Characterization of Histone Deacetylase Expression Within In Vitro and In Vivo Bladder Cancer Model Systems.

Epigenetic aberrations are prominent in bladder cancer (BC) and contribute to disease pathogenesis. We characterized histone deacetylase (HDAC) expression, a family of deacetylation enzymes, in both in vitro and in vivo BC model systems and analyzed expression data from The Cancer Genome Atlas (TCGA). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis was used to determine the expression status of Class I and II HDACs in ten human BC cell lines, while qRT-PCR was used to determine HDAC expression in 24 human tumor specimens. The TCGA cohort consists of 408 muscle invasive BC (MIBC) clinical samples and analysis of this data set identified expression of HDAC4 and -9 as being associated with basal-squamous disease. These findings agree with qRT-PCR results identifying increased expression of HDAC4, -7, and -9 in basal BC cell lines (p < 0.05; Kruskal-Wallis test) and in clinical specimens with invasive bladder cancer (not statistically significant). We also observed increased expression in Hdac4, -7, and -9 in commonly used BC mouse models. Here, we identify suitable preclinical model systems for the study of HDACs, and show increased expression of Class IIa HDACs, specifically HDAC4 and HDAC9, in basal BC cell lines and in invasive clinical specimens. These results suggest this class of HDACs may be best suited for targeted inhibition in patients with basal BC.

Metastatic renal cell carcinoma risk according to tumor size.

PURPOSE: Recent evidence suggests significantly discordant findings regarding tumor size and the metastasis risk in renal cell carcinoma cases. We present our experience with renal cell carcinoma. We evaluated the association between tumor size and the metastasis risk in a large patient cohort. MATERIALS AND METHODS: Using our prospectively maintained nephrectomy database we identified 2,691 patients who were treated surgically for a sporadic renal cortical tumor between 1989 and 2008. Associations between tumor size and synchronous metastasis at presentation (M1 renal cell carcinoma) were evaluated with logistic regression models. Metastasis-free survival after surgery was estimated using the Kaplan-Meier method in 2,367 patients who did not present with M1 renal cell carcinoma and were followed postoperatively. RESULTS: Of the 2,691 patients 162 presented with metastatic renal cell carcinoma. Only 1 of 781 patients with a tumor less than 3 cm had M1 renal cell carcinoma at presentation and tumor size was significantly associated with metastasis at presentation (for each 1 cm increase OR 1.25, p <0.001). Of the 2,367 patients who did not present with metastasis metastatic disease developed in 171 during a median 2.8-year followup. In this group only 1 of the 720 patients with renal cell carcinoma less than 3 cm showed de novo metastasis during followup. Metastasis-free survival was significantly associated with tumor size (for each 1 cm increase HR 1.24, p <0.001). CONCLUSIONS: In our experience tumor size is significantly associated with synchronous and asynchronous metastases after nephrectomy. Our results suggest that the risk of metastatic disease is negligible in patients with tumors less than 3 cm.

Contemporary use of partial nephrectomy at a tertiary care center in the United States.

PURPOSE: The use of partial nephrectomy for renal cortical tumors appears unacceptably low in the United States according to population based data. We examined the use of partial nephrectomy at our tertiary care facility in the contemporary era. MATERIALS AND METHODS: Using our prospectively maintained nephrectomy database we identified 1,533 patients who were treated for a sporadic and localized renal cortical tumor between 2000 and 2007. Patients with bilateral disease or solitary kidneys were excluded from study and elective operation required an estimated glomerular filtration rate of 45 ml per minute per 1.73 m(2) or greater. Predictors of partial nephrectomy were evaluated using logistic regression models. RESULTS: Overall 854 (56%) and 679 patients (44%) were treated with partial and radical nephrectomy, respectively. In the 820 patients treated electively for a tumor 4 cm or less the frequency of partial nephrectomy steadily increased from 69% in 2000 to 89% in 2007. In the 365 patients treated electively for a 4 to 7 cm tumor the frequency of partial nephrectomy also steadily increased from 20% in 2000 to 60% in 2007. On multivariate analysis male gender (p = 0.025), later surgery year (p <0.001), younger patient age (p = 0.005), smaller tumor (p <0.001) and open surgery (p <0.001) were significant predictors of partial nephrectomy. American Society of Anesthesiologists score, race and body mass index were not significantly associated with treatment type. CONCLUSIONS: The use of partial nephrectomy is increasing and it is now performed in approximately 90% of patients with T1a tumors at our institution. For reasons that remain unclear certain groups of patients are less likely to be treated with partial nephrectomy.

Positive surgical margins in soft tissue following radical cystectomy for bladder cancer and cancer specific survival.

PURPOSE: We evaluated risk factors for positive soft tissue surgical margins and the impact of soft tissue surgical margins on metastatic progression and disease specific survival in patients treated with radical cystectomy for bladder cancer. MATERIALS AND METHODS: A total of 1,589 patients who underwent radical cystectomy for primary urothelial cancer at our institution were included in the study. Several variables were analyzed including gender, age, use of perioperative chemotherapy, tumor stage, tumor grade, presence of carcinoma in situ, pathological vascular invasion, bladder pathology, status of soft tissue surgical margins, lymph node status, number of lymph nodes removed and number of positive lymph nodes. End points were freedom from progression to metastases and disease specific survival. RESULTS: Positive soft tissue surgical margins were detected in 67 patients (4.2%). Risk factors for positive soft tissue surgical margins were female gender (p = 0.04), pathological stage, vascular invasion in the radical cystectomy specimen, lymph node metastases (all p < or = 0.001) and median number of positive lymph nodes (p = 0.002). In addition, nonpure transitional cell carcinoma histology (p = 0.001) was associated with positive soft tissue surgical margins. In the 5 years after cystectomy, rates of disease specific survival for the negative and positive soft tissue surgical margin groups were 72% (95% CI 69-75) and 32% (95% CI 19-54), respectively. On multivariate analysis disease specific death was associated with tumor stage, positive soft tissue surgical margins, vascular invasion, presence of positive lymph nodes, number of nodes removed and number of positive nodes. CONCLUSIONS: Risk factors for positive soft tissue surgical margins are female gender, locally advanced cancer, presence of vascular invasion and mixed histology. Patients with positive soft tissue surgical margins have poor prognosis, and positive soft tissue surgical margins were found to be independently associated with disease specific death.