Regulation of inhibitors of differentiation family proteins by thyroid-stimulating hormone in FRTL-5 thyroid cells.

Members of the inhibitors of differentiation (Id) family of helix-loop-helix (HLH) proteins are known to play important roles in the proliferation and differentiation of many cell types. Thyroid-stimulating hormone (TSH) regulates proliferation and differentiation by activating TSH receptor (TSHR) in thyrocytes. In this study, we found that Id2, one of the Id family proteins, is a major target for regulation by TSH in FRTL-5 thyroid cells. TSH rapidly increases the Id2 mRNA level in FRTL-5 thyroid cells but the Id2 protein showed biphasic regulatory patterns, being transiently reduced and subsequently induced by TSH treatment. Transient reduction of Id2 protein was noted within 2 hr of TSH treatment and was mediated by proteasomal degradation. Moreover, reduced Id2 expression correlated with the activity of the phosphatidylinositol 3 kinase pathway, which is activated by TSH. Although TSH increases the activity of the Id2 promoter, TSH-induced activation of this promoter was independent of c-Myc. Id2 did not alter TTF-1- and Pax-8-mediated effects on the regulation of the Tg promoter. Thus, in summary, we found that TSH regulates Id2 expression, but that Id2 does not alter the expression of thyroid-specific genes, such as Tg, in FRTL-5 thyroid cells.

Significance of the expression of major histocompatibility complex class II antigen, HLA-DR and -DQ, with recurrence of papillary thyroid cancer.

Normal thyroid epithelial cells lack major histocompatibility complex (MHC) Class II antigen. Oncogenic kinases involved in papillary thyroid carcinoma (PTC) trigger the expression of Class II transactivator and MHC Class II complex. However, the relationship between MHC Class II antigen expression and clinical outcome in PTC is unknown. To investigate the frequency of MHC Class II antigen expression in PTC and to identify the effects of MHC Class II antigen expression on clinical outcomes in PTC patients, the expression of HLA-DR/-DQ antigen was analyzed in surgical specimens from 77 PTCs and 44 benign nodules (23 nodular hyperplasias, 21 follicular adenomas). Of the 77 PTC cases, 36 (46.8%) cases expressed HLA-DR and 41 (53.2%) cases expressed HLA-DQ. Next, we investigated clinicopathological characteristics and found that HLA-DR(+) and/or HLA-DQ(+) PTC tended to present without nodal metastasis. Multivariate analyses clearly showed that HLA-DR(+) or HLA-DQ(+) PTC has a low risk of recurrence (HLA-DR OR = 0.22, CI, 0.06-0.9; p = 0.03, HLA-DQ OR = 0.25, CI, 0.07-0.9, p = 0.03). The Kaplan-Meier estimate revealed a significantly lower recurrence-free probability in patients with HLA-DR(-) PTC and HLA-DQ(-) PTC (Log-rank test; chi(2) = 4.59 and 6.07, p = 0.03 and 0.01, respectively). In conclusion, PTC frequently expresses MHC Class II antigen, and the expression of MHC Class II antigen correlated inversely with the risk of recurrence of PTC.

Predictive value of the preablation serum thyroglobulin level after thyroidectomy is combined with postablation 131I whole body scintigraphy for successful ablation in patients with differentiated thyroid carcinoma.

OBJECTIVES: To investigate the clinical importance of the combined use of serum thyroglobulin (Tg) levels measured just before ablation (ablation-Tg) and postablation 131I whole body scintigraphy (WBS) patterns for predicting ablation success in patients with differentiated thyroid carcinoma who received total thyroidectomy and 131I ablation therapy. METHODS: We retrospectively studied the early clinical outcomes for 81 differentiated thyroid carcinoma patients treated with total thyroidectomy and high-dose 131I ablation therapy between June 2001 and July 2004. RESULTS: Ablation success was achieved in 42 (97.7%) of the 43 patients with uptake in the thyroid bed only and ablation-Tg levels less than 10 ng/mL, whereas successful ablation was achieved in 9 (75.0%) of the 12 patients with uptake in the thyroid bed only and ablation-Tg levels equal to or greater than 10 ng/mL (P = 0.029). Among 15 patients with uptake including a lymph node and ablation-Tg levels less than 10 ng/mL, 14 patients (93.3%) showed ablation success, whereas successful ablation was achieved in only 2 (18.2%) of the 11 patients with uptake including a lymph node and ablation-Tg levels equal to or greater than 10 ng/mL (P < 0.001). CONCLUSIONS: These data indicate that the combined use of serum Tg levels measured just before ablation and the 131I WBS patterns after ablation may be an early predictor of ablation success in patients with differentiated thyroid carcinoma who received total thyroidectomy and high-dose 131I ablation therapy.

An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.

CONTEXT: The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC. OBJECTIVE: The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC. DESIGN: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells. RESULTS: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1. CONCLUSION: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer.

CONTEXT: The BRAF mutation may influence the expression patterns of molecular markers that are related to the development and progression of thyroid cancer. OBJECTIVE: The objective of the study was to investigate the effects of the BRAF V600E mutation on expression of galectin-3, cyclooxygenase-2, cyclin D1, p53, and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC). DESIGN, SETTING, AND SUBJECTS: One hundred sixty-three PTC and 28 nodular hyperplasia patients were selected retrospectively. The presence of the BRAF V600E mutation and the level of expression of the molecular markers were determined. RESULTS: Of 161 PTC patients, 102 patients (63.4%) were BRAF V600E(+), and these cases had significantly larger tumor sizes (P = 0.01), compared with V600E(-) cases (n = 59, 36.6%). Although PTC tissues had higher expression levels of the selected molecular markers than nodular hyperplasia tissues, expression levels of several molecular markers in BRAF V600E(+) PTC were not significantly different from those of BRAF V600E(-) PTC. But VEGF was significantly up-regulated in BRAF V600E(+) PTC, compared with BRAF V600E(-) PTC. VEGF expression levels were strongly positively correlated to tumor size (P < 0.001), extrathyroidal invasion (P = 0.02), and tumor stage (P = 0.04). Multivariate analysis clearly showed that VEGF expression was up-regulated in BRAF V600E(+) PTC (odds ratio 2.5, confidence interval 1.1-5.6; P = 0.03). CONCLUSIONS: BRAF V600E(+) PTC tended to have larger tumor volumes and higher expression of VEGF. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. The relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.

Lymphocytic hypophysitis with diabetes insipidus: improvement by methylprednisolone pulse therapy.

Lymphocytic hypophysitis is a rare inflammatory disorder in the pituitary gland. The lesion is usually confined to the adenohypophysis. Although the involvement of the posterior pituitary gland or the stalk is rare, such patients with diabetes insipidus have been reported. Surgery has been used to make the definitive diagnosis. Recent studies suggest, however, that the pathologic diagnosis may not be necessary always. We reported a case of Lymphocytic hypophysitis managed by methylprednisolone pulse therapy. A 50-year-old premenopausal woman with Lymphocytic hypophysitis and diabetes insipidus was treated with methylprednisolone pulse therapy. Her adenopituitary lesion disappeared and the diabetes insipidus resolved. The optimal management for patients with lymphocytic hypophysitis may be the high index of the suspicion prior to the extensive surgical resection. In addition, methylprednisolone pulse therapy may improve the clinical and MRI findings.