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Objective: The 5 alpha-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5 alpha-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5 alpha-reductase activity of the gland in men with BPH treated with the drug for 3 months., Design and Patients: Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months., Measurements: Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5 alpha-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels., Results: There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT (P = 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5 alpha-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5 alpha-reductase activity of the gland and tissue DHT concentrations., Conclusions: Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5 alpha-reductase responsible for the accumulation of DHT in the gland.

Background: Controversy regarding the relative efficacy of treatments for the relief of the symptoms of benign prostatic hyperplasia (BPH)., Methods: This was a 6-month double-blind randomized equivalence study that compared the effects of a plant extract (320 mg Permixon) with those of a 5 alpha-reductase inhibitor (5 mg finasteride) in 1,098 men with moderate BPH using the International Prostate Symptom Score (IPSS) as the primary end-point., Results: Both Permixon and finasteride decreased the IPSS (-37% and -39%, respectively), improved quality of life (by 38 and 41%), and increased peak urinary flow rate (+25% and +30%, P = 0.035), with no statistical difference in the percent of responders with a 3 ml/sec improvement. Finasteride markedly decreased prostate volume (-18%) and serum PSA levels (-41%); Permixon improved symptoms with little effect on volume (-6%) and no change in PSA levels. Permixon fared better than finasteride in a sexual function questionnaire and gave rise to less complaints of decreased libido and impotence., Conclusions: Both treatments relieve the symptoms of BPH in about two-thirds of patients but, unlike finasteride, Permixon has little effect on so-called androgen-dependent parameters. This suggests that other pathways might also be involved in the symptomatology of BPH.

We studied the metabolism of testosterone in primary cultures of prostate epithelial cells and fibroblasts obtained from patients with benign prostatic hyperplasia (BPH). The conversion of 3H-testosterone in both cell cultures was predominantly to the oxidative pathway, with the formation of 3H-androstenedione increasing with cell number and time of incubation. Although we also detected some 5 alpha-reductase activity in these cells, the activity in the stroma component (0.00688 pmol/mg protein/min) was nonetheless insignificant when compared to the 5 alpha-reductase activity in the tissue of origin (0.0616 pmol/mg protein/min) and well below the 17 beta-hydroxysteroid dehydrogenase activity of the same cells (0.0518 pmol/mg protein/min). The aromatase activity in our cells was also measured by two separate techniques, but neither the deuterium procedure nor the production of oestrone from androgen precursors yielded any positive results, suggesting that under these experimental conditions there was no aromatase activity within the cells. The shift from the reductive to the oxidative pathways in these primary cell cultures was reminiscent of the androgen-metabolizing enzyme profiles seen in poorly differentiated prostate cancer. Whether this transition is an obligatory step in the development of hormone refractiveness remains to be elucidated.

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.

Purpose: To determine whether BCG therapy could upregulate interleukin-6 (IL-6) production in human transitional cell carcinomas (TCC)., Materials and Methods: Immunohistochemistry of tumor biopsies and urinary cytospins and ELISA studies of urine from bladder cancer patients and TCC cell-line supernatants, before and after exposure to BCG, were performed., Results: Constitutive staining for IL-6 was found in the majority of bladder tumors. Interleukin-6 was detected in the urine of all 13 patients with carcinoma in situ and increased 5-fold during BCG therapy. Levels were variable but were greater in nonresponders (p < 0.01). During therapy both detached bladder urothelial cells and polymorphonuclear leukocytes stained for IL-6. Production of IL-6 increased in only 3 cell lines after exposure to BCG, but all 7 cell lines showed increases after exposure to interferon-gamma (p = 0.015). Grade 3 cell lines showed much greater upregulation than grade 1 and 2 cell lines., Conclusions: The increase in IL-6 during BCG therapy may be caused by urothelial cells as well as leukocytes. The higher levels seen in nonresponders may be due to either higher grade or persisting tumor.

The present study was undertaken mainly to investigate whether prolactin manipulation combined with maximal androgen blockage improves the effectiveness of treatment in advanced prostatic cancer. The efficacy of oral hydrocortisone as an alternative to commercial anti-androgens in reducing the adrenal androgens, and of bromocriptine in reducing the prolactin level were also examined. A consecutive series of 30 patients with untreated and advanced prostatic cancer were entered into a three-arm prospective randomised trial. 10 patients received subcapsular orchiectomy alone (arm 1), another 10 had subcapsular orchiectomy plus flutamide (arm 2), and the remaining 10 had subcapsular orchiectomy plus oral hydrocortisone and bromocriptine (arm 3). Clinical and biochemical parameters, including trans-rectal ultrasound-determined prostatic volumes, hormonal profiles and radionuclide bone scan were evaluated at regular intervals. At 12 months, serum testosterone was reduced by more than 90% in all arms, however, maximum suppression of androstenedione, prolactin, and reduction of prostatic volumes were only observed in arm 3; this was reflected by the significant improvement in clinical response in arm 3 compared with other arms. This study suggests that a combined maximal suppression of androgens and prolactin offers a significant improvement in response over conventional treatments without prolactin suppression in the treatment of advanced prostatic cancer. Importantly, a better clinical outcome in arm 3 was still apparent at the end of 36 months.

Objectives: To evaluate the safety, feasibility, and efficacy of transurethral ablative prostatectomy (TURAPY), a radiofrequency method of thermal tissue ablation of benign prostatic hyperplasia (BPH)., Methods: Twenty men, ages 55 to 81 years (mean, 67), with symptomatic BPH and with peak flow rate 12 mL/s or less, were treated with the TURAPY device (Direx Medical Systems). A 2 cm long heating element and 2 thermoprobes (for simultaneous prostatic temperature monitoring) are mounted on a Foley-like catheter and used for TURAPY treatment administration. This TURAPY catheter was modified by placing an extra set of thermoprobes in the sphincter region to allow sphincteric temperature monitoring. The treatment was administered at a maximum temperature of 70 degrees to 75 degrees C for 1 hour under local anesthesia as a day case., Results: All 20 patients completed the treatment. The maximum recorded rectal temperature was 39.5 degrees C. The maximum sphincter temperature was not allowed to exceed 42 degrees C. The post-treatment morbidity included dysuria and minor urethral bleeding in 12 patients. Three patients developed urinary infection requiring antibiotic treatment. All 20 patients were followed up 3 months after treatment. The mean International Prostate Symptom Score (IPSS) improved from 19.4 to 6.2 (68%), the mean peak flow rate increased from 7.9 to 12.9 mL/s (63%), and the mean postvoid residue decreased from 222 to 81 mL (64%). Overall, 80% of patients exhibited at least a 50% improvement in either the IPSS or the peak flow rate. There was a mean reduction in prostatic volume measured by transrectal ultrasound of 14 mL (29% reduction). The subjective and objective improvements, in 8 patients followed up 6 months after treatment, have been maintained. There was extensive coagulative heat necrosis of periurethral tissue with sparing of subcapsular tissue in prostate biopsy specimens taken from 1 patient 5 days after treatment. There was endoscopic and sonographic evidence of canalization of the obstructed prostatic urethra 3 months after treatment., Conclusions: Treatment with the TURAPY device was found to be safe, feasible, and effective in improving both subjective and objective measurements of benign prostatic obstruction in this pilot study on 20 patients.

The prostate gland has attracted a remarkable increase in interest in the past few years. The two most common diseases of this gland, benign prostatic hyperplasia and carcinoma of the prostate, have been brought into greater prominence by new diagnostic methods, public interest, and a wider choice of surgical and non-surgical treatments. Uncertainty about the significance of these changes has occurred because of the rapidity of change, the profusion of statements, opinions and promotions, and the relatively little guidance available from the profession. Ten urologists and two general practitioners have reviewed the relevant evidence about these two prostate diseases and the newer diagnostic methods; their conclusions are summarised here. Management options and guidance on clinical practice are also discussed. Because of a number of unresolved diagnostic and management issues, detailed requirements for practice guidelines have not been specified.

Intravesical immunotherapy for carcinoma in situ of the bladder is arguably the most effective form of tumour immunotherapy described to date. Following repeated instillations of BCG organisms into the bladder, large quantities of cytokines are detected in patients' urine. This study concerns the production of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and soluble ICAM-1 (sICAM-1) throughout the six weekly instillations which comprise a therapeutic course. Sequential instillations of BCG induced secretion of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and sICAM-1 into urine. The responses were heterogeneous between patients and cytokines, but some general trends were evident. Although cytokine levels were initially low, their concentration increased with repeated instillation of BCG. Certain cytokines (e.g. IL-6, IL-8 and IL-10) could be detected after the first instillation, whilst others (e.g. IL-2 and IFN-gamma) were not detected until after the third or fourth instillation. Interestingly, IL-4 was not detected, perhaps suggesting a differential effect on Th2-like responses. Some patients produced particularly elevated or non-detectable levels of cytokines, and a positive correlation was found between the production of various cytokines. The production of a particular cytokine did not correspond with lack of production of another species. Whether monitoring the production of cytokines following therapy may be of prognostic value will be determined in a larger series of patients. However, as these potent immunomodulators are thought to be important for the 75% complete clinical response observed with BCG therapy, there remains the possibility that detection of the products of an activated immune system may correlate with eventual clinical outcome. This study is a necessary forerunner to full prognostic evaluation of such immunological data.

Objective: To assess the results of radiotherapy in the treatment of localized prostate cancer. End points for assessment were survival, local control, development of metastases, and the toxicity of therapy., Materials and Methods: The case notes of 191 patients who were treated with radical radiotherapy between 1982 and 1992 were reviewed. The pathology of 130 patients was reviewed by a single pathologist. A multivariate analysis was performed to identify significant prognostic factors with regard to survival and relapse., Results: One-hundred and eighty-two patients were assessable. The minimum length of follow-up was one year (median = 40 months). The actuarial cause-specific 5 and 10 year survival rates were 63% and 35% respectively. Local progression occurred in 41% of patients with 37% developing metastases. Multivariate statistical analysis demonstrated that T stage and Gleason Score were significant predictors for survival. Late complications were usually mild, with only 4% developing serious bladder toxicity., Conclusion: Radical radiotherapy has a role in the curative treatment of prostate cancer. Survival is significantly related to T stage at the time of presentation, and to the Gleason Score of the tumour. Survival in this series was not as good as the best surgical series, but it is still not clear which patients should receive radiotherapy and which surgery as their primary management.

Current reports suggest a role for intercellular adhesion molecule-1 (ICAM-1) in the progression of malignancy. The availability of a new antibody makes it possible to measure circulating ICAM-1 (cICAM-1) in human body fluids including serum; this might help in monitoring tumour burden and in providing additional prognostic information. In this study, serum levels of cICAM-1 were measured by an ELISA assay in patients with benign prostatic hyperplasia (BPH; n = 20) and metastatic cancer of the prostate (CaP; n = 25). Serum ICAM-1 concentrations were also measured in a group of healthy men (n = 8). The mean +/- S.E.M. cICAM-1 level for BPH was 339.52 +/- 15.30 ng/ml compared with 263.55 +/- 18.54 ng/ml for CaP. Even though the difference between the two groups was significant (P < 0.005), there was a marked overlap between the individual values in both groups, thus minimising the prognostic value of these measurements in prostate cancer. Endocrine therapy had no notable effect on the serum levels of cICAM-1. The mean +/- S.E.M. cICAM-1 concentrations in serum from a younger group of healthy volunteers was 204.1 +/- 10.38 ng/ml, and this value was significantly lower than that measured in serum from either BPH or CaP. We also undertook some immunohistochemical studies to examine the distribution of ICAM-1 in prostate tissue. We observed focal epithelial cell membrane staining which was exceedingly patchy in both the BPH and cancer specimens. On the basis of these studies, we suggest that cICAM-1 levels do not provide additional information on patients with metastatic CaP.

Objective: To examine the clinical course following surveillance and symptomatic treatment, and compare the outcomes of immediate and delayed hormonal treatment in men with locally advanced prostatic cancer., Patients and Methods: Of a consecutive series of 199 men (mean age 74 years) with T2-T4 Nx M0 prostatic cancer, 110 (55%) were followed until death and the rest had a mean follow-up of 4.2 years. Fifty-one men received immediate orchidectomy, 88 had this treatment delayed until metastatic progression, and 60 had the treatment in the intervening period. The actuarial survival was compared with the expected survival for an age-matched healthy population in Scotland. The adjusted effect of the timing for hormonal manipulation was assessed by including it with age, Gleason score and clinical stage in a multiple Cox regression., Results: The actuarial survival for the whole group was 17% less at 5 years and 15% less at 10 years when compared with the expected survival for an age-matched population in Scotland. This was despite the fact that their nodal status was unknown and also those with occult metastasis (elevated serum prostatic acid phosphatase, M1a) at presentation were not excluded. In terms of metastatic progression, overall survival and cause-specific survival, there was no significant difference between immediate and delayed hormonal treatment., Conclusion: A conservative approach with surveillance and symptomatic treatment for locally advanced prostatic cancer is justified by the present evidence on disease progression and survival, which do not differ from alternative methods of treatment as reported in contemporary literature. This study has the limitations relative to the ideal of a prospective randomized trial on immediate versus delayed hormonal treatment, but the lack of significant differences in outcome even after adjustment for other established prognostic factors does suggest that there may be little to be gained from an immediate orchidectomy.

Objectives: To investigate the effect of upper tract decompression on the prognosis of uraemia secondary to bilateral ureteric obstruction in prostate cancer, with particular reference to the hormone dependency of the tumour., Patients and Methods: Prospectively collected data, over the period 1978-1993, were selected from the departmental database and from hospital case code data. Inclusion criteria were: blood urea > or = 15 mM, radiological evidence of bilateral ureteric obstruction, a histological diagnosis of prostate cancer, and the exclusion of out-flow tract obstruction. Of the 820 patients recorded in the departmental database, 27 (3.3%) fulfilled the criteria. Thirty-six patients were identified in total. Statistical analysis was by the Mann-Whitney non-parametric test., Results: Of the 36 patients with bilateral ureteric obstruction and renal failure, in those in whom androgen depletion had been undertaken after ureteric obstruction (i.e. androgen depletion was a treatment option), the mean survival was 646 days (n = 12, SD = 786). Among these patients upper tract decompression improved survival and reduced the amount of time patients spent in hospital. In those in whom androgen depletion had been carried out before obstruction (i.e. the tumour had escaped from hormonal control), survival was significantly worse (80 days, n = 24, SD = 86.8, P < 0.01). In this group the use of decompression improved survival little. Percutaneous nephrostomy was the commonest means of decompression (nephrostomy, 9; stent, 5; ureteroneocystostomy, 2)., Discussion: In patients for whom hormonal therapy remains an option, upper tract decompression offers a worthwhile improvement in terms of increased survival and reduced in-patient time. However, if ureteric obstruction is diagnosed after hormone manipulation has been used, upper tract decompression has little effect on survival and should only be used in exceptional circumstances.

Objective: To compare air insufflation with water irrigation during routine diagnostic flexible cystoscopy., Patients and Methods: A total of 200 consecutive patients scheduled for routine diagnostic flexible cystoscopy under topical anaesthesia were randomized prospectively to either air insufflation or water irrigation. Their tolerance to the procedure and post-operative symptoms were assessed from a questionnaire completed immediately after the procedure and then 1 week later., Results: Air insufflation offered a better cystoscopic view than water irrigation. With regard to tolerance, in the air insufflation group, 72% reported the procedure to be comfortable, 22% uncomfortable and 6% painful compared to 44%, 45% and 11% respectively in the water irrigation group. This difference in favour of air insufflation was highly significant (Chi-square, P < 0.001). There was no statistical difference in either post-operative symptoms a week later or in the diagnostic yield between the two study groups. There were no complications in either group., Conclusion: Air insufflation cystoscopy is as safe and effective as water irrigation but better tolerated by patients. This, together with its more obvious advantages of the ease of administration and low cost, should prompt more routine use of air insufflation cystoscopy for day case procedures.

Objective: To identify the various presenting symptoms in patients with metastatic prostate cancer, quantify the metastatic load for each symptom group and compare their case-specific survival., Patients and Methods: A prospective and consecutive series of 279 men with metastatic cancer of the prostate was analysed. Based on the symptom at presentation, six different groups were identified: bladder outflow obstruction, bone pain, anaemia, weight loss, paraplegia and alteration of bowel habit., Results: Significant variations were observed in their metastatic load (Kruskal-Wallis test, P = 0.0035) and in case-specific survival (log-rank test, P = 0.0038)., Conclusion: Bladder outflow obstruction, bone pain and anaemia not only dictate treatment selection but we provide evidence that each of these symptoms has considerable prognostic significance in patients with metastatic cancer of the prostate.

We report 3 cases of urinary leakage occurring in male kidney transplant recipients within 6 weeks of renal transplantation. Voiding cystometrography showed that high voiding detrusor pressure was the contributing factor. Endoscopic bladder outlet surgery restored normal detrusor voiding pressure and led to spontaneous resolution of urinary leakage without recurrence in all cases.

Aims: To determine the expression of intercellular adhesion molecule 1 and 2 (ICAM 1 and 2) in transitional cell carcinoma cells before and after immunotherapy with Calmette-Guérin bacillus (BCG)., Methods: Frozen sections from 22 untreated bladder carcinomas were immunohistochemically examined with monoclonal antibodies to ICAM 1 and 2. Urinary cytospin slides were made for six patients for each of the six clinical instillations which constitute a therapeutic course. These slides were also stained for ICAM 1 and for leucocyte function associated antigen 1 (LFA 1)., Results: Bladder cancer cells did not essentially express either ICAM 1 or 2, but cells in the stromal areas surrounding tumour expressed both these antigens. After repeated instillations of BCG organisms ICAM 1 positive normal and neoplastic epithelial cells were observed in the urine. Cells obtained from the first three instillations expressed lower densities of ICAM 1 than those from the later instillations. Many neutrophils expressing LFA-1 and some lymphocytes were also noted in the cytospin slides and some of these were conjugated to tumour cells expressing ICAM 1. Six months after treatment a single maintenance dose of BCG induced ICAM 1 expression., Conclusion: Untreated superficial bladder carcinoma cells do not express ICAM 1 or 2, but these important immunological molecules were expressed in the stromal areas of tissue. Importantly, neoplastic cells in the urine expressed ICAM 1 after immunotherapy. This molecule can render bladder tumour cells vulnerable to non-antigen specific cytotoxicity mediated by activated lymphocytes.

Background: The selection of treatment for patients with localized prostate cancer requires reliable information about the outcome of conservative management. Previous studies of this question are generally considered unreliable because they were uncontrolled and nonrandomized., Methods: We performed a pooled analysis of 828 case records from six nonrandomized studies, published since 1985, of men treated conservatively (with observation and delayed hormone therapy but no radical surgery or irradiation) for clinically localized prostate cancer. A Cox regression analysis was performed to determine which factors influenced survival among patients who did not die of causes other than prostate cancer (disease-specific survival). Kaplan-Meier curves for overall and metastasis-free survival among such patients were compared with use of the log-rank method and the Mantel-Haenszel test., Results: Factors that had a significant effect on disease-specific survival were grade 3 tumors (risk ratio, 10.04), residence in Israel (risk ratio, 2.48) or New York (risk ratio, 0.37), and age under 61 years (risk ratio, 0.32). Ten years after diagnosis, disease-specific survival (with data on men who died from causes other than prostate cancer censored) was 87 percent for men with grade 1 or 2 tumors and 34 percent for those with grade 3 tumors; metastasis-free survival among men who had not died of other causes was 81 percent for grade 1, 58 percent for grade 2, and 26 percent for grade 3 disease. These findings were not affected by the inclusion of men who had early-stage cancer, were older, had worse-than-average health, or underwent delayed radiation therapy or radical prostatectomy., Conclusions: The strategy of initial conservative management and delayed hormone therapy is a reasonable choice for some men with grade 1 or 2 clinically localized prostate cancer, particularly for those who have an average life expectancy of 10 years or less. New treatment strategies are needed for men with grade 3 prostate cancer.

In a random group of five patients undergoing thermotherapy with Thermex II (Direx Systems), the temperature in the region of the external sphincter was measured using a modified Thermex catheter. In all five patients the measured temperature exceeded 44.5 degrees C for more than half the duration of treatment. Further temperature mapping studies and studies on the assessment of sphincter function after Thermex II thermotherapy are in progress.

The TNM working group acknowledges the multinational agreement reached in the 1992 TNM classification, but nevertheless gives some suggestions for modifications. The main interest of the group has been to evaluate parameters suitable for further ramification of the system. The group found that parameters such as DNA ploidy, PSA, nuclear roundness factor, are not yet ready for this purpose. Grade is an established parameter and should be incorporated into the TNM-categories of localized disease. In metastatic disease a number of parameters are available to subdivide this category according to prognosis, and these will be more uniformly and extensively studied in the several large trials that are now in progress.

The control of integrin activation is fundamental to an understanding of the integrin-dependent cellular adhesion thought to be important for a plethora of basic cellular functions. Using a cell-cell conjugation assay the role of divalent cations in leucocyte function-associated antigen-1 (LFA-1)-dependent cellular adhesion was further investigated. The conjugation of interleukin-2 (IL-2)-activated lymphocytes to tumour cells was found to be energy dependent and required the presence of various divalent cations, removal of which decreased the level of conjugation. Increased concentrations of calcium, magnesium and manganese ions resulted in a corresponding increase in levels of conjugation. This increase in conjugation was LFA-1 dependent. Interestingly, when calcium ions were first removed from LFA-1, treatment of lymphocytes with magnesium and manganese ions gave significantly higher levels of conjugation than in the presence of calcium. Using a simple displacement study, calcium ions were shown to displace magnesium ions resulting in decreased conjugation. However, calcium ions were unable to displace manganese ions for binding to LFA-1. That manganese was exerting its effect via an LFA-1-dependent mechanism was confirmed using monoclonal antibodies to CD11a which negated the increased conjugation frequency due to manganese.

The different patterns of bone metastasis, metastatic load and their prognostic significance were examined in a consecutive series of 169 men with prostatic cancer and bone metastasis at presentation. Patients with an isolated metastasis in the pelvis or dorsal vertebrae had a better prognosis than those whose metastases were either diffuse or involved more distal sites such as the skull or the sternum, although all of these patients were classified as having M1 disease. Bone metastasis involving an area equivalent to 1 vertebral body equalled a metastatic load of 2. Based on their total metastatic load, 3 prognostic groups were identified with significant differences in case-specific survival despite receiving the same hormonal treatment. When comparing the potential efficacy of various treatments one must stratify the metastatic load, which is a powerful prognostic indicator of the outcome in patients with metastatic carcinoma of the prostate.

From a prospective database of 614 consecutive men with newly diagnosed prostatic cancer an audit of outcome was studied in 169 men who presented with bone metastases and subsequently received hormonal manipulation in the form of monotherapy. The cohort was divided into 2 groups according to serum alkaline and acid phosphatase enzyme levels. Men with normal alkaline phosphatase levels (41.5%) had a better prognosis (median survival 38 months) than those with elevated levels at presentation (58.5%) (median survival 19 months). This difference was highly significant. A similar stratification on prostatic acid phosphatase levels did not yield any prognostic significance. With regard to cause-specific survival, serum alkaline phosphatase was an even more powerful prognosticator, with a median survival of 45 and 21 months for patients with normal and elevated levels respectively. Thus monotherapy is recommended for metastatic prostate cancer patients with normal serum alkaline phosphatase, but for those with elevated alkaline phosphatase the alternative avenues of treatment must be explored.

To evaluate the hypothesis that testicular descent is mediated by the action of high local concentrations of dihydrotestosterone in the gubernaculum, testis, or epididymis, we obtained tissues from 30 male pig fetuses between 63 and 101 days of gestation. We assayed the 5 alpha-reductase activity in homogenates of pooled tissue by following the conversion of (3H)testosterone to (3H)dihydrotestosterone. The 5 alpha-reductase activity in the urethra and prostate increased prior to and during, but decreased after, the period of testicular descent. The 5 alpha-reductase activity in the gubernaculum remained constant throughout gestation and was not significantly higher than the background activity found in umbilical cord, testis plus epididymis, striated thigh muscle and heat inactivated samples of prostate and urethra. Prior to testicular descent, the 5 alpha-reductase activity was approximately 60 to 300 times higher in the urethra than in the gubernaculum, and approximately 20 to 55 times higher in the prostate than in the gubernaculum. These findings indicate that local conversion of testosterone to dihydrotestosterone in the gubernaculum or epididymis does not play a role in the mediation of testicular descent in the pig fetus.

We have studied the Major Histocompatibility Class II-modulating and antiproliferative actions of recombinant interferon-gamma, tumor necrosis factor-alpha, interleukin-1 alpha, interleukin-2 and granulocyte macrophage-colony stimulating factor on bladder cancer cells in vitro. Indirect immunofluorescent staining employing monoclonal antibody probes in conjunction with flow cytometric analysis and tritiated thymidine incorporation assays were used. Interferon-gamma was a strong inducer and enhancer of class II antigens. Tumor necrosis factor-alpha could not induce the expression of class II antigens on tumor cells, which were initially class II-negative, but enhanced the expression on cells which already demonstrated low levels of the antigen. Interleukin-1, interleukin-2 and granulocyte macrophage-colony stimulating factor did not affect the major histocompatibility class II expression. Interferon-gamma and tumor necrosis factor-alpha both demonstrated powerful anti-proliferative effects on the bladder cancer cells, particularly those derived from low grade tumors (G1 and G2). Interleukin-1 alpha had no effect on tumor cell proliferation. In contrast interleukin-2 and granulocyte macrophage-colony stimulating factor had significant stimulatory effects on the proliferation of the low grade tumor cells (G1).

Recent studies have shown an increased late mortality rate due to cardiovascular causes after transurethral compared with open prostatectomy. This has been linked to the demonstration of haemodynamic changes during transurethral prostatectomy, which may cause ischaemic myocardial injury. We used transoesophageal echocardiography (currently the most sensitive modality for detecting myocardial ischaemia) to study 26 patients during prostatectomy under general anaesthesia. Evidence of myocardial ischaemia (as shown by the development of new regional wall motion abnormalities of the left ventricle) occurred in 4 of 22 patients during transurethral and in 3 of 4 patients during retropubic prostatectomy. An intra-operative fall in systolic as well as diastolic blood pressure occurred in 21 of 22 patients during the transurethral procedure and in all 4 patients during retropubic prostatectomy. The duration of anaesthesia and the operation, and the intra-operative blood loss did not differ significantly between patients with and without evidence of intra-operative myocardial ischaemia. However, the maximum intra-operative fall in systolic and diastolic blood pressure, as well as the mass of the prostatic tissue removed, were significantly greater in patients with than in those without evidence of intra-operative myocardial ischaemia, suggesting that the latter may be related to the extent of surgery and the degree of intraoperative hypotension. In this study, 7 of 26 patients (27%) showed evidence of myocardial ischaemia during prostatectomy. However, it remains difficult to explain why intra-operative myocardial ischaemia should result in an increased cardiovascular mortality rate several years after the operation.

An analysis was made of a prospective database of 614 men with newly diagnosed carcinoma of the prostate who presented between January 1978 and December 1990; 3-monthly updates were available on their clinical, haematological and biochemical parameters and 6-monthly updates on chest X-rays, bone scans and skeletal X-rays. It was found that 107 men (mean age 73.5 years) had early disease at presentation. Their management was based on regular surveillance and the treatment deferred until disease progression or development of symptoms. The audit of outcome measured various clinical events. Four patients (3.7%) developed local failure, 11 (10.3%) developed bone metastases, 3 (2.8%) died of cancer with a median survival of 6.3 years, and 34 (31.8%) died of intercurrent disease with a median survival of 2.6 years. The observed survival for 12 years of the whole group was similar to the expected survival for an age-matched population in Scotland. The standardised mortality ratio was 81 (95% confidence limits 57-112).

The prognosis of bladder cancer is worsened by delay in its management. To reduce such delay we have organised a clinic where intravenous urography and cystoscopy, using a flexible cystoscope, are carried out at the patient's first visit. In a two-year period 321 patients attended this clinic. The results of investigation in 305 patients are reported. A total of 6% of patients with microscopic haematuria (n = 52) and 15% of patients with macroscopic haematuria (n = 253) had transitional cell carcinomata. This difference was not significant (P = 0.08, chi-squared). The delay between referral and trans-urethral resection of tumour for patients with bladder tumours was reduced from a mean of 60 days to a mean of 33 days by the institution of the clinic (P < 0.01, Mann-Whitney). We recommend that all patients referred to a urological service with haematuria, whether macroscopic or microscopic, should be investigated. The integration of that investigation in a single day decreases delays in diagnosis and management.

The outcome of conservative management in a consecutive series of 107 localized prostate cancers (mean age 73.5 years) has been analyzed. Follow-up ranged from 1 to 12 years. Following regular surveillance and no initial treatment, 3 died from prostate cancer with a median survival of 6.3 years compared to 34 who died from intercurrent disease with a median survival of only 2.6 years. The observed survival for the whole group was similar to the expected survival for an age-matched population in Scotland. This was despite the fact that the nodal status and the capsular invasion were unknown.

The constitutive expression by eight human bladder cancer cell lines of the cell adhesion molecules intercellular adhesion molecule-1 and intercellular adhesion molecule-2 was studied using monoclonal antibody probes in conjunction with flow-cytometry. Tumour lines of low grade (G1) did not constitutively express intercellular adhesion molecule-1, rather they were found to express intercellular adhesion molecule-2. The G2 cells expressed no intercellular adhesion molecule-2, however, a low percentage did express intercellular adhesion molecule-1. High grade cells (G3) only expressed intercellular adhesion molecule-1 on their cell surface but at higher levels than the G2 cell line. Exposure of the bladder cancer cell lines to interferon-gamma induced and augmented the expression of intercellular adhesion molecule-1 by all except one of the cell lines (UMUC3). Intercellular adhesion molecule-2 expression remained unaltered. The modulation of intercellular adhesion molecule-1 expression was dependent on the concentration of interferon-gamma and the duration of stimulus. De novo intercellular adhesion molecule-1 expression, induced by interferon-gamma, was rapid (< 4 hours) with only a short period of stimulation being required (< 10 seconds). The rapid increase in expression of intercellular adhesion molecule-1 required de novo protein synthesis and was not the result of release of intercellular adhesion molecule-1 from an intracellular pool. Interferon-gamma and tumour necrosis factor-alpha were found to act synergistically in the induction and augmentation of intercellular adhesion molecule-1 expression. Optimal induction occurred with 10 Uml-1 of both molecules. These results suggest a correlation between constitutive adhesion molecule expression and the histopathological grade of the tumour. The implications of these findings for Bacillus Calmette Guerin and interferon-gamma immunotherapy of bladder cancer is discussed.

Previous studies have demonstrated that is is the local immune response which is of importance for the anti-tumour activity of BCG therapy. We have investigated this by quantitative immunohistochemical analysis of serial bladder mucosal biopsies taken before, during and after an eight week course of intravesical Evans strain BCG therapy and three monthly thereafter in 16 patients (15 extensive CIS and one extensive G2pTa papillary tumour). This particular group of patients had a 67% complete response rate at six months post-treatment. The main findings on immunohistochemical analysis were the universal induction of MHC Class II antigens by urothelial cells which was statistically significant up to 6 months after completion of therapy, coupled with a T cell dominated cystitis. Increases in CD3+ T cell infiltration of the lamina propria and that of the CD4+ "Helper" subset which predominated were significant up to 3 months post-therapy and these cells showed evidence of increased immunological activation as shown by increased interleukin-2 receptor and MHC Class II antigen expression. There were also significant increases in CD68+ macrophage and the incidence of CD22+ B cell aggregates but CD57+ NK cells were sparse both before and after therapy. The degree of mononuclear cell infiltration for all markers examined (except CD57) was significantly greater in those biopsies in which the urothelial cells expressed MHC Class II antigens than in those that did not. Also the degree of T cell infiltration (CD3, CD4 and CD8) was significantly greater in the eight patients deemed to have had a complete response compared to those seven with a partial response or treatment failure. These results are discussed in terms of possible mechanisms of action for BCG therapy and in particular the role of enhanced antigen presentation by tumour cells.

The lysis of eight human bladder cancer cell lines by lymphokine-activated killer cells (LAK) was found to be partially dependent upon the expression by the target cell of either intercellular adhesion molecule-1 (ICAM-1) or intercellular adhesion molecule-2 (ICAM-2). Using adhesion blockade studies these molecules were found to contribute towards sensitivity to lysis. Tumour lines of low grade (G1) did not constitutively express ICAM-1, but were found to express ICAM-2. High grade cells (G2, G3), however, only constitutively expressed ICAM-1 on their cell surface. Interferon-gamma (IFN-gamma) induced and augmented the expression of ICAM-1 by all except one of the cell lines (UMUC3) in a dose- and time-dependent manner. This was accompanied by an increased susceptibility to lymphokine-activated killer mediated cytolysis. Anti-ICAM-1 antibodies partially inhibited the increase in cell lysis due to IFN-gamma. However, this inhibition was not complete. When effector cells were treated with antibodies to leucocyte function-associated antigen-1 (LFA-1) the inhibition of lysis was greater and ranged from 72 to 96% with a mean of 87% inhibition. These results suggest that the increased sensitivity of IFN-gamma-treated bladder cancer cell lines to LAK cells is partially attributable to the induction of ICAM-1. However, blocking of ICAM-1 with antibodies could only partially inhibit the increased LFA-1-dependent lysis. This supports recent evidence for the existence of an additional ligand for LFA-1, other than ICAM-1 and ICAM-2.