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PubMed1997

Mutation of RET proto-oncogene in Japanese patients with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

To determine whether patients with medullary thyroid carcinoma (MTC) develop other endocrine neoplasms or their relatives develop MTC, we investigated the mutations in the RET proto-oncogene in patients with multiple endocrine neoplasia type 2B (MEN 2B, N = 1) and sporadic MTC (N = 6). DNA from MTC tissue and the peripheral blood was screened by polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP) analysis of exons 10 and 11. PCR products of exons 13 and 16 were also analyzed by AluI and FokI restriction enzyme digestion methods, respectively, and then sequenced. We did not find structural abnormalities in exon 10 or 11, or at codon 768 in exon 13, but a mutation at codon 918, ATG to ACG, was found in the peripheral blood and the MTC tissue from a patient with MEN 2B. The same mutation was also found in tumor tissue from 2 of 6 patients with sporadic MTC, but not in their peripheral blood.

Adult↗

PubMed2004

Medullary thyroid carcinoma: nationwide Japanese survey of 634 cases in 1996 and 271 cases in 2002.

Medullary thyroid carcinoma (MTC) occurs sporadically or as an inherited disease, with the latter occurring in the form of multiple endocrine neoplasia (MEN) type 2A, MEN type 2B, or familial non-MEN medullary carcinoma (FMTC). MTC is inherited as an autosomal dominant trait and is associated with germline mutations of the RET proto-oncogene. Genetic testing identifies carriers of the mutant gene and enables preventive thyroidectomy. A nationwide questionnaire-based survey was conducted in 1996 and again in 2002, and we report here the results of the two surveys that characterize the clinical course of the inherited form of MTC. The data show a higher rate of inherited MTC than previously described, although MEN2A was found to be the most common inherited form of MTC, the same as in earlier studies. The most important finding was the difference in method of detection of MTC between the two surveys. Since the discovery of the genetic association with the disease, genetic testing has become the diagnostic method of choice, replacing indicators such as neck mass and elevated non-stimulated serum calcitonin level. Genetic testing enables early detection of the disease, which provides patients with the possibility of better outcome.

Adult↗

PubMed2001

High plasma amylin/islet amyloid polypeptide levels in patients with residual medullary thyroid carcinoma after total thyroidectomy.

OBJECTIVE: We have previously reported that amylin/islet amyloid polypeptide (IAPP) mRNA is detected in a substantial subset of medullary carcinomas of the thyroid (MTCs). The aim of this study was to determine if the amylin/IAPP gene is expressed as the IAPP peptide in MTC tissues. DESIGN AND METHODS: In 10 patients with a histological diagnosis of MTC and with persisting or recurrent disease (basal calcitonin levels >250 pg/ml), the fasting serum insulin and plasma glucose, IAPP and calcitonin levels were measured and compared with those of 18 normal control subjects matched for age and body mass index. IAPP expression was studied by immunohistochemistry in MTCs and lymph-node metastasis tissues. RESULTS: Seven of ten MTC patients had abnormally elevated IAPP levels. Plasma IAPP and serum insulin levels were correlated in both patients and controls, but the slope of the regression line was significantly higher for MTC patients. IAPP staining was detected in four out of 12 random MTC samples and in two out of five lymph-node metastases, using immunohistochemistry. CONCLUSIONS: These results indicate that MTC cells express IAPP at the peptide level and that this raises the peripheral plasma levels. Further studies may reveal whether this is a feature of malignant disease.

Amyloid↗

PubMed2001

CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome.

Apart from the RET proto-oncogene (RET) no other genes have been found to be involved in medullary thyroid carcinoma (MTC) tumorigenesis. Germline RET mutations are seen virtually in all familial forms of MTC and somatic RET mutations are often detected in sporadic MTC. In sporadic MTCs the RET gene is mutated in codon 918, where a methionine is substituted to a threonine (M918T). In this study 24 MTCs were analyzed by comparative genomic hybridization (CGH) for chromosomal imbalances. Overall, alterations were detected in approximately 60% of the samples. The most common aberrations were gains on chromosome 19q (29%), 19p (21%), 11c-q12 (12.5%), and 22q (12.5%) and losses on 13q21 (21%) and 3q23-qter (12.5%). Gain of chromosome 11c-q12 was only detected in samples from patients whom died of MTC (p=0.001). These MTCs also harbored the somatic RET M918T mutation and also showed the highest numbers of CGH alterations in the series (p<0.003). Although there was a tendency towards a higher number of CGH imbalances in the tumors with RET M918T mutation, this difference was not significant. The results indicate that MTC is a comparatively genetically stable tumor, and that chromosomal regions 19q, 19p, 13q and 11q may be involved in MTC carcinogenesis.

Adolescent↗

PubMed2002

Dendritic cells pulsed with viral oncolysates potently stimulate autologous T cells from cancer patients.

We demonstrated before that primary operated breast cancer patients contain in their bone marrow (BM) cancer reactive memory T cells (MTC) which have to be re-activated to become tumor infiltrating effector cells. The aim of this study was to optimize an ex vivo stimulation protocol for MTC based on autologous dendritic cells (DC). As source of tumor antigens we used lysates from unmodified tumor cells or from tumor cells infected with Newcastle Disease Virus (NDV) which contain IFN-alpha inducing viral dsRNA as one danger signal. DC from breast cancer patients were pulsed with lysates from the MCF-7 breast cancer line (Tu-L) or from NDV infected MCF-7 cells (TuN-L, viral oncolysates) and compared for stimulatory capacity in an ELISPOT response of autologous BM derived MTC. To analyze potential further danger signals derived from NDV infection, we employed MALDI mass spectrometry, Western blots, FACS cytometry and ELISA tests. DC pulsed with viral oncolysates showed increased expression of co-stimulatory molecules in comparison to Tu-L pulsed DC and induced significantly higher ELISPOT MTC responses. Supernatants from co-cultures of MTC and TuN-L pulsed DC contained increased titers of IFN-alpha and IL-15. NDV infection of tumor cells resulted in a number of differences in protein expression including a heat-shock protein (HSP27) which became phosphorylated. The results suggest that a DC preparation pulsed with viral oncolysate includes danger signals (e.g. dsRNA, cytokines, HSP molecules) and is superior for MTC stimulation to a DC preparation pulsed with lysate from non-infected tumor cells.

Blotting, Western↗

PubMed2005

[G691S, L769L and S836S ret proto-oncogene polymorphisms are not associated with higher risk to sporadic medullary thyroid carcinoma in Chilean patients].

BACKGROUND: Medullary thyroid carcinoma (MTC) may occur either as sporadic or as hereditary. Even though the sporadic form corresponds to the majority of cases, the pathogenesis is still unclear. Several polymorphisms of the ret proto-oncogene, including those located in exon 11, 13, 14 and 15 have been described in the general population and some of them seem to be over-represented in sporadic MTC patients from European countries, especially G691S, L769L and S836S. AIM: To evaluate the allele frequencies of these variants in Chilean patients and controls and to determine if these polymorphisms would be associated with the development of sporadic MTC from a different genetic population base. SUBJECTS AND METHODS: Fifty sporadic MTC patients and 50 normal subjects were tested for G691S, L769L, S836S and S904S polymorphisms. The extracted genomic DNA was initially analyzed by direct sequencing of PCR products in patients. The presence or absence of each polymorphism was also assessed in patients and in control by restriction digestion. RESULTS: The allele frequencies showed a similar level of the G691S, L769L and S904S variants in both groups. Of interest, we found an under-representation of S836S polymorphism in the sporadic MTC group but this number was not statistically significant (p=0.141). CONCLUSIONS: We did not find an over representation of the G691S, L769 and S836S. These results argue against the validity of the association of these polymorphisms as contributing factors in the development of sporadic MTC based on a Chilean population and raise questions about the importance of these polymorphisms overall.

Carcinoma, Medullary↗

PubMedDate not supplied

Potential absence of prognostic implications of severe preoperative hypercalcitoninemia in medullary thyroid carcinoma.

OBJECTIVE: To evaluate preoperative hypercalcitonine-mia further as a marker of prognosis in patients with medullary thyroid carcinoma (MTC). METHODS: We reviewed the clinical and laboratory data in six patients (four men and two women, 39 to 76 years old)--three with sporadic MTC, one with familial MTC, and two with multiple endocrine neoplasia type 2A--who had preoperative basal serum calcitonin levels of 400 to 16,000 pg/mL (normal, 0 to 19). Pentagastrin stimulation was performed in patients who had preoperative basal calcitonin levels less than 1,000 pg/mL, and responses ranged from 2,600 to 8,500 pg/mL. Thyroidectomy revealed intrathyroidal MTC in four patients; MTC and nodal metastatic lesions were present in two. The tumor cells were immunoreactive with anti-calcitonin immunoperoxidase staining. RESULTS: Serum calcitonin and carcinoembryonic antigen levels were normal postoperatively. In serial postoperative evaluation during a follow-up period of 2 to 9 years, stimulated peak plasma calcitonin levels after pentagastrin or calcium infusion were normal (in five patients) or near normal (in one patient), without clinical evidence of recurrent disease. The two patients with nodal metastatic disease have had normal calcitonin levels during a mean duration of follow-up of approximately 3 years. CONCLUSION: Pronounced preoperative hypercalci-toninemia does not necessarily preclude a favorable short-term outcome in patients with MTC.

Adult↗

PubMed2000

Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

BACKGROUND: The results and consequences of genetic testing in a family with familial medullary thyroid carcinoma (FMTC) are described. METHODS: In the screening of relatives, serum calcitonin is replaced by RET mutation analysis that was performed in families suspected of hereditary medullary thyroid carcinoma (MTC). In 4 of 10 families, mutation in exon 10 was found in codon 611. RESULTS: One hundred fifty persons belonging to 30 families were tested, of which 10 families were carriers of RET mutation in exon 10. In 1 of these families with MTC only, 2 brothers were gene carriers of a RET codon 611 mutation and lived without any sign of MTC. One is aged 79 years, and the other died at the age of 71 of other causes. CONCLUSIONS: The results indicate that the gene carrier in families with MTC without other endocrine tumors (FMTC) exhibits a highly variable disease course. A 611 codon mutation is most often a rather mild and slow progression form of MTC. Because 2 gene carriers were still alive at age 70 years without showing any sign of the disease, it is tempting to ask if all gene carriers with a 611 codon mutation without other endocrine tumors should be operated on, and if so, at what age? In the authors' opinion, more information is needed to be able to answer these questions. The current guidelines for treatment of patients with hereditary MTC are discussed.

Adolescent↗

PubMed2001

[Preliminary trial of three-dimensional water-excitation magnetization transfer contrast MR imaging of articular cartilage].

MR images of articular cartilage were evaluated with a three-dimensional (3D) water-excitation sequence (repetition time/echo time/flip angle = 28 msec/14 msec/20 degrees) with and without on-resonance magnetization transfer contrast (MTC) pulse in-vitro and in-vivo. 3D water-excitation images with MTC pulse showed a significantly higher contrast-to-noise ratio between normal saline or joint effusion and articular cartilage than images without MTC pulse. In 2 patients with osteoarthritis of the knee, joint effusion showed higher signal intensity than cartilage (arthrogram-like effect) on 3D water-excitation MTC images. The contrast between joint effusion and articular cartilage on 3D water-excitation MTC images was similar to that on fat-suppressed 2D protondensity-weighted fast spin echo images. In conclusion, 3D water-excitation MTC imaging is a promising method by which to evaluate articular cartilage in osteoarthritis and cartilage defect with thin sections and a reasonable scan time.

Adult↗

PubMed1992

[Medullary carcinoma of the thyroid gland and the APUD system].

Medullary thyroid carcinoma, MTC, accounts for 8-10% of all thyroid malignancies. It occurs in the sporadic form (70-75%) and the familial variant (25-30%). In familial MTC the autosomal dominant type of heredity is involved. This variant is found frequently in association with other endocrine hyperplasias or tumours within the framework of the APUD system and is thus an indispensible condition of the MEN 2 syndrome, either MEN 2A (MTC and pheochromocytoma and/or hyperparathyroidism) or MEN 2B with the frequent concurrent presence of pheochromocytoma and a typical phenotype, in particular multiple neurofibromas on the lips and tongue. The type of MTC determines also to a certain extent the prognosis of the disease. MTC in the framework of MEN 2A are usually most benign, while the prognosis is poorest for MEN 2B. The sporadic variant has a poorer prognosis, as compared with differentiated thyroid carcinoma. The only effective and rational treatment of MTC is radical surgery. In all instances where we confirm the diagnosis before surgery we indicate bilateral total thyroidectomy. In the familial variant where the tumour is usually multifocal and in both lobes this indication is absolute, in sporadic forms with possible early intrathyroid dissemination of the primary tumour also to the other side, bilateral surgery is also indicated. Moreover we know that a certain ratio of assumed sporadic forms are genetically conditioned tumours and thus are familial. The histological finding of hyperplasia of the C-cells suggests the familial variant even when tumourous transformation did not occur yet.(ABSTRACT TRUNCATED AT 250 WORDS)

APUD Cells↗

PubMed1992

[Medullary carcinoma of the thyroid gland. Personal experience].

The authors present their experience with the diagnosis and treatment of medullary thyroid carcinoma (MTC) in a group of 175 patients in the records of the RI in Motol. From the above number 106 are alive, 69 of the patients who died were diagnosed at the time of the clinical manifestation of the disease, frequently an advanced stage of the disease. Of the living patients one third was treated by total thyroidectomy after active screening. MTC accounts under our conditions in recent years for 8.6% of all thyroid malignancies. The familial variant with autosomal dominant heredity accounts for 26.5% of the above number. Within the framework of the familial variant the most frequent finding is non-MEN MTC, only 30% MTC are part of the MEN 2A or MEN 2B syndromes. MTC in childhood belongs practically always to the familial variant. At present the authors' group comprises 13 children and adolescents under 18 years, incl. one boy with the MEN 2B syndrome who succumbed to the disease. In 8 children based on active screening total thyroidectomy was indicated, incl. 5 patients were by histological examination only hyperplasia of the C-cells, i.e. a precancerous condition, was detected. After operation repeatedly in all these patients the level of immunoreactive calcitonin is low which indicates an excellent prognosis. The authors draw attention to the importance of active screening in families of all direct relations of the patient where MTC was diagnosed. Complete removal of thyroid tissue at the time of hyperplasia of C-cells or the presence of tumourous microfoci has a marked positive effect on the subsequent fate of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMedDate not supplied

Calcitonin gene-related peptide as a tumor marker for medullary thyroid carcinoma.

We have established a radioimmunoassay method for calcitonin gene-related peptide (CGRP) to monitor changes in plasma CGRP levels in patients with medullary thyroid carcinoma (MTC). Preoperative plasma CGRP levels (normal level less than 12.7 pg/ml) were as high as 128 pg/ml to 2,010 pg/ml in all five patients with MTC. Ten of 17 postoperative patients with MTC were positive for CGRP. A provocation test was performed in 12 patients with MTC. Plasma CGRP changes roughly paralleled serum calcitonin levels. In particular, in three patients with poorly-differentiated MTC which progressed aggressively, plasma CGRP levels were increased to 1.4 to 2.0 times levels before the test, i.e., lower than the 2.8- to 23.3-fold increase in nine patients with the well-differentiated MTC. These results suggest that CGRP may be a humoral marker of medullary carcinoma and be related to degree of malignancy.

Adult↗

PubMed2006

[Determination of metacycline in mixture sample by synchronous-derivative fluorimetry].

A new synchronous-derivative fluorimetric method for the determination of metacycline (MTC) in the presence of oxytetracycline (OTC) is proposed. The degradation products of MTC in 0.1 mol x L(-1) NaOH are strongly fluorescent. The addition of cetyltrimethylammonium bromide (CTMAB) enhances the fluorescence intensity 2-fold. The synchronous fluorescence spectra of MTC and OTC degradation products do not interfere with each other under the condition that deltalambda = 100 nm. MTC can be determined in the presence of OTC in the range of OTC+MTC ratio of 1+116-1+1. The recoveries of MTC in the mixture sample are in the range of 94%-102%.

Cetrimonium↗

PubMed1990

Prognostic significance of nondiploid DNA determined by flow cytometry in sporadic and familial medullary thyroid carcinoma.

To clarify the role of DNA measurements in predicting outcome after surgical treatment of medullary thyroid carcinoma (MTC), we performed flow cytometric analysis in nuclear suspensions of 119 MTC tumors. Of the 119 patients, 63 (53%) patients had sporadic tumors and 56 (47%) patients had familial tumors; survivors were followed for a mean of 13 years. DNA content was normal in 92 (77%) patients and abnormal (nondiploid) in 27 (23%) patients. Ten-year cause-specific mortality rates were 12%, 42%, and 49% with diploid, tetraploid/polyploid, or aneuploid tumors (p = 0.0009) and were greater with nondiploid tumors both in the sporadic (p = 0.012) and multiple endocrine neoplasia (familial) cases (p = 0.114). None of 27 patients with TNM stage I disease died of MTC. In patients with TNM stages II, III, and IV disease, DNA nondiploid tumors were associated with increased deaths from MTC. In a Cox proportional hazards model involving all 119 patients and adjusted for disease stage and inheritance pattern, nondiploid DNA was independently associated with increased deaths from MTC (p = 0.008). In an identical Cox model restricted to the 92 DNA diploid tumors, an S-phase fraction of 15.0% or more remained a significant variable (p = 0.034) after adjustment for stage and inheritance pattern. We therefore conclude that DNA measurements do have a role to play in predicting outcome after surgical treatment of MTC.

Adolescent↗

PubMed1990

[Measurement of plasma calcitonin gene-related peptide (CGRP) level in patients with thyroid disease].

To elucidate the pathophysiology of CGRP in patients with medullary thyroid carcinoma (MTC), we measured the plasma CGRP level in patients with thyroid disease employing RIA. The plasma CGRP level (normal level 12.7 pg/ml) was elevated in all five preoperative patients with MTC, ranging from 128 pg/ml to 2010 pg/ml, and in ten of 17 postoperative patients who indicated possible recurrence. On the other hand, CGRP levels showed low frequencies of elevation in 96 patients with other thyroid tumors (anaplastic carcinoma, malignant lymphoma, follicular adenoma and adenomatous goiter), subacute thyroiditis, chronic thyroiditis and Graves' disease. Provocation test (calcium gluconate plus pentagastrin) in 12 MTC patients showed that, although the CGRP level fluctuated in parallel with the calcitonin level, the elevation rate (maximum level after administration/basal level) of CGRP was lower than that of calcitonin. Particularly, the rate of elevation of CGRP in three virulent and advanced patients with poorly differentiated MTC was below 2.0, while that in nine patients with well-differentiated MTC ranged from 2.8 to 23.3. These results suggest that CGRP may be a humoral marker of MTC and is possibly related to the degree of malignancy.

Calcitonin Gene-Related Peptide↗

PubMed1989

Low incidence of loss of chromosome 10 in sporadic and hereditary human medullary thyroid carcinoma.

Genetic linkage has been recently documented between a centromeric region of chromosome 10 and familial multiple endocrine neoplasia type II (MEN II). This syndrome consists of initial thyroid C-cell and adrenal chromaffin cell hyperplasia which result in multifocal medullary thyroid carcinomas and bilateral adrenal pheochromocytomas. Other hereditary cancers, such as retinoblastoma, appear to result from a series of genetic events involving, first the inheritance of a germ line abnormality, and subsequent loss of chromosome loci opposite this initial defect. In these cancers, this loss of the normal alleles in both familial and sporadic cases, is frequently manifest as a reduction to homozygosity for polymorphic DNA markers near the involved locus. It might then be expected that chromosome 10 regions would be lost with high frequency in tumor DNA from patients with MEN II and sporadic medullary thyroid carcinoma (MTC). We now demonstrate that only two of 16 MTC tumors studied by analysis of restriction fragment length polymorphisms for multiple regions of the short and long arms of chromosome 10 showed loci reduced to homozygosity. One of these tumors was from a patient with MEN II and the other from a patient with nonfamilial MTC. Importantly, no such chromosome 10 changes were noted in pheochromocytomas from the patient with MEN II or his sister. These findings strongly suggest that the sequence of genetic events for familial MTC is either different from that for retinoblastoma or that loss of normal alleles opposite the germ line genetic defect occurs by mechanisms other than gross loss of chromosomal material in MTC. A model is proposed suggesting that the mechanism involving loss of alleles opposite one another is operative in hereditary tumors, such as retinoblastoma, which do not arise within a setting of initial polyclonal cellular hyperplasia. In contrast, in tumors such as familial MTC and polyposis coli which arise as individual clones of neoplastic cells from a setting of preexistent polyclonal hyperplasia, the first genetic event may underlie hyperplasia, and additional events, frequently at other chromosomal loci, may cause individual clonal neoplasms.

Adrenal Gland Neoplasms↗

PubMed1989

Comparison of sporadic and hereditary forms of medullary thyroid carcinoma.

Between 1960 and 1988, 185 patients with medullary thyroid carcinoma (MTC) were followed at the Institut Gustave Roussy in France. The screening of the family members by calcitonin measurement (basal or after pentagastrin stimulation) has led to the characterization of 38 sporadic cases and 44 hereditary cases. Among the hereditary cases are seven families with MTC only and two families with multiple endocrine neoplasia type 2A (MEN 2A). MTC only cases and MEN 2B cases are present as apparently sporadic forms. Hereditary cases consisted of 26 females and 18 males; the male:female ratio was 21:17 in sporadic cases. Ten of the sporadic patients were deceased (mean age 46 years) compared to three of the hereditary cases (mean age 59 years). The age at diagnosis was 44 years for the sporadic patients and 35 years for the hereditary MTC only patients with clinical manifestations. Histologic data from the sporadic and hereditary patients showed that the tumor is mostly unilateral without C-cell hyperplasia in sporadic cases and bilateral with C-cell hyperplasia in hereditary cases. The location of tumors was quite variable among the sporadic cases and mostly localized to the middle part of the thyroid lobes in the hereditary cases. Our data suggest that the age at diagnosis is later in sporadic forms of MTC and that the age at diagnosis is later in the hereditary forms of MTC only compared to those with MEN 2A.

Adult↗

PubMed1989

The molecular biology of medullary thyroid carcinoma. A model for cancer development and progression.

Medullary thyroid carcinoma (MTC) is an important human cancer for the study of molecular abnormalities that underlie initiation of neoplasia and subsequent cellular changes during tumor progression. This tumor can occur in different inherited forms, each mediated by autosomal dominant genetic events. Germline abnormalities on chromosome 10 are linked to at least one type of genetic MTC, multiple endocrine neoplasia type II. Our studies of chromosome 10 in DNA from MTC tumors failed to detect frequent loss of polymorphic DNA markers, suggesting that the genetic mechanisms involved in MTC development may be different from those for other inherited cancers such as retinoblastoma. During tumor progression of MTC, abnormalities develop in expression of the mature phenotype of the endocrine cell from which the tumor arises. In cell culture, chemical modulation or gene insertion can lead to partial correction of these defects in differentiation capacity by activating cellular signaling processes. These studies offer opportunities to dissect the molecular events that regulate endocrine cell differentiation, to determine the precise abnormalities that may underlie the initiation and tumor progression events in MTC and related cancers, and, thereby, to identify new targets for therapeutic intervention.

Calcitonin↗