Dynamic estimates of survival in patients with follicular thyroid cancer: a retrospective cohort study.

BACKGROUND: Few studies have been conducted on the dynamic survival rates of follicular thyroid cancer (FTC). This study aimed to ascertain how the survival probability of patients with FTC changes over time. METHODS: In this retrospective analysis, 10,617 patients diagnosed with FTC between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database were included. Actuarial disease-specific survival (DSS) was estimated using the Kaplan-Meier method, and the log-rank test was used for comparisons. The annual hazard of mortality was determined using the hazard function, and the conditional survival (CS) was calculated using the life table method. RESULTS: A total of 459 (4.3%) patients died of FTC, and the 5-year and 10-year DSS rates were 96.6 ± 0.2% and 94.6 ± 0.3%, respectively. There was a statistically significant difference in the DSS rate between patients with different SEER combined summary stages (P < 0.001). The annual hazard curve for cancer mortality in the entire study cohort displayed a steep downward trend with a slight peak at 2.5 years after diagnosis, followed by a gradual decline. Patients with distant metastases exhibited a higher mortality hazard curve and more notable declining trend. CS demonstrated an upward trend across the entire study population, with the most pronounced trend in patients with distant metastases. CONCLUSION: Prognosis improved over time in a stage-dependent manner in patients with FTC after diagnosis. The most significant improvement was observed in the patients with distant metastases. Notably, dynamic survival estimations, such as death hazard and conditional survival analysis, provide more precise survival projections than traditional survival analysis for FTC survivors.

Symmetrical acral keratoderma associated with new variants in the filaggrin gene.

Symmetrical acral keratoderma (SAK) is a rare skin disorder with symmetric hyperkeratotic patches on the acral regions. Variants in the filaggrin gene (FLG) have been associated with SAK since 2020. To explore the clinical and genetic basis in six patients with SAK. Whole-exome sequencing, direct sequencing, and prediction of protein structure and function were performed. In this study, we identified two novel variants, c.3320del and c.4909del, and seven previously reported variants, c.3099C>G, c.4544C>A, c.6950_6957del, c.7264G>T, c.7945del, c.8117C>G, c.12064A>T. The findings of this study bolster the existing evidence implicating FLG variants in SAK, introducing two novel variants to the database of FLG variants associated with the condition.

Exploring the bidirectional relationship between metabolic syndrome and thyroid autoimmunity: a Mendelian randomization study.

Background: Observational studies have reported a possible association between metabolic syndrome (MetS) and thyroid autoimmunity. Nevertheless, the relationship between thyroid autoimmunity and MetS remains unclear. The objective of this research was to assess the causal impact of MetS on thyroid autoimmunity through the utilization of Mendelian randomization (MR) methodology. Methods: We performed bidirectional MR to elucidate the causal relationship between MetS and their components and thyroid autoimmunity (positivity of TPOAb). Single nucleotide polymorphisms (SNPs) of MetS and its components were obtained from the publicly available genetic variation summary database. The Thyroidomics Consortium conducted a genome-wide association analysis, which provided summary-level data pertaining to thyroid autoimmunity. The study included several statistical methods, including the inverse variance weighting method (IVW), weighted median, simple mode, weight mode, and MR-Egger methods, to assess the causal link. In addition, to ensure the stability of the results, a sensitivity analysis was conducted. Results: IVW showed that MetS reduced the risk of developing thyroid autoimmunity (OR = 0.717, 95% CI = 0.584 - 0.88, P = 1.48E-03). The investigation into the causative association between components of MetS and thyroid autoimmune revealed a statistically significant link between triglycerides levels and the presence of thyroid autoimmunity (IVW analysis, OR = 0.603, 95%CI = 0.45 -0.807, P = 6.82E-04). The reverse analysis did not reveal any causal relationship between thyroid autoimmunity and MetS, including its five components. Conclusions: We have presented new genetic evidence demonstrating that MetS and its triglyceride components may serve as potential protective factors against thyroid autoimmunity.

Dynamic estimates of survival in oncocytic cell carcinoma of the thyroid.

BACKGROUND: Little is known about death hazard and conditional survival of oncocytic cell carcinoma of the thyroid (OCC). METHODS: Patients diagnosed with OCC between 2004 to 2019 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to estimate the actuarial disease-specific survival (DSS). The annual hazard rate of death was depicted employing the hazard function. Based on the life-table method, the conditional DSS was calculated. RESULTS: In terms of DSS rates, there were statistically significant differences among the different stages (P < 0.01). Annual hazard curves for mortality from OCC in the entire study participants demonstrated an overall decreasing tendency with two peaks at 3 and 10 years. In patients with distant disease, the death risk curve was the steepest and decreased quickly and evidently. Conditional DSS tended to increase over time in the entire study population. Patients with distant disease showed more significant alterations than those patients with local or regional disease. CONCLUSIONS: Prognosis improved over time in patients with OCC. The largest increase in conditional DSS was observed in patients with distant disease. Conditional survival may provide more relevant prognostic information than conventional survival estimates and allow personalized follow-up and counseling.

Risk factors associated with preferential lateral lymph node metastasis in papillary thyroid carcinoma.

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 < 0.05). Multivariate analysis revealed that LLNM without CLNM was more likely to occur in patients aged ≥55 years (odds ratio [OR], 2.309; 95% confidence interval [CI], 1.133-4.704; p = 0.021), and primary tumor in the upper portion of the thyroid (OR, 0.524; 95% CI, 0.295-0.934; p = 0.028). CONCLUSION: The lymph node metastasis pattern in patients with PTC is not constant. Therefore, surgeons should evaluate the lateral lymph nodes, especially in patients older than 55 years or when the primary tumor is in the upper portion of the thyroid.

Risk factors for death of follicular thyroid carcinoma: a systematic review and meta-analysis.

BACKGROUND: There are conflicting reports on the factors that increase the likelihood of patients dying from follicular thyroid carcinoma (FTC). Therefore, it is critical to identify risk factors of patients with FTC. This study aimed to identify the factors that increase the risk of death of patients with FTC and help clinicians make better treatment and follow-up decisions. METHODS: A systematic literature review was conducted in PubMed and Web of Science databases for relevant studies published before January 31, 2023. Their reference lists were also analyzed. Two reviewers extracted data and evaluated the quality of eligible studies independently. Studies on patients who had open thyroidectomy procedures with or without neck dissection were included in this review. The RevMan 5.3 software was used to analyze the data. RESULTS: This meta-analysis included thirteen studies with a total of 2075 patients. The following variables were associated with an increased risk of death in FTC patients: age > 45 years, male, tumor diameter > 4 cm, multifocality, extrathyroidal extension (ETE), widely invasive (WI), cervical lymph node metastasis (CLNM), distant metastases (DM) and non-radical resection tumor. Lobectomy and no radioactive iodine (RAI) treatment was not associated with the death of FTC patients. CONCLUSION: Clinicians should pay closer attention to the following significant risk factors associated with the death of FTC patients: age (> 45), male, multifocality, tumor diameter > 4 cm, ETE, WI, non-radical resection tumor, CLNM, and DM. Individualized initial treatment and close follow-up are needed FTC patients who have these risk factors.

NEAT1_2/RRAD/EHF Positive Feedback Loop Facilitates Aerobic Glycolysis in Papillary Thyroid Cancer Cells.

Papillary thyroid carcinoma (PTC) is the most prevalent endocrine-related malignancy. In spite of the good prognosis, a more aggressive disease can develop in some PTC patients, leading to poor survival. Nuclear paraspeckle assembly transcript 1 (NEAT1) enhances tumorigenesis; however, the relationship between NEAT1_2 and glycolysis in PTC has not been identified. The expressions of NEAT1_2, KDM5B, Ras-related associated with diabetes (RRAD), and EHF were determined by quantitative reverse transcription polymerase chain reaction and immunocytochemistry. The effects of NEAT1_2, KDM5B, RRAD, and EHF on PTC glycolysis were ascertained employing in vitro as well as in vivo experiments. Chromatin immunoprecipitation (ChIP), RNA binding protein immunoprecipitation, luciferase reporter assays, and co-immunoprecipitation were utilized to analyze the binding abilities among NEAT1_2, KDM5B, RRAD, and EHF. Overexpression of NEAT1_2 was associated with glycolysis in PTC. NEAT1_2 could activate glycolysis by regulating the expression of RRAD in PTC. NEAT1_2 mediated H3K4me3 modification at the promoter of RRAD by recruiting KDM5B. RRAD further negatively regulated glycolysis by binding and regulating the subcellular location of the transcription factor EHF. EHF could activate the transcription of NEAT1_2, hexokinase 2, and pyruvate kinase M2, thereby forming the NEAT1_2/RRAD/EHF feedback loop. Our study revealed that the NEAT1_2/RRAD/EHF positive feedback loop facilitated glycolysis in PTC, which might avail meaningful insight for PTC management.

A bibliometric review on vitamins and Alzheimer's disease between 1996 and 2023.

Objective: Alzheimer's disease (AD) is a major disease that affects the elderly worldwide. Several studies have revealed that vitamins may influence the risk of developing AD. However, information in this field remains ambiguous. Therefore, this study aimed to examine the relationship between AD and vitamins, identify journal publications and collaborators, and analyze keywords and research trends using a bibliometric method. Methods: We systematically searched the Web of Science (WOS) Core Collection for papers published on AD and vitamins. Retrieved data regarding institutions, journals, countries, authors, journal distribution, keywords, and so on. SPSS 25 software was used for the statistical analysis, and CiteSpace V.6.1.R6 was used to visualize the information through collaborative networks. Results: A total of 2,838 publications were ultimately included in accordance with the specified inclusion criteria. The number of publications gradually increased from 1996 to 2023, with papers published in 87 countries/regions and 329 institutions. China (centrality: 0.02) and the University of Kentucky (centrality: 0.09) were the major research countries and institutions, respectively. NEUROLOGY was cited most frequently, reaching 1,573, and had the greatest impact. The cited keywords show that "Alzheimer's disease," "oxidative stress," "vitamin E," and "dementia" have been research hotspots in recent years. Beta-carotene emerged in 2023 and was identified as a developmental trend in this field. Conclusion: This is the first bibliometric analysis of vitamins associated with AD. We identified 2,838 articles in the field of vitamins and AD, analyzed the information of major countries/regions, institutions, and core journals in this field, and summarized the research hotspots and frontiers. These findings provide useful information for researchers to explore the role of vitamins in AD further.

ALKBH5-induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2.

Although circular RNAs (circRNAs) are involved in cell proliferation, differentiation, apoptosis, and invasion, the underlying regulatory mechanisms of circRNAs in thyroid cancer have not been fully elucidated. This article aimed to study the role of circRNA regulated by N6-methyladenosine modification in papillary thyroid cancer (PTC). Quantitative real-time PCR, western blotting, and immunohistochemistry were used to investigate the expressions of circRNA nuclear receptor-interacting protein 1 (circNRIP1) in PTC tissues and adjacent noncancerous thyroid tissues. In vitro and in vivo assays were carried out to assess the effects of circNRIP1 on PTC glycolysis and growth. The N6-methyladenosine mechanisms of circNRIP1 were evaluated by methylated RNA immunoprecipitation sequencing, luciferase reporter gene, and RNA stability assays. Results showed that circNRIP1 levels were significantly upregulated in PTC tissues. Furthermore, elevated circNRIP1 levels in PTC patients were correlated with high tumor lymph node metastasis stage and larger tumor sizes. Functionally, circNRIP1 significantly promoted glycolysis, PTC cell proliferation in vitro, and tumorigenesis in vivo. Mechanistically, circNRIP1 acted as a sponge for microRNA (miR)-541-5p and miR-3064-5p and jointly upregulated pyruvate kinase M2 (PKM2) expression. Knockdown of m6 A demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) significantly enhanced circNRIP1 m6 A modification and upregulated its expression. These results show that ALKBH5 knockdown upregulates circNRIP1, thus promoting glycolysis in PTC cells. Therefore, circNRIP1 can be a prognostic biomarker and therapeutic target for PTC by acting as a sponge for oncogenic miR-541-5p and miR-3064-5p to upregulate PKM2 expression.

Clinical and ultrasonic risk factors for high-volume central lymph node metastasis in cN0 papillary thyroid microcarcinoma: A retrospective study and meta-analysis.

OBJECTIVE: Papillary thyroid microcarcinoma (PTMC) comprises more than 50% of all newly detected cases of papillary thyroid carcinoma (PTC). High-volume lymph node metastasis (involving >5 lymph nodes) (hv-LNM) is associated with PTMC recurrence. In half of the clinically node-negative (cN0) PTMC patients, central lymph node metastasis (CLNM) is pathologically present. However, clinical risk factors for high-volume CLNM (hv-CLNM) in cN0 PTMC have not been defined well. Therefore, we aimed to obtain evidence for hv-CLNM risk factors in cN0 PTMC. DESIGN: Data on patients who visited our hospital between January 2020 and December 2021 were collected; a preoperative diagnosis of cN0 and a postoperative pathological confirmation of PTMC were obtained. After filtering by inclusion versus exclusion criteria, the obtained data (N = 2268) were included in the meta-analysis. Relevant studies published as of 10 April 2022, were identified from the Web of Science, PubMed, WANFANG, and CNKI databases. These eligible studies were included in the meta-analysis and the association between clinicopathological factors and hv-CLNM in cN0 PTMC was assessed. SPSS and MetaXL were used for statistical analyses. RESULTS: The meta-analysis included 10 previous studies (11,734 patients) and 2268 patients enroled in our hospital for a total of 14,002 subjects. The results of which suggested that younger age (<40, odds ratio [OR] = 3.28, 95% confidence interval [CI] = 2.75-3.92, p < .001 or <45 odds ratio [OR] = 2.93, 95% CI = 2.31-3.72, p < .001), male sex (OR = 2.81, 95% CI = 2.25-3.52, p < .001), tumour size >5 mm (OR = 1.85, 95% CI = 1.39-2.47, p < .001), multifocality (OR = 1.88, 95% CI = 1.56-2.26, p < .001), extrathyroidal extension (OR = 2.58, 95% CI = 2.02-3.30, p < .001), capsule invasion (OR = 2.02, 95% CI = 1.46-2.78, p < .001), microcalcification (OR = 3.25, 95% CI = 2.42-4.36, p < .001) and rich blood flow (OR = 1.65, 95% CI = 1.21-2.25, p = .002) were the significant factors related to an elevated hv-CLNM risk in cN0 PTMC patients. Hashimoto thyroiditis (OR = 0.76, 95% CI = 0.55-1.07, p = .114), irregular margin (versus regular margin, OR = 0.96, 95% CI = 0.68-1.33, p = .787) and hypoechoic (versus nonhypoechoic, OR = 1.27, 95% CI = 0.84-1.92, p = .261) showed no significant association with hv-CLNM. CONCLUSIONS: Younger age, tumour size >5 mm, males, extrathyroidal extension, multifocality, microcalcification, capsular invasion, and rich blood flow were the significant clinicopathological risk factors for hv-CLNM risk in cN0 PTMC patients. These predictors may compensate for the sensitivity of imaging diagnosis in the preoperative period, thus helping in the effective identification of PTMCs with an invasive phenotype.

Risk factors of cervical lymph node metastasis in multifocal papillary thyroid cancer.

Introduction: Identifying risk variables for cervical lymph node metastases in multifocality papillary thyroid cancer (MPTC) could assist surgeons in determining whether cervical lymph node dissection would be an appropriate surgical option. Methods: A retrospective cohort of 2006 patients with papillary thyroid cancer were selected. MPTC (N = 460) was defined as the presence of two or more foci of PTC. The risk factors for central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) in MPTC were investigated by univariate and multivariate analyses, including the following items: age at diagnosis, gender, Hashimoto's thyroiditis, extrathyroidal extension (ETE), maximal axial diameter (MAD) and the sum of axial diameters (SAD) of tumor. In addition, CLNM was used to evaluate LLNM. Results: The incidence of CLNM and LLNM was 44.57% and 17.17%, respectively. The multivariate analysis demonstrated that gender, extrathyroidal extension (ETE), age, maximal axial diameter (MAD), and the sum of axial diameters (SAD) were related to increased risk for CLNM in MPTC (p < 0.05). The area under the receiver operating characteristic (ROC) curve (AUC) for age at diagnosis of CLNM was 0.647, the cut-off value was 50 years old. Additionally, by multivariate analysis, CLNM, ETE, MAD, and SAD were independent risk factors for LLNM in MPTC (p < 0.05). ROC curve analysis demonstrates that AUC for MAD and SAD diagnosis of LLNM were 0.639 and 0.757, and the cut-off values were 16 and 26 mm, respectively. Conclusions: MPTC patients who have risk factors for CLNM were advised to perform prophylactic central lymph node dissection (CLND). Additionally, the presence of risk factors for LLNM should be individually evaluated and analyzed for the necessity of lateral lymph node dissection.

Different types of diabetes mellitus and risk of thyroid cancer: A meta-analysis of cohort studies.

Objective: Sex-specific thyroid cancer risk exists in patients diagnosed with diabetes mellitus (DM). However, thyroid cancer risk in different types of DM is still unclear. This meta-analysis aims to identify the real correlation between different types of DM and thyroid cancer risk in both sexes. Methods: Studies were identified by an electronic search of PubMed, EMBASE, and Cochrane Library on 16 January 2022. A random-effects model was used to estimate the relative risks (RRs). The Cochran's Q and I2 statistics were computed to detect heterogeneity between studies. Results: In comparison with non-DM counterparts, patients with DM had a 1.32-fold higher risk of thyroid cancer (95% CI, 1.22-1.44) with 1.26-fold (95% CI, 1.12-1.41) in men and 1.36-fold (95% CI, 1.22-1.52) in women, respectively. Subgroup analysis by the type of DM showed that the RR of thyroid cancer in patients with type 2 diabetes was 1.34 (95% CI, 1.17-1.53) in the study population with 1.32 (95% CI, 1.12-1.54) in men and 1.37 (95% CI, 1.12-1.68) in women, respectively; the RR of thyroid cancer was 1.30 (95% CI, 1.17-1.43) in patients with gestational diabetes; the risk of thyroid cancer in patients with type 1 diabetes was 1.51-fold in women but not in men. Although there were some heterogeneities, it did not affect the above results of this study. Conclusion: This study indicates that, compared with non-DM individuals, patients with any type of DM have an elevated thyroid cancer risk. This positive correlation between type 2 diabetes and thyroid cancer risk exists in both men and women. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42022304028.

A novel necroptosis-related gene signature associated with immune landscape for predicting the prognosis of papillary thyroid cancer.

Background: Necroptosis, a type of programmed cell death, has been implicated in a variety of cancer-related biological processes. However, the roles of necroptosis-related genes in thyroid cancer yet remain unknown. Methods: A necroptosis-related gene signature was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis and Cox regression analysis. The predictive value of the prognostic signature was validated in an internal cohort. Additionally, the single-sample gene set enrichment analysis (ssGSEA) was used to examine the relationships between necroptosis and immune cells, immunological functions, and immune checkpoints. Next, the modeled genes expressions were validated in 96 pairs of clinical tumor and normal tissue samples. Finally, the effects of modeled genes on PTC cells were studied by RNA interference approaches in vitro. Results: In this study, the risk signature of seven necroptosis-related genes was created to predict the prognosis of papillary thyroid cancer (PTC) patients, and all patients were divided into high- and low-risk groups. Patients in the high-risk group fared worse in terms of overall survival than those in the low-risk group. The area under the curve (AUC) of the receiving operating characteristic (ROC) curves proved the predictive capability of created signature. The risk score was found to be an independent risk factor for prognosis in multivariate Cox analysis. The low-risk group showed increased immune cell infiltration and immunological activity, implying that they might respond better to immune checkpoint inhibitor medication. Next, GEO database and qRT-PCR in 96 pairs of matched tumorous and non-tumorous tissues were used to validate the expression of the seven modeled genes in PTCs, and the results were compatible with TCGA database. Finally, overexpression of IPMK, KLF9, SPATA2 could significantly inhibit the proliferation, invasion and migration of PTC cells. Conclusion: The created necroptosis associated risk signature has the potential to have prognostic capability in PTC for patient outcome. The findings of this study could pave the way for further research into the link between necroptosis and tumor immunotherapy.

Prognostic Factors for Excellent Response to Initial Therapy in Patients With Papillary Thyroid Cancer From a Prospective Multicenter Study.

Prognostic factors for excellent response (ER) to initial therapy in patients with papillary thyroid cancer (PTC) have not been determined. In this study, we investigated the response to initial therapy in PTC patients and independent prognostic factors for ER in a prospective multicenter study in China. A total of 506 PTC patients from nine centers in China were enrolled in this study, all of whom underwent total or near total thyroidectomy with lymph node dissection and subsequent radioiodine therapy. Univariate and multivariable logistic regression analyses were carried out to determine the independent prognostic factors for ER. The optimal cutoff value of the number of metastatic lymph nodes for predicting ER was determined by the receiver operating characteristic curve. A total of 139 patients (27.5%) achieved ER after initial therapy. Extrathyroidal extension, the number of metastatic lymph nodes, and preablative-stimulated thyroglobulin (Ps-Tg) were independent risk factors for ER for the entire population. In a subgroup analysis, extrathyroidal extension and Ps-Tg were independent risk factors for ER in pathological N1a patients, while the number of metastatic lymph nodes and Ps-Tg were independent risk factors for ER in pathological N1b patients. The appropriate cutoff values of the number of metastatic lymph nodes in predicting ER were 5 and 13 for the entire population and pathological N1b PTC patients, respectively. PTC patients with more metastatic lymph nodes were more likely to fail to achieve ER. Extrathyroidal extension, the number of metastatic lymph nodes, and Ps-Tg were important prognostic factors for ER after initial therapy in PTC patients.

Predictive value of metastatic lateral lymph node ratio for recurrence in pathologically lateral lymph node-positive papillary thyroid cancer patients with palpable lymph nodes.

BACKGROUND: This study aimed to identify the predictive value of the extent of metastatic lymph nodes in the central and lateral neck compartment for recurrence in papillary thyroid cancer (PTC) patients with pathologically lateral lymph node metastasis (pN1b). METHODS: This study enrolled 252 patients with pN1b from PTC. RESULTS: During a mean follow-up of 17.6 years, 55 (21.8%) patients experienced recurrence. Patients with palpable lymph nodes were more likely to have a recurrence than those with nonpalpable lymph nodes (30.1% vs. 17.8%, relative risk 1.7, 95%CI: 1.1-2.7). For patients with palpable metastatic lymph nodes, lymph node ratio of lateral lymph nodes ≥0.5 (aHR = 2.906, 95%CI: 1.29-6.54) and age ≥55 years (aHR = 2.508, 95%CI: 1.12-5.63) were independent prognostic factors. For those without palpable nodes, age ≥55 years (aHR = 2.224, 95%CI: 1.08-4.60) and tumor size >4 cm (aHR = 2.168, 95%CI: 1.01-4.66) were independently predictive of worse RFS. CONCLUSIONS: Palpable lymph nodes were approximately twice as likely to recur as nonpalpable nodes. Metastatic lateral lymph node ratio predicts recurrence in pN1b PTC patients with palpable lymph nodes, but not those without ones.