Ashish M. Kamat

Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration

The literature on upper tract urothelial carcinoma (UTUC) has been limited to small, single center studies. A large series of patients treated with radical nephroureterectomy for UTUC were studied, and variables associated with poor prognosis were identified.

CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients

Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody. All clinical trials to date, comprising over 3,000 patients, have been conducted in the metastatic disease setting, which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment. We conducted a pre-surgical clinical trial in six patients with localized bladder cancer, which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome. We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS). These CD4+ICOShi T cells produced IFN-gamma (IFNγ) and could recognize the tumor antigen NY-ESO-1. Increase in CD4+ICOShi cells led to an increase in the ratio of effector to regulatory T cells. To our knowledge, these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of this agent to improve clinical responses.

Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial

Purpose: Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti–CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder. Experimental Design: Six patients were treated with 3 mg/kg/dose of anti–CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring. Results: Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti–CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival. Conclusions: Our trial shows that anti–CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting. Clin Cancer Res; 16(10); 2861–71. ©2010 AACR.

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.

Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients.

Micropapillary bladder carcinoma is a rare variant of urothelial carcinoma. To improve understanding of this disease, the authors performed a retrospective review of their experience.

The Case for Early Cystectomy in the Treatment of Nonmuscle Invasive Micropapillary Bladder Carcinoma

PURPOSE Micropapillary bladder carcinoma is a rare variant of UC. Due to paucity of data regarding treatment outcomes, patients with nonmuscle invasive micropapillary UC often receive intravesical therapy in an attempt at bladder preservation. MATERIALS AND METHODS We reviewed the records of all patients evaluated at our institution who had micropapillary UC of the bladder. Of these, 44 had nonmuscle invasive disease at presentation and form the basis of this report. RESULTS Mean patient age was 64.3 years (range 45 to 81) with a male-to-female ratio of 13:1. Stage distribution at presentation was 5 Ta (11%), 4 CIS (9%) and 35 T1 (80%). Median CSS was 81 months. Kaplan-Meier estimates of 5 and 10-year CSS rates were 64% and 26%, respectively. Intravesical BCG therapy was attempted in 27 patients (61%). Of these 27 patients, 67% (18 of 27) had progression (cT2 or greater), including 22% in whom metastatic disease developed. Only 19% of patients (5 of 27, all T1) remain disease-free with an intact bladder at a median followup of 30 months. A total of 30 patients (68%) underwent cystectomy. Among patients who underwent cystectomy after progression (18), median CSS was 61.7 months with no patient surviving 10 years, whereas among those undergoing cystectomy as initial therapy (12), median survival was not reached and the 10-year CSS rate was 72%. CONCLUSIONS Intravesical BCG therapy appears to be ineffective against micropapillary UC. Our results suggest that the optimal treatment strategy for nonmuscle invasive micropapillary UC is radical cystectomy performed before progression.

Lymph Node Density Is Superior to TNM Nodal Status in Predicting Disease-Specific Survival After Radical Cystectomy for Bladder Cancer: Analysis of Pooled Data From MDACC and MSKCC

PURPOSE To compare the utility of lymph node density (LND) with TNM nodal status in predicting disease-specific survival (DSS) after radical cystectomy. PATIENTS AND METHODS We identified 248 patients with nodal metastasis after radical cystectomy (without neoadjuvant chemotherapy): 162 patients from Memorial Sloan-Kettering Cancer Center (MSKCC) and 86 patients from M.D. Anderson Cancer Center (MDACC). We assessed the effect of several variables on DSS. RESULTS After a median follow-up duration of 24 months, 134 patients died of their disease. The median DSS was 36 months, and the 1-year, 2-year, and 5-year DSS rates were 83.7%, 57.4%, and 36.6%, respectively. The median LND was 20%. The 5-year DSS rate was 54.6% for patients with LND < or = 20% v 15.3% for patients with LND higher than 20% (P < .01). Pathologic nodal (pN) status in patients was 78 for pN1 (32%), 127 for pN2 (51%), and 43 for pN3 (17%). On univariate analysis, pN status and LND were significant predictors of DSS (P < .01). However, when pN status and LND were considered jointly in a multivariate model, only LND higher than 20% predicted decreased DSS (hazard ratio [HR], 2.75; P < .01). In addition, while nonorgan-confined (ie, > pT2) primary tumor (HR, 2.40; P < .01) and adjuvant chemotherapy (HR, 0.47; P < .01) were predictors of DSS, LND remained a predictor of DSS even after accounting for adjuvant chemotherapy. CONCLUSION LND is superior to TNM nodal status in predicting DSS for patients with lymph node-positive disease after radical cystectomy, even in the context of adjuvant chemotherapy.

Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high‐risk upper tract transitional cell carcinoma

The authors evaluated the incidence of pathologic downstaging and complete remission (CR) in patients with high‐grade ureteral and renal pelvic transitional cell carcinoma (TCC) (upper tract TCC) who received neoadjuvant chemotherapy followed by surgery.

Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues

Cytotoxic lymphocyte antigen-4 (CTLA-4) blockade is an active immunotherapeutic strategy that is currently in clinical trials in cancer. There are several ongoing trials of anti-CTLA-4 in the metastatic setting of prostate cancer patients with reported clinical responses consisting of decreases in the prostate specific antigen (PSA) tumor marker for some patients. Immunologic markers that correlate with these clinical responses are necessary to guide further development of anti-CTLA-4 therapy in the treatment of cancer patients. We recently reported that CD4+ inducible co-stimulator (ICOS)hi T cells that produce interferon-γ (IFN-γ) are increased in the peripheral blood and tumor tissues of bladder cancer patients treated with anti-CTLA-4 antibody. Here we present data from the same clinical trial in bladder cancer patients demonstrating a higher frequency of CD4+ICOShi T cells and IFN-γ mRNA levels in nonmalignant prostate tissues and incidental prostate tumor tissues removed at the time of radical cystoprostatectomy. Our data suggest immunologic markers that can be used to monitor prostate cancer patients who receive anti-CTLA-4 therapy and indicate that the immunologic impact of anti-CTLA-4 antibody can occur in both tumor and nonmalignant tissues. These data should be taken into consideration for evaluation of efficacy as well as immune-related adverse events associated with anti-CTLA-4 therapy.

Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in IFN-α-sensitive and IFN-α-resistant human bladder cancer cells

Bladder cancer mortality varies between the countries; whereas being highest in Western countries, it is lowest in Eastern countries, such as India. Cigarette smoking is one of the major risk factors for bladder cancer in affluent nations, such as United States. Localized early-stage bladder cancer is treated with resection and intravesical cytokine therapy, whereas metastatic cancer is typically treated with various combinations of systemic chemotherapy. Whether curcumin, a yellow curry pigment commonly consumed in countries, such as India, has any role in prevention or treatment of bladder cancer was investigated. We found that curcumin inhibited the proliferation, induced cell cycle arrest, and DNA fragmentation in both IFN-α–sensitive (RT4V6) and IFN-α–resistant (KU-7) bladder cancer cells. Curcumin also potentiated the apoptotic effects of the chemotherapeutic agents (gemcitabine and paclitaxel) and of cytokines [tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand]. This effect of curcumin was independent of sensitivity and resistance to IFN-α, commonly used for treatment of bladder cancer. Whether the effects of curcumin are mediated through modulation of the nuclear factor-κB (NF-κB) pathway known to mediate antiapoptosis was investigated. Both gemcitabine and TNF activated NF-κB in bladder cancer cells and curcumin suppressed this activation. Similarly, cigarette smoke, a major risk factor for bladder cancer, also activated NF-κB and curcumin suppressed it. Cigarette smoke–induced expression of the NF-κB–regulated gene products cyclooxygenase-2 and vascular endothelial growth factor, linked with proliferation and angiogenesis, respectively, was also down-regulated by curcumin. [Mol Cancer Ther 2007;6(3):1022–30]