Biomedical subjects
Publications and source records attributed to B J Norlén.
Two patients with the rare entity of arterio-ureteral fistula are presented. Both highlight the predisposing factors of radiation, major surgery in the region, history of vascular surgery and presence of double-J-stent. Both patients presented with the clinical sign of intermittent gross hematuria. Both patients were successfully treated by endovascular intervention using graft covered stent.
BACKGROUND: The expression of cytochrome P450 (CYP)-dependent mono-oxygenases in the prostate is important, as it will determine the rate of activation of potential carcinogens as well as the metabolism of hormones with implications in diseases of the prostate. In addition, the levels of cytochromes P450 in prostatic tumours may well be determinants of the outcome of therapy involving P450 substrates such as anti-androgens. METHODS: The gene expression of 12 different CYP genes was measured by reverse transcription-polymerase chain reaction (RT-PCR) in a total of 28 human prostatic tumour and nontumour samples. RESULTS: Intriguingly, a large number of CYP mRNAs were detected in the prostate samples, including CYP1A2, -1B1, -2C19, -2D6, -3A4, -3A5, -3A7 and -4B1. CYP1B1 was consistently expressed and CYP3A5 and CYP4B1 were expressed in a majority of the samples tested. CONCLUSIONS: These data demonstrate a wide range of CYP genes being expressed in the prostate. The relative importance of these enzymes in the pathogenesis and treatment of prostatic disease remains an important theme for further study.
OBJECTIVE: To evaluate the accuracy of Gleason grading of prostate cancer in multiple core biopsies, compared with the final Gleason score of total prostatectomy specimens, and to investigate whether the prediction of the correct Gleason score is improved by increasing the number of biopsies. PATIENTS AND METHODS: Before total prostatectomy, 121 men had a mean (range) of 10.0 (8-14) transrectal ultrasonography (TRUS)-guided core biopsies taken from the apex, mid-medial, mid-lateral and basal regions, from the transition zone and from lesions detected on TRUS. The biopsies and prostatectomy specimens were reviewed and the Gleason scores assessed. RESULTS: The preoperative biopsies predicted the prostatectomy Gleason score exactly in 45.5% of the patients and within one Gleason score in 93.4%. The biopsies under-graded the prostate cancer in 38.8% and overgraded it in 15.7%. The weighted kappa value for exact agreement was 0.502. If one biopsy was positive for cancer, the prostatectomy Gleason score was predicted correctly in 43.8% and within one score in 93.8%, compared with 53.8% and 92.3%, respectively, if cancer was found in at least seven biopsies. If the mid-lateral and transition zone biopsies had been excluded from the biopsy protocol, 5% of the cancers would have been undetected. Among the remaining 115 cancers, grading accuracy only improved from 43.5% to 45.2% by adding biopsies to the sextant protocol. CONCLUSION: Despite a statistically significant agreement between biopsy and prostatectomy Gleason score, under-grading remains a major problem. The prediction of the prostatectomy Gleason score is only marginally improved by increasing the number of biopsies.
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.
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PURPOSE: We report the 5-year followup of a randomized comparison of mitomycin C and bacillus Calmette-Guerin (BCG) in patients with superficial bladder carcinoma. Recurrence, progression and survival rates, crossover results, prognostic factors and long-term side effects were analyzed. MATERIALS AND METHODS: A total of 261 patients were enrolled in the study, and the inclusion criteria were primary Tis, dysplasia G2, T1 G3 and multiple recurrent Ta/T1 G1-2 disease. Intravesical instillations of 40 mg. mitomycin C and 120 mg. Pasteur BCG, Danish strain 1331, were given for 2 years. RESULTS: After a median followup of 64 months 101 of the 250 evaluable patients (42%) were disease-free. A significant difference was noted in disease-free survival with BCG (p = 0.04), which was most pronounced for stage Tis disease. No difference in tumor progression, or crude or corrected survival was found between the 2 arms. Crossover treatment was successful in 39% of patients with second line BCG and 19% with second line mitomycin C. Independent risk factors for progression were initial p53 status and stage. Only the completion of treatment was predictive of outcome for patients treated with BCG. Bladder shrinkage occurred in 2.4% of patients. CONCLUSIONS: Therapy with BCG was superior to mitomycin C for recurrence prophylaxis but no difference was found for progression and survival.
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.
OBJECTIVE: Radical retropubic prostatectomy (RRP) involves removal of the bladder neck where the proximal urethral sphincter is located. Assuming that this sphincter participates in urinary continence mechanisms, removal of this sphincter might increase the interference pattern in the distal urethral sphincter as a compensatory mechanism. MATERIAL AND METHODS: We examined the distal (striated) urethral sphincter before and after surgery with quantitative EMG techniques in ten patients. RESULTS: No compensatory activity was demonstrated, but tendencies towards a decreased number of turns at rest (41 pre-op/27 post-op) and an increased mean amplitude at maximal activation (334 microV pre-op/408 microV post-op) in the interference pattern in the muscle were recorded using the turns/amplitude (T/A) analysis. The fibre density was 1.71 before and 1.96 after surgery (p = 0.08), indicating a peripheral nerve lesion. CONCLUSIONS: The numerical reduction of turns during rest can be explained by disturbed feedback, indicating that not only efferent, but also sensory afferent nerve fibres can be involved in an iatrogen lesion during prostatic surgery. The increased mean amplitude at maximal activation was probably due to reinnervated motor units with increased amplitudes.
The study aimed at assessing alterations in muscular activity in the external urethral sphincter when the internal sphincter located at the bladder neck was resected during TUR-P, and at determining whether activity in the external urethral sphincter increased to compensate for the loss of the internal sphincter. Perineal muscles were examined with quantitative EMG recordings, including interference pattern and fiber density before and after surgery. Fiber density increased in the external urethral sphincter after surgery. This indicates a reinnervation in the muscle, probably due to a peripheral nerve lesion that occurs during TUR-P, and may also explain the reduction in penile erectibility observed after surgery. The lack of compensatory activity in the external urethral sphincter expressed as unchanged number of turns may be explained as a disturbed feedback mechanism and a decreased central activation or to the lithotomy position at examination. The internal part of the external sphincter not available for measurement may compensate for the loss in bladder-neck sphincter function.
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.
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.
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.
The role of prostate-specific antigen in the management of prostatic adenocarcinoma is still not fully ascertained. Its place in the monitoring of patients who have undergone radical treatment is without question but its role in the primary assessment of a lesion is a point of continuous discussion. This study reports the analysis of prostate-specific antigen (PSA) in 92 patients with different stages of prostatic adenocarcinoma prior to treatment; in the case of the localized lesions, this was based to a great extent on the findings at lymphadenectomy. Apart from PSA analysis, deoxythymidine kinase (dTK) analyses were also performed in an attempt to discover whether the latter could provide additional information about the tumor load in the different patient categories, viz. those with lymph node involvement (group 1), those with lymph node involvement but without distant metastases (group 2), and those with disseminated disease (group 3). The median PSA and dTK values in groups 1-3 were 6.5 micrograms/L and 2.7 U/microliter, 16 micrograms/L and 2.6 U/microL, and 90 micrograms/L and 7.8 U/microL, respectively. If the two analyses were used concomitantly, they could differentiate true localized disease from metastatic in approximately 92% of cases. The combination should prove of value in the primary assessment of a patient with a newly diagnosed prostatic adenocarcinoma.
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.
Telephone interviews concerning urinary continence and sexual potency in 152 men who had undergone radical prostatectomy for localized cancer were conducted by an investigator who had not been involved in the patients' treatment. The obtained data were compared with the surgeons' recorded follow-up notes. Continence was defined according to ICS criteria and potency as the capacity for vaginal penetration. At the interviews, 74 men (49%) reported total continence and 39 others (26%) were acceptably dry; 32 required more than two small protective pads per day, five had received an artificial sphincter implant and two had supravesical urinary diversion (Kock pouch), making 39 (25%) classified as incontinent. The surgeons' records, however, showed an 89% continence rate and 87% of these men had regained continence within 24 weeks of the operation. Of 134 preoperatively potent men, only 21 (14%) remained potent in the first postoperative year. That earlier reported excellent results regarding continence and potency were not reproduced in our study, possible was partly due to our inclusion of more advanced tumours in somewhat older patients, but the fact that the interviewer was independent of the surgeon significantly influenced the results.
The formation of urinary calculi following renal transplantation is a rare event with a frequency of less than 1% (4). Although 133 cases were described up to 1988, only 5 of these had pure uric acid stones (3). We report a case in which an excessive purine-rich diet probably caused the stone formation. Three modalities of treatment were used, percutaneous nephrolithotripsy, shock wave lithotripsy (ESWL) and chemolysis.
PURPOSE: We attempt to elucidate the performance of serum prostate specific antigen (PSA) as a screening test for prostate cancer. MATERIALS AND METHODS: We analyzed sera stored since 1980 in a nested case-control study. RESULTS: The 36 patients with prostate cancer had a markedly greater mean serum PSA level than did 68 subjects without cancer (22.71 versus 2.67, respectively, p < 0.0001). Among the controls 24% had a serum PSA of greater than 4.0 micrograms/l. A serum PSA value exceeding 4.0 micrograms/l. in 1980 was associated with a 20-fold excess risk of cancer between 1981 and 1986, and an 8-fold risk between 1987 and 1991. CONCLUSIONS: Diagnosis of clinically significant prostate cancer can be advanced substantially by serum PSA testing. However, the large number of high serum PSA values in men who remained free of clinical disease emphasizes the need for a more specific screening test.
The serological results from apparently healthy individuals and prostate cancer patients were evaluated with a new assay called TPAcyk ELISA. This assay has a biochemical specificity for fragments of cytokeratins 8 and 18, and exhibits a low within- and between-assay imprecision. The data indicate a significant difference between the results of males and females, but no significant age-dependent relation was found. The cut-off value (95% specificity) for healthy individuals was estimated to be 1.27 ng/mL (n = 190) for males and 0.95 ng/mL (n = 81) for females. When using a cut-off value of 1.27 ng/mL, we found a sensitivity for prostate cancer patients with T2-3 N0M0 of about 20%. For patients with metastatic disease, a sensitivity of 75% was found. A higher sensitivity was obtained with patient sera analyzed with PSA than with TPAcyk, particularly in patients with early stages of the disease. We conclude that the results from this new TPAcyk assay were significantly elevated in patients initially diagnosed with poorly differentiated tumors, that patients with localized tumors exhibited low concentrations, and that patients with metastatic disease showed, on average, 8 times higher concentrations than patients with localized disease. The combination of the TPAcyk and PSA results increased the sensitivity for prostate cancer, particularly in patients with metastatic disease.