Objective: To determine the association of macrocalcification and rim calcification with malignancy and to stratify the malignancy risk of thyroid nodules with macrocalcification and rim calcification based on ultrasound (US) patterns. Materials and Methods: The study included a total of 3603 consecutive nodules (≥ 1 cm) with final diagnoses. The associations of macrocalcification and rim calcification with malignancy and malignancy risk of the nodules were assessed overall and in subgroups based on the US patterns of the nodules. The malignancy risk of the thyroid nodules was categorized as high (> 50%), intermediate (upper-intermediate: > 30%, ≤ 50%; lower-intermediate: > 10%, ≤ 30%), and low (≤ 10%). Results: Macrocalcification was independently associated with malignancy in all nodules and solid hypoechoic (SH) nodules (p < 0.001). Rim calcification was not associated with malignancy in all nodules (p = 0.802); however, it was independently associated with malignancy in partially cystic or isoechoic and hyperechoic (PCIH) nodules (p = 0.010). The malignancy risks of nodules with macrocalcification were classified as upper-intermediate and high in SH nodules, and as low and lowerintermediate in PCIH nodules based on suspicious US features. The malignancy risks of nodules with rim calcification were stratified as low and lower-intermediate based on suspicious US features. Conclusion Macrocalcification increased the malignancy risk in all and SH nodules with or without suspicious US features, with low to high malignancy risks depending on the US patterns. Rim calcification increased the malignancy risk in PCIH nodules, with low and lower-intermediate malignancy risks based on suspicious US features. However, the role of rim calcification in risk stratification of thyroid nodules remains uncertain.

Purpose: This study was conducted to determine the malignancy risk and diagnostic value of various types of nonshadowing echogenic foci (NEF) in the risk stratification of thyroid nodules. Methods: A total of 1,018 consecutive thyroid nodules (≥1 cm) with final diagnoses were included. The presence of NEF was determined and types of NEF were classified according to the presence of a comet tail artifact (CTA), location, and size through a prospective evaluation. The associations with malignancy, malignancy risk, and diagnostic value of various types of NEF were assessed. Results: Intrasolid punctate NEF without CTA was the only type of NEF that was an independent predictor of malignancy (P<0.001). The malignancy risk of intrasolid punctate NEF without CTA was substantially higher in solid hypoechoic nodules than in isoechoic or nonsolid nodules (71.3% vs. 9.2%, P<0.001). In solid hypoechoic nodules, slightly increased sensitivity (70.8% vs. 67.9%) for malignancy and a similar malignancy risk (71.4% vs. 71.3%) were observed for intrasolid punctate NEF (with or without CTA) and intrasolid punctate NEF without CTA, respectively. NEF with CTA at the margin of the cystic component was not associated with malignancy or benignity in nonsolid nodules (P>0.05). Conclusion Intrasolid punctate NEF without CTA was the only independent predictor of malignancy. However, solid hypoechoic nodules with intrasolid punctate NEF should be classified as high-suspicion nodules regardless of coexisting CTA. Other types of NEF had no added value for detecting malignancy compared to intrasolid punctate NEF without CTA.

Purpose: The aim of this study was to evaluate the diagnostic performance of the modified Korean Thyroid Imaging Reporting and Data System (K-TIRADS) compared with five society risk stratification systems (RSSs) according to nodule size. Methods: In total, 3,826 consecutive thyroid nodules (≥1 cm) with final diagnoses in 3,088 patients were classified according to five RSSs. The K-TIRADS was modified by raising the biopsy size threshold for low-suspicion nodules and subcategorizing intermediate-suspicion nodules. We assessed the performance of the RSSs as triage tests and their diagnostic accuracy according to nodule size (with a threshold of 2 cm). Results: Of all nodules, 3,277 (85.7%) were benign and 549 (14.3%) were malignant. In small thyroid nodules (≤2 cm), the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) had the highest reduction rate of unnecessary biopsies (76.3%) and the lowest sensitivity (76.1%). The modified K-TIRADS had the second highest reduction rate of unnecessary biopsies (67.6%) and sensitivity (86.6%). The modified K-TIRADS and ACR TI-RADS had the highest diagnostic odds ratios (P=0.165) and the highest areas under the curve (P=0.315). In large nodules (>2 cm), the sensitivity of the ACR TI-RADS for malignancy was significantly lower (88.8%) than the sensitivities of the modified K-TIRADS and other RSSs, which were very high (98.7%-99.3%) (P<0.001). Conclusion The modified K-TIRADS allows a large proportion of unnecessary biopsies to be avoided, while maintaining high sensitivity and diagnostic accuracy for small malignant tumors and very high sensitivity for large malignant tumors.

Objective: To determine the association of macrocalcification and rim calcification with malignancy and to stratify the malignancy risk of thyroid nodules with macrocalcification and rim calcification based on ultrasound (US) patterns. Materials and Methods: The study included a total of 3603 consecutive nodules (≥ 1 cm) with final diagnoses. The associations of macrocalcification and rim calcification with malignancy and malignancy risk of the nodules were assessed overall and in subgroups based on the US patterns of the nodules. The malignancy risk of the thyroid nodules was categorized as high (> 50%), intermediate (upper-intermediate: > 30%, ≤ 50%; lower-intermediate: > 10%, ≤ 30%), and low (≤ 10%). Results: Macrocalcification was independently associated with malignancy in all nodules and solid hypoechoic (SH) nodules (p < 0.001). Rim calcification was not associated with malignancy in all nodules (p = 0.802); however, it was independently associated with malignancy in partially cystic or isoechoic and hyperechoic (PCIH) nodules (p = 0.010). The malignancy risks of nodules with macrocalcification were classified as upper-intermediate and high in SH nodules, and as low and lowerintermediate in PCIH nodules based on suspicious US features. The malignancy risks of nodules with rim calcification were stratified as low and lower-intermediate based on suspicious US features. Conclusion Macrocalcification increased the malignancy risk in all and SH nodules with or without suspicious US features, with low to high malignancy risks depending on the US patterns. Rim calcification increased the malignancy risk in PCIH nodules, with low and lower-intermediate malignancy risks based on suspicious US features. However, the role of rim calcification in risk stratification of thyroid nodules remains uncertain.

Objective: To determine the malignancy risk of isolated macrocalcifications (a calcified nodule with complete posterioracoustic shadowing) detected on ultrasonography (US) and to evaluate the postoperative American Thyroid Association (ATA)risk stratification of malignant tumors manifesting as isolated macrocalcifications. Materials and Methods: A total of 3852 thyroid nodules (≥ 1 cm) of 3061 consecutive patients who had undergone biopsybetween January 2011 and June 2018 were included in this study. We assessed the prevalence, malignancy rate, and sizedistribution of isolated macrocalcifications and evaluated the histopathologic features and postoperative ATA risk stratificationof malignant tumors manifesting as isolated macrocalcifications. Results: Isolated macrocalcifications were found in 38 (1.2%) of the 3061 patients. Final diagnosis was established in 30(78.9%) nodules; seven malignant tumors were diagnosed as papillary thyroid carcinomas (PTCs). The malignancy rate of theisolated macrocalcifications was 23.3% in the 30 nodules with final diagnoses and 18.4% in all nodules. Among the sixsurgically-treated malignant tumors, five (83.3%) had an extrathyroidal extension (ETE) (minor ETE 1, gross ETE 4), and two(33.3%) had macroscopic lymph node metastasis. Four (66.7%) malignant tumors were categorized as high-risk tumors, one asan intermediate-risk tumor, and one as a low-risk tumor using the ATA risk stratification. Histopathologically, out of the sixmalignant tumors, ossifications were noted in four (66.7%) and predominant calcifications in two (33.3%). Conclusion The US pattern of isolated macrocalcifications (≥ 1 cm) showed an intermediate malignancy risk (at least 18.4%).All malignant tumors were PTCs, and most showed an aggressive behavior and a high or intermediate postoperative ATA risk.

Purpose: A thyroid nodule with an isolated macrocalcification is visualized as a calcified nodule with complete posterior shadowing on ultrasonography (US). This study aimed to determine the computed tomography (CT) features of isolated macrocalcifications detected using US. Methods: This study included 20 patients who had thyroid nodules with isolated macroalcifications and underwent neck CT or chest CT. The patients were enrolled from a sample of 82 patients with isolated macrocalcifications detected by US drawn from 7,142 consecutive patients who underwent thyroid biopsy at two institutions. We evaluated the CT features of nodules with isolated macrocalcifications and categorized them as central or rim calcifications. We assessed the nodule size and the frequency of nondiagnostic fine-needle aspiration (FNA) results and malignant tumors according to the CT features of isolated macrocalcifications. Results: CT scans showed central calcifications in 18 (90.0%) and rim calcifications in two (10.0%) of the 20 nodules with isolated macrocalcifications. Among the 18 nodules with central isolated macrocalcifications, complete compact calcification was found in six nodules and partial coarse calcification in 12 nodules. In 18 nodules with central isolated macrocalcifications, the nondiagnostic FNA rate and frequency of malignant tumors were not significantly different between complete and partial central calcifications (P=0.620 and P=0.999, respectively). Malignant tumors were only found in nodules with central isolated macrocalcifications. Conclusion The majority of nodules with isolated macrocalcifications showed central calcifications on CT. Thyroid nodules with isolated macrocalcifications detected by US should not be classified as having a type of rim or peripheral calcification.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. MATERIALS AND METHODS: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. RESULTS: Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). CONCLUSION: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.
Biomarkers ; Carcinoma, Squamous Cell* ; Cisplatin ; Epithelial Cells* ; Head* ; Humans ; Korea ; Molecular Targeted Therapy ; Neck* ; Precision Medicine ; Statistics as Topic

BACKGROUND: The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.METHODS: We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.RESULTS: Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with thein vivoresults, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.CONCLUSION: The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.
Animals ; Atrophy ; Blotting, Western ; Diabetic Nephropathies ; Dipeptidyl-Peptidase IV Inhibitors ; Down-Regulation ; Fibrosis ; Humans ; Hypoglycemic Agents ; In Vitro Techniques ; Inflammasomes ; Inflammation ; Kidney ; Mice ; Ureteral Obstruction

BACKGROUND: Renal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice. METHODS: We examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study. RESULTS: Through hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway. CONCLUSION: The present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.
Actins ; Animals ; Atrophy ; Blotting, Western ; Collagen Type I ; Diabetic Nephropathies ; Fibroblasts ; Fibrosis* ; In Vitro Techniques ; Mesangial Cells ; Mice* ; Peroxisomes* ; Phosphorylation ; Plasminogen Activator Inhibitor 1 ; Polymerase Chain Reaction ; Rats ; Renal Insufficiency, Chronic ; Reverse Transcription ; Transforming Growth Factor beta ; Transforming Growth Factors ; Up-Regulation ; Ureter* ; Ureteral Obstruction*

Hepatic steatosis is common in obese individuals with hyperinsulinemia and is an important hepatic manifestation of metabolic syndrome. Sterol regulatory binding protein-1c (SREBP-1c) is a master regulator of lipogenic gene expression in the liver. Hyperinsulinemia induces transcription of SREBP-1c via activation of liver X receptor (LXR) and specificity protein 1 (Sp1). Cilostazol is an antiplatelet agent that prevents atherosclerosis and decreases serum triglyceride levels. However, little is known about the effects of cilostazol on hepatic lipogenesis. Here, we examined the role of cilostazol in the regulation of SREBP-1c transcription in the liver. The effects of cilostazol on the expression of SREBP-1c and its target genes in response to insulin or an LXR agonist (T0901317) were examined using real-time RT-PCR and western blot analysis on cultured hepatocytes. To investigate the effect of cilostazol on SREBP-1c at the transcriptional level, transient transfection reporter assays and electrophoretic mobility shift assays (EMSAs) were performed. Cilostazol inhibited insulin-induced and LXR-agonist-induced expression of SREBP-1c and its downstream targets, acetyl-CoA carboxylase and fatty acid synthase, in cultured hepatocytes. Cilostazol also inhibited activation of the SREBP-1c promoter by insulin, T0901317 and Sp1 in a luciferase reporter assay. EMSA analysis showed that cilostazol inhibits SREBP-1c expression by repressing the binding of LXR and Sp1 to the promoter region. These results indicate that cilostazol inhibits insulin-induced hepatic SREBP-1c expression via the inhibition of LXR and Sp1 activity and that cilostazol is a negative regulator of hepatic lipogenesis.
Animals ; Cells, Cultured ; Hep G2 Cells ; Hepatocytes/drug effects/*metabolism ; Humans ; Hydrocarbons, Fluorinated/pharmacology ; Insulin/pharmacology ; Lipogenesis ; Mice ; Mice, Inbred C57BL ; Orphan Nuclear Receptors/agonists/*metabolism ; Promoter Regions, Genetic ; Protein Binding ; Rats ; Sp1 Transcription Factor/*metabolism ; Sterol Regulatory Element Binding Protein 1/genetics/*metabolism ; Sulfonamides/pharmacology ; Tetrazoles/*pharmacology