The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

Failure to void after transurethral resection of the prostate and mode of presentation.

OBJECTIVES: Contemporary audits and reviews of outcome after transurethral resection of the prostate (TURP) make little reference to failure to void following catheter removal after this operation. There have been few reports of the likelihood of a successful trial without a catheter after TURP related to mode of presentation. We report the results of a retrospective review of outcome of TURP related to mode of presentation, age, and prostate histologic findings in a consecutive series of patients in a London Teaching Hospital. METHODS: A consecutive series of 379 patients (381 TURPs) was reviewed to document the incidence of and risk factors for failure to void following initial trial without a catheter after TURP. RESULTS: Twelve percent of men failed to void after TURP on the initial trial without a catheter. In those patients presenting with lower urinary tract symptoms, there were no instances of failure to void. Ten percent of patients with acute retention (painful inability to void, urine volume less than 800 mL), 38% with chronic retention (maintenance of spontaneous voiding, bladder volume greater than 500 mL), and 44% with acute on chronic retention (painful retention, urine volume greater than 800 mL) failed to void after TURP. Only 1% of patients required management by long-term catheterization. Failure to void on catheter removal was not related to age or prostate histologic findings. CONCLUSIONS: Bladder volume at initial presentation in patients with urinary retention provides important information about the likelihood of re-establishing spontaneous voiding catheter removal following TURP. Patients should be warned that there is a significant chance of failure to void after TURP, the exact risk depending on their mode of presentation, but that most will ultimately not require a permanent indwelling catheter.

[Basic principles and initial results of adjuvant hormone therapy and irradiation of prostatic carcinoma]. / Grundprinzipien und erste Ergebnisse der adjuvanten Hormontherapie und Bestrahlung des Prostatakarzinoms.

Radiotherapy is an effective treatment for localized prostate cancer. A dose response relationship has been demonstrated for both local tumor control and complications. Reducing the volume of normal tissue treated may allow dose escalation without an increase in RT induced side effects. Androgen blockade before RT could, by reducing tumor volume, increase local control, disease-free (DFS) and overall survival in patients (pts) with prostatic adenocarcinoma. A total of 79 patients with T2-T4 prostate cancer have been treated initially with LHRH agonists and cyproterone acetate followed by radical irradiation between 1988 and 1993. The first cohort of 22 patients were monitored intensively by transrectal ultrasound and computed tomography. For each patient conformal photon beam radiotherapy and conventional treatment plans were produced and dose volume histograms compared for total volume, rectal volume, and bladder volume. Overall mean reduction of prostate volume was about 50%, and radiotherapy target volume was reduced by 37%. 53 further patients without clinical evidence of regional or distant metastases were given 3 months preradiotherapeutic hormonal cytoreduction with a short course of cyproterone acetate and LHRH. PSA level fell rapidly in most patients and after 3 months treatment the median PSA level was 1 ng/ml and 83% had PSA level 10 ng/ml. At 18 months PSA levels continued to be < 2 ng/ml in 70% of the patients. Combined modality treatment with the neoadjuvant or adjuvant androgen deprivation and conformal therapy show considerable promise as novel methods to improve the therapeutic ratio. This treatment approach may be used to explore the possibility of dose escalation in prostate cancer to enhance local control, and therapeutic randomised studies are underway to test these approaches.

Should all patients with ureteric colic be admitted?

A two-part study was undertaken to determine if all patients with uncomplicated ureteric colic require admission. The analgesic requirements and outcome in 31 patients admitted with ureteric colic were assessed; 20/31 (64%) required no further analgesia after admission and 8/31 (26%) required only oral/rectal analgesia. In the second part of the study a protocol was introduced allowing patients with no complicating factors to be discharged directly from the A&E department. Of 58 patients seen in the A&E department, 29 were discharged for outpatient follow-up. Of these patients, 19 required no additional acute hospital treatment, five returned for further parenteral analgesia but outside the time they would have stayed in hospital under our previous protocol (ie beyond 48 h) and three returned within 48 h of their first attendance with pain which had not responded to oral analgesics. No patient discharged from A&E subsequently required intervention for obstruction or infection. We conclude that it is not necessary to admit patients with uncomplicated ureteric colic if the initial colic has been relieved and there is adequate social support.

Shared care for benign prostatic hyperplasia: a feasibility study.

OBJECTIVE: To determine the proportion of patients with symptoms of urinary outflow obstruction secondary to benign prostatic hyperplasia (BPH) who could be managed in the community after assessment in a shared-care clinic (managed by nursing staff, supervised by a consultant) to which they had direct access. PATIENTS AND METHODS: A total of 127 men were referred to one consultant urologist in a 9-month period for assessment of possible urinary outflow obstruction. All were investigated using urine analysis, serum prostate-specific antigen level, urea and electrolytes, plain abdominal X-ray, renal ultrasonography and urinary flow rate. Additional investigations were undertaken as required. The proportion of men who could have been investigated in a shared-care clinic and then managed in the community was determined. RESULTS: Of 127 men, 88 (69%) were found to have uncomplicated outflow obstruction secondary to BPH; of these 49 (38%) could have been managed in the community after assessment in the shared-care clinic and a further 27 (21%) could have been managed in the community after additional investigation by a specialist. Twelve men (9%) were found to have uncomplicated outflow obstruction and chose to undergo transurethral resection of the prostate. CONCLUSION: Many men with uncomplicated outflow obstruction could be assessed in a shared-care clinic and then managed in the community. A shared-care protocol for the management of these men has now been introduced in this unit.

Superficial bladder cancer: for how long should a tumour-free patient have check cystoscopies?

OBJECTIVE: To determine the probability of a patient with superficial bladder cancer developing a recurrent tumour after having remained tumour free for 2 or more years. PATIENTS AND METHODS: One-hundred and seventy-nine patients with Ta or T1 tumours at diagnosis, a minimum follow-up of 3 years and a minimum of 2 years remaining tumour free were identified. Thirteen patients had more than one episode that was eligible for inclusion and there were therefore 192 tumour-free episodes for analysis. Survival curves of the probability of being recurrence-free against time were constructed for the whole group, for subgroups of Ta and T1 tumours and for subgroups with characteristics at diagnosis suggesting a good, intermediate and poor prognosis. RESULTS: The probability of a patient developing a recurrence after 2, 5 and 10 years of being tumour free was 43, 22 and 2% respectively. No patient had a recurrence after remaining tumour free for 12 years. No patient who had been tumour free for at least 2 years progressed to muscle invasion or metastases. There was no significant difference in the probability of recurrence between Ta and T1 tumours after 2 years of remaining tumour free. CONCLUSION: The optimum length of cystoscopic follow-up for patients with superficial bladder cancer is unknown, but patients continue to develop recurrences even after many years of being tumour free. If a patient is to discontinue cystoscopic follow-up, then alternative methods of assessment should be applied.

Rapid processing in the management of prostatic cancer.

OBJECTIVE: To carry out rapid histological processing of prostatic biopsies for the management of patients who present with urinary retention or other urological problems, or with a suspected diagnosis of prostatic cancer. PATIENTS AND METHODS: Biopsies were taken from each of 26 patients who presented with urinary retention or other urological problems, or with a suspected diagnosis of prostatic cancer. The biopsies were processed in a Shandon Hypercenter using a 3-hour programme and were stained on a Shandon Linistainer automatic staining machine. The slides were reviewed both immediately and at weekly histopathology audit meetings. RESULTS: Results were available within 4 h of receipt of the specimen in the laboratory. One false negative, due to a sampling error at the time of biopsy, was identified. CONCLUSION: We believe that this facility is of benefit to both surgeon and patient and should be more widely available.

Vacuolation in prostate cancer cells following luteinizing hormone releasing hormone analogue treatment.

OBJECTIVE: To assess whether the 'oestrogen effect' of vacuolation in treated prostatic cancer cells is seen after luteinizing hormone releasing hormone (LHRH) analogue therapy. PATIENTS AND METHODS: Eight patients with locally advanced prostate cancer were treated with the LHRH analogue, leuprorelin acetate. Biopsies taken pretreatment and after 3 months were assessed for the presence or absence of microscopic vacuolation. RESULTS: Seven out of eight patients had evidence of vacuolation induced or accentuated by treatment. CONCLUSIONS: Recent research suggests that both stilboestrol and LHRH analogues have a direct cytotoxic effect on prostate cell lines in vitro, which appears to be supported by these findings. Vacuolation seems to be a normal consequence of treatment with LHRH analogues.

Induction of transforming growth factor beta in hormonally treated human prostate cancer.

Transforming growth factor beta-1 (TGF-beta 1) has been proposed as a mediator of tumour growth in a number of tumours and cell lines including prostate, and in a recent study was shown to be up-regulated in the stroma of breast cancer tissue following treatment with the anti-oestrogen tamoxifen. Immunolocalisation of the intracellular form of TGF-beta 1 confirmed that the source of the stromal TGF-beta 1 was the peritumoral fibroblasts. We present here the results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment. These were stained for TGF-beta expression prior to treatment and at either relapse or 3 months later respectively. Six of seven clinically responding tumours and three of five relapsed tumours showed up-regulation of extracellular TGF-beta 1, again primarily in the stroma, with no apparent up-regulation of intracellular TGF-beta 1, TGF-beta 2 or TGF-beta 3. These data illustrate that the epithelial growth inhibitor TGF-beta 1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse. This suggests that relapse of hormonally treated prostate cancer may be associated with a failure of the epithelium to respond to stromal TGF-beta 1.

Superficial bladder cancer: timing of check cystoscopies in the first year.

We report a prospective study of 141 patients presenting for the first time with a small, solitary, non-invasive, moderately or well differentiated transitional cell carcinoma of the bladder. The pattern of recurrence in the first year was assessed and recurrence rates calculated; 80% of patients without recurrence at 3 months remained clear in the first year. There was a highly significant reduction in recurrence rates for those free of recurrence at 3 months. It has been suggested that this group should have the second check cystoscopy at 1 year and yearly cystoscopies thereafter. Our findings support that proposal.

Post-operative retention associated with acute prostatic infarction.

Twenty-one patients with post-operative retention following unassociated surgery and requiring transurethral resection of the prostate were compared with patients with acute retention (control group). Histological evidence of acute prostatic infarction was significantly increased in the post-operative retention group. Prolonged operative hypotension was associated with acute prostatic infarction, as were smoking and pre-existing cardiovascular disease.

LHRH analogues as primary treatment for urinary retention in patients with prostatic carcinoma.

Thirty-one patients with retention of urine and carcinoma of the prostate were treated with LHRH analogues as primary therapy rather than prostatectomy; 21 patients voided without the need for surgical intervention. Patients presenting in acute retention of urine voided more readily than those presenting in chronic retention, with only 20% requiring surgery. This approach to treatment is safe, efficacious and cost effective.

Aromatase inhibition: 4-hydroxyandrostenedione (4-OHA, CGP 32349) in advanced prostatic cancer.

We report the use of the steroidal aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA, CGP 32349), in the management of patients with advanced, hormone resistant, prostatic cancer. Eighteen of 25 patients (72%) showed a subjective response, mainly in the form of pain relief and increased performance. There were no objective improvements. A tumour flare occurred in 17/25 (68%). Detailed endocrine studies were performed during treatment. These showed that suppression of serum oestradiol levels occurred in 19/25 (76%) of patients during treatment with 4-OHA. Serum levels of androstenedione increased in 9/14 patients (64%). Concentration of serum testosterone and 5 alpha-dihydrotestosterone were elevated in 3/14 (21%) and 2/11 (18%) patients respectively. There appeared to be no correlation between response or tumour flare and changes in steroid levels during treatment with 4-OHA. The mechanism of action of 4-OHA in palliating patients with advanced prostatic cancer remains obscure. 4-OHA or its metabolites may be acting on metastatic bone metabolism via effects on oestrogen related osteoclastic and osteoblastic activity. Further investigation of the effects of aromatase inhibitors on prostatic biology, and bone metabolism in patients with metastatic prostate cancer, would appear worthwhile.

Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.

We report the effect on prostatic volume of the administration of the luteinising hormone-releasing hormone (LHRH) analogue goserelin in 22 patients with locally advanced carcinoma of the prostate; 20 achieved a significant reduction in volume, the median volume being 66 ml before treatment (range 40-130) and 30 ml after 17 weeks (range 13-47). If used before external beam radiotherapy (RT), volume reduction will permit smaller boost fields and thus potentially reduce adverse radiotherapy effects. In addition, reducing tumour volume before RT may lead to an increase in local control. We discuss the possible role of hormonal volume reduction in the management of prostatic cancer.