Comparison of prostate size in university and Veterans Affairs Health Care System patients with negative prostate biopsies.

OBJECTIVES: Many important prostate studies take place at Veterans Affairs hospitals. We have examined whether the patient population at these institutions is comparable to the population presenting for prostate evaluation at university hospitals. METHODS: We included all patients presenting for transrectal ultrasound (TRUS) and biopsy in whom systematic biopsies failed to reveal prostate cancer at both Stanford University Medical Center (90 patients) and the Palo Alto Veterans Affairs Health Care System (103 patients) from August 1, 1995 to July 31, 1996. Identical techniques and equipment for TRUS examination and prostate size determination were used at both institutions. RESULTS: There was no significant difference in the age or prostate-specific antigen (PSA) levels of the patients at the two institutions. The mean prostatic volume of the Stanford University patients was 71 cm3 (median 63 cm3), whereas the mean prostatic volume of patients at the Palo Alto Veterans Affairs hospital was 52 cm3 (median 43 cm3), a highly statistically significant difference (P = 0.0009). CONCLUSIONS: The smaller size of the prostate glands in Veterans Affairs patients may be the result of differences in referral base, socioeconomic factors, or environmental factors. These data may have significance for trials conducted only on the prostates of men who are seen at Veterans Affairs hospitals.

Can free and total prostate specific antigen and prostatic volume distinguish between men with negative and positive systematic ultrasound guided prostate biopsies?

PURPOSE: We evaluated the role of free and total serum prostate specific antigen (PSA) and prostate volume in discriminating between men with negative and positive transrectal ultrasound guided biopsies. MATERIALS AND METHODS: A total of 104 consecutive men with a positive biopsy and at least 3 mm. of prostate cancer was compared to 110 consecutive men with a negative biopsy. Prostate volume was determined by transrectal ultrasound. Total PSA was determined by the Tosoh AIA-600 PSA assay and free PSA was measured by the PSA II Dianon assay. We determined the free-to-total PSA ratio, free and total PSA densities, and the relationship of free PSA and free-to-total PSA ratio to prostate volume. RESULTS: Using a 23% cutoff value of free-to-total PSA, only 22.7% of biopsies were preventable in patients with a negative biopsy but 9.6% of the cancers were missed. At a total PSA of 4 to 10 ng./ml. 44.4% of the biopsy negative cases were correctly identified while missing 9.1% of the cancers if a 20% free PSA cutoff is used. For total PSA more than 10 ng./ml. an 18% free PSA cutoff properly identified 30.2% of the biopsy negative cases while missing 9.3% of the cancers. Percent free PSA is a better discriminant than prostate volume for total PSA more than 4 ng./ml. and the combination was not helpful. Free PSA density was identical in patients with negative and positive biopsies. There was no relationship between free PSA or free-to-total PSA ratio levels and prostate volume. CONCLUSIONS: Use of a single discriminant criterion of free-to-total PSA ratio in the practical clinical setting of distinguishing negative and positive biopsies appears useful in patients with a total PSA of 4 to 10 ng./ml. Since free PSA is unrelated to prostate volume in biopsy negative and positive cases the physiological basis of free PSA is an enigma.

A comparison of the free fraction of serum prostate specific antigen in men with benign and cancerous prostates: the best case scenario.

PURPOSE: In most previous studies of free-to-total serum prostate specific antigen (PSA) ratios, the specimens from patients with prostate cancer or those with benign prostatic hyperplasia (BPH) have not been highly characterized. We compared preoperative sera from post-radical prostatectomy patients with clinically significant cancers of at least 2 cm.3 to sera from those with BPH and large, biopsy negative prostates. MATERIALS AND METHODS: We used 2 different time resolved immunofluorometric assays for free and total PSA, and a combination of a chemoluminescent immunoassay for free PSA detection with an immunoradiometric assay for total PSA to measure free and total PSA. The serum ratios of free-to-total PSA in these assays were compared to those obtained previously from gel filtration studies. Sera from 51 men with prostate cancer volumes of 2 to 18 cm.3 were compared to those from 48 men with BPH and a mean prostate volume of 78 +/- 7 cm.3. The respective mean serum PSA levels plus or minus standard deviation were 10.0 +/- 6.3 and 8.9 +/- 7.2 ng./ml. RESULTS: Monoclonal assays for free PSA confirmed the previous study with gel filtration. For PSA 4 to 10 ng./ml., 94 to 95% of the men with prostate cancer were correctly diagnosed, with a cutoff of less than 15% for free-to-total PSA on immunofluorometric assay and less than 14% for chemoluminescent immunoassay with immunoradiometric assay. However, 46% (immunofluorometric assay) and 36% (chemoluminescent immunoassay and immunoradiometric assay) of men with BPH did not have enough free PSA for diagnosis of BPH (that is 36 to 46% false-positive rate). CONCLUSIONS: For total PSA 4 to 10 ng./ml., the sensitivity of approximately 15% free-to-total PSA for prostate cancer is high (94 to 95%) but 36 to 46% of men with BPH and a large gland will not be correctly identified. For PSA 2 to 4 ng./ml., no ratio of percent free-to-total PSA discriminated BPH from prostate cancer.

Physiological variation of serum prostate specific antigen in the 4.0 to 10.0 ng./ml. range in male volunteers.

PURPOSE: Because some patients show a surprising variation in serial serum prostate specific antigen (PSA) values, we determined the intra-individual or physiological variation in serum PSA by collecting sera 2 to 3 week apart without any prostatic manipulation. MATERIALS AND METHODS: Because 4.0 to 10.0 ng./ml. PSA is the critical range for decision making, we asked all men with a PSA in this range to return 2 to 3 weeks later for a second measurement. Total serum PSA was determined by the Hybritech Tandem-R, automated Tosoh AIA-600 and Delfia section immunoassays. Free and complexed serum PSA was determined by the Delfia assays. Between assay variation (first blood specimen retested on a separate day with the second blood specimen) was compared to the physiological variation (first versus second blood specimens). RESULTS: Mean coefficient of variation (95% confidence limits) was 10.5% for between assay and 23.5% for physiological evaluations. The preferred analysis of ratio difference variation provided a factor of 0.138 (between assay) and 0.298 (physiological) for 95% confidence limits. Changes in free or complexed PSA were not the cause of physiological variation. CONCLUSIONS: The intra-individual physiological variation is 2 to 3 times the between assay variation for sera drawn 2 to 3 weeks apart with a PSA of 4 to 10 ng./ml. A serum PSA of 4.0 ng./ml. can increase to 5.2 ng./ml. (4.0 x 0.298) and still be within the physiological variability for 95% confidence limits.

Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population.

OBJECTIVES: We measured the intraindividual variation of prostate-specific antigen (PSA) in the serum of healthy men screened for prostate cancer. METHODS: We used a fully automated PSA assay system (ACS: 180 assay) to evaluate a screening population of 814 men (mean age, 63.3 years; range, 50 to 79 years) without documented prostate cancer or prostate surgery. A second blood sample was drawn 15 to 183 days after the first specimen (mean, 80 days). RESULTS: In the ACS PSA ranges of 0 to 7.2 ng/mL, 7.3 to 17.9 ng/mL, and 18.0 ng/mL or greater (O to 4 ng/mL, 4 to 10 ng/mL, and 10.0 ng/mL or greater by the Tandem-R assay), the mean coefficient of variation of the first and second blood drawn was 20%, 12%, and 10%, respectively. In 435 men whose first blood samples were measured twice for PSA difference (interassay or run-to-run variation), the intraindividual variation in the range of 0 to 7.2 ng/mL was significantly larger than the interassay variation, which was also true the 7.3 to 17.9 ng/mL range. In the range of 0 to 7.2 ng/mL, 251 of 695 (36%) showed a 20% or greater relative increase and 69 of 695 (10%) showed a 1.3 ng/mL (0.75 ng/mL by the Tandem-R assay) or greater absolute increase of PSA at the second blood sample. CONCLUSIONS: We conclude that in the low ranges of PSA concentrations, one should consider the possibility of substantial intraindividual variation when interpreting serial PSA measurements.

Ultrasensitive assay of prostate-specific antigen used for early detection of prostate cancer relapse and estimation of tumor-doubling time after radical prostatectomy.

We used an ultrasensitive prostate-specific antigen (PSA) assay with a detection limit of 0.02 microgram/L for long-term monitoring of PSA changes in 5 patients who were cured by radical prostatectomy and in 10 patients who had failed prostatectomies; 5 patients who underwent cystoprostatectomy were also evaluated with one sample after surgery. Relapse-free periods, determined on the basis of criteria designed specifically for the ultrasensitive assay or proposed for other currently available PSA assays, were calculated for the patients with failed prostatectomies. Tumor-doubling times were also calculated, postsurgery, according to a model that assumes exponential tumor growth over time. We found that prostate cancer relapse, on average, could be diagnosed 420 or 883 days earlier with the ultrasensitive assay than with assays having detection limits of 0.1 or 0.3 microgram/L, respectively. Tumor-doubling times, calculated after radical prostatectomy, ranged from 67 to 568 days among the 10 patients. We also present evidence that even more-sensitive PSA assays might be able to further reduce the relapse-free periods in approximately 50% of the prostate cancer patients who ultimately relapse.

Clinical usefulness of free and complexed PSA.

We selected serums from 51 fully characterized prostate cancer patients and 48 biopsy-proven BPH patients in order to test the ability of the ratio of the free/total PSA in distinguishing between CaP and BPH patients in the best case scenario. The 51 cancer patients had cancer volumes ranging from 2.0-17.8 mL and had a median % free PSA of 8.9%. The 48 BPH patients, which had prostate volumens ranging from 36.9-313.8 mL, had a median % free PSA of 16.5%, almost twice that of the CaP patients. We also examined the physiological variation of serums drawn on the same patient over a reasonably short time (mean of 22 days). The variation between consecutive redraws on the same patient was measured to be 30% (95% confidence interval) in the PSA range of 4-10 micrograms/L, measured on the Hybritech Tandem-R PSA Assay.

A universal calibrator for prostate specific antigen (PSA).

We describe for the first time a protocol to purify an in vitro made PSA-ACT complex to apparent homogeneity by using a combination of gel filtration and ion-exchange chromatography. The purity of the PSA-ACT complex was confirmed by gel electrophoresis and Western blot. Purification of the PSA-ACT complex was highly reproducible. An extinction coefficient of 1.0 and 280 nm (L x g-1 x cm-1) was assigned to the PSA-ACT complex based on amino acid analysis. Molecular weight was assigned by taking cDNA of ACT (plus 26% carbohydrate) and the molecular weight of PSA (28,430) which totals 89,280. Two common calibrators were made consisting of 100% PSA-ACT complex and/or 90% PSA-ACT complex plus 10% free PSA (90:10 calibrator). The 90:10 calibrator is recommended as a universal calibrator for the international standardization of PSA immunoassays.

A comparison of 4 ultrasensitive prostate specific antigen assays for early detection of residual cancer after radical prostatectomy.

The Yang Pros-Check, Abbott IMx, Tosoh AIA-PACK PA and Nichols Institute reference laboratory prostate specific antigen (PSA) assays were compared in 30 patients (138 sera) known to have no residual prostate cells. The mean + 3 standard deviations of these sera was used to define a level of PSA that would indicate residual cancer. This residual cancer detection limit for each of the 4 assays is 0.06, 0.01, 0.07 and 0.05 ng./ml., respectively, but the 0.01 level for the IMx assay is an artifact caused by setting the zero calibrator too high. All 4 assays were then used to compare the number of days from radical prostatectomy to the detection of residual cancer in 23 cases (211 sera) that ultimately failed radical prostatectomy. The Yang, Tosoh and Nichols Institute assays were all similar, with an average of 569 to 589 days. The Abbott IMx assay was relatively insensitive in detecting the first appearance of PSA after radical prostatectomy (average 821 days) and it showed the earliest detection among the 4 assays in only 1 of 23 patients.