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PubMed1983

Medullary thyroid carcinoma: prognostic factors and treatment.

Seventy-five patients with medullary thyroid carcinoma (MTC) have been treated at Institut Gustave-Roussy from 1932 to 1979. Of these, 13 patients had distant metastases and received palliative treatment, their median survival was 3 years. Sixty-two patients with MTC limited to the neck received curative treatment; 6 had exclusive external radiotherapy for inoperable disease and 56 were surgically treated: 23 by total thyroidectomy and 33 by partial thyroidectomy. After surgery 29 patients received external radiotherapy for cervical lymph node involvement (25/29) and/or incomplete surgical resection (12/27). The survival rate was 69% at 5 years and 48% at 10 years. It was lower in patients with distant metastases at presentation (p less than 10(-5)), with tumoral infiltration of the posterior tissue planes (p less than 0.025) and in patients in whom surgical excision had not been satisfactory (p less than 0.01). It was not correlated with cervical lymph node involvement probably because those patients with lymph node involvement had been irradiated. The 29 patients who received post-operative cervical radiotherapy had initially more extensive local disease (p less than 0.05) than the 27 patients treated by surgery alone, nevertheless their survival was slightly higher. No difference in survival rate was observed between patients treated by total thyroidectomy or partial thyroidectomy, among whom only 4 local recurrences occurred. Three of the 6 patients treated with external radiotherapy alone experienced long survival (4, 7 and 10 years) and a fourth is still in clinical remission 4 years after treatment. The effectiveness of chemotherapy in patients with metastases was poor, only one patient out of 6 had a partial remission following a treatment by adriamycin. In the familial form and multiple endocrine neoplasia type II, total thyroidectomy appears to be indicated. In the sporadic cases, partial thyroidectomy is usually sufficient. External radiotherapy is effective in MTC and seems to be able to eradicate small foci of residual tumor; it is indicated when surgical excision is impossible or incomplete.

Adolescent↗
PubMed1994

Omega-3 and omega-6 fatty acids and PGE2 stimulate the growth of normal but not tumor mouse mammary epithelial cells: evidence for alterations in the signaling pathways in tumor cells.

The direct effect of omega-3 and omega-6 fatty acids on the proliferation of mouse mammary tumor cells (MTC) was examined in a serum-free cell culture system. While the EGF-induced proliferation of normal mammary epithelial cells was shown to be enhanced by omega-3 and omega-6 fatty acids and prostaglandins (PGs), a majority (75-80%) of primary mammary tumors were not stimulated by these agents. Compared to normal cells, some MTC cultures showed a higher susceptibility to inhibition by omega-3 fatty acids. The general lack of response of MTC cultures to PGE2 and cyclic adenosine monophosphate (cAMP) suggests some alterations in the cAMP-mediated pathway. However, the PGE2-induced cAMP levels and cAMP-dependent protein kinase (PKA) activities in the tumor cells were comparable to normal cells. We conclude that the proliferation of mammary tumor cells either follow a cAMP-PKA-independent pathway or have some alterations in the serine/threonine kinase mediated signaling pathway.

1-Methyl-3-isobutylxanthine↗
PubMed2004

A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human colon adenocarcinoma.

To seek the genes involved in the development of colorectal cancer, we analyzed the microarray gene expression profiles of human normal and cancerous colon tissues using the BioExpress database platform. Through the analysis we found one gene named DKFZp586G1517 that was upregulated in colon adenocarcinomas. The full-length cDNA of the DKFZp586G1517 cloned by polymerase chain reaction (PCR) encodes a protein with 978 amino acids, which is homologous to the human cytosolic C(1)-tetrahydrofolate synthetase and contains a mitochondrial target signal at N-terminus. The gene product expressed in 293 cells was localized in mitochondria and processed at the predicted signal cleavage site, supporting the idea that DKFZp586G1517 is a novel mitochondrial C(1)-tetrahydrofolate synthetase (mtC(1)-THFS). The overexpression of mtC(1)-THFS in 293 cells stimulated the colony formation. These results suggest that mtC(1)-THFS may participate in the progression of colorectal cancer by conferring growth advantage and could be a new molecular target for cancer therapy.

Adenocarcinoma↗
PubMed2006

Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1.

Recent evidence indicates that the success of molecular targeted therapies may depend on the identification of drug targets which are essential for the survival of subsets of tumors. RET oncogenes that have been implicated in the development of thyroid carcinomas are emerging as potential therapeutic targets. In the present study, we investigated the efficacy and the cellular bases of antitumor activity of the indolinone Ret tyrosine kinase inhibitor RPI-1 against large established s.c. TT tumor xenograft, a human medullary thyroid carcinoma (MTC) harboring oncogenic MEN-2A-type RET mutation. Oral treatment with RPI-1 caused growth arrest or regression in 81% treated tumors. Following treatment suspension, tumor inhibition was maintained (51%, P<0.05, 100 days) and cures were achieved in 2/11 mice. In treated tumors, Ret was tyrosine dephosphorylated. Moreover, compared to control tumors, a significant increase in apoptotic cells (210%, P<0.0001), loss of cellularity (47%, P<0.0001) and reduction of microvessel density (36%, P<0.0005) were detected. In vivo effects of RPI-1 were reflected in activation of BAD, cleavage of caspases, apoptotic DNA fragmentation and inhibition of VEGF production observed in in vitro RPI-1-treated TT cells. These findings thus indicate that RPI-1 antitumor effect on the MTC was characterized by apoptosis induction and angiogenesis inhibition. The results, consistent with a dependence on RET oncogene activation for maintenance and survival of MEN2A-type MTC, provide further preclinical rationale for a pharmacological RET-targeted intervention in thyroid cancer.

Administration, Oral↗
PubMed2005

The origin and evolution of Mycobacterium tuberculosis.

This article introduces the tools and terminology used for the classification of specific isolates of the Mycobacterium tuberculosis complex (MTC). The utility of these tools and terminology is illustrated by discussing work from independent laboratories that have established a genome-based phylogeny for the MTC. It considers the use of these markers to distinguish atypical isolates not conforming to attributes of traditional MTC members. Finally, it discusses the current genomic evidence regarding the origin and evolution of M. tuberculosis in the context of its relevance for tuberculosis control in humans and other mammalian hosts.

Animals↗
PubMed2004

RET polymorphisms in codons 769 and 836 are not associated with predisposition to medullary thyroid carcinoma.

The study was undertaken to verify whether the RET gene polymorphisms are associated with MTC in patients negative for germline mutations. Two hundred five patients with apparent sporadic MTC were subjected to genetic analysis of RET exons 10, 11, 13, 14, 16 and 22 RET germline mutation carriers were identified with 10.7% frequency. The frequency among 26 patients not older than 30 was 27%. In patients excluded for known mutations we analyzed two polymorphic sites: RET codon 769 and 836. As control group, 90 healthy subjects were investigated. In young patients the observed allelic frequencies were 32% for variant L769/CTG and 5% for variant S836/AGT. Although these values were higher than in older MTC patients (22 and 3%, respectively), as well as in the control group (27 and 2%) the difference was insignificant. We conclude that in Polish patients polymorphisms at RET codons 769 and 836 are not associated with medullary thyroid carcinoma.

Adolescent↗
PubMed2004

Familial medullary thyroid cancer: clinical aspects and prognosis.

OBJECTIVE: To assess clinical features and long-term results of treatment of familial medullary thyroid carcinoma (FMTC). DESIGN: Retrospective analysis of all patients with familial forms of MTC diagnosed between 1949-2000 and treated in our unit. RESULTS: Fifty five patients (25 males, 30 females) were identified with at least two first-degree relatives affected by medullary thyroid cancer; 26 were classified as MEN 2A, 1 as MEN 2B and 28 as FMTC. Median age at diagnosis was 35 years (MEN 2A), 25 (MEN 2B) and 47.5 (FMTC). Median follow-up was 9 years (range: 4-24). Total or near-total thyroidectomy was performed in all patients and 11 received adjuvant external beam radiotherapy. Cause specific survival was 89% at 10 years and 77% at 20 years for MEN patients, 51% and 32% for those with sporadic MTC, and 46% and 26% for those with FMTC. In multivariate analysis, factors predicting survival were presence of metastases, nodal status and age at diagnosis. CONCLUSIONS: Improved survival rates associated with familial types of MTC can be accounted for by the earlier stage at which disease is detected and the younger age at presentation. These observations emphasize the need for early detection in those at risk.

Adult↗
PubMed2005

Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a.

AIMS: To evaluate the value of prophylactic total thyroidectomy in multiple endocrine neoplasia 2a (MEN 2a), based on results of genetic testing, in a presymptomatic early stage of the disease. METHODS: Fourteen presymptomatic patients genetically diagnosed and surgically treated at our centre. We analysed age, gender, location of the RET mutation, calcitonin tests, surgery, histologic findings, TNM classification, and postoperative follow-up. RESULTS: The 14 patients belonged to two families with MTC (MEN 2a). Median age was 16 years. The RET mutation was located in codon 618 and 634. Basal calcitonin (CT) levels were normal in all patients. Twelve had pathologic peak CT measurements. Total thyroidectomy was performed in all and associated central neck dissection in 12 patients. Pathohistologic assessment showed C-cell hyperplasia in all specimens and 11 MTCs; the median size of the tumours was 0.2 cm; two patient had lymph-node metastases. According to TNM, three had stage 0, nine had stage I, one had stage II, and one had stage III disease. Postsurgery basal and peak CT values were normal in all but one patients, indicating a biochemical curative rate of 95%. Calcitonin determination did not distinguish between MTC and C-cell hyperplasia. CONCLUSION: Prophylactic thyroidectomy based on genetic testing allows identification and treatment of patients at an early stage of the disease. Pathologic peak CT values are markers for the presence of microscopic MTC and should be considered in selecting operative procedures for these patients.

Adolescent↗
PubMed2006

Characterization of Yarrowia lipolytica mutants affected in hydrophobic substrate utilization.

In order to get deeper insights into oxidative degradation of the hydrophobic substrates (HS) triglycerides and alkanes by yeasts, tagged mutants affected in these pathways were generated by random insertion of a mutagenesis cassette MTC into the genome of Yarrowia lipolytica. About 9.600 Ura+ transformants were screened in plate tests for utilization of alkanes (C10, C16), oleic acid and tributyrin. HS degradation mutants were recovered as unable to grow on alkane or on intermediates of the pathway (AlkA-AlkE phenotype classes). To identify the disrupted genes, insertion points of the MTC were sequenced using convergent and divergent PCR. Sequence analysis evidenced both known and new genes required for HS utilization, e.g. for AlkD/E mutants MTC insertion had occurred in genes of thioredoxin reductase, peroxines PEX14 and PEX20, succinate-fumarate carrier SFC1, and isocitrate lyase ICL1. Several mutants were affected in alkane utilization depending on chain length. Mutant Z110 (AlkAb: C10- C16+) was shown to be disrupted for ANT1 encoding a peroxisomal membrane localized adenine nucleotide transporter protein, providing ATP for the activation of short-chain fatty acids by acyl-CoA synthetase II in peroxisomes. Mutants N046 and B095 (AlkAc: C10+ C16-) were disrupted for the ABC transporter encoded by ABC1 gene, thus providing first evidence for its participation in chain length dependent alkane transport processes.

ATP-Binding Cassette Transporters↗
PubMed2005

Antimicrobial and mutagenic properties of organotin(IV) complexes with isatin and N-alkylisatin bisthiocarbonohydrazones.

A new series of ligands is synthesised starting from thiocarbonohydrazide and isatin (H(2)itc) or N-alkylisatin (methyl, H(2)mtc; butyl, H(2)btc; pentyl, H(2)ptc); the X-ray structure of H(2)mtc is discussed. The bis imine ligands are reacted with diorganotin(IV) compounds, obtaining monometallic complexes. In order to establish unequivocally their coordination geometry, the X-ray structures of (C(2)H(5))(2)Sn(Hmtc)Cl.THF (THF, tetrahydrofuran) and (C(6)H(5))Sn(Hptc)Cl(2) are determined. In (C(2)H(5))(2)Sn(Hmtc)Cl.THF, the ligand results monodeprotonated and, essentially, monodentate through the sulphur atom, while in (C(6)H(5))Sn(Hptc)Cl(2) the ligand is still monodeprotonated but SNO tridentate. The organotin(IV) complexes of isatin and N-methylisatin exhibit good antibacterial activity, better than that of the corresponding N-butyl and N-pentylisatin derivatives. Gram positive bacteria are the most sensitive microorganisms. No growth inhibition of fungi is detected up to the concentration of 100 microg/ml. H(2)mtc shows mutagenic activity with and without metabolic activation, whereas no mutagenicity is found for its organotin complexes and for the other compounds.

Anti-Bacterial Agents↗
PubMed2005

A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease.

PURPOSE: The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together. METHODS: This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16. RESULTS: Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR. CONCLUSION: The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR.

Adult↗
PubMed2004

Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation.

BACKGROUND: Individual germline mutations in the RET (REarranged during Transfection) proto-oncogene may set the time window for malignant progression from C-cell hyperplasia to familial medullary thyroid carcinoma. Owing to the close genotype-phenotype correlation, genetic information may lend to individual timing of prophylactic thyroidectomy according to RET genotype. Limited information exists on the Cys630 RET genotype. Most of the few published carriers of this genotype who developed medullary thyroid carcinomas (MTCs) were in their mid-30s. METHODS: This case series of a German RET family with the Cys630Arg genotype was assembled to study malignant progression of MTC in this rare RET genotype. RESULTS: There was considerable variability of malignant progression from C-cell hyperplasia to MTC in carriers of the Cys630Arg genotype. In these persons, MTCs had developed by the age of 32 years (index patient, pT2bN0M0), and 15 years and 1 year (non-index patients; pT1apN1bM0 and pT1bpN0M0, respectively). The Cys630Arg genotype always segregated with the familial medullary thyroid carcinoma phenotype. CONCLUSIONS: The Cys630 RET genotype may have a more vigorous transforming activity than currently thought and can cause MTC in RET gene carriers within the first year of life. Starting in early infancy, identified RET gene carriers should be scrutinized until stimulated serum calcitonin levels become positive or, when these remain normal, should undergo prophylactic thyroidectomy before they reach 5 years of age.

Arginine↗
PubMed2005

Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma.

BACKGROUND: Hepatic metastases from medullary thyroid carcinoma (MTC) may impair quality of life by hypercalcitonemia-associated diarrhea and pain. In this prospective study, the effect of selective arterial chemoembolization (SACE) was evaluated. METHODS: Eleven patients with hepatic metastases from MTC received 1 to 9 courses of SACE using epirubicine. Symptomatic, biochemical, and morphologic responses on SACE were recorded. RESULTS: Symptomatic response was observed in all symptomatic patients. However, biochemical and radiologic response occurred only in 6 patients. Liver function was not affected by SACE. One patient with unexpected concurrent pheochromocytoma metastases died after the first course. Development of side effects in the course was observed in 8 patients but were only World Health Organization grade 1. Patients' satisfaction with SACE was excellent. Long-term follow-up found 7 patients alive (1-72 months). Three patients died with tumor 6, 12, and 24 months after SACE, respectively. CONCLUSION: SACE provided good symptom palliation for the majority of patients with hepatic metastases from MTC. However, transient remission or stabilization of hepatic metastases resulted in only 60%. Further studies using a randomized protocol are required.

Adult↗
PubMed2006

C-cell hyperplasia.

Routine calcitonin assay programs and recent studies on the natural history of familial medullary thyroid carcinoma (MTC) have greatly added to our understanding of C-cell hyperplasia (CCH) and refined its classification. This article is an update on CCH physiopathology related to clinical presentation. With this combined approach, two types of CCH that differ by their physiological characteristics can be identified: neoplastic CCH and reactive (also called physiological) CCH. Neoplastic CCH is caused by a germline mutation of the RET protooncogene in a multiple endocrine neoplasia type 2 (MEN 2) syndrome. It progresses to MTC following a time line that depends on the RET mutation involved. CCH may actually be a misnomer for a neoplastic condition that some authors have proposed to call "in situ-MTC". Reactive CCH is considered to be caused by a stimulus that is external to the C-cell, and its premalignant potential is not documented. Many situations such as hypercalcemia, hyperparathyroidy, chronic lymphocytic thyroiditis or follicular tumors have been associated with reactive CCH, the pathogenesis of which remains unclear. But C-cell density in normal patients is subject to important variability, and several studies have demonstrated the dramatic male predominance in physiological CCH when hypercalcitoninemia was a random discovery. These data suggest that a number of conditions which were previously associated with reactive CCH might be purely fortuitous. Our clinical/pathological confrontation contributes to appropriately distinguishing between various CCH types, and in turn to identify the best way of managing patients.

Animals↗
PubMed2002

Somatostatin receptor subtype 1-selective activation reduces cell growth and calcitonin secretion in a human medullary thyroid carcinoma cell line.

Medullary thyroid carcinoma (MTC) is a rare and aggressive tumor and so far medical therapy has provided inconclusive results. In the human MTC cell line TT, expressing all somatostatin (SST) receptor subtypes, cell proliferation decreases with SST and SST receptor subtype 2 (sst(2)), but not sst(5), selective agonist treatment, whereas calcitonin (CT) expression and secretion are reduced by SST, but not by sst(2) and sst(5) agonists. The effectiveness of two new SST analogs, BIM-23926 and BIM-23745, selectively interacting with sst(1), was investigated in the TT cell line. DNA synthesis is significantly reduced by BIM-23926 (27-40% at 10(-10)-10(-6)M) and BIM-23745 (32-90% at 10(-8)-10(-6)M). Viable cell number is also significantly reduced by both BIM-23926 (40% at 10(-12)-10(-6)M) and BIM-23745 ( approximately 40% at 10(-10)-10(-6)M). Treatment with sst(1)-selective agonists significantly reduces CT secretion and gene expression, with a reduction of CREB phosphorylation. These findings suggest that potent sst(1)-selective agonists could have a therapeutic role in MTC.

Base Sequence↗
PubMed2003

A prestressed cable network model of the adherent cell cytoskeleton.

A prestressed cable network is used to model the deformability of the adherent cell actin cytoskeleton. The overall and microstructural model geometries and cable mechanical properties were assigned values based on observations from living cells and mechanical measurements on isolated actin filaments, respectively. The models were deformed to mimic cell poking (CP), magnetic twisting cytometry (MTC) and magnetic bead microrheometry (MBM) measurements on living adherent cells. The models qualitatively and quantitatively captured the fibroblast cell response to the deformation imposed by CP while exhibiting only some qualitative features of the cell response to MTC and MBM. The model for CP revealed that the tensed peripheral actin filaments provide the key resistance to indentation. The actin filament tension that provides mechanical integrity to the network was estimated at approximately 158 pN, and the nonlinear mechanical response during CP originates from filament kinematics. The MTC and MBM simulations revealed that the model is incomplete, however, these simulations show cable tension as a key determinant of the model response.

Actin Cytoskeleton↗
PubMed1985

Gonadotropin secretion before and during acute and chronic dopamine-receptor blockade in insulin-dependent diabetic patients with amenorrhea.

The dopaminergic influence on luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) was studied in 12 diabetic patients with amenorrhea (DMAM) and in 10 normal menstruating diabetic patients (DM). DMAM patients had a reduction in LH pulsatility (P less than 0.05) and basal LH levels (P less than 0.02), compared with DM patients, whereas they had an LH and FSH response to intravenous metoclopramide (MTC) at 30, 45, and 60 minutes and at 30 minutes, respectively (P less than 0.05). Basal (P less than 0.05) and MTC-stimulated (P less than 0.05) PRL levels were lower in DMAM than in DM patients. Serum PRL and FSH increased significantly (P less than 0.02) in six DMAM patients during 10 weeks of oral MTC administration, whereas no significant (P greater than 0.05) alterations occurred in serum LH and estradiol levels. These data point toward increased dopaminergic activity in DMAM patients.

Adolescent↗
PubMed1975

The syndrome of multiple aucosal neuromas and medullary thyroid carcinoma in childhood. Importance of recognition of the phenotype for the early detection of malignancy.

Recognition of the syndrome of OF MMN can identify individuals at risk for the early appearance of MTC. Three such patients are described. Each had the characteristic neuromas and facies, present since infancy. In each, MTC was found in childhood. In the last two patients, the diagnosis was made because of elevated serum CT concentrations. Venous drainage from the tumor, as well as tumor tissue itself, contained high levels of CT. Prompt recognition of persons with MMN is essential for proper investigation and treatment of the associated MTC.

Adolescent↗