Clinical characteristics and long-term outcomes for parapharyngeal metastases of well-differentiated thyroid cancer during 131 I therapy and follow-up.

OBJECTIVE: Parapharyngeal metastases (PPM) are rarely observed in patients with well-differentiated thyroid cancer (WDTC). Radioiodine (131 I) therapy has been the main treatment for metastatic and recurrent DTC after thyroidectomy. This study was performed to evaluate the clinicopathological features and long-term outcomes associated with survival of patients with PPM at the end of follow-up. DESIGN: In total, 14,984 consecutive patients with DTC who underwent 131 I therapy after total or near-total thyroidectomy from 2004 to 2021 were retrospectively reviewed. Therapeutic efficacy was evaluated using the Response Evaluation Criteria in Solid Tumours v1.1 and logistic regression analysis. The disease status was determined using dynamic risk stratification. Disease-specific survival (DSS) was assessed using the Kaplan-Meier method and a Cox proportional hazards model. PATIENTS: Seventy-five patients with PPM from WDTC were enroled in this study. Their median age at the initial diagnosis of PPM was 40.2 ± 14.1 years, and the patients comprised 32 men and 43 women (male:female ratio, 1.00:1.34). Of the 75 patients, 43 (57.33%) presented with combined distant metastases. Fifty-seven (76.00%) patients had 131 I avidity and 18 had non-131 I avidity. At the end of follow-up, 22 (29.33%) patients showed progressive disease. Sixteen of the 75 patients died; of the remaining 59 patients, 6 (8.00%) had an excellent response, 6 (8.00%) had an indeterminate response, 10 (13.33%) had an biochemical incomplete response, and 37 (49.33%) had a structural incomplete response. Multivariate analysis confirmed that age at initial PPM diagnosis, the maximal size of PPM, and 131 I avidity had significant effects on progressive disease of PPM lesions (p = .03, p= .02, and p < .01, respectively). The 5- and 10-year DSS rates were 98.49% and 62.10%, respectively. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with a poor prognosis (p = .03 and p = .04, respectively). CONCLUSION: The therapeutic effect for PPM was closely associated with 131 I avidity, age at initial PPM diagnosis, and maximal size of PPM at the end of follow-up. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with poor survival.

Interleukin 6 regulates the expression of programmed cell death ligand 1 in thyroid cancer.

Programmed cell death ligand 1 (PD-L1), inducing T cell exhaustion to facilitate immune escape of tumor cells, is upregulated by interleukin 6 (IL-6) in T cell lymphoma and ovarian cancer. The purpose of this study is to investigate the expression of IL-6 and PD-L1 in thyroid cancer, and whether IL-6 regulates PD-L1 expression. As a result, IL-6 and PD-L1 were highly expressed in thyroid cancer tissues. Multivariate logistic analysis showed that tumor size, distant metastasis, and risk stratification were significantly associated with IL-6 expression (P < .05), and multifocality, lymph node metastasis, distant metastasis, risk stratification, and IL-6 expression were identified as the independent predictors of PD-L1 expression (P < .05). The invasiveness of thyroid cancer was significantly enhanced after IL-6 treatment or PD-L1 overexpression. PD-L1 positive rate correlated with IL-6 expression in cancer tissues (P < .001), and after IL-6 treatment, the PD-L1 expression in TPC-1 and BCPAP significantly increased. The mitogen-activated protein kinase pathway (MAPK) and the Janus-activated kinase (JAK)-signal transducers and activators of transcription 3 (STAT3) signaling pathways were activated by IL-6, and the IL-6-induced PD-L1 expression decreased after treatment with these two signaling pathway inhibitors. Knockdown of transcription factors c-Jun and stat3 suppressed the expression of PD-L1 induced by IL-6, and these two factors could bind to PD-L1 gene promoter directly and promote its transcription. It is concluded that IL-6 and PD-L1 are overexpressed in thyroid cancer and are related to tumor invasiveness. IL-6 upregulates PD-L1 expression through the MAPK and JAK-STAT3 signaling pathways, which function via transcription factors c-Jun and stat3.

Diagnostic Value of Whole-Body DWI With Background Body Suppression Plus Calculation of Apparent Diffusion Coefficient at 3 T Versus 18F-FDG PET/CT for Detection of Bone Metastases.

OBJECTIVE. The purpose of this study is to evaluate the diagnostic performance of whole-body (WB) DWI with background body suppression (DWIBS) combined with calculation of the apparent diffusion coefficient (ADC) value at 3 T compared with the diagnostic performance of 18F-FDG PET/CT for detecting bone metastases in patients with malignant tumors. SUBJECTS AND METHODS. Thirty-nine consecutive patients with suspected bone metastases underwent both WB DWIBS and FDG PET/CT. Imaging findings were independently interpreted using qualitative and quantitative analyses. Pathologic findings or clinical or radiologic follow-up data were used as the diagnostic reference standard. The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of both modalities were calculated. The ADCs of benign lesions and metastases were compared. RESULTS. A total of 213 metastatic bone segments were confirmed among 39 patients. The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value were 93.0%, 87.8%, 89.6%, 79.8%, and 96.0%, respectively, for WB DWIBS and 92.5%, 92.0%, 92.1%, 85.7% and 95.9%, respectively, for FDG PET/CT. The specificity of WB DWIBS in detecting bone metastases was significantly lower than that of FDG PET/CT (p < 0.05), whereas the sensitivity, overall accuracy, positive predictive value, and negative predictive value in detecting bone metastases were not significantly different between WB DWIBS and FDG PET/CT (p > 0.05). The ADCs for benign lesions were significantly higher than those for metastases (p < 0.001). In ROC curve analysis, the AUC value was 0.901. A cutoff ADC value of 920.5 × 10-6 mm2s-1 distinguished benign lesions from bone metastases with a sensitivity of 92.9% and a specificity of 73.4%. CONCLUSION. WB DWIBS coupled with ADC analysis at 3 T is effective for detecting bone metastases.

Can pretreatment 18F-FDG PET tumor texture features predict the outcomes of osteosarcoma treated by neoadjuvant chemotherapy?

PURPOSE: To investigate whether tumor texture features derived from pretreatment with 18F-fluorodeoxyglucose positron emission tomography (FDG PET) can predict histological response or event-free survival (EFS) in patients with localized osteosarcoma of the extremities treated by neoadjuvant chemotherapy (NAC). METHODS: We retrospectively reviewed 35 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with NAC and surgery. Primary tumor traditional parameters and texture features were measured for all 18F-FDG PET images prior to treatment. After surgery, histological responses to NAC were evaluated on the postsurgical specimens. A receiver operating characteristic curve (ROC) was constructed to evaluate the optimal predictive performance among the various indices. EFS was calculated using the Kaplan-Meier method and prognostic significance was assessed by Cox proportional hazards analysis. RESULTS: Pathologic examination revealed 16 (45.71%) good responders and 19 (54.29%) poor responders. Although both the texture features (least axis, dependence nonuniformity, run length nonuniformity, and size zone nonuniformity) and metabolic tumor volume (MTV) can predict tumor response of osteosarcoma to NAC, the traditional indicator MTV has the best performance according to ROC curve analysis (area under the curve = 0.918, p < 0.0001). In multivariate analysis, MTV (p < 0.0001), histological response (p = 0.0003), and texture feature of coarsenessNGTDM (neighboring gray tone difference matrix) (p = 0.005) were independently associated with EFS. CONCLUSIONS: Intratumoral heterogeneity of baseline 18F-FDG uptake measured by PET texture analysis can predict tumor response and EFS of patients with extremity osteosarcoma treated by NAC, but the conventional parameter MTV provides better predictive power and is a strong independent prognostic factor. KEY POINTS: • The baseline 18 F-FDG PET tumor texture features can predict tumor NAC response for patients with osteosarcoma. • Coarseness NGTDM is a new and independent prognostic factor for osteosarcoma. • MTV provides the best predictive power and is a strong independent prognostic factor for patients with osteosarcoma.

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.

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.

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.

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.

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.

MicroRNAs as a potential tool in the differential diagnosis of thyroid cancer: a systematic review and meta-analysis.

OBJECTIVE: Thyroid cancer is the most common endocrine malignancy, and its incidence has been increasing over the last 30 years. Several studies have suggested that miRNAs may play a significant role in the differential diagnosis of indeterminate thyroid nodules. To systematically evaluate the utility of miRNAs in discriminating malignant thyroid nodules from benign ones on fine-needle aspiration biopsy (FNAB) samples, a systematic review and meta-analysis of the published literatures were carried out. PATIENTS AND DESIGN: Three hundred and sixty-one samples, obtained from 341 patients, were included in the research, and summary sensitivities (SEN), specificities (SPE), positive likelihood ratios, negative likelihood ratios and diagnostic odds ratio were calculated. Then, summary receiver operating characteristic curves (SROCs) and areas under the SROC curves (AUCs) were calculated to further estimate the overall diagnostic value of miRNAs in thyroid cancer. RESULTS: The overall pooled SEN, SPE and AUC are 0·75, 0·81 and 0·89, respectively. For multiple miRNAs assays, the pooled SEN, SPE and AUC are 0·87, 0·75 and 0·68, respectively. For single miRNA assays, the corresponding results are 0·71, 0·84 and 0·87, respectively. The corresponding statistical results for differentiating indeterminate FNAB samples are 0·92, 0·68 and 0·86, respectively. CONCLUSION: Our current meta-analysis suggests that miRNAs may serve as a novel diagnostic tool in distinguishing malignant thyroid nodules from benign ones on FNAB specimens. In addition, subgroup analysis suggests that a panel of miRNAs may have a higher sensitivity but a relatively lower specificity than that of single miRNA in distinguishing thyroid nodules.

Comparison of SPET/CT, SPET and planar imaging using 99mTc-MIBI as independent techniques to support minimally invasive parathyroidectomy in primary hyperparathyroidism: A meta-analysis.

OBJECTIVE: Successful performance of minimally invasive parathyroidectomy (MIP) is based on the accuracy of preoperative parathyroid localization studies. Despite the various methodologies available, no consensus has been reached so far on the optimal imaging technique. The aim of our meta-analysis was to determine the accuracy of technetium-99m-hexakis methoxyisobutylisonitrile single photon emission tomography/computed tomography ((99m)Tc-MIBI SPET/CT), SPET and MIBI scintigraphy for the preoperative localization of primary hyperparathyroidism (PHPT) lesions, thus facilitating better management of these patients. METHODS: Publications were screened by a comprehensive computer search of PubMed and EMBASE for 25 years. Data were extracted from included articles and forest plots of sensitivity and positive predictive value were calculated to investigate the diagnostic accuracy of SPET/CT, SPET and MIBI scintigraphy. RESULTS: Eighteen articles were included in our study. The sensitivities of SPET/CT, SPET and planar scintigraphy were 84% (95% CI: 78%-90%), 66% (95% CI: 57%-74%) and 63% (95% CI: 51%-74%), respectively. The PPV of the above three imaging modalities were: 95% (95% CI: 92%-98%), 82% (95% CI: 73%-89%) and 90% (95% CI: 96%-99%), respectively. CONCLUSION: Our present meta-analysis showed that using (99m)Tc-MIBI, combining anatomical information of CT and functional abnormalities on SPET, as presented on SPET/CT was by far more sensitive and accurate than SPET or planar scintigraphy in localizing PHPT lesions. We firmly believe that this technique will be the main diagnostic means, to detect PHPT lesions and support minimally invasive parathyroidectomy.

Repurposing homoharringtonine for thyroid cancer treatment through TIMP1/FAK/PI3K/AKT signaling pathway.

Homoharringtonine (HHT), an alkaloid isolated from Cephalotaxus, is an effective anti-leukemia agent and exhibits inhibitory effects in various solid tumors. However, the impacts of HHT treatment on thyroid cancer (TC) remain unclear. Our findings demonstrated that HHT exhibited remarkable anti-TC activity that involved inhibiting cell proliferation, invasion, and migration, as well as inducing apoptosis. Proteomics analysis revealed that the expression of the tissue inhibitor of metalloproteinase 1 (TIMP1) was downregulated in TC cells after HHT treatment. TIMP1 overexpression promoted TC progression and partially reversed the anti-TC effects of HHT, while TIMP1 downregulation inhibited TC progression and enhanced the anti-TC effects of HHT. Furthermore, TIMP1 re-expression attenuated the enhancement of anti-TC effects of HHT induced by TIMP1 knockdown. Mechanistically, HHT exerted anti-TC effects by downregulating TIMP1 expression and then inactivating the FAK/PI3K/AKT signaling pathway. Taken together, our study demonstrated that HHT could inhibit TC progression by inhibiting the TIMP1/FAK/PI3K/AKT signaling pathway.

Value of ¹³¹I SPECT/CT for the evaluation of differentiated thyroid cancer: a systematic review of the literature.

PURPOSE: In the present study, we performed a systematic review of the current literature to assess the incremental value of (131)I single photon emission computed tomography (SPECT)/CT for the management of patients with differentiated thyroid cancer (DTC). METHODS: The search of PubMed/MEDLINE and EMBASE databases to identify studies and reference lists for articles was conducted using the terms "SPECT or SPECT/CT or SPECT-CT or single photon emission computed tomography/computed tomography and thyroid carcinoma or thyroid cancer." Studies reporting the clinical value of (131)I SPECT/CT were selected. All studies included were assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). Two independent reviewers selected the studies, summarized and tabulated the data, and pooled estimates were obtained. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: A total of 14 studies involving 1,066 patients met the inclusion criteria. Data obtained included the impact of (131)I SPECT/CT on staging or risk classification (three studies), diagnostic accuracy (six studies), and follow-up (five studies). CONCLUSION: Integrated SPECT/CT is a useful tool for the diagnosis, staging, risk stratification, and follow-up of DTC. The impact of (131)I SPECT/CT on the management of patients with thyroid cancer was evaluated.

Iodine-131 SPET/CT and 18F-FDG PET/CT for the identification and localization of mediastinal lymph node metastases from differentiated thyroid carcinoma.

Mediastinal lymph node metastases (MLNM) from differentiated thyroid carcinoma (DTC) are considered difficult to diagnose. The aim of this study was to assess the value of iodine-131 (131I) single photon emission tomography/computed tomography (SPET/CT) and of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for the diagnosis of MLNM from DTC. Five hundred and eleven consecutive patients operated for DTC and treated with 131I for ablation of the remnant thyroid and/or for treatment of metastases were enrolled in the study and underwent an 131I whole body scan (131I-WBS). Thirty seven sites of increased 131I uptake, on the 131I-WBS that could be an indication for MLNM were re-evaluated by a 131I-SPET/CT scan. Thirty four other patients with negative 131I-WBS but having elevated serum thyroglobulin (Tg), were examined by 18F-FDG PET/CT to possibly diagnose MLNM. A total of 44 DTC patients with MLNM were identified, among the above 37 and 34 cases: 25/37 (67.6%) cases were examined and identified by 131I-SPET/CT and 19/34 (55.9%) cases by 18F-FDG PET/CT. A total of 25 and 19 cases were identified. The male-to-female ratio and the average age in patients with 18F-FDG-avid MLNM were significantly higher than in patients with 131I-avid MLNM. Among the above 44 patients, 40 patients had superior mediastinal nodal metastases, 9 had aortic nodal metastases and only 1 inferior mediastinal nodal metastases. A patient could have metastases in more than one site. In conclusion, our study suggests that in 511 operated DTC patients, treated for remnant ablation and/or for metastases and examined by 131I-WBS, there were 37 cases doubtful of having MLNM in the 131I-WBS and 34 cases doubtful, because of negative 131I-WBS and elevated Tg. The 131I-SPET/CT scan was sensitive for detecting MLNM in 25 of the 37 cases and the 18F-FDG PET/CT in 19 of the 34 cases. These hybrid imaging modalities, when applied as above, were suitable for detecting more MLNM and thus, better supporting treatment planning in these DTC patients.

Graves' disease in an adolescent with dual congenital ectopia and no orthotopic thyroid gland identified by Tc-99m-pertechnetate SPET/CT imaging.

This is the first case of Graves' disease in an adolescent with lingual and prelaryngeal dual congenital ectopia and no orthotopic thyroid gland identified by technetium-99m-pertechnetate (99mTcO-4) SPET/CT imaging in a 15 years old boy. After 8 weeks treatment with methimazole, Graves' disease subsided. Fine needle aspiration cytology of the mass revealed the normal colloid and normal follicular cells without an atypia or lymphoid elements, suggesting a benign ectopic thyroid gland. In conclusion, there is no report in the literature with DETT lingual and prelaryngeal absence of orthotopic thyroid tissue and Graves' disease as in our case. This case also highlights the potential ascendancy of 99mTcO-4 SPET/CT in diagnosing the DETT.

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression.

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. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

TSH ≥30 mU/L may not be necessary for successful 131I remnant ablation in patients with differentiated thyroid cancer.

Purpose: To determine whether thyroid-stimulating hormone level ≥ 30 mU/L is necessary for radioiodine (131I) remnant ablation (RRA) in patients with differentiated thyroid cancer (DTC), as well as its influencing factors and predictors. Methods: A total of 487 DTC patients were retrospectively enrolled in this study. They were divided into two groups (TSH < 30 and ≥ 30 mU/L) and further divided into eight subgroups (0-<30, 30-<40, 40-<50, 50-<60, 60-<70, 70-<80, 80-<90, and 90-<100 mU/L). The simultaneous serum lipid level, successful rate of RRA and its influencing factors in different groups were analyzed. The receiver operating characteristic curves derived from pre-ablative thyroglobulin (pre-Tg) and pre-Tg/TSH ratio were compared for RRA success prediction performance. Results: There was no statistical difference in success rates of RRA between the two groups (P = 0.247) and eight subgroups (P = 0.685). Levels of total cholesterol (P < 0.001), triglyceride (P = 0.006), high-density lipoprotein cholesterol (P = 0.024), low-density lipoprotein cholesterol (P = 0.001), apolipoprotein B (P < 0.001), and apolipoprotein E (P = 0.002) were significantly higher while apoA/apoB ratio (P = 0.024) was significantly lower at TSH ≥ 30 mU/L group. Pre-Tg level, gender, and N stage were influencing factors for RRA. The area under the curve of pre-Tg level and pre-Tg/TSH ratio was 0.7611 (P < 0.0001) and 0.7340 (P < 0.0001) for all enrolled patients and 0.7310 (P = 0.0145) and 0.6524 (P = 0.1068) for TSH < 30 mU/L, respectively. Conclusion: TSH ≥ 30 mU/L may not be necessary for the success of RRA. Patients with higher serum TSH levels prior to RRA will suffer from severer hyperlipidemia. Pre-Tg level could be used as a predictor for the success of RRA, especially when TSH < 30 mU/L.

Interleukin-6 promotes the dedifferentiation of papillary thyroid cancer cells.

Radioiodine treatment is a fundamental therapy for patients with papillary thyroid cancer (PTC). Sodium/iodide symporter (NIS)-mediated iodine uptake is a prerequisite for the efficacy of radioiodine therapy. Interleukin-6 (IL-6) is a pro-tumor cytokine, but its regulation of NIS expression in PTC has not been elucidated. In this study, we found that IL-6 enhanced the proliferation ability of PTC cells. Moreover, the negative association between IL-6 and NIS expression in thyroid cancer tissues was demonstrated. IL-6 downregulated thyroid-specific genes such as NIS, thyroid peroxidase, and thyroid-stimulating hormone receptor and thyroid-specific transcription factors including thyroid transcription factor-1 (TTF-1) and paired box protein-8 (PAX-8). The inhibitory effects of IL-6 on NIS expression were alleviated by mitogen-activated protein kinase and Janus kinase inhibitors. Depletion of c-Jun or STAT3 also rescued IL-6-induced NIS downregulation, with STAT3 depletion exerting a stronger effect. TTF-1 protein expression was also restored by depleting c-Jun or STAT3. STAT3 depletion, but not c-Jun depletion, alleviated the inhibitory effect of IL-6 on PAX-8 expression. Moreover, the downregulation of NIS by IL-6 was rescued by overexpressing TTF-1 and PAX-8. Tocilizumab, an IL-6 receptor blocker, did not have any cytostatic activity in PTC cells, and it also failed to induce redifferentiation in vitro. However, we found that the drug blocked the inhibitory effect of IL-6 on NIS expression. In summary, IL-6 inhibits NIS transcription in PTC cells by activating mitogen-activated protein kinase and Janus kinase signaling.

Transiently impaired endothelial function during thyroid hormone withdrawal in differentiated thyroid cancer patients.

Purpose: Endothelial dysfunction, which was associated with chronic hypothyroidism, was an early event in atherosclerosis. Whether short-term hypothyroidism following thyroxine withdrawal during radioiodine (RAI) therapy was associated with endothelial dysfunction in patients with differentiated thyroid cancer (DTC) was unclear. Aim of the study was to assess whether short-term hypothyroidism could impair endothelial function and the accompanied metabolic changes in the whole process of RAI therapy. Methods: We recruited fifty-one patients who underwent total thyroidectomy surgery and would accept RAI therapy for DTC. We analyzed thyroid function, endothelial function and serum lipids levels of the patients at three time points: the day before thyroxine withdrawal(P1), the day before 131I administration(P2) and 4-6 weeks after RAI therapy(P3). A high-resolution ultrasound named flow-mediated dilation (FMD) was used to measure endothelial function of the patients. Results: We analyzed the changes of FMD, thyroid function and lipids at three time points. FMD(P2) decreased significantly compared to FMD(P1) (P1vsP2, 8.05 ± 1.55vs 7.26 ± 1.50, p<0.001). There was no significant difference between FMD(P3) and FMD(P1) after restoring TSH (thyroid stimulating hormone) suppression therapy (P1 vs P3, 8.05 ± 1.55 vs 7.79 ± 1.38, p=0.146). Among all parameters, the change of low-density lipoprotein (ΔLDL) was the only factor correlated negatively with the change of FMD (ΔFMD) throughout the RAI therapy process (P1-2, r=-0.326, p=0.020; P2-3, r=-0.306, p=0.029). Conclusion: Endothelial function was transiently impaired in DTC patients at short-term hypothyroidism state during the RAI therapy, and immediately returned to the initial state after restoring TSH suppression therapy.

Uncommon metastases from differentiated thyroid carcinoma.

Differentiated thyroid carcinoma (DTC) usually behaves in an indolent manner with low metastatic potential. The major sites of distant metastases are the lung and bone. Metastases to the brain, eye, breast, liver, kidney, muscle and skin are rare or relatively rare. These metastases have almost always appeared in patients with advanced disease and are often associated with poor prognosis but overlooked in clinical practice. Recognizing them has a significant impact on clinical decision-making and prognosis of the patients. Treatment in these patients should be individualized and an alternative therapeutic approach should be considered. Care should be taken to determine whether a (131)I uptake focus found at an unexpected site of (131)I- whole body scan (WBS) is a DTC metastasis or a false-positive (131)I uptake. Imaging with (131)I-SPET/CT is of incremental value in the finding of rare metastases from DTC. In conclusion, DTC can have unusual metastatic presentations and patterns. Post-therapy (131)I-WBS and (131)I-SPET/CT play an important role in the management of patients with DTC.