Objectives: To investigate the clinical characteristics and prognoses of patients with anaplastic thyroid carcinoma(ATC), and to explore the value of multi-modality treatment in improving overall survival(OS) of ATC patients. Methods: Medical records including clinicopathological data of patients diagnosed with ATC at Cancer Hospital, Chinese Academy of Medical Sciences between 2001 and 2020 were retrospectively analyzed. The cohort were divided into surgery-only and multi-modality subgroups, and the latter included patients treated with surgery plus radiotherapy and/or medical therapy(including chemotherapy, target therapy and immunotherapy). Univariate survival analysis was conducted through Kaplan-Meier method, and multivariate survival analysis was performed using Cox proportional hazard model. Results: A total of 47 patients were included in the study, including 24 males and 23 females, with a median age of 63 years. After a median follow-up duration of 3.37 months, 42 patients died due to tumor recurrence or progression. The median OS of the cohort was 4.33 months. Univariate survival analysis demonstrated that symptoms of recurrent laryngeal nerve(RLN) involvement, distant metastasis, leukocyte elevation, and treatment modality were significantly associated with OS (P values all<0.05). Multivariate analysis showed that symptoms of RLN involvement(HR=2.49, 95%CI: 1.16-5.32, P=0.019), distant metastasis(HR=2.33, 95%CI: 1.06-5.16, P=0.036), and leukocyte elevation(HR=2.50, 95%CI: 1.16-5.40, P=0.020) were all independent risk factors for OS, while multi-modality therapy significantly prolonged OS compared with surgery alone(HR=0.22, 95%CI: 0.10-0.47, P<0.001). Conclusions: Among ATC patients, absence of symptoms of RLN invasion, normal leukocyte level and absence of distant metastasis at initial diagnosis are all independent protective factors for OS and multi-modality treatment can help to improve the prognosis.
Female ; Male ; Humans ; Middle Aged ; Retrospective Studies ; Thyroid Carcinoma, Anaplastic/therapy* ; Neoplasm Recurrence, Local ; Prognosis ; Thyroid Neoplasms/therapy*

OBJECTIVE: To determine the prognostic value of surgical interventions done among patients with anaplastic thyroid carcinoma (ATC)

METHODS: A five-year retrospective chart review of 25 patients was done and baseline characteristics determined. Patients discharged alive as of the time of last chart entry were followed up by phone interview or personal visit. Overall survival was the main outcome measure which was plotted as Kaplan-Meier estimates and compared via log-rank test. The incidence of complications surrounding tracheostomy and thyroidectomy were also noted.

Methods:

Design: Ambispective Cohort Study

Setting: Tertiary National University Hospital

Participants: All private and public (charity) patients seen at the wards or clinics diagnosed with ATC via fine needle cytology or tissue histopathology.

RESULTS: All patients presented with either stage IV-B or stage IV-C disease. A significant difference in survival curves was noted when comparing between the two stages (p<.05). Subgroup analysis per stage revealed no significant difference in overall survival when comparing patients who did not undergo surgery, those who underwent tracheostomy or those who underwent thyroidectomy for both IV-B (p=.244) or IV-C (p=.165) disease. The incidence of complications for tracheostomy was 60%, the most common being mucus plugging. For thyroidectomy, the incidence of complications was 80% with hypocalcemia being the most common.

CONCLUSION: The current available data fails to demonstrate any significant survival advantage of tracheostomy or thyroidectomy when performed among similarly staged patients.

Human ; Animal ; Male ; Female ; Aged 80 And Over ; Aged (a Person 65 Through 79 Years Of Age) ; Middle Aged (a Person 45-64 Years Of Age) ; Anaplastic Thyroid Cancer ; thyroidectomy ; tracheostomy ; survival

BACKGROUND: We previously reported the frequent neurofibromatosis 2 (NF2) gene mutations in anaplastic thyroid cancers in association with the BRAF V600E mutation. We aimed to investigate the role of NF2 in thyroid cancer with BRAF mutation. METHODS: To identify the function of NF2 in thyroid cancers, we investigated the changes in cell proliferation, colon formation, migration and invasion of thyroid cancer cells (8505C, BHT101, and KTC-1) with BRAF V600E mutation after overexpression and knock-down of NF2. We also examined how cell proliferation changed when NF2 was mutagenized. Human NF2 expression in papillary thyroid carcinoma (PTC) was analyzed using the The Cancer Genome Atlas (TCGA) data. RESULTS: First, NF2 was overexpressed in 8505C and KTC-1 cells. Compared to control, NF2 overexpressed group of both thyroid cancer cells showed significant inhibition in cell proliferation and colony formation. These results were also confirmed by cell migration and invasion assay. After knock-down of NF2 in 8505C cells, there were no significant changes in cell proliferation and colony formation, compared with the control group. However, after mutagenized S288* and Q470* sites of NF2 gene, the cell proliferation increased compared to NF2 overexpression group. In the analysis of TCGA data, the mRNA expression of NF2 was significantly decreased in PTCs with lateral cervical lymph node (LN) metastasis compared with PTCs without LN metastasis. CONCLUSION: Our study suggests that NF2 might play a role as a tumor suppressor in thyroid cancer with BRAF mutation. More studies are needed to elucidate the mechanism how NF2 acts in thyroid cancer with BRAF mutation.
Cell Movement ; Cell Proliferation ; Colon ; Genes, Neurofibromatosis 2 ; Genes, Tumor Suppressor ; Genome ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Neurofibromatosis 2 ; RNA, Messenger ; Thyroid Carcinoma, Anaplastic ; Thyroid Gland ; Thyroid Neoplasms

BACKGROUND/OBJECTIVES: Although anaplastic thyroid carcinoma (ATC) is rare, it is one of the deadliest forms of thyroid cancer. The fatality rate for ATC is high, and the survival rate at one year after diagnosis is <20%. The present study aimed to investigate the anti-tumor activities of paclitaxel, radiation, and tyrosine kinase inhibitor (TKI) combined therapy in anaplastic thyroid cancer cells both in vitro and in vivo and explore its effects on apoptotic cell death pathways.MATERIALS #SPCHAR_X0026; METHODS: ATC cell line was exposed to TKI, lenvatinib in the presence or absence of paclitaxel with radiation, and cell viability was determined by MTT assay. Effects of the combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell line xenograft model was used to examine the anti-tumor activity in vivo.RESULTS: Our data revealed that the combined administration of paclitaxel, TKI, and radiation decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as demonstrated by the cleavage of caspase-3 and DNA fragmentation. This combination therapy reduced anti-apoptotic factor levels in ATC cells, while significantly decreasing tumor volume and increasing survival in ATC xenografts.CONCLUSION: These results indicate that administering the combination of paclitaxel, TKI, and radiation therapy may exert significant anticancer effects in preclinical models, potentially suggesting a new clinical approach for treating patients with ATC.
Blotting, Western ; Caspase 3 ; Cell Cycle ; Cell Death ; Cell Line ; Cell Survival ; Diagnosis ; DNA Fragmentation ; Flow Cytometry ; Heterografts ; Humans ; In Vitro Techniques ; Paclitaxel ; Protein-Tyrosine Kinases ; Survival Rate ; Thyroid Carcinoma, Anaplastic ; Thyroid Neoplasms ; Tumor Burden

PURPOSE: Anaplastic thyroid cancer (ATC) is a rare tumor with a lethal clinical course despite aggressive multimodal therapy. Intensity-modulated radiotherapy (IMRT) may achieve a good therapeutic outcome in ATC patients, and the role of IMRT should be assessed. We retrospectively reviewed outcomes for ATC treated with three-dimensional conformal radiotherapy (3D-CRT) or IMRT to determine the optimal treatment option and explore the role of radiotherapy (RT). MATERIALS AND METHODS: Between December 2000 and December 2015, 41 patients with pathologically proven ATC received RT with a sufficient dose of ≥40 Gy. Among them, 21 patients (51%) underwent surgery before RT. Twenty-eight patients received IMRT, and 13 received 3D-CRT. Overall survival (OS) and progression-free survival (PFS), patterns of failure, and toxicity were examined. RESULTS: The median follow-up time for survivors was 38.0 months. The median and 1-year OS and PFS rates were 7.2 months and 29%, 4.5 months and 15%, respectively. Surgery significantly improved the prognosis (median OS: 10.7 vs. 3.9 months, p = 0.001; median PFS: 5.9 vs. 2.5 months, p = 0.007). IMRT showed significantly better PFS and OS than 3D-CRT, even in multivariate analysis (OS: hazard ratio [HR] = 0.30, p = 0.005; PFS: HR = 0.33, p = 0.005). Significantly higher radiation dose could be delivered with IMRT than 3D-CRT (EQD210 66 vs. 60 Gy, p = 0.005). Only 2 patients had grade III dermatitis after IMRT. No other severe toxicity ≥grade III occurred. CONCLUSION: Patients with ATC showed better prognosis through multimodal treatment. Furthermore, IMRT could achieve favorable survival rates by safely delivering higher dose than 3D-CRT.
Combined Modality Therapy ; Dermatitis ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Multivariate Analysis ; Prognosis ; Radiotherapy ; Radiotherapy, Conformal ; Radiotherapy, Intensity-Modulated ; Retrospective Studies ; Survival Rate ; Survivors ; Thyroid Carcinoma, Anaplastic

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Docetaxel, a microtubule stabilizer, is a common chemotherapeutic agent used to treat various metastatic cancers. However, prolonged use results in various side effects and drug resistance. Flavonoids, such as baicalein, are accepted chemotherapeutic and dietary chemopreventive agents with many advantages, such as greater accessibility, affordability, and lower toxicity, compared with traditional chemotherapy agents. In this study, we evaluated whether baicalein enhances the effects of docetaxel on apoptosis and metastasis in 8505c ATC cells. METHODS: The 8505c cells were treated with baicalein or docetaxel individually and in combination. Cell viability was measured by MTT (thiazolyl blue tetrazolium bromide) assay, and apoptosis was detected by fluorescence microscopy of Hoechst-stained cells. The expression of apoptotic (Bax and caspase-3), anti-apoptotic (Bcl-2), angiogenic (vascular endothelial growth factor [VEGF], transforming growth factor β [TGF-β], E-cadherin, and N-cadherin), and signaling (extracellular signal-regulated kinase [ERK] mitogen activated protein kinase [MAPK], Akt, and mammalian target of rapamycin [mTOR]) proteins was determined by Western blot analysis. RESULTS: The combination of baicalein (50 or 100 µM) and docetaxel (10 nM) significantly inhibited proliferation and induced apoptosis compared with monotherapies. The combination treatment significantly inhibited the expression of Bax, caspase-3, VEGF, TGF-β1, E-cadherin, N-cadherin, and mTOR, but decreased the expression of Bcl-2 and significantly decreased the phosphorylation of ERK and Akt. CONCLUSION: The combination of baicalein and docetaxel effectively induced apoptosis and inhibited metastasis in 8505c cells through downregulation of apoptotic and angiogenic protein expression and blocking of the ERK and Akt/mTOR pathways in 8505c cells. These results suggest that baicalein enhances the anticancer effects of docetaxel in ATC.
Apoptosis* ; Blotting, Western ; Cadherins ; Caspase 3 ; Cell Survival ; Down-Regulation* ; Drug Resistance ; Drug Therapy ; Endothelial Growth Factors ; Flavonoids ; Humans ; Microscopy, Fluorescence ; Microtubules ; Neoplasm Metastasis ; Phosphorylation ; Phosphotransferases ; Protein Kinases ; Sirolimus ; Thyroid Carcinoma, Anaplastic* ; Transforming Growth Factors ; Vascular Endothelial Growth Factor A

OBJECTIVETo identify hub genes and key pathways associated with anaplastic thyroid carcinoma (ATC), and to explore possible intervention strategy.

METHODSThe differentially expressed genes (DEGs) in ATC were identified by Gene Expression Omnibus (GEO) combined with using R language; the pathway enrichment of DEGs were performed by using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The protein-protein interaction (PPI) network of DEGs was constructed by STRING database and visualized by Cytoscape. Furthermore, the hub genes and key nodes were calculated by MCODE. Finally, the drug repurposing was performed by L1000CDS.

RESULTSA total of 2087 DEGs were identified. The DEGs were clustered based on functions and pathways with significant enrichment analysis, among which PI3K-Akt signaling pathway, p53 signaling pathway, inflammatory response, extracellular matrix organization were significantly upregulated. The PPI network was constructed and the most significant three modules and nine genes were filtered. Twenty-two potential compounds were repurposed for ATC treatment.

CONCLUSIONSUsing integrated bioinformatics analysis, we have identified hub genes and key pathways in ATC, and provide novel strategy for the treatment of ATC.

Computational Biology ; Drug Repositioning ; Gene Expression Profiling ; Humans ; Phosphatidylinositol 3-Kinases ; Protein Interaction Maps ; Thyroid Carcinoma, Anaplastic ; Thyroid Neoplasms

Thyroid carcinoma is the most common neoplasm of endocrine malignancies. Differentiated thyroid carcinoma (DTC) constitutes 90% of the thyroid carcinomas, rest being medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). Distant metastases occur in up to 10% of patients with DTC. Metastases to axillary lymph nodes (ALN) are very rare. As per literature, only 25 cases have been reported. We report an unusual case of 47-year-old male with Hürthle cell carcinoma of the thyroid presenting with a solitary axillary lymph node metastasis 17 years after thyroidectomy, along with review of literature.
Humans ; Lymph Nodes ; Male ; Middle Aged ; Neoplasm Metastasis ; Positron-Emission Tomography and Computed Tomography ; Recurrence ; Thyroid Carcinoma, Anaplastic ; Thyroid Gland ; Thyroid Neoplasms ; Thyroidectomy

PURPOSE: The Notch signaling pathway is widely expressed in normal, reactive, and neoplastic tissues; however, its role in thyroid tissues has not been fully elucidated. Therefore, this study was conducted to characterize the expression of the Notch signaling pathway in papillary thyroid cancer (PTC) cells and anaplastic thyroid cancer (ATC) cells. MATERIALS AND METHODS: Expression of activated Notch1 in ATC and PTC paraffin-embedded tissues was determined by immunohistochemistry. The small interfering RNA techniquewas employed to knock down Notch1 expression in ATC and PTC cell lines. RESULTS: The expression of activated Notch1 was higher in ATC cases than in PTC cases. Inhibition of Notch1 significantly reduced proliferation and migration of ATC cells, but not PTC cells. In addition, inhibition of Notch1 in ATC cells significantly reduced the expression of key markers of epithelial-mesenchymal transition and cancer stem cells. Conversely, changes in the expression of these proteins were not observed in PTC cells. CONCLUSION: The results of this study suggest that Notch1 expression plays different roles in tumor progression in ATC and PTC cells. We also found that Notch1 expression was significantly related to the highly invasive or proliferative activity of ATC cells.
Cell Line ; Epithelial-Mesenchymal Transition ; Immunohistochemistry ; Neoplastic Stem Cells ; RNA, Small Interfering ; Thyroid Carcinoma, Anaplastic* ; Thyroid Gland ; Thyroid Neoplasms

Anaplastic thyroid carcinoma (ATC) is difficult to distinguish from other cancers, especially when its pathological features are atypical for ATC or when the tumor is totally undifferentiated and occurs after a considerable lapse of time, in an area remote from the original site of the tumor. Here, we present two patients (68-year-old man and 56-year-old woman) with rare manifestations of ATC, which were initially thought to be other malignancies. Immunohistochemical tests, using various markers, failed to provide information about the origin of these tumors. However, both patients had a history of papillary thyroid carcinoma (PTC) from several years ago and BRAF mutations were observed in the undifferentiated tumors, as well as in the previous PTCs. Therefore, we could make a diagnosis of ATC derived from PTC. As such, BRAF mutation analysis may serve as a useful tool for ATC diagnosis in challenging ATC cases.
Diagnosis ; Humans ; Immunohistochemistry ; Middle Aged ; Thyroid Carcinoma, Anaplastic* ; Thyroid Neoplasms