Prognostic prediction of patients having classical papillary thyroid carcinoma with a 4 mRNA-based risk model.

The dysregulation of protein-coding genes involved in various biological functions is closely associated with the progression of thyroid cancer. This study aimed to investigate the effects of dysregulated gene expressions on the prognosis of classical papillary thyroid carcinoma (cPTC). Using expression profiling datasets from the Cancer Genome Atlas (TCGA) database, we performed differential expression analysis to identify differentially expressed genes (DEGs). Cox regression and Kaplan-Meier analysis were used to identify DEGs, which were used to construct a risk model to predict the prognosis of cPTC patients. Functional enrichment analysis unveiled the potential significance of co-expressed protein-encoding genes in tumors. We identified 4 DEGs (SALL3, PPBP, MYH1, and SYNDIG1), which were used to construct a risk model to predict the prognosis of cPTC patients. These 4 genes were independent of clinical parameters and could be functional in cPTC carcinogenesis. Furthermore, PPBP exhibited a strong correlation with poorer overall survival (OS) in the advanced stage of the disease. This study suggests that the 4-gene signature could be an independent prognostic biomarker to improve prognosis prediction in cPTC patients older than 46.

Natural History and Prognostic Model of Untreated Papillary Thyroid Cancer: A SEER Database Analysis.

PURPOSE: This investigation leveraged the SEER database to delve into the progression patterns of PTC when left untreated. Furthermore, it aimed to devise and authenticate a nomogram for prognosis prediction for such patients. METHODS: We extracted data from the SEER database, focusing on PTC-diagnosed individuals from 2004-2020. To discern disease progression intervals, median survival times across stages were gauged, and the disease progression time was estimated by subtracting the median survival time of a more severe stage from its preceding stage. Prognostic determinants in the training set were pinpointed using both univariate and multivariate Cox regression. Using these determinants, a prognostic nomogram was crafted. RESULTS: In untreated PTC patients, those in stages I and II had a favorable prognosis, with 10-year overall survival rates of 86.34% and 66.03%, respectively. Patients in stages III and IV had a relatively poorer prognosis. The median survival time of stage III, stage IVA, stage IVB and stage IVC patients was 108months, 43 months, 20 months and 8 months, respectively. The deduced progression intervals from stages III-IVC were 65, 23, and 12 months. In the training set, age, tumor stage, gender, and marital status were identified as independent risk factors influencing the prognosis of untreated PTC, and a nomogram was constructed using these variables. CONCLUSION: In the absence of treatment intervention, early-stage PTC progressed slowly with an overall favorable prognosis. However, in mid to advanced-stage PTC, as tumor stage increased, disease progression accelerated, and prognosis gradually worsened. Age, tumor stage, marital status, and gender were independent risk factors influencing the prognosis of untreated PTC, and the nomogram based on these factors demonstrated good prognostic capability.

PurposeThis investigation leveraged the SEER database to delve into the progression patterns of PTC when left untreated. Furthermore, it aimed to devise and authenticate a nomogram for prognosis prediction for such patients.MethodsWe extracted data from the SEER database, focusing on PTC-diagnosed individuals from 2004-2020. To discern disease progression intervals, median survival times across stages were gauged, and the disease progression time was estimated by subtracting the median survival time of a more severe stage from its preceding stage. Prognostic determinants in the training set were pinpointed using both univariate and multivariate Cox regression. Using these determinants, a prognostic nomogram was crafted.ResultsIn untreated PTC patients, those in stages I and II had a favorable prognosis, with ten-year overall survival rates of 86.34% and 66.03%, respectively. Patients in stages III and IV had a relatively poorer prognosis. The median survival time of stage III, stage IVA, stage IVB and stage IVC patients was 108months, 43 months, 20 months and 8 months, respectively. The deduced progression intervals from stages III-IVC were 65, 23, and 12 months. In the training set, age, tumor stage, gender, and marital status were identified as independent risk factors influencing the prognosis of untreated PTC, and a nomogram was constructed using these variables.ConclusionIn the absence of treatment intervention, early-stage PTC progressed slowly with an overall favorable prognosis. However, in mid to advanced-stage PTC, as tumor stage increased, disease progression accelerated, and prognosis gradually worsened. Age, tumor stage, marital status, and gender were independent risk factors influencing the prognosis of untreated PTC, and the nomogram based on these factors demonstrated good prognostic capability.

Patterns in the Reporting of Aggressive Histologic Subtypes in Papillary Thyroid Cancer.

INTRODUCTION: The tall cell, columnar, and diffuse sclerosing subtypes are aggressive histologic subtypes of papillary thyroid cancer (PTC) with increasing incidence, yet there is a wide variation in reporting. We aimed to identify and compare factors associated with the reporting of these aggressive subtypes (aPTC) to classic PTC (cPTC) and secondarily identify differences in outcomes. METHODS: The National Cancer Database was utilized to identify cPTC and aPTC from 2004 to 2017. Patient and facility demographics and clinicopathologic variables were analyzed. Independent predictors of aPTC reporting were identified and a survival analysis was performed. RESULTS: The majority of aPTC (67%) were reported by academic facilities. Compared to academic facilities, all other facility types were 1.4-2.0 times less likely to report aPTC (P < 0.05). Regional variation in reporting was noted, with more cases reported in the Middle Atlantic, despite there being more total facilities in the South Atlantic and East North Central regions. Compared to the Middle Atlantic, all other regions were 1.4-5 times less likely to report aPTC (P < 0.001). Patient characteristics including race and income were not associated with aPTC reporting. Compared to cPTC, aPTC had higher rates of aggressive features and worse 5-y overall survival (90.5% versus 94.5%, log rank P < 0.001). CONCLUSIONS: Aggressive subtypes of PTC are associated with worse outcomes. Academic and other facilities in the Middle Atlantic were more likely to report aPTC. This suggests the need for further evaluation of environmental or geographic factors versus a need for increased awareness and more accurate diagnosis of these subtypes.

Young and resilient: Unraveling papillary thyroid cancer outcomes in males under 40.

BACKGROUND: While males present with more adverse clinicopathologic features in papillary thyroid carcinoma (PTC), younger age has previously been shown to be a favorable prognostic factor. We examined the combined effect of male sex and young age on PTC outcomes. METHODS: We conducted a retrospective analysis of a prospectively maintained database of thyroid cancer surgery patients (2000-2020) at a single quaternary care institution. We included papillary thyroid carcinoma cases and excluded those with prior cancer-related thyroid surgery. We examined demographics, cancer stage, surgical outcomes, and complications by age and sex, analyzing groups below and above the age of 40 years. RESULTS: A total of 680 patients with PTC were included. Females constituted 68% (age ≥40 years: 44% and <40 years: 24%) and males 32% (≥40 years: 24% and <40 years: 8%). A significant difference (p < 0.001) of N1 disease distribution was found between the groups. N1a metastasis was greater in patients younger than 40 regardless of sex ((M < 40 (15%), F < 40 (15%), M ≥ 40 (12%), and F ≥ 40 (9%)). While, M < 40 had greater N1b metastasis (36%) than all other groups (M ≥ 40 (28%), F < 40 (22%), and F ≥ 40 (10%)). There was no significant difference in the distribution of T stages between groups. Groups showed no differences in 30-day outcomes, recurrence at 1 year, reoperation, mortality, nerve injury, or hypocalcemia. CONCLUSIONS: Young males with PTC face increased occurrence of nodal metastasis yet experience similar recurrence rates as their female and older counterparts. Subgroup analysis underscores the predictive role of sex and age in advanced PTC cases.

Radioactive iodine does not improve overall survival for patients with aggressive variants of papillary thyroid carcinoma less than 2 cm.

BACKGROUND: Tall cell and diffuse sclerosing variants of papillary thyroid cancer are associated with aggressive features. Radioactive iodine after total thyroidectomy is poorly studied. METHODS: Patients ≥18 years in the National Cancer Data Base from 2004 to 2016 with classic papillary thyroid cancer, tall cell, or diffuse sclerosing 1 mm to 40 mm were identified. Logistic regression identified factors associated with aggressive features. Overall survival was assessed using Kaplan-Meier method and log-rank tests, after propensity score matching for clinicopathological and treatment variables. RESULTS: A total of 155,940 classic papillary thyroid cancer patients, 4,011 tall cell, and 507 diffuse sclerosing were identified. Tall cell patients represented an increasing proportion of the study population during the analysis period, whereas diffuse sclerosing and classic papillary thyroid cancer patients showed a statistically significant decline. Extrathyroidal extension and nodal involvement were more prevalent among tall cell and diffuse sclerosing patients when compared to those diagnosed with classic papillary thyroid cancer (P < .01). Adjuvant radioactive iodine was less frequently used in patients with classic papillary thyroid cancer when compared to tall cell and diffuse sclerosing patients (42.6% vs 62.4%, 59.0%; P < .001, respectively). Aggressive variants receiving total thyroidectomy versus total thyroidectomy + radioactive iodine propensity score matched across clinicopathologic variables were analyzed. There was no difference in overall survival between the 2 treatment groups for tumors <2 cm (01-1.0 cm, 92.2% vs 84.8%; P = .98); (1.0-2.0 cm, 72.7% vs 88.1%; P = .82). However, overall survival was improved for total thyroidectomy + radioactive iodine propensity score matched patients with tumor sizes 21 to 40 mm versus total thyroidectomy (83.4% vs 70.0%, P = .004). CONCLUSION: For aggressive tumor variants ≤2 cm treated with total thyroidectomy, there is no overall survival advantage provided by the addition of adjuvant radioactive iodine.

Thyroid lobectomy as a cost-effective approach in low-risk papillary thyroid cancer versus active surveillance.

BACKGROUND: An ongoing debate exists over the optimal management of low-risk papillary thyroid cancer. The American Thyroid Association supports the concept of active surveillance to manage low-risk papillary thyroid cancer; however, the cost-effectiveness of active surveillance has not yet been established. We sought to perform a cost-effectiveness analysis comparing active surveillance versus surgical intervention for patients in the United States. METHODS: A Markov decision tree model was developed to compare active surveillance and thyroid lobectomy. Our reference case is a 40-year-old female who was diagnosed with unifocal (<15 mm), low-risk papillary thyroid cancer. Probabilistic outcomes, costs, and health utilities were determined using an extensive literature review. The willingness-to-pay threshold was set at $50,000/quality-adjusted life year gained. Sensitivity analyses were performed to account for uncertainty in the model's variables. RESULTS: Lobectomy provided a final effectiveness of 21.7/quality-adjusted life years, compared with 17.3/quality-adjusted life years for active surveillance. Furthermore, incremental cost effectiveness ratio for lobectomy versus active surveillance was $19,560/quality-adjusted life year (

Overall survival is improved with total thyroidectomy and radiation for male patients and patients older than 55 with T2N0M0 Stage 1 classic papillary thyroid cancer.

BACKGROUND: We examine whether surgery extent and radiation administration affect overall survival for cT2N0M0 classic papillary thyroid cancer according to age and sex. METHODS: Patients with cT2N0M0 classic papillary thyroid cancer tumors in the National Cancer Data Base (2004-2016) were selected. Multivariable Cox regression analysis compared patients (combined male + female cohorts) having lobectomy to those having total thyroidectomy with or without radiation (primarily radioactive iodine) for ages: 18 to 45, 46 to 55, and >55 years. In addition, 1:1 propensity score matching and Kaplan-Meier curves with 10-year overall survival estimates, and log-rank test were stratified by age and sex. RESULTS: Lobectomy had equivalent overall survival to total thyroidectomy without and with radiation for patients (combined male + female cohorts) aged 18 to 45 and 46 to 55 years on multivariable analysis. On propensity score matching there was overall survival advantage for total thyroidectomy with radiation over both lobectomy and total thyroidectomy for men (ages 18-90+ combined) and overall survival advantage in patients (combined male + female cohort) aged >55 years having total thyroidectomy with radiation versus lobectomy. On propensity score matching there were no overall survival differences in women (ages 18-90+ combined) or patients (combined male + female cohort) aged 18 to 45 and 46 to 55 years having either lobectomy, total thyroidectomy, or total thyroidectomy with radiation. CONCLUSION: For cT2N0M0 classic papillary thyroid cancer, total thyroidectomy with radiation improves 10-year overall survival for patients (combined male + female cohort) aged >55 years and men (ages 18-90+ combined).

Expression of cancer stem cell markers in tall cell variant papillary thyroid cancer identifies a molecular profile predictive of recurrence in classic papillary thyroid cancer.

BACKGROUND: Tall cell variant of papillary thyroid carcinoma is an aggressive subtype of papillary thyroid carcinoma. We examined expression of cancer stem cell markers in tall cell variant compared with other well-differentiated thyroid cancers. METHODS: Expression of cancer stem cell markers was examined in 572 thyroid tumors from The Cancer Genome Atlas Thyroid Cancer database and tall cell variant and papillary thyroid carcinoma tumors by immunohistochemistry. RESULTS: Expression of the PROM1 gene, encoding the cancer stem cell marker CD133, was elevated in tall cell variant compared to classic papillary thyroid carcinoma in a large cohort of unmatched samples from The Cancer Genome Atlas Thyroid Cancer database (P < .001). By immunohistochemistry in age and stage matched samples, CD133 protein was confirmed to be significantly increased in tall cell variant versus classic papillary thyroid carcinoma (P = .006). Analyzing all thyroid cancers, high PROM1 expression was associated with worse disease-specific survival. Optimal cutoffs were determined to define a tall cell variant-like cancer stem cell signature characterized by high PROM1, high ALDH1A3, and low CD24 expression. Classic papillary thyroid carcinoma with a tall cell variant-like gene signature had worse recurrence disease-free survival compared to classic papillary thyroid carcinoma with a non-tall cell variant signature (P = .02). CONCLUSION: Tall cell variant of papillary thyroid carcinoma has increased expression of cancer stem cell markers compared to classic papillary thyroid carcinoma. The tall cell variant-like cancer stem cell gene signature identified a molecular subtype of classic papillary thyroid carcinoma that has a worse recurrence-free survival.

A prospective randomized controlled trial to assess the efficacy and safety of prophylactic central compartment lymph node dissection in papillary thyroid carcinoma.

BACKGROUND: The efficacy of prophylactic central compartment lymph node dissection for papillary thyroid carcinoma remains controversial. We performed a randomized controlled trial to evaluate the efficacy and safety of prophylactic central compartment lymph node dissection in patients with papillary thyroid carcinoma. METHODS: In this parallel-group randomized controlled trial, we assessed 101 patients aged 20 to 70 years with small/noninvasive papillary thyroid carcinoma and no clinical metastases or history of cervical surgery/radiation exposure. Randomization ran from April 2015 to November 2017. Data were collected between April 2015 and October 2020. Of the 101 enrolled patients, 50 underwent total thyroidectomy (TTx group) and 51 underwent total thyroidectomy as well as prophylactic central compartment lymph node dissection (TTx+pCND group). Surgical completeness, local recurrence, successful ablation, postoperative complication, and papillary thyroid carcinoma upstaging were compared between the 2 groups. RESULTS: No patient showed structural recurrence after 46.6 ± 9.1 months of follow-up. Both groups had similar rates of surgical completeness and successful ablation. There was no difference in the incidence of complications. More patients were upstaged to pN1a in the TTx+pCND group compared to those in the TTx group (P < .05). CONCLUSIONS: Prophylactic central compartment lymph node dissection detected more lymph node metastases but did not affect recurrence. The 2 groups showed similar outcomes with regard to surgical completeness, successful ablation, and complications. In conclusion, for small/noninvasive papillary thyroid carcinoma without clinical evidence of lymph node metastases, prophylactic central compartment lymph node dissection may not be required if total thyroidectomy is planned.

Low expression of TFF3 in papillary thyroid carcinoma may correlate with poor prognosis but high immune cell infiltration.

Background: Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignancies and has a favorable prognosis. However, optimal treatments and prognostic markers have not been clearly identified. Methods: Gene expression data from primary PTC were downloaded from the Gene Expression Omnibus database and subjected to two analyses of differentially expressed genes (DEGs), followed by intersecting individual and integrated DEGs analyses as well as gene set enrichment analysis. Analysis of data from Sequence Read Archive and The Cancer Genome Atlas, immunohistochemistry and qRT-PCR of TFF3 were performed to validate the results. Finally, the relationship between gene expression and disease-free survival as well as immune cell infiltration were investigated. Results: Six critical DEGs and several tumor-enriched signaling pathways were identified. Immunohistochemistry and qRT-PCR validated the low expression of TFF3 in PTC. TFF3 and FCGBP are coexpressed in PTC, and patients with lower gene expression had worse disease-free survival but higher immune cell infiltration. Conclusion: TFF3 was significantly underexpressed and may function with FCGBP synergistically in PTC.

Lay abstract Thyroid cancers are some of the most common endocrine malignancies. However, the optimal treatments and prognostic markers have not been clearly identified. We identified six critical differentially expressed genes and several tumor-enriched signaling pathways in papillary thyroid carcinoma, and found that TFF3 was the most underexpressed gene, as validated by experiment. In addition, TFF3 and FCGBP worked synergistically and may mark prognosis and tumor immune cell infiltration, which may benefit patients with papillary thyroid carcinoma by providing early indication and prompting further basic investigation.

Extranodal Extension Is an Independent Prognostic Factor in Papillary Thyroid Cancer: A Propensity Score Matching Analysis.

Purpose: To investigate the prognostic significance of extranodal extension (ENE) in papillary thyroid cancer (PTC). Methods: Seven hundred forty-three PTC patients were enrolled in the study from January 2014 to December 2017. The patients were dichotomized according to the presence of ENE. Logistic analysis was used to compare differences between the two groups. Kaplan-Meier (K-M) curve and propensity score matching (PSM) analyses were used for recurrence-free survival (RFS) comparisons. Cox regression was performed to analyze the effects of ENE on RFS in PTC. Results: Thirty-four patients (4.58%) had ENE. Univariate analysis showed that age, tumor size, extrathyroidal extension, and nodal stage were associated with ENE. Further logistic regression analysis showed that age, extrathyroidal extension, and nodal stage remained statistically significant. Evaluation of K-M curves showed a statistically significant difference between the two groups before and after PSM. Cox regression showed that tumor size and ENE were independent risk factors for RFS. Conclusions: Age ≥55 years, extrathyroidal extension, and lateral cervical lymph node metastasis were identified as independent risk factors for ENE. ENE is an independent prognostic factor in PTC.

Comprehensive analysis of aberrant alternative splicing related to carcinogenesis and prognosis of papillary thyroid cancer.

As a key mechanism, alternative splicing (AS) plays a role in the cancer initiation and development. However, in papillary thyroid cancer (PTC), data for the comprehensive AS event profile and its clinical implications are lacking. Herein, a genome-wide AS event profiling using RNA-Seq data and its correlation with matched clinical information was performed using a 389 PTC patient cohort from the project of The Cancer Genome Atlas (TCGA). We identified 1,925 cancer-associated AS events (CASEs) by comparing paired tumors and neighboring healthy tissues. Parent genes with CASEs remarkably enriched in the pathways were linked with carcinogenesis, such as P53, KRAS, IL6-JAK-STAT3, apoptosis, and MYC signaling. The regulatory networks of AS implied an obvious correlation between the expression of splicing factor and CASE. We identified eight CASEs as predictors for overall survival (OS) and disease-free survival (DFS). The established risk score model based on DFS-associated CASEs successfully predicted the prognosis of PTC patients. From the unsupervised clustering analysis results, it is found that different clusters based on AS correlated with prognosis, molecular features, and immune characteristics. Taken together, the comprehensive genome-wide AS landscape analysis in PTC showed new AS events linked with tumorigenesis and prognosis, which provide new insights for clinical monitoring and therapy for PTC.

Development and validation of a ferroptosis-related prognostic model for the prediction of progression-free survival and immune microenvironment in patients with papillary thyroid carcinoma.

BACKGROUND: Ferroptosis is an iron-dependent and regulated cell death that has been widely reported in a variety of malignancies. The overall survival of papillary thyroid cancer (PTC) is excellent, but the identification of patients with poor prognosis still faces challenges. Nevertheless, whether ferroptosis-related genes (FRGs) can be used to screen high-risk patients is not clear. METHODS: We obtained the clinical data of patients with PTC and FRGs from the UCSC Xena platform and the FerrDb respectively. Differentially expressed genes (DEGs) of FRGs were obtained from the entire The Cancer Genome Atlas (TCGA). Subsequently, the entire TCGA dataset was randomly split into two subsets: training and test datasets. Based on DEGs, we constructed a predictive model which was tested in the test dataset and the entire TCGA dataset to predict progression-free survival (PFS). Patients were categorized into high- or low-risk groups based on their median risk score. We analyzed differences in some aspects, including pathway enrichment analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), tumor microenvironment (TME), human leukocyte antigen (HLA) genes, and tumor mutation burden (TMB) analyses, between high-risk and low-risk groups. RESULTS: A predictive model with three FRGs (HSPA5, AURKA, and TSC22D3) was constructed. Patients in the high-risk group had worse PFS compared with patients in the low-risk group. Functional analysis results revealed that ssGSEA, immune cell infiltration, TME, HLA, and TMB were closely associated with ferroptosis. CONCLUSION: The prognostic model constructed in this study can effectively predict PFS for patients with PTC.

Downregulation of miR-519d-3p is Associated with Poor Outcomes and Facilitates Tumor Progression in Papillary Thyroid Cancer by Regulating FOXQ1.

MicroRNA-519d-3p (miR-519d-3p) has emerged as a tumor suppressor in several human cancers. But whether miR-519d-3p is involved in papillary thyroid cancer (PTC) remains elusive. In this study, we investigated the potential relevance of miR-miR-519d-3p in PTC. A retrospective study of 119 PTCs was carried out. The RT-qPCR analysis was used to measure the expression of miR-519d-3p and FOXQ1 in PTC tissues and cells. Chi-square test, Kaplan-Meier curve analysis, and multivariate Cox regression analyses were performed to assess the clinical and prognostic value of miR-519d-3p in PTC. Then cellular experiments were used to explore its biological effects on PTC cells. Finally, the Pearson correlation coefficient, dual-luciferase reporter assay, and rescue experiments were used to analyze the association between miR-519d-3p and FOXQ1. miR-519d-3p was significantly downregulated in PTC tissues and cell lines. The decreased expression of miR-519d-3p was associated with reduced overall survival and progression-free survival of patients. The proliferative, migratory, and invasive abilities of cells were blocked or elevated after upregulation or downregulation of miR-519d-3p, while FOXQ1 reversed these cellular behaviors caused after upregulation or knockdown of miR-519d-3p. In conclusion, miR-519d-3p was downregulated in PTC and associated with OS and PFS of patients. MiR-519d-3p may be a tumor-inhibiting miRNA in PTC, and that miR-519d-3p/FOXQ1 axis mediated PTC tumor progression from cell proliferation, migration, and invasion in PTC cells.

A Metabolic-associated Nomogram Predicts Recurrence Survival of Thyroid Cancer.

OBJECTIVE: Various studies have suggested that metabolic genes play a significant role in papillary thyroid cancer (PTC). The current study aimed to identify a metabolic signature related biomarker to predict the prognosis of patients with PTC. METHODS: We conducted a comprehensive analysis on the data obtained from the Cancer Genome Atlas (TCGA) database. The correlation between survival result and metabolic genes was evaluated based on the univariate Cox analyses, least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses. The performance of a 7-gene signature was assessed according to Kaplan-Meier and receiver operating characteristic (ROC) analysis. Multivariate Cox regression analysis was adopted to unearth clinical factors related to the recurrence free survival (RFS) of patients with PTC. Finally, a prognostic nomogram was developed based on risk score, cancer status and cancer width to improve the prediction for RFS of PTC patients. RESULTS: Seven metabolic genes were used to establish the prognostic model. The ROC curve and C-index exhibited high value in training, testing and the whole TCGA datasets. The established nomogram, incorporating the 7-metabolic gene signature and clinical factors, was able to predict the RFS with high effectiveness. The 7-metabolic gene signature-based nomogram had a good performance to predict the RFS of patients with PTC. CONCLUSION: Our study identified a 7-metabolic gene signature and established a prognostic nomogram, which were useful in predicting the RFS of PTC.

Association of Multifocality With Prognosis of Papillary Thyroid Carcinoma: A Systematic Review and Meta-analysis.

Importance: Multifocality is common in papillary thyroid carcinoma (PTC), but it is unclear whether multifocal tumors are associated with tumor recurrence or cancer-specific survival. Objective: To compare tumor recurrence rates in patients with multifocal vs unifocal PTCs. Data Sources: We searched PubMed, SCOPUS, Web of Science Core Collection, and Cochrane Database of Systematic Reviews for pertinent studies published in English from inception to June 30, 2020. Study Selection: The search strategy yielded 26 studies that compared tumor recurrence in patients with multifocal vs unifocal PTC. Data Extraction and Synthesis: Data was extracted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Characteristics of study populations and hazard ratio (HR) of multifocality were independently extracted by 2 investigators. Main Outcomes and Measures: The primary outcome was tumor recurrence and the secondary outcome was cancer-specific survival. Subgroup analysis of the primary outcome was based on primary tumor size, number of tumor foci, and patient age. Results: Among 26 studies with a total of 33 976 patients, recurrence rates were significantly higher in patients with multifocal PTC than in those with unifocal PTC (pooled HR, 1.81; 95% CI, 1.52-2.14). Cancer-specific survival was comparable between the groups (HR, 1.19; 95% CI, 0.85-1.68). In subgroup analyses, the HRs of multifocality for recurrence were associated with primary tumor size (HRs for PTC ≤1 cm and >1 cm were 1.81 and 1.90, respectively), number of tumor foci (HRs for 2 foci and ≥3 foci were 1.45 and 1.95, respectively), and patient age (HRs for pediatric and adult patients were 3.19 and 1.89, respectively). Conclusions and Relevance: This systematic review with meta-analysis found that multifocality was significantly associated with an increased risk of recurrence in patients with PTC, while cancer-specific survival showed no difference. Differences in tumor size, number of tumor foci, and patient age should be considered when interpreting the multifocality and the risk of recurrence.

Ferroptosis-related gene model to predict overall survival of papillary thyroid carcinoma.

BACKGROUND: Ferroptosis is a form of programmed cell death that is closely associated with the development of various tumors. However, the correlation between ferroptosis and papillary thyroid carcinoma (PTC) is unclear. This study was performed to investigate the expression and prognostic value of ferroptosis-related genes (FRG) in PTC. METHODS: mRNA expression profiles and corresponding clinical data of patients with PTC were analyzed to identify factors affecting prognosis. Independent risk factors were used to establish a predictive receiver operating characteristic model. Single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the correlation between ferroptosis and immune cells. RESULTS: Most genes related to FRG (78.8%) were differentially expressed between the tumor and adjacent normal tissues. In univariate Cox regression analysis, 12 differentially expressed genes were associated with prognostic survival. We constructed a prognostic model of eight FRG, including DPP4, GPX4, GSS, ISCU, MIOX, PGD, TF, and TFRC, and divided patients into two groups: high and low risk. The high-risk group exhibited a significantly reduced overall survival rate. In multivariate Cox regression analysis, the risk score was used as an independent prognostic factor. ssGSEA showed that immune cell types and their expression in the high- and low-risk groups were significant. CONCLUSION: This study constructed a prognostic model of ferroptosis-related genes and determined its usefulness as an independent prognostic factor, providing a reference for the treatment and prognosis of patients with PTC.

Development and validation of a nomogram based on stromal score to predict progression-free survival of patients with papillary thyroid carcinoma.

BACKGROUND: Growing evidence has proved that stromal cells, as the critical component of tumor microenvironment (TME), are closely associated with tumor's progression. However, the model based on stromal score to predict progression-free survival (PFS) in papillary thyroid carcinoma (PTC) has not been developed. The study aimed at exploring the relation between stromal score and prognosis, then establishing a nomogram to predict PFS of patients with PTC. METHOD: We obtained the stromal score and clinicopathological characteristics of PTC patients from The Cancer Genome Atlas (TCGA) database. Cox regression analysis assisted in selecting prognosis-related factors. A stromal score-based nomogram was built and verified in the training and validation cohorts, respectively. The calibration curve, concordance index (C-index), decision curve analysis (DCA) as well as receiver operating characteristic (ROC) curve assisted in measuring the performance exhibited by the nomogram. RESULTS: We divided 381 PTC patients into the training cohort (n = 269) and the validation cohort (n = 112) randomly. Compared with patients who had a low stromal score, patients with a high stromal score appeared with significantly better PFS [Hazard ratio (HR) and 95% confidence interval (CI): 0.294, 0.130-0.664]. The C-index of the PFS nomogram was 0.764 (0.662-0.866) in the training cohort and 0.717 (0.603-0.831) in the validation cohort. The calibration curves for PFS prediction in the nomogram were remarkably consistent with the actual observation. DCA indicated superior performance of the nomogram to predict PFS than the American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) staging system. The ROC curves showed the favorable sensitivity and specificity of the novel nomogram. CONCLUSION: High stromal score was significantly associated with improved PFS in patients with PTC. The nomogram based on the stromal score and clinicopathological patterns yielded a reliable performance to predict the prognosis of PTC.

BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer.

CONTEXT: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. OBJECTIVE: To study whether BRAF V600E affected LNM-associated mortality in PTC. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. RESULTS: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. CONCLUSIONS: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.

OGT regulated O-GlcNAcylation promotes papillary thyroid cancer malignancy via activating YAP.

The incidence of thyroid cancer is growing rapidly during the past decades worldwide. Although most thyroid tumors are curable, some patients diagnosed with distant metastases are associated with poor prognosis. The molecular mechanisms underlying these cases are still largely unknown. Here we found that the upregulated O-Linked N-Acetylglucosamine Transferase (OGT) expression and O-GlcNAcylation (O-GlcNAc) modification in papillary thyroid cancer (PTC) were essential in tumor growth and metastasis. Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation. Our work clearly showed the critical role of OGT and YAP played in PTC tumors and made it possible for us to seek the clinical potential of manipulating OGT/YAP activity in PTC targeted therapies. These findings also confirmed OGT worked in collaboration with classical Hippo pathway kinases as an upstream regulator of YAP in PTC tumors.