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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.

Background: We investigated the role of the transforming growth factor beta (TGF-beta) family in the neoplastic progression of the human prostate., Methods: Expression of TGF-beta mRNA was measured by Northern blot analysis of tissue extracts, and TGF-beta protein by immunohistochemical analysis of tissue sections. Proliferating cells were detected by their expression of Ki-67 antigen., Results: The level of TGF-beta 1 mRNA was equal among normal prostate, benign prostatic hyperplasia (BPH), and prostate carcinoma. TGF-beta 2 mRNA was not detectable, and TGF-beta 3 mRNA was expressed 20-fold lesion in carcinoma compared to BPH and normal prostate. TGF-beta 1 protein was expressed in the stromal cells in all three tissues and TGF-beta 3 protein in the basal layer of epithelial cells, but not in carcinoma. Proliferating epithelial cells fail to express TGF-beta 3., Conclusions: TGF-beta 1 and TGF-beta 3 are independently regulated, and carcinoma of the prostate is characterized by the loss of basal epithelial cells expressing TGF-beta 3.

Purpose: The use of bowel segments as bladder substitutes may result in chronic, impaired vitamin D and calcium metabolism, and ultimately in bone demineralization., Materials and Methods: Bone metabolism was examined in 14 patients who lived for 5 to 8 years with an ileal low pressure bladder substitute after radical cystectomy for bladder cancer. Bone mineral density was measured using dual energy x-ray absorptiometry of the total skeleton, lumbar spine, femoral neck, and tibial epiphysis and diaphysis. Laboratory studies included serum levels of 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, intact parathyroid hormone, plasma alkaline phosphatase, electrolytes, creatinine and blood gas analysis., Results: Bone mineral density was normal in all patients. There was no evidence of deficient vitamin D stores. There was a tendency toward slightly elevated serum creatinine values in patients with preexisting impaired renal function, including 1 who also had slight acidosis. No patient had hyperchloremia., Conclusions: We found no evidence of osteomalacia, osteoporosis or significant metabolic acidosis in 14 patients with an ileal bladder substitute for 5 to 8 years. However, it is not known whether the absence of osteopenia would also apply to patients with poor renal function, to those not followed meticulously and, thus, at risk for major long-term functional or metabolic disturbances from the ileal bladder substitute or to patients with orthotopic bladder substitutes made from longer or other bowel segments than we used.

Between April 1985 and April 1993, 100 consecutive men underwent lower urinary tract reconstruction after cystectomy. An ileal low pressure reservoir using the Goodwin cup-patch principle was combined with an afferent ileal tubular segment. The early complication rate was 11%, including 2 postoperative deaths due to septicemia. After a median followup of 27 months (range 3 to 96) 14 patients required surgery for late complications (intestinal obstruction, urethral stricture or tumor recurrence, hernia or ureteral stenosis). A total of 32 patients died of metastatic bladder cancer and 7 died of other causes. The functional capacity of the bladder substitute was increased to the desired 450 to 500 ml. after 3 to 12 months, which was paralleled by improving urinary continence. After 1 year 92% of the patients were continent by day and after 2 years 80% were continent at night. Upper tract surveillance with excretory urography, renal ultrasound and serum creatinine estimation has shown 4 left ureteral strictures but not significant upper tract deterioration or ureteral recurrence. Significant reflux was not observed during video urodynamics unless the reservoir was overfilled. During voiding, by outlet relaxation and straining if necessary, the intra-abdominal pressure increase with straining acted equally on the reservoir and ureters. Therefore, unlike voiding with a normal bladder, no isolated intravesical pressure increase occurred and, thus, there was no reflux from the reservoir. The combination of an ileal low pressure reservoir with an afferent isoperistaltic ileal segment and an open end-to-side ureteroileal anastomosis allows for radical cancer surgery with resection of the ureters where they cross the iliac vessels and minimizes the risk of ureteral stenosis. The unidirectional peristalsis of the ureters and the afferent tubular ileal segment seem to protect the upper urinary tract sufficiently. The surgical technique is straightforward and allows for later conversion to an ileal conduit if necessary. The functional results of the bladder substitute are comparable to other similar reservoir techniques, provided that the patients are carefully selected, well rehabilitated and meticulously followed.

Objective: To analyse the clinical and therapeutic consequences of early treatment failure after bacille Calmette-Guérin (BCG) instillation therapy for carcinoma in situ of the bladder., Patients and Methods: A total of 115 patients with carcinoma in situ (Tis) of the bladder were treated by intravesical instillation of living BCG vaccine (Immun BCG Pasteur F). Twenty five patients had primary Tis and 90 had secondary Tis with synchronous or prior superficial papillary tumours. All papillary tumours were resected before instillation of BCG. All patients completed one series of 6 weekly instillations of 120 mg BCG., Results: Twenty-two of 25 patients (88%) with primary Tis responded completely, with negative cytology and cystoscopy findings within a median follow-up period of 44 months. Three of the 25 (12%) had cytological evidence of disease within 9 months of therapy and were considered to be early treatment failures. One patient had muscle-invasive bladder cancer, one had Tis and invasive cancer of the prostatic urethra, and the last, in whom a second BCG course also failed, had Tis of both ureters. Seventy of 90 patients (78%) with secondary Tis had a complete response after treatment with BCG, with repeated negative cytology and cystoscopy examinations within a median follow-up time of 40 months. Twenty of the 90 (22%) with secondary Tis had positive cytology within 9 months after BCG therapy and were considered early treatment failures. Five of these 20 had a cystectomy, three for persistent Tis of the bladder and two for a solid urothelial carcinoma of the prostate. The remaining 15 early failures received a second course of BCG. Four of these 15 patients responded and the remaining 11 failed the second course. The 11 failures included two patients with multifocal T1 G3 bladder cancers. four with invasive bladder cancer, two with solid urothelial carcinomas of the prostatic urethra, and three with Tis of the upper urinary tract., Conclusions: According to these data, early treatment failure after 6 weekly instillations of 120 mg Immun BCG Pasteur F is an alarming signal which requires immediate re-assessment of the patient to exclude a muscle-invasive bladder cancer or an extravesical carcinoma in situ, either in the upper urinary tract or in the prostatic urethra.

Mouse prostate reconstitution is a useful model for studying the progression of ras + myc-induced carcinomas. When these oncogenes were introduced into both the epithelial and the mesenchymal compartments, poorly differentiated adenocarcinomas resulted. Restricted introduction of both oncogenes into the epithelium produced epithelial hyperplasia. Malignancies were produced in two out of 17 cases of selectively transformed epithelium, suggesting that the hyperplastic condition represents a premalignant phenotype. Restricted introduction of both oncogenes into the mesenchyme produced only mesenchymal dysplasia. Transforming growth factor-beta 1 (TGF-beta 1) and beta 3 (TGF-beta 3) mRNA levels were elevated in the ras + myc-induced carcinomas when compared to the normal controls or to the epithelial hyperplasias. In contrast, TGF-beta 2 mRNA levels were similar in all control and ras + myc-induced carcinomas. Elevated TGF-beta 1 mRNA levels were also found in mesenchymal dysplasia pointing to a potential paracrine activity by the ras + myc transformed mesenchyme. We conclude that elevated TGF-beta 1 and beta 3 are correlated with progression to malignancy and that mesenchyme derived TGF-beta 1 may play an important role in the promotion of ras + myc-induced carcinomas in this model system.

The mouse prostate reconstitution model exploits the ability of the fetal urogenital sinus to differentiate into a mature prostate when grafted under the renal capsule of an adult isogenic male host. By use of a recombinant retroviral vector, the ras and myc oncogenes are introduced singly or in combination into the fetal urogenital sinus--resulting in distinct phenotypes of prostatic pathology: dysplasia (caused by ras), hyperplasia (caused by myc) and frank carcinomas (caused by a combination of ras+myc). This unique experimental model creates in vivo conditions that mimic the natural initiation and progression of cancer. An expanded MPR protocol allows restricted retrovirus infection of the mesenchyme or epithelial compartments to evaluate paracrine activities. It enables almost unparalleled flexibility in addressing fundamental questions in prostate cancer. We have identified genetic variance in the susceptibility to tumour induction between two different strains of mice (mimicking the observation of racial variability in the predisposition to clinical prostate cancer). The MPR model supports data from other tumour models and implicates TGF-beta 1 and TGF-beta 3 as being strongly associated with tumour progression. Finally, with this model, we have established clonal prostate adenocarcinomas to study directly the affects of castration on gene expression. Not only are TGF-beta 1 and TGF-beta 3 mRNA levels increased in association with malignancy but they are also further enhanced by castration treatment. Based on these experimental studies, we believe that TGF-beta 1 and TGF-beta 3 expression strongly influences the progression of prostate cancer. This information will hopefully impact on the development of more effective therapy for this important malignancy.