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Background: Although the long-term prognosis of papillary thyroid cancer (PTC) is favorable, distant metastasis significantly compromises the prognosis and quality of life for patients with PTC. The Cadherin family plays a pivotal role in tumor metastasis; however, the involvement of Cadherin 4 (CDH4) in the metastatic cascade remains elusive. Methods: The expression and subcellular localization of CDH4 were determined through immunohistochemistry, immunofluorescence, and western blot analyses. The impact of CDH4 on cell migration, invasion, angiogenesis, and metastasis was assessed using transwell assays, tube formation assays, and animal experiments. Immunoprecipitation assay and mass spectrometry were employed to examine protein associations. The influence of CDH4 on the subcellular expression of β-catenin and active β-catenin was investigated via western blotting and immunofluorescence. Protein stability and ubiquitination assay were employed to verify the impact of CDH4 on β-catenin degradation. Rescue experiments were performed to ensure the significance of CDH4 in regulating nuclear β-catenin signaling. Results: CDH4 was found to be significantly overexpressed in PTC tissues and predominantly localized in the cytoplasm. Furthermore, the overexpression of CDH4 in tumor tissues is associated with lymph node metastasis in PTC patients. Cytosolic CDH4 promoted the migration, invasion, and lung metastasis of PTC cells and stimulated the angiogenesis and tumorigenesis of PTC; however, this effect could be reversed by Tegavivint, an antagonist of β-catenin. Mechanistically, cytosolic CDH4 disrupted the interaction between β-catenin and β-TrCP1, consequently impeding the ubiquitination process of β-catenin and activating the nuclear β-catenin signaling. Conclusions: CDH4 induces PTC angiogenesis and metastasis via the inhibition of β-TrCP1-dependent ubiquitination of β-Catenin. [ABSTRACT FROM AUTHOR]

Simple Summary: CHK2 has functions in DNA damage repair. Germline CHEK2 mutations impair these functions, increasing the risk of PTC. The aim of this study was to determine whether CHK2 and p53 expression in patients with a germline CHEK2 mutation in tumor tissue can serve as a prognostic marker for papillary thyroid cancer (PTC), and whether copy number aberrations in CHEK2 and TP53 correlate with the course of PTC. This study included 156 patients with PTC who had been selected from a group of 1547 people previously tested for the presence of CHEK2 mutations in their peripheral blood. Higher CHK2 expression was associated with poorer treatment responses and disease outcomes in PTC patients. Higher CHK2 expression and positive p53 together with a TP53 deletion could have potential as a prognostic marker of unfavorable disease outcomes in patients with germline truncating mutations in CHEK2. The aim of this study was to determine whether the expression of CHK2 and p53 in tumor tissue in carriers of germline CHEK2 mutations can serve as a prognostic marker for PTC, and whether CHEK2 and TP53 copy numbers correlates with the course of PTC disease. This study included 156 PTC patients previously tested for the presence of CHEK2. Clinicopathological features, treatment response, disease outcome, and germline mutation status of the CHEK2 gene were assessed with respect to CHK2 and p53 expression, and CHEK2 and TP53 gene copy statuses. In patients with and without a germline mutation in CHEK2 and with higher CHK2 expression, the chances of an excellent treatment response and no evidence of disease were lower than in patients without or with lower CHK2 expression. TP53 deletion was associated with angioinvasion. In patients with a truncating mutation, the chance of a CHEK2 deletion was higher than in patients with WT CHEK2 alone or those with WT CHEK2 and with the missense I157T mutation. Higher CHK2 expression was associated with poorer treatment responses and disease outcomes. Higher CHK2 expression and positive p53 together with a TP53 deletion could be a prognostic marker of unfavorable disease outcomes in patients with germline truncating mutations in CHEK2. [ABSTRACT FROM AUTHOR]

Background: This study was performed to evaluate the differences in oral function and psychological well-being between patients with PTC after the gasless transoral endoscopic thyroidectomy vestibular approach (gasless-TOETVA) and patients with PTC after open surgery. Methods: PTC patients who underwent radical surgery from May 2021 to August 2022 were included in this study. Postoperative data on oral function and psychological well-being, including the Oral Health Impact profile-14 (OHIP-14) and State-Trait Anxiety Inventory Form Y, were collected and analyzed. Results: 212 patients were included in the analysis. Among them, 102 patients who received gasless-TOETVA were assigned to the gasless-TOETVA group, while the remaining 110 patients who underwent open surgery were categorized as the open group. Although the OHIP-14 score in the gasless-TOETVA group was higher than that of the open group from 6 months to 1 year after surgery (p = 0.012), the difference in OHIP-14 scores between the two groups disappeared 1 year after surgery (p = 0.155). There were no differences between the gasless-TOETVA group and the open group in state-anxiety scores. However, the gasless-TOETVA group had significantly lower trait-anxiety scores than the open group at all follow-up time periods. Furthermore, within the gasless-TOETVA group, patients who were more than 1 year post-surgery showed significantly increased trait-anxiety scores compared to those of patients who were less than 1 year post-surgery (Δ = 3.4; p = 0.032). In contrast, the open group showed a decreasing trend in trait-anxiety scores, but there was no statistically significant difference between patients who had surgery less than 1 year ago and those who had surgery more than 1 year ago (Δ = − 2.2; p = 0.094). Conclusion: Gasless TOETVA had a temporary impact on oral function, but it did not alleviate the state of anxiety. Furthermore, we observed a significant increase in trait-anxiety scores among PTC patients who underwent gasless-TOETVA after 1 year. [ABSTRACT FROM AUTHOR]

Objective To compare the American Thyroid Association (ATA) risk staging of histologically proven papillary thyroid cancer (PTC) in patients who received a presurgery cytologic result of either indeterminate thyroid nodules (ITNs, Bethesda III/IV) or suspicious for malignancy/malignant (TIR 4/5, Bethesda V/VI). Methods Clinical, ultrasonographic, cytological data from patients with histologically diagnosed PTC were retrospectively collected. Results Patients were stratified according to the preoperative fine-needle aspiration cytology into 2 groups: 51 ITNs (TIR3A/3B) and 118 suspicious/malignant (TIR 4/5). Male/female ratio, age, and presurgery TSH level were similar between the 2 groups. At ultrasound, TIR 4/5 nodules were significantly more frequently hypoechoic (P =.037), with irregular margins (P =.041), and with microcalcifications (P =.020) and were more frequently classified as high-risk according to the European Thyroid Imaging and Reporting Data System (EU-TIRADS; P =.021). At histology, the follicular PTC subtype was significantly more prevalent among ITNs while classical PTC subtype was more frequent in TIR 4/5 group (P =.002). In TIR 4/5 group, a higher rate of focal vascular invasion (P <.001) and neck lymph node metastasis (P =.028) was observed. Intermediate-risk category according to ATA was significantly more frequent in TIR 4/5 group while low-risk category was more frequently found among ITNs (P =.021), with a higher number of patients receiving radioiodine in TIR 4/5 group (P =.002). At multivariate logistic regression, having a TIR 4/5 cytology was associated with a significant risk of having a higher ATA risk classification as compared to ITN (OR 4.6 [95% CI 1.523-14.007], P =.007), independently from presurgery findings (nodule size at ultrasound, sex, age, and EU-TIRADS score). Conclusions Papillary thyroid cancers recorded among ITNs are likely less aggressive and are generally assessed as at lower risk according to ATA classification. [ABSTRACT FROM AUTHOR]

Background: The global prevalence of thyroid cancer is on the rise. About one-third of newly diagnosed thyroid cancer cases comprise low-risk papillary thyroid cancer (1.5 cm or more minor). While surgical removal remains the prevailing approach for managing low-risk papillary thyroid cancer (LPTC) in patients, other options such as active surveillance (AS), radiofrequency ablation (RFA), microwave ablation (MWA), and laser ablation (LA) are also being considered as viable alternatives. This study evaluated and compared surgical thyroid resection (TSR) versus non-surgical (NS) methods for treating patients with LPTC. Methods: The study encompassed an analysis of comparisons between surgical thyroid resection (TSR) and alternative approaches, including active surveillance (AS), radiofrequency ablation (RFA), microwave ablation (MWA), or laser ablation (LA). The focus was on patients with biopsy-confirmed low-risk papillary thyroid cancer (LPTC) of less than 1.5 cm without preoperative indications of local or distant metastasis. The primary outcomes assessed were recurrence rates, disease-specific mortality, and quality of life (QoL). Data were collected from prominent databases, including Cochrane Database, Embase, MEDLINE, and Scopus, from inception to June 3rd, 2020. The CLARITY tool was utilized to evaluate bias risk. The analysis involved odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes, as well as mean differences (MD) and standardized mean differences (SMD) for continuous outcomes. The study is registered on PROSPERO under the identifier CRD42021235657. Results: The study incorporated 13 retrospective cohort studies involving 4034 patients. Surgical thyroid resection (TSR), active surveillance (AS), and minimally invasive techniques like radiofrequency ablation (RFA), microwave ablation (MWA), and laser ablation (LA) were performed in varying proportions of cases. The analysis indicated that specific disease mortality rates were comparable among AS, MWA, and TSR groups. The risk of recurrence, evaluated over different follow-up periods, showed no significant differences when comparing AS, RFA, MWA, or LA against TSR. Patients undergoing AS demonstrated better physical health-related quality of life (QoL) than those undergoing TSR. However, no substantial differences were observed in the overall mental health domain of QoL when comparing AS or RFA with TSR. The risk of bias was moderate in nine studies and high in four. Conclusion: Low-quality evidence indicates comparable recurrence and disease-specific mortality risks among patients with LPTC who underwent ablation techniques or active surveillance (AS) compared to surgery. Nevertheless, individuals who opted for AS exhibited enhanced physical quality of life (QoL). Subsequent investigations are warranted to validate these findings. [ABSTRACT FROM AUTHOR]

Purpose: The 2015 American Thyroid Association risk stratification system (2015-RSS) is used to assess the tumor recurrence rate and guide the initial treatment. At the current moment, patients with one or multiple intermediate risk factors (IRF) have the same treatment. This study was conducted to evaluate the impact of the number of IRF characteristics on tumor persistence or recurrence rates. Methods: Patients with intermediate risk papillary thyroid cancer (PTC) were selected and analyzed, furthermore, they were divided into two subgroups, one with 1–2 IRF and another with ≥3 IRF. Those data were analyzed in relation to response to therapy at the end of the first year and in last appointment, time to reach non evidence of disease (NED) state and time in NED state. Results: A total of 257 patients were evaluated. Extrathyroidal invasion, vascular invasion, the total number of IRF and the subgroup of ≥3 IRF were associated with non-excellent response in last consultation; IRF lymph node metastasis was associated with non-excellent response in the first year and in last appointment and prolonged time in NED state; vascular invasion was associated with a shorter time in NED state; total number of IRF and aggressive histology were related to delay in the achievement of NED state. Conclusions: Higher number of IRF was a predictive factor of non-excellent response in the last visit and was associated with longer time to reach the NED state. Those data suggest a benefit from closer follow-up and more intensive treatment in these patients. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common endocrine malignancy worldwide. Although significant progress has been made in understanding the genetic and molecular alterations that drive thyroid cancer, the mechanisms underlying thyroid tumor progression remain unclear. In this study, we explored the involvement of Plastin‐3 (PLS3) in the progression of papillary thyroid cancer and elucidated the underlying molecular mechanisms. We first analyzed clinical samples from papillary thyroid cancer patients and found that PLS3 expression was significantly upregulated in tumor tissues compared to adjacent normal tissues. Moreover, high PLS3 expression was associated with advanced tumor stage and poor prognosis. Further in vitro and in vivo experiments showed that PLS3 could promote the proliferation, migration, and invasive behavior of papillary thyroid cancer cells, while PLS3 knockdown suppressed these processes. Mechanistically, we found that PLS3 promoted papillary thyroid cancer progression by activating the Notch signaling pathway. Specifically, PLS3 upregulated the expression of Notch receptors (Notch1) and downstream target gene (Hes1) in papillary thyroid cancer cells. In summary, our findings collectively indicate that PLS3 plays a pivotal role in driving the progression of papillary thyroid cancer and holds promise as a viable therapeutic target for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Objective: Keratin 15 (KRT15) is identified as a useful biomarker in several solid tumors, while its clinical role in papillary thyroid cancer (PTC) remains unknown. Herein, this study is intended to explore the correlation of tumor KRT15 with clinical features and survival in PTC patients who received tumor resection. Methods: This study retrospectively screened 350 PTC patients who received tumor resection and 50 thyroid benign lesions (TBL) patients. KRT15 in formalin-fixed paraffin-embedded lesion specimens of all subjects was detected by immunohistochemistry (IHC). Results: KRT15 was reduced in PTC patients compared to TBL patients (P < 0.001). Furthermore, KRT15 was negatively associated with tumor size (P = 0.017), extrathyroidal invasion (P = 0.007), pathological tumor (pT) stage (P < 0.001), and postoperative radioiodine application (P = 0.008) in PTC patients. Regarding prognostic value, high KRT15 (cut-off by an IHC value of 3) is linked with prolonged accumulating disease-free survival (DFS) (P = 0.008) and overall survival (OS) (P = 0.008) in PTC patients. Also, the multivariate Cox regression model showed that high KRT15 (vs. low) was an independent factor for longer DFS (hazard ratio = 0.433, P = 0.049), but not for OS (P > 0.050) in PTC patients. Subgroup analyses revealed that KRT15 possessed a better prognostic value in PTC patients with age ≥ 55 years, tumor size > 4 cm, pathological node stage 1, or pathological tumor-node-metastasis stage ≤ 2 (all P < 0.050). Conclusion: Increased tumor KRT15 associates with a lower invasive degree, prolonged DFS, and OS, revealing its prognostic utility in PTC patients undergoing tumor resection. [ABSTRACT FROM AUTHOR]

The recent incorporation of immune checkpoint inhibitors targeting the PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways into the therapeutic armamentarium of cancer has increased the need to understand the correlation between the immune system, autoimmunity, and malignant neoplasms. Both autoimmune thyroid diseases and thyroid cancer are common clinical conditions. The molecular pathology of autoimmune thyroid diseases is characterized by the important impact of the PD-1/PD-L1 axis, an important inhibitory pathway involved in the regulation of T-cell responses. Insufficient inhibitory pathways may prone the thyroid tissue to a self-destructive immune response that leads to hypothyroidism. On the other hand, the PD-1/PD-L1 axis and other co-inhibitory pathways are the cornerstones of the immune escape mechanisms in thyroid cancer, which is a mechanism through which the immune response fails to recognize and eradicate thyroid tumor cells. This common mechanism raises the idea that thyroid autoimmunity and thyroid cancer may be opposite sides of the same coin, meaning that both conditions share similar molecular signatures. When associated with thyroid autoimmunity, thyroid cancer may have a less aggressive presentation, even though the molecular explanation of this clinical consequence is unclear. More studies are warranted to elucidate the molecular link between thyroid autoimmune disease and thyroid cancer. The prognostic impact that thyroid autoimmune disease, especially chronic lymphocytic thyroiditis, may exert on thyroid cancer raises important insights that can help physicians to better individualize the management of patients with thyroid cancer. [ABSTRACT FROM AUTHOR]

In the realm of clinical management, Papillary Thyroid Cancer (PTC) stands out as a prevalent thyroid malignancy, characterized by significant metabolic challenges, particularly in the context of carbohydrate metabolism. Recent studies have unveiled promising applications of Dipeptidyl Peptidase-IV (DPPIV) and Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, which are conventionally employed in the treatment of type 2 diabetes mellitus (T2DM), as potential adjuncts in anticancer therapy. DPP-IV and SGLT2 inhibitors can be imply to counteract the Warburg effect in cancer, with a specific focus on PTC, owing to their potential metabolic advantages and their influence on the tumor microenvironment, achieved by imposing restrictions on glucose accessibility. Consequently, a comprehensive review has been undertaken, involving meticulous examination of the existing body of evidence pertaining to the utilization of DPP-IV and SGLT2 inhibitors in the context of PTC. The mechanisms of action inherent to these inhibitors have been thoroughly explored, drawing upon insights derived from preclinical investigations. Furthermore, this review initiates discussions concerning the implications for future research directions and the formulation of innovative therapeutic strategies for PTC. As the intricate interplay between carbohydrate metabolism, the Warburg effect, and cancer progression garners increasing attention, attaining a comprehensive understanding of the roles played by DPP-IV and SGLT2 inhibitors in PTC management may serve as the cornerstone for novel approaches aimed at enhancing patient care and broadening the spectrum of available therapeutic modalities. [ABSTRACT FROM AUTHOR]

Background: Pediatric papillary thyroid cancer presents with a more advanced stage of disease than adult PTC; and it is more likely to be aggresive and distant metastases, although the survival rate is high. Methods: A retrospective observational study was performed in children and adults with PTC. Fisher's exact, chi-square, and rank-sum tests were used to examine the differences. Univariate and multivariate Cox regression analyses were applied to determine the possible risk factors for prognosis. A Kaplan-Meier curve analysis was performed to investigate the relationship between the clinicopathological characteristics and recurrence rate. Results: The study involved 156 children and 1,244 adults with PTC. Compared to the group without recurrence, proportions of tumors measuring > 1 cm (48.3% vs. 90.9%) and multifocality (30.3% vs. 63.6%) were higher, N1b stage occurred more frequently (33.8% vs. 100%). However, among adult PTC patients, those with recurrence were older (76.1% vs. 59.4%) than those without recurrence. Risk factors for pediatric PTC recurrence included tumor size and multifocality. However, in adult PTC, the risk factor was LLNM. The newly constructed Stratification.N showed better performance, as illustrated by the fact that patients who were classified into Stratification.N 3 showed an obviously poorer prognosis (P=0.01 and P=0.00062), especially in those aged >14 years (P=0.0052). Conclusion: Compared with adult PTC, pediatric PTC showed unique characteristics in terms of clinical pathology and recurrence. Tumor size and multifocality were strong risk factors for pediatric PTC. Accordingly, the novel proposed risk stratification method could effectively predict the recurrence of pediatric PTC. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the effectiveness and safety of carbon nanoparticles-guided lymph node dissection during thyroidectomy in patients with papillary thyroid cancer(PTC). Methods: Clinical trials consisted of two subgroups: unilateral lobectomy (UL; n=283) and total thyroidectomy (TT; n=286). From each subgroup, the patients were randomly assigned to two groups: the carbon nanoparticle group and control group. Primary endpoints included parathyroid hormone (PTH) levels, number of lymph nodes (LNs) detected, number of tiny lymph nodes detected, and recognition and retention of the parathyroid glands. Secondary endpoint was recognition and protection of the recurrent laryngeal nerve. Results: A total of 569 patients with PTC were recruited. There were no statistically significant differences in demographics between the carbon nanoparticles and control groups (P > 0.05). In the UL subgroup, there were no significant differences in PTH levels between the two groups at preoperative, intraoperative, and postoperative day one, and postoperative month one (P>0.05). There was no significant difference in the serum Ca2+ levels between the two groups preoperatively and at postoperativemonth one (P>0.05). The number of lymph nodes dissected in the carbon nanoparticles group was significantly higher than that in the control group (P<0.0001). The detection rate of tiny lymph nodes in the carbon nanoparticles group was higher than that in the control group (P=0.0268). In the TT subgroup, therewas no significant difference in PTH levels between the two groups at preoperative, intraoperative, and postoperative day one (P>0.05). However, the mean PTH level in the carbon nanoparticles group was significantly higher than that of the control group at postoperative month one (P=0.0368). There was no significant difference in the serum Ca2+ levels between the two groups preoperatively and at postoperative month one (P>0.05). There were no significant differences between the two groups in the number of dissected LNs (P>0.05) or the detection rate of tiny lymph nodes (P>0.05). No drugrelated AE and complications due to the injection of carbon nanoparticleswere recorded in this study. There were no significant differences between the two groups in terms of parathyroid preserved in situ and recurrent laryngeal nerve injury in the UL and TT subgroups. Conclusions: Carbon nanoparticles demonstrated efficacy and safety in thyroidectomy. The application of carbon nanoparticles could significantly facilitate the identification and clearance of LNs and the optimum preservation of parathyroid function. [ABSTRACT FROM AUTHOR]

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Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue. [ABSTRACT FROM AUTHOR]

Introduction: Mutations of CHEK2 are usually inherited and have been implicated in breast cancers, colorectal cancers, thyroid cancers, kidney cancers, and prostate cancers. The CHEK2 gene codes for checkpoint kinase 2 protein which is an effector in the ATM-CHEK2-p53 pathway and responds to DNA double-strand breaks. Case Presentation: We describe a unique case of a 29-year-old Canadian female who presented with synchronous papillary thyroid carcinoma and rectal adenocarcinoma who was subsequently found to have a sporadic CHEK2 (checkpoint kinase 2) mutation. She presented with an 8-month history of bright red blood per rectum and saw two different physicians who diagnosed hemorrhoids and possible rectal ulcers, respectively. When the symptoms continued, the patient pursued a colonoscopy exam which found a large rectal tumor. Subsequent clinical staging diagnosed a rectal adenocarcinoma and a synchronous papillary thyroid carcinoma. Due to her synchronous tumors, a genetic panel was performed, which revealed a low-risk CHEK2 mutation. Our patient had a full response to neoadjuvant brachytherapy of the rectum and surgical treatment of her cancers. Conclusion: This is the first case report, to our knowledge, of a patient with a CHEK2 mutation who presented with synchronous papillary thyroid carcinoma and invasive colonic adenocarcinoma. The incidence of colorectal cancers and papillary thyroid cancers in those under 30 with no family history is very low, which signifies the rarity of their simultaneous occurrence at such a young age. [ABSTRACT FROM AUTHOR]

Background Regarding papillary thyroid cancer, comparisons between lobectomy (LT) and total thyroidectomy (TT) have not addressed major risks to reliable conclusions drawn from observational data. This research aimed to evaluate the survival rate following thyroidectomy (TT) and LT for papillary thyroid carcinoma. Methods A total of 155 patients with papillary thyroid cancer who had LT or TT at Menoufia University Hospitals between January 2018 and April 2023 were included in this retrospective cohort analysis. Overall survival was the main result, which was assessed using inverse probability weighting on the propensity score and flexible parametric survival models. Results Of the patients receiving treatment, 78% were female and the median age was 48 (range: 37-59). There were no statistically significant differences in the 5-year overall survival between individuals who underwent a complete thyroidectomy or LT. Furthermore, we did not find any statistically significant variation in survival by subgroups, such as age (<65 or ≥65), tumor size (<4cm or ≥4 cm), or projected risk of death. Conclusion Based on our data, TT, independent of tumor size, patient age, or overall risk of mortality, is unlikely to provide a survival benefit over lobectomy. [ABSTRACT FROM AUTHOR]

Background Leptin is a neuroendocrine hormone produced from adipose tissue with many vital functions. There is a well-known association between leptin and papillary thyroid cancer (PTC). Preoperative prediction of lymph node metastasis is one of the interesting topics in PTC. This study aimed to determine whether the serum leptin peptide is a significant predictor marker for node metastasis in cases with PTC. Patients and methods This is a prospective comparative study which was conducted at Ain Shams University Hospitals and El-Sheikh Zayed specialized hospital between January 2021 and January 2023. Forty patients with PTC were enrolled in this study and according to postoperative histopathology, we divided them into two groups: group A, 24 cases, those with pathological negative node and group B, 16 cases, those with pathological positive node. Results We had no statistically significant difference in the preoperative demographics data between both groups. Postoperatively, the median serum leptin level and percentage of leptin decrease were significantly higher in in group B. Multivariate logistic regression analysis showed that preoperative serum leptin level, thyroid imaging reporting and data system, multifocality, extra thyroid extension, and size of dominant nodule were significant predictors for node metastasis. There was a significant negative correlation between leptin level and age, while there was a significant positive correlation between leptin level and lymph node metastasis. Conclusion Preoperative serum leptin level is considered a significant predictor marker for lymph node metastasis in 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]

N6-Methyladenosine (m6A) mRNA methylation modification is regarded as an important mechanism involved in diverse physiological processes. YT521-B homology (YTH) domain family members are associated with the tumorigenesis of several cancers. However, the role of YTHDC2 in papillary thyroid cancer (PTC) progression remains unknown. Results showed that YTHDC1, YTHDF1, YTHDF2, and YTHDF3 showed no observable difference in thyroid cancer samples. YTHDC2 was significantly downregulated in thyroid cancer samples and cells. YTHDC2 inhibited cell proliferation in PTC cells. YTHDC2 elicited apoptosis in PTC cells, as demonstrated by the elevated expression of pro-apoptotic factors cl-caspase-3/caspase-3 and Bcl-2-associated (Bax), and the reduced anti-apoptotic B cell lymphoma-2 (Bcl-2) expression. There was a positive correlation between YTHDC2 and cylindromatosis (CYLD) expression based on GEPIA database. YTHDC2 increased CYLD expression in PTC cells. CYLD knockdown abolished the effects of YTHDC2 on PTC cell proliferation and apoptosis. Additionally, YTHDC2 inactivated the protein kinase B (Akt) pathway by increasing CYLD in PTC cells. Overall, YTHDC2 inhibited cell proliferation and induced apoptosis in PTC cells by regulating CYLD-mediated inactivation of Akt pathway. [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer (PTC) is a prevalent malignancy worldwide. Spleen tyrosine kinase (SYK) is a crucial enzyme that participates in various biological processes, including cancer progression. This study aims to uncover the biological function of SYK in PTC. SYK expression patterns in PTC were evaluated using quantitative real time polymerase chain reaction (qRT‐PCR), immunohistochemistry (IHC), and western blot. Cell function assays were performed to assess the effects of SYK on PTC. Bioinformatics analysis was conducted to identify intriguing microRNA (miRNA) and circular RNA (circRNA). Dual‐Luciferase Reporter or RNA immunoprecipitation assays were used to investigate the correlation among SYK, miR‐377‐3p, and hsa_circ_0006417. SYK was upregulated in PTC. Overexpression of SYK exhibited a positive correlation with tumor size, lymph node metastasis, and unfavorable disease‐free survival. Functional assays revealed that SYK exerted tumorigenic effect on PTC cells through mTOR/4E‐BP1 pathway. Mechanistically, hsa_circ_0006417 and miR‐377‐3p regulated SYK expression, offering modulating its tumor‐promoting effects. Collectively, SYK acts as an oncogene in PTC through mTOR/4E‐BP1 pathway, which is regulated by the hsa_circ_0006417/miR‐377‐3p axis, thereby providing a potential alternative for PTC treatment. [ABSTRACT FROM AUTHOR]

Recent research has revealed the importance of miRNAs in the diagnosis and clinical evolution of papillary thyroid cancer (PTC). We aim to identify a specific miRNA profile that could differentiate between specific subtypes of PTC. Methods: In this cross-sectional study, total RNA was extracted from paraffin-embedded tissues of 43 patients, 17 with an infiltrative follicular variant of PTC (iFVPTC) and 26 with a conventional variant of PTC (cPTC). Nine miRNAs were evaluated using qRT-PCR technology and specific miRNA assays. Results: We found specific patterns for cPTC and iFVPTC, such as miRNA altered in both types of tumours (miR-146b-5p, miR-181a-5p, miR-221-3p, miR-21-5p and miR-222-3p) and two miRNAs significantly expressed only in cPTC (miR-20b-5p, miR-21-5p). The iFVPTC group presented strong and moderate correlations between miRNA expression and clinical data. miR-221-3p, miR-195-5p, miR-181-5p, miR-146b-5p and miR-222 were correlated with age, tumour size (TS) or lymph node metastases (N), while only miR-20b-5p, miR-195-5p and miR-181-5p were correlated with TS, N and age in the cPTC group. Conclusions: The present study allowed the identification of a signature of two miRNAs to confirm miRNA differences between the two histological subtypes of TC. Our results provide advances in the molecular diagnosis of TC and could help to improve the diagnostic performance of already existing molecular classifiers. [ABSTRACT FROM AUTHOR]

Background It has been identified that ionising radiation is the definitive cause of human cancer. One-third of the tumours that develop after radiation exposure are malignant, with papillary thyroid cancer (PTC) being the most common cancer type. This study investigated the relationship between total radiation dose (TRD) received during imaging tests and thyroid cancer occurrence in patients diagnosed with PTC. Methods The study was designed to retrospectively review the data of adult patients aged =18 years diagnosed with PTC between 2005 and 2022. Patients diagnosed with a condition other than PTC were excluded from the study. Results Three hundred seven patients with papillary thyroid cancer were 256 (83.4%) women, with a mean age of 44.7±13.5 years. A statistically significant relationship was observed between TRD and multifocality (p=0.02). Tumour size (r=0.200, p=0.07) weakly correlated with TRD, and TRD (OR: 0.9, 95% CI: 1.0-1.1, p=0.006) was found to be significant according to multifocality. Conclusion This study found an association between TRD taken during imaging tests and multifocality. As a result, the authors aimed to remind clinicians that the disease may progress more aggressively and that thyroid cancer may develop in patients exposed to radiation due to excessive imaging tests. [ABSTRACT FROM AUTHOR]

Objectives: Precise determination of cervical lymph node metastasis (CLNM) involvement in patients with early-stage thyroid cancer is fairly significant for identifying appropriate cervical treatment options. However, it is almost impossible to directly judge lymph node metastasis based on the imaging information of early-stage thyroid cancer patients with clinically negative lymph nodes. Methods: Preoperative US images (BMUS and CDFI) of 1031 clinically node negative PTC patients definitively diagnosed on pathology from two independent hospitals were divided into training set, validation set, internal test set, and external test set. An ensemble deep learning model based on ResNet-50 was built integrating clinical variables, BMUS, and CDFI images using a bagging classifier to predict metastasis of CLN. The final ensemble model performance was compared with expert interpretation. Results: The ensemble deep convolutional neural network (DCNN) achieved high performance in predicting CLNM in the test sets examined, with area under the curve values of 0.86 (95% CI 0.78–0.94) for the internal test set and 0.77 (95% CI 0.68–0.87) for the external test set. Compared to all radiologists averaged, the ensemble DCNN model also exhibited improved performance in making predictions. For the external validation set, accuracy was 0.72 versus 0.59 (p = 0.074), sensitivity was 0.75 versus 0.58 (p = 0.039), and specificity was 0.69 versus 0.60 (p = 0.078). Conclusions: Deep learning can non-invasive predict CLNM for clinically node-negative PTC using conventional US imaging of thyroid cancer nodules and clinical variables in a multi-institutional dataset with superior accuracy, sensitivity, and specificity comparable to experts. Critical relevance statement: Deep learning efficiently predicts CLNM for clinically node-negative PTC based on US images and clinical variables in an advantageous manner. Key points: • A deep learning-based ensemble algorithm for predicting CLNM in PTC was developed. • Ultrasound AI analysis combined with clinical data has advantages in predicting CLNM. • Compared to all experts averaged, the DCNN model achieved higher test performance. [ABSTRACT FROM AUTHOR]

Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic. [ABSTRACT FROM AUTHOR]

Background: Characterizing tumor microenvironment using single-cell RNA sequencing has been a promising strategy for cancer diagnosis and treatment. However, a few studies have focused on diagnosing papillary thyroid cancer (PTC) through this technology. Therefore, our study explored tumor microenvironment (TME) features and identified potential biomarkers to establish a diagnostic model for papillary thyroid cancer. Methods: The cell types were identified using the markers from the CellMarker database and published research. The CellChat package was conducted to analyze the cell–cell interaction. The SCEVAN package was used to identify malignant thyroid cells. The SCP package was used to perform multiple single-cell downstream analyses, such as GSEA analysis, enrichment analysis, pseudotime trajectory analysis, and differential expression analysis. The diagnostic model of PTC was estimated using the calibration curves, receiver operating characteristic curves, and decision curve analysis. RT-qPCR was performed to validate the expression of candidate genes in human papillary thyroid samples. Results: Eight cell types were identified in the scRNA-seq dataset by published cell markers. Extensive cell–cell interactions like FN1/ITGB1 existed in PTC tissues. We identified 26 critical genes related to PTC progression. Further, eight subgroups of PTC tumor cells were identified and exhibited high heterogeneity. The MDK/LRP1, MDK/ALK, GAS6/MERTK, and GAS6/AXL were identified as potential ligand-receptor pairs involved in the interactions between fibroblasts/endothelial cells and tumor cells. Eventually, the diagnostic model constructed by TRPC5, TENM1, NELL2, DMD, SLC35F3, and AUTS2 showed a good efficiency for distinguishing the PTC and normal tissues. Conclusions: Our study comprehensively characterized the tumor microenvironment in papillary thyroid cancer. Through combined analysis with bulk RNA-seq, six potential diagnostic biomarkers were identified and validated. The diagnostic model we constructed was a promising tool for PTC diagnosis. Our findings provide new insights into the heterogeneity of thyroid cancer and the theoretical basis for diagnosing thyroid cancer. [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer (PTC) is the most common endocrine malignant tumour. The purpose of this study was to explore the potential molecular mechanism of circRNA regulating immune-related mRNA through sponge miRNA in the occurrence and immune regulation of PTC. All data were downloaded from public databases, such as GEO, Immport and TCGA. Differentially expressed (DE) mRNAs (DEmRNAs), DEmiRNAs and DEcircRNAs were identified using metaMA and limma packages. Subsequently, immune-related DEmRNAs were screened, and circRNA-miRNA-mRNA (ceRNA) regulatory network was constructed. In addition, functional annotation, protein-protein interaction (PPI) network construction, immune cell infiltration analysis and Pearson correlation analysis were performed. Finally, qRT-PCR validation and cell experiments were also performed. In total, 2962 DEmRNAs, 78 DEmiRNAs and 51 DEcircRNAs were obtained. Subsequently, 195 immune-related DEmRNAs were obtained based on Immport database. Cytokine-cytokine receptor interaction was the only signalling pathway obtained in KEGG analysis. Then, 8 hub immune-related DEmRNAs were identified based on PPI network and CytoHubba plug-in. Subsequently, ceRNA sub-network containing hub immune-related DEmRNAs was extracted from ceRNA regulatory network. In ceRNA sub-network, hsa_circ_0082182-hsa-miR-18b-5p-FGF1/PDGFC, hsa_circ_0016404-hsa-miR-1275-FGF1/CTSB/IL13RA1, hsa_circ_0070100-hsa-miR-27a-3p/hsa-miR-27b-3p-TGFBR3, hsa_circ_0060055/hsa_circ_0038718-hsa-miR-150-3p-CXCL14, hsa_circ_0030427/hsa_circ_0002917-hsa-miR-22-3p-BMP7 and hsa_circ_0030427/hsa_circ_0002917-hsa-miR-125a-5p-LIFR axes were identified. Moreover, FGF1, PDGFC, CTSB, IL13RA1, TGFBR3, CXCL14, BMP7, LIFR, hsa-miR-125a-5p, hsa-miR-1275, hsa-miR-150-3p, hsa-miR-18b-5p and hsa-miR-27b-3p were also found to have good diagnostic accuracy and may be potential novel diagnostic markers for PTC. XCell analysis showed that the levels of immune cell infiltration (including Tregs, HSC, DC and Monocytes) were significantly different between the PTC and the control groups. Knockdown of the expression of hsa_circ_0082182 significantly inhibits the activity, proliferation, migration and invasion of TPC-1 cells. Several circRNA-miRNA-mRNA axes identified in this study may be related to the occurrence, progression and survival of PTC. This lays a theoretical foundation for further understanding the molecular mechanism of PTC, and also contributes to clinical management and research. In ceRNA sub-network, hsa_circ_0082182-hsa-miR-18b-5p-FGF1/PDGFC, hsa_circ_0016404-hsa-miR-1275-FGF1/CTSB/IL13RA1, hsa_circ_0070100-hsa-miR-27a-3p/hsa-miR-27b-3p-TGFBR3, hsa_circ_0060055/hsa_circ_0038718-hsa-miR-150-3p-CXCL14, hsa_circ_0030427/hsa_circ_0002917-hsa-miR-22-3p-BMP7 and hsa_circ_0030427/hsa_circ_0002917-hsa-miR-125a-5p-LIFR axes were identified. FGF1, PDGFC, CTSB, IL13RA1, TGFBR3, CXCL14, BMP7, LIFR, hsa-miR-125a-5p, hsa-miR-1275, hsa-miR-150-3p, hsa-miR-18b-5p and hsa-miR-27b-3p were also found to have good diagnostic accuracy and may be potential novel diagnostic markers for PTC. Knockdown the expression of hsa_circ_0082182 significantly inhibits the activity, proliferation, migration and invasion of TPC-1 cell. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignancy. Intraparotid recurrence of PTC is, however, rare. Most parotid malignancies are either primary or metastatic from cancer outside the head and neck. We report a case of a 71-year-old man who had undergone lobectomy and completion thyroidectomy for PTC and presented to our clinic with an insidious intraparotid recurrence, for which he underwent a superficial parotidectomy and radioactive iodine therapy. We also present a review of the literature on similar cases. Intraparotid metastasis of PTC should be considered in the differential diagnosis of a parotid mass. [ABSTRACT FROM AUTHOR]

Aim: The aims of the study are to evaluate the predictive value of early post-operative stimulated thyroglobulin (sTg) analysis on the recurrence risk, and to define a cut-off value that is related to recurrence risk in low to intermediate risk papillary thyroid cancer (PTC). Methods: This retrospective cohort study included individuals who were diagnosed with PTC aged 18 years or older and had been operated by experienced surgeons of a tertiary university hospital between the years 2011 and 2021. The American Thyroid Association thyroid cancer guidelines version 2015 was used as the risk stratification system. Early sTg measurement obtained at 3-4 weeks after surgery when TSH >30 µIU/mL. Data was collected from the hospital database. A total of 328 patients who had post-operative early sTg values with negative anti-Tg antibodies were included. Results: The median age was 44 years. Of the 328 patients, 223 (68%) were women. The median tumor diameter was 11 mm. One hundred ninety-one patients (58.2%) had low risk and 137 (41.8%) had intermediate risk for recurrent disease. Of the 328 patients, 4.0% had recurrent disease. In multivariate Cox regression, post-operative early sTg value [OR: 1.070 (1.038-1.116), P = .000], and the pre-operative malign cytology [OR: 1.483 (1.080-2.245), P = .042] were independent risk factors for recurrence. On the ROC curve analysis, the cut-off value of early sTg was 4.1 ng/mL for those with recurrent disease. Conclusion: This study demonstrated that early sTg could predict recurrent disease in patients with low to intermediate risk PTC. A cut-off of 4.1 ng/mL was identified with a high negative predictive value. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid carcinoma (PTC) is the most common type of differentiated TC, while medullary TC (MTC) accounts for 4%. The concomitant presence of PTC and MTC is rare. Methods: This is a retrospective, single-center observational study conducted over 16 years (2001–2017). The data were collected from the clinical records of patients who underwent total thyroidectomy at the Endocrine Unit-Department of Medicine of the University Hospital of Pisa, Italy. Results: Over 690 analyzed cases, 650 (94.2%) were exclusive DTC, 19 exclusive MTC (2.75%) and 5 PTC/MTC (0.7%). No case of mixed medullary/follicular TC or hereditary MTC (familial MTC/multiple endocrine neoplasia type 2) was found. Among the five PTC/MTC cases, there was a male prevalence (M:F = 3:2), and all PTC components were at stage I, whereas 40% of MTC were at stage I and III and 20% of MTC were at stage II; microPTC (mPTC) was prevalent (80%) and also microMTCs were frequent (40%); 60% of MTC patients recovered, while 40% of patients developed metastatic disease. The search for germline mutations of the RET gene resulted in being negative in all cases. Conclusions: The incidence of PTC/MTC has been increasing over the past 30 years. The etiology of PTC/MTC forms is still unknown, and although this simultaneous occurrence could be only a coincidence, we cannot exclude the hypothesis of a shared genetic origin. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the endocrine tumor with the highest incidence at present. It originates from the thyroid follicular epithelium or follicular paraepithelial cells. There is an increasing incidence of thyroid cancer all over the world. We found that SRPX2 expression level was higher in papillary thyroid tumors than in normal thyroid tissues, and SRPX2 expression was closely related to tumor grade and clinical prognosis. Previous reports showed that SRPX2 could function by activating PI3K/AKT signaling pathway. In addition, in vitro experiments showed that SRPX2 promoted the proliferation and migration of papillary thyroid cancer (PTC). In conclusion, SRPX2 could promote the malignant development of PTC. This may be a potential treatment target for PTC. [ABSTRACT FROM AUTHOR]

The human microbiome plays an integral role in health. In particular, it is important for the development, differentiation, and maturation of the immune system, 70% of which resides in the intestinal mucosa. Microbiome studies conducted to date have revealed an association between disturbances in the microbiota (dysbiosis) and various pathological disorders, including changes in host immune status. Autoimmune thyroid diseases are one of the most common organ-specific autoimmune disorders, with a worldwide prevalence higher than 5%. The predominant autoimmune thyroid diseases are Hashimoto's thyroiditis and Grave's disease. Several factors, such as genetic and environmental ones, have been studied. In accordance with recent studies, it is assumed that the gut microbiome might play a significant role in triggering autoimmune diseases of the thyroid gland. However, the exact etiology has not yet been elucidated. The present review aims to describe the work carried out so far regarding the role of gut microflora in the pathogenesis of autoimmune thyroid diseases and its involvement in the appearance of benign nodules and papillary thyroid cancer. It appears that future work is needed to elucidate more precisely the mechanism for gut microbiota involvement in the development of autoimmune thyroid diseases. [ABSTRACT FROM AUTHOR]

Objectives: Microwave ablation (MWA) has been widely used for unifocal papillary thyroid carcinoma (U-PTC) and has recently been preliminarily used in multifocal papillary thyroid carcinoma (M-PTC). However, the efficacy and safety of MWA for M-PTC have not been investigated in large samples. The aim of the present study was to evaluate the efficacy and safety of MWA for M-PTC and compare them with MWA for U-PTC. Materials and methods: This retrospective multicentre study enrolled 504 patients (376 females) who underwent MWA for U-PTC (340 cases) or M-PTC (164 cases) from Jan 2015 to Dec 2020. The median age of the patients was 43 years (age range, 20–80 years). Propensity score matching (PSM) was used to balance the baseline characteristics between M-PTC group and U-PTC group. The tumour progression, tumour disappearance, and complication rates were compared between the two groups. Results: The complete ablation was achieved in all enrolled cases in one session. According to the statistical results, no significant differences were shown in tumour progression-free survival (p = 0.29) or cumulative tumour progression rate (6.7% vs. 4.3%, p = 0.33) between the M-PTC and U-PTC groups during the follow-up time. However, the tumour disappearance rate in the M-PTC group was lower in the U-PTC group (40.9% vs. 62.8%, p < 0.001), and tumour disappearance was slower in the M-PTC group (p < 0.001). The complication rate showed no significant difference (3.0% vs. 4.9%, p = 0.571). Conclusions: MWA is an effective and safe treatment for selected patients with M-PTC, and the prognosis is similar to that of U-PTC. Clinical relevance statement: The present study provided evidence that compared with unifocal papillary thyroid cancer, microwave ablation could also treat multifocal T1N0M0 papillary thyroid cancer safely with similar clinical outcome, which could promote the application of minimally invasive treatment for papillary thyroid cancer. Key Results: • Microwave ablation for multifocal and unifocal T1N0M0 papillary thyroid carcinoma had similar tumour progression rates after propensity score matching (6.7% vs. 4.3%, p = 0.33). • The tumour disappearance rate in the multifocal group was lower than that in the unifocal group (40.9% vs. 62.8%, p < 0.001), and tumour disappearance was slower in the multifocal group (p < 0.001). • Tumour size, number, and location were not risk factors for tumour progression in the multifocal papillary thyroid cancer group. [ABSTRACT FROM AUTHOR]

Objective: Based on ultrasound (US) images, this study aimed to detect and quantify calcifications of thyroid nodules, which are regarded as one of the most important features in US diagnosis of thyroid cancer, and to further investigate the value of US calcifications in predicting the risk of lymph node metastasis (LNM) in papillary thyroid cancer (PTC). Methods: Based on the DeepLabv3+ networks, 2992 thyroid nodules in US images were used to train a model to detect thyroid nodules, of which 998 were used to train a model to detect and quantify calcifications. A total of 225 and 146 thyroid nodules obtained from two centers, respectively, were used to test the performance of these models. A logistic regression method was used to construct the predictive models for LNM in PTCs. Results: Calcifications detected by the network model and experienced radiologists had an agreement degree of above 90%. The novel quantitative parameters of US calcification defined in this study showed a significant difference between PTC patients with and without cervical LNM (p < 0.05). The calcification parameters were beneficial to predicting the LNM risk in PTC patients. The LNM prediction model using these calcification parameters combined with patient age and other US nodular features showed a higher specificity and accuracy than the calcification parameters alone. Conclusions: Our models not only detect the calcifications automatically, but also have value in predicting cervical LNM risk of PTC patients, thereby making it possible to investigate the relationship between calcifications and highly invasive PTC in detail. Clinical relevance statement: Due to the high association of US microcalcifications with thyroid cancers, our model will contribute to the differential diagnosis of thyroid nodules in daily practice. Key Points: • We developed an ML-based network model for automatically detecting and quantifying calcifications within thyroid nodules in US images. • Three novel parameters for quantifying US calcifications were defined and verified. • These US calcification parameters showed value in predicting the risk of cervical LNM in PTC patients. [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: The thyroid cancer (THCA) subtype that occurs more frequently is papillary thyroid cancer (PTC). Despite a favorable postoperative outcome, traditional antitumor therapy does not offer ideal results for patients with metastasis, relapse, and radioiodine resistance. Recent studies demonstrated the remarkable effects of immune checkpoint inhibitors on solid tumors, of which the immunoglobulin superfamily member SIGLEC10 and SIGLEC15 act as novel immunotherapy targets for tumors. Nevertheless, their role in PTC prognosis is still indefinite. Methods: Immunohistochemistry was utilized to examine the expression of SIGLEC10 and SIGLEC15 in 244 PTC tissue specimens. Then the expression correlation between the two was analyzed in normal tissues (NT), tumor cells (TC), and tumor stroma (TS), respectively. Subsequently, the retrospective data on patients with PTC were collected to examine whether the two immunosuppressive SIGLEC family members could affect their prognosis. Results: We confirmed that TC expressed higher levels of SIGLEC10 than NT. However, SIGLEC10 was down-regulated in TS and predicted poor outcomes. Meanwhile, down-regulation of SIGLEC15 expression was observed in both TC and TS, indicating a favorable prognosis. PTC patients with both SIGLEC10-SIGLEC15+ expression in TC and TS had a significantly higher recurrence risk. The expression of SIGLEC10 in TS and SIGLEC15 in TC or TS was an independent predictor of PFS, and a positive correlation was shown between SIGLEC10 and SIGLEC15 expression in TS. Conclusions: Therefore, our results indicate that SIGLEC10 and SIGLEC15 may be applied as significant prognostic markers for PTC and attractive targets for THCA immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Trajectory changes of quality of life (QOL) and psychological status in patients with T1N0M0 papillary thyroid cancer (PTC) after microwave ablation (MWA) treatment. Methods: Patients with T1N0M0 PTC who underwent MWA from March to August 2021 were included in this study. Patients completed the European Organisation for Research and Treatment of Cancer questionnaire (QLQ-C30), Thyroid Cancer–Specific Quality of Life Questionnaire (THYCA-QOL) and Hospital Anxiety and Depression Scale (HADS) at baseline, 3 months, 6 months, 9 months and 12 months after MWA. Results: 181 patients were enrolled in this study. All patients met a minimum of 12 months of follow-up. The QOL at baseline and 12 months after MWA were 14.95 ± 1.78 and 14.19 ± 1.73 (P < 0.01), respectively. Patients' anxiety was 3.33 ± 1.81 and 1.49 ± 2.14 (P < 0.01), respectively. Patients' depression was 2.14 ± 2.10 and 1.40 ± 2.22 (P < 0.01), respectively. In the trajectory analysis, 73%, 19% and 8% of patients achieved significant improvement, slight improvement and stable in QOL, respectively, with older, female, lower education and lower monthly income as the risk factors of QOL. 63%, 31% and 6% of patients achieved significant improvement, slight improvement and stable in anxiety, respectively, with younger, female, lower education, lower monthly income, unmarried or divorced and higher T3, T4 levels as the risk factors of anxiety. 72%, 21% and 7% of patients achieved significant improvement, slight improvement and stable in depression, respectively, with younger, lower monthly income and unmarried or divorced as the risk factors of depression. Conclusions: MWA can effectively improve the QOL and emotional distress of patients with T1N0M0 PTC. [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer (PTC) is the most common form of thyroid cancer and is characterized by its tendency for lymphatic metastasis, leading to a poor prognosis. Tetraspanin 1 (TSPAN1) is a member of the tetra‐transmembrane protein superfamily and has been implicated in tumorigenesis and cancer metastasis in various studies. However, the role of TSPAN1 in PTC tumor development remains unclear. In this study, we aimed to investigate the impact of TSPAN1 on PTC cell behavior. Our results demonstrate that knockdown of TSPAN1 inhibits PTC cell proliferation, migration, and invasion, while overexpression of TSPAN1 has the opposite effect. These findings suggest that TSPAN1 might play a role in the tumorigenesis and invasiveness of PTC. Mechanistically, we found that TSPAN1 activates the ERK pathway by increasing its phosphorylation, subsequently leading to upregulated expression of c‐Myc. Additionally, we observed that TSPAN1‐ERK‐c‐Myc axis activation promotes glycolytic activity in PTC cells, as evidenced by the upregulation of glycolytic genes such as LDHA. Taken together, our findings indicate that TSPAN1 acts as an oncogene in PTC by regulating glycolytic metabolism. This discovery highlights the potential of TSPAN1 as a promising therapeutic target for PTC treatment. Further research in this area could provide valuable insights into the development of targeted therapies for PTC patients. [ABSTRACT FROM AUTHOR]

The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC. [ABSTRACT FROM AUTHOR]

Purpose: The study investigates the value of the BRAFV600E mutation in determining the aggressiveness of papillary thyroid cancer (PTC) and its correlation with ultrasound features. Methods: The study selected 176 patients with BRAFV600E mutation and 80 without the mutation who underwent surgery at Guangxi Medical University Cancer Hospital. Clinical and pathological data were collected, focusing on BRAFV600E mutations and associated ultrasonic features. Correlation analysis, as well as univariate and multivariate logistic regression analysis, were conducted to identify independent risk factors for BRAFV600E mutation. The results were verified using a nomogram model. Results: The analysis results indicate that the BRAFV600E mutation correlates with tumor size, nodule size, taller-than-wide shape, margin, and shape of papillary thyroid cancer. The receiver operating characteristic curve was used to analyze the diagnostic effect of these features on BRAFV600E mutation. The results showed that nodule size had the most significant area under the curve (AUC = 0.665). Univariate and multivariate logistic regression analyses revealed that taller-than-wide shape ≥1, ill-defined margin, irregular shape, nodule size (≤1.40 cm), TT4 (>98.67 nmol/L), and FT3 (

ObjectivesTo investigate the association between contrast-enhanced ultrasound (CEUS) features of PTC and central lymph node metastasis (CLNM) and to develop a predictive model for the preoperative identification of CLNM.MethodsThis retrospective study evaluated 750 consecutive patients with PTC from August 2020 to April 2023. Conventional ultrasound and qualitative CEUS features were analyzed for the PTC with or without CLNM using univariate and multivariate logistic regression analysis. A nomogram integrating the predictors was constructed to identify CLNM in PTC. The predictive nomogram was validated using a validation cohort.ResultsA total of 684 patients were enrolled. The 495 patients in training cohort were divided into two groups according to whether they had CLNM (pCLNM, n= 191) or not (nCLNM, n= 304). There were significant differences in terms of tumor size, shape, echogenic foci, enhancement direction, peak intensity, and score based on CEUS TI-RADS between the two groups. Independent predictive US features included irregular shape, larger tumor size (≥ 1.0cm), and score. Nomogram integrating these predictive features showed good discrimination and calibration in both training and validation cohort with an AUC of 0.72 (95% CI: 0.68, 0.77) and 0.79 (95% CI: 0.72, 0.85), respectively. In the subgroup with larger tumor size, age ≤ 35 years, irregular shape, and score > 6 were independent risk factors for CLNM.ConclusionThe score based on preoperative CEUS features of PTC may help to identify CLNM. The nomogram developed in this study provides a convenient and effective tool for clinicians to determine an optimal treatment regimen for patients with PTC.

Papillary thyroid cancer (PTC) is the most prevalent endocrine cancer worldwide. Approximately 30 % of PTC patients will progress into the advanced or metastatic stage and have a relatively poor prognosis. It is well known that epithelial-mesenchymal transition (EMT) plays a pivotal role in thyroid cancer metastasis, resistance to therapy, and recurrence. Clarifying the molecular mechanisms of EMT in PTC progression will help develop the targeted therapy of PTC. The aberrant expression of some transcription factors (TFs) participated in many pathological processes of cancers including EMT. In this study, by performing bioinformatics analysis, adipocyte enhancer-binding protein 1 (AEBP1) was screened as a pivotal TF that promoted EMT and tumor progression in PTC. In vitro experiments indicated that knockout of AEBP1 can inhibit the growth and invasion of PTC cells and reduce the expression of EMT markers including N-cadherin, TWIST1, and ZEB2. In the xenograft model, knockout of AEBP1 inhibited the growth and lung metastasis of PTC cells. By performing RNA-sequencing, dual-luciferase reporter assay, and chromatin immunoprecipitation assay, Bone morphogenetic protein 4 (BMP4) was identified as a downstream target of AEBP1. Over-expression of BMP4 can rescue the inhibitory effects of AEBP1 knockout on the growth, invasion, and EMT phenotype of PTC cells. In conclusion, these findings demonstrated that AEBP1 plays a critical role in PTC progression by regulating BMP4 expression and the AEBP1-BMP4 axis may present novel therapeutic targets for PTC treatment.

Background: Papillary thyroid carcinoma (PTC) is the most common type of differentiated TC, while medullary TC (MTC) accounts for 4%. The concomitant presence of PTC and MTC is rare. Methods: This is a retrospective, single-center observational study conducted over 16 years (2001–2017). The data were collected from the clinical records of patients who underwent total thyroidectomy at the Endocrine Unit-Department of Medicine of the University Hospital of Pisa, Italy. Results: Over 690 analyzed cases, 650 (94.2%) were exclusive DTC, 19 exclusive MTC (2.75%) and 5 PTC/MTC (0.7%). No case of mixed medullary/follicular TC or hereditary MTC (familial MTC/multiple endocrine neoplasia type 2) was found. Among the five PTC/MTC cases, there was a male prevalence (M:F = 3:2), and all PTC components were at stage I, whereas 40% of MTC were at stage I and III and 20% of MTC were at stage II; microPTC (mPTC) was prevalent (80%) and also microMTCs were frequent (40%); 60% of MTC patients recovered, while 40% of patients developed metastatic disease. The search for germline mutations of the RET gene resulted in being negative in all cases. Conclusions: The incidence of PTC/MTC has been increasing over the past 30 years. The etiology of PTC/MTC forms is still unknown, and although this simultaneous occurrence could be only a coincidence, we cannot exclude the hypothesis of a shared genetic origin.

Background. Due to the low sensitivity and specificity of neck ultrasound in the evaluation of the central lymph nodes, it is necessary to find alternative ways to predict central lymph node metastases in patients with papillary thyroid cancer (PTC). The purpose of the study is to develop a prognostic model for assessing the risk of local metastasis of papillary thyroid cancer based on preoperative ultrasound and demographic predictors. Materials and methods. A retrospective monocenter cohort study was conducted. The data of 401 patients who underwent surgery for PTC were processed. The main group included 179 patients in whom central lymph node metastases were detected during histopathological examination. The comparison group consisted of 222 patients without metastases according to the results of histopathological examination. When conducting the analysis, the following signs were considered as risk factors: subcapsular location of the tumor; size; blurred boundaries; the presence of calcification areas (microcalcifications); age of a patient. Inclusion criteria: PTC that was cytologically confirmed at the preoperative stage; surgeries (thyroidectomy/hemithyroidectomy and central neck lymph node dissection). Exclusion criteria: history of neck surgery; multifocal lesions of the thyroid gland. Results. The following logistic equation was obtained using the StatPlus program: y = –1.839 – 0.037 × X1 + 0.097 × X2 + 1.123 × X3 + 1.198 × X4 + + 0.692 × X5, where X1, X2, X3, X4, X5 are age (years), size (mm), subcapsular location (presence), blurred boundaries (presence), calcifications (presence), respectively. The obtained prognostic model provided the following operational characteristics when specifying the threshold value for P, which is equal to 0.44 (the decisive rule X > T): sensitivity — 75.4 %, specificity — 79.3 %, diagnostic efficiency — 75.1 %. To assess the quality of the model, the receiver operator characteristic (ROC) analysis was performed. The following data were obtained: area under the ROC curve = 0.797 (95% confidence interval: 0.753–0.841), which corresponds to the good quality of the model, and Youden index J = 0.5155. Checking the quality of the model on a control group of 100 people gave the following results: sensitivity — 72.2 %, specificity — 76.1 %, diagnostic efficiency — 75.8 %. Conclusions. The application of a prognostic model based on ultrasound data and the patient’s age makes it possible to predict the presence of local metastases of the PTC at the preoperative stage with a diagnostic efficiency of 75.8 %. No prognostic model gives 100% prediction accuracy. When choosing the treatment, additional influencing factors (history of radiation exposure, burdened family history, etc.) for a specific patient should be considered.

Abstract Background Lateral lymph node metastasis (LLNM) is common in patients with papillary thyroid cancer (PTC), usually occurring after central lymph node metastasis (CLNM). However, some patients experience LLNM without first developing CLNM. This study aimed to identify the risk factors for developing LLNM without CLNM. Methods We retrospectively reviewed 421 patients diagnosed with PTC who underwent lobectomy or total thyroidectomy with central and ipsilateral lateral lymph node dissection. We collected clinicopathological data and used univariate and multivariate logistic regression analyses to determine the risk factors associated with LLNM without CLNM. Results The LLNM without CLNM frequency was 18.3% (77/421). Univariate analyses demonstrated that age over 55 years, primary tumor in the upper portion of the thyroid, the number of central lymph node (CLN) and LLNM, primary tumor size, and the summed size of multi‐foci tumors smaller than 1 cm were significantly associated with LLNM without CLNM (p

Background: Incidence rates of papillary thyroid cancer (PTC) have increased rapidly, with incidentally detected cancers contributing a large proportion. We aimed to explore the impact of incidental detection on thyroid cancer-specific and competing mortality among PTC patients. Methods: We conducted a retrospective cohort study of PTC patients at a cancer center in Guangzhou. Baseline information on detection route and other covariates were collected between 2010 and 2018, and death outcome was followed up for each patient. Cumulative incidence functions were used to estimate the mortality risk of thyroid cancer and competing risk. Cause-specific hazard models were the n utilized to explore the association between detection routes and PTC-specific and competing mortality. Results: Of the 2874 patients included, 2011 (70.0%) were detected incidentally, and the proportion increased from 36.9% in 2011 to 82.3% in 2018. During a median follow-up of 5.6 years, 42 deaths occurred, with 60% of them due to competing causes. The probability of competing mortality at 5 years in the non-incidental group and incidental group was 1.4% and 0.4%, respectively, and PTC-specific mortality in the non-incidental group and incidental group was 1.0% and 0.1%, respectively. After adjusting for covariates, the HRs of incidental detection were 0.13 (95% CI: 0.04–0.46; P = 0.01) and 0.47 (95% CI: 0.20–1.10; P = 0.10) on PTC-specific mortality and competing mortality, respectively. Conclusions: Incidental detection is associated with a lower risk of PTC-specific and competing mortality. Under the context of increasing magnitude of overdiagnosis, incorporation of detection route in clinical decision-making might be helpful to identify patients who might benefit from more extensive or conservative therapeutic strategies.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have changed considerably the management of type 2 diabetes (T2D). However, recently published data from retrospective cohort studies suggest that chronic exposure to GLP-1RAs in T2D may increase the risk of papillary and medullary thyroid cancer. In this perspective, the role of the incretin system in thyroid carcinogenesis has been reviewed and critically commented on, aiming to understand if the time has arrived to be concerned about the risk. Although evidence suggested, speculative hypotheses should be verified, and further studies are urgently needed to clarify the issue.

Emerging evidence suggests that microbial dysbiosis plays vital roles in many human cancers. However, knowledge of whether the microbial community in thyroid tumor is related to tumorigenesis remains elusive. In this study, we aimed to explore the microbial community in thyroid tissues and its contribution to papillary thyroid cancer (PTC). In parallel, we performed microbial profiling and transcriptome sequencing in the tumor and adjacent normal tissues of a large cohort of 340 PTC and benign thyroid nodule (BTN) patients. Distinct microbial signatures were identified in PTC, BTN, and their adjacent non-tumor tissues. Intra-thyroid tissue bacteria were verified by means of bacteria staining, fluorescence in situ hybridization, and immunoelectron microscopy. We found that 17 bacterial taxa were differentially abundant in PTC compared with BTN, which included enrichment in PTC of the pathobionts Rhodococcus, Neisseria, Streptococcus, Halomonas, and Devosia, and depletion of the beneficial bacteria Amycolatopsis. These differentially abundant bacteria could differentiate PTC tumor tissues (PTC-T) from BTN tissues (BTN-T) with an area under the curve (AUC) of 81.66%. Microbial network analysis showed increased correlation strengths among the bacterial taxa in PTC-T in comparison with BTN-T. Immune-function-corresponding bacteria (i.e., Erwinia, Bacillus, and Acinetobacter) were found to be enriched in PTC with Hashimoto’s thyroiditis. Moreover, our integrative analysis revealed that the PTC-enriched bacteria had a positive association with key PTC-oncogenic pathway-related genes, including BRAF, KRAS, IRAK4, CTNNB1, PIK3CA, MAP3K7, and EGFR. In conclusion, our results suggest that intratumor bacteria dysbiosis is associated with the thyroid tumorigenesis and oncogenic signaling pathways of PTC.

Abstract Introduction Thyroid swellings are prevalent in 4 to 7% of the Indian population and are commonly present in females. Thyroid swelling has been attributed to various causes, such as ingestion of goitrogens and low iodine in the diet in benign, radiation exposure, and genetic in malignancies. Eastern Hyderabad and Nalgonda have a high fluoride content in the ground water, which can potentially disrupt thyroid functioning. Moreover, the region also harbors high uranium content and environmental radiation; hence, a retrospective analysis of the FNAC and histopathology of the thyroid swellings was done to evaluate the paradigm. Method A retrospective analysis of the patient’s records from February 1, 2022, to January 31, 2023, was conducted considering all the patients who presented with thyroid swelling. The variables taken into consideration were age, gender, and FNAC findings. A correlation was also made with the histopathology of the specimen of operated patients. Result A total of 88 medical records of the patients were evaluated, and it was determined that there was a preponderance of females with a ratio of 8.77:1. Majority of the swellings were Benign labeled as Bethesda category 2 (n = 61) followed by category 3 (n = 11). To be considered are the cases of malignancies falling into category 6, which comprise 7.95% (n = 7). The majority of the patients were seen between the ages of 31 to 40 (n = 28), followed by 41 to 50 (n = 25). On comparing with the histopathological reports, two cases of category 5 were found to be having papillary thyroid carcinoma and another with follicular thyroid carcinoma making the number of proven malignancies to be 10.22% (n = 9). Other histopathological findings correlated with the results of FNAC. Conclusion Through this pilot study, we conclude that most thyroid swellings were benign, but there is a higher incidence of thyroid malignancies (10.22%), significantly higher than the country average of 2 to 4%. The higher number of malignant cases can be attributed to many factors, including high fluoride content and environmental radiation. Further studies need to be conducted, taking each element individually.

This study aimed to investigate the expression of microRNAs (miRNAs) -146b-3p, -221-5p, -222-3p, and -21a-3p and the methylation pattern of the thyroid-stimulating hormone receptor (TSHR) gene in blood plasma samples from papillary thyroid cancer (PTC) patients before and after thyroidectomy compared to healthy controls (HCs). This study included 103 participants, 46 PTC patients and 57 HCs, matched for gender and age. Significantly higher preoperative expression levels of miRNAs and TSHR methylation were determined in the PTC patients compared to HCs. Post-surgery, there was a notable decrease in these biomarkers. Elevated TSHR methylation was linked to larger tumor sizes and lymphovascular invasion, while increased miRNA-222-3p levels correlated with multifocality. Receiver operating characteristic (ROC) analysis showed AUCs below 0.8 for all candidate biomarkers. However, significant changes in the expression of all analyzed miRNAs and TSHR methylation levels indicate their potential to differentiate PTC patients from healthy individuals. These findings suggest that miRNAs and TSHR methylation levels may serve as candidate biomarkers for early diagnosis and monitoring of PTC, with the potential to distinguish PTC patients from healthy individuals. Further research is needed to validate these biomarkers for clinical application.