Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene.
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Vascular endothelial growth factor A (VEGF) is a potent mitogen for endothelial cells in vitro and promotes neo-angiogenesis in vivo. VEGF overexpression occurs in most human malignancies including thyroid carcinomas in which elevated VEGF expression is associated with a high tumorigenic potential. To investigate the role of VEGF in angiogenesis associated with development of thyroid carcinomas, we constitutively expressed VEGF121 into a poorly tumorigenic cell line (NPA) expressing minimal levels of endogenous VEGF. Here we report that VEGF overexpressing NPA cells showed the same growth potential as untransfected NPA in vitro but formed well-vascularized tumors when injected subcutaneously into nude mice with markedly reduced latency compared to parental cells. A complementary approach was to suppress VEGF expression in a highly tumorigenic anaplastic cell line (ARO) by the transfection of an antisense construct. Antisense-transfected ARO cells expressed reduced constitutive levels of VEGF, showed the same growth potential as untransfected ARO cells in vitro and formed small tumors characterized by minimal vascularization, extensive necrosis and longer latency compared to parental or vector-transfected ARO cells in vivo. Finally, we investigated the expression of both VEGF tyrosine kinase receptors (Flt-1 and Flk-1/KDR) in tumor specimens by RT - PCR. Expression of (Flt-1 and Flk-1/KDR) was low in tissue specimens derived from NPA tumors, but was found enhanced in NPA VEGF tumors; conversely, the expression of VEGF receptors was high in tissue specimens derived from ARO tumors but was decreased in tumors derived from VEGF depleted ARO cells. These results clearly demonstrate that VEGF indirectly promotes the growth of thyroid tumors by stimulating angiogenesis. (+info)
Comparison of 99mTc-methoxyisobutyl isonitrile and 201Tl scintigraphy for detection of residual thyroid cancer after 131I ablative therapy.
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In this study, we compared 99mTc-methoxyisobutyl isonitrile (MIBI) with 201Tl scintigraphy for the detection of residual thyroid cancer not found by 131I scans in patients with increased risk of recurrence after 131I therapy. METHODS: 201Tl and MIBI scans were obtained in 54 patients with negative 131I scans 3-25 y (median 7.9 y) after the first postsurgical 131I therapy. Serum thyroglobulin (Tg) levels were measured while patients were receiving thyroid hormone and again 6 wk after withdrawal of hormone therapy. RESULTS: The overall results were the same for both 201Tl and MIBI imaging, with a sensitivity of 19 of 36 (53%), specificity of 17 of 17 (100%) and accuracy of 36 of 54 (69%). Planar images missed residual cancer in high cervical lymph nodes adjacent to salivary gland activity, in small nodes (<1 cm) deep in the neck or chest and with diffuse pulmonary micrometastases. Serum Tg was elevated in 24 of 36 (67%) patients with residual cancer; 201Tl detected tumor sites in 13 of 24 (54%) of these patients, and MIBI detected tumor sites in 14 of 24 (58%) of these patients. Of the 12 patients who had residual cancer and false-negative serum Tg levels, 6 had true-positive 201Tl and 5 had true-positive MIBI scans. CONCLUSION: 201Tl and MIBI planar imaging yield the same high specificity and positive predictive value for residual thyroid cancer in patients with high-risk profiles and negative radioiodide scans. Both imaging agents detected residual cancer in more than half of the patients in whom conventional staging techniques did not reliably detect either the presence or the extent of residual thyroid cancer and changed the management in patients with surgically resectable cancer. (+info)
Preoperative diagnosis of thyroid papillary and anaplastic carcinomas by real-time quantitative reverse transcription-polymerase chain reaction of oncofetal fibronectin messenger RNA.
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The restricted expression of oncofetal fibronectin (onfFN) mRNA in thyroid papillary and anaplastic carcinomas was recently reported. In this study, we measured the copy number of onfFN mRNA in RNAs extracted from fine needle aspiration biopsies by real-time quantitative reverse transcription-PCR using thyroglobulin mRNA as an internal control. By measuring the onfFN:thyroglobulin mRNA ratio, preoperative aspirates from 31 papillary carcinomas and an anaplastic carcinoma can be distinguished from those from 5 adenomatous goiters, 5 follicular adenomas, and 4 follicular carcinomas. Thus, quantification of onfFN by real-time quantitative reverse transcription-PCR may be useful for the preoperative diagnosis of papillary and anaplastic carcinomas. (+info)
A progress report of the Marshall Islands nationwide thyroid study: an international cooperative scientific study.
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The objective of this report is to present a summary of progress of the Marshall Islands Nationwide Thyroid Study. As well known, the US atomic weapons testing program in the Pacific was conducted primarily between 1946 and 1958 in the Marshall Islands. The nuclear tests resulted in radioactive contamination of a number of atolls and resulted in exposure of Marshallese to undefined levels before our study. Little information has been paid to health consequences among residents of the nearly twenty inhibited atolls except for some information about nodular thyroid disease which was reported on by an US group. In a cooperative agreement with the Government of the Marshall Islands, between 1993 and 1997 we studied the prevalence of both thyroid nodules and thyroid cancer among 4766 Marshallese potentially exposed to radioiodines from bomb test fallout. That group represents more than 65% of the population at risk. We diagnosed 45 thyroid cancers and 1398 benign thyroid nodules. In addition, 23 study participants had been operated on prior to our study for thyroid cancer. Presently, we are developing a database of information to estimate radiation doses and planning a statistical analysis to determine if a dose-response relationship exists. These data will be important for the health promotion of exposed people all over the world including Hiroshima, Nagasaki, Semipalatinsk, Chernobyl and other locations. A timely completion is important for purpose of assisting Marshallese as well as to add the global understanding of radiation induced thyroid cancer. (+info)
Screening of specific changes in mRNAs in thyroid tumors by sequence specific differential display: decreased expression of c-fos mRNA in papillary carcinoma.
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To examine the specific changes in gene expression in thyroid carcinomas, we performed sequence specific-differential display (SS-DD) analysis by using a specific degenerate primer for the superfamily of the small G protein. After subcloning and sequencing analysis, one of the genes that showed decreased expression in thyroid papillary carcinomas was revealed to be the proto-oncogene c-fos. Expression of c-fos mRNA in benign and malignant tissues was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blotting. The expression of c-fos was detected in all twelve normal thyroid tissues, whereas it decreased in thirteen of fifteen papillary carcinomas. These results indicate that the increased expression of c-fos mRNA is not necessarily to be an oncogenic feature of thyroid tumors. Further, its constant expression in normal thyroid tissues may play a role in the maintenance of thyroid function. (+info)
CD30 positive (non-anaplastic) peripheral T-cell lymphoma of the thyroid gland.
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Primary non-Hodgkin's lymphoma of the thyroid gland are infrequent tumors. They almost exclusively derive from B cells of mucosa-associated lymphatic tissue and only a very small minority of them is represented by T cell lymphomas. CD30 molecule, other than in Hodgkin's and Redd-Sternberg' cells, is strictly associated with anaplastic large cell lymphoma and ALK lymphomas, the latter being identified by the monoclonal antibody ALK1. We report a case of CD30-positive non-anaplastic (ALK1-negative) peripheral T cell lymphoma of the thyroid gland and speculate on aspects concerning diagnosis and the morphologic and immunohistochemical findings. (+info)
Overexpressed cyclin D3 contributes to retaining the growth inhibitor p27 in the cytoplasm of thyroid tumor cells.
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The majority of thyroid carcinomas maintain the expression of the cell growth suppressor p27, an inhibitor of cyclin-dependent kinase-2 (Cdk2). However, we find that 80% of p27-expressing tumors show an uncommon cytoplasmic localization of p27 protein, associated with high Cdk2 activity. To reproduce such a situation, a mutant p27 devoid of its COOH-terminal nuclear-localization signal was generated (p27-NLS). p27-NLS accumulates in the cytoplasm and fails to induce growth arrest in 2 different cell lines, indicating that cytoplasm-residing p27 is inactive as a growth inhibitor, presumably because it does not interact with nuclear Cdk2. Overexpression of cyclin D3 may account in part for p27 cytoplasmic localization. In thyroid tumors and cell lines, cyclin D3 expression was associated with cytoplasmic localization of p27. Moreover, expression of cyclin D3 in thyroid carcinoma cells induced cytoplasmic retention of cotransfected p27 and rescued p27-imposed growth arrest. Endogenous p27 also localized prevalently to the cytoplasm in normal thyrocytes engineered to stably overexpress cyclin D3 (PC-D3 cells). In these cells, cyclin D3 induced the formation of cytoplasmic p27-cyclin D3-Cdk complexes, which titrated p27 away from intranuclear complexes that contain cyclins A-E and Cdk2. Our results demonstrate a novel mechanism that may contribute to overcoming the p27 inhibitory threshold in transformed thyroid cells. (+info)
Evaluation of lymph node reactivity in differentiated thyroid carcinoma.
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CONTEXT: The development of metastases is the most notable characteristic of malignant neoplasias. The filter function of lymph nodes, which led to the idea of including lymphatic treatment in surgical management of metastases. OBJECTIVES: To evaluate morphological alterations in neck nodes in the presence of differentiated thyroid carcinoma (DTC): hyperplasia, histiocytosis, desmoplasia, capsular rupture, necrosis and their relation to the biological behavior of these neoplasias. DESIGN: Retrospective study. SETTING: University referral unit. PARTICIPANTS: 98 DTC patients, from 1977 to 1992, 18 cases were selected for histological analyses, of which 14 were female and 4 males, with an average age of 50.2 years. From these cases, 290 lymph nodes were analyzed (81 with metastasis), with an average of 16 lymph nodes/patient. MAIN MEASUREMENTS: Morphological evaluation of paraffin cuts stained by HE was done using an optical microscope, looking for presence of the above mentioned neoplasias and their UICC-TNM (1997) staging. RESULTS: Sinus histiocytosis was 2.4 times more frequent in the absence of lymph node metastasis (pNo). Disease recurrence occurred in 5 patients, all of whom were more than 40 years old (p= 0.24) and 4 of whom had necrosis (p= 0.02). Six patients with predominance of paracortical hyperplasia (p= 0.02) did not show as much relapse into disease as those with less than 6 metastasis lymph nodes (p= 0.009). CONCLUSIONS: The presence of paracortical hyperplasia is associated with a better prognosis. The existence of necrosis or metastasis in more than 6 lymph nodes in patients over 40 years of age is related to higher risk of relapse of disease in DTC. (+info)