Alpha 1a-adrenoceptor polymorphism: pharmacological characterization and association with benign prostatic hypertrophy.

Shibata K; Hirasawa A; Moriyama N; Kawabe K; Ogawa S; Tsujimoto G
Department of Molecular, Cell Pharmacology, National Children's Medical Research Center, Tokyo, Japan.
Br J Pharmacol (England) Jul 1996, 118 (6) p1403-8

1. Two restriction fragment length polymorphisms of the human alpha 1a-adrenoceptor gene digested with PstI restriction enzyme exist; the nucleotide change causes the substitution of C residue for T at nucleotide 1441, thereby Arg492 to Cys492 transition, which might confer an additional putative palmitoylation site in the carboxy-terminal segment of the alpha 1a-adrenoceptor. In the present study, we compared their pharmacological properties and examined whether this alpha 1a-adrenoceptor polymorphism is associated with benign prostatic hypertrophy (BPH).

2. The frequency of alpha 1a-adrenoceptor polymorphism was not differently distributed between patients with benign prostatic hypertrophy (BPH) and normal subjects in Japan; thus, the relative frequencies of the C and T alleles were 0.90 : 0.10 in normal male subjects (n = 45) and 0.87 : 0.13 in BPH patients (n = 222), respectively. However, the frequency distribution of this polymorphism was significantly different between the Japanese and U.S. populations; thus, C and T alleles were 0.34 and 0.66 in U.S. populations.

3. Utilizing Chinese hamster ovary (CHO) cells stably expressing the two polymorphic alpha 1a-adrenoceptors (Arg492 and Cys492), we compared their binding affinity and signal transduction. Radioligand binding studies with 2-[beta-(4-hydroxy-3[125I]-iodophenyl) ethylamino-methyl]tetralone ([125I]- HEAT) showed no marked difference in the antagonist or agonist binding affinities between the two receptors. Also, both receptors were found to be coupled to the calcium signaling, and the concentration-cytosolic Ca2+ concentrations ([Ca2+]i) response relationships for noradrenaline were similar for the two polymorphic receptors. Furthermore, the receptor-mediated [Ca2+]i response was markedly desensitized after a 2 h exposure of phenylephrine (10 microM), and the extent of the desensitization was not significantly different between the two receptors.

4. In summary, the results showed that the two alpha 1a-adrenoceptors generated by genetic polymorphism have similar pharmacological characteristics, and the receptor-mediated [Ca2+]i response can be desensitized in a similar manner. The study did not provide any evidence to support the hypothesis that alpha 1a-adrenoceptor gene polymorphism is associated with BPH.

[Double-blind evaluation of mepartricin 150.000 U (40 mg) compared with placebo in benign prostatic hypertrophy]

Prezioso D; Mirone V; Fabrizio F; Lotti T
Cattedra di Urologia, II Facolta di Medicina, Universita degli Studi, Napoli.
Minerva Urol Nefrol (Italy) Dec 1996, 48 (4) p207-11

The therapeutic efficacy and tolerance of a new 150,000 U (40 mg) formulation of mepartricin (to be administered once-a-day in the evening) were evaluated during a double-blind study against placebo in 2 groups of uncomplicated BPH patients treated for 60 days. The data obtained disclosed a positive pharmaco-therapeutic effect of this new formulation coupled with excellent local and systemic tolerance. At the end of trial the various objective and subjective parameters considered showed marked improvement in the group treated with mepartricin, with statistically significant differences from the placebo-treated group. The treatment efficacy was judged positive in 74-78% of cases by patients and physicians in the mepartricin group and in 36.4% of cases in the placebo group.

[Alternative treatment of benign prostatic hypertrophy]

Fiorelli C; Menghetti I; Razmjouei K; Macchiarella A; Celso M
Clinica Urologica I, Universita degli Studi, Firenze.
Minerva Urol Nefrol (Italy) Dec 1996, 48 (4) p177-82

In our study we propose to find an alternative to surgery management of IPB usable in DH regime with current instrumentation or with new technology from physics. We retrospectively reviewed techniques commonly mentioned in the literature to value benefits about cost, comfort, outcomes, and, at the same time, we stress disadvantages regarding each of these. TUI is economical, can be done in a few minutes, involves minimum bleeding, but can't be utilized in III lobe prostate and it doesn't provide material for histological tests. TUBT, feasible with light patient sedation, provides not satisfying results. Hyperthermia is necessary in selected cases. TULIP must be effected in anesthesia, needs complicated and expensive instrumentation, and it isn't practicable in III lobe prostate. Urethral stent application is expensive and not satisfactory in large size and III lobe prostate. The outcomes we obtained with TUI are similar to TUR; TUBT obtains good symptomatological results only in 20% of cases at 12 months. Hyperthermia and TULIP obtain an improvement in urinary flow rate from 20 to 60% and 50% respectively. Stent application provides good results. We think that the most modern, effective and economical alternative to the surgery of prostate adenoma is endoscopic surgery in TUI model. (19 Refs.)

Transition zone ratio and prostate-specific antigen density: the index of response of benign prostatic hypertrophy to an alpha blocker.

Kurita Y; Ushiyama T; Suzuki K; Fujita K; Kawabe K
Department of Urology, Hamamatsu University School of Medicine, Japan.
Int J Urol (Japan) Sep 1996, 3 (5) p361-6

BACKGROUND: The aim of the present study was to determine whether the indices of transrectal ultrasonography (TRUS) are related to the clinical response to tamsulosin, a long-acting selective alpha 1-blocker.

METHODS: Sixty patients with symptomatic benign prostatic hypertrophy (BPH) were treated with tamsulosin hydrochloride (0.2 mg/day) for 2 months. The findings on TRUS and uroflowmetry and the AUA symptom score before treatment were compared with those obtained at the end of the 2 month treatment period. For the indices of TRUS, transition zone (TZ) volume, transition zone ratio (TZ ratio = TZ volume/total prostate volume), total prostate volume, and prostate specific antigen density (PSAD) were calculated.

RESULTS: There was a significant correlation between the pretreatment TZ ratio and the residual urine volume (r = 0.421, P = 0.0005). Patients with a lower TZ ratio and/or PSAD responded well to the treatment. The correlation between the PSAD value and the percent change in peak urinary flow rate was statistically significant (r = -0.432, P = 0.0009).

CONCLUSION: TRUS provides simple parameters of PSAD that can be used to predict the response of patients to tamsulosin hydrochloride.

[A case of prostate cancer diagnosed one and half year after retropubic prostatectomy for benign prostatic hypertrophy]

Kato Y; Nakata S; Sato J; Mayuzumi T; Shimizu T
Department of Urology, Gunma Cancer Center.
Hinyokika Kiyo (Japan) Nov 1996, 42 (11) p907-9

A 77-year-old male patient underwent retropubic prostatectomy for benign prostatic hypertrophy. Fourteen months after operation, a hard nodule was palpated on the left lobe on digital examination. Transrectal needle biopsy was performed, and the pathological diagnosis was poorly differentiated adenocarcinoma of the prostate. It was one and half year after prostatectomy that we diagnosed prostate cancer (stage D2). (8 Refs.)

The use of alpha-adrenoceptor antagonists in the pharmacological management of benign prostatic hypertrophy: an overview.

Hieble JP; Ruffolo RR Jr
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
Pharmacol Res (England) Mar 1996, 33 (3) p145-60

Benign prostatic hypertrophy (BPH) produces symptomatic urethral obstruction in a significant percentage of older men. Since the incidence of BPH is age related, the clinical and economic impact of this disease will continue to progress as average lifespan increases. BPH is associated with growth of both glandular and stromal elements of the prostate gland. Glandular hyperplasia can be partially reversed by withdrawal of androgenic tone with androgen receptor antagonists or steroid-5-alpha-reductase inhibitors. However, the reduction in prostatic size produced by these agents has little effect on the dynamic tone induced by nerve mediated contraction of stromal smooth muscle. This tone is mediated by activation of alpha-adrenoceptors. Therefore the alpha-adrenoceptor antagonists represent a useful pharmacological approach to the treatment of BPH. Studies in isolated strips of human prostate show that either exogenous alpha-adrenoceptor agonists or electrical field stimulation will induce contraction. Studies with selective antagonists such as prazosin show that this response is mediated by the alpha 1-adrenoceptor, even though radioligand binding studies show the presence of alpha 1 and alpha 2 adrenoceptor subtypes in approximately equal density. Following the cloning of multiple alpha 1-adrenoceptors, the contractile response in human prostate has been assigned to the alpha 1A adrenoceptor. However, recent data would suggest a functional role for another subtype, which has not yet been cloned, and designated as alpha 1L based on a relatively low affinity for prazosin. Clinical trials have shown efficacy of a variety of alpha-adrenoceptor antagonists in BPH, including non-selective agents such as phenoxybenzamine, as well as a variety of selective alpha 1-adrenoceptor antagonists, most structurally related to prazosin. The agents most commonly employed at the present time include the prazosin analogs terazosin, doxazosin and alfuzosin, as well as the structurally unrelated indoramin and tamsulosin. The design of new alpha 1-antagonists for BPH has concentrated on agents producing preferential blockage of urogenital vis-a-vis vascular alpha 1-adrenoceptors, based either on selectivity for the alpha 1A-adrenoceptor subtype or on functional uroselectivity in animal models. While these newer agents offer the prospect of reducing the incidence of the cardiovascular side effects associated with current therapy their superiority over nonselective alpha 1-adrenoceptor antagonists remains to be demonstrated in the clinical setting. (158 Refs.)

Clinical application of basic arginine amidase in human male urine.

Matsuda Y; Miyashita A; Fujimoto Y; Umeda T; Akihama S
Department of Biochemistry, Meiji College of Pharmacy, Tokyo, Japan.
Biol Pharm Bull (Japan) Aug 1996, 19 (8) p1083-5

Basic human urinary arginine amidase (or esterase, called BHUAE) which is only found in male urine, was measured from normal volunteers between the age of 4 and 70 years using D-valyl-L-leucyl-L-arginine-p-nitroanilide as a substrate. BHUAE increases during early adolescence, between 8 to 17 years of age. Then, BHUAE decreases in the twenties and takes a certain range of value in the mature age group, between the late thirties and fifties. In patients with prostate cancer, a significant increase in BHUAE was demonstrated in comparison with the healthy male group (control) over 55 years old. On the other hand, patients with benign prostatic hypertrophy showed no significant elevation of this enzyme activity. It would appear that the measurement of BHUAE in urine can be used as a marker of prostate cancer in an advanced age group.

Free to total prostate-specific antigen (PSA) ratio is superior to total-PSA in differentiating benign prostate hypertrophy from prostate cancer.

Van Cangh PJ; De Nayer P; Sauvage P; Tombal B; Elsen M; Lorge F; Opsomer R; Wese FX
Department of Urology, Saint Luc University Hospital, Brussels, Belgium.
Prostate Suppl (United States) 1996, 7 p30-4

BACKGROUND: Serum prostate-specific antigen (PSA) exists in different molecular forms, and their respective concentration has been proposed as a useful tool to improve discrimination between benign prostatic hypertrophy (BPH) and prostate cancer (PC).

METHODS: The relevance of the free to total PSA ratio was prospectively studied in a selected urology clinic population of 420 patients. Total serum PSA ranged from 2.1 to 30 ng/ml; 154 had PC and 266 had BPH.

RESULTS: Receiver operating characteristic (ROC) curves were constructed for the total population (total-PSA range from 2.1 to 30 ng/ml) and for the diagnostic gray zone of 2.1-10 ng/ml. For the two groups, the free to total PSA ratio had a higher specificity than total-PSA for all sensitivity levels. Cut-off values were found to, vary with prostate weight.

CONCLUSIONS: Although free to total PSA ratio demonstrated better performances than total-PSA, its use in screening appears problematic, due to the low prevalence of prostate cancer.

Clinical study on estramustine binding protein (EMBP) in human prostate.

Shiina H; Igawa M; Ishibe T
Department of Urology, Shimane Medical University, Izumo, Japan.
Prostate (United States) Sep 1996, 29 (3) p169-76

To elucidate the characteristics of estramustine binding protein (EMBP) in human prostate, tissue EMBP concentration was examined in 42 benign prostatic hypertrophy (BPH), 34 untreated prostatic carcinoma (PC), 8 hormone refractory PC (hr-PC), as well as 13 control prostate human tissue samples by RIA using rat-EMBP antibody, and the concentration thus obtained was compared with dihydrotestosterone (DHT), prostatic acid phosphatase (PAP), prostate-specific antigen (PSA), and zinc, indices exhibiting androgen dependency in the prostate. EMBP concentration correlated significantly with DHT and PSA levels in the control prostate and BPH, but not in untreated PC. In BPH, EMBP concentration increased significantly after administration of fluoxymesterone (4 mg/day for 2 weeks), whereas it decreased significantly after estramustine phosphate (280 mg/day for 2 weeks). The EMBP/DHT ratio in moderately and poorly differentiated, and the hr-PC was significantly higher than in controls, BPH, and well-differentiated PC. In addition, untreated PC with an EMBP/DHT ratio of more than 40 showed significantly lower progression-free probability as compared with PC with an EMBP/DHT of less than 40. These results suggest that (1) EMBP in BPH and well-differentiated PC preserves androgen dependency, but not in moderately and poorly differentiated, nor in hr-PCs, indicating that EMBP is a protein different from PAP and PSA, and (2) that the tissue EMBP/DHT ratio might be useful as a marker for predicting disease progression.

Three-year followup of patients treated with lower energy microwave thermotherapy.

de Wildt MJ; D'Ancona FC; Hubregtse M; Carter SS; Debruyne FM; de la Rosette JJ
Department of Urology, Nijmegen University Hospital, The Netherlands.
J Urol (United States) Dec 1996, 156 (6) p1959-63

PURPOSE: A retrospective study was done to investigate the long-term outcome of patients treated with lower energy transurethral microwave thermotherapy.

MATERIALS AND METHODS: A total of 305 patients with lower urinary tract symptoms and benign prostatic hypertrophy underwent transurethral microwave thermotherapy according to a similar protocol at 2 centers.

RESULTS: After 3 years of followup 133 patients who had undergone transurethral microwave thermotherapy alone were available for study. During this observation period significant symptomatic improvement from baseline and an improved maximum flow rate of 2.6 ml. per second were noted. Of the patients 125 underwent invasive or medical treatment.

CONCLUSIONS: After 3 years of followup lower energy transurethral microwave thermotherapy showed significant and durable improvements in baseline parameters in 52% of the patients.

Detection of Chlamydia trachomatis in the prostate by in-situhybridization and by transmission electron microscopy.

Corradi G; Bucsek M; Panovics J; Verebelyi A; Kardos M; Kadar A; Frang D
Semmelweis University of Medicine, Budapest, Hungary.
Int J Androl (England) Apr 1996, 19 (2) p109-12

Chlamydia trachomatis infection has been investigated in the prostate gland using in-situ DNA hybridization and transmission electron microscopy. Sixty-four samples of tissue removed by trans-urethral resection or by open surgery from men with benign prostatic hypertrophy (BPH), were examined histologically and 20 of the cases were found to be positive for mononuclear cell infiltration. Some samples were then investigated using in-situ hybridization and transmission electron microscopy. Out of 20 tissue samples with mononuclear cell infiltration, nine were found to be positive for C. trachomatis infection.

Breast and prostate cancer in the relatives of men with prostate cancer.

McCahy PJ; Harris CA; Neal DE
Department of Surgery, University of Newcastle upon Tyne, UK.
Br J Urol (England) Oct 1996, 78 (4) p552-6

OBJECTIVE: To assess the risk of breast, ovarian and prostate cancer in the families of men with prostate cancer.

PATIENTS AND METHODS: A case-control study was performed by interviewing patients with prostate cancer and obtaining detailed information on family histories of cancer. Controls were hospital-based patients, of a similar age to the cases, with bladder cancer or benign prostatic hypertrophy.

RESULTS: A total of 209 cases and 322 controls were interviewed; of the cases, 22.5% had family members with a history of one or more of breast, ovarian or prostate cancers, compared with 15.2% of controls (P < 0.05). The odds ratio (OR) of having prostate cancer when there was a positive family history was 8.22 and the OR of a female relative of a patient with prostate cancer having breast cancer was 1.51. There was no apparent increased risk of ovarian or any other cancer.

CONCLUSIONS: We confirm previous reports of an increased incidence of prostate cancer in the families of men with prostate cancer and report a similarly increased incidence of breast cancer in female relatives. We suggest that detailed family histories be taken routinely and intend to analyse blood samples provided from this study for genetic abnormalities.

Effect of finasteride on free and total serum prostate-specific antigen in men with benign prostatic hyperplasia.

Matzkin H; Barak M; Braf Z
Department of Urology, Tel-Aviv University, Israel.
Br J Urol (England) Sep 1996, 78 (3) p405-8

OBJECTIVE: To examine changes in the free-to-total (f/t) serum prostate-specific antigen (PSA) ratio among men treated with finasteride for benign prostatic hypertrophy.

PATIENTS AND METHODS: Blood samples were taken from 20 men (mean age 71 years, range 61-87) before and after a minimum of 9 months of treatment with finasteride and the f/tPSA ratio determined using the Immulite assay system.

RESULTS: Although mean total and free PSA levels decreased significantly, the mean f/tPSA ratio increased only slightly and not significantly; the ratios remained unchanged in men with an initially low or high (< > 10%) ratio.

CONCLUSIONS: Concern has been expressed over the loss of the discriminatory power of serum PSA in a patient receiving treatment with finasteride. The f/tPSA ratio, currently used to help differentiate benign from malignant processes in the prostate, remains valid during treatment with finasteride; it does not affect the f/tPSA ratio.

The safety of finasteride used in benign prostatic hypertrophy: a non-interventional observational cohort study in 14,772 patients.

Wilton L; Pearce G; Edet E; Freemantle S; Stephens MD; Mann RD
Drug Safety Research Unit, Southampton, UK.
Br J Urol (England) Sep 1996, 78 (3) p379-84

OBJECTIVE: To examine the safety of finasteride as used in general medical practice to treat benign prostatic hypertrophy (BPH).

PATIENTS AND METHODS: Information was collected on 14,772 patients who were included in an observational cohort study conducted using Prescription-Event Monitoring.

RESULTS: Finasteride was reported to have been effective in 60% of the patients in whom an opinion on efficacy was recorded. Impotence or ejaculatory failure was reported in 2.1% of the patients, decreased libido in 1% and gynaecomastia and related conditions in 0.4%. Impotence was the most frequent reason for stopping treatment with finasteride and was the most commonly reported adverse reaction to the drug. Of the patients included in the elderly cohort involved in this study, 819 (5.5%) died; none of these deaths was attributed to finasteride.

CONCLUSION: Impotence or ejaculatory failure, decreased libido and gynaecomastia in a small proportion of patients were associated with the use of finasteride. The results of this study strongly suggest that this drug is acceptably safe when used in accordance with the current prescribing information.

[Transurethral thermotherapy with microwaves in patients with benign prostatic hypertrophy and urinary retention: comparative study between high energy (25) and standard energy (2.0)]

Mompo Sanchis JA; Paya Navarro JJ; Prosper Rovira F
Centro Medico Urotecno, Clinica Casa de Salud, Valencia, Espana.
Arch Esp Urol (Spain) May 1996, 49 (4) p337-46

OBJECTIVES: During a 36-month period, 63 patients with benign prostatic hypertrophy (BPH) who presented urinary retention, were treated on an outpatient basis by transurethral microwave thermotherapy (TUMT) with the Prostatron device using analgosedation.

METHODS: Treatment consisted of a single one hour session with Prostasoft 2.0 for the first group of 11 patients. The second group of 19 patients received 2 hours Prostasoft 2.0. The third group comprised of 33 patients were treated with higher energy TUMT (Prostasoft 2.5/1 h 30 min). The number of sessions (144) depended on prostate length: L < 45 mm: one session (Prostanec catheter); L < 55 mm: two sessions (additional black catheter session); L < 65 mm: three sessions (additional white catheter session).

RESULTS: In the first group of patients, 54% were catheter-free after one year (5 TURP); 84% (3 TURP) in the second group; 96% (1 TURP) in the third group. The morbidity was similar for all groups.

CONCLUSIONS: Only high energy TUMT (Prostasoft 2.5/1 h 30 min) appears to be a minimally reasonable alternative to surgery in elderly patients with urinary retention secondary to prostatism and concomitant diseases. Longer followup is warranted to determine if the beneficial effects will persist.

Detection of alpha 1-adrenoceptor subtypes in human hypertrophied prostate by insituhybridization.

Moriyama N; Kurimoto S; Horie S; Nasu K; Tanaka T; Yano K; Hirano H; Tsujimoto G; Kawabe K
Department of Urology, Faculty of Medicine, University of Tokyo, Japan.
Histochem J (England) Apr 1996, 28 (4) p283-8

Adrenergic stimulation induces contraction of hypertrophied prostatic tissue via the alpha 1 adrenoceptor, and the results of pharmacological studies suggested the existence of adrenoceptor subtypes. Recently three subtypes (alpha 1a, alpha 1b, and alpha 1d) were cloned. Using probes for these subtypes, we demonstrated their expression in the tissues of ten cases of benign prostatic hypertrophy, using in situ hybridization. To determine the ratio between these subtypes, an RNase protection assay was also performed in three cases. Expression of the alpha 1a and alpha 1d adrenoceptors was diffuse in the smooth muscles of the interstitium, but was absent in glandular epithelial cells. On the contrary, the alpha 1b adrenoceptor was hardly detectable. The RNase protection assay confirmed the absence of the alpha 1b adrenoceptor, the ratio of alpha 1a and alpha 1d being 4:1. These results supported the idea that the differences in prostatic contractile response to several adrenergic drugs are based on the affinities of these drugs for the different subtypes.

Safety profile of 3 months' therapy with alfuzosin in 13,389 patients suffering from benign prostatic hypertrophy.

Lukacs B; Blondin P; MacCarthy C; Du Boys B; Grippon P; Lassale C
Service Urologie, Hopital Tenon, Paris, France.
Eur Urol (Switzerland) 1996, 29 (1) p29-35

The safety profile of alfuzosin, a selective alpha 1-adrenergic antagonist, was assessed in a total of 13,389 patients (mean age 66.9 +/- 8.5 years) with symptomatic benign prostatic hypertrophy in two open, noncontrolled, multicentre, post-marketing surveillance studies, both conducted in France. Alfuzosin was prescribed at the recommended dose of 2.5 mg t.i.d., according to the current labelling recommendations, for a 3-month period. Clinical safety was assessed using spontaneous reporting of adverse events leading to discontinuation of treatment. Overall, 89.7% of the patients completed the treatment period. Drop outs were recorded in 10.3% of patients: 3.7% for intolerance; 1.5% for resolution of urinary symptoms; 2.1% for lack of efficacy, and 3.0% for loss to follow-up, noncompliance, and miscellaneous reasons. Two thirds of the adverse events leading to discontinuation were vasodilatory and occurred in 2.7% of the patients: vertigo/dizziness (1.4%); malaise (0.6%); hypotension (0.4%), and headache (0.4%). Other adverse events (predominantly gastrointestinal disorders) were recorded in < 1.2% of the patients. Three quarters of the adverse events occurred during the first week of therapy. As expected, adverse events were more frequent in the elderly (aged over 75 years) and in patients taking cardiovascular drugs or with concomitant cardiovascular disease. Overall, alfuzosin was very well tolerated and the adverse event profile was consistent with the cumulative experience of the drug. No unexpected or serious adverse events considered to be related to alfuzosin were recorded. Particular care must be taken when prescribing for very elderly patients and/or those with concomitant cardiovascular disease for which they are receiving therapy.

Estramustine-binding protein in carcinoma and benign hyperplasia of the human prostate.

Shiina H; Urakami S; Shirakawa H; Igawa M; Ishibe T; Usui T
Department of Urology, Shimane Medical University, Izumo, Japan.
Eur Urol (Switzerland) 1996, 29 (1) p106-10

For the purpose of elucidating whether the biological characteristics of estramustine-binding protein (EMBP) are different in benign prostatic hypertrophy (BPH) and prostatic carcinoma (PC) and also to determine the clinical value of EMBP in the tissue, the EMBP concentration in 19 patients with BPH and 26 with untreated PC was measured by means of radioimmunoassay (RIA) using an antibody raised against EMBP obtained from the rat ventral prostate and compared simultaneously with the dihydrotestosterone (DHT) level in the same tissue. The level of serum prostate-specific antigen (PSA) was also measured in these patients. The EMBP concentration was significantly correlated with the tissue DHT level in BPH and well-differentiated PC (r = 0.745, p < 0.0001), whereas it did not correlate in moderately and poorly differentiated PC (r = -0.159, p = 0.542). By comparing well-differentiated PC with moderately and poorly differentiated PC, the EMBP concentration was significantly lower in the former than in the latter two conditions (p < 0.005) in spite of the highest tissue DHT level in well-differentiated PC. The ratio of the EMBP concentration to the DHT level in moderately and poorly differentiated PC was significantly higher when compared with that observed in either BPH or well-differentiated PC (p < 0.005, respectively). However, the level of serum PSA did not reflect the histological differentiation of PC. These results suggest that: (i) the correlation of the EMBP concentration to the DHT level changed with the progression of the histological grade, and (ii) the ratio of the EMBP concentration to the DHT level in the tissue is clinically valuable in elucidating the biological potential of individual tumors.

Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family.

Su ZZ; Lin J; Shen R; Fisher PE; Goldstein NI; Fisher PB
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Proc Natl Acad Sci U S A (United States) Jul 9 1996, 93 (14) p7252-7

The selective production of monoclonal antibodies (mAbs) reacting with defined cell surface-expressed molecules is now readily accomplished with an immunological subtraction approach, surface-epitope masking (SEM). Using SEM, prostate carcinoma (Pro 1.5) mAbs have been developed that react with tumor-associated antigens expressed on human prostate cancer cell lines and patient-derived carcinomas. Screening a human LNCaP prostate cancer cDNA expression library with the Pro 1.5 mAb identifies a gene, prostate carcinoma tumor antigen-1 (PCTA-1). PCTA-1 encodes a secreted protein of approximately 35 kDa that shares approximately 40% sequence homology with the N-amino terminal region of members of the S-type galactose-binding lectin (galectin) gene family. Specific galectins are found on the surface of human and marine neoplastic cells and have been implicated in tumorigenesis and metastasis. Primer pairs within the 3' untranslated region of PCTA-1 and reverse transcription-PCR demonstrate selective expression of PCTA-1 by prostate carcinomas versus normal prostate and benign prostatic hypertrophy. These findings document the use of the SEM procedure for generating mAbs reacting with tumor-associated antigens expressed on human prostate cancers. The SEM-derived mAbs have been used for expression cloning the gene encoding this human tumor antigen. The approaches described in this paper, SEM combined with expression cloning, should prove of wide utility for developing immunological reagents specific for and identifying genes relevant to human cancer.

[The significance of free-type PSA and complex-type PSA in patients with prostatic carcinoma--the characteristics of ACS-PSA method compared with that of Delfia- and Eiken-PSA method]

Arai K; Honda M; Hosoya Y; Sumi S; Umeda H; Yoshida K
Department of Urology, Dokkyo University School of Medicine, Tochigi, Japan.
Rinsho Byori (Japan) Apr 1996, 44 (4) p345-50

We studied the clinical significance of free-type prostate specific antigen (PSA) and bound-type PSA in serum of the patients with prostatic carcinoma and benign prostatic hypertrophy. The levels of PSA, gamma-seminoprotein and prostatic acid phosphatase (PAP) in 17 healthy adult males, 20 patients with benign prostatic hypertrophy and 23 patients with prostatic carcinoma were measured by ACS-PSA, Delfia and Eiken-PSA method. The levels of PSA in serum from prostatic carcinoma patients was significantly elevated as compared with that from benign prostatic hypertrophy. Linear regression analysis of the data showed that, although overall correlations were well, different assays gave different PSA concentrations. We have studied the forms of PSA in serum by gel filtration technique and measured PSA levels in each fractions using three methods. Moreover, the characteristics of ACS-PSA method was compared with that of Delfia and Eiken-PSA method. Two peaks of PSA were detected on the elution profiles from three prostatic carcinoma patients sera. Those were estimated complex-type PSA (90kDa) and free-type PSA (30kDa). The complex-type PSA fractions detected by ACS-PSA method were almost identical with that detected by Delfia-PSA method, while free-type PSA fractions detected by ACS-PSA method were greater quantity than those by Delfia and Eiken method. Many factors were contributory to the difference between the assay kits on serum complex-type PSA and free-type PSA levels. The present results suggest that there are some quantitative differences in the immunorecognition of complex-type PSA and free-type PSA between the assay kits.

The Oxford Laser Prostate Trial: a double-blind randomized controlled trial of contact vaporization of the prostate against transurethral resection; preliminary results.

Keoghane SR; Cranston DW; Lawrence KC; Doll HA; Fellows GJ; Smith JC
Department of Urology, Churchill Hospital, University of Oxford, UK.
Br J Urol (England) Mar 1996, 77 (3) p382-5

OBJECTIVE: To compare the results of contact laser vaporization and transurethral resection of the prostate (TURP) in a double-blind randomized controlled clinical trial.

PATIENTS AND METHODS: The study comprised 148 patients with clinical benign prostatic hypertrophy (BPH) who were recruited and allocated randomly to undergo either TURP (72 patients) or laser ablation of the prostate (76 patients). The outcome was assessed using the American Urological Association (AUA -7) symptom score after 1 and 3 months as the primary measure and by urinary flow rates, haematological factors and the duration of hospital stay and length of catheterization.

RESULTS: With 90% statistical power, the results at 3 months showed no clinical or statistical difference between the treatments in change in AUA symptom score. A lower blood loss, hospital stay and duration of catheterization significantly favoured the laser treatment, although the failure rate of trial without catheter and the rate of re-operation were higher after laser treatment.

CONCLUSIONS: These early data are encouraging for this technique, although the outcome after one year requires evaluation before advocating the widespread uptake of this method.

A case-control study of cancer of the prostate in Somerset and east Devon.

Ewings P; Bowie C
Somerset Health Authority, Taunton, UK.
Br J Cancer (England) Aug 1996, 74 (4) p661-6

A case-control study in Somerset and east Devon was undertaken to investigate possible risk factors for prostatic cancer. A total of 159 cases, diagnosed at Taunton. Yeovil and Exeter hospitals between May 1989 and May 1991, were identified prospectively and interviewed with a structured questionnaire. A total of 161 men diagnosed with benign prostatic hypertrophy and 164 non-urological hospital controls were given identical questionnaires. The questionnaire covered a wide range of factors identified from previous studies, but the central hypotheses for this study related to diet (fat and green vegetables), sexual activity and farming as an occupation. This study found no association between farming and risk of prostatic cancer (odds ratio = 0.74, 95% confidence interval 0.46-1.18), nor with sexual activity as measured by number of sexual partners (chi-squared test for trend P = 0.52). A history of sexually transmitted disease was not significantly associated with prostatic cancer, but the numbers involved were very small and the odds ratio of 2.06 (0.38-11.2) is consistent with the hypothesis. A range of questions aimed at eliciting dietary fat intake produced no significant associations, although meat consumption showed increasing risk with increasing consumption (test for trend P = 0.005). Increased consumption of leafy green vegetables was associated with lower risk, but not significantly so (test for trend P = 0.16). As expected with so many factors investigated, some statistically significant associations were found, although these can only be viewed as hypothesis generating in this context. These included apparent protective effects of circumcision and high fish consumption.

Usefulness of PSA density and PSA excess in the differential diagnosis between prostate cancer and benign prostatic hypertrophy.

Diaz F; Morell M; Rojo G
Urology Department, Carlos Haya Regional Hospital, Malaga, Spain.
Int J Biol Markers (Italy) Jan-Mar 1996, 11 (1) p12-7

The usefulness of PSA density (PSAD) was evaluated in relation to the volume of the transitional zone (PSAT) and PSA excess. With this purpose we conducted a study including 27 patients diagnosed as having prostatic cancer (PC) and 46 patients with benign prostatic hypertrophy (BPH). In all of them, the PSA concentration in the serum was determined as well as the total prostatic volume and the transitional zone volume; digital rectal examination (DRE) was also performed. The major diagnostic efficacy was obtained with the excess of PSA (73%, cutoff = -13 ng/ml), followed by DRE (68%), PSAT (64%, cutoff = 0.5), PSAD (64%, cutoff = 0.2), and lastly PSA and ultrasonography (60%). Multivariate analysis (logistic regression) demonstrated PSA excess and DRE to be the best predictors. The model obtained by regression shows the best positive predictive value, and PSA excess the best negative predictive value. Consequently, PSA excess could be relevant in prostate cancer diagnosis.

[Detection of prostate cancer in urological practice: clinical establishment of serum PSA reference values by age]

Yamazaki H; Suzuki Y; Madarame A; Katoh N; Masuda F; Ohishi; Endo K
Department of Urology, Jikei Daisan Hospital, Tokyo, Japan.
Nippon Hinyokika Gakkai Zasshi (Japan) Mar 1996, 87 (3) p702-9

BACKGROUND: Determinations of serum levels of prostate specific antigen (PSA) are widely used for the detection of prostate cancer, but have not demonstrated sufficient sensitivity and specificity to be useful in urological practice. In order to enhance the diagnostic value of serum PSA, we studied the distribution of serum PSA levels by age in urological patients without clinical evidence of prostate cancer and determined clinical PSA reference values by age decades.

METHODS: The study included a total of 590 male patients aged 40 to 89 years who visited our urological clinic complaining of voiding symptoms from January 1991 to October 1994, but had no clinically evident prostate cancer. We defined patients to be without clinical evidence of prostate cancer if they had negative test results in digital rectal examination, ultrasonography, and serum PSA assay, or had positive test results in one or more of these tests but had a nonmalignant prostate biopsy. Serum PSA levels were measured by E-Test Tosoh II (AIA-PACK PA, normal range; 0 to 5.3 ng/ml). The patients were grouped by age decades and serum PSA values were given as percentiles.

RESULTS: Analyzed by Pearson's correlation coefficient, serum PSA levels were correlated significantly with patient age (r = 0.24, p < 0.001). Prostatic volume was correlated weakly but significantly with patient age (r = 0.12, p = 0.005), and PSA density was also correlated significantly with patient age (r = 0.20, p < 0.001). Thus, serum PSA levels were demonstrated to increase with advancing patient age. Factors other than benign prostatic hypertrophy were also suggested to explain the increase in serum PSA levels in older patients. With the 95th percentile for serum PSA as the upper limit, the clinical PSA reference values by age decades were determined to be 2.6 ng/ml for patients aged 40 to 49 years, 5.0 ng/ml for 50 to 59 years, 7.5 ng/ml for 60 to 69 years, 10.1 ng/ml for 70 to 79 years, and 12.4 ng/ml for 80 to 89 years.

CONCLUSION: We found a significant increase in serum PSA levels with advancing patient age. Thus, it is appropriate to have serum PSA reference values by age decades. Prospective clinical trials are necessary to define the usefulness of the PSA reference values by patient age in urological practice.

Free-to-total prostate specific antigen ratio as a single test for detection of significant stage T1c prostate cancer.

Elgamal AA; Cornillie FJ; Van Poppel HP; Van de Voorde WM; McCabe R; Baert LV
Department of Urology, University Hospitals of KU Leuven, Belgium.
J Urol (United States) Sep 1996, 156 (3) p1042-7; discussion 1047-9

PURPOSE: We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels.

MATERIALS AND METHODS: The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77% underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens.

RESULTS: Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-toal PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84% of stage T1c cancers were significant and comparable to stage T2 or greater cancers.

CONCLUSIONS: Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.

[Transurethral thermotherapy with microwaves in symptomatic prostatic benign hypertrophy: comparison between the high-energy (2.5) protocol and the standard protocol (2.0)]

Mompo Sanchis JA; Paya Navarro JJ; Prosper Rovira F
Centro Medico Urotecno, Clinica Casa de Salud, Valencia, Espana.
Arch Esp Urol (Spain) Mar 1996, 49 (2) p99-109

OBJECTIVES: The efficacy of three therapeutic protocols of transurethral microwave thermotherapy (TUMT), was compared in a study comprised of 355 patients that had been treated for benign prostatic hypertrophy (BPH) between March, 1992 and March, 1995.

METHODS: TUMT were performed with the Prostatron device with intravenous analgosedation and on an outpatient basis. In the first group (Protocol A), 122 patients received a standard treatment (Prostasoft 2.0/hour); the second group of 81 patients were included into Protocol B (Prostasoft 2.0/2 hours); 152 patients were treated with higher-energy in Protocol C (Prostasoft 2.5/1 hour). The number of sessions (635) performed were based on prostatic length: L < 45 mm - one session (Prostanec catheter); L < 55 mm - two sessions (additional black catheter session); L < 65 mm - three session (additional white catheter session).

RESULTS: All groups improved significantly for subjective symptoms (symptom score) and objective parameters (peak flow, residual urine). Comparison of the results between the three groups at 6 and 12 months showed a significantly better clinical outcome in protocol C >> B > A: Morbidity was higher in group C than in group B than in group A.

CONCLUSION: Our results indicate that transurethral microwave thermotherapy is a safe and effective procedure which improves objective and subjective parameters. Better outcomes were obtained with long session times (2H) and overall higher energy (2.5) input, which may be explained by the creation by cavities within the prostate, but at the cost of increased morbidity. However, TUMT can still be delivered as an anesthesia-free and outpatient non-surgical alternative treatment for BPH.

Two-dimensional outcome analysis as a guide for quality assurance of prostatectomy.

Cohen YC; Olmer L; Mozes B
Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Int J Qual Health Care (England) Feb 1996, 8 (1) p67-73

PURPOSE: To find outlier centers in different aspects of quality of care by comparing two different outcomes and adjusting to case mix in benign prostatic hypertrophy (BPH) patients undergoing prostatectomy.

MATERIALS AND METHODS: An observational study including 537 consecutive patients undergoing prostatectomy for BPH in three medical centers in Israel between 1991 and 1992. Data were collected from medical charts and by a structured interview. Outcomes examined included immediate surgical complications and postoperative symptom effect level. Regression analysis was employed to adjust for case mix and to determine the additional contribution of medical centers.

RESULTS: We found significant variability among centers in crude symptom effect, but not after case mix adjustment. An outlier was detected in both the crude and case mix-adjusted urological complications.

CONCLUSIONS: Centers may differ with various outcomes. This may reflect variability in different levels of performance within different aspects of the process of care in prostatectomy procedures.

Alpha blockers: a reassessment of their role in therapy.

Cauffield JS; Gums JG; Curry RW Jr
University of Florida College of Medicine, Gainesville, USA.
Am Fam Physician (United States) Jul 1996, 54 (1) p263-6

Intended for the treatment of hypertension, alpha blockers offer advantages in treating patients who also have other risk factors for coronary artery disease. Alpha blockers lower blood pressure by decreasing vascular resistance and are effective for the treatment of mild to moderate hypertension. In addition, alpha blockers have beneficial effects on lipid levels; they increase high-density lipoprotein levels and decrease total cholesterol, low-density lipoprotein and triglyceride levels. Alpha blockers do not induce glucose intolerance or hyperinsulinemia. Although they appear to decrease left ventricular mass, the clinical significance of this action is unknown. Alpha blockers are also effective for improving the symptoms of benign prostatic hypertrophy, although surgery is recommended for patients with severe symptoms. (22 Refs.)

Effect of prostatic growth factor, basic fibroblast growth factor, epidermal growth factor, and steroids on the proliferation of human fetal prostatic fibroblasts.

Luo D; Lin Y; Liu X; Qin Z; Zhao C; Zhang Y; Yu Z
Department of Biochemistry, Shandong Medical University, Jinan, People's Republic of China.
Prostate (United States) Jun 1996, 28 (6) p352-8

To study the relationship between androgen metabolism and the pathogenesis of benign prostatic hypertrophy, we purified a growth factor from benign hyperplastic tissue of human prostates and assayed the proliferative responses of human fetal prostatic fibroblasts to the purified growth factor (hPGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), dihydrotestosterone (DHT), and estradiol (E2). Prostatic tissue extracts were fractionated using heparin-Sepharose chromatography. The fraction that eluted with 1.3-1.7 M NaCl contained the majority of mitogenic activity. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS/PAGE) of the lyophilyzed active fraction showed a band at 17,000 daltons. Human prostatic fibroblasts were isolated from fetal prostate and tested for their proliferative responses to hPGF, bFGF, EGF, DHT, and E2. hPGF, as well as bFGF and EGF, did increase tritiated thymidine incorporation into the cultured fibroblasts. DHT(10(-7) M) had a significant stimulatory effect on cell growth in serum-free media after 6 days of culture. E2(10-7 M) had no effect on cell proliferation. The combination of DHT and E2 showed no synergistic effect. We conclude that our purified hPGF, bFGF, and EGF promote cell growth directly, DHT indirectly, while E2 does not. The effect of DHT appears to be mediated via the increased production and/or secretion of growth factor(s). Possibly, the bFGF-like hPGF purified from human benign hyperplastic prostatic tissue is such a mediator.

The impact of prostate-specific antigen density in predicting prostate cancer when serum prostate-specific antigen levels are less than 10 ng/ml.

Akdas A; Tarcan T; Turkeri L; Cevik I; Biren T; Ilker Y
Department of Urology, Marmara University School of Medicine, Istanbul, Turkey.
Eur Urol (Switzerland) 1996, 29 (2) p189-92

OBJECTIVE: To evaluate the impact of prostate-specific antigen density (PSAD) when serum levels of prostate-specific antigen (PSA) are less than 10 ng/ml.

METHODS: We retrospectively analyzed 134 patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsies according to Cooner's algorithm.

RESULTS: Histopathological examination revealed prostate cancer (PCa) in 22 (16%) and benign prostatic hypertrophy (BPH) in 112 (84%) patients. Five patients (23%) with PCa had PSAD < 0.15 of whom 3 had PSA < 4 ng/ml and 2 had PSA between 4 and 10 ng/ml. In the BPH group, 60 patients (54%) had PSAD below 0.15 whereas 52 patients (46%) had PSAD over 0.15. With 0.15 as the cutoff level of PSAD, the sensitivity and specificity of PSAD was found as 77 and 54%, respectively. In this patient population, PSA with the cutoff level of 4 ng/ml has sensitivity and specificity levels of 77 and 33%, respectively. According to these results, a statistically significant difference was found between PSA and PSAD only in terms of diagnostic specificity (chi-square, p < 0.05). There were 29 patients with negative digital rectal examination (DRE) and TRUS and PSA 4-10 ng/ml who underwent biopsy because of PSAD > 0.15. No cancer was detected in this group of patients, suggesting that biopsy in this subgroup may be unnecessary.

CONCLUSION: Although PSAD seemed to increase the specificity without any decrease in sensitivity in the diagnosis of prostate cancer, it did not bring any practical advantage in our selected population since all PCa cases had abnormal DRE and/or TRUS findings.

Usefulness of prostate-specific antigen density as a diagnostic test of prostate cancer.

Filella X; Alcover J; Molina R; Carrere W; Carretero P; Ballesta AM
Department of Clinical Biochemistry, (Unit Cancer Research), Hospital Clinic i Provincial, Barcelona, Spain.
Tumour Biol (Switzerland) 1996, 17 (1) p20-6

To evaluate the diagnostic usefulness of prostate-specific antigen density (PSAD) in prostate cancer (PC) prostate-specific antigen (PSA) concentrations were measured in 175 patients with benign prostatic hypertrophy (BPH) and 50 patients with PC. Patients with BPH were classified according to the presence of complications of the disease: urinary infection or the presence of a bladder catheter. PSAD levels were observed to be greater than 0.15 in 3% of the patients with uncomplicated BPH and in 40% of the patients with complicated BPH. PSA levels were higher than 10 micrograms/l in 3 and 27% of these patients, respectively. High levels of PSAD were observed in 80% of the patients with cancer. Sixty-four percent of the patients with cancer presented PSA levels greater than 10 micrograms/l. These results indicate that PSAD is a useful parameter in the differential diagnosis of PC and BPH with the diagnostic efficacy of PSAD being greater than that of the serum determination of PSA..