Prostate cancer detection following diagnosis of atypical small acinar proliferation.

INTRODUCTION: To report the incidence and characteristics of cancer following a diagnosis of atypical small acinar proliferation (ASAP) and comment on current clinical practice recommendations. MATERIALS AND METHODS: We reviewed patients that underwent prostate biopsy between 2008 and 2013 at a single institution. Men with ASAP without previous cancer were included. Clinicopathologic features including prostate-specific antigen (PSA), presence of ASAP or cancer, tumor volume, number of involved cores, and Gleason score were analyzed in men that received a repeat prostate biopsy. RESULTS: Of 1450 men, ASAP was found in 75 (5%) patients. Repeat biopsy was performed in 49 (65%) patients. Fifteen (31%) were diagnosed with cancer, 10 (20%) with ASAP, and 24 (49%) were benign. PSA, age, and number of cores with ASAP were not associated with cancer. Gleason 6 disease was diagnosed in 12 (80%) patients. Gleason ≥ 7 cancer was found in 3 patients, or 6% of all patients with a repeat biopsy. The average linear amount of tumor was 3.2 mm, and the average tumor volume was 14.2%. CONCLUSION: In a contemporary prostate biopsy series, the incidence of ASAP was 5%. Among men with ASAP, incidence of cancer at repeat biopsy was 31%, with the overwhelming majority being low grade and low volume. Patients with ASAP may not require repeat biopsy within 6 months in the appropriate clinical context.

The impact of running versus interrupted anastomosis on ureterointestinal stricture rate after radical cystectomy.

PURPOSE: Benign ureterointestinal anastomotic stricture is not uncommon after radical cystectomy and urinary diversion. We studied the impact of the running vs the interrupted technique on the ureterointestinal anastomotic stricture rate. MATERIALS AND METHODS: From July 2007 to December 2008 interrupted end-to-side anastomoses were created and from January 2009 to July 2010 running anastomoses were created. The primary study end point was time to ureterointestinal anastomotic stricture. RESULTS: Of 266 consecutive patients 258 were alive 30 days after radical cystectomy, including 149 and 109 with an interrupted and a running anastomosis, respectively. The groups did not differ in age, gender, body mass index, age adjusted Charlson comorbidity index, receipt of chemotherapy or radiation, blood loss, operative time, diversion type or postoperative pathological findings. The stricture rate per ureter was 8.5% (25 of 293) and 12.7% (27 of 213) in the interrupted and running groups, respectively (p = 0.14). Univariate analysis suggested that postoperative urinary tract infection (HR 2.1, 95% CI 1.1-4.1, p = 0.04) and Clavien grade 3 or greater complications (HR 2.6, 95% CI 1.4-4.9, p <0.01) were associated with ureterointestinal anastomotic stricture. On multivariate analysis postoperative urinary tract infection (HR 2.4, 95% CI 1.2-5.1, p = 0.02) and running technique (HR 1.9, 95% CI 1.0-3.7, p = 0.05) were associated with ureterointestinal anastomotic stricture. Median time to stricture and followup was 289 (IQR 120-352) and 351 days (IQR 132-719) in the running cohort vs 213 (IQR 123-417) and 497 days (IQR 174-1,289) in the interrupted cohort, respectively. Of the 52 strictures 33 (63%) developed within 1 year. Kaplan-Meier analysis controlling for differential followup showed a trend toward higher freedom from stricture for the interrupted ureterointestinal anastomosis (p = 0.06). CONCLUSIONS: A running anastomosis and postoperative urinary tract infection may be associated with ureterointestinal anastomotic stricture. Larger series with multiple surgeons are needed to confirm these findings.

Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

The impact of mechanical bowel preparation on postoperative complications for patients undergoing cystectomy and urinary diversion.

PURPOSE: The benefit of routine mechanical bowel preparation for patients undergoing radical cystectomy is not well established. We compared postoperative complications in patients who did or did not undergo mechanical bowel preparation before radical cystectomy. MATERIALS AND METHODS: In 2008 a single surgeon (GDS) performed open radical cystectomy with an ileal conduit or orthotopic neobladder in 105 consecutive patients with preoperative mechanical bowel preparation consisting of 4 l GoLYTELY®. In 2009 radical cystectomy with an ileal conduit or orthotopic neobladder was performed in 75 consecutive patients without mechanical bowel preparation. A comprehensive database provided clinical, pathological and outcome data. RESULTS: All patients had complete perioperative data available. The 2 groups were similar in age, Charlson comorbidity score, diversion type, receipt of neoadjuvant radiation or chemotherapy, blood loss, hospital stay, time to diet and pathological stage. Postoperative urinary tract infection, wound dehiscence and perioperative death rates were similar in the 2 groups. Clostridium difficile infection developed within 30 days of surgery in 11 of 105 vs 2 of 75 patients with vs without mechanical bowel preparation (p = 0.08). When adjusted for the annual hospital-wide C. difficile rate, the difference remained insignificant (p = 0.21). Clavien grade 3 or greater abdominal and gastrointestinal complications, including fascial dehiscence, abdominal abscess, small bowel obstruction, bowel leak and entero-diversion fistula, developed in 7 of 105 patients with (6.7%) vs 11 of 75 without (14.7%) mechanical bowel preparation (p = 0.08). CONCLUSIONS: The use of mechanical bowel preparation for patients undergoing radical cystectomy with an ileal conduit or orthotopic neobladder does not seem to impact the rates of perioperative infectious, wound and bowel complications. Larger series with multiple surgeons are necessary to confirm these findings.

Deregulation of a Hox protein regulatory network spanning prostate cancer initiation and progression.

PURPOSE: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare. EXPERIMENTAL DESIGN: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein-protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets. RESULTS: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors. CONCLUSION: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression.

Bladder cancer risk from occupational and environmental exposures.

Approximately 50% of bladder cancer incidence in the United States has been attributed to known carcinogens, mainly from cigarette smoking. Following the identification of this important causative factor, many investigators have attempted to identify other major causes of bladder cancer in the environment. Genetic and epigenetic alterations related to carcinogenesis in the bladder have been linked to environmental and occupational factors unrelated to cigarette smoking and may account for a significant portion of bladder cancer cases in non-smokers. The interaction between genetics and exposures may modulate bladder cancer risk and influence the differing incidence, progression, and mortality of this disease in different genders and races. Comparative molecular studies are underway to measure the relative effects of environment and inheritance to account for observed differences in the epidemiology of bladder cancer. The use of geospatial tools and population-based data will offer further insight into the environmentally-linked causes of bladder cancer.

Laparoscopic partial nephrectomy versus laparoscopic ablative therapy: a comparison of surgical and functional outcomes in a matched control study.

BACKGROUND AND PURPOSE: Patients who are undergoing laparoscopic ablative therapy (LAT) are often older with more comorbidities in comparison with patients who are undergoing laparoscopic partial nephrectomy (LPN). A matched control study was performed to compare the surgical and functional outcomes of LPN and LAT. PATIENTS AND METHODS: A prospectively maintained database of 250 patients who underwent nephron-sparing surgery was explored. Fifty-one LAT patients (21 and 30 laparoscopic radiofrequency and cryoablation, respectively) were matched with 51 LPN patients. A comparison of preoperative, operative, and postoperative outcomes was performed. RESULTS: The groups were similar in age, sex, body mass index, preoperative estimated glomerular filtration rate (eGFR), number of comorbidities and tumor size. Patients who were undergoing LAT had a lower incidence of endophytic tumor and higher incidence of upper pole and midpolar tumors. Hilar vessels clamping was performed in LPN (47/51 patients). Mean estimated blood loss and operative time were higher in those undergoing LPN (P<0.01). There was no significant difference in transfusion rate and hospital stay, however. Mean follow-up was 27 and 18 months in LAT and LPN, respectively (P<0.01). The mean percent decline of eGFR at the last follow-up was 10 (95% confidence interval [CI]: 4-15) and 7.5 (95% CI: 4-11), respectively (P<0.43). In comparison with baseline, eGFR declined significantly (P<0. 01), but there was no difference between the groups. CONCLUSION: Despite renal ischemia, longer operative time, and higher blood loss associated with LPN, the hospital stay and long-term functional outcomes are similar to those of LAT in a matched control study.