Feasibility of the enhanced neuromuscular blockade recovery protocol with selective use of sugammadex in thyroid surgery with intraoperative neuromonitoring.

BACKGROUND: To investigate feasibility of utilizing enhanced neuromuscular blocking agents with selective recovery protocol during thyroid surgery with intraoperative neuromonitoring (IONM). METHODS: Two-hundred and ninety patients were randomized into two groups: group A 0.3 mg/kg rocuronium and group B 0.6 mg/kg. Sugammadex 2 mg/kg was injected if needed followed initial vagal stimulation (V0). Electromyography signals from vagus and recurrent laryngeal nerves before and after resection were recorded as V1, V2, R1, and R2. RESULTS: In group B, 30 patients (20.7%) had V0 signals <100 µV, compared to 9 (6.2%) in group A. After sugammadex administration, 144 patients (99.3%) in both groups achieved positive V1 signals. Group B demonstrated a shorter surgical time from rocuronium injection to V2 stimulation compared to group A, accompanied by a significantly lower incidence of intraoperative body movement (0 vs. 16 patients). CONCLUSIONS: 0.6 mg/kg rocuronium with selective use 2 mg/kg sugammadex for IONM in thyroid surgery can meet both anesthesia and surgery demands.

Integrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks.

Although papillary thyroid cancer (PTC) has a good prognosis, its recurrence rate is high and remains a core concern in the clinic. Molecular factors contributing to different recurrence risks (RRs) remain poorly defined. Here, we perform an integrative proteogenomic and metabolomic characterization of 102 Chinese PTC patients with different RRs. Genomic profiling reveals that mutations in MUC16 and TERT promoter as well as multiple gene fusions like NCOA4-RET are enriched by the high RR. Integrative multi-omics analyses further describe the multi-dimensional characteristics of PTC, especially in metabolism pathways, and delineate dominated molecular patterns of different RRs. Moreover, the PTC patients are clustered into four subtypes (CS1: low RR and BRAF-like; CS2: high RR and metabolism type, worst prognosis; CS3: high RR and immune type, better prognosis; CS4: high RR and BRAF-like) based on the omics data. Notably, the subtypes display significant differences considering BRAF and TERT promoter mutations, metabolism and immune pathway profiles, epithelial cell compositions, and various clinical factors (especially RRs and prognosis) as well as druggable targets. This study can provide insights into the complex molecular characteristics of PTC recurrences and help promote early diagnosis and precision treatment of recurrent PTC.

Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

Integrated proteogenomic characterization of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy derived from parafollicular cells (C cells) of the thyroid. Here we presented a comprehensive multi-omics landscape of 102 MTCs through whole-exome sequencing, RNA sequencing, DNA methylation array, proteomic and phosphoproteomic profiling. Integrated analyses identified BRAF and NF1 as novel driver genes in addition to the well-characterized RET and RAS proto-oncogenes. Proteome-based stratification of MTCs revealed three molecularly heterogeneous subtypes named as: (1) Metabolic, (2) Basal and (3) Mesenchymal, which are distinct in genetic drivers, epigenetic modification profiles, clinicopathologic factors and clinical outcomes. Furthermore, we explored putative therapeutic targets of each proteomic subtype, and found that two tenascin family members TNC/TNXB might serve as potential prognostic biomarkers for MTC. Collectively, our study expands the knowledge of MTC biology and therapeutic vulnerabilities, which may serve as an important resource for future investigation on this malignancy.

Different clinicopathologic features predispose to different patterns of distant metastasis with heterogeneous short-term prognosis in patients with differentiated thyroid cancer.

BACKGROUND: Limited studies have focused on the associated clinicopathologic features and short-term prognostic impacts of metastatic patterns at initial diagnosis in differentiated thyroid cancer (DTC). METHODS: Overall, 530 individuals with distant DTC diagnosed between 2010 and 2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Multinomial logistic regression model was used to assess the clinicopathologic factors influencing the pattern of distant metastasis. Kaplan-Meier method and multivariable Cox regression were used to estimate the short-term effects of metastatic patterns on overall (OS) and thyroid cancer-specific survival (TCSS). RESULTS: Fifty, 111, 263, 59 and 47 patients presented with distant lymph node (LN)-only, bone-only, lung-only, bone plus lung, and liver and/or brain metastases (Mets), respectively. Regional lymph node metastasis (LNM) and follicular histotype were the only confirmed risk factors for distant LN-only Mets and bone-only Mets, respectively. Larger tumour size, extrathyroidal extension (ETE) and papillary histotype were associated with lung-only Mets. Synchronous bone and lung Mets were more likely to occur in older patients. In addition, patients with distant LN-only Mets had hardly any negative effect on OS and TCSS, whereas those with synchronous bone and lung or liver/brain Mets predicted unfavourable short-term outcomes, regardless of whether they received total thyroidectomy and radioisotopes. CONCLUSIONS: Different clinicopathologic factors predispose to different patterns of metastases with profound short-term survival differences among DTC patients. Our findings may help to determine effective pretreatment screening for aggressive metastatic patterns at initial diagnosis, and thus to provide additional treatment or access of clinical trials for these patients.

Identification of lipid metabolism-related genes as prognostic indicators in papillary thyroid cancer.

Lipid metabolism plays important roles not only in the structural basis and energy supply of healthy cells but also in the oncogenesis and progression of cancers. In this study, we investigated the prognostic value of lipid metabolism-related genes in papillary thyroid cancer (PTC). The recurrence predictive gene signature was developed and internally and externally validated based on PTC datasets including The Cancer Genome Atlas (TCGA) and GSE33630 datasets. Univariate, LASSO, and multivariate Cox regression analysis were applied to assess prognostic genes and build the prognostic gene signature. The expression profiles of prognostic genes were further determined by immunohistochemistry of tissue microarray using in-house cohorts, which enrolled 97 patients. Kaplan-Meier curve, time-dependent receiver operating characteristic curve, nomogram, and decision curve analyses were used to assess the performance of the gene signature. We identified four recurrence-related genes, PDZK1IP1, TMC3, LRP2 and KCNJ13, and established a four-gene signature recurrence risk model. The expression profiles of the four genes in the TCGA and in-house cohort indicated that stage T1/T2 PTC and locally advanced PTC exhibit notable associations not only with clinicopathological parameters but also with recurrence. Calibration analysis plots indicate the excellent predictive performance of the prognostic nomogram constructed based on the gene signature. Single-sample gene set enrichment analysis showed that high-risk cases exhibit changes in several important tumorigenesis-related pathways, such as the intestinal immune network and the p53 and Hedgehog signaling pathways. Our results indicate that lipid metabolism-related gene profiling represents a potential marker for prognosis and treatment decisions for PTC patients.

Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study.

CONTEXT: Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC). OBJECTIVE: We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients. DESIGN AND PATIENTS: In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed. RESULTS: TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression. CONCLUSIONS: Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future.

Genomic and Transcriptomic Characterization of Sporadic Medullary Thyroid Carcinoma.

Background: Sporadic medullary thyroid carcinoma (MTC) is a relatively uncommon neuroendocrine malignancy and the molecular tumorigenesis of its sporadic type (sMTC) is only partially understood. In this study, we performed a study focusing on the genomic and transcriptomic characterization of sMTC. Methods: Twenty-nine sMTC patients were included. Whole-exome sequencing (WES) was carried out in 18 patients, including both tumor samples and matched noncancerous tissues. Whole transcriptome sequencing (RNA-Seq) was performed in all 29 tumors. WES, RNA-Seq, and copy number alteration (CNA) data were analyzed. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Results: Among the somatic mutations, RET was the only recurrently cancer-related mutated gene (5/18, 27.8%). In the germline, FAT1 and FAT4, two members of the FAT gene family, were identified as the two most common mutated genes. CNA analysis found that FAT1 and FAT4, both located on chromosome 4q, were also two of the genes most commonly affected by somatic chromosomal deletions (4/18, 22.2%). Using TT and MZ-CRC-1 cell lines, the CCK-8 assay showed that FAT1 and FAT4 knockdown could promote MTC cell proliferation. Based on the gene expression profile, patients were clustered into two molecular subtypes: the mesenchymal-like subtype is characterized by epithelial-mesenchymal transition, while the proliferative-like subtype is associated with enrichment of cell cycle pathways. Most events of structural recurrence (80%) occurred in the proliferative-like subtype. Conclusion: In addition to RET, these findings demonstrate that FAT1/FAT4 genomic alterations appear to be frequent in sMTC. Two molecular subtypes of sMTC with distinct biological behavior could be identified. However, these results need to be validated by larger samples and more comprehensive experiments in the future, especially for the frequency and function of FAT1/FAT4 germline variants.

Germline Missense Mutation of Deleted in Malignant Brain Tumor 1 (DMBT1) in Familial Mediastinal Neuroendocrine Cancer and in vitro Effects in Thyroid Cancer Cells.

BACKGROUND: Neuroendocrine tumors (NETs) rarely occur in the mediastinum and their etiology and pathogenesis are still unclear. OBJECTIVES: This study assessed inherited or de novo mutations in familial mediastinal NETs. METHOD: DNA samples from 4 patients were subjected to the whole-exome sequencing, and Sanger sequencing was used to identify Deleted in malignant brain tumor 1 (DMBT1) mutations in all 45 family members. RESULTS: All patients showed a germline DMBT1 mutation at 4971C. Sanger sequencing data showed that 4 NETs and 2 carriers in the first patient's family and 2 NETs and 4 carriers in the second patient's family, respectively, had this DMBT1 mutation. The in vitro data showed that the ectopic expression of DMBT1 reduced tumor cell viability and migration by arresting the G1/S phase of the cell cycle. CONCLUSIONS: We identified a germline missense mutation in DMBT1D1657E as a susceptibility gene for familial mediastinal NETs.

The association between tumor's location and cervical lymph nodes metastasis in papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) has a strong propensity to metastasize to the cervical lymph nodes. Little was known currently about whether tumor's location would influence the risk of lymph node metastasis in PTC. METHODS: The study enrolled PTC patients who underwent primary surgical therapy in our center for small unifocal tumor. The tumor's location was evaluated by ultrasound in three axes, three planes and 3D space. Logistic univariate and multivariate analysis were applied to explore the association between tumors' location and the risk of lymph node metastasis in PTC. Different localization methods of thyroid tumors were evaluated using ROC curve. RESULTS: Totally 1,266 PTC patients were enrolled in this study. Univariate and multivariate analyses showed that gender, age, tumor size and tumor's location (in longitudinal axis, longitudinal sagittal plane, longitudinal coronal plane, sagittal coronal plane and 3D space) was associated with central lymph node dissection (CLND); gender, tumor size and tumor's location (in longitudinal axis, coronal axis, longitudinal sagittal plane, longitudinal coronal plane, sagittal coronal plane and 3D space) was related with lateral lymph node dissection (LLND) (P<0.05). In the ROC curve analysis, the 3D location showed the highest predictive value of lymph node metastasis (C-statistics: 0.724 for CLNM; 0.763 for LLNM). The middle posterior lateral (OR=2.575, P=0.028), inferior anterior central (OR=2.829, P=0.016), inferior posterior lateral (OR=2.759, P=0.039) and isthmus tumors (OR=4.526, P=0.001) were at a higher risk of CLNM, and the middle anterior central tumors (OR=0.102, P=0.015) were related with lower risk of LLNM. CONCLUSIONS: Stereotactic localization showed the highest predictive value of lymph node metastasis. The middle posterior lateral, inferior anterior central, inferior posterior lateral and isthmus tumors were at a higher risk of CLNM when compared to other locations. For such patients, careful preoperative evaluation of nodal status should be done.

Metabolic reprogramming and its clinical application in thyroid cancer.

Warburg found that tumor cells exhibit high-level glycolysis, even under aerobic condition, which is known as the 'Warburg effect'. As systemic changes in the entire metabolic network are gradually revealed, it is recognized that metabolic reprogramming has gone far beyond the imagination of Warburg. Metabolic reprogramming involves an active change in cancer cells to adapt to their biological characteristics. Thyroid cancer is a common endocrine malignant tumor whose metabolic characteristics have been studied in recent years. Some drugs targeting tumor metabolism are under clinical trial. This article reviews the metabolic changes and mechanisms in thyroid cancer, aiming to find metabolic-related molecules that could be potential markers to predict prognosis and metabolic pathways, or could serve as therapeutic targets. Our review indicates that knowledge in metabolic alteration has potential contributions in the diagnosis, treatment and prognostic evaluation of thyroid cancer, but further studies are needed for verification as well.

Association Between Programmed Death-Ligand 1 Expression and Clinicopathological Characteristics, Structural Recurrence, and Biochemical Recurrence/Persistent Disease in Medullary Thyroid Carcinoma.

Background: Expression of the programmed death-ligand 1 (PD-L1) in medullary thyroid carcinoma (MTC) has been rarely reported. In this study, we evaluated PD-L1 positivity in MTC and analyzed its correlation with clinicopathological characteristics, structural recurrence (SR), and biochemical recurrence/persistent disease (BcR/BcPD). We also evaluated the prevalence of PD-L1 expression in patients developing distant or unresectable locoregional recurrence. Methods: In total, 201 consecutive MTC patients who underwent initial surgery in our institution from January 2006 to December 2015 were included. PD-L1 expression was evaluated by immunohistochemical staining and was considered positive in case of a combined positive score ≥1. The association of PD-L1 positivity with clinicopathological characteristics, structural recurrence-free survival (SRFS), and BcR/BcPD was retrospectively investigated. Results: The median follow-up length of the entire cohort was 73 months. We observed positive PD-L1 staining in 29 (14.4%) patients who were more likely to have a larger tumor size (p = 0.002), lymph node metastases (p = 0.036), and advanced TNM staging (p = 0.019). The five-year SRFS of the PD-L1-negative and PD-L1-positive groups was 85.4% and 57.9% (p = 0.001). Multivariate Cox analysis showed that PD-L1 positivity was independently associated with SR (hazard ratio = 2.19 [95% confidence interval (CI) 1.01-4.77], p = 0.047). Furthermore, multivariate logistic analysis showed that PD-L1 positivity was significantly associated with BcR/BcPD (odds ratio = 3.16 [CI 1.16-8.66], p = 0.025). During the study period, 20 patients developed distant or unresectable locoregional recurrence, among whom 8 (40%) were PD-L1 positive, which was much higher than in the entire MTC population. Conclusions: Using a large cohort of MTC patients, we demonstrate that PD-L1 positivity is associated with aggressive clinicopathological features and is independently predictive of SR and BcR/BcPD. Furthermore, a higher rate of PD-L1 expression in patients with incurable recurrence has been observed. Therefore, immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-L1 pathway may be a potential therapeutic strategy to treat advanced MTC.

The application of selective neck dissection while preserving the cutaneous branches of cervical plexus in the surgical treatment of differentiated thyroid cancer-experiences from thousands of cases.

Differentiated thyroid cancer (DTC) is associated with the highest propensity for lymph node metastases, given the significant morbidity associated with sacrificing the spinal accessory nerve, surgeons increasingly looked to minimizing functional deficits while maintaining oncologic outcome. We have detailed the technique of a selective neck dissection with more attention to preserving the cervical sensory nerves since 1999 in Fudan University Shanghai Cancer Center. We found that the radical dissection with preservation of the cutaneous branches including the great auricular nerve, the less occipital nerve and the supraclavicular nerve can maximally decrease the complications of paresthesia and dysesthesia postoperatively in the lower neck, the shoulders and the area around the ear in DTC cases when indications were allowed. As long as the principles of cancer surgery are strictly followed, our approach guarantees radical tumor removal and exhibit more functional preservation.

Effects of tumor size on prognosis in differentiated thyroid carcinoma smaller than 2 cm.

Benefits of subdividing small-differentiated thyroid carcinoma (sDTC) by tumor size are controversial. We conducted a meta-analysis to investigate whether tumor size is associated with prognosis of sDTC. PubMed and Web of Science databases were searched from their inception to September 2018. The identified studies according to the inclusion/exclusion criteria were analyzed using fixed/random-effects models. Data were calculated and results of the meta-analysis were expressed as odd ratio (OR). sDTC was classified as S1 (≤1 cm) and S2 (>1 cm and ≤2 cm). A systematic analysis was performed to compare the difference of recurrence, survival and clinicopathological factors between the two subgroups of sDTC (S1 vs. S2). A total of 21 studies published between 2004 and 2017 enrolling 219,291 patients were included. Findings showed that, S2 was associated with higher recurrence risk compared with S1 (OR=1.575, 95% CI=1.428-1.738; P<0.05). There was no statistical difference in survival between S1 and S2, but significant statistical heterogeneity (OR=1.160, 95% CI=0.810-1.662; P=0.448; I2=75.8%). Meta-regression analysis revealed publication year potentially caused the heterogeneity (P<0.05). Comparison of small papillary thyroid carcinoma alone agreed with the results of sDTC. T1b increased the risk of recurrence (OR=1.520; 95% CI=1.072-2.155; P<0.05) and death (OR=1.504; 95% CI 1.353-1.672; P<0.05) compared with T1a. S2 associated with extrathyroidal extension (OR=2.575; 95% CI=1.603-4.135; P<0.05), bilaterality (OR=2.278; 95% CI=1.905-2.723; P<0.05), vascular invasion (OR=4.494; 95% CI=2.812-7.183; P<0.05) and lymph node metastases (OR=1.12; 95% CI=1.10-1.14; P<0.05). Our analysis suggested it is necessary to subdivide sDTC into S1 and S2 owing to their different effects on prognosis, especially recurrence.

Prognostic value of primary tumor surgery in minor salivary-gland carcinoma patients with distant metastases at diagnosis: first evidence from a SEER-based study.

PURPOSE: The prognostic value of primary tumor surgery (PTS) in minor salivary-gland carcinoma (MiSGC) with distant metastasis (DM) at diagnosis has never been investigated. In this study, we aimed to provide the first evidence. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was employed to identify MiSGC patients with DM at diagnosis. The prognostic value of PTS was evaluated by Kaplan-Meier methods, log-rank analyses, and multivariate Cox proportional-hazard regression models. RESULTS: Of the 152 eligible patients included in our study, 50 (32.9%) had undergone PTS. Kaplan-Meier analyses showed that the PTS group had >20% increase in 1- and 2-year overall survival (OS) and cancer-specific survival (CSS) compared with their counterparts without PTS (PTS group vs no-PTS group, 1-year OS 66.1% vs 43.9%, 1-year CSS 69.9% vs 44.9%, 2-year OS 56.6% vs 24.2%, 2-year CSS 59.9% vs 25.7%). Compared with the no-PTS group, multivariate analyses also demonstrated a significantly decreased risk of overall mortality (HR 0.601, 95% CI 0.379-0.952; P=0.031) and cancer-specific mortality (HR 0.547, 95% CI 0.336-0.891; P=0.015) in the PTS group. Subgroup multivariate analyses revealed patients with T1-T3 oropharynx, nasal cavity, or paranasal sinus primary MiSGC, especially adenoid cystic carcinoma, might benefit from PTS (all P<0.05). CONCLUSION: PTS is associated with improved survival in highly selected MiSGC patients and may be considered in future clinical practice. However, prospective studies with larger sample size are still necessary to validate our findings.

NRG1 regulates redox homeostasis via NRF2 in papillary thyroid cancer.

Thyroid cancer is a common endocrine cancer, of which papillary thyroid cancer (PTC) is the most common type. Neuregulin 1 (NRG1), a glycoprotein mediating cell­cell signaling, plays vital roles in cellular activities; however, its role in PTC progression remains poorly understood. In this study, we performed immunohistochemistry in 196 samples from patients and found that NRG1, a potential prognostic marker is highly expressed in PTC compared with adjacent normal tissues. Cell Counting kit­8 (CCK­8) and clone formation assays indicated that NRG1 is essential for PTC cell viability and proliferation, probably by regulating redox homeostasis, which was implied by ROS generation analysis and intracellular GSH activity assay. Western blot analysis and RT­qPCR revealed that NRG1 regulates ERK pathway and the pivotal regulator of cellular redox status, nuclear factor E2­related factor 2 (NRF2), which maintains moderate reactive oxygen species (ROS) levels through a set of antioxidant response element (ARE)­containing genes. The immunohistochemical scoring of 196 PTC samples and the analysis of the data of 490 patients from The Cancer Genome Atlas (TCGA) reveled a positive association between the expression of NRG1 and NRF2. Since the presence of NRG1 regulates redox homeostasis through NRF2, protecting PTC cells from the accumulation of ROS and ROS­induced cell death, NRG1 may thus prove to be a potential therapeutic target in the treatment of thyroid cancer.

Central Lymph Node Status has Significant Prognostic Value in the Clinically Node-Negative Tall-Cell Variant of Papillary Thyroid Cancer Regardless of T-Staging and Radioactive Iodine Administration: First Evidence From a Population-Based Study.

BACKGROUND: The prognostic value of central lymph node (CLN) status in papillary thyroid cancer (PTC) remains controversial. This study aimed to provide the first evidence on this issue for the aggressive tall-cell variant (TCV) subtype. METHODS: The study identified TCV patients from the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method, log-rank test, and multivariate Cox regression models were used for analysis. RESULTS: Of the 744 patients included, 404 were recorded as N0, which were pathologically or only clinically confirmed. Overall survival (OS) and cancer-specific survival (CSS) did not differ significantly between the N0 and pN1a patients (p > 0.05). To investigate the reason, the N0 patients were subdivided according to the number of examined lymph nodes (ELN). The patients with a N0 diagnosis confirmed by two or more ELNs (N0-e2+) showed significantly better outcomes than the pN1a patients and their N0 counterparts without ELN (N0-e0) (p < 0.05), whereas the N0-e0 and pN1a groups demonstrated comparable outcomes in both the log-rank and multivariate analyses (p > 0.05). Moreover, the subgroup analyses showed that even among the patients with early T-staging (T1-T2) or receipt of radioactive iodine (RAI) therapy, the N0-e0 patients still demonstrated compromised OS compared with the N0-e2+ group (p < 0.05). CONCLUSION: The cN0 patients without ELN (N0-e0) had outcomes similar to those of the pN1a patients, but showed a poorer OS than the N0-e2+ group regardless of T-staging and RAI administration, suggesting that occult CLN metastases might act as a negative prognosticator in cN0 TCV. Therefore, prophylactic central neck dissection might be considered for biopsy-proven cN0 TCV patients. Prospective studies are expected to further validate our conclusions.

Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro.

KMT5A (known as PR-Set7/9, SETD8 and SET8), a member of the SET domain containing methyltransferase family specifically targeting H4K20 for methylation, has been implicated in multiple biological processes. In the present study, we identified that KMT5A was elevated in 50 pairs of papillary thyroid cancer tissue samples and in cell lines K1 and TPC-1 by qRT-PCR and western blotting, as well as by immunohistochemical staining. CCK-8 assay and flow cytometric analysis revealed that inhibition of KMT5A attenuated proliferation and induced apoptosis. Transwell assays revealed that cell migration and invasion were suppressed in KMT5A-knockdown cells. Moreover, the inhibition of KMT5A arrested the cell cycle in the G1/S phase of papillary thyroid cancer cells. The TCGA data revealed that elevated KMT5A expression was significantly correlated with extrathyroidal extension, lymph node metastasis and advanced pathological stage of papillary thyroid cancer. Furthermore, we observed that inhibition of KMT5A suppressed the expression of SREBP1, SCD, FASN and ACC, key molecules involved in lipid metabolism and decreased the level of malondialdehyde in papillary thyroid cancer cells. In conclusion, KMT5A may be a novel oncogenic factor, specifically a regulator for lipid metabolism in papillary thyroid carcinoma.

Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/ß-catenin signaling and sensitizes cancer cells to FH535 therapy.

The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short-hairpin RNA-mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated ß-catenin expression was also analyzed. CSN6 levels were determined by real-time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK-8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized ß-catenin and facilitated the epidermal-to-mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated ß-catenin expression in a ß-Trcp-dependent manner and triggered expression of several EMT-related genes regulated by ß-catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/ß-catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/ß-catenin signaling pathway.