Thyroid carcinoma is a common endocrine cancer with a favorable prognosis if subjected to timely treatment. However, the clinical identification of follicular thyroid carcinoma (FTC) among patients with benign thyroid nodules is still a challenge. Preoperative fine needle aspiration-based cytology cannot always differentiate follicular carcinomas from benign follicular neoplasias. Because current methods fail to improve preoperative diagnosis of thyroid nodules, new molecular-based diagnoses should be explored. We conducted a microarray-based study to reveal the genetic profiles unique to FTC and follicular adenomas (FAs), to identify the most parsimonious number of genes that could accurately differentiate between benign and malignant follicular thyroid neoplasia. We confirmed our data by quantitative RT-PCR and immunohistochemistry in two independent validation sets with a total of 114 samples. We were able to identify three genes, cyclin D2 (CCND2), protein convertase 2 (PCSK2), and prostate differentiation factor (PLAB), that allow the accurate molecular classification of FTC and FA. Two independent validation sets revealed that the combination of these three genes could differentiate FTC from FA with a sensitivity of 100%, specificity of 94.7%, and accuracy of 96.7%. In addition, our model allowed the identification of follicular variants of papillary thyroid carcinoma with an accuracy of 85.7%. Three-gene profiling of thyroid nodules can accurately predict the diagnosis of FTC and FA with high sensitivity and specificity, thus identifying promising targets for further investigation to ultimately improve preoperative diagnosis.

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With the increasing cure rate of patients treated for Hodgkin's and non-Hodgkin's lymphoma, the evaluation of late effects on gonadal function remains an important issue. The gonadal function of relapse-free long-term survivors with high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) were studied; 24 of 119 patients with NHL treated between 1980 and 1990 and 66 of 364 patients with HD treated between 1975 and 1990 at Hannover University Medical School, who were younger than 45 years of age and in complete remission at the time of evaluation for at least 24 months after completion of therapy, were included into the analysis. Of 24 patients with NHL, 1/10 women (10%) and only 3/14 men (21%) showed signs of gonadal dysfunction. Three of these four patients had been treated with combined modality therapy followed by maintenance COP chemotherapy, resulting in high cumulative doses of cyclophosphamide (range: 12-43 g). In comparison, 13/26 (50%) women with HD suffered from premature ovarian failure, and 26/40 (65%) men showed signs of gonadal dysfunction with significant FSH elevations. No significant difference in the incidence of gonadal toxicity existed in patients treated with combined modality who received irradiation to either supra- or infradiaphragmatic radiation fields in combination with chemotherapy (70% versus 62%). A comparison of the chemotherapy regimens used in patients with NHL or HD shows that patients from both groups had received comparable median cumulative doses of cyclophosphamide, vincristine, and adriamycin, but only patients with HD had additionally received a median cumulative dose of 13.3 g of procarbazine per patient. A tendency towards a higher incidence of gonadal toxicity with higher cumulative doses of procarbazine received was found in patients with HD. The frequency of gonadal dysfunctions is markedly lower in patients treated for non-Hodgkin's lymphoma than in patients treated for Hodgkin's disease, approximately half of whom will be affected by long-term gonadal toxicity. Although the use of more intensive radiotherapy in patients with HD compared with NHL patients makes the evaluation of the influence of radiotherapy on gonadal toxicity more difficult, the current retrospective analysis raises the concern that, in addition to infradiaphragmatic radiotherapy, the use of procarbazine in regimens for the treatment of HD, like COPP or MOPP, may be a possible explanation for the differences in gonadal toxicity observed between patients with HD and those with NHL. Regimens including procarbazine should be avoided in patients wanting to preserve fertility since alternative chemotherapies with at least equal efficacy are available.

Cytokines are thought to mediate the initiation and perpetuation of autoimmune thyroiditis. However, this concept is mainly based on in vitro findings and to date only interleukin (IL)-6 and interferon-gamma (IFN-gamma) have been detected in Graves' disease in vivo. The cytokine pattern produced by T-helper (Th) cells has important regulatory effects on the nature of the immune response. We therefore determined these cytokine mRNAs in Graves' disease and Hashimoto's thyroiditis. RNA was extracted by cesium chloride gradient centrifugation from the thyroid tissue of 12 patients undergoing thyroid resection for Graves' disease and from two patients being treated for Hashimoto's thyroiditis. Two patients with parathyroid adenomas and one patient with a goiter were used as controls. RNA was also extracted from normal human thyroid epithelial cells in primary culture. The cDNAs were prepared by reverse transcription and amplified for IL-2, -4, -5, -6 and -10 and IFN-gamma by polymerase chain reaction. All the cytokine mRNAs were detected in the Hashimoto's thyroid glands in large quantities. Six of the 12 Graves' disease thyroid glands showed, when compared with controls, an increased accumulation of transcripts for: IFN-gamma, IL-2, -4 and -10 or IL-2, -4 and IFN-gamma or IL-2 and IFN-gamma or IFN-gamma alone, each in one case or IL-2 alone in two cases. These cytokine profiles were not representative of a Th1 or Th2 phenotype. Increased amounts of cytokine mRNA in thyroid glands from Graves' disease patients were mostly associated with high microsomal antibody titres and/or prominent intrathyroidal lymphocytic infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of distant metastasis is the most important predictor of death from thyroid cancer. KiSS-1 is a recently cloned human metastasis suppressor gene whose product, metastin, was recently identified as the endogenous agonist for a novel Gq/11 coupled receptor (metastin receptor). The expression and functional consequences of metastin and the metastin receptor have not been evaluated in thyroid cancer. We measured metastin and metastin receptor mRNA levels in 10 FCs and 13 papillary carcinomas (PCs), 2 benign non-functioning follicular adenomas (FAs), and 11 normal thyroid samples, and evaluated the signaling pathways activated by metastin in ARO thyroid cancer cells that express the metastin receptor endogenously. Paired normal and tumor samples were available for 4 PC and 3 PFC samples. Metastin mRNA was detected in 6/11 normal samples, and 0/2 FA, 2/10 FC, and 9/13 PC samples (p < 0.05 for PC vs. FC). Metastin receptor was not expressed in any normal thyroid or benign FA samples, and was expressed in only a minority (2/10) of FC samples. However, the receptor was expressed in the majority (10/13) of PCs (p = 0.002 for PC vs. normal tissue). Increased levels of metastin receptor were detected in all four PCs compared to adjacent normal tissue. Incubation levels of metastin receptor were detected in all four PCs compared to adjacent normal tissue. Incubation of metastin receptor expressing ARO thyroid cancer cells with metastin resulted in activation of ERK, but not Akt. Taken together, these data suggest a potential role for metastin and/or metastin receptors in modulating the biological behavior of thyroid cancers.

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.

The aim of the present study was to investigate the N-terminal part (the translated part of exon 1) of the human thyrotropin receptor (TSHR) for the presence of mutations. Patients with Graves' disease (n = 160) and healthy controls (blood donors; n = 140) were screened using single-stranded conformational polymorphism (SSCP) in combination with restriction enzyme digestion for the two previously known mutations in this part of the receptor, viz. D36H and P52T TSHR-variants. We did not find any novel mutation in this region. However, D36H and P52T variants were found both in the TSHR of Graves' patients and in the healthy controls. The overall frequency of the D36H-receptor variant was 5.0% (15/300) and of the P52T-receptor, 7.3% (22/300). There was no major difference in the frequency for either of the TSHR alleles between the 2 groups. Thus, these 2 polymorphic variants of the TSHR seem to occur in a relatively high frequency in the population.

This study evaluated the diagnostic value of D-dimer, CRP, and leucocytes count to detect an underlying pulmonary embolism (PE) in patients with pneumonia. A predictive model of an underlying PE, based on laboratory markers and clinical symptoms, was our ultimate objective. Overall 100 patients underwent a computed tomography angiography (CTA) of the lung: 54 with coexistence of PE and pneumonia (cases) and 46 with pneumonia without PE (controls). Cases and controls were matched 1 : 1. Symptoms and paraclinical findings were registered on admission. Receiver operating characteristic (ROC) curves, search for an optimal threshold, and conditional logistic regression analysis were conducted. D-dimer has a moderate ability to detect PE in pneumonia. Sensitivity of D-dimer was estimated at 97.78% and specificity at 11.11%. No optimal cut-point has acceptable diagnostic ability. After excluding patients with sepsis, sensitivity was reduced to 96.97%, whereas specificity increased to 16.13%. Consolidation in chest X-ray and positive D-dimer predict better an underlying PE as D-dimer itself. Thus, discriminatory power of the prediction model (AUC of 0.740) is not much greater than D-dimer (AUC of 0.703). No threshold that could increase the diagnostic value of D-dimer or a prediction model which is significantly better than D-dimer itself was identified.