The effect of bicalutamide on prostate histology.

BACKGROUND: Nonsteroidal antiandrogens are commonly used in the treatment of prostate cancer, but more clinical and laboratory studies on patients with benign as well as malignant prostate diseases are required to define their exact role. METHODS: Light microscopic examination of perineal prostate biopsies of 21 men with BPH was performed pretreatment, after 24 weeks of therapy with 50 mg bicalutamide (Casodex) or placebo and 24 weeks after end of treatment. We assessed whether it was possible to distinguish between patients having received bicalutamide or placebo based on a general histological examination. In addition, the volume fractions of the prostatic epithelial, luminal, and stromal compartments were determined by morphometry. RESULTS: Histological changes following treatment were uncharacteristic and patients treated with bicalutamide were not identified. At morphometry prior to therapy, the prostates of the study participants consisted of 91.8% stroma (range 78.9-97.2), 5.5% epithelium (range 1.4-14.1) and 2.7% glandular lumen (range 0.8-7.5). Changes in the relative content of the three tissue components following treatment were not statistically significant. CONCLUSIONS: We did not observe consistent morphological changes in the prostate following treatment with bicalutamide at a dose of 50 mg daily. However, this dose is lower than the 150 mg dose presently recommended for bicalutamide monotherapy.

No randomised trial of prostate-cancer screening in Norway.

The Norwegian Urological Cancer Group (NUCG) decided against participating in the European Randomised Study on Screening for Prostate Cancer, to which they had planned to contribute data from a population of 75 000 men aged between 50 and 65. The plan was abandonned for three main reasons: Norwegian doubts about the statistical power of the trial, the possible ethical implications of screening a large number of men with no symptoms, and the belief that the trial would not produce clinically important results. In this review, the NUCG's reasons for not participating in the trial are discussed in full.

Effects of bicalutamide and leuprolide on prostate-specific antigen (PSA), acid phosphatase (ACP) and prostatic acid phosphatase (PAP) in men with benign prostatic hyperplasia (BPH).

The effects of the nonsteroidal antiandrogen bicalutamide (Casodex(TM)) and the luteinizing hormone releasing hormone agonist leuprolide depot (Procren Depot(TM), Lupron Depot(TM)) on serum prostate-specific antigen (PSA), acid phosphatase (ACP), and prostatic acid phosphatase (PAP) in patients with benign prostatic hyperplasia (BPH) were determined. Thirty patients with BPH were randomised to receive bicalutamide 50 mg orally once daily or a placebo for 24 weeks, followed by 24 weeks of follow-up (bicalutamide study). In another study 55 men were randomised between 3.75 mg leuprolide depot intramuscularly at every 28 days for 24 weeks or placebo injections (leuprolide study). In both studies blood sampling was performed at baseline, at week 12 at week 24 and 24 weeks after the end of therapy. Androgen suppression with bicalutamide 50 mg daily for 24 weeks resulted in a median of 56% reduction of PSA (P<0.001 when compared to placebo). Acid phosphatase and PAP did not change. Leuprolide resulted in a median of 87% reduction of serum PSA (P<0.001) and a 39% reduction of PAP (P=0.023), whereas ACP was unchanged. Both bicalutamide and leuprolide induced a pronounced decline in serum PSA in BPH patients. The studies suggest a stronger androgen suppressive effect of leuprolide than of bicalutamide, but this difference might largely be due to too low a dosage of bicalutamide. ACP and PAP were relatively insensitive to androgen suppression. Our study suggests a different degree of androgen suppression on PSA originating from benign tissue versus cancer tissue, and that the direction of this discrepancy might be different for various androgen suppressive regimens.Prostate Cancer and Prostatic Diseases (2001) 4, 173-177.

[Treatment of renal carcinoma with distant metastases]. / Behandling av nyrekreft med fjernmetastaser.

BACKGROUND: There is no effective standard therapy for patients with distant metastases from renal cell carcinoma. Physicians should, however, know about the different treatment options and their efficacy in order to adequately inform and treat their patients. MATERIAL AND METHODS: Current relevant literature and experience at the Norwegian Radium Hospital are reviewed with emphasis on systemic therapy. RESULTS: Nephrectomy is indicated if the aim is to palliate or prevent local symptoms due to a large primary tumour, or if the operation renders a patient eligible for a clinical trial. Local symptoms due to metastatic lesions should be managed surgically or by radiotherapy. Hormone treatment and current chemotherapy are ineffective. In selected patients interferon-alpha (IFN-alpha) results in an approximately 15% response rate and 4-6 months' prolongation of life. Combination therapy with interleukins or with other drugs is experimental. INTERPRETATION: Patients with metastatic renal cell carcinoma should primarily be included in clinical trials. If this is not possible, interferon-alpha monotherapy represents today's standard systemic treatment, to be offered to selected and informed patients.

Prognostic factors in patients with metastatic (stage D2) prostate cancer: experience from the Scandinavian Prostatic Cancer Group Study-2.

PURPOSE: Nuclear texture reflects the overall structures of the chromatin organization. We recently reported the principles and prognostic importance of image analysis of nuclei from metastatic prostate cancer. Immunohistochemical up regulation of the adhesion molecule sialyl Lewis(x) is also reported to be a prognostic parameter. Presently we analyzed statistically the prognostic impact of these 2 new parameters compared to well-known clinical parameters in metastatic prostate cancer. MATERIALS AND METHODS: Prognostic factors, such as sedimentation rate, alkaline and acid phosphatases, hemoglobin, testosterone, performance status, pain due to metastasis, T category, histological grade and patient age, were included in a multivariate Cox proportional hazards regression analysis based on 262 patients from the Scandinavian Prostatic Cancer Group Study-2. Extent of bone lesions, deoxyribonucleic acid ploidy, texture analysis and sialyl Lewis(x) molecules based on subsets of these 262 patients were also analyzed in the same multivariate model. RESULTS: This test identified chromatin texture as the most important factor (p < 0.001), followed by reaction of the oligosaccharide sialyl Lewis(x) (p < 0.01). Among the routine clinical and laboratory data, sedimentation rate, alkaline phosphatase and hemoglobin (p < 0.05) showed prognostic importance. Performance status, pain due to metastasis and extent of bone lesions showed prognostic value in the univariate analysis (p < 0.05). CONCLUSIONS: These data indicate that computerized nuclear texture analysis as well as up regulation of sialyl Lewis(x) molecules may be new important prognostic factors in metastatic prostate cancer. Furthermore the prognostic importance of sedimentation rate, alkaline phosphatase and hemoglobin was confirmed.

[Urosepsis]. / Urosepsis.

Septicemia as a result of urinary infection is a serious condition, almost always caused by gram-negative bacteria. The bacterial toxins have a profound influence on haemostasis, microcirculation, and cardiac anf respiratory function. This article contains a brief review of aetiology, pathogenesis, pathophysiology, diagnostic work-up and treatment of this life-threatening condition. As soon as specimens from urine and blood are sent for bacteriological examination, intravenous antibiotics are given. It is essential that free drainage of urine from both kidneys is established by means of a bladder catheter, retrograde catheterization or percutaneous nephrostomy. The development of septic shock is a life-threatening condition which should be treated in an intensive care unit with continuous monitoring of vital parameters.

Treatment of benign prostatic hyperplasia. A pharmacoeconomic perspective.

Men with moderate symptoms of benign prostatic hyperplasia (BPH) are the best candidates for medical treatment, while surgery is usually indicated for patients with severe symptoms. Men with mild symptoms do not usually need treatment, but they might be re-evaluated annually if desirable. Finasteride, which produces selective hormonal deprivation, is now established as a well tolerated drug for the long term medical therapy of BPH. Recent studies suggest that finasteride is most effective in men with large prostates (> 40 ml), and the drug should probably be reserved for these patients. alpha-Blockers work in men with small or large prostates, and their rapid onset of action facilitates the identification of responders. alpha-Blockers are more effective than finasteride during the first year of treatment, but only finasteride induces regression of the prostate and offers increased efficacy over time. Even if drug therapy reduces the need for prostate surgery, the total economic cost of BPH treatment is likely to rise because of the increasing application of medical treatment. The magnitude of this increase depends largely on what percentage of the male population embark on long term therapy, at what age treatment is started, and how successful it is. At present, the answers to these questions are largely unknown. The personal economic expenses for men who begin long term medical therapy will probably be an important factor in deciding how common drug treatment for BPH will become in the future. For many men, the main benefit of drug treatment will be the relief of urinary symptoms, but whether this improvement is substantial enough to improve their overall quality of life has not yet been clearly demonstrated in controlled studies.

[Maximal androgen blockade in metastatic prostatic carcinoma]. / Maksimal androgenblokade ved metastaserende carcinoma prostatae.

In Norway the standard treatment for metastatic prostatic cancer has been surgical or medical castration. Only recently have antiandrogens been approved for treatment of advanced cancer of the prostate. The authors examine the principles for total or maximal androgen blockade and discuss American and European studies that indicate an improvement in survival as a result of maximal androgen blockade therapy in patients with low volume disease and good performance. Though not yet statistically proven in prospective trials, it is recommended that such patients should be given maximal androgen blockade therapy, also in Norway.

[Treatment of benign prostatic hyperplasia with Proscar (finasteride). Results of a 10-year Scandinavian study]. / Behandling av benign prostatahyperplasi med Proscar (finasterid). Resultater av en toårig skandinavisk undersøkelse.

707 patients with moderate prostatic hyperplasia were recruited to a two-year Scandinavian multicenter study. The study was randomized, prospective and double-blind. Half of the patients were treated with finasteride (5 mg daily) and the controls were given placebo. The patients were monitored with regard to symptoms, urinary flow rate and prostate volume. In addition, various laboratory examinations were performed. A statistically significant difference was found between the groups with regard to symptom improvement and increase in urinary flow rate in favour of finasteride. Finasteride reduced prostate volume and stopped further growth, leading to a difference of 30% in prostate volume between the two groups after two years of treatment. Thus, finasteride was able to stop the continuous growth of the prostate in the elderly male. The proportion of patients with adverse clinical experiences was similar in both treatment groups. However, the finasteride-treated group contained more patients with sexual dysfunction. We conclude that finasteride is an alternative to vigilant waiting for patients with moderate symptoms of benign prostatic hyperplasia.

[Diagnosis and treatment of benign prostatic hyperplasia in general practice. Norwegian Medical Society]. / Utredning og behandling av benign prostatahyperplasi i allmennpraksis.

The prevalence of benign prostatic hyperplasia increases with increasing age. The growing number of elderly men in the population will cause a marked increase in the number of men suffering from this condition. The magnitude of the problem necessitates close cooperation between urologists and general practitioners in future in order to take care of patients with benign prostatic hyperplasia. The purpose of the present survey is to present guidelines for general practitioners to enable them to diagnose this condition and to present the various alternative treatments currently available. Patients with mild and modest symptoms do not need to be referred to an urologist and can be taken care of by the general practitioners themselves.

[Finanseride in symtomatic benign prostatic hyeprtrophy. A 2-year placebo-controlled study]. / Finasterid ved symptomgivende benign prostatahypertrofi. Et toårs placebokontrolleret studie. Skandinaviske BPH-Studiegruppe.

The efficacy and safety of treatment with finasteride 5 mg daily for 24 months was assessed in this multicentre double blind placebo-controlled study including 707 patients with moderately symptomatic benign prostatic hyperplasia. Efficacy parameters were changes in voiding- and bladder storage symptoms assessed by a validated symptom score, changes in maximum urinary flow rate and changes in the prostate volume. In the finasteride patients, symptom score improved during the whole study with a significant difference between active treatment and placebo after 24 months (p < 0.01). Maximum flow rate increased in finasteride treated patients resulting in a difference between these and the placebo treated patients of 1.8 ml/s after 24 months (p < 0.01). Prostate volume was reduced by 19% in the finasteride treated patients versus an increase of 12% in the placebo treated patient group (p < 0.01). Finasteride was well tolerated. Patients receiving placebo progressed in symptoms after 16 months. Finasteride can halt the natural progression of moderately symptomatic BPH over a 24 month period.

A randomized prospective study comparing long-term intravesical instillations of mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma.

PURPOSE: We compared the efficacy and toxicity of long-term mitomycin C versus bacillus Calmette-Guerin (BCG) instillation in patients at high risk for recurrence and progression of superficial bladder carcinoma. MATERIALS AND METHODS: Our randomized comparison study included 261 patients with primary dysplasia, or stage Tis, stage T1, grade 3 and multiple recurrent stage Ta/T1, grade 1 or 2 disease. Mitomycin C (40 mg.) or Pasteur strain BCG (120 mg.) was instilled weekly for 6 weeks, then monthly for up to 1 year and every 3 months during year 2. RESULTS: After a median followup of 39 months 49% of the patients given BCG and 34% given mitomycin C were disease-free (p < 0.03), compared to 48 and 35%, respectively, of those with stage Ta or T1 disease, and 54 and 33%, respectively, of those with dysplasia or stage Tis tumor. Tumor progressed in 13% of patients, with no statistically significant difference observed regarding progression between the mitomycin C and BCG groups. Side effects were more common after BCG instillation, with 5 cases of severe side effects compared to 1 in the mitomycin C group. Treatment was stopped due to toxicity in 10% of the patients. CONCLUSIONS: The majority of patients tolerated long-term intravesical therapy well. BCG instillation was hampered by more frequent side effects. BCG was superior regarding recurrence prophylaxis, since patients given BCG had fewer recurrences and a significantly longer time to treatment failure compared to those treated with mitomycin C. No statistically significant difference was observed regarding progression.

Effects on the endocrine system of long-term treatment with the luteinizing hormone-releasing hormone agonist leuprolide in patients with benign prostatic hyperplasia.

Hormonal changes resulting from long-term use of the luteinizing hormone-releasing hormone agonist leuprolide depot were studied in a randomized placebo-controlled study comprising 50 evaluable patients with benign prostatic hyperplasia (BPH). A total of 26 patients received 3.75 mg leuprolide depot intramuscularly every 28 days for 24 weeks and 24 received a placebo. The patients were followed up for a further 24-week period. Serum concentrations of luteinizing hormone decreased by 90% and follicle-stimulating hormone by 55% during the treatment period. Mean testosterone levels decreased by 96% to 0.7 nmol l-1 and dihydrotestosterone decreased by 90%. The adrenal androgens androstenedione and dehydroepiandrosterone sulphate decreased by 48 and 24%, respectively. In most patients, estradiol decreased to non-detectable values, while the decrease in estrone was 35%. There was no change in prolactin and sex hormone-binding globulin as compared to the placebo group. Hormonal changes were reversible, but the suppression of testicular hormone production was not completely normalized in all patients 24 weeks after discontinuation of the treatment.

Entropy-based texture analysis of chromatin structure in advanced prostate cancer.

A new texture operator, gray-level entropy matrix (GLEM), was developed, and nine new textural features were extracted from this matrix. These textural features were applied to light microscopy images of nuclei taken from monolayers of advanced prostate cancer cells representing two different prognostic groups: hormone-sensitive (good prognosis) and hormone-resistant (poor prognosis) tumors. A comparison between the classification results obtained from GLEM features and those obtained from standard textural estimators is also discussed. Single features that gave correct classification rates better than 65% were included in a discriminant analysis in order to find the optimal set of features to discriminate between the two prognostic groups in the training data set. The best combination of features includes three GLEM features together with ENTROPY extracted from gray-level cooccurrence matrix, and this combination gave a correct classification rate of 95% using the leaving-one-out technique. The influences of image sharpness and number of cells were also investigated. The features based on entropy or degree of scatter of minute structures can be used to discriminate between hormone-sensitive and hormone-resistant prostate carcinomas.

Nuclear texture analysis: a new prognostic tool in metastatic prostate cancer.

This report describes the prognostic value of computerized nuclear texture analysis in metastatic prostate cancer. Seventy-seven patients with histologically verified prostate carcinomas and skeletal metastases were selected from a Scandinavian multicenter study (SPCG-2). Thirty-six therapy-resistant patients experienced objective progression and cancer-related death within 2 years after orchiectomy. Thirty patients responded well to orchiectomy, i.e., showed objective disease remission and no signs of progression during 3 years of follow-up. From this data set, 10 randomly chosen therapy-resistant and 10 randomly chosen therapy-sensitive carcinomas were used in our previous study to find the optimal combination of features that can discriminate between the two groups (Yogesan et al.: Cytometry 24:268-276, 1996). In addition to these two groups, 11 patients experienced stable disease or disease remission during the first year and a secondary progression during the second or third year of follow-up, with subsequent cancer-related death. Traditional clinical prognostic factors such as histopathological grading and serum markers could not discriminate between these groups of patients. Therefore, image analysis techniques based on texture analysis have been utilized in this study of prognosis of prostate cancer. Feulgen-stained monolayers of nuclei were prepared from paraffin-embedded material taken from the primary tumor before endocrine ablation. Four different textural features were selected from the training data set to calculate the discriminating function. This function separated the therapy-sensitive and the therapy-resistant patients with 87% accuracy in the independent data set. This study demonstrates that it is possible to predict tumor progression and survival for endocrine-ablated metastatic prostate carcinomas using computerized nuclear texture analysis on light microscopy images from prostate biopsies taken at the time of diagnosis.

Randomised study of Casodex 50 MG monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group.

The effect of Casodex (ICI 176,334), a new, once-daily, selective antiandrogen, given as 50 mg monotherapy, was compared with orchidectomy in a randomised, multicentre, open study in 376 patients with metastatic prostate cancer. At 3 months, PSA was reduced by 86% in the Casodex group and by 96% in the orchidectomy group. Treatment failed in 51 patients in the orchidectomy group and 66 showed a subjective response. Treatment failed in 86 patients treated with Casodex and 40 patients showed a subjective response. Patients treated with Casodex maintained their sexual interest better than those in the orchidectomy group. Median survival was significantly longer in the orchidectomy group. Casodex was well-tolerated. The most likely reason for the differences between the groups regarding time to treatment failure and survival is that the dose of Casodex was too small. Further studies with higher doses of Casodex are in progress.

Scanning electron microscopy of the accessory sex glands of the adult male rat.

This study describes the morphology of the accessory sex glands of the adult male rat as observed by scanning electron microscopy (SEM). The purpose was to obtain a systematic and comparative SEM description of these glands and to evaluate different preparation techniques. A common morphological feature is polyhedral delineation of the cells, which exhibited a variable convexity of their apical surface. The cell apices were more or less studded with microvilli. Nevertheless, it was possible to distinguish the glands by their surface morphology. In the ventral prostate, there was a considerable heterogeneity in cell surface appearance. The lateral lobe had a characteristic brush border, and in the dorsal lobe, surface blebbing and intracellular cisternae were observed. The cells of the seminal vesicle were covered by long microvilli, while particularly distinct, elevated cell borders and intracellular cisternae were typical for the coagulating gland. The secretory mechanism was merocrine in the ventral and lateral prostate and the seminal vesicle, and was mainly apocrine in the dorsal prostate. Surprisingly, only merocrine secretion was obvious in the coagulating gland. The most controversial observation, which needs further investigation, was the discovery of large orifices in the apical surface of individual seminal vesicle cells. These orifices may be indicative of an additional apocrine secretion in this gland. In studying this organ system, SEM provides information that adds to previous transmission electron microscopical investigations.