OBJECTIVE: Anaplastic thyroid cancer (ATC) is the most aggressive and fatal thyroid malignancy. Currently, there still exists a paucity of literature studying the relationship between available ATC-targeted therapy, immunotherapy, and survival. We aim to investigate how systemic therapies affect survival outcomes in ATC.
METHODS: A single-tertiary-institution chart review of patients diagnosed with advanced-stage ATC, and who underwent surgery as part of their treatment, was performed between 2000 and 2023, with 41 patients included. Demographics, clinical characteristics, and survival data were collected and analyzed via Kaplan-Meier and Cox proportional hazards analyses.
RESULTS: 54% of patients were female, and average age was 67.4 years old. The most common mutations identified were BRAF (15 patients), p53 (9 patients), and p63 (2 patients). A total of 18 patients utilized targeted or immunotherapy, with Trametinib and Dabrafenib (9 patients) as the most common agents used. Two-year overall survival was 24%, and 5-year overall survival was 23%, with median survival time of 7.6 months. Kaplan-Meier analysis demonstrated improved survival in patients who received chemotherapy (p = 0.048). Cox proportional hazards analysis demonstrated that patients treated with immunotherapy or targeted therapy had a statistically significant increase in survival compared with patients who did not receive these therapies (p = 0.016). Additionally, females and those with a p63 mutation demonstrated improved survival outcomes (p = 0.010, p = 0.001).
CONCLUSIONS: Targeted therapy and immunotherapy use should be strongly considered when treating patients with ATC. Further studies into novel drugs targeting immune checkpoints and combination therapy are needed to better optimize treatment of patients with ATC.
METHODS: 3 Laryngoscope, 2024.

Anaplastic thyroid cancer (ATC), an aggressive malignancy with virtually 100% disease-specific mortality, has long posed a formidable challenge in oncology due to its resistance to conventional treatments and the severe side effects associated with current regimens such as doxorubicin chemotherapy. Consequently, there was urgent need to identify novel candidate compounds that could provide innovative therapeutic strategies for ATC. Ophiopogonin D\' (OPD\'), a triterpenoid saponin extracted, yet its roles in ATC has not been reported. Our data demonstrated that OPD\' potently inhibited proliferation and metastasis of ATC cells, promoting cell cycle arrest and apoptosis. Remarkably, OPD\' impeded growth and metastasis of ATC in vitro and in vivo, displaying an encouraging safety profile. Regulator of G-protein signalling 4 (RGS4) expression was significantly up-regulated in ATC compared to normal tissues, and this upregulation was suppressed by OPD\' treatment. Mechanistically, we elucidated that the transcription factor JUN bound to the RGS4 promoter, driving its transactivation. However, OPD\' interacted with JUN, attenuating its transcriptional activity and thereby disrupting RGS4 overexpression. In summary, our research revealed that OPD\' bound with JUN, which in turn resulted in the suppression of transcriptional activation of RGS4, thereby eliciting cell cycle arrest and apoptosis in ATC cells. These findings could offer promise in the development of high-quality candidate compounds for treatment in ATC.

Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatment options. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated with a poor prognosis. We have previously shown that paracrine signals released by ATC cells induced pro-tumor M2-like polarization of human monocytes. However, which soluble factors derived from ATC cells drive monocyte activation, are largely unknown. In this study we investigated the participation of transforming growth factor β1 (TGFβ1) on the phenotype of macrophage activation induced by ATC cell-derived conditioned media (CM). THP-1 cells exposed to CM derived from ATC cells and recombinant human TGFβ1 induced M2-like macrophage polarization, showing high CD163 and Dectin1 expression. Moreover, we showed that TGFβ1 induced the messenger RNA (mRNA) and protein expression of the transcription factors SNAIL and SLUG. Accordingly, increased TGFβ1 secretion from ATC cells was confirmed by enzyme-linked immunosorbent assay (ELISA). Addition of SB431542, a TGFβ receptor inhibitor, significantly decreased the Dectin1, CD163, SNAIL and SLUG expression stimulated by ATC cell-derived CM. We validated the clinical significance of the expression of TGFβ ligands, their receptors, as well as SNAIL and SLUG in human ATC by analyzing public microarray datasets. We found that the expression of the main TGFβ ligands, TGFβ1 and TGFβ3, along with their receptors, TGFR1 and TGFR2, as well as SLUG, was significantly higher in human ATC tissue samples than in normal thyroid tissues. Our findings indicate that ATC cell-secreted TGFβ1 may play a key role in M2-like macrophage polarization of human monocytes and in the up-regulation of SNAIL and SLUG transcription factors. Thus, ours results uncovered a novel mechanism involved in the activation of TAMs by soluble factors released by ATC cells, which suggest potential therapeutic targets for ATC.

UNASSIGNED: The effect of combined radiation and chemotherapy (combination therapy) versus monotherapy on anaplastic thyroid carcinoma (ATC) has not yet been clear.
UNASSIGNED: We identified 516 ATC patients during 2010-2015 from the Surveillance, Epidemiology and End Results (SEER) database and evaluated their survival outcome using the Kaplan-Meier method, Cox regression analysis and propensity score matching (PSM) technique.
UNASSIGNED: The median overall survival (OS) among the entire cohort was 3 months (95 % confidence interval [CI], 2.58-3.42 months), and the 6- and 12-month OS rates were 29 % (95 % CI, 25.01%-32.88 %) and 13 % (95 % CI, 10.60%-16.58 %), respectively. Multivariable analysis demonstrated that ATC patients not receiving radiotherapy or chemotherapy were unquestionably associated with worse OS (hazard ratio [HR] 3.000, 95 % CI, 2.390-3.764) and cancer-specific survival (CSS) (HR = 3.107, 95 % CI, 2.388-4.043), compared with those receiving combination therapy. However, combination therapy did not predict better prognosis compared with monotherapy (all P > 0.05). After PSM, the median OS and CSS were also not significantly improved in patients undergoing chemoradiotherapy versus chemotherapy alone (OS, P = 0.382; CSS, P = 0.420) or radiotherapy alone (OS, P = 0.065; CSS, P = 0.251).
UNASSIGNED: Combination therapy, compared to monotherapy, does not have the expected improvement in survival beyond the benefits achievable with each single-modality treatment, necessitating further prospective research to tailor its treatment management.

The review article by Pavlidis et al published in World J Clin Oncol provides a meticulous analysis of the intricacies surrounding anaplastic carcinoma of the thyroid. Thyroid carcinoma encompasses a spectrum of diseases, each characterized by distinct behaviors and outcomes. Diagnostic approaches encompass a diverse array of tools. Surgery remains the pivotal treatment for anaplastic thyroid carcinoma. Radiotherapy and chemotherapy offer the best overall survival in aggressive disease. Combinations of immunotherapy with targeted therapies, such as dabrafenib-trametinib, demonstrate potential for enhanced effectiveness and improved survival outcomes. Multifaceted approach fuelled by precision medicine and interdisciplinary collaboration is imperative in charting a course toward improved outcomes in this formidable malignancy.

UNASSIGNED: Tyrosine kinase inhibitors (TKIs) and immunotherapy have been proposed for advanced metastatic anaplastic thyroid cancer (ATC). We report a case of BRAF V600E-mutated ATC in which lenvatinib (L) plus pembrolizumab (P) enabled neoadjuvant treatment.
UNASSIGNED: A male patient aged 65 years presented with a rapidly enlarging left latero-cervical mass. Fine needle aspiration was suggestive of ATC. Surgical consultation excluded radical surgery. While awaiting molecular profile analysis and considering the fast evolution of the disease, treatment with L and P was started. L was started at a dose of 14 mg daily, while P was started at the standard regimen (200 mg every 3 weeks). After 1 month, computerized tomography showed a reduction in the mass with almost complete colliquative degeneration, and the carotid artery wall was free from infiltration. Radical surgery was performed. Histology confirmed papillary thyroid cancer (PTC) in the left lobe and ATC with extensive necrosis in the left latero-cervical lymph node metastasis. The margins were free of tumors (R0). A BRAF V600E mutation was present in both PTC and ATC. At the 1-year follow-up, the patient was free of disease.
UNASSIGNED: L and P in combination also appeared to be effective as a neoadjuvant treatment for BRAF V600E-mutated ATC. This combination treatment could be used when there is an opportunity for complete resection of the cancer, and as soon as possible. The intermediate dose of 14 mg of L appeared to be well tolerated and effective.

UNASSIGNED: Anaplastic thyroid cancer (ATC) is highly invasive, prone to distant metastasis (DM), and has a very poor prognosis. This study aims to construct an accurate survival prediction model for ATC patients with DM, providing reference for comprehensive assessment and treatment planning.
UNASSIGNED: We extracted data of ATC patients with DM diagnosed between 2004 and 2019 from the SEER database, randomly dividing them into a training set and a validation set in a ratio of 7:3. Univariate and multivariate Cox regression analyses were sequentially performed on the training set to identify independent prognostic factors for overall survival (OS) and construct nomograms for 3-month, 6-month, and 8-month OS for ATC patients with DM based on all identified independent prognostic factors. Receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA) curve analysis, and calibration curves were separately plotted on the training and validation sets to demonstrate the model\'s performance. Furthermore, patients were stratified into high- and low-risk groups based on their risk scores, and the Kaplan-Meier (KM) survival curves were used to illustrate the survival differences between the two groups.
UNASSIGNED: A total of 322 patients were included in this study. Univariate and multivariate Cox regression analyses identified five independent prognostic factors for OS in ATC patients with DM: surgery, tumor size, age, chemotherapy, and radiotherapy. Nomograms for 3-month, 6-month, and 8-month OS were established based on these factors. The training set AUC values (3-month AUC: 0.767, 6-month AUC: 0.789, 8-month AUC: 0.795) and validation set AUC values (3-month AUC: 0.753, 6-month AUC: 0.798, 8-month AUC: 0.806) as well as the calibration curves demonstrated excellent applicability and accuracy of the model. Additionally, the DCA curves indicated substantial clinical net benefit of the model. The KM curves also confirmed the model\'s excellent stratification ability for patient OS.
UNASSIGNED: The nomogram developed in this study accurately predicts OS for ATC patients with DM. It can assist clinicians in formulating appropriate treatment strategies for these patients.

Anaplastic thyroid cancer (ATC) is a rare disease with a poor prognosis and accounts for a high proportion of thyroid cancer deaths. The present study reported on a 56-year-old male patient with ATC and examined the clinical manifestations, pathological features, differential diagnosis and genetic mutations. Immunohistochemical analysis showed positivity for vimentin, Ki-67 and cytokeratin in the tumor specimen. In addition, pathological mitotic figures of tumor cells and intra-lymph node metastasis were observed. Genetic analysis revealed the presence of a novel mutation (c.388C>T, p.R130X) in exon 5 of the phosphatase and tensin homolog (PTEN) gene, which was first detected in ATC. Gene conservation analysis showed that R130 is a highly conserved amino acid. Protein structure model predictions implied that p.R130X mutation results in a severe defect of the C2 domain and the TAD domain of PTEN, which may be a reason for the high malignancy of the tumor. The present case report highlights a novel mutation of PTEN in ATC, which expands the molecular spectrum of PTEN and further underlines the importance of PTEN.

UNASSIGNED: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively.
UNASSIGNED: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs).
UNASSIGNED: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%).
UNASSIGNED: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in \"primary human ATC cells\" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.