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Yukiko Yano, Hiroshi Shibuya, Wataru Kitagawa, Mitsuji Nagahama, Kiminori Sugino, Kunihiko Ito, and Koichi Ito

Objective: The objective was to evaluate the clinical behavior and outcome of 202 papillary thyroid cancers in Graves’ disease patients during the period 1994–2004.

Design: This was a retrospective, non-randomized case–control study.

Methods: Since 1994, we have included an ultrasonogram of the neck in the initial examination of thyroid disease patients who consult our outpatient clinic. We evaluated the tumor status and long-term outcome of Graves’ disease patients with thyroid cancer and of age- and tumor size-matched euthyroid papillary thyroid cancer patients as controls. Serum TSH receptor antibody (TRAb) was measured in the Graves’ disease group.

Results: A total of 154 papillary thyroid cancers were diagnosed in the Graves’ disease patients and were treated surgically. At surgery, no significant differences in multifocality, lymph node metastasis, or distant metastasis were found between the Graves’ disease group and the euthyroid group. On the whole, the clinical course of the cancers in both the Graves’ disease group and euthyroid group was relatively good. No significant correlations were found between the TRAb levels in the Graves’ disease group and multifocality or the presence of lymph node metastasis. Papillary thyroid cancer was discovered as an incidental finding in 2% of the 2356 surgically treated Graves’ disease patients, but none of them developed metastasis during the follow-up period.

Conclusion: The results in this series of patients do not support the claim that thyroid cancer is more aggressive in Graves’ disease patients than in euthyroid patients.

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Akimasa Okuno, Koichi Yano, Fumie Inyaku, Yutaka Suzuki, Nobutaka Sanae, Megumi Kumai, and Yoshihiro Naitoh

Abstract. Methimazole concentrations in plasma and in the thyroid glands were measured by means of high-performance liquid chromatography. Pharmacokinetics of methimazole were studied after a single oral dose (175 μmol/m2) in nine children and adolescent who were in the thyrotoxic state. Plasma levels of methimazole showed peak concentrations of 4.4 to 12.6 (median 9.2) μmol/l at 0.5 to 4 h after drug administration. Plasma half-life, area under the curve, and distribution volume ranged from 2.73 to 6.04 h, 32.8 to 77.9 μmol · l−1 · h−1, and 0.516 to 0.913 l/kg, respectively. These pharmacokinetic parameters showed a wide variation among the patients, but were quite reproducible in the same subject. Intrathyroidal concentrations of methimazole were measured in another nine subjects including four adolescents and five adults who underwent thyroidectomy. The drug concentrations in the thyroid glands ranged between 3.5 and 23.8 μmol/kg tissue and were far higher than those in the plasma obtained at the time of surgery. In this series of experiments, the dose of the drug varied from 76 to 319 μmol/m2, time after the last dose to surgery from 5 to 24 h, and the mode of drug administration from a single to three divided doses. Among these variable factors, only the daily dose of methimazole corrected by body surface area showed significant correlation with the intrathyroidal concentration, whereas the time after the last dose of the drug and the mode of drug administration did not. Our results revealed that methimazole was concentrated in the thyroid gland and that the intrathyroidal concentrations were maintained for 16 to 24 h in spite of a short plasma half-life. It is suggested that a single daily dose of methimazole is adequate for the treatment of Graves' disease in children and adolescents.

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Shigeru Suzuki, Kumihiro Matsuo, Yoshiya Ito, Atsushi Kobayashi, Takahide Kokumai, Akiko Furuya, Osamu Ueda, Tokuo Mukai, Koichi Yano, Kenji Fujieda, Akimasa Okuno, Yusuke Tanahashi, and Hiroshi Azuma

Background: POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and GH, PRL and TSHB expression, and the alternatively spliced isoform PIT-1β, which contains an insertion of 26-amino acids (β-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1β is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although POU1F1 mutations lead to combined pituitary hormone deficiency (CPHD), no patients with β-domain mutations have been reported.

Results: Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel POU1F1 heterozygous variant (c.143-69T>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>G (p.Ile51Ser) in exon 2 of PIT-1β (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1β transcript without other transcripts. Lymphocyte PIT-1β mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1β-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells.

Conclusions: We describe, for the first time, that PIT-1β mutation can cause CPHD through a novel genetic mechanism, such as PIT-1β overexpression, and that POU1F1 mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1β mutations.