Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer.

PURPOSE: Determining serum total prostate specific antigen (PSA) has proved to be a valuable diagnostic aid for detecting prostatic carcinoma, although the lack of specificity has limited its usefulness. Studies indicate that the use of percent free PSA would improve specificity while maintaining sensitivity. Since complexed PSA represents the major proportion of measurable PSA in serum, we determined whether it represents a single test alternative to the use of percent free PSA for the early detection of prostate cancer. MATERIALS AND METHODS: Archival serum was obtained from 385 men with no evidence of malignancy on biopsy and 272 with biopsy confirmed prostate cancer. We determined the concentration and proportion of total, complexed and free PSA. RESULTS: Receiver operating characteristics analysis using total PSA results from all samples (range 0.32 to 117 ng./ml.) indicated that the areas under the curve for complexed PSA alone as well as the free-to-total and complexed-to-total PSA ratios were similar and significantly greater than those for total PSA alone. Within the range of 85% to 95% sensitivity receiver operating characteristics analysis revealed that the specificity of complexed PSA was higher than that of total PSA and equivalent to that of the free-to-total PSA ratio. We noted a similar improvement in specificity in the 4 to 10 ng./ml. total PSA range. Using published cutoff values for complexed, total and percent free PSA when total PSA was in the 4 to 10 ng./ml. range the sensitivity and specificity of complexed and percent free PSA were similar. Within the 4 to 10 ng./ml. total PSA range the population of patients with no evidence of malignancy and complexed PSA below the upper limit was different with respect to total PSA from that with no evidence of malignancy and free PSA greater than 25%. CONCLUSIONS: The measurement of complexed PSA represents an alternative to the use of percent free PSA, although the patient populations identified by the 2 tests are different.

Clinical evaluation comparing AxSYM CA 15-3, IMx CA 15-3 and Truquant BRTM RIA.

A retrospective clinical study was conducted to compare results obtained by AxSYM(R) CA 15-3(TM), IMx(R) CA 15-3 and Truquant(R) BRTM RIA using surplus serum specimens from healthy volunteers and patients with benign and malignant diseases. Linear regression analysis of AxSYM and IMx CA 15-3 versus Truquant BR RIA for specimens with results 0-250 U/ml gave correlation coefficients of 0. 888 and 0.910 and slopes of 0.67 and 0.69, respectively. For specimens with results 0-2,000 U/ml, slopes were 0.95 and 0.91, respectively. Receiver operator characteristic analyses, based on results from healthy females plus nonmalignant disease patients versus breast cancer patients, for all three assays gave essentially equivalent areas under the curves. Concordance between AxSYM or IMx CA 15-3 and Truquant BR RIA was greater than 92%. Serial dilution of seven serum specimens yielded linear regression correlation coefficients ranging from 0.997 to 1.000 for AxSYM and IMx CA 15-3, and from 0.962 to 0.998 for Truquant BR RIA. The average percent CVs of the calculated assay values for the 7 specimens were 4.9, 2.7 and 18.1 for AxSYM CA 15-3, IMx CA 15-3 and Truquant BR RIA, respectively. Average percent recoveries ranged from 96.2 to 110.7 for AxSYM and IMx CA 15-3, and 81.8 to 93.3 for Truquant BR RIA. Although assay values differ between the two methodologies, AxSYM CA 15-3, IMx CA 15-3 and Truquant BR RIA showed comparable trending results for the 24 breast cancer patients evaluated for serial monitoring.

Influence of radical prostatectomy on serum hormone levels.

PURPOSE: The influence of radical prostatectomy on the hypothalamic pituitary axis has not been well studied. It is also unclear how alterations in serum androgen levels that result from surgical removal of the prostate might influence the recovery of libido and sexual function following radical prostatectomy. We determined the influence of radical prostatectomy on the hypothalamic pituitary testicular axis of 63 men with clinically localized prostate cancer treated only with radical prostatectomy. MATERIALS AND METHODS: A total of 63 healthy men 43 to 67 years old were enrolled in this prospective study. Phlebotomy was performed immediately before and 1 year following radical retropubic prostatectomy. Sera were stored frozen and analyzed as a group at the end of the study. We measured serum testosterone, percent free testosterone, dihydrotestosterone (DHT), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin and prolactin. RESULTS: Following radical prostatectomy there was a statistically significant increase in serum testosterone, free testosterone, estradiol, LH and FSH (p <0.0001), and statistically significant decrease in serum DHT (p <0.0001). No difference was noted in serum sex hormone binding globulin or prolactin levels. There was no statistically significant correlation between any serum hormone and sample storage time, patient age or prostate volume that could limit potential bias in study design. Serum hormone changes did not correlate with pathological stage or histological grade for this group of patients. CONCLUSIONS: Radical prostatectomy influences the hypothalamic pituitary axis by increasing serum testosterone, percent free testosterone, estradiol, LH and FSH while decreasing serum DHT levels. These findings suggest that the sexual dysfunction associated with radical prostatectomy cannot be explained by androgen deficiency alone. These data further suggest that the normal prostate and/or prostate neoplasm could secrete a substance or substances that give negative feedback control to pituitary gonadotropin secretion. Further investigation is warranted to identify this substance or substances.

Identifying markers for pancreatic cancer by gene expression analysis.

To begin to identify new tumor markers, we recently performed a systematic study of gene expression in cancers of the colon and pancreas. Of the 45,000 genes identified, 183 were found to be expressed at significantly elevated levels in pancreatic cancer. One of the genes was tissue inhibitor of metalloproteinase type I (TIMP-1), which encodes a secreted protein. Analysis of TIMP-1 serum levels revealed significant increases in pancreatic cancer patients, but TIMP-1 by itself was inadequate as a serum marker for cancer. However, a combination of individually suboptimal markers (TIMP-1, CA19-9, and carcinoembryonic antigen) detected 60% of 85 patients with pancreatic cancers in a highly specific manner. These results suggest that a systematic analysis of gene expression can reveal novel serum markers and that individually suboptimal markers can be combined to yield higher sensitivity and specificity.

Bayer Immuno 1 PSA Assay: an automated, ultrasensitive method to quantitate total PSA in serum.

The Bayer Immuno 1 PSA Assay measures total PSA in human serum and demonstrates excellent performance with an interassay CV < or = 3.4% and a biological detection limit of 0.03 microgram/L. No significant interference from common hormonal and chemotherapeutic drugs, kallikrein, prostatic acid phosphatase, and trypsin, or elevated levels of total bilirubin, hemoglobin, triglycerides, and IgG was observed. The 95th percentile values for healthy individuals increased with age from 3.0 micrograms/L for males 50-59 years and 3.3 micrograms/L for males 60-69 years, to 4.6 micrograms/L for males > or = 70 years. Clinical studies with retrospective samples demonstrated correspondence between serial measurements of PSA and clinical outcome for 98% of 159 prostate cancer patients. Clinical sensitivity for patients with clinical evidence of disease, untreated at the time of specimen draw, increased with increasing stage from 77.5-100%. Specificity of 60-70% for BPH and other benign urogenital diseases was consistent with previous findings. Bayer Immuno 1 PSA Assay values for 2131 specimens from healthy subjects and patients with prostate cancer, BPH, and other malignant and nonmalignant diseases correlated well with the Abbott IMx PSA Assay over the range 0.0-6,238 micrograms/L (Y = 1.10 x + 0.02). The Bayer Immuno 1 PSA Assay provides automated ultrasensitive, precise, and equimolar measurement of total PSA in human serum.

Prospective evaluation of percent free-PSA and complexed-PSA for early detection of prostate cancer.

Aims of the study: Retrospective studies investigating the use of percent free-PSA for early detection of prostate cancer were limited for various reasons: by their use of long-term stored sera, poor mix of non-cancer to cancer cases and the use of only men with PSA values between 4.0 and 10.0 ng/mL. This prospective study investigates the clinical utility of percent free-PSA and complexed-PSA for early detection of prostate cancer in 219 consecutive men presenting for prostate biopsy. Methods: Of 246 consecutive men who underwent ultrasound guided sextant biopsy of the prostate for PSA elevation and/or suspicious digital rectal exam, 219 men had serum total PSA levels between 2.0 and 20.0 ng/mL and were included in this study. Serum total, free and complexed (PSA-ACT) were measured (Hybritech Inc.). Results: Pathologic examinations demonstrated that 72% and 28% of the biopsies were non-cancer and cancer respectively. The mean percent free-PSA was statistically different between the groups (cancer 14%+/-6.4 and non-cancer 18+/-9%, P<0.001) and improved cancer detection. PSA-ACT provided only modest improvement in cancer detection over that of total PSA. Among this cohort of men, the optimal total PSA reflex range for percent free-PSA was 3.0-7.0 ng/mL (38% specificity) with a percent free-PSA cut-off of 20% (95% sensitivity) yet only affected 56% of the cases. Conclusions: PSA-ACT added very little additional value to the clinical utility of total PSA for early detection. Percent free-PSA performed well for all reflex ranges. A sensitivity and specificity of 95% and 20% respectively were obtained using a single cut-off of 25% for percent free-PSA for the group of men with total PSA values between 4.0 and 10.0 and correlated well with recently reported prospective analyses.

Molecular forms of prostate-specific antigen and human kallikrein 2 (hK2) in urine are not clinically useful for early detection and staging of prostate cancer.

OBJECTIVES: Prostate-specific antigen (PSA), a member of the human kallikrein (hK) family, is the most important tumor marker for early detection, staging, and monitoring of men with prostate cancer today. However, the sensitivity of serum PSA is not sufficient to be used alone for prostate cancer screening. Recently, it was reported that the serum-to-urinary total PSA ratio improves the detection of men with prostate cancer, especially in men with a serum total PSA level between 4.0 and 10.0 ng/mL. We tested this hypothesis by evaluating the clinical usefulness of this PSA ratio as well as the use of the different molecular forms of PSA and human kallikrein 2 (hK2) in urine for detection and staging of prostate cancer. METHODS: One hundred ten fresh, midstream urine specimens (prostate cancer 62, benign prostatic hyperplasia [BPH] 38, healthy male control 5, women 5) were collected. Serum total PSA, urine total PSA, urinary free PSA, urinary alpha 1-antichymotrypsin-bound PSA, and urinary hK2 levels were determined by monoclonal antibody assays (Hybritech Inc.). The serum-to-urinary total PSA ratio was calculated. RESULTS: The serum-to-urinary total PSA ratio did not accurately distinguish between men with BPH and men with prostate cancer. There was no significant difference between the urinary levels of any of the molecular forms of PSA or hK2 between men with prostate cancer and men with BPH. Among men with prostate cancer, neither urinary hK2 nor urinary levels of any of the molecular forms of PSA correlated with age, pathologic stage, or Gleason grade. CONCLUSIONS: In our study, the serum-to-urinary total PSA ratio did not improve the detection of men with prostate cancer. Furthermore, measurement of the molecular forms of PSA and hK2 in urine did not improve the detection or staging of prostate cancer over serum PSA alone.

The value of prostate-specific antigen in the management of localized prostatic cancer.

Prostate-specific antigen has proven to be a new useful marker for the evaluation of men with prostatic cancer. In addition to its proven value for immunohistochemical staining and for the followup evaluation of men treated with hormonal therapy, the monoclonal immunoradiometric assay for PSA has proven to be a unique, sensitive, and specific marker for the followup evaluation of men who have undergone radical prostatectomy.

Monitoring breast cancer with CA 549.

CA 549, a new marker for breast cancer, was measured in serum of 719 patients by an immunoradiometric assay involving two monoclonal antibodies: BC4E 549, developed against a breast-tumor cell line, and BC4N 154, developed against milk fat-globule membrane. The reference interval for healthy women was 0-11 kilo-units/L. The percentages of patients with CA 549 greater than 11 kilo-units/L for benign conditions are: 0% pregnancy, 1% breast, 26% liver; and for nonbreast metastatic cancers: 12% endometrial, 33% lung, 40% prostatic, and 50% ovarian. In women with breast cancer who were receiving or had completed adjuvant therapy with no evidence of disease there was an 11% increase in CA 549. For patients with metastatic breast cancer, 19% of those in complete remission, 63% of those in partial remission, and 88% of those with systemic progression had increased CA 549. CA 549 is a more specific marker than carcinoembryonic antigen (CEA) in nonmalignant disease, nonbreast malignancies, and adjuvant breast-cancer patients, and it is more sensitive in breast-cancer patients with progressive disease than is CEA. We could show CA 549 to be superior to CEA for detecting active breast cancer in patients with malignant or nonmalignant breast diseases. In monitoring 19 adjuvant-treated patients, CA 549 correlated more closely with the clinical course than did CEA values and, when increased, predicted a clinical recurrence. In 18 breast-cancer patients with metastasis, monitored for two to three years, the change of CA 549 values paralleled disease courses more often than did CEA values.

Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy.

The usefulness of prostate specific antigen to predict final pathological stage was studied in 178 consecutive patients. Prostate specific antigen was determined preoperatively in all patients by a monoclonal immunoradiometric assay. All pathological specimens were examined for capsular penetration, seminal vesicle involvement and lymph node involvement. Prostate specific antigen correlated directly with capsular penetration (p less than 0.002), seminal vesicle involvement (p less than 0.02) and lymph node involvement (p less than 0.05). However the diagnostic accuracy of an elevated serum antigen level on an individual basis was only 55 per cent for capsular penetration and 50 per cent for seminal vesicle involvement and lymph node involvement. With a log-linear regression model, the half-life of prostate specific antigen was calculated to be 3.15 +/- 0.09 days. From the equation PSA (t) equals PSA (2) e[-0.2197(t-2)], prostate specific antigen can be used to detect residual cancer on day t in the immediate postoperative period. With respect to long-term followup, 127 patients have been monitored for longer than 2 months postoperatively with prostate specific antigen (mean followup 2 years, range 2 months to 8.6 years). Of the 101 patients who had favorable pathological findings at operation (organ-confined cancer or capsular penetration only) 92 (91 per cent) had a followup antigen concentration in the female range (0.0 to 0.2 ng. per ml.), whereas only 5 of 26 men (19 per cent) with either seminal vesicle involvement or lymph node involvement had an antigen value that was less than 0.2 ng. per ml. All patients with a documented clinical recurrence (8 of 127, 6 per cent) had an elevated followup serum prostate specific antigen concentration. These findings suggest that preoperative levels of prostate specific antigen are not sufficiently reliable to predict final pathological stage on an individual basis in patients with early prostatic cancer, and that the antigen is a sensitive tumor marker for the detection of residual disease after radical prostatectomy and subsequent recurrence of tumor on long-term followup.

Monitoring hepatocellular carcinoma by using a monoclonal immunoenzymometric assay for alpha-fetoprotein.

A monoclonal immunoenzymometric assay for alpha-fetoprotein (M-AFP) was evaluated with respect to its utility in monitoring hepatocellular carcinoma (HCC) patients. Earlier (Clin Chem 1986;32:1318-22), we found this immunoassay to demonstrate abilities similar to polyclonal AFP assays, and we suggested that changes in M-AFP correlated with changes in intrahepatic tumor volume in most HCC patients. In the present study, 107 HCC patients were evaluated between 1978 and 1986. Patient demographics characterized this study population as being similar to those seen in regions with low incidence of HCC. Changes in serum M-AFP concentration correlated moderately (r = 0.55) with changes in intrahepatic tumor volume. The AFP concentration in serum was found to be a statistically significant independent predictor of survival; patients with above-normal M-AFP (AFP[+]) at presentation demonstrated a median survival time of 10 months, compared with 16 months for patients with "normal" values for M-AFP (AFP[-]) (P = 0.008). This prognostic pattern persisted when adjusted for serum bilirubin concentration (AFP[+] 12 months vs AFP[-] 29 months, P = 0.01).

Prostate-specific antigen as a marker for prostatic cancer: a monoclonal and a polyclonal immunoassay compared.

We evaluated the clinical utility of prostate-specific antigen (PSA) in diagnosis and management of prostatic cancer, using a monoclonal immunoradiometric assay (M-PSA) and a polyclonal radioimmunoassay (P-PSA). Assay CVs ranged from 1.3% to 4.9% (M-PSA) and from 5.1% to 8.0% (P-PSA). Detection limits were 0.1 microgram/L (M-PSA) and 0.2 microgram/L (P-PSA). Reference intervals established for healthy men were: 0-2.8 micrograms/L (M-PSA) and 0-4.2 micrograms/L (P-PSA). The regression equation for the PSA concentrations (0-100 micrograms/L) measured in normal men, men with primary prostatic cancer, and men with benign prostatic hypertrophy (BPH) was: P-PSA = 1.603 M-PSA - 0.120 microgram/L (r = 0.9923, n = 201). The P-PSA calibrators yielded one-half their assigned values when analyzed by the M-PSA assay. With either assay there were proportional increases in PSA values with advancing cancer. The proportion of PSA values exceeding the reference interval was 50% for patients with stage A prostatic cancer, 80% (stage B), 100% (stages C and D), and 65% for men with BPH. After radical prostatectomy, the follow-up PSA values for most patients were within the reference intervals for women (0-0.2 microgram/L for M-PSA, 0-0.8 microgram/L for P-PSA). Most patients with above-normal PSA values have clinically detectable disease.