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Objectives: A low-pressure ileal bladder replacement does not have any coordinated contraction during micturition, which is why we have evaluated various antireflux mechanisms in the context of a randomized prospective study., Material and Methods: 70 patients undergoing low-pressure ileal bladder replacement were randomized into 2 groups. An antireflux mechanism was performed in 35 patients and an afferent tubular segment was performed in the other 35 patients., Results: After a median follow-up of 57 and 45 months respectively, the functional capacity of the reservoir, incidence of urinary tract infections, urinary continence, voiding havits, and serum urea and creatinine were similar in the two groups. 11/67 (16.5%) evaluable ureteropelvic units with an antireflux mechanism and 2/69 (3%) units with an afferent tubular segment developed major dilatation due to stenosis of the antireflux mechanism or the ureteroileal anastomosis (Fisher's exact test, p < 0.009). No radiological reflux could be demonstrated during micturition in either group. A simultaneous increase of intravesical, intraabdominal and intrapelvic pressure was observed during a Valsalva manoeuvre., Conclusion: Protection of the upper urinary tract by an ileal afferent tubular segment has yet to be confirmed in a larger series of patients with a longer follow-up. Our results show that prevention of reflux is less important in the case of orthotopic low-pressure ileal bladder replacement. Consequently, creation of an antireflux mechanism, associated with a high complication rate, is probably not justified.

Purpose: We assessed whether interleukin-8 (IL-8), one of the first cytokines expressed in the urine after bacillus Calmette-Guerin (BCG) therapy for superficial urothelial tumors, may serve as a prognostic factor for treatment response., Materials and Methods: Of 20 patients with superficial urothelial cancer of the urinary tract treated with BCG 13 had superficial bladder cancer and 7 received BCG perfusion of the upper urinary tract due to inoperability, solitary kidney, renal insufficiency or bilateral disease. After intravesical instillation of 120 mg. BCG or after 2-hour perfusion of the upper urinary tract with 360 mg. BCG urine was collected at 6-hour intervals. IL-8 was determined by solid phase double ligand enzyme-linked immunosorbent assay., Results: IL-8 was stable in the urine for more than 48 hours. At a median followup of 36.5 months treatment failure occurred in 10 of the 20 patients, including 3 with recurrence, 6 with progressive disease and 1 with extensive carcinoma in situ. IL-8 excretion was more than 4,000 ng. in the first 6 hours after BCG therapy in all 10 patients who remained disease-free. In 9 of the 10 patients with recurrent disease IL-8 excretion was less than 4,000 ng. in the first 6 hours after BCG therapy. Patients secreting less than 4,000 ng. IL-8 into the urine during the first 6 hours after BCG therapy had a significantly higher risk of tumor recurrence and progression (p <0.0002)., Conclusions: Due to its stability and kinetics IL-8 determined in urine collected during the first 6 hours after BCG therapy may prove to be a prognostic factor for tumor recurrence and progression after BCG therapy.

Background: We assessed the frequency and molecular basis of p53 mutations in clinically localized prostatic adenocarcinoma., Methods: Prostate specimens were examined from 100 patients with clinically localized prostatic adenocarcinoma and 13 patients with benign prostatic hyperplasia (BPH). Mutations producing nuclear accumulation of p53 were detected immunohistochemically. Exon-specific mutations were analyzed by polymerase chain reaction amplification and single strand conformation polymorphism (PCR-SSCP) and sequenced., Results: p53 accumulation was detected in 5 tumors using antibody DO-1, and in 4 of these using antibody PAb 1801, but not in BPH. PCR-SSCP detected mutations in all 5 tumors, with alterations in exon 5 for 1 tumor, exon 6 for 3 tumors, and exon 7 for 1 tumor. An exon 6 mutation was also found in a tumor with no anti-p53 staining., Conclusions: p53 mutations are uncommon in clinically localized prostatic adenocarcinoma and absent from BPH. 5 of the 6 mutations were derived from locally invasive, prostate carcinomas, supporting the hypothesis that mutation of p53 is a late event in prostate carcinoma progression.

Overexpression of p53, as determined by immunohistochemical staining with the murine monoclonal antibody DO7, was determined in specimens of 46 primary superficial transitional cell bladder tumours (14 TaG2, 10 T1G2, 22 T1G3). A colon cancer specimen served as a positive control and normal mesenchymal cells in the specimens served as an internal negative control. An exceptionally high proportion 36/46 (78%) of the specimens were found to stain positively for p53 in over 20% of the cell nuclei. After a median follow-up of 7 years, ten patients developed progressive disease. Of these ten patients nine demonstrated p53 positivity, resulting in a sensitivity of 90%. However, 27 of the overall 36 patients (75%) with p53-positive tumours did not progress to a higher stage or metastatic disease. These findings suggest that p53 overexpression is not of predictive prognostic value in superficial transitional cell carcinoma. With 7 of 14 specimens (50%) of Ta tumours overexpressing p53, the results were suggestive of p53 mutation being an early event in carcinogenesis. When the threshold was set at 50% of the cell nuclei overexpressing p53, 16/46 (35%) classified as p53 positive. Of the 16 tumours staining positively for p53, 7 (46%) progressed and 9 (56%) did not. None of the Ta and 16 (50%) of the T1 tumours classified as positive. This more stringent definition of positivity still does not identify p53 positivity as a single prognostic factor. With 50% of T1 tumours classifying as positive, we still find that p53 mutation may be an early event in carcinogenesis of bladder cancer.

Purpose: Intestinal low pressure orthotopic bladder substitutes have no major coordinated contractions during micturition. Therefore, the importance and type of reflux prevention were assessed in a prospective randomized study., Materials and Methods: A total of 70 patients with an ileal low pressure bladder substitute was randomized to receive a nipple valve or an isoperistaltic afferent ileal tubular segment for reflux prevention., Results: After median observation times of 57 and 45 months, respectively, the results regarding functional reservoir capacity, incidence of infected urine, urinary continence, voiding habits and serum electrolytes, urea and creatinine were similar in both groups. Severe upper tract dilatation due to ureteroileal or nipple stenosis occurred in 9 of 67 evaluable reno-ureteral units (13.5%) in patients with antireflux nipples and in 2 of 69 (3%) in patients with an afferent tubular segment. This difference in favor of the latter cases is significant (Fisher's exact test p < 0.03). Video urodynamics did not show reflux of contrast medium during voiding in either group. A simultaneous intravesical, intra-abdominal and intrapelvic pressure increase was noted during the Valsalva maneuver., Conclusions: While long-term upper tract preservation by an afferent tubular ileal segment must be confirmed in larger patient series with longer followup, our results indicate that reflux prevention in patients with orthotopic low pressure bladder substitutes is not a major concern and does not justify the use of antireflux mechanisms with a high complication rate.

The lethal phenotypes of advanced prostate cancer are androgen independent (AI) and metastatic to the axial skeleton. Our laboratory has developed an AI mouse model of metastatic human prostate cancer. In this communication, we report the development of tumor suppressor gene therapy in this AI and metastatic (C4-2) cancer model. By using recombinant adenovirus as a delivery vehicle, we introduced a wild-type p53 tumor suppressor gene into prostate cancer cell lines. Despite a silent mutation at codon 152 of the p53 gene, C4-2 cells express functional, but low, levels of p53 protein. However, the other prostatic cell lines, PC-3 and DU145, have a deletion mutation and two point mutations of the p53 gene, respectively. In vitro studies showed that cell growth, as measured by the thymidine incorporation assay, was inhibited in the C4-2, PC-3, and DU145 cells infected with wild-type p53 adenovirus in comparison to control viruses. Recombinant wild-type p53 adenovirus inhibited prostate tumor growth and its production of prostate-specific antigen (PSA) when injected into C4-2 tumors in nude mice. All p53-treated mice were tumor free as long as 12 weeks after cessation of the 8-week treatment regimen. Two of 8 p53-treated mice developed small tumors growing at distant sites after a prolonged period of follow-up observation. Moreover, other AI prostate cancer cells, PC-3 and DU145, treated with Ad5-CMV-p53 failed to develop into tumors in vivo. This gene therapy strategy may be used against AI prostatic cancer regardless of p53 gene mutation status.

Background: Suramin, a polysulfonated naphthylurea and a recognized antitrypanosomal agent, has shown some promise in phase II clinical trials in the management of hormone-refractory human prostate cancer. Reduction of serum prostate-specific antigen (PSA) levels has been proposed as an end point for evaluating the antitumor efficacy of treatments for hormone-refractory prostate cancer., Purpose: We examined the antitumor effect of suramin in an in vivo mouse model of hormone-refractory human prostate cancer to determine whether a decrease in PSA levels reflects a reduction in tumor growth (volume). The tumors were induced in castrated, athymic nude mice by use of the androgen-independent, tumorigenic human prostate cancer cell line C4-2, which is a subline of the androgen-dependent, parental nontumorigenic cell line LNCaP. We also evaluated the effects of suramin in vitro on cell growth and the expression of PSA messenger RNA (mRNA) in both LNCaP and C4-2 cells., Methods: For the in vivo studies, 24 mice were given a subcutaneous injection of 5 x 10(6) C4-2 cells at each of four sites. Animals (n = 20) with tumor volumes greater than 1 mm3 or less than 5 mm3 were divided equally into two groups. Drug treatment was initiated in one group by administration of 1 mg suramin intraperitoneally, followed by 0.1 mg suramin at 10-day intervals to maintain constant serum levels. Tumor growth and PSA expression levels were monitored. For the in vitro studies, both LNCaP and C4-2 cells were exposed to 100-400 microgram/mL suramin, and cell growth was monitored by a quantitative crystal violet assay. PSA mRNA expression was assessed by northern blot analysis in cells treated with either 250 microgram/mL suramin, 400 ng/mL dihydrotestosterone (DHT) (positive control), or 0.5-75 microgram/mL hydrocortisone (to mimic the clinical use of hydrocortisone during suramin treatment to compensate for the loss of adrenocortical function). In some studies, the combined effect of DHT and suramin on PSA mRNA expression was also evaluated. A two-way analysis of variance was performed to evaluate the treatment differences, and P values were obtained from two-sided tests for statistical significance., Results: In vivo, suramin did not significantly affect the growth of androgen-independent C4-2 tumors (relative to the growth of tumors in 5% glucose-treated control animals; P = .76). However, suramin significantly decreased the ratio of PSA level to tumor volume (ng/mL PSA per mm(3) of tumor) (P<.001). Mice developed bone metastases in both treatment arms. Suramin affected the in vitro growth of LNCaP cells but not of C4-2 cells. Suramin diminished PSA mRNA expression in both LNCaP and C4-2 cells grown in vitro. Hydrocortisone had no effect on PSA mRNA levels., Conclusions: Although suramin inhibited the growth of androgen-dependent LNCaP cells, it did not inhibit the growth of androgen-independent C4-2 cells either in vitro or in vivo. Suramin significantly decreased PSA mRNA expression in both cell lines in vitro and depressed serum PSA levels in mice bearing androgen-independent C4-2 tumors., Implications: PSA level should be used with caution as an end point in clinical trials using suramin therapy for hormone-refractory prostate cancer.

Our laboratory has previously reported on the derivation of LNCaP cell sublines from LNCaP tumors maintained in castrated and intact athymic male mice. These LNCaP sublines differ from the parental line in tumorigenicity and androgen dependence. This paper demonstrates that one of these sublines acquired metastatic potential. When inoculated either s.c. or orthotopically, the C4-2 subline metastasized to the lymph node and bone with an incidence of 11-50%. Interestingly, the incidence of osseous metastasis was higher in castrated than in intact male hosts. We evaluated the chromosomal, immunohistochemical, and biochemical characteristics of the LNCaP sublines derived from C4-2 tumors that metastasized to the lymph node and bone. Cytogenetic analysis showed that all sublines were human and shared common marker chromosomes with the parental LNCaP cells. This experimental human prostate cancer model may permit, for the first time, the study of the molecular mechanisms underlying human prostate cancer metastasis.