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Biomedical subjects

M R Feneley

Publications and source records attributed to M R Feneley.

At least 19 recordsLinked to original sources
PubMed1999

Selectivity of finasteride as an in vivo inhibitor of 5alpha-reductase isozyme enzymatic activity in the human prostate.

The type II 5alpha-reductase inhibitor finasteride is used in the treatment of benign prostatic hyperplasia (BPH), reducing local production of the growth promoting androgen dihydrotestosterone (DHT). The effect of prolonged treatment with this time-dependent irreversible inhibitor on the recently described prostatic type I 5alpha-reductase, however, is not clear. Therefore, we assessed the effects of 5 mg. finasteride per day for 6 months on prostatic 5alpha-reductase isozymes, and prostatic tissue composition and androgen content of patients suffering from BPH. In prostatic tissue from these patients, the type II enzymatic activity is inhibited 100-fold compared with tissues obtained from placebo treated patients. The type II immunoreactivity is up regulated 2-fold. The type I isozyme is inhibited 3-fold and potentially still contributes to DHT production. In conclusion, finasteride is a selective type II inhibitor in vivo. Further research is warranted to assess the possibly distinct roles of the 5alpha-reductase isozymes in the normal prostate, in BPH, and during finasteride treatment.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1999

Funding clinical research: the need for information and longer term strategies.

The Chief Medical Officer's Working Group on Specialist Medical Training recommended that training in research methodology should be a recognised component of all postgraduate training programmes and that further consideration be given by those responsible for postgraduate education, training and research to establishing how this might be achieved. Funding of the trainee in research is a crucial aspect of this directive, yet both trainers and trainees have described this as haphazard, invariably reliant on 'soft' money. The subject has raised wide discussion and debate. A questionnaire was sent to 205 consultant urologists in the UK, 154 (75%) replied and 130 (84%) had experience of research during their training. The first report examined their opinion about the contribution of research to their training; this report covers the questions directed towards funding, the source of their funding, whether sufficient funds, advice and information were available and where they might expect to obtain such details. The replies indicated a variety of sources of funding; knowledge about the financial support available for research was sparse and the majority considered there was insufficient advice and information available for trainees on the subject. Substantial funds are available for high quality scientific research programmes providing unprecedented opportunities for multidisciplinary collaboration that is essential for advancing clinical practice alongside technological developments. The process of obtaining support can be a time-consuming exercise, raising the need for an administrative infrastructure to select, prioritise and co-ordinate an appropriate research strategy for the future.

Education, Medical, Continuing↗
PubMed1999

Does screening for prostate cancer identify clinically important disease?

In this study the combination of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) is shown to be effective for detecting early prostate cancer in a urological out-patient setting. PSA provides the means to detect cancer in men with normal DRE that may otherwise present as so-called incidental cancer at transurethral resection of the prostate (TURP) for apparently benign disease or later in the course of its natural history as locally advanced or metastatic disease. PSA progression in men with incidental cancer has been previously demonstrated to be predicted more reliably by residual cancer on needle biopsy after TURP than by tumour in the resected specimen and, therefore re-staging such patients is worthwhile when further treatment would be considered. Among men selected for radical prostatectomy, non-palpable tumours detected with PSA more predictable in pathological extent than incidental cancer and their particular pathological characteristics suggest they include clinically significant tumours that would progress if untreated to palpable and eventually metastatic disease. In view of this progressive behaviour, cancer detected by PSA should be considered clinically significant particularly in men with a life expectancy of at least 10 years. Therefore screening should be offered for such individuals, to detect and treat tumours at a curable stage and thereby eliminate the high mortality and often protracted morbidity commonly associated with metastatic disease.

Adult↗
PubMed1998

The contribution of research to urological training in the United Kingdom.

OBJECTIVES: To report the findings of a questionnaire survey among consultant urologists in the United Kingdom (UK) designed to examine their personal experience of research and their opinion of its contribution in urological training. METHODS: A questionnaire was sent to 205 consultant urologists in the UK and 154 (75%) replied. Their replies were examined to ascertain the time spent in research, the production of publications, presentations and in gaining a higher university degree. Subsequent research activity was also related to the achievement of these endpoints. RESULTS: Among the 154 consultant urologists who replied. 130 (84%) had undertaken research during their training, for a period varying from 6 months to more than 2 years. Among the 130, 99 (76%) considered this to have been well spent; 76 (58%) obtained a higher degree, 86 (66%) achieved at least three publications in peer-reviewed journals and 90 (69%) had given at least five presentations to learned societies. Inadequate supervision in particular was cited as contributing to underachievement and motivation was also considered important to success. CONCLUSIONS: The contribution of research in urological training has been assessed traditionally by the presentation of a thesis to a university for a higher degree, but alternative methods of assessment should perhaps be sought for those wishing to spend less than 18 months in research.

Career Choice↗
PubMed1997

Retrograde embolization and causes of failure in the primary treatment of varicocele.

OBJECTIVE: To assess retrograde embolization for the treatment of varicocele and to examine the causes of surgical and radiological treatment failure. PATIENTS AND METHODS: Of 154 patients with clinical varicocele associated with subfertility or symptoms who were treated, 100 underwent surgical high ligation, retrograde embolization under fluoroscopic control was attempted in 84 and 30 had both forms of treatment. Venographic findings were defined in those patients for whom embolization proved impossible and in those in whom prior high ligation had failed. Among subfertile patients, 64 had semen analyses before and at least 3 months after the procedure available for comparison. Those patients undergoing both radiological and surgical procedures were sent questionnaires to evaluate their experience. RESULTS: Retrograde embolization was technically successful in 68 (81%) of the 84 patients. Two early failures were associated with venous spasm provoked by technical inexperience, while difficulties in the remainder were caused by anomalous venous anatomy. In patients who had recurrent varicocele after previous ligation, venography showed incomplete ligation of collateral channels; 14 of 18 patients were successfully re-treated by embolization. The sperm concentration improved significantly in 83% of patients undergoing embolization and in 63% of those surgically ligated. Patients who underwent both procedures expressed a strong preference for embolization. CONCLUSION: In centres where there is a skilled interventional radiologist, embolization is an effective alternative to surgical ligation of varicocele. Carried out under local anaesthesia as an out-patient procedure, it is cost-effective, associated with minimal morbidity and most patients are able to return to normal daily activities immediately.

Adolescent↗
PubMed1997

Imaging prostate cancer with technetium-99m-7E11-C5.3 (CYT-351).

UNLABELLED: To evaluate the performance of the 99mTc-labeled monoclonal antibody CYT-351 in visualizing prostate cancer, radioimmunoscintigraphy (RIS) was performed in 35 patients. METHODS: Antibody (0.5 mg) labeled with 600 MBq 99mTc was injected intravenously after obtaining informed consent. Planar and SPECT imaging was performed at 10 min and 6-8 and 22-24 hr postinjection. The scans were evaluated for visualization of the primary focus or local recurrence, extraprostatic invasion, lymph node involvement and uptake in bone and soft tissue metastases. RESULTS: Thirty-six studies in 35 patients were performed. In 13/14 evaluable studies with clinically localized prostate cancer, RIS had a true-positive rate of 92% (12/13). In eight patients with previous incidental carcinoma detected during transurethral resection undertaken for clinically benign disease, there were 86% true-positive results (6/7) and one true-negative result, which were confirmed by systematic needle biopsies. In six patients with evidence of local recurrence after a previous radical prostatectomy, the true-positive rate was 100% (6/6), which was confirmed by raised or rising prostate-specific antigen levels (PSA) and/or by biopsy. In the eight patients with known metastases, the disease was visualized in 4/4 with progression but not in the 3/3 with regression; one patient demonstrated regressing disease as determined by PSA levels. The overall accuracy was 92%. CONCLUSION: RIS with 99mTc CYT-351 is capable of providing good quality images and yielding clinically useful information safely. It has a potentially important clinical role for patients with rising PSA levels but negative images by conventional modalities.

Antibodies, Monoclonal↗
PubMed1996

Reproducibility of uroflow measurement: experience during a double-blind, placebo-controlled study of doxazosin in benign prostatic hyperplasia.

OBJECTIVES: To evaluate the interindividual and intraindividual variation of uroflow measurements in men with benign prostatic hyperplasia (BPH). METHODS: A total of 147 men with clinical evidence of BPH underwent two uroflow measurements at each of two screening visits prior to recruitment into a placebo-controlled study of doxazosin in the treatment of BPH. The maximum and mean flow rates were determined on each occasion. Differences in the mean value of both parameters for the cohort were examined. The intraindividual variability was evaluated using intraclass correlation coefficients and differences in maximum uroflow at each visit were examined. RESULTS: Uroflow measurements for the cohort were reproducible and there was no clinically significant difference in maximum and mean flow rate on each occasion. However, the intraclass correlation coefficients for the mean and maximum flow rate varied between 0.70 and 0.82, indicating that intraindividual variation accounted for a substantial component of the total variation in uroflow observed among these patients. For many individuals, test-retest differences were clinically relevant. CONCLUSIONS: For a group of patients, maximum and mean uroflow measurements are reproducible. However, for an individual, these parameters are subject to clinically significant variation and a single measurement may not be representative. This may be important when considering the need for therapeutic intervention.

Adrenergic alpha-Antagonists↗
PubMed1996

A review of radical prostatectomy from three centres in the UK: clinical presentation and outcome.

OBJECTIVE: To examine critically the clinical presentation, pathological stage and outcome in patients selected for radical prostatectomy combining data from three centres where the operation has been carried out routinely for more than 5 years. Comparisons were made between impalpable tumours presenting at transurethral resection of the prostate (TURP) for clinically benign disease, tumours diagnosed at needle biopsy performed because the serum prostate-specific antigen (PSA) was elevated, and palpable, clinically localized cancer detected by digital rectal examination (DRE). PATIENTS AND METHODS: Clinical and pathological findings recorded in the hospital notes of 183 patients who had undergone exploration for radical prostatectomy at St Bartholomew's Hospital, London, Southmead Hospital, Bristol, and the Royal Infirmary, Stirling, between 1987 and 1994 were transcribed onto a proforma and analysed. Patients were categorized by clinical stage and the relationships between clinical presentation, serum PSA level, pathological stage, tumour grade and outcome were examined. RESULTS: The pathological extent of clinically unsuspected cancer identified at TURP was highly variable. Well-differentiated tumours occupying < 5% of the TURP specimen were generally found to be less extensive at subsequent radical prostatectomy than either impalpable malignancy diagnosed by needle biopsy performed because PSA levels were raised or palpable tumours associated with a unilateral abnormality on DRE. Unsuspected tumours diagnosed at TURP that were less than well differentiated or occupied > 5% of the surgical specimen were more commonly associated with extra-prostatic invasion or metastatic disease than were tumours detected by raised PSA levels or an abnormal DRE. Serum PSA did not reliably predict either clinical stage or pathological extent, but no patient with nodal metastases had a PSA level of < 12 ng/mL. Similarly, pathological stage could not be predicted confidently from the whole-tumour grade ascertained after surgery. The extent of malignancy in patients referred because of lower urinary tract symptoms was not significantly different from that among patients referred specifically because the PSA level was raised or the DRE was abnormal. However, there was a trend for patients found to have cancer in specific screening programmes to have a malignancy that was less extensive and therefore more frequently confined to the gland than in those not identified by screening. CONCLUSION: Among patients with unsuspected malignancy diagnosed at TURP, those with well differentiated tumours in < 5% of the specimen had significantly less advanced disease than men found to have less differentiated or more extensive malignancy in the resected specimen. Impalpable cancer associated with a raised PSA level diagnosed by needle biopsy represented an intermediate group comparable to those with unilateral palpable malignancy. This suggests that needle biopsies may be worthwhile in some patients with an apparently benign prostate and raised PSA level with a view to identifying clinically significant but potentially curable cancer. Screening may detect less extensive tumours, but the natural history of these cancers is unknown and observed survival will be subject to lead-time and length bias when compared to symptomatic disease. Prospective randomized studies of both screening and treatment modalities, including surgery and radiotherapy, are required to define the impact of radical prostatectomy on disease-specific survival in men with early stage prostate cancer.

Adult↗
PubMed1996

Prostatic radioimmunoscintigraphy: preliminary results using technetium-labelled monoclonal antibody, CYT-351.

OBJECTIVE: To investigate the clinical application of a new technique for imaging prostatic malignancy using planar imaging and single-photon emission tomography (SPET) with technetium-99m-labelled antibody to a prostatic cell surface membrane antigen. PATIENTS AND METHODS: Prostatic malignancy was imaged by radioimmunoscintigraphy (RIS) using a 99mTc-labelled monoclonal antibody, CYT-351, raised against a newly identified membrane antigen present in normal and malignant prostatic tissues. The protocol involved taking serial images and assessing the changes in activity, as the uptake of specific antibody increased with time and non-specific uptake decreased. Data from planar images were collected at 10 min, 6 and 24 h after injection with antibody, and by SPET at 6 and 24 h using a Siemens Orbiter Large Field of View gamma camera. Twenty-two RIS scans were evaluated, which included six patients with clinically localized disease, six patients with previous incidental carcinoma at prostatectomy for apparently benign disease, four patients with evidence of local recurrence after radical prostatectomy and six patients with metastatic disease. RESULTS: Primary tumours and secondary lymphatic and bone metastases were demonstrated. Only one minor side-effect was experienced. CONCLUSION: This RIS technique was capable of imaging primary prostatic malignancy and metastatic disease in lymph nodes and bone. Its clinical application remains to be defined, but potentially it provides a new means for tumour staging based upon tissue characterization. It may be particularly useful before radical prostatectomy and it is capable of imaging local recurrence following radical treatment of localized disease. Future applications include monitoring the progression of disease and the response to treatment.

Antibodies, Monoclonal↗
PubMed1996

Ki-67 expression in early prostate cancer and associated pathological lesions.

AIM: To assess cell proliferation in early prostate cancer and associated pathological lesions. METHODS: Using the Ki-67 antibody, the cell proliferation index was measured in early stage prostatic carcinoma in 37 incidental tumours diagnosed at transurethral prostatectomy (TURP) and in 20 low volume cancers treated by radical prostatectomy. Proliferation indexes have also been measured in areas of normal peripheral zone, transition zone hyperplasia, atrophic appearing lobules, and high grade prostatic intraepithelial neoplasia in the radical prostatectomy cases. RESULTS: In the TURP series the proliferation index correlated with grade and stage. Logistic regression analysis, however, showed that Gleason grade was the most reliable predictor of biopsy proven residual disease and clinical progression. In the radical series transition zone carcinoma the proliferation index was half that of peripheral zone carcinoma. The atrophic lobules also showed a high proliferation index of the same order as seen in the peripheral zone carcinoma. Normal peripheral zone showed the lowest proliferation index and in hyperplastic transition zone it was also less than the other areas. CONCLUSIONS: There is only limited support for the correlation of proliferation index with grade in early stage prostatic carcinoma. The findings do not suggest that proliferation index adds to the prognostic information given by grade and stage in pT1 disease. The significant difference in proliferation index in transition zone and peripheral zone carcinomas supports the morphological distinction of these tumour types and is consistent with differences in biological behaviour. The high proliferation index in lobules considered morphologically atrophic is reminiscent of previous observations in which carcinoma was spatially associated with atrophy.

Adenocarcinoma↗
PubMed1995

Post-operative serial prostate-specific antigen and transrectal ultrasound for staging incidental carcinoma of the prostate.

OBJECTIVES: To examine the value of post-operative serum prostate-specific antigen (PSA), PSA density, incremental change in serial serum PSA (PSA slope) and transrectal ultrasound (TRUS) in the assessment of residual malignancy after the diagnosis of clinically unsuspected prostatic adenocarcinoma at transurethral resection of the prostate (TURP). PATIENTS AND METHODS: Forty-eight untreated patients with incidental carcinoma of the prostate, demonstrated at TURP for a clinically benign gland, were evaluated post-operatively with serum PSA and TRUS with multiple systematic prostatic biopsies. Prostatic volume was determined from TRUS measurements and PSA density was defined as serum PSA divided by gland volume. Those patients who did not undergo further treatment were monitored with serial PSA levels, and PSA slope was calculated as the overall annual percentage increase in serum PSA. RESULTS: Among 36 patients staged T1A (A1), 11 (31%) had histologically proven residual carcinoma, and five of the 12 patients (42%) with T1B (A2) disease had no residual disease on biopsy. Serum PSA levels following TURP were greater in those patients with residual disease than those without (P = 0.001), but at a cut-off of 4.0 ng/mL--providing a sensitivity of 89%--the specificity of PSA alone was 57%. PSA density had an 83% sensitivity and a 67% specificity with a cut-off of 0.15 ng/mL/cm3. TRUS had a sensitivity of 63% and a specificity of 52%. An incremental rise in PSA exceeding 20% per year in untreated patients gave a sensitivity of 90% and specificity of 79% for biopsy proven residual malignancy. CONCLUSION: This study demonstrates the inaccuracy of staging incidental prostatic malignancy by TURP. Although the performance of PSA density is better than that of PSA alone, the reliability of both are limited by the lack of specificity, and TRUS imaging lacks both sensitivity and specificity. The PSA slope has sufficient sensitivity and specificity to distinguish reliably most patients with biopsy proven residual malignancy. Although ultrasound-guided systematic biopsies provide a means for confirming residual malignancy, they may not be indicated in all patients with incidental carcinoma: for such patients, PSA progression may provide a rational basis for subsequent treatment.

Aged↗
PubMed1995

Zonal biochemical and morphological characteristics in BPH.

OBJECTIVE: To compare androgen, oestrogen, progesterone and epidermal growth factor receptor concentrations in the transition zone and peripheral zone of the prostate in benign prostatic hyperplasia (BPH), and to relate these findings to epithelial and stromal composition. PATIENTS AND METHODS: Tissue from both the transition and peripheral zone of the prostate was obtained from 26 patients undergoing transurethral prostatectomy for benign prostatic obstruction and used for both receptor binding studies and morphometric analysis. Androgen receptor (AR), oestrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor (EGFR) concentrations were assayed by saturation binding with a competitive inhibitor. The epithelial, stromal and luminal composition of the tissue was determined using a Zeiss AxioHOME microscope workstation. RESULTS: The epithelial content was significantly greater in the transition zone than in the peripheral zone. No overall zonal difference in AR concentration was detected; however, when values were expressed relative to the epithelial component, the AR content was significantly higher in the peripheral zone. Conversely, overall EGFR concentrations were significantly greater in the transition zone, although not when expressed per unit epithelium. Higher concentrations of oestrogen receptor were measured in the transition zone per unit stroma. No zonal difference in PR was detected. However, there was a significant correlation between AR and PR in the peripheral zone and between EGFR and AR in the transition zone. CONCLUSION: These data demonstrate that receptor concentrations should be related to tissue composition. Concentrations of AR were higher in the peripheral zone epithelium than in transition zone epithelium, suggesting greater androgen dependence. This may be important in determining its greater propensity for malignancy. Although EGFR concentrations were greater in the transition zone, there was no zonal difference after correction for the amount of epithelium. Finally, higher concentrations of ER were detected in the transition zone stroma which may reflect important zonal differences in regulating growth and provides further evidence of a role for oestrogens in BPH.

ErbB Receptors↗