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PubMed1997

Cervical lymph node metastases of medullary thyroid carcinoma: CT findings.

Medullary thyroid carcinoma (MTC) is a rare malignancy which spreads frequently to cervical lymph nodes. We report the CT findings of MTC metastatic cervical adenopathies in two patients with previously resected MTC. The CT scans showed calcifications (one patient) and massive homogeneous postcontrast nodal enhancement. Medullary thyroid carcinoma should be included in the differential diagnosis of entities showing calcifications and intense homogeneous adenopathic enhancement on CT studies.

Aged↗
PubMed2002

Diagnostic and therapeutic approach to multiple endocrine neoplasia type 2B in pediatric patients.

Multiple endocrine neoplasia (MEN) 2B is a hereditary syndrome including medullary thyroid carcinoma (MTC), pheochromocytoma, gastrointestinal (GI) disorders, marfanoid facies, and multiple ganglioneuromas. MTC is the major cause of mortality, and often appears during the 1st decade of life. RET proto-oncogene mutations are responsible for MEN 2B. Other RET mutations cause MEN 2A syndrome, familial MTC, or Hirschsprung's disease. We studied three MEN 2B patients with the aim of delineating the best diagnostic and therapeutic protocol. The gold standards for diagnosis are histochemical study of the rectal mucosa and molecular analysis of RET, which in familial cases detects MEN 2B at a preclinical stage so that early total prophylactic thyroidectomy can be performed. In non-familial cases, the diagnosis can be suggested by the presence of GI symptoms, ganglioneuromas, and/or the typical facies. The intestinal innervation pattern, analyzed with the acetylcholinesterase technique, is pathognomonic for MEN 2B. In our protocol a rectal biopsy is, therefore, the first measure. The surgical treatment of MEN 2B is total thyroidectomy with cervical lymphadenectomy of the central compartment of the neck. When possible, this intervention should be performed prophylactically before 1 year of age.

Adolescent↗
PubMed2003

Multiple endocrine neoplasias type 2A and thyroid medullary carcinoma: an interdisciplinary challenge.

The diagnosis and treatment of multiple endocrine neoplasias type 2A (MEN 2A) requires interdisciplinary management. The association of RET proto-oncogene mutations and medullary thyroid carcinoma (MTC) in children is well-known, but the optimal timing for elective surgery is controversial. Besides the risk of MTC, associated anomalies like hyperparathyroidism have to be considered. We report the results of molecular genetic investigations, the pentagastrin stimulation test, pre- and postoperative staging, and histologic examinations of four children who had a positive family history for MEN 2A. Histologic specimens of the removed thyroid glands showed MTC in all four cases. The patients had an uneventful postoperative clinical course. In view of the recent literature and our patients' results, we suggest a concept for diagnostic strategy and timing of the elective thyroidectomy.

Adolescent↗
PubMed2006

Knee extensor muscle oxygen consumption in relation to muscle activation.

Recently, fatigability and muscle oxygen consumption (mVO(2)) during sustained isometric contractions were found to be less at shorter (30 degrees knee angle; 0 degrees = full extension) compared to longer knee extensor muscle lengths (90 degrees ) and, at low torques, less in the rectus femoris (RF) muscle than in the vastus lateralis and medialis. In the present study we hypothesized that these findings could be accounted for by a knee angle- and a muscle-dependent activation respectively. On two experimental days rectified surface EMG (rsEMG) was obtained as a measure of muscle activation in nine healthy young males. In addition, on day 1 maximal torque capacity (MTC) was carefully determined using superimposed nerve stimulation on brief high intensity contractions (> 70%MVC) at 30, 60 and 90 degrees knee angles. On day 2, subjects performed longer lasting isometric contractions (10-70%MTC) while mVO(2) was measured using near-infrared spectroscopy (NIRS). At 30 degrees , maximal mVO(2) was reached significantly later (11.0 s +/- 6.5 s) and was 57.9 +/- 8.3% less (average +/- SD, across intensities and muscles) than mVO(2) at 60 and 90 degrees (p < 0.05). However, rsEMG was on average only 18.0 +/- 11.8% (p = 0.062) less at the start of the contraction at 30 degrees . At 10%MTC at all knee angles, maximal mVO(2) of the RF occurred significantly later (28.8 +/- 36.0 s) and showed a significantly smaller increase in rsEMG compared to both vasti. In conclusion, it is unlikely that the tendency for less intense muscle activation could fully account for the approximately 60% lower oxygen consumption at 30 degrees , but the later increase in RFmVO(2) seemed to be caused by a less strong activation of the RF.

Adult↗
PubMed2003

Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of RET proto-oncogene.

BACKGROUND: Multiple endocrine neoplasia (MEN) type 2, a cancer syndrome inherited in the dominant fashion, is defined by the occurrence of medullary thyroid carcinoma (MTC), either as a singular lesion (familial medullary thyroid carcinoma, FMTC) or with the variable expression of pheochromocytoma, hyperparathyroidism (MEN 2A), ganglioneuromas, buccal neuromas and Marfanoid-like phenotype (MEN 2B). DISCUSSION: Germline mutations of the RET proto-oncogene, localized on chromosome 10q11.2, have been identified as the underlying genetic cause of the disorder. In the majority of patients with MEN 2A/FMTC missense mutations at exon 10 or exon 11 are identifiable. Cysteine to arginine exchange at codon 634 is the mutation most frequently found. In MEN 2B approximately 95% of patients present with a mutation at codon 918 (exon 16). Additionally, less frequent mutations in other codons have been found in both syndromes. The DNA-based genotype analysis enables the identification of gene carriers at risk of developing MTC and offer them prophylactic thyroidectomy prior to development of any thyroid pathologies. Prophylactic surgery is generally recommended for MEN 2A/FMTC gene carriers at the age of 4-6 years. Due to the aggressiveness of the MEN 2B syndrome gene carriers should be operated by the age of 1 year. Presumably some less virulent mutations allow postponement of the prophylactic treatment to the second to fourth decade of life. CONCLUSIONS: Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.

Genotype↗
PubMed1998

German medullary thyroid carcinoma/multiple endocrine neoplasia registry. German MTC/MEN Study Group. Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia Type 2.

INTRODUCTION: A national registry for medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN2) was set up to evaluate epidemiological, clinical and prognostic factors of the sporadic and hereditary forms of MTC. PATIENTS AND METHODS: Coded data from 1217 patients with MTC from 57 participating centers in Germany were registered and statistically analyzed. The series included 515 (42%) males (mean age 43.1+/-16.1 years) and 702 (58%) females (mean age 44.4+/-17.6 years), with a mean follow-up of 5.2 years; 865 (71%) exhibited the sporadic form and 352 (29%) the familial form (244 MEN2a, 32 MEN2b, 76 FMTC). The mean age at diagnosis was 49 years for sporadic and 30 years for the familial form. RESULTS: Of the patients, 17% presented at stage I, according to the UICC, and 30%, 45%, and 8% presented at stages II, III, and IV, respectively. There were 12% of patients who died of the disease. The overall adjusted survival rate was 87% at 5 years, and 76% at 10 years. In a univariate analysis, the stage of disease at diagnosis, age, gender, and form were relevant prognostic factors. In a multivariate proportional-hazards analysis, the difference between patients with sporadic and familial disease disappeared. CONCLUSION: As the tumor stage at presentation is the major prognostic factor, early diagnosis and surgical intervention before cervical lymph node metastases appear is necessary to improve survival especially in sporadic cases.

Adult↗
PubMed1998

Is there an ectopic secretion of monomeric calcitonin in the human being?

INTRODUCTION: Persistent detectable calcitonin (CT) values can be frequently observed after treatment of medullary thyroid carcinomas (MTCs). Apart from residual C cells or incomplete tumor extirpation, ectopic CT production should be taken into account. CT determination in patients without MTC and after total thyroidectomy should reveal to what extent, apart from the C cells, other neuroendocrine cells show a relevant CT production. OBJECTIVES: The objective of this study was to find out whether ectopic CT production can be detected using an assay specifically recognizing the monomeric form of CT. METHODS: The CT serum values were obtained from 94 healthy individuals and 64 patients who had undergone total thyroidectomy and radioiodine therapy because of follicular or papillary carcinoma. RESULTS: In the group of thyroidectomized patients, the CT values were below the detection limit of the assay. In the tested patients, there was neither a physiological (C cell) nor a pathological (MTC cell) secretion of monomeric CT. CONCLUSION: A relevant ectopic monomeric CT production could be excluded because the patients were without detectable CT concentration. For this reason, postoperative CT concentrations of the monomeric form in MTC patients can be traced either to remaining C cells or to tumor cells. For a differentiation of these two possibilities further diagnostics is necessary.

Adult↗
PubMed2001

Diagnosis and therapy of sporadic and familial medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy. About 75% are sporadic (sMTC) while the remaining 25% are hereditary (hMTC). The treatment of choice for both sMTC and hMTC is surgery. An adequate initial operation provides the best chance of cure. Hence, the diagnosis of MTC should be made preoperatively. In sMTC, ultrasound, ultrasound-guided fine-needle aspiration cytology and measurement of calcitonin levels (basal and after injection of calcitonin-stimulating reagents, e.g., pentagastrin) are sensitive diagnostic tools. In hMTC, identification of a germline mutation in the proto-oncogene RET is sufficient for making the diagnosis. Total thyroidectomy is recommended in all patients, sporadic and hereditary. In addition, lymphadenectomy of the cervicocentral and both cervicolateral compartments should be performed. The only indication to perform a less extensive operation may be given in young patients with hMTC. Sufficient treatment of MTC beyond local disease is still non-existent. Future research should concentrate on this issue.

Adolescent↗
PubMed1998

Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma.

Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinomas (FMTC) are caused by germline mutations in the RET proto-oncogene. To investigate the spectrum of RET mutations among Japanese patients, we screened the RET gene in 71 patients with thyroid carcinomas. The panel included representatives of 44 families carrying FMTC or MEN2, 22 sporadic medullary thyroid carcinomas (MTCs), and five MTCs without familial information. Mutations in nucleotide sequences encoding one of three specific cysteine residues in the extracellular domain of the RET protein were found in 33 of the 34 MEN2A patients and in five of the six FMTC patients examined. A mutation at codon 918, causing the substitution of threonine for methionine in the tyrosine kinase domain of the protein, was found in germline DNAs of all four patients with MEN2B and in two of the 22 patients with sporadic MTCs; codon 918 was mutated somatically in tumor DNAs from three other sporadic cases. Germline mutations of codon 768, GAG to GAC (Glu to Asp), were detected in one FMTC, in one patient with sporadic MTC, and in one of the patients without familial information. Two somatic mutations, an Asp to Gly substitution at codon 631 and a Cys to Arg substitution at codon 634, had not been reported previously. Of five germline mutations found among the 22 sporadic cases, four were confirmed as de novo mutations since in each case neither parent carried the mutation. As nearly one-fourth of the patients with sporadic MTCs carried germline mutations and 50% of their children are expected to develop MTC and other endocrine tumors, these results indicated the importance of careful clinical surveillance of family members of any patient with MTC.

Asian People↗
PubMed2005

Multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome. Predisposition to MEN 2 is caused by germline mutations of the RET proto-oncogene on chromosome 10q11.2 [1]. There are three clinically distinct forms of MEN 2 syndrome -- MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. In all of these subtypes, medullary thyroid carcinoma (MTC) is a key. MEN 2A is the most common subtype of MEN 2. Clinical features of the MEN 2A syndrome include medullary thyroid carcinoma (MTC) and/or C-cell hyperplasia (CCH) in almost all affected individuals, pheochromocytoma (approximately 50%) and hyperparathyroidism (HPT) (15-30%). MEN type 2B is the most aggressive of the MEN 2 variants and accounts for approximately 5% of all cases of MEN 2. MEN 2B is similar to MEN 2A but is characterized by the earlier onset of the disease and by developmental abnormalities. In FMTC, the third form of MEN 2, MTC is the only clinical feature. Introduced in recent years and still developing genetic testing of individuals at highest hereditary risk of MEN 2 syndrome holds the possibility of early detection and improved treatment and prognosis.

Carcinoma, Medullary↗
PubMed2005

Medullary thyroid cancer: medical management and follow-up.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy that occurs in hereditary (25%) and sporadic (75%) clinical settings. MTC is present in all patients with the multiple endocrine neoplasia type 2 (MEN 2) syndromes. MTCs produce calcitonin, measurement of which indicates the presence of tumor in at-risk individuals and the effectiveness of therapy in treated patients. Surgery is the mainstay of therapy for primary and recurrent disease. Routine serial postoperative measurement of calcitonin levels should be done. Patients with elevated calcitonin levels should have imaging by computed tomography scan, magnetic resonance imaging, and/or fluorodeoxyglucose positron emission tomography to identify sites of recurrence and metastasis. The role of radiation therapy is not well defined. There is no effective systemic therapy for MTC at present. Activating mutations in a tyrosine kinase receptor gene are present in the majority of MTCs, and experience with tyrosine kinase inhibitors and other agents in the setting of clinical trials is critical for the identification of effective systemic treatment.

Animals↗
PubMed1995

Marijuana and other drug use among automobile and motorcycle drivers treated at a trauma center.

Serum from injured automobile and motorcycle drivers treated at a trauma center was tested for delta-9-tetrahydrocannabinol activity to determine precrash marijuana use. From June 1990 to March 1991, samples from approximately 20 automobile drivers per month and all motorcycle drivers were available for testing. Also, toxicology screens were performed for ethyl alcohol, cocaine, and phencyclidine (PCP) among the driver groups. Six (2.7%) of the 225 automobile (AUT) drivers and 34 (32.0%) of the 106 motorcycle (MTC) drivers were THC+ (p < .001). Compared with a prior study, the THC+ rate decreased significantly from 31.8% among AUT drivers (p < .001) but had not changed significantly from the 38.6% rate among MTC drivers. Positive toxicology rates were higher among the 261 MTC drivers compared to the 1,077 AUT drivers tested for ETOH, CO, and PCP, being 47.1% vs 35.2% (p < .001), 5.0% vs 8.0% (p < .08), and 1.5% vs 3.1% (NS), respectively.

Accidents, Traffic↗
PubMed1990

Cloning and characterization of two alternatively spliced rat alpha-amidating enzyme cDNAs from rat medullary thyroid carcinoma.

The alpha-amidating enzyme activity in rat medullary thyroid carcinoma (MTC) consists of multiple, active enzymes that can be resolved by ion-exchange chromatography. Amino acid sequences from one form of purified rat MTC alpha-amidating enzyme have been utilized to design oligonucleotide probes for isolating cDNAs encoding this protein. Sequence analysis of multiple cDNA clones indicates that there are at least two types of cDNA in rat tissues. These cDNAs differ primarily by the absence (type A) or the presence (type B) of a 315-base internal sequence. Additional heterogeneity in the 3' coding regions of the different mRNAs has also been found. Both types of cDNA predict primary translation products that are preproenzymes which must be post-translationally processed at both their amino and carboxyl termini. Sequence analysis of the purified peak III protein from rat MTC demonstrates that the type A mRNA encodes this 75-kDa protein. This analysis also provides support for the assignment of the C-terminal processing site. In addition, data are presented which demonstrate that type B mRNA is also functional. The implications of the internal and carboxyl-end heterogeneity are discussed.

Amino Acid Sequence↗
PubMed1985

Differences in NMR spectra between tumor clones of defined metastatic potential.

NMR can discriminate between malignant and normal tissues. This study attempts to determine if NMR can discriminate between tumor clones of differing metastatic potential derived from the same parent tumor. Rat 13762NF mammary adenocarcinoma clones of either high (MTLn3), intermediate (MTC), or low (MTPa) metastatic potential were grown in roller-bottle tissue culture, harvested during exponential growth phase, centrifuged to form a 0.75-cm3 pellet, and analyzed in a Varian 360L spectrometer operating at 60.0 MHz. Dimethyl sulfoxide (10%) was used as an internal standard at 3.1 ppm downfield from tetramethyl silane (TMS). NMR spectra of replicate samples were analyzed and compared. The position of the water peak for MTLn3 (n = 7) was 5.14 +/- 0.0301 vs 5.07 +/- 0.0207 for MTC (n = 5) and 5.05 +/- 0.009 for MTPa (n = 5) (P less than or equal to 0.001). Integrated area of upfield peaks (where glycoproteins residues are expected to resonate) was 47.43 +/- 7.17 for MTLn3 (n = 6) and 40.95 +/- 5.48 for MTC (n = 4) vs 32.06 +/- 10.1 for MTPa (n = 5) (P less than or equal to 0.05). Previous work with these tumor clones suggests quantitative changes in surface glycoproteins are associated with differences in metastatic behavior. This study demonstrates differences in water peaks between cells of high, intermediate, and low metastatic potential and differences in the integrated area of upfield spectral peaks. How these observations relate to the biologic properties of the cells is uncertain. If they prove to have general validity, NMR could be used to profile biologic potential of human malignancies.

Adenocarcinoma↗
PubMed1993

Thyroglobulin in medullary thyroid carcinoma: immunohistochemical study with polyclonal and monoclonal antibodies.

The presence of thyroglobulin (TG) was investigated by immunohistochemistry with one polyclonal and three distinct monoclonal anti-TG antibodies in 19 primary and 15 metastatic medullary thyroid carcinoma (MTC) cases. In two primary tumors possessing a mixed trabecular and follicular growth pattern, a significant number of tumor cells were positive with the four antibodies in all parts of the tumor; these tumors were considered to be genuine mixed follicular and parafollicular tumors. The 17 other primary tumors looked like "classical" (ie, predominantly compact) MTC. Eight contained tubular or microfollicle-like structures that were consistently TG-negative. Eight contained residual entrapped normal follicles positive with the four anti-TG antibodies. In six cases isolated foci of tumor cells reacted with polyclonal antibody or monoclonal antibody 11. In 10 cases circulating TG stained positively with polyclonal antibody in vascular channels, five cases stained positively for TG with monoclonal antibody 11, four cases stained positively for TG with monoclonal antibody 7, and three cases stained positively for TG with monoclonal antibody 1. In metastases TG was found in tumor cells in only one instance, but positive reactions were obtained in vascular channels and macrophages in several cases. We conclude from this study that there is no genuine secretion of TG in classical, compact MTC, which differs morphologically and functionally from mixed follicular and parafollicular tumors secreting both TG and thyrocalcitonin.

Antibodies, Monoclonal↗
PubMed1994

C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases.

Since the first description by Wolfe et al of C-cell hyperplasia (CCH) in asymptomatic relatives of patients suffering from a medullary thyroid carcinoma (MTC), several investigators have described CCH associated with a chronic lymphocytic thyroiditis (CLT) not within the context of MTC or multiple endocrine neoplasia (MEN). We report the study of C-cell density in 112 cases of CLT on retrospective surgical material to determine the frequency of the association between CCH and CLT. The cases of CLT were compared with 19 normal thyroid glands obtained at necropsy. C cells, immunoreactive with a polyclonal anti-calcitonin (CT) antibody, were counted at high magnification (X400) and the number of low-power magnification (X100) microscopic fields (LPFs) containing at least 50 C cells per slide was assessed. Image analysis was performed to determine the C-cell density expressed in number of C cells/cm2. C-cell hyperplasia was defined by the following criteria: C-cell density > 40 cells/cm2 and the presence of at least three LPFs containing more than 50 C cells. Twenty percent of the cases of CLT showed a CCH thus defined, and four of them had an elevated serum CT level. Statistical analysis showed no clinical or biological correlation with the presence of CCH. However, the frequency of CCH was higher if a follicular cell carcinoma was associated with CLT. This study confirms a pathological association between CCH and CLT, provides new criteria for the definition of CCH on surgical pathology material, and reports four cases with an elevated serum CT level not within the context of MTC or MEN.

Adolescent↗
PubMed1995

Further evidence for the interactions between angiotensin II and GABAergic transmission in pentylenetetrazol kindling seizures in mice.

The effects of the GABAergic drugs nipecotic acid, Gabrene, baclofen and metatolylcarbamide (MTC), when given alone or in combination at subthreshold doses with AT II also at a subthreshold dose effective on PTZ-kindling in mice were studied. PTZ-kindling was provoked by intraperitoneal (i.p.) injections of PTZ (40 mg/kg) every other day in male albino mice until clonic seizures appeared. Nipecotic acid (100 and 200 micrograms/mouse intracerebroventricularly [i.c.v.]) tended to decrease seizure intensity. Gabrene (25, 50, 100 and 250 mg/kg i.p.) inhibited PTZ-kindled seizures. Baclofen at a doses of 2.5 and 5 mg/kg i.p. tended to decrease seizure intensity and at a dose of 10 mg/kg was ineffective at all. MTC (50 and 75 mg/kg i.p.) tended to decrease and at a dose of 100 mg/kg significantly decreased seizure intensity. Combinations of subthreshold dose of AT II (0.05 micrograms/mouse i.c.v.) and subthreshold doses of nipecotic acid (100 micrograms/mouse) or Gabrene (10 mg/kg) or baclofen (10 mg/kg) or MTC (50 mg/kg) significantly decreased the intensity of PTZ-kindled seizures in mice. The observed potentiation of the anticonvulsive activity on PTZ-kindling suggests interactions of AT II receptors with GABA receptors (GABAA, GABAB or both), effected through allosteric mechanisms.

Angiotensin II↗
PubMed1992

Cytogenetics of multiple endocrine neoplasia syndromes. I. Two different, unique clonal chromosome changes in a medullary thyroid carcinoma and in a C-cell thyroid hyperplasia.

In short-term cultures of tumor tissue from a medullary thyroid carcinoma (MTC), we found a large clone of cells with a balanced translocation t(9;12)(p24;q22). A large clone with a balanced translocation t(10;16)(p11;q24) was also found in cultures from a C-cell thyroid hyperplasia. No clearcut evidence for chromosome instability was observed in the lymphocytes of the two patients. The mother of the first patient died of MTC; two relatives of the second patient had MTC and one of them had pheochromocytoma. These findings classify the two subjects as MEN 2A patients with different phenotypic expression but with the same type of chromosomal abnormality.

Adult↗