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N Zamcheck

Publications and source records attributed to N Zamcheck.

At least 37 records · Page 2Linked to original sources
PubMed1985

Effect of heterogeneity of carcinoembryonic antigen on liver cell membrane binding and its kinetics of removal from circulation.

Carcinoembryonic antigen (CEA) is a glycoprotein metabolized primarily by the liver. Subcellular fractions of rat liver were examined for CEA binding activity. Hepatocyte plasma membrane and microsome fractions bound CEA, and this binding shared the calcium requirement, neuraminidase sensitivity, and carbohydrate specificity of the hepatocyte asialoglycoprotein receptor. CEA had previously been shown to react with this galactose-specific receptor, in vivo, only following neuraminidase treatment. Galactose receptor binding of CEA was measured in three different purified CEA preparations. The fraction of CEA capable of binding to excess levels of galactose receptor on membranes varied (46.5%, 40.2%, and 4.7% for CEA-1, -2, and -3, respectively). These CEAs were shown to be 2.3%, 7.9%, and 0.7% as effective, respectively, as asialo-alpha 1-acid glycoprotein in inhibiting the binding of radiolabeled asialo-alpha 1-acid glycoprotein to liver cell membranes. Each of the three CEA preparations showed different clearance kinetics from the circulation of mice. Coinjection of asialo-alpha 1-acid glycoprotein with the CEAs revealed differing inhibition of the clearances. These results show that differences in the carbohydrate components of purified CEA preparations affect their rate of removal from circulation and thus possibly the relationship between CEA production and observed plasma levels in patients. The possible origin of these CEA differences is discussed with their clinical implications.

Animals↗
PubMed1985

The use of carcinoembryonic antigen in the clinical management of patients with colorectal cancer.

It has taken approximately 18 years to define the clinical utility of carcinoembryonic antigen (CEA) as a marker in patients with colorectal cancer. Hopefully, the use of CEA as a prototype and the knowledge of the many clinical studies designed to define its use in patients with colorectal cancer will help avoid the need for 18 years of studies in determining the biologic and clinical applicability of the many promising new candidate tumor markers now being developed. In this paper we will review our own studies which have helped to define the clinical utility of CEA in the care of patients with colorectal cancer.

Carcinoembryonic Antigen↗
PubMed1984

Signet ring carcinoma of the pancreas, a rare variant with very high CEA values. Immunohistologic comparison with adenocarcinoma.

Signet ring carcinoma of the pancreas is rare. We report a case which was remarkable for (1) diffuse, infiltrating growth which suggested chronic pancreatitis at laparotomy, and (2) an associated very high circulating carcinoembryonic antigen (CEA) level of 6400 ng/ml. The case report and autopsy are presented. Twelve other cases of pancreatic adenocarcinoma (non-signet ring) are compared with the signet ring carcinoma with respect to CEA staining and circulating levels. We conclude immunocytochemical staining of biopsy tissue for CEA is a useful adjunct in the interpretation of circulating CEA levels in pancreatic carcinoma.

Adenocarcinoma↗
PubMed1984

Patterns of failure after surgical cure of large liver tumors. A change in the proximate cause of death and a need for effective systemic adjuvant therapy.

During a period of 7 years, we have aggressively treated liver tumors whether primary or metastatic. Our experience after 43 curative major liver resections has shown an excellent overall survival: 34 of 43 patients still alive a median of 12 months after liver resection (patient ages ranged from 21 to 85 years, median 57 years). Nineteen patients underwent right hepatic lobectomy, 9 trisegmentectomy, 5 left hepatic lobectomy, 5 extended left hepatic lobectomy, 4 right lobectomy plus left lobe wedge resection, and 1 patient underwent a major hilar wedge resection. Two patients died from sepsis and hepatic failure on or before the 60th postoperative day. One patient with no evidence of recurrent colorectal cancer was lost to follow-up after 2.5 years. One patient died without cancer 12 months after left hepatic lobectomy for colon cancer metastases. Cumulative survival for the entire series and for patients after resection of colorectal cancer metastases was the same: 1 year survival 90 percent; 2 year survival 75 percent, and 3 year survival 65 percent. Seventeen of 30 patients remain disease-free after resection of liver metastases. Of the 13 who had recurrence, 8 are still alive. Ten recurrences were outside of the residual liver (predominantly multiple pulmonary metastases). One recurrence was in the right hemidiaphragm, and only three were in the residual or regenerated liver. Serial carcinoembryonic antigen analysis was the best indicator of recurrence in these 13 patients, 12 of whom were asymptomatic. These data confirm that major liver resection can be performed with minimum postoperative mortality (4.7 percent in this series). More importantly, the majority of patients were cured of their liver metastases. The next goal should be the initiation of adjuvant systemic therapy trials after liver resection in such patients.

Adult↗
PubMed1984

Acute-phase proteins or tumour markers: the role of SAA, SAP, CRP and CEA as indicators of metastasis in a broad spectrum of neoplastic diseases.

Two hundred and seventy-seven patients with a broad spectrum of neoplastic diseases, including 10 classes of solid tumours and three classes of haematologic malignancies, were retrospectively surveyed, and from the same sample of plasma or serum their concentrations of serum amyloid A (SAA), serum amyloid P component (SAP), C-reactive protein (CRP), and carcinoembryonic antigen (CEA) were measured. SAA levels varied from 105 ng/ml to 105,000 ng/ml, and mean SAA levels were higher in patients with metastatic tumours than in those with limited disease (P less than 0.001). Similarly, CRP levels varied from less than 8 micrograms/ml to 328 micrograms/ml and were significantly higher in the metastatic disease category. In contrast, SAP levels varied from 32 micrograms/ml to 120 micrograms/ml and showed no difference in patients with limited or metastatic disease, although an overall slight elevation was present. CEA levels were available in 150 patients and were significantly higher in patients with advanced lung or breast cancer than in patients with limited disease. The correlation between mean SAA and CRP levels was significant (r = 0.74, P less than 0.001), suggesting that SAA originates as an acute-phase protein rather than as a tumour cell product. However, the consistent elevation of SAA in all tumour types and the more marked elevation in metastatic disease may make its measurement useful in malignancy.

Acute Disease↗
PubMed1984

Plasma clearance of carcinoembryonic antigen following hepatic metastatectomy.

Four patients with isolated hepatic metastases from primary colonic cancer presented with elevated plasma carcinoembryonic antigen (CEA) levels and underwent surgical metastatectomy . Plasma levels were monitored at two to six hour intervals in the immediate postoperative period and daily measurements were obtained for an extended period thereafter, up to 34 days. CEA clearance demonstrated a two-phase decrement with an initial rapid decay followed by a logarithmic decline with plasma half-lives of 66, 75, 150, and 208 hours. The first phase decline of 63% to 89% in circulating CEA levels immediately following tumor removal may reflect the fact that the plasma CEA is in dynamic equilibrium with the tumor CEA. The kinetics of the second-phase decline of CEA is variable and may be related to the quantitative circulating pool or to pathophysiologic processes influencing CEA metabolism or secretion in the liver. Quantitative assessment of tumor CEA content by immunoperoxidase techniques suggests a direct relationship between tissue levels and circulating plasma levels. The study of CEA kinetics may help in understanding the biology of tumor marker production and improve the capacity for clinical monitoring of plasma levels in conjunction with tumor therapy.

Carcinoembryonic Antigen↗
PubMed1984

Identification of material with paternal HLA antigen immunoreactivity from purported circulating immune complexes in patients with gestational trophoblastic neoplasia.

Circulating immune complex(es) (CIC) have been shown to rise progressively only when patients with hydatidiform molar pregnancy enter gonadotropin-documented remission. The CIC in 3 patients with gestational trophoblastic neoplasia (GTN)--1 with hydatidiform mole and 2 with choriocarcinoma--were characterized. Their clinical course was monitored by serial antigen-nonspecific polyethylene glycol (PEG) 6000-CIC assay and simultaneous human chorionic gonadotropin (HCG) assay from presentation until sustained gonadotropin-documented remission. As serial HCG progressively decreased to normal following surgical or chemotherapeutic reduction in tumor burden, PEG-CIC concurrently rose. Serum obtained at or near peak PEG-CIC levels was precipitated by 3.75% PEG 6000 and fractionated by column chromatography on Sephadex G-200 (exclusion limit, greater than 600,000 mol wt) in glycine-HCl and 1 M NaCl buffer at pH 2.8. None of the 5 elution fractions obtained from the 3 patients contained HCG or anti-HCG activity. However, in the hydatidiform molar patient, fractions 1 through 3 (mol wt greater than 67,000--and containing immunoglobulin) were shown to competitively inhibit complement-dependent antibody lysis on 1 of 4 paternal HLA haplotype (AW32) targets. In 2 of the 3 patients studied, low-molecular-weight fractions (not containing immunoglobulin) significantly inhibited reference anti-HLA binding of antisera directed against only 1 of 4 paternal HLA haplotypes. The immunospecificity of this inhibition was confirmed by criss-cross control assays in which elution fractions obtained from both of these patients were tested for inhibition of lymphocytolysis of both sets of paternal lymphocytes. None of these fractions were immunoreactive to maternal HLA haplotypes. Further analysis of serum from the hydatidiform molar patient revealed that no free complement-fixing antibody against paternal antigens could be found by conventional screening assays in unfractionated patient sera. Three of 4 paternal HLA antigens or non-complement-fixing anti-HLA immunoglobulin was detected in unfractionated pretreatment, treatment, and remission sera of the hydatidiform molar patient. Only in this patient's remission sera was unbound AW32 antigen or non-complement-fixing anti-AW32 antibody detected. These data demonstrate the successful characterization of at least 1 specific antigen fractionated from a tumor-associated immune complex. The implication that some patients with GTN may recognize and react to immunogenic paternal HLA antigens as part of their successful response to therapy for trophoblastic tumor is discussed.

Antigen-Antibody Complex↗
PubMed1984

Modified radioassay for measuring asialoglycoprotein in serum.

Asialoglycoproteins are removed from the circulation by the carbohydrate-specific hepatic binding protein in the rat. Asialoglycoprotein in human serum can be detected by an inhibition assay in which the binding of 125I-labeled asialo-alpha 1-acid glycoprotein (ASAG) to purified hepatocyte membranes is inhibited by known amounts of ASAG or patient's serum. We were able to reproducibly measure inhibition equivalent to that of 1 to 20 ng of ASAG. The mean concentration of inhibitor in 11 healthy control patients was equivalent to 0.153 (SD = 0.051) mg of ASAG per liter, measured in 20 microL of serum. Significant increases of inhibitor were observed in patients with malignant extrahepatic biliary obstruction, alcoholic liver disease, viral hepatitis, or liver metastases, but not in those with benign biliary obstruction. For a set of six control sera the intra- and interassay CVs were 9.1% and 25.2%, respectively (n = 3 each).

Adult↗
PubMed1983

Immunocytochemical staining for CEA in small cell carcinoma of lung predicts clinical usefulness of the plasma assay.

Recent studies have shown plasma CEA levels are useful in both staging and monitoring response to treatment in patients with small cell cancer of the lung (SCCL). CEA elevations do not occur in all patients however, and have been of less value in patients with limited disease. Immunoperoxidase staining for CEA performed on tumor tissue from 48 patients (17 extensive, 31 limited disease) with SCCL revealed: (1) A strong correlation between positive CEA tissue staining and plasma CEA elevation. Plasma CEA elevations occurred in 18/21 CEA tissue positive patients and correlated with the clinical course in all 18. In contrast elevated plasma CEAs were seen in only 3/27 CEA tissue negative patients; (2) CEA tissue positive patients had a higher incidence of extensive disease (62% versus 18%) and a higher incidence of liver metastases (43% versus 7%); and (3) No correlation between histologic subtype and CEA tissue staining was apparent.

Carcinoembryonic Antigen↗
PubMed1983

Role of the liver in clearance and excretion of circulating carcinoembryonic antigen (CEA).

CEA is a glycoprotein with a molecular weight of 200,000 containing 55%-65% carbohydrate. The removal of only two sialic acid residues result in rapid uptake from the circulation by the liver and catabolism in the lysosomes. There is a receptor on the plasma membrane of the hepatocyte (hepatic binding protein) which recognizes galactosyl residues. About 70% of 125I-labeled intact CEA is cleared by the liver in 1 hr. The exposure of terminal galactose residues by removing sialic acids determines the rate of clearance. CEA is probably initially taken up by Kupffer cells and transferred to hepatocytes. About 10% of CEA added to an isolated perfused liver appears in bile. Biliary duct obstruction and cholestasis may elevate plasma CEA levels due to detergent effects on the liver cell receptors.

Animals↗
PubMed1983

CEA and genetics. Gardner's syndrome.

During an eight-year period, serial plasma determinations were made on members of a Gardner's syndrome family in order to see if 1. levels rise when polyps first appear, and when cancer occurs; and 2. levels fall after colectomy with ileoproctostomy, ileostomy, or rectal mucosal replacement surgery. CEA analyses were carried out in the laboratory of Norman Zamcheck, M.D., using the Roche method. Small increases in CEA titer accompanied the appearance of polyps and small decreases accompanied their removal. Further serial studies are needed to determine whether changes in CEA titer can be indicators of polyp and/or cancer occurrence.

Adult↗
PubMed1983

Circulating immune complexes in patients with colorectal cancer.

We have attempted to better define host humoral immune response in neoplasia by quantitating serial circulating immune complex values before and after surgery in patients with primary or metastatic colorectal cancer. Circulating immune complex levels were correlated with serial carcinoembryonic antigen values and tumor courses in patients with primary resectable colorectal cancer (four patients), resectable liver metastases (three patients), diffuse liver metastases treated with regional chemotherapy (three patients), and untreated intrahepatic (one patient) and extrahepatic metastases (one patient). Circulating immune complex levels, as measured by an antigen-nonspecific assay, which utilized 4 percent polyethylene glycol insolubilization, were increased in all patients at presentation (734 delta OD450 +/- 381) when compared with normal human control sera (202 +/- 4, p less than 0.05). No particular relation was found between presenting circulating immune complex levels and tumor burden. Progressive circulating immune complex increases were demonstrated only in patients whose tumors were either completely removed or dramatically responded to regional therapy (that is, when the tumor antigen load, as reflected by the carcinoembryonic antigen value, rapidly diminished). Serum samples obtained at times of presumed antibody excess in the patients with gastrointestinal cancers were found to contain unexpectedly high concentrations of IgA. We believe these data demonstrate the kinetics of circulating immune complex change during tumor course and they have allowed us to begin to identify circulating immune complex components in patients with colorectal cancer. The results confirm our earlier findings in patients with gestational tumors and differ from accepted relations between immune complexes and tumor growth.

Antigen-Antibody Complex↗
PubMed1982

The role of tumor markers in the management of colorectal cancer.

Among the tumor-associated antigens evaluated for the diagnosis and management of cancer, carcinoembryonic antigen (CEA) is the only established and clinically useful tumor marker for colorectal cancer and other CEA-producing tumors. Because of the exhaustive studies in the past decade, a consensus development conference was held at NIH in September 1980, to address the issue concerning the role of CEA as a marker in the management of cancer. This conference concluded that the use of regular and sequential assays of blood CEA is the best noninvasive technique for postoperative surveillance of patients to detect disseminated recurrence of colorectal cancer. The CEA level can serve as an indicator of successful or incomplete resection, and is useful in monitoring the effect of chemotherapy or radiotherapy. CEA can also provide a useful estimate of prognosis. CEA is neither sensitive nor specific enough to be used in routine screening for possible malignancy in an asymptomatic population. Nor can this test independently establish a diagnosis of cancer, but it can be used as an adjunct to clinical staging methods in known cancer patients. Radioimmunodetection and radioimmunotherapy with anti-CEA antibodies are currently being evaluated. Study of the pathophysiology and metabolism of CEA is needed. CEA remains the prototype tumor marker and is a valuable comparative tool, when investigating the clinical value of other newly developed tests for tumor markers.

Carcinoembryonic Antigen↗
PubMed1982

A new Kupffer cell receptor mediating plasma clearance of carcinoembryonic antigen by the rat.

Native human carcinoembryonic antigen is rapidly removed from the circulation by the rat liver Kupffer cell after intravenous injection. The molecule is subsequently transferred to the hepatocyte in an immunologically identifiable form. Carcinoembryonic antigen has a circulatory half-life of 3.7 (+/- 0.8) min, and cellular entry is by receptor-mediated endocytosis. Non-specific fluid pinocytosis and phagocytosis can be excluded as possible mechanisms by the kinetics of clearance and failure of colloidal carbon to inhibit uptake. Substances with known affinity for the hepatic receptors for mannose, N-acetylglucosamine, fucose and galactose all fail to inhibit carcinoembryonic antigen clearance. After two cycles of the Smith degradation, carcinoembryonic antigen is still able to inhibit clearance of the native molecule. Receptor specificity is apparently not dependent on those non-reducing terminal sugars of the native molecule. Performic acid-oxidized carcinoembryonic antigen also inhibits clearance of carcinoembryonic antigen in vivo. Receptor binding is not dependent on tertiary protein conformation. Non-specific cross-reacting antigen, a glycoprotein structurally similar to carcinoembryonic antigen, is cleared by the same mechanism.

Animals↗
PubMed1982

Circulating CEA levels in patients with fulminant hepatitis.

CEA levels were determined in blood specimens from 14 persons suffering from fulminant hepatitis. Values ranged from 1.9 to 21 ng/ml with a mean of 7.0 ng/ml. All except one patient had a CEA level greater than 2.5 ng/ml, but only three exceeded 10 ng/ml. There was no correlation between single CEA levels and prognosis, routine liver chemistries, or histopathologic characterization of hepatic tissue obtained at postmortem examination. These data show that patients with fulminant hepatitis commonly had increased circulating levels of CEA, but these elevations were far less than may be found in patients with hepatic metastases. In severe hepatic dysfunction reduced hepatic clearance of CEA may be responsible for the increased levels.

Adolescent↗
PubMed1982

CEA monitoring among patients in multi-institutional adjuvant G.I. therapy protocols.

The Gastrointestinal Tumor Study Group (GITSG) has since 1975 included protocols for monitoring carcinoembryonic antigen (CEA) levels in its colorectal cancer adjuvant trials. Among the 563 patients on the colon cancer study (GI 6175) and the 207 patients on the rectal cancer study (GI 7175), one third had preoperative CEA determinations and more than 90% had some postoperative CEA monitoring. Colon cancer patients whose preoperative CEA was greater than 5 ng/ml had a greater probability of recurring than those whose values were lower (33% versus 18% recurrence with 21 months minimum follow-up; p < 0.05). The prognostic value of preoperative CEA was apparent only in patients with Dukes' C1 colon tumors. Preoperative CEA values were not of prognostic significance among the rectal adenocarcinoma patients. Although elevated levels of CEA after resection of either colon or rectum cancers were strongly associated with subsequent tumor recurrence, no single CEA value, arbitrarily defined as "elevated", provided an adequate screening test with both high sensitivity and high specificity. Postoperative CEA elevations were more strongly predictive of recurrence when part of a steadily rising trend. In the colon cancer study, the median monthly increase in CEA for disease-free patients was estimated to be zero, and for the relapsed patients 5.8%. The corresponding estimates for patients on the rectal cancer protocol were zero and 7.8%. Only 36 of the 344 disease-free patients on the colon protocol and 14 of the 94 disease-free patients on the rectal protocol (15%) exhibited a rate of increase of CEA as high as 3% per month over the entire period of observation. Two thirds of the relapsed patients on both studies showed a rate of increase this high or higher. The patterns of CEA rise in individual patients were quite varied, however, and monthly rates of increase as established in our study are not to be used as guidelines in patient management.

Carcinoembryonic Antigen↗