Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite recent advances in the understanding of the role of the RET proto-oncogene in the development of familial and approximately 30% of sporadic medullary thyroid carcinomas (MTC), little is known about other genetic events that modify the course and outcome of the disease. We compared the expression of genes in intrathyroidal MTCs to autologous local lymph node metastases by means of mRNA differential display (DDRT-PCR). This is the first report of differential display using surgical specimens of a primary cancer and its metastases. Total RNA was extracted from tumor tissue of two patients with MTC associated with multiple endocrine neoplasia (MEN 2B) and sporadic MTC, respectively. Following reverse transcription (RT), the products were PCR-amplified and separated on a denaturating polyacrylamide gel. RT-PCR products demonstrating differential expression were reamplified and used as probes for Northern blot analysis. Six fragments for which differential expression was confirmed were cloned and sequenced. Resultant sequences were tested for homology to sequences in public data bases, and two novel MTC-derived fragments (MDF-1, MDF-2) were identified. Sensitivity of the method was confirmed by identification of a sequence encoding the calcitonin precursor flanking peptide which is expressed almost exclusively in MTC and normal thyroid C cells. Overexpression of the ribosomal genes S3a and P0 was found in the metastases. Recent reports suggest that components of the translational apparatus act as regulatory mediators of growth, proliferation, and neoplastic change. The altered expression of ribosomal proteins and gene products encoded by MDF-1 or MDF-2 may play an important role in the progression and metastatic spread of MTC.
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PMID:Differential display in primary and metastatic medullary thyroid carcinoma. 920 53

Recent advances in the diagnosis and treatment of medullary thyroid carcinoma (MTC) have been significant, but some issues remain controversial. MTC may occur either as a hereditary or a nonhereditary entity. Hereditary MTC can occur either alone--familial MTC (FMTC)--or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B). These hereditary disorders are due to germline mutations in the RET proto-oncogene. Early diagnosis and treatment considerably improve the prognosis in patients with MTC. Genetic testing can identify almost all affected individuals with hereditary disease and permits early thyroidectomy in gene carriers. Plasma CT is an excellent marker for postoperative follow-up. Imaging studies help delineate recurrent or metastatic lesions. Treatment of recurrent or metastatic disease is primarily surgical, including either palliative or microdissective surgery. Radiation therapy is reserved for skeletal metastasis or nonresectable metastatic MTC. Efficacy of current chemotherapy programs is not well established. Overall, the 10-year survival rates are approximately 65%.
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PMID:Advances and controversies in the diagnosis and management of medullary thyroid carcinoma. 923 87

A 16-year-old boy had a swollen neck that was a result of multiple endocrine neoplasia Type 2B (MEN 2B). CT revealed bilateral thyroid tumors, swelling of right cervical lymph nodes, and slight enlargement of the right adrenal gland. I-131 metaiodobenzylguanidine (MIBG) scintigraphy demonstrated increased uptake in the right adrenal gland and the left thyroid tumor, but no abnormal uptake in the right thyroid tumor and the right cervical lymph nodes. Postoperative pathologic findings were consistent with the diagnosis of right adrenal medullary hyperplasia, which is a precursor of pheochromocytoma. In patients with MEN 2B, I-131 MIBG scintigraphy in conjunction with CT of the adrenal glands should be performed to determine the disease stage of the adrenal medullae. In the cervical region, the diagnosis was medullary thyroid carcinoma (MTC) in both thyroid tumors and metastases in the right cervical lymph nodes. The right MTC was more aggressive than the left MTC. It is interesting that not all sites of known MTC take up I-131 MIBG to the same degree.
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PMID:Iodine-131 MIBG imaging in multiple endocrine neoplasia type 2B. 944 58

Clinical and histopathological features do not reliably distinguish between benign and malignant pheochromocytomas. Additional markers that might be useful prognostic indicators in the pathological assessment of these tumors are sought. Immunohistochemical expression of MIB-1, Bcl-2, cathepsin B, cathepsin D, basic fibroblast growth factor (bFGF), c-met, and type IV collagenase were studied on formalin-fixed tissue from 33 nonconsecutive cases of pheochromocytoma, selected on the basis of reliable long-term follow-up, to determine associations with malignancy. The study group included 33 patients, 19 men and 14 women, with a mean age of 45 years, including five cases of neurofibromatosis (NF), three familial, and one MEN IIb. Mean follow-up was 63.2 months. Ten patients were determined to have malignant pheochromocytomas by the presence of metastatic disease. Features found to be associated with malignancy included MIB-1 labeling index (5% vs 1%) (P = .0009), male gender (90% vs 43%) (P = .008), extra-adrenal location (40% vs 9%) (P = .03), tumor weight (481 g vs 124 g) (P = .05), and young age (38 years vs 49 years) (P = .05). None of the five cases with NF were malignant (P = .04). S-100 positivity showed a significant (P = .02) but nonlinear association with benign tumors. Absent S-100 correlated with greater tumor weight. Malignancy was not associated with right versus left side or bilaterality, although bilateral tumors were smaller. C-met, bFGF, cathepsin B, cathepsin D, and collagenase were strongly expressed in most tumors and were not predictive of outcome, nor was bcl-2, which was variably expressed. Using multiple logistic regression with malignancy as the dependent variable, MIB-1 continued to show a significant association with malignancy (P = .005) independent of any association with sex, age, or extra-adrenal location. Using a cutoff value of MIB-1 labeling of greater than 3% yielded a specificity of 100% and a sensitivity of 50% in predicting malignancy.
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PMID:Prognostic markers in pheochromocytoma. 1020 74

This article describes the findings of a retrospective analysis of data obtained on 78 patients with medullary thyroid carcinoma (MTC), recorded between 1969 and 1986, and then followed at the Thyroid Center of Padua (Italy). The ages of the patients ranged between 15 and 89 years, with a median age of 45. The female to male (F:M) ratio was 2.9:1. All patients except 2 had total thyroidectomy. In 70 cases the tumor was of sporadic type; there were 3 familial non-multiple endocrine neoplasia (MEN) MTC; 3 MEN IIa; and 2 MEN IIb. The median duration of follow-up was 15.9 years (13 patients were followed up between 15 and 20 years, and 9 longer than 20). At diagnosis, the tumor was intrathyroid (stage I and II) in 31 patients, with local lymphnodes involved (stage III) in 41 patients, and with distant metastases (stage IV) in 6 patients. A total of 34 patients died (4 were at stage II at diagnosis, 26 at stage III, and 4 at stage IV); 4 of them died of unrelated causes, the others with tumor. The median survival rate of the deceased patients was 6 years (41% of these patients died within 3 years and 24% after more than 10 years); 76% of the deceased patients were older than 45 years at diagnosis. A total of 44 patients are still alive, 22 are alive free of disease (with follow-up between 10 and 24 years, median 14.2 years) and 22 are alive with disease (median follow-up 12.2 years). Only 30% of the patients of both these groups was older than 45 years at diagnosis. Survival is strongly related to tumor stage and to age at diagnosis, because only 8 of the 34 deceased patients were younger than 45 years (and 2 of them died of unrelated causes); moreover, patients who were treated at earlier stages of the disease had better prognosis. Survival rate at 10 and 20 years was 95% for patients with tumor limited to the thyroid, whereas it was 55% and 28.6%, respectively, for patients at stage III and IV. Bone metastases were correlated with worse prognosis than distant metastases only to soft tissues. The sex did not affect survival. None of the patients who had postoperative low serum calcitonin (CT) levels and no response to pentagastrin stimulation showed recurrences in the follow-up. In patients with postoperative elevated serum CT levels, recurrences of the tumor increased over time. However, 30% of these patients continued to show only elevated CT levels without evidence of the disease, even after 15 years.
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PMID:Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986. 966 90

RET proto-oncogene mutation results in a dominant autosomic inherited syndrome (MEN 2) presenting three distinct subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). Detection of RET proto-oncogene mutation is a predictor before clinical or biochemical evidence of the disease is present and leads to preventive thyroid removal since there is no effective treatment for metastases. The aim of the present study was to characterize mutations in the RET proto-oncogene in affected patients and to identify potential carriers in their families. Two families with FMTC (5 and 6 members), 4 with MEN 2A (5, 5, 4 and 3 members) and 2 with MEN 2B (5 and 1 members), were studied. DNA was obtained from blood samples in all patients and from thyroid or from pheonochromocytoma tissues in patients submitted to surgery. PCR amplification was performed using specific primers for exons 10, 11 and 16, followed by direct sequencing. Mutations at codon 634 in exon 11 were found in 16 subjects with FMTC and MEN 2A: TGC --> CGC (cysteine to arginine) in 9 cases, TGC --> TAC (cysteine to tyrosine) in 3, and TGC --> TTC (cysteine to phenilalanine) in 4. A unique mutation of codon 918 in exon 16, ATG --> ACG (methionine to threonine), was found in both MEN 2B affected patients. The mutations detected in DNA from peripheral blood were the same as those present in DNA extracted from tumor material. RET mutations were detected in all affected patients, confirming the diagnosis, and in 10 members of their families. In five of the carriers total thyroidectomy was performed. Anatomopathological study showed C-cells hyperplasia or in-situ microcarcinoma in two children (9 and 12 y) with no clinical signs of diseases and medullary thyroid carcinoma in three adults, who were previously unaware of the presence of thyroid nodules. The early detection of RET mutation followed by total thyroidectomy may prevent the development of the disease, specially in affected families, and avoid the fatal outcome of delayed medullary thyroid carcinoma diagnosis.
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PMID:[Early diagnosis of multiple endocrine neoplasia type 2 (MEN 2) by detection of mutated RET proto-oncogene carriers]. 970 52

Mutations of the RET gene, encoding a receptor tyrosine kinase, have been associated with the inherited cancer syndromes MEN 2A and MEN 2B. They have also further been associated with both familial and sporadic medullary thyroid carcinomas. Missense mutations affecting cysteine residues within the extracellular domain of the receptor causes constitutive tyrosine kinase activation through the formation of disulfide-bonded homodimers. We have recently reported that a somatic 6 bp in-frame deletion, originally coding for Glu632-Leu633, potently activates the RET gene. This activation is increased with respect to the frequent MEN 2A-associated missense mutation Cys634Arg. This finding specifically correlated to the clinic behavior of the corresponding tumor, which was characterized by an unusually aggressive progression with both multiple and recurrent metastases. By examining the possibility that this deletion acts in a manner similar to cysteine substitution, we have analysed the molecular mechanism by which this oncogenic activation occurs. Phosphorylated dimers of the deleted Ret receptor were detected in immunoprecipitates separated under non-reducing conditions. Like other Cys point mutations, this 6 bp deletion affecting two amino acid residues between two adjacent Cys, is capable of activating the transforming ability of Ret by promoting receptor dimerization. These results suggest that alteration to cysteine residue position or pairing is capable of inducing ligand independent dimerization. Furthermore, we present data demonstrating that the processing and sorting of the Ret membrane receptor to the cell surface is affected by mutation type.
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PMID:The Glu632-Leu633 deletion in cysteine rich domain of Ret induces constitutive dimerization and alters the processing of the receptor protein. 1049 Aug 16

Medullary carcinoma of the thyroid (MTC) is a rare tumour derived from thyroid C cells with serum calcitonin as a specific and sensitive marker. MTC is inherited in 25% of cases, with an autosomal dominant transmission, age-related penetrance and variable expressivity. MTC is an obligatory component of multiple endocrine neoplasia type 2 (MEN2), which comprises three well defined syndromes: MEN2A, which may be associated with pheochromocytoma and/or hyperparathyroidism; the much rarer MEN2B, which occurs early and is accompanied by developmental abnormalities; while in contrast, familial MTC (FMTC) is not associated with any endocrinopathy. The RET proto-oncogene is the causative gene of the MEN2 syndromes and mutations in this gene are found in >90% of inherited cases, allowing easier and more reliable family screening than pentagastrin stimulation tests. Nevertheless, the correlation between the genotype and the different clinical phenotypes is not perfect. The prognosis of MTC depends on its staging at presentation, and the early appearance of cervical lymph node metastases emphasizes the need for extensive surgery, although many patients still do not normalize calcitonin levels post-operatively, and they remain a challenge for the further management.
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PMID:Diagnosis and treatment of medullary thyroid cancer. 1128 39

Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.
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PMID:Multiple endocrine neoplasia type 2B--genetic basis and clinical expression. 1135 39

Medullary thyroid carcinoma is a rare neoplasm (3-9% of all thyroid tumors). Surgery represents the only strategy for potential cure of the disease in whichi. Medullary thyroid carcinoma in which locoregional lymph node metastases are an early occurrence cannot be treated with radioiodine therapy and it is minimally sensitive to chemotherapy and external beam radiation therapy. Therefore total thyroidectomy with lymphadenectomy is the treatment of choice. Ipsilateral laterocervical lymphadenectomy is essential for neoplasms > 10 mm in size in case of central and ipsilateral laterocervical lymph node involvement; bilateral laterocervical lymphadenectomy should be performed in all patients with bilateral lymphadenopathy and in some cases of MEN 2B. In recurrence, reoperation is the single possible treatment with satisfactory results in terms of prognosis.
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PMID:Medullary thyroid carcinoma: surgical management of primary tumor and locoregional recurrence. 1137 May 44


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