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Several studies demonstrated a reduction in bone mineral content (BMC) in idiopathic renal stone formers (RSF). We found this reduction in association with a chronic low-calcium diet. Low calcium intake could theoretically result in calcitonin deficiency, responsible for increased bone resorption. This hypothesis was tested in 22 male RSF eating a low-calcium diet (350 +/- 72 SD mg/day) for 2 years or more, who showed a significant reduction in their BMC. When compared to 15 normal male subjects eating a free diet, RSF showed increases in serum alkaline phosphatase activity and fasting urinary excretion of hydroxyproline and calcium, suggesting increased bone turnover. Plasma calcitonin levels were measured by radioimmunoassay following an extraction-concentration technique (exCT). Basal plasma exCT levels were higher (P less than 0.005) in RSF (4.1 +/- 0.8 SEM pg/ml) than in normal subjects (2.8 +/- 0.4). Following a 5 minute infusion of 2 mg elemental calcium per kg, levels of plasma exCT tended to increase more, although not significantly, in RSF (51.3 +/- 9.4 pg/ml) than in normal subjects (36.6 +/- 9.7). The CT secretory response, taking into account changes in serum calcium concentration (delta exCT/delta Ca), was higher (P less than 0.05) in RSF (50.0 +/- 10.0) than in normal subjects (25.6 +/- 6.6). Our study thus demonstrates that RSF chronically fed a low-calcium diet have increased basal plasma CT levels and increased CT cells responsiveness. CT deficiency cannot therefore be considered a cause for the low BMC associated with a chronic low-calcium diet in RSF.

Carbetimer is a new antineoplastic agent whose main side effects consist of neurotoxicity and long-term dose-dependent hypercalcemia. We previously showed that Carbetimer is a potent calcium chelator responsible for an acute decrease in ionized Ca levels observed in vivo. However, the mechanism of the progressive increase in serum Ca remains unknown. We have evaluated the bone-resorbing effects of Carbetimer on 45Ca-prelabelled neonatal mouse calvariae. Carbetimer induced a dose-dependent increase in 45Ca release which started at a concentration of 1 mg/ml and reached a mean of 3.3 times the control values at 10 mg/ml. This marked increase in 45Ca release was similar on previously killed bones and could not be inhibited by calcitonin. Such concentrations are probably therapeutically relevant given the known affinity of Carbetimer for bone and the large daily doses administered to cancer patients (10-15 g). Since Carbetimer could exert its antineoplastic action through immunomodulation, we also studied its effects on the production of TNF-alpha and IFN-gamma which are also known to affect bone metabolism. Carbetimer did not stimulate TNF-alpha release from isolated normal human monocytes or lymphocytes, but it markedly inhibited T-lymphocyte production of IFN-gamma, which became undetectable at a concentration of 1 mg of Carbetimer/ml. In summary, Carbetimer-induced hypercalcemia appears to be due to a direct stimulation of osteolysis, but possibly also to an inhibition of IFN-gamma production.

Circulating human lymphocytes possess specific and functional receptors for calcitriol and PTH. We sought to determine if they also possessed receptors for calcitonin (CT), the third classical calciotropic hormone. We isolated blood mononuclear cells from healthy volunteers to separate monocytes, total lymphocytes, and T-lymphocytes; the purity of the three cell populations was more than 90%, 95%, and 85%, respectively. Salmon CT (sCT) was labeled by the chloramine-T method (SA, 254 muCi/micrograms) without loss of biological activity. We found saturable (16 h at 8 C), specific, high affinity binding sites for [125I]sCT on unstimulated lymphocytes. As for CT receptors on other cells, binding of [125I]sCT was poorly reversible. Binding specificity was demonstrated by the total absence of competing effect of several unrelated hormones; human CT and CT gene-related peptide competed much less efficiently than sCT for the binding sites, whereas PDN-21 had no effect. When plotted according to the method of Scatchard, binding data on the mixed population of T- and B-lymphocytes showed an apparent Kd (mean +/- SD) of 2.9 +/- 1.0 x 10(-10) M (n = 34), with an estimation of 91-8338 (median, 1971) binding sites/cell. The data were repeatedly compatible with an aspect of positive cooperativity between the binding sites, as confirmed by a Hill coefficient greater than 1 (1.18 +/- 0.13). However, this aspect of positive cooperativity in CT binding was not observed on isolated T-lymphocytes (Hill coefficient, 0.96 +/- 0.08; n = 9; P less than 0.001 vs. the mixed population of lymphocytes). CT did not induce a significant increase in cAMP levels, but regulation of receptor concentration was demonstrated by the finding of down-regulation of CT-binding sites after sCT or human CT preincubation. In summary, we have found saturable, specific, high affinity receptors for CT on unstimulated normal human T-lymphocytes, which could, thus, be target sites for CT action on bone metabolism or on the immune system.

Carcinoembryonic antigen (CEA) is the only tumor marker of proven, although limited, value for the management of patients with non-small cell lung cancer (NSCLC). The authors have prospectively assessed the potential value of a new tumor marker, squamous cell carcinoma antigen (SCC Ag), in a large series of patients with advanced lung cancer (LC). Squamous cell carcinoma antigen and CEA levels were measured in 382 healthy persons (N1 group), 90 patients with benign pulmonary diseases, and 291 patients with LC (129 with SCLC and 162 with NSCLC, including 96 with squamous LC). Carcinoembryonic antigen levels were higher in smokers than in nonsmokers, but smoking habits did not influence the serum concentrations of SCC Ag. Elevated values (above the 95th percentiles of N1, i.e., 7.5 ng/ml for CEA and 3.0 ng/ml for SCC Ag) were observed in 11.1% of patients with benign pulmonary diseases for both markers. Carcinoembryonic antigen was more sensitive than SCC Ag, even for squamous LC (56% versus 35% of elevated values, P less than 0.01). The specificity toward squamous LC was better, however, for SCC Ag, for which levels were elevated in only 8.5% of SCLC and in 18% of other forms of NSCLC, compared with 49% and 55%, respectively, for CEA. Moreover, measurement of SCC Ag and CEA levels did not give redundant information: thus, in squamous LC and SCC Ag level was elevated in 32% of the patients with a normal CEA level, increasing from 57% to 71% the proportion of patients with at least one elevated marker. Lastly, elevation of CEA or SCC Ag levels was an adverse prognostic factor in squamous LC (P = 0.05 for CEA; P = 0.07 for SCC Ag). In conclusion, SCC Ag appears to be worthwhile of further investigation in squamous LC. The authors found that this new marker provided additional information on CEA and that it was more specific for squamous LC than CEA.

Calcitonin (CT) deficiency and its possible repercussions on bone mass were studied in a group of 9 adult patients (7 females, 2 males) with congenital hypothyroidism of dysgenetic origin. Using a new extraction method (exCT) which considerably improves the sensitivity and the specificity of the assay for CT-monomer, we measured CT levels before and after a short calcium (Ca) stimulation test (2 mg Ca/kg over 5 minutes) to evaluate C-cell secretory reserve. Mean basal plasma CT concentrations were lower in the hypothyroid women (mean +/- SEM: 0.6 +/- 0.1 pg/ml) than in 30 normal female controls (1.7 +/- 0.2 pg/ml, P less than 0.001). Serum calcium increased similarly in the two groups, but postinfusion CT levels were lower in the hypothyroid women, (1.7 +/- 0.2 pg/ml) than in normal women (16.8 +/- 2.9 pg/ml), P less than 0.001. Hypothyroid women showed a 10% reduction in bone mineral content at the diaphyseal site in the radius, 0.840 +/- 0.037 g/cm, compared with normal age-matched controls, 0.930 +/- 0.020 g/cm, (P less than 0.05). Our study demonstrates the existence of a profound CT-monomer deficiency in adult patients with thyroid agenesis or dysgenesis. Both calcitonin deficiency and thyroid hormone treatment could play a role in the observed bone loss. Attention should therefore be paid to bone metabolism during treatment of congenital hypothyroidism to avoid further bone loss.

Unlabelled: To elucidate the role of thyroid ultrasound (TU) in the diagnosis of congenital hypothyroidism (CH), we compared 1) TU and thyroid scintigraphy (TS) in 6 CH newborns and 2) TU results in the 6 CH newborns, in 8 newborns with "false positive" results at screening, in 13 CH children aged 2 mo to 12 yr treated since the neonatal period and in 235 controls aged 0-12 yr., Results: 1) In all 6 CH newborns with no thyroid uptake at TS, TU evidenced small posterior hyperechogenic masses in the thyroid area [Vol: 322 +/- 180 (SD) mm3]; 2) In all normal controls and in the 8 "false positive" cases at screening TU showed normal thyroid structures. The thyroid volume was 831 +/- 383 mm3 in normal newborns and progressively increased with age. In the older CH children, TU also demonstrated the hyperechogenic masses, but their volume barely increased with age: as a consequence, the difference between the volume of the masses in CH patients and the thyroid tissue in controls, already significant in newborns (p less than 0.01), markedly increased with age. The exact nature of these masses is unknown; they could represent poorly vascularized ultimobranchial remnants containing the calcitonin - secreting cells: this hypothesis is supported by our finding that serum concentrations of calcitonin (measured by a sensitive extraction method) (mean +/- SD, pg/ml) were lower in the CH patients (2.9 +/- 1.5) than in controls (13.0 +/- 6.9; p less than 0.001) at birth. In conclusion, in all cases of CH, TU showed abnormal structures in the thyroid area. TU and TS provide complementary information in the diagnosis of CH, and TU should be routinely performed in all newborns suspected of CH to avoid unnecessary use of TS in unaffected infants.

We studied the pharmacokinetics of recombinant methionyl human interleukin-2 alanine (r-met-Hu IL-2 [ala 125]) given at high doses by i.v. bolus according to Rosenberg's initial schedule in seven patients with advanced cancer. Serum concentrations of IL-2 were measured by radio-immunoassay. The drug followed second-order kinetics. During the administration of repeated high doses of IL-2, we noted a progressive increase in the volume of distribution (from 5,984 +/- 1,850 to 9,084 +/- 4,345 ml) and a progressive decrease in the AUC (from 32,643 +/- 3,817 to 22,397 +/- 511 IU min ml-1) and beta-half-life (from 61 +/- 14 to 48 +/- 6 min); the peak serum IL-2 concentrations also decreased significantly. We attribute these findings to an expansion of the extracellular fluid space and an increase in the number of IL-2 target cells during the treatment.

To determine whether the hCG-like substance found in the plasma of normal nonpregnant subjects is secreted and regulated like a pituitary gonadotropic hormone or prohormone, we measured its concentration before and 60 min after the acute iv injection of 500 microgram Gonadotropin-releasing hormone (GnRH). The study was performed in 12 normal young men. The hCG-like substance was purified from the other plasma proteins by 2 successive diethylaminoethyl-Sephadex A-50 chromatographies and by gel filtration on Sephadex G-100. Its concentration was measured by a specific RIA, corrected for losses and for possible contamination with human LH (hLH). The median basal concentration in plasma was 19 pg/ml (mean, 41; range less than 5 to 169), and there was no correlation with corresponding hLH concentrations. After the injection of GnRH, the median, mean, and range of concentrations remained constant, whereas the mean hLH concentration increased over 8-fold. This indicates that no significant amounts of the hCG-like substance are acutely releasable from the pituitary gland and that its plasma concentrations are not modulated by GnRH in a fashion similar to hLH. It also constitutes an argument for an extrapituitary origin of the plasma hCG-like substances in normal men.

Radioimmunoassay of calcitonin in normal human plasma is hindered by immunochemical heterogeneity in plasma, variable susceptibility of antisera to non-specific factors, limited assay sensitivity, and other problems. Many controversial points in the literature arise from these difficulties. Measurement of calcitonin after various extraction procedures yields greater consistency of results. Recent advances in calcitonin assay technology offer the promise of measuring calcitonin monomer with sufficient sensitivity to permit studies of normal calcitonin physiology and of the hormone's role in human disease.

Occasional seemingly healthy individuals have above-normal concentrations of calcitonin-like immunoreactivity in their plasma, which can lead to mistaken diagnosis of thyroidal or other cancer. We measured immunoreactive calcitonin (CT) before and after extracting the plasma on columns of silica (to improve sensitivity and specificity of the assay for monomeric calcitonin) in five "healthy high-CT" men (I), five patients with known medullary thyroid carcinoma (II), and 30 normal controls (III). Median (and range) values (pg/mL = ng/L) for whole-plasma immunoreactive CT in these groups were, respectively, 379 (157-526), 429 (174-563), and 33 (less than 25-92). Dose-dilution curves for plasma samples from group I did not parallel the standard curve, in contrast to samples from the other two groups. Values for extractable CT from plasma from groups I and III, however, were indistinguishable, but remained significantly increased in group II. Infusions of Ca, 2 mg/kg body wt. in 5 min, produced the expected (normal) increases in extractable CT in group I. The occasional factor (or factors) in plasma of healthy persons that interferes in assays for CT is eliminated by the silica extraction method, and in this way such cases can be distinguished from cases of medullary thyroid carcinoma.

Intravenous aminohydroxypropylidene bisphosphonate (APD) normalizes serum calcium in most hypercalcemic cancer patients, however the optimal therapeutic scheme has not been established. We compared in a randomized prospective trial the efficacy and the tolerance of APD given as a 3-day treatment of daily 2-h infusions of 0.5 mg/k.d in 250 ml of saline (group A) with single 24-h infusions of 1.5 mg/kg (group B) or of 0.5 mg/kg in 1 liter of saline (group C). Thirty-three cancer patients remaining hypercalcemic after a 48-h rehydration period were included and monitored daily until normocalcemia or treatment failure was documented. Serum calcium became normal in all but 1 patient (in group C) but remained normal for only 1 or 2 days in 4 other patients (1 in A, 1 in B, 2 in C). The decline in total or ionized serum calcium was slightly less marked in group C than in the two other groups, but the differences were not significant. The fall of fasting urinary calcium excretion was however significantly less rapid in group C (p less than 0.05 from day 1 to day 4). Serum concentrations of iPTH and 1,25-dihydroxyvitamin D [1,25-(OH)2D] increased significantly in the three groups. Serum magnesium concentrations fell slightly from 1.41 +/- 0.05 to 1.28 +/- 0.04 mEq/liter (p less than 0.001) after rehydration but returned to normal after APD administration (day 5, 1.52 +/- 0.04 mEq/liter, p less than 0.001 versus day 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of malignancy-associated hypercalcemia remains unsatisfactory. We have prospectively treated 26 consecutive hypercalcemic cancer patients with intravenous (IV) aminohydroxypropylidene diphosphonate (APD). The drug was administered daily as a 15-mg two-hour IV infusion until both serum and urinary calcium had been normalized for 48 hours. Twenty-four patients were fully evaluable (eight head and neck tumors, seven breast cancers, three epidermoid tumors of the lung, and six miscellaneous neoplasms). Whereas rehydration had only inconsistent effects, APD normalized serum calcium in all patients after a mean of three daily doses: serum calcium decreased from 13.3 +/- 0.4 mg/dL (mean +/- SEM) before APD to 8.0 +/- 0.1 mg/dL at the end of treatment. Ionized calcium declined in parallel to total calcium. APD was as effective in hypercalcemia due to bone metastases as in paraneoplastic hypercalcemia. The drug was tolerated without toxicity and had a prolonged effect: serum calcium remained normal during 3+ weeks (1 + to 8 +) in 17 patients who did not receive or did not respond to antitumoral treatment. APD normalized serum calcium by inhibiting bone resorption, as evidenced by the dramatic decrease in urinary excretion of calcium and hydroxyproline. Inhibition of bone resorption was probably also responsible for the decrease in serum phosphorus from 2.9 +/- 0.2 to 2.0 +/- 0.1 mg/dL. In summary, IV APD constitutes a major advance in the treatment of malignancy-associated hypercalcemia: it is very effective, well tolerated, and has a prolonged efficacy.

The relative lack of sensitivity and specificity of current assays for plasma calcitonin (CT) have made it difficult to study possible CT deficiency conditions. Using a new extraction method that considerably improves the sensitivity of the assay for CT monomer, CT levels were measured before and after a short calcium (Ca) stimulation test (2 mg Ca/kg over 5 min) to determine C-cell secretory reserve in women with autoimmune primary hypothyroidism and normal women. Mean basal plasma CT concentrations were lower in the hypothyroid women [0.9 +/- 0.1 (+/- SEM) pg/ml] than in the normal women (1.5 +/- 0.2 pg/ml; P less than 0.01). Serum Ca increased similarly in both groups, but postinfusion CT levels were lower in the women with primary hypothyroidism (3.8 +/- 1.3 pg/ml) than in normal women (15.9 +/- 3.0 pg/ml; P less than 0.001). The functional thyroid status at the time of the study did not influence CT levels; both hypothyroid patients (n = 10) and patients who were euthyroid during T4 treatment (n = 11) were CT deficient to the same extent. Unlike that in primary hypothyroidism, CT secretion was normal in four patients with hypothyroidism of pituitary origin. We conclude that the process that causes hypothyroidism in patients with autoimmune thyroid disease can also cause marked CT deficiency. This first demonstration of spontaneous CT deficiency in adults should contribute to the understanding of CT physiology; it also suggests that bone metabolism should be closely monitored during the treatment of primary hypothyroidism.

Occult primary and recurrent medullary thyroid carcinomas (MTC) detected only by elevated calcitonin levels in the peripheral blood, generally after pentagastrin-test stimulation, are difficult to localize. Some new imaging procedures with radionuclide tracers or radiolabelled monoclonal antibodies against carcinoembryonic antigen seem to bring some potentially therapeutic benefits. We report our results with cell cultures and xenotransplants of human MTC with the intention of establishing reproducible models in vitro and in vivo. Cell cultures secrete calcitonin at up to 1200 pg/ml for periods ranging from 3 to 13 weeks. Immunocytochemistry detects cytoplasmic granules positive for calcitonin in polygonal epithelioid cells with dendritic processes. Xenotransplants in nude mice fare better in the subcutaneous axilla than in the subrenal capsule assay. In the former location the tumor-take is good and calcitonin is detected in the blood of the tumor-bearing animals, at levels ranging from 286 to more than 20,000 pg/ml. These models would be potentially usable as targets for radionuclide tracers and/or radiolabelled monoclonal antibodies.

TSH serum levels and thyroid function in 32 patients with primary hyperparathyroidism and hypercalcemia were compared to those of 30 age and sex-matched normal subjects. Serum T3 and T4 concentrations in hyperparathyroidism were not different from normal. However, basal serum TSH concentrations measured with an ultrasensitive immunoradiometric assay were significantly lower than normal (1.09 +/- 0.49 vs 2.06 +/- 0.85 mU/l, p less than 0.001). In hyperparathyroidism, TSH, but not T4 or T3, was negatively correlated with serum calcium, not with iPTH. The increase in TSH (delta TSH) 30 min after the iv injection of TRH was also significantly blunted in patients with primary hyperparathyroidism; delta TSH was highly correlated with basal TSH in hypercalcemic patients. The basal TSH concentration was higher and no longer different from normal (1.70 +/- 1.2 mU/l) 2 to 12 months after removal of the parathyroid adenoma, when serum calcium was normalized, whereas T3 and T4 did not change. A low basal TSH with normal T4 and low T3 was found in 13 patients with hypercalcemia of malignancy. In these patients, TSH increased after treatment of hypercalcemia with 3-amino-l,hydroxypropylidene-1, 1-bisphosphonate, whereas T4 did not change. The results suggest that the set point of pituitary thyroid feedback control could be decreased in chronic hypercalcemia and that hypercalcemia could render the thyroid more sensitive to TSH.

Serum osteocalcin (BGP) is a new marker of bone turnover that reportedly evaluates bone formation. Thus, its measurement could assess the bone formation rate in tumor-associated hypercalcemia. We measured concentrations of BGP and other parameters of bone metabolism in 54 untreated hypercalcemic cancer patients as compared to 109 healthy subjects. Primary tumor sites were breast (19), lung (11), head and neck (6), multiple myeloma (3), kidney (2), and various (11) or multiple (2). Mean BGP levels were higher in the hypercalcemic subjects, 4.6 +/- 0.4 (SEM) ng/ml, than in the normal subjects, 3.6 +/- 0.1 ng/ml (p less than .05), and were normalized in the 22 patients who could be reevaluated after successful treatment of hypercalcemia with intravenous aminohydroxypropylidene diphosphonate (APD). There was no correlation of BGP levels with age, sex, or renal function. Compared with the Gaussian distribution in the normal subjects, there was a considerable scatter of the data in hypercalcemic patients, suggesting the existence of defined subgroups with abnormally low or abnormally high values. However, we found no significant relationship of BGP concentrations with tumor site or histology or with bone metastatic involvement. We found also no significant correlation between concentrations of serum BGP and total or ionized calcium, alkaline phosphatase, parameters of bone resorption, and indices of parathyroid function. In summary, serum BGP levels were slightly elevated in tumor-associated hypercalcemia and were normalized after successful treatment of hypercalcemia. More importantly, BGP concentrations varied widely even in the subgroups of patients with hypercalcemia accompanying massive bone metastatic involvement or in the patients without detectable skeletal metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Some data suggest that human calcitonin (CT) secretion is lower in women than in men, decreases with age and the menopause, and is absent in thyroidectomized persons. To further explore CT secretory physiology, we have studied basal and calcium-stimulated plasma immunoreactive CT (iCT) and silica-extractable monomeric CT concentrations in 148 healthy volunteers and 33 patients with a history of thyroid damage (total or subtotal thyroidectomy, radioiodine treatment for thyrotoxicosis). Both whole-plasma iCT and extractable CT levels were lower basally and after calcium infusion in women than in men, basal levels being reduced about 50% and calcium-stimulated values about 75% from those of male subjects. There were no significant changes in basal iCT or extractable CT concentrations with age, and CT secretory capacity (CT response to calcium infusion) likewise did not change with age. Infusion of monomeric CT to constant concentration in 27 persons permitted estimates of CT metabolic clearance rates (MCRs) and secretion rates (SRs). Calculated MCRs of about 9 ml/min.kg-1 (persons aged 21-30 yr) and 6 ml/min.kg-1 (persons aged 54-70 yr) were in good agreement with published data, and did not differ between the sexes. SRs were dependent upon the assay method used to estimate basal plasma CT concentrations, being highest when whole-plasma iCT values were used. Based on estimates of plasma monomeric CT from the silica extraction procedure, the SR of CT was 59 +/- 6 (SE) ng/d.kg-1 in men, and 22 +/- 3 ng/d.kg-1 in women. Thyroid damage reduced, but did not abolish, apparent CT immunoreactivity, even in silica extracts of plasma. However, all subsets of thyroid-damaged patients had absent-to-markedly-impaired CT secretion in response to calcium infusion. We conclude that CT secretion is substantially lower both basally and after stimulation in women than in men, and that this difference in CT immunoreactivity probably reflects differences in circulating CT bioactivity. The sex difference in plasma CT concentrations probably results from lower rates of CT secretion in women, not increased MCR. There is no age-related decrease of plasma CT concentrations (or CT secretory reserve), calling into question the concept that a progressive deficiency of CT is partly responsible for age-related ("senile") osteoporosis. Surgical or radiation damage to the thyroid gland commonly abolishes C-cell response to calcium; such CT-deficient patients form a population suitable for determining whether or not reduced CT secretion can impair skeletal homeostasis.

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.

To avoid the limitations of present human calcitonin (hCT) assays, we have developed a silica extraction and concentration method for plasma hCT that lowers the detection limit of the assay 40-fold (to 0.5-1.0 pg/ml), and markedly improves specificity of the assay for the CT monomer (hCT-M). Extraction recoveries of radioiodinated and unlabeled synthetic hCT-M added to 20 ml plasma were, respectively, 90 +/- 1% and 99 +/- 4% (mean +/- SE). Gel filtration chromatography of plasma from patients with medullary thyroid carcinoma demonstrated that the extract was markedly enriched in hCT-M. Basal plasma immunoreactive hCT was measured before (iCT) and after extraction (exCT) in 60 normal individuals; basal exCT levels were higher in young men than in young women [8.0 +/- 0.8 (+/- SE) vs. 4.6 +/- 0.5 pg/ml; P less than 0.001] and higher in elderly men than in elderly women (9.4 +/- 0.8 vs. 4.7 +/- 0.6 pg/ml; P less than 0.05), but not different with age. Calcium infusions (2 mg Ca/kg over 5 min) in 36 subjects showed a significantly greater secretory capacity for exCT in men than in women, but showed no decline of exCT response with age. There was no correlation between basal iCT and exCT concentrations, but there was a good correlation between peak Ca-stimulated iCT and peak Ca-stimulated exCT levels (r = 0.94; P less than 0.001), suggesting that hCT-M was the main form released by acute stimulation. The mean extractable CT level in 6 totally thyroidectomized individuals was 2.7 +/- 0.3 pg/ml and did not increase after Ca challenge. We found no significant differences in basal or Ca-stimulated exCT levels measured in 5 women on 3 different occasions over the span of 1 menstrual cycle. After a meal, exCT levels did not change in women, but there was a consistent increase in the men (28 +/- 7% over baseline at 3 h; P less than 0.01). In summary, plasma concentrations of exCT and, most likely, hCT-M were very low (less than 10 pg/ml in most healthy adults) and always increased after calcium infusion. The measurement of plasma exCT is a useful technique that provides new sensitivity and specificity for the study of hCT physiology.

Immunoreactive calcitonin (iCT) can be ectopically secreted by lung cancer cells and has been proposed as a tumor marker for bronchial neoplasms. Since PDN-21 (katacalcin or the carboxyl-terminal flanking peptide of the calcitonin gene) and CT are cosecreted in normal subjects and in patients with medullary thyroid carcinoma (MTC), we sought to determine the potential utility of PDN-21 as a tumor marker for lung cancer. We measured carcinoembryonic antigen (CEA), neurone-specific enolase (NSE), iCT, and PDN-21 in 119 to 378 healthy subjects, 88 to 91 patients with benign pulmonary disease, and 249 patients with advanced lung cancer (108 small cell lung cancers and 141 other forms). Tumor marker specificity was satisfactory: the percentage of increased values (greater than the 95th percentile of normal subjects) in patients with benign pulmonary diseases varied from 9% (NSE, PDN-21) to 12% (CEA). PDN-21 was a more sensitive marker for lung cancer than iCT: the percentage of increased values was 44% for PDN-21 versus 19% for iCT, and 51% versus 23% for the subgroup of patients with small cell lung cancer (SCLC). PDN-21 concentrations were increased in 69 (34%) of 202 patients with a normal iCT level, whereas iCT concentrations were increased in only six (4%) of 139 patients with a normal PDN-21 level. However, markedly elevated concentrations of the two markers generally occurred in the same patients and the correlation between the two markers was significant (rs = 0.60; P less than 0.01). PDN-21 provided complementary information to that from the classical markers NSE and CEA.(ABSTRACT TRUNCATED AT 250 WORDS)

Infections constitute the main complication of parenteral nutrition, particularly in cancer patients, but prediction of catheter-related septicemias (CRS) has been little investigated. We have evaluated, in 200 consecutive episodes of parenteral nutrition (PN) in cancer patients, the factors contributing to infectious complications, and the predictive value of weekly blood cultures performed through the nutrition catheter. The median duration of PN was 22 days with a total of 5816 patient-days of PN, neutropenia (neutrophils < 1,000/microl) being present in 872 (15%). Catheters were placed either in a jugular vein (71% single-lumen silicone catheters, 18.5% double-lumen Hickman-Broviac catheters) or in a femoral vein (10.5%). We observed 62 episodes of septicemia of which 22 were CRS (11% incidence for the 200 cycles) and 40 were non-CRS (20% incidence); CRS were mostly due to Staphylococcus epidermidis (14/22). Neutropenic patients as a group did not suffer more CRS than non-neutropenic patients, but the risk of CRS was slightly increased when expressed per day of neutropenia (8 CRS/872 days vs 14 CRS/4942 days without neutropenia, P < 0.05). On the other hand, a femoral insertion site was associated with a much higher incidence of CRS (9 CRS/21 femoral catheters vs 13 CRS/179 jugular catheters, P < 0.0001). It was possible to evaluate 20 episodes of CRS for their predictability by weekly blood cultures: the sensitivity for detecting CRS due to Staphylococcus epidermidis was 67%, the specificity 92%, the negative predictive value 98% and the positive predictive value 36%. The simple and widely available procedure of routine surveillance blood cultures performed through the PN catheter should be further investigated, because it could help the clinician to determine the origin of recent fever, particularly to exclude CRS and avoid unnecessary removal of PN catheters.

Adoptive immunotherapy of cancer consists of using interleukin-2 to induce the formation of lymphokine-activated killer (LAK) cells which are toxic to tumoral cells. Six patients, 3 with hypernephroma and 3 with melanoma, were treated with interleukin-2. Drug toxicity consisted of capillary leakage syndrome in one case and reversible renal impairment in another. One patient showed an objective response; transient subjective improvement was observed in all patients.

Calcitonin deficiency has been implicated in the pathogenesis of accelerated bone loss, especially in postmenopausal osteoporosis. To investigate this issue, we studied 25 patients with untreated postmenopausal osteoporosis, 14 age-matched and sex-matched healthy controls (spinal bone mineral density greater than or equal to age-specific and sex-specific mean), and 5 women who had undergone total thyroidectomy. Each subject received an intravenous infusion of 2 mg of elemental calcium per kilogram of body weight over 5 minutes, to test the C-cell secretory reserve. We measured calcitonin by radioimmunoassay in whole plasma and in silica-cartridge extracts of plasma, the latter method providing greatly improved sensitivity and specificity for monomeric calcitonin. Basal immunoreactive calcitonin concentrations, whether measured in whole plasma or in extracts, were significantly higher in the subjects with osteoporosis (P less than 0.01) than in the healthy controls. The calcitonin secretory reserve, as assessed by calcium stimulation, was normal in the osteoporotic group but virtually absent in the thyroidectomy group. We conclude that postmenopausal osteoporosis is not associated with and does not result from calcitonin deficiency. On the contrary, excessive skeletal calcium release may stimulate calcitonin secretion in patients with the disorder.

Bisphosphonates (or diphosphonates) constitute a major advance in the treatment of tumor-associated hypercalcemia and also have the potential to prevent or reverse osteolysis in normocalcemic patients. Available information on adequate therapeutic doses and potential toxicity is, however, very fragmentary. This report describes a phase I study of one of the most promising bisphosphonates currently available, aminohydroxypropylidene bisphosphonate (AHPrBP or APD), in tumor-associated hypercalcemia. Only patients remaining hypercalcemic after 48 hours of rehydration were evaluated, and antineoplastic therapy was delayed at least until a normal serum calcium level was reached. AHPrBP was given as two-hour daily infusions for three days, and three different patients were treated at each of the six following dosage levels: 0.01, 0.05, 0.25, 0.75, 1.5, and 3.0 mg/kg per day. The two lowest dosages levels were insufficient to normalize serum and urinary calcium levels, but the efficacy of the four other dosages was very similar. Plasma immunoreactive parathyroid hormone levels increased as a function of calcium levels, whereas urinary hydroxyproline levels did not prove to be a very useful measure of AHPrBP's effects on bone resorption. The drug was generally very well tolerated: only six patients had transient fever and/or decreases in lymphocyte count that were not clearly related to AHPrBP dosage. The only real problem was observed at the highest dosage of 3.0 mg/kg per day in an obese woman in whom high fever and hypotension developed. Efficacy and tolerance in dehydrated patients were verified by treating seven other patients, not previously rehydrated, at 1.0 mg/kg per day for three days. In summary, the therapeutic range of AHPrBP, given for three days as a two-hour infusion daily, lies between 0.25 and 1.5 mg/kg per day. Fasting urinary calcium levels are probably the most reliable and easily measured parameter to monitor AHPrBP's inhibition of bone resorption in normocalcemic patients.

The authors present a case of cholestatic jaundice which developed during total parenteral nutrition. The histology of the liver mimicked the picture of large bile duct obstruction. However, there was no duct obstruction and the symptoms regressed after the caloric input was reduced. At postmortem examination, the portal inflammatory infiltrate had cleared and was replaced by fibrosis. Alterations in bile chemistry could be responsible for the similarity between the lesions induced by parenteral feeding and those classically described in large bile duct obstruction.

An acute increase in serum calcium stimulates calcitonin (CT) secretion, but the effects of chronic hypercalcemia are controversial. Histopathological studies have shown C-cell hyperplasia in primary hyperparathyroidism (1 degree HPT), although circulating levels of CT have been variously reported to be normal, elevated, or depressed. We reexamined this relationship using CT RIA in conjunction with a silica extraction technique that conveys improved sensitivity and specificity for monomeric CT. Nine men and seven women with surgically documented 1 degree HPT were studied preoperatively before and after a short calcium infusion (2 mg Ca/kg, for 5 min), as were 72 normal men and 76 normal women. Basal whole plasma immunoreactive CT and silica-extractable CT concentrations in 1 degree HPT were indistinguishable from normal, regardless of sex. In addition, the whole plasma and silica-extractable CT responses to calcium stimulation were normal or blunted in patients with 1 degree HPT. We conclude that hypercalcemia resulting from 1 degree HPT is not associated with augmented CT secretion in response to an iv calcium infusion.

This case report of giant cell granuloma involving the maxilla is of particular interest for two reasons: the locally aggressive clinical course contrasting with the diagnosis of a benign disease and the spectacular, although transient, response under steroid treatment. Corticotherapy should be further tested in cases of invasive or recurring giant cell granuloma.

To understand ectopic hormone secretion in cancer we compared the plasma concentrations of the hCG-like substance in normal nonpregnant subjects and in women with breast cancer. In 45 normal men the plasma concentrations did not vary with age (median, 5 pg/ml; range, less than 3-169) whereas in 45 normal women they increased after menopause (median, 48 pg/ml; range, less than 5 -569, n = 20, P less than 0.0001). In 56 women with breast cancer the plasma concentrations of the hCG-like substance after menopause were much higher than in normal women (median, 202 pg/ml; range, 14-1561; n = 35; P less than 0.001), with no abnormally high pituitary gonadotropin values and no relationship with the tumor burden (same median after mastectomy, 198 pg/ml; n = 21). This hCG-like substance was glycosylated and similar to standard hCG according to molecular size, ionic strength, and immunoreactivity. Our data are compatible with the following conclusions: 1) the plasma concentration of the hCG-like substance is normally very low but dependent on gonadal function in women. Its source might be the pituitary gland or peripheral tissues. 2) Its concentration is much increased in postmenopausal women with breast carcinoma. This increase is found with normal pituitary gonadotropin values and is independent of the tumor burden, suggesting it is of extrapituitary and nontumoral origin.

Since the binding sites of hormone receptors may be similar to those of antihormone antibodies, we wondered whether the former might not be recognized by the idiotypic network. To test this hypothesis we investigated the interaction of plasma immunoglobulin G (IgG) with the binding sites of estrogen receptors (ER) from uterine or mammary tissue. Using ER isolated from uterine cytosol we found that IgG from normal subjects shifted the position of purified receptor in sucrose gradients and displaced [3H]estradiol (E2) from its receptor-binding sites. Equilibrium studies revealed competitive inhibition by IgG of E2 binding to the ER. IgG isolated by adsorption on a rat uterine cytosol-Blue B matrix gel column also bound to the ER, and this binding was inhibited by an excess of E2. After an 18-h exposure of MCF-7 mammary carcinoma cells in monolayer culture to IgG (2 mg/ml), Scatchard analysis of [3H]E2 binding revealed a reproducible decrease in the available receptor sites from 2.52 +/- 0.56 (+/- SEM) to 0.68 +/- 0.48 fmol/microgram DNA (n = 10). This effect was selective, since enriched anti-ER IgG obtained by adsorption on purified receptor was 20 times more potent than total IgG, whereas IgG identically prepared but not retained by affinity chromatography had no activity. Exposure of the cells to the IgG for 45 min also revealed, as with isolated ER, specific competition of the IgG with E2 for the E2-binding sites; the Kd increased from 10.5 +/- 1.6 to 27.5 +/- 7.2 X 10(-11) M (n = 7). Enriched antireceptor IgG was a 20 times more effective competitor, and the IgG not retained by affinity chromatography had no activity. In conclusion, our observations indicate the presence of ER on the cell surface, interaction of ER with IgG from plasma of normal subjects, and competitive antagonism of these IgG with E2 uptake leading to a decrease in effective ER concentrations.

Carbetimer, a low molecular weight polymer derived from ethylene and maleic anhydride, belongs to a class of chemical compounds different from previously available anticancer agents. It has shown moderate antitumor activity against the Madison 109, Lewis lung, colon 26 and M5076 ovarian carcinomas. In the human tumor stem cell assay, antitumor activity was seen against carcinomas of the breast, ovary, lung, colon and kidney. A total of 26 patients with solid tumors were entered into this trial; carbetimer was given on 5 consecutive days as a 1-2-h intravenous infusion. The dose was escalated from 1.08 to 11 g/m2/day. The drug did not induce the usual side-effects of chemotherapy: leukopenia, thrombocytopenia, alopecia and mucositis were minimal or totally absent. Gastrointestinal toxicity was limited to mild to moderate nausea and vomiting; these were observed at all dose levels and required antimetics in only two patients. The major side-effects of carbetimer consisted of hypercalcemia and neurotoxicity. Hypercalcemia was dose- and treatment duration-dependent. The precise mechanism of hypercalcemia is presently under investigation, but remains unclear. Neurotoxicity was observed only after prolonged therapy; two patients, who received cumulative doses higher than 250 g/m2, developed a peripheral neuropathy with paresthesia, decrease in sensory perception and motor weakness. One patient recovered completely; the other patient improved slightly before developing fatal brain metastases. Two patients with malignant melanoma exhibited major antitumor response; both were previously treated; after excellent partial responses to carbetimer, both were operated on and one is presently disease-free 2 1/2 years after completion of therapy with carbetimer. In conclusion, carbetimer is a new compound with an unusual pattern of side-effects and interesting antitumor activity against malignant melanoma. Its antitumor activity is presently being investigated in phase II trials.