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[Display omitted] • The suspicious ultrasonography features are related to immune response in thyroid cancer. • The features were also related to epithelial to mesenchymal transition (EMT). • Immune response and EMT were related to aggressive clinical behaviors. • Immune response and EMT reflected in the decision by radiologists and convolutional neural networks. Ultrasonography (US) features of papillary thyroid cancers (PTCs) are used to select nodules for biopsy due to their association with tumor behavior. However, the molecular biological mechanisms that lead to the characteristic US features of PTCs are largely unknown. This study aimed to investigate the molecular biological mechanisms behind US features assessed by radiologists and three convolutional neural networks (CNN) through transcriptome analysis. Transcriptome data from 273 PTC tissue samples were generated and differentially expressed genes (DEGs) were identified according to US feature. Pathway enrichment analyses were also conducted by gene set enrichment analysis (GSEA) and ClusterProfiler according to assessments made by radiologists and three CNNs - CNN1 (ResNet50), CNN2 (ResNet101) and CNN3 (VGG16). Signature gene scores for PTCs were calculated by single-sample GSEA (ssGSEA). Individual suspicious US features consistently suggested an upregulation of genes related to immune response and epithelial-mesenchymal transition (EMT). Likewise, PTCs assessed as positive by radiologists and three CNNs showed the coordinate enrichment of similar gene sets with abundant immune and stromal components. However, PTCs assessed as positive by radiologists had the highest number of DEGs, and those assessed as positive by CNN3 had more diverse DEGs and gene sets compared to CNN1 or CNN2. The percentage of PTCs assessed as positive or negative concordantly by radiologists and three CNNs was 85.6% (231/273) and 7.1% (3/273), respectively. US features assessed by radiologists and CNNs revealed molecular biologic features and tumor microenvironment in PTCs. [ABSTRACT FROM AUTHOR]

Background: This study investigated the prevalence and subtype distribution of circulating tumor cells (CTCs) in patients with papillary thyroid cancer (PTC) before and after thyroidectomy to determine the potential of CTC count as a noninvasive marker of the efficacy of surgical treatment in PTC. Materials and methods: Between January 2021 and January 2022, 62 PTC patients who underwent thyroidectomy at Seoul National University Bundang Hospital were prospectively evaluated. Peripheral blood samples (7.5 ml) were collected from each patient for CTC analysis before surgery and at 2 weeks and 3 months after surgery. CTC count and the distribution of CTC subtypes, including epithelial, epithelial-mesenchymal, and mesenchymal phenotypes, were analyzed using the negative selection method and immunofluorescence staining. The relationship between CTC count and clinicopathological characteristics was analyzed before and after surgery. Results: Before surgery, CTCs were detected in 87% (54/62) of patients; the mean CTC count was 8.0 and the median was 5.0 in 7.5 ml of peripheral blood. The mesenchymal or epithelial-mesenchymal phenotypes were predominant. After thyroidectomy, the mean and median CTC count values decreased to 5.3 and 2.5, respectively, at 2 weeks and to 4.3 and 3.0, respectively, at 3 months. This postoperative reduction in CTCs was more pronounced in patients with lymphatic invasion, lymph node metastasis, or BRAF V600E mutation. Conclusion: CTCs were detected in patients with PTC with a predominance of cells undergoing epithelial-mesenchymal transition. The CTC count decreased postoperatively, suggesting that liquid biopsy with CTC detection could be a valuable noninvasive tool for monitoring the efficacy of surgery in PTC. [ABSTRACT FROM AUTHOR]

Polo‐like kinase 1 (PLK1; also known as serine/threonine‐protein kinase PLK1) serves as a central player in cell proliferation, exerting critical regulatory roles in mitotic processes and cell survival. We conducted an analysis of PLK1 protein expression in a large cohort of samples from papillary thyroid carcinoma (PTC) patients and examined its functional significance in PTC cell lines, both in vitro and in vivo. PLK1 overexpression was noted in 54.2% of all PTC and was significantly associated with aggressive clinicopathological parameters; it was also found to be an independent prognostic marker for shorter recurrence‐free survival. Given the significant association between PLK1 and forkhead box protein M1 (FoxM1), and their concomitant overexpression in a large proportion of PTC samples, we explored their correlation and their combined inhibitions in PTC in vitro and in vivo. Inhibition of PLK1 expression indeed suppressed cell proliferation, leading to cell cycle arrest and apoptosis in PTC cell lines. Significantly, the downregulation of PLK1 reduced the self‐renewal capability of spheroids formed from PTC cells. Immunoprecipitation analysis shows that PLK1 binds to FoxM1 and vice versa in vitro. Mechanistically, PLK1 knockdown suppresses FoxM1 expression, whereas inhibition of FoxM1 does not affect PLK1 expression, which suggests that PLK1 acts through the FoxM1 pathway. The combined treatment of a PLK1 inhibitor (volasertib) and a FoxM1 inhibitor (thiostrepton) demonstrated a synergistic effect in reducing PTC cell growth in vitro and delaying tumor growth in vivo. This study highlights the important role of PLK1 in PTC tumorigenesis and prognosis. It also highlights the synergistic therapeutic potential of dual‐targeting PLK1 and FoxM1 in PTC, unveiling a potential innovative therapeutic strategy for managing aggressive forms of PTC. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies with different risk levels. However, preoperative risk assessment of PTC is still a challenge in the worldwide. Here, the authors first report a Preoperative Risk Assessment Classifier for PTC (PRAC-PTC) by multidimensional features including clinical indicators, immune indices, genetic feature, and proteomics. Materials and Methods: The 558 patients collected from June 2013 to November 2020 were allocated to three groups: the discovery set [274 patients, 274 formalin-fixed paraffin-embedded (FFPE)], the retrospective test set (166 patients, 166 FFPE), and the prospective test set (118 patients, 118 fine-needle aspiration). Proteomic profiling was conducted by FFPE and fine-needle aspiration tissues from the patients. Preoperative clinical information and blood immunological indices were collected. The BRAFV600E mutation were detected by the amplification refractory mutation system. Results: The authors developed a machine learning model of 17 variables based on the multidimensional features of 274 PTC patients from a retrospective cohort. The PRAC-PTC achieved areas under the curve (AUC) of 0.925 in the discovery set and was validated externally by blinded analyses in a retrospective cohort of 166 PTC patients (0.787 AUC) and a prospective cohort of 118 PTC patients (0.799 AUC) from two independent clinical centres. Meanwhile, the preoperative predictive risk effectiveness of clinicians was improved with the assistance of PRAC-PTC, and the accuracies reached at 84.4% (95% CI: 82.9-84.4) and 83.5% (95% CI: 82.2-84.2) in the retrospective and prospective test sets, respectively. Conclusion: This study demonstrated that the PRAC-PTC that integrating clinical data, gene mutation information, immune indices, high-throughput proteomics and machine learning technology in multicentre retrospective and prospective clinical cohorts can effectively stratify the preoperative risk of PTC and may decrease unnecessary surgery or overtreatment. [ABSTRACT FROM AUTHOR]

Thyroid malignancy status is usually confirmed through histopathological examination (HPE) following thyroidectomy. In Malaysia, the application of molecular markers in pre-operative diagnosis of thyroid cancer remains unexplored. In this study, BRAF and NRAS gene mutation panel was assessed, and the results were compared with retrospective HPE findings. Malaysian patients with benign goitre (BTG: n=33) and papillary thyroid cancer (PTC: n=25; PTCa: n=20, PTCb: n=5) were recruited at Universiti Malaya Medical Centre from September 2019 to December 2022. PCR-direct DNA sequencing of BRAFV600, NRASG12, NRASG13, and NRASQ61 was conducted on DNA extracted from the patients' thyroid tissue specimens following thyroidectomy and HPE. BRAFV600E and NRASQ61R mutations showed absolute PTC-specificity with PTC-sensitivity of 32% and 28%, respectively. NRASQ61H demonstrated lower PTC-specificity (94%) but higher PTC-sensitivity (72%) compared to the BRAFV600E and NRASQ61R mutations. Although the NRASG12 and NRASG13 variants were absent in this study, a novel NRASV14D mutation was detected in a PTCa patient. Unlike PTCb, coexistence of BRAFV600E and NRASQ61 variants was commonly observed among the PTCa patients. Notably, all PTCb patients had NRASQ61H mutation with one patient carried both the NRASQ61H and BRAFV600E mutations. Association analysis revealed potential link between gender, BRAFV600E mutation and lymph node metastasis. In conclusion, mutation panel comprising BRAFV600E, NRASQ61R, and NRASQ61H did not discriminate the two PTC subtypes but replicated the retrospective HPE findings in differentiating BTG from PTC. The application of this mutation panel in pre-operative diagnosis of thyroid nodules requires further validation in a larger sample size, preferably incorporating fineneedle aspirate biopsies. [ABSTRACT FROM AUTHOR]

Background: Preoperative evaluation of the metastasis status of lateral lymph nodes (LNs) in papillary thyroid cancer is challenging. Strategies for using deep learning to diagnosis of lateral LN metastasis require additional development and testing. This study aimed to build a deep learning-based model to distinguish benign lateral LNs from metastatic lateral LNs in papillary thyroid cancer and test the model's diagnostic performance in a real-world clinical setting. Methods: This was a prospective diagnostic study. An ensemble model integrating a three-dimensional residual network algorithm with clinical risk factors available before surgery was developed based on computed tomography images of lateral LNs in an internal dataset and validated in two external datasets. The diagnostic performance of the ensemble model was tested and compared with the results of fine-needle aspiration (FNA) (used as the standard reference method) and the diagnoses made by two senior radiologists in 113 suspicious lateral LNs in patients enrolled prospectively. Results: The area under the receiver operating characteristic curve of the ensemble model for diagnosing suspicious lateral LNs was 0.829 (95% CI: 0.732-0.927). The sensitivity and specificity of the ensemble model were 0.839 (95% CI: 0.762-0.916) and 0.769 (95% CI: 0.607-0.931), respectively. The diagnostic accuracy of the ensemble model was 82.3%. With FNA results as the criterion standard, the ensemble model had excellent diagnostic performance (P= 0.115), similar to that of the two senior radiologists (P =1.000 and P=0.392, respectively). Conclusion: A three-dimensional residual network-based ensemble model was successfully developed for the diagnostic assessment of suspicious lateral LNs and achieved diagnostic performance similar to that of FNA and senior radiologists. The model appears promising for clinical application. [ABSTRACT FROM AUTHOR]

Age is one of the important prognostic indicators of papillary thyroid cancer (PTC). However, the distinct metastatic patterns and prognosis of age-related lymph node metastasis (LNM) are unclear. This study aims to investigate the impact of age on LNM. We conducted two independent cohort studies to assess age–nodal disease association using logistic regression analysis and a restricted cubic splines model. A multivariable Cox regression model was utilized to test the impact of nodal disease on cancer-specific survival (CSS) after age stratification. For this study, we included 7572 and 36,793 patients with PTC in Xiangya and SEER cohorts, respectively. After adjustment, advanced age was linearly associated with decreasing risk of central LNM. Patients of age ≤18 years (OR = 4.41, P < 0.001) and 19–45 years (OR = 1.97, P = 0.002) had a higher risk of developing lateral LNM than patients of age >60 years in both cohorts. Furthermore, CSS is significantly reduced in N1b disease (P < 0.001), not N1a disease, regardless of age. The incidence of high-volume LNM (HV-LNM) was significantly higher in patients of age ≤18 years and 19–45 years than in those of age >60 years (P < 0.001), in both cohorts. In addition, CSS was compromised in patients with PTC of age 46–60 years (HR = 1.61, P = 0.022) and those of age >60 (HR = 1.40, P = 0.021) after developing HV-LNM. Patient age is significantly associated with LNM and HV-LNM. Patients with N1b disease or patients with HV-LNM of age >45 years have significantly shorter CSS. Age can, thus, be a useful guide for determining treatment strategies in PTC. [ABSTRACT FROM AUTHOR]

When metastatic ipsilateral central lymph nodes from thyroid cancer are identified pre- or intraoperatively (cN1a), ipsilateral central lymph node dissection should be performed concomitantly with thyroidectomy. When the patient is N1a on one side, contralateral prophylactic central lymph node dissection can also be considered. Prophylactic ipsilateral lymph dissection is not recommended. Ipsilateral compartment lymph node dissection is recommended in the corresponding sector for treatment of thyroid cancer with lymph node involvement (cN1b). Lymph node dissection can be limited to sectors III and IV when one of these sectors (or both) is involved and ultrasound does not demonstrate involvement of the other lateral sectors. Associated prophylactic lymph node dissection of sectors IIA and IIB is not recommended, while lymph node dissection of sector V (and exceptionally sector I) is indicated only when metastatic lymph nodes are proven. Prophylactic lymph node dissection of sector VB can be considered when positive lymph nodes are identified in sectors II, III and IV. When isolated metastatic lateral lymph nodes are identified (cN1b), prophylactic central (sector VI) lymph node dissection is recommended on the same side as the lateral compartment in addition to ipsilateral lateral lymph node compartment dissection. The level of evidence is insufficient to recommend prophylactic lateral lymph node dissection on the contralateral side for unilateral cN1b tumors. This type of lymph node dissection can be discussed for tumors that are at high risk of recurrence, bilateral tumors, in case of ipsilateral lateral lymph nodes > 3 cm or in presence of > 4 metastatic lymph nodes in the central compartment. [ABSTRACT FROM AUTHOR]

Current guidelines favor thyroid lobectomy for intrathyroidal cT1bT2cN0 papillary thyroid carcinoma. Prophylactic neck dissection (PND) is not recommended for these low-risk tumors due to the lack of high-level evidence on improvement in outcomes, but the information from PND may be used for staging. The aim of this study was to evaluate the rate of upstaging with ipsilateral PND. Retrospective study of patients with intrathyroidal unifocal cT1bT2cN0 papillary thyroid carcinoma from 2008 to 2021. All patients underwent total thyroidectomy and PND. Tumors were classified as low or intermediate risk based on the information from pathological analysis of the primary tumor and then from adding the analysis of the lymph nodes. The difference between the tumor-only and the PND-added risk staging was evaluated. Three hundred three patients (241 women, median age 45, median tumor size 17 mm) were included. Microscopic extrathyroidal extension was found in 23.4%, aggressive histology in 6.6%, vascular invasion in 29.3%, and lymph node metastases in 37.3%. One hundred ten patients (36.3%) were intermediate-risk based on the primary tumor. An additional 26 (8.6%) were upstaged to intermediate-risk based on the ipsilateral PND and 2% based on the contralateral PND. Kaplan-Meier 10-year event-free survival in tumors upstaged with ipsilateral PND was not statistically different from intermediate-risk tumors based on the primary tumor characteristics (92% versus 90.9%, Log Rank p = 0.943). Ipsilateral PND upstaged low-risk cT1bT2cN0 patients to intermediate risk in only 8.6% of cases, and contralateral PND in an additional 2%. Routinely performing PND may not be warranted. [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer is associated with lymph node metastasis and tumor recurrence that need repeated surgery, entailing surgical challenges with a high risk of complications such as nerve damage and bleeding. Magseed is a metal coil used to detect non-palpable lesions and is an established modality in breast cancer surgery. In this case series, we explore the feasibility of Magseed in metastasis surgery of papillary thyroid cancer. Under the guidance of ultrasonography, Magseed is injected into the target tissue and intraoperatively detected with a handheld magnetometer probe, Sentimag®. Five patients with recurrence of papillary thyroid cancer were operated on with focused Magseed-guided localization. All patients had repeated surgery and radioiodine treatments. Four of the patients had lymph node metastasis hidden in the fibrosis, and one patient had recurrent tumor tissue on the left side of the larynx. Magseed was easy to use, safe, and precise in detecting the target tissue. [ABSTRACT FROM AUTHOR]

• Rhodiolin extracted from the medicinal plant Rhodiola rosea show an excellent anti-PTC activity in vitro and in vivo. • Rhodiolin treatment significantly inhibits PTC cells proliferation and induces apoptosis. • Rhodiolin inhibits glycolysis in human PTC cells by inhibiting the expression of the glycolytic enzyme GPI. • glycolysis inhibition downregulate activation of the PI3K/Akt/mTOR signaling pathway in human PTC cells. Papillary thyroid carcinoma (PTC) is an endocrine malignant tumor of the head and neck. Surgery and chemotherapy are PTC treatments, but have adverse effects. Exploration of new non-toxic anti-PTC drugs for PTC treatment is an unmet need. We aimed to identify anti-PTC drugs that could inhibit PTC-cell proliferation through high-throughput screening of a library of well-characterized naturally occurring small-molecule compounds. Then, the anti-PTC function of rhodiolin was validated by in vitro cell models and xenograft tumor models We initially demonstrated that rhodiolin inhibited the growth and induced the apoptosis of PTC cells significantly in vitro and in vivo. At the metabolic level, rhodiolin blocked glycolysis through glucose 6-phosphate isomerase (GPI), which suggested that glycolytic inhibition may be involved in mediating the anti-PTC function of rhodiolin. Transcriptomics analysis combined with bioinformatics analysis identified rhodiolin treatment to inhibit phosphorylation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Collectively, our findings demonstrated that rhodiolin inhibited the proliferation and induced the apoptosis of PTC cells by blocking glycolysis through the glycolytic enzyme GPI, thereby inhibiting phosphorylation of the PI3K/Akt/mTOR signaling pathway. Our study demonstrates the potential use of rhodiolin in inhibiting the proliferation and inducing the apoptosis of PTC cells. Inhibition of phosphorylation of the PI3K/Akt/mTOR signaling pathway mediated by GPI plays an extremely important part in the ant-PTC function of rhodiolin. These results suggest that rhodiolin is a promising drug in the treatment of PTC progression. Our results provide a novel target and cell signaling pathway for PTC therapy from the perspective of energy metabolism, which could provide new perspectives and new drug choices for PTC therapy. In addition to that, our study will help to make up for the lack of drug research for PTC. [Display omitted] [ABSTRACT FROM AUTHOR]

Lateral cervical lymph node metastases (LNM) for pediatric patients with papillary thyroid cancer (PTC) is a poor prognostic factor. We aimed to identify risk factors for lateral LNM. This retrospective study had included 48 pediatric patients with papillary thyroid cancer underwent total thyroidectomy and central cervical lymphadenectomy at K hospital from 2016 to 2020. The number of patients in each T stage was as follows: 24 (50.0%) in stage 1, 9 (18.7%) in Stage 2, 8 (16.7%) in Stage 3, and 7 (14.6%) in Stage 4. Most of the patients had LNM with N1a and N1b rates of 83.3% and 62.5%, respectively. Lung metastases were observed at presentation in three patients (6.3%). Univariate analysis revealed that age (p = 0.021), male (p = 0.011), tumor size > 10 mm (p = 0.002), multifocality (p < 0.001), extrathyroidal extension (p = 0.001) and central LNM (p < 0.001) were factors that increase the risk of metastasis to lateral LNM. Approximately 62.5% of pediatric patients with PTC exhibited lateral LNM at the time of diagnosis. Our study confirmed that multifocality, maximum tumor diameter, extrathyroidal extension and central LNM were independent risk factors for lateral LNM in pediatric PTC. Level IV. [ABSTRACT FROM AUTHOR]

Background: Total thyroidectomy is the treatment of choice for multinodular goiter (MNG). In some of these cases, incidental thyroid cancer (ITC) is detected postoperatively. Papillary thyroid microcarcinoma (PTMC), the most common type of ITC, has clinical factors and pathologic similarities with ITC that have not been well clarified previously. We investigated the incidence and characteristics of ITC and PTMC in euthyroid patients undergoing total thyroidectomy for MNG. Methods: We retrospectively investigated the data of 151 euthyroid patients who underwent total thyroidectomy for MNG between January 2016 and December 2020. Patients with PTMC were then selected from among those with ITC for further data analysis. Results: The incidence rates of ITC and PTMC were 31.1% (47/151) and 21.1% (32/151), respectively. The mean age of patients with ITC was 52.8±11.7 years, which was younger than that of patients with benign MNG (57.2±12.5 years, p < 0.05). Bilateral cancer was observed in 17 patients with ITC (17/47, 36.2%) and nine with PTMC (9/32, 28.1%). The numbers of patients in the ITC and PTMC groups whose cancer was not on the side comprising the dominant tumor were 15 (15/47, 31.9%) and 13 (13/32, 40.6%), respectively. The multivariate analysis demonstrated that younger age was a clinical factor associated with ITC and PTMC. Conclusion: Younger age is a clinical factor for ITC and PTMC. We recommend taking considering clinical factors and pathologic characteristics of ITC and PTC when considering total thyroidectomy in euthyroid patients with MNG. [ABSTRACT FROM AUTHOR]

The surgical management of patients diagnosed with papillary thyroid carcinoma (PTC) and tracheal invasion has been a subject of ongoing discussion, particularly regarding the approach to tracheal functional reconstruction. The objective of this study was to examine the surgical technique and prognosis of PTC patients with tracheal invasion. This study employed both univariate and multivariate Cox proportional hazard models to determine predictive factors that affect the progression-free survival (PFS) of PTC patients with tracheal invasion. Cox regression analysis was conducted by using R software version 4.3.1. In our study, we included 247 patients with T4a PTC. Among them, 146 patients (59.1 %) were classified as Shin I, 57 patients (23.1 %) as Shin II-III, and 44 patients (17.8 %) as Shin IV. Patients in the Shin I group underwent shaving of the tumours in the airway. The preferred surgical methods in the Shin II, III and IV groups were window resection (66.7 %), sleeve resection (34.8 %) and partial tracheal resection and skin fistula (61.8 %), respectively. Multivariate analysis demonstrated that neither tracheal surgery nor reconstruction procedures had an impact on PFS in T4a PTC patients with tracheal invasion. The 5-year DSS rate for patients receiving radioiodine (RAI) therapy was 87.3 % (p = 0.033). This study confirmed that tracheal surgery and reconstruction methods had no impact on PFS in T4a PTC patients with tracheal invasion in different Shin groups. Furthermore, RAI therapy has the potential to increase the survival rate of patients with preoperative distant metastasis of T4a PTC. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: To develop and validate 2 iodine maps based radiomics nomograms for preoperatively predicting cervical lymph node metastasis (LNM) and central lymph node metastasis (CLNM) in papillary thyroid cancer (PTC).Materials and Methods: A total of 346 patients with PTC were enrolled and allocated to training (242) and validation (104) sets. Radiomics features were extracted from arterial and venous phase iodine maps, respectively. Aggregated machine-learning strategy was applied for features selection and construction of 2 radiomics scores (LN rad-score; CLN rad-score). Logistic regression model was employed to establish two radiomics nomograms (nomogram 1: predicting LNM; nomogram 2: predicting CLNM) after incorporating LN or CLN rad-score with clinical predictors. Nomograms performance was determined by discrimination, calibration and clinical usefulness.Results: Nomogram 1 incorporated LN rad-score, age (categorized by 55) and CT reported LN status; Nomogram 2 incorporated CLN rad-score, capsule contact >25% and CT reported CLN status. 2 nomograms both showed good discrimination and calibration in the training (AUC = 0.847; AUC = 0.837) and validation cohorts (AUC = 0.807; AUC = 0.795). Significant improved AUC, net reclassification index (NRI) and integrated discriminatory improvement (IDI) confirmed additional great predictive value of 2 rad-scores, compared with clinical models without radiomics. Decision curve analysis indicated clinical utility of nomograms. 2 nomograms both demonstrated favorable predictive efficacy in CT reported LN or CLN negative subgroup (AUC = 0.766; AUC = 0.744).Conclusion: The presented 2 radiomics nomograms are useful tools for preoperative prediction of LNM and CLNM in PTC. [ABSTRACT FROM AUTHOR]