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Biomedical subjects

F Raue

Publications and source records attributed to F Raue.

At least 19 recordsLinked to original sources
PubMed2006

Late diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia results from 21-hydroxylase deficiency in more than ninety percent of cases. The classical form of 21-hydroxylase deficiency presents in the neonatal period with virilization or adrenal insufficiency, with or without concurrent salt wasting. We report on a rare case of classic 21-hydroxylase deficiency diagnosed in late adulthood. A 39-year-old male patient presented for workup of infertility. Urologic investigation revealed small testes, bilateral testicular masses, and asthenozoospermia. The patient's steroid metabolism showed markedly increased levels of adrenal androgens, in particular of 17-hydroxyprogesterone amd 21-deoxycortisol. The gas chromatographic-mass spectrometric (GC-MS) urinary steroid profile was dominated by metabolites of 17-hydroxyprogesterone, while the endogenous glucocorticoid production was subnormally low. ACTH levels in plasma were elevated. These hormonal findings were consistent with 21-hydroxylase deficiency. Therapy with dexamethasone was initiated. The CTP21A2 gene analysis revealed the mutation I172N (ATC --> AAC) in exon 4 of allele 1 and a large gene deletion in allele 2. Cases of 21-hydroxylase deficiency diagnosed in late adulthood are rare; however, clinicians should be alert of this possibility.

17-alpha-Hydroxyprogesterone↗
PubMed2006

The role of the extracellular calcium-sensing receptor in health and disease.

The calcium-sensing receptor has a key role in calcium homeostasis, it is involved in the regulation of the serum calcium level within minutes via the secretion and action of parathyroid and the excretion of calcium in the kidney in a negative feedback manner. Mutations of the calcium sensing receptor gene leads to inactivating and activating mutations resulting in diseases with hypercalcaemia and hypocalcaemia. The loss of function mutations are associated with familial benign hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease characterised by lifelong mild hypercalcaemia, low urinary calcium excretion, and inappropriate high parathyroid hormone levels, sometimes difficult to distinguish from mild asymptomatic primary hyperparathyroidism. Patients with FHH did not profit from parathyroidectomy, a calcium lowering therapy is not necessary. The gain of function mutations of the calcium-sensing receptor are associated with autosomal dominant hypocalcaemia (ADH), a disease characterised by a generally asymptomatic hypocalcaemia, inappropriately high urinary calcium excretion and normal PTH levels. A therapy to raise the serum calcium concentration has to be done carefully and is only indicated in symptomatic patients, because of enhancement of hypercalciuria with the risk of nephrocalcinosis and nephrolithiasis. Molecular genetic analysis of the calcium sensing receptor gene facilitates the sometimes difficult diagnosis. The development of compounds modulating the calcium sensing receptor function and thereby the section of PTH may become an important role in treatment of diseases of calcium metabolism.

Adult↗
PubMed2006

Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype.

OBJECTIVE: In children with RET proto-oncogene mutation, curative treatment of medullary thyroid carcinoma (MTC) is possible by prophylactic thyroidectomy. Recommendations on the timing and extent of thyroidectomy are based upon a model that utilises genotype-phenotype correlations to stratify mutations into three risk groups. DESIGN: We evaluated the long-term outcome (mean follow-up 6.4 years, 15 patients more than 10 years, 26 patients more than 5 years) of operated gene carriers stratified into two risk groups (levels 1 and 2) based on the biological aggressiveness of MTC. RESULTS: In 46 RET gene carriers, prophylactic thyroidectomy was carried out between the ages of 4 and 21 years. Level 1 mutations were harboured by 11 patients (codons 790, 791, 804 and 891). Histology was completely normal in two patients; in seven patients C-cell hyperplasia (CCH) and in two patients T1 tumours were diagnosed. All patients with level 1 mutations were cured. Level 2 mutations were harboured by 35 patients (codons 618, 620, 630 and 634). Histology of these patients showed CCH in 11 patients, T1 tumours in 21, T2 tumour in 1, T3 tumour in 1 and Tx in 1 patient. Histology showed no lymph node involvement. Five patients with level 2 mutations failed to be cured; in two patients, persistence of MTC was diagnosed directly after thyroidectomy and in three during follow-up. In two patients carrying a 634 mutation, other endocrinopathies (hyperparathyroidism and bilateral pheochromocytoma) manifested during follow-up. CONCLUSIONS: If prophylactic thyroidectomy is done at early ages, cure rate is high. Timing and extent of prophylactic thyroidectomy can be modified by individual RET mutation.

Adolescent↗
PubMed2004

Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter. To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.

Calcitonin↗
PubMed2003

[Hereditary medullary thyroid carcinoma--genotype-phenotype characterization].

BACKGROUND AND OBJECTIVE: Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations of the RET proto-oncogene. A genotype - phenotype correlation has been established, showing clustering of mutations in exons 10 and 11 in classical MEN 2 A syndrome, in exon 16 codon 918 in MEN 2 B syndrome and in exons 13-15 in familial MTC. A line of evidence suggested that the development and the aggressiveness of MTC in the different cancer syndromes is variable. Aim of this study was to compare the phenotype of exon 13-15 mutations with that of exon 11 mutation and possibly draw therapeutical consequences. PATIENTS AND METHODS: We compared the phenotype of 47 patients with mutations in exon 13-15 with 66 patients with exon 11, codon 634 mutation, the classical MEN2A. Patients were further subdivided as index and screening patients. RESULTS: Mean age of 19 index patients with codon 790, 791, 804 or 891 mutation was significant higher compared with 18 index patients with codon 634 mutation (mean age at diagnosis 50+/-12 years; range 30-69 y vs mean age 31+/-9 years; range 17-49 y), tumor stage at operation was favourable (C-cell hyperplasia n = 1; stage I n = 8; II n = 3; III n = 2; IV n = 2; no operation n = 1; no information n = 2 vs stage I n = 3; stage II n = 6; stage III n = 4, no information n =5), cure rate was better (56 % vs 38 %) and the death rate was lower (n = 2 vs n = 4). In screening patients no differences concerning the age, tumor stage, cure and death rate between patients with exons 13-15 and codon 634 mutations were seen. CONCLUSIONS: MTC in patients with exon 790, 791, 804, 891 mutations displayed a late onset and an indolent course compared to codon 634 mutation, this has to be taken into account when recommending timing and extent of prophylactic surgery.

Adolescent↗
PubMed2001

Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p < 0.005, log-rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.

Adult↗
PubMed2001

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Humans↗
PubMed1999

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.

Carcinoma, Medullary↗
PubMed1999

Radiolabeled peptides for targeting cholecystokinin-B/gastrin receptor-expressing tumors.

UNLABELLED: The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies have demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, some ovarian cancers, astrocytomas and potentially a variety of adenocarcinomas. The aim of this study was to systematically screen and optimize, in a preclinical model and a pilot clinical study, suitable radioligands for targeting CCK-B receptors in vivo. METHODS: A variety of CCK/gastrin-related peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing subcutaneous human MTC xenografts. Diethylenetriamine pentaacetic acid (DTPA) derivatives of suitable peptides were synthesized successfully, and their preclinical and initial clinical evaluations were performed, labeled with 111In. RESULTS: All members of the CCK or gastrin families were stable in serum (with half-lives of several hours at 37 degrees C); nevertheless, the stability of those peptides bearing N-terminal pGlu residues or D-amino acids was significantly higher. In accordance with their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues. Sulfated CCK derivatives performed significantly better but also displayed a comparably high uptake in normal CCK-A receptor-expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC-bearing animals showed significant antitumor efficacy compared with untreated controls. DTPA derivatives of minigastrin were successfully developed. In a pilot clinical study, radioiodinated and 111In-labeled derivatives showed excellent targeting of physiological CCK-B receptor-expressing organs, as well as all known tumor sites. CONCLUSION: CCK/gastrin analogs may be a useful new class of receptor-binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, hence lower accretion in normal CCK-A receptor-expressing organs.

Adult↗
PubMed1999

Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential.

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in >90% of MTCs but in a high percentage of small cell lung cancers and potentially a variety of gastrointestinal adenocarcinomas. In a pilot study, we have demonstrated the feasibility of radiolabeled gastrin-I to target CCK-B receptor-expressing tissues in vivo in animals and patients (T. M. Behr et al., Eur. J. Nucl. Med., 25: 424-430, 1998). The aim of the present study was to systematically optimize, in a preclinical model, suitable radioligands for targeting CCK-B receptors in vivo. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK-receptor binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the Iodogen or Bolton-Hunter procedures. The peptides tested were members of the gastrin- or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety (occurring in native or sulfated form). Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing s.c. human MTC xenografts. Diethylene-triamine-pentaacetate derivatives of suitable peptides were synthesized, evaluated, and labeled with (111)In. All members of the CCK or gastrin family were stable in serum (with t(1/2)s of several hours at 37 degrees C); nevertheless, the stability of those peptides was highest that bore the NH2-terminal pGlu residues (e.g., big gastrin, gastrin-I, caerulein, and others) or D-amino acids. In accordance to their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues (e.g., the stomach). Sulfated CCK derivatives performed significantly better but additionally displayed a high uptake in normal, CCK-A receptor-expressing tissues (such as the liver/gallbladder, pancreas, and bowel). Best tumor uptake and tumor:nontumor ratios were obtained with members of the gastrin family, probably because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC bearing animals showed significant antitumor efficacy as compared with untreated controls. (111)In-Labeled diethylene-triamine-pentaacetate derivatives of minigastrin showed excellent targeting of CCK-B receptor-expressing tissues in animals and a normal human volunteer. These data suggest that CCK/gastrin analogues may be a useful new class of receptor binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, and hence, lower accretion in normal CCK-A receptor-expressing organs. Further preclinical as well as clinical studies are ongoing.

Amino Acid Sequence↗
PubMed1999

Measurements of bone mineral density. Mineral density in metabolic bone disease.

Bone metabolism and thus bone remodelling and bone mineral content are profoundly influenced by many hormonal and metabolic factors. This review presents the state of the art procedures for bone mineral absorptiometry and examines the interactions of endocrine and metabolic diseases and bone mineral content. Preventive and therapeutic modalities of osteoporosis are discussed in this context.

Bone Density↗
PubMed1998

Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin.

The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioiodinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the human MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastatic MTC. At a peptide amount of approximately 1 microg, maximum tumour uptake (8.9+/-2.9%ID/g) was observed in animals at 1 h post injection, with tumour-to-blood ratios as high as 6.3+/-1.9. Physiological CCK-B receptors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with 131I-labelled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was observed in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diagnosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents potentially useful candidates for in vivo scintigraphy and radionuclide therapy.

Aged↗