Jared M. Whitson

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

Histone deacetylases (HDACs) are frequently overexpressed in broad range of cancer types, where they alter cellular epigenetic programming to promote cell proliferation and survival. However, the mechanism by which HDACs become overexpressed in human cancers remains somewhat of a mystery. In this study, we investigated the expression and functional significance of miR-449a in prostate cancer cells. Using real-time PCR, we found that miR-449a is downregulated in prostate cancer tissues relative to patient-matched control tissue. Introduction of miR-449a into PC-3 prostate cancer cells resulted in cell-cycle arrest, apoptosis and a senescent-like phenotype. In silico analysis of 3′-UTR regions identified a number of genes involved in cell-cycle regulation as putative targets of miR-449a. Using a luciferase 3′-UTR reporter system, we established that HDAC-1 (histone deacetylase 1), a gene that is frequently overexpressed in many types of cancer, is a direct target of miR-449a. Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells. Our findings provide new insight into the function of miRNA in regulating HDAC expression in normal versus cancerous tissue.

Changes in Prostate Cancer Grade on Serial Biopsy in Men Undergoing Active Surveillance

PURPOSE Active surveillance is now considered a viable treatment option for men with low-risk prostate cancer. However, little is known regarding changes in Gleason grade on serial biopsies over an extended period of time. PATIENTS AND METHODS Men diagnosed with prostate cancer between 1998 and 2009 who elected active surveillance as initial treatment, with 6 or more months of follow-up and a minimum of six cores at biopsy, were included in analysis. Upgrading and downgrading were defined as an increase or decrease in primary or secondary Gleason score. Means and frequency tables were used to describe patient characteristics, and treatment-free survival rates were determined by life-table product limit estimates. RESULTS Three hundred seventy-seven men met inclusion criteria. Mean age at diagnosis was 61.9 years. Fifty-three percent of men had prostate-specific antigen of 6 ng/mL or less, and 94% had Gleason score of 6 or less. A majority of men were cT1 (62%), had less than 33% of biopsy cores involved (80%), and were low risk (77%) at diagnosis. Median number of cores taken at diagnostic biopsy was 13, mean time to follow-up was 18.5 months, and 29% of men had three or more repeat biopsies. Overall, 34% (129 men) were found to have an increase in Gleason grade. The majority of men who experienced an upgrade (81%) did so by their second repeat biopsy. CONCLUSION A proportion of men experience an upgrade in Gleason score while undergoing active surveillance. Men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation.

Multivariate Analysis of Risk Factors for Long-Term Urethroplasty Outcome

PURPOSE We studied the patient risk factors that promote urethroplasty failure. MATERIALS AND METHODS Records of patients who underwent urethroplasty at the University of California, San Francisco Medical Center between 1995 and 2004 were reviewed. Cox proportional hazards regression analysis was used to identify multivariate predictors of urethroplasty outcome. RESULTS Between 1995 and 2004, 443 patients of 495 who underwent urethroplasty had complete comorbidity data and were included in analysis. Median patient age was 41 years (range 18 to 90). Median followup was 5.8 years (range 1 month to 10 years). Stricture recurred in 93 patients (21%). Primary estimated stricture-free survival at 1, 3 and 5 years was 88%, 82% and 79%. After multivariate analysis smoking (HR 1.8, 95% CI 1.0-3.1, p = 0.05), prior direct vision internal urethrotomy (HR 1.7, 95% CI 1.0-3.0, p = 0.04) and prior urethroplasty (HR 1.8, 95% CI 1.1-3.1, p = 0.03) were predictive of treatment failure. On multivariate analysis diabetes mellitus showed a trend toward prediction of urethroplasty failure (HR 2.0, 95% CI 0.8-4.9, p = 0.14). CONCLUSIONS Length of urethral stricture (greater than 4 cm), prior urethroplasty and failed endoscopic therapy are predictive of failure after urethroplasty. Smoking and diabetes mellitus also may predict failure potentially secondary to microvascular damage.

The Relationship Between Prostate Specific Antigen Change and Biopsy Progression in Patients on Active Surveillance for Prostate Cancer

PURPOSE We assessed whether an association exists between a change in prostate specific antigen and biopsy progression in men on active surveillance. MATERIALS AND METHODS A cohort of patients undergoing active surveillance for prostate cancer was identified from the urological oncology database at our institution. Multivariate logistic regression was performed to determine whether prostate specific antigen velocity, defined as the change in ln(prostate specific antigen) per year, is associated with biopsy progression, defined as a Gleason upgrade or volume progression on repeat biopsy within 24 months of diagnosis. RESULTS A total of 241 men with a mean ± SD age of 61 ± 7 years and mean prostate specific antigen 4.9 ± 2.2 ng/ml met study inclusion criteria. Median time to repeat biopsy was 10 months (IQR 6-13). Biopsy progression developed in 55 men (23%), including a Gleason score upgrade in 46 (19%), greater than 33% positive cores in 11 (5%) and greater than 50% maximum single core positive in 12 (5%). The median prostate specific antigen ratio per year was 1.0 (IQR 0.95-1.03), although 1 man had a ratio of greater than 1.26 (doubled over 3 years) and 7 had a ratio of less than 1/1.26 (halved over 3 years). On multivariate analysis prostate specific antigen doubling within 3 years was associated with a 1.4-fold increase in the odds of biopsy progression (OR 1.4, 95% CI 0.6-3.4, p = 0.46). CONCLUSIONS There is little change in prostate specific antigen during the first 24 months of surveillance in men with well staged, low risk prostate cancer. We believe that these findings highlight the importance of repeat biopsy during surveillance.

Lymphadenectomy Improves Survival of Patients With Renal Cell Carcinoma and Nodal Metastases

PURPOSE In a population based cohort we determined whether an increase in the number of lymph nodes removed is associated with improved disease specific survival of patients with renal cell carcinoma treated with nephrectomy. MATERIALS AND METHODS Patients in the Surveillance, Epidemiology and End Results database with renal cell carcinoma and no evidence of distant metastases were identified. Those patients included in the study underwent radical or partial nephrectomy with lymphadenectomy. Cox regression analyses were performed to identify factors associated with disease specific survival including an interaction between lymph node status and the number of lymph nodes removed. RESULTS Between 1988 and 2006, 9,586 patients with renal cell carcinoma met the study inclusion criteria. Median followup was 3.5 years (range 1.4 to 6.8). Of the patients 2,382 (25%) died of renal cell carcinoma, including 1,646 (20%) with lymph node negative disease and 736 (58%) with lymph node positive disease. There was no effect on disease specific survival with increasing the extent of lymphadenectomy in patients with negative lymph nodes (HR 1.0, 95% CI 0.9-1.1, p = 0.93). However, patients with positive lymph nodes had increased disease specific survival with extent of lymphadenectomy (HR 0.8 per 10 lymph nodes removed, 95% CI 0.7-1.0, p = 0.04). An increase of 10 lymph nodes in a patient with 1 positive lymph node was associated with a 10% absolute increase in disease specific survival at 5 years (p = 0.004). CONCLUSIONS This study shows an association between increased lymph node yield and improved disease specific survival of patients with lymph node positive nonmetastatic renal cell carcinoma who underwent lymphadenectomy. Patients at high risk for nodal disease should be considered for regional or extended lymphadenectomy. Clinical variables to predict risk and validation of dissection templates are important areas for future research.

Effect of a minimum lymph node policy in radical cystectomy and pelvic lymphadenectomy on lymph node yields, lymph node positivity rates, lymph node density, and survivorship in patients with bladder cancer.

Extended pelvic lymphadenectomy (PLND) during radical cystectomy (RC) reportedly improves bladder cancer‐specific survival. Lymph node counts are often a proxy for the extensiveness of a dissection. In the current study, the impact of an institutional policy requiring a minimum number of lymph nodes was assessed.

Long-Term Efficacy of Distal Penile Circular Fasciocutaneous Flaps for Single Stage Reconstruction of Complex Anterior Urethral Stricture Disease

PURPOSE We determined the overall efficacy and predictors of success of the distal penile circular fasciocutaneous flap in the management of complex anterior urethral stricture disease not due to lichen sclerosus. MATERIALS AND METHODS We performed a retrospective review of all patients undergoing reconstruction of complex anterior urethral strictures without lichen sclerosus repaired from 1985 to 2006. Primary and overall stricture-free survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was used to identify univariate and multivariate predictors of flap success. RESULTS A total of 124 patients met the inclusion and exclusion criteria. Median patient age was 48 years (range 16 to 83). Median followup was 7.3 years (range 1 month to 19.5 years). Median stricture length was 8.2 cm (range 0.5 to 24). At 1, 3, 5 and 10 years the overall estimated stricture-free survival rates were 95%, 89%, 84% and 79%, respectively. On multivariate analysis smoking (HR 4.0, 95% CI 1.2-12.9, p = 0.02), history of hypospadias repair (HR 4.4, 95% CI 1.3-14.6, p = 0.01) and stricture length 7 to 10 cm (HR 7.0, 95% CI 1.4-34.7, p = 0.02) were predictive of failure. CONCLUSIONS Fasciocutaneous flap urethroplasty has good and durable success rates in the treatment of complex anterior urethral strictures. Predictors of failure included smoking, history of hypospadias repair and longer stricture length.

Evolving practice patterns for the management of small renal masses in the USA

Study Type – Therapy (trend analysis)

A multicolour fluorescence in situ hybridization test predicts recurrence in patients with high‐risk superficial bladder tumours undergoing intravesical therapy

To determine whether a multicolour fluorescence in situ hybridization test (UroVysionTM, Abbott Molecular Inc., Des Plaines, IL, USA) in patients with high‐risk superficial bladder tumours maintains its predictive ability in a multivariate model for recurrence and progression, incorporating clinical and pathological predictors of outcome.

Natural history of untreated renal cell carcinoma with venous tumor thrombus.

OBJECTIVES The natural history of untreated renal cell carcinoma (RCC) with venous tumor thrombus (VTT) is poorly characterized. We aimed to describe the natural history of this disease, and to identify prognostic factors associated with disease-specific survival. MATERIALS AND METHODS We identified patients in the Surveillance, Epidemiology, and End Results (SEER) database with untreated renal cell carcinoma and venous tumor thrombi. Disease-specific median and 1-year survival rates were determined, and disease-free survival curves were plotted using the Kaplan-Meier method. Multivariable Cox regression analyses were performed to identify factors associated with disease-specific and overall survival in this patient group. RESULTS Of 2,265 patients with RCC and VTT, 390 (17%) underwent no treatment; 278 (71%) patients died during follow-up; of these, 243 deaths (87%) were due to RCC. Median and 1-year disease-specific survival for this group was 5 months and 29%, respectively. On multivariable analysis, the extent of tumor thrombus (HR 1.7 for T3c vs. T3b, 95% CI 1.0-2.7) and the presence of metastases (HR 3.1 for M+ vs. M0, 95% CI 1.7-5.5) were most strongly associated with disease-specific mortality. CONCLUSIONS Prognosis is poor for the majority of untreated patients with RCC and VTT. Supradiaphragmatic thrombi and distant metastases are adverse prognostic factors in this patient group. This information is important when counseling patients as to the risk and benefits of surgical vs. nonoperative management of RCC and VTT.