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F Raue

Publications and source records attributed to F Raue.

At least 73 records · Page 4Linked to original sources
PubMed1995

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.

Adolescent↗
PubMed1995

Response to methimazole in Graves' disease. The European Multicenter Study Group.

OBJECTIVE: A variety of regimens continue to be used in the treatment of Graves' disease with antithyroid drugs. We have investigated the factors which determine the initial response to methimazole (time until euthyroidism is achieved) in Graves' disease. PATIENTS: Five hundred and nine patients with Graves' disease in different European countries with normal and subnormal iodine supply. Patients were randomized to treatment with either 10 or 40 mg of methimazole per day for one year, with levothyroxine supplementation as required to maintain euthyroidism. Investigations were carried out before treatment and at 3 and 6 weeks and 3, 6, 9 and 12 months. MEASUREMENTS: Response was assessed by serial measurements of serum thyroid hormones. TSH receptor antibodies, thyroid autoantibodies and urinary iodide excretion were measured centrally. Twenty-minute thyroid uptake was measured by standard techniques. Data were collected and analysed centrally. Standard techniques as well as a stepwise logistic regression model were used to examine the relations between methimazole dose, age, goitre size, presence of endocrine eye signs, thyroid hormone levels, urinary iodide excretion, thyroid uptake, index of disease severity (Crooks), presence of TSH receptor antibodies and duration of the hyperthyroid phase. RESULTS: Within 3 weeks, 40.2% of patients responded to 10 mg of methimazole and 77.5% responded within 6 weeks. The corresponding figures for 40 mg of methimazole were 64.6 and 92.6%. Significant associations were found between duration of hyperthyroidism and the following variables: goitre size, urinary iodide excretion, methimazole dose, presence of TSH receptor antibodies (TBIAb), index of disease severity (Crooks) and pretreatment thyroid hormone levels. Response to methimazole was delayed in patients with large goitres, iodine excretion of > or = 100 micrograms/g creatinine, high pretreatment thyroid hormone levels, elevated levels of TBIAb and treatment with only 10 mg of methimazole. In the 10-mg group, 46% of patients were euthyroid within 3 weeks when urinary iodide was < 50 microgram/g of creatinine, and only 27% when iodide was above 100 micrograms/g. By stepwise logistic regression, the main factors for the response to methimazole were daily dose, pretreatment T3 levels, and goitre size. CONCLUSION: Methimazole dose, pretreatment serum T3 levels, and goitre size are the main determinants of the therapeutic response to methimazole in Graves' disease, at least in areas comprising low, subnormal and normal iodine supply.

Adult↗
PubMed1995

Somatostatin receptor imaging in persistent medullary thyroid carcinoma.

OBJECTIVE: Somatostatin is secreted from thyroid C-cells and seems to play an important part in the regulation of calcitonin secretion. We therefore evaluated the usefulness of somatostatin receptor scintigraphy in the localization of tumour tissue in patients with persistent medullary thyroid carcinoma. DESIGN: A prospective clinical study. PATIENTS: The series consisted of 26 patients with elevated calcitonin levels after total thyroidectomy for histologically proven medullary thyroid carcinoma. METHODS: Somatostatin receptor scintigraphy using 111In-pentetreotide (Octreoscan) was performed in all patients and the results correlated with histology, ultrasonography, computerized tomography, magnetic resonance imaging, plain radiography, bone scintigraphy and selective venous catheterization. Calcitonin and carcinoembryonic antigen levels were measured. RESULTS: The sensitivity of somatostatin receptor scintigraphy for localization of persistent medullary thyroid carcinoma was 57% in patients with histologically proven disease. The results depended on tumour mass (low sensitivity (33%) in minimal residual disease) and on the location of metastases (insensitive in detecting liver metastases). CONCLUSIONS: Somatostatin receptor scintigraphy is of value as an additional diagnostic tool in localizing medullary thyroid carcinoma, especially pulmonary metastases. It is of minor importance in detecting minimal residual disease.

Adolescent↗
PubMed1995

Primary hyperparathyroidism in multiple endocrine neoplasia type 2A.

The rarity of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) led us to study clinical findings, surgical therapy and outcome in 67 patients in order to evaluate our therapeutic strategy. The retrospective study was based on cases registered by the EUROMEN study group (nine participating centres) from 1972 to 1993. Characteristics of PHPT in 67 patients (41 females, 26 males) with MEN 2A were reviewed. All patients underwent exploratory neck surgery; PHPT was confirmed histologically and/or biochemically. The median age at diagnosis of PHPT was 38 years. In 75% of the patients, PHPT and medullary thyroid carcinoma were diagnosed synchronously, while in 4%. PHT was diagnosed earlier. In 18% of the patients, PHPT was diagnosed after thyroidectomy, and in 3%, after discovery of pheochromocytoma. Primary hyperparathyroidism was asymptomatic in 84% of the patients; 15% suffered from renal stones. Serum calcium was slightly elevated in 69% (2.9 +/- 0.2 mmol-1) and normal in 16% of subjects. A single adenomectomy was performed in 42% of the patients, subtotal parathyroidectomy in 31% and total parathyroidectomy with autotransplantation in 16%. Independent from the extent of resection, cure was achieved in 94% of the patients, including 13% with hypoparathyroidism; hypercalcaemia persisted in 3% and no information was available in 3%. In an 8-year follow-up, hypercalcaemia recurred in 12% of the patients, although half had undergone parathyroidectomy totally or subtotally. CONCLUSION. MEN 2A-related PHPT is characterized by a mild hypercalcemia which is mostly asymptomatic and can be cured by simple resection of an enlarged parathyroid gland in most cases.

Adolescent↗
PubMed1995

Extracellular calcium sensitivity and voltage-dependent calcium channels in C cells.

An essential function of C cells is to monitor [Ca2+]e and to increase CT secretion in response to small increments in [Ca2+]e. CT, in turn, decreases [Ca2+]e via its effects on bone and kidney. [Ca2+]e-dependent CT secretion is known to be mediated by corresponding changes in [Ca2+]i. The [Ca2+]e-sensing of C cells is mediated by DHP-sensitive, voltage-dependent Ca2+ channels, which allow Ca2+ influx even at the resting membrane potential. An increase of [Ca2+]e stimulates transmembrane Ca2+ influx via DHP-sensitive Ca2+ channels, thereby increasing [Ca2+]i and consequently CT secretion. Moreover, [Ca2+]e and cAMP-dependent oscillations of [Ca2+]i are observed in C cells. Various neuropeptides and hormones involved in the control of CT secretion act by regulating Ca2+ channel activity via G proteins. One of these endogenous modulators is SS, which is produced by the C cells themselves and tonically inhibits CT secretion by inhibiting voltage-dependent Ca2+ channels.

Animals↗
PubMed1995

1,25-Dihydroxyvitamin D3 stimulates growth and inhibits calcitonin secretion in a human C cell carcinoma cell line.

1,25-Dihydroxyvitamin D3 (1,25D3), calcitonin (CT) and parathyroid hormone are the major calcium-regulating hormones. In addition, 1,25D3 has been reported to be a modulator of cell growth and differentiation in many tissues. Recently, a suppressive effect of 1,25D3 on CT secretion and synthesis in C cells was demonstrated in vivo and also in vitro, but there are no data about its effects on thyroid C cell growth. We investigated the effects of 1,25D3 on basal and stimulated CT secretion and on [3H]thymidine incorporation, using a human medullary thyroid carcinoma cell line (TT cells). After a 4-day exposure to 1,25D3, TT cells showed a dose-dependent inhibition of basal CT secretion (64% of the value for the control group at 100 nM 1,25D3). Calcium (3 mM) plus K+ (50 mM) greatly increased CT secretion in both the control and vitamin D-treated groups. However, in the cells preincubated with 1,25D3 the stimulated CT levels were less than observed in controls. A dose-dependent increase in [3H]thymidine incorporation (200% of the value for the control group at 100 nM 1,25D3) and in cell number (150% of the value for the control group at 100 nM 1,25D3 after 72 h) was observed in the groups treated with 1,25D3. 24,25D3 had no effect on CT secretion or cell growth compared to the control group. These data show that 1,25D3 decreased basal and Ca(2+)-stimulated CT secretion, a specialized function of these cells, and stimulated their growth. Hence, in contrast to its effects on other cell lines, 1,25D3 appears to induce a dedifferentiation on TT cells.

Calcitonin↗
PubMed1994

[Neutralizing antibodies against salmon calcitonin. The cause of a treatment failure in Paget's disease].

A 72-year-old woman with Paget's disease of the femur (increasing curvature of the femur in the last 20 years, lately with ever more pain on walking) was at first treated with salmon calcitonin, daily 400 IU nasally, for 2 years. As a result, alkaline phosphatase (AP) concentration fell from initially 703 U/l, to 401 U/l after 7 months' treatment. An increase in AP concentration was first noted after 10 months of treatment, rising after 24 months to 688 U/l. The symptoms, initially having responded rather well to therapy, markedly progressed. In parallel, titres were recorded for binding (maximally 1:100) and neutralizing antibodies (neutralizing action maximally 75%) against salmon calcitonin. Because of the development of secondary resistance to salmon calcitonin the medication was changed to human calcitonin (100 IU daily, subcutaneously). This again resulted in a fall of the AP concentration (to 319 U/l), which remained essentially unchanged (401 U/l) over a period of 17 months on 100 IU human calcitonin three times weekly.

Aged↗
PubMed1994

[Diagnosis, therapy and screening of multiple endocrine neoplasia type I (MEN I) in four endocrinologic centers].

BACKGROUND: Multiple endocrine neoplasia type I (MEN I) is a hereditary disease characterised by involvement of several endocrine organs (parathyroid, anterior pituitary, pancreatic islet cells and other). In order to build up a German MEN I-register a questionnaire was developed. PATIENTS: In four centres we diagnosed 29 cases of MEN I (average age 53 years, range 27 to 72 years, 21 women, eight men). RESULTS: In 25 patients (86%) we found a primary hyperparathyroidism, in 15 patients (52%) an adenoma of the anterior pituitary (seven patients with growth hormone-secreting adenomas, five patients with prolactinomas, two patients with hormone-inactive and one patient with an ACTH-secreting adenoma), in ten patients (34%) a neoplasm of the pancreatic islet cells (six patients with gastrinomas, four patients with insulinomas and two patients with multihormone tumors) and in ten patients (34%) other endocrine tumors (five carcinoid tumors, three adenomas of the adrenal cortex, one papillary thyroid carcinoma and one thymic tumor). In nine cases nephrolithiasis was the leading symptom of primary hyperparathyroidism. All female patients with prolactinomas developed secondary amenorrhea. In three cases gastrinomas caused duodenal ulcers and three insulinomas were detected by fasting hypoglycemia. A primary hyperparathyroidism was most frequently combined with an adenoma of the anterior pituitary (21%). Detailed screening of 13 families early revealed MEN I in eleven cases. CONCLUSIONS: The manifestation of an endocrine disease in MEN I should initiate further diagnostics. Having established the diagnosis of MEN I, a meticulous work-up of all family members is warranted. The set-up of a register by the successfully tested questionnaire will support these activities and facilitate further research of new genetic markers, follow-up and treatment.

Adult↗
PubMed1994

Differential effects of 1,25-dihydroxyvitamin D3 on cell proliferation and calcitonin gene expression.

1,25-Dihydroxyvitamin D3 (1,25D3) inhibits cell growth and induces differentiation in many cell systems by inhibition of c-myc gene expression. In the human medullary thyroid carcinoma cell line (TT), c-myc gene expression appears to be closely related to cell proliferation and differentiation. TT cells are also a well known target system for 1,25D3, which inhibits calcitonin (CT) gene expression in these cells. So far, no direct cis-acting vitamin D-responsive element could be identified in the promoter region of the CT gene. We, therefore, investigated potential indirect mechanisms of 1,25D3-mediated CT gene expression by examining the hormone's effects on proliferation. In contrast to its well established antiproliferative action in other cell systems, addition of 1,25D3 to TT cells led to a 2.3-fold stimulation of DNA synthesis, which was maximal after 48 h and was preceded by a 4.8-fold increase in c-myc gene expression. c-Myc antisense DNA oligomers abolished the proliferative effect of 1,25D3, but not the latter's inhibition of CT gene expression. Here we present evidence that activation of c-myc gene expression mediates 1,25D3-stimulated TT cell proliferation, but not the 1,25D3-induced inhibition of CT gene expression.

Base Sequence↗
PubMed1994

Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients.

We determined the effect of raised serum levels of midregional (53-84) parathyroid hormone-related protein (PTHrP) on life expectancy in 59 cancer patients with first presentation of hypercalcemia. The patients were stratified according to the serum PTHrP levels measured on day 0 after fluid repletion prior to bisphosphonate therapy. Twenty-nine patients were assigned to group N (PTHrP < or = 21 pmol/L) and 30 to group E (PTHrP > 21 pmol/L). Breast cancers were more common in group N, squamous cell cancers predominated in group E (p < 0.02). More patients with normal PTHrP had skeletal metastases, whereas group E was characterized by a higher incidence of prognostically unfavorable visceral involvement (p < 0.001). Bisphosphonates (pamidronate or BM.210955) were administered on day 0. Within one week, normocalcemia (serum calcium < or = 2.6 mmol/L) was restored in 96% of patients in group N, compared to 70% of patients in group E (p < 0.01). On day 12, 7 patients with elevated PTHrP were still hypercalcemic. Although a comparable number of patients in the two groups received cytostatic treatment after day 12, objective tumor responses were seen only in group N (n = 6; p < 0.05). Calculated from the first occurrence of hypercalcemia, the median survival was 66 days in group N and 33 days in group E (log-rank test: p = 0.0456; Wilcoxon-Breslow test: p = 0.0475). We conclude that in hypercalcemia of malignancy raised serum levels of PTHrP indicate a reduced hypocalcemic response to bisphosphonates, a more advanced tumor state and, therefore, an extremely poor prognosis.

Adult↗
PubMed1994

Increased prevalence of colonic adenomas in patients with acromegaly.

Forty-nine acromegalics and 57 controls matched for age and sex underwent colonoscopy. The control group consisted of patients investigated because of atypical abdominal complaints compatible with irritable bowel syndrome or constipation. The exclusion criteria for both groups included: age over 75 years, previous colonic polyps or cancer, previous colonic surgery, rectal blood loss, anemia, previous abdominal radiation, sigmoidoscopy, colonoscopy or barium enema performed for any indication within 3 years prior to the present study. Colonoscopy was successful in reaching the cecum in 72 and 77% of the controls and acromegalics, respectively (p = NS). Eleven (22%) of 49 acromegalics had biopsy-proven colonic adenomas versus only five (9%) of the control group (p < or = 0.05). Multiple adenomas were found in three of the 11 acromegalics and in none of the controls. In five of these 11 patients and in only one of the controls, at least one adenoma was located in the right colon. In addition, acromegalics tended to have larger adenomas. The group of acromegalics with and without adenomas did not differ significantly in age or duration of active disease. In conclusion, the present study shows that acromegalic patients have an increased risk of developing colonic adenomas.

Acromegaly↗
PubMed1994

Multiple endocrine neoplasia type 2. Clinical features and screening.

Prospective screening programs have changed the presenting clinical features of MEN 2, the association of medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Currently, all manifestations of MEN 2 syndrome can be diagnosed at an early stage. Gene carrier status can be identified by characterization of specific mutations. Prospective screening for early medullary thyroid carcinoma by calcitonin testing and for pheochromocytoma by several techniques routinely permits identification of early manifestations.

Adrenal Gland Neoplasms↗
PubMed1993

Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma. Three-year results.

BACKGROUND: Medullary thyroid carcinoma (MTC) metastasizes early into the regional lymph nodes, but distant metastases occur late. Modified radical neck dissection might improve the treatment results for occultly metastasizing MTC. METHODS: The authors report 23 patients after a minimal follow-up of 2 years (median, 36 months). There were 11 female and 12 male patients. The mean age was 43 years (+/- 13 years). The surgical technique included the meticulous dissection of all compartments of the neck, resulting in a unilateral or bilateral modified radical neck dissection with the complete removal of the lymphatic and fatty tissue between important anatomical structures. The surgical boundaries extended cranially to the mastoid, caudally to the brachiocephalic vein involving a transcervical mediastinal dissection, and laterally to the edge of the trapezoid muscle. Ten patients were treated bilaterally and 13 patients unilaterally. RESULTS: The basal calcitonin values of 18 of the 23 patients were postoperatively normalized with 4 patients having normal basal and pentagastrin-stimulated calcitonin levels. Five patients with persistently elevated basal serum calcitonin values had a marked reduction of the postoperative calcitonin levels compared with their preoperative concentrations. However, in these five patients histologic abnormalities precluded a surgical cure. The permanent complication rates were tolerable (4 of 33 neck dissections). CONCLUSIONS: The microsurgically extended neck dissection can reduce basal and pentagastrin-stimulated serum calcitonin values to normal levels even after long intervals following primary thyroidectomy.

Adolescent↗