Prostate cancer screening within a prostate specific antigen range of 3 to 3.9 ng./ml.: a comparison of digital rectal examination and free prostate specific antigen as supplemental screening tests.

PURPOSE: Performing biopsy in all men with a serum prostate specific antigen (PSA) of 3 to 3.9 ng./ml. increases the sensitivity of prostate cancer screening compared with a PSA cutoff of 4 ng./ml. but decreases specificity and may contribute to over diagnosis. Therefore, we evaluated the detection rate and specificity attributable to digital rectal examination and percent free PSA within the PSA range of 3 to 3.9 ng./ml. MATERIALS AND METHODS: Serum PSA was determined in 20,716 participants in the Finnish population based screening trial. Supplementary digital rectal examination was offered to men with a PSA of 3 to 3.9 ng./ml. during 1996 to 1998 (protocol 1). Those with a suspicious digital rectal examination finding were referred for biopsy. The screening algorithm was modified by substituting percent free PSA for digital rectal examination with a cutoff of 16% as a biopsy criterion in 1999 (protocol 2). In addition, biopsies were performed in all men with PSA 4 ng./ml. or greater. RESULTS: A total of 23 cancers (2.9%) were detected by digital rectal examination among 801 men, while percent-free PSA resulted in the diagnosis of 13 cases (4.8%) among 270 men with a PSA of 3 to 3.9 ng./ml. The detection rate of tumors with a Gleason score of 5 or greater increased from 1.6% (13 of 801 cases) to 4.4% (12 of 270) in the modified screening program. The PSA cutoff of 3 ng./ml. alone showed 88.6% and 87.5% specificity in protocols 1 and 2 but specificity increased to 93.3% and 91.7% using digital rectal examination and percent free PSA, respectively. CONCLUSIONS: Using percent free PSA increased the detection rate of aggressive disease compared with digital rectal examination and provided higher specificity than PSA alone.

Prostatic MR imaging. Accuracy in differentiating cancer from other prostatic disorders.

PURPOSE: We assessed the accuracy of MR imaging in differentiating between cancer and other prostatic disorders, and evaluated the diagnostic criteria for various prostatic diseases. MATERIAL AND METHODS: A total of 74 endorectal coil MR studies were performed on 72 patients. Twenty patients had prostatic cancer, 20 benign prostatic hyperplasia (BPH), 4 acute bacterial prostatitis, 5 chronic bacterial prostatitis (2 also belonging to the previous category), 19 chronic non-bacterial prostatitis/chronic pelvic pain syndrome, and 6 were symptomless voluntary controls. All studies were interpreted by two experienced radiologists in random order. Radiologists were blinded to all clinical data including the age of the patients. Based on MR findings, both radiologists filled in a form covering diagnostic criteria and diagnosis. RESULTS: Accuracy in diagnosing prostate cancer was 74%. Sensitivity was 50% and specificity 83%, and positive and negative predictive values were 53 and 82%, respectively. Bacterial prostatitis showed some features similar to carcinoma. Abundant BPH rendered cancer detection more difficult. No diagnostic criterion was clearly better than the others. Interobserver agreement on the MR diagnosis ranged from moderate to good. CONCLUSION: Without knowledge of accurate clinical data, MR seems to be too insensitive in detecting prostate cancer to be used as a primary diagnostic tool.

Endorectal magnetic resonance imaging of prostatic cancer: comparison between fat-suppressed T2-weighted fast spin echo and three-dimensional dual-echo, steady-state sequences.

The aim of this study was to develop an endorectal MRI strategy for prostatic cancer. We evaluated the MR images from 44 consecutive prostatic cancer patients treated by radical prostatectomy. Each sequence from every examination was assessed separately with a specific tumor map drawn. Tumor localization, capsular penetration, and seminal vesicle invasion were marked on maps on the basis of T2 and DESS (dual-echo steady-state) sequences. Thirty patients also had T1-weighted images, and these were assessed with regard to possible tumor outgrowth. The maps were compared with histopathological findings from radical prostatectomy specimens. According to our study, DESS equaled T2 in every respect. No statistically significant differences between the sequences were found with respect to detecting either tumor localization, outgrowth, or seminal vesicle invasion. DESS is a potential new sequence in prostatic MRI as it has been proven to parallel the routinely used T2-weighted imaging.

Optimal timing of post-biopsy MR imaging of the prostate.

PURPOSE: To assess the quantity and frequency of hemorrhage after prostatic biopsy. As post-biopsy blood products may interfere with interpretation of MR images, we also investigated the optimal timing for MR examination after biopsy. MATERIAL AND METHODS: Fifteen patients scheduled for prostatic biopsies were imaged with endorectal MR before and after the procedure. In addition, MR studies of 42 patients with prostate cancer were retrospectively analyzed. The amount of post-biopsy blood product and the degree of its interference with image interpretation were assessed. RESULTS: Of a total of 57 patients, 44 (77%) had visible post-biopsy hemorrhage. However, the presence of blood products were considered to interfere with interpretation of the images in only 12 (21%) cases. This disturbing effect seems to diminish after 21 days from biopsy. The total amount of blood clearly decreased after 28 days. CONCLUSION: Deferring MR imaging for at least 3 weeks after prostatic biopsy is advisable. T1-weighted images are necessary to rule out false-positive findings caused by post-biopsy hemorrhage.

Use of the complex between prostate specific antigen and alpha 1-protease inhibitor for screening prostate cancer.

PURPOSE: We assess whether the complex between prostate specific antigen (PSA) and alpha1-protease inhibitor in serum can be used to reduce further the number of false-positive PSA screen results independent of total and free PSA. MATERIALS AND METHODS: Sera from 304 consecutive screen positive subjects, including 78 with and 226 without prostate cancer, and serum PSA of 4 to 10 microg./l. or higher in the Finnish, randomized, population based prostate cancer screening trial were analyzed for PSA-alpha-protease inhibitor, and total and free PSA. Main outcome measures were specificity, sensitivity and area under receiver operating characteristics curve for proportions of free PSA and PSA-alpha 1-protease inhibitor, and for a combination of these among screen positive cases. RESULTS: The proportion of serum PSA-alpha 1-protease inhibitor of total PSA was lower in cancer cases than in controls (0.9% versus 1.6%, p <0.001). Logistic regression analysis of total PSA, free PSA and PSA-alpha 1-protease inhibitor showed that PSA-alpha 1-protease inhibitor in serum was an independent variable for discrimination between subjects with and without prostate cancer (p = 0.006) in the PSA range of 4 to 10 microg./l. The proportion of PSA-alpha 1-protease inhibitor alone improved specificity less than the proportion of free PSA but when these were combined by logistic regression they performed better than the proportion of free PSA alone at sensitivities of 85% to 95% (p <0.001). CONCLUSIONS: Serum PSA-alpha 1-protease inhibitor improves the specificity of total and free PSA in a screening population with total PSA 4 to 10 microg./l.

Insulin-like growth factor I is not a useful marker of prostate cancer in men with elevated levels of prostate-specific antigen.

High serum levels of insulin-like growth factor I (IGF-I) and low levels of IGF-binding protein-3 (IGFBP-3) have been shown to correlate with increased prostate cancer risk. To evaluate this, IGF-I, IGFBP-3, and prostate-specific antigen (PSA) were measured in serum from 665 consecutive men (179 with prostate cancer), aged 55-67 yr, with elevated serum prostate-specific antigen (PSA; > or = 4 microg/L) in a screening trial. Men in the highest quartile of IGF-I levels had an odds ratio (OR) for prostate cancer of 0.50 [95% confidence interval (CI) 0.26-0.97] when adjusting for serum IGFBP-3. IGFBP-3 itself was not significantly associated with prostate cancer risk (OR, 1.24; 95% CI, 0.68-2.24). Prostate volume was larger in men without than in those with prostate cancer (P < 0.001), and after adjustment for prostate volume, the negative association between serum IGF-I and prostate cancer risk was no longer significant (OR, 0.57; 95% CI, 0.28-1.16). In screen-positive men with elevated serum PSA, serum IGF-I is not a useful diagnostic test for prostate cancer, but it may be associated with benign prostatic hyperplasia and enlargement.

Predicting the outcome of prostate biopsy in screen-positive men by a multilayer perceptron network.

OBJECTIVES: To assess whether an artificial neural network (multilayer perceptron, MLP) and logistic regression (LR) could eliminate more false-positive prostate-specific antigen (PSA) results than the proportion of free PSA in a prostate cancer screening. METHODS: MLP and LR models were constructed on the basis of data on total PSA, the proportion of free PSA, digital rectal examination (DRE), and prostate volume from 656 consecutive men (aged 55 to 67 years) with total serum PSA concentrations of 4 to 10 ng/mL in the randomized population-based prostate cancer screening study in Finland. The MLP and LR models were validated using the "leave-one-out" method. RESULTS: Of the 656 men, 23% had prostate cancer and 77% had either normal prostatic histology or a benign disease. At a 95% sensitivity level, 19% of the false-positive PSA results could be eliminated by using the proportion of free PSA versus 24% with the LR model and 33% with the MLP model (P < 0.001). At 80% to 99% sensitivity levels, the accuracy of the MLP and LR models was significantly higher than that of the proportion of free PSA. At 89% to 99% sensitivities, the accuracy of the MLP was higher than that of LR (P

Factors influencing patient radiation doses from barium enema examinations.

PURPOSE: To analyse factors behind the variation of patient doses from barium enema (BE) examinations. MATERIAL AND METHODS: The patients' (n=89) organ and effective doses (E) due to BE examinations were computed with the ODS-60 program. An average risk factor for BE examinations was derived using the BEIR V schema. The correlation of E with several independent variables was analysed. RESULTS: Median Es at five hospitals were 4.4, 6.1, 7.1, 13 and 16 mSv. The E of the female patients (median 9.2 mSv) was higher than that of the males (median 5.4 mSv) (p<0.001) due to the higher female doses to the gonads, bladder and uterus, resulting from different body structure. An average fatal risk factor of 0.02%. per one BE examination was derived. Factors controlled by the radiologist (screening time, number of exposures) explained 40% and patient-related factors explained 16% of the total variation of E. The equipment-related factors are included in the residual 44%. CONCLUSION: Due to the large contribution of the radiologists' examination technique in the value of E, an optimal examination technique is essential in reducing doses and the stochastic risk to patients.

Magnetic resonance imaging of prostatic cancer: does detection vary between high and low gleason score tumors?

BACKGROUND: Both Gleason score and prostate-specific antigen (PSA) concentration are prognostic factors for prostate cancer. We assessed our ability to localize cancer lesions based on Gleason scores and PSA values by endorectal coil magnetic resonance imaging (MRI). We also evaluated whether the size of the prostate affects tumor detectability. METHODS: We compared the findings of MRI and histopathological results of radical prostatectomy specimens from 63 patients; they were divided into four groups, based on Gleason score and also on serum PSA concentration. Furthermore, the possible effect of prostatectomy specimen weight on MRI interpretation was examined. RESULTS: A highly significant difference appeared in detection of cancer lesions based on their differentiation grade. No statistically significant difference existed between PSA groups in detection of tumors, but the large size of the prostate seemed to render image interpretation more difficult. CONCLUSIONS: Endorectal MRI detects poorly differentiated prostate cancer lesions more accurately than clinically insignificant tumors.

Pretreatment plasma testosterone and estradiol levels in patients with locally advanced or metastasized prostatic cancer. FINNPROSTATE Group.

BACKGROUND: Studies concerning pretreatment plasma hormonal environment in relation to stage of prostatic cancer have given conflicting results. The aim of the present study was to compare the pretreatment plasma testosterone (T), free T (fT), estradiol (E2), and free E2 (fE2) levels in patients with locally advanced (T3-4 M0) and metastatic (T1-4 M1) prostatic cancer, and to further examine the effect of the patients' general condition on these levels. METHODS: The present series consisted of 238 patients (Finnprostate 6 study). The variables analyzed were E2, fE2, T, fT, age, body mass index (BMI), sex hormone binding globulin capacity (SHBG), prostate-specific antigen (PSA), alkaline phosphatase (ALP), hemoglobin concentration (Hb), erythrocyte sedimentation rate (ESR), and performance status (PS). RESULTS: The E2 and fE2 levels were significantly higher in M0 patients than in M1 patients, with no significant differences in T and fT levels. In multivariate analyses, a decline in performance status (PS), an increase in ESR, or a decrease in Hb, were related to a decrease in T, fT, E2, or fE2 levels. CONCLUSIONS: Pretreatment plasma estradiol was significantly lower in M1 patients than in M0 patients, but there were no significant differences in T levels, although the poor general condition was related to a decrease in the pretreatment levels of both testosterone and estradiol.

The role of parenteral polyestradiol phosphate in the treatment of advanced prostatic cancer on the threshold of the new millennium.

Orchiectomy and estrogens have been used for over 50 years in the treatment of advanced prostatic cancer. Although orchiectomy is a simple procedure, it may cause psychological stress. Oral estrogen therapy is as effective as orchiectomy in terms of cancer inhibitory effect, but its acceptance as primary hormonal treatment is overshadowed by an increased risk of cardiovascular complications. Parenteral estrogen, polyestradiol phosphate (PEP), is effective, but also associated with cardiovascular complications, although to a lesser extent. During the last 20 years, well tolerated luteinizing hormone releasing hormone (LHRH) analogues have been replacing orchiectomy and estrogens. Efforts have been made to increase the efficacy of the treatment by adding antiandrogens to LHRH analogues and also to orchiectomy (combined androgen blockade, CAB). However, the efficacy of LHRH analogues and CAB has not proved to be superior to that of simple orchiectomy and, moreover, they are expensive treatment modalities. Orchiectomy and LHRH analogues are associated with negative effects on bone mass and may cause osteoporosis, whereas PEP treatment has an opposite effect. Parenteral polyestradiol phosphate is still a cheap potential treatment for advanced prostatic cancer, but further studies should be conducted to establish its future role, e.g. combining acetylsalicylic acid to prevent cardiovascular complications.

European randomized study of prostate cancer screening: first-year results of the Finnish trial.

Approximately 20000 men 55-67 years of age from two areas in Finland were identified from the Population Registry and randomized either to the screening arm (1/3) or the control arm (2/3) of a prostate cancer screening trial. In the first round, the participation rate in the screening arm was 69%. Of the 5053 screened participants, 428 (8.5%) had a serum prostate-specific antigen (PSA) concentration of 4.0 ng/ml or higher, and diagnostic examinations were performed on 399 of them. A total of 106 cancers were detected among them corresponding to a positive predictive value of 27%, which is comparable with mammography screening for breast cancer. The prostate cancer detection rate based on a serum PSA concentration of 4.0 ng ml(-1) or higher was 2.1%. Approximately nine out of ten screen-detected prostate cancers were localized (85% clinical stage T1-T2) and well or moderately differentiated (42% World Health Organization (WHO) grade I and 50% grade II), which suggests a higher proportion of curable cancers compared with cases detected by other means.

Characterization and immunological determination of the complex between prostate-specific antigen and alpha2-macroglobulin.

Prostate-specific antigen (PSA) rapidly forms a complex with alpha2-macroglobulin (A2M) in vitro; however, PSA complexed with A2M (PSA-A2M) is not detected by conventional immunoassays for PSA because it is encapsulated by the A2M. In this study, we show that denaturation of PSA-A2M at high pH renders PSA immunoreactive. Part of the complexed PSA is released in free form and part remains bound to denatured A2M. These forms can be measured by a conventional immunoassay for PSA. This finding enabled us to design a dissociation assay for the detection of PSA-A2M, which was based on the removal of immunoreactive PSA in serum by immunoadsorption, denaturation of PSA-A2M at high pH, and measurement of the released PSA immunoreactivity by a conventional PSA immunoassay. This PSA-A2M assay was calibrated with PSA-A2M formed in vitro. The detection limit of the assay was 0.14 microg/L. Inter- and intraassay coefficients variation were 4-9% and 8-14%, respectively. When purified PSA was incubated with A2M, the loss of PSA immunoreactivity was highly correlated with the PSA-A2M formed, as measured by the dissociation assay for PSA-A2M (r = 0.99; P <0.0001). The concentration of PSA-A2M in serum correlated with that of total PSA both in prostate cancer (PCa) and benign prostatic hyperplasia (BPH); however, the ratio of PSA-A2M in relation to total PSA was significantly higher in BPH than in PCa (P <0.0003). ROC curve analysis suggested that measurement of the ratio of PSA-A2M to total PSA in serum improves the diagnostic accuracy for PCa compared with assays for total PSA only.

Parenteral polyoestradiol phosphate vs orchidectomy in the treatment of advanced prostatic cancer. Efficacy and cardiovascular complications: a 2-year follow-up report of a national, prospective prostatic cancer study. Finnprostate Group.

OBJECTIVE: To evaluate the clinical efficacy and cardiovascular complications of orchidectomy or polyoestradiol phosphate (PEP) in the treatment of advanced prostatic cancer. PATIENTS AND METHODS: In a prospective, randomized study 444 patients (mean age 73 years, range 45-91) with T3-4 M0 or T1-4 M1 prostatic cancer were treated either by orchidectomy (group 1, n = 217) or parenteral PEP (group 2, n = 227; 240 mg/month). The patients were examined at 3 and 6 months after start of the therapy and thereafter every 6 months; they were also assessed whenever they had symptoms indicating progression. Possible cardiovascular complications included myocardial infarction, cerebrovascular accident, pulmonary embolism and deep vein thrombosis. RESULTS: After a follow-up of 2 years there was no statistically significant difference between the groups in progression-free time; 65 of 217 (30%) patients in group 1 showed evidence of progression, including seven (3%) who died from prostate cancer. In group 2, 64 of 227 (28%) patients showed progression and eight (3.5%) died from prostatic cancer. There were 10 (5%) cardiovascular complications in patients in group 1, including five (2%) cardiovascular deaths; in group 2 there were 24 (11%) and 14 (6%), respectively. During the first year of treatment there were three (1.4%) cardiovascular complications in group 1 and 14 (6%) in group 2 (P < 0.05), and during the second year, seven (4%) and 10 (6%), respectively. CONCLUSION: Parenteral PEP (240 mg/month) seems to be as efficient as orchidectomy in inhibiting disease in patients with advanced prostatic cancer (T3-4 M0 and T1-4 M1). There were more cardiovascular complications in patients treated with PEP than after orchidectomy; the difference was statistically significant during the first year of treatment.

Magnetic resonance imaging of clinically localized prostatic cancer.

PURPOSE: We assess the accuracy of endorectal coil magnetic resonance imaging (MRI) for detecting tumor localization, capsular penetration and seminal vesicle invasion in clinically organ confined prostate cancer. We also evaluate intra-observer and interobserver agreement in interpreting MRI studies. MATERIALS AND METHODS: MRI studies of 51 consecutive patients a mean of 61 years old with biopsy proved prostate cancer were retrospectively read twice by 2 radiologists in random order. Both radiologists marked tumor localization, capsular penetration and seminal vesicle invasion on standard tumor maps. These findings were compared with the histopathological results of radical prostatectomy specimens. RESULTS: The overall accuracy of detecting cancer localization was 61%. The detection rate for cancer foci less than 5 mm. was only 5% but for lesions greater than 10 mm. it was 89%. There was 91 and 80% accuracy for detecting capsular penetration and seminal vesicle invasion, respectively. Sensitivity and specificity were 60 and 63, 13 and 97, and 59 and 84% for localization, capsular penetration and seminal vesicle invasion, respectively. Intra-observer and interobserver agreement ranged from fair to good (kappa coefficient 0.240 to 0.647). CONCLUSIONS: Endorectal MRI seems to be better than previously reported for detecting seminal vesicle invasion and tumor foci in the anterior half of the prostate. Sensitivity in detecting minor capsular penetration of the tumor was low, which can probably be improved by methodological development. MRI may be useful for locating cancer foci in patients with high prostate specific antigen values but repeatedly negative biopsy findings.

Testosterone regulates apoptosis in adult human seminiferous tubules in vitro.

In the present study an in vitro model was developed and characterized for evaluation of the role of apoptosis in adult human testes. The samples came from adult men undergoing orchidectomy for prostate or testicular cancer. Segments of seminiferous tubules were isolated and incubated under serum-free conditions in the absence or presence of testosterone. Apoptosis was assessed by low mol wt DNA fragmentation (185-bp multiples) by use of 3'-end-labeled DNA, in situ end labeling, and morphological detection under light and electron microscopy. During the 4-h incubation, a 15-fold increase was seen in apoptotic DNA fragmentation. The extent of low mol wt DNA showed a time-dependent increase and reached a 20-fold intensity in 24 h of incubation compared to the level at 0 h. Apoptosis was significantly suppressed by testosterone concentrations of 10(-7) and 10(-6) mol/L during the first 4 h of incubation. Apoptotic cells were identified mainly as spermatocytes and occasionally as spermatids. We conclude that apoptosis is induced in human seminiferous tubules under serum-free conditions in vitro. That this apoptosis is suppressed by testosterone indicates that testosterone in the human male is a critical germ cell survival factor. The model created in the present study provides a valuable tool for further investigation of hormonal and gene regulation of human germ cell death and survival.

Computing patient doses of X-ray examinations using a patient size- and sex-adjustable phantom.

Both the use of traditional fluoroscopy and the increasing use of modern digital techniques in radiology and interventional radiology demand the development of versatile computer programs for patient dose determinations. Long computing times restrict the use of Monte Carlo (MC) methods in dose monitoring applications where the radiological views change frequently. In the Organ Doses Calculation Software application (ODS-60), the phantom model is similar in principle to the Alderson-Rando (A-R) phantom, but its sex, size and shape is modified according to a particular patient. Organ and effective doses are computed online (in a few seconds) using a method similar to the traditional dose planning systems used in radiotherapy. In this paper, the new ODS-60 software is presented in detail and its capabilities are demonstrated. Software performance was determined by comparing the results with those from independent methods. In the case of a reference man-sized male, the effective dose was about 7% larger than the effective dose given in another publication. In the case of a reference woman-sized female, the disagreement with the other method was greater (33%). Anatomical differences between the phantom models (ODS-60 and MC) were found to be the main reasons for these findings. This paper shows the advantage of using a patient size- and sex-adaptable phantom for patient dose determinations; the conversion coefficient from entrance surface dose-to-effective dose ratio between male (170 cm, 85 kg) and a female (160 cm, 43 kg) varies in the range 1.5-2.

Radioiodinated estramustine phosphate and estramustine binding protein antibody accumulate in the prostate of a mouse.

BACKGROUND: The purpose of this study was to determine the distribution of radioiodinated estramustine (RI-EMP) and a radioiodinated antibody against estramustine binding protein (RI-EMBP-AB) in mice. METHODS: RI-EMP and RI-EMBP-AB were injected in male mice intravenously, and the activities of tissue samples were measured 1-31 hr from the injection. Pure iodine-125 (RI) was used as a control. RESULTS: RI-EMP accumulated in the prostate, which contained 2.6% of injected activity (ID) per gram tissue at 7 hr. The liver had an activity of 21.4% ID/g at 1 hr, which decreased as RI-EMP was secreted in bile. The lung contained 2.3% ID/g at 7 hr, and it retained the activity longer than the prostate. RI-EMBP-AB accumulated in the prostate: The activity was 2.9% ID/g at 7 hr. The gallbladder contained 6.5% ID/g at 7 hr. CONCLUSIONS: Due to its cytotoxic and radiosensitizing properties, RI-EMP can possibly be used for treating prostate cancer and other tumors.