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PubMed2004

Estimation of thyroid radiation doses for the hanford thyroid disease study: results and implications for statistical power of the epidemiological analyses.

Residents of eastern Washington, northeastern Oregon, and western Idaho were exposed to I released into the atmosphere from operations at the Hanford Nuclear Site from 1944 through 1972, especially in the late 1940's and early 1950's. This paper describes the estimated doses to the thyroid glands of the 3,440 evaluable participants in the Hanford Thyroid Disease Study, which investigated whether thyroid morbidity was increased in people exposed to radioactive iodine from Hanford during 1944-1957. The participants were born during 1940-1946 to mothers living in Benton, Franklin, Walla Walla, Adams, Okanogan, Ferry, or Stevens Counties in Washington State. Whenever possible someone with direct knowledge of the participant's early life (preferably the participant's mother) was interviewed about the participant's individual dose-determining characteristics (residence history, sources and quantities of food, milk, and milk products consumed, production and processing techniques for home-grown food and milk products). Default information was used if no interview respondent was available. Thyroid doses were estimated using the computer program Calculation of Individual Doses from Environmental Radionuclides (CIDER) developed by the Hanford Environmental Dose Reconstruction Project. CIDER provided 100 sets of doses to represent uncertainty of the estimates. These sets were not generated independently for each participant, but reflected the effects of uncertainties in characteristics shared by participants. Estimated doses (medians of each participant's 100 realizations) ranged from 0.0029 mGy to 2823 mGy, with mean and median of 174 and 97 mGy, respectively. The distribution of estimated doses provided the Hanford Thyroid Disease Study with sufficient statistical power to test for dose-response relationships between thyroid outcomes and exposure to Hanford's I.

Adolescent↗
PubMed1996

Assessment of completeness of thyroid ablation by estimation of neck uptake of 131I on whole-body scans: comparison of quantification and visual assessment of thyroid bed uptake.

Thyroid cancer is treated by thyroidectomy followed by radioiodine ablation of the residual active tissue in the thyroid bed. Completeness of ablation can be assessed from neck images of whole-body 131I scans by visual estimation or quantitative analysis By visual assessment, ablation can be considered complete if there is no uptake in the neck or the uptake is empirically considered too small. By quantification, ablation is considered complete if neck uptake is < 1%. Further radioiodine therapy is considered necessary only if neck uptake exceeds 1% of the administered dose. Both visual assessment and quantification of thyroid bed uptake were applied to 46 scans after diagnostic or therapeutic doses of 131I had been administered to 25 patients who were being followed up for follicular or papillary carcinoma of the thyroid. The results were compared to assess the effect of either method on determining the need for a further ablative dose of 131I. Visual assessment overestimated thyroid bed uptake in 10 of 46 (22%) of the scans. Bearing in mind the unpleasantness of radioiodine ablation and the potential for bone marrow toxicity, it is recommended that quantification of neck uptake should be routinely performed as a guide to completeness of ablation and to determine the need for a therapeutic dose of the isotope. This should help to avoid unnecessary radioiodine treatment in patients with thyroid cancer.

Adult↗
PubMed1979

TSH and thyroid stimulating antibodies (TSAb) activate thyroid adenylate cyclase through different pathways.

Adenylate cyclase activity in human thyroid homogenates was studied after stimulation with thyrotropin (TSH) and thyroid stimulating antibodies (TSAb). The results show: 1) TSAb prepared from different patients with Graves' disease show different adenylate cyclase activation patterns and a lag phase is frequently observed. 2) TSH and TSAb appear to cause mutually inhibitory activation of thyroid adenylate cyclase. 3] The maximal adenylate cyclase activation is higher with TSH than with TSAb, but this could possibly be due to contamination of TSAb preparations with an adenylate cyclase inhibitor. 4) There is no absolute copurification of TSH sensitive and TSAb sensitive adenylate cyclase in various subcellular fractions of thyroid homogenate. 5) Incubation of thyroid homogenate with cortisol cause a dose dependent decrease in the adenylate cyclase response to TSAb whereas the response to TSH is either increased or unchanged. The results indicate that TSH and TSAb activate thyroid adenylate cyclase through different pathways in the plasma membrane.

Adenylyl Cyclases↗
PubMed1994

Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease.

Infiltration of the thyroid gland by lymphocytes is a hall-mark of autoimmune thyroid disease; it is particularly evident in Hashimoto's thyroiditis but is also seen in most patients with Graves' disease. Infiltrating cells are comprised primarily of T lymphocytes, of which only a minority appears to be activated. Their precise pathogenic role is largely unknown. Since perforin has been a marker for functionally activated cytotoxic T cells in situ we elected to assess the presence of perforin-containing cells in thyroid-infiltrating lymphocytes and establish their phenotype. Cells were isolated from seven subtotal thyroidectomy specimens, five from patients with Graves' disease and two with Hashimoto's thyroiditis. The novel findings were as follows: CD4+ perforin-containing T cells occurred only in Hashimoto's glands, suggesting a class II-restricted component of cytotoxicity; in Graves' disease, and to a lesser extent in Hashimoto's, perforin-expressing cells were primarily T cell receptor alpha beta- CD4-CD8- (double negative); double negative perforin-containing cells in peripheral blood of normal individuals were largely gamma delta + T cells. In Hashimoto's samples, the predominant population of T cells expressing perforin was CD8+. By comparison, in studies of the synovial fluid of knee joints from patients with rheumatoid arthritis only a minor population of the perforin-containing cells was double-negative. The data suggest significant differences in cytotoxic autoimmune mechanisms between the two autoimmune thyroid diseases. Functional characterization of double-negative T cells is necessary to define their role in autoimmunity.

Arthritis, Rheumatoid↗
PubMed1985

Free thyroid hormone levels and TSH response to TRH in patients with autonomous thyroid adenomata and normal T3 and T4.

Free thyroid hormone levels together with basal and TRH stimulated TSH levels, have been determined in 50 patients with autonomous thyroid adenomata, who had normal serum total T3 and T4 values. Similar measurements were made in 33 healthy subjects. FT3 and FT4 plasma levels were significantly higher (P less than 0.01 and P less than 0.05 respectively), and basal and TRH stimulated TSH were significantly lower (P less than 0.05 and P less than 0.001 respectively) in the patients than in the controls. The TSH response to TRH was decreased in spite of normal free thyroid hormones in 25 patients and in a further ten both the delta TSH after TRH and the free fractions were normal. Eighteen patients were studied over periods from 4 37 months by repeating thyroid hormone levels and TRH tests. In six of them a change of these parameters toward toxicity was observed. The data obtained in the longitudinal study indicate that the values of free thyroid hormones and the result of the TRH test obtained by a single determination may represent different steps in the evolution of autonomous thyroid adenomata rather than a distinct pathophysiological condition.

Adenoma↗
PubMed1986

Subacute thyroiditis: activated HLA-DR and interferon-gamma expressing T cytotoxic/suppressor cells in thyroid tissue and peripheral blood.

Using a two-colour direct immunofluorescence staining technique, we investigated activated HLA-DR-expressing T helper and T cytotoxic/suppressor cells in peripheral blood of six patients with subacute thyroiditis at referral and at follow-up and in blood from 20 controls. In three of the patients, thyroid fine-needle aspirates were examined as well. At referral, all patients had elevated blood levels of activated T helper and T cytotoxic/suppressor cells 2 (2-4)%, median and range, vs 0 (0-2)%, P less than 0.001 and 12.5 (2-24)%, vs 0 (0-1)% P less than 0.001). At follow-up, the activated proportion of T helper cells had become normal whereas some activated T cytotoxic/suppressor cells remained, 7 (0-8)%. No significant changes in total T cell number were detected when data at referral and at follow-up were compared. In thyroid aspirates, HLA-DR expressing thyrocytes were observed; the total proportion of T cytotoxic/suppressor cells was elevated (70% compared with 35% in blood) and 70% of the T cytotoxic/suppressor cells were HLA-DR+. Furthermore, 55% of the thyroid-infiltrating lymphoid cells were positive for interferon (IFN-gamma+). The finding of activated T cytotoxic/suppressor cells in the blood and thyroid tissue in subacute thyroiditis is consistent with a viral aetiology. Furthermore, intrathyroidal IFN-gamma+ lymphocytes are likely to contribute to expression of major histocompatibility complex (MHC) class II antigens on thyrocytes. No autoantibodies, however, were detected, which suggests that aberrant expression of MHC class II molecules alone is not sufficient to provoke an autoimmune response.

Adult↗
PubMed2005

Thyroid dysfunction in the offspring of mothers with autoimmune thyroid diseases.

UNLABELLED: An integrated three-compartment thyroid model exists during gestation: pregnancy influences thyroid function in several ways, the placenta plays an active role in TRH-thyroid and iodide transport and metabolism, and the fetus develops its own hypothalamic-pituitary-thyroid axis. This commentary reviews some basic and new data, especially in the maternal-offspring relationship in the case of maternal autoimmune thyroid diseases. CONCLUSION: The careful control of maternal autoimmune thyroid disease is essential in order to avoid pathological changes in the offspring.

Female↗
PubMed1987

Thyroid, lipid and other biological variables in elderly patients with asymptomatic autoimmune thyroiditis: a statistical analysis.

Asymptomatic autoimmune thyroiditis (AAT), especially prevalent in elderly women and associated with the presence of thyroid antibodies (HT), is recognized as a precursor of hypothyroidism and is an intermediate between euthyroidism and hypothyroidism. This paper is concerned with the possible modifications of biochemical variables - some of which are not directly related to the thyroid - in patients with AAT. Thirty-seven serum factors were investigated in euthyroid, AAT, and HT subjects over 69 years of age. They were thyroglobulin; microsomal, gastric and adrenal antibodies; LE cells, and thyroid, lipid and immunological variables linked to the inflammatory process. In women the only variable, other than those related to the thyroid, which showed any modification in the AAT state was the cholesterol level. Wholly different observations were made in men, stressing the necessity of separate analysis of male and female data: the thyroid-related variables which were modified in the AAT state are not the same as in women, the cholesterol is not increased but triglycerides, HDL, albumin and inflammatory variables are modified. Furthermore, the lipid variables showed an unexpected age dependency in AAT, but not in euthyroid women (between 69-90 years of age).

Aged↗
PubMed1992

The effect of mast cell chymase on extracellular matrix: studies in autoimmune thyroiditis and in cultured thyroid cells.

In the first part of the study we analyzed the morphology of mast cells in autoimmune thyroiditis of BB/W rats. In the early stage of thyroiditis mast cells showed exocytosis of granules into the interstitium; this was associated with disorganization of the extracellular matrix and the appearance of a translucent ground substance in stroma. Mast cells were not seen in the mononuclear infiltrates in the later stages of thyroiditis. In order to further study the effect of mast cells on the extracellular matrix, we evaluated the effect of mast cell lysate and purified chymase on the matrix of cultured thyroid cells. Mast cells were obtained from peritoneal cavity; mast cell chymase was purified by anion exchange chromatography. After exposure to chymase there was a reduction of pericellular fibronectin in cultured thyroid cells, while laminin in matrix remained unchanged. Similarly, as found by gel electrophoresis, soluble fibronectin and vitronectin were digested by chymase in the reaction mixture. Cell attachment on both fibronectin and vitronectin was significantly decreased upon exposure of matrix proteins to chymase. The effects of chymase were abolished by enzyme inhibitor phenylmethane sulfonyl fluoride. These data suggest that mast cells possess proteolytic enzymes capable of digesting different host proteins which may have a role in the thyroid cell interaction with the surrounding matrix.

Animals↗
PubMed2004

Transgenic mice producing major histocompatibility complex class II molecules on thyroid cells do not develop apparent autoimmune thyroid diseases.

The expression of major histocompatibility complex (MHC) class II molecules on thyrocytes has been demonstrated in autoimmune thyroid diseases. However, the role of this aberrant MHC class II in disease development is controversial. In particular, it remains unknown whether MHC class II expression on thyrocytes, which are nonprofessional antigenpresenting cells, plays a role in inducing autoimmune processes. To clarify this issue, we have produced transgenic mice harboring an MHC class II gene ligated to the promoter of the rat TSH receptor. We obtained three lines of transgenic mice, and the expression of MHC class II by the thyrocytes was demonstrated by immunofluorescence staining and flow cytometry. Our examination revealed no obvious abnormalities in thyroid histology or in thyroid autoantibody production in these transgenic mice. Although serum-free T(4) levels were slightly lower than those of their nontransgenic littermates, no transgenic mouse suffered from clinical hypothyroidism or hyperthyroidism. Furthermore, thyroid lymphocytic infiltration was absent, and MHC class II-expressing thyrocytes obtained from transgenic mice failed to stimulate the proliferation of autologous T cells in vitro. Taken together, these results show that transgenic mice with MHC class II molecules on their thyrocytes do not develop apparent autoimmune thyroid diseases, suggesting that aberrant MHC class II expression alone is not sufficient to induce thyroid autoimmunity.

Animals↗
PubMed1978

Metabolism of thyroid hormones by rat thyroid tissue in vitro.

Rat thyroid lobes or hemilobes have been incubated in Krebs-Ringer phosphate buffer containing labeled T4 and/or T3, and the products were separated by paper chromatography. Labeled T4 was actively degraded; about half of the T4 metabolized was recovered as T3. Labeled T3 was also metabolized, but less rapidly than T4. Other than T3 produced from T4, the major products from both hormones were inorganic iodide and iodoprotein; the latter was presumably a secondary product of iodide organification because its formation was inhibited by hypoxia and methimazole. Feeding the animals a low iodine diet increased their hormone-metabolizing activity. Incubation under nitrogen did not affect the rate of T4 degradation, but partially inhibited T3 degradation. Degradation of both hormones was unchanged in the presence of methimazole and ascorbate, was markedly inhibited by 1 mM propylthiouracil (PTU), and was partially inhibited by azide and cyanide. Thyroid tissues concentrated both hormones, tissue to medium gradients averaging 5.4 for T4 and 20.7 for T3; none of the conditions affecting hormone degradation (incubation under nitrogen or with azide, cyanide, or PTU) significantly altered these gradients. It is concluded that the thyroid can metabolize both of its major hormones by a system distinct from thyroidal peroxidase. Hormone metabolism, therefore, is a potentially important factor in net hormone secretion. In its resistance to hypoxia, methimazole, and ascorbate and its sensitivity to PTU, the thyroid's system for generating T3 from T4 resembles T3-forming systems of liver and kidney. The thyroid, because T3 formation is its dominant pathway for T4 metabolism, may provide a useful model for study of this reaction.

Animals↗
PubMed1985

Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function.

Embryonic tissues were obtained from normal (C) and thyroidectomized (T) rats between 9 and 21 days of pregnancy. We determined the number and weight, as well as the T4 and T3 contents (RIA), of 9- to 12-day-old embryotrophoblasts, of 13- to 21-day-old embryos and placentas, and of liver, lung, and brain from 20- and 21-day-old fetuses. T4 and T3 were found in all samples obtained from C dams, both before and after onset of fetal thyroid function. Despite low levels of both iodothyronines in fetal plasma near term, their concentrations in fetal brain and lung had reached half the maternal values. The T3/T4 ratio in fetal organs was the same, or higher, than in adult rats. Maternal thyroidectomy resulted in a marked decrease of the number and individual weights of viable conceptuses, throughout gestation. Fetal organ weights near term were also decreased, and changes were found in brain DNA and protein concentrations. T4 and T3 were undetectable in all embryotrophoblasts, embryos and placentas obtained from T dams before onset of fetal thyroid secretion. They were still markedly reduced in 21-day-old placentas. Total extrathyroidal contents of T3 and T4 in 20- and 21-day-old fetuses from T dams were also low as compared to those from normal mothers, but individual organs were not affected to the same degree. Thus concentrations were decreased in the carcass (whole embryo minus the trachea + thyroid + liver + lung + brain), but normal in the brain. These results show that maternal hypothyroidism is accompanied by thyroid hormone deficiency of the conceptus before the fetal thyroid functions. After this, alterations of T4 and T3 concentrations persist until term. Development is also delayed. Thus, adverse effects of maternal hypothyroidism may be due, at least in part, to the thyroid hormone deficiency of the embryonic tissues, and not only to the hypothyroid condition of the mother.

Animals↗
PubMed1986

Binding of thyroid hormones to nuclear extracts of thyroid cells.

Binding of T3 and T4 to soluble nuclear extracts of FRTL-5 cells, rabbit thyroid glands, and rat liver was studied. [125I]Iodo-T3 or [125I]iodo-T4 in concentration ranges of 100-fold (10-fold on each side of measured Kd) was incubated with extract at 4 C, pH 8.2, and the quantity of bound hormone was determined by collection on nitrocellulose filters. The results were corrected for nonspecific binding. Steady state (equilibrium) binding was achieved by 36 h. Apparent dissociation constants (Kd) were determined from Scatchard analysis of data pertaining to extent of binding at 36 h as a function of hormone concentration and were also calculated from kinetics of binding as the ratio of rate constants. A single class of saturable, high affinity hormone-binding sites was found. Kd values for T3 and nuclear extracts of FRTL-5 cells, rabbit thyroid gland, and rat liver were, respectively, 3.9 X 10(-11) M, 2.8 X 10(-11) M, and 4.3 X 10(-11) M from Scatchard analysis; when calculated from kinetics of hormone association, the value was 3.6 X 10(-11) M for both FRTL-5 cell and rat hepatic nuclear extract. No analysis of the time course of binding of T3 to rabbit thyroid nuclear extract was made. Kd values for T4 and FRTL-5 cell extract were 6.2 X 10(-10) M from Scatchard analysis and 5.0 X 10(-10)M from kinetic data. Half-times (t1/2) of dissociation of T3 from FRTL-5 cell and rat liver nuclear extract, calculated from association curves, were 7 and 5 h, respectively, while corresponding values determined directly and experimentally were 10.5 and 13 h. For T4 and FRTL-5 cell extract, the t1/2 of dissociation calculated from kinetics of association was 5 h; no direct experimental determination of the value was made. Numbers of T3-binding sites of FRTL-5 cell, rabbit thyroid gland, and rat liver nuclear extracts were, respectively, 71 X 10(-15), 62 X 10(-15), and 208 X 10(-15) mol/mg protein. For T4 and FRTL-5 cell extract, the value was 70 X 10(-15) mol/mg protein. The data indicate that the reaction of T3 and T4 with the various nuclear extracts can be described as reversible and bimolecular. The presence in thyroid cells of thyroid hormone nuclear binding sites suggests that they may be receptors that mediate cellular actions of these hormones within the gland itself.

Animals↗
PubMed1995

Assessment of transcript polyadenylation by 3' RACE: the response of epidermal growth factor messenger ribonucleic acid to thyroid hormone in the thyroid and submaxillary glands.

The complementary DNA (cDNA) sequence of epidermal growth factor (EGF) indicates that its 3' untranslated region (3' UTR) is 745 bases long, with polyadenylation occurring at residue 4749. However, when we used reverse transcriptase-polymerase chain reaction (RT-PCR) with an anchored 3' primer [3'rapid amplification of cDNA ends (RACE)] to amplify the 3' ends of cDNA, we actually detected two major products [800 and 600 base pairs (bp)] and a minor product (400 bp) in the thyroid or submaxillary glands (SMGs) of male mice. Analysis of genomic DNA with a battery of primer pairs gave only the predicted PCR products from the 3' UTR, demonstrating the lack of introns in this region of genomic DNA and eliminating alternate splicing as the explanation of the transcript diversity we detected. We confirmed that two potential polyadenylation sites proximal to residue 4749 are used in vivo by hybridizing the same 3' RACE products with probes specific for the 5' end of the 3' UTR, and also for poly-A tails. To assess the distribution of poly-A tail lengths on transcripts using the terminal polyadenylation site (4749), we used several different approaches to analyze 3' RACE products. Solution hybridization with 3' UTR probes revealed a striking difference between transcripts in SMG and thyroid: SMG contained two large 3' RACE populations (approximately 770 and 870 bp), whereas thyroid only contained one (approximately 770 bp). EGF transcript heterogeneity due to different poly-A tail lengths was confirmed using an upstream primer 400 bases closer to the 3' end of the 3' UTR, and TaqI digestion. Again we found two major populations in SMG (approximately 380 and 480 bp), but only one (380 bp) in thyroid, which upon TaqI digestion showed tissue-specific heterogeneity only in the 3' fragment. T4 treatment of male mice (0.25 microgram T4/gm ip) increased the intensity of both populations in SMG and the smaller population in thyroid within 24 h. However, after a week of T4 injections, only the intensity of the population with the longer poly-A tails in the SMG remained elevated, a finding consistent with tissue-specific enhanced stability of transcripts due to polyadenylation. Finally, to resolve poly-A tail lengths more precisely, we used an upstream primer that was specific for the 3' end of murine 3' UTR. This approach revealed that the thyroid contains three major populations of EGF transcripts, with poly-A tail lengths of approximately 20, 50, and 70 A's. After T3 treatment for 24 h, the intensity of transcripts containing 20 A's increased 52% (P < 0.02) and those with 50 A's increased 130% (P < 0.01), whereas there was no change in transcripts with tails > or = 70 A's. On the other hand, there were no distinct bands in SMG samples, but rather a heterogeneous distribution of poly-A tail lengths from approximately 20-120 A's that showed an overall increase of approximately 60% in response to T3.

Alternative Splicing↗
PubMed1999

Three novel mutations at serine 314 in the thyroid hormone beta receptor differentially impair ligand binding in the syndrome of resistance to thyroid hormone.

The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone beta receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T3 concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor beta shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.

Adolescent↗
PubMed2003

Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients.

The follow-up of patients with papillary and follicular thyroid carcinoma after thyroidectomy and radioiodine ablation is mainly based on serum thyroglobulin (Tg) level deter-mination. The positive predictive value (PPV) of serum Tg level after thyroid hormone withdrawal, measured during the first 6-12 months of follow-up (initial off L-T(4) Tg), was studied in 256 consecutive differentiated thyroid cancer patients. All underwent a total thyroidectomy and 3.7 GBq (131)I ablation; 37 patients had an elevated initial off L-T(4) Tg level. This study focuses on these 37 patients, 9 of whom had a clinical recurrence. The present data confirm that in this selected cohort of patients, 74-185 MBq (131)I-total body scan (TBS) has no clinical interest in the initial work-up and during the subsequent follow-up because it was negative in all patients, except in one with recurrent disease. The PPV of initial serum off L-T(4) Tg level above 5 ng/ml and 10 ng/ml was 42% and 53%, respectively; this PPV was only 50% at the time of recurrence or subsequent control. This relatively low PPV is related to the low recurrence rate in this series of patients, despite a prolonged follow-up, and to the subsequent decrease of serum Tg level in 14 of 37 (38%) patients in the absence of any further treatment. In contrast, the PPV of the increasing slope of serum Tg levels obtained after thyroid hormone withdrawal (83%) was excellent. In conclusion, we confirm that (131)I-TBS has a limited interest for the follow-up of thyroid cancer patients. Follow-up should rely on serum Tg level and prognostic parameters; however, initial serum Tg may be produced by thyroid tissues of various significance, an increase at two consecutive determinations indicating disease progression and a decrease being related to late effects of therapy. The best PPV is brought by the slope of serum Tg levels.

Adenocarcinoma, Follicular↗
PubMed2006

Meta- and reanalysis of gene expression profiles of hot and cold thyroid nodules and papillary thyroid carcinoma for gene groups.

CONTEXT: There are an increasing number of studies analyzing gene expression profiles in various benign and malignant thyroid tumors. This creates the opportunity to validate results obtained from one microarray study with those from other data sets. This process requires rigorous methods for accurate comparison. OBJECTIVE: The ability to compare data sets derived from different Affymetrix GeneChip generations and the influence of intra- and interindividual comparisons of gene expression data were evaluated to build multigene classifiers of benign thyroid nodules to verify a previously proposed papillary thyroid carcinoma (PTC) classifier and to look for molecular pathways essential for PTC oncogenesis. METHODS: Gene expression profile data sets from autonomously functioning and cold thyroid nodules and from PTC were analyzed by support vector machines. GenMAPP analysis was used for PTC data analysis to examine the expression patterns of biologically relevant gene sets. RESULTS: Only intraindividual reference samples allowed the identification of subtle changes in the expression patterns of relevant signaling cascades, such as the MAPK pathway in PTC. Using an artificial intelligence approach, the autonomously functioning and cold thyroid nodule multigene classifiers were derived and evaluated by cross-comparisons. CONCLUSION: We recommend defining classifiers within one generation of gene chips and subsequently checking them across different array generations. Using this approach, we have demonstrated the specificity of a previously reported PTC classifier on an independent collection of benign tumors. Moreover, we propose multigene classifiers for different types of benign thyroid nodules.

Algorithms↗
PubMed2006

Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules.

CONTEXT: Routine serum calcitonin (CT) measurement in patients with thyroid nodules for diagnosis of medullary thyroid carcinoma (MTC) is controversial. OBJECTIVE: The objective of this study was to evaluate the diagnostic accuracy of systematic CT measurement in non-multiple endocrine neoplasia type 2 patients with nodular thyroid disease. SETTINGS: This study was conducted at a national healthcare system hospital (outpatient and inpatient sectors). SUBJECTS: Consecutive patients with nodular thyroid disease (n = 5817) were studied. MAIN OUTCOME MEASURES: Serum CT levels were measured under basal conditions, and when basal values were more than or equal to 20 and less than 100 pg/ml, testing was repeated after pentagastrin stimulation. Basal or stimulated levels more than 100 pg/ml were indication for surgery. RESULTS: Fifteen cases of MTC and seven of C cell hyperplasia (CCH) were identified. MTCs were diagnosed in all patients with basal CT more than 100 pg/ml. The four patients with basal CT more than or equal to 50 and less than 100 pg/ml included two diagnosed with MTC and two with CCH. In 10 patients with basal levels more than or equal to 20 and less than 50 pg/ml, histology confirmed the presence of MTC in four, four others had CCH, and the remaining two were negative for thyroid malignancy. Positive predictive values for basal CT levels in the preoperative diagnosis of MTC were: 23.1% for values more than or equal to 20 pg/ml, 100% for values more than 100 pg/ml, 25% for levels more than or equal to 50 and less than 100 pg/ml, and 8.3% for values more than or equal to 20 and less than 50 pg/ml. Positive predictive values for the pentagastrin test (>100 pg/ml) were 40% in the entire series. CONCLUSIONS: CT screening of thyroid nodules is a highly sensitive test for early diagnosis of MTC, but confirmatory stimulation testing is necessary in most cases to identify true positive increases.

Adolescent↗