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Background: Activating mutations in the BRAF oncogene occur in 45% of papillary thyroid carcinomas (PTCs). Though less studied, K601E may identify a clinically distinct subset of thyroid neoplasms. Methods: A bioinformatics assessment was conducted using the COSMIC database and in silico data analysis. A systematic search was conducted through August 2024 to identify studies reporting BRAF mutation in thyroid neoplasms. Pooled prevalence, histopathological subtype distribution, extrathyroidal extension, lymph node metastasis, recurrence, and survival were extracted/analyzed from 32 studies (13 191 patients). Results: In the COSMIC database, BRAF K601E was found in various tissue types but mainly in the thyroid. In silico data analysis revealed a structural and functional basis for differences between K601E and V600E. Upon systematic review, the BRAF K601E mutation was identified in 2.8% of PTCs compared to 22% with V600E. The stratified analysis revealed geographical differences, with higher rates in Italy (5.23%) and the United States of America (3.31%). The K601E mutant was enriched for follicular‐patterned variants like NIFTP (11.2% of cases). Meta‐analysis demonstrated significantly reduced extrathyroidal extension for K601E versus V600E mutants (RR = 0.22, 95% CI = 0.10–0.50, p = 0.0003). Conclusion: K601E‐mutated neoplasms could be a unique clinicopathological entity associated with low‐risk histology and reduced extrathyroidal extension, consistent with a more indolent course than V600E mutants. Although detecting K601E may potentially guide conservative management, further prospective studies are needed. [ABSTRACT FROM AUTHOR]

Purpose: To perform a molecular profiling of the metastases from papillary thyroid carcinomas (PTCs) and poorly differentiated thyroid carcinomas (PDTCs). Methods: We retrieved and analyzed the molecular and clinical features of 136 metastases from PTCs and 35 metastases from PDTCs subjected to targeted DNA sequencing, from cBioPortal. The clinicopathological data included the number and location of the metastases, and genomic data included mutations, translocations, copy number alterations and fraction of the genome altered (FGA). Results: Bone metastases from PTCs had a lower frequency of BRAF mutations than the lymph node metastases (LNMs) (43% vs 88%, p < 0.01), and a higher frequency of RBM10 and NRAS mutations than the LNMs (21% vs 3% for both, p < 0.05). The FGA of the bone metastases was higher than the FGA of the lung metastases (5.6% vs 1.3%, p < 0.05). The frequency of RET translocations was higher in the lung metastases from PTCs than the LNMs (15% vs 3%, p < 0.05). The LNMs from PTC patients harboring 4 or more distant metastases (DMs) had a higher frequency of TERT promoter mutations than the LNMs from patients harboring less than 4 DMs (96% vs 65%, p < 0.001). SDHA gene amplifications were enriched in the bone metastases from PDTCs and absent in the LNMs (38% vs 0%, p < 0.05). Conclusion: Metastases from PTCs and PDTCs harbor clinically relevant alterations affecting distinct body locations, such as NRAS and RBM10 mutations, RET translocations and SDHA amplifications that may be explored therapeutically. [ABSTRACT FROM AUTHOR]

TERT promoter mutations C228T and C250T are associated with disease aggressiveness and poor clinical outcomes in patients with papillary thyroid carcinomas. However, very little is known about the transcriptional consequences of these mutations and whether they both carry similar oncogenic potential. Here we characterized the transcriptional disturbances and clinical outcomes associated with the presence of each of these two mutations using data derived from The Cancer Genome Atlas. We observed that tumors harboring the C228T mutation (n = 27) exhibited a 16-fold increase in TERT mRNA levels (P = 5.3 × 10−42), whereas C250T tumors (n = 8) showed only a two-fold increase in expression (P = 0.034). The C228T mutation was associated with the activation of signaling pathways controlling the cell cycle, cellular division, and extracellular matrix degradation. Univariate analysis demonstrated that the C228T mutation was associated with older age at diagnosis, large tumor size, lymph node invasion, and distant metastases at diagnosis. The C228T mutation was also associated with worse progression-free interval (PFI) in comparison to WT tumors (HR = 5,04; P < 0.001). This association remained significant in a multivariate analysis (HR = 3.74, P = 0.003) adjusting for BRAF-V600E status and ATA risk group. Our data indicate that TERT promoter mutations C228T and C250T have distinct transcriptional consequences in papillary thyroid carcinoma (PTC), suggesting a greater oncogenic potential for the C228T mutation. TERT promoter mutation C228T may be a useful prognostic marker to identify patients at high risk of distant recurrence. Clinical data for the C250T mutation is still limited, with no evidence up to date to confirm its prognostic significance. [ABSTRACT FROM AUTHOR]

Context Distant metastases are the primary cause of therapy failure and mortality in patients with papillary thyroid carcinomas (PTCs). However, the underlying mechanism responsible for the initiation of tumor cell dissemination and metastasis in PTCs has rarely been investigated. Objective The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs. Methods The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT–PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases. Results We determined that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1-mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2. Conclusion Our findings highlight the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms. [ABSTRACT FROM AUTHOR]

This study aimed to assess the predictive value of systemic inflammatory parameters and the prognostic nutritional index (PNI) in identifying lymphatic metastases in papillary thyroid cancers (PTC). PTCs, characterized by their in dolent nature and favorable prognosis, frequently disseminate to cervical lymphnodes, impacting recurrence and prognosis. However, the preoperative identification rate of cervical lymphnode metastases ranges from 20% to 75%, necessitating supplemental examinations for precise detection and surgical planning. A retrospective analysis of 441 thyroidectomy cases, encompassing 272 PTC patients, was conducted. Patients were categorized into two cohorts: 221 lacked lymphnode metastases, while 51 exhibited lymphatic metastases. Parameters including age, gender, systemic inflammatory markers derived from hemogram tests, serum albumin levels, and postoperative histopathology findings were scrutinized to evaluate the predictive potential of systemic inflammatory parameters and PNI in discerning between the two cohorts. The findings revealed that neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) values bore statistically significant predictive capacity (p<0.05) in preoperatively detecting cervical lymphnode metastases in PTC. Receiver operating characteristic (ROC) curves delineated the efficacy of NLR, PLR, and SII in prognostication. NLR exhibited an area under the curve (AUC) value of 0.932 (95% CI, 0.902-0.962; p<0.001), while PLR yielded an AUC value of 0.638 (95% CI, 0.555-0.721; p=0.002). SII analysis yielded an AUC value of 0.798 (95% CI, 0.736-0.861; p<0.001). Conversely, the prognostic nutritional index (PNI) demonstrated meager predictive utility, registering an AUC value of 0.192 (95% CI, 0.124-0.260; p<0.001), positioning below the reference line on the ROC curve. In conclusion, this study under scores NLR's utility in identifying cervical lymphnode metastases in PTC. While PLR and SII evince some association with lymphnode metastasis detection, their predictive efficacy remains constrained. Additionally, despite statistical significance, PNI exhibited in efficacy in forecasting lymphnode metastases. [ABSTRACT FROM AUTHOR]

Objective: Papillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancers and has a high recurrence rate. We aimed to screen key genes involved in PTC to provide novel insights into the mechanisms of PTC. Methods: Seven microarray datasets of PTC were downloaded from gene expression omnibus database. Differentially expressed genes (DEGs) between PTC and normal samples were screened in the merged dataset. Then, protein-protein interaction (PPIs) functional modules analysis and weighted gene co-expression network analysis (WGCNA) were utilized to identify PTC-associated key genes. The identified key genes were then characterized from various aspects, including gene set enrichment analysis (GSEA) and the associations with immune infiltration, methylation levels and prognosis. Results: A large numbers of DEGs were identified, and these DEGs are involved in several cancer pathways. Nine key genes (including down-regulated genes GNA14, AVPR1A, and WFS1, and up-regulated genes LAMB3, PLAU, MET, MFGE8, PRSS23, and SERPINA1) were identified. Patients in the AVPR1A and GNA14 high expression groups had better disease-free survival (DFS) than those in the low expression group. Key genes were mainly involved in P53 pathway, estrogen response, apoptosis, glycolysis, NOTCH signaling, epithelial mesenchymal transition, WNT_beta catenin signaling, and inflammatory response. The expression of key genes was associated with immune cell infiltration and corresponding methylation levels. The verification results of key gene proteins and mRNA expression levels using external validation datasets were consistent with our expectations, implying the involvements of key genes in PTC. Conclusion: The key genes may serve as potential therapeutic targets for PTC. This study provides novel insights into the mechanisms underlying PTC development.

Aim: Capsule thickness and papillary carcinoma nuclear features are common diagnostic criteria for invasive follicular variant papillary thyroid carcinoma (IEFVPTC), noninvasive follicular thyroid neoplasm with papillary nuclear features (NIFT-P), and encapsulated papillary thyroid carcinoma (E-PTC). Our goal in this study is to evaluate these two histomorphological criteria using computerized image analysis systems and to determine whether they can serve as auxiliary criteria for distinguishing these diagnostic groups. Materials and Methods: 10 patients were selected from IEFVPTC, NIFT-P, and E-PTC diagnostic groups. Slides containing the largest tumor diameter were scanned and digitized. Using computerized image analysis systems, tumor capsule thickness was measured from 4 areas of 4 equal quadrants, and the average tumor capsule thickness (TCT) was determined. Furthermore, from these 4 equal quadrants, the nucleus diameter of 10 clearly distinguishable cells was measured to determine the average tumor cell nucleus diameter (ND). Results: TCT and ND histomorphological criteria were statistically significant among the diagnostic groups. For IFVPTC diagnosis, both TCT and ND were found to be significant diagnostic tools. We demonstrated that ND can easily be used as a diagnostic tool for NIFT-P, whereas more caution is required for TCT. Conclusion: Differentiating papillary nuclear feature-containing follicular variant thyroid papillary carcinomas is challenging. In this study with a limited number of patients, we demonstrated that the TCT and ND criteria can, to some extent, contribute to differential diagnosis between diagnostic groups. Future studies with larger patient groups and more advanced computerized image analysis programs will yield more promising results. [ABSTRACT FROM AUTHOR]

The comparative analysis of the expression of the reactive oxygen species-generating NADPH oxidase NOX4 from TCGA data shows that the NOX4 transcript is upregulated in papillary thyroid carcinomas (PTC)-BRAFV600E tumors compared to PTC-BRAFwt tumors. However, a comparative analysis of NOX4 at the protein level in malignant and non-malignant tumors is missing. We explored NOX4 protein expression by immunohistochemistry staining in malignant tumors (28 classical forms of PTC (C-PTC), 17 follicular variants of PTC (F-PTC), and three anaplastic thyroid carcinomas (ATCs)) and in non-malignant tumors (six lymphocytic thyroiditis, four Graves’ disease, ten goiters, and 20 hyperplasias). We detected the BRAFV600E mutation by Sanger sequencing and digital droplet PCR. The results show that NOX4 was found to be higher (score ≥ 2) in C-PTC (92.9%) compared to F-PTC (52.9%) and ATC (33.3%) concerning malignant tumors. Interestingly, all C-PTC-BRAFV600E expressed a high score for NOX4 at the protein level, strengthening the positive correlation between the BRAFV600E mutation and NOX4 expression. In addition, independent of the mutational status of BRAF, we observed that 90% of C-PTC infiltrating tumors showed high NOX4 expression, suggesting that NOX4 may be considered a complementary biomarker in PTC aggressiveness. Interestingly, NOX4 was highly expressed in non-malignant thyroid diseases with different subcellular localizations.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, comparising various subtypes including classical PTC (accounting for approximately 55–65 % of cases) and several variants. The identified variants include papillary microcarcinoma, encapsulated variant, follicular variant, diffuse sclerosing variant, tall cell variant, columnar cell variant, cribriform-morular variant, and Warthin-like variant (WLV-PTC). WLV-PTC is a rare malignant neoplasm. The present study introduced two cases of WLV-PTC from Affiliated Hospital of Chengde Medical College in retrospect. The macroscopic characteristics, histological feature, immunophenotyping, gene mutations, local invasion, and distant metastasis of the tumors were observed, and the relevant literature on WLV-PTC was reviewed. The tumor cells exhibited nuclear the characteristics similar to those of classic papillary thyroid carcinoma. Immunohistochemical analysis showed strong positivity for thyroid transcription factor 1, cytokeratin 19, Galectin-3, and CK, weak positivity for thyroglobulin, and the Ki-67 proliferation index ranging from 5 to 10 %. Gene mutation analysis revealed that Case 1 had a BRAF V600E mutation, whereas Case 2 had a wild-type mutation. WLV-PTC has histological features similar to those of Warthin tumor originating from salivary gland. The prognosis of WLV-PTC is similar to that of conventional PTC of comparable size and stage. [ABSTRACT FROM AUTHOR]

The genetics underlying non-syndromic familial non-medullary thyroid carcinoma (FNMTC) is still poorly understood. To identify susceptibility genes for FNMTC, we performed whole-exome sequencing (WES) in a Brazilian family affected by papilla ry thyroid carcinoma (PTC) in three consecutive generations. WES was performed in four affe cted and two unaffected family members. Manual inspection in over 100 previously reported susceptibility genes for FNMTC showed that no variants in known genes co-segregated with disease phenotype in this family. Novel candidate genes were investigated using PhenoDB and filtered using Genome Aggregation (gnomAD) and Online Archive of Brazilian Mutations (ABraOM) population databases. The missense variant p.Ile657Met in the NID1 gene was the only variant that co-segregated with the disease, while abs ent in unaffected family members and controls. The allele frequency for this variant was G) identified in this study fulfills several criteria th at suggest it as a new FNMTC predisposing gene.

Objective: This meta-analysis was performed to evaluate the effectiveness and safety of prophylactic central neck dissection (PCND) in patients with clinically node-negative (cN0) papillary thyroid carcinoma. Materials and methods: A meta-analysis of the literature was performed using the key words “papillary thyroid carcinomas” and “lymph node ecisions” for searches of electronic databases. Complications such as transient hypocalcemia, permanent hypocalcemia, transient and permanent hypoparathyroidism, transient and permanent vocal cord paralysis, transient recurrent and permanent recurrent laryngeal nerve injury, and local recurrence were pooled by meta-analysis. Stata17.0 was used to carry out the meta-analysis. Results: Data were extracted from 15 studies. In the present review, the group of patients who had total thyroidectomy (TT) with PCND had a lower local recurrence than the group with TT alone (OR 0.22, 95% CI 0.10-0.45, P = 0.000), whereas the incidence of permanent hypocalcemia (OR 4.24, 95% CI 1.05-17.22, P = 0.043) and transient hypoparathyroidism (OR 2.14, 95% CI 1.34-3.42, P =0.001) were higher. No significant differences were recorded in the incidence of other complications: transient hypocalcemia (OR 2.24, 95% CI 0.77-6.51, P = 0.138), permanent hypoparathyroidism (OR 1.70, 95% CI 0.89-3.27, P = 0.111), transient vocal cord paralysis (OR 1.48, 95% CI 0.78-2.83, P = 0.231), permanent vocal cord paralysis (OR 1.44, 95% CI 0.53-3.94, P = 0.477), transient recurrent laryngeal nerve injury (OR 1.47, 95% CI 0.93-2.32, P = 0.102) and permanent recurrent laryngeal nerve injury (OR 1.24, 95% CI 0.56-2.74, P = 0.587) between the two groups. Conclusion: Compared with TT alone, TT with PCND was more effective in reducing local recurrence without increasing the risk of recurrent laryngeal nerve, thyroid and vocal cord, except for hypocalcemia and transient hypoparathyroidism. Therefore, we believe that TT with PCND should be recommended for patients with cN0 PTC. [ABSTRACT FROM AUTHOR]

Background: Activating mutations in the BRAF oncogene occur in 45% of papillary thyroid carcinomas (PTCs). Though less studied, K601E may identify a clinically distinct subset of thyroid neoplasms., Methods: A bioinformatics assessment was conducted using the COSMIC database and in silico data analysis. A systematic search was conducted through August 2024 to identify studies reporting BRAF mutation in thyroid neoplasms. Pooled prevalence, histopathological subtype distribution, extrathyroidal extension, lymph node metastasis, recurrence, and survival were extracted/analyzed from 32 studies (13 191 patients)., Results: In the COSMIC database, BRAF K601E was found in various tissue types but mainly in the thyroid. In silico data analysis revealed a structural and functional basis for differences between K601E and V600E. Upon systematic review, the BRAF K601E mutation was identified in 2.8% of PTCs compared to 22% with V600E. The stratified analysis revealed geographical differences, with higher rates in Italy (5.23%) and the United States of America (3.31%). The K601E mutant was enriched for follicular-patterned variants like NIFTP (11.2% of cases). Meta-analysis demonstrated significantly reduced extrathyroidal extension for K601E versus V600E mutants (RR = 0.22, 95% CI = 0.10-0.50, p = 0.0003)., Conclusion: K601E-mutated neoplasms could be a unique clinicopathological entity associated with low-risk histology and reduced extrathyroidal extension, consistent with a more indolent course than V600E mutants. Although detecting K601E may potentially guide conservative management, further prospective studies are needed., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

This study evaluated the preoperative diagnostic value of lymph node ultrasonography in distinguishing between benign and malignant central cervical lymph nodes (CCLNs) in patients with papillary thyroid carcinoma (PTC). A total of 176 patients who had PTC with 216 CCLNs (49 benign and 155 malignant) were enrolled in this study and preoperatively imaged by ultrasonography, including conventional ultrasound (US) and contrastenhanced ultrasound (CEUS). We evaluated the ultrasonography parameters for each lymph node. Binary logistic regression analysis indicated thatmultifocality of PTC and the absence of Hashimoto's thyroiditis are independent clinical features related to patients with PTC who also have malignant CCLNs. For preoperative ultrasonography features, heterogeneous enhancement and centripetal perfusion are independent ultrasonographic features to identify malignant and benign CCLNs. This study demonstrated that preoperative CEUS characteristics help to distinguish malignant CCLNs from benign CCLNs. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the association between clinicopathologic variables and metastasis of the lymph node (LN) between the sternocleidomastoid and sternohyoid muscles (LNSS) to clarify the necessity of LNSS dissection in papillary thyroid carcinomas (PTCs). Methods: A total of 219 patients undergoing unilateral or bilateral neck dissection for PTCs were prospectively enrolled. The associations between clinicopathologic variables and LNSS metastasis were evaluated by univariate and multivariate analyses. Results: LNSS was present in 108 (40.1%) neck dissection samples and in 76 (34.7%) patients. Positive LNSS occurred in 40/269 (14.9%) neck dissection samples and in 20/219 (9.1%) patients. Univariate analysis showed that tumor stage, number of positive nodes in level III, and number of positive nodes in level IV were related to LNSS metastasis. Multivariate analysis confirmed that T3/4 stage tumors and >2 positive LNs in level IV independently increased the risk of LNSS metastasis. Conclusions: The low rate of LNSS metastasis would deem routine dissection unnecessary; however, LNSS would require excision if advanced stage tumors or level IV LN metastasis were present. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) in distinguishing between benign and malignant cervical lymph nodes (LNs) in patients with papillary thyroid carcinoma (PTC). Two hundred and one cervical LNs (157 metastatic from PTC and 44 benign) were evaluated using conventional ultrasonography (US) and CEUS before biopsy or surgery. Histopathology was used as the gold standard. We evaluated the size, long axis/short axis ratio (L/S), fatty hilum, hyper-echogenicity, calcification, cystic change, peripheral vascularity and CEUS parameters for each lymph nodule. The CEUS parameters included enhancement type, homogeneity, perfusion type, ring enhancement, peak intensity (PI) index and area under the curve (AUC) index. Univariate analysis demonstrated that compared with benign LNs, malignant LNs more frequently had L/S < 2, absence of a fatty hilum, presence of hyper-echogenicity, presence of calcification, peripheral vascularity, hyper-enhancement, heterogeneous enhancement, centripetal perfusion, ring enhancement, PI index > 1 and AUC index > 1 on preoperative US and CEUS. Binary logistic regression analysis demonstrated that hyper-enhancement, centripetal perfusion, and ring enhancement are independent CEUS characteristics related to malignant LNs for their differentiation from benign LNs (all p < 0.05). Our study indicated that preoperative CEUS characteristics may serve as a useful tool to identify malignant cervical LNs from benign cervical LNs. [ABSTRACT FROM AUTHOR]

BackgroundThis study aimed to evaluate the association between clinicopathologic variables and metastasis of the lymph node (LN) between the sternocleidomastoid and sternohyoid muscles (LNSS) to clarify the necessity of LNSS dissection in papillary thyroid carcinomas (PTCs).MethodsA total of 219 patients undergoing unilateral or bilateral neck dissection for PTCs were prospectively enrolled. The associations between clinicopathologic variables and LNSS metastasis were evaluated by univariate and multivariate analyses.ResultsLNSS was present in 108 (40.1%) neck dissection samples and in 76 (34.7%) patients. Positive LNSS occurred in 40/269 (14.9%) neck dissection samples and in 20/219 (9.1%) patients. Univariate analysis showed that tumor stage, number of positive nodes in level III, and number of positive nodes in level IV were related to LNSS metastasis. Multivariate analysis confirmed that T3/4 stage tumors and >2 positive LNs in level IV independently increased the risk of LNSS metastasis.ConclusionsThe low rate of LNSS metastasis would deem routine dissection unnecessary; however, LNSS would require excision if advanced stage tumors or level IV LN metastasis were present.

The aim of the study was to evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) in distinguishing between benign and malignant cervical lymph nodes (LNs) in patients with papillary thyroid carcinoma (PTC). Two hundred and one cervical LNs (157 metastatic from PTC and 44 benign) were evaluated using conventional ultrasonography (US) and CEUS before biopsy or surgery. Histopathology was used as the gold standard. We evaluated the size, long axis/short axis ratio (L/S), fatty hilum, hyper-echogenicity, calcification, cystic change, peripheral vascularity and CEUS parameters for each lymph nodule. The CEUS parameters included enhancement type, homogeneity, perfusion type, ring enhancement, peak intensity (PI) index and area under the curve (AUC) index. Univariate analysis demonstrated that compared with benign LNs, malignant LNs more frequently had L/S < 2, absence of a fatty hilum, presence of hyper-echogenicity, presence of calcification, peripheral vascularity, hyper-enhancement, heterogeneous enhancement, centripetal perfusion, ring enhancement, PI index > 1 and AUC index > 1 on preoperative US and CEUS. Binary logistic regression analysis demonstrated that hyper-enhancement, centripetal perfusion, and ring enhancement are independent CEUS characteristics related to malignant LNs for their differentiation from benign LNs (all p < 0.05). Our study indicated that preoperative CEUS characteristics may serve as a useful tool to identify malignant cervical LNs from benign cervical LNs.

Our objective was to provide the various sonographic characteristics of clinically atypical subacute thyroiditis (CAST) in distinguishing CAST from papillary thyroid carcinomas (PTCs) by using conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS). Forty-six CAST patients and 50 PTC patients were enrolled in this study. We evaluated the size, shape, margin, echogenicity, calcification, vascularity and CEUS parameters for each nodule. The final diagnosis of CAST was confirmed via fine-needle aspiration (FNA) or surgery. Of the 46 CASTs, 13 (28.3%) were confirmed by surgery to be benign, and 33 (71.7%) were proven by FNA to be benign. Univariate analysis indicated that compared with PTCs, CAST lesions more frequently had wider-than-taller shapes, blurred margins, the absence of microcalcifications, peripheral high echogenicity, the absence of internal vascularity, hypo-enhancement, centrifugal perfusion and a peak intensity index <1 and area under the curve index <1 on pre-operative US and CEUS. A multivariate analysis revealed that clear margins, microcalcifications and centripetal perfusion were independent characteristics related to PTCs for their differentiation from CAST (all p values <0.05). Our study indicated that the pre-operative multiparameter US characteristics may serve as a useful tool for distinguishing CAST from malignant thyroid nodules to avoid surgical excisions or unnecessary FNAs. [ABSTRACT FROM AUTHOR]

Wisely differentiating high-risk papillary thyroid carcinoma (PTC) patients from low-risk PTC patients preoperatively is necessary when comes to making a personalized treatment plan. It is not easy to stratify the risk of patients according to sonography or lab results before surgery. This study aims to seek out potential mutation gene markers that may be helpful in stratifying the risk of PTC. A custom panel of 439 PTC relevant and classic tumor metabolic pathway relevant genes was designed. Targeted capture sequencing was performed on 35 pairs of samples from 35 PTC tumors and 35 para-tumor thyroid tissues obtained during surgery. Variant calling and detection of cancer gene mutations were identified by bio-information analysis. Ingenuity Pathway Analysis (IPA) was performed to do functional enrichment analysis of high-frequency mutant genes. Immunohistochemistry (IHC) was performed on 6 PTC patients to explore the expression of protein associated with interested genes. Event-free survival (EFS) was calculated to determine which genes might affect the prognosis of patients. We have identified 32 high-frequency mutant genes in PTC including BRAF. RBL2 was found to be significantly correlated to event-free survival, FOXO1, MUC6, PCDHB9, NOTCH1, FIZ1, and RTN1 were significantly associated with EFS, while BRAF mutant was not correlated to any of the prognosis indicators. Our findings in this study might open more choices when designing thyroid gene panels used in FNA samples to diagnose PTC and predict the potentially aggressive behavior of PTC.

Wisely differentiating high-risk papillary thyroid carcinoma (PTC) patients from low-risk PTC patients preoperatively is necessary when comes to making a personalized treatment plan. It is not easy to stratify the risk of patients according to sonography or lab results before surgery. This study aims to seek out potential mutation gene markers that may be helpful in stratifying the risk of PTC. A custom panel of 439 PTC relevant and classic tumor metabolic pathway relevant genes was designed. Targeted capture sequencing was performed on 35 pairs of samples from 35 PTC tumors and 35 para-tumor thyroid tissues obtained during surgery. Variant calling and detection of cancer gene mutations were identified by bio-information analysis. Ingenuity Pathway Analysis (IPA) was performed to do functional enrichment analysis of high-frequency mutant genes. Immunohistochemistry (IHC) was performed on 6 PTC patients to explore the expression of protein associated with interested genes. Event-free survival (EFS) was calculated to determine which genes might affect the prognosis of patients. We have identified 32 high-frequency mutant genes in PTC including BRAF. RBL2 was found to be significantly correlated to event-free survival, FOXO1 , MUC6 , PCDHB9 , NOTCH1 , FIZ1 , and RTN1 were significantly associated with EFS, while BRAF mutant was not correlated to any of the prognosis indicators. Our findings in this study might open more choices when designing thyroid gene panels used in FNA samples to diagnose PTC and predict the potentially aggressive behavior of PTC. [ABSTRACT FROM AUTHOR]

Purpose Our purpose is to assess the efficacy and safety of percutaneous US-guided microwave ablation (MWA) for cervical metastatic lymph nodes from papillary thyroid carcinomas (PTC). Methods In total, 37 patients with 98 cervical metastatic lymph nodes from PTC were enrolled in this retrospective study. Among them, 8 had subtotal thyroidectomy, 4 lobectomy, 2 no operation, and the rest total thyroidectomy. A multipoint and multiplane fixed ablation method was used. Monitoring of ablation process and clinical follow-up consisted of US or CEUS. Results All 98 metastatic lymph nodes successfully treated in a single session with 100% complete ablation. The average longest and shortest diameter of the tumors were reduced from 13.21 ± 5.86 mm to 6.74 ± 5.66 mm (p =.00) and from 9.29 ± 4.09 mm to 4.31 ± 3.56 mm (p =.00) at the final follow-up. There were no evidence of recurrence at ablated sites. The common intraoperative complications were a burning sensation and pain. Only 3 patients had vagal reflex. Conclusions US-guided MWA can effectively control cervical metastatic lymph nodes from PTC. MWA may become an alternative therapy in selected PTC patients with cervical lymph node metastasis.

Thyroid nodules are neoplasms commonly found among adults, with papillary thyroid carcinoma (PTC) being the most prevalent malignancy. However, current diagnostic methods often subject patients to unnecessary surgical burden. In this study, we developed and validated an automated, highly accurate multi-study-derived diagnostic model for PTCs using personalized biological pathways coupled with a sophisticated machine learning algorithm. Surprisingly, the algorithm achieved near-perfect performance in discriminating PTCs from non-tumoral thyroid samples with an overall cross-study-validated area under the receiver operating characteristic curve (AUROC) of 0.999 (95% confidence interval [CI]: 0.995–1) and a Brier score of 0.013 on three independent development cohorts. In addition, the algorithm showed excellent generalizability and transferability on two large-scale external blind PTC cohorts consisting of The Cancer Genome Atlas (TCGA), which is the largest genomic PTC cohort studied to date, and the post-Chernobyl cohort, which includes PTCs reported after exposure to radiation from the Chernobyl accident. When applied to the TCGA cohort, the model yielded an AUROC of 0.969 (95% CI: 0.950–0.987) and a Brier score of 0.109. On the post-Chernobyl cohort, it yielded an AUROC of 0.962 (95% CI: 0.918–1) and a Brier score of 0.073. This algorithm also is robust against other various types of clinical scenarios, discriminating malignant from benign lesions as well as clinically aggressive thyroid cancer with poor prognosis from indolent ones. Furthermore, we discovered novel pathway alterations and prognostic signatures for PTC, which can provide directions for follow-up studies. [ABSTRACT FROM AUTHOR]

TERT promoter mutations C228T and C250T are associated with disease aggressiveness and poor clinical outcomes in patients with papillary thyroid carcinomas. However, very little is known about the transcriptional consequences of these mutations and whether they both carry similar oncogenic potential. Here we characterized the transcriptional disturbances and clinical outcomes associated with the presence of each of these two mutations using data derived from The Cancer Genome Atlas. We observed that tumors harboring the C228T mutation (n = 27) exhibited a 16-fold increase in TERT mRNA levels (P = 5.3 × 10-42), whereas C250T tumors (n = 8) showed only a two-fold increase in expression (P = 0.034). The C228T mutation was associated with the activation of signaling pathways controlling the cell cycle, cellular division, and extracellular matrix degradation. Univariate analysis demonstrated that the C228T mutation was associated with older age at diagnosis, large tumor size, lymph node invasion, and distant metastases at diagnosis. The C228T mutation was also associated with worse progression-free interval (PFI) in comparison to WT tumors (HR = 5,04; P < 0.001). This association remained significant in a multivariate analysis (HR = 3.74, P = 0.003) adjusting for BRAF-V600E status and ATA risk group. Our data indicate that TERT promoter mutations C228T and C250T have distinct transcriptional consequences in papillary thyroid carcinoma (PTC), suggesting a greater oncogenic potential for the C228T mutation. TERT promoter mutation C228T may be a useful prognostic marker to identify patients at high risk of distant recurrence. Clinical data for the C250T mutation is still limited, with no evidence up to date to confirm its prognostic significance.

Context: Distant metastases are the primary cause of therapy failure and mortality in patients with papillary thyroid carcinomas (PTCs). However, the underlying mechanism responsible for the initiation of tumor cell dissemination and metastasis in PTCs has rarely been investigated., Objective: The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs., Methods: The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT-PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases., Results: We determined that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1-mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2., Conclusion: Our findings highlight the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most clinicians are well aware of the coexistence of medullary thyroid cancer and hyperparathyroidism in hereditary and sporadic multiple endocrine neoplasia syndromes. Тhe reported incidence of nonmedullary thyroid carcinoma in patients with primary hyperparathyroidism (pHPT) is only approximately 3%. Papillary thyroid carcinomas (PTC) is a malignant epithelial tumour. PTC represent up to 87% of all thyroid carcinomas. Atypical parathyroid adenoma (APA) are a subset of parathyroid neoplasms that exhibit some of the features of parathyroid carcinoma but lack unequivocal invasive growth. APA represents about 0.54% of cases of PHPT. As a group, they may be considered tumors of uncertain malignant potential. The clinical importance, and long-term outcomes as well as appropriate operative management and surveillance are not well defined for APA probably due to the overall low prevalence as well as the lack of a standard definition of APA. We report two cases of a 63-year-old woman and 57-year-old man with a synchronous atypical parathyroid adenoma and papillary thyroid carcinoma. One of this patients had a classic symptoms of pHPT, including severe metabolic bone disease and renal disease, but another didnt have. The mean preoperative calcium was 3,48 and 4,1 (range 2.122.6) mmol/l and a mean parathyroid hormone (PTH) of 1300 and 1533 (range 1565) pg/ml, respectively. Thyroid ultrasound didnt show a nodule with features of the thyroid carcinoma in both cases. The thyroid cancer was suspected after intraoperative revision. The patients underwent a total thyroidectomy and surgical excision of the parathyroid adenoma. Surgical pathology showed papillary microcarcinoma in both cases (in the first unilateral, in the second bilateral) and APA. Awareness of this condition will enable clinicians to evaluate for possible thyroid pathology in patients with primary hyperparathyroidism. Both of these endocrine conditions could then be managed with a single surgery involving concomitant resection of the thyroid and parathyroid glands.

Tumors modulate the host immune cells within their microenvironment to avoid recognition and elimination by our immune system, a phenotype called cancer immune escape. Different mechanisms responsible for cancer immune escape that result either in decreased tumor immunogenicity or in increased tumor immunosuppressive activity have been identified. Recently, various immunotherapeutic approaches have been developed with the aim to revert tumor immune escape. The aims of this review are to explore the immunological aspects of thyroid cancer and to assess whether these features can be exploited in the prognosis and treatment of advanced forms of this disease. Therefore, we will describe the immune landscape and phenotypes of thyroid cancer, summarize studies investigating the expression of immunomodulatory molecules, and finally describe the preclinical and clinical trials investigating the utility of immunotherapies in the management of thyroid cancer. The aim of this review is to explore the immunological aspects of thyroid cancer and to assess whether these features can be exploited in the prognosis and treatment of advanced forms of this disease. Therefore, we will describe the immune-landscape and phenotypes of thyroid cancer, we will summarize studies investigating the expression of immunomodulatory molecules, and we will finally describe the preclinical and clinical trials investigating the utility of immunotherapies in the management of thyroid cancer.

Objective: Papillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancers and has a high recurrence rate. We aimed to screen key genes involved in PTC to provide novel insights into the mechanisms of PTC., Methods: Seven microarray datasets of PTC were downloaded from gene expression omnibus database. Differentially expressed genes (DEGs) between PTC and normal samples were screened in the merged dataset. Then, protein-protein interaction (PPIs) functional modules analysis and weighted gene co-expression network analysis (WGCNA) were utilized to identify PTC-associated key genes. The identified key genes were then characterized from various aspects, including gene set enrichment analysis (GSEA) and the associations with immune infiltration, methylation levels and prognosis., Results: A large numbers of DEGs were identified, and these DEGs are involved in several cancer pathways. Nine key genes (including down-regulated genes GNA14, AVPR1A, and WFS1, and up-regulated genes LAMB3, PLAU, MET, MFGE8, PRSS23, and SERPINA1) were identified. Patients in the AVPR1A and GNA14 high expression groups had better disease-free survival (DFS) than those in the low expression group. Key genes were mainly involved in P53 pathway, estrogen response, apoptosis, glycolysis, NOTCH signaling, epithelial mesenchymal transition, WNT&#95;beta catenin signaling, and inflammatory response. The expression of key genes was associated with immune cell infiltration and corresponding methylation levels. The verification results of key gene proteins and mRNA expression levels using external validation datasets were consistent with our expectations, implying the involvements of key genes in PTC., Conclusion: The key genes may serve as potential therapeutic targets for PTC. This study provides novel insights into the mechanisms underlying PTC development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignant tumors. Existing methods for clustering high-noise ultrasound images tend to degrade the clustering performance. In order to realize accurate segmentation of thyroid nodule in noisy environment, this paper proposes an improved segmentation algorithm based on adaptive fast generalized clustering. Firstly, the parameter balance factor is adaptively determined according to the noise probability of non-local pixels so as to reflect the spatial structure information in the image more accurately. Then, the balance factor is used to effectively combine the linear weighted filtered image in the AFGC algorithm so as to create the adaptive filtered image. Since the filtering degree depends on the probability whether the pixel is noise in the image, the dynamic noise suppression performance of the proposed method can be greatly improved. A large number of qualitative and quantitative experimental results show that the proposed generalized clustering algorithm can obtain more accurate results when clustering images with high noise. It is suitable for intelligent diagnosis of papillary thyroid convolution in clinical examination. [ABSTRACT FROM AUTHOR]

Background: Based on the new TNM classification, differentiated thyroid carcinomas with extrathyroidal extension (ETE) into the strap muscles are designated as T3b. The current study analyzed the clinical significance of this new stage in patients with papillary thyroid cancer (PTC). Subjects and Methods: This retrospective cohort study included 4045 eligible PTC patients. The patients were divided into four groups according to the extent of ETE: no ETE, ETE into perithyroidal tissue, T3b (ETE into the strap muscles), and ETE beyond the strap muscles. Differences in the clinical characteristics and prognosis of the four groups were assessed. Results: Of these 4045 patients, 2300 (56.9%) had no ETE, 1004 (24.8%) had ETE into perithyroidal tissue, 371 (9.2%) had ETE into the strap muscles, and 370 (9.1%) had ETE beyond the strap muscles. Tumor size, multifocality, lymph node metastasis (LNM), distant metastasis (DM), recurrence, and recurrence-free survival (RFS) between patients with ETE into perithyroidal tissue and patients without ETE did not show differences, but significant differences were observed between patients with T3b and patients without ETE, and only patients with ETE beyond the strap muscles had significantly worse overall survival (OS) than the other three groups. However, T3b did not independently predict worse RFS in univariable and multivariable analyses. Conclusions: T3b, distinguished from minimal ETE, may be related to larger tumor size, higher prevalence of multifocality, LNM, DM, recurrence, and worse RFS than no ETE, but it may not affect OS and may not independently predict recurrence in PTC patients. [ABSTRACT FROM AUTHOR]

The mechanisms of B‐type Raf kinase (BRAF) V600E mutation in papillary thyroid cancer (PTC) remain to be elucidated. With the aim to investigate the key candidate genes distinctive to BRAFV600E‐PTC, we analyzed the transcriptomics data from three microarray datasets (GSE27155, GSE54958, and GSE58545) and identified 491 differentially expressed genes (DEGs) between BRAFV600E‐PTC and BRAFwild type‐PTC. Functional enrichment analysis of DEGs revealed that negative regulation of wound healing may be involved in the BRAFV600E‐related pathogenesis in PTC. Weighted gene coexpression network analysis revealed BRAFV600E‐related coexpressed genes in PTC, from which hub genes were selected. The intersection of DEGs and hub genes revealed 31 candidates, wherein GRB7, SNAP25, SLC35F2, FAM155B, HGD, and ITPR1 were rendered the key candidate genes via receiver operating characteristic curve analysis. On further characterization, the six key genes displayed significantly different expression patterns at different cytomorphology, however, with no significant difference in overall survival. These results provide novel insights into the key genes distinctive to of BRAFV600E in PTC and might be suggestive as therapeutic targets for further application. [ABSTRACT FROM AUTHOR]

Aim: To summarize the clinical, ultrasonographic (US) and pathological characteristics of Warthin-like variant papillary thyroid carcinomas (WVPTC).Material and Methods: Medical records and US images of 32 cases of WVPTCs diagnosed between December, 2006 and September, 2018 were reviewed. Clinical, pathological and US characteristics of these cases were collected and summarized. ACR TI-RADS was followed during the analysis of the US features of the lesions. Results: Totally, 32 patients with 33 WVPTC nodules were reviewed. WVPTC was more often seen in female patients (27/32,84.4%) with a relatively high age (mean age, 51.0±10.8 years old). Hyperthyroidism was observed in 14 patients; 2 patients were diagnosed as subclinical hyperthyroidism and 1 patient as subclinical hypothyroidism. Abnormal thyroglobulin antibody was detected in 22 patients. Mean size of the nodule was 1.2±0.5 cm (range, 0.5~2.99 cm) on US. Pathologically, tumor margin of 63.6% carcinomas were infiltrative but most (72.9%) of the enrolled carcinomas were intra-thyroidal. Lymphocytic thyroiditis was detected in 87.5% (28/32) patients. On US, most WVPTCs were solid or almost complete solid (32/33, 97.0%) and very hypoechoic (26/33, 78.8%). Taller-than-wide shape (6/33, 18.2%) and punctate echogenic foci (9/33, 27.3%) were not popular. All the nodules were scored higher than 5 points according to the ACR TI-RADS, including 9 nodules that were classified into TR4 and 24 nodules as TR5. Follow-up information was available in 31 patients and no recurrence or distal metastasis was detected.Conclusions: WVPTC is a rare variant of PTCs with favorable outcomes. Very hypoechoic echogenicity, solid or almost complete solid composition are the vital indicators for biopsy, even though the nodule may be wider-than-tall and have a lack of punctuate echoic foci. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that ultrasonography is the recommended imaging modality for preoperative staging of papillary thyroid carcinomas (PTCs). However, only a few studies have kept watch on preoperative evaluation of capsular invasion (CI) or extracapsular extension (ECE) and cervical lymph node metastasis using preoperative ultrasonography. This study aimed to investigate the relationship between the CI or ECE and the cervical lymph node metastasis in PTCs using preoperative ultrasonography and postoperative pathology in Chinese patients. Methods: The data of preoperative ultrasonography and postoperative pathology of 166 patients who had a definitive diagnosis of PTCs from October 2011 to July 2014 at Xuanwu Hospital, Beijing were collected and reviewed. Preoperative ultrasonic parameters of thyroid nodules were compared with those of postoperative pathological diagnoses. All the patients were divided into bilateral PTCs group (n = 42, 78 nodules) and unilateral PTCs group (n = 124, 124 nodules), and the data of the nodule sizes, CI or ECE, and cervical lymph node metastasis by preoperative ultrasonography were compared between two groups. Results: A total of 202 nodules of 166 patients which were confirmed by preoperative ultrasonography and postoperative pathology were analyzed. Hypoechogenicity (n = 201, 99.5%) and irregular margins (n = 167, 82.7%) were the main ultrasonic characteristics of PTCs. A significant moderate agreement between preoperative ultrasonic examination and postoperative pathology for CI or ECE (κ = 0.622, P< 0.001) was observed. The diagnostic sensitivity was 92.0%, and specificity was 71.1%. In bilateral PTCs group, 81.0% had CI or ECE, and 61.9% had cervical lymph node metastasis. In unilateral PTCs group, 76.6% had CI or ECE, and 58.1% had cervical lymph node metastasis. There were no significant differences in the incidence of CI or ECE and cervical lymph node metastasis between two groups (all P > 0.05). Conclusions: Ultrasonography was proved to be a valuable method for preoperative diagnosis of PTCs. Hypoechogenicity and irregular margins were strongly associated with PTCs. CI or ECE in unilateral PTCs strongly implied the cervical lymph node metastasis. Therefore, the cervical lymph nodes should be carefully examined by ultrasonography in patients with PTCs.

The present study aimed to screen all types of RNAs involved in the development of papillary thyroid carcinoma (PTC). RNA-sequencing data of PTC and normal samples were used for screening differentially expressed (DE) microRNAs (DE-miRNAs), long non-coding RNAs (DE-lncRNAs) and genes (DEGs). Subsequently, lncRNA-miRNA, miRNA-gene (that is, miRNA-mRNA) and gene-gene interaction pairs were extracted and used to construct regulatory networks. Feature genes in the miRNA-mRNA network were identified by topological analysis and recursive feature elimination analysis. A support vector machine (SVM) classifier was built using 15 feature genes, and its classification effect was validated using two microarray data sets that were downloaded from the Gene Expression Omnibus (GEO) database. In addition, Gene Ontology function and Kyoto Encyclopedia Genes and Genomes pathway enrichment analyses were conducted for genes identified in the ceRNA network. A total of 506 samples, including 447 tumor samples and 59 normal samples, were obtained from The Cancer Genome Atlas (TCGA); 16 DE-lncRNAs, 917 DEGs and 30 DE-miRNAs were screened. The miRNA-mRNA regulatory network comprised 353 nodes and 577 interactions. From these data, 15 feature genes with high predictive precision (>95%) were extracted from the network and were used to form an SVM classifier with an accuracy of 96.05% (486/506) for PTC samples downloaded from TCGA, and accuracies of 96.81 and 98.46% for GEO downloaded data sets. The ceRNA regulatory network comprised 596 lines (or interactions) and 365 nodes. Genes in the ceRNA network were significantly enriched in ‘neuron development’, ‘differentiation’, ‘neuroactive ligand-receptor interaction’, ‘metabolism of xenobiotics by cytochrome P450’, ‘drug metabolism’ and ‘cytokine-cytokine receptor interaction’ pathways. Hox transcript antisense RNA, miRNA-206 and kallikrein-related peptidase 10 were nodes in the ceRNA regulatory network of the selected feature gene, and they may serve import roles in the development of PTC. [ABSTRACT FROM AUTHOR]

The comparative analysis of the expression of the reactive oxygen species-generating NADPH oxidase NOX4 from TCGA data shows that the NOX4 transcript is upregulated in papillary thyroid carcinomas (PTC)-BRAF V600E tumors compared to PTC-BRAF wt tumors. However, a comparative analysis of NOX4 at the protein level in malignant and non-malignant tumors is missing. We explored NOX4 protein expression by immunohistochemistry staining in malignant tumors (28 classical forms of PTC (C-PTC), 17 follicular variants of PTC (F-PTC), and three anaplastic thyroid carcinomas (ATCs)) and in non-malignant tumors (six lymphocytic thyroiditis, four Graves' disease, ten goiters, and 20 hyperplasias). We detected the BRAF V600E mutation by Sanger sequencing and digital droplet PCR. The results show that NOX4 was found to be higher (score ≥ 2) in C-PTC (92.9%) compared to F-PTC (52.9%) and ATC (33.3%) concerning malignant tumors. Interestingly, all C-PTC-BRAF V600E expressed a high score for NOX4 at the protein level, strengthening the positive correlation between the BRAF V600E mutation and NOX4 expression. In addition, independent of the mutational status of BRAF, we observed that 90% of C-PTC infiltrating tumors showed high NOX4 expression, suggesting that NOX4 may be considered a complementary biomarker in PTC aggressiveness. Interestingly, NOX4 was highly expressed in non-malignant thyroid diseases with different subcellular localizations.

Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that has emerged as an important regulator of cancer development; however, its cancer-related function remains controversial. Here, we investigated the possible role of ZNRF3 in thyroid carcinoma (TC). We found that ZNRF3 is downregulated in papillary thyroid carcinoma (PTC) compared to normal thyroid tissues and inversely correlated with the degree of cell differentiation. Overexpression of ZNRF3 significantly suppressed cell malignant behaviors, including cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Consistent with recent studies showing that ZNRF3 is involved in the Wnt/β-catenin pathway, ZNRF3 overexpression negatively regulated β-catenin activation, modulating PTC cell behaviors. Clinical specimens revealed a significant inverse correlation between ZNRF3 and β-catenin mRNA levels. Taken together, these results provide insight into a potential tumor suppressor role of ZNRF3 in PTC progression, and may have potential clinical relevance for the prognosis and treatment of PTC. [ABSTRACT FROM AUTHOR]

The incidence of thyroid cancer has appeared as an increasing trend globally, especially in Asian countries. In this study, the expression of mucin-1 (MUC1) and Thomsen-Friedenreich antigen, Galβ1-3GalNAcα1-R (CD176) was investigated by immunohistochemistry in papillary thyroid carcinomas (PTCs), which accounts for approximately 80 % of all thyroid cancer. We found that 78 % of PTC overexpressed MUC1. Importantly, we observed firstly that CD176 was expressed in 63 % of PTC, but was faintly or not expressed in normal thyroid tissues and benign thyroid disease tissues, indicating that CD176 is also a tumour-associated antigen for PTCs. Moreover, expression of CD176 was strongly correlated with MUC1 by immunohistochemical staining in PTCs. Furthermore, we used the immunochemical method to confirm that MUC1 is a common and main carrier of CD176 in PTCs. Our data demonstrated that MUC1 and CD176 might be promising biomarkers for thyroid cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Collagenase-3 (MMP-13), a matrix metalloproteinase, is a recently identified member of the matrix metallo-proteinases (MMPs) with broad substrate specificity, and a potential role in tumor metastasis and invasion has been proposed. Collagenase-3 expression has been reported in many carcinomas. However, the presence and possible implication of MMP-13 in the progression of papillary thyroid carcinomas are unknown. MATERIALS AND METHODS: In the present study, we examined MMP-13 gene expression in 208 papillary thyroid carcinomas who underwent surgery without preoperative treatment and 100 matched samples of adjacent normal thyroid tissue (Paraffin-embedded tissue samples) by immunohistochemistry analysis. In vitro and in vivo studies were done in order to investigate the effect of MMP-13 overexpression or silencing on cancer cells invasion and metastasis. RESULTS: We found MMP-13 expression was significantly increased in the tumours from local regional lymph node metastases patients. The MMP-13 was stained more intensely in invading fronts than in central portions of local regional lymph node. No MMP-13 staining was observed in matched samples of adjacent normal thyroid tissue. MMP-13 expression was significantly related withTNM and recurrent disease, no relation was found with age extent of tumour and size of tumour. Studies with cell and mice models indicated that overexpression of MMP-13 increased cell migration and promoted metastasis, and MMP-13 sliencing decreased cell migration. CONCLUSIONS: The data suggest that MMP-13 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

This study evaluated the preoperative diagnostic value of lymph node ultrasonography in distinguishing between benign and malignant central cervical lymph nodes (CCLNs) in patients with papillary thyroid carcinoma (PTC). A total of 176 patients who had PTC with 216 CCLNs (49 benign and 155 malignant) were enrolled in this study and preoperatively imaged by ultrasonography, including conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS). We evaluated the ultrasonography parameters for each lymph node. Binary logistic regression analysis indicated that multifocality of PTC and the absence of Hashimoto's thyroiditis are independent clinical features related to patients with PTC who also have malignant CCLNs. For preoperative ultrasonography features, heterogeneous enhancement and centripetal perfusion are independent ultrasonographic features to identify malignant and benign CCLNs. This study demonstrated that preoperative CEUS characteristics help to distinguish malignant CCLNs from benign CCLNs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ye, Gong, Tang, Xu, Zhang, Chen, Li, Zhang, Liao, Zuo and Niu.)

RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation. [ABSTRACT FROM AUTHOR]

Human chromosomal fragile sites are regions of the genome that are prone to DNA breakage, and are classified as common or rare, depending on their frequency in the population. Common fragile sites frequently coincide with the location of genes involved in carcinogenic chromosomal translocations, suggesting their role in cancer formation. However, there has been no direct evidence linking breakage at fragile sites to the formation of a cancer-specific translocation. Here, we studied the involvement of fragile sites in the formation of RET/PTC rearrangements, which are frequently found in papillary thyroid carcinoma (PTC). These rearrangements are commonly associated with radiation exposure; however, most of the tumors found in adults are not linked to radiation. In this study, we provide structural and biochemical evidence that the RET, CCDC6 and NCOA4 genes participating in two major types of RET/PTC rearrangements, are located in common fragile sites FRA10C and FRA10G, and undergo DNA breakage after exposure to fragile site-inducing chemicals. Moreover, exposure of human thyroid cells to these chemicals results in the formation of cancer-specific RET/PTC rearrangements. These results provide the direct evidence for the involvement of chromosomal fragile sites in the generation of cancer-specific rearrangements in human cells. [ABSTRACT FROM AUTHOR]

Simple Summary: The present study focused on patients affected by stage pT1a papillary thyroid micro-carcinomas that were treated with surgery and central lymph node dissection. In this study, male sex, low age, and sub-capsular carcinoma localization resulted as independent predictive factors for central lymph node metastases. Papillary thyroid micro-carcinomas are considered relatively indolent carcinomas, often occult and incidental, with good prognosis and favorable outcomes. Despite these findings, central lymph node metastases are common, and are related to a poor prognosis for the patient. We performed a retrospective analysis on patients treated with surgery for stage pT1a papillary thyroid micro-carcinomas. One hundred ninety-five patients were included in the analyses. The presence of central lymph node metastases was identified and studied. A multivariate analysis employing binary logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals of possible central lymph node metastases risk factors. In the performed multivariate analysis, male gender, younger age, and histopathological characteristics, such as a tumor sub-capsular localization, were significantly associated with central lymph node metastases in pT1a patients. Central compartment lymph node metastases are present in a non-negligible number of cases in patients with papillary thyroid micro-carcinoma undergoing surgical resection. Studying these factors could be an effective tool for predicting patients' central lymph node metastases in papillary thyroid micro-carcinomas, defining a tailored surgical treatment in the future. [ABSTRACT FROM AUTHOR]