Development and validation of a preoperative prediction model for follicular thyroid carcinoma.

OBJECTIVE: The low pre- and intraoperative diagnostic rates in follicular thyroid carcinoma (FTC) often lead to inadequate surgical resection and necessitate further completion surgery. Therefore, the preoperative prediction of FTC in thyroid nodules is essential. DESIGN AND PATIENT: Patients were categorized into two data sets: the modelling data set, which included 3649 patients admitted to our centre between January 2014 and December 2016, and the validation data set, which included 1253 patients admitted between January and December 2017. Patient data from the FTC and non-FTC groups were initially included in a modelling data set to establish a preoperative prediction model. This model was subsequently employed in a validation data set for external validation of the predictive value. The positivity rate for FTC predicted by the model was compared with that of the intraoperative frozen sections. RESULTS: The preoperative serum thyroglobulin level, nodule diameter, calcification status, solidity and blood supply were selected as predictors for the model. The regression equation was as follows: Y = 0.010 × (thyroglobulin level) + 0.556 × (nodule diameter) + 0.675 × (calcification status) + 2.355 × (nodule component) + 1.072*(blood flow) - 9.787. The model positively predicted FTC at values of Y ≥ -4.11. The accuracy, sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of the prediction model were 89.2%, 90.2%, 87.7%, 39.2 and 0.11, respectively. External validation of the model demonstrated acceptable results. The positive prediction rate of the model was 90.7% (78/86), which was significantly higher than that of the intraoperative frozen sections (10.5% [9/86]; P < 0.0001). CONCLUSIONS: We successfully established and validated a simple and reliable preoperative prediction model for FTC using the preoperative thyroglobulin level and ultrasonographic features of the thyroid nodules. This model may improve the preoperative evaluation of FTC in clinical settings and facilitate the development of a reasonable surgical programme for FTC.

Application of Continuous and Intermittent Intraoperative Nerve Monitoring in Thyroid Surgery.

BACKGROUND: Whether continuous intraoperative nerve monitoring (C-IONM) can further reduce the incidence of recurrent laryngeal nerve injury compared with intermittent intraoperative nerve monitoring (I-IONM) in high-risk thyroid surgery is still controversial. This observational study aimed to evaluate the incidence of vocal cord paralysis (VCP) in high-risk thyroid surgeries performed with I-IONM and C-IONM. MATERIALS AND METHODS: High-risk thyroid surgical patients operated with I-IONM or C-IONM by the same group of surgeons in the thyroid surgery department of our institution between January 2014 and February 2018 were analyzed. Differences in the incidence rates of temporary and permanent VCP between the two groups were compared. A P-value < 0.05 was considered statistically significant. RESULTS: A total of 344 patients who underwent high-risk thyroid surgery (550 nerves at risk [NARs]) were observed, with 238 patients (374 NARs) operated with I-IONM and 106 patients (173 NARs) operated with C-IONM. The incidence of temporary and permanent VCP was 1.9% (7/374) and 0.8% (3/374) in the I-IONM group and 1.2% (2/173) and 0% (0/173) in the C-IONM group, respectively, showing no statistical difference (P = 0.726 and P = 0.555). The incidence rate of impending recurrent laryngeal nerve injuries successfully prevented in the C-IONM group was 5.2% (9/173). CONCLUSIONS: Both I-IONM and C-IONM are equally safe and effective in high-risk thyroid surgery. C-IONM can help predict impending recurrent laryngeal nerve injury in real time and has a good warning feature, thereby minimizing critical maneuvers in high-risk thyroid surgery.

TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting the M2 polarization of tumor-associated macrophages.

BACKGROUND: The endoplasmic reticulum (ER) regulates critical processes, including lipid synthesis, which are affected by transmembrane proteins localized in the ER membrane. One such protein, transmembrane protein 147 (TMEM147), has recently been implicated for its role in hepatocellular carcinoma (HCC) tumorigenesis; however, the mechanisms remain unclear. We investigated the role of TMEM147 in HCC and the underlying mechanisms. METHODS: TMEM147 expression was examined in human HCC cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of TMEM147 on the progression of HCC. Proteins interacting with TMEM147 were identified via RNA-seq, immunoprecipitation, and mass spectrometry analyses. Lipidomic analysis and enzyme-linked immunosorbent assay (ELISA) were employed to determine and analyze cholesterol and 27-hydroxycholesterol (27HC) contents. Extensive experimental techniques were used to study ferroptosis in HCC cells. The fatty acid content of macrophages affected by TMEM147 was quantified using ELISA. Macrophage phenotypes were determined using immunofluorescence assay and flow cytometric analysis. RESULTS: TMEM147 mRNA and protein levels were increased in HCC cells, and the increased TMEM147 expression was associated with a poor survival. TMEM147 promoted tumor cell proliferation and metastases in vitro and in vivo. The protein was found to interact with the key enzyme 7-dehydrocholesterol reductase (DHCR7), which affected cellular cholesterol homeostasis and increased the extracellular levels of 27HC in HCC cells. TMEM147 also promoted the expression of DHCR7 by enhancing the activity of signal transducer and activator of transcription 2. 27HC expression upregulated glutathione peroxidase 4 in HCC, leading to ferroptosis resistance and promotion of HCC proliferation. HCC cell-derived 27HC expression increased the lipid metabolism in macrophages and activated peroxisome proliferator-activated receptor-γ signaling, thereby activating M2 macrophage polarization and promoting HCC cell invasion and migration. CONCLUSIONS: Our results indicate that TMEM147 confers ferroptosis resistance and M2 macrophage polarization, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27HC secretion, leading to cancer growth and metastasis. These findings suggest that the TMEM147/STAT2/DHCR7/27HC axis in the tumor microenvironment may serve as a promising therapeutic target for HCC.

BIRC7 promotes epithelial-mesenchymal transition and metastasis in papillary thyroid carcinoma through restraining autophagy.

Papillary thyroid carcinoma (PTC) is the most common cancer of the endocrine system, which is usually associated with a favorable therapeutic response and prognosis. However, metastatic spreading occurs in around 5% of the PTC patients. Identification of molecular markers could early predict the metastatic potential, which is essential for reducing the patient's overtreatment. Baculoviral IAP Repeat Containing 7 (BIRC7) is an inhibitor of apoptosis protein (IAP) family gene that is known to be linked to tumor progression, but its role in the setting of PTC metastasis remains unknown. This study, therefore, aims to explore the role of BIRC7 in the metastasis and autophagy of PTC and elucidate its underlying molecular mechanisms. BIRC7 expression was assessed in fresh samples of human PTC and normal tissues via qRT-PCR and immunohistochemistry. In addition, BIRC7 was overexpressed and silenced in PTC cell lines followed by transmission electron microscopy, western blotting, immunofluorescence microscopy, wound healing and invasion assays. We further explored the relevance of BIRC7 in vivo using a tumor xenograft model. Our results demonstrated that BIRC7 plays a pro-invasive role in PTC. BIRC7 expression is significantly upregulated in PTC compared with matched thyroid normal tissues. In addition, we found that BIRC7 knockdown induced a significant reduction in PTC cell EMT and metastasis in vitro and in vivo, while overexpression of BIRC7 markedly enhanced PTC cell migration and invasion. Moreover, our data showed that BIRC7 was able to suppress autophagy through modulating the expression of ATG5 and BECN1, and that this suppression is responsible for BIRC7 silence induced suppression of EMT and metastasis of PTC cell. We further found that targeting both BIRC7 and mTOR enhances autophagy in PTC cells and to achieve synergistic antimetastatic efficacy in vitro and in vivo. These findings indicate that the suppression of autophagy by BIRC7 drives the invasion and metastasis of PTC cells, thus suggesting that the activation of autophagy may inhibit metastasis of PTC with high BIRC7 expression.

Do Symptoms and Serum Calcium Levels Affect the Results of Surgical Treatment of Primary Hyperparathyroidism?

INTRODUCTION: The purpose of this study was to investigate the difference in surgical outcomes between symptomatic and asymptomatic patients with primary hyperparathyroidism (PHPT) and between patients with high serum calcium and those with normal blood calcium, as well as to explore the epidemiological trend of PHPT in northern China. METHODS: Clinicopathologic data of 197 patients (50 men and 147 women) with PHPT who underwent surgery at the First Affiliated Hospital of Harbin Medical University from 2008 to 2017 were analyzed. Changes in clinicopathology were compared among different subgroups of patients. Patients were categorized into subgroups based on serum calcium levels, whether or not they presented with symptoms, and admission time. RESULTS: Of the total patients, 82.23% had hypercalcemic primary hyperparathyroidism (HCPHPT), 17.77% had normocalcemic primary hyperparathyroidism (NCPHPT), 45.18% had symptomatic primary hyperparathyroidism (SPHPT), and 54.82% had asymptomatic primary hyperparathyroidism (ASPHPT). Seventy-seven cases of PHPT involved thyroid nodules, with 22 confirmed as papillary thyroid carcinoma, and 29 confirmed as nodular goiter. There was no significant difference in the success rate of surgery, postoperative recurrence rate, and the symptoms of temporary hypocalcemia between the HCPHPT and NCPHPT groups, and between the SPHPT and ASPHPT groups. The incidence of PHPT has increased threefold since 2013. CONCLUSIONS: Symptoms and serum calcium levels did not affect the results of surgical treatment for PHPT. The incidence of PHPT in northern China is increasing. Moreover, PHPT manifestation has shifted from the symptomatic to the asymptomatic form. Thyroid surgery should be performed in PHPT patients with thyroid nodules.

Sodium orthovanadate inhibits growth and triggers apoptosis of human anaplastic thyroid carcinoma cells in vitro and in vivo.

Vanadium and its compounds exhibit concentration- and time-dependent anticancer effects on various types of tumor; however, the effects of sodium orthovanadate (SOV) on anaplastic thyroid carcinoma (ATC) have not yet been reported. In the present study, the anticancer effects of SOV on ATC were evaluated. In vitro experiments, including cell viability assays, plate colony formation assays, cell cycle analysis and apoptosis analysis were used to study the role of SOV in ATC. Using in vivo experiments, the effects of SOV on the growth and apoptosis of an ATC-xenograft tumor were studied by comparing the SOV-treatment with the control group. The results revealed that treatment of the human ATC cell line 8505C with SOV inhibited cell viability, induced G2/M phase cell cycle arrest, stimulated apoptosis and reduced mitochondrial membrane potential in a concentration-dependent manner. These findings were confirmed in vivo in a nude mouse ATC xenograft model. In conclusion, the present study demonstrated that SOV inhibited human ATC by regulating proliferation, cell cycle progression and apoptosis, thus suggesting that SOV may be considered a novel option for the treatment of ATC.

Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis.

Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas. The purpose of this study was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroid cancer. To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecified fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35; 95% confidence interval [CI] 1.12-1.64; P = 0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12-1.88; P = 0.005). After pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61-1.58, P = 0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.

PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect.

PGC1α acts as a central regulator of mitochondrial metabolism, whose role in cancer progression has been highlighted but remains largely undefined. Especially, it is completely unknown about the effect of PGC1α on cholangiocarcinoma (CCA). Here we showed that PGC1α overexpression had no impact on CCA growth despite the decreased expression of PGC1α in CCA compared with adjacent normal tissue. Instead, PGC1α overexpression-promoted CCA metastasis both in vitro and in vivo. Mechanistically, for the first time, we illuminated that PGC1α reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation. On the one hand, enhanced mitochondrial oxidation metabolism correlated with elevated reactive oxygen species (ROS) production; on the other hand, increased PGC1α expression upregulated the expression levels of mRNA for several ROS-detoxifying enzymes. To this end, the ROS levels, which were elevated but below a critical threshold, did not inhibit CCA cells proliferation. And the moderately increased ROS facilitated metastatic dissemination of CCA cells, which can be abrogated by antioxidants. Our study suggests the potential utility of developing the PGC1α-targeted therapies or blocking PGC1α signaling axis for inhibiting CCA metastasis.