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CLIA ‘88 superseded CLIA ‘67. CLIA ‘88 set standards designed to improve quality and expanded federal oversight to virtually all clinical laboratories in the United States. Presumably because genetics testing was then in its infancy, CLIA ‘88 did not devote a special section to genetics testing. Biochemical and immunochemical tests used to evaluate inborn errors of metabolism and other genetic entities were categorized as analytes in the Clinical Chemistry section, and DNA probes used primarily in infectious disease were included in Microbiology. The legal, social, economic, and ethical implications of genetic testing and the rapid commercialization of these tests led to recommendations that genetic testing be defined as a laboratory specialty with a subsection in CLIA. The advisory committee created under CLIA was assigned to review these recommendations. The committee agreed that genetics testing was sufficiently different from other areas already included in CLIA to warrant a separate section. Two definitions were adopted. The more clear-cut one is for molecular genetic and cytogenic tests. This includes the analysis of human DNA/RNA in evaluating genetic diseases. The second definition is not as clear-cut and is for the analysis of proteins and metabolites used predominantly to detect inborn errors of metabolism. Many of these analytes already are categorized according to their uses for other purposes. The recommendations for genetic testing include detailed and specific proposals concerning personnel, confidentiality and informed consent, quality control, contamination, proficiency testing, validation of tests, special reporting, retention of records, and reuse of tested specimens.

We conducted a multicenter evaluation of the analytical and clinical features of the automated Bayer Immuno 1™ CA 15-3™ assay and compared assay performance to two manual tests. Results of the 10-day imprecision study of the Bayer Immuno 1 assay pooled across four evaluation sites and three lots of reagent produced total CV ≤4%. Lot-to-lot reproducibility for 26 different lots of reagents and calibrators manufactured over a 2-year period was demonstrated (CV, 1.1%). Results for the Bayer Immuno 1 assay correlated well with the Biomira TRUQUANT® BR™ 27.29 and Centocor® CA 15-3 RIAs (r ≥0.94). The upper limit of the reference interval for the Bayer Immuno 1 assay was 35.9 kilounits/L (35.9 units/mL); values were similar for all methods. Longitudinal monitoring of healthy women yielded assay values with an average CV of 11% and 21% for the Bayer Immuno 1 and Biomira assays, respectively. The Bayer Immuno 1 assay demonstrated the analytical features, intermethod correlation, and long-term performance characteristics that are essential for longitudinal monitoring of breast cancer patients.

Screening is defined as the presumptive identification of unrecognized disease or defect by the application of tests, examinations, or other procedures that can be applied rapidly and carried out in the general population or in individuals at high risk. When considering immunochemical or biochemical cancer markers, it might be more appropriate to describe these tests as risk-factor monitors and introduce the concept of two interpretations of these tests: in asymptomatic populations as indicators of probability of cancer, and in patients with previously treated cancer as predictors of recurrence despite initial treatment described as "curative." The successes of screening with alpha-fetoprotein for hepatocellular carcinoma and with catechol metabolites in neuroblastoma are discussed. The major emphasis will be the possible use of CA 125 and prostate-specific antigen (PSA) in risk-factor assessment of ovarian cancer and prostate cancer, respectively. It is important to understand in what context a PSA value > 10 micrograms/L indicates a 67% probability of cancer.

Critical-care medicine requires rapidity of treatment decisions and clinical management. To meet the objectives of critical-care medicine, the critical-care laboratory must consider four major aspects of laboratory organization in addition to analytical responsibilities: specimen collection and delivery, training of technologists, selection of reliable instrumentation, and efficient data dissemination. One must also consider the advantages and disadvantages of centralization vs decentralization, the influence of such a laboratory on patient care and personnel needs, and the space required for optimal operation. Centralization may lead to workflow interruption and increased turnaround time (TAT); decentralization requires redundancy of instrumentation and staff but may shorten TAT. Minimal TAT is the hallmark of efficient laboratory service. We surveyed 55 laboratories in 33 hospitals and found that virtually all hospitals with 200 or more beds had a critical-care laboratory operating as a satellite of the main laboratory. We present data on actual TAT, although these were available in only eight of the 15 routine laboratories that provided emergency service and in eight of the 40 critical-care laboratories. In meeting the challenges of an increasing workload, a reduced clinical laboratory work force, and the need to reduce TAT, changes in traditional laboratory practice are mandatory. An increased reliance on whole-blood analysis, for example, should eliminate delays associated with sample preparation, reduce the potential hazards associated with centrifugation, and eliminate excess specimen handling.

Prostate-specific antigen (PSA) is a widely used biochemical marker for prostate cancer (1). PSA, a serine protease, forms complexes with serine protease inhibitors such as α2-macroglobulin and α1-antichymotrypsin (ACT) (2). The major immunoreactive forms of serum PSA are PSA-ACT complex and free PSA. PSA complexed to α2-macroglobulin is not measured by current immunoassays (3). Because the proportion of PSA complexed to ACT is higher in men with prostate cancer than in men with benign prostatic hyperplasia (BPH) (3)(4), the use of a ratio of free-to-total PSA may improve discrimination between men with BPH and prostate cancer (5)(6). Results obtained with different PSA immunoassays are not interchangeable (7)(8)(9)(10). The variation among immunoassays reflects, in large part, the specificity of different PSA antibodies (7). To a lesser extent, the composition of the calibrator, the PSA values assigned to the calibrator, the test diluent, and the physical design of the immunoassays contribute to intermethod differences (6)(7). Assays using a monoclonal-monoclonal sandwich format yield, in general, an equimolar response to free and ACT-complexed PSA, whereas monoclonal-polyclonal formats tend to yield higher values for samples containing greater proportions of free PSA (8). We have recently described the Bayer Immuno 1TM PSA Assay (Bayer Corporation), which uses a monoclonal-polyclonal antibody format that yields an equimolar response to varying proportions of free and complexed PSA (11). This has now been found to be a result of the unique binding properties of the monoclonal antibody used for the capture of PSA (manuscript in submission). Proficiency testing among clinical laboratories has indicated large intermethod variability in the quantitation of total PSA (12). The aim of this study was to determine the magnitude and cause of this intermethod variation. Here we report our multi-site analysis of …

We evaluated a new fully automated procedure for quantitative measurement of prostate-specific antigen (PSA) by the Microparticle Enzyme Immunoassay (MEIA) technology developed for the Abbott IMx automated immunoassay system. The performance characteristics of the Abbott IMx PSA assay (y) were evaluated and compared with those of the Hybritech Tandem-E PSA assay (x), a solid-phase two-site immunoenzymometric assay. PSA values for both assays were well correlated (r = 0.99); regression analysis yielded the equation y = 0.92x - 0.23 micrograms/L. The Abbott assay proved reliable and reproducible, as shown by the intra- and interassay coefficients of variation (2.0-3.4% and 3.1-4.7%, respectively). The assay gave a linear standard curve up to 100 micrograms/L and was very sensitive (detected PSA < 0.1 microgram/L). This analytical sensitivity was comparable with that of the Tandem-E PSA assay. Overall, the IMx PSA assay demonstrated the accuracy, precision, linearity, and intermethod correlation required for monitoring patients with prostate cancer.

CLIA '88 superseded CLIA '67. CLIA '88 set standards designed to improve quality and expanded federal oversight to virtually all clinical laboratories in the United States. Presumably because genetics testing was then in its infancy, CLIA '88 did not devote a special section to genetics testing. Biochemical and immunochemical tests used to evaluate inborn errors of metabolism and other genetic entities were categorized as analytes in the Clinical Chemistry section, and DNA probes used primarily in infectious disease were included in Microbiology. The legal, social, economic, and ethical implications of genetic testing and the rapid commercialization of these tests led to recommendations that genetic testing be defined as a laboratory specialty with a subsection in CLIA. The advisory committee created under CLIA was assigned to review these recommendations. The committee agreed that genetics testing was sufficiently different from other areas already included in CLIA to warrant a separate section. Two definitions were adopted. The more clear-cut one is for molecular genetic and cytogenic tests. This includes the analysis of human DNA/RNA in evaluating genetic diseases. The second definition is not as clear-cut and is for the analysis of proteins and metabolites used predominantly to detect inborn errors of metabolism. Many of these analytes already are categorized according to their uses for other purposes. The recommendations for genetic testing include detailed and specific proposals concerning personnel, confidentiality and informed consent, quality control, contamination, proficiency testing, validation of tests, special reporting, retention of records, and reuse of tested specimens.

We conducted a multicenter evaluation of the analytical and clinical features of the automated Bayer Immuno 1 CA 15-3 assay and compared assay performance to two manual tests. Results of the 10-day imprecision study of the Bayer Immuno 1 assay pooled across four evaluation sites and three lots of reagent produced total CVor = 4%. Lot-to-lot reproducibility for 26 different lots of reagents and calibrators manufactured over a 2-year period was demonstrated (CV, 1.1%). Results for the Bayer Immuno 1 assay correlated well with the Biomira TRUQUANT BR 27.29 and Centocor CA 15-3 RIAs (ror = 0.94). The upper limit of the reference interval for the Bayer Immuno 1 assay was 35.9 kilounits/L (35.9 units/mL); values were similar for all methods. Longitudinal monitoring of healthy women yielded assay values with an average CV of 11% and 21% for the Bayer Immuno 1 and Biomira assays, respectively. The Bayer Immuno 1 assay demonstrated the analytical features, intermethod correlation, and long-term performance characteristics that are essential for longitudinal monitoring of breast cancer patients.

Screening is defined as the presumptive identification of unrecognized disease or defect by the application of tests, examinations, or other procedures that can be applied rapidly and carried out in the general population or in individuals at high risk. When considering immunochemical or biochemical cancer markers, it might be more appropriate to describe these tests as risk-factor monitors and introduce the concept of two interpretations of these tests: in asymptomatic populations as indicators of probability of cancer, and in patients with previously treated cancer as predictors of recurrence despite initial treatment described as "curative." The successes of screening with alpha-fetoprotein for hepatocellular carcinoma and with catechol metabolites in neuroblastoma are discussed. The major emphasis will be the possible use of CA 125 and prostate-specific antigen (PSA) in risk-factor assessment of ovarian cancer and prostate cancer, respectively. It is important to understand in what context a PSA value10 micrograms/L indicates a 67% probability of cancer.

Laboratory Initiative For The Year 2000 (LIFT), the laboratory response to the Healthy People 2000 program, includes the following in its definition of chronic disease: cancer, diabetes, hypertension, end-stage renal disease, stroke, and cardiovascular disease. All are priority health targets for which the laboratory must play an active support role if we are to achieve the goal of controlling these diseases by the year 2000. What are the laboratory procedures needed to assist in the prevention and detection of chronic disease? In this review I consider the traditional tests now used in these efforts, emphasize how and where screening for diabetes, cardiovascular disease, and cancer is now done, and describe the current status of the clinical laboratory in supporting these activities, including new and promising procedures that may be useful in identifying individuals at high risk for disease. It is important to initiate good clinical laboratory practice for these new tests as they are transferred from the research laboratory to the clinical laboratory. The laboratory will be required to provide for this need rapidly and at the same time comply with federal and state controls and regulations.

Critical-care medicine requires rapidity of treatment decisions and clinical management. To meet the objectives of critical-care medicine, the critical-care laboratory must consider four major aspects of laboratory organization in addition to analytical responsibilities: specimen collection and delivery, training of technologists, selection of reliable instrumentation, and efficient data dissemination. One must also consider the advantages and disadvantages of centralization vs decentralization, the influence of such a laboratory on patient care and personnel needs, and the space required for optimal operation. Centralization may lead to workflow interruption and increased turnaround time (TAT); decentralization requires redundancy of instrumentation and staff but may shorten TAT. Minimal TAT is the hallmark of efficient laboratory service. We surveyed 55 laboratories in 33 hospitals and found that virtually all hospitals with 200 or more beds had a critical-care laboratory operating as a satellite of the main laboratory. We present data on actual TAT, although these were available in only eight of the 15 routine laboratories that provided emergency service and in eight of the 40 critical-care laboratories. In meeting the challenges of an increasing workload, a reduced clinical laboratory work force, and the need to reduce TAT, changes in traditional laboratory practice are mandatory. An increased reliance on whole-blood analysis, for example, should eliminate delays associated with sample preparation, reduce the potential hazards associated with centrifugation, and eliminate excess specimen handling.

We evaluated assays of Tissue Polypeptide Antigen in serum and urine, as an index to the presence of cancer. In the assay, serum, which is first absorbed with human albumin-labeled sheep erythrocytes, or untreated urine (diluted with an equal volume of TPA-free serum) is incubated with antibody specific to Tissue Polypeptide Antigen and then reacted with sheep erythrocytes labeled with Tissue Polypeptide Antigen. We found an increased concentration of Tissue Polypeptide Antigen in the serum of 378 of 513 (74%) and in the urine of 49 of 77 (64%) patients with cancer, as compared with 40/112 (36%) and 7/29 (24%), respectively, for individuals with benign neoplasms. Normal individuals were defined as those with less than 0.09 unit of the antigen per milliliter of specimen. Concentrations exceeding this were found in 2/67 (3%) sera and 6/56 (11%) urines from supposedly normal persons. Tissue Polypeptide Antigen was found in above-normal concentrations in patients with cancer, regardless of neoplasm type and extension, with a higher proportion of abnormal values in patients with distal metastases.

We evaluated the effect of human anti-murine antibodies (HAMA) on apparent concentrations of carcinoembryonic antigen (CEA) as measured in serum with commercial enzyme immunoassay (EIA) kits manufactured by Abbot ("two-step" double monoclonal antibody assay), Roche, and Hybritech (room-temperature protocol). In sera from patients given parenteral murine monoclonal antibody for experimental diagnostic and immunotherapy studies, HAMA titers were determined with Immunomedics' "ImmuSTRIP HAMA-EIA" kit reagents. "True" CEA titers were established by using the ImmuCEA/MA-EIA and heat-extraction to destroy HAMA before assay for CEA. The concordance of the ImmuCEA/MA assay with the Abbott and Roche CEA EIAs was established with sera from normal individuals and from patients who had not received parenteral injections of murine monoclonal antibody. At high (100 mg/L) concentrations of HAMA, false-positive results were observed with all three kits. The Hybritech and Roche assays were more sensitive to interference by HAMA than was the Abbott CEA-EIA, false-positive results being observed at HAMA concentrations between 1 and 10 mg/L. Similar sensitivity of the three kits to interference by primate anti-MAb sera was demonstrated. Use of primate anti-MAb sera to create controls with HAMA activity and of analyte is recommended to evaluate MAb assays for potential HAMA interference and for use to devise methods to eliminate HAMA interference.

In the RA-1000, a random-access discrete analyzer, an inert fluorocarbon fluid is used to prevent interaction and carryover. Production-model instruments were evaluated in two laboratories with respect to determination of glucose, creatinine, total protein, inorganic phosphorus, cholesterol, alkaline phosphatase, lactate dehydrogenase, creatine kinase, gamma-glutamyltransferase, and aspartate and alanine aminotransferases. Within-run, among-run, and day-to-day (for 15 days) precision was assessed, and results were correlated with those obtained by the methods routinely in use in our departments. Precision was excellent, correlation acceptable.

We determined estrogen receptor protein and carcinoembryonic antigen in cytosols prepared from 189 human breast carcinoma tissues, 85 benign or normal breast biopsies, and 101 tissue specimens metastatic from breast carcinoma. Carcinoembryonic antigen was observed in 70% of the primary carcinomatous tissues, 15% of the benign or normal specimens, and 51% of the metastases. Ninety-six of the 189 primary carcinomatous specimens with increased concentrations of carcinoembryonic antigen were also positive for estrogen receptor protein, whereas 67 of the 72 benign or normal biopsies with low concentrations of carcinoembryonic antigen were also negative for estrogen receptor protein. All five fenign specimens with positive estrogen receptor protein and normal carcinoembryonic antigen concentrations were from fibroadenomas. The concordance between estrogen receptor protein and carcinoembryonic antigen in the primary carcinomatous tissue was 66%, in metastatic carcinoma 51%, and in benign and normal tissue 85%.

We evaluated two multi-analyte analyzers, the NOVA Stat Profile 1 (SP 1) and the NOVA Stat Profile 5 (SP 5). The SP 1 measures pH, pCO2, pO2, sodium, potassium, ionized calcium, and hematocrit in heparinized whole blood; the SP 5 determines all these analytes, plus chloride (not evaluated because it was unavailable at the time this study was initiated) and glucose. Interassay precision for pH, pCO2, pO2, sodium, potassium, ionized calcium, and hematocrit (all on the SP 1) and glucose (on the SP 5) was excellent, the respective CVs (%) being: less than 0.006, 2.1, less than or equal to 3.0, less than or equal to 0.5, less than or equal to 1.7, less than or equal to 2.1, less than or equal to 3.9, and less than or equal to 1.2. Correlation with results obtained with Corning's Model 178, NOVA Biomedical's Model 6, Beckman's Astra 8, and Roche's Cobas-Bio was also excellent (r greater than 0.975 for all analytes, r for hematocrit 0.865). Temperature-stability studies on whole-blood specimens maintained at 1 degree C indicated that results for all measured analytes were essentially uncharged for at least 2 h, except for potassium, which increased by 13% in 2 h. At 22 degrees C, values for pH, pCO2, pO2, and glucose changed significantly within 2 h. Advantages of the NOVA Stat Profile series include decreased specimen requirements (250 microL), analysis time (72-90 s), turnaround time (about 4.5 min), and overall cost of operation.

We have evaluated Roche Diagnostics' RIA-CEA and Abbott Diagnostics' EIA-CEA methods for precision, normal reference interval, concordance, and correlation of malignant disease with increase in carcinoembryonic antigen (CEA) in plasma. In examining concordance, we used data on 138 patients with primary carcinomas of the breast, colon, lung, or pancreas, each further classified by extent of dissemination. We find the two methods to be comparably precise. The respective upper reference limits of normal for the Roche and Abbott methods were determined to be 5.0 micrograms/L and 4.6 micrograms/L. The regression equation for a log transformation of the 177 data points is y = 0.966x + 0.03, where x = Roche and y = Abbott, with a correlation coefficient of 0.948. According to the criteria we used, the concordance was 78.7%. The largest discordance was observed in widely disseminated disease states and in cancers of the colon and pancreas. Paired data analysis of discordance indicated greater increases in apparent CEA by the Abbott method in most colon cancers with liver involvement; six of the eight discordant pancreatic cancers had higher Roche-CEA values. CEA heterogeneity and the role of the liver in CEA metabolism appear to contribute to the observed differences. We show why the two methods should not be used interchangeably, and that baseline values for CEA must be established for each method.

Using 600 clinical specimens, we compared the concordance of four methods for carcinoembryonic antigen: the Roche RIA (I); the Roche EIA (II); Hybritech EIA (III); and Abbott EIA (IV). EDTA-treated plasma was used for Methods I and II and serum for Methods III and IV. However, no significant difference was found between results for serum and plasma in Method II. The normal reference interval (in micrograms/L) was I (222 specimens), 1.94 +/- 1.54; II (57 specimens), 0.8 +/- 0.5; III (100 specimens), 2.94 +/- 2.47; and IV (614 specimens), less than 5.0. The precision of all four methods was acceptable. Concordance among all of the methods exceeded 90%.

"SMAC" (Sequential Multiple Analyzer plus Computer) is a high-speed computer-controlled multitest analyzer. A 20-channel prototype SMAC (glucose, urea nitrogen, creatinine, carbon dioxide content, total bilirubin, calcium, phosphorus, cholesterol, iron, uric acid, chloride, sodium, potassium, total protein, albumin, creatine kinase, alkaline phosphatase, lactate dehydrogenase, and aspartate and alanine aminotransferases) has been evaluated for: (a) method precision during within-day runs and on a day-to-day basis over a period of time; (b) method linearity over a range established on a chemical basis and related to clinical requirements, with use of both aqueous standards and protein matrix reference material; and (c) correlation of SMAC values with those obtained by the methods routinely in use in our department.

We evaluated a newly developed solid-phase immunoassay (EIA) of terminal deoxynucleotidyl transferase (TdT, EC 2.7.7.3) and compared it with the enzymatic assay of TdT involving DNA polymerase. We assessed the precision, performance characteristics, and clinical efficacy of the EIA procedure, using 249 specimens of peripheral blood and bone marrow and 118 specimens of whole blood. On linear regression analysis of results for these 249 samples as measured by the two procedures, the correlation coefficient was 0.87. Distribution of TdT in mononuclear cells isolated from whole blood and bone marrow of subjects in several disease categories indicated good concordance between the two assay procedures. The EIA procedure is precise, can be performed on whole blood without first isolating mononuclear cells, is nonisotopic, and shows potential as a quantitative indicator for the differential diagnosis and monitoring of human leukemia.

An automated method has been devised for determining 5'-nucleotidase activity in serum. A modified creatine phosphokinase cartridge (Technicon Instrument Corp., Tarrytown, N. Y.) is used to prepare a reaction mixture containing, per liter: barbital buffer (pH 7.5), 16.1 mmol; adenosine-5'-phosphate, 5.4 mmol; Mg2+, 20.2 mmol; phenyl phosphate, 7.8 mmol; adenosine deaminase, 0.78 mg; and sample, 0.21 ml/ml of reaction mixture. After incubation, the liberated ammonium ion is determined by use of the alkaline hypochlorite-phenol reaction. Nucleotidase activity as determined by the automated method correlated well with activities as determined manually by a Ni2+ inhibition—phosphate analysis procedure. Respective values obtained by the manual and by this procedure were: for sera with activities within the normal range, 7.9 ± 3.2 and 8.2 ± 3.3 U/liter; for activities between 16 and 50 U/liter, 26.3 ± 9.3 and 26.5 ± 8.8 U/liter; and for serum with activities greater than 50 U/liter, 79.1 ± 42.5 and 78.7 ± 41.3 U/liter.

There is a well-recognized need for a reliable, convenient, and simple method for determining whole blood pH, PaCOaCO2, and PaOaO2. We have designed a specimen collection set that facilitates collection of the specimen and permits convenient and reliable analysis by the laboratory. Specimens are collected in newly designed "Vacutainer" tubes containing heparin and nitrogen gas. Without removing the Vacutainer stopper, the specimen may be anaerobically introduced into the analytical equipment through a unique aspirating needle. Atmospheric contamination of the specimen is eliminated.

By means of a sensitive fluorometric technic, serum bile acids were determined in patients with various liver diseases. Correlations were shown between the bile acid values and those of transaminase and alkaline phosphatase in cases of liver metastases, and bile acid and transaminase values in cases of viral hepatitis. For most clinical purposes, however, the determination does not yield information which cannot be obtained more readily using currently accepted methods.

During determination of the oxygen capacity of blood by the Van Slyke method (1), the following adaptations were made in order to reduce errors: (1) Blood was equilibrated with water-saturated air in a siliconized tonometer. (2) The determination of the oxygen content of the sample was carried out immediately after equilibration. (3) Triton was used instead of saponin in the ferricyanide reagent. (4) Special care was taken in the preparation and storage of the dithionite reagent, which should be prepared fresh daily and stored in the dark at 4°. The hemoglobin content and oxygen capacity, measured by the modified technic, were compared in a series of 36 samples of human blood.

We evaluated lipid-bound sialic acid as a "marker" in cancer patients and assessed the individual and combined value of lipid-bound sialic acid and carcinoembryonic antigen determinations in these patients. Plasma was sampled from 62 normal subjects and 125 cancer patients. Lipid-bound sialic acid was determined by the resorcinol method after total lipid extraction and isolation of the sialolipid fraction from plasma. Neither marker was increased in many breast cancer patients. Carcinoembryonic antigen was increased more commonly and to a greater degree in colon cancer patients and seems to be the preferred marker. Both markers were increased in lung cancer patients and their combined evaluation improved the rate of detection. Lipid-bound sialic acid was increased in more patients with leukemias, lymphomas, Hodgkin's disease, and melanomas, suggesting that it may be a useful biochemical marker in these types of cancer.

Urinary excretions of cystathionine, catecholamines, and vanillymandelic acid were compared in 27 patients with neuroblastoma and in nine other patients with non-neurogenic tumors. Eleven of the 27 patients were without clinical evidence of active neuroblastoma at the time of the study and excreted no or relatively small amounts of urinary cystathionine. Thirteen of the remaining 16 patients with progressive neuroblastoma had elevated cystathionine values. Elevated values were also detected in three of nine patients with other tumors. There was no correlation between the excretion of cystathionine and either catecholamines or vanillymandelic acid. The assay of cystathionine in addition to catecholamines and vanillymandelic acid is recommended for the complete biochemical evaluation of patients with neuroblastoma.

We evaluated assays of Tissue Polypeptide Antigen in serum and urine, as an index to the presence of cancer. In the assay, serum, which is first absorbed with human albumin-labeled sheep erythrocytes, or untreated urine (diluted with an equal volume of TPA-free serum) is incubated with antibody specific to Tissue Polypeptide Antigen and then reacted with sheep erythrocytes labeled with Tissue Polypeptide Antigen. We found an increased concentration of Tissue Polypeptide Antigen in the serum of 378 of 513 (74%) and in the urine of 49 of 77 (64%) patients with cancer, as compared with 40/112 (36%) and 7/29 (24%), respectively, for individuals with benign neoplasms. Normal individuals were defined as those with less than 0.09 unit of the antigen per milliliter of specimen. Concentrations exceeding this were found in 2/67 (3%) sera and 6/56 (11%) urines from supposedly normal persons. Tissue Polypeptide Antigen was found in above-normal concentrations in patients with cancer, regardless of neoplasm type and extension, with a higher proportion of abnormal values in patients with distal metastases.

We evaluated a newly developed solid-phase immunoassay (EIA) of terminal deoxynucleotidyl transferase (TdT, EC 2.7.7.3) and compared it with the enzymatic assay of TdT involving DNA polymerase. We assessed the precision, performance characteristics, and clinical efficacy of the EIA procedure, using 249 specimens of peripheral blood and bone marrow and 118 specimens of whole blood. On linear regression analysis of results for these 249 samples as measured by the two procedures, the correlation coefficient was 0.87. Distribution of TdT in mononuclear cells isolated from whole blood and bone marrow of subjects in several disease categories indicated good concordance between the two assay procedures. The EIA procedure is precise, can be performed on whole blood without first isolating mononuclear cells, is nonisotopic, and shows potential as a quantitative indicator for the differential diagnosis and monitoring of human leukemia.

We evaluated lipid-bound sialic acid as a "marker" in cancer patients and assessed the individual and combined value of lipid-bound sialic acid and carcinoembryonic antigen determinations in these patients. Plasma was sampled from 62 normal subjects and 125 cancer patients. Lipid-bound sialic acid was determined by the resorcinol method after total lipid extraction and isolation of the sialolipid fraction from plasma. Neither marker was increased in many breast cancer patients. Carcinoembryonic antigen was increased more commonly and to a greater degree in colon cancer patients and seems to be the preferred marker. Both markers were increased in lung cancer patients and their combined evaluation improved the rate of detection. Lipid-bound sialic acid was increased in more patients with leukemias, lymphomas, Hodgkin's disease, and melanomas, suggesting that it may be a useful biochemical marker in these types of cancer.

We evaluated the effect of human anti-murine antibodies (HAMA) on apparent concentrations of carcinoembryonic antigen (CEA) as measured in serum with commercial enzyme immunoassay (EIA) kits manufactured by Abbot ("two-step" double monoclonal antibody assay), Roche, and Hybritech (room-temperature protocol). In sera from patients given parenteral murine monoclonal antibody for experimental diagnostic and immunotherapy studies, HAMA titers were determined with Immunomedics' "ImmuSTRIP HAMA-EIA" kit reagents. "True" CEA titers were established by using the ImmuCEA/MA-EIA and heat-extraction to destroy HAMA before assay for CEA. The concordance of the ImmuCEA/MA assay with the Abbott and Roche CEA EIAs was established with sera from normal individuals and from patients who had not received parenteral injections of murine monoclonal antibody. At high (100 mg/L) concentrations of HAMA, false-positive results were observed with all three kits. The Hybritech and Roche assays were more sensitive to interference by HAMA than was the Abbott CEA-EIA, false-positive results being observed at HAMA concentrations between 1 and 10 mg/L. Similar sensitivity of the three kits to interference by primate anti-MAb sera was demonstrated. Use of primate anti-MAb sera to create controls with HAMA activity and of analyte is recommended to evaluate MAb assays for potential HAMA interference and for use to devise methods to eliminate HAMA interference.

We determined estrogen receptor protein and carcinoembryonic antigen in cytosols prepared from 189 human breast carcinoma tissues, 85 benign or normal breast biopsies, and 101 tissue specimens metastatic from breast carcinoma. Carcinoembryonic antigen was observed in 70% of the primary carcinomatous tissues, 15% of the benign or normal specimens, and 51% of the metastases. Ninety-six of the 189 primary carcinomatous specimens with increased concentrations of carcinoembryonic antigen were also positive for estrogen receptor protein, whereas 67 of the 72 benign or normal biopsies with low concentrations of carcinoembryonic antigen were also negative for estrogen receptor protein. All five fenign specimens with positive estrogen receptor protein and normal carcinoembryonic antigen concentrations were from fibroadenomas. The concordance between estrogen receptor protein and carcinoembryonic antigen in the primary carcinomatous tissue was 66%, in metastatic carcinoma 51%, and in benign and normal tissue 85%.

We evaluated two multi-analyte analyzers, the NOVA Stat Profile 1 (SP 1) and the NOVA Stat Profile 5 (SP 5). The SP 1 measures pH, pCO2, pO2, sodium, potassium, ionized calcium, and hematocrit in heparinized whole blood; the SP 5 determines all these analytes, plus chloride (not evaluated because it was unavailable at the time this study was initiated) and glucose. Interassay precision for pH, pCO2, pO2, sodium, potassium, ionized calcium, and hematocrit (all on the SP 1) and glucose (on the SP 5) was excellent, the respective CVs (%) being: less than 0.006, 2.1, less than or equal to 3.0, less than or equal to 0.5, less than or equal to 1.7, less than or equal to 2.1, less than or equal to 3.9, and less than or equal to 1.2. Correlation with results obtained with Corning's Model 178, NOVA Biomedical's Model 6, Beckman's Astra 8, and Roche's Cobas-Bio was also excellent (r greater than 0.975 for all analytes, r for hematocrit 0.865). Temperature-stability studies on whole-blood specimens maintained at 1 degree C indicated that results for all measured analytes were essentially uncharged for at least 2 h, except for potassium, which increased by 13% in 2 h. At 22 degrees C, values for pH, pCO2, pO2, and glucose changed significantly within 2 h. Advantages of the NOVA Stat Profile series include decreased specimen requirements (250 microL), analysis time (72-90 s), turnaround time (about 4.5 min), and overall cost of operation.

In the RA-1000, a random-access discrete analyzer, an inert fluorocarbon fluid is used to prevent interaction and carryover. Production-model instruments were evaluated in two laboratories with respect to determination of glucose, creatinine, total protein, inorganic phosphorus, cholesterol, alkaline phosphatase, lactate dehydrogenase, creatine kinase, gamma-glutamyltransferase, and aspartate and alanine aminotransferases. Within-run, among-run, and day-to-day (for 15 days) precision was assessed, and results were correlated with those obtained by the methods routinely in use in our departments. Precision was excellent, correlation acceptable.

Using 600 clinical specimens, we compared the concordance of four methods for carcinoembryonic antigen: the Roche RIA (I); the Roche EIA (II); Hybritech EIA (III); and Abbott EIA (IV). EDTA-treated plasma was used for Methods I and II and serum for Methods III and IV. However, no significant difference was found between results for serum and plasma in Method II. The normal reference interval (in micrograms/L) was I (222 specimens), 1.94 +/- 1.54; II (57 specimens), 0.8 +/- 0.5; III (100 specimens), 2.94 +/- 2.47; and IV (614 specimens), less than 5.0. The precision of all four methods was acceptable. Concordance among all of the methods exceeded 90%.