Individual prostate-specific antigen (PSA) forms as prostate tumor markers

Prostate-specific antigen (PSA) is a kallikrein-like serine protease mainly expressed in the human prostate. It is responsible for the proteolysis of the gel-forming proteins in human semen. Two major extracellular protease inhibitors, alpha-1-antichymotrypsin (ACT) and alpha-2-macroglobulin (AMG) may inactivate PSA escaping from the prostate. The predominant immunodetected form of PSA in serum is complexed to ACT but PSA exists also in a free non-complexed form despite the large excess of inhibitors. The concentrations of PSA in serum are normally less than 4 micrograms/l. but elevated concentrations are found in a majority of patients with prostate cancer (CAP) and the analysis of PSA in serum has become invaluable in the detection and monitoring of patients with CAP. However, it is not an ideal tumor marker in the sense that there are CAP patients with normal PSA concentrations in serum and patients with benign hyperplasia of the prostate (BPH) with elevated PSA concentrations. Analysis of the various PSA forms in serum attracts much interest as there is a higher proportion of PSA in complex with ACT in patients with CAP than in those with BPH. Optimal combinations of monoclonal antibodies have been used to design sensitive noncross-reacting immunoassays for the detection of free PSA, PSA-ACT complexes and the detection of both free PSA and PSA complexes in an equimolar fashion (i.e. total PSA). Several studies have demonstrated that the analysis of the proportions of the free-to-total PSA in serum may increase the diagnostic specificity by 15-20% without significant loss in the sensitivity for detection of CAP.     

Prostate specific antigen (PSA) value adjusted for transition zone volume and free PSA (gamma-seminoprotein)/PSA ratio in the diagnosis of prostate cancer in patients with intermediate PSA levels

OBJECTIVE: To identify binding proteins of leptin in human plasma. METHODS: Binding was evaluated by electrophoresis, size exclusion chromatography (SEC), Western blotting, and radioisotope labeling. Quantification of leptin and the different forms of alpha2-macroglobulin (alpha2-M) was performed by ELISA. RESULTS: Leptin interacts with the proteinase inhibitor, alpha2-M. 125I-labeled leptin specifically binds to the transformed inhibitor, which arises by reaction with proteinases or with reactive primary amines. No leptin binding was observed to the native alpha2-M, which abundantly occurs in plasma. The complex formation between leptin and alpha2-M was found to proceed within minutes and was stable, as it resisted separation by SEC and electrophoresis. The Kd of the complex was 2.14 +/- 0.78 micromol/l. Complex formation with transformed alpha2-M did not interfere with the immunological determination of leptin in plasma. The leptin-alpha2-M complex was found to be recognized by the alpha2-M receptor/low density lipoprotein receptor-related protein. By computer analysis, a simple model is presented showing that the degree of transformation of alpha2-M may significantly influence the leptin concentration in blood. CONCLUSIONS: The proteinase inhibitor, alpha2-M, may act as a leptin-binding protein in human plasma. Binding of leptin to transformed alpha2-M and its rapid clearance by the alpha2-M receptor may significantly influence the bioavailability of leptin in human plasma.     

Determination and analysis of antigenic epitopes of prostate specific antigen (PSA) and human glandular kallikrein 2 (hK2) using synthetic peptides and computer modeling

In comparison with pyeloplasty, endourologic procedures for the treatment of ureteropelvic junction obstruction offer good success rates with less morbidity and a shorter hospitalization; however, studies have found lower success rates and increased complications in patients with crossing vessels. Conventional diagnostic angiography and intravenous urography have both been used to identify crossing vessels at the UPJ; but, a reliable, less invasive, less costly, and simpler preoperative procedure to identify crossing vessels is needed. Helical CT with CT angiography is a promising noninvasive technique for the identification of crossing vessels at the ureteropelvic junction, which can be used for surgical planning of endourologic treatment of UPJ obstruction.     

Clinical utility of the free prostate specific antigen (PSA), alpha 1-antichymotrypsin-complexed PSA, and free/total PSA ratio using the specific and sensitive enzyme-linked immunosorbent assay "E-plate EIKEN PSA"

We studied the clinical significance of serum prostate specific antigen (PSA) ratio: free-PSA/total-PSA and free-PSA/complex-PSA to discriminate between prostate cancer (PC) and prostate benign disease (non-PCa) by using total-PSA, alpha 1-antichymotrypsin complexed (complex)-PSA and free-PSA enzyme-linked immunosorbent assay (ELISA) kits newly developed at EIKEN Chemical Co, Ltd. Fre-PSA and complex-PSA ELISA kits demonstrated high sensitivity and specificity. Total-PSA ELISA kit also demonstrated equimolarity for free-PSA and complex-PSA. On the total-PSA range of 4-10 ng/ml, free-PSA/total-PSA% (f/t%) and free-PSA/complex-PSA% (f/c%) were very useful to discriminate between PCa and non-PCa by receiver operating characteristic curve analysis as well as PSA density (PSA-D) but not free-PSA level. F/t% and f/c% were even useful to discriminate early stage PCa (i.e. A1 or B0) from non-PCa by the Mann-Whitney U-test.     

Substrate specificity of prostate-specific antigen (PSA)

BACKGROUND: The serine protease prostate-specific antigen (PSA) is a useful clinical marker for prostatic malignancy. PSA is a member of the kallikrein subgroup of the (chymo)trypsin serine protease family, but differs from the prototypical member of this subgroup, tissue kallikrein, in possessing a specificity more similar to that of chymotrypsin than trypsin. We report the use of two strategies, substrate phage display and iterative optimization of natural cleavage sites, to identify labile sequences for PSA cleavage. RESULTS: Iterative optimization and substrate phage display converged on the amino-acid sequence SS(Y/F)Y decreases S(G/S) as preferred subsite occupancy for PSA. These sequences were cleaved by PSA with catalytic efficiencies as high as 2200-3100 M-1 s-1, compared with values of 2-46 M-1 s-1 for peptides containing likely physiological target sequences of PSA from the protein semenogelin. Substrate residues that bind to secondary (non-S1) subsites have a critical role in defining labile substrates and can even cause otherwise disfavored amino acids to bind in the primary specificity (S1) pocket. CONCLUSION: The importance of secondary subsites in defining both the specificity and efficiency of cleavage suggests that substrate recognition by PSA is mediated by an extended binding site. Elucidation of preferred subsite occupancy allowed refinement of the structural model of PSA and should facilitate the development of more sensitive activity-based assays and the design of potent inhibitors.     

Free/total ratio of prostate-specific antigen (PSA) for prostate cancer detection in patients with gray zone PSA level

Thirty seven patients complaining of voiding disturbance who showed gray zone total prostate-specific antigen (t-PSA) level (upper limit of normal approximately 10 ng/ml) but did not reveal apparent cancerous findings in the prostate were examined for free PSA (f-PSA) and prostate volume. According to histological diagnosis, 9 were cancer cases and the other 28 were non-cancer cases. The free/total (F/T) ratio was 0.10 and 0.16 in the cancer and non-cancer groups, respectively (t-PSA; DPC kit, p = 0.03). The t-PSA (DPC and Dinabott kits), f-PSA and PSA density alone did not distinguish these two groups. For diagnosis of cancer, the ratio seemed to be F/T, the most reliable followed by PSA density and t-PSA. When using a 13% F/T, the sensitivity and specificity for cancer detection were 88.9 and 70.8%, respectively. t-PSA measured with the Dinabott kit, showed a similar tendency except that the F/T ratio showed a slight variation. Prostate volume and patient age influenced the F/T slightly, but these factors may not impair the usefulness of F/T.     

Free-to-total prostate-specific antigen (PSA) ratio improves the specificity for detecting prostate cancer in patients with prostatism and intermediate PSA levels

OBJECTIVE: To investigate the clinical significance of the free-to-total prostate-specific antigen (PSA) ratio in improving the specificity of PSA measurement for detecting prostate cancer within the diagnostic intermediate range (4-10 ng/mL total PSA) in patients referred for the treatment of urinary symptoms. PATIENTS AND METHODS: Serum samples were obtained from 333 consecutive patients with obstructive and irritative urinary symptoms. Of these men, 114 had total PSA levels of 4-10 ng/mL; 22 had prostate cancer (group 1) and 71 had benign prostatic hyperplasia (BPH, group 2). Group 3 consisted of 21 patients with BPH and a chronic indwelling catheter. The concentrations of free and total PSA (ProStatus, Wallac Oy, Turku, Finland) and PSA complexed to alpha-1-antichymotrypsin were measured and the free-to-total PSA ratio calculated. All patients under 70 years of age or with suspicious findings on digital rectal examination or transrectal ultrasonography underwent ultrasound-guided sextant prostate biopsies. Of the 114 patients, 105 (92%) underwent transurethral resection of the prostate and six (5%) radical retropubic prostatectomy. RESULTS: Patients in group 1 had significantly lower median free PSA concentrations (0.78 ng/mL vs 1.13 ng/mL, P < 0.001) and a lower free-to-total PSA ratio (12.1% vs 19.9%, P < 0.001) than those in group 2. The differences were similar between group 1 and group 3 (median free PSA in group 3, 1.06 ng/mL, P = 0.03, and free-to-total PSA ratio 18.7%, P = 0.007). There were no significant differences between patients in groups 2 and 3. The free-to-total PSA ratio had a higher specificity than total PSA at all sensitivity levels, e.g. a threshold free-to-total PSA ratio of 0.20 detected 91% of cancers and spared 48% (group 2) or 46% (group 3) from unnecessary biopsies. The area under the receiver operating characteristic curve for group 1 vs group 2 was 0.56 (total PSA) and 0.78 (free-to-total PSA ratio) and for group 1 vs group 3 was 0.56 (total PSA) and 0.81 (free-to-total PSA ratio). CONCLUSION: In those patients with extensive symptoms from BPH and requiring surgical treatment, the free-to-total PSA ratio improves the specificity for detecting prostate cancer in the diagnostic 'grey zone' of 4-10 ng/mL total PSA. This improvement occurred in patients with or without a chronic indwelling catheter for urinary retention.     

PSATZ (prostate specific antigen adjusted for the transition zone volume)

This brief review discusses the diagnostic ability of prostate specific antigen adjusted for the transition zone volume (PSATZ) for the detection of prostate cancer in patients with intermediate prostate specific antigen (PSA) levels. PSATZ was defined as the quotient of the PSA value and the calculated transition zone volume. In comparison with standard parameters including PSA and prostate specific antigen density, PSATZ could be a useful indicator for the detection of prostate cancer in patients with PSA values between 4.1 and 10.0 ng/ml, especially in those with normal digital rectal examinations. Similar observations consistent with our results have been also reported by other investigators. PSATZ has some disadvantages including volumetry and expensive cost. Further study is necessary to discuss whether PSATZ is superior to other new modalities such as free-to-total PSA ratio with regard to diagnostic cost and efficacy.     

Comparison of percent free prostate specific antigen and prostate specific antigen density as methods to enhance prostate specific antigen specificity in early prostate cancer detection in men with normal rectal examination and prostate specific antigen between 4.1 and 10 ng./ml

PURPOSE: We analyzed the behavior of prostate specific antigen (PSA) density and percent free PSA to enhance the specificity of PSA in the early diagnosis of prostate cancer in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. MATERIALS AND METHODS: PSA serum level, PSA density and percent free PSA were analyzed in 74 men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. All men underwent systematic prostate biopsy, and the diagnosis was benign prostate hyperplasia in 52 and prostate cancer in 22. Furthermore, we determined the decrease in unnecessary biopsies and the cancer detection rate using 0.10 versus 0.15 as cut points for PSA density, and 20 versus 25 as cut points for percent free PSA. RESULTS: In patients with benign prostatic hyperplasia and prostate cancer, respectively, the median PSA level was 6.7 and 7.0 ng./ml. (p > 0.05), median prostate volume was 50 and 37 cc (p < 0.04), median PSA density was 0.14 and 0.19 (p < 0.007) and median percent free PSA was 18.9 and 10.1 (p < 0.005). Using PSA density cut points of 0.15 and 0.10, the decrease in negative biopsies was 53.8 and 36.5% with a sensitivity of 86.4 and 90.9%, respectively. However, using percent free PSA cut points of 20 and 25, the decrease in negative biopsies was 36.5 and 26.9% with a sensitivity of 77.3 and 95.5%, respectively. CONCLUSIONS: Although both methods could minimize unnecessary biopsies in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml., the percent free PSA was more cost-effective since transrectal ultrasound was not required. In this small series of symptomatic patients a percent free PSA cut point of 25 could detect at least 95% of prostate cancers and decrease 26.9% of negative biopsies.     

The clinical utility of measuring free-to-total prostate-specific antigen (PSA) ratio and PSA density in differentiating between benign prostatic hyperplasia and prostate cancer

OBJECTIVE: To evaluate the role of free-to-total prostate-specific antigen ratio (f/tPSA), prostate volume and PSA density in differentiating between men with prostate cancer and benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: The study comprised 51 patients who were assessed after transurethral electroresection of the prostate (16 with prostate cancer and 35 with BPH). Patients with a tPSA of < or = 4.0 ng/mL and > or = 30.0 ng/mL were excluded from the analysis. Total and fPSA were measured using an immunoradiometric assay and prostate volume was determined by transrectal ultrasonography. The incidence of prostate cancer and BPH was then compared with the PSA variables to determine specificity and predictive value. RESULTS: Most patients with BPH had a tPSA of 4.0-6.0 ng/mL; no patients with BPH had a tPSA of > 20.0 ng/mL. Most patients with prostate cancer had a f/tPSA of 6-10%. The area under the receiver operating characteristic curve for f/tPSA was significantly greater than that for tPSA (P < 0.003). CONCLUSIONS: The measurement of f/tPSA and PSA density increase the specificity of the differential diagnosis between BPH and prostate cancer.     

Isolation and characterization of free form prostate specific antigen (f-PSA) in sera of men with prostate cancer

PURPOSE: The free uncomplexed form of prostate specific antigen (f-PSA) from prostate cancer sera was partially isolated and characterized because the molecular form of f-PSA in the serum is unknown. MATERIALS AND METHODS: 230 ml. of sera from 59 men with bone metastasis and individual PSA values of >2000 ng./mL were combined and centrifuged for 60 minutes at 30,000 RPM (4C). The sera were fractionated by gel filtration column chromatography (Sephacryl S-200, 2.5 cm. x 92 cm.). Free and complexed PSA in the eluted fractions were isolated by measuring immunoreactivity of PSA (Tosoh AIA-600 assay); f-PSA from 23 separate runs were combined, concentrated and re-chromatographed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to immobilize the isolated proteins onto a nitrocellulose membrane and a polyvinylidene difluoride (PVDF) membrane. Monoclonal antibody (F5) was used to probe PSA on nitrocellulose membrane and the PSA band was detected by Emission Chemoluminescence (ECL) kit. Amino terminal sequence analysis of the isolated f-PSA was performed with a gas-phase sequentor (Applied Biosyntens 4760 A) using the program designed by the manufacturer. RESULTS: 0.5 cc of f-PSA (27,000 ng./mL) was obtained from serums after rechromatography. SDS-PAGE showed one double band around 30 kDa; with ECL technique, one major band at 30-kDa was identified as PSA. The amino terminal sequence analysis of this band showed residue 1 through 9 and 146 through 152. CONCLUSIONS: In our preliminary experiment, the free form of serum PSA is partially isolated directly from human sera. Amino terminal sequence analysis has shown that serum f-PSA is not a pre-mature or zymogen form of PSA because serum f-PSA has a N-terminus identical to that of seminal fluid PSA. A nicked form of f-PSA is also found in these patient sera.     

Age specific prostate specific antigen reference ranges: population specific

BACKGROUND: Anastomosis of the left internal thoracic artery to the left anterior descending artery without sternotomy and without cardiopulmonary bypass is a standard approach in minimally invasive coronary artery bypass grafting. To expand the indications for minimally invasive coronary artery bypass grafting from one-vessel disease to two-vessel disease, we began to perform anastomosis of the right gastroepiploic artery (RGEA) to the right coronary artery (RCA). METHODS: From February to November 1996, an RGEA graft was used in 25 of the 100 patients who underwent minimally invasive coronary artery bypass grafting at our clinic. Eleven of the patients had only RCA disease and 14 had both RCA and left anterior descending artery disease. One of the operations was a redo coronary artery bypass grafting. The RGEA was anastomosed to the RCA through a laparotomy incision and the left internal thoracic artery was anastomosed to the left anterior descending artery through a left anterior thoracotomy. In 5 patients, the RGEA was lengthened by venous grafting. RESULTS: All patients underwent angiography after operation; 82.6% of the RGEA grafts and all the left internal thoracic artery grafts were functioning well. In three of the four nonvisualized RGEA grafts, the percentage of proximal stenosis of the RCA seen on postoperative angiography was not critical (40%, 50%, and 50%, respectively), allowing significant competitive flow through the native bypassed RCA. The patency of all the RGEA grafts without competitive flow was 95%, with a 95% confidence interval of 75.1% to 99.9%. CONCLUSIONS: The indications for minimally invasive coronary artery bypass grafting could be extended to primary operations in patients with left anterior descending artery and RCA lesions by using both the left internal thoracic artery and the RGEA.     

A long follow-up on prostate specific antigen density and prostate biopsy

OBJECTIVE: To determine prostate specific antigen density (PSAD) in a risk population without evidence of prostatic cancer, and to assess the long-term usefulness of PSAD as a parameter for determining the need for a prostatic biopsy in patients with a normal digital rectal examination (DRE) and transrectal ultrasound (TRUS). METHODS: The records of 582 patients referred to the clinic between February, 1992 and February, 1994 were studied retrospectively. All these patients with lower urinary tract symptoms (LUTS) were evaluated based on the following parameters: digital rectal examination, serum PSA levels, prostate volume measured using transrectal ultrasound and PSAD. Prostatic biopsy was performed on 431 patients who had a serum PSA level greater than 4.0 ng/mL. A total of 299 patients (69.3%) had PSA levels between 4.0 and 10.0 ng/mL and represented the target population. The study had two parts, in the first one cancer was diagnosed just by one biopsy and in part II, the patients with negative biopsy in part I were followed for a two-year period and required 2 or 3 biopsies for diagnosis. Of the total of patients who had a negative prostate biopsy in part I of the study, 269 were followed for a period of two years with repeated prostate biopsies. RESULTS: Overall prostate cancer was detected in 22/299 (13.9%) patients, 6/105 (5.7%) with PSAD up to 0.15 and 16/194 (8.2%) with PSAD over 0.15 (p = 0.569). CONCLUSION: PSAD is a useful indicator in decreasing the number of negative biopsies in patients with benign prostatic hyperplasia. However, in a long-term follow-up the PSAD (cutoff level 0.15) was unable to predict which patients had a positive biopsy. According to our results, 5.6% of patients with prostate cancer will be missed using the PSAD criteria.     

Do prostate specific antigen and prostate specific antigen density enhance the detection of prostate carcinoma after initial diagnosis of prostatic intraepithelial neoplasia without concurrent carcinoma?

BACKGROUND: Prostatic intraepithelial neoplasia (PIN) is considered to be a precursor of prostate carcinoma in which serum levels of prostate specific antigen (PSA) have been correlated with PIN grades. The aim of this study was to determine whether PSA and prostate specific antigen density (PSAD), obtained at the time of initial diagnosis of PIN without concurrent carcinoma, can be used as predictive factors to discriminate patients with subsequent cancer on repeat biopsy. METHODS: We studied, retrospectively, the records of 93 patients with PIN (low and high grade) without concurrent carcinoma at the time of their first needle biopsy. We assessed the relationship between initial PIN grade, PSA, and PSAD with later detection of carcinoma on repeat biopsy. Patients were divided into 3 subgroups for analysis according to their initial PSA level (0-4, 4.1-10, >10 ng/mL). RESULTS: Carcinoma detection rate on repeat biopsy was 13.3% for patients with low grade PIN and 47.7% for patients with high grade PIN (P < 0.006). High grade PIN was frequently associated with subsequent carcinoma whatever the PSA level (33.3-61.9%). Low grade PIN was associated with subsequent carcinoma in 42.8% of the cases when PSA was greater than 10 ng/mL. When PSA was between 4 and 10 ng/mL, low grade PIN carcinoma was found on repeat biopsies in only 10.7% of the cases (P = 0.05). In none of the PSA subgroups did PSAD enhance later cancer detection. CONCLUSIONS: For patients with high grade PIN, the incidence of subsequent carcinoma is high, whatever the PSA values. For these cases repeat biopsies should be recommended. Patients with low grade PIN and PSA greater than 10 ng/mL should have repeat biopsies because the incidence of subsequent carcinoma is high and comparable to high grade PIN. PSAD did not provide additional information.     

Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate

Recent studies on human kallikrein 2 (hK2) have revealed striking similarities and significant differences with the closely related kallikrein PSA. Both PSA and hK2 are primarily localized to the prostate and share close structural similarities. Although both kallikreins are produced by the same secretory epithelial cells in the prostate, hK2 is associated more with prostate tumors than PSA and is highly expressed in poorly differentiated cancer cells. The potent trypsin-like activity of hK2 contrasts with the weak chymotrypsin-like activity of PSA. The inactive precursor form of PSA, proPSA, is converted rapidly to active PSA by hK2, suggesting an important in vivo regulatory function by hK2 on PSA activity. The high homology between hK2 and PSA results in significant cross-reactivity to hK2 by polyclonal and some monoclonal antibodies to PSA. Future studies on both PSA and hK2 need to take into account this potential for cross-reactivity. Specific monoclonal antibodies to hK2 have now demonstrated that serum levels of hK2, like PSA, are correlated with prostate cancer. The production of hK2 protein in active protease form and specific monoclonal antibodies to the hK2 antigen will allow extensive future studies delineating the physiological and clinical utility of this new prostate antigen.     

Molecular genetic and biochemical analysis of Brassica napus proliferating cell nuclear antigen function

A cDNA encoding the proliferating cell nuclear antigen (PCNA) from Brassica napus (oilseed rape) was shown to complement the lethal deletion mutation in the PCNA gene (delta POL30) of Saccharomyces cerevisiae. We provide unequivocal evidence that the B. napus PCNA can perform all the essential functions of the yeast PCNA in DNA replication, although some species-specific differences may exist. In addition, the B. napus PCNA expressed as a fusion polypeptide with glutathione S-transferase (GST) was shown to stimulate the activity and processivity of two delta-like DNA polymerases from wheat in vitro. These experiments provide direct biochemical evidence that the B. napus PCNA may function as an auxiliary factor in plant cell DNA replication.     

The lack of predictive value of prostate specific antigen density in the detection of prostate cancer in patients with normal rectal examinations and intermediate prostate specific antigen levels

PURPOSE: The management of patients with a normal digital rectal examination and a prostate specific antigen (PSA) level of 4.0 to 10.0 ng./ml. remains controversial. To improve the specificity of cancer detection in this group, PSA density has been recommended with biopsies based on a PSA density of 0.15 or more. To evaluate PSA density as a discriminator of prostate cancer we enrolled patients in a prospective study. MATERIALS AND METHODS: A prospective evaluation was done of 44 consecutive patients with a palpably normal digital rectal examination and a serum PSA level of 4.0 to 10.0 ng./ml. enrolled during a 13-month period. All patients underwent transrectal ultrasound with sextant biopsies regardless of calculated PSA density. RESULTS: Overall, 8 of 44 men (18%) had prostate cancer. There was no significant difference in the mean PSA density between the patients with positive and negative biopsies (mean 0.12 and 0.15, respectively, p = 0.258). Also, there was no significant association between PSA or PSA density and a positive biopsy in multivariate analysis (p = 0.863). Receiver operating characteristic curves for PSA and PSA density failed to demonstrate any superior benefit for PSA density in this patient population. A PSA density of 0.15 was an unreliable indicator of cancer (sensitivity 12.5%, specificity 61.1% and positive predictive value 6.7%). CONCLUSIONS: In our study, PSA density did not discriminate between patients with positive and negative biopsies, and in fact most cancers would not have been detected if a PSA density of 0.15 or more had been used as the sole indication for biopsy. Therefore, we recommend systematic biopsies in these patients independent of calculated PSA density.     

The role of prostate-specific antigen (PSA) testing patterns in the recent prostate cancer incidence decline in the United States

OBJECTIVES: Trends in first-time and later PSA procedure rates are ascertained using longitudinal data from a population-based cohort. These trends are compared to trends in prostate cancer incidence to determine the role of PSA in the recent decline in prostate cancer incidence. METHODS: Medicare data were linked with tumor registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. A 5 percent random sample (n = 39985) of Medicare beneficiaries from the SEER areas without a previous diagnosis of prostate cancer as of January 1, 1988 was followed through 1994. Trends in first-time PSA use were distinguished from those of second or later for men without diagnosed prostate cancer. RESULTS: Trends in the rate of first-time PSA procedures track closely with trends in prostate cancer incidence rates, increasing until 1992 and decreasing thereafter. Similar patterns were observed by race and age group. Geographic variability in the dissemination of PSA screening was observed, yet the association between testing and incidence remained. Men in the cohort had a 4.7 percent chance of being diagnosed within three months of an initial PSA test, with the percentage falling for subsequent tests. CONCLUSIONS: It is informative to distinguish first from later tests when assessing the effect of the diffusion of a test in a population. Taking this approach was useful in illuminating the role of PSA testing in a reversal of a long-term increase in prostate cancer incidence rates.     

Influence of age on serum prostate specific antigen concentration

322 men who had not prostatic diseases were selected at random for defining the characteristics of serum prostate specific antigen (PSA) in order to use PSA more appropriately in detecting clinically significant prostate cancer. The serum PSA concentration is correlated with patient age (r = 0.301; P < 0.0001), PSA is increased with age. The recommended upper limits (mean +2 standard deviations) for serum PSA for men aged 20-49 years was 2.71 ng/ml; for 50-59 years, 5.01ng/ml; for 60-69 years, 6.05 ng/ml; and for greater than or equal to 70 years, 7.92 ng/ml. Our findings led to proposals for using age-specific PSA reference range instead of a single reference range for men of all age groups. These age-specific reference ranges have the potential to increase the specificity of using PSA for detecting prostate cancer.     

Generation of human cytolytic T lymphocyte lines directed against prostate-specific antigen (PSA) employing a PSA oligoepitope peptide

Prostate-specific Ag (PSA), which is expressed in a majority of prostate cancers, is a potential target for specific immunotherapy. Previous studies have shown that two 10-mer PSA peptides (designated PSA-1 and PSA-3) selected to conform to human HLA class I-A2 motifs can elicit CTL responses in vitro. A longer PSA peptide (30-mer) designated PSA-OP (oligoepitope peptide), which contains both the PSA-1 and PSA-3 HLA-A2 epitopes and an additional potential CTL epitope (designated PSA-9) for the HLA-class I-A3 allele, was investigated for the ability to induce cytotoxic T cell activity. T cell lines from different HLA-A2 and HLA-A3 donors were established by in vitro stimulation with PSA-OP; the CTL lines lysed PSA-OP as well as PSA-1- or PSA-3-pulsed C1R-A2 cells, and PSA-OP and PSA-9-pulsed C1R-A3 cells, respectively. The CTL lines derived from the PSA-OP peptide also lysed PSA-positive prostate cancer cells. PSA-OP-derived T cell lines also lysed recombinant vaccinia-PSA-infected targets but not targets infected with wild-type vaccinia. PSA-OP did not bind HLA-A2 and HLA-A3 molecules. The decrease in cytotoxicity in the presence of protease inhibitors suggests that the PSA-OP is cleaved into shorter peptides, which in turn can interact with HLA-class I molecules and, as a consequence, induce CTL-mediated lysis. We have also demonstrated that it is possible to induce CTL responses in HLA-A2.1/Kb transgenic mice by immunization with PSA-OP with adjuvant. These studies thus provide evidence that oligopeptides such as PSA-OP may be useful candidates for peptide-based cancer vaccines.