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Biomedical subjects

F Raue

Publications and source records attributed to F Raue.

At least 109 records · Page 6Linked to original sources
PubMed1993

The use of octreotide in the treatment of medullary thyroid carcinoma.

The long-term treatment of metastasizing medullary thyroid carcinoma with octreotide was evaluated in seven patients with progressive disease. All patients had persistently elevated serum calcitonin and carcinoembryonic antigen (CEA) concentrations. Daily doses of 200-1000 micrograms octreotide were administered by means of two or three subcutaneous injections for 3-9 months. In one patient treatment was stopped after 3 days because of aggravation of preexisting diarrhea. No beneficial effect on preexisting diarrhea was observed in three other patients during long-term treatment; in these patients further weight loss occurred. In five of six patients, serum calcitonin concentrations further increased; serum CEA concentrations increased in four of six patients. A therapeutic effect on tumor growth could not be demonstrated; in three patients, metastases continued to grow. We conclude that octreotide does not improve the natural course of advanced stages of medullary thyroid carcinoma.

Adult↗
PubMed1993

Somatostatin receptor scintigraphy and magnetic resonance imaging in recurrent medullary thyroid carcinoma: a comparative study.

In a prospective study, 18 patients with recurrent medullary thyroid carcinoma (MTC) underwent magnetic resonance imaging (MRI) of the neck and mediastinum and somatostatin receptor scintigraphy (SRS) with 111In-labeled pentetreotide. In nine patients with macroscopic MTC, 17 corresponding lesions were found on MRI and SRS; in addition, 13 suspicious lesions were seen on SRS only. Histological confirmation was available for 19 metastatic lesions, showing MRI to be true positive in 13 metastases, SRS in 18. In minimal residual disease (n = 10), MRI and SRS were compared with the histological findings in three patients and with selective venous catheterization (SVC) in seven patients. Corresponding findings on MRI and SVC were seen in one of seven, whereas SRS and SVC showed concordant localization of tumor recurrence in five of seven. Histological examination demonstrated MTC tissue in one of three cases; MRI and SRS were false positive in one of three cases, while in the others the interpretation remained uncertain. In conclusion, SRS is a promising imaging modality for localization of MTC recurrence. MRI provides better spatial resolution and thus facilitates the planning of surgery for macroscopic metastases. In minimal residual disease, SRS turned out to be superior in detecting occult MTC recurrence, confirming SVC findings.

Adolescent↗
PubMed1992

[Endocrinously active parathyroid cysts. Their diagnosis by the determination of intact parathormone in the cyst fluid].

A 53-year-old woman with recurrent nephrolithiasis was found to have hypercalcaemia of 3.12 mmol/l and an intact parathormone level of 166 pg/ml, indicating primary hyperparathyroidism. Preoperative ultrasound examination to localize the parathyroid adenoma revealed a clear fluid-containing cyst in the right lobe of the thyroid. The aspirated fluid had an intact parathormone level of 306 pg/ml, twice that in serum. The cyst was removed surgically. 14 days postoperatively calcium and parathormone levels in serum had become normal without any calcium administration. Measuring the concentration of intact parathormone in the aspirated cyst fluid made possible not only the distinction from a thyroid cyst but also the precise preoperative localization of the parathyroid cyst.

Body Fluids↗
PubMed1992

Tumor necrosis factor alpha inhibits the stimulatory effect of the parathyroid hormone-related protein on cyclic AMP formation in osteoblast-like cells via protein kinase C+.

Tumor necrosis factor alpha (TNF alpha) and parathyroid hormone-related protein (PTHrP) are both factors that have been implicated in the mechanism of hypercalcemia of malignancy. In this study we investigated the effect of TNF alpha on the PTHrP-stimulated accumulation of intracellular cyclic AMP in osteoblast-like cells. In the clonal cell line Saos-2 and in primary cell cultures from fetal rat calvaria, PTHrP-stimulated accumulation of cAMP was time- and dose-dependently inhibited by exposure to TNF alpha. Significant inhibition occurred at concentrations as low as 2 x 10(-12) M and was maximal at 1 x 10(-9) M. Inhibition was observed after 6 h and was maximal after 18 h. Inhibition by TNF alpha was probably mediated by protein kinase C, since the phorbol ester PMA mimicked the effect of TNF alpha, and the protein kinase C inhibitor H-7 completely abolished the effect of TNF alpha. In conclusion, these observations suggest a possible mechanism by which TNF alpha may modulate the effect of PTHrP on osteoblast function in the syndrome of humoral hypercalcemia of malignancy.

Animals↗
PubMed1992

Regulation of calcitonin gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

High calcium leads to the secretion of calcitonin, and the administration of 1,25-dihydroxyvitamin D3 leads to a decreased transcription of the calcitonin gene. We now report the effect of chronic hypercalcemia, hypocalcemia, and vitamin D deficiency on calcitonin gene expression in vivo in the rat. Hypercalcemia was created by calcium infusions for 6 h, a high-calcium diet given to weanling rats for 3 weeks, and the transplantation of the Walker carcinosarcoma 256 cell line. Despite serum calcium as high as 22 mg/dl, there was no difference in calcitonin mRNA levels among these rats. The control genes studied, actin and somatostatin, which is specific for C cells in the thyroparathyroid tissue, also did not differ among the different groups of rats. Injected 1,25-(OH)2D3 decreased calcitonin mRNA levels at 6 h, as previously reported. Hypocalcemia, created by feeding diets deficient in calcium and vitamin D to weanling rats for 3 weeks, had no effect on calcitonin mRNA levels, in contrast to the large increases in PTH mRNA levels. These results demonstrate that calcitonin gene expression in vivo in the rat is regulated by administered 1,25-(OH)2D3 but not by changes in serum calcium.

Actins↗
PubMed1992

Evaluation of sensitive PDN-21 (katacalcin) determination as tumor marker in medullary thyroid carcinoma.

PDN-21 (katacalcin), a peptide from the calcitonin (CT) gene, was measured in plasma from healthy persons and patients with medullary thyroid carcinoma (MTC). PDN-21 was detectable (greater than or equal to 10 ng/l) in 73% of normal persons (n = 40). In 17 normal persons with undetectable basal plasma levels, PDN-21 became detectable (greater than or equal to 10 ng/l) by stimulation with iv pentagastrin in 7 cases. Basal levels were more often detectable in men than in women. In 65 patients with MTC, PDN-21 levels were highly correlated with CT levels as determined by an "in house" RIA (r = 0.99); the mean ratio of CT/PDN-21, on a molar base, was 0.96 +/- 0.33 over the entire range. In iv stimulation tests with pentagastrin, PDN-21 and CT showed good parallelism (mean ratio of CT/PDN-21: 1.1 +/- 0.62); in MTC patients with normal basal levels, however, peak to basal ratios during iv pentagastrin testing were higher for PDN-21 than for CT, due to the more sensitive PDN-21 assay. In a selective venous catheter study of a patient with MTC, the mean CT/PDN-21 ratio for all samples was 1.04 +/- 0.12, but the peak to peripheral levels were higher for PDN-21 (4.1-fold) than for CT (2.8-fold). In conclusion, determination of PDN-21 by RIA is equivalent to determination of CT in diagnosing MTC patients. In few patients, it might be even slightly more sensitive. PDN-21 should be determined in all cases with borderline CT results.

Biomarkers, Tumor↗
PubMed1992

A new in vitro bioassay for human calcitonin: validation and comparison to the rat hypocalcemia bioassay.

The human breast cancer cell line T 47 D expresses calcitonin (CT) receptors that are coupled to adenylate cyclase and which reveal a dose-dependent cyclic AMP response to CT. We used this model to establish an in vitro bioassay for synthetic human CT (hCT) preparations to overcome some of the obstacles of the standard rat hypocalcemia in vivo bioassay. The detection limit of the in vitro bioassay was 1 x 10(-10) M hCT (EC 50: 8.7 pM +/- 26%) compared to 7.3 x 10(-9) M (EC 50: 7.2 microM +/- 32%) for the in vivo bioassay. The relative potencies of test preparations revealed a good correlation (r = 0.89) and several hCT-related substances produced comparable results when tested by the two methods. The standard deviations of precision and accuracy, however, were significantly smaller (P less than 0.05) for the in vitro bioassay. According to these data the T 47 D in vitro bioassay is more sensitive, superior in precision and accuracy, and comparable in specificity to the rat hypocalcemia bioassay.

Adenylyl Cyclases↗
PubMed1992

Inhibitory effect of somatostatin on cAMP accumulation and calcitonin secretion in C-cells: involvement of pertussis toxin-sensitive G-proteins.

The effect of somatostatin on cAMP accumulation and calcitonin secretion in C-cells of the rat medullary thyroid carcinoma cell line rMTC 6-23 was investigated. Intracellular cAMP accumulation as well as calcitonin secretion could be dose-dependently stimulated by rat growth hormone releasing factor (rGRF). The long-acting somatostatin analogue octreotide inhibited rGRF-stimulated cAMP accumulation and calcitonin secretion dose dependently but failed to block 8-bromo-cAMP-stimulated calcitonin secretion. The inhibitory effect of octreotide on rGRF-induced calcitonin secretion was partially abolished by pretreating the cells with pertussis toxin. The octreotide effect was not due to changes in the degradation of cAMP, as it was similarly seen in the presence of isobutylmethylxanthine. Thus we conclude that pertussis toxin-sensitive G-proteins are involved in the cAMP-mediated regulation of calcitonin secretion in C-cells.

Animals↗
PubMed1992

Inhibition of Ca(2+)-induced calcitonin secretion by somatostatin: roles of voltage dependent Ca2+ channels and G-proteins.

Somatostatin has recently been applied therapeutically for hypercalcitonemia in patients with calcitonin-producing tumours. Using calcitonin-secreting cells (C-cells) of the medullary thyroid carcinoma cell line rMTC 44-2, we investigated the inhibitory action of somatostatin on calcitonin release, cytosolic Ca2+ and Ca2+ channel currents. The Ca(2+)-induced rises of the cytosolic Ca2+ and calcitonin secretion were greatly inhibited by somatostatin or its stable analogue octreotide. The effects of somatostatin were pertussis toxin-sensitive. Under voltage clamp conditions, C-cells exhibited slowly inactivating Ca2+ channel currents. Bath application of 100 nM somatostatin reversibly reduced the Ca2+ channel current by about 30%. The Ca2+ channel current and its inhibition by somatostatin were not affected by intracellularly applied cyclic AMP. Moreover, pretreating the cells with pertussis toxin had no effect on the control Ca2+ channel currents but greatly abolished its inhibition by somatostatin. The data show that somatostatin suppresses the Ca(2+)-stimulated calcitonin secretion by inhibiting voltage-dependent Ca2+ channel currents and by lowering cytosolic Ca2+. These actions of somatostatin involve pertussis toxin-sensitive G-proteins and occur independently of changes in the cyclic AMP concentration.

Animals↗
PubMed1992

In vitro secretion of calcitonin from a rat C cell line: effect of repetitive stimulation with the calcium channel agonist BAY K 8644.

Calcium and BAY K 8644 acutely stimulate calcitonin secretion by influx of extracellular calcium (Ca) through voltage-dependent calcium channels, leading to an increase in cytosolic free Ca. Repetitive exposure to BAY K 8644 (10(-6) M) resulted in an increase in calcitonin (CT) secretion in the rat C-cell line (rMTC 6-23) lasting 9 hours, in comparison to that of 3 mM Ca2+ which lasted 6 hours. Equimolar concentration of nifedipine did not inhibit the stimulatory effect of BAY K 8644 as compared to the nifedipine only group. The decrease in stimulated CT secretion during long-term exposure to BAY K 8644 is due to desensitization of cells which may be attributed to down-regulation of dihydropyridine receptors. After 12 h exposures to 3 mM Ca2+ alone, BAY K 8644 (10(-6) M) alone or in combination with nifedipine (10(-6) M), CT content decreased below the control level, indicating a decrease in synthesis. Overall cellular protein content was not affected by the test agents. Repetitive exposure of C-cells to BAY K 8644 revealed a desensitization of the stimulatory effect on CT secretion and a decrease in CT cell content.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Localization of occult persisting medullary thyroid carcinoma before microsurgical reoperation: high sensitivity of selective venous catheterization.

In 14 patients with occult persisting medullary thyroid carcinoma, tumor tissue was removed by microsurgical reoperation in 13 of 14 patients. This resulted in biochemical improvement in all but 1 patient and biochemical cure in 3 patients (21%). The lateral compartment of the neck or the upper mediastinum was involved in all but 1 patient. Before microsurgical reoperation, selective venous catheterization (SVC) for serum sampling along with serum calcitonin (CT) determination was done and compared to other localization methods. Tumor tissue could be localized correctly by SVC in 89% (CT gradient 1.21-2.02), computed tomography in 38%, and ultrasound in 28%. In patients with an elevated CT level after initial surgery and clinically occult disease, SVC is recommended for localization of tumor tissue. The affected side of the neck should be reoperated on with microdissection of the central and lateral compartment of the neck and the upper mediastinum. With this procedure, the cure rate of reoperation in patients with persistent occult MTC can be improved.

Calcitonin↗
PubMed1992

Chromogranin A as tumor marker in medullary thyroid carcinoma.

We measured plasma levels of chromogranin A (CgA) and calcitonin (CT) in 61 patients with surgically confirmed medullary thyroid carcinoma (MTC). CT was elevated in 46 patients, whereas CgA was elevated in 14 patients. Plasma levels of CgA and CT were moderately correlated (r = 0.87), but CgA became elevated in most patients only in advanced disease. Patients with high plasma CT values (greater than 10 micrograms/L) also had elevated CgA in 83% of cases. An elevated plasma CgA level despite normal CT levels was found in only 1 patient. In 8 MTC patients with moderately elevated basal CT levels, pentagastrin as a secretagogue usually was not able to release detectable amounts of CgA from MTC tissue. In 2 MTC patients, i.v. catheter sampling gave sharp gradients for CT concentrations (greater than 2.7-fold peak to peripheral ratios) and, therefore, precise MTC tissue localization, whereas no gradients were demonstrable for CgA (less than 1.2-fold). One patient with MTC and elevated CgA reached normal CgA plasma levels within 8 days after thyroidectomy. In metastatic tissue from 8 patients with MTC, CgA and CT were detectable immunohistologically in all cases, but plasma CgA was elevated only in 2 and CT in 7 of them. Plasma CgA levels in patients with MTC usually became elevated only in advanced disease and were not able to detect early disease stages, were correlated with CT levels, were not useful in stimulation tests or venous localization studies, and probably resulted from the release from MTC tissue as the major tissue source, as shown in the sporadic cases.

Biomarkers, Tumor↗
PubMed1992

Circulating levels of midregional parathyroid hormone-related protein in hypercalcaemia of malignancy.

OBJECTIVE: We have developed and evaluated a sensitive radioimmunoassay directed against the midregional part of parathyroid hormone-related protein (PTHrP), which is involved in the syndrome of humoral hypercalcaemia of malignancy. PATIENTS: Midregional PTHrP levels were studied in 41 consecutive inpatients with malignancy and hypercalcaemia, 32 normocalcaemic patients with malignancy, 21 patients with primary hyperparathyroidism, 34 patients with renal failure, and 87 normals. MEASUREMENTS: The assay used an antiserum against the midregional amino acid residues 53-84 of PTHrP and PTHrP(1-86) as label and standard. Midregional PTHrP was stable in serum and plasma and could be measured directly without sample extraction. RESULTS: Normal plasma concentrations ranged from undetectable (< 5 pmol/l) to 21 pmol/l. In renal failure, PTHrP was positively correlated with serum creatinine, but PTHrP elevations of up to 30 pmol/l were found only in severe renal dysfunction with creatinine > 850 mumol/l. In hypercalcaemia caused by solid tumours, midregional PTHrP was elevated in 81% (22 of 27) of patients, ranging from undetectable to 203 pmol/l (median: 40 pmol/l). In these patients serum calcium correlated positively with PTHrP (P < 0.01). Mean PTHrP levels were indistinguishable in subgroups with and without metastatic skeletal disease. The mechanism of hypercalcaemia in 14 patients with haematological malignancy was apparently different, since all but one had normal or only marginally elevated PTHrP levels. In 21 patients with primary hyperparathyroidism midregional PTHrP was normal in 20. The assay was therefore especially useful in distinguishing the latter condition from humoral hypercalcaemia of malignancy as the second major cause of hypercalcaemia. PTHrP was normal in all 32 patients with normocalcaemic malignancy. CONCLUSION: This radioimmunoassay of midregional PTHrP provides high diagnostic sensitivity in the identification of humoral hypercalcaemia of malignancy caused by solid tumours. The assay should therefore be useful in the differential diagnosis of hypercalcaemia.

Diagnosis, Differential↗