Over 20 years ago, two Japanese institutions initiated an active surveillance policy for papillary microcarcinomas (PMCs) without high-risk features (such as clinical lymph node and distant metastases) and suspected trachea or recurrent laryngeal nerve invasion. Since the most recent American Thyroid Association (ATA) guidelines adopt active surveillance as a therapy option for low-risk PMCs, the number of institutions worldwide carrying out this policy can be expected to increase. However, before adopting an active surveillance strategy, some important clinical questions must be considered. In this review, conceivable clinical questions with our answers based on the present accumulation of low-risk PMC surveillance data are presented.
Warthin-like variant of papillary thyroid carcinoma (WVPTC) is a rare entity recently characterized. We evaluated ultrasonographic (US) features and clinical characteristics of WVPTC. Nine patients were diagnosed with WVPTC through surgery in our institution from May 2005 to January 2015. Eight of nine patients had available preoperative US images. A retrospective review of the US and clinical characteristics was performed. WVPTC compromised of 0.06% of 14,071 PTCs surgically confirmed. A mean age of nine patients was 53.2 years (range, 32-75 years). The mean nodule size of nine WVPTCs was 0.9 cm (range, 0.5-1.5 cm). Two patients showed central nodal metastasis and one patient with conventional PTC as an index tumor underwent central and lateral neck dissection. No one showed recurrence or distant metastasis during the follow-up period (mean, 4.6 years; range, 0.6-10 years). The most common US features of WVPTCs were solid composition (62.5%), hypoechogenicity (75%), and wider-than-tall shape (100%), respectively. Four (50%) of eight nodules showed well-defined margin and three (37.5%) of them had cystic component. One of eight resembled focal thyroiditis. Three nodules were considered as probably benign with US. All nine cases demonstrated underlying heterogeneous parenchymal echogenicity and accompanied chronic lymphocytic thyroiditis in permanent sections. Thyroid function tests in all patients were normal except for one with subclinical hypothyroidism. WVPTC is an uncommon subtype of PTC and has favorable prognosis, which can be misdiagnosed as a probably benign nodule or focal thyroiditis with US. All cases are associated with heterogeneous parenchyma in the background.
Pegvisomant is a GH receptor antagonist and strong inhibitor of insulin-like growth factor I (IGF-I) production. The treatment goal for acromegaly is to normalize serum IGF-I levels and attenuate associated symptoms. The efficacy and safety of pegvisomant as treatment for acromegaly have been reported in Caucasians, but not in Japanese. Here we report the clinical experience of using pegvisomant in Japanese patients with acromegaly. The efficacy and safety data for pegvisomant from two open-labeled clinical studies in Japan, conducted from 2004 to 2007, were re-analyzed using the new Japanese age- and sex-matched normative ranges for IGF-I. Eighteen patients with active acromegaly were enrolled in an initial pivotal study, and 16 of them were moved to a long-term (max 168 weeks) extension study. The dose of pegvisomant in the extension study was adjusted to 10-30 mg per day according to IGF-I levels. IGF-I normalization was observed in 81.3% (13/16 patients) during the extension study. The mean percentage decrease from baseline in serum IGF-I level was 64.7% at the time of last observation. The clinical symptoms and overall health status were improved, and the ring size was reduced over time until Week 12 and maintained. For safety, no clinically significant changes were observed both in the pituitary tumor size and the anti-GH antibody level. Three subjects were withdrawn from the studies due to an abnormal elevation of liver enzymes which resolved after discontinuation. Pegvisomant demonstrated excellent clinical efficacy and was well tolerated in Japanese patients with acromegaly.
The impact of lymph node (LN) metastasis on survival or tumor recurrence in patients with papillary thyroid carcinoma (PTC) is controversial. The objective of this study was to investigate the effect of superior mediastinal metastasis on the prognosis of patients with PTC and to identify any correlations between such metastasis and clinical indicators. Medical records of PTC patients who underwent surgery as their initial treatment between 1981 and 2008 at our institution were retrospectively reviewed. Patients with or without superior mediastinal metastasis were selected. Prognosis was determined using the Kaplan-Meier method and Cox-hazard regression model with the forward stepwise method. Correlations between multiple factors and superior mediastinal metastasis were investigated using a binary logistic regression analysis. The study cohort included 488 patients of whom 75 (15.4%) had superior mediastinal metastasis. The survival differences between patients with superior mediastinal metastasis dissected via the transcervical approach and patients without metastasis were not significant. The prognosis of patients with superior mediastinal metastasis dissected by sternotomy was significantly poorer. As for disease-free survival, significant differences were found between patients with superior mediastinal metastases dissected by either method and patients without metastases. The main variables predicting superior mediastinal metastasis were an age of 45 years or older and the total number of cervical LN metastases. Superior mediastinal metastasis was an independent predictive factor for recurrence-free survival in PTC patients. The main variables predicting superior mediastinal metastasis were being 45 years of age or older, and having a greater total number of cervical LN metastases.
Fibroblast growth factor 1 (FGF1) has been recently characterized as a potent insulin sensitizer that regulates adipose tissue remodeling, but the physiological role of FGF1 remains unclear. This study measured serum FGF1 levels for the first time in patients with newly diagnosed type 2 diabetes mellitus (T2DM), and further explored the correlations between FGF1 levels and various metabolic parameters in T2DM. Serum FGF1 levels were determined using ELISA in age-, sex- and BMI- matched subjects with normal glucose tolerance (NGT) (n=80) and newly diagnosed T2DM (n=80). Oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1C), blood lipids, and insulin secretion were also measured. Insulin resistance and pancreatic β-cell function were assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta cell function (HOMA-β), respectively. Serum FGF1 levels were significantly higher in T2DM patients than in normal glucose tolerance subjects (74.52 [55.91∼101.34] vs. 60.31 [48.99∼83.91] pg/mL; P<0.05). In addition, serum FGF1 level positively correlated with body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), fasting plasma glucose (FPG), 2-h post-OGTT glucose (2h PG), and HbA1C (all P values <0.05) in T2DM subjects. Multivariate regression analyses showed that BMI and HbA1C were the independent factors influencing serum FGF1 levels. Logistic regression analyses demonstrated that serum FGF1 was significantly associated with type 2 diabetes (P<0.01). Circulating concentrations of FGF1 are significantly increased in T2DM patients. Our results suggest that FGF1 may play a role in the pathogenesis of T2DM.
In oncology, the early cancer detection is recognized as associated with good patient’s prognosis. Then, one could expect that differentiated thyroid carcinoma (DTC) undergone fine-needle aspiration cytology (FNA) early have better outcome. Aim of this study was to investigate if DTC prognosis is improved by early FNA diagnosis. DTCs followed-up at our institution were included. Information about initial management of thyroid lesion, FNA, surgery, and postoperative follow-up was collected. Cytologies were classified according to British Thyroid Association (BTA). The final series comprised 219 DTCs, of which 22 (10%) recurred. The length of time between nodule appearance and cancer treatment was significantly (p<0.0001) shorter in patients who had undergone FNA than those who had not. In the FNA group, 73 patients underwent biopsy within six months, 25 at 7-12 months, and 43 after at least one year. Regardless of this highly significant (p<0.0001) difference, the results of TNM staging and cancer recurrence rate were no different between these three subgroups. This result was confirmed in DTCs larger than 1 cm submitted to FNA within 12 months or later. When we evaluated the impact of nodule’s presentation on DTC outcome, clinically discovered cancers were significantly associated with relapse (OR 2.81) and advanced TNM stages (p=0.03). These data show a lack of clinical impact of the delayed diagnosis of DTC. Also, the postoperative outcome of these patients should not be influenced by the timing of FNA. Instead, DTC patients with preoperative clinical nodule appearance should be considered at higher risk of relapse.
MicroRNA (miRNA) is a family of non-coding RNAs that have important roles in various vital functions. It has been reported that let-7e, a miRNA, may be involved in the regulation of interleukin (IL)-10 production. The purpose of this study was to evaluate the role of let-7e as a regulator of IL-10 production in the pathological processes of autoimmune thyroid diseases (AITDs). We evaluated the association between let-7e expression and intracellular expression of IL-10 in the peripheral blood mononuclear cells (PBMCs) collected from 11 healthy volunteers. Then we investigated the expression levels of let-7e in the PBMCs of 50 patients with Graves’ disease (GD), 42 patients with Hashimoto’s disease (HD) and 28 healthy controls. We found negative correlations between the expression level of let-7e and IL-10 messengerRNA (mRNA) and between the expression level of let-7e and proportion of IL-10+ cells in stimulated PBMCs from healthy volunteers (r = -0.44, p = 0.0267 and r = -0.49, p = 0.0166, respectively). The expression levels of let-7e were significantly increased in HD patients compared with those in GD patients and healthy volunteers (p = 0.0003 and p = 0.0011, respectively). let-7e may be associated with the pathogenesis of HD through the regulation of intracellular IL-10 expression.
The aim of our study is to establish the reference intervals (RIs) of thyroid hormones in a previously iodine-deficient area but presently more than iodine-adequate area of Western China, and also to investigate the factors which affect thyroid function. The cross-sectional study conducted in Xi’an, was based on 2007-2008 China National Diabetes and Metabolic Disorders Survey. Among 1286 participating adults, 717 were finally included as reference population. Thyrotropin (TSH), total triiodothyronine (T3), free triiodothyronine (FT3), total thyroxine (T4), free thyroxine (FT4), thyroperoxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) were measured. Thyroid ultrasound examination was also performed. The present study established the new RIs of serum TSH (0.43-5.51 mIU/L), FT4 (11.0-20.4 pmol/L), FT3 (3.63-5.73 pmol/L), T4 (67.8-157 mmol/L) and T3 (1.08-2.20 mmol/L), which were different from the data provided by the manufacturers. Significant differences among all the age groups were observed in FT3, but neither in TSH nor in FT4. The TSH levels in adults with pathologic ultrasonography results or positive thyroid autoantibody were significantly higher than those in reference adults. Our present results provide valuable references for the diagnosis of thyroid diseases in population of Western China. Considering that most inland areas of China have faced the challenge of the transition from iodine deficiency to adequacy or more than adequacy, we recommend physicians utilize our RIs to determine thyroid diseases in the similar areas with Xi’an in China.
Clinical studies have shown that hyperhomocysteinemia is associated with bone fragility. Homocysteine (Hcy) induces apoptosis of osteoblastic cell lineage by increasing oxidative stress, which may contribute to Hcy-induced bone fragility. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, ameliorate oxidative stress by regulating oxidant and anti-oxidant enzymes. However, the effects of statins on Hcy-induced apoptosis of osteocytes are unknown. This study was thus aimed to investigate whether or not statins prevent Hcy-induced apoptosis of osteocytic MLO-Y4 cells and regulate NADPH oxidase (Nox) expression. TUNEL staining showed that 5 mM Hcy induced apoptosis of MLO-Y4 cells, and that co-incubation of 10-9 or 10-8 M simvastatin significantly suppressed the apoptotic effect. Moreover, we confirmed the beneficial effect of simvastatin against Hcy’s apoptotic effect by using a DNA fragment ELISA assay. However, TUNEL staining showed no significant effects of pravastatin, a hydrophilic statin, on the Hcy-induced apoptosis. Real-time PCR showed that Hcy increased the mRNA expressions of Nox1 and Nox2, whereas simvastatin inhibited the stimulation of Nox1 and Nox2 expressions by Hcy. In contrast, neither Hcy nor simvastatin had any effect on Nox4 expression. These findings indicate that simvastatin prevents the detrimental effects of Hcy on the apoptosis of osteocytes by regulating the expressions of Nox1 and Nox2, suggesting that statins may be beneficial for preventing Hcy-induced osteocyte apoptosis and the resulting bone fragility.
Carboxy-terminal telopeptide of type I collagen (ICTP) is generated through matrix metalloproteinase (MMP)-dependent type I collagen digestion, and has been widely utilized as a biomarker for bone turnover. The fact that atherosclerotic lesions are rich in both type I collagen and MMP-producing macrophages led to the hypothesis that serum ICTP concentrations may serve as a non-invasive clinical biomarker for atherosclerosis. Therefore, the association of serum ICTP concentrations with the maximum intima-media thickness (IMT) of carotid arteries, a surrogate index of systemic atherosclerosis, or brachial-ankle pulse wave velocity (baPWV) in patients with atherosclerotic risk factors was evaluated. A total of 52 male and 65 female (mean age: 62.8 yrs) patients without renal failure, malignancies or bone diseases known to affect serum ICTP concentrations were recruited. Patients with max IMTs ≥1.1 mm showed significantly higher serum ICTP concentrations compared with patients with max IMTs <1.1 mm (3.33 ± 0.97 vs 2.82 ± 0.65 ng/mL, p<0.05). Serum ICTP concentration was also positively correlated with max IMT (p<0.001) or baPWV values (p<0.05). Multivariate analyses also revealed that serum ICTP concentrations were correlated with max IMT (p<0.001; 95% CI 0.200 to 0.454). These results suggest that serum ICTP concentrations can be used as a non-invasive biomarker for systemic atherosclerosis.
Heterozygous and/or homozygous HESX1 mutations have been reported to cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), in association with septo optic dysplasia (SOD). We report a novel heterozygous HESX1 mutation in a CPHD patient without SOD phenotypes. The propositus was a one-year-old Japanese girl. Shortly after birth, she was found to be hypoglycemic. She was diagnosed with central adrenal insufficiency based on low cortisol and ACTH at a time of severe hypoglycemia. Further endocrine studies indicated that the patient also had central hypothyroidism and growth hormone deficiency. Using a next-generation sequencing strategy, we identified a novel heterozygous HESX1 mutation, c.326G>A (p.Arg109Gln). Western blotting and subcellular localization revealed no significant difference between wild type and mutant HESX1. Electrophoretic mobility shift assays showed that the mutant HESX1 abrogated DNA-binding ability. Mutant HESX1 was unable to repress PROP1-mediated activation. In conclusion, this study identified Arg109 as a critical residue in the HESX1 protein and extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in HESX1. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.