dickstein, Parikh Sahil, Louis Pisters, H. Barton Grossman, Colin Dinney, and Ashish Kamat Daniel WillisDaniel Willis Houston, TX More articles by this author , Mario FernandezMario Fernandez Houston, TX More articles by this author , Charles GuoCharles Guo Houston, TX More articles by this author , Bogdan CzerniakBogdan Czerniak Houston, TX More articles by this author , Rian DicksteinRian Dickstein Houston, TX More articles by this author , Parikh SahilParikh Sahil Houston, TX More articles by this author , Louis PistersLouis Pisters Houston, TX More articles by this author , H. Barton GrossmanH. Barton Grossman Houston, TX More articles by this author , Colin DinneyColin Dinney Houston, TX More articles by this author , and Ashish KamatAshish Kamat Houston, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2302AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It has been postulated that the clinical behavior of micropapillary bladder cancer (MPBC) is dependent on the extent of MPBC component relative to conventional urothelial carcinoma. As no formal definition of what constitutes focal or extensive MPBC exists, we sought to quantify focal vs. extensive MPBC and study the impact of extent of disease on clinical outcome. METHODS An IRB approved institutional review of our bladder cancer database identified 253 patients with MPBC described as being “focal” or “extensive” at the time of TUR. In 40 of these cases, the percentage of MPBC was numerically quantified by a GU pathologist. Clinical, pathologic, and outcome data were correlated with extent of disease using chi square test, Kaplan-Meier estimator, and Cox Regression analysis. RESULTS Overall, 169 (67%) patients were reported as having focal MPBC and 84 (33%) patients as extensive micropapillary histology. In this group, the median disease specific survival (DSS) for focal and extensive MPBC was 59 vs. 25 months, respectively (p=0.004). Extensive MPBC continued to predict DSS on multivariate analysis after including the following covariates: age, cT stage, cN status, and lymphovascular invasion (LVI) (p=0.028). Analysis of the 40 patients with a quantified percentage of MPBC demonstrated that a cutoff of 15% had the greatest association with survival and cT stage (p<0.001). Among these, 18 (45%) had ≤15% and 22 (55%) had >15% component of MPBC. The 5 year estimated DSS was 77% and 13% for ≤15% and >15% MPBC, respectively (p<0.001, Figure 1). Further comparison between patients with ≤15% MPBC vs. >15% MPBC demonstrated relevant differences in LVI (17% vs. 57%, p=0.01), lymph node metastasis at presentation (11% vs. 43%, p=0.03), distant metastatic disease at presentation (6% vs. 32%, p=0.04), and cT stage (cT1: 50% vs. 9%; cT2: 44% vs. 64%; cT3: 6% vs. 14%; cT4: 0% vs. 14%; p=0.02), respectively. CONCLUSIONS Extensive micropapillary architecture in the TUR specimen is associated with more advanced disease and a worse disease specific survival when compared to focal MPBC. Our review suggests that any MPBC comprising greater than 15% of the TUR specimen may be considered as “extensive” micropapillary disease, and treated as such. Further pathologic review is underway to further validate this definition of focal vs. extensive MPBC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e772 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Willis Houston, TX More articles by this author Mario Fernandez Houston, TX More articles by this author Charles Guo Houston, TX More articles by this author Bogdan Czerniak Houston, TX More articles by this author Rian Dickstein Houston, TX More articles by this author Parikh Sahil Houston, TX More articles by this author Louis Pisters Houston, TX More articles by this author H. Barton Grossman Houston, TX More articles by this author Colin Dinney Houston, TX More articles by this author Ashish Kamat Houston, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyUrothelial Cancer: Medical & Surgical Therapy1 Apr 2013523 CLINICAL OUTCOMES OF PATIENTS WITH MICROPAPILLARY BLADDER CANCER TREATED WITH NEOADJUVANT THERAPY AND/OR RADICAL CYSTECTOMY Mario Fernandez, Daniel Willis, Rebecca Slack, Rian Dickstein, Sahil Parikh, Arlene Siefker-Radtke, Charles Guo, Bogdan Czerniak, Jay Shah, Louis Pisters, H. Barton Grossman, Colin Dinney, and Ashish Kamat Mario FernandezMario Fernandez Houston, TX More articles by this author , Daniel WillisDaniel Willis Houston, TX More articles by this author , Rebecca SlackRebecca Slack Houston, TX More articles by this author , Rian DicksteinRian Dickstein Houston, TX More articles by this author , Sahil ParikhSahil Parikh Houston, TX More articles by this author , Arlene Siefker-RadtkeArlene Siefker-Radtke Houston, TX More articles by this author , Charles GuoCharles Guo Houston, TX More articles by this author , Bogdan CzerniakBogdan Czerniak Houston, TX More articles by this author , Jay ShahJay Shah Houston, TX More articles by this author , Louis PistersLouis Pisters Houston, TX More articles by this author , H. Barton GrossmanH. Barton Grossman Houston, TX More articles by this author , Colin DinneyColin Dinney Houston, TX More articles by this author , and Ashish KamatAshish Kamat Houston, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1917AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Micropapillary Bladder Cancer (MPBC) is a rare variant of urothelial carcinoma associated to poor prognosis for which the role of neoadjuvant chemotherapy (NAC) remains to be defined. Here we report the outcome and analysis of patients with MPBC undergoing radical cystectomy (RC) with and without NAC. METHODS An IRB approved review of our radical cystectomy database revealed the presence of 172 patients with preoperative diagnosis of MPBC; of these 138 patients presented with surgically resectable (¡(cT4aN0M0) disease and were selected for this report. Disease-specific survival (DSS) was estimated using the Kaplan-Meier method and compared by log-rank test. RESULTS The clinical stage of patients was cT1: 52; cT2: 69; cT3: 15 and cT4a: 2. NAC was administered to 62 patients (45%), with 81% receiving cisplatin-based regimens. After a median follow-up of 44 months, 47% patients recurred and 40% died of disease; resulting in a 5-year estimated DSS of 59% for all 136 patients with cause of death information. Survival analysis was performed for comparable groups according to our established risk factors (high risk is cT3 disease or cT2 with hydronephrosis or lymphovascular invasion (LVI) in the transurethral resection (TUR) specimen). For the low risk patients (i.e. cT1 or cT2 with no hydronephrosis and no LVI) RC upfront (n=56) resulted in a 76% 5-yr DSS compared to 67% with NAC (n=31) (p=0.88). In the high-risk group, 17 patients were treated initially with RC and 5-yr DSS was 20% compared to 43% (p=0.27) in those undergoing NAC (n=31). The most important overall prognostic factor was pathologic downstaging to