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To explore the effect of active insulin titration versus usual titration on glycaemic control in patients with type 2 diabetes mellitus uncontrolled with oral antidiabetic drugs (OADs).In a 24-week, prospective and randomized study, 172 patients with uncontrolled type 2 diabetes were randomly assigned to either active titration or usual titration. Efficacy and safety outcomes included changes in glycated haemoglobin (HbA1c) and fasting plasma glucose, percentage of individuals achieving HbA1c53 mmol/mol, and hypoglycaemic events.At Week 24, change in HbA1c was -1.08% ± 1.60% in the active titration group and -0.95% ± 1.34% in the usual titration group (P = 0.569). The percentages of individuals achieving HbA1c53 mmol/mol were 29.4% and 16.1% in the active and usual titration groups, respectively (P = 0.037). There was no significant difference in the incidence of hypoglycaemia between the two groups. Multivariate logistic regression indicated that, with active titration, baseline HbA1c levels and postprandial glucose excursion were significantly associated with achieving HbA1c53 mmol/mol.Addition of basal insulin using active titration for 24 weeks provided a higher rate of HbA1c target achievement without significant hypoglycaemia compared to usual titration in individuals with uncontrolled type 2 diabetes.

IntroductionMale patients with type 2 diabetes (T2D) have a high prevalence of low testosterone (LT) or metabolic syndrome (MetS). While LT or MetS are associated with arterial stiffness, few studies have investigated the effect of these conditions when manifested together. Our study was performed to explore the influence of coexistence of LT and MetS on arterial stiffness in male patients with T2DM.Material and methodsWe recruited 332 male patients with T2D at the endocrine and metabolic clinic of the Taitung branch of the Mackay Memorial hospital. Subjects were divided according to the presence of LT or MetS as follows: normal (neither condition present), LT only, MetS only and the coexistence of LT and MetS. All enrolled subjects consecutively underwent brachial-ankle pulse wave velocity (PWV) to evaluate arterial stiffness.ResultsPatients with LT have a higher prevalence of MetS than those without LT (80.1% vs. 64.2%; P=0.03). Age, weight, triglycerides and PWV were significantly higher in patients with coexisting LT and MetS than in the groups with LT or MetS alone. Multiple linear regression analysis was performed to demonstrate that PWV was significantly positively associated with age (P ConclusionsIn our study, the coexistence of MetS and LT was significantly associated with a high risk of increased arterial stiffness in male patients with T2D.

Diabetes is associated with increased risk of fracture. This study aims to evaluate the correlation between anti-diabetic agents and fracture risk in patients with type 2 diabetes.Literature research was conducted using PubMed, Embase, and ClinicalTrials.gov. Search-term included "type 2 diabetes," "fracture," "randomized controlled trial," and seven kinds of anti-diabetic agents. Random-effect models established fractures in the follow-up period as the primary outcome. A network meta-analysis was performed to compare available treatments within a single Bayesian analytical framework.A total of 191,361 patients were included in 161 studies, with 2916 fractures. DPP-4i (risk ratio [RR] 1.76 [95 % confidence interval (CI) 1.21-2.55]), SGLT-2i (RR 1.5 [95 % CI 1.05-2.16]) and placebo (RR 1.44 [95 % CI 1.04-1.98]) increased fracture risk when compared to GLP1-RA. GLP1-RA (RR 0.5 [95 % CI 0.31-0.79]) and SU (RR 0.56 [95 % CI 0.41-0.77]) provided greater protection against fracture than TZD. DPP-4i increased fracture risk when compared to SU (RR 1.55 [95 % CI 1.08-2.22]), and was comparable in effect to TZD.GLP1-RA offered better protection against fracture than placebo. Insulin and SU had effects comparable with GLP1-RA. SU offered greater protection against fractures than TZD and DPP-4i. SGLT-2i increased risk of fracture when compared to GLP1-RA.

Introduction Lymphovascular invasion (LVI) is associated with disease recurrence and compromised survival in patients with thyroid cancer. Nonetheless, LVI is not identifiable on preoperative ultrasound or cytologic assessment. We aimed to explore the clinicopathological features associated with LVI. Patients and methods We conducted a retrospective review of our prospectively maintained database from 2009 to 2018. Multivariate analyses were performed to determine the associations between clinicopathological parameters and LVI. Generalized additive models were used to examine the nonlinear relationship between continuous variables and LVI. Results A total of 795 patients were included in the analysis, and 174 (22%) had LVI. Patients’ age (odds ratio [OR] = 0.982), tumor size (OR = 1.466), clinical lymphadenopathy (OR = 6.975), and advanced extrathyroidal extension (OR = 2.938) were independently associated with LVI. In the subset analysis of 198 patients with available genetic information, tumor size (OR = 1.599), clinical lymph node metastasis (OR = 3.657), and TERT promoter mutation (OR = 4.726) were predictive of LVI. Among 573 patients who had no clinical lymphadenopathy or advanced extrathyroidal extension, tumor size was the only predictor of LVI. Tumor size >1.5 cm had an increased risk of LVI based on the generalized additive model plot and receiver operating characteristic curve analysis. Conclusion Tumor size is positively associated with the risk of LVI in papillary thyroid cancer. To avoid delayed treatment in patients with LVI, a tumor size of 1.5 cm may be considered as the safe upper limit for active surveillance.

Background: Fatigue is a complicated syndrome associated with multiple factors. The development of fatigue after incidental radiotherapy (RT) to the adrenal gland has been observed in clinical practice. This study aimed to investigate the effect of adrenal RT on fatigue and related physiological impacts.Methods: Three patients with inevitable RT to the adrenal gland were enrolled. Serum levels of cortisol, aldosterone, and adrenocorticotropic hormone (ACTH) were measured before, during, and after RT. Fatigue was scored according to the validated fatigue severity scale, and dosimetric parameters were collected. BALB/c mice were surgically explored for the identification of the left adrenal gland. Intra-operative RT was delivered with an electron beam. The swimming endurance test was applied for endurance assessment to represent fatigue. Plasma levels of stress hormones and histopathological features were examined.Results: In the enrolled patients, serum baseline cortisol levels declined after RT. Alterations in levels of morning cortisol and aldosterone showed a similar trend to baseline cortisol, whereas ACTH levels increased, indicating possible compensatory feedback from the hypothalamic-pituitary-adrenal axis. In an experimental mouse model, RT to a unilateral adrenal gland decreased baseline cortisol levels and swimming endurance time. In the histopathological assessment, the irradiated adrenal glands showed characteristic RT injury features in the adrenal cortex.Conclusions: The preliminary clinical observation of fatigue development and characteristic hormone alterations indicated that the adrenal glands could be regarded as an organ at risk from RT adverse effects. This observation was supported by functional and histopathological evidence from an experimental animal model.

Aberrant lipid metabolism provides bioenergetic, biosynthetic, and redox supplies to cancer cells. Previous studies have reported differential lipid profiling in thyroid malignancies. Sterol regulatory element-binding protein 1 (SREBP1), encoded by the SREBF1 gene, is a master regulator of cellular lipid homeostasis. The clinical and functional significance of SREBP1 in thyroid cancer is not well understood. Here, we showed that SREBP1 expression is significantly upregulated in invasive thyroid cancer than in normal thyroid tissue or benign thyroid nodules. High tumoral SREBP1 expression was associated with extrathyroidal extension, advanced disease stage, and shorter disease-specific survival in patients with differentiated thyroid cancer. SREBP1 overexpression significantly increased the oxygen consumption rate, filopodia formation, and migratory and invasive capacities of thyroid cancer cells. Knockdown of SREBF1 or treatment with an SREBP1 activation inhibitor fatostatin had the opposite effect. RNA-Seq analysis showed that modulation of SREBP1 expression was accompanied by corresponding changes in the expression of epithelial–mesenchymal transition markers and CYR61/CTGF. SREBP1-facilitated cell invasion could be abrogated by treatment with a YAP inhibitor such as verteporfin or genetic silencing of CYR61 or CTGF. In summary, SREBP1 upregulation can be used as a prognostic indicator for thyroid cancer and SREBP1 overexpression is involved in cancer invasiveness, at least partly, through upregulation of CYR61/CTGF via the Hippo-YAP pathway.

A variety of epigenetic dysregulations are observed in thyroid malignancies. EZH2, the catalytic subunit of polycomb repressive complex 2, is upregulated in advanced thyroid cancers. EZH2 can catalyze trimethylation of histone H3 at lysine 27 (H3K27me3) and contribute to transcriptional silencing of target genes. Here, we investigated the immunohistochemical expression of H3K27me3 in neoplastic and normal thyroid tissues. Normal thyroid epithelial cells typically exhibited nuclear staining of moderate intensity. A similar expression pattern was observed in nodular goiters and follicular adenomas. By contrast, strong H3K27me3 expression was evident in 80% (8/10) lymphocytic thyroiditis, 63% (80/127) papillary thyroid cancer, 41% (7/17) follicular thyroid cancer, and 73% (8/11) poorly differentiated and anaplastic thyroid cancer. In differentiated thyroid cancer, strong H3K27me3 expression was associated with extrathyroidal extension (p

While metabolic syndrome can independently predict the development of diabetic kidney disease (DKD) in patients with type 2 diabetes, the risk factors for DKD progression have rarely been discussed. The purpose of this study is to evaluate the association between metabolic syndrome and the progression of DKD in patients with type 2 diabetes.This retrospective observational cohort study lasted approximately five years. We defined metabolic syndrome using the criteria of the National Cholesterol Education Program Adult Treatment Panel III with the Asian definition of obesity. The progression of DKD was demonstrated by either the progression of albuminuria or worsening renal function. Progression of albuminuria was defined by the transition from normoalbuminuria (30 mg/g) to microalbuminuria (30-300 mg/g) or from micro- to macroalbuminuria (300 mg/g). Worsening renal function was defined by a reduction of eGFR to 50% of the baseline or the doubling of serum creatinine. We adopted multivariate Cox-regression analysis to determine the risk factors associated with DKD progression.This study consisted of 935 type 2 diabetic patients with a mean age of 64.62 years. We found progression of albuminuria in 172 patients (18.4%) and worsened renal function in 41 patients (4.4%). After Cox regression analysis, the multivariable-adjusted HR for the progression of albuminuria and worsened renal function was 1.65 (95% C.I.:1.07-2.53 P = 0.022) and 2.62 (95% C.I.:1.01-6.79 P = 0.047) respectively, for those with metabolic syndrome compared to those without metabolic syndrome.The presence of metabolic syndrome independently predicts DKD progression in patients with type 2 diabetes.

Background The optimal extent of surgery for differentiated thyroid cancer may not be well recognized initially. Identification of intermediate-risk features on surgical pathology may prompt the need for completion thyroidectomy if a lobectomy is performed. In this study, we examined the factors in relation to the need for completion thyroidectomy. Methods We studied consecutive patients who underwent thyroidectomy for differentiated thyroid cancer from 2008 to 2017. Total thyroidectomy was indicated when tumor size >4 cm, clinical extrathyroidal extension, clinical lymph node metastasis, or distant metastasis was present. The need for completion thyroidectomy was defined as the presence of aggressive histology, extrathyroidal extension, lymphovascular invasion, or non–low-risk nodal metastasis. Results Among 771 patients, 155 (20%) were definitely indicated for total thyroidectomy. The need for completion thyroidectomy was identified in 273 (44%) of the 616 patients initially eligible for lobectomy. The proportions of patients requiring completion thyroidectomy were 18% and 57% for microcarcinomas and tumors of 1–4 cm, respectively. Receiver operating characteristic curve analysis indicated that tumor size ≥1.1 cm had the highest accuracy of prediction. Multivariate logistic regression revealed that tumor size and BRAF V600E mutation were independent factors predicting the risk of requiring completion thyroidectomy. Conclusion A substantial portion of patients with differentiated thyroid cancer who are preoperatively eligible for lobectomy would be found to have intermediate-risk pathologic features. This should be incorporated into the shared decision making before surgery.

SPINT1, also known as HAI-1, is a Kunitz-type serine protease inhibitor that inhibits multiple proteases including hepatocyte growth factor (HGF) activator and matriptase. SPINT1 has been shown to modulate HGF/MET activation in certain cancer types. In the present study, we analyzed microarray datasets and found that SPINT1 was consistently upregulated in differentiated thyroid cancer. SPINT1 protein expression was investigated using tissue microarrays and independent samples of our 143 patients. Strong SPINT1 expression was observed in 61-68% of papillary thyroid cancer and 41-50% of follicular thyroid cancer. The overexpression diminished in anaplastic thyroid cancer. The SPINT1 expression in normal thyroid tissues and benign thyroid lesions was low. Furthermore, we noted that the SPINT1 expression was associated with extrathyroidal invasion, lymphovascular invasion, lymph node metastasis, advanced TNM stage, and a higher risk of recurrence in differentiated thyroid cancer. The results were in accordance with our analysis of The Cancer Genome Atlas data. In conclusion, an overexpression of SPINT1 appears to be associated with an invasive phenotype in differentiated thyroid cancer.

Background: Previously we have shown that an elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a high risk of recurrence in patients with differentiated thyroid cancer. The clinical significance of the longitudinal changes in NLR following treatment remained unestablished. Methods: Adults patients with differentiated thyroid cancer were included in the study if the follow-up NLR data at 6 to 18 months after initial treatment were available. The response to treatment was categorized as excellent, indeterminate, biochemical incomplete, and structural incomplete as per guidelines of the American Thyroid Association. Results: Among 151 patients with thyroid cancer, a significant decrease in NLR following treatment was observed in those with stage I disease, those with low risk of recurrence, and those with an excellent response to therapy. Patients with a structural incomplete response had a significant increase in NLR at follow-up (p = 0.012). On multivariate analysis, incomplete response to therapy was associated with male sex (odds ratio [OR] = 3.35), tumor size (OR = 1.63), lymph node metastasis (OR = 4.80), distant metastasis (OR = 12.95), and increased NLR (OR = 13.68). Conclusions: An increase in systemic inflammation following treatment as measured by NLR is independently associated with an incomplete response to therapy in differentiated thyroid cancer.

Background Recurrence of papillary thyroid cancer is not uncommon, but incorporating clinicopathologic parameters to predict recurrence is suboptimal. The aim of this study was to identify systemically recurrence-associated genes using The Cancer Genome Atlas RNA sequencing database. Methods A total of 504 patients with transcriptome sequencing data of the primary neoplasm were included in this study. High and low levels of expression of each gene were defined by median splits. Differences in recurrence-free survival were compared using Kaplan-Meier curves and log-rank tests. Recurrence-associated genes were subjected to functional enrichment analyses with Kyoto Encyclopedia of Genes and Genomes annotation databases and Ingenuity Pathway Analysis. Results We found that 1,807 genes were associated with recurrence-free survival. There were 676 genes of which high expression was associated with a greater risk of recurrence. These genes were enriched in pathways involved in cell cycle regulation and DNA repair. Among 1,131 genes of which low expression was associated with recurrence, Kyoto Encyclopedia of Genes and Genomes–annotated functions were metabolism, calcium signaling, glycan biosynthesis, and the Notch signaling pathway. Canonical pathways identified by Ingenuity Pathway Analysis included RXR function, nitric oxide signaling, interleukin-8 signaling, and nutrient sensing. In addition, low expression of the majority of thyroid differentiation genes was associated with a significantly less recurrence-free survival. Conclusion Upregulation of cell cycle–regulating and DNA repair genes appears to have a negative impact on recurrence-free survival in patients with papillary thyroid cancer. Furthermore, recurrence is associated with thyroid dedifferentiation.

Context Dipeptidyl peptidase IV (DPP4) is overexpressed in thyroid cancer and certain malignancies. Furthermore, DPP4 has been identified as a discriminatory marker for thyroid cancer. However, it remains unclear whether DPP4 expression plays a prognostic role. Objective The aim of this study was to investigate the expression and function of DPP4 in thyroid cancer and the mechanisms involved. Design We determined the expression of DPP4 by immunohistochemistry in tissue microarrays of thyroid tumors. In vitro functional studies were performed after genetic and pharmacological inhibition of DPP4. Gene expression and pathway analyses were used to identify downstream targets. The therapeutic potential of DPP4 inhibition was evaluated in a mouse xenograft model. Results High DPP4 expression was associated with extrathyroidal extension (P < 0.001), BRAF mutation (P < 0.001), and advanced tumor stage (P = 0.007) in papillary thyroid cancer. Patients in the high-DPP4 expression group were less likely to be classified as having no evidence of disease at final follow-up (P = 0.042). DPP4 silencing or treatment with DPP4 inhibitors significantly suppressed colony formation, cell migration, and invasion. Analysis of differentially expressed genes after DPP4 knockdown suggested that the transforming growth factor-β signaling pathway is involved. In vivo experiments revealed that sitagliptin treatment reduced tumor growth and xenograft transforming growth factor-β receptor I expression. Conclusions Increased DPP4 expression is associated with cellular invasion and more aggressive disease in papillary thyroid cancer. Targeting DPP4 may be a therapeutic strategy for DPP4-expressing thyroid cancer.

Objective: Extrathyroidal extension may not be accurately recognized during thyroidectomy and can increase the risk of positive margins and even recurrence. This study aimed to investigate the preoperative factors associated with extrathyroidal extension. Methods: We analyzed 887 patients with papillary thyroid cancer (PTC) who underwent surgery in the period of 2005–2017. Binary logistic regression analyses and generalized additive models were used to identify associations. Results: Minimal extrathyroidal extension was present in 233 (26%) patients and advanced extrathyroidal extension was found in 60 (7%) patients. Age, BMI, and tumor size were independent predictors of all or advanced extrathyroidal extension. Among the 493 patients whose BRAF mutation status was available, age (OR = 1.025), BMI (OR = 1.091), tumor size (OR = 1.544), and BRAF V600E mutation (OR = 2.311) were independently associated with extrathyroidal extension. Conclusions: Older age, a greater BMI, a larger tumor size, and presence of the BRAF mutation were predictive of extrathyroidal extension. These factors should be taken into consideration in decision-making before surgery is performed.

Background Papillary thyroid microcarcinoma exhibits an indolent clinical course and could be a candidate for active surveillance in the appropriate setting. It remains unknown whether papillary microcarcinoma is biologically different from larger papillary carcinoma >1 cm. Methods We analyzed clinicopathological information and transcriptome data of papillary thyroid cancer samples from The Cancer Genome Atlas. Propensity-score matching was used to construct a matched cohort consisting of 29 microcarcinomas and 58 carcinomas. Principal component analysis and unsupervised hierarchical cluster analysis were carried out to investigate the similarity of gene expression profiles. Results After adjustment for differences in baseline clinicopathological and genetic factors, transcriptome could be grouped mainly on the basis of tumor class (BRAF-like vs RAS-like) and tumor size (microcarcinoma vs carcinoma). The gene set enrichment analysis showed that extracellular matrix-associated pathways were enriched in the MSigDB database. Conclusion Papillary thyroid microcarcinomas display a distinct gene expression pattern different from the corresponding carcinomas. We hypothesize that tumor microenvironment may play a role in the microcarcinoma/carcinoma phenotypic divergence.

Background and Objectives The induction of tumor-associated carbohydrate antigen results from altered glycosylation in transformed cells. Globo H is a hexasaccharide glycosphingolipid overexpressed on malignancies of epithelial origin and has become an attractive vaccine target. We aimed to investigate the expression patterns and prognostic value of Globo H in thyroid neoplasms. Methods Globo H expression was examined by immunohistochemical analysis using commercial and in-house tissue microarrays. The expression was correlated with clinicopathologic characteristics in papillary thyroid cancer. Results Normal or benign thyroid lesions were negative for Globo H expression. Globo H was positive in 33% medullary, 24% papillary, 11% undifferentiated, and 8% follicular thyroid cancer. Globo H expression in papillary thyroid cancer was associated with extrathyroidal invasion (P = 0.017), BRAF mutation (P = 0.010), AMES high risk (P = 0.045), and increased ATA risk of recurrence (P = 0.022). Conclusions Globo H is specifically expressed in a subset of thyroid malignancies. In papillary thyroid cancer, Globo H expression is associated with invasiveness and BRAF mutation. Immunotherapy targeting Globo H may have potential applications in thyroid cancer. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Aim: Addition of 1-3 dose of bolus insulin is recommended by ADA/EASD guidelines when basal insulin (BI) therapy becomes insufficient for T2DM patients to achieve HbA1c target of Method: 328 T2DM patients completed 48 weeks of stepwise intensification of PI + BI therapy (Main group). The primary objective of the study was to determine the mean change in HbA1c. Secondary objectives included; evaluation of change in FPG, 2h-PPG, PI and BI dose and the rate of HbA1c Result: Mean HbA1c was 9.16% in Main group at baseline. At week 48, significant difference in mean HbA1c change (-0.59 ± 1.16% vs. -0.07 ± 1.06%; p Conclusion: This study demonstrated the introduction of stepwise intensification of prandial insulin leads to greater improvements in HbA1c levels than basal insulin monotherapy in T2DM patients in Taiwan and this effect can be maintained during the study period of 48 weeks. Disclosure Y. Hung: Advisory Panel; Self; Sanofi. Y. Huang: Research Support; Self; Sanofi. H. Chen: Research Support; Self; Sanofi. R. Liu: Research Support; Self; Sanofi. N.C. Yu: None. H. Lam: None. C. Huang: Research Support; Self; Sanofi. C. Chen: Research Support; Self; Sanofi. P. Hsiao: Advisory Panel; Self; Sanofi. H. Chen: None. M. Chien: Research Support; Self; Sanofi. T. Lee: None. C.Y. Yang: None. C. Chen: Advisory Panel; Self; Sanofi-Aventis. S. Tu: None. H. Chen: None. W. Sheu: Advisory Panel; Self; Sanofi.

CD74, the invariant chain of major histocompatibility complex class II, is also a receptor for macrophage migration inhibitory factor (MIF). CD74 and MIF have been associated with tumor progression and metastasis in hematologic and solid tumors. In this study, we found that 60 and 65% of papillary thyroid cancers were positive for CD74 and MIF immunohistochemical staining respectively. Anaplastic thyroid cancer was negative for MIF, but mostly positive for CD74 expression. Normal thyroid tissue and follicular adenomas were negative for CD74 expression. CD74 expression in papillary thyroid cancer was associated with larger tumor size (P=0.043), extrathyroidal invasion (P=0.021), advanced TNM stage (P=0.006), and higher MACIS score (P=0.026). No clinicopathological parameter was associated with MIF expression. Treatment with anti-CD74 antibody in thyroid cancer cells inhibited cell growth, colony formation, cell migration and invasion, and vascular endothelial growth factor secretion. In contrast, treatment with recombinant MIF induced an increase in cell invasion. Anti-CD74 treatment reduced AKT phosphorylation and stimulated AMPK activation. Our findings suggest that CD74 overexpression in thyroid cancer is associated with advanced tumor stage and may serve as a therapeutic target.

Introduction Primary hyperparathyroidism (PHPT) is associated with adverse cardiovascular outcomes which may result from an increase in systemic inflammation. Previously we have shown that serum parathyroid hormone (PTH) levels are independently associated with inflammatory indicators. The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive, widely available marker of inflammation. In the present study, we aimed to assess the longitudinal changes in NLR before and after parathyroidectomy. Material and methods This retrospective study included 95 patients diagnosed with PHPT who underwent parathyroidectomy between 2006 and 2016. Follow-up complete blood counts were available in 31 patients. Results At diagnosis, 43 (45%) patients presented with overt clinical symptoms and had higher serum calcium and PTH levels. Preoperative NLR was positively correlated with total white blood cell count (p = 0.001), serum calcium (p = 0.001), and PTH level (p = 0.013). The NLR was not associated with sex, age, comorbidities, or parathyroid weight. Among patients who were cured of PHPT, the median NLR decreased from 2.26 to 1.77 after parathyroidectomy (p = 0.037). There was no difference in hemoglobin, total white blood cells, or platelet count before and after surgery. Conclusions We found a positive correlation of preoperative NLR with calcium and PTH levels in PHPT patients. After curative parathyroidectomy, NLR modestly decreased without changes in other hematological parameters.

Background Telomerase reverse transcriptase (TERT) promoter mutations have recently been identified as an important prognostic factor in thyroid cancer. Studies suggest that TERT may have noncanonical functions beyond telomere maintenance. Methods Clinicopathological information and transcriptome data for papillary thyroid carcinoma (PTC) samples were obtained from The Cancer Genome Atlas (TCGA). Propensity score matching was performed to adjust for potential confounding variables between the TERT promoter wild-type group and the mutant group. Gene expression data of 36 patients in the mutant group were systemically compared to those of 72 patients in the wild-type group. Results Tumors with TERT promoter mutations had a higher TERT expression. Pathways central to DNA damage responses and cell cycle regulation were significantly enriched among 888 upregulated genes. Transporter and metabolic activities were overrepresented among 799 downregulated genes. There was no difference in the expression of most of the thyroid differentiation genes. Conclusion The TERT promoter mutations were associated with proliferative and metabolic alterations in PTC.

Somatic BRAF mutation is frequently observed in papillary thyroid carcinoma (PTC). Recent evidence suggests that PTCs are heterogeneous tumors containing a subclonal or oligoclonal occurrence of BRAF mutation. Conflicting results have been reported concerning the prognostic significance of the mutant allele frequency. Our present aim was to investigate the association between the percentage of BRAF c.1799T > A (p.Val600Glu) alleles and clinicopathological parameters in PTC. Genomic DNA was extracted from fresh-frozen specimens obtained from 50 PTC patients undergoing total thyroidectomy. The BRAF mutation status was determined by Sanger sequencing. The percentage of mutant BRAF alleles was quantified by mass spectrometric genotyping, pyrosequencing, and competitive allele-specific TaqMan PCR (castPCR). Positive rate of BRAF mutation was 72 % by Sanger sequencing, 82 % by mass spectrometric genotying, and 84 % by pyrosequencing or castPCR. The average percentage of mutant BRAF alleles was 22.5, 31, and 30.7 %, respectively. There was a good correlation among three quantification methods (Spearman’s rho = 0.87–0.97; p

Although papillary thyroid cancer is a relatively indolent malignancy, its progression may be associated with dedifferentiation and resistance to radioactive iodine treatment. In this study, patterns of differentially expressed genes in association with disease progression were systemically evaluated. We firstly performed transcriptome analyses for four matched cancerous and noncancerous tissue pairs of the classical subtype of papillary thyroid cancer. Among the upregulated and downregulated genes, the expression of 164 and 183 genes increased and decreased, respectively, from stage I to stage IV. Functional enrichment and pathway analysis showed that angiogenesis pathway was upregulated, whereas oxidation–reduction and metabolism of reactive oxygen species were downregulated. Teneurin transmembrane protein 1 (TENM1) expression was highly upregulated in cancerous tissues and negative in benign thyroid tissues. By immunohistochemistry, TENM1 expression in papillary thyroid cancer was associated with the classical subtype (p = 0.018), extrathyroidal invasion (p = 0.001), BRAF V600E mutation (p

The induction of tumor-associated carbohydrate antigen results from altered glycosylation in transformed cells. Globo H is a hexasaccharide glycosphingolipid overexpressed on malignancies of epithelial origin and has become an attractive vaccine target. We aimed to investigate the expression patterns and prognostic value of Globo H in thyroid neoplasms.Globo H expression was examined by immunohistochemical analysis using commercial and in-house tissue microarrays. The expression was correlated with clinicopathologic characteristics in papillary thyroid cancer.Normal or benign thyroid lesions were negative for Globo H expression. Globo H was positive in 33% medullary, 24% papillary, 11% undifferentiated, and 8% follicular thyroid cancer. Globo H expression in papillary thyroid cancer was associated with extrathyroidal invasion (P = 0.017), BRAF mutation (P = 0.010), AMES high risk (P = 0.045), and increased ATA risk of recurrence (P = 0.022).Globo H is specifically expressed in a subset of thyroid malignancies. In papillary thyroid cancer, Globo H expression is associated with invasiveness and BRAF mutation. Immunotherapy targeting Globo H may have potential applications in thyroid cancer. J. Surg. Oncol. 2016;114:853-858. © 2016 2016 Wiley Periodicals, Inc.

Tuberculosis (TB) risk might be increased in patients with diabetes by factors other than hyperglycaemia, such as dyslipidaemia. Host lipids are essential energy sources used by mycobacteria to persist in a latent TB state. A potential therapy targeting cholesterol catabolism of mycobacteria has been proposed, but the potential of cholesterol-lowering drugs as anti-TB therapy is unclear. The purpose of this study was to determine the effects of ezetimibe, a 2-azetidinone cholesterol absorption inhibitor, on intracellular mycobacteria survival and dormancy.Intracellular mycobacteria survival was determined by measurements of ATP activity and colony-formation units (CFUs). Gene expression profiles of hypoxia-induced dormant Mycobacterium tuberculosis (Mtb) were analysed by real-time PCR. Flow cytometry and microscopy analysis were used to measure the lipid loads of human macrophages with or without ezetimibe treatment. QuantiFERON-TB Gold In-Tube (QFT-G-IT) assays were performed to diagnose latent TB infection. The levels of intracellular cholesterol/ triglyceride were measured by an enzymatic fluorometric method.Ezetimibe was capable of effectively lowering intracellular growth of Mtb and hypoxia-induced dormant Mtb. There was a significant decrease in Mtb growth in leucocytes from ezetimibe-treated patients with diabetes in terms of ATP levels of intracellular mycobacteria and CFU formation. Also, patients receiving ezetimibe therapy had a lower prevalence of latent TB and had lower intracellular lipid contents.Ezetimibe, which is a currently marketed drug, could hold promise as an adjunctive, host-directed therapy for TB.

Background: To evaluate the effectiveness and tolerability of add-on sitagliptin in elderly Taiwanese patients with Type 2 diabetes mellitus who have inadequate glycemic control to existing oral antidiabetic agents (OADs) combination regimens. Methods: Patients were randomized to receive the existing OAD combinations or add-on with sitagliptin (100 mg daily) for 24 weeks. We measured HbA1c, fasting plasma glucose, 2-hours postprandial plasma glucose, body mass index, and recorded the hypoglycemic episodes before and after 24 weeks of adding sitagliptin 100 mg once daily to existing maximal dose of OAD combination therapy for 24 weeks. Results: Compared with the change of 0.0% (95% confidence interval: −0.6% to 0.5%) from a baseline of 10.0% in the controlled arm, HbA1c change from a mean baseline of 9.5% was −1.14%±1.18 after add-on sitagliptin. Confirming significant differences (p

Background: Mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene have recently been described in thyroid cancer and have been linked with poor prognosis. The mutations result in cancer-specific telomerase reactivation. However, functional effects of TERT promoter mutations other than telomere maintenance remain elusive. Methods: We examined papillary thyroid cancer data from The Cancer Genome Atlas. Clinicopathologic characteristics were compared between patients with or without TERT promoter mutations. A control cohort was selected from patients without TERT promoter mutations by propensity score matching. Differentially expressed genes were generated by comparing transcriptome profiling between the two groups. Results: A total of 382 patients with papillary thyroid cancer were included for analysis. TERT promoter mutations were identified in 36 patients. TERT promoter mutations were associated with older age, larger tumor size, the presence of extrathyroidal extension, more advanced TNM stage, and high risk of recurrence. Following propensity score matching, pathway analysis of differentially expressed genes indicated that TERT promoter mutations were associated with upregulation of DNA damage response and downregulation of nitric oxide signaling and fatty acid β-oxidation. Conclusion: Our results confirmed that acquisition of TERT promoter mutations in papillary thyroid cancer leads to bypass of replicative senescence. Furthermore, the mutations may be associated with other signaling and metabolic alterations. Our findings can potentially identify extended therapeutic targets. Citation Format: Shih-Ping Cheng, Ming-Nan Chien, Chien-Liang Liu, Yi-Chiung Hsu, Po-Sheng Yang, Jie-Jen Lee. Transcriptome evaluation of papillary thyroid cancer with TERT promoter mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A194.

Aims/Introduction The aim of the present study was to assess the glycemic control, adherence and treatment satisfaction in a real-world setting with basal insulin therapy in type 2 diabetes patients in Taiwan. Materials and Methods This was a multicenter, prospective, observational registry. A total of 836 patients with type 2 diabetes taking oral antidiabetic drugs with glycated hemoglobin (HbA1c) >7% entered the study. Basal insulin was given for 24 weeks. All treatment choices and medical instructions were at the physician's discretion to reflect real-life practice. Results After 24-week treatment, 11.7% of patients reached set HbA1c goals without severe hypoglycemia (primary effectiveness end-point). HbA1c and fasting blood glucose were significantly decreased from (mean ± SD) 10.1 ± 1.9% to 8.7 ± 1.7% (−1.4 ± 2.1%, P < 0.0001) and from 230.6 ± 68.8 mg/dL to 159.1 ± 55.6 mg/dL (−67.4 ± 72.3 mg/dL, P < 0.0001), respectively. Patients received insulin therapy at a frequency of nearly one shot per day on average, whereas self-monitoring of blood glucose was carried out approximately four times a week. Hypoglycemia was reported by 11.4% of patients, and only 0.7% of patients experienced severe hypoglycemia. Slight changes in weight (0.7 ± 2.4 kg) and a low incidence of adverse drug reactions (0.4%) were also noted. The score of 7-point treatment satisfaction rated by patients was significantly improved by 1.9 ± 1.7 (P < 0.0001). Conclusions Basal insulin therapy was associated with a decrease in HbA1c and fasting blood glucose, and an improved treatment satisfaction. Most patients complied with physicians' instructions. The treatment was generally well tolerated by patients with type 2 diabetes, but findings pointed out the need to reinforce the early and appropriate uptitration to achieve treatment targets.

Oral squamous cell carcinoma is a common neoplasm that is known to be causally associated with genetic factors and environmental carcinogens. The receptor for advanced glycosylation endproducts (RAGE) is a transmembrane protein of the immunoglobulin superfamily with broad specificity for multiple ligands, and it has been shown to play vital roles in several pathophysiologic processes, including diabetes, Alzheimer disease, renal disease, cardiovascular disease, and cancer. The present study aimed to assess the influences of RAGE gene polymorphisms, combined with environmental carcinogens on the predisposition to oral tumorigenesis. Five polymorphisms of the RAGE gene—including −374T>A (rs1800624), −429T>C (rs1800625), 1704G>T (rs184003), Gly82Ser (rs2070600), and a 63-bp deletion allele (−407 to −345)—were examined from 592 controls and 618 patients with oral cancer. We found that individuals carrying the polymorphic allele of rs1800625 are more susceptible to oral cancer (odds ratio [OR], 1.899; 95% confidence interval [CI], 1.355 to 2.661; adjusted OR [AOR], 2.053; 95% CI, 1.269 to 3.345) after adjustment for age, sex, betel nut chewing, and tobacco consumption. Moreover, we observed a significant association of rs1800625 variants with late-stage tumors (stage III/IV, OR, 1.736; 95% CI, 1.126 to 2.677; AOR, 1.771; 95% CI, 1.101 to 2.851) and large-size tumors (>2 cm in the greatest dimension; OR, 1.644; 95% CI, 1.083 to 2.493; AOR, 1.728; 95% CI, 1.089 to 2.741). Based on behavioral exposure of environmental carcinogens, the presence of 4 RAGE single-nucleotide polymorphisms (SNPs), combined with betel quid chewing and/or tobacco use, greatly augmented the risk of oral cancer. In addition, carriers of particular haplotypes of the 4 RAGE SNPs examined are more prone to develop oral cancer. These results indicate an involvement of RAGE SNP rs1800625 in the development of oral squamous cell carcinoma and implicate the interaction between RAGE gene polymorphisms and environmental mutagens as a predisposing factor of oral carcinogenesis.