Messenger ribonucleic acid levels of steroid 5 alpha-reductase 2 in human prostate predict the enzyme activity.

Testosterone is converted to dihydrotestosterone by 5 alpha-reductase2 in the prostate. Dihydrotestosterone controls cell division, and interindividual differences in prostatic 5 alpha-reductase 2 expression and activity may be a determinant of the risk of developing prostate cancer. However, little is known about interindividual differences in intraprostatic hormonal activity in vivo. To determine whether 5 alpha-reductase-specific messenger RNA (mRNA) is predictive of 5 alpha-reductase activity in prostatic tissue, we analyzed 30 prostatic tissue specimens from 15 Caucasian patients, 47--82 yr old. The mRNA was measured by RT-PCR. Five specimens consisted of cancer, whereas the remaining 25 were derived from benign prostate hyperplasia (BPH). We found a strong association between enzyme activity at pH 5.5 and the 5 alpha-reductase 2-specific mRNA expression when expressed on the basis of beta-actin [Spearman's rank-correlation coefficient (r(s)) = 0.81; 95% confidence interval, 0.64-0.91; P < 0.0001]. The expression of 5 alpha-reductase 2-specific mRNA in the cancer specimens was significantly lower than in the BPH tissue (P = 0.03). There was no difference in the expression of 5 alpha-reductase 1-specific mRNA in the cancer specimens, compared with BPH (P = 0.56). The strong association between 5 alpha-reductase activity at pH 5.5 and the 5 alpha-reductase 2-specific mRNA expression makes it possible to predict prostatic 5 alpha-reductase activity using core needle biopsies.

Differential gene expression of steroid 5 alpha-reductase 2 in core needle biopsies from malignant and benign prostatic tissue.

Androgens are implicated in the development of prostate cancer (CAP) and benign prostate hyperplasia. The conversion of testosterone to the more potent metabolite dihydrotestosterone by prostatespecific steroid 5 alpha-reductase type 2 (5 alpha-red2) is a key mechanism in the action of androgens in the prostate and is important in the promotion and progression of prostate diseases. Manipulation of the turnover of androgens is thus fundamental in the pharmacological treatment strategy. We have developed a sensitive solution hybridization method for quantification of the gene expression of 5 alpha-red2 in core needle biopsies of the prostate. The 5 alpha-red2-specific messenger RNA (mRNA) levels were measured in 50 human prostate transrectal ultrasound-guided core biopsies obtained from 31 outpatients (median age 72, range 67-88 yr) undergoing biopsy for diagnostic purposes. Significant differences were observed in the gene expression of 5 alpha-red2 between cancerous and noncancerous tissue. In the 14 biopsies judged cancerous, the median 5 alpha-red mRNA levels were 3.5 amol/ng total RNA compared with 12.0 amol/ng total RNA in the biopsies showing no cancer (P = 0.0018). The median 5 alpha-red2 mRNA level in noncancerous tissue was thus 3.4 times higher than in the cancerous specimens.

Flow cytometric analysis of DNA content of deparaffinized nuclei in urinary bladder carcinomas. Comparison of different isolation methods and relation to histological grade and stage.

A consecutive series of 230 patients with transitional cell carcinoma of the urinary bladder was analyzed with respect to the DNA content of the primary tumor, as determined by flow cytometry on material obtained from paraffin blocks. A new method for this analysis was elaborated, based on proteolytic digestion with protease (type VII, Sigma) and density separation of the nuclei by Percoll centrifugation. The method provided DNA flow histograms with less baseline debris and a smaller coefficient of variation in the peaks than published techniques. In eight of 70 cases tested (11%) the method revealed aneuploid peaks that were not distinguished with the original technique and in 197/230 case (86%) interpretable DNA histograms were obtained. The distribution of diploid and aneuploid tumors in different grades and T categories was assessed. None of the grade 1 tumors was aneuploid; 11% of grade 2A, 63% of grade 2B and 83% of grade 3-4, respectively, were aneuploid. The corresponding figures for categories Ta, T1, T2, T3 and T4 were 16, 55, 72, 65 and 100%, respectively.

Filling defect in ureter after ileal conduit surgery.

Two cases with a filling defect in the distal part of the ureter after operation with a nippled ureteroileal anastomosis are presented. The filling defects were due to an inversion of the nipple.

Estimation of prostate cancer volume by multiple core biopsies before radical prostatectomy.

OBJECTIVES: To investigate whether tumor volume, an important prognostic factor in prostate cancer, could be estimated from the amount of cancer in multiple core biopsies. METHODS: In 80 men, transrectal ultrasound-guided biopsies were taken from focal lesions detected by ultrasound and 8 to 10 standardized positions, including sextant biopsies (apex, midmedial, base) and midlateral and transition zone biopsies. The cancer length in the biopsies was measured. After radical prostatectomy, the prostates were totally embedded, whole-mounted, and tumor volume was measured planimetrically. RESULTS: The tumor volume correlated significantly with the total cancer length of all biopsies (r = 0.56) and of the sextant biopsies (r = 0.39). It was found that midlateral and transition zone biopsies provided independent information when included in a multiple regression model with tumor volume as the dependent variable and the sextant biopsies as explanatory variables. All men (n = 6) with less than 3 mm cancer length in only one positive biopsy and a Gleason score less than 7 had a tumor volume less than 1 mL. Nine of 10 men with less than 7 mm of cancer in one positive biopsy and Gleason score less than 7 had tumors smaller than 1 mL. Sextant biopsies did not reliably predict cancer volumes less than 1 mL. CONCLUSIONS: The cancer yield of 8 to 10 biopsies correlated better with the volume of prostate cancer than sextant biopsies. This extended biopsy protocol could be used to predict cancers of less than 1 mL in volume.

Planning controlled clinical trials. Prostatic cancer.

OBJECTIVE: To address principles in the design and conduct of clinical trials on prostate cancer (PC) with special reference to localized disease. METHODS: In advance of and during the World Health Organization (WHO) conference on Prostate Cancer in Stockholm in September 1996, 6 members of a working group evaluated and reached consensus on key points for the planning and conduction of controlled clinical trials in PC. The key points discussed were 1) hypothesis formulation, 2) general methodological principles, 3) special problems of PC trials, 4) alternatives to randomization, and 5) trial organization. RESULTS: The hypothesis must be clearly formulated and also clinically relevant enough to justify the expenses (in a broad sense) of a randomized clinical trial. Patient selection, definition of endpoints, and sample size calculations must be carefully considered and correspond to the aims of the study. Stratification on important prognostic factors should be contemplated. Maintaining the accrual rate and ensuring compliance are critical for a quality study. Survival is the main endpoint and intention to treat analysis is the standard methodology. Secondary endpoints (eg, quality of life and costs) are important for the evaluation of many treatment modalities. The use of surrogate endpoints for survival, such as prostate-specific antigen (PSA) elevation, may be misleading. Surrogate endpoints require further validation. Special features, such as long natural history in localized disease and difficulties in assessing objective responses in advanced disease, need consideration in PC trials. The controlled randomized trial is the gold standard methodology. Nonrandomized trials are often hampered by severe methodological problems, such as selection bias and biased ascertainment of endpoints due to the doctor's or patient's preferences. For the organization of a successful trial, a well-constructed study protocol is essential. Good clinical practice as defined within the European Community helps define and solve practical problems. CONCLUSIONS: The past 30 years of poorly designed clinical research on PC has left us without reliable answers in key clinical issues regarding, for example, the efficacy of primary treatment of localized PC. It is a stimulating and important challenge to the urological scientific community to conduct well-organized controlled clinical trials.

The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer.

OBJECTIVES: The aim of this prospective study was to evaluate the sensitivity of the sextant biopsy protocol compared with a more extensive procedure for the detection of prostate cancer and to define a biopsy model with the minimal number of biopsies necessary to maintain diagnostic accuracy. METHODS: A total of 512 consecutive patients with suspected prostate cancer were examined with transrectal ultrasound (TRUS) and underwent TRUS-guided core biopsy. All patients had 8 or 10 standardized biopsy samples taken, with the number depending on the size of the gland. Additional biopsy samples were taken from hypoechoic or hyperechoic lesions located outside the predetermined location for the standardized biopsies (ie, target biopsies). The sensitivity of the detection of cancer for different combinations of biopsy samples was analyzed and compared with that of our model with 8 to 10 biopsies. RESULTS: In all, 276 cancers were detected, of which 88 (32%) had an isoechoic appearance. Sensitivity was 59% for focal lesions detected by TRUS, 85% to 97% for different combinations of systematic biopsy samples, and 93% to 98% for a combination of systematic and target biopsy samples. The sensitivity for the standard sextant protocol was 85%. By adding target biopsies, the sensitivity increased to 93%. CONCLUSIONS: The standard sextant protocol leaves 15% of cancers undetected compared with results obtained from a more extensive biopsy procedure. By combining systematic and target sampling, the sensitivity increases; however, a major concern is that the clinical importance of cancers detected by multiple biopsies needs to be evaluated.

Postoperative radiotherapy after prostatectomy can be associated with severe side effects.

This retrospective study was initiated to evaluate the efficacy and side effects of post-prostatectomy external beam radiation therapy (XRT) with a short time interval between surgery and irradiation in patients with prostate adenocarcinoma. Sixteen patients were investigated. The overall results in this study were 3 deaths due to recurring disease and two relapses after an average follow-up of 60 months. Severe side effects were observed. Two patients required surgical intervention due to severe post-radiotherapy side effects. The reason for this could be the high dose delivered to peripheral organs and/or a too short time interval between surgery and postoperative XRT. The results of this study confirmed that postoperative XRT can improve local control frequency in prostate carcinomas. It is recommended that the time interval between surgery and postoperative radiotherapy should to be 3-6 month.

A grading system for the immunostaining of A, B and H blood group isoantigens in bladder carcinoma.

A test system for the evaluation of ABH blood group isoantigens in bladder carcinoma was developed. A highly standardized staining technique and a set of criteria for the judgement of staining extent and intensity was used. These variables are given numerical values which are multiplied to give a score (0-12) representing a semiquantitative estimate of the ABH-antigen expression. A consecutive series of 230 patients with bladder carcinoma was analyzed, using the test. The correlation between staining scores on the one hand and the tumor grade and stage on the other was assessed. Thirty-three percent of the tumors, irrespective of grade or stage, were completely negative, whereas 15% were positive to the same extent and intensity as normal mucosa. The remaining tumors showed intermediate patterns with respect to both extent and intensity of the expression with a progressive loss of detectable antigens with increasing grade and stage. The material was categorized with respect to the staining patterns for future analysis of the influence on prognostic parameters.

Salvage cystectomy for bladder and gynaecologic cancer after irradiation failure.

From November 1981 through 1983, salvage cystectomy was performed on five men with recurrent bladder carcinoma after definitive irradiation; three of the men were 75 years or older. There were no deaths, but the complication rate was fairly high, though acceptable. Salvage cystectomy was further performed, together with radical extirpation of reproductive organs, in two women with recurrent gynaecologic malignancy and a history of local irradiation. The authors conclude that salvage cystectomy is a fairly safe procedure, even in elderly patients, relieving discomfort and probably also prolonging survival.

Perspectives on serum acid phosphatase in prostatic disease. An evaluation of two methods.

Acid phosphatase in serum was measured in 116 patients with prostatic disease, benign in 59 and malignant in 57 cases. Comparisons were made between radioimmunoassay (RIA) and an enzymatic method. The correlation coefficient between the respective values was 0.96 in patients with untreated prostatic cancer, indicating that no significant difference between results with the two methods was to be expected. The correlation coefficient between RIA values and cancer stage was 0.48, and between catalytic activity and cancer stage it was 0.50. The validity of the two methods consequently was equal. RIA, however, was the more sensitive method, giving elevated values in 10 of 11 patients with untreated stage III or stage IV prostatic cancer, as compared with only 4 of the same 11 in the enzymatic assay. This seeming paradox most probably was attributable to differing intrinsic properties of the methods when the upper limits of normal range were established. Neither RIA nor enzymatic analysis discriminated early prostatic cancer (stages I and II) from benign lesions.

Current procedures for bladder substitution and urinary diversion at King Faisal Specialist Hospital and Research Centre.

Following radical cystectomy for bladder cancer, 14 male patientts had a detubularized colic or ileocolic bladder substitute anastomosed to the membranous urethra and two female patients had urinary diversion to the valved and augmented rectum. There were no early deaths and the complication rate was low. The patients were followed for a mean of 12 months (2-28 months). During this short-term follow-up, no patients suffered deterioration of renal function or symptomatic urinary tract infection. Of the male patients, nine were perfectly continent, four had some incontinence during sleep, and one patient was incontinent day and night. Four had normal erections and three weak erections. Three have received penile implants, but it is too early to assess the need for this in the others. The two female patients were continent. Continent urinary diversion without a stoma appears to be a safe and reliable procedure, and patients should be offered one of these newer alternatives for replacement of the urinary bladder after cystectomy for cancer.

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.