Enhanced stiffness in peri-cancerous tissue: a marker of poor prognosis in papillary thyroid carcinoma with lymph node metastasis.

BACKGROUND: The prognostic significance of lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) remains controversial. Notably, there is evidence suggesting an association between tissue stiffness and the aggressiveness of the disease. We therefore aimed to explore the effect of tissue stiffness on LNM-related invasiveness in PTC patients. METHOD: A total of 2492 PTC patients from 3 hospitals were divided into an LNM group and a non-LNM group based on their pathological results. The effects of interior lesion stiffness (E) and peri-cancerous tissue stiffness (Eshell) on the LNM-related recurrence rate and mortality in each patient with PTC subgroup were analyzed. The activation of cancer-associated fibroblasts (CAFs) and extracellular matrix component type 1 collagen (COL-I) in the lesion were compared and analyzed across different subgroups. The underlying biological basis of differences in each subgroup was identified using RNA sequencing (RNA-seq) data. RESULTS: The Eshell value and Eshell/E in the LNM group were significantly higher than those in the non-LNM group of patients with PTC (Eshell: 72.72 ±â€…5.63 vs 66.05 ±â€…4.46; Eshell/E: 1.20 ±â€…1.72 vs 1.09 ±â€…1.10, P < .001). When Eshell/E > 1.412 and LNM were both present, the recurrence rate and mortality were significantly increased compared to those of group of patients with LNM (91.67% and 7.29%, respectively). The CAF activation and COL-I content in the Eshell/E+ group were significantly higher than those in the Eshell/E- group (all P < .001), and the RNA-seq results revealed significant extracellular matrix (ECM) remodeling in the LNM-Eshell/E+ group. CONCLUSIONS: Stiff peri-cancerous tissue induced CAF activation, COL-I deposition, and ECM remodeling, resulting in a poor prognosis for PTC patients with LNM.

Trends in papillary thyroid cancer mortality in Denmark according to stage and education.

OBJECTIVE: Few studies exist on trends in papillary thyroid cancer (PTC) survival and mortality according to stage and level of socioeconomic status. DESIGN: Nationwide cohort study. PATIENTS AND MEASUREMENTS: Patients diagnosed with PTC during 2000-2015 in Denmark were identified from the Danish Cancer Registry and followed until the end of 2020. We evaluated 5-year all-cause mortality and relative survival according to stage and 5-year mortality rates with corresponding average annual percentage changes (AAPCs) according to stage and education. Finally, we assessed the association between several factors and mortality of PTC using Cox regression. RESULTS: For the 2006 cases of PTC diagnosed during 2000-2015, relative survival tended to increase and mortality rates tended to decrease for all stages. For localized PTC, mortality rates tended to decrease among individuals with medium education (AAPC = -7.0, 95% confidence interval [CI]: -14.7 to 1.5), but showed an increasing pattern among individuals with long education (AAPC = 19.8, 95% CI: -4.2 to 50.0). For nonlocalized PTC, mortality rates showed a decreasing tendency among individuals with medium and long education (AAPC = -5.5, 95% CI: -13.2 to 2.9, and AAPC = -10.4, 95% CI: -20.8 to 1.4, respectively). Being diagnosed with PTC in a more recent calendar period and long education were associated with a lower mortality rate in the Cox regression analysis. CONCLUSIONS: A pattern of an increasing relative survival and decreasing mortality rates of PTC across all stages was seen in Denmark during 2000-2015. The decreasing pattern in mortality rates was most evident in individuals with localized stage and medium education, and in individuals with nonlocalized stage and medium or long education.

Prognostic nutritional index predicts lateral lymph node metastasis and recurrence free survival in papillary thyroid carcinoma.

BACKGROUND: Preoperative hematological parameters are predictors of pathological features and recurrence-free survival (RFS) in various malignancies. However, comprehensive studies of preoperative indicators associated with papillary thyroid carcinoma (PTC) are scarce. The present study investigated the association between preoperative indicators and RFS in patients with PTC. Accordingly, we explored the clinical impact of the prognostic nutritional index (PNI) on lymph node metastasis and RFS in patients with PTC. METHODS: A total of 619 PTC patients were retrospectively reviewed between Jan 2013 and Dec 2017. Laboratory values were measured and calculated. Receiver operating characteristic curves were generated to calculate the cutoff value. Univariate and multivariate analyses using the COX proportional hazard model were performed for RFS. The effects of PNI and age on RFS were investigated by the Kaplan-Meier method. Clinical characteristics and PNI were tested with the chi-square test. Univariate and multivariate logistic analyses were conducted to evaluate the predictive value of PNI for lymph node metastasis. RESULTS: In the multivariate Cox analysis, age, PNI and lymph node metastasis were independent prognostic indicators for RFS. The Kaplan-Meier method showed that the lower PNI group and age older than 55 years group displayed poor RFS. A low preoperative PNI was remarkably correlated with age, sex, extrathyroidal invasion, T stage, N stage and TNM stage. PNI was the only preoperative hematological indicator for lateral lymph node metastasis. CONCLUSIONS: Among the preoperative hematological indicators, PNI may serve as a promising and effective predictor for RFS and lateral lymph node metastasis in PTC patients.

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.

Clinical, Pathological, and Immunohistochemical Predictors of Cause-Specific Mortality in Papillary Thyroid Cancer: Multivariate Analysis.

The association of clinical, pathological, and immunohistochemical characteristics of papillary thyroid cancer with cause-specific mortality was analyzed in a case-control study within a cohort of patients from the Altai Regional Oncology Center. According to multivariate analysis, the independent predictors of fatal outcome within 10 years after surgery in patients living in Altai region are nuclear pattern of Hsp70 expression, thyroid capsular invasion, Ki-67 expression index >7%, and patient's age >45 years for men and >50 years for women. The prognostic model based on these features contributes to a significant improvement in the individual prognostic performance for papillary thyroid cancer in the modeling sample. The model has high statistical significance (χ2=64.73; p<0.001) and discriminative power (AUC=0.950, prediction accuracy 88.5%).

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.

Does Aggressive Variant Histology Without Invasive Features Predict Overall Survival in Papillary Thyroid Cancer?: A National Cancer Database Analysis.

OBJECTIVE: We aimed to clarify whether aggressive histology of papillary thyroid cancer (PTC) impacts overall survival (OS). SUMMARY BACKGROUND DATA: Aggressive variants of PTC (AVPTC) are associated with invasive features. However, their behavior in the absence of these features is not well characterized. METHODS: Patients treated from 2004 to 2015 for classic PTC (cPTC) or AVPTCs were identified from the National Cancer Database. Patients were further stratified based on presence of at least 1 invasive feature-extrathyroidal extension, multifocality, lymphovascular invasion, nodal or distant metastasis. Demographics, treatments, and OS were compared. RESULTS: A total of 170,778 patients were included-162,827 cPTC and 7951 AVPTC. Invasive features were more prevalent in AVPTC lesions compared to cPTC (70.7% vs 59.7%, P < 0.001). AVPTC included tall cell/columnar cell (89.5%) and diffuse sclerosing (10.5%) variants. Patients with invasive features had worse OS irrespective of histology. Furthermore, when controlling for demographics, tumor size, and treatment variables in patients with noninvasive lesions, AVPTC histology alone was not associated with worse OS compared to cPTC (P = 0.209). In contrast, among patients who had at least 1 invasive feature, AVPTC histology was independently predictive of worse OS (P < 0.05) {TCV/Columnar hazard ratio [HR] 1.2; [95% confidence interval (CI) 1.1-1.3] and diffuse sclerosing HR 1.3; 95% CI 1.0-1.7]}. All invasive features, except multifocality, were independently associated with worse OS, with metastasis being the most predictive [HR 2.9 (95% CI 2.6-3.2) P < 0.001]. CONCLUSIONS: In the absence of invasive features, AVPTC histology has similar OS compared to cPTC. In contrast, diffuse sclerosing and tall cell/columnar variants are associated with worse OS when invasive features are present.

MKL1 overexpression predicts poor prognosis in patients with papillary thyroid cancer and promotes nodal metastasis.

Papillary thyroid cancer (PTC), the most common thyroid malignancy, has a strong propensity for cervical lymph node metastasis (LNM), which increases the risk of locoregional recurrence and decreases survival probability in some high-risk groups. Hence, there is a pressing requirement for a reliable biomarker to predict LNM in thyroid cancer. In the present study, MKL1 (also known as MRTFA) expression was significantly increased in PTC patients with LNM compared with those without. Further receiver operating characteristic (ROC) analysis showed that MKL1 expression had a diagnostic value in the differentiation of LNM in PTC. Furthermore, Kaplan-Meier analysis revealed that high MKL1 expression was associated with significantly decreased survival in PTC. Additionally, our study indicated that MKL1 promoted the migration and invasion of PTC cells. MKL1 interacted with and recruited Smad3 to the promoter of MMP2 to activate MMP2 transcription upon treatment with TGF-ß. Moreover, there was significant correlation between expression of TGF-ß, MKL1 and MMP2 in our clinical cohort of specimens from individuals with PTC. Our results suggest that the detection of MKL1 expression could be used to predict cervical LNM and inform post-operative follow-up in individuals with PTC.

Long-term outcomes of lobectomy for papillary thyroid carcinoma with high-risk features.

BACKGROUND: Lobectomy is not advocated for papillary thyroid carcinoma (PTC) with high-risk features, although there is no high-level evidence showing that this is an inferior strategy. This study aimed to examine the association between the extent of surgery and survival of patients with PTC and high-risk features. METHODS: Consecutive patients with PTC and at least one high-risk feature treated in 2000-2012 were included in the study. High-risk features were defined as: primary tumour larger than 4 cm, gross extrathyroidal extension, macroscopic multifocality, and confirmed nodal metastasis including pathological lateral neck metastasis (pN1b) or more than five central lymph node metastases. Cox proportional hazards models were employed to measure the association between the extent of surgery and disease-specific survival (DSS) in the whole cohort and in a matched-pair analysis. RESULTS: Among a total of 2059 patients with high-risk features, 1224 underwent lobectomy and 835 had total thyroidectomy. Patients who underwent total thyroidectomy had significantly higher rates of bilateral cancer than those who had a lobectomy (79.4 versus 2.7 per cent respectively), macroscopic multifocality (80.8 versus 32.8 per cent) and bilateral neck metastasis (30.9 versus 3.3 per cent) (all P < 0.001). With a median follow-up of 93 months, multivariable analysis showed that the extent of surgery was not associated with DSS in the whole cohort (hazard ratio 1.36, 95 per cent c.i. 0.75 to 2.48; P = 0.310). After 1 : 1 case-control matching of 528 patients, no significant difference between lobectomy and total thyroidectomy groups was observed with respect to the 10-year DSS rate (94.3 versus 95.2 per cent respectively; P = 0.323) or 10-year recurrence-free survival rate (75.8 versus 79.2 per cent; P = 0.784). CONCLUSION: Lobectomy was not associated with significantly worse outcomes for patients with PTC and high-risk features.

Overexpression of miR-127 Predicts Poor Prognosis and Contributes to the Progression of Papillary Thyroid Cancer by Targeting REPIN1.

Papillary thyroid cancer (PTC) is a major kind of thyroid cancer with increasing recurrence and metastasis. MiR-127 has been demonstrated to play roles in many cancers with dysregulation. However, the function of miR-127 is still unknown. This study aimed to explore a novel biomarker for the progression and prognosis of PTC. A set of 118 patients with PTC were collected from the Affiliated Hospital of Qingdao University. qRT-PCR was used to detect the expression of miR-127 in PTC tissues and cells. The association between miR-127 expression and the clinicopathological features of patients were evaluated by the χ2 test, and the prognostic value of miR-127 was evaluated by Kaplan-Meier analysis and Cox regression analysis. The effect of miR-127 on cell proliferation, migration, and invasion of PTC was analyzed by CCK-8 and transwell assay. miR-127 was found to be upregulated in PTC tissues and cells correlated with the TNM stage and poor prognosis of PTC patients. MiR-127 and the TNM stage were considered as two independent prognostic indicators for PTC. Moreover, overexpression of miR-127 significantly enhanced cell proliferation, migration, and invasion of PTC by targeting REPIN1. miR-127 may be involved in the progression of PTC, which provides a new therapeutic strategy for 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.

ALDH5A1 acts as a tumour promoter and has a prognostic impact in papillary thyroid carcinoma.

Thyroid cancer is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for 80%-90% of thyroid cancers. Accumulating studies reported that mitochondria plays an important role in the regulation of cell proliferation. ALDH5A1, may function as an oncogene or tumour suppressor in various human cancers, and the role of ALDH5A1 in PTC is still unclear. The aim of this study was to investigate the clinical significance of ALDH5A1 expression and its functions in PTC. In this present study, we studied ALDH5A1 expression on primary papillary thyroid carcinoma (PTC) in The Cancer Genome Atlas (TCGA) database. Results showed that the levels of ALDH5A1 were found positively correlated with tumour stage, metastasis, lymph node stage, and higher levels of ALDH5A1 demonstrated poor disease-free survival (DFS). Immunohistochemistry (IHC) revealed that significantly higher expression of ALDH5A1 was found in PTC tissues. On the other hand, knockdown of ALDH5A1 significantly inhibited PTC cell proliferation, migration and invasion detection found the migration and invasion of cells also were hindered when ALDH5A1 level was reduced. The knockdown of ALDH5A1 inhibited the expression of Vimentin and promoted the expression of E-cadherin. In brief, knockdown of ALDH5A1may act as a novel molecular target for the prevention and treatment of PTC. SIGNIFICANCE OF THE STUDY: The present study focused on the role and the potential mechanism of ALDH5A1 in papillary thyroid carcinoma. We demonstrated that reduced expression of ALDH5A1 might inhibit the progression of TC by inhibiting cell proliferation, migration and invasion and reversing epithelial-mesenchymal transition (EMT). The findings ensured the interaction relation between ALDH5A1 and EMT in PTC, providing a novel biological marker for PTC and enriching the potential strategies for TC treatment.

Higher circular RNA_0015278 correlates with absence of extrathyroidal invasion, lower pathological tumor stages, and prolonged disease-free survival in papillary thyroid carcinoma patients.

BACKGROUND: Circular RNA_0015278 (circ_0015278) inhibits the progression of several cancers and is greatly reduced in papillary thyroid carcinoma (PTC) tissues compared with benign thyroid lesions by microarray profiling. This study aimed to further investigate the correlation of circ_0015278 with tumor characteristics and prognosis in PTC patients. METHODS: Totally, 206 PTC patients who underwent tumor resection were retrospectively enrolled; subsequently, circ_0015278 expression in their tumor and adjacent tissues was detected by reverse transcriptional-quantitative polymerase chain reaction. Besides, disease-free survival (DFS) and overall survival (OS) were calculated. RESULTS: Circ_0015278 was reduced in tumor tissues compared with adjacent tissues (p < 0.001), and receiver operating characteristic analysis showed that it well discriminated tumor tissues from adjacent tissues (area under curve: 0.903, 95% confidence interval: 0.874-0.932). Besides, higher tumor circ_0015278 expression was correlated with absence of extrathyroidal invasion (p = 0.036), lower pathological tumor (pT) stage (p = 0.05), pathological node (pN) stage (p = 0.002), and pathological tumor-node-metastasis (pTNM) stage (p = 0.001). Moreover, higher tumor circ_0015278 expression was associated with a reduced relapse rate (p = 0.011), but not mortality rate (p = 0.110); meanwhile, it was also correlated with prolonged DFS (p = 0.017), but not OS (p = 0.136). Additionally, multivariate Cox's regression analyses showed that higher tumor circ_0015278 expression independently associated with favorable DFS (p = 0.026, hazard ratio = 0.529). CONCLUSION: Circ_0015278 is reduced in tumor tissues, while its' higher expression in tumor correlates with absence of extrathyroidal invasion, lower pT, pN, and pTNM stage, as well as prolonged DFS in PTC patients.

Identifying the tumor-progressive gene expression profile in high-risk papillary thyroid cancer.

PURPOSE: Papillary thyroid cancer (PTC) is generally associated with a favorable prognosis. However, some patients have fatal disease, with locally infiltrating tumors or progressive distant metastases; yet few studies have investigated the characteristics of the tumor-progressive gene expression profile in advanced PTC. We conducted this study to clarify the gene expression status in advanced PTC and identify candidate molecules for prognostic biomarkers. METHODS: We analyzed 740 tumor-progressive gene expression levels from formalin-fixed paraffin-embedded blocks of samples from six patients with low-risk PTC and six patients with high-risk PTC, using the nCounter PanCancer Progression panel. Then, we investigated the association between the expression levels of focused genes and pathological factors in PTC patients in The Cancer Genome Atlas (TCGA) database. RESULTS: The expression levels of 14 genes in the high-risk PTC specimens were more than two-fold those in the low-risk PTC specimens. In the TCGA database, expression levels of four genes (CCL11, COL6A3, INHBA, and SRPX2) were significantly higher in patients with advanced PTC. Among the patients with advanced PTC, those with high SRPX2 expression levels had poor disease-free survival. Univariate and multivariate analyses revealed that high SRPX2 expression was an independent prognostic factor. CONCLUSION: Based on the findings of this study, CCL11, COL6A3, INHBA, and SRPX2 are potential biomarkers that indicate advanced PTC. SRPX2, in particular, is considered a prognostic biomarker.

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.

Solid variant of papillary thyroid carcinoma: An analysis of 28 cases with current literature.

INTRODUCTION: Solid variant papillary thyroid cancer (SVPTC) is a rare variant of papillary thyroid carcinoma (PTC) and its prognostic value is still unclear. Therefore, we re-evaluate the histopathological and clinicopathological features of 28 patients with SVPTC in the light of current literature. MATERIAL-METHODS: Of the 1308 cases were previously diagnosed with PTC and 28 (2,1%) of them which had been diagnosed with SVPTC were re-evaluated retrospectively. RESULTS: Of the 28 patients with SVPTC, 85.7% were female, mean age was 45.18 years and mean tumor diameter was 2.96 cm. Microscopically; tumors had a solid growth pattern amounting to at least 50.0% of the tumor volume. In all cases the tumor cells had characteristic nuclear features of conventional PTC. 11 patients had multifocal tumors, extrathyroidal extension was present in 4 patients and vascular invasion was observed in 7 cases. Regional lymph node metastases were noted in 2 (7.1%) cases at the time of diagnosis. One patient died because of locally advanced disease. Another patient is alive with lung metastases after 48 months from the initial surgery. There was no evidence of local recurrence in other patient. CONCLUSIONS: SVPTC is a rare variant of PTC that should be considered in the differential diagnosis of tumors which show a solid/trabecular growth pattern in the thyroid. It has poor prognostic features such as widespread angioinvasion, extrathyroidal extention, lymph node metastasis, and distant organ metastasis. Multicenter studies involving large number of cases are needed to reveal the prognostic significance of SVPTC, with standardized diagnostic criteria.

Immortalization up-regulated protein promotes tumorigenesis and inhibits apoptosis of papillary thyroid cancer.

The incidence of thyroid cancer is increasing in recent years worldwide, but the underlying mechanisms await further exploration. We utilized the bioinformatic analysis to discover that Immortalization up-regulated protein (IMUP) could be a potential oncogene in the papillary thyroid cancer (PTC). We verified this finding in several databases and locally validated cohorts. Clinicopathological features analyses showed that high expression of IMUP is positively related to malignant clinicopathological features in PTC. Braf-like PTC patients with higher IMUP expression had shorter disease-free survival. The biological function of IMUP in PTC cell lines (KTC-1 and TPC-1) was investigated using small interfering RNA. Our results showed that silencing IMUP suppresses proliferation, migration and invasion while inducing apoptosis in PTC cell lines. Changes of the expression of apoptosis-related molecules were identified by real-time quantitative polymerase chain reaction and Western blotting. We also found that YAP1 and TAZ, the critical effectors in the Hippo pathway, were down-regulated when the IMUP is silenced. Rescue experiments showed that overexpression of YAP1 reverses the tumour inhibitory effect caused by IMUP knockdown. Our study demonstrated that IMUP has an oncogenic function in PTC and might be a new target gene in the treatment of PTC.

Recurrence following hemithyroidectomy in patients with low- and intermediate-risk papillary thyroid carcinoma.

BACKGROUND: This study evaluated the incidence, patterns and risk factors for recurrence after hemithyroidectomy in patients with low- and intermediate-risk papillary thyroid carcinoma (PTC), and verified the predictive role of the risk staging systems in current use. METHODS: The clinicopathological characteristics and risk categories were analysed according to recurrence in patients who underwent hemithyroidectomy for low- and intermediate-risk conventional PTC, and were followed up for at least 24 months. Five risk staging systems were used to stratify risk: the 2015 American Thyroid Association (ATA) system; Age, Metastases, Extent and Size (AMES) system; Metastases, Age, Complete resection, Invasion and Size (MACIS) system; Grade, Age, Metastases, Extent and Size (GAMES) system; and the eighth AJCC system. RESULTS: The study included 561 patients; 93·9 per cent of the study population (527 of 561) had a papillary thyroid microcarcinoma 1 cm or smaller in size. At a mean follow-up of 83 months, 25 patients (4·5 per cent) had recurrence; among these patients, 23 (92%) presented with a remaining thyroid lobe. Multifocality was significantly associated with recurrence in univariable and multivariable analyses (adjusted hazard ratio 3·16, 95 per cent c.i. 1·25 to 7·98; P = 0·015). Disease-free survival (DFS) varied according to multifocality (P = 0·010). The five risk staging systems were not associated with recurrence, and their Harrell's C-index ranged from 0·500 to 0·531. DFS rates did not differ between the risk categories in each system. CONCLUSION: Although the recurrence rate after hemithyroidectomy in patients with low- and intermediate-risk PTC was low, meticulous follow-up focusing on the remaining thyroid lobe is needed for early detection and timely management of recurrence. The risk scoring systems in current use have no predictive role in these patients.

ANTECEDENTES: Este estudio evaluó la incidencia, patrones y factores de riesgo de recidiva tras hemitiroidectomía en pacientes con carcinoma papilar de tiroides (papillary thyroid carcinoma, PTC) de riesgo bajo e intermedio y verificó el papel predictivo de los sistemas de estadificación del riesgo utilizados en la actualidad (risk staging systems, RSSs). MÉTODOS: Se analizaron las características clinicopatológicas y las categorías de riesgo en base a la recidiva en 561 pacientes que fueron sometidos a hemitiroidectomía por PTC convencional de riesgo bajo e intermedio y seguidos durante ≥ 24 meses. Para estratificar el riesgo se utilizaron cinco RSSs, incluyendo el sistema de la American Thyroid Association (ATA) de 2015; la edad, las metástasis, la extensión y el tamaño del sistema AMES; las metástasis, la edad, la resección completa, la invasión y el tamaño del sistema GAMES; y la octava edición de la American Joint Committee on Cancer system (AJCC). RESULTADOS: La proporción de la población de estudio con microcarcinoma papilar de tiroides de tamaño ≤ 1 cm fue 93,9% (527/561). A los 83 meses de seguimiento, 25 pacientes (4,5%) presentaron recidiva y entre estos pacientes, 23 (92%) no habían sido sometidos a tiroidectomía total. La multifocalidad se asoció significativamente con la recidiva en los análisis univariado y multivariable con un cociente de riesgos instantáneos (hazard ratio, HR) ajustado de 3,163; i.c. del 95% 1,253-7,983; P = 0,015. La supervivencia libre de enfermedad (disease-free survival, DFS) varió según la multifocalidad (P = 0,010). Los cinco RSSs no se asociaron con la recidiva, y su índice C de Harrell fue 0,500-0,531. Las DFSs no fueron diferentes entre las categorías de riesgo de cada RSS. CONCLUSIÓN: La tasa de recidiva tras hemitiroidectomía en pacientes con PTC de riesgo bajo e intermedio fue baja. Sin embargo, es necesario efectuar un seguimiento meticuloso, centrándose en el lóbulo tiroideo restante, para la detección precoz y el tratamiento oportuno de la recidiva. Los RSSs que se utilizan en la actualidad no tienen valor predictivo en estos pacientes.