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Biomedical subjects

M D Ringel

Publications and source records attributed to M D Ringel.

At least 19 recordsLinked to original sources
PubMed2001

Overexpression and overactivation of Akt in thyroid carcinoma.

Enhanced activation of Akt occurs in Cowden's disease, an inherited syndrome of follicular thyroid, breast, colon, and skin tumors, via inactivation of its regulatory protein, PTEN. Whereas PTEN inactivation is uncommon in sporadic thyroid cancer, activation of growth factor pathways that signal through Akt is frequently identified. We hypothesized that Akt overactivation could be a common finding in sporadic thyroid cancer and might be important in thyroid cancer biology. We examined thyroid cancer cells lines and benign and malignant thyroid tissue for total Akt activation and isoform-specific Akt expression. In thyroid cancer cells, Akt 1, 2, and 3 proteins were expressed, total Akt was activated by insulin phosphatidylinositol 3'-kinase, and inhibition of phosphatidylinositol 3'-kinase reduced cell viability. In human thyroid tissue, increased levels of phosphorylated total Akt were identified in follicular but not papillary cancers compared with normal tissue. Levels of Akt 1 and 2 proteins and Akt 2 RNA were elevated only in the follicular cancers. In paired samples, Akt 1, 2, 3, and phospho-Akt levels were higher in five of six cancers, including three of three follicular cancers. These data suggest that Akt activation may play a role in the pathogenesis or progression of sporadic thyroid cancer.

Adenocarcinoma, Follicular↗
PubMed2001

Management of hypothyroidism and hyperthyroidism in the intensive care unit.

Thyroid storm and myxedema coma are uncommon problems in the ICU, but both usually present with typical findings, and when recognized early, are treatable. Thus, rapid recognition with early institution of therapy may be life saving. It is always important to search diligently to determine the underlying cause of the decompensation and to treat that aggressively.

Coma↗
PubMed2001

Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer.

Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 +/- 41 picogram equivalents [pg Eq]), than did benign nodules (829 +/- 385 pg Eq), or normal tissues (1907 +/- 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40-96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2-96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 +/- 245 pg Eq vs. 1854 +/- 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.

Antisense Elements (Genetics)↗
PubMed2001

Regulation of FRTL-5 thyroid cell growth by phosphatidylinositol (OH) 3 kinase-dependent Akt-mediated signaling.

Thyrotropin (TSH)-initiated cell cycle progression from G1 to S phase in FRTL-5 thyroid cells requires serum, insulin, or insulin-like growth factor 1 (IGF-1) and involves activation of 3-hydroxy-3-methylglutaryl-CoA reductase, geranylgeranylation of RhoA, p27Kip1 degradation, and activation of cyclin-dependent kinase (cdk) 2. In the present report, we show that the serine-threonine kinase Akt is an important mediator of insulin/IGF-1/serum effects on cell cycle progression in FRTL-5 thyroid cells. The phosphoinositol (OH) 3 kinase inhibitors, Wortmannin (WM) and Ly294002 (LY), block the ability of insulin/IGF-1 to reduce p27 expression, to induce expression of cyclins E, D1, and A as well as cdk 2 and 4, and to phosphorylate retinoblastoma protein. They also inhibit insulin/IGF-1-increased DNA synthesis and cell cycle entrance (S+G2/M). Insulin/IGF-1 rapidly induced activation of Aktl in a PI3 kinase-dependent manner, and increased Aktl RNA levels. Most importantly, FRTL-5 cells transfected with a constitutively active form of Aktl have higher basal rates of DNA synthesis and no longer require exogenous insulin/IGF-1 or serum for TSH-induced growth. In sum, Aktl appears to have an important role in insulin/IGF-1 regulation of FRTL-5 thyroid cell growth and cell cycle progression.

Animals↗
PubMed2001

Thyroglobulin messenger ribonucleic acid levels in the peripheral blood of children with benign and malignant thyroid disease.

Reverse transcriptase-PCR has identified thyroglobulin mRNA (Tg mRNA) in peripheral blood of normal adults and adults with thyroid cancer. However, no children were studied. The primary objective of this study was to determine whether whole blood Tg mRNA levels differ between benign and malignant thyroid disease in children. The secondary goals were to determine whether whole blood Tg mRNA levels vary with age or pubertal development among children with thyroid disease. Whole blood Tg mRNA levels were determined in 38 children (29 girls, nine boys; median age, 14.5 y; range, 4.8-20.4 y) with benign and malignant thyroid disease and correlated with diagnosis, age, pubertal status, thyroid size, and serum levels of free thyroxine, TSH, and Tg protein. Tg mRNA levels ranged from 3.3 to 104 pg Eq/microg total thyroid RNA (mean, 28 +/- 20.2 pg Eq/microg total thyroid RNA) and were similar in benign and malignant disorders (p = 0.67). However, in children with previously treated papillary thyroid cancer, Tg mRNA levels directly correlated with total body (131)I uptake (p = 0.026) and serum Tg protein (p = 0.037). There was no difference between boys and girls, and no change with pubertal maturation. In children with benign thyroid disease, Tg mRNA levels correlated with serum TSH (p = 0.031), but not with diagnosis, age, Tanner stage, or thyroid size. We conclude that Tg mRNA levels are similar in children with benign and malignant thyroid disease and unchanged by age or pubertal status, but correlated with tumor burden in previously treated papillary thyroid cancer.

Adolescent↗
PubMed2001

Sudden enlargement of local recurrent thyroid tumor after recombinant human TSH administration.

Chronic endogenous TSH stimulation of neoplastic tissue has been reported to stimulate tumor enlargement. However, little is known about changes in normal and neoplastic thyroid tissue after sudden rather than chronic stimulation with TSH. Acute thyroidal tissue reactions, reflected by rapid tumor expansion and/or possible vascular changes, have been reported to occur after bovine TSH stimulation and, more recently, after recombinant human TSH (rhTSH). In this report, we describe two patients with papillary thyroid carcinoma with local recurrent tumor. Both patients developed tumor growth 12-48 h after the second rhTSH injection, reflected by acute respiratory distress or a palpable, tender mass. In both situations, the enlargement was documented by imaging techniques, showing tumor expansion compared with previous examinations. Rapid improvement with glucocorticoid supports inflammation as the likely etiology. Based on these cases, and other reports of rapid tumor expansion after rhTSH injection, we recommend glucocorticoid coverage before rhTSH administration for patients with known or suspected neoplasia located in a limited space.

Aged↗
PubMed2000

Prognostic importance of vascular invasion in papillary thyroid carcinoma.

BACKGROUND: The prognostic importance of vascular invasion has not been extensively studied in patients with papillary thyroid cancer. OBJECTIVE: To determine whether the presence of vascular invasion in papillary thyroid carcinoma, even within the thyroid gland, is associated with more aggressive disease at diagnosis and a higher incidence of tumor recurrence. PATIENTS AND METHODS: We identified 410 patients who had been diagnosed with papillary thyroid cancer since 1986 who had a follow-up period of longer than 1 year (median follow-up, 5.5 years). Pathology reports were reviewed and patients were separated into 3 groups: no vascular invasion, intrathyroidal vascular invasion, and extrathyroidal vascular invasion. MAIN OUTCOME MEASURES: Statistical comparison was performed by univariate and multivariate analysis. RESULTS: Patients with intrathyroidal vascular invasion were more likely to have distant metastasis at the time of diagnosis (26.1% vs 2.2%, P = .001). Similarly, patients with extrathyroidal vascular invasion had a higher incidence of distant metastases at diagnosis (40% vs 4.4%, P = .02). Patients with tumors identified to have intrathyroidal vascular invasion were more likely to develop distant recurrence (20% vs 3%, P = .002). CONCLUSIONS: These associations were found to be independent by multiple regression analysis. Patient age, sex, palpable or fixed lymph nodes, radiation exposure, and race did not differ between the patient group with and those without vascular invasion. Preliminary analysis of our data suggests that the presence of vascular invasion in papillary, thyroid carcinoma, even within the thyroid gland, is associated with more aggressive disease at diagnosis and with a higher incidence of tumor recurrence.

Adolescent↗
PubMed2000

Hyperthyroid heart disease.

The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiac performance are detected with small variations in thyroid hormone serum concentrations. Most patients with hyperthyroidism experience cardiovascular manifestations, and the most serious complications of hyperthyroidism occur as a result of cardiac involvement. Recent studies provide important insights into the molecular pathways that mediate the action of thyroid hormone on the heart and allow a better understanding of the mechanisms that underlie the hemodynamic and clinical manifestations of hyperthyroidism. Several cardiovascular conditions and drugs can interfere with thyroid hormone levels and may pose a difficulty in interpretation of laboratory data in patients with suspected thyroid heart disease. The focus of this report is a review of the current knowledge of thyroid hormone action on the heart and the clinical and hemodynamic laboratory findings as well as therapeutic management of patients with hyperthyroid heart disease.

Atrial Fibrillation↗
PubMed2000

Tall cell variant: an aggressive form of papillary thyroid carcinoma.

Twenty-four cases of the tall cell variant (TCV), a subset of papillary thyroid carcinoma, were identified in a group of 624 patients with thyroid cancer. All pathology specimens were reviewed, and each patient's carcinoma was categorized according to characteristics on presentation, local recurrence, distant metastases, follow-up, and tumor-related mortality. The TCV group was compared with a historical control group (Mazzaferri and Jhiang: 1355 patients). The TCV group had a statistically higher percentage of stage 3 and 4 carcinoma, extrathyroidal invasion, and tumor size less than 1.5 cm than the control group. There was no statistical relationship between age greater than 50 years and stage in the TCV group. No relationship could be found between TCV histology and recurrence or mortality. These findings, combined with those of studies that link stage on presentation to poor outcomes, have led to our conclusion that TCV is an aggressive malignancy warranting appropriate treatment and close follow-up.

Adult↗
PubMed2000

Molecular diagnostic tests in the diagnosis and management of thyroid carcinoma.

The application of molecular analysis of gene expression to clinical tissue samples represents one of the most exciting new areas in "translational" thyroid cancer research. Current data suggest that molecular diagnostic assays may improve the sensitivity and accuracy of fine needle aspiration of thyroid nodules, fine needle aspiration of metastases, and detection of recurrent disease in peripheral blood samples. It is likely that at least some of these tests will become useful adjuncts in the diagnostic armamentarium of clinical endocrinologists in the future.

Biomarkers, Tumor↗
PubMed2000

Ultrasound-guided fine-needle aspiration and thyroid disease.

BACKGROUND: Fine-needle aspiration represents a critical diagnostic test in determining proper management of thyroid disease and the use of ultrasound-guided fine-needle aspiration (USGFNA) has increased over the years. METHODS: A retrospective chart review of patients undergoing USGFNA. Two hundred fifteen patients underwent 234 procedures with 362 nodules aspirated within a 2 (1/2)-year period. RESULTS: The mean ages of women and men were 51.9 and 57.8, respectively. The average size of nodules was 2.1 cm. A difficult to assess gland or nodule was the most common indication for USGFNA (33%). The sensitivity was 88.2%, specificity was 80.0%, the PPV was 65.2%, the negative predictive value was 94.1%, and the accuracy was 82.5%. The cancer yield, inadequacy, and complication rates were 44%, 10.5%, and 8.5%, respectively. CONCLUSIONS: USGFNA aspiration is a safe and effective diagnostic modality in the management of thyroid disease, especially for nodules that are difficult to palpate.

Biopsy, Needle↗
PubMed2000

Cytotoxic activity of 2',2'-difluorodeoxycytidine (gemcitabine) in poorly differentiated thyroid carcinoma cells.

Poorly differentiated and anaplastic thyroid cancers are aggressive and usually fatal neoplasms, despite aggressive treatment. We performed an in vitro study to assess the activity of gemcitabine (2',2' difluorodeoxycytidine), a new fluorinated nucleoside analogue, against three poorly differentiated human thyroid carcinoma cell lines (ARO, WRO, and NPA). Each cell line was exposed to increasing concentrations of gemcitabine (0.0003 to 3000 mumol/L) for 24, 48, and 72 hours. Maximal reduction in cell viability was seen after 72 hours of gemcitabine for all three cell lines as measured by 3-(4,5-dimethyl thiazolyl-2)-2,5-diphenyl tetrazolium bromide (MTT) assay. NPA cells were more sensitive than the other two lines after 24 and 48 hours of exposure, but all cell lines were similarly sensitive at 72 hours. A cytotoxic effect was confirmed by DNA assay of adherent cells. IC50 concentrations for reduction in cell viability ranged from 0.731 and 0.986 mumol/L for each cell line after 72 hours of exposure. These concentrations are lower than serum levels in phase 1 clinical trials of gemcitabine for other malignancies. In summary, gemcitabine has activity against poorly differentiated thyroid cancer cell lines in vitro. In vivo studies using xenograft models are warranted to confirm these promising observations.

Antimetabolites, Antineoplastic↗
PubMed2000

The role of radioactive iodine in salivary gland dysfunction.

The use of radioactive iodine has become an important adjunct to the treatment of thyroid cancer. Many normal tissues--including salivary glands, gastrointestinal mucosa, gonads, and lactating breast tissue--have the ability to concentrate radioactive iodine under normal circumstances. Although the mechanism is just beginning to be elucidated, it is this ability that might contribute to the immediate and long-term complications associated with radioactive iodine treatment. In some patients, the salivary complications can be permanent and might compromise daily functioning. In this article, we examine the salivary gland complications associated with radioactive iodine therapy, and we suggest potential protective mechanisms to circumvent these problems.

Cytoprotection↗
PubMed1999

Quantitative reverse transcription-polymerase chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma.

Patients with thyroid cancer are monitored for disease recurrence by measurement of serum thyroglobulin (Tg) and iodine-131 (131I) scanning. To enhance sensitivity and to circumvent antibodies that interfere with Tg immunoassays, we have developed RT-PCR assays that detect circulating thyroid messenger RNA (mRNA) transcripts. We now report results using a sensitive quantitative Tg mRNA assay (Taqman; ABI, Foster City, CA) in comparison with immunoassay in patients previously treated for thyroid cancer. We evaluated 107 patients: 84 during T4 therapy, 14 after T4 withdrawal, and 9 at both time points. All patients had near-total thyroidectomy, and 92% received postoperative 131I. Serum TSH, Tg protein, and Tg mRNA were measured. Patients were grouped based on most recent 131I scan or pathologically confirmed disease as having no detectable thyroid tissue (n = 33), thyroid bed uptake (n = 37), cervical/regional adenopathy (n = 21), or distant metastases (n = 16). During T4 therapy, median (range) Tg mRNA values (pg Tg Eq/microg thyroid RNA) for the groups were 1.5 (0-26.8), 9.4 (0.5-90.0), 15.4 (0.2-92), and 12.4 (1.9-16.6), respectively. Using a value of 3 pg Tg Eq/microg thyroid RNA as cut-point, Tg mRNA was positive in 38% of patients with no uptake, 75% with thyroid bed uptake, 84% with cervical/regional disease, and 94% with distant metastases. The median Tg mRNA value for patients with no uptake was lower than the median values for patients with thyroid bed uptake (P = 0.009) or with detectable thyroid tissue at any site (P = 0.010). Patients with negative 131I whole body scans were also less likely to have detectable Tg mRNA levels than were patients with thyroid bed uptake (P < 0.001) or any detectable thyroid tissue at any location (P < 0.001). Similar differences between these groups were seen after T4 withdrawal and for the 23 patients with circulating anti-Tg antibodies, when analyzed separately. Eight of the nine patients studied with low and high TSH concentrations displayed greater amounts of circulating Tg mRNA after T4 withdrawal. In three patients followed prospectively, the amount Tg mRNA correlated with the presence and absence of cervical metastases. In conclusion, we have demonstrated that a quantitative Tg mRNA assay can identify thyroid cancer patients with recurrent or residual thyroid tissue with greater sensitivity and similar specificity to Tg immunoassay during T4 therapy. The assay was unaffected by anti-Tg antibodies, responded to TSH-stimulation, and was reduced after surgical removal of metastases. These data suggest that this quantitative Tg mRNA assay may be a sensitive marker of tumor recurrence or response to therapy, particularly in patients with anti-Tg antibodies.

Adenocarcinoma, Follicular↗
PubMed1999

Quantitative reverse transcription-PCR measurement of thyroglobulin mRNA in peripheral blood of healthy subjects.

BACKGROUND: Thyroglobulin mRNA can be detected qualitatively in the peripheral blood of patients with metastatic thyroid cancer, thyroid cancer patients with residual thyroid bed uptake, and individuals with no known thyroid disease with intact thyroid glands by use of a lengthy, highly sensitive extraction technique. To improve and broaden the clinical usefulness of this assay, we developed a quantitative reverse transcription (RT)-PCR assay for thyroglobulin mRNA, using RNA recovered from whole blood with a simplified extraction technique. METHODS: Whole blood was drawn from 32 healthy subjects in standard EDTA blood collection tubes. Total RNA was extracted from whole blood, using the PUREscript RNA Isolation Kit. RT-PCR using intron-spanning primers was used to quantitatively amplify thyroglobulin mRNA, using the ABI PRISM 7700 Sequence Detection System with a fluorescent-labeled, thyroglobulin-specific oligonucleotide probe. Thyroid RNA calibration curves were created using total RNA recovered from a single nondiseased thyroid gland. RESULTS: Qualitative RT-PCR demonstrated the presence of thyroglobulin mRNA in the whole blood sample of each healthy subject. The mean concentration of thyroglobulin mRNA detected in these subjects was 433 +/- 69 ng of total thyroid RNA per liter of whole blood (range, 26-1502 ng/L). Overall assay imprecision (CV) was 24% for five samples analyzed 10 times each in separate analytical runs on different days. CONCLUSIONS: Thyroglobulin mRNA can be accurately detected and quantified in peripheral blood from healthy subjects. This new quantitative technique may improve the clinical utility of circulating thyroglobulin mRNA detection in patients with thyroid disease.

Humans↗
PubMed1998

Molecular diagnosis of residual and recurrent thyroid cancer by amplification of thyroglobulin messenger ribonucleic acid in peripheral blood.

Serum thyroglobulin measurement by immunoassay is used to detect residual or recurrent thyroid cancer after thyroid ablation. However, the usefulness of immunoassay is limited by both the requirement for thyroid hormone withdrawal to attain optimal test sensitivity and interference by antithyroglobulin antibodies. To circumvent these problems, we amplified thyroglobulin messenger ribonucleic acid (mRNA) in peripheral blood using RT-PCR and compared the accuracy of this test to serum thyroglobulin immunoassay in patients with thyroid cancer. Thyroglobulin mRNA was amplified from peripheral blood of 77 patients who had undergone thyroidectomy for well differentiated thyroid cancer, 68 of whom while taking thyroid hormone for TSH suppression. Patient staging was based on the most recent radioiodine scan after thyroid hormone withdrawal. Ten normal control subjects were also studied. Among patients taking T4, thyroglobulin mRNA was detected in 26 of 33 patients with either thyroid bed or metastatic iodine-avid tissue on most recent withdrawal scan (79%), whereas serum thyroglobulin was detected in 12 of these 33 patients (36%; P < 0.001). Thyroglobulin mRNA was detected in 7 of 35 patients (20%) with negative radioiodine scans, 12 of 19 patients (63%) with radioiodine uptake in the thyroid bed, and all 14 patients with metastases, including 2 patients with antithyroglobulin antibodies. Thyroglobulin mRNA was detected in all 10 normal subjects. Epithelioid cells that stained strongly with antithyroglobulin antibodies were identified in blood. Detection of circulating thyroglobulin mRNA is a more sensitive marker of residual thyroid tissue or cancer than immunoassay for serum thyroglobulin, particularly in patients treated with thyroid hormone or who have circulating antithyroglobulin antibodies.

Adult↗
PubMed1998

Absence of activating mutations of the genes encoding the alpha-subunits of G11 and Gq in thyroid neoplasia.

Activating mutations of the TSH receptor and alpha-subunit of Gs (G alpha s) that increase adenylyl cyclase activity have been identified in a subset of hyperfunctioning benign thyroid follicular adenomas and, less commonly, in hypofunctioning adenomas and carcinomas. In addition some thyroid tumors exhibit inappropriate activation of phospholipase C (PLC), a signaling pathway that has been implicated in the growth and dedifferentiation of thyroid cells. We therefore hypothesized that some thyroid tumors might be caused by somatic mutations in the genes encoding the alpha-chain of Gq or G11 that result in constitutive activation of the PLC pathway. We amplified regions of the alpha q and alpha 11 genes that encode amino acids, Q209 and R183, and we screened the DNA for mutations by sequence analysis and denaturing gradient gel electrophoresis. No mutations were identified after analysis of DNA from 38 thyroid tumors and 2 poorly differentiated thyroid carcinoma cell lines, including: 13 follicular adenomas, 10 follicular carcinomas, 5 papillary carcinomas, and 10 hyperplastic nodules from multinodular goiters. We conclude that activating mutations of alpha q and alpha 11 are absent or rare in hypofunctioning thyroid neoplasms and that other mechanisms must explain the elevated PLC activity reported in thyroid carcinoma.

Adenocarcinoma, Follicular↗