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Purpose: Endothelial dysfunction, which was associated with chronic hypothyroidism, was an early event in atherosclerosis. Whether short-term hypothyroidism following thyroxine withdrawal during radioiodine (RAI) therapy was associated with endothelial dysfunction in patients with differentiated thyroid cancer (DTC) was unclear. Aim of the study is to assess whether short-term hypothyroidism could impair endothelial function in the whole process of RAI therapy. Methods: We recruited fifty-one patients who underwent surgery and would accept RAI therapy for DTC. We analyzed thyroid function, endothelial function and serum lipids levels in patients at three time points: the day before thyroxine withdrawal (P1), the day before RAI administration (P2) and 4–6 weeks after RAI therapy (P3). A high-resolution ultrasound named flow-mediated dilation (FMD) was used to measure endothelial function of the patients. Results: We defined the FMD(%) value decreasing by more than 1% as impaired value. We analyzed the changes of FMD, thyroid hormone and lipids at three time points. FMD (%) was impaired at P2 compared to P1 and was recovered at P3 after restoring LT4 therapy (P1 vs P2 vs P3, 8.05±1.55 vs 7.26±1.50 vs 7.79 ± 1.38, P = 0.438). Among all parameters, the change of LDL cholesterol (ΔLDL) was the only factor correlated negatively with the change of FMD (ΔFMD) throughout the RAI therapy process (P1 − 2, r=-0.326, P = 0.020; P2 − 3, r=-0.306, P = 0.029). Conclusion: Endothelial function was transiently impaired in DTC patients at short-term hypothyroidism state during the RAI therapy, and immediately returned to the same state before RAI therapy after restoring LT4 therapy.

Programmed cell death ligand 1 (PD‐L1), inducing T cell exhaustion to facilitate immune escape of tumor cells, is upregulated by interleukin 6 (IL‐6) in T cell lymphoma and ovarian cancer. The purpose of this study is to investigate the expression of IL‐6 and PD‐L1 in thyroid cancer, and whether IL‐6 regulates PD‐L1 expression. As a result, IL‐6 and PD‐L1 were highly expressed in thyroid cancer tissues. Multivariate logistic analysis showed that tumor size, distant metastasis, and risk stratification were significantly associated with IL‐6 expression (P, IL‐6 and PD‐L1 are highly expressed in thyroid cancer and correlate with disease aggressiveness. IL‐6 activates the MAPK and JAK‐STAT3 signaling pathways in thyroid cancer. In addition, IL‐6 promotes PD‐L1 transcription through the MAPK and JAK‐STAT3 signaling pathways, which function via transcription factors c‐Jun and stat3.

Background: It is important to properly understand the molecular mechanisms of aggressive tumors among papillary thyroid carcinomas (PTCs) that are often the most indolent. Hypoxia inducible factor-1α (HIF-1α), induced by hypoxia, plays pivotal roles in the development and metastasis of the many tumors, including PTCs. Upregulation of telomerase reverse transcriptase (TERT) activity is found in highly invasive PTCs. Further, previous studies have reported that autophagy serves as a protective mechanism to facilitate PTC cell survival. We, therefore, hypothesized that there was a link between HIF-1α, TERT, and autophagy in promoting PTC progression. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of HIF-1α, TERT, and autophagy marker, LC3-II, in matched PTC tumors and corresponding nontumor tissues. Two PTC cell lines (TPC-1 and BCPAP) were used in subsequent cytological function studies. Cell viability, proliferation, apoptosis, migration, and invasion were assessed during hypoxia, genetic enhancement and inhibition of TERT, and chemical and genetic inhibition of autophagy. The protein expression levels of the corresponding biomarkers were determined by Western blotting, and autophagy flow was detected. We characterized the molecular mechanism of PTC cell progression. Results: The protein expression levels of HIF-1α, TERT, and LC3-II were upregulated in PTCs and were significantly correlated with high tumor-node-metastasis stage. Further, an in vitro study indicated that HIF-1α induced by hypoxia functioned as a transcriptional activator by binding with sequences potentially located in the TERT promoter and was positively correlated with the malignant behavior of PTC cell lines. Overexpression of TERT inhibited the kinase activity of mammalian target of rapamycin (mTOR), resulting in the activation of autophagy. Functionally, TERT-induced autophagy provided a survival advantage to PTC cells during hypoxia stress. Conclusions: We identified a novel molecular mechanism involving the HIF-1α/TERT axis, which promoted PTC progression by inducing autophagy through mTOR during hypoxia stress. These findings may provide a basis for the new treatment of aggressive PTCs.

Distant metastases are rarely observed in patients with initial pathologically proven benign follicular nodules of the thyroid. This study aimed to evaluate the clinicopathological features and independent variables associated with survival in such patients with distant metastases. In total, 10,992 consecutive differentiated thyroid cancer (DTC) patients treated with 131I after total or near-total thyroidectomy from 2000 to 2018 were retrospectively reviewed. Thirty-nine patients with initial pathologically proven benign follicular nodules of the thyroid were enrolled. Among them, 26 were pathologically diagnosed as thyroid adenoma, 8 as benign nodular goiter, 4 as thyroid adenoma combined with benign nodular goiter, and 1 as normal thyroid tissue. Of 26 patients with the initial pathological slides obtained, eight cases were rediagnosed as minimally invasive thyroid carcinoma (MI-FTC), 10 as follicular tumor of uncertain malignant potential (FT-UMP), and five as well-differentiated tumor of UMP (WDT-UMP). Monitoring of thyroglobulin (Tg) changes after initial thyroidectomy and preablation-stimulated Tg (psTg) level were significantly associated with 5-year OS rate (P = 0.007 and P = 0.005, respectively). The presence of radioactive-refractory DTC (RR-DTC), monitoring of Tg changes after initial thyroidectomy, and psTg level had significant effects on 10-year OS rate (P = 0.002, P

To investigate whether tumor texture features derived from pretreatment with 18F-fluorodeoxyglucose positron emission tomography (FDG PET) can predict histological response or event-free survival (EFS) in patients with localized osteosarcoma of the extremities treated by neoadjuvant chemotherapy (NAC). We retrospectively reviewed 35 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with NAC and surgery. Primary tumor traditional parameters and texture features were measured for all 18F-FDG PET images prior to treatment. After surgery, histological responses to NAC were evaluated on the postsurgical specimens. A receiver operating characteristic curve (ROC) was constructed to evaluate the optimal predictive performance among the various indices. EFS was calculated using the Kaplan-Meier method and prognostic significance was assessed by Cox proportional hazards analysis. Pathologic examination revealed 16 (45.71%) good responders and 19 (54.29%) poor responders. Although both the texture features (least axis, dependence nonuniformity, run length nonuniformity, and size zone nonuniformity) and metabolic tumor volume (MTV) can predict tumor response of osteosarcoma to NAC, the traditional indicator MTV has the best performance according to ROC curve analysis (area under the curve = 0.918, p

Programmed cell death-ligand 1 (PD-L1) expression on tumor tissue has been associated with favorable response to anti-programmed cell death-receptor 1/PD-L1 therapy in many human cancers. Studies have reported that PD-L1 is also expressed in thyroid cancer. The objective of this paper is to introduce the potential predictive and therapeutic values of PD-L1 in thyroid cancer.A literature search was conducted in the PubMed database using the terms "PD-L1," "B7-H1," and "thyroid cancer." PD-L1 positivity was determined by immunohistochemical assay.The frequency of PD-L1 positivity in different studies ranged from 6.1 to 82.5% in papillary thyroid cancer (PTC) patients and 22.2 to 81.2% in anaplastic thyroid cancer (ATC) patients. PD-L1 positivity rate was higher in ATC than in PTC within the same studies, and its expression intensity was significantly higher in tumor tissue than in the corresponding nontumor thyroid tissues. Moreover, PD-L1 expression was positively associated with the aggressiveness and recurrence of thyroid cancers and negatively associated with the differentiation status and outcomes. PD-L1 checkpoint pathway blockade may emerge as a promising therapeutic target in the treatment of thyroid cancers.PD-L1 is a potential biomarker to predict the recurrence and prognosis of thyroid cancers. It is also a novel immunotherapy target for optimizing the management landscape of radioiodine-refractory and ATCs.ATC = anaplastic thyroid cancer; DTC = differentiated thyroid cancer; IHC = immunohistochemical; OS = overall survival; PD-1 = programmed cell death-receptor 1; PD-L1 = programmed cell death-ligand 1; PD-L2 = programmed cell death-ligand 2; PTC = papillary thyroid cancer; TNM = tumor-node-metastasis; Treg = regulatory T cell.

ObjectiveThe objective of this study was to investigate the clinicopathological characteristics, long-term outcomes, and prognostic factors of elderly patients with distant metastases at initial diagnosis from well-differentiated thyroid cancer (WDTC) during radioactive iodine (131I) treatment and follow-up.MethodsA retrospective review of medical records identified 183 elderly patients with DTC who underwent 131I treatment at our institution between 2006 and 2019.ResultsIn total, 57 elderly WDTC patients with distant metastases were enrolled in this study. After 131I treatment, 32 (56.14%) patients had 131I avidity and 25 (43.86%) had non-131I avidity; 35 (61.40%) cases were classified as radioiodine refractory (RR)-WDTC and 22 (38.60%) as non-RR-WDTC. At the end of follow-up, 25 (43.86%) patients had died and 32 (56.14%) were alive. The 5- and 10-year overall survival (OS) rates were 71.50% and 30.49%, respectively, while the 5- and 10-year disease-specific survival (DSS) rates were 76.89% and 48.71%, respectively. Multivariate analyses showed that gross extrathyroidal extension and RR-DTC were independent prognostic factors for poor OS (P=0.04 and P=0.03, respectively), while gross extrathyroidal extension, extrapulmonary distant metastases, and RR-WDTC were independent prognostic factors for poor DSS at the end of follow-up (P=0.02, P=0.03, and P=0.02, respectively).ConclusionsWDTC with distant metastases at initial diagnosis accounted for 31.15% of all elderly patients with DTC. Gross extrathyroidal extension and RR-DTC were the major factors associated with poor OS; gross extrathyroidal extension, extrapulmonary distant metastases, and RR-DTC were independent prognostic factors for poor DSS in elderly DTC patients with distant metastases.

Context Pregnancy-related hormones may stimulate thyroid cancer growth, but whether pregnancy affects the prognoses of patients with lung metastases from differentiated thyroid cancer (DTC-LM) after surgery and radioiodine therapy is unclear. Objective To assess the impact of pregnancy on DTC-LM through the comparison of prognoses between female patients with DTC-LM who did and did not become pregnant after surgery and radioiodine therapy. Methods We retrospectively analyzed the records of 124 female patients aged 16 to 35 years who underwent surgery and radioiodine therapy for DTC-LM. These patients were divided into pregnancy group (n = 37) and nonpregnancy group (n = 87) according to whether they became pregnant after surgery and radioiodine therapy, regardless of whether they had a pregnant history before treatment. Results The 5- and 10-year progression-free survival rates were 94.52% and 63.22% in pregnancy group versus 89.82% and 58.13% in nonpregnancy group. The 5- and 10-year cumulative overall survival rates of pregnancy group were 97.30% and 85.77% versus 93.50% and 81.95% in nonpregnancy group (all P > 0.05). The median time of follow-up in the pregnancy and nonpregnancy groups was 82 months (25-136 months) and 68 months (13-133 months), respectively. Non–radioiodine-avid LM and primary tumors needing repeated resection were independent predictors of poor progression-free survival for patients in pregnancy group. Conclusion Pregnancy does not affect the prognoses of patients with DTC-LM after surgery and radioiodine therapy. Non–radioiodine-avid LM and repeated primary tumor surgeries are independent risk factors for poor prognoses of pregnant patients.

Inflammation is crucial to tumorigenesis and progression of many cancers. Inflammatory molecules in tumor microenvironment exert pro- or anti-tumor effects. Among them, interleukin, mainly produced by CD3+ and CD4+ T lymphocytes, is a class of small molecule proteins which play an important role in intercellular communication. Numerous studies have confirmed that interleukins are closely related to thyroid cancer. Interleukins regulate the proliferation and migration of thyroid cancer cells and they have prospects in discriminating benign and malignant thyroid diseases, predicting the risk of tumorigenesis, evaluating the prognosis and monitoring the recurrence of thyroid cancer. Besides, the effective application of interleukins in treatment of thyroid cancer has been confirmed by some cell and animal researches. The present review will introduce the potential mechanisms of interleukins in thyroid cancer and focus on the applications of interleukins in clinical practice of thyroid cancer, which will help update understanding of the progress of interleukins researches in thyroid cancer.

Background: The inflammatory microenvironment is closely related to the occurrence and development of cancer. Members of the interleukin-12 (IL-12) cytokine family play synergistic or antagonistic roles in the tumor microenvironment, in the form of classic heterodimers or newly discovered monomers or homodimers. Objective: The purpose of this study was to investigate the association between IL-12A and the clinicopathology and prognosis of differentiated thyroid cancer (DTC). Methods: A total of 101 pathologically confirmed DTC patients were included in this study. Immunohistochemistry was performed to assess IL-12A expression in DTC and corresponding paracancerous tissues. The associations of IL-12A with clinicopathology and prognosis were evaluated. Results: IL-12A was expressed in both normal thyroid tissues and DTC, but its expression level was significantly higher in DTC than in normal thyroid tissues (p < 0.001). IL-12A was positively correlated with tumor size (p = 0.027), risk stratification (p = 0.020), and TNM (Tumor-Node-Metastasis) stage (p = 0.024), but not with age, sex, pathological type, multifocality, extrathyroid extension, lymph node metastasis, and distant metastasis (all p > 0.05). Lymphocytic thyroiditis was found in 26/101 patients (25.7%), which was negatively associated with IL-12A expression (p = 0.018). Multivariate logistic regression analysis showed that risk stratification was the significant independent predictor of IL-12A expression. The rate of disease persistence or recurrence (P&R) was 13/101 (12.9%), and a positive relationship was found between IL-12A expression and P&R (p = 0.020). Disease-free survival was affected by factors such as tumor size, extrathyroid extension, tumor stage (T stage), and IL-12A expression, with p values of 0.006, 0.048, 0.002, and 0.012, respectively. Multivariate Cox proportional-hazards analysis showed that tumor size ≥2 cm (hazard ratio [HR] = 4.041 [95% CI: 1.144–14.274], p = 0.031) and high IL-12A expression (HR = 4.027 [95% CI 1.014–15.994], p = 0.049) were independent predictors of prognosis of DTC patients. Conclusions: IL-12A is highly expressed in DTC and is associated with disease aggressiveness. In addition, IL-12A is an independent predictor of the outcome of DTC.

Background: The lung is the most frequent site of distant metastasis from differentiated thyroid cancer (DTC). However, lung metastasis from papillary thyroid cancer (PTC) with persistently negative thyroglobulin (Tg) and elevated Tg antibody (TgAb) levels is an extremely rare entity, and the prognosis is therefore elusive. We investigated the clinical characteristics, long-term outcomes, and prognostic factors of lung metastases in PTC patients with persistently negative thyroglobulin (Tg) and elevated Tg antibody (TgAb) levels during radioactive iodine (131I) treatment and follow-up.Methods: We retrospectively reviewed 10,482 patients with DTC who underwent postoperative 131I treatment from 2007 to 2017 at Shanghai Sixth's People's Hospital. The relationships between progression-free survival (PFS) and several variables were assessed by univariate and multivariate analyses using the Kaplan–Meier method and a Cox proportional hazards model, respectively.Results: Forty-seven patients with PTC were enrolled in this study (4.48‰ of all patients with DTC). The median age at the initial diagnosis of lung metastasis was 39.6 ± 15.4 years, and the patients comprised 14 male and 33 female patients (male: female ratio = 1.00:2.36). Twenty-five patients had 131I avidity and 22 had non-131I avidity. At the end of the 5-years follow-up, 12 patients exhibited progressive disease (PD), and 2 patients had died. At the end of the 10-years follow-up, 21 patients showed PD and five patients had died. The 5- and 10-year PFS rates were 74.47 and 53.32%, respectively; the 5- and 10-years overall survival (OS) rates were 95.74 and 89.36%, respectively. The timing of diagnosis of lung metastases, maximal size of lung metastases, and 131I avidity were significantly associated with the 5-years PFS rate (P = 0.035, P = 0.030, and P

Papillary thyroid carcinoma (PTC) with pulmonary metastases is rare in children and adolescents. Unlike adults, limited data are available on children with this disease. Thus, this study evaluated the therapeutic efficacy and prognostic factors of individuals less than 21 years of age with pulmonary metastases from PTC. Seventy-six children and adolescents with pulmonary metastases from PTC treated with 131I were retrospectively analyzed. Therapeutic efficacy was evaluated by changes in serum thyroglobulin (Tg) and chest computed tomography (CT). Factors predictive of progression-free survival and overall survival were measured by the Kaplan-Meier method. Among the 76 patients included in this study, 22.4% (17 of 76) were less than 15 years old and 65.8% (50 of 76) were female. Under the evaluation of stimulated serum Tg levels, RAI treatment were effective in 55.9% (38 of 68), stable in 26.5% (18 of 68) and ineffectvie in 17.6% (12 of 68) of patients. Changes on anatomical imaging suggested complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) in 8.5, 62.0, 15.5, and 14.1% of individuals, respectively. Univariate analysis showed that size and tumor doubling time of pulmonary metastases were independent factors affecting therapeutic efficacy. Extra-thyroidal extension, tumor diameter of pulmonary metastases and tumor doubling time were significant independent factors regarding progression-free survival rates, while only tumor doubling time and tumor diameter were significant risk factors associated with overall survival rate. Radioactive iodine therapy is an effective treatment for children and adolescents with pulmonary metastases from PTC. Extra-thyroid extension was associated with disease progression while did not show significant influence on overall survival. Tumor doubling time and tumor diameter were the main factors influencing both progression-free survival and overall survival.

SummaryBackground Although the incidence rate for thyroid cancer seems to have begun stabilizing in recent years, an increased rate of advanced stage of this disease has been reported. Additionally, distant metastasis is one of the most important prognostic factors of patients with papillary thyroid carcinoma (PTC). Unfortunately, the underlying mechanisms of distant metastasis as well as cell status like metabolism changes in distant metastatic tumors have not been clearly elucidated. Objective To identify serum metabolic signature of distant metastatic PTC. Design, patients and measurementsIn this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) was used to analyze the serum from 77 patients diagnosed with PTC (37 in distant metastasis group and 40 in ablation group). Principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA)scores plots were used to analyze the data. Results PCA and OPLS-DA analyses demonstrated an evident trend of separation between 40 serum samples from the ablation group and 37 samples from distant metastasis group. A total of 31 metabolites were identified which are related to amino acid, lipid, glucose, vitamin metabolism and diet/gut microbiota interaction. Pathway analysis showed ‘alanine, aspartate and glutamate metabolism’ and ‘inositol phosphate metabolism’ were the most relevant pathways. Conclusion Serum metabolomics profiling could significantly discriminate papillary thyroid cancer patients according to distant metastasis. Potential metabolic aberration in distant metastatic PTC could be involved in different biologic behaviors of tumor cells including proliferation, invasion/migration, and immune escape. Diet/gut microbiota produced metabolites could play an important role in these effects. This work may provide new clues to find the underlying mechanisms regarding to the distant metastasis of PTC as well as potential adjuvant therapy targets. This article is protected by copyright. All rights reserved.

The purpose of this study was to evaluate the diagnostic potential of dual time-point18F-FDG PET/CT imaging with multiple metabolic parameters in malignancy-suspected bone/joint lesions. Fifty seven consecutive patients were recruited. PET parameters including SUVmax, SUVmean, metabolic tumor volume (MTV), total lesional glycolysis (TLG) and retention indexes (RIs) were obtained. Thirty five malignant and 22 benign lesions were confirmed by pathology. In all, 48 receiver operating characteristic (ROC) curves were derived. For SUVmax, MTV2.0, TLG2.0, MTV2.5 and TLG2.5, areas under the curves (AUCs) of early time-point imaging were similar to those of delayed time (P > 0.05), while higher than those of dual time (P< 0.05). For MTV50%max, TLG50%max, MTV75%max and TLG75%max, AUCs of early time-point imaging were lower than those of delayed time (P< 0.05), while similar to those of dual time (P> 0.05). In conclusion, dual time-point18F-FDG PET/CT imaging shows limited value in the differential diagnosis of malignancy-suspected bone/joint lesions. However, MTV and TLG at a fixed SUV threshold (50% or 75% of SUVmax) in delayed time-point imaging may provide better diagnostic accuracy

More aggressive thyroid cancer cells show a higher activity of glycometabolism. Targeting cancer cell metabolism has emerged as a novel approach to prevent or treat malignant tumors. Glucose metabolism regulation effect of metformin in papillary thyroid cancer was investigated in the current study. Human papillary thyroid carcinoma (PTC) cell lines BCPAP and KTC1 were used. Cell viability was detected by CCK8 assay. Glucose uptake and relative gene expression were measured in metformin (0–10 mM for 48 h)-treated cells by 18F-FDG uptake assay and western blotting analysis, respectively. MicroPET/CT imaging was performed to detect 18F-FDG uptake in vivo. After treatment with metformin at 0, 2.5, 5 and 10 mM for 48 h, the ratio of p-AMPK to total AMPK showed significant rising in a dose-dependent manner in both BCPAP and KTC1, whereas p-AKT and p-mTOR expression level were downregulated. 18F-FDG uptake reduced after metformin treatment in a dose-dependent manner, corresponding to the reduced expression level of HK2 and GLUT1 in vitro. Xenograft model of PTC using BCPAP cells was achieved successfully. MicroPET/CT imaging showed that in vivo 18F-FDG uptake decreased after treatment with metformin. Immunohistochemistry staining further confirmed the reduction of HK2 and GLUT1 expression in the tumor tissue of metformin-treated PTC xenograft model. In conclusion, metformin could reduce glucose metabolism of PTC in vitro and in vivo. Metformin, by targeting glycometabolism of cancer cells, could be a promising adjuvant therapy alternative in the treatment modality of advanced thyroid carcinoma.

Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAFV600E mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.

Purpose: The aims of the current study were to explore plasma lncRNAs as a novel biomarker panel for the diagnosis of non-131I-avid lung metastases of PTC and to investigate the plasma lncRNA expression levels associated with survival in PTC patients with lung metastases. Methods: The expression of lncRNAs was examined using an lncRNA microarray chip. The lncRNAs with the most significant difference in expression between PTC patients with non-131I-avid lung metastases and PTC patients with 131I-avid lung metastases were verified by quantitative reverse-transcription polymerase chain reaction. The Kaplan-Meier method was used to determine whether the plasma lncRNA levels might be indicative of patient prognosis. Results: Compared with 131I-avid lung metastases, we discovered that two lncRNAs (ENST00000462717 andENST00000415582) were upregulated and two (TCONS_00024700 and NR_028494) were downregulated in the non-131I-avid lung metastases of PTC. Receiver operating characteristic curve (ROC) analyses indicated that the use of these four lncRNAs had high diagnostic sensitivity and specificity for predicting non-131I-avid lung metastases of PTC. The merged areas under the curve for ENST00000462717, ENST00000415582, TCONS_00024700,and NR_028494 in the training and validation sets were 0.890, 0.936, 0.975, and 0.918, respectively. Low (ENST00000462717 and ENST00000415582) and high plasma lncRNA levels(TCONS_00024700and NR_028494) were also found to be associated with better prognosis of PTC patients with lung metastases(P

The purpose of this study was using next-generation sequencing technique to explore the potential association between germline variants of 14 targeted genes and papillary thyroid carcinoma (PTC) predisposition as well as disease progression. In all, 516 subjects were enrolled in this study including 416 PTC patients and 100 healthy controls. PTC patients were divided into distant metastasis group and non-distant metastasis group. Patients in distant metastasis group were further divided into radioiodine-refractory PTC (RR-PTC) and non-RR-PTC depending on their response to radioiodine therapy. Genomic DNA was extracted from peripheral blood sample and MiSeq Benchtop Sequencer was used for sequencing. We found rs11246050 in NLRP6 (dominant model, OR/95% CI: 2.028/1.091–3.769, p = 0.025), rs2286742 and rs3740530 in HABP2 (recessive model, OR/95% CI: 9.644/1.307–71.16, p = 0.026 and 3.989/1.413–11.26, p = 0.009), rs2736098 in TERT (recessive model, OR/95% CI: 2.322/1.028–5.242. p = 0.042) and rs62054619 in GAS8-AS1 (recessive model, OR/95% CI: 2.219/1.067–4.617, p = 0.033) were associated with the risk of PTC. rs1137282 in KRAS (dominant model, OR/95% CI: 0.5430/0.3192–0.9236, p = 0.024), rs1347591 and rs4461062 in NUP93 (dominant model, OR/95% CI: 0.6121/0.4128–0.9076, p = 0.015 and 0.6156/0.4157–0.9117, p = 0.015) were associated with low risk of distant metastatic disease in PTC patients. rs33954691 in TERT was associated with the risk of RR-PTC under dominant model (OR/95% CI: 3.161/1.596–6.262). Germline variants of related genes could be associated with the susceptibility of PTC as well as disease progression (distant metastasis and radioiodine-refractory status). However, these results must be further verified and the potential biological functions of these germline variants in the pathogenesis of PTC remain to be determined in future studies.

Treatment options for advanced metastatic or progressive thyroid cancers are limited. Although targeted therapy specifically inhibiting intracellular kinase signaling pathways has markedly changed the therapeutic landscape, side-effects and resistance of single agent targeted therapy often leads to termination of the treatment. The objective of the present study was to identify the antitumor property of the non-selective β-adrenergic receptor antagonist propranolol for thyroid cancers. Human thyroid cancer cell lines 8505C, K1, BCPAP and BHP27 were used in the present study. Broad β-blocker propranolol and β2-specific antagonist ICI118551, but not β1-specific antagonist atenolol, inhibited the growth of 8505C and K1 cells. Propranolol treatment inhibited growth and induced apoptosis of 8505C cells in vitro and in vivo, which are closely associated with decreased expressions of cyclin D1 and anti-apoptotic Bcl-2. Expression of hexokinase 2 (HK2) and glucose transporter 1 (GLUT1) also decreased following propranolol intervention. 18F-FDG PET/CT imaging of the 8505C xenografts validated shrinkage of the tumors in the propranolol-treated group when compared to the phosphate‑buffered saline treated group. Finally, we found that propranolol can amplify the cytotoxicity of vemurafenib and sensitize thyroid cancer cells to cytotoxic effect of vemurafenib. Our present results suggest that propranolol has potential activity against thyroid cancers and investigation of the combination with targeted molecular therapy for progressive thyroid cancers could be beneficial.

Metastatic differentiated thyroid carcinoma (DTC) with positive (131)I scintigraphy, but negative stimulated Tg (sTg) is relatively rare in clinical practice. The clinical characteristics of these patients were analyzed in the current study. A total of 3367 consecutive histologically proven DTC patients were analyzed retrospectively from January 2007 to June 2013. Tg negativity was defined as a sTg level of

Introduction Loss of the ability to concentrate 131 I is one of the important causes of radioiodine-refractory disease in papillary thyroid carcinoma (PTC). Recent advantages of serum microRNAs (miRNAs) open a new realm of possibilities for noninvasive diagnosis and prognosis of many cancers. The aim of the current study was to identify differential expression profiling of circulation miRNAs in PTC patients with non- 131 I and 131 I-avid lungs metastases. Methods The expressions of miRNAs were examined using miRNA microarray chip. The most significantly changed miRNAs from microarray were verified by using qRT-PCR. The potential miRNAs regulating target genes and their preliminary biological functions were forecasted by Bioinformatic analysis. Results Compared to 131 I-avid lung metastases, 13 kinds of significantly differential serum miRNAs including 5 upregulated miRNAs (miR-1249, miR-106a, miR-503, miR-34c-5p, miR-1281) and 8 downregulated miRNAs (miR-1915, miR-2861, miR-3196, miR-500, miR-572, miR-33b, miR-554, miR-18a) in PTC patients with non- 131 I-avid lung metastases were identified. Bioinformatic analysis demonstrated that miR-106a was the core miRNA regulating 193 genes in the network. The results of validation confirmed the up-regulation of miR-106a in non- 131 I-avid lungs metastatic PTC patients. Conclusion Differentially expressed serum miRNA profiles between PTC patients with non- 131 I and 131 I-avid lungs metastases were analyzed. These findings in our present study could represent new clues for the diagnostic and therapeutic strategy in PTC patients with non- 131 I-avid metastatic disease.

SummaryObjective Thyroid cancer is the most common endocrine malignancy, and its incidence has been increasing over the last 30 years. Several studies have suggested that miRNAs may play a significant role in the differential diagnosis of indeterminate thyroid nodules. To systematically evaluate the utility of miRNAs in discriminating malignant thyroid nodules from benign ones on fine-needle aspiration biopsy (FNAB) samples, a systematic review and meta-analysis of the published literatures were carried out. Patients and Design Three hundred and sixty-one samples, obtained from 341 patients, were included in the research, and summary sensitivities (SEN), specificities (SPE), positive likelihood ratios, negative likelihood ratios and diagnostic odds ratio were calculated. Then, summary receiver operating characteristic curves (SROCs) and areas under the SROC curves (AUCs) were calculated to further estimate the overall diagnostic value of miRNAs in thyroid cancer. Results The overall pooled SEN, SPE and AUC are 0·75, 0·81 and 0·89, respectively. For multiple miRNAs assays, the pooled SEN, SPE and AUC are 0·87, 0·75 and 0·68, respectively. For single miRNA assays, the corresponding results are 0·71, 0·84 and 0·87, respectively. The corresponding statistical results for differentiating indeterminate FNAB samples are 0·92, 0·68 and 0·86, respectively. Conclusion Our current meta-analysis suggests that miRNAs may serve as a novel diagnostic tool in distinguishing malignant thyroid nodules from benign ones on FNAB specimens. In addition, subgroup analysis suggests that a panel of miRNAs may have a higher sensitivity but a relatively lower specificity than that of single miRNA in distinguishing thyroid nodules.

Metastatic malignant fibrous histiocytoma (MFH) in the colon is extremely rare, although MFH is one of the most common soft tissue sarcomas in adults. We report the case of a 45-year-old woman with metastatic MFH in the sigmoid colon, descending colon, and right lung with FDG PET/CT findings.

The relationship between thyroid autoimmunity and thyroid cancer remains controversial. The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma (PTC). Patients were divided into different groups according to their final diagnoses after radioiodine therapy as well as their serum anti-thyroglobulin antibody (TgAb) and anti-thyroidperoxidase antibody (TPOAb) titers. Clinicopathologic characteristics were then compared between groups. In all, 1126 PTC patients met the inclusion criteria. When compared with thyroid autoimmune antibody negative group, patients in positive group were young female predominant. After age and gender adjusted, patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment. Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403 (95% CI 0.216–0.622, p

Although fibrous dysplasia is not considered a potentially premalignant disorder, malignant transformation occurs. Because of its rarity, radiographic features of malignantly transformed fibrous dysplasia on cross-sectional imaging modalities are less recognized, making diagnosis and differential diagnosis of the disease quite difficult in clinical practice. In this study, we analyzed the clinical characteristics, imaging features, pathology findings and surgery strategies of 19 malignantly transformed fibrous dysplasia. We found that there was significant male predominance in this specific cohort (13/6). While osteosarcoma (63.2%) was the most frequently occurring neoplasm secondary to fibrous dysplasia, other less commonly malignantly changed types included fasciculated sarcoma, malignant fibrous histiocytoma, fibrosarcoma and chondrosarcoma. We found that the diagnostic value of single modality imaging method, like conventional X-ray, computed tomography or non-contrast magnetic resonance imaging, was limited mainly because of a lack of whole-body metabolic information. In contrast, we highlighted that 99mTc-MDP SPECT/CT and/or 18F-FDG PET/CT scanning could exert a pivotal role in the management of malignantly transformed fibrous dysplasia by guiding precise biopsy and optimizing surgery options.

Differentiated thyroid cancer (DTC) patients with negative serum thyroglobulin (Tg), negative 131I whole–body scintigraphy (131I-WBS) at first post-ablation and progressively increased TgAb level are a relatively rare entity in the follow-up after total thyroidectomy and radioactive iodine therapy. The value of 18F-FDG PET/CT in detecting the recurrence of disease in these patients has only been reported in a small case series. The goal of this study was to investigate the diagnostic accuracy of 18F-FDG PET/CT in detecting recurrent disease in these specific PTC patients and to identify risk factors for patients with positive 18F-FDG PET/CT results. Eighty-two PTC patients who had 18F-FDG PET/CT scans with negative Tg, negative 131I-WBS at first post-ablation and progressively increased TgAb levels were included. We found that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT in this patient group were determined as 84%, 72%, 92%, 57% and 82%, respectively. 18F-FDG PET/CT scan had a good diagnostic performance and should be performed routinely in PTC patients with negative Tg, negative 131I-WBS at first postablation and progressively increased TgAb level, especially when span for progressively increased TgAb level ≥ 3 years and/or progressively increased TgAb value up to 150 IU/mL.

Single Particle Aerosol Mass Spectrometry (SPAMS) was performed to characterize the PM2.5 in Nanning from 15 to 24 February 2015. The correlation (R2) between the PM2.5 number concentration and the mass concentration of PM2.5 obtained using SPAMS was 0.76. The particle number concentration could reflect the atmospheric pollution situation to some degree. The Art-2a classification method was used to classify the chemical composition of PM2.5. The results showed that the principal chemical constituents were elemental carbon, organic elements carbon hybrid particles, organic carbon, rich potassium particles, mineral substance, rich sodium particles, second inorganic particles, levoglucosan and other heavy metals. Among them, the composition of elemental carbon was the highest, followed by organic carbon and rich potassium particles. The particle size of 80% of PM2.5 was mainly concentrated in the range of 0.2 microm to 1.0 microm with a peak value occurring at 0. 62 microm. The particle size distribution characteristics of different chemical components were similar. The number concentration of the chemical components in PM2.5 had the same variation tread with the mass concentration of PM2.5 over time. To a certain extent, the change in chemical composition could reflect the instantaneous pollution source.

Background Serum miRNAs profiles between papillary thyroid carcinoma (PTC) patients with non-131I and 131I-avid lung metastases are differentially expressed. These miRNAs have to be further validated and the role of these miRNAs in the molecular function level of thyroid cancer cell lines has not been investigated. Methods Expression levels of six identified miRNAs were assessed via quantitative real-time PCR (qRT-PCR) in the serum of eligible patients. Dual-luciferase reporter assay was used to determine the potential target of miR-106a. Cell viability and apoptosis were evaluated by MTT assay and flow cytometry analysis, respectively. The change of gene expression was detected by qRT-PCR and western blotting analysis. In vitro iodine uptake assay was conducted by a γ-counter. Results Compared to PTC patients with 131I-avid lung metastases, miR-106a was up-regulated in the serum of patients with non-131I-avid lung metastases. The results of dual-luciferase reporter assay demonstrated that miR-106a directly targeted retinoic acid receptor beta (RARB) 3′-UTR. miR-106a-RARB promoted viability of thyroid cancer cells by regulating MEKK2-ERK1/2 and MEKK2-ERK5 pathway. miR-106a-RARB inhibited apoptosis of thyroid cancer cells by regulating ASK1-p38 pathway. Moreover, miR-106a-RARB could regulate the expression of sodium iodide symporter, TSH receptor and alter the iodine uptake function of thyroid cancer cells. Conclusions miRNA-106a, directly targeting RARB, associates with the viability, apoptosis, differentiation and the iodine uptake function of thyroid cancer cell lines by regulating MAPK signaling pathway in vitro. These findings in the present study may provide new strategies for the diagnosis and treatment in radioiodine-refractory differentiated thyroid carcinoma.

Circulating afamin (AFM) concentrations have been investigated as a tumor biomarker in various types of carcinomas. However, suitable cell lines expressing human afamin have not yet been reported and current knowledge of the functions of afamin, particularly at the mechanistic molecular level, is very limited. In the current study, thyroid cancer cell lines 8505c and K1 were used to investigate the potential functions of afamin. AFM over-expression models and vector controls of 8505c (8505c + AFM and 8505c + NC) and K1 (K1 + AFM and K1 + NC) were successfully established by Lenti-LV5-AFM and Lenti-LV5-NC transfection. The change of gene expression was detected by qRT-PCR and western blotting analysis. (18)F-FDG imaging in xenografts model was performed using a micro PET/CT. We found that protein level of GAPDH, GLUT1, HK2, p-AKT, AKT, p-mTOR and PARP1 were up-regulated in K1 + AFM cells when compared to K1 and K1 + NC. While in 8505c, 8505c + NC and 8505c cells, the expression level of these genes were not significantly changed. (18)F-FDG uptake was much higher in K1 + AFM cells when compared to K1 and K1 + NC in vitro and in vivo. In conclusion, afamin could promote glycometabolism by up-regulating the glucose metabolism key enzymes in papillary thyroid carcinoma. These findings reveal new clues of the molecular function of AFM.

Background: Solitary pulmonary nodules (SPNs) are common imaging findings. Many studies have indicated that 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is an accurate test for distinguishing benign and malignant SPNs. The aim of this study was to investigate the value of 18F-FDG-PET/CT in the diagnosis of malignant SPNs. Methods: We systematically searched the PubMed and Embase databases up to March 2017, and published data on sensitivity, specificity, and other measures of diagnostic accuracy of 18F-FDG-PET/CT in the diagnosis of malignant SPNs were meta-analyzed. Statistical analyses were undertaken using Meta-DiSc 1.4 software and Stata version 12.0. The measures of accuracy of 18F-FDG-PET/CT in the diagnosis of malignant SPNs were pooled using random-effects models. Results: A total of 20 publications reporting 21 studies were identified. Pooled results indicated that 18F-FDG-PET/CT showed a diagnostic sensitivity of 0.89 (95% confidence interval [CI], 0.87–0.91) and a specificity of 0.70 (95% CI, 0.66–0.73). The positive likelihood ratio was 3.33 (95% CI, 2.35–4.71) and the negative likelihood ratio was 0.18 (95% CI, 0.13–0.25). The diagnostic odds ratio was 22.43 (95% CI, 12.55–40.07). Conclusions: 18F-FDG-PET/CT showed insufficient sensitivity and specificity for diagnosing malignant SPNs; it cannot replace the “gold standard” pathology by resection or percutaneous biopsy. Larger studies are required for further evaluation.

Background: Prostate carcinoma is a common disease that occurs in men over 50 years old. Many studies have explored the effect of free/total prostate-specific antigen (f/t PSA) ratio in monitoring prostate cancer. We conducted a meta-analysis to identify the accuracy of the f/t PSA ratio in the diagnosis of prostate cancer in patients who have PSA levels of 4 to 10 ng/mL. Methods: Databases searched included PubMed and OVID databases, from inception to March 2017, after a systematical review, sensitivity, specificity, and other measures of accuracy of the f/t PSA ratio in the diagnosis of prostate cancer were pooled. We used summary receiver operating characteristic curves to summarize overall test performance. Results: Fifteen case–control studies from 14 articles were identified. The results indicated that the sensitivity of the f/t PSA ratio in the diagnosis of prostate cancer ranged from 0.5 to 0.94 (pooled sensitivity 0.70, 95% CI: 0.67–0.72), whereas its specificity ranged from 0.31 to 0.93 (pooled specificity 0.55, 95% CI: 0.57–0.60). The positive likelihood ratio was 1.85 (95% CI: 1.56–2.20), negative likelihood ratio was 0.42 (95% CI: 0.34–0.53), and diagnostic odds ratio was 4.81 (9.53% CI: 3.33–6.94). Conclusions: The f/t PSA ratio determination has a low sensitivity and specificity for the diagnosis of prostate cancer; it would not be useful for the diagnosis of prostate cancer by itself. The results of f/t PSA ratio measurements should refer to the clinical manifestations and the results of conventional tests such as biopsies.

To analyze the sediment phosphorus (P) fractions and sorption characteristics and P release from sediment of reservoir in Yangtze estuary, the sediment was investigated during April, 2011 to January, 2012. Results of chemical fractionation analysis showed that total P (TP) content in sediment ranged from 535.07 to 910.9 mg x kg(-1), inorganic P (IP) was a dominant component of TP and the content of organic P (OP) was low. IP presented in the form of P bounded to calcium ( HCl-P) and dominated 75.57% of TP. The batch experiments showed that sediments had the maximum P adsorption capacity from 9.78 to 39.84 mg x kg(-1), sorption data fitted the modified Langmuir isotherm model. However, EPC0 ( equilibrium phosphorus concentration) in all sampling sites was higher than the soluble-reactive P concentration in water column, which was from 0.024-0.12 mg x L(-1). Accordingly, the sediments from those sampling sites would release phosphorus into the overlying water as a P release source. The maximum released amount from sediment was 11.03 mg x kg(-1) about 6 hours. Correlation between P released amount and NaOH-P was found (P0.01), and sediment P release would mainly originate from the NaOH-P, OP and HCl-P fraction. It is evident that the inherent phosphorus present in sediments would be a major threat to the water quality in Yangtze River estuary reservoir.