Interleukins in Thyroid Cancer: From Basic Researches to Applications in Clinical Practice.

Inflammation is crucial to tumorigenesis and progression of many cancers. Inflammatory molecules in tumor microenvironment exert pro- or anti-tumor effects. Among them, interleukin, mainly produced by CD3+ and CD4+ T lymphocytes, is a class of small molecule proteins which play an important role in intercellular communication. Numerous studies have confirmed that interleukins are closely related to thyroid cancer. Interleukins regulate the proliferation and migration of thyroid cancer cells and they have prospects in discriminating benign and malignant thyroid diseases, predicting the risk of tumorigenesis, evaluating the prognosis and monitoring the recurrence of thyroid cancer. Besides, the effective application of interleukins in treatment of thyroid cancer has been confirmed by some cell and animal researches. The present review will introduce the potential mechanisms of interleukins in thyroid cancer and focus on the applications of interleukins in clinical practice of thyroid cancer, which will help update understanding of the progress of interleukins researches in thyroid cancer.

Distant metastases from pathologically proven benign follicular nodules of the thyroid: clinicopathological features and predictors of long-term survival.

OBJECTIVE: Distant metastases are rarely observed in patients with initial pathologically proven benign follicular nodules of the thyroid. This study aimed to evaluate the clinicopathological features and independent variables associated with survival in such patients with distant metastases. METHODS: In total, 10,992 consecutive differentiated thyroid cancer (DTC) patients treated with 131I after total or near-total thyroidectomy from 2000 to 2018 were retrospectively reviewed. RESULTS: Thirty-nine patients with initial pathologically proven benign follicular nodules of the thyroid were enrolled. Among them, 26 were pathologically diagnosed as thyroid adenoma, 8 as benign nodular goiter, 4 as thyroid adenoma combined with benign nodular goiter, and 1 as normal thyroid tissue. Of 26 patients with the initial pathological slides obtained, eight cases were rediagnosed as minimally invasive thyroid carcinoma (MI-FTC), 10 as follicular tumor of uncertain malignant potential (FT-UMP), and five as well-differentiated tumor of UMP (WDT-UMP). Monitoring of thyroglobulin (Tg) changes after initial thyroidectomy and preablation-stimulated Tg (psTg) level were significantly associated with 5-year OS rate (P = 0.007 and P = 0.005, respectively). The presence of radioactive-refractory DTC (RR-DTC), monitoring of Tg changes after initial thyroidectomy, and psTg level had significant effects on 10-year OS rate (P = 0.002, P < 0.001, and P = 0.005, respectively). Lack of monitoring of Tg changes after initial thyroidectomy and RR-DTC were independent factors associated with poor prognosis (P = 0.003 and P = 0.008, respectively). CONCLUSIONS: MI-FTC, FT-UMP, and WDT-UMP tended to be ignored and/or misdiagnosed as benign follicular lesions. Lack of monitoring of Tg changes after initial thyroidectomy and the presence of RR-DTC were identified as independent factors associated with poor survival.

Long-Term Outcomes and Prognoses of Elderly Patients (≥65-Years-Old) With Distant Metastases From Well-Differentiated Thyroid Cancer During Radioiodine Therapy and Follow-Up.

Objective: The objective of this study was to investigate the clinicopathological characteristics, long-term outcomes, and prognostic factors of elderly patients with distant metastases at initial diagnosis from well-differentiated thyroid cancer (WDTC) during radioactive iodine (131I) treatment and follow-up. Methods: A retrospective review of medical records identified 183 elderly patients with DTC who underwent 131I treatment at our institution between 2006 and 2019. Results: In total, 57 elderly WDTC patients with distant metastases were enrolled in this study. After 131I treatment, 32 (56.14%) patients had 131I avidity and 25 (43.86%) had non-131I avidity; 35 (61.40%) cases were classified as radioiodine refractory (RR)-WDTC and 22 (38.60%) as non-RR-WDTC. At the end of follow-up, 25 (43.86%) patients had died and 32 (56.14%) were alive. The 5- and 10-year overall survival (OS) rates were 71.50% and 30.49%, respectively, while the 5- and 10-year disease-specific survival (DSS) rates were 76.89% and 48.71%, respectively. Multivariate analyses showed that gross extrathyroidal extension and RR-DTC were independent prognostic factors for poor OS (P=0.04 and P=0.03, respectively), while gross extrathyroidal extension, extrapulmonary distant metastases, and RR-WDTC were independent prognostic factors for poor DSS at the end of follow-up (P=0.02, P=0.03, and P=0.02, respectively). Conclusions: WDTC with distant metastases at initial diagnosis accounted for 31.15% of all elderly patients with DTC. Gross extrathyroidal extension and RR-DTC were the major factors associated with poor OS; gross extrathyroidal extension, extrapulmonary distant metastases, and RR-DTC were independent prognostic factors for poor DSS in elderly DTC patients with distant metastases.

Targeted next-generation sequencing in papillary thyroid carcinoma patients looking for germline variants predisposing to the disease.

PURPOSESS: The purpose of this study was using next-generation sequencing technique to explore the potential association between germline variants of 14 targeted genes and papillary thyroid carcinoma (PTC) predisposition as well as disease progression. METHODS: In all, 516 subjects were enrolled in this study including 416 PTC patients and 100 healthy controls. PTC patients were divided into distant metastasis group and non-distant metastasis group. Patients in distant metastasis group were further divided into radioiodine-refractory PTC (RR-PTC) and non-RR-PTC depending on their response to radioiodine therapy. Genomic DNA was extracted from peripheral blood sample and MiSeq Benchtop Sequencer was used for sequencing. RESULTS: We found rs11246050 in NLRP6 (dominant model, OR/95% CI: 2.028/1.091-3.769, p = 0.025), rs2286742 and rs3740530 in HABP2 (recessive model, OR/95% CI: 9.644/1.307-71.16, p = 0.026 and 3.989/1.413-11.26, p = 0.009), rs2736098 in TERT (recessive model, OR/95% CI: 2.322/1.028-5.242. p = 0.042) and rs62054619 in GAS8-AS1 (recessive model, OR/95% CI: 2.219/1.067-4.617, p = 0.033) were associated with the risk of PTC. rs1137282 in KRAS (dominant model, OR/95% CI: 0.5430/0.3192-0.9236, p = 0.024), rs1347591 and rs4461062 in NUP93 (dominant model, OR/95% CI: 0.6121/0.4128-0.9076, p = 0.015 and 0.6156/0.4157-0.9117, p = 0.015) were associated with low risk of distant metastatic disease in PTC patients. rs33954691 in TERT was associated with the risk of RR-PTC under dominant model (OR/95% CI: 3.161/1.596-6.262). CONCLUSIONS: Germline variants of related genes could be associated with the susceptibility of PTC as well as disease progression (distant metastasis and radioiodine-refractory status). However, these results must be further verified and the potential biological functions of these germline variants in the pathogenesis of PTC remain to be determined in future studies.

A Preliminary Study of Ankle Single Photon Emission Computed Tomography/Computed Tomography in Patients With Bony Impingement Syndrome: Association With the Visual Analogue Scale Pain Score.

Both osteoarthritis and impingement syndrome are the disorders commonly observed in sports medicine. However, failure in pain alleviation by surgical intervention introduces challenges in the diagnosis and decision-making for orthopedists. Hybrid single photon emission computed tomography/computed tomography (SPECT/CT) provides both functional and structural information of ankle pathology. The purpose of this retrospective study was to evaluate whether bone tracer uptake by ankle SPECT/CT is related to the lesion type and visual analog scale (VAS) pain score for patients with osteoarthritis and bony impingement. Fifty individuals with chronic ankle pain who underwent pretreatment ankle SPECT/CT were included in the current study. The median follow-up period was 2.5 (range 1.8 to 3.2) years. The lesion types were categorized by the positions of anatomical changes and bone tracer uptake. The VAS pain score was recorded 2 weeks before and 1.5 year after surgical intervention. Twenty-nine (58%) of 50 patients had osseous impingement. Among them, 16 (55.2%), 4 (13.8%), and 9 (31%) patients had anterior, posterior, and both types of ankle impingement, respectively. The uptake grade of bone tracer was significantly related to the lesion type of ankle impingement (p < .001). The VAS pain score was significantly correlated with bone tracer uptake before treatment (p < .001). Bone tracer uptake was related to the lesion type of impingement detected by SPECT/CT and was confirmed by surgical findings. The VAS pain score was significantly correlated with the bone tracer uptake. Preoperative ankle SPECT/CT may be helpful to clinically correlate the VAS pain score in the pre- and postsurgical periods for patients with osteoarthritis and bony impingement syndrome.

PROGRAMMED CELL DEATH-LIGAND 1 OVEREXPRESSION IN THYROID CANCER.

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) expression on tumor tissue has been associated with favorable response to anti-programmed cell death-receptor 1/PD-L1 therapy in many human cancers. Studies have reported that PD-L1 is also expressed in thyroid cancer. The objective of this paper is to introduce the potential predictive and therapeutic values of PD-L1 in thyroid cancer. METHODS: A literature search was conducted in the PubMed database using the terms "PD-L1," "B7-H1," and "thyroid cancer." PD-L1 positivity was determined by immunohistochemical assay. RESULTS: The frequency of PD-L1 positivity in different studies ranged from 6.1 to 82.5% in papillary thyroid cancer (PTC) patients and 22.2 to 81.2% in anaplastic thyroid cancer (ATC) patients. PD-L1 positivity rate was higher in ATC than in PTC within the same studies, and its expression intensity was significantly higher in tumor tissue than in the corresponding nontumor thyroid tissues. Moreover, PD-L1 expression was positively associated with the aggressiveness and recurrence of thyroid cancers and negatively associated with the differentiation status and outcomes. PD-L1 checkpoint pathway blockade may emerge as a promising therapeutic target in the treatment of thyroid cancers. CONCLUSION: PD-L1 is a potential biomarker to predict the recurrence and prognosis of thyroid cancers. It is also a novel immunotherapy target for optimizing the management landscape of radioiodine-refractory and ATCs. ABBREVIATIONS: ATC = anaplastic thyroid cancer; DTC = differentiated thyroid cancer; IHC = immunohistochemical; OS = overall survival; PD-1 = programmed cell death-receptor 1; PD-L1 = programmed cell death-ligand 1; PD-L2 = programmed cell death-ligand 2; PTC = papillary thyroid cancer; TNM = tumor-node-metastasis; Treg = regulatory T cell.

Lung Metastases From Papillary Thyroid Cancer With Persistently Negative Thyroglobulin and Elevated Thyroglobulin Antibody Levels During Radioactive Iodine Treatment and Follow-Up: Long-Term Outcomes and Prognostic Indicators.

Background: The lung is the most frequent site of distant metastasis from differentiated thyroid cancer (DTC). However, lung metastasis from papillary thyroid cancer (PTC) with persistently negative thyroglobulin (Tg) and elevated Tg antibody (TgAb) levels is an extremely rare entity, and the prognosis is therefore elusive. We investigated the clinical characteristics, long-term outcomes, and prognostic factors of lung metastases in PTC patients with persistently negative thyroglobulin (Tg) and elevated Tg antibody (TgAb) levels during radioactive iodine (131I) treatment and follow-up. Methods: We retrospectively reviewed 10,482 patients with DTC who underwent postoperative 131I treatment from 2007 to 2017 at Shanghai Sixth's People's Hospital. The relationships between progression-free survival (PFS) and several variables were assessed by univariate and multivariate analyses using the Kaplan-Meier method and a Cox proportional hazards model, respectively. Results: Forty-seven patients with PTC were enrolled in this study (4.48‰ of all patients with DTC). The median age at the initial diagnosis of lung metastasis was 39.6 ± 15.4 years, and the patients comprised 14 male and 33 female patients (male: female ratio = 1.00:2.36). Twenty-five patients had 131I avidity and 22 had non-131I avidity. At the end of the 5-years follow-up, 12 patients exhibited progressive disease (PD), and 2 patients had died. At the end of the 10-years follow-up, 21 patients showed PD and five patients had died. The 5- and 10-year PFS rates were 74.47 and 53.32%, respectively; the 5- and 10-years overall survival (OS) rates were 95.74 and 89.36%, respectively. The timing of diagnosis of lung metastases, maximal size of lung metastases, and 131I avidity were significantly associated with the 5-years PFS rate (P = 0.035, P = 0.030, and P<0.001, respectively). Only 131I avidity was associated with the 10-years PFS rate (P < 0.001). The multivariate analyses also showed that non-131I avidity were the independent poor prognostic factors for 10-years PFS at the end of follow-up (P < 0.001). Conclusions: Lung metastases from PTC in patients with persistently negative Tg and elevated TgAb levels had an excellent prognosis and survival rate during 131I treatment and follow-up. The loss of 131I avidity remained the strongest independent predictor of a poor prognosis and survival in these patients.

99mTc-MDP Bone Scan and 18F-FDG PET/CT Imaging of Multiple Extraskeletal Osteosarcomas.

Extraskeletal osteosarcomas are uncommon entities in clinical practice, which account for 1% to 2% of all soft tissue sarcomas. We here reported a case of multiple extraskeletal osteosarcomas and nuclear medicine imaging findings of this disease in Tc-MDP bone scan as well as F-FDG PET/CT.

Pulmonary metastases in children and adolescents with papillary thyroid cancer in China: prognostic factors and outcomes from treatment with 131I.

PURPOSE: Papillary thyroid carcinoma (PTC) with pulmonary metastases is rare in children and adolescents. Unlike adults, limited data are available on children with this disease. Thus, this study evaluated the therapeutic efficacy and prognostic factors of individuals less than 21 years of age with pulmonary metastases from PTC. METHODS: Seventy-six children and adolescents with pulmonary metastases from PTC treated with 131I were retrospectively analyzed. Therapeutic efficacy was evaluated by changes in serum thyroglobulin (Tg) and chest computed tomography (CT). Factors predictive of progression-free survival and overall survival were measured by the Kaplan-Meier method. RESULTS: Among the 76 patients included in this study, 22.4% (17 of 76) were less than 15 years old and 65.8% (50 of 76) were female. Under the evaluation of stimulated serum Tg levels, RAI treatment were effective in 55.9% (38 of 68), stable in 26.5% (18 of 68) and ineffectvie in 17.6% (12 of 68) of patients. Changes on anatomical imaging suggested complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) in 8.5, 62.0, 15.5, and 14.1% of individuals, respectively. Univariate analysis showed that size and tumor doubling time of pulmonary metastases were independent factors affecting therapeutic efficacy. Extra-thyroidal extension, tumor diameter of pulmonary metastases and tumor doubling time were significant independent factors regarding progression-free survival rates, while only tumor doubling time and tumor diameter were significant risk factors associated with overall survival rate. CONCLUSIONS: Radioactive iodine therapy is an effective treatment for children and adolescents with pulmonary metastases from PTC. Extra-thyroid extension was associated with disease progression while did not show significant influence on overall survival. Tumor doubling time and tumor diameter were the main factors influencing both progression-free survival and overall survival.

Circulating Tumor Cells Correlate with Clinicopathological Features and Outcomes in Differentiated Thyroid Cancer.

BACKGROUND/AIMS: As biomarkers, circulating tumor cells (CTCs) from solid tumors can predict metastases and prognoses, and help monitor treatment efficacy. However, conventional CellSearch methods have low sensitivity to differentiated thyroid cancer (DTC) CTCs. In this study, for the first time, we used negative enriching (NE) immunofluorescence-in situ hybridization (iFISH) of chromosome 8 to capture and identify CTCs in DTC patients; and investigated how CTCs correlate with clinicopathological factors and prognosis in DTC patients with distant metastases (DM). METHODS: In this prospective study, we enrolled 72 patients with DTC before they underwent 131I treatment, and 30 healthy controls (HC). Their CTCs were measured in 7.5 ml peripheral blood using the NE-iFISH technique. CTC was defined by the aneuploidy. RESULTS: We detected CTCs in 62 (86.1%) of the 72 subjects with DTC. The mean number of CTCs in patients with DTC with DM (DM+) was significantly higher than in the HC group (P< 0.001) and DTC patients without DM (DM-; P=0.0016). We found CTCs ≥ 5 was significantly associated with DM+ DTC (P=0.009; sensitivity: 64.3%; specificity: 83.8%); CTCs ≥ 7 was related to poor response to 131I treatment (sensitivity: 73.7 %; specificity: 69.6 %), and was also associated with worse prognosis in DM+ DTC (P< 0.001). CONCLUSION: We found CTCs ≥ 5 to be a potential predictive index for DM+ DTC; and CTCs ≥7 as a possible indicator of poor response to 131I treatment and worse prognosis in DM+ DTC.

Dual time-point 18F-FDG PET/CT imaging with multiple metabolic parameters in the differential diagnosis of malignancy-suspected bone/joint lesions.

The purpose of this study was to evaluate the diagnostic potential of dual time-point18F-FDG PET/CT imaging with multiple metabolic parameters in malignancy-suspected bone/joint lesions. Fifty seven consecutive patients were recruited. PET parameters including SUVmax, SUVmean, metabolic tumor volume (MTV), total lesional glycolysis (TLG) and retention indexes (RIs) were obtained. Thirty five malignant and 22 benign lesions were confirmed by pathology. In all, 48 receiver operating characteristic (ROC) curves were derived. For SUVmax, MTV2.0, TLG2.0, MTV2.5 and TLG2.5, areas under the curves (AUCs) of early time-point imaging were similar to those of delayed time (P > 0.05), while higher than those of dual time (P< 0.05). For MTV50%max, TLG50%max, MTV75%max and TLG75%max, AUCs of early time-point imaging were lower than those of delayed time (P< 0.05), while similar to those of dual time (P> 0.05). In conclusion, dual time-point18F-FDG PET/CT imaging shows limited value in the differential diagnosis of malignancy-suspected bone/joint lesions. However, MTV and TLG at a fixed SUV threshold (50% or 75% of SUVmax) in delayed time-point imaging may provide better diagnostic accuracy.

Thyroid autoimmune antibodies in patients with papillary thyroid carcinoma: a double-edged sword?

PURPOSE: The relationship between thyroid autoimmunity and thyroid cancer remains controversial. The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma (PTC). METHODS: Patients were divided into different groups according to their final diagnoses after radioiodine therapy as well as their serum anti-thyroglobulin antibody (TgAb) and anti-thyroidperoxidase antibody (TPOAb) titers. Clinicopathologic characteristics were then compared between groups. RESULTS: In all, 1126 PTC patients met the inclusion criteria. When compared with thyroid autoimmune antibody negative group, patients in positive group were young female predominant. After age and gender adjusted, patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment. Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403 (95% CI 0.216-0.622, p < 0.001). Additionally, subgroup analysis demonstrated single TgAb positivity and combined positivity of TgAb and TPOAb were shown to be related to less distant metastatic disease. CONCLUSIONS: Positive thyroid auto-antibody status could be a risk factor of more metastatic cervical lymph nodes while a protective factor of distant metastatic disease in PTC patients. The association between thyroid autoimmunity and thyroid cancer can be patient and antibody specific. A systemic immunosupression status may exist in PTC patients with distant metastasis.

A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma.

BACKGROUND: Although the incidence rate for thyroid cancer seems to have begun stabilizing in recent years, an increased rate of advanced stage of this disease has been reported. Additionally, distant metastasis is one of the most important prognostic factors of patients with papillary thyroid carcinoma (PTC). Unfortunately, the underlying mechanisms of distant metastasis, as well as cell status like metabolism changes in distant metastatic tumours have not been clearly elucidated. OBJECTIVE: To identify serum metabolic signature of distant metastatic PTC. DESIGN, PATIENTS AND MEASUREMENTS: In this study, gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS) was used to analyse the serum from 77 patients diagnosed with PTC (37 in distant metastasis group and 40 in ablation group). Principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA) scores plots were used to analyse the data. RESULTS: Principal component analysis and OPLS-DA analyses demonstrated an evident trend of separation between 40 serum samples from the ablation group and 37 samples from distant metastasis group. A total of 31 metabolites were identified, which are related to amino acid, lipid, glucose, vitamin metabolism and diet/gut microbiota interaction. Pathway analysis showed "alanine, aspartate and glutamate metabolism" and "inositol phosphate metabolism" were the most relevant pathways. CONCLUSION: Serum metabolomics profiling could significantly discriminate papillary thyroid cancer patients according to distant metastasis. Potential metabolic aberration in distant metastatic PTC could be involved in different biological behaviours of tumour cells including proliferation, invasion/migration and immune escape. Diet/gut microbiota-produced metabolites could play an important role in these effects. This work may provide new clues to find the underlying mechanisms regarding the distant metastasis of PTC as well as potential adjuvant therapy targets.

Value of 99mTc-MDP SPECT/CT and 18F-FDG PET/CT scanning in the evaluation of malignantly transformed fibrous dysplasia.

Although fibrous dysplasia is not considered a potentially premalignant disorder, malignant transformation occurs. Because of its rarity, radiographic features of malignantly transformed fibrous dysplasia on cross-sectional imaging modalities are less recognized, making diagnosis and differential diagnosis of the disease quite difficult in clinical practice. In this study, we analyzed the clinical characteristics, imaging features, pathology findings and surgery strategies of 19 malignantly transformed fibrous dysplasia. We found that there was significant male predominance in this specific cohort (13/6). While osteosarcoma (63.2%) was the most frequently occurring neoplasm secondary to fibrous dysplasia, other less commonly malignantly changed types included fasciculated sarcoma, malignant fibrous histiocytoma, fibrosarcoma and chondrosarcoma. We found that the diagnostic value of single modality imaging method, like conventional X-ray, computed tomography or non-contrast magnetic resonance imaging, was limited mainly because of a lack of whole-body metabolic information. In contrast, we highlighted that 99mTc-MDP SPECT/CT and/or 18F-FDG PET/CT scanning could exert a pivotal role in the management of malignantly transformed fibrous dysplasia by guiding precise biopsy and optimizing surgery options.

Adefovir-Induced Hypophosphatemic Osteomalacia Mimicking Bone Metastases From Primary Hepatocarcinoma.

Adefovir-induced hypophosphatemic osteomalacia in the context of hepatocarcinoma is rare and needs to be differentiated from metastatic hepatocarcinoma. We here report a case of severe osteomalacia whose focal uptakes of radiotracer on the Tc-MDP SPECT/CT images mimicked that of metastatic hepatocarcinoma.

Diagnostic Performance of 18F-FDG PET/CT in Papillary Thyroid Carcinoma with Negative 131I-WBS at first Postablation, Negative Tg and Progressively Increased TgAb Level.

Differentiated thyroid cancer (DTC) patients with negative serum thyroglobulin (Tg), negative 131I whole-body scintigraphy (131I-WBS) at first post-ablation and progressively increased TgAb level are a relatively rare entity in the follow-up after total thyroidectomy and radioactive iodine therapy. The value of 18F-FDG PET/CT in detecting the recurrence of disease in these patients has only been reported in a small case series. The goal of this study was to investigate the diagnostic accuracy of 18F-FDG PET/CT in detecting recurrent disease in these specific PTC patients and to identify risk factors for patients with positive 18F-FDG PET/CT results. Eighty-two PTC patients who had 18F-FDG PET/CT scans with negative Tg, negative 131I-WBS at first post-ablation and progressively increased TgAb levels were included. We found that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT in this patient group were determined as 84%, 72%, 92%, 57% and 82%, respectively. 18F-FDG PET/CT scan had a good diagnostic performance and should be performed routinely in PTC patients with negative Tg, negative 131I-WBS at first postablation and progressively increased TgAb level, especially when span for progressively increased TgAb level ≥ 3 years and/or progressively increased TgAb value up to 150 IU/mL.

Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer.

Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAFV600E mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.

Metformin reduces glycometabolism of papillary thyroid carcinoma in vitro and in vivo.

More aggressive thyroid cancer cells show a higher activity of glycometabolism. Targeting cancer cell metabolism has emerged as a novel approach to prevent or treat malignant tumors. Glucose metabolism regulation effect of metformin in papillary thyroid cancer was investigated in the current study. Human papillary thyroid carcinoma (PTC) cell lines BCPAP and KTC1 were used. Cell viability was detected by CCK8 assay. Glucose uptake and relative gene expression were measured in metformin (0-10 mM for 48 h)-treated cells by 18F-FDG uptake assay and western blotting analysis, respectively. MicroPET/CT imaging was performed to detect 18F-FDG uptake in vivo After treatment with metformin at 0, 2.5, 5 and 10 mM for 48 h, the ratio of p-AMPK to total AMPK showed significant rising in a dose-dependent manner in both BCPAP and KTC1, whereas p-AKT and p-mTOR expression level were downregulated. 18F-FDG uptake reduced after metformin treatment in a dose-dependent manner, corresponding to the reduced expression level of HK2 and GLUT1 in vitro Xenograft model of PTC using BCPAP cells was achieved successfully. MicroPET/CT imaging showed that in vivo 18F-FDG uptake decreased after treatment with metformin. Immunohistochemistry staining further confirmed the reduction of HK2 and GLUT1 expression in the tumor tissue of metformin-treated PTC xenograft model. In conclusion, metformin could reduce glucose metabolism of PTC in vitro and in vivo Metformin, by targeting glycometabolism of cancer cells, could be a promising adjuvant therapy alternative in the treatment modality of advanced thyroid carcinoma.

Circulating Long Non-Coding RNAs Act as Biomarkers for Predicting 131I Uptake and Mortality in Papillary Thyroid Cancer Patients with Lung Metastases.

PURPOSE: The aims of the current study were to explore plasma lncRNAs as a novel biomarker panel for the diagnosis of non-131I-avid lung metastases of PTC and to investigate the plasma lncRNA expression levels associated with survival in PTC patients with lung metastases. METHODS: The expression of lncRNAs was examined using an lncRNA microarray chip. The lncRNAs with the most significant difference in expression between PTC patients with non-131I-avid lung metastases and PTC patients with 131I-avid lung metastases were verified by quantitative reverse-transcription polymerase chain reaction. The Kaplan-Meier method was used to determine whether the plasma lncRNA levels might be indicative of patient prognosis. RESULTS: Compared with 131I-avid lung metastases, we discovered that two lncRNAs (ENST00000462717 andENST00000415582) were upregulated and two (TCONS_00024700 and NR_028494) were downregulated in the non-131I-avid lung metastases of PTC. Receiver operating characteristic curve (ROC) analyses indicated that the use of these four lncRNAs had high diagnostic sensitivity and specificity for predicting non-131I-avid lung metastases of PTC. The merged areas under the curve for ENST00000462717, ENST00000415582, TCONS_00024700,and NR_028494 in the training and validation sets were 0.890, 0.936, 0.975, and 0.918, respectively. Low (ENST00000462717 and ENST00000415582) and high plasma lncRNA levels(TCONS_00024700and NR_028494) were also found to be associated with better prognosis of PTC patients with lung metastases(P<0.001). CONCLUSIONS: ENST00000462717, ENST00000415582, TCONS_00024700, and NR_028494 may be used as novel and minimally invasive markers for the diagnosis and prognostic assessment of non-131I-avid lung metastases from PTC.

Safety and efficacy of percutaneous vertebroplasty and interventional tumor removal for metastatic spinal tumors and malignant vertebral compression fractures.

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of percutaneous vertebroplasty and interventional tumor removal in the management of metastatic spinal tumors and malignant vertebral compression fractures. SUBJECTS AND METHODS: Thirty-one patients with metastatic spinal tumors and malignant vertebral compression fractures were treated with percutaneous vertebroplasty and interventional tumor removal. Insertion of a 14-gauge needle and guidewire into the vertebral body was followed by sequential dilation of the track with working cannulae until the last cannula reached the anterior portions of the pedicle. Interventional tumor removal was performed with marrow nucleus rongeurs, and 5-10 mL of cement was injected into the treated vertebra. Outcome data (visual analog scale score, Oswestry disability index score, and Karnofsky performance scale score) were collected preoperatively; 1 week and 1, 3, and 6 months after the procedure; and every 6 months thereafter until death. RESULTS: The overall clinical assessment at the last follow-up evaluation showed that pain was completely resolved in 23 patients, decreased in six patients, and unimproved in two patients, yielding a pain relief rate of 94%. The average preoperative visual analog scale score was 7.2, which decreased to 2.4 at 1 month, 1.9 at 6 months, and 1.6 at 1 year and was maintained at 1.3 at the follow-up evaluations performed after more than 1 year. Statistically significant improvement in Oswestry disability index and Karnofsky performance scale scores was also seen between the preoperative evaluation and every follow-up assessment postoperatively (p<0.001). CONCLUSION: Percutaneous vertebroplasty and interventional tumor removal are safe, effective, and minimally invasive palliative therapies for reducing pain and improving function in patients with metastatic spinal tumors and malignant vertebral compression fractures.