Jay B. Shah

Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer

Epithelial-to-mesenchymal transition (EMT) is a process that plays essential roles in development and wound healing that is characterized by loss of homotypic adhesion and cell polarity and increased invasion and migration. At the molecular level, EMT is characterized by loss of E-cadherin and increased expression of several transcriptional repressors of E-cadherin expression (Zeb-1, Zeb-2, Twist, Snail, and Slug). Early work established that loss of E-cadherin and increased expression of MMP-9 was associated with a poor clinical outcome in patients with urothelial tumors, suggesting that EMT might also be associated with bladder cancer progression and metastasis. More recently, we have used global gene expression profiling to characterize the molecular heterogeneity in human urothelial cancer cell lines (n = 20) and primary patient tumors, and unsupervised clustering analyses revealed that the cells naturally segregate into two discrete “epithelial” and “mesenchymal” subsets, the latter consisting entirely of muscle-invasive tumors. Importantly, sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) or type-3 fibroblast growth factor receptor (FGFR3) was confined to the “epithelial” subset, and sensitivity to EGFR inhibitors could be reestablished by micro-RNA-mediated molecular reversal of EMT. The results suggest that EMT coordinately regulates drug resistance and muscle invasion/metastasis in urothelial cancer and is a dominant feature of overall cancer biology.

ICUD-EAU international consultation on bladder cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder

CONTEXT Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. OBJECTIVE To critically review the recent data on the management of NMIBC to arrive at a general consensus. EVIDENCE ACQUISITION A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. CONCLUSIONS Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Neoadjuvant Chemotherapy in Small Cell Urothelial Cancer Improves Pathologic Downstaging and Long-term Outcomes: Results from a Retrospective Study at the MD Anderson Cancer Center

BACKGROUND Small cell urothelial carcinoma (SCUC) is a rare, aggressive malignancy with a propensity for early microscopic metastases. Data suggest that neoadjuvant chemotherapy may lead to improved survival compared with initial surgery. OBJECTIVE To determine the influence of neoadjuvant chemotherapy on survival of SCUC patients in a large single-institution cohort. DESIGN, SETTING, AND PARTICIPANTS Between 1985 and 2010, 172 patients were treated for SCUC at MD Anderson Cancer Center (MDACC). Clinical, pathologic, and surgical data were collected and analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to evaluate the effects of neoadjuvant chemotherapy on survival. RESULTS AND LIMITATIONS Of 125 patients with resectable disease (≤ cT4aN0M0), 95 were surgical candidates. Forty-eight received neoadjuvant chemotherapy, and 47 underwent initial surgery. Neoadjuvant treatment was associated with improved OS and DSS compared with initial cystectomy (median OS: 159.5 mo vs 18.3 mo, p<0.001; 5-yr DSS: 79% vs 20%, p<0.001). Neoadjuvant chemotherapy resulted in pathologic downstaging to ≤ pT1N0 in 62% of tumors compared with only 9% treated with initial surgery (odds ratio: 44.55; 95% confidence interval, 10.39-191). Eight patients with clinically node-positive disease had surgical consolidation with cystectomy and extended lymph node dissection after clinical complete response to chemotherapy. Median OS and DSS in this group of patients were 23.3 mo and 21.8 mo, respectively, with 5-yr OS and DSS of 38%. CONCLUSIONS Neoadjuvant chemotherapy is associated with a high rate of pathologic downstaging and correlates with significantly higher survival compared with historical expectations. Although limited by a small sample size and retrospective analysis, in the context of a rare disease, this experience suggests neoadjuvant chemotherapy as a standard approach in treating SCUC.

p63 expression defines a lethal subset of muscle-invasive bladder cancers.

Background p63 is a member of the p53 family that has been implicated in maintenance of epithelial stem cell compartments. Previous studies demonstrated that p63 is downregulated in muscle-invasive bladder cancers, but the relationship between p63 expression and survival is not clear. Methodology/Principal Findings We used real-time PCR to characterize p63 expression and several genes implicated in epithelial-to-mesenchymal transition (EMT) in human bladder cancer cell lines (n = 15) and primary tumors (n = 101). We correlated tumor marker expression with stage, disease-specific (DSS), and overall survival (OS). Expression of E-cadherin and p63 correlated directly with one another and inversely with expression of the mesenchymal markers Zeb-1, Zeb-2, and vimentin. Non-muscle-invasive (Ta and T1) bladder cancers uniformly expressed high levels of E-cadherin and p63 and low levels of the mesenchymal markers. Interestingly, a subset of muscle-invasive (T2–T4) tumors maintained high levels of E-cadherin and p63 expression. As expected, there was a strongly significant correlation between EMT marker expression and muscle invasion (p<0.0001). However, OS was shorter in patients with muscle-invasive tumors that retained p63 (p = 0.007). Conclusions/Significance Our data confirm that molecular markers of EMT are elevated in muscle-invasive bladder cancers, but interestingly, retention of the “epithelial” marker p63 in muscle-invasive tumors is associated with a worse outcome.

New Strategies in Muscle-Invasive Bladder Cancer: On the Road to Personalized Medicine

Bladder cancer remains one of the most deadly and expensive diseases affecting modern society. The options currently available to patients with muscle-invasive bladder cancer have remained essentially unchanged for the last generation. As the roles for surgery and chemotherapy in the management of this lethal disease have become better defined, so too have the limitations of these two treatment modalities. Despite the lack of groundbreaking clinical advances over the past two decades, recent years have witnessed a notable increase in the amount of promising preclinical and early translational research that will greatly improve our understanding of the molecular underpinnings of bladder cancer. If this momentum in bladder cancer research continues to build, it is likely that in the next 5 to 10 years we will be able to achieve our goal of bringing bladder cancer treatment into the age of personalized medicine. Clin Cancer Res; 17(9); 2608–12. ©2011 AACR.

A Multi-Institutional Analysis of Outcomes of Patients with Clinically Node Positive Urothelial Bladder Cancer Treated with Induction Chemotherapy and Radical Cystectomy

PURPOSE Selected patients with bladder cancer with pelvic lymphadenopathy (cN1-3) are treated with induction chemotherapy followed by radical cystectomy. However, the data on clinical outcomes in these patients are limited. In this study we assess pathological and survival outcomes in patients with cN1-3 disease treated with induction chemotherapy and radical cystectomy. MATERIALS AND METHODS Data were collected on patients from 19 North American and European centers with cT1-4aN1-N3 urothelial carcinoma who received chemotherapy followed by radical cystectomy between 2000 and 2013. The primary end points were pathological complete (pT0N0) and partial (pT1N0 or less) response rates, with overall survival as a secondary end point. Logistic regression and Cox proportional hazard ratios were used for multivariate analysis of factors predicting these outcomes. RESULTS The total of 304 patients had clinical evidence of lymph node involvement (cN1-N3). Methotrexate/vinblastine/doxorubicin/cisplatin was used in 128 (42%), gemcitabine/cisplatin in 132 (43%) and other regimens in 44 (15%) patients. The pN0 rate was 48% (cN1-56%, cN2-39%, cN3-39%, p=0.03). The complete and partial pathological response rates for the entire cohort were 14.5% and 27%, respectively. The estimated median overall survival time for the cohort was 22 months (IQR 8.0, 54). On Cox regression analysis overall survival was associated with pN0, negative surgical margins, removal of 15 or more pelvic nodes and cisplatin therapy. CONCLUSIONS Complete pathological nodal response can be achieved in a proportion of patients with cN1-3 disease receiving induction chemotherapy. The best survival outcomes are observed in male patients on cisplatin regimens with subsequent negative radical cystectomy margins and complete nodal response (pN0) with excision of 15 or more pelvic nodes.

Clinical Outcomes of cT1 Micropapillary Bladder Cancer

PURPOSE While many urologists recommend radical cystectomy for micropapillary bladder cancer invading the lamina propria (cT1), contradictory small reports exist on the efficacy of conservative management with intravesical bacillus Calmette-Guérin for this disease. We report our updated experience in what to our knowledge is the largest series of patients with cT1 micropapillary bladder cancer. MATERIALS AND METHODS An institutional review board approved review of our cancer database identified 283 patients with micropapillary bladder cancer, including 72 staged with cT1N0M0 disease at diagnosis and initiation of therapy. Survival analysis was performed using the Kaplan-Meier estimator and compared using the log rank test. RESULTS In this cohort of 72 patients 40 received primary intravesical bacillus Calmette-Guérin and 26 underwent up-front radical cystectomy. Of patients who received bacillus Calmette-Guérin 75%, 45% and 35% experienced disease recurrence, progression and lymph node metastasis, respectively. Patients treated with up-front cystectomy had improved survival compared to patients treated with primary bacillus Calmette-Guérin (5-year disease specific survival 100% vs 60% p = 0.006) and patients who underwent delayed cystectomy after recurrence (5-year disease specific survival 62%, p = 0.015). Prognosis was especially poor in patients who waited for progression before undergoing radical cystectomy with an estimated 5-year disease specific survival of only 24% and a median survival of 35 months. In patients treated with up-front cystectomy pathological up-staging was found in 27%, including 20% with lymph node metastasis. CONCLUSIONS While certain patients with T1 micropapillary bladder cancer may respond to intravesical bacillus Calmette-Guérin, survival is improved in those who undergo early radical cystectomy. Further molecular studies are needed to identify subsets of patients in whom the bladder can be safely spared.

Blebbishields, the emergency program for cancer stem cells: Sphere formation and tumorigenesis after apoptosis

Caspases mediate apoptosis and have also been implicated in stem-cell biology. How caspases are linked to stem-cell biology is not known. Here, we show that the apoptotic blebs of cancer cells fuse together to form novel structures called ‘blebbishields’. Blebbishields form spheres by fusion. Both blebbishield formation and sphere formation involve active caspases and N-linked glycosylation. Sphere formation is enhanced by acidic pH and is counteracted by inhibitors of proton pump, caspases, and cholesterol. The blebbishields from VEGFR2High cells are capable of enhanced sphere formation. Blebbishields express transiently downregulated stem-cell markers and the sphere-forming blebbishield-derived cells are tumorigenic. Our study demonstrates that the cancer stem cells can survive after apoptosis by blebbishield formation and subsequent sphere formation.

Robot-assisted extended pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP): a video-based illustration of technique, results, and unmet patient selection needs

Whats known on the subject? and What does the study add?