Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis.

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF-V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C-index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non-DM PTC but significantly higher in PTC with DM.

Diagnostic values of thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis diagnostic values of FNA-Tg.

Thyroglobulin measurement in the needle washout after fine-needle aspiration (FNA-Tg) served as an important measurement for suspicious recurrent or metastatic lesions. We conducted a pooled analysis to evaluate the diagnostic accuracy of FNA-Tg and searched electronic databases for original articles in English from 1993 through 2017. Finally, a total of 22 studies containing 2,670 lymph nodes (LNs) that enrolled participants with suspicious neck LNs during thyroid nodule workup or papillary thyroid cancer (PTC) follow-up were included. In our analysis, the overall pooled sensitivity for FNA-Tg was 0.91 (95%CI: 0.87-0.93), specificity was 0.94 (95% CI: 0.91-0.96). Meta regression revealed that the cutoff value and status of serum Tg were sources of heterogeneity for sensitivity, and the cutoff value was source of heterogeneity for specificity. Additionally, the cutoff value and status of serum Tg were sources of heterogeneity in the joint model. Subgroup analysis about cut-off value showed that the choice of 1 ng/mL had highest sensitivity, 40 ng/mL had highest specificity. At last, we arrived at the conclusion that FNA-Tg measurement had high specificity and sensitivity in the early detection of LNs metastases from PTC by our meta-analysis. The technique was simple and could be recommended to apply in any FNA facility, especially when LN were small-sized. Significantly, a better standardization of criteria for FNA-Tg detection and cutoff value was required to provide useful data and to improve management of PTC patients in the future.

The Landscape of Circular RNA Expression Profiles in Papillary Thyroid Carcinoma Based on RNA Sequencing.

BACKGROUND/AIMS: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, the molecular mechanisms responsible for its tumorigenesis and progression remain largely unknown. Circular RNA (circRNA) is a novel type of noncoding RNA that can serve as an ideal biomarker due to its stability. Recent evidence suggests that circRNAs play important roles in tumorigenesis. This study aims to investigate circRNA expression profiles and their potential biological functions in PTC. METHODS: High-throughput RNA sequencing was used to assess circRNA expression profiles in PTC, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate dysregulated circRNAs. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of circRNAs for PTC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to determine the biological functions of differentially expressed circRNAs. Bioinformatic analyses were applied to predict interactions between circRNAs and microRNAs (miRNAs), and a circRNA-miRNA-mRNA network was constructed using Cytoscape software. RESULTS: We identified a number of differentially expressed circRNAs in PTC tissues compared with paired normal thyroid tissues, with chr5: 160757890-160763776-, chr12: 40696591-40697936+, chr7: 22330794-22357656-, and chr21: 16386665-16415895- being upregulated, and chr7: 91924203-91957214+, chr2: 179514891-179516047-, chr9: 16435553-16437522-, and chr22: 36006931-36007153- being downregulated. These findings were confirmed by qRT-PCR, and ROC curves indicated that they can serve as potential biomarkers for PTC. GO and KEGG pathway analyses showed that some of these circRNAs are related to cancers. Additionally, bioinformatic analyses revealed a potential competing-endogenous-RNA-regulating network among circRNAs, miRNAs, and mRNAs. CONCLUSIONS: Our study results depict the landscape of circRNA expression profiles in PTC and also provide potential biomarkers for PTC. Further functional and mechanistic studies of these circRNAs may improve our understanding of PTC tumorigenesis.

Decreased expression of hsa_circ_0137287 predicts aggressive clinicopathologic characteristics in papillary thyroid carcinoma.

BACKGROUND: Circular RNA (circRNA) is a new type of noncoding RNA that can serve as ideal biomarkers. Evidence has showed that circRNAs play an important role in carcinogenesis and cancer development. However, little is known about the diagnostic value of circRNAs in papillary thyroid carcinoma (PTC) as well as their associations with clinicopathologic characteristics of patients with PTC. METHODS: The expression levels of hsa_circ_0137287 were detected in 120 PTC and 60 adjacent noncancerous thyroid tissues by quantitative real-time polymerase chain reaction. The relationships between the expression of hsa_circ_0137287 in PTC and the clinicopathologic factors were analyzed. Finally, receiver operating characteristic (ROC) curves were generated to assess the diagnostic value of hsa_circ_0137287 as a biomarker for PTC. RESULTS: The expression of hsa_circ_0137287 was significantly downregulated in PTC tissues compared with adjacent noncancerous tissues (P < .0001). Downregulation of hsa_circ_0137287 correlated with aggressive clinicopathologic characteristics of PTC such as extrathyroidal extension (P < .001), lymph node metastasis (P = .022), advanced T stage (P < .001) and larger tumor size (P < .001). The ROC curves revealed that hsa_circ_0137287 had a potential diagnostic value in predicting malignancy, extrathyroidal extension and lymph node metastasis. The area under curves were 0.8973 (95% CI = 0.8452-0.9494, P < .0001), 0.6885 (95%CI = 0.5908-0.7862, P = .0009), and 0.6691(95%CI = 0.5641-0.7742, P = .0034), respectively. CONCLUSIONS: Our findings suggest that hsa_circ_0137287 may serve as a novel biomarker for PTC.

In Silico Screening and Validation of PDGFRA Inhibitors Enhancing Radioiodine Sensitivity in Thyroid Cancer.

Aberrant activation of platelet-derived growth factor receptor α (PDGFRA) has been implicated in tumorigenesis and radioiodine resistance of thyroid cancer, indicating its therapeutic potential. In the present study, we confirmed the association between PDGFRA and radioiodine resistance in thyroid cancer using bioinformatics analysis and constructed a prediction model of PDGFRA inhibitors using machine learning and molecular docking approaches. We then performed a virtual screening of a traditional Chinese medicine (TCM) derived compound library and successfully identified 4',5,7-trimethoxyflavone as a potential PDGFRA inhibitor. Further characterization revealed a significant inhibitory effect of 4',5,7-trimethoxyflavone on PDGFRA-MAPK pathway activation, and that it could upregulate expression of sodium iodide symporter (NIS) as well as improve radioiodine uptake capacity of radioiodine-refractory thyroid cancer (RAIR-TC), suggesting it a potential drug lead for the development of new RAIR-TC therapy.

The synergistic antitumor effect of IL-6 neutralization with NVP-BEZ235 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) still ranks among the top cancers worldwide with high incidence and mortality. Due to abnormal activation of the PI3K/AKT/mTOR signalling pathway in HCC, targeting this pathway represents a potential therapeutic strategy. NVP-BEZ235 is a novel dual-targeted ATP-competitive PI3K/mTOR inhibitor that has shown effective antitumor effects. In this study, we found that interleukin-6 (IL-6) was significantly increased after exposure to NVP-BEZ235, and we proposed a treatment in which an anti-IL-6 antibody was combined with NVP-BEZ235 for HCC. In vitro results revealed that targeted inhibition of IL-6 potentiated the antitumor effects of NVP-BEZ235 in HCC cells. The mechanism might be attributed to their synergistic inhibitory activity on the PI3K/AKT/mTOR signalling pathway. Furthermore, an in vivo study demonstrated that combined administration of NVP-BEZ235 and anti-IL-6 Ab reduced HCC tumour load more effectively than either NVP-BEZ235 or anti-IL-6 Ab treatment alone. These findings add guidance value to the analysis of HCC and provide a reference for clinical treatment.

BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.

TCR-Seq Identifies Distinct Repertoires of Distant-Metastatic and Nondistant-Metastatic Thyroid Tumors.

CONTEXT: Malignant thyroid tumor with distant metastasis is associated with poor outcome. Early detection of distant metastasis is of great clinical importance. OBJECTIVE: Thyroid tumor infiltrated with T cells can serve as a biomarker for monitoring metastasis. DESIGN: A retrospective analysis was performed of patient clinical samples collected between 2012 to 2018, using T-cell receptor sequencing (TCR-seq) for clinical exploration. SETTING: This study took place at Zhejiang Cancer Hospital. PATIENTS: Sixty-eight patients with papillary thyroid cancer (PTC) (distinct metastatic status) and 21 patients with benign nodules were enrolled. All patients had not received any treatment before surgery. MAIN OUTCOME MEASURE: The characteristics of TCRß complementary-determining region 3 (CDR3) for each patient were determined by high-throughput sequencing. RESULTS: The TCRß diversity of malignant tumors is significantly higher than benign nodules both in blood and tumor samples (Shannon index, blood, P < .01; tumor, P < .001). The malignant tumors with distant metastasis or invasiveness showed lower TCRß diversity than nonmetastasis (Shannon index, P < .01) or noninvasive (Shannon index, P < .01) malignant tumors. Analysis of the Morisita-Horn similarity index indicated significant TCRß repertoire similarity between tumor and blood in distant-metastatic patients (comparison with nonmetastasis, P < .05). According to the discrepancy of the CDR3 among patients with different clinicopathological status, the classifier was constructed to discriminate distant-metastatic individuals. A promising area under the curve value of 83.8% was obtained with the number of overlapping CDR3 clonotypes. CONCLUSION: The availability and reliability of TCR-seq render it prospective to translate these intrinsic attributes into clinical practice for monitoring distant metastasis in PTC patients.

Clinicopathological and Prognostic Significance of WW Domain Binding Protein 5 Expression in Papillary Thyroid Carcinoma.

OBJECTIVES: Many patients with papillary thyroid cancer (PTC) have a high recurrence risk and poor prognosis, and the main obstacle to the clinical diagnosis and treatment of PTC is lack of effective predictive molecular markers. The purpose of this study was to investigate the clinicopathological and prognostic implications of WW domain binding protein 5 (WBP5) expression in PTC. MATERIALS AND METHODS: Immunohistochemistry of WBP5 was performed using tissue microarrays of 131 patients with PTC who underwent surgery during January 2006 and January 2010 in the Zhejiang Cancer Hospital. Statistical analyses were conducted to evaluate the association between WBP5 expression and the clinicopathological features and to analyze the disease-free survival (DFS) and prognostic factors. RESULTS AND CONCLUSION: The positive expression rate of WBP5 in PTC and the adjacent normal tissues was 42.75% (56/131) and 45.45% (10/22), respectively. WBP5 expression was significantly correlated with bilaterality, capsule invasion, and N-stage, and it was a favorable factor of DFS. Moreover, patients with a high WBP5 expression exhibited reduced risk of disease recurrence compared with that in patients with low WBP5 expression in the univariate analysis, whereas the multivariate analysis suggested that WBP5 was not an independent prognostic factor. Our results indicate that WBP5 might be a favorable prognosis indicator of PTC.

Concomitant papillary thyroid carcinoma and mucosa-associated lymphoid tissue thyroid lymphoma in the setting of Hashimoto thyroiditis.

The simultaneous occurrence of papillary thyroid carcinoma (PTC) and mucosa-associated lymphoid tissue (MALT) lymphoma of the thyroid gland is extremely rare, and many questions about their diagnosis and treatment remain unsolved. We report three cases of patients with both PTC and MALT thyroid lymphoma in the setting of Hashimoto thyroiditis (HT). Patient characteristics, pre-operative examination, histological findings, treatments, and follow-up were reviewed. In addition, we searched PubMed, Embase, and ISI Web of Science databases for articles published in the English language using the key words "lymphoma" and "thyroid", and we reviewed almost all the reports about simultaneous occurrence of PTC and MALT thyroid lymphoma. In conclusion, PTC and MALT thyroid lymphoma can exist concomitantly, especially in patients with longstanding HT. These rare cases highlight the importance of close communication between clinicians, histopathologists, and radiologists to ensure that such rare cases are not missed; a multidisciplinary approach and careful surveillance are also needed.

Corrigendum to "Clinicopathological Characteristics and Prognosis of Papillary Thyroid Carcinoma in Naturally Menopausal Women with Various Durations of Premenarche, Reproductive Periods, and Postmenopausal Stages".

[This corrects the article DOI: 10.1155/2017/5702716.].

Clinicopathological Characteristics and Prognosis of Papillary Thyroid Carcinoma in Naturally Menopausal Women with Various Durations of Premenarche, Reproductive Periods, and Postmenopausal Stages.

Background. Papillary thyroid cancer (PTC) exhibits a higher incidence in women. Due to various ages at menarche and menopause, estrogen levels vary, which may account for the differences in the occurrence, development, and prognosis of female patients with PTC. Objective. The aim of this study was to investigate the association between various durations in different estrogen levels and PTC and to provide important information to guide clinical management and treatment of this disease. Methods. First, we selected naturally menopausal female study subjects diagnosed with PTC at Zhejiang Cancer Hospital from 2007 to 2012 and then compared the differences in clinicopathological characteristics and prognosis among subjects with various lengths of premenarche, reproductive periods, and postmenopausal stages. Results. We found that all patients showed a significantly higher incidence of tumor multicentricity and intrathyroidal dissemination as the time after menopause increased. Additionally, women with shorter (<30) or longer (>38) reproductive lives had increased recurrence rates of PTC. Conclusions. In this study, we did not find any relationship of self-reported menarche and menopausal ages with the prognosis of PTC patients. More importantly, natural postmenopausal PTC patients with shorter or longer reproductive life, compared to the normal groups, had a higher rate of cancer recurrence and the patients with these characteristics could be recommended a more aggressive surgical treatment.

Parotid metastases from thyroid carcinomas.

Parotid metastases (PMs) that originate from thyroid carcinomas (TCs) are extremely rare, and many questions about their diagnosis and management remain unanswered. Of the 15,780 patients with TC that we had prospectively recorded in our institutional databases between 1996 and 2015, we retrospectively retrieved only three patients (0.019%) with PM. Patient characteristics, histological findings on initial thyroidectomy and parotidectomy specimens, treatments, and times of recurrence and death were reviewed. In addition, we searched PubMed, Embase, and ISI Web of Science databases (1996-2015) for articles published in the English language using the key words "parotid" and "thyroid", and reviewed almost all reports that described PM that were derived from TC. These rare cases of thyroid carcinoma presenting as metastasis in the parotid gland highlight the importance of maintaining close communication between clinicians, radiologists, and histopathologists to ensure that such rare cases are not missed.

[The clinical significance of the Delphian lymph node metastasis in papillary thyroid carcinoma].

Thyroid cancer is one of the commonest head and neck cancer. According to the recent research, VI lymph nodes (also called the front area, including thyrocricoid lymph nodes, tracheal surrounding lymph nodes, thyroid surrounding lymph node,recurrent laryngeal nerve lymph nodes, retropharyngeal lymph nodes) is the most common site of involvement in the differentiated thyroid carcinoma. Thyrocricoid lymph nodes known as the Delphian lymph node(DLN) is located between the thyroid cartilage and the cricoid cartilage. The DLN is one of the most accurate predictor. This paper reviewed the clinical significance of the DLN, the role of DLN metastasis in papillary thyroid cancer, and the relationship between tumor size, multicentricity and DLN metastasis. We also discussed the association between DLN metastasis and additional central compartment metastasis, as well as lateral compartment metastasis.