Risk Factors for Recurrence of Follicular Thyroid Cancer: A Systematic Review.

Background: In risk assessment of recurrence, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are often grouped together as differentiated thyroid cancer (DTC). However, while risk factors affecting recurrence of PTC are well established, risk factors for recurrence of FTC are not. This systematic review examines risk factors for recurrence of FTC and evaluates their significance. Methods: A systematic search on PubMed and Embase was performed in September 2020, including studies evaluating risk factors for recurrence of FTC. A quality assessment of the enrolled studies was performed. Results: Nine studies (n = 1544 patients) from eight countries were included. The average recurrence rate was 13.6%, and distant metastasis (DM) constituted 64.8% of the recurrent cases. The risk factors examined were sex, age at diagnosis, primary tumor size, degree of invasiveness, focality, positive resection margin, lymph node (LN) metastasis, and DM at diagnosis. Risk factors correlated with recurrence of FTC were age older than 45 years, primary tumor size above 40 mm, widespread invasion, multifocality, positive resection margin, LN metastasis, and DM at diagnosis. Sex was not a statistically significant risk factor. Conclusions: We identified seven risk factors associated with recurrence of FTC. Age and multifocality were found to be of greater impact regarding recurrence risk of FTC compared with PTC. Future research needs to address the impact of different risk factors for recurrence of FTC particularly including age, primary tumor size, angioinvasion, and mutational status.

Is sonographic intra-nodular vascularity a reliable predictor of thyroid malignancy? A UK tertiary centre study.

OBJECTIVE: British Thyroid Association 2014 guidelines emphasised ultrasound assessment of nodules. One ultrasonographic differentiator of debatable relevance is intra-nodular vascularity. This is the first UK study conducted to address this question. METHODS: Ultrasound reports for thyroid surgery patients over 10 years were retrospectively reviewed. Reports documenting 'intra-nodular vascularity or flow' were analysed. Reports identifying peripheral vascularity only or no intra-nodular flow formed the control group. Concordance with final histology was used to determine the odds ratio for malignancy. RESULTS: A total of 306 patients were included, and 119 (38.9 per cent) nodules demonstrated intra-nodular vascularity. Of these, 60 (50.4 per cent) were malignant compared with 42 per cent in the control group. Intra-nodular vascularity was not a statistically significant predictor of malignancy with an odds ratio of 1.39 (p = 0.18, 95 per cent confidence interval, 0.86-2.23). CONCLUSION: Intra-nodular vascularity in isolation was not a reliable predictor of malignancy. This supports other world literature studies. Although intra-nodular flow should not be relied upon in isolation, interpretation in conjunction with other suspicious findings enhances the predictive value.

Vandetanib versus Cabozantinib in Medullary Thyroid Carcinoma: A Focus on Anti-Angiogenic Effects in Zebrafish Model.

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in Tg(fli1a:EGFP)y1 transgenic fluorescent zebrafish embryos by analyzing the effects on the physiological development of the sub-intestinal vein plexus and the tumor-induced angiogenesis after TT and MZ-CRC-1 xenotransplantation. VAN and CAB exert comparable effects on TT and MZ-CRC-1 viability inhibition and cell cycle perturbation, and stimulated apoptosis with a prominent effect by VAN in MZ-CRC-1 and CAB in TT cells. Regarding zebrafish, both drugs inhibit angiogenesis in a dose-dependent manner, in particular CAB shows a more potent anti-angiogenic activity than VAN. To conclude, although VAN and CAB show comparable antiproliferative effects in MTC, the anti-angiogenic activity of CAB appears to be more relevant.

Treatment of anaplastic thyroid cancer with tyrosine kinase inhibitors targeted on the tumor vasculature: initial experience in clinical practice.

Anaplastic thyroid cancer (ATC) is a rarely occurring refractory disease. While recent clinical trials have demonstrated the efficacy of tyrosine kinase inhibitor (TKI) therapy for ATC, evidence is scarce in clinical practice. In this study, we reviewed our initial experiences with TKI treatment in ATC patients with the aim of revealing the efficacy and safety of the same in clinical practice. We retrospectively reviewed our experiences with TKI treatment use in ATC patients diagnosed at our institute from 2014 to 2019. Changes in the patients' neutrophil-to-lymphocyte ratio (NLR) by TKI therapy introduction as well as their clinical factors to indicate the efficacy were examined. Seven patients showed no indication for TKI treatment, while 13 (65%) received treatment. The median duration of TKI treatment was 1.9 months. All patients died, and the overall survival period from diagnosis was 4.7 (95% confidence interval: 2.0-11.5) months. Adverse events ≥Grade 3 were observed commonly (92.3%), and resulted in the termination of TKI treatment in six cases (46.1%). Existence of multiple unfavorable characteristics (higher Prognostic Index) was associated with poor survival. The NLR decreased after the introduction of TKIs and increased again when treatment failed. The response rate to TKI among the ATC patients were approximately 30% in practice. Although the duration of the response was short, several patients demonstrated long survival durations when TKI treatment was provided after successful multidisciplinary treatment to control local disease. Decreases in high NLR values during treatment may suggest the continued effect of TKIs.

Mebendazole inhibits tumor growth and prevents lung metastasis in models of advanced thyroid cancer.

The most common thyroid malignancy is papillary thyroid cancer. While a majority respond to therapy and have a favorable prognosis, some papillary thyroid cancers persist. This subset may dedifferentiate to anaplastic thyroid cancer, an aggressive, highly invasive and rapidly fatal cancer. Thyroid cancer patients at risk for disease progression and metastasis need earlier, safer and more effective therapies. The purpose of this translational study was to determine if mebendazole could be repurposed to effectively treat thyroid cancer, in particular before metastasis. In vitro, mebendazole potently inhibited the growth of a panel of human papillary and anaplastic thyroid cancer cells. In papillary (B-CPAP) and anaplastic (8505c) cell lines, mebendazole increased the percentage of cells in G2/M cell cycle arrest and induced late stage apoptosis by activation of the caspase-3 pathway. In aggressive 8505c cells, mebendazole significantly repressed migratory and invasive potential in a wound healing and transwell invasion assay and inhibited expression of phosphorylated Akt and Stat3 and reduced Gli1. In vivo, mebendazole treatment resulted in significant orthotopic thyroid tumor regression (B-CPAP) and growth arrest (8505c), with treated tumors displaying reduced expression of the proliferation maker KI67 and less vascular epithelium as indicated by CD31+ immunohistochemistry. Most importantly, daily oral mebendazole prevented established thyroid tumors from metastasizing to the lung. Given the low toxicity and published anticancer mechanisms of mebendazole, this novel preclinical study of mebendazole in thyroid cancer has promising therapeutic implications for patients with treatment refractory papillary or anaplastic thyroid cancer.

Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination.

It is well known that Prospero homeobox 1 (PROX1) is a crucial regulator of lymphangiogenesis, that reprograms blood endothelial cells to lymphatic phenotype. However, the role of PROX1 in tumor progression, especially in angiogenesis remains controversial. Herein, we studied the role of PROX1 in angiogenesis in cell lines derived from follicular thyroid cancer (FTC: FTC-133) and squamous cell carcinoma of the thyroid gland (SCT: CGTH-W-1) upon PROX1 knockdown. The genes involved in angiogenesis were selected by RNA-seq, and the impact of PROX1 on vascularization potential was investigated using human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium collected from FTC- or SCT-derived cancer cell lines after PROX1 silencing. The angiogenic phenotype was examined in connection with the analysis of focal adhesion and correlated with fibroblast growth factor 2 (FGF2) levels. Additionally, the expression of selected genes involved in angiogenesis was detected in human FTC tissues. As a result, we demonstrated that PROX1 knockdown resulted in upregulation of factors associated with vascularization, such as metalloproteinases (MMP1 and 3), FGF2, vascular endothelial growth factors C (VEGFC), BAI1 associated protein 2 (BAIAP2), nudix hydrolase 6 (NUDT6), angiopoietin 1 (ANGPT1), and vascular endothelial growth factor receptor 2 (KDR). The observed molecular changes resulted in the enhanced formation of capillary-like structures by HUVECs and upregulated focal adhesion in FTC-133 and CGTH-W-1 cells. The signature of selected angiogenic genes' expression in a series of FTC specimens varied depending on the case. Interestingly, PROX1 and FGF2 showed opposing expression levels in FTC tissues and seven thyroid tumor-derived cell lines. In summary, our data revealed that PROX1 is involved in the spreading of thyroid cancer cells by regulation of angiogenesis.

Exosomes increased angiogenesis in papillary thyroid cancer microenvironment.

Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.

The roles and role-players in thyroid cancer angiogenesis.

Thyroid cancer is the most prevalent endocrine cancer worldwide. Angiogenesis, the formation of new blood vessels, plays a pivotal role in the development and progression of tumors. Over the past years, cancer research has focused on the ability of tumors to induce newly formed blood vessel, because tumor growth and the process of cancer metastasis mainly depends on angiogenesis. Tumor neovascularization occurs following the imbalance between pro-angiogenic and anti-angiogenic factors until the tumor switches to an angiogenic phenotype. A number of signaling factors and receptors that are implicated in the regulation of angiogenesis have been identified and characterized; most notably, the vascular endothelial growth factors (VEGFs) family and their receptors, which are the main pro-angiogenic molecules during early development and in pathological conditions such as cancer. Although thyroid is a highly vascularized organ, angiogenic switch in tumors of this organ leads to the formation of a vast network of blood vessels that favors the dissemination of tumor cells to distant organs and results in deterioration of patient conditions. Accordingly, the identification of key angiogenic biomarkers for thyroid cancer can facilitate diagnosis, prognosis and clinical decision-making and also may help to discover targeting factors for effective cancer therapy as well as monitoring response to therapy. Hence, the main purposes of this review are to summarize the types and mechanisms of angiogenesis emphasizing the prominent factors implicated in thyroid cancer angiogenesis.

Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models.

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.

Neovascularization: an attractive but tricky target in thyroid cancer.

INTRODUCTION: Neovascularization in carcinogenesis and tumor progression is well-established. Molecular mediators implicated in different modes of vascular remodeling and expansion (e.g. sprouting angiogenesis (SA), vasculogenesis, vascular mimicry) are evaluated as prognostic biomarkers and therapeutic targets in different malignant tumors. Significant progress has been made in the understanding of the complex interplay between thyroid cancer (TC) cells and the tumor microenvironment, thus unraveling the role of angiogenic mediators. Areas covered: This review summarizes current research on neovascularization and TC. Current knowledge on vascular remodeling, in the context of carcinogenesis, is presented. Preclinical and clinical data from TC studies are also discussed. Expert opinion: There is a remarkable effort to pharmacologically target several key molecules of vessel-forming cascades. Despite encouraging preclinical results, clinical outcomes in TC are not optimal, possibly reflecting knowledge gaps in the pathophysiology of neovascularization in thyroid tissue. Increasing amounts of data support the possibility that redundancy of pathways that regulate vascular network remodeling allows tumors to adapt in different conditions. Hypothesizing that alternative forms of neovascularization upregulate when SA is pharmacologically blocked, targeting two or more different pathways of neovascularization could be a promising future strategy. Further research is required to explore molecular mechanisms of neovascularization in TC.

Anti-cancer Effects of HNHA and Lenvatinib by the Suppression of EMT-Mediated Drug Resistance in Cancer Stem Cells.

Anaplastic thyroid cancer (ATC) constitutes less than 2% of total thyroid cancers but accounts for 20-40% of thyroid cancer-related deaths. Cancer stem cell drug resistance represents a primary factor hindering treatment. This study aimed to develop targeted agents against thyroid malignancy, focusing on individual and synergistic effects of HNHA (histone deacetylase), lenvatinib (FGFR), and sorafenib (tyrosine kinase) inhibitors. Patients with biochemically and histologically proven papillary thyroid cancer (PTC) and ATC were included. Cell samples were obtained from patients at the Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. PTC and ATC cells were treated with lenvatinib or sorafenib, alone or in combination with HNHA. Tumor-bearing mice (10/group) were administered 10 mg/kg lenvatinib (p.o.) or 40 mg/kg sorafenib (p.o.), alone or in combination with 25 mg/kg HNHA (i.p.) once every three days. Gene expression in patient-derived PTC and ATC cells was compared using a microarray approach. Cellular apoptosis and proliferation were examined by immunohistochemistry and MTT assays. Tumor volume and cell properties were examined in the mouse xenograft model. HNHA-lenvatinib combined treatment induced markers of cell cycle arrest and apoptosis and suppressed anti-apoptosis markers, epithelial-mesenchymal transition (EMT), and the FGFR signaling pathway. Combined treatment induced significant tumor shrinkage in the xenograft model. HNHA-lenvatinib combination treatment thus blocked the FGFR signaling pathway, which is important for EMT. Treatment with HNHA-lenvatinib combination was more effective than either agent alone or sorafenib-HNHA combination. These findings have implications for ATC treatment by preventing drug resistance in cancer stem cells.

LncRNA-MALAT1 Promotes Angiogenesis of Thyroid Cancer by Modulating Tumor-Associated Macrophage FGF2 Protein Secretion.

Tumor-associated macrophages (TAMs) in the tumor microenvironment have been associated with enhanced tumor progression. In this study, we investigated the role and molecular mechanisms of MALAT1 in TAMs derived from thyroid cancer. The expression of MALAT1 and FGF2 in thyroid cancer tissues and cells were measured by quantitative real-time PCR and Western blot. TAMs were transfected with indicated constructs. Then the culture medium (CM) from TAMs was harvested for assay. Secreted FGF2 protein levels and TNF-α, IL-12, and IL-10 levels were detected by ELISA. The cell proliferation, migration, and invasion of FTC133 cells were determined with a CCK-8 assay and a Transwell assay, respectively. In addition, HUVEC vasculature formation was measured by matrigel angiogenesis assay. The higher levels of MALAT-1 and FGF2 were observed in thyroid cancer tissues and in thyroid cancer cells compared to that in the control. Besides, in the presence of si-MALAT1, the levels of TNF-α and IL-12 were significantly up-regulated whereas IL-10 was down-regulated in the CM from TAMs. Moreover, down-regulation of MALAT1 in TAMs reduced proliferation, migration, and invasion of FTC133 cells and inhibited angiogenesis. However, overexpression of FGF2 blocked the effects of MALAT1 siRNAs on cell migration, invasion, and angiogenesis. Our results suggest that MALAT1-mediated FGF2 protein secretion from TAMs inhibits inflammatory cytokines release, promotes proliferation, migration, and invasion of FTC133 cells and induces vasculature formation. J. Cell. Biochem. 118: 4821-4830, 2017. © 2017 Wiley Periodicals, Inc.

Antitumor activity of fucoidan in anaplastic thyroid cancer via apoptosis and anti-angiogenesis.

The present study demonstrated the effect of fucoidan, isolated from Fucus vesiculosus, on cell growth and apoptosis in anaplastic thyroid cancer cells. The cell viability was analyzed using a Cell Counting Kit­8 cell proliferation kit. Diamidino-2-phenylindole and terminal deoxynucleotidyl transferase-mediated dUTP nick­end labeling assays were used to examine the apoptotic effect of fucoidan, which revealed the presence of apoptotic bodies and DNA fragmentation. Fucoidan inhibited the growth of FTC133 and TPC1 ATC cells in a dose­dependent manner. It also induced the apoptosis of FTC133 cells by promoting the expression levels of cleaved poly ADP­ribose polymerase and caspase­3. Significant decreases in the levels expression of hypoxia-inducible factor 1α and vascular endothelial growth factor were observed in the FTC133 cells following treatment of the cells with fucoidan. In addition, inhibition in tube formation and the migration of FTC133 cells were observed in the cells treated with fucoidan, compared with the cells in the control group. Therefore, fucoidan inhibited cell growth, induced apoptosis and suppressed angiogenesis in the thyroid cancer cells.

Angiogenic and lymphangiogenic profiles in histological variants of papillary thyroid carcinoma.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is a well­differentiated tumor that occurs in several histological variants whose biological behaviors remain unclear. Angiogenesis and lymphangiogenesis are critical processes that enable tumor progression. OBJECTIVES: The aim of this study was to evaluate the angiogenic and lymphangiogenic phenotypes of PTC, considering the differences between histological variants. PATIENTS AND METHODS: Angiogenic and lymphangiogenic profiles were analyzed by determining microvascular density (MVD) and lymphatic vessel density (LVD) in 73 cases of PTC, using immunohistochemistry. To assess the biological markers involved in blood and lymph vessel formation, the expression of vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX­2), and p27kip1 (p27) was determined. RESULTS: MVD was significantly higher in patients with high­risk PTC and in those with local extrathyroidal and vascular invasion. Positive VEGF expression was strongly associated with high MVD and age­related tumor enlargement. The presence of lymph vessel invasion was associated with the expression of either VEGF or COX­2. The analysis of angiogenesis and lymphangiogenesis in different histological variants of PTC revealed elevated LVD rather than MVD in the follicular variant of PTC (FV­PTC).Lower MVD was observed in FV­PTC relative to the classic variant of PTC (CV­PTC). The frequency of VEGF­positive tumors was higher in CV­PTC than in FV­PTC. A significant association between COX­2 and p27 expression was observed in FV­PTC but not in CV­PTC. CONCLUSIONS: These results suggest that VEGF, COX­2, and p27 may be important biological markers that determine the angiogenic and lymphangiogenic potentials of PTC, particularly between the follicular and classic variants.

Predicting lymph node metastasis in patients with papillary thyroid carcinoma by vascular index on power Doppler ultrasound.

BACKGROUND: For patients with papillary thyroid carcinoma (PTC), lymph node metastasis is associated with an increased recurrence rate. The purpose of this study was to investigate whether the vascular endothelial growth factor (VEGF), microvessel density (MVD), and vascular index (VI) can predict lymph node metastasis in patients with PTC. METHODS: From January 2011 to October 2011, 202 patients with PTCs underwent preoperative staging ultrasound evaluation. To evaluate vascularity, we measured the VI, VEGF expression, and MVD. RESULTS: The VI was significantly correlated with MVD (p = .009). On multivariate analysis, young age showed a significant correlation with lymph node metastasis (p < .001; p < .001; p < .001). However, the other clinicopathologic features, VEGF, MVD, and VI failed to show any significant correlations with lymph node metastasis. CONCLUSION: Although the VI showed significant correlation with MVD, it was not significantly correlated to lymph node metastasis. © 2016 Wiley Periodicals, Inc. Head Neck 39: 334-340, 2017.

[The clinical anatomy of the inferior thyroid arteries and veins and the safety of the modified tracheotomy].

Objective:To evaluated the clinical anatomy of the inferior thyroid arteries and veins and the safety of clinical application of the modified tracheotomy. Method:Sixty patients who need partial resection or full resection of thyroid cancer and 50 patients with laryngeal or hypopharyngeal cancer required tracheotomy were enrolled in this study. The distribution of the inferior thyroid arteries and veins closely related to tracheotomy is further dissected. The inverted "U" type of tracheal flap tracheotomy was further improved based on anatomical findings. Finally, the further modified tracheotomy was used for clinical practice and compared with the conventional tracheotomy and the inverted "U" type of tracheal flap tracheotomy. Result:Of the 110 cases, the lowest thyroid artery was found in 11 cases, with a rate of 10%. The inferior thyroid vein has 2-4 branches, which originates from the lower lobe or isthmus of the thyroid lateral lobe, descending in the anterior tracheal space. According to the characteristics of the static reflux of the thyroid gland, the lower thyroid vessels are classified into four types: intravenous dry type (28 cases); intravenous double dry without traffic type (43 cases); intravenous double trunk with traffic (28 cases); mixed type (11 cases). At present, the further modified tracheotomy can effectively avoid the rebleeding of the lower thyroid arteries and veins. There were no bleeding and other complications in all cases. Conclusion:It provides a basis for the further modified of tracheotomy based on the clinical anatomy of the inferior thyroid artery and vein, which is closely related to tracheotomy. The further modified tracheotomy has certain advantages than the conventional tracheotomy and the inverted "U" type of tracheal flap tracheotomy.

Interactive role of miR-126 on VEGF-A and progression of papillary and undifferentiated thyroid carcinoma.

MicroRNA-126 (miR-126) expression has been shown to be associated with angiogenesis. The aim of the current study is to evaluate the functional roles of miR-126 in dysregulation of VEGF expression and cancer progression in thyroid carcinomas. The expression of VEGF-A and miR-126 were measured in 101 thyroid carcinomas tissues (including 51 conventional papillary thyroid carcinoma, 37 follicular variant of papillary thyroid carcinoma, and 13 undifferentiated thyroid carcinomas), 13 matched lymph nodes with metastatic thyroid carcinoma, 21 benign thyroid tissues, and 5 thyroid carcinoma cell lines (both papillary and undifferentiated carcinomas). Then, exogenous miR-126 was transfected, and the expressions of VEGF-A were determined (Western blot technique). Proliferation assay, cell cycle analysis, and apoptosis assays were used to evaluate the role of miR-126 in these events. Significant underexpression of miR-126 levels in thyroid cancer tissues and cell lines was detected using real-time polymerase chain reaction. Introducing exogenous miR-126 into the cancer cell lines resulted in a significant reduction of VEGF-A protein expression. Marked inhibition in proliferation, cell cycle arrest in G0-G1, and promotion of total apoptosis were also noted. The modulatory role of miR-126 on expression of VEGF-A and its tumor suppressive roles were demonstrated for the first time in thyroid cancer. The current experiments provided specific information on the functional consequences of VEGF manipulation via microRNA on cancer.

Vascular invasion is an independent prognostic factor for distant recurrence-free survival in papillary thyroid carcinoma: a matched-case comparative study.

OBJECTIVE: It is still unclear whether the clinicopathological and outcome characteristics of vascular invasion (VI) (+) papillary thyroid carcinoma (PTC) differ from VI (-) PTC. This study aims to establish distinguishing features of patients with VI (+) and VI (-) PTC and to investigate the biological and clinical aggressiveness of the disease in these patient groups. DESIGN: A matched-case comparative study. METHODS: 412 patients (VI (+) PTC study group n=103, and VI (-) PTC control group n=309). These two patient groups were matched 1:3 for variables of age, gender, histological variants, tumour/node/metastasis (TNM) staging and approximate duration of follow-up. Clinicopathological factors and prognosis were compared across the two patient groups. RESULTS: The median age at the time of diagnosis was 42.0 years, and 68.9% were females. Across the patient groups, the incidence of tumour multifocality in patients with VI (+) PTC was slightly higher than in those with VI (-) PTC (p=0.049). In addition, when undergoing more aggressive therapy regimens patients with VI (+) PTC showed decreased distant recurrence-free survival (DRFS), but not regional recurrence-free survival (RRFS) and disease-specific survival (DSS) compared with patients who were VI (-). VI was found to be an independent predictor of DRFS, combined with tumour size >3 cm and total thyroidectomy. CONCLUSIONS: VI was an independent risk factor for DRFS, necessitating the need for appropriate postoperative treatment and careful follow-up.

Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF(V600E).

Cachexia is the result of complex metabolic alterations which cause morbidity and mortality in patients with advanced cancers including undifferentiated (anaplastic) thyroid carcinoma (ATC). ATC is a lethal disease with limited therapeutic options and unclear etiology for cachexia. We hypothesize that the BRAF(V600E) oncoprotein triggers microvascular endothelial cell tubule formation (in vitro angiogenesis) by means of factors which play a crucial role in angiogenic switch, inflammation/immune response and cachexia. We use human ATC cells and applied multiplex ELISA assay to screen for and measure angiogenic/cachectic and pro-inflammatory factors in the ATC-derived secretome. We find that vemurafenib anti-BRAF(V600E) therapy significantly reduces secreted VEGFA, VEGFC and IL6 protein levels compared to vehicle-treated ATC cells. As a result, the secretome from vemurafenib-treated ATC cells inhibits microvascular endothelial cell-related in vitro angiogenesis. Furthermore, ATC clinical samples express VEGFA, VEGFC and IL6 proteins. Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAF(V600E)-positive human ATC aggressiveness. Understanding the extent to which microenvironment-associated angiogenic factors participate in cachexia and cancer metabolism in advanced thyroid cancers will reveal new biomarkers and foster novel therapeutic approaches.

Quantitative Evaluation of Vascularity Using 2-D Power Doppler Ultrasonography May Not Identify Malignancy of the Thyroid.

The purpose of this study was to evaluate the usefulness of a quantitative vascular index in predicting thyroid malignancy. A total of 1309 thyroid nodules in 1257 patients (mean age: 50.2 y, range: 18-83 y) were included. The vascularity pattern and vascular index (VI) measured by quantification software for each nodule were obtained from 2-D power Doppler ultrasonography (US). Gray-scale US + vascularity pattern was compared with gray-scale US + VI with respect to diagnostic performance. Of the 1309 thyroid nodules, 927 (70.8%) were benign and 382 (29.2%) were malignant. The area under the receiver operating characteristics curve (Az) for gray-scale US (0.82) was significantly higher than that for US combined with vascularity pattern (0.77) or VI (0.70, all p < 0.001). Quantified VIs were higher in benign nodules, but did not improve the performance of 2-D US in diagnosing thyroid malignancy.