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)

Cloning, functional characterisation, and diagnostic proof of the expression of sodium-iodide-symporter (NIS) in the thyroid are essential steps for a better understanding of function and regulation of thyroid hormone synthesis, which is limited by the availability of the trace element iodide. The physiological or pharmacological modulation of NIS function can now be used for a rational functional diagnosis and therapy of thyroid diseases. Diagnostic procedures based on analysis of the this gene or its expression are already in use for the analysis of benign and malignant alterations of the thyroid. Experimental protocols aiming at the functional expression of NIS in thyroid tumors or their metastases which lost capability for iodide uptake are currently developed. Furthermore, techniques are under investigation to express functional NIS by gene transfer in those benign or malignant tissues, tumors, metastases, which normally do not accumulate iodide. This would allow application of radioiodide therapy, a save and established technique to non-thyroid-related fatal diseases.
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PMID:[The sodium-iodide-symporter (NIS): function, regulation and clinical importance]. 1035 44

To investigate whether circulating thyroglobulin (Tg) messenger ribonucleic acid (mRNA) and sodium/iodide symporter (NIS) mRNA transcripts in peripheral blood are valuable in the follow-up of patients with thyroid cancer, we developed highly sensitive nested Tg and NIS mRNA detection assays and compared their accuracy with serum thyroglobulin (sTg) and whole body scan with 131I during the monitoring of 34 patients with well differentiated thyroid carcinoma who had undergone total thyroidectomy (17 of 34 also submitted to thyroid ablation with radioiodine) and were taking T4. Circulating Tg mRNA was found in 13 of 34 patients, 5 of 13 with detectable and 8 of 13 with undetectable sTg. From these 8 patients with undetectable Tg, 6 showed no cervical radioiodine uptake, and 3 presented proven metastatic disease (2 of them positive for antithyroglobulin antibodies). NIS mRNA was detected in 11 of 34 patients, but its measurement did not improve the ability to detect patients with metastases. Overall, identification of metastatic thyroid cancer was better associated with Tg mRNA than with NIS mRNA, sTg, or whole body scan (83% vs. 16.6% vs. 50% vs. 50%; P < 0.001). These data showed that circulating Tg mRNA is not only a more sensitive marker of residual thyroid tissue or thyroid cancer than sTg, particularly in patients during T4 therapy and with positive antithyroglobulin antibodies, but also was more sensitive than NIS mRNA in all patients.
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PMID:Detection of recurrent thyroid cancer by sensitive nested reverse transcription-polymerase chain reaction of thyroglobulin and sodium/iodide symporter messenger ribonucleic acid transcripts in peripheral blood. 1106 12

Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A 61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2. In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract residual radionuclide activity.
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PMID:Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression. 1152 75

The sodium-iodide symporter (NIS) is expressed by papillary (PTC) and follicular (FTC) thyroid carcinoma, and is essential for iodine uptake. We hypothesized that PTC and FTC with detectable NIS immunostaining would be more amenable to radioactive iodine ((131)I) treatment and follow a more benevolent course. To test this, we determined NIS expression by immunohistochemistry in 23 PTC, 9 FTC, and 12 benign thyroid lesions from children and adolescents. NIS expression was determined by two blinded examiners and graded as absent = 0, minimal = 1, moderate = 2, intense = 3, and very intense = 4. NIS was detected in 35% (eight of 23) of PTC, 44% (four of 9) of FTC, 25% (two of eight) of benign tumors, and 100% (four of four) of autoimmune lesions. The intensity of NIS expression was similar in PTC (0.61 +/- 0.24), FTC (0.56 +/- 0.24), and benign tumors (0.50 +/- 0.33) but was more intense in autoimmune lesions (3.0 +/- 0.7, p < 0.005). Distant metastases were found only among PTC with undetectable NIS (two of 15, 13%), and recurrence developed exclusively from PTC and FTC with undetectable NIS (four of 20, 20% versus zero of 12, p = 0.043). The dose of iodine 131 required to achieve remission in the five patients with PTC who had undetectable NIS (213.3 +/- 53 mCi) was greater than that required by patients with similar age and extent of disease for whom NIS expression is unknown (109 +/- 22 mCi, p = 0.06). We conclude that NIS expression is associated with a lower risk of recurrence for PTC and FTC of children and adolescents.
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PMID:Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents. 1240 22

The Na(+)/I(-) symporter (NIS) is an integral plasma membrane glycoprotein that mediates active I(-) transport into the thyroid follicular cells, the first step in thyroid hormone biosynthesis. NIS-mediated thyroidal I(-) transport from the bloodstream to the colloid is a vectorial process made possible by the selective targeting of NIS to the basolateral membrane. NIS also mediates active I(-) transport in other tissues, including salivary glands, gastric mucosa, and lactating mammary gland, in which it translocates I(-) into the milk for thyroid hormone biosynthesis by the nursing newborn. NIS provides the basis for the effective diagnostic and therapeutic management of thyroid cancer and its metastases with radioiodide. NIS research has proceeded at an astounding pace after the 1996 isolation of the rat NIS cDNA, comprising the elucidation of NIS secondary structure and topology, biogenesis and posttranslational modifications, transcriptional and posttranscriptional regulation, electrophysiological analysis, isolation of the human NIS cDNA, and determination of the human NIS genomic organization. Clinically related topics include the analysis of congenital I(-) transport defect-causing NIS mutations and the role of NIS in thyroid cancer. NIS has been transduced into various kinds of cancer cells to render them susceptible to destruction with radioiodide. Most dramatically, the discovery of endogenous NIS expression in more than 80% of human breast cancer samples has raised the possibility that radioiodide may be a valuable novel tool in breast cancer diagnosis and treatment.
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PMID:The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance. 1258 8

Circulating thyroid-specific transcripts have been suggested as potential molecular markers of residual or recurrent thyroid cancer. We assessed the accuracy of real-time RT-PCR-based detection of a panel of thyroid-specific markers, including TG, TPO, TSHR, NIS and PDS, in comparison with serum TG measurements in a series of 55 patients operated for differentiated thyroid cancer (DTC). Serum TG levels were higher in patients with residual thyroid tissue or metastatic cancer than in disease-free patients during thyroid hormone suppressive therapy (THST) and after stimulation with rhTSH (P < 0.05). Recombinant hTSH increased serum TG values in patients with tumor relapse (P < 0.05), but not in disease-free patients. This assay showed high specificity and good sensitivity in detecting tumor relapse (accuracy under THST = 81.4%; after rhTSH stimulation = 90.9%). TPO and TSHR mRNA, either under THST or after rhTSH, showed a significant correlation with disease status for molecular assays. Qualitative analysis of baseline and stimulated TG, NIS and PDS mRNA showed high sensitivity but low specificity in the prediction of thyroid cancer recurrence or metastases (accuracy under THST = 51%, 43% and 54%, respectively), whereas TPO and TSHR mRNA assays had higher specificity but low sensitivity, with accuracy under THST of 67% and 61%, respectively, that improved when these tests were combined. Our findings indicate that serum TG assay after TSH stimulation is the most accurate test for monitoring DTC. Combined measurements of TPO and TSHR mRNA levels during THST may represent a specific test for early detection of DTC relapse.
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PMID:Evaluation of circulating thyroid-specific transcripts as markers of thyroid cancer relapse. 1517 Jun 76

The use of radioactive iodine ((131)I) for the treatment of thyroid carcinoma has changed over the past 50 y. These changes are based on increasing awareness of the biophysical properties of (131)I and new discoveries concerning the biology of iodine handling by thyroid cells. The therapeutic administration of (131)I for thyroid remnant ablation and for metastases requires an appreciation of iodine clearance kinetics, of factors that can alter the occupancy time of (131)I within lesions, and of the role of thyroid-stimulating hormone in stimulating the sodium-iodide symporter. The potential complications and adverse events associated with (131)I are discussed. (131)I will continue to be a major weapon in the fight against metastatic thyroid carcinoma. Its future role will be modified by expanding knowledge of its relative risks and benefits.
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PMID:The evolving role of (131)I for the treatment of differentiated thyroid carcinoma. 1565 49

Well under 15% of differentiated thyroid carcinoma (DTC) is diagnosed at < or =18 years of age. The population is heterogenous and the differences between prepubertal children and pubertals and adolescents are to be considered. Although very little has been reported on children with sporadic DTC under the age of 10 years, juvenile DTC has at least some undeniable differences with adult DTC: (1) larger primary tumor at diagnosis; (2) metastatic pattern and features, namely: (a) greater prevalence of neck lymph node and distant metastases at diagnosis, (b) lungs almost the sole distant metastatic site, (c) pulmonary metastases nearly always functional; (3) closer-to-normal and more frequent sodium-iodide symporter (NIS) expression; and (4) higher recurrence rate but longer overall survival. These differences are especially distinct in prepubertal children. The goals of primary treatment of juvenile DTC are to eradicate disease and extend not only overall, but recurrence-free survival (RFS). Extending RFS is itself a desirable goal in children because it improves quality-of-life, alleviates anxiety during psychologically formative years, reduces medical resource consumption, and may increase overall survival. Primary treatment of DTC generally comprises a combination of surgery, radioiodine ((131)I) ablation, and thyroid hormone therapy applied at varying levels of intensity. Therapeutic decision-making must rely on retrospective adult and/or pediatric outcome studies and on treatment guidelines formulated mostly for adults. Differences between juvenile and adult DTC and physiology dictate distinct treatment strategies for children. We, and many others, advocate a routine intensive approach because of the more advanced disease at diagnosis, propensity for recurrence, and greater radioiodine responsiveness in children, as well as published evidence of significant survival benefits, especially regarding RFS. This intensive approach consists of total thyroidectomy and central lymphadenectomy in all cases, completed by modified lateral lymphadenectomy when necessary and followed by radioiodine administration. However, absence of prospective studies and of universal proof of overall cause-specific survival benefits of this approach have led some to propose more conservative strategies. Most European centers give radioiodine ablation to the vast majority of juvenile DTC patients. Ablation seeks to destroy any residual cancer, including microfoci, as well as healthy thyroid remnant. Large studies have documented the procedure to decrease cause-specific death rates and, in children, to significantly lessen locoregional recurrence rates (by factors of 2-11) independent of the extent of surgery. There is universal agreement on treating inoperable functional metastases with large radioiodine activities. Treatment is especially effective in small tumor foci up to 1 cm in diameter, and should be administered every 6-12 months until complete response, loss of functionality, or attainment of cumulative activities between 18.5-37 GBq (500-1000 mCi). Radioiodine therapy is generally safe. Short-term side effects include nausea and vomiting (more frequent in children than in adults), transient neck pain and edema, sialadenitis (<5% incidence), mild myelosuppression (approximately 25%), transient impairment of gonadal function both in females and males (sperm quality in boys), or nasolacrimal obstruction (approximately 3%), with most cases generally being asymptomatic-moderate, self-limiting, or easily prevented or treated. If pregnancy is ruled out before each (131)I administration, and conception avoided in the year afterward, radioiodine therapy appears not to impair fertility. However, therapeutic (131)I carries a small but definite increase in cancer risk, particularly in the salivary glands, colon, rectum, soft tissue and bone. To better guide primary treatment, different therapeutic combinations should be prospectively compared using RFS as the primary endpoint. Efforts also should be made to identify molecular signatures predicting recurrence, metastasis and mortality.
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PMID:Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. 1632 22

Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is highly aggressive with no uniformly effective chemotherapy available for metastatic disease. The sodium-iodide symporter (NIS) is a transmembrane protein responsible for uptake of iodide into cells. The presence of NIS in thyroid cells permits diagnostic imaging and therapy of thyroid tumors, using radioiodide. Previous studies from this laboratory reported mucin-1 (MUC1)-driven expression of NIS in cancer cells. MUC1 overexpression has also been reported in 90% of pancreatic tumors. In this study Ad5/MUC1/NIS was used to infect pancreatic cancer cells both in vitro and in vivo, to investigate the potential for radioiodide imaging and ablation of this disease. In vitro studies revealed a 43-fold increase in iodide uptake in NIS-transduced cells compared with controls. In vivo imaging revealed effective iodide uptake and retention at the site of NIS-transduced tumors, with optimal uptake (13% of injected dose) observed 5 hr after iodide administration. Intravenous delivery was performed to investigate potential hepatotoxicity of the construct in the event of virus leakage. Intravenous injection of Ad5/CMV/NIS resulted in robust iodide uptake throughout mouse liver, whereas no uptake was detected in the liver of animals given Ad5/MUC1/NIS intravenously. Administration of therapeutic doses of 131I resulted in significant regression of NIS-transduced tumors, with a mean 50% reduction in volume within 10 weeks of therapy (p<0.0001). The ability to target NIS expression to pancreatic cancer, which has such limited treatment options, may be highly beneficial and warrants further investigation.
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PMID:Adenovirus-mediated and targeted expression of the sodium-iodide symporter permits in vivo radioiodide imaging and therapy of pancreatic tumors. 1677 74

The sodium/iodide symporter (NIS) mediates iodide uptake in the thyroid gland and lactating breast. NIS mRNA and protein expression are detected in most thyroid cancer specimens, although functional iodide uptake is usually reduced resulting in the characteristic finding of a 'cold' or non-functioning lesion on a radioiodine image. Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated thyroid cancer to utilize beta-emitting radioactive iodide for the treatment of residual and metastatic disease. Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma membrane, increasing radioiodide uptake. Approximately 10-20% differentiated thyroid cancers, however, do not express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis. Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer specimens, but the fraction with functional iodide transport is relatively low. Lactogenic hormones and various nuclear hormone receptor ligands increase iodide uptake in breast cancer cells in vitro, but TSH has no effect. A wide range of 'differentiation' agents have been utilized to stimulate NIS expression in thyroid and breast cancer using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in 'scan-negative' thyroid cancer and some breast cancer.
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PMID:Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. 1695 31


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