Basal Calcitonin Research Articles

Adrenocorticotropin, calcitonin, and antidiuretic hormone as tumor markers in patients with bronchogenic carcinoma of various histological types.

We measured basal and dexamethasone-suppressed plasma ACTH in 246 patients with bronchogenic carcinoma (105 with small-cell carcinoma); in 138 of these patients (67 with small-cell carcinoma) basal and pentagastrin-stimulated serum calcitonin was also determined. In addition, in a subgroup of 120 patients (58 with small-cell carcinoma) plasma ADH with reference to plasma osmolality was also assayed. Non-suppressible plasma ACTH was found in 45% of patients with small-cell carcinoma but only in isolated cases of large-cell carcinoma, adenocarcinoma, and squamous-cell carcinoma. Serum calcitonin was increased in 28% of patients with small-cell carcinoma but only in few patients with other tumor types. Stimulation of calcitonin by pentagastrin was ineffective. Plasma ADH was inappropriately high in 47% of patients with small-cell carcinoma. Strikingly high also was the incidence of increased ADH concentrations in patients with large-cell (40%), adenocarcinoma (46%), and squamous-cell carcinoma (29%). By measuring plasma ACTH after dexamethasone suppression and ADH with reference to osmolality, the sensitivity of these tumor markers in detecting pathological hormone secretion is markedly increased. In small-cell carcinoma the simultaneous measurement of ACTH, ADH, and calcitonin gives a high yield of positive results (74%), indicating that this set of tumor markers is a promising aid in diagnosis and therapy control.

Diagnostic and Prognostic Values of Carcinoembryonic Antigen in Medullary Carcinoma of the Thyroid*

This study was conducted to compare the diagnostic and prognostic values of calcitonin (CT) and carcinoembryonic antigen (CEA) measurements in patients with medullary carcinoma of the thyroid (MCT). Plasma CEA, basal CT (BCT), and peak CT (PCT) levels after pentagastrin stimulation were determined in 15 patients with occult familial MCT before treatment. CEA was elevated in 11 patients (73%), BCT in 8 patients (53%), and PCT in all patients. The prognostic values of serial CEA and BCT determinations were studied in 24 other MCT patients followed for a period of 1.5-8 yr. These patients were divided into 2 groups; group I consisted of 11 patients with normal serial CEA levels, and group II consisted of 13 patients with persistently elevated CEA levels. In group I, 2 patients (18%) developed metastases compared with 10 patients (77%) in group II (P less than 0.001). Elevated BCT levels were found in all patients with metastases as well as in 63% of patients with no evidence of disease. When CEA time curves were studied, three patterns could be identified: 1) a steep slope with rapidly rising CEA levels in patients with rapidly progressive disease, 2) a flat slope in patients with no metastasis or nonprogressive disease, and 3) an intermediate type of slope in patients with slowly progressive disease. Slope analysis of BCT time curves was not done because of marked fluctuations in BCT levels. PCT after pentagastrin stimulation remains the best diagnostic marker for MCT. However, CEA may be a better prognostic indicator, as it discriminated more efficiently between patients with and without metastasis. Slope analysis of CEA time curve and calculation of the doubling time are recommended, as they correlated well with the course of the disease.

Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma.

Plasma calcitonin (CT) levels were measured serially in 54 patients surgically treated for medullary thyroid carcinoma. Patients with postoperative basal CT levels higher than 1 ng/ml measured within 1 month after surgery had a higher recurrence rate than those with lower CT levels (p less than 0.002). Patients with postoperative basal CT levels higher than 2 ng/ml had a lower survival rate than those with lower CT levels (p less than 0.01). However, preoperative basal CT levels had no significant correlation with life expectancy or recurrence during the present observation period. Serial measurements in 23 patients with elevated postoperative CT levels showed exponential increases in basal CT levels in 19 patients (p less than 0.05 in nine patients, 0.05 less than p less than 0.1 in four patients) and slight decreases in four (p less than 0.05 in one patient). Doubling time of CT levels calculated from the regression line in each patient showed the highest correlation with 3-year survival, recurrence within 5 years, and time interval between surgery and clinical recurrence of the tumor, allowing quantitative prediction of the prognosis.

Glucocorticoids stimulate the production of preprocalcitonin-derived secretory peptides by a rat medullary thyroid carcinoma cell line.

A rat medullary thyroid carcinoma cell line, CA-77, has been established as a model system for investigating calcitonin biosynthesis and secretion. Growth of this cell line in serum-free defined medium provided suitable conditions for studying steroid hormone effects on the production of calcitonin and related peptides. After exposure for 5 days to a variety of steroids, only dexamethasone and corticosterone increased cellular content of calcitonin and a second secretory peptide (CCAP) derived from the same mRNA translation product as calcitonin. Glucocorticoids had no effect on cellular somatostatin, another secretory product of these cells. Increasing doses of dexamethasone progressively elevated cellular calcitonin and CCAP, with a maximal effect at 10(-8) M; 10(-9) M and lower doses were ineffective. On a molar basis, corticosterone was approximately 50-fold less potent than the synthetic glucocorticoid. An increase in cellular calcitonin content was observed only after 48 h of glucocorticoid treatment; a maximum increase (13-fold) occurred after 7 days. Glucocorticoids also increased basal calcitonin secretion. Similar effects were observed for cellular and secreted CCAP. Withdrawal of dexamethasone after 4 days of treatment lowered cellular calcitonin toward the level of control cultures. Dexamethasone pretreatment potentiated the acute secretory response to calcium for both calcitonin and CCAP, while no such enhancement was noted for calcium stimulation of somatostatin secretion. We conclude that the glucocorticoids specifically stimulate the production and secretion of calcitonin and CCAP, two secretory peptides derived from preprocalcitonin.

Thyroid venous catheterization in the early diagnosis of familial medullary thyroid carcinoma.

In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520+/-635 pg/ml) and C (6322+/-2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.

An estimate of the endogenous secretion rate of calcitonin in man.

1. The metabolic clearance rate (MCR) of human calcitonin was measured in 12 normal subjects and four patients with Paget's disease by the infusion of synthetic human calcitonin (15-40 microgram/h for 2-24 h), and in 10 additional patients with Paget's disease from the disappearance rate of immunoreactive calcitonin from plasma after the intravenous injection of large doses of synthetic human calcitonin (0.5-1.0 mg). 2. The estimated MCR during the infusion studies (range 531-1224 litres/day) was similar to that calculated from the disappearance of large doses of synthetic human calcitonin injected intravenously in patients with Paget's disease (mean = 1035 litres/day; range = 593-1408 litres/day). 3. An eightfold range in the basal values of plasma immunoreactive calcitonin, in spite of the presence of a relatively constant MCR, suggests that the variation in basal plasma calcitonin was due principally to variation in the endogenous secretion rate for calcitonin. 4. The results suggest that the endogenous secretion rate for calcitonin is low in normal subjects (mean 124 +/- SEM 24 microgram/day), and give a basis for selecting the doses of calcitonin which can be considered physiological.

Radioimmunoassay of calcitonin in unextracted human serum: A sensitive method

A sensitive sequential direct radioimmunoassay of calcitonin (CT) is described. Human synthetic monomer CT was used for 125I-labelling and for preparation of standard sera. The antibody (rabbit) was directed against mid-portion and C-terminal parts of the human CT molecule. No significant cross reactivity with salmon or porcine CT was found. Separation of free from antibody-bound 125I-labelled CT was performed using a double antibody-polyethyleneglycol mixture. Dilution curves of sera from normal controls and patients with medullary thyroid carcinoma (MCT) were parallel to the standard curve. Recoveries of 25-400 ng/l CT were in the range of 88-138%. The intraassay coefficients of variation (CV) were 6% and 3% at serum concentrations of 90 and 230 ng/l respectively. The interassay CV were 13% and 10% at mean serum CT concentrations of 50 and 210 ng/l respectively. The lower limit of detection was 20 ng/l. Thirty-one healthy controls had serum CT levels in the range of 35-135 ng/l. Elevated basal serum CT concentrations were found in all of 11 patients with MCT and the serum concentrations increased markedly after pentagastrin stimulation. Subsequent thyroidectomy in eight of the 11 patients with MCT reduced basal serum CT levels, in six to within the reference range for normals.

Effect of prostaglandin E l, E 2 or indomethacin on serum parathyroid hormone and calcitonin in the rat

Infusion of 100 or 200 ng/min of Prostaglandin El (PGEl) or of 100 ng/min of PGE2 increased serum parathyroid hormone (PTH) in the rat. These infusions, however, had no significant effect on serum calcitonin (CT). Administration of 10 mg/kg of indomethacin for 3 days had no significant effect on basal serum PTH, CT or Calcium (Ca). EDTA infusion increased serum PTH to a similar degree in the vehicle- or indomethacin-treated rats. Therefore, endogenous prostaglandins do not appear to play a role in the secretion of PTH or CT.

Calcitropic hormone responsiveness during pregnancy

Release of the calcitropic hormones parathyroid hormone (PTH) and calcitonin (CT) in response to provocative stimuli was assessed in pregnant rhesus monkeys tested three times during gestation (corresponding to the end of each trimester) and again 6 weeks post partum. In the case of PTH, although basal levels were higher during pregnancy than post partum and tended to increase with advancing gestation, similar to observations in human subjects, the incremental response of the hormone to a hypocalcemic stimulus was diminished in pregnant animals and tended to lessen with advancing gestation. Basal CT levels were also increased during pregnancy but, in contrast to PTH, the incremental CT response to a provocative stimulus was generally greater during pregnancy than post partum and tended to increase with advancing gestation. The explanation of these findings may lie in differing degrees of hormone storage. These adjustments in maternal endocrine physiology regulating calcium metabolism would have the net effect of tending to preserve the maternal skeleton by protecting it from excessive resorption at times of hypocalcemia and promoting increased calcium storage during episodes of hypercalcemia.

Role of Calcitonin in Osteosclerosis of Myeloma?

To the Editor. —In the August 1979Archives(139:892-896), Driedger and Pruzanski analyzed 68 cases of plasma cell neoplasia with osteosclerotic lesions. They perfectly stressed the main clinical features—younger age at diagnosis, higher incidence of peripheral polyneuropathy, hepatosplenomegaly, and lymphadenopathy as compared with large series of myeloma in general—and the essential laboratory data in these rare forms of plasma cell neoplasia, but they did not give any positive explanation for osteosclerosis. They proposed two theoretical hypotheses, either failure of osteosclerotic activating factor production by the plasmocytes or ability of the host tissues to respond to the proliferation of myeloma cells by prompt osteoblastic activity. Recently, we reported one case of osteosclerotic myeloma with polyneuropathy and lympadenopathy, in which unexplained and marked hypercalcitoninemia (between 3,000 and 6,000 pg/mL during follow-up) was discovered.1In our laboratory, mean values of basal calcitonin (CT) are 180 ± 150 pg mL.2 Although, to

Basal plasma immunoreactive calcitonin in postmenopausal osteoporosis

Calcitonin (CT) deficiency has been suggested as an etiologic factor in postmenopausal osteoporosis (PM-OP). Basal immunoreactive calcitonin (iCT) was measured with a sensitive radioimmunoassay (RIA) in 62 PM-OP women with compressin fractures (CF) and in 28 normal age-matched women. Mean iCT values in the two groups were not significantly different (43.5 and 45.1 pg/ml, p > 0.10). In the 62 PM-OP females, no significant correlation was noted between basal plasma iCT levels and (1) age; (2) severity of disease as assessed by number of CF; (3) serum calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone; and (4) total bone mass as assessed by neutron activation analysis determinations of total body calcium (TBC). In 20 PM-OP patients treated for 24 mo with 100 Medical Research Council (MRC) units daily of synthetic salmon CT, no correlation was observed between basal plasma iCT and response of bone mass (TBC) to therapy. These data suggest that basal CT is not decreased in women with PM-OP, and that the level of circulating CT does not influence therapeutic changes in bone mass during CT therapy. CT is probably not a major etiologic or pathogenetic factor in PM-OP.

Nonfamilial medullary thyroid carcinoma

On the basis of this report and the current literature, we conclude that the familial type of medullary thyroid carcinoma can be diagnosed early using basal and poststimulation levels of calcitonin. However, most of the patients with sporadic disease present with a neck mass later in life. The tumor has a tendency to invade locally and metastasize to lymph nodes early in its course. Prognosis is negatively influenced by the extent of disease, lymph node involvement and elderly age. The surgical procedures of choice should be total thyroidectomy with clearance of central nodes of the neck as well as neck dissection when indicated. All parathyroid glands should be inspected. For patients treated for cure, the determinant 10 year survival is 48 percent, and 20 year survival is 33 percent. Recurrence of local disease should be treated aggressively, as important palliation and prolongation of life can be achieved. Radiotherapy may be helpful in the management of residual tumor or recurrent disease. Basal calcitonin assays and poststimulation studies are useful in diagnosing residual or recurrent disease. In the familial cases, the existence of other endocrinopathies has to be considered in the management of the patients.

Calcitonin secretion in congenital nongoitrous cretinism.

Plasma calcitonin (CT) was measured in the basal state and/or during provocative tests of hormone secretion in 11 children with congenital non-goitrous cretinism (CNC), in 1 girl with a lingual thyroid, and in 11 normal children. Basal and stimulated CT concentrations were significantly lower in the patients with CNC than in the normal subjects. Mean basal CT (+/- SE) was 41 +/- 4 pg/ml in the normal children, 24 +/- 3 pg/ml in the children with CNC, and 20 +/- 2 pg/ml in the patient with the lingual thyroid. The mean incremental CT responses to calcium infusion were 7.0 +/- 2 pg/ml in the children with CNC, 6.0 pg/ml in the patient with the lingual thyroid, and 146 +/- 47 pg/ml in the normal children. The children with CNC also demonstrated a significant delay in the return of the total serum calcium to basal level after the calcium infusion. The mean incremental CT response after infusion of pentagastrin was 7.6 +/- 2 pg/ml in the children with CNC, 10.0 pg/ml in the child with the lingual thyroid, and 34.4 +/- 11 pg/ml in the normal children. These data indicate that CT deficiency is present in children with CNC and suggest that the deficiency is a consequence of the defective embryologic development of the thyroid gland.

No effect of cimetidine on calcitonin secretion from medullary thyroid carcinoma.

The effect of cimetidine on basal and pentagastrin-stimulated serum immunoreactive calcitonin (S-iCT) concentrations was studied in six patients with medullary carcinoma of the thyroid (MCT). Basal S-iCT was elevated in all patients and showed a marked increase after i.v. injection of pentagastrin, 0.5 micrograms/kg b.wt. Cimetidine, 200 mg i.v., 30 min before administration of pentagastrin had no effect on either basal or pentagastrin-stimulated S-iCT. Thus, the mechanisms of basal and pentagastrin-stimulated calcitonin secretion from MCT do not seem to involve agonism with histamine H2-receptors.

Serum concentrations of immunoreactive calcitonin in patients with hypergastrinaemia.

In order to test tthe hypothesis that chronically elevated serum gastrin levels induce hypercalcitoninaemia, we have measured serum calcitonin levels in patients with chronic hypergastrinaemia. Basal serum calcitonin concentrations were found to be elevated in 2 of 23 patients with Zollinger-Ellison syndrome, but not in 16 patients with hypergastrinaemia due to achlorhydria or a single patient with primary hypergastrinaemia of antral origin. Both Zollinger-Ellison patients with hypercalcitoninaemia (0.31 and 0.79 ng/ml) had multiple endocrine adenomatosis type 1, but no medullary carcinoma of the thyroid. The hypercalcitoninaemia in these patients does not seem to be related to multiple endocrine adenomatosis type 1, since serum calcitonin was normal in 12 normogastrinaemic patients with hyperparathyroidism from families with multiple endocrine adenomatosis type 1. We conclude that chronically elevated serum gastrin levels do not result in hypercalcitoninaemia.

Inhibition ofin VivoSecretion of Calcitonin in the Pig by Somatostatin*

The ability of somatostatin (somatotropin release-inhibiting factor or SRIF) to inhibit or reverse the increased secretion of calcitonin (CT) induced by Ca or pentagastrin (Pg) was examined in eight pigs. Except for Ca, test agents were administered directly into the thyroid circulation (0.1 ml/ min for 10–20 min) via a catheter in the thyroid artery. Thyroid venous effluent blood was continuously and completely collected from the surgically isolated in situ thyroid gland and CT was measured by RIA. In four of five pigs, infusion of a high dose of SRIF alone (10 μg/min) produced a small but significant fall in basal thyroid venous CT (mean decrease, 43% P < 0.005–0.001). In all five pigs, there was a significant return of CT to basal levels after the infusion of SRIF was discontinued (mean increase, 160% P < 0.05–0.001). Infusion of the high dose of SRIF (10 μg/min) together with Pg (0.25 μg/min) significantly inhibited the rise in CT observed with Pg alone in three of four pigs (mean decrease,68% P < 0.0...

The Effects of L-Dopa on inVitroandin VivoCalcitonin Release from Medullary Thyroid Carcinoma*

The in vivo and in vitro effects of the dopamine precursor L-dopa on basal and stimulated calcitonin release from medullary thyroid carcinoma have been studied. In six studies of five patients, including 7- to 8-h control and test periods, oral L-dopa depressed basal calcitonin secretion by an average of 35%; the peak effects occurred within 30 min of drug administration and lasted for as long as 4 h. In seven of eight patients with medullary thyroid carcinoma (three infused with calcium and five with pentagastrin), L-dopa inhibited to varying degrees peak levels of stimulated calcitonin release and total calcitonin secretion; basal calcitonin levels, where directly tested, also again generally fell after L-dopa by an average of 50%. In a short term organ culture system using medullary thyroid carcinoma tissues, calcitonin secretion into the medium was linear with time for 2 h and could be stimulated by dibutyryl cAMP and pentagastrin. L-Dopa, in concentrations from 0.5--3.0 mM, inhibited basal calcitonin secretion (ranging from 25--55%). Addition of the L-dopa decarboxylase inhibitor, alpha-methyldopa, abolished the inhibitory effects of L-dopa. Another L-dopa decarboxylase inhibitor, carbidopa, stimulated calcitonin secretion in vitro; this effect may be independent of the L-dopa decarboxylase-inhibiting properties of this drug since alpha-methyldopa alone did not stimulate calcitonin secretion. It is concluded that the amine precursor L-dopa inhibits calcitonin release in patients with medullary thyroid carcinoma; the in vitro studies suggest that a portion of this effect may involve direct metabolism of L-dopa to dopamine in the tumor tissue itself. The importance of considering the uptake of amine precursors and the subsequent metabolism of these compounds as a modulating site for peptide hormone release from peripheral endocrine tissues is stressed.

Urine Calcitonin as a Test for Medullary Thyroid Cancer

Although the radioimmunoassay of serum calcitonin (CT) has facilitated the diagnosis of medullary thyroid cancer (MTC) one may encounter patients whose basal serum levels of CT are normal or nearly normal. In such cases clinicians have utilized intravenous stimulation tests such as calcium or pentagastrin to obtain a diagnostic increase in serum CT. We have reported finding immunoreactive CT in the urine of man and have found it to be a useful technique for the diagnosis and study of patients at risk for MTC or other hypercalcitonemic diseases. Using basal urine CT alone we were able to separate 73% of patients at risk for MTC into clearly normal or abnormal groups. For the remaining 27% a stimulation test with subsequent determination of urine CT was required. The radioimmunoassay of urine CT is a simple, reliable, accurate test for the screening diagnosis of MTC. A protocol for the screening workup of a patient at risk for MTC is given.

Medullary thyroid carcinoma: relationship of method of diagnosis to pathologic staging.

Medullary thyroid carcinoma (MTC) develops in virtually all patients affected with multiple endocrine neoplasia type II (MEN II), a disease inherited as an autosomal dominant trait. The thyroid tumor cells secrete calcitonin (CT) and the detection of elevated plasma levels (>300 pg/ml) of this hormone in MEN II kindred members strongly suggests the presence of MTC even though it may not be evident clinically. Intravenously administered calcium ion (Ca(++)) and pentagastrin (Pg) are potent CT secretagogues which are of particular value in establishing the early diagnosis of MTC. In evaluating seven kindreds with MEN II, we detected 90 patients with MTC. Depending on the method of diagnosis, they could be divided into three categories: Group 1; patients with no clinical evidence of MTC whose undetectable basal plasma calcitonin levels became elevated following intravenous Ca(++) or Pg, Group II; patients with no clinical evidence of MTC who had elevated basal plasma CT levels, and Group III; patients with clinically evident MTC. At the time of diagnosis of MTC, the patients in Group I were younger (20.5 +/- 1.9 years) than the patients in Group II (32.5 +/- 4.7 years, p < 0.005) and Group III (34.3 +/- 2.0, p < 0.00005). The incidence of residual MTC, as indicated by an elevated plasma CT level following provocative testing postoperatively, was less frequent in patients diagnosed biochemically ([6/34]; Group I, 4/26 and Group II, 2/8) than in those diagnosed clinically (Group III, 15/26, p < 0.002). Furthermore, regional nodes were involved less often in patients diagnosed biochemically ([5/28]; Group I, 2/22 and Group II, 3/6) than in those diagnosed clinically (Group III, 15/24, p < 0.02). Distant metastases were only evident in Group III patients. Patients with MEN II who had the diagnosis of MTC established biochemically rather than clinically, had a more favorable pathological stage of disease at the time of thyroidectomy. This was especially true if the biochemical diagnosis had been by provocative testing.

The detection of elevated plasma levels of carcinoembryonic antigen in patients with suspected or established medullary thyroid carcinoma.

Plasma levels of carcinoembryonic antigen (CEA) and calcitonin (CT) were measured in 35 normal control subjects and in 37 patients with suspected or established medullary thyroid carcinoma (MTC). None of the normal control subjects had elevated basal plasma levels of either CEA (greater than 5 ng/ml) or CT (greater than 0.25 ng/ml). However, of the 37 patients with suspected or established MTC, 23 (62%) had elevated basal plasma levels of CEA (range 9.8--7,000 ng/ml) and 27 (73%) had elevated basal plasma CT values (range 0.30--500 ng/ml). Generally, patients with clinically apparent MTC, either primary or metastatic, had higher plasma CEA and CT levels than those with occult disease. A positive correlation was found (r = 0.785, p less than 0.01) when comparing basal plasma CEA and stimulated plasma CT levels in 20 patients. A marked increase above the basal plasma level of CT but not CEA was detected in each of six MTC patients following intravenous calcium or pentagastrin. These data demonstrate that basal plasma levels of CEA and CT were increased in a large percentage of patients with MTC. Plasma calcitonin levels unlike plasma CEA levels were more often elevated in patients with occult disease and were increased above basal following the intravenous administration of either calcium gluconate or pentagastrin.