Context: Data from a large cohort of patients with pulmonary metastases from differentiated thyroid cancer (DTC) were retrospectively analyzed.Objective: To assess the effect of radioiodine therapy and investigate the prognostic factors of survival for patients with pulmonary metastasis secondary to DTC.Methods: A total of 372 patients with pulmonary metastasis from DTC treated with¹³¹I entered the study. According to the results of¹³¹I whole-body scan (WBS), pulmonary metastases were classified as¹³¹I-avid and non-¹³¹I-avid. For patients with¹³¹I-avid lung metastases, treatment response was measured by three parameters: serum thyroglobulin (Tg) levels, chest computed tomography (CT) and post-therapeutic¹³¹I-WBS. Overall survival was calculated by the Kaplan–Meier method. Factors predictive of the outcome were determined by multivariate analyses.Results: Among patients demonstrating¹³¹I-avid pulmonary metastases (256/372, 68.8%), 156 cases (156/256, 60.9%) showed a significant decrease in serum Tg levels after¹³¹I therapy and 138 cases (138/229, 60.3%) showed a reduction in pulmonary metastases on follow-up CT. A complete cure, however, was only achieved in 62 cases (62/256, 24.2%). Multivariate analysis showed that only age, the presence of multiple distant metastases and pulmonary metastatic node size were significant independent variables between the groups of¹³¹I-avid and non-¹³¹I-avid.Conclusion: This study indicated that, most¹³¹I-avid pulmonary metastases from DTC can obtain partial or complete remission after¹³¹I therapy. Younger patients (<40 years old) with only pulmonary metastases and small (‘fine miliaric’ or micronodular) metastases appear to have relative favorite outcomes. Patients who do not respond to¹³¹I treatment have a worse prognosis.

Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling.

This study aimed to evaluate the diagnostic accuracy of F-fluoride PET or PET/CT compared with Tc-MDP bone scintigraphy and F-FDG PET/CT in the detection of bone metastases. An electronic search was conducted using PubMed/MEDLINE and EMBASE. The methodological quality of the included studies was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. All analyses were performed on Stata version 12.0 and Meta-DiSc version 1.4. Twenty articles containing 1170 patients were identified. On a patient basis, the pooled sensitivity, specificity, and the area under the summary receiver operating characteristic curve of F-fluoride PET or PET/CT were 92% (95% confidence interval [CI], 89%-95%), 93% (95% CI, 91%-95%), and 0.985, respectively. On a lesion basis, the pooled sensitivity, specificity, and area under the summary receiver operating characteristic curve of F-fluoride PET or PET/CT were 87% (95% CI, 85%-88%), 95% (95% CI, 94%-96%), and 0.979, respectively. When compared with Tc-MDP bone scintigraphy, F-fluoride PET or PET/CT showed both higher sensitivity (96% vs. 88%, P = 0.002) and specificity (91% vs. 80%, P = 0.001). When compared with F-FDG PET/CT, F-fluoride PET/CT showed higher sensitivity (94% vs. 73%, P = 0.003), whereas no significant difference was observed in specificity (88% vs. 98%, P = 0.06). F-fluoride PET or PET/CT has an excellent diagnostic capacity for the detection of bone metastases and shows advantages when compared with Tc-MDP bone scintigraphy and F-FDG PET/CT.

The advent of biologically targeted agents and increased understanding of thyroid carcinogenesis have generated much interest in the development of biologically targeted therapeutic agents for thyroid cancer. Among them, sorafenib is the most commonly studied drug. The current meta-analysis was carried out to estimate the efficacy and safety of sorafenib administered in radioiodine-refractory differentiated thyroid cancer patients. An electronic search was conducted using PubMed/MEDLINE and EMBASE. Statistical analyses were carried out using either random-effects or fixed-effects models according to heterogeneity. All the statistical analyses were carried out using the Stata version 12.0 software. Seven eligible studies were identified. The final results indicated that 22% of the patients (95% CI: 15–28) achieved a partial response. Hand–foot syndrome, diarrhea, fatigue, rash, weight loss, and hypertension were the most frequently observed adverse effects (AEs) associated with sorafenib use and the incidence of these AEs (all grades) was 80% (95% CI: 68–91), 68% (95% CI: 59–77), 67% (95% CI: 57–78), 66% (95% CI: 50–82), 52%(95% CI: 33–72), and 31% (95% CI: 21–42) respectively. Sixty-two percent (95% CI: 36-89) patients required dose reductions due to toxicity of sorafenib. As far as PR and AEs are concerned, the results of this meta-analysis indicate that sorafenib has a modest effect in patients with radioiodine-refractory differentiated thyroid cancer and the high incidence of AEs associated with this agent may affect the quality of patients' lives. Though the use of sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer is considered promising by most physicians working in this field, more effective agents with less toxicity and cost are still needed.

Serum miRNAs profiles between papillary thyroid carcinoma (PTC) patients with non-131I and 131I-avid lung metastases are differentially expressed. These miRNAs have to be further validated and the role of these miRNAs in the molecular function level of thyroid cancer cell lines has not been investigated. Expression levels of six identified miRNAs were assessed via quantitative real-time PCR (qRT-PCR) in the serum of eligible patients. Dual-luciferase reporter assay was used to determine the potential target of miR-106a. Cell viability and apoptosis were evaluated by MTT assay and flow cytometry analysis, respectively. The change of gene expression was detected by qRT-PCR and western blotting analysis. In vitro iodine uptake assay was conducted by a γ-counter. Compared to PTC patients with 131I-avid lung metastases, miR-106a was up-regulated in the serum of patients with non-131I-avid lung metastases. The results of dual-luciferase reporter assay demonstrated that miR-106a directly targeted retinoic acid receptor beta (RARB) 3′-UTR. miR-106a-RARB promoted viability of thyroid cancer cells by regulating MEKK2-ERK1/2 and MEKK2-ERK5 pathway. miR-106a-RARB inhibited apoptosis of thyroid cancer cells by regulating ASK1-p38 pathway. Moreover, miR-106a-RARB could regulate the expression of sodium iodide symporter, TSH receptor and alter the iodine uptake function of thyroid cancer cells. miRNA-106a, directly targeting RARB, associates with the viability, apoptosis, differentiation and the iodine uptake function of thyroid cancer cell lines by regulating MAPK signaling pathway in vitro. These findings in the present study may provide new strategies for the diagnosis and treatment in radioiodine-refractory differentiated thyroid carcinoma.

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 BRAF^V600E 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.