Faculty Bibliography

PURPOSE: In a prospective manner we sought to determine the cause of lower urinary tract symptoms in young men and whether noninvasive testing and symptoms scores are useful in deciding which patients to evaluate with videourodynamics. MATERIALS AND METHODS: We evaluated 85 men 18 to 45 years old with lower urinary tract symptoms. Patients with a history of known neurological disease or urethral stricture were excluded from the study. Patients were evaluated with the American Urological Association (AUA) symptom index, noninvasive uroflowmetry post-void residual and videourodynamics, and classified by specific urodynamic diagnoses. Noninvasive uroflowmetry (normal versus abnormal), post-void residual and AUA symptom index (total, voiding and storage scores) were evaluated as predictors of urodynamic abnormalities. RESULTS: Mean patient age was 35.1 (range 18 to 45) and mean symptom duration was 53.8 months. Mean AUA scores were total 19.3, voiding 10.8 and storage 8.5. Videourodynamic diagnoses were primary bladder neck obstruction in 40 (47%) cases, dysfunctional voiding in 12 (14%), impaired contractility in 8 (9%), sensory urgency in 7 (8%), detrusor instability alone in 5 (6%), detrusor instability and impaired contractility in 1 (1%), external detrusor-sphincter dyssynergia in 1 (1%) and normal in 5 (6%). Of these patients, 9 could not void during urodynamics and in 6 (7%) no urodynamic diagnosis was made. Videourodynamics were not considered helpful in patients with a normal or nondiagnostic study or sensory urgency only (group 1) but were helpful or diagnostic in the remaining patients (group 2). Only 5 of 18 patients (28%) in group 1 had an abnormal uroflow compared to 56 of 67 (84%) in group 2 (p <0.0001). Mean post-void residual volumes were not different between the 2 groups (40.3 versus 40.0 ml.). Mean total and storage symptom scores were also not different between the 2 groups but voiding scores were significantly higher in group 2 (11.5 versus 8.3, p <0.03). CONCLUSIONS: Lower urinary tract symptoms in young men have a variety of underlying causes. Videourodynamics is an extremely helpful diagnostic test especially in men with abnormal uroflow and high voiding scores

B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in approximately 50% of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative epithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non-malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC-3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased proteosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53

PURPOSE: Contemporary treatment of lower pole renal calculi includes extracorporeal shock wave lithotripsy, percutaneous nephrostolithotomy and retrograde ureteropyeloscopy. Success rates for shock wave lithotripsy are reduced in this setting, especially for stones greater than 1 cm. and/or in patients with anatomical variants. Percutaneous treatment, although effective, subjects the patient to increased morbidity. We studied the safety and efficacy of retrograde ureteroscopic treatment of lower pole intrarenal calculi. MATERIALS AND METHODS: We evaluated 90 stone burdens localized to the lower pole and treated with a small diameter, actively deflectable, flexible ureteropyeloscope and a 200 micron holmium laser fiber. Stone burdens were classified as group 1--10 or less, group 2--11 to 20 and group 3--greater than 20 mm. in largest diameter. Patients with calculi less than 2.5 cm. were treated as outpatients unless concurrent medical conditions required hospitalization. Larger stones and partial staghorn calculi (group 3) frequently required 2-stage endoscopic procedures with retrograde intrarenal irrigation for 36 hours to clear debris. An acceptable immediate surgical outcome was defined as complete fragmentation reducing the stone burden to dust and 2 mm. or less fragments. Success was defined as clear imaging (that is stone-free) on renal sonography with minimum 3-month followup. Extreme anatomical variants, including a long infundibulum, acute infundibulopelvic angle and a dilated collecting system, were noted and correlated with surgical failures. RESULTS: Endoscopic access and complete stone fragmentation were achieved in 94, 95 and 45% of groups 1, 2 and 3, respectively. After a second treatment the success rate increased to 82% in group 3, with an overall rate of 91%. Of the 19 surgical failures 8 were secondary to inability to access the lower pole and 11 were secondary to inability to render the patient stone-free. In 2 of the 19 cases infundibular strictures hindered ureteroscopic access. In addition, of the anatomical variants a long lower pole infundibulum was the most statistically significant predictor of failure. Mean operative time ranged from 38 minutes for small to 126 for the largest calculi. There were no major complications. Overall stone-free rates with minimum 3-month followup were 82, 71 and 65% in groups 1, 2 and 3, respectively, and 88, 77 and 81%, respectively, in patients with an acceptable initial surgical outcome (that is excluding those with access failures from analysis). CONCLUSIONS: Retrograde ureteropyeloscopy is a safe and effective surgical treatment for lower pole intrarenal calculi

Despite the well-characterized histology associated with benign prostatic hyperplasia, very little is known about the underlying etiology of the disease on a molecular basis. The objective of this study was to use the technique of mRNA differential display in order to identify genes differentially expressed in human transition zone prostate tissue with high stromal density, with high epithelial density, and with nonhyperplastic histology. The extracellular matrix chondroitin/dermatan sulfate proteoglycan (CDSP) mRNA was more abundantly expressed in tissue with high stromal density, consistent with earlier findings that dermatan and chondroitin 6-sulfate glycosaminoglycans are increased in hyperplastic prostates. Messenger RNA encoding the negative regulator of cell cycle progression, BTG2, was more abundantly expressed in tissue with high epithelial densities. CDSP mRNA was abundantly expressed in primary cultures of stromal cells but was undetectable in epithelial cells. BTG2 mRNA was expressed in primary cultures of both cell types, but more abundantly in epithelial cells. BTG2 mRNA, but not CDSP mRNA, was subject to significant growth cycle regulation in cultured stromal and epithelial cells, with maximum expression occurring in quiescent cells. Generation of specific antibodies to BTG2 revealed that this protein was expressed at low levels in stroma, nonhyperplastic glands, and in hyperplastic glands. Consistent with a role in cell-cycle regulation, BTG2 protein was abundantly expressed in atrophic glands and preatrophic glands.

Prostate cancer is the most common neoplasm in men and a significant cause of mortality in affected patients. Despite significant advances, current methods of treatment are effective only in the absence of metastatic disease. Gene therapy offers a renewed hope of using the differential characteristics of normal and malignant tissue in constructing treatment strategies. Several clinical trials in prostate cancer gene therapy are currently under way, using immunomodulatory genes, anti-oncogenes, tumor suppressor genes and suicide genes. A continued understanding of the etiological mechanisms involved in the establishment and progression of prostate cancer, along with advances in gene therapy technology, should make gene therapy for prostate cancer therapeutically valuable in the future

PURPOSE: We evaluated men with post-radical prostatectomy incontinence to determine the incidence of intrinsic sphincter deficiency and bladder dysfunction, and the contribution of each to incontinence. In addition, we determined if subjective symptoms of stress urinary incontinence and urge incontinence correlated with urodynamic findings of intrinsic sphincter deficiency and bladder dysfunction, respectively. MATERIALS AND METHODS: A total of 60 consecutive patients (mean age 64.8 years) were prospectively evaluated with multichannel video urodynamics. All patients were evaluated at least 6 months postoperatively and had achieved a stable level of continence. Patients characterized incontinence as stress or urge related, and stress urinary incontinence was graded from 0 to 3. Intrinsic sphincter deficiency was defined as incontinence associated with increased intraabdominal pressure and was further assessed by Valsalva's leak point pressure. Bladder dysfunction included urodynamic findings of detrusor instability or decreased compliance. RESULTS: Intrinsic sphincter deficiency was demonstrated in 54 patients (90%). Some component of bladder dysfunction was seen in 27 patients (45%), including detrusor instability in 24 and decreased compliance in 3, but incontinence was actually a result of bladder dysfunction in only 16 (27%). Incontinence was due to intrinsic sphincter deficiency alone in 40 patients (67%), intrinsic sphincter deficiency and bladder dysfunction in 14 (23%), and bladder dysfunction alone in only 2 (3%). Incontinence was not demonstrated on video urodynamics in 4 patients (7%). Of the 57 men who complained of stress urinary incontinence 54 demonstrated intrinsic sphincter deficiency for a positive predictive value of 95%. The 3 patients without stress urinary incontinence did not demonstrate intrinsic sphincter deficiency for a negative predictive value of 100%. Positive and negative predictive values for urge incontinence were 44 and 81%, respectively. CONCLUSIONS: Incontinence after radical prostatectomy is associated with intrinsic sphincter deficiency in the overwhelming majority of patients. Bladder dysfunction rarely is an isolated cause. When present on urodynamic tests bladder dysfunction may not always be a significant contributor to incontinence. The symptom of stress urinary incontinence (or its absence) accurately predicts the finding (or absence) of intrinsic sphincter deficiency on urodynamics. Urge incontinence is not as reliable in predicting incontinence due to bladder dysfunction