Familial prostate cancer: the evidence and the Cancer Research Campaign/British Prostate Group (CRC/BPG) UK Familial Prostate Cancer Study.
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Biomedical subjects
Publications and source records attributed to R J Shearer.
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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.
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.
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.
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.
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.
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.
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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.
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.
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.
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.
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.
The steroidal aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione (4OHA) and its metabolites, 4-hydroxytestosterone (4OHT), 3 beta,17-dihydroxy-5 alpha-androstan-4-one (metabolite A) and 3 alpha, 17-dihydroxy-5 beta-androstan-4-one (metabolite B) were evaluated as inhibitors of the human prostatic 5 alpha-reductase enzyme and for binding to the rat prostatic androgen receptor. 4OHA and 4OHT were weak inhibitors of 5 alpha-reductase with IC50 values of 15-29 microM. Metabolites A and B had no significant inhibitory activity. 4OHA and metabolites A and B bound weakly to the androgen receptor. The binding affinities (RBA) relative to mibolerone (RBA = 100) were 0.085, 0.485 and 0.016, respectively. However, 4OHT (RBA = 75) was a more potent binder than the endogenous androgen 5 alpha-dihydrotestosterone (RBA = 66). The ability of these metabolites, in particular 4OHT, to bind to the androgen receptor may explain the in vivo androgenic activity of 4OHA.
Thirty-five patients with advanced malignant disease have been treated as outpatients with increasing doses (0.1-100 mcg) of interleukin 2 (IL2) by once daily self-administered subcutaneous (s.c.) injection, 5 days weekly for 8 weeks followed by a 4 week observation period. Systemic side effects were not experienced by patients at the 3 lower doses. Three patients required dose reduction from 100 mcg daily because of intolerance (fever, rash, lethargy, nausea and vomiting) and one patient was discontinued because of dyspnoea. We observed immunological effects at the 100 mcg dose (but not at the lower doses). These consisted of (a) a modest sustained lymphocytosis, (b) eosinophilia in six (out of nine) patients and (c) a significant rise in IL2-stimulated peripheral blood lymphocyte activated killer (LAK) cell activity in six (out of nine) patients to a mean of 2.0 times pretreatment levels (P less than 0.01). Two (out of nine) patients with renal cell carcinoma treated with 100 mcg daily had partial responses of duration 4 and 9 months respectively and a further three had disease stabilisation for at least 3 months. Low dose long-term s.c. IL2 is clinically and immunologically active, and in comparison to other IL2 regimens it has minor toxicity and is easy to administer. These characteristics make low dose s.c. IL2 suitable for study in the adjuvant setting.
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