Detection and diagnosis of prostate cancer.
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Biomedical subjects
Publications and source records attributed to T M Chu.
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Analysis of carcinoembryonic antigen (CE)-reactive glycoproteins from liver metastasis of primary colon and breast tumors and from primary breast tumors has been carried out by affinity chromatography on concanavalin A (Con A)-Sepharose. Three CEA-reactive glycoproteins from colon tumors (liver metastasis) with different binding capacity to Con A have been separated and further purified by gel filtration. Of the 3 CEA-reactive glycoproteins, 1 of them did not bind to Con A. Both Con A-binding and nonbinding CEA-reactive glycoproteins were immunologically indistinguishable when tested with a reference goat anti-CEA (ACE, 67-70; Dr. C.W. Todd and Dr. M.L. Egan), as well as with a variety of rabbit anti-CEA and anti-CEA (nonbinding) prepared in this laboratory. Carbohydrate analysis showed that mannose content of different purified CEA preparations or nonbinding CEA did not differ appreciably. N-Acetylglucosamine content of purified CEA preparations, however, varied considerably, suggesting that this sugar may impart the specificity of binding of CEA to Con A. The purified CEA preparations differed in their ability to inhibit the binding of 125l-labeled CEA to goat anti-CEA. One of the purified CEA preparations had 3- to 8-fold greater inhibitory capacity when compared to other preparations and shared a partial identity with a glycoprotein present in the extracts of fetal colon. The glycoprotein extracts of primary breast tumors did not contain a CEA that was immunologically identical to CEA present in colon tumors, whereas the liver metastasis of primary breast tumors showed several CEA-reactive glycoproteins as judged by radioimmunoassay. However, these CEA-reactive glycoproteins did not have any antigenic relationship with CEA from colon tumors when tested by double diffusion and immunoelectrophoresis. In conclusion, when Con A affinity chromatography of tumor glycoproteins is carried out under defined conditions and with the use of appropriate antisera, it is possible to delineate the presence or absence of CEA in tumors of nonentodermal origin.
Ninety-four patients with carcinoma of the colon have been followed with serial determinations of plasma CEA (carcinoembryonic antigen) levels over a 3-year period using the Hansen assay. Nine hundred twelve CEA determinations have been made in these patients. Plasma CEA levels rose in 90% of the instances of clinical progression documented in these patients. In 30% of patients, this rise indicated progression 6 months or more before it was detected by standard clinical methods. Unfortunately, a few patients never developed elevated CEA levels even though disease clearly progressed. False positive results have also been encountered, with significant elevations occurring in patients who have since remained without evidence of disease for several months. Our data indicate that at least two sequential elevated CEA values, the second being higher, must be a minimal criterion for consideration of possible progression of disease. Even with this standard, we have encountered false positive results in 10% of our patients, indicating recurrence or progression where none has occurred clinically. CEA measurement is of limited usefulness for 30 days after curative surgery, because the elevation of CEA levels due to the original amount of tumor present as well as due to surgery per se may persist for this length of time in a significant number of patients. On the other hand, CEA levels have responded to chemotherapy in close correlation with observed clinical course in those patients with metastatic disease treated in this series. Initial pretherapy CEA values have so far proved to be good prognostic indicators of disease course following complete resection. With an initial CEA value of less than 2.5 ng/ml of plasma, recurrent has been rare (1/20). If the pretreatment CEA was greater than 7.0 ng/ml, it has been the rule (7/9).
Two hundred and twenty-eight patients who were treated for carcinoma of the lung were followed and their plasma CEA levels assessed at intervals during the course of the disease. In addition, plasma samples were taken from 487 healthy blood donors for comparison as a control. CEA assay is not selective or specific enough, at this time, to be used for screening purposes even though 68% of the patients who have lung cancer will have an elevated concentration of CEA regardless of the histological cell type. In patients with plasma levels of CEA above 15 ng/ml the prognosis is uniformly poor. CEA in the author's view does have value as a prognostic marker capable of suggesting the successful resection of a tumor and to a lesser degree confirming the clinical objective response to the radiotherapy or chemotherapy. It was found that the presence of CEA was not necessarily related to the volume of the tumor or the site of organ metastasis, but reflects the metabolic properties and characteristics of the individual tumor as it occurs in the patient.
The results of simultaneous plasma and urinary CEA levels in 14 patients are described. The aim was to determine whether urinary CEA derived from plasma or arose independently in the urinary tract. The method of reductio ad absurdum is followed. It is assumed that CEA in the urine is derived from plasma, and CEA clearance values for each patient are calculated. These varied widely from zero to a theoretical infinity. On this basis and from previous experimental evidence, it is concluded that urine is independent of plasma CEA. The finding, however, in some individuals of "anti-CEA"-like factor(s) distorting urinary CEA determination makes for some reservations about the safety of the conclusion. It is, however, certain that with the presently available technology, present urinary and plasma CEA values cannot be correlated.
Serum acid phosphatase activity, urinary total cholesterol, and ratio of deoxy to oxy urinary 17-ketosteroids were measured in a group of 42 patients with prostatic carcinoma and in a group of 14 age-matched normal healthy individuals. Our purpose was to evaluate whether or not the simultaneous determinations of these tests would increase the rate of detection obtained by the single assay alone. The results of single assay revealed for the following detection rate: 67 per cent (28 of 42 patients) for serum acid phosphatase, 62 per cent for urinary total cholesterol, and 22 per cent for ratio of 17-ketosteroids. A significant increase of detection rate was observed when simultaneous determinations of two assays were performed; 86 per cent for serum acid phosphatase activity and total urinary cholesterol; 74 per cent for serum acid phosphatase and ratio of 17-ketosteroids; and 74 per cent for total urinary cholesterol and ratio of 17-ketosteroids. A detection rate of 88 per cent (37 of 42 patients) was obtained as all three assays were analyzed, though it was not significantly different from a ratio of 86 per cent for simultaneous assays of acid phosphatase and total cholesterol. It was concluded that simultaneous determinations of serum acid phosphatase activity, urinary total cholesterol, and androgens are of values in diagnosis for patients with prostatic neoplasia.
The carcinoembryonic antigen (CEA) is a glycoprotein that can be measured by radioimmunoassay and other immunologic techniques. The CEA reagent is currently commercially available in kit form and has been found to be satisfactory for laboratory use. The highest percentage of elevated plasma CEA and the highest CEA titer have been found in patients with entodermally derived tumors. CEA has also been detected in patients with other tumors and in patients with nonneoplastic disease, as well as in heavy cigarette smokers. The present CEA assay cannot be used to screen for cancer in the general population. The greatest clinical usefulness of current CEA assay is in assessing prognosis, in the detection of residual tumors and recurrent disease, and in monitoring chemotherapy and radiotherapy. The use of anti-CEA antiserum as a tumor-localizing agent may be of potential value in the future.
The value of biological markers of bladder cancer was studied in 66 patients. The markers included serum and urine carcinoembryonic antigens, serum and urine fibrinogen degradation products, total lymphocyte counts, urine lymphocytes and urine cytology. A high degree of accuracy (90 per cent) was found in correlating cytology and urinary fibrinogen degradation products with the activity of the disease. Serum and urine carcinoembryonic antigens, serum fibrinogen degradation products, total lymphocyte counts and urine lymphocytes were found to have no value in screening bladder cancer patients. Urinary fibrinogen degradation products and cytology in combination are recommended for screening and followup of patients at high risk.
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Growth characteristics, survival time, sex differences and hormonal effects, and various biochemical parameters were evaluated in a transplantable Furth/Wistar rat Wilms' tumor model. Survival time was dependent on site of tumor transplant and ranged from a mean of 28 days for intrarenal implantation to 44 days intramusculary. Maximum tumor weight (130 g) was obtained via subcutaneous implant. Lung metastasis was evident in the majority of animals with the exception of those receiving the tumor implant intraperitoneally. The levels of erythropoietin and serum calcium and phosphatase were comparable to control values whereas hematocrit levels declined. Tumor tissue arginase or total protein remained unchanged during tumor growth. In these same tissues DNA, content and 5-alpha-reductase activity significantly and progressively increased with concomitant tumor growths. Measurements of lactic dehydrogenase, alkaline phosphatase, and their isoenzymes indicated patterns of liver involvement which were not macroscopically evident. After 31 days of subcutaneous tumor transplant, male and female rats had tumors of comparable weights. Orchiectomy or estradiol treatment significantly reduced tumor weight in males. In female rats testosterone treatment significantly increased tumor weights. DNA concentration in tumor tissue was unaffected by treatment. Similiarly, although 5-alpha-reductase activity was higher in tumors from males, and arginase higher in females, these enzymes were not affected by surgical or hormonal treatment.
In order to establish a more reliable profile of the function of the adrenal cortex, a study has been made of this simultaneous estimation of plasma and urinary unconjugated cortisol by competitive protein binding (CPB) radioassay. Both plasma and urinary cortisol were measured by CPB radioassay after solvent extraction. Normal ranges were found for plasma and urinary cortisol. The samples obtained in the morning (8:00 am) established a normal plasma cortisol range of 9.0-21.6 mug% with a mean of 15.3. range for urinary unconjugated cortisol was 12.0-41.5 mug/day (mean 26.9). Dexamethasone suppression and adrenocorticotrophic hormone stimulation of plasma and urinary cortisol were tested with individuals having normal and abnormal adrenal cortical function. RESULTS INDICATED A GOOD CLINICOPATHOLOGICAL CORRELATION. It was concluded that plasma and urinary unconjugated cortisol are reliable laboratory tests for adrenocortical function and would be the methods of choice rather than urinary 17-ketogenic steroids.
The carcinoembryonic antigen (CEA) active glycoproteins from perchloric acid extract of liver-metastasized primary colon tumor have been separated by concanavalin A Sepharose (Con A Sepharose) chromatography. The CEA activities separated by Con A Sepharose chromatography were designated as loosely bound and tightly bound which, respectively, eluted on the Con A Sepharose column between 0.12 and 0.15 M and 0.3 M alpha-methylmannose in a linear gradient of alpha-methylmannose. Further purification of these activities by Sephadex G-200, Bio-Gels A-1.5m and P-300 yielded two variants of glycoproteins (B1 and C2) with CEA activity. Both purified preparations of CEA had similar immunochemical properties. Their A280/A260 ratios were 1.30 and 1.56, respectively. The purified loosely bound CEA (B1) had immunological, chromatographic, and electrophoretic properties similar to those of 125I-CEA, whereas the tightly bound CEA (C2) had a lower molecular weight (120,000 to 140,000). Further, specificity to these two CEA's was established by their reactions in immunoelectrophoresis with preparations of specific goat anti-CEA anti-serum obtained from other investigators. The results indicate the practical use of Con A Sepharose affinity chromatography for the separation and characterization of glycoprotein tumor antigens.
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