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.

Maximum Ki-67 staining in prostate cancer provides independent prognostic information after radical prostatectomy.

BACKGROUND: We have evaluated the prognostic value of Ki-67 growth fraction after radical prostatectomy, especially focusing on intermediate grade carcinomas. MATERIALS AND METHODS: 104 patients treated by radical prostatectomy for clinically localized prostate cancer were studied. The area of highest tumour grade was selected from the prostatectomy specimens and used for Ki-67 immunostaining The fraction of Ki-67 positive tumour nuclei in the area of most intense proliferation ("hot spot") was estimated, and related to biochemical failure. RESULTS: Ki-67 expression (median 6.7%, range 1.2-42.6%) was significantly associated with WHO histological grade. In univariate analysis of all 104 carcinomas, Ki-67 expression was associated with time to biochemical failure as were age, tumour dimension, WHO histological grade, pathological stage, positive surgical margins and pre-operative s-PSA. In multivariate Cox' analysis, Ki-67 expression, pathological stage and pre-operative s-PSA remained as independent predictors of time to biochemical failure. Ki-67 expression (HR 4.8, p < 0.001) was also found to be an independent predictor among moderately-differentiated carcinomas. CONCLUSION: Estimates of Ki-67 growth fraction in areas of highest tumour grade may prove to be a useful prognostic biomarker after radical prostatectomy.

Prognostic significance of p16 and CDK4 proteins in localized prostate carcinoma.

BACKGROUND: In prostate carcinoma, a very low frequency of point mutations of the tumor suppressor gene CDKN2/MTS1 (p16(INK4) ) has been reported, but deletions of 9p21 and inactivation by promoter methylation are observed more frequently. In the current study the authors evaluated the expression of p16 and CDK4 proteins and their prognostic significance in patients with clinically localized prostate carcinoma. METHODS: The levels of p16 and CDK4 proteins were quantitated by immunofluorescence flow cytometry, using paraffin embedded material, in 104 adenocarcinomas of the prostate after radical prostatectomy. These levels then were compared with 25 cases of benign prostate hyperplasia (BPH). RESULTS: In prostatic carcinoma specimens, p16 protein was elevated significantly compared with BPH, with a median fluorescence index (FI) of 15.4 versus 10.7, respectively (P = 0.010). This was not the case for CDK4 protein, although p16 protein expression correlated significantly with CDK4 protein expression in BPH (Spearman rank correlation [R(S)] = 0.63) and carcinoma (R(S) = 0.78). In univariate survival analysis of the first 5 years, high levels of p16 protein expression (FI > 11.7) (P = 0.005), tumor greatest dimension, World Health Organization (WHO) histologic grade, capsular penetration, seminal vesicle invasion, positive surgical margins, lymph node involvement, and preoperative serum prostate specific antigen > 20 ng/mL all were significant predictors of biochemical failure. In multivariate survival analysis, high p16 protein expression (P = 0.015), age, WHO histologic grade, capsular penetration, and seminal vesicle involvement remained as independent predictors of biochemical failure. CONCLUSIONS: These data suggest that increased expression of p16 protein, but not CDK4 protein, may be involved in the development of prostate carcinoma and may represent an independent predictor of biochemical failure after radical prostatectomy.

Independent prognostic importance of microvessel density in clinically localized prostate cancer.

BACKGROUND: Previous studies have reported a possible prognostic importance of microvessel density (MVD) in prostate cancer, although the significance after radical prostatectomy is not clear. The purpose of this study was to assess the prognostic value of MVD in clinically localized prostatic adenocarcinomas, focusing on moderately-differentiated tumours. MATERIALS AND METHODS: We examined a series of 104 patients treated for presumed organ-confined cancer in the period 1988-94. The area of highest tumour grade was selected from the prostatectomy specimens and vessels were high-lighted by staining for factor-VIII-related antigen. MVD was quantitated in the "hot spot" area and related to biochemical failure and clinical recurrence. RESULTS: In moderately differentiated tumours (WHO grade) (n = 66), MVD was associated with preoperative s-PSA and positive surgical margins. In univariate 5-year analysis, microvessel density (MVDmean > 122 mm-2, median) (p = 0.0074), s-PSA, tumour dimension, capsular penetration, seminal vesicle invasion and positive surgical margins were all significant predictors of biochemical failure, while MVDmean (p = 0.0084) was the only statistically significant predictor of clinical recurrence. In multivariate Cox' analysis, MVDmean (p = 0.0003), capsular penetration and tumour dimension remained as independent predictors of biochemical failure. CONCLUSION: Assessment of MVD in moderately differentiated prostatic adenocarcinomas may improve the prognostic stratification of patients after radical prostatectomy.

Phase II studies on prostate cancer.

OBJECTIVES: To evaluate different study designs and the general utility of phase II trials on prostate cancer. METHODS: Extensive literature studies and correspondance within the working group during 1 year were summarized in a preliminary manuscript. The manuscript was finalized at a 1 day meeting and is presented here as a consensus document. RESULTS: The main objectives of phase II studies are to assess whether a treatment is sufficiently active to justify comparative phase III studies, and to obtain further information on adverse reactions. Bidimensionally measurable lesions are traditionally studied, allowing objective criteria for response and progression to be applied. However, as skeletal metastases do not fulfill the criteria for such lesions, the majority of patients with metastatic prostate cancer are not eligible for traditionally-designed phase II trials. Therefore, ancillary response parameters, especially serum prostate-specific antigen (PSA), have been proposed for use. For the evaluation of adverse reactions, the criteria of the World Health Organization were proposed for use. A review of various statistical designs was presented, with a focus on their advantages and disadvantages in phase II trials. CONCLUSIONS: The role of PSA in phase II trials has not yet been firmly established. Further study of its correlation with other endpoints is needed. In future phase II trials, a shift to softer endpoints than traditionally used may enhance the process of evaluation of new antitumor drugs. Phase II studies may even be replaced by early phase III studies, especially in situations where new drugs do not have very heavy adverse effects.

Physical predictors of infection in patients treated with clean intermittent catheterization: a prospective 7-year study.

OBJECTIVE: To study urinary tract complications in patients treated using long-term clean intermittent catheterization (CIC), and to evaluate the physical factors which might be implicated in these complications. PATIENTS AND METHODS: During 1995, 170 patients (84 men and 86 women, mean age 56.9 years) with a mean duration of use of CIC for 8.8 years were assessed for complications related to CIC. The same patients had participated in a thorough follow-up study during 1988-9 and were examined again using questionnaires and the analysis of urine samples. CIC was practised by two-thirds of the patients because they had neurogenic bladder dysfunction and for non-neurogenic dysfunction in the remainder. RESULTS: In this prevalence study, 111 patients (65%) had no signs of clinical urinary tract infection (UTI), while 10 patients (6%) had pronounced symptoms. The remaining 29% had only minor signs of UTI. There were three predictive factors of clinical UTI: women reported more infections than men, the patients most affected by UTI in the present study were those suffering UTI during the 1988-9 study and patients with UTI had the highest mean catheterization volume now, and the highest increase in mean catheterization volume from 1989 to 1995. Bacteriuria was found in 61% of the urine samples, with Escherichia coli the dominant species among women and Gram-positive cocci among men. Patients who did not use anti-infective agents had a 31% rate of sterile urine while the corresponding value among those using antibiotics was 54%. The frequency of catheterization was the only variable predictive of bacteriuria apart from the use of antibiotics. CONCLUSION: This study confirms previous reports showing CIC to be an excellent procedure for minimizing urinary tract complications and supports the current recommendations, e.g., restricting the use of antibiotics in patients using CIC and ensuring that they catheterize sufficiently often to ensure that the mean volume of each catheterization is kept to < 400 mL in adults.

Expression of p 16 protein in prostatic adenocarcinomas, intraepithelial neoplasia, and benign/hyperplastic glands.

The tumor suppressor gene CDKN2/MTSI(p16(INK4)) may be inactivated by point mutations, deletions, or methylation in many tumor types. In prostate cancer, a very low frequency of point mutations has been reported, but deletions of 9p21 and inactivation by methylation are observed more frequently. The purpose of this study was to assess the expression pattern of the CDKN2 protein product p 16 in a series of 104 prostatic adenocarcinomas treated by radical prostatectomy, using immunohistochemical detection on archival, paraffin-embedded material. Nuclear staining was completely absent in 13 (13%) of 104 cases, whereas cytoplasmic staining was found in 99 (95%) of 104 carcinomas. Significant differences were found when comparing the staining intensity of carcinomas and coexisting prostatic intraepithelial neoplasia (PIN) with benign/hyperplastic glands. In 86 (95%) of 91 cases the overall staining intensity of carcinomas was stronger than the reactivity in benign/hyperplastic glands, which were most often weakly stained. In 71 (95%) of 75 cases the staining intensity of PIN was stronger than in benign/hyperplastic glands, a contrast also observed within single glands. However, p16 immunostaining in carcinomas was not prognostically important and it was not associated with standard clinicopathologic parameters. Our results support that CDKN2/plb is inactivated in only a small proportion of localized prostate cancers. The increased p16 staining of carcinomas/PIN in comparison with benign/hyperplastic glands suggests that p 16 protein may be involved in early stages of prostate tumorigenesis by mechanisms other than CDKN2/p16 gene inactivation, and the possibility of using p(16) immunostaining as a marker for PIN is discussed.

[Interstitial laser coagulation in the treatment of benign prostatic hyperplasia. Preliminary results]. / Interstitiell laserkoagulasjon ved behandling av benign prostatahyperplasi. Preliminaere erfaringer.

51 patients aged 68 (range 52-81) years with lower urinary tract symptoms compatible with obstruction from benign prostatic hyperplasia were treated with interstitial laser coagulation (ILC). Postoperative urinary retention lasting less than one week was seen in the majority of cases. All patients were followed up for three months and ten cases had further follow-up after one year. Three months after treatment the international prostate symptom score decreased from 23.3 +/- 0.7 to 8.9 +/- 0.8 and was 10.2 +/- 2.1 after one year. Peak urinary flow increased concomitantly from 8.3 +/- 0.4 to 12.2 +/- 0.7 at three months and was 11.5 +/- 1.4 ml/sec after one year. Three patients received other, additional treatment because the ILC-treatment failed. In conclusion, interstitial laser coagulation had marked effects on symptoms, whereas the effects on objective parameters were less pronounced in this selected group of patients. However, more extensive follow-up, is essential for further evaluation of this new treatment procedure.

Follow-up after torsion of the spermatic cord.

Fifty-two patients were examined 4-10 1/2 years after operation for torsion of the spermatic cord. The testicular salvage rate was 56%. Loss of testicular tissue was correlated to preoperative duration of symptoms. Serum testosterone concentration was found to be within the reference range. FSH was elevated in patients with the longest duration of symptoms (> 24 h), suggesting an impairment of testicular function in these patients. There were two our of 13 patients with a severe oligo-azoospermia, both had a previous orchiopexy for undescended contralateral testis.

[Prostate-specific membrane antigen. A new sensitive molecular indicator in metastasizing prostatic cancer]. / Prostataspesifikt membranantigen. Ny sensitiv molekylaer indikator ved metastaserende cancer prostatae.

Prostate cancer is the most common malignant disease in men in western societies. Extracapsular spread of carcinoma is found in approximately half of the patients that are treated by radical prostatectomy. Recently, a new prostate-specific membrane glycoprotein was cloned and sequenced. A highly sensitive and specific nested reverse transcriptase polymerase chain reaction has been developed to detect early occult haematogeneous micrometastatic prostate cells. We analysed venous samples from 17 patients with metastatic prostate cancer using a modified reaction assay. This showed presence of micrometastatic prostate cells in 14 patients. Molecular detection of circulating prostatic epithelial cells could improve clinical staging and treatment of early prostate cancer.

Ureteroscopy in pregnancy.

PURPOSE: We report our experience with ureteroscopy in pregnancy. MATERIALS AND METHODS: From 1984 to 1994, 24 pregnant women with lasting symptoms of ureteral obstruction underwent diagnostic and therapeutic ureteroscopy. Most of the women were in the second or third trimester of gestation. RESULTS: A rigid ureteroscope was introduced easily to the upper third of the ureter or into the renal pelvis in all patients. Ureteral calculi were extracted in 13 cases. There were no serious complications. CONCLUSIONS: Ureteroscopy is a safe procedure that may be used to diagnose and extract obstructing ureteral calculi during pregnancy when conservative measures fails.

Imaging in the diagnosis and assessment of prognosis in localized prostate cancer. Consensus Conference on Diagnosis and Prognostic Parameters in Localized Prostate Cancer. Stockholm, Sweden, May 12-13, 1993.

As part of a WHO consensus conference on diagnosis and prognostic parameters in localized prostate cancer, a working group of experts discussed the role of various modern imaging techniques. Special attention was focused on transrectal ultrasound (TRUS) in combination with biopsies, magnetic resonance imaging (MRI) using endorectal coil and recent advances in these techniques. Some experimental techniques, especially hormone receptor scintigraphy and positron emission tomography were also discussed and new results were presented. We concluded that MRI seems to be superior to other imaging techniques in the preoperative assessment of local tumor stage. TRUS defends its place in the diagnostic armament; it is easily combined with multiple biopsies, the results of which are important in the assessment of the biological aggressiveness of prostate cancer. The present development in the field of nuclear medicine may result in techniques for in vivo characterization of tumors and will most certainly have important implications for diagnosis of prostate cancer in the future.

Staging of early prostate cancer: a proposed tumor volume-based prognostic index.

Current staging of early prostate cancer separates patients into two groups: those with palpable and non-palpable tumors. Such staging relies on digital rectal examination in making this separation, despite the low sensitivity, low specificity, and low positive predictive value of this method. As an alternative, tumor volume may be useful for staging because of its powerful prognostic ability and its potential to be assessed clinically due to recent advances in imaging techniques such as transrectal ultrasound. In this study, we evaluate the utility of tumor volume in predicting progression of early prostate cancer based on the composite published evidence from nine pathologic studies of serially-sectioned prostates. Logistic regression revealed that tumor volume was a good positive predictor of all measures of tumor progression. There was a 10 percent probability of capsular invasion in tumors measuring about 0.5 cm3; 10 percent probability of seminal vesicle invasion in tumors measuring about 4.0 cm3; and 10 percent probability of metastases in tumors measuring about 5.0 cm3. These composite results suggest that tumor volume is a significant predictor of cancer progression. A volume-based prognostic index is proposed as an adjunct to staging for early prostate cancer.

Clean intermittent catheterisation-performing abilities, aversive experiences and distress.

A total of 407 patients participated in a one year follow up study concerning their personal experiences and attitudes towards clean intermittent catheterisation (CIC). Most patients (90%) were able to perform CIC themselves, approximately 70% having no problems with the procedure. However, one third of the patients experienced CIC as aversive with significantly higher distress scores on the general health questionnaire (GHQ-28). Aversion and distress were more often reported by younger patients and females, and by patients with non neuropathic bladders. The patients' physical disabilities and their length of previous CIC experiences did not seem to influence the feelings of aversion. These findings demonstrate the importance of considering the psychological implications of CIC, and the emotional needs of these patients in order to improve compliance and quality of life.

Physical complications in patients treated with clean intermittent catheterization.

To characterize and quantify complications related to clean intermittent catheterization (CIC) 302 out-patients were followed for a mean period of 13 months. The main problems were minor bleeding in connection with the procedure and infections. Except for two patients with recurrent strictures, no serious urethral complications were detected. One or more episodes of cystopyelitis were experienced by 5.6% of the patients. Long term major problems of infectious origin affected only 2.6% while 24.5% had no signs of clinical infection during the follow-up period. UTI was more frequent in young patients, women, and men with supranuclear affection. Eight patients suffered from bladder stones and 1 patient from epididymitis. No serious radiological changes were detected in the upper urinary tract. No association was found between reported problems and changes in the patients' general condition, physical disability and length of previous CIC experience.

Clinical background of patients treated with clean intermittent catheterization in Norway.

This study reports on the use of clean intermittent catheterization (CIC) in Norway in 1988/89. A total of 407 adult out-patients was studied. CIC was used in all age-groups and equally in both sex. The patients were divided into five diagnostic groups. There were twice as many patients suffering from neurogenic diseases as non-neurogenic ones. A neurourological index was constructed based on neurological examination and urodynamic data giving a good differentiation and expression of the bladder affection. It appeared that CIC could be performed even by highly disabled persons. A statistically significant correlation was found between the neuro-urological results in patients with decompensated bladder and their over all disability.