A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer. First report from the Scandinavian Prostatic Cancer Group Study No. 6.

OBJECTIVES: To assess the efficacy and tolerability of bicalutamide 150 mg ('Casodex'(1)) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with early (T1b-T4, any N, M0) prostate cancer. METHODS: This randomised, double-blind study was conducted in the Nordic countries as part of the 'Casodex' Early Prostate Cancer programme. Patients received bicalutamide 150 mg (n=607) or placebo (n=611) in addition to standard care. RESULTS: More than 80% of patients had not received therapy of primary curative intent. Median follow-up in both groups was 3 years. Median exposure to study treatment in the bicalutamide and standard care alone groups was 2.5 and 2.3 years, respectively. Bicalutamide reduced the risk of objective disease progression by 57% compared with standard care alone (HR 0.43; 95% CI 0.34, 0.55; p<<0.0001). Survival data were immature (11.4% deaths) with no difference between the two treatment groups. CONCLUSIONS: Bicalutamide 150 mg as immediate therapy, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with early prostate cancer. The trial is ongoing to assess whether the reduction in risk of objective progression translates into an overall survival benefit.

The TMPRSS2 gene encoding transmembrane serine protease is overexpressed in a majority of prostate cancer patients: detection of mutated TMPRSS2 form in a case of aggressive disease.

The serine protease TMPRSS2 gene expression was studied by in situ hybridization using benign prostatic hyperplasia and prostate cancer tissue samples from 32 patients. Expression of TMPRSS2 gene was higher in cancer cells than that in benign cells in 84% of the specimens containing both benign and malignant tissues. The TMPRSS2 mRNA level was significantly increased in poorly differentiated (p = 0.014, n = 7) and untreated (p = 0.022, n = 13) primary prostate adenocarcinomas compared to benign tissues. In addition, androgen-deprivation therapy significantly decreased the expression of TMPRSS2 in benign prostate tissue (p = 0.07), which is in accordance with the androgen-inducible expression of the gene. The gene copy number of TMPRSS2, analyzed by competitively differential PCR, was duplicated in the malignant cells of about 38% of the prostate cancer patients analyzed. Thus, the increase in the gene copy number is probably not the primary reason for the detected overexpression of the TMPRSS2 gene. Mutations in the TMPRSS2 gene were screened using DNA isolated from paraffin-embedded prostate cancer tissues from 9 patients with aggressive prostate cancer and from 9 patients with nonaggressive disease. Thirteen exons covering the coding region were checked using enzymatic mutation detection and direct sequencing. One patient with aggressive prostate cancer carried a deletion and a stop codon in exon 11, leading to inactivation of the serine protease domain in TMPRSS2.

Fears, sexual disturbances and personality features in men with prostatitis: a population-based cross-sectional study in Finland.

OBJECTIVE: To determine the occurrence of mental distress related to prostatitis in Finnish men. SUBJECTS AND METHODS: A population-based cross-sectional survey was conducted of 2500 men aged 20--59 years living in the two northernmost provinces of Finland (Oulu and Lapland). The final response rate was 75% (1832 men). RESULTS: The fear of undetected prostate cancer was reported by 17% of the men in the population who had had prostatitis, a value significantly higher (P < 0.001) than in healthy men. Fears of having a sexually transmitted disease and suicidal thinking were also slightly more common. The men who had had prostatitis preferred to be alone in a public toilet during voiding (58% vs 44%, P < 0.001). Erectile dysfunction was reported by 43% of the men with symptomatic prostatitis and decreased libido by 24%. Self-assessment of personality, adjusted for age, showed that the men with prostatitis were more often busy and nervous than the healthy controls (P < 0.001), and that they had a more meticulous attitude to life and its problems. Marital difficulties were reported by 17% of the men who had had prostatitis at some point in their lives, and 4% were convinced that their illness had caused their divorce. Socio-economic status and social well-being had no apparent influence on the occurrence of prostatitis. CONCLUSIONS: This survey showed that psychological stress is common in men with prostatitis. Urologists and general practitioners should consider that a consultation with a psychiatrist may be appropriate for selected men with prostatitis.

Surgical organ perfusion method for gene transfer into cells of the perifollicular area of the spleen: an experimental trial on farm pigs.

In an attempt to develop a gene therapy method for splenic and systemic diseases, an evaluation was made of surgical methods for gene transfer into porcine spleen. We have developed a continuous closed-circuit organ perfusion method for gene transfer into porcine spleen. For gene transfer, we used a type-5 replication defective adenovirus vector expressing the E. coli beta-galactosidase gene as a reporter gene. In eight young 22-35 kg farm pigs, the spleen was perfused in vivo with the viral solution via laparotomy, for 30 or 60 min. Gene transfer was determined visually on histological cryosections after X-gal and PAS staining. Infusion of the viral solution through the splenic artery did not result in gene expression. Perfusion of spleen in vivo resulted in beta-galactosidase reporter gene expression in the macrophages located around capillaries terminating in the perifollicular zone and in the red pulp examined after four days. The present results suggest that the surgically performed spleen perfusion method can be used for gene transfer in the treatment of diseases having splenic manifestations and in systemic diseases.

Analysis of false-positive BTA STAT test results in patients followed up for bladder cancer.

OBJECTIVES: To evaluate the role of a positive BTA stat Test result in patients with negative cystoscopic findings. METHODS: Five hundred one consecutive patients in follow-up for bladder cancer were studied. A voided urine sample was obtained before cystoscopy and split for culture, cytology, and BTA stat testing. In the case of a positive BTA stat Test, but negative cystoscopic findings, patients underwent additional investigations. RESULTS: Of 501 patients, 133 (26.5%) had bladder cancer recurrence at cystoscopy, of which the BTA stat Test detected 71 (53.4%); only 21 of the cases (17.9%) were detected by cytologic examination. Of the remaining 368 patients with no visible tumor at cystoscopy, 96 (26.1%) had a positive BTA stat Test result. Fifty-five of those (57.3%) underwent intravenous urography or renal ultrasound and random biopsies, and an additional 9 recurrences (16.4%) were detected. Of those 46 patients who had a true false-positive BTA stat Test, 3 (3 of 43, 7.0%) had recurrence at the next follow-up cystoscopy, 4 (8.7%) had a urine infection, and 8 (17.4%) had ongoing intravesical instillations; the latter two percentages were significantly higher than among those with true-negative BTA stat Test results (0% and 6.8%, respectively). CONCLUSIONS: Patients with a positive BTA stat Test result but negative cystoscopic findings have about a 16% risk of an undetected recurrence. False-positive results may be due to present instillation treatment and urine infection, and the predictive value of a BTA stat Test for subsequent recurrence seems relatively low.

Closed-circuit organ perfusion technique for gene transfer into the lungs. An experimental trial on farm pigs.

In an attempt to develop gene therapy for lung diseases, we have explored a closed-circuit surgical perfusion method for gene transfer into the lung. For gene transfer we used a replication defective type 5 adenovirus carrying the E. coli beta-galactosidase gene as a reporter gene. The middle lobe of the right lung of eight young farm pigs was perfused in vivo via thoracotomy for up to 60 min with the viral solution. The gene transfer was performed using a closed-circuit organ perfusion method in vivo. The efficiency of gene transfer was assessed visually by analysis of histologic sections after X-gal, PAS and immunohistochemical stainings. The lung perfusion resulted in transgene expression in the alveolar epithelial cells, capillary endothelial cells, airway epithelial cells and alveolar macrophages of the lung examined seven days after perfusion. The present results suggest that operatively performed closed-circuit warm lung perfusion method may be used for gene transfer in treatment of diseases that have pulmonary manifestations.

Treatment of renal cysts with single-session percutaneous drainage and ethanol sclerotherapy: long-term outcome.

OBJECTIVES: To evaluate the safety, efficacy, and long-term outcome of single-session ethanol sclerotherapy for non-neoplastic renal cysts. METHODS: In a prospective study, 32 patients with a simple renal cyst were treated with ultrasound-guided percutaneous aspiration, and no more than 100 mL sterile 99% ethanol was injected into the cyst. The procedure was performed under local anesthesia, and the patients were hospitalized overnight. The serum concentrations of alcohol immediately after the sclerotherapy and 1 hour later and the corresponding urine concentrations were measured. The mean follow-up period was 55 months (range 12 to 156). Control checkups were scheduled at 1, 3, 6, 9, and 12 months after the sclerotherapy. During the control visits, the patients underwent ultrasound measurement of the size of the cyst. The history concerning renal pain especially was evaluated by the urologist. The patients were asked if they did or did not have pain. The severity of pain was not evaluated. RESULTS: Sclerotherapy with ethanol was performed successfully in all 32 patients with a simple renal cyst. The cyst disappeared completely in 7 patients (22%). The mean size of all cysts decreased from 7.8 cm (range 3 to 16) to 1.7 cm (range 0 to 9; P <0.0001). Before the sclerotherapy, 24 patients had symptoms due to the cyst, and 18 of these (75%) were asymptomatic after the ethanol sclerotherapy. In 2 patients the pain decreased, 2 patients were without change, and in 2 patients the pain increased. There was no correlation between the size of the cyst and the intensity of pain. No major complications occurred. The serum concentration of alcohol varied from 0 to 0.30 g/L and that in urine from 0.04 to 0.27 g/L. CONCLUSIONS: Percutaneous aspiration and sclerotherapy with ethanol for simple renal cysts is simple, fast, safe, effective, and inexpensive. The results are comparable to those reported earlier. The treatment is without major complications. We propose sclerotherapy with 99% ethanol as the primary treatment of simple renal cyst. The treatment can be done in an outpatient clinic.

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy.

BACKGROUND: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. METHODS: Reproductive endocrine function was evaluated in 90 men taking VPA (n = 21), CBZ (n = 40), or OXC (n = 29) as monotherapy for epilepsy and in 25 healthy control men. RESULTS: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormone-binding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (< 900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose > or = 900 mg. CONCLUSIONS: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not.

Prostatic tissue pressure measurement as a possible diagnostic procedure in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome.

Forty-two patients with chronic nonbacterial prostatitis (CNP) and twelve men without any urological complaints or history underwent intraprostatic tissue pressure measurement with a Stryker intracompartmental pressure monitor device. The pressures were measured under spinal anesthesia in connection with various surgical procedures. Tissue pressure was monitored at 10, 60 and 120 s after an injection of 1 ml saline. Significantly (P < 0.001) higher intraprostatic pressure values were registered at all the three time points in the patients with CNP compared to the controls. Our study shows that patients with CNP have elevated intraprostatic tissue pressures, probably reflecting increased tissue resistance and a poor tissue microcirculation status. It seems that this method can be used as a diagnostic tool to differentiate between various causes of chronic pelvic pain in the male. The aim is to develop further this method so that it is also suitable for outpatient use.

Epidemiology of prostatitis in Finnish men: a population-based cross-sectional study.

OBJECTIVE: To study the lifetime occurrence of prostatitis in Finnish men and their exposure to the disease. Subjects and methods A population-based cross-sectional survey was conducted in the two most northerly provinces of Finland (Oulu and Lapland). Altogether, 2500 male residents aged 20-59 years were chosen at random to complete a questionnaire on prostatitis. The data were collected between June 1996 and October 1997. Replies were received from 1832 men, giving a response rate of 75%. RESULTS: The overall lifetime prevalence of prostatitis was 14.2%. The risk of having or having had prostatitis increased with age, being 1.7 times greater in men aged 40-49 years than in those aged 20-39 years, and 3.1 times greater in those aged 50-59 years. The overall incidence was 37.8/10 000 person years. More than a quarter of the 261 men who had or had had prostatitis symptoms (27%) suffered from them at least once a year, while 16% suffered from persistent symptoms; 63% of the men with prostatitis had their worst symptoms during the winter (November-March). Neither education nor profession had much influence on the occurrence of prostatitis, but divorced and single men had a lower risk than married men. Most patients felt they had not received enough information about the disease at their first visit to a general practitioner. CONCLUSIONS: The results of this survey showed that the occurrence of prostatitis symptoms in men living in northern Finland is higher than that reported in other parts of the world. This could be partly caused by the cold climate.

Prostatic expression of human 5alpha-reductase type 2 during finasteride therapy: a randomized, double-blind, placebo-controlled study.

This study was aimed at exploring the effect of finasteride, a non-steroidal competitive inhibitor of the enzyme 5alpha-reductase, on 5alpha-reductase type 2 at the mRNA level in human prostate, using an in situ hybridization technique. After randomization, 10 men with benign prostatic hyperplasia (BPH) received oral finasteride (5 mg daily) and five men with BPH received placebo daily. Careful clinical examination was carried out and 2 biopsy samples were taken transrectally before the treatment and after 3, 6, and 12 months of treatment. In situ hybridization was carried out and expression of 5alpha-reductase type 2 mRNA was measured. The results showed that finasteride treatment had no permanent effect on expression of 5alpha-reductase type 2 in prostatic epithelium, compared with placebo treatment. Expression varied during treatment, but there was no clear tendency in this expression. The signal was localized in the epithelial cells. We conclude that finasteride treatment had no clear effect on human 5alpha-reductase type 2 expression in the prostate.

Increased intraprostatic pressure in patients with chronic prostatitis.

The purpose of this prospective study was to develop a method for measuring intraprostatic pressure. Intraprostatic, extraprostatic and perineal subcutaneous pressures were measured in 43 patients. Twenty-four patients had chronic nonbacterial prostatitis (CNP) and prostatic hyperplasia (group A), 10 patients had benign prostatic hyperplasia (BPH) (group B) and 9 patients served as controls (group C). The pressure measurements were performed with a Stryker pressure monitor under transrectal ultrasonographic control at three different points: perineal subcutaneous tissue, paraprostatic tissue and the apex of the prostate beneath the capsule. Significantly higher intraprostatic pressure values (P < 0.001) were recorded in the patients with CNP compared with the BPH patients or the controls. We conclude that this novel method of measuring intraprostatic pressure, which has not been reported earlier, could be a new tool in the diagnosis of CNP and in the evaluation of the therapeutic effects of the different treatment modalities used in CNP.

Three independently deleted regions at chromosome arm 16q in human prostate cancer: allelic loss at 16q24.1-q24.2 is associated with aggressive behaviour of the disease, recurrent growth, poor differentiation of the tumour and poor prognosis for the patient.

Loss of heterozygosity at chromosome arm 16q is a frequent event in human prostate cancer. In this study, loss of heterozygosity at 16q was studied in 44 prostate cancer patients exhibiting various clinical features. Fifteen polymorphic polymerase chain reaction (PCR) markers were used to identify the separately deleted areas and the findings were compared with clinicopathological variables and 5-year survival of the patients. The results indicated that there are at least three independently deleted regions at 16q. Allelic losses at the central and distal areas were associated significantly with aggressive behaviour of the disease (16q24.1-q24.2, P < 0.01, and 16q24.3-qter, P < 0.05), and the central area of deletion was further significantly associated with poorly differentiated tumour cells (P < 0.05) and with recurrent (P < 0.01) growth of the tumour. During the follow-up period, 28% of the patients initially with M0 disease developed distant metastases. Of the patients showing allelic loss at 16q24.1-q24.2, distant metastasis were found in 45% during the 5-year follow-up period, and 31% of the patients showing loss at 16q21.1 also developed distant metastases. After the 5-year follow-up period, 14 (32%) of the patients remained alive, whereas 19 (43%) had died because of their prostate cancer. The overall survival rate of the patients showing allelic loss at 16q21.1 or 16q24.1-q24.2 was significantly lower than that of the patients with retained heterozygosity.

A novel surgical organ perfusion method for effective ex vivo and in vivo gene transfer into renal glomerular cells.

In an attempt to develop gene therapy for Alport syndrome, we have evaluated surgical methods for gene transfer into pig kidneys. For gene transfer we used an adenovirus expressing the Escherichia coli beta-galactosidase gene as a reporter gene. The viral preparation was first infused in vivo into the porcine renal artery. Then explanted kidneys were perfused ex vivo at body temperature for 12 hours with the viral solution and, finally the kidney perfusions were carried out in vivo via laparotomy for 60 and 120 minutes. Gene transfer was determined visually on histological cryosections after 5-bromo-4-chloro-3-indoyl-beta-galactopyranoside (X-gal) and periodic acid-Schiff (PAS) staining. Perfusion of whole porcine kidneys ex vivo resulted in strong expression in about 80% of glomeruli. The in vivo kidney perfusion via laparotomy for 120 minutes resulted in reporter gene expression of about 75% of the glomeruli examined after 4 days. Expression was observed almost exclusively in glomeruli, while little if any expression was found in other renal structures. The present results suggest that operatively performed kidney perfusion may be used for gene transfer in treatment of glomerular disease. This surgical approach may also prove useful for somatic gene therapy of other organs.

Transurethral resection with perioperative instilation on interferon-alpha or epirubicin for the prophylaxis of recurrent primary superficial bladder cancer: a prospective randomized multicenter study--Finnbladder III.

PURPOSE: We evaluated the efficacy of single dose of interferon or epirubicin administered immediately after transurethral resection compared with transurethral resection only on the recurrence of primary (not recurrent) superficial bladder cancer. MATERIALS AND METHODS: A total of 283 patients with stages Ta to T1 primary superficial, grades 1 to 3 bladder cancer was randomized into study groups 1-transurethral resection only, 2-transurethral resection plus 50 million units interferon-a2b and 3-transurethral resection plus 100 mg. epirubicin. Eligible for final analysis were 200 patients, including 66 in group 1, 66 in group 2 and 68 in group 3. Patients were followed with cystoscopy every 3 months for 2 years or until the initial recurrence. RESULTS: Group 3 had the most favorable outcome, since 45 of the 68 patients (66%) were without recurrence after 2 years compared to 24 of the 66 (37%) in group 2 and 26 of the 66 (40%) in group 1 (log rank test p <0.001). Side effects were mostly mild and transient, and no differences were found among the groups. CONCLUSIONS: A single 100 mg. dose of epirubicin given intravesically immediately after transurethral resection is safe, and significantly decreases the recurrence of primary superficial bladder cancer. A 50 million unit dose of interferon-alpha2b is well tolerated but it has no effect on recurrence as a single dose. The long-term effect of this treatment remains to be studied.

Effects of finasteride in patients with inflammatory chronic pelvic pain syndrome: a double-blind, placebo-controlled, pilot study.

OBJECTIVES: To investigate whether treatment of inflammatory chronic pelvic pain syndrome (ICPPS) with finasteride has any influence on symptoms associated with ICPPS. METHODS: Forty-one patients with ICPPS were randomized (1:3) to treatment with either placebo (25%, n = 10) or finasteride 5 mg daily (75%, n = 31 ) for 1 2 months. Efficacy was evaluated by analysis of symptomatic improvement through responses to symptom questionnaires, pain evaluation on an analytical visual scale, analgesic use as reported in patient diaries, urine flow and residual volume, and prostate volume. RESULTS: Prostatitis Symptom Severity Index and prostatism scores dropped significantly in patients in the finasteride group (P < 0.001 and P < 0.05, respectively). There were no statistically significant differences in pain between the groups. There were significant differences in the changes of prostate volume and in serum prostate-specific antigen concentrations between the finasteride and placebo groups (P < 0.03 and P < 0.02, respectively). The groups did not differ with regard to side effects. CONCLUSIONS: Our results indicate that finasteride has an effect in ICPPS. The mechanisms by which finasteride works in these patients are unclear and could not be solved in this pilot study, which had relatively few patients. A further trial with larger numbers is required to confirm these results.

Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction.

In a three-year follow-up study of 69 patients found that erectile dysfunction (ED) impairs many elderly men's life: up to 25% of the men aged 65 y and 80% of those aged 75 y suffer from erectile dysfunction. The most effective non-surgical treatment of ED is intracavernosal pharmacotherapy, and the most common vasoactive agent currently used is prostaglandin E1 (PGE1). The purpose of this study was to assess the long-term outcome of PGE1 treatment and the patients' overall satisfaction with their sexual life. Sixty-nine patients who had started ICI therapy three years earlier were invited to a control examination. The mean age of the patients was 60.5 y. The patients filled in a questionnaire, which included questions about the use of PGE1 treatment at home. All the patients evaluated their own satisfaction with their erection, ejaculation, orgasm and libido on a visual analytical scale (VAS, 0-100%). A clinical examination was made, and the penile shaft was examined by ultrasonography. Erection with the home dose of PGE1 was estimated by Rigiscan, and the degree of erection was also estimated clinically (grades 0-5) by a doctor. The most common doses of PGE1 used at home were between 10 and 20 m (58%), 46.4% of the patients had discontinued PGE1 therapy, the mean time of using PGE1 was 23.3 months. The mean coital frequency with PGE1 was 2.8 times per month. 34.8% of the patients (24 out of 69) reported that their own spontaneous erections had improved after the beginning of PGE1 therapy. The most common problem was hematomas in 10.1% of the patients (7 out of 69), which, however, were small and did not cause discontinuation of the therapy. There were three instances of priapism (4.3%), and four patients (5.8%) had fibrosis in ultrasonography. The patients' satisfaction with their erection at home was 67.3% with PGE1. The mean coital frequency with PGE1 therapy was quite low, 2.8 times per month, even though the patients' mean age was only 60.5 y, one reason may be the high price of PGE1 injections. The rate of improvement of spontaneous erections while using PGE1 was quite high, accounting for 34.8% of the patients. Most of the patients who discontinued the PGE1 therapy had a psychogenic etiology. There were no systemic side-effects with PGE1. Only 7.2% of the patients had prolonged pain after the injection, leading to drug discontinuation. It can be concluded that treatment with intracavernous injections of PGE1 is well tolerated and involves only minor problems. The patients' satisfaction with their erections at home with PGE1 therapy was good. Precise determination of the home dose of PGE1 and the teaching of the technique of injection are important at the beginning of this treatment modality.