Zhen-Kui Sun

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.

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.

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.

Diagnostic Performance of 18 F-FDG PET/CT in Papillary Thyroid Carcinoma with Negative 131 I-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.

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

PurposeThe 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).MethodsPatients 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.ResultsIn 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.ConclusionsPositive 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.

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

PurposePapillary 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.MethodsSeventy-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.ResultsAmong 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.ConclusionsRadioactive 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 18 F-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 accuracyThe purpose of this study was to evaluate the diagnostic potential of dual time-point 18F-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-point 18F-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.

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.

A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma

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.