Molecular classification of follicular thyroid carcinoma based on TERT promoter mutations.

Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P < 0.001] but not in minimally invasive (MI)-FTC and widely invasive (WI)-FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI-FTC with WT-TERT and M-TERT; EA-FTC with WT-TERT), Group 2 (WI-FTC with WT-TERT), and Group 3 (EA-FTC with M-TERT; WI-FTC with M-TERT). Both PVE (22.44 vs. 9.63, respectively) and C-index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C-index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups. Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability.

Disseminated Primary Pulmonary Choriocarcinoma Successfully Treated by Chemotherapy: A Case Report and Literature Review.

Primary pulmonary choriocarcinoma (PPC) is frequently fatal due to difficulties in diagnosis. Few cases of PPC are bilateral and involve exceptionally large nodules. Here, we report an unusual case of PPC involving disseminated bilateral nodules, which was misdiagnosed as tuberculosis, but successfully treated using chemotherapy. A review of 65 cases revealed six cases of bilateral disease, including the present one. Patients treated with surgery, chemotherapy, or a combination of both showed similar treatment outcomes; however, chemotherapy may be the preferred option. Despite its rarity, PPC should be included in the differential diagnosis for all lung nodules to enable early detection.

Radiofrequency endometrial ablation with a novel endometrial tip for the management of heavy menstrual bleeding and abnormal uterine bleeding: a prospective study.

Aim: To evaluate the safety and efficacy of a radiofrequency ablation system with a novel endometrial tip (RFA-EMT) for the management of heavy menstrual bleeding (HMB) or abnormal uterine bleeding (AUB).Methods: This is a prospective study including a total of 38 premenopausal women with heavy menstrual bleeding (HMB) or abnormal uterine bleeding (AUB) that failed to respond to medical therapy. Hysteroscopic evaluation and curettage biopsy were performed just before the procedure. The procedure was timed to occur during the early proliferative phase (cycle days 4-10). RFA-EMT procedures were performed by a single surgeon with the patient under general anesthesia with a laryngeal mask airway. Primary outcome was reduction in bleeding, reported as amenorrhea, hypomenorrhea, and eumenorrhea, which were measured via hemoglobin level and pictorial blood assessment chart (PBAC) score. Secondary outcomes were adverse events, dysmenorrhea with numeric rating scale (NRS) score, and endometrial thickening in the early proliferative phase, as assessed by transvaginal ultrasonography.Results: There were no peri- or post-procedural complications. Combined amenorrhea, hypomenorrhea, and eumenorrhea rates at 3 and 6 months were 97.4% and 100%, respectively. The hemoglobin level was significantly increased, and the PBAC score, NRS score, and endometrial thickening were significantly decreased after 3 months. These trends were maintained for 6 months after the procedure.Conclusion: RFA-EMT, a new technique, is safe and effective for women with HMB or AUB for which medical therapy has failed.

Echogenic foci in thyroid nodules: diagnostic performance with combination of TIRADS and echogenic foci.

BACKGROUND: The malignancy risks of various echogenic foci in thyroid nodules are not consistent. The association between malignancy and echogenic foci and various Thyroid Imaging Reporting and Data System (TIRADS) in thyroid nodules has not been evaluated. We evaluated the malignancy probability and diagnostic performance of thyroid nodules with various echogenic foci and in combination with TIRADS. METHODS: This retrospective study was approved by Institutional Review Board. The data were retrospectively collected from January 2013 to December 2014. In total, 954 patients (mean age, 50.8 years; range, 13-86 years) with 1112 nodules were included. Using χ2 test, we determined the prevalence of benign and malignant nodules among those with and without echogenic foci; we associated each of 6 echogenic foci types with benign and malignant nodules. Diagnostic performance was compared between the 6 types alone and in combination with various TIRADS. RESULTS: Among 1112 nodules, 390 nodules (35.1%) were found to have echogenic foci, and 722 nodules (64.9%) were not. Among nodules with echogenic foci, 254 nodules (65.1%) were malignant. The punctate echogenic foci with comet-tail artifact showed malignancy rate of 77.8% in solid and predominantly solid nodules. Our study demonstrated relatively low PPV (33.3-56.4%) in nodules with large echogenic foci without shadowing, macrocalcification, and peripheral curvilinear or eggshell echogenic foci with or without shadowing. However, when combined with high suspicion category of TIRADS, PPV increased to 50.0-90.9%. CONCLUSION: Combination with TIRADS with different types of echogenic foci offer better stratification of the malignancy risk.

25-hydroxyvitamin D status is associated with chronic cerebral small vessel disease.

BACKGROUND AND PURPOSE: The aim of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) and neuroimaging correlates of cerebral small vessel disease. METHODS: We identified 759 consecutive patients with acute ischemic stroke or transient ischemic attack. Lacunes, white matter hyperintensity, and cerebral microbleed (CMB) were assessed using MR images. Deep CMB was defined as the presence of CMB in basal ganglia, thalamus, or brain stem. The association between 25(OH)D and small vessel disease was tested using linear and logistic regression analyses. RESULTS: Mean age was 68 (±13) years. Mean level of 25(OH)D was 34.1±17.8 nmol/L. On bivariate analysis, a 25-nmol/L decrease in 25(OH)D was associated with lacunes (regression coefficient, 0.23; 95% confidence interval [CI], 0.02-0.45), severe white matter hyperintensity (odds ratio, 2.05; 95% CI, 1.41-3.08), and deep CMB (odds ratio, 1.28; 95% CI, 1.01-1.63). Also, 25(OH)D deficiency (≤25 nmol/L) was associated with lacunes (regression coefficient, 0.5; 95% CI, 0.04-0.95), severe white matter hyperintensity (odds ratio, 2.74; 95% CI, 1.31-6.45), and deep CMB (odds ratio, 1.68; 95% CI, 1.03-2.78). The association remained significant even after multivariable adjustment and in the subgroup of previously healthy patients. CONCLUSIONS: 25(OH)D is inversely associated with lacunes, white matter hyperintensity, and deep CMB. Our findings suggest that 25(OH)D is linked to small vessel disease, and in future trials it should be tested whether 25(OH)D supplementation can prevent small vessel disease.

Effect of Pravastatin on Kidney Function in Patients with Dyslipidemia and Type 2 Diabetes Mellitus: A Multicenter Prospective Observational Study.

INTRODUCTION: Several studies have reported that pravastatin can mitigate the progression of kidney disease, but limited evidence exists regarding its effects on kidney function in Asian patients. This multicenter prospective observational study aimed to assess the effect of pravastatin on kidney function in Korean patients with dyslipidemia and type 2 diabetes mellitus (T2DM) in clinical practice. METHODS: This 48-week prospective multicenter study included 2604 of 2997 eligible patients with dyslipidemia and T2DM who had available estimated glomerular filtration rate (eGFR) measurements. The primary endpoint was eGFR percent change at week 24 from baseline. We also assessed secondary endpoints, which included percent changes in eGFR at weeks 12 and 48 from baseline, as well as changes in eGFR, metabolic profiles (lipid and glycemic levels) at 12, 24, and 48 weeks from baseline, and safety. RESULTS: We noted a significant improvement in eGFR, with mean percent changes of 2.5%, 2.5%, and 3.0% at 12, 24, and 48 weeks, respectively (all adjusted p < 0.05). The eGFR percent changes significantly increased in subgroups with baseline eGFR 30-90 mL/min/1.73 m2, glycated hemoglobin (HbA1c) ≥ 7 at baseline, no hypertension history, T2DM duration > 5 years, or previous statin therapy. Lipid profiles were improved and remained stable throughout the study, and interestingly, fasting glucose and HbA1c were improved at 24 weeks. CONCLUSION: Our findings suggest that pravastatin may have potential benefits for improving eGFR in Korean patients with dyslipidemia and T2DM. This could make it a preferable treatment option for patients with reduced kidney function. TRIAL REGISTRATION NUMBER: NCT05107063 submitted October 27, 2021.

Anti-proliferative effect and action mechanism of dexamethasone in human medullary thyroid cancer cell line.

INTRODUCTION: Dexamethasone is known to inhibit the cell proliferation of certain transformed cell lines. In this study, the effect and action mechanism of dexamethasone were examined in the human medullary thyroid cancer cell line, TT cells. METHODS: TT cells were treated with or without dexamethasone. 5-Bromo-2'-deoxyuridine uptake assay was used to evaluate cell proliferation. Cell cycle and its regulatory proteins were assessed by flow cytometry and western blot analysis, respectively. Apoptosis was analyzed by Hoechst staining and Annexin V assay. RESULTS: Dexamethasone significantly reduced TT cell proliferation by 60% (p < 0.01). A substantial portion of cells was arrested at the G1 phase. The expression levels of cyclin D1, cyclin-dependent kinase (CDK)4, and CDK2 were decreased. In addition, the phosphorylation of retinoblastoma protein, which is a critical checkpoint protein in the transition of G1 to S phase, was decreased. On the other hand, the expression level of p27(Kip1), which is a cyclin/CDK inhibitor, was enhanced. Hoechst staining showed many fragmented nuclei in the dexamethasone-treated cells. The proportion of early apoptotic cells was also increased in the Annexin V assay. CONCLUSION: Dexamethasone inhibited the proliferation of TT cells through cell cycle arrest at the G1 phase and increased apoptosis.

A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report.

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.

Malignancy Rate of Bethesda Class III Thyroid Nodules Based on the Presence of Chronic Lymphocytic Thyroiditis in Surgical Patients.

Background: Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis (CLT), may interfere with the accurate cytological diagnosis of thyroid nodules. Recently, HT has been considered a premalignant condition for thyroid cancer development. The diagnosis of atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) thyroid nodules is challenging and evidence for the malignancy risk of AUS/FLUS thyroid nodules coexisting with CLT is scarce. Therefore, we assessed the malignancy risk of AUS/FLUS thyroid nodules according to the presence of background CLT. Methods: This study included 357 surgically resected thyroid nodules with AUS/FLUS cytology. Cases with concomitant malignant nodules were excluded. CLT was defined based on the pathologic report after thyroid surgery. Results: Among 357 tumors, 130 tumors (36%) were confirmed to have coexisting CLT, and 170 tumors (48%) were determined to be malignant after thyroidectomy. Malignancy rates were similar in both groups (48% in each) regardless of background CLT (62/130 with CLT vs. 108/227 without CLT). In the group with CLT, thyroiditis was more frequent in the final pathology (12% with CLT vs. 1% without CLT, P = 0.003). In multivariate analysis, positive BRAFV600E mutation, highly suspicious sonographic features (K-TIRADS 5), and smaller thyroid nodules were significant factors for thyroid malignancies. Conclusion: The malignancy rate of thyroid nodules with AUS/FLUS cytology was comparable irrespective of the presence of underlying CLT.

Sentinel lymph node identification with radiopharmaceuticals in patients with breast cancer: a comparison of 99mTc-tin colloid and 99mTc-phytate efficiency.

Sentinel lymph node biopsy with lymphoscintigraphy has become the standard method for the detection of axillary lymph node metastasis in breast cancer patients. However, there is no standardized radiopharmaceutical. For the detection of axillary lymph node metastasis by lymphoscintigraphy and sentinel node biopsy in patients with breast cancer, we compared the results between subareolar injection of (99m)Tc-tin colloid and injection of (99m)Tc-phytate. This study included 516 breast cancer patients who underwent surgery between 2001 and 2010. Among the 516 patients, (99m)Tc-tin colloid (37-185 MBq) was administered to 412 patients by subareolar injection, and (99m)Tc-phytate (37-185 MBq) was injected in 104 patients. Lymphoscintigraphy was performed with the patients in the supine position, and sentinel node identification was performed by hand-held gamma probe during surgery. Among 412 patients with (99m)Tc-tin colloid, the sentinel node was identified by lymphoscintigraphy in 364 cases (88.3%) and by a gamma probe in 369 cases (89.6%). Among 104 patients with (99m)Tc-phytate, 101 cases (97.1%) were identified by lymphoscintigraphy and 101 cases (97.1%) were identified by a gamma probe. The identification rates by lymphoscintigraphy and gamma probe were superior with (99m)Tc-phytate, as compared with (99m)Tc-tin colloid, with a statistically significant difference (P < 0.05 for both methods). (99m)Tc-phytate is a better choice than (99m)Tc-tin colloid for identification of the sentinel node in breast cancer patients.

Vitamin D supplementation does not prevent the recurrence of Graves' disease.

Recent literature has reported a higher prevalence of vitamin D deficiency among people with Graves' disease. No study has examined the effect of vitamin D supplementation on the clinical outcomes of Graves' disease. We aimed to evaluate whether daily vitamin D supplementation reduces Graves' disease recurrence. We enrolled 210 subjects with Graves' disease and vitamin D deficiency and followed them for at least one year after anti-thyroid drug (ATD) discontinuation. Among 210 individuals, 60 (29%) were amenable to taking vitamin D supplements, resulting in sufficient vitamin D levels (from 10.6 to 25.7 ng/mL), whereas the mean vitamin D level was 11.6 ng/mL in the 150 patients who did not take vitamin D supplements. The recurrence rate was similar in both groups (38% vs. 49%, P = 0.086). However, recurrence occurred earlier in the latter group (7 months vs. 5 months, P = 0.016). In the multivariate analysis, vitamin D levels and TSH-binding inhibitory immunoglobulin (TBII) titers at ATD discontinuation remained significant factors for recurrence. Vitamin D levels and TBII titers at ATD discontinuation exhibited a weak negative correlation (R = -0.143, P = 0.041). Vitamin D supplementation might have a protective effect against Graves' disease recurrence with a borderline significant recurrence rate reduction.

Malignancy rate of Bethesda category III thyroid nodules according to ultrasound risk stratification system and cytological subtype.

The risk of malignancy is considered to be 10% to 30% for cases of thyroid nodules with atypia or follicular lesion of undetermined significance (AUS/FLUS). However, only a minority of patients with AUS/FLUS undergo surgery; therefore, the risk of malignancy might be overestimated due to selection bias. To overcome this problem, we categorized cases of thyroid nodules with AUS/FLUS using the ultrasound risk stratification system (US-RSS) to calculate the malignancy rate and identify the patients most suitable for surgical treatment.In this retrospective observational study, we subcategorized 382 pathologically confirmed thyroid nodules with AUS/FLUS using current US-RSSs (American Thyroid Association, Korean-Thyroid Imaging Report and Data System, American College of Radiology-Thyroid Imaging, Reporting and Data System, European Thyroid Imaging Report and Data System) and calculated the malignancy rate. Additionally, cases of nodules with AUS/FLUS were categorized according to their cytological subtypes, and the malignancy rate was calculated.Current US-RSSs showed good or moderate agreement among them. The overall malignancy rate for thyroid nodules with AUS/FLUS was 38.7%. On categorization of the nodules with AUS/FLUS, the malignancy rates were found to be 60% to 67.5% for the high suspicion category, 32.2-36.6% for the intermediate suspicion category, and 12.4% to 16.3% for the low suspicion category. The malignancy rate for nodules with cytologic atypia was significantly higher than that for nodules with architectural atypia, especially in the intermediate suspicion category.Categorization of thyroid nodules with AUS/FLUS using current US-RSSs helps to determine the optimal course of management of patients, especially when combined with cytological subtype characterization.

Cytoplasmic localization of Jab1 and p27 Kip1 might be associated with invasiveness of papillary thyroid carcinoma.

p27(kip1) is a well known negative regulator of cell cycle progression. Jab1 directly binds to p27(kip1) and induces nuclear export and subsequent degradation. Recent studies have shown that overexpression of Jab1 and reduced expression of p27(kip1) are associated with advanced tumor stage and poor prognosis in several human cancers. Here, we evaluated 50 papillary thyroid carcinomas (PTC) and adjacent normal thyroid tissue samples by immunohistochemistry for Jab1 and p27(kip1) to elucidate expression levels and subcellular localization. Expression of Jab1 was markedly increased and that of p27(kip1) was reduced in the tumors compared with paired normal samples. Jab1 expression was inversely related to p27(kip1) expression. Jab1 was especially overexpressed within the invasive region compared to center of the tumors. Among clinicopathologic parameters, only tumor size was related with Jab1 (positively) and p27(kip1) expression (negatively) in the invasive region of the tumors. Both Jab1 and p27(kip1) were found predominantly in the cytoplasm of the tumor cells from the invasive regions compared to center of the tumors. The Ki-67 proliferative index was higher in the invasive region than in center of the tumors. A much stronger correlation with the Ki-67 index was noted when both Jab1 and p27(kip1) were simultaneously localized in the cytoplasm than when either Jab1 or p27(kip1) was localized in the cytoplasm alone. These data suggest that in addition to overexpression of Jab1 and reduced expression of p27(kip1), cytoplasmic localization of Jab1 and p27(kip1) are associated with increased cancer cell proliferation and might be related to the invasiveness of PTC.

AKT in thyroid tumorigenesis and progression.

AKT (protein kinase B) is a central signaling molecule in the phosphatidyl inositol 3-kinase pathway that is frequently activated in human cancer. AKT activation regulates energy metabolism, apoptosis, proliferation, and migration in many cell systems. In thyroid cancer, AKT activation is involved in tumorigenesis, particularly in both inherited and sporadic forms of follicular thyroid cancer. Phosphatidyl inositol 3-kinase and AKT signaling also appear to play an important role in progression of both papillary and follicular cancers. In this review, the role of AKT in thyroid cancer development and progression are discussed with a focus on areas of current debate in the literature.

Serum 25-hydroxyvitamin D might be an independent prognostic factor for Graves disease recurrence.

Graves disease is the most common cause of thyrotoxicosis. Although medical intervention with antithyroid drugs (ATDs) is commonly the first choice of treatment in Korea, the remission rate associated with this approach is not satisfactory. During ATD therapy, low or undetectable serum levels of thyroid-stimulating hormone (TSH) receptor antibodies (TRAbs) have been reported to affect the incidence of Graves disease remission. This study evaluated the correlation between serum 25-hydroxyvitamin D levels and TRAb levels, as well as the effect of 25-hydroxyvitamin D on the recurrence of Graves disease.A total of 143 patients, who were diagnosed with Graves disease and treated with ATDs, were retrospectively included in our observational study. These patients were followed for more than 1 year after ATD discontinuation. The levels of serum 25-hydroxyvitamin D and TRAb (ie, thyroid-stimulating antibody [TSAb], as detected by bioassay, and TSH-binding inhibitory immunoglobulins [TBIIs]) were measured, and a thyroid function test was performed upon ATD discontinuation. Recurrence was evaluated every 3 months, and was defined as an occurrence of overt thyrotoxicosis during the follow-up period.A total of 95 patients (66.4%) experienced recurrence with a median latency period of 182 days (ranging 28-1219 days). The serum 25-hydroxyvitamin D levels at the time of ATD discontinuation were not correlated with either TBII or TSAb. In the Cox proportional hazard regression analysis, higher free T4 levels (>1.4 ng/dL; hazard ratio [HR], 3.252; 95% confidence interval [CI], 1.022-10.347) and low levels of 25-hydroxyvitamin D (≤14.23 ng/mL) were associated with a higher probability of Graves disease recurrence (HR, 3.016; 95% CI, 1.163-7.819).Lower serum 25-hydroxyvitamin D levels were associated with a higher incidence of Graves disease recurrence. Therefore, serum 25-hydroxyvitamin D might be an independent risk factor for predicting Graves disease recurrence after ATD discontinuation.

Validation of Three Scoring Risk-Stratification Models for Thyroid Nodules.

BACKGROUND: To minimize potential harm from overuse of fine-needle aspiration, Thyroid Imaging Reporting and Data Systems (TIRADSs) were developed for thyroid nodule risk stratification. The purpose of this study was to perform validation of three scoring risk-stratification models for thyroid nodules using ultrasonography features, a web-based malignancy risk-stratification system, and a model developed by the Korean Society of Thyroid Radiology and the American College of Radiology. METHODS: Using ultrasonography images, radiologists assessed thyroid nodules according to the following criteria: internal content, echogenicity of the solid portion, shape, margin, and calcifications. A total of 954 patients (Mage = 50.8 years; range 13-86 years) with 1112 nodules were evaluated at the authors' institute from January 2013 to December 2014. The discrimination ability of the three models was assessed by estimating the area under the receiver operating characteristic curve. Additionally, Hosmer-Lemeshow goodness-of-fit statistics (calibration ability) were used to evaluate the agreement between the observed and expected number of nodules that were benign or malignant. RESULTS: Thyroid malignancy was present in 37.2% (414/1112) of nodules. According to the 14-point web-based scoring risk-stratification system, malignancy risk ranged from 4.5% to 100.0% and was positively associated with an increase in risk scores. The areas under the receiver operating characteristic curve of the validation set were 0.884 in the web-based model, 0.891 in the Korean Society of Thyroid Radiology model, and 0.875 in the American College of Radiology model. The Hosmer-Lemeshow goodness-of-fit test indicated that the web-based scoring system showed the best-calibrated result, with a p-value of 0.078. CONCLUSION: The three scoring risk-stratification models using the ultrasonography features of thyroid nodules to stratify malignancy risk showed acceptable predictive accuracy and similar areas under the curve. The web-based scoring system demonstrated the strongest agreement in calibration ability analysis. The easily accessible automated web-based scoring risk-stratification system may overcome the complexity of the various Thyroid Imaging Reporting and Data System guidelines and provide simplified guidance on personalized and optimal management in real practice.

Continued suppression of serum TSH level may be attributed to TSH receptor antibody activity as well as the severity of thyrotoxicosis and the time to recovery of thyroid hormone in treated euthyroid Graves' patients.

The cause of continued suppression of serum thyroid-stimulating hormone (TSH) levels during antithyroid drug therapy in some Graves' patients is unclear. Recently, there has been a notable explanation involving the direct inhibition of TSH receptor antibody (TRAb) on TSH secretion in the pituitary gland. The purpose of this study is to verify the relation between TRAb or other clinical parameters and the continued suppression of serum TSH level during antithyroid drug therapy in patients with Graves' disease. We reviewed the medical records of patients with Graves' disease between 1995 and 2002 at Samsung Medical Center. We selected 167 Graves' patients who had been euthyroid for at least 12 months after recovery of serum T3 and T4 levels during the antithyroid drug therapy. We analyzed the correlation of the interval until recovery of serum TSH with the pretreatment clinical parameters. We compared the recovery rates of suppressed TSH levels between pretreatment thyrotrophin-binding inhibitory immunoglobulin (TBII)-positive (>15%) and TBII-negative patients. We also compared the clinical parameters between two groups at the time of diagnosis and after recovery of thyroid hormone. Pretreatment serum T3 level, (131)I uptake, TBII activity, and the time to recovery of T3 or T4/free T4 level showed significant positive correlations with the interval until recovery of serum TSH level ( p < 0.05). Recovery rates of serum TSH levels at 3 months after recovery of thyroid hormone were significantly lower in pretreatment TBII-positive patients than those in TBII-negative patients ( p < 0.01). Serum TSH levels were significantly lower in TBII-positive patients at 3 months after recovery of thyroid hormone ( p < 0.05). TBII activities inversely correlated only with serum TSH levels at 3months after recovery of thyroid hormone ( p < 0.001). In conclusion, continued suppression of serum TSH level may be attributed to TRAb activity as well as the pretreatment severity of thyrotoxicosis and the time to recovery of thyroid hormone in patients with Graves' disease during antithyroid drug therapy.

Serum 25-Hydroxyvitamin D Level Does Not Affect the Aggressiveness and Prognosis of Papillary Thyroid Cancer.

BACKGROUND: Vitamin D deficiency has been known to be associated with the aggressiveness and prognosis of several cancers. This study evaluated the effect of preoperative serum vitamin D levels on the aggressiveness and prognosis of papillary thyroid cancer (PTC). METHODS: In total, 820 patients with PTC were enrolled. 25-hydroxyvitamin D levels were measured in blood samples before surgery. Clinical, pathologic, and recurrence data were accessed to examine the prognostic effects of vitamin D. Patients were categorized into four quartiles by preoperative serum vitamin D levels. RESULTS: Of the enrolled patients, 795 (97%) had insufficient vitamin D levels (<30 ng/mL). Vitamin D levels showed positive correlations with age and body mass index (BMI), and negative correlations with serum thyrotropin levels and antithyroid peroxidase antibody titers. The association between vitamin D quartile and the risks of extrathyroidal invasion, lymph node metastasis, advanced cancer stages (III or IV), and risk of recurrence were not significant after adjusting for age, sex, BMI, preoperative ionized calcium, and parathyroid hormone. Additionally, serum vitamin D was not associated with recurrent or persistent PTC. CONCLUSION: Serum vitamin D levels are not associated with either disease aggressiveness or poor outcomes among patients with PTC and vitamin D insufficiency.

Heterogeneity of early-onset and ketosis-resistant diabetes in Korean subjects--is it possible to determine cut-off age of early-onset type 2 diabetes?

OBJECTIVE: To investigate the heterogeneity of early-onset and ketosis-resistant diabetes and to define a not-arbitrary cut-off age for early-onset diabetes based on its clinical and metabolic characteristics, and diabetes complications. METHODS: We classified 1015 early-onset diabetes subjects aged 21-40 into four groups (group I, age at diagnosis 21-25 years; group II, 26-30; group III, 31-35; group IV, 36-40). Familial and diabetic history, statue of insulin secretion, metabolic parameters, and diabetes complications were analyzed. RESULTS: No significant difference in family history or the rate of diabetic complication was found in the four groups. Subjects with a 21 to a 25-year-old diabetes onset had the lowest serum C-peptide levels, with 50% of the cumulative 24-h urine C-peptide levels of the other three groups (p<0.0001). This group also had the lowest prevalence of hyperlipidemia and arterial hypertension (p<0.01 and <0.0001, respectively). Group III was found to have a higher prevalence of insulin insufficiency and hypertension than group IV. CONCLUSION: Our data based on insulin secretory function and metabolic factors might suggest that a cut-off age of 26 years might be warranted in Korean patients. Korean early-onset type 2 diabetes patients tend to be non-obese and insulin secretory dysfunction.

Clinicopathologic correlations of the BRAFV600E mutation, BRAF V600E immunohistochemistry, and BRAF RNA in situ hybridization in papillary thyroid carcinoma.

BACKGROUND: The BRAF(V600E) mutation is the most common genetic alteration in papillary thyroid carcinoma (PTC). The aim of this study is to analyze the clinicopathologic correlations of the BRAF(V600E) mutation, BRAF V600E immunohistochemistry (IHC) and BRAF RNA in situ hybridization (ISH) in PTC. METHODS: This study included 467 patients with PTC who underwent surgical resection. We studied the BRAF(V600E) mutation using real-time PCR and BRAF V600E and BRAF RNA ISH using tissue microarray (TMA). RESULTS: The frequencies of a positive BRAF(V600E) mutation by real-time PCR, positive BRAF V600E IHC, and high BRAF RNA ISH were 84%, 86%, and 70%, respectively, in PTC. Conventional PTC had higher positive rates in all three tests than other histologic types. The BRAF(V600E) mutation, BRAF V600E IHC, low ΔCt, and high BRAF RNA ISH were significantly associated with lymph node metastasis. The BRAF(V600E) mutation was significantly associated with positive immunostaining for BRAF V600E mutant protein (P<0.001) overall, with high BRAF RNA ISH only in the follicular variant (P=0.035). No significant correlation was noted between BRAF V600E IHC and BRAF RNA ISH. The sensitivity of BRAF V600E IHC for the BRAF(V600E) mutation was 95%, and the specificity was 61% overall, 96% and 54% in the conventional type, and 85% and 70% in the follicular variant. CONCLUSIONS: Our results showed that positive BRAF V600E IHC significantly correlated with the BRAF(V600E) mutation. This suggests its clinical utility as a screening tool for the BRAF(V600E) mutation. In addition, a high BRAF RNA ISH score could be a candidate marker of aggressive behavior in BRAF(V600E) mutation-positive cases of PTC.