In this review, we focused on the patient age as an indicator of tumor growth and prognostic significance in both clinical papillary thyroid carcinoma (PTC) and subclinical papillary microcarcinoma (PMC: PTC ≤ 1 cm). In clinical PTC, young age (< 30 years) and old age (≥ 60 years) significantly affected the disease-free survival of patients, and old age was a strong predictor of carcinoma death. In contrast, in subclinical PMC, growth activity significantly decreased with patient age, and young age (< 40 years) was an independent predictor of carcinoma growth, indicating that old patients with subclinical PMC are the best candidates for observation without immediate surgery. Taken together, our findings indicate that the role of patients’ age as an indicator of tumor growth differs significantly between clinical PTC and subclinical PMC.

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Elevated serum ferritin levels are associated with insulin resistance, type 2 diabetes, cardiovascular disease, and metabolic syndrome. To date, however, no cohort studies have examined whether serum ferritin levels are an independent risk factor for the obesity. Therefore, we conducted a prospective cohort study to evaluate the temporal relationship between serum ferritin levels and obesity development in Korean men. Total 17,812 healthy Korean men who participated in a medical health check-up program in 2005 were followed-up until 2010. Obesity was defined as a body mass index ≥25 kg/m². Cox proportional hazards model was used to measure the hazard ratio of the quartile groups of serum ferritin levels. During 64,446.5 person-years of follow-up carried out, 2,627 patients became obese. After adjusting for multiple covariates, we found that the hazard ratios (95% confidence interval) for incident obesity when we compared the second, third and fourth quartiles of serum ferritin levels with the first quartile were 1.08 (0.95-1.23), 1.14 (1.00-1.30), and 1.24 (1.09-1.41), respectively (p for trend = 0.003). Both severe obesity (body mass index ≥ 30 kg/m²) and abdominal obesity based on waist circumference (>90 cm) showed consistent longitudinal associations (p for trend <0.001). Elevated serum ferritin levels may have been a predictive factor for obesity during the 5-year follow-up in 17,812 Korean men.

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We evaluated the efficacy of technetium-sestamibi (^99m Tc-MIBI) SPECT/CT for planning parathyroidectomy in cases with primary hyperparathyroidism (pHPT), comparing with planar scintigraphy and ultrasound (US), in an aim to establish the proper surgical strategy according to the preoperative imaging studies. A retrospective review of consecutive 75 pHPT patients who had been operated on was conducted. The results of preoperative imaging modalities and the operative finding were analyzed. Seven cases were found to have multiple hyperplastic glands, and no responsible gland was found in three cases. Four cases underwent only US scan for preoperative imaging. Remaining 61 cases were found to have single adenoma, and were included in the evaluation of localization imaging. US scan, ^99m Tc-MIBI planar scan and ^99m Tc-MIBI SPECT/CT showed accurate localization in 77.0% (47/61), 75.4% (46/61) and 88.5% (46/52) of the evaluable cases, respectively. US and ^99m Tc-MIBI planar scan demonstrated consistent result in 42 cases (68.9%), and those cases showed accurate localization in 90.5% (38/42). When both US and ^99m Tc-MIBI SPECT/CT was consistent, all 37 lesions had been correctly indicated. No clinico-pathological features were suggested to influence in demonstrating the localization, other than only ^99m Tc-MIBI SPECT/CT exhibited 100% sensitivity in ectopic glands. Combination of US and ^99m Tc-MIBI SPECT/CT certainly contributes to the planning of minimally invasive operation in cases with pHPT by indicating correct localization of single adenoma.

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Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play important roles in maintaining bone metabolism and bone mineral density (BMD) in adulthood, in addition to stimulating longitudinal bone growth in childhood. However, information on the effect of GH excess on bone metabolism and BMD is incomplete and requires further analysis. The aim of this study is to clarify the effect of rapid decline in GH levels after transsphenoidal surgery (TSS) on bone metabolism in acromegalic patients. In this prospective study, 22 patients (11 males and 11 females) with active acromegaly underwent TSS. Bone formation marker (serum bone alkaline phosphatase: BAP), bone resorption marker (urinary type I collagen cross-linked N-telopeptide: urinary NTx) and BMD were measured before and at 3 and 12 months after TSS. BAP was significantly decreased at 12 months after TSS, but not at 3 months. Urinary NTx was significantly decreased at 3 and 12 months after TSS. BMD did not change after TSS. In conclusion, the rapid fall in GH level after TSS had no effect on BMD for up to 12 months after TSS despite the decrease in markers of bone formation and resorption.

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Some published criteria for intraoperative monitoring of PTH serum concentrations may cause misleading results, since the timing of samples measured between the pre-incision and pre-excision phase of surgery is often unrecorded. In our opinion this information is critical, as the time of an intermediate sample during surgical manipulation may represent the “true” beginning of the PTH decay. We modified the usual criterion of monitoring (cut-off at 10 minutes after clamping) proposing a further check at manipulation in case the primary check at clamping produces an apparently negative result. On the basis of a mathematical model, false negative curves were simulated by means of a time shift. This shift was assumed to be the interval between manipulation and clamping. Analysing the decay curve, we used the 50% cut-off at 10 minutes after the supposed “true” origin (clamping or manipulation). Using a rapid immunochemiluminometric assay (ICMA), data were collected from 22 patients successfully operated for parathyroid adenoma. The check at clamping correctly diagnosed 13 patients. Among the 9 false negative cases, 6 were correctly diagnosed considering the manipulation as the baseline value. In the remaining 3 patients, diagnosis required prolonged observation of the curves. In case the iPTH decay does not follow the expected curve, it can be useful to check the decay normalising to a pre-excision value. The advantages of our criterion are both the prompt recognition of false negative results and the construction of a “true” decay curve for each patient, supporting the surgeon during the excision of hyperfunctioning parathyroid tissue.

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We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY_1-36 and PYY_3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.

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Oxidative stress has detrimental effects on bone metabolism, and gamma-glutamyl transferase (GGT) is known to play an important role in the generation of free radical species through the extra-cellular hydrolysis of glutathione, the main cellular antioxidant. We performed a large longitudinal study with an average follow-up period of 3 years to investigate the association between baseline serum GGT levels and the development of future osteoporotic fractures (OFs) in men. A total of 16,036 Korean men aged 50 years or older who had undergone comprehensive routine health examinations were enrolled. Incident fractures at osteoporosis-related sites (e.g., hip, spine, distal radius, and proximal humerus) that occurred after baseline examinations were identified from the nationwide claims database of the Health Insurance Review and Assessment Service of Korea using selected ICD-10 codes. Among the study subjects, 156 cases (1.0%) developed incident OFs during the study period. The event rate was 32.7 (95% CI = 28.0-38.3) per 10,000 person-years. Multivariable adjusted Cox proportional hazard analyses adjusted for age, body mass index, lifestyle factors, and medical and drug histories revealed that the hazard ratio per standard deviation increase of the baseline GGT levels for the development of incident fractures was 1.115 (95% CI = 1.011-1.230). These data provide the first epidemiological evidence, in support of previous in vitro and animal studies, of the harmful effects of GGT on bone metabolism, and indicate that the serum GGT level may be a useful biomarker of poor bone health outcomes in men.

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Follicular thyroid carcinoma (FTC) is the second most common malignancy arising from follicular cells. It is classified into two categories based on the degree of invasion: widely and minimally invasive FTC. Here we focused on the prognostic value of patient age in FTC. We enrolled 292 minimally invasive and 79 widely invasive FTC patients who underwent initial surgery between 1983 and 2007. We classified these patients into three groups based on patient age: < 20 years (children and adolescents), 20-44 years (young adults) and ≥ 45 years (middle-aged or older), and compared their prognoses disease-free survival (DFS) and cause-specific survival (CSS). Among the minimally invasive FTC patients, those aged ≥ 45 years showed a poorer DFS and CSS than those < 45 years. In the subset of patients < 45 years, the DFS of patients < 20 years tended to be poorer than those aged 20-44 years, but none of the patients < 20 years died of FTC. Among the patients with widely invasive FTC, only three were younger than 20 years old. Two patients showed carcinoma recurrence, but neither died of FTC. In minimally invasive FTC, the DFS showed a biphasic pattern, but the CSS became poorer with increasing age. In widely invasive FTC, similar to minimally invasive FTC, patients < 20 years might be likely to show recurrence but are unlikely to die of FTC, although studies using larger number of patients are necessary before drawing any conclusions.

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Follicular thyroid carcinoma (FTC) usually has a good prognosis unless there is distant metastasis (DM). In this retrospective study we evaluated the outcome of FTC patients with DM and attempted to identify prognostic factors. The subjects of this study were the 106 of FTC patients who underwent thyroidectomy at our hospital between 1989 and 2010 who had been diagnosed with DM at presentation or had developed DM after the initial surgery. Their cumulative cause-specific survival (CSS) rate from diagnosis of DM to date of last follow-up was calculated by the Kaplan-Meier method. Prognostic factors were identified by univariate analysis (the log-rank test) and multivariate analysis (Cox’s proportional hazards model). The site of the DM was the lung in 36 patients, bone in 33 patients, both lung and bone in 28 patients and other sites in 9 patients. During the follow-up period, 22 patients died of their disease. The DMs were treated by radioactive iodine (RI) therapy in 80 patients, by surgical treatment in 36 patients and by external beam radiation therapy (EBRT) in 27 patients. The CSS rates at 5, 10, and 15 years after the first DM was diagnosed were 82.2%, 63.8%, and 23.9%, respectively. Univariate analyses and multivariate analysis identified age at diagnosis of DM and primary tumor size as significant factors related to CSS. In this study, we could not show RI therapy, EBRT or surgical treatment for DM had an impact on the outcome.

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Recent research has indicated a relationship between skeletal muscle mass and insulin resistance in patients with type 2 diabetes mellitus (T2DM). However, no study has examined the relationship between skeletal muscle mass and insulin secretion in patients with Japanese T2DM. This study aimed to fill this research gap by investigating the relationship between skeletal muscle mass and clinical parameters of T2DM with special reference to the effect of sex or age on the relationship. We examined 138 consecutive T2DM patients who presented at a single center. Anthropomorphic measurement was conducted and skeletal muscle mass was determined by bioelectrical impedance analysis for calculating skeletal muscle index (SMI) as the ratio of appendicular muscle mass (AMM) to total body weight. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) were levels, and values of stimulated C-peptide immunoreactivity (CPR) were determined by glucagon stimulation testing. Statistical analysis showed that AMM was negatively correlated with age in T2DM patients, whereas SMI had no correlation with either FPG or HbA1c levels. On the other hand, SMI was found to be negatively correlated with the log-transformed stimulated CPR values in male patients <65 years (r = -0.40, p < 0.05) and in female patients <65 years (r = -0.40, p < 0.05). The results of multivariate analysis suggest a strong association between the log-transformed stimulated CPR value and SMI. These findings indicate that increased endogenous insulin secretion is associated with lower skeletal muscle mass in T2DM patients who are <65 years of age.

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Recent research has revealed that genetic defects due to mutation in the Thyroid Peroxidase (TPO ) gene can lead to thyroid dysfunction in the population. We aimed to study the association between genetic defects in TPO gene and patients with hypothyroidism found in adult age. Two hundred consecutive treatment naive hypothyroid patients (age ≥ 18 years) (cases) who were negative for anti TPO antibody and their corresponding sex and age matched two hundred normal individuals (controls) were enrolled. The 17 exonic regions of the TPO gene were amplified and sequenced directly. We identified 6 different previously known single nucleotide polymorphisms (SNPs) and 2 novel deletions in TPO gene. Two of the six SNPs revealed a significant association with hypothyroidism; Thr725Pro (rs732609) and Asp666Asp (rs1126797). The c.2173C allele of the Thr725Pro in TPO showed a significant association among hypothyroid patients compared to controls (p = 0.01; Odds ratio=1.45; 95% CI: 1.09-1.92) suggesting it to be a potential risk allele toward disease predisposition. Analysis of genotype frequencies of the polymorphism between the two groups demonstrated CC as a potential risk genotype (p = 0.006; Odds ratio=1.95; 95% CI: 1.2-3.15) for the disease while another SNP Asp666Asp (c.1998T allele) showed protectiveness towards the disease (p = 0.006; Odds ratio = 0.67; 95%CI: 0.50-0.89). To our knowledge, this is first study reporting the role of TPO gene with hypothyroidism in a population of Asian Indian origin. The study threw up the possibility of TPO gene polymorphisms as a possible pathogenetic mechanism of hypothyroidism.

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Transforming growth factor β (TGF-β) members, pleiotropic cytokines, play a critical role for carcinogenesis generally as a tumor suppressor in the early cancer development, but as a tumor promoter in the late stage of cancer progression. The present study was designed to clarify the role for TGF-β signaling in early thyroid carcinogenesis using the conditional Tgfbr2^{floxE2/floxE2} knock-in mice, having 2 loxP sites at introns 1 and 2 of Tgfb2r gene. When these mice were crossed with thyroid peroxidase (TPO)-Cre or fibroblast-specific protein-1 (FSP1)-Cre, the resultant mice, Tgfbr2^tpoKO and Tgfbr2^fspKO, lost TGF-β II receptor expression (thereby TGF-β signaling) specifically in the thyroid follicular epithelial cells or fibroblasts, respectively. The thyroid morphology was monitored up to 52 weeks in these mice, showing no tumor development, except one Tgfbr2^tpoKO mouse developing follicular adenoma like-lesion. Our data suggest that TGF-β signaling in mesenchymal or follicular epithelial cells of the thyroid does not appear to function as a tumor suppressive barrier at the early stage of thyroid carcinogenesis.

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