The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer

PURPOSE: Trials have demonstrated decreased relapse with perioperative methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy in patients with muscle invasive bladder cancer. We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. MATERIALS AND METHODS: We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. RESULTS: Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). CONCLUSIONS: Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.     

The modern endoscopic approach to ureterocele

PURPOSE: During the last 20 years the surgical approach to ureterocele has evolved from major open surgery to minimally invasive endoscopic puncture. We believe that the endoscopic approach decreases the need for open surgical procedures. We identified specific factors that predict the need for repeat surgery. MATERIALS AND METHODS: We reviewed the charts of 60 new patients with ureterocele treated with primary endoscopic incision between 1991 and 1995. Followup ranged from 4 to 62 months (mean 20). Mode of presentation, ureterocele location, associated vesicoureteral reflux and association of the ureterocele with a duplex system were evaluated. Ureterocele wall thickness was assessed subjectively via radiographic and cystoscopic methods, and categorized as thin, intermediate and thick. RESULTS: All 9 patients with a single system ureterocele had an intravesical ureterocele. No patient had associated reflux nor did any require a secondary open procedure. In 3 cases new onset ipsilateral reflux into the ureterocele spontaneously resolved. Of the 51 patients with a duplex system and associated ureterocele 19 (37%) required a secondary open procedure. The ureterocele was intravesical and ectopic in 22 (43%) and 29 (57%) cases, respectively. Reflux was associated with the ureterocele in 27 patients (53%), and 12 (44%) required a secondary open procedure. A total of 11 patients underwent ureteral reimplantation of 15 refluxing renal units and only 2 renal units required ureteral tapering. Reflux is no longer present in 14 of the 15 renal units (93%). Patients with a thick walled ureterocele required repeat puncture more frequently than those with a nonthick ureterocele. CONCLUSIONS: With the use of modern endoscopic techniques children with intravesical and single system ureteroceles require secondary open surgery less frequently than those with ectopic and duplex system ureteroceles. The mode of presentation does not predict the need for a repeat open procedure. Thick walled ureteroceles require repeat endoscopic puncture more frequently than thin and intermediate walled ureteroceles.     

Hypospadias and urethral development

PURPOSE: Hypospadias is a common congenital anomaly that may be treated with surgical reconstruction. In the majority of cases the etiology remains elusive. Although androgens are clearly critical for penile development, defects in androgen metabolism and/or the androgen receptor explain only a small subset of cases of hypospadias. Strategies are presented for understanding the etiology of hypospadias. MATERIALS AND METHODS: Current scientific reports on the etiology of hypospadias were reviewed, and the embryology and possible mechanisms of urethral and penile formation are presented. RESULTS: A new theory of glandular human urethral development via endodermal cellular differentiation is proposed to replace the classic explanation of ectodermal intrusion. CONCLUSIONS: Careful studies of penile and urethral development have led to a better understanding of genital embryology. Future areas of study, such as endocrine disrupters, mesenchymal-epithelial interactions and mechanisms of penile growth, are proposed to explain the etiology of hypospadias.     

Percutaneous needle bladder neck suspension for the treatment of stress urinary incontinence in women: long-term results

PURPOSE: We evaluated the long-term results of percutaneous needle suspension using bone anchor devices for treating stress urinary incontinence in women. MATERIALS AND METHODS: We retrospectively evaluated the long-term results of percutaneous bladder neck needle suspension performed at our institution. None of the women had undergone any anti-incontinence surgery before percutaneous needle suspension. A telephone survey was done for all available patients. Subjective cure was defined as no evidence of incontinence, significant improvement as 0 to 1 protective pad soaked daily and patient satisfaction with incontinence level, and failure as more than 1 pad used daily, lack of patient satisfaction or a secondary procedure required to treat stress urinary incontinence. In cases considered failures a detailed video urodynamic study was performed when possible before any secondary procedure. RESULTS: In 1996 and 1997, 49 patients underwent percutaneous needle bladder neck suspension with bone anchors, of whom 42 (86%) were available for telephone interview. Mean patient age was 57 years (range 31 to 77) and mean followup was 29 months (range 16 to 52). As defined, subjective outcome in the 42 women was cure in 2 (5%), significant improvement in 5 (12%) and failure in 35 (83%). Of the 35 patients with treatment failure who did not undergo a secondary procedure 25 were asked to present for video urodynamics and 18 were evaluated. Urodynamics revealed demonstrable urinary incontinence, urethral hypermobility in 16 (88%), intrinsic sphincter deficiency in 1 (6%) and detrusor instability in 1 (6%). In 2 cases x-ray revealed that a bone anchor had dislodged and migrated into the pelvis. Serious osteomyelitis at the bone anchor site in 1 case required surgical débridement and 6 weeks of intravenous antibiotics. CONCLUSIONS: Percutaneous needle suspension is associated with poor long-term results in women with stress urinary incontinence. Other procedures should be considered.     

Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer

PURPOSE: Determining serum total prostate specific antigen (PSA) has proved to be a valuable diagnostic aid for detecting prostatic carcinoma, although the lack of specificity has limited its usefulness. Studies indicate that the use of percent free PSA would improve specificity while maintaining sensitivity. Since complexed PSA represents the major proportion of measurable PSA in serum, we determined whether it represents a single test alternative to the use of percent free PSA for the early detection of prostate cancer. MATERIALS AND METHODS: Archival serum was obtained from 385 men with no evidence of malignancy on biopsy and 272 with biopsy confirmed prostate cancer. We determined the concentration and proportion of total, complexed and free PSA. RESULTS: Receiver operating characteristics analysis using total PSA results from all samples (range 0.32 to 117 ng./ml.) indicated that the areas under the curve for complexed PSA alone as well as the free-to-total and complexed-to-total PSA ratios were similar and significantly greater than those for total PSA alone. Within the range of 85% to 95% sensitivity receiver operating characteristics analysis revealed that the specificity of complexed PSA was higher than that of total PSA and equivalent to that of the free-to-total PSA ratio. We noted a similar improvement in specificity in the 4 to 10 ng./ml. total PSA range. Using published cutoff values for complexed, total and percent free PSA when total PSA was in the 4 to 10 ng./ml. range the sensitivity and specificity of complexed and percent free PSA were similar. Within the 4 to 10 ng./ml. total PSA range the population of patients with no evidence of malignancy and complexed PSA below the upper limit was different with respect to total PSA from that with no evidence of malignancy and free PSA greater than 25%. CONCLUSIONS: The measurement of complexed PSA represents an alternative to the use of percent free PSA, although the patient populations identified by the 2 tests are different.     

Antitumor activity of interleukin-12 against murine bladder cancer

PURPOSE: We investigated the antitumor activity of interleukin-12 (IL-12) against MBT-2, a murine bladder carcinoma, to clarify whether or not IL-12 is effective against urothelial tumors. MATERIALS AND METHODS: MBT-2, a murine carcinogen-induced, poorly differentiated transitional cell carcinoma of C3H/He origin, was used. Three or 10 days after the subcutaneous administration of MBT-2 cells, C3H/He mice were injected intraperitoneally with IL-12 five times per wk. for 2 wk. Tumor growth was measured twice weekly. Spleen cells from the C3H/He mice that had rejected MBT-2 after the IL-12 treatment were examined for MBT-2-specific cytolytic T lymphocytes (CTL) activity and cytokine production. RESULTS: Tumor growth and acceptance was obviously suppressed when C3H/He mice were treated with IL-12 from 3 days after the tumor inoculation. In the spleen cells from the C3H/He mice that had rejected MBT-2, MBT-2-specific CTL activity and secretion of IL-2 and interferon (IFN)-gamma were clearly detected. However, the established MBT-2 tumor cells were not rejected when C3H/He mice were given IL-12 from 10 days after the tumor inoculation, although the tumor growth was transiently suppressed during the IL-12 treatment. CONCLUSION: These data demonstrate that IL-12 is considerably effective against murine bladder cancer and suggest the clinical application of IL-12 against human bladder cancer.     

Characterization of ureteral dysfunction in an experimental model of congenital bladder outlet obstruction

PURPOSE: Ureteral dysfunction is a significant sequela of congenital bladder outlet obstruction. However, the structural and functional alterations associated with ureteral dysfunction are not well defined. A model of fetal bladder obstruction in sheep was used to characterize the changes in ureteral smooth muscle, extracellular matrix (ECM) and functional properties in response to bladder outlet obstruction. MATERIALS AND METHODS: Partial bladder outlet obstruction was created in fetal sheep at gestational age 95 days via placement of a metal ring around the proximal urethra as well as ligation of the urachus. Ureters were harvested at 109 and 135 days (full term = 140 days) to determine the relative composition of smooth muscle, ECM and urothelium by morphometric analysis and to measure DNA and protein concentrations. Ureteral tissue from 135 day gestation obstructed and control sheep was harvested and immediately placed in Krebs solution. Smooth muscle strips (2-3 mm. x 7-8 mm.) were suspended in organ baths. The frequency and amplitude of spontaneous ureteral contractions was as well as the response to electric field stimulation (EFS) were determined. RESULTS: Bladder outlet obstruction caused a significant increase in ureteral weight, smooth muscle mass and total ECM at both 109 and 135 days gestation. Total ureteral DNA was greater in obstructed compared with sham ureters at 135 days gestation. Obstructed ureters demonstrated greater amplitude and frequency of spontaneous contractions as well as more pronounced response to EFS when compared to sham ureters. CONCLUSIONS: The fetal ureter responds to bladder obstruction with smooth muscle hyperplasia and hypertrophy which is associated with increased spontaneous activity and augmented response to EFS. ECM content is markedly increased indicating a shift in the balance of connective tissue synthesis and degradation. Congenital post-obstructive ureteral dysfunction therefore appears to be the result of dysregulated smooth muscle cell growth and altered ECM homeostasis producing abnormal ureteral contractility.     

Cell-cell adhesion molecules and signaling intermediates and their role in the invasive potential of prostate cancer cells

PURPOSE: The highly variable natural history of prostate carcinoma may be reflected in heterogeneity of invasive potential between tumors. MATERIALS AND METHODS: We have examined two prostate cancer cell lines of low invasive potential (CAHPV10 and PZHPV7) and three cell lines of high invasive potential (DU-145, PC-3, LNCapFGC), to determine whether specific adhesion molecule profiles correlated with their invasive behavior. RESULTS: Using an in vitro invasion assay, we demonstrated that DU-145, LNCapFGC and PC-3 cells were highly invasive compared with CA-HPV-10 and PZ-HPV-7 cells. LNCapFGC cells expressed high levels of E-cadherin, alpha-, beta- and gamma-catenin, desmoglein, desmoplakin and GSK3beta using immunoblotting. This was, in general, comparable to immunohistochemical staining. PC-3 cells had no E-cadherin or alpha-catenin, but expressed a high level of the HGF/SF receptor c-Met. In contrast, DU-145 cells were found to express E-cadherin and low levels for all other protein molecules, except c-Met. The DU-145 cell line also lacked alpha-catenin expression. In CA-HPV-10 and PZ-HPV-7 cells, there was no detection of APC, PECAM-1, P-cadherin or Wnt-1. DU-145, LNCapFGC and PC-3 cells formed cell-cell aggregates, which were reduced by inclusion of anti-E-cadherin antibody and the motogen HGF/SF. CONCLUSION: These results show that prostate cancer cells exhibit a diverse expression of cell-cell adhesion molecules and their signaling intermediates. The expression of these adhesion molecules bears an important relationship with the invasive phenotype of these cells.