Faculty Bibliography

The QT interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. Drug-induced long QT syndrome is characterized by acquired, corrected QT (QTc) interval prolongation that is associated with increased risk of torsade de pointes. Every physician must recognize if the drugs he or she prescribes prolongs the QTc interval, especially if the drug is prescribed for a chronic condition in older patients who are on polypharmacy. The evolution of alpha-blockers for the treatment of benign prostatic hyperplasia has allowed the development of drugs that are easier to administer and better tolerated. Because alpha-blockers generally have equivalent efficacy, this class of drugs is typically differentiated by safety and side effects. Studies suggest that alpha-blockers may vary in regard to their effect on the QT interval, and, therefore, on their predisposition to cause potentially life-threatening ventricular arrhythmias

Although ras is a potent mitogenic oncogene, its tumorigenicity depends on cellular context and cooperative events. Here we show that low-level expression of a constitutively active Ha-ras in mouse urothelium induces simple urothelial hyperplasia that is resistant to progression to full-fledged bladder tumors even in the absence of Ink4a/Arf. In stark contrast, doubling of the gene dosage of the activated Ha-ras triggered early-onset, rapidly growing, and 100% penetrant tumors throughout the urinary tract. Tumor initiation required superseding a rate-limiting step between simple and nodular hyperplasia, the latter of which is marked by the emergence of mesenchymal components and the coactivation of AKT and STAT pathways as well as PTEN inactivation. These results indicate that overactivation of Ha-ras is both necessary and sufficient to induce bladder tumors along a low-grade, noninvasive papillary pathway, and they shed light on the recent findings that ras activation, via point mutation, overexpression, or intensified signaling from FGF receptor 3, occurs in 70%-90% of these tumors in humans. Our results highlight the critical importance of the dosage/strength of Ha-ras activation in dictating its tumorigenicity - a mechanism of oncogene activation not fully appreciated to date. Finally, our results have clinical implications, as inhibiting ras and/or its downstream effectors, such as AKT and STAT3/5, could provide alternative means to treat low-grade, superficial papillary bladder tumors, the most common tumor in the urinary system

As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathologic parameter, the tumor's biological behavior, or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or nontumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63 of 74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104 of 202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33 of 50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including microluminal, basal-laminal, cytoplasmic, or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression, or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence, and bladder cancer-specific mortality (P = .042, P = .035, P = .023, and P = .022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27, and cyclin D1, thus excluding a functional link between these 2 groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and -negative carcinomas have different clonal origins or may be derived from different cancer stem cells

PURPOSE: We determined the long-term effect of radical prostatectomy on lower urinary tract symptoms. MATERIALS AND METHODS: Between October 1, 2000 and January 30, 2003, 587 men underwent open radical retropubic prostatectomy. Of these men 453 completed the American Urological Association symptom index at baseline, and 12 and 48 months. Mean changes in American Urological Association total, voiding and storage symptom scores were ascertained between baseline and 12 months (short term), baseline and 48 months (long term), and between 12 and 48 months (natural history of lower urinary tract symptoms without a prostate). Symptom scores were ascertained independently for men with baseline mild vs moderate/severe lower urinary tract symptoms. RESULTS: Clinically and statistically significant short-term and long-term improvements were observed in mean American Urological Association total, storage and voiding symptom scores for men presenting with moderate/severe lower urinary tract symptoms. The previously reported progression of lower urinary tract symptoms in the general population of men older than 40 years was not observed in our patients with an absent prostate. CONCLUSIONS: The current study provides compelling evidence that radical prostatectomy prevents the progression of lower urinary tract symptoms in men with and without baseline clinically significant lower urinary tract symptoms. This beneficial effect of radical prostatectomy on the natural history of lower urinary tract symptoms should be considered when weighing the risks and benefit of the treatment option for localized prostate cancer

OBJECTIVES: To determine the incidence of inguinal hernias in men undergoing open radical retropubic prostatectomy (RRP). METHODS: The incidence of preoperative and postprostatectomy inguinal hernias were determined by a retrospective chart review and questionnaire survey of 1130 consecutive men who underwent open RRP by a single surgeon from October 2000 to October 2005. A preoperative inguinal hernia was diagnosed by the physical examination or abdominal computed tomography findings. The incidence of new postoperative hernias was ascertained by the patients' responses to a survey indicating the development of a new groin bulge or hernia. RESULTS: Of the 1130 patients, 146 (13%) had a preoperative inguinal hernia. Increasing age and lower body mass index were significantly associated with the detection of a preoperative inguinal hernia. The sensitivity of detecting an inguinal hernia by physical examination and routine abdominal computed tomography preoperatively was 96.3% and 42.5%, respectively. Also, 8% of men developed a new hernia. CONCLUSIONS: Although abdominal computed tomography can identify inguinal hernias in men undergoing open RRP, the test's sensitivity is inferior to that of a simple physical examination. All candidates for open RRP should undergo a careful physical examination to identify asymptomatic inguinal hernias. Our findings suggest that the previously reported high incidence of symptomatic inguinal hernias that developed after open RRP can be explained by a failure to diagnose preexisting inguinal hernias and the development of new hernias