Search

Background: Anaplastic Thyroid Carcinoma (ATC) is a rare and deadly malignant tumor in humans. It is prone to developing resistance to radiotherapy and chemotherapy. Molecular targeted therapy offers a novel way to treat ATC. The BRAF mutation is closely associated with many cancers, including thyroid carcinoma. Vemurafenib, a small-molecule inhibitor, is specifically designed to target the mutant serine/threonine kinase BRAF. The objective of this study is to elucidate the regulatory mechanisms underlying the effects of vemurafenib on human anaplastic thyroid carcinoma cell line FRO and to assess its potential therapeutic role. Methods: The effects of vemurafenib on the proliferation of FRO cells were assessed by the CCK-8 method and Colony-forming assay. Transwell chambers and scratch tests were employed to examine the impact of vemurafenib on the invasion and migration of FRO cells. Apoptosis and cycle distribution of FRO cells were analyzed by tunel assay and flow cytometry. The effects of vemurafenib on the expression of BRAF-activated non-protein coding RNA (BANCR), Bax, Bcl2, and E-cadherin were evaluated by qRT-PCR. Furthermore, the effects of vemurafenib on the expression of phosphoinositol-3-kinase (PI3K)/phosphoinositol-3-kinase (AKT) pathway-related proteins, BRAF, CyclinD1, Bcl-2, Bax, and E-cadherin proteins in FRO cells were investigated through the western-blot method. All experiments were conducted in three replicates. Results: Vemurafenib was observed to inhibit proliferation and induce apoptosis in a dose- and time-dependent manner (P

Background: Anaplastic thyroid carcinoma (ATC), a rare but highly aggressive endocrine malignancy, is characterized by a significant presence of cancer stem-like cells (CSCs). These CSCs, known for their self-renewal and differentiation capacities, contribute to various aggressive tumor properties, including recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Despite their critical role, the regulatory mechanisms of CSCs in ATC remain poorly elucidated, posing challenges in effectively targeting these cells for treatment. Methods: To delve into this, we employed the single sample gene set enrichment analysis (ssGSEA) algorithm to evaluate the stemness of samples in combined datasets. Samples were then classified into high and low stemness subgroups based on their average stemness scores. Differential gene expression between these subgroups was analyzed. We further explored the association of candidate genes with patient prognosis. Additionally, we conducted gene set enrichment analysis (GSEA) and a series of cell biology experiments to validate the role of DEP domain-containing protein 1 (DEPDC1) in fostering CSC-like traits and regulating the malignant phenotypes of ATC. Results: Our investigation demonstrated that DEPDC1 was significantly upregulated in CSCs and is abundantly expressed in ATC tissues. In vitro assays revealed that knockdown of DEPDC1 markedly inhibited tumor sphere formation and attenuated the proliferation, invasion, and migration of ATC cells. This silencing also resulted in reduced expression of stemness markers associated with CSCs. Furthermore, our GSEA findings linked high DEPDC1 expression to cell cycle progression and the maintenance of tumor cell stemness, with DEPDC1 knockdown disrupting these signaling pathways. Collectively, our results position DEPDC1 as a pivotal regulator of CSC-like characteristics in ATC, where aberrant DEPDC1 expression amplifies stemness properties and fuels the cancer's aggressive behavior. Consequently, DEPDC1 emerges as a promising therapeutic target for ATC management. In summary, this study underscores the pivotal role of DEPDC1 in modulating CSC-like features in ATC, offering new avenues for targeted therapy in this challenging malignancy.

Aim: Among the endocrine malignancies, thyroid carcinoma (TC) is the most common. However, anaplastic TC accounts for 1-2% of these cancers. The aim of this study was to evaluate the demographic and pathologic features, treatments, and survival of patients with anaplastic TC. Methods: Anaplastic TC patients who applied to our medical oncology clinics between 01.01.2012 -01.12.2018 were retrospectively evaluated. Results: A total of 8 patients were included in the study. There were 4 female and 4 male patients with a median age of 68 (minimum 61-maximum 83) years. The initial complaint of all patients was a fast-growing swelling in the neck. Six patients had total thyroidectomy. Two patients had anaplastic TC with a differential TC. Six patients were at stage 4C. The most common site of metastasis was the lung (75%). Five patients had received a median of 3 (1-6) cycles of chemotherapy. Radiotherapy was applied to 7 patients. All patients except one died during the follow-up period. The median survival time of the patients was 3 (2-15) months. Conclusion: Anaplastic TC, an aggressive tumor with high metastasic potential, has no effective treatment at present. Effective treatments are needed for this rare and aggressive disease. Developments in the molecular field are promising for the treatment of ATC.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal neoplasms in humans, and just limited progresses have been made to extend patient survival and decrease ATC-associated mortality. Thus, the identification of novel therapeutic strategies for treating ATC is needed. Recently, our group has identified two proteins with oncogenic activity, namely HMGA1 and EZH2, with pivotal roles in ATC cancer progression. Therefore, we tested the ability of trabectedin, a HMGA1-targeting drug, and GSK126, an inhibitor of EZH2 enzymatic activity, to impair cell viability of four ATC-derived cell lines. In the present study, we first confirmed the overexpression of HMGA1 and EZH2 in all ATC-derived cell lines and tissues compared to the normal primary thyroid cells and tissues. Then, treatment of the ATC cell lines with trabectedin and GSK126 resulted in a drastic induction of apoptotic cell death, which increased when the ATC cell lines were treated with a combination of both drugs. Conversely, normal primary human thyroid cells did not show any significant reduction in their viability when exposed to the same drugs. Noteworthy, both drugs induced the deregulation of EZH2- and HMGA1-controlled genes. Altogether, these findings propose the combination of trabectedin and GSK126 as possible novel strategy for ATC therapy. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma (ATC) was a rare malignancy featured with the weak immunotherapeutic response. So far, disorders of immunogenic cell death genes (ICDGs) were identified as the driving factors in cancer progression, while their roles in ATC remained poorly clear. Datasets analysis identified that most ICDGs were high expressed in ATC, while DE-ICDGs were located in module c1_112, which was mainly enriched in Toll-like receptor signalings. Subsequently, the ICD score was established to classify ATC samples into the high and low ICD score groups, and function analysis indicated that high ICD score was associated with the immune characteristics. The high ICD score group had higher proportions of specific immune and stromal cells, as well as increased expression of immune checkpoints. Additionally, TLR4, ENTPD1, LY96, CASP1 and PDIA3 were identified as the dynamic signature in the malignant progression of ATC. Notably, TLR4 was significantly upregulated in ATC tissues, associated with poor prognosis. Silence of TLR4 inhibited the proliferation, metastasis and clone formation of ATC cells. Eventually, silence of TLR4 synergistically enhanced paclitaxel-induced proliferation inhibition, apoptosis, CALR exposure and release of ATP. Our findings highlighted that the aberrant expression of TLR4 drove the malignant progression of ATC, which contributed to our understanding of the roles of ICDGs in ATC. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma (ATC) is a deadly disease with a poor prognosis. Thus, there is a pressing need to determine the mechanism of ATC progression. The homeobox D9 (HOXD9) transcription factor has been associated with numerous malignancies but its role in ATC is unclear. In the present study, the carcinogenic potential of HOXD9 in ATC was investigated. We assessed the differential expression of HOXD9 on cell proliferation, migration, invasion, apoptosis, and epithelial–mesenchymal transition (EMT) in ATC and explored the interactions between HOXD9, microRNA-451a (miR-451a), and proteasome 20S subunit beta 8 (PSMB8). In addition, subcutaneous tumorigenesis and lung metastasis in mouse models were established to investigate the role of HOXD9 in ATC progression and metastasis in vivo. HOXD9 expression was enhanced in ATC tissues and cells. Knockdown of HOXD9 inhibited cell proliferation, migration, invasion, and EMT but increased apoptosis in ATC cells. The UCSC Genome Browser and JASPAR database identified HOXD9 as an upstream regulator of miR-451a. The direct binding of miR-451a to the untranslated region (3′-UTR) of PSMB8 was established using a luciferase experiment. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of HOXD9 interference or overexpression on ATC progression. The PI3K/AKT signaling pathway was involved in HOXD9-stimulated ATC cell proliferation and EMT. Consistent with in vitro findings, the downregulation of HOXD9 in ATC cells impeded tumor growth and lung metastasis in vivo. Our research suggests that through PI3K/AKT signaling, the HOXD9/miR-451a/PSMB8 axis may have significance in the control of cell proliferation and metastasis in ATC. Thus, HOXD9 could serve as a potential target for the diagnosis of ATC. [ABSTRACT FROM AUTHOR]

Summary: Background: To compare the ability of the Cox regression and machine learning algorithms to predict the survival of patients with Anaplastic thyroid carcinoma (ATC). Methods: Patients diagnosed with ATC were extracted from the Surveillance, Epidemiology, and End Results database. The outcomes were overall survival (OS) and cancer-specific survival (CSS), divided into: (1) binary data: survival or not at 6 months and 1 year; (2): time-to-event data. The Cox regression method and machine learnings were used to construct models. Model performance was evaluated using the concordance index (C-index), brier score and calibration curves. The SHapley Additive exPlanations (SHAP) method was deployed to interpret the results of machine learning models. Results: For binary outcomes, the Logistic algorithm performed best in the prediction of 6-month OS, 12-month OS, 6-month CSS, and 12-month CSS (C-index = 0.790, 0.811, 0.775, 0.768). For time-event outcomes, traditional Cox regression exhibited good performances (OS: C-index = 0.713; CSS: C-index = 0.712). The DeepSurv algorithm performed the best in the training set (OS: C-index = 0.945; CSS: C-index = 0.834) but performs poorly in the verification set (OS: C-index = 0.658; CSS: C-index = 0.676). The brier score and calibration curve showed favorable consistency between the predicted and actual survival. The SHAP values was deployed to explain the best machine learning prediction model. Conclusions: Cox regression and machine learning models combined with the SHAP method can predict the prognosis of ATC patients in clinical practice. However, due to the small sample size and lack of external validation, our findings should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) is a rare and frequently fatal type of thyroid cancer. The degree of heterogeneity in survival rates for ATC is incompletely studied. This study evaluated the factors associated with overall survival (OS) of patients with ATC using multicenter real-world data from a national tertiary care center network in France. Methods: In this multicenter, retrospective cohort study, all patients with ATC diagnosed between 2010 and 2020 were identified from the national database of the French ENDOCAN-TUTHYREF network. Factors associated with OS were examined in multivariable analyses using Cox proportional hazards models. Results: The study included 360 patients. Of these, 220 (61%) were female and the median age was 72 years (interquartile range: 62–80). The percentages of patients with pure and mixed (synchronously-transformed) ATC (p-ATC and st-ATC) were 62.5% and 26.7%, respectively. The median OS was 6.8 months [confidence interval, CI: 5.5–8.1]: not reached for stage IVa, 11.4 months [8.2–17.8] for IVb, and 4.6 months [3.5–5.7] for IVc. Surgery, radiation therapy to the neck, chemotherapy, and best supportive care were administered to 69 (19.2%), 214 (59.4%), 254 (70.6%), and 66 (18.3%) patients, respectively. In a multivariable analysis, including stage IVb–IVc patients, significantly higher OS was observed in patients with Eastern Cooperative Oncology Group performance-status of 0–1 (hazard ratio [HR], 0.6; [CI, 0.4–0.9], p < 0.02), stage IVb [HR, 0.5; CI, 0.4–0.8, p < 0.001], and multimodal treatment (surgery and chemoradiotherapy) [HR, 0.07; CI, 0.04–0.1, p < 0.001]. Variables associated with significantly worse OS included: p-ATC (vs. st-ATC) [HR, 1.83; CI, 1.33–2.51, p = 0.001] and a neutrophil-to-lymphocyte ratio (NLR) >5.05 [HR, 2.05, CI, 1.39–3.05, p < 0.001]. Conclusions: Factors independently associated with improved OS in ATC included: European Cooperative Oncology Group performance status, disease stage, multimodality treatment, synchronously transformed ATC, and lower NLR. Long-term OS was observed in selected patients with ATC who underwent multimodal treatment. [ABSTRACT FROM AUTHOR]

Xiang-Zhe Shi,1,2 Sheng Zhao,3 Yan Wang,1,2 Meng-Yao Wang,1,2 Su-Wen Su,1,2 Yan-Zhao Wu,3 Chen Xiong1,2 1The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 2The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhung, 050017, People’s Republic of China; 3Department of Otorhinolaryngology-Head and Neck Surgery, 4th Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of ChinaCorrespondence: Chen Xiong; Yan-Zhao Wu, Email bearmorning@sina.com; wyz315@163.comIntroduction: Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid carcinoma. Doxorubicin (DOX) is the only drug approved for anaplastic thyroid cancer treatment, but its clinical use is restricted due to irreversible tissue toxicity. Berberine (BER), an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been proposed to have antitumor activity in many cancers. However, the underlying mechanisms by which BER regulates apoptosis and autophagy in ATC remain unclear. Thus, the present study aimed to assess the therapeutic effect of BER in human ATC cell lines CAL-62 and BHT-101 as well as the underlying mechanisms. In addition, we assessed the antitumor effects of a combination of BER and DOX in ATC cells.Methods: The cell viability of CAL-62 and BTH-101 with treatment of BER for different hours was measured by CCK-8 assay, and cell apoptosis was assessed by clone formation assay and flow cytometric analysis. The protein levels of apoptosis protein, autophagy-related proteins and PI3K/AKT/mTORpathway were determined Using Western blot. Autophagy in cells was observed with GFP-LC3 plasmid using confocal fluorescent microscopy. Flow cytometry was used to detect intracellular ROS.Results: The present results showed that BER significantly inhibited cell growth and induced apoptosis in ATC cells. BER treatment also significantly upregulated the expression of LC3B-II and increased the number of GFP-LC3 puncta in ATC cells. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed BER-induced autophagic cell death. Moreover, BER induced the generation of reactive oxygen species (ROS). Mechanistically, we demonstrated that BER regulated the autophagy and apoptosis of human ATC cells through the PI3K/AKT/mTOR pathways. Furthermore, BER and DOX cooperated to promote apoptosis and autophagy in ATC cells.Conclusion: Taken together, the present findings indicated that BER induces apoptosis and autophagic cell death by activating ROS and regulating the PI3K/AKT/mTOR signaling pathway.Keywords: anaplastic thyroid carcinoma, berberine, autophagy, apoptosis, PI3K/AKT/mTOR, reactive oxygen species

A rapid growing cervical mass mobile while swallowing is the most common clinical presentation of severe thyroid malignancy. A 91-year-old female patient with a history of Hashimoto thyroiditis presented with clinical compressive neck symptoms. The patient had gastric Maltoma diagnosed that was surgically resected thirty years ago. A straightforward process was needed to reach full histological diagnosis and initiate prompt therapy. Ultrasound (US) showed a 67 mm hypoechoic left thyroid mass with reticulated pattern without signs of locoregional invasion. Percutaneous trans isthmic US-guided 18G core needle biopsy (CNB) disclosed diffuse large B cell lymphoma of the thyroid gland. FDG PET revealed two distinct thyroid and gastric foci (both SUVmax 39.1). Therapy was initiated rapidly to decrease clinical symptoms in this aggressive stage III primitive malignant thyroid lymphoma. The prognostic nomogram was calculated by using a seven-item scale, which disclosed a one-year overall survival rate of 52%. The patient underwent three R-CVP chemotherapy courses, then refused further treatment and died within five months. Real-time US-guided CNB approach led to rapid patient’s management that was tailored to patient’s characteristics. Transformation of Maltoma into diffuse large B cell lymphoma (DLBCL) into two body areas is deemed to be extremely rare.

Summary Background To compare the ability of the Cox regression and machine learning algorithms to predict the survival of patients with Anaplastic thyroid carcinoma (ATC). Methods Patients diagnosed with ATC were extracted from the Surveillance, Epidemiology, and End Results database. The outcomes were overall survival (OS) and cancer-specific survival (CSS), divided into: (1) binary data: survival or not at 6 months and 1 year; (2): time-to-event data. The Cox regression method and machine learnings were used to construct models. Model performance was evaluated using the concordance index (C-index), brier score and calibration curves. The SHapley Additive exPlanations (SHAP) method was deployed to interpret the results of machine learning models. Results For binary outcomes, the Logistic algorithm performed best in the prediction of 6-month OS, 12-month OS, 6-month CSS, and 12-month CSS (C-index = 0.790, 0.811, 0.775, 0.768). For time-event outcomes, traditional Cox regression exhibited good performances (OS: C-index = 0.713; CSS: C-index = 0.712). The DeepSurv algorithm performed the best in the training set (OS: C-index = 0.945; CSS: C-index = 0.834) but performs poorly in the verification set (OS: C-index = 0.658; CSS: C-index = 0.676). The brier score and calibration curve showed favorable consistency between the predicted and actual survival. The SHAP values was deployed to explain the best machine learning prediction model. Conclusions Cox regression and machine learning models combined with the SHAP method can predict the prognosis of ATC patients in clinical practice. However, due to the small sample size and lack of external validation, our findings should be interpreted with caution.

Tracheal AERO stent collapse is a rare complication compared to bronchial AERO stent collapse due to differences in the nitinol framework thickness. A 58‐year‐old man with a bulky anaplastic thyroid carcinoma was referred to our hospital due to exacerbation of tracheal stenosis despite the administration of lenvatinib. His tracheal stenosis exhibited a severe extrinsic compression pattern with a length of 8 cm. Because tracheotomy was inappropriate, we placed an 18 × 80 mm AERO stent. Five months later, he was readmitted with severe dyspnea due to collapse of the distal portion of the stent caused by tumor growth. Because stent removal was difficult, we placed an additional AERO stent (18 × 60 mm) to cover the collapsed portion. The additional stent successfully expanded the collapse and improved his dyspnea. To our knowledge, this is the first case where a tracheal AERO stent collapse due to a poor prognosis tumor was treated with the stent‐in‐stent method. [ABSTRACT FROM AUTHOR]

Summary: Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.

Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies with no effective treatment. In this study, we investigated the efficacy and safety of anlotinib-based chemotherapy as first-line therapy for ATC. Methods: Locally advanced or metastatic (LA/M) ATC patients who never received antitumor treatment of any sort were eligible for this study. The patients received 2–6 cycles anlotinib12mg on days 1–14 per 21 days. Chemotherapy regimens consisted of paclitaxel, capecitabine, or paclitaxel plus carboplatin/capecitabine. The end points including Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Disease Specification Survival (DCS) were analyzed. Results: A total of 25 patients were enrolled. 1 patient achieved a Complete Response (CR) and 14 patients achieved Partial Response (PR). The best ORR was 60.0%, and the DCR was 88.0%. The median PFS was 25.1 weeks, and the median DCS was 96.0 weeks. Approximately 56% (14 patients) had at least one Adverse Event (AE) of any grade. Most AEs were well tolerated. The most common AEs was palmar–plantar erythrodysesthesia syndrome (28.0%). Conclusions: Anlotinib-based chemotherapy as first-line therapy is a safe and effective intervention for the treatment of LA/M ATC patients. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer with the distinct hallmark of high proportion of cancer stem cell-like characteristics. Therapies aiming to cancer stem-like cells (CSCs) were emerging as a new direction in cancer treatment, but targeting ATC CSCs remained challenging, mainly due to incomplete insights of the regulatory mechanism of CSCs. Here, we unveiled a novel role of ISG15 in the modulation of ATC CSCs. Methods: The expression of ubiquitin-like proteins were detected by bioinformatics and immunohistochemistry. The correlation between ISG15 expression and tumor stem cells and malignant progression of ATC was analyzed by single-cell RNA sequence from the Gene Expression Omnibus. Flow cytometry combined with immunofluorescence were used to verify the enrichment of ISG15 and ISGyaltion in cancer stem cells. The effect and mechanism of ISG15 and KPNA2 on cancer stem cell-like characteristics of ATC cells were determined by molecular biology experiments. Mass spectrometry combined with immunoprecipitation to screen the substrates of ISG15 and validate its ISGylation modification. Nude mice and zebrafish xenograft models were utilized to demonstrate that ISG15 regulates stem cell characteristics and promotes malignant progression of ATC. Results: We found that among several ubiquitin proteins, only ISG15 was aberrantly expressed in ATC and enriched in CSCs. Single-cell sequencing analysis revealed that abnormal expression of ISG15 were intensely associated with stemness and malignant cells in ATC. Inhibition of ISG15 expression dramatically attenuated clone and sphere formation of ATC cells, and facilitated its sensitivity to doxorubicin. Notably, overexpression of ISGylation, but not the non-ISGylation mutant, effectively reinforced cancer stem cell-like characteristics. Mechanistically, ISG15 mediated the ISGylation of KPNA2 and impeded its ubiquitination to promote stability, further maintaining cancer stem cell-like characteristics. Finally, depletion of ISG15 inhibited ATC growth and metastasis in xenografted mouse and zebrafish models. Conclusion: Our studies not only provided new insights into potential intervention strategies targeting ATC CSCs, but also uncovered the novel biological functions and mechanisms of ISG15 and ISGylation for maintaining ATC cancer stem cell-like characteristics. [ABSTRACT FROM AUTHOR]

Abnormal spindle‐like microcephaly‐associated (ASPM) protein is crucial to the mitotic spindle function during cell replication and tumor progression in multiple tumor types. However, the effect of ASPM in anaplastic thyroid carcinoma (ATC) has not yet been understood. The present study is to elucidate the function of ASPM in the migration and invasion of ATC. ASPM expression is incrementally upregulated in ATC tissues and cell lines. Knockout (KO) of ASPM pronouncedly attenuates the migration and invasion of ATC cells. ASPM KO significantly reduces the transcript levels of Vimentin, N‐cadherin, and Snail and increases E‐cadherin and Occludin, thereby inhibiting epithelial‐to‐mesenchymal transition (EMT). Mechanistically, ASPM regulates the movement of ATC cells by inhibiting the ubiquitin degradation of KIF11 and thus stabilizing it via direct binding to it. Moreover, xenograft tumors in nude mice proved that KO of ASPM could ameliorate tumorigenesis and tumor growth accompanied by a decreased protein expression of KIF11 and an inhibition of EMT. In conclusion, ASPM is a potentially useful therapeutic target for ATC. Our results also reveal a novel mechanism by which ASPM inhibits the ubiquitin process in KIF11. [ABSTRACT FROM AUTHOR]

Purpose: Anaplastic thyroid carcinoma (ATC) is an orphan disease with a fatal outcome. Surgery to the primary tumor in metastatic ATC is controversial. Determination of specific surgical techniques may help facilitate local control and, hence, beneficial overall and disease-specific survival. Methods: Using individualized patient data derived from our systematic review of literature and our single center study (n = 123), conducting a Surveillance, Epidemiology, and End Results register (SEER)-based study (n = 617) we evaluated surgery, its combination with systemic and local therapies in metastatic ATC. Results: Pooled cohort study showed surgery (p < 0.001), RT ≥ 30 Gy (p < 0.001), ChT (p < 0.001) and multimodal treatment (p = 0.014) to result in improved OS univariately. In the multivariate analysis, surgery (1.997 [1.162–3.433], p = 0.012) and RT ≥ 30 Gy (1.877 [1.232–2.843], p = 0.012) were independent predictors for OS. In SEER-based study of patients undergoing any tumor-directed treatment (n = 445) total thyroidectomy (p = 0.031), administration of ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS univariately. On the multivariate analysis, debulking surgery was an independent predictor for a worse outcome (HR 0.535, 95%CI 0.332–0.862, p = 0.010), whereas RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362–3.939, p = 0.002). Among operated patients from SEER register total thyroidectomy (p = 0.031), ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS in the univariate analysis, whereas debulking surgery was inversely correlated with the DSS (p < 0.001). On the multivariate analysis, debulking surgery was an independent predictor for a worse DSS (HR 0.535, 95%CI 0.332–0.862, p = 0.010), whilst RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362–3.939, p = 0.002). Conclusions: Surgery to the primary tumor with the aim of R0/R1 resection, but not debulking, is associated with a significant OS and DSS benefit even in systemically metastasized disease. [ABSTRACT FROM AUTHOR]

Anaplastic (undifferentiated) thyroid carcinoma (ATC) is a rare malignancy which may arise from transformation of a pre-existing differentiated carcinoma. We report the unique case where a lesion of thyroid origin presented with the histological features of mature plasma cells. Immunohistochemistry confirmed the lesion to be an anaplastic thyroid carcinoma arising from papillary thyroid carcinoma. A tumor mimicking a malignancy of a different cellular origin can lead clinicians to incorrect treatment approaches. Careful correlation with clinical details and knowledge of these unique presentations is important for reaching the correct diagnosis.

Abstract Background Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies, representing less than 5% of all thyroid carcinomas. Τhe median survival is limited to months due to the resistance of ATC to surgery, radioiodine therapy, radiotherapy and chemotherapy. This review will cover novel agents involving several cellular signaling pathways including the BRAF pathway. The BRAF inhibitor vemurafenib improves survival among patients with metastatic melanoma, hairy-cell leukemia and intracranial neoplasms with BRAF gene mutations. The frequency of a BRAF (V600E) mutation in ATC is about 25%. Case presentation We report the first case of a marked partial response to adjuvant first line monotherapy with vemurafenib in BRAF V600E-mutated ATC. The 78-year-old man showed a sustained response for 7 months, thereafter scans revealed progressive disease and the patient died 10 months after first diagnosis. This case report is accompanied by a comprehensive review of current strategies and tools for ATC treatment. Conclusions This case and the review of current data confirm the benefit of BRAF inhibition in BRAF-mutated ATC, limited by acquired resistance to targeted therapy.

Abstract Background Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid carcinoma. Lenvatinib, a multikinase inhibitor, is rarely used in preoperative settings due to adverse effects including delayed wound healing and fistula formation. Herein, we report the use of lenvatinib treatment prior to conversion surgery for the treatment of ATC. Case presentation A 71-year-old woman was referred to our hospital with suspected thyroid cancer with recurrent laryngeal nerve invasion and cervical lymph node metastasis based on the results of ultrasonography. Computed tomography demonstrated the presence of a thyroid tumor invading the trachea and esophagus with no evidence of distant metastasis. Fine needle aspiration of the left cervical lymph node indicated the lymph node metastasis of ATC. As the tumor had widely invaded the trachea and esophagus, unresectable ATC was diagnosed and treatment with lenvatinib was initiated at a dose of 24 mg/day. On day 13 of lenvatinib treatment, the primary tumor and lymph node metastases demonstrated a partial response to therapy. As the tumor was now considered resectable, the decision was made to perform conversion surgery. Total thyroidectomy and left lateral neck node dissection were performed 7 days after the withdrawal of lenvatinib. The patient was discharged on postoperative day 5 with no complications. Histopathological examination demonstrated that the tumor contained the component of papillary thyroid carcinoma, squamoid ATC cells, and granulation tissue. In areas of granulation tissue, atypical cells with spindle-shaped or polygonal morphology, pyknotic nuclei, and scant cytoplasm were observed. Immunohistochemically, these cells were positive for cytokeratin AE1/AE3, TTF-1, and p53 and negative for thyroglobulin and PAX8. Therefore, the areas of granulation tissue observed within tumor samples were also considered ATC that were affected by lenvatinib treatment. In total, approximately 50% of resected tumor comprised ATC, and 70% of them had been changed to granulation tissue. Conclusions The findings in the present case indicate that lenvatinib may have significant antitumor effects in preoperative settings. Lenvatinib may represent a promising candidate therapy for unresectable ATC by increasing tumor resectability.

Abstract Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. Results In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin–proteasome pathway. Conclusion Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress.

Abstract The clinical utilities of paclitaxel in anaplastic thyroid carcinoma (ATC) have been reported. The current study investigated the outcomes in ATC patients treated by paclitaxel as neoadjuvant setting. Furthermore, the prognostic factor for overall survival (OS) and predictive marker for response to paclitaxel were investigated. Records of ATC patients treated by paclitaxel as neoadjuvant setting in our hospital were reviewed. The median OS for the patients with (n = 43) and without (n = 23) resection were 14.7 (95% CI, 11.0–21.7) and 4.2 (95% CI, 3.0–5.4) months, respectively (p

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors. ATC is frequently diagnosed at advanced stages with unresectable disease and palliative care is often indicated. Recently, several patient-tailored therapies for ATC are emerging due to advances in molecular profiling of these tumors. Entrectinib is a potent oral selective inhibitor of neutrotrophic tropomyosin receptor kinase (NTRK), ROS1, and anaplastic lymphoma kinase fusions. The experience regarding ATC and other thyroid carcinomas, particularly in the neoadjuvant setting, is minimal. Case report: We present a case of a 51-year-old female patient presenting with a bulky mass of the left thyroid lobe measuring 100 × 108 × 80 mm that was considered surgically unresectable. While waiting for next-generation sequence (NGS) profiling, lenvatinib was initiated. There was an initial clinical and imagiologic response; however, progression occurred after 12 weeks, and at this time NGS ident ified an ETV6-NTRK3 fusion and entrectinib was started. After 12 weeks, tumor diameters reduced to a minimum of 68×60×49 mm, and the patient underwent total thyroidectomy plus central lymphadenectomy. Histological diagnosis confirmed an ATC (pT4a R 2 N1a). Adjuvant radiotherapy (RT) (60 Grays) with weekly paclitaxel (45 mg/m2) was then administered followed by maintenance entrectinib 600 mg daily. Fluorodeoxyglucose positron emission tomography performed 3 months after completion of RT showed only non-specific uptake in the posterior wall of the hypopharynx and lar ynx, suggestive of inflammation. Conclusion: We report the first case of an ATC with a dramatic response to neoadjuvant therapy with entrectinib, which enabled surgical resection of an ab initio unresectable tumor.

Introduction: Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer with a bleak prognosis. Favorable outcomes are rare but help decipher molecular pathophysiology, investigate prognosis factors, and discover new therapeutic targets. Case presentation: Two patients were diagnosed with locally advanced nonresectable ATC, one with metastatic extension. Each patient received chemotherapy and radiotherapy, allowing thyroid surgical resection. In both cases, the pathological examination was consistent with complete response with no viable tumor cells. After follow-ups of 48 and 70 months, both patients remain disease-free. Molecular explorations on thyroid biopsies revealed microsatellite instability (MSI) and alterations on mismatch repair– gene complex, also PTEN and ATM variants in both cases. Both also presented with non-classical immune infiltrate composed of equal parts T CD4 + lymphocytes and macrophages. Conclusion: We report two cases of patients cured from advanced ATC and fo r the first time provide genetic and immunological explorations in this setting. It seems with these two cases that MSI-ATCs may indicate a better prognosis. Our study hypothesizes different responsible mechanisms including increased sensitivity to chemoradiotherapy and/or immune tumor infiltrate modulation.

Glioma-associated oncogene (Gli) antagonist-61 (GANT61) not only suppresses the malignant behavior of several cancers but also presents synergistic effects with other anticancer agents on suppressing the progression of cancers, while relevant information is rare in anaplastic thyroid carcinoma (ATC). This study aimed to explore the therapeutic effect of GANT61 in ATC and its molecular mechanism. ATC cells (8505C and CAL-62) were treated with GANT61, followed by detection of cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) markers. Subsequently, RNA sequencing was performed to explore the potential downstream pathway. Following that, rescue experiments were conducted by SC79 (AKT activator) or colivelin (STAT3 activator) monotreatment or combined with GANT61 in ATC cells. GANT61 reduced Gli1 expression, suppressed proliferation at several time settings, promoted apoptosis, inhibited invasion and increased E-cadherin while decreased Vimentin and Snail expressions (EMT markers) in ATC cells. The subsequent RNA sequence identified 85 upregulated differentially expressed genes (DEGs) and 71 downregulated DEGs in GANT61-treated ATC cells, which were mainly enriched in PI3K/AKT, JAK/STAT, Hedgehog and mTOR pathways. Next, the inactivation of AKT/mTOR and JAK/STAT3 pathways by GANT61 treatment was verified by western blot. The following rescue experiments showed that SC79 or colivelin treatment promoted the malignant behaviors of ATC cells. More importantly, SC79 or colivelin treatment compensated the effect of GANT61 treatment on cell proliferation at several time settings and apoptosis, invasion, and part of that on EMT in ATC cells. GANT61 suppresses cell survival, invasion and EMT through inactivating AKT/mTOR or JAK/STAT3 pathways in ATC.

Abstract Background Anaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer. In this study, we used a three-dimensional in vitro system to evaluate the effect of a dual MEK/Aurora kinase inhibitor, BI-847325 anticancer drug, on several cellular and molecular processes involved in cancer progression. Methods Human ATC cell lines, C643 and SW1736, were grown in alginate hydrogel and treated with IC50 values of BI-847325. The effect of BI-847325 on inhibition of kinases function of MEK1/2 and Aurora kinase B (AURKB) was evaluated via Western blot analysis of phospho-ERK1/2 and phospho-Histone H3 levels. Sodium/iodide symporter (NIS) and thyroglobulin (Tg), as two thyroid-specific differentiation markers, were measured by qRT-PCR as well as flow cytometry and immunoradiometric assay. Apoptosis was assessed by Annexin V/PI flow cytometry and BIM, NFκB1, and NFκB2 expressions. Cell cycle distribution and proliferation were determined via P16, AURKA, and AURKB expressions as well as PI and CFSE flow cytometry assays. Multidrug resistance was evaluated by examining the expression of MDR1 and MRP1. Angiogenesis and invasion were investigated by VEGF expression and F-actin labeling with Alexa Fluor 549 Phalloidin. Results Western blot results showed that BI-847325 inhibits MEK1/2 and AURKB functions by decreasing phospho-ERK1/2 and phospho-Histone H3 levels. BI-847325 induced thyroid differentiation markers and apoptosis in ATC cell lines. Inversely, BI-847325 intervention decreased multidrug resistance, cell cycle progression, proliferation, angiogenesis, and invasion at the molecular and/or cellular levels. Conclusion The results of the present study suggest that BI-857,325 might be an effective multi-targeted anticancer drug for ATC treatment.

Abstract Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC. Graphical Abstract

Abstract Background Anaplastic thyroid carcinoma is a rare and lethal disease that accounts for 1–2% of thyroid malignancies. It is an aggressive locoregional disease with a high rate of distant metastasis, a poor prognosis, and a mean survival rate of 3–6 months after diagnosis. This retrospective study aimed to analyse the clinical and pathological features of ATC to assess treatment procedures and its outcome. Methods We analysed data from 22 patients diagnosed with ATC from 2018 to 2021, using the Kaplan-Meier method and log-rank test to determine overall survival. Results Patients’ median age was 64.3 ± 17.1 years. Females were more affected (male/female ratio: 1:1.7); 14 cases occurred in females (63.6.4%), and eight in males (36.4%). The most common manifestations were neck enlargement (81.8%) and dyspnoea (72.27%), and the tumour size was > 4 cm in 17 (77.3%) patients. The percentage of cases that presented in clinical-stage IVA was 36.4%, with 31.8% presenting in clinical-stage IVB and 31.8% presenting in clinical-stage VIB. Among 22 cases, 14 (63.6%) were operable, and 8 (36.4) were inoperable (p = 0.015). Multimodal therapies were associated with better survival (surgery plus radiotherapy without systemic treatment, P = 0.063). The median overall survival was three months (IC 95%, 0.078–5.922). One-year and two-year survival rates were 9% and 4.5%, respectively. Conclusion ATC is a rapidly growing cancer that, fortunately, is rare. Early diagnosis and multimodality treatment may provide a better quality of life and survival time for this group of patients.

A rapid growing cervical mass mobile while swallowing is the most common clinical presentation of severe thyroid malignancy. A 91-year-old female patient with a history of Hashimoto thyroiditis presented with clinical compressive neck symptoms. The patient had gastric Maltoma diagnosed that was surgically resected thirty years ago. A straightforward process was needed to reach full histological diagnosis and initiate prompt therapy. Ultrasound (US) showed a 67 mm hypoechoic left thyroid mass with reticulated pattern without signs of locoregional invasion. Percutaneous trans isthmic US-guided 18G core needle biopsy (CNB) disclosed diffuse large B cell lymphoma of the thyroid gland. FDG PET revealed two distinct thyroid and gastric foci (both SUVmax 39.1). Therapy was initiated rapidly to decrease clinical symptoms in this aggressive stage III primitive malignant thyroid lymphoma. The prognostic nomogram was calculated by using a seven-item scale, which disclosed a one-year overall survival rate of 52%. The patient underwent three R-CVP chemotherapy courses, then refused further treatment and died within five months. Real-time US-guided CNB approach led to rapid patient's management that was tailored to patient's characteristics. Transformation of Maltoma into diffuse large B cell lymphoma (DLBCL) into two body areas is deemed to be extremely rare. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid cancer (ATC) is a rare but highly fatal form of thyroid cancer. This highly malignant tumor progresses rapidly and is prone to relapse and metastasis, with a poor prognosis. Novel treatments have improved survival in recent years, but the outcome of treatment is not satisfactory. Case presentation: We report a case of multiple postoperative recurrences of papillary thyroid carcinoma that later transformed into undifferentiated carcinoma. The patient’s neck mass was huge and the operation was unsuitable. Then, she achieved remarkable tumor shrinkage by tislelizumab immunotherapy combined with radiotherapy. Conclusion: This case indicates that radiotherapy combined with immunotherapy is a promising treatment for ATC. Such a combined approach warrants further study. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC) is the rarest (1–2%) form of thyroid cancer, but also the most aggressive and associated with the worst prognosis. The survival median rate is 5–6 months, whereas only 20% of patients survive more than one year from the diagnosis, even though the usage of radiotherapy and surgical resection. The growing incidence rate of thyroid cancer and ATC determine the need for new prophylactic, diagnostic and therapeutic solutions. Metformin was first introduced as an oral antidiabetic drug. The beneficial effect of metformin on anaplastic thyroid cancer cells was confirmed, however, the mechanism of this interaction is still unclear. The usage of metformin in thyroid cancer prevention is still under discussion — nevertheless, studies conducted on larger groups support this beneficial impact, at least in patients with insulin resistance or metabolic syndrome. Both the synergistic effect of metformin in anaplastic thyroid cancer chemotherapy and its protective effect in radiotherapy are still concerns and need additional confirmation in randomized clinical trials. This review aims to sum up the recent knowledge on metformin usage in ATC. [ABSTRACT FROM AUTHOR]

Purpose: To present our real-life experience with dabrafenib and trametinib (D-T) treatment in patients with BRAF V600E-mutated ATC in Argentina. Patients y methods: We included five patients from four different hospitals. The median age was 70 years, and 60% were male. The performance status at diagnosis was grade 0 in 60% and grade 2 in 40% of patients. Four patients could undergo total thyroidectomy; in one of them, surgical treatment was amenable due to the indication of D-T as neoadjuvant therapy. From the total cohort, the best response to treatment was complete response in 40%, partial response in 20%, and stable disease in 20%. The median duration of response was 20 weeks, ranging from 16 to 92 weeks. All patients experienced at least one adverse event (AE). Grade ≥3 AEs were observed in two (40%) patients. They were upper gastrointestinal bleeding and subclavian vein thrombosis. The median follow-up was 20 weeks (range: 16 to 92). Conclusion: This report contributes to illustrate the feasibility and effectiveness of D-T treatment in five patients with loco-regionally advanced and metastatic BRAF V600E-mutated ATC in a real-life setting. A multidisciplinary approach and rapid molecular-tailored testing are essential to begin this therapeutic option. [ABSTRACT FROM AUTHOR]

Introduction: Anaplastic thyroid cancer, also called undifferentiated, is an uncommon and highly aggressive thyroid neoplasm that usually occurs in patients above 60 years of age (mean 65 years). Incidence is about 1-2 cases per million persons a year. [11] It accounts for 1-2% of thyroid cancer cases and probably develops from previously differentiated thyroid neoplasms. [1] Mutations of TP53 gene are most common and exist in 17-80% of patients. Other frequently mutated genes are RAS, BRAF and β-catenin. [3] The metastatic spread tends to occur through hematogenous and lymphatic pathways. The neoplasm presents as a rapidly enlarging neck mass that can cause compression on the neck structures giving symptoms such as dysphagia and dyspnea. Patients with established diagnosis of anaplastic thyroid cancer have very poor prognosis. Mean survival time of patients after confirmed diagnosis is 3 to 6 months and 5-year survival rate is estimated to be 5-14%. [2] Aim: The aim of this study is to portray the clinical presentation, course and complications of a patient suffering from anaplastic thyroid cancer. This case report includes performed procedures and implemented treatment. Description of the case: We present a case of an 87-year-old female that was admitted to the hospital with a large thyroid mass, symptoms of dysphagia, dyspnea and significant weight loss. Clinical picture was suspicious of anaplastic thyroid cancer. Further workup included laboratory testing, imaging and FNA biopsy. Surgical procedure of tracheostomy was conducted due to life-threatening dyspnea with consecutive patient’s monitoring in Intensive Care Unit. After achieving clinically stable state the patient was transferred to Clinical Department of Radiotherapy where palliative radiotherapy was initiated.

Abstract Background Immune checkpoint proteins have not been fully examined in follicular cell-derived thyroid carcinoma and medullary thyroid carcinoma (MTC). Anaplastic thyroid carcinoma (ATC) is one of the most aggressive carcinomas. Even multimodal treatment does not result in favorable clinical outcomes for patients with ATC. Anti-tumor immunity has therefore been highlighted as having therapeutic promise for ATC. Methods We examined a novel immune checkpoint receptor, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT), in variable thyroid lesions: adenomatous goiter, follicular adenoma, and thyroid carcinoma (TC) using immunohistochemistry (IHC). Results Our IHC results showed that TIGIT expression was detected in cancer cells of MTC and high-grade TC: poorly differentiated thyroid carcinoma (PDTC) and ATC. Neoplastic cells were positive for TIGIT in four of five MTCs (80.0%), 17 of 31 ATCs (54.8%) and in 3 of 12 PDTCs (25.0%). TIGIT was not detected in any adenomatous goiters, thyroid benign tumors, or differentiated thyroid carcinoma (DTCs). Intriguingly, ATC cells showing pleomorphic/giant cell features were positive for TIGIT, while ATC cells with other cell morphologies lacked the immunoreactivity. Intra-tumoral immune cell was inclined to be enriched in TIGI-positive ATC. Although coexisting papillary thyroid carcinoma (PTC) components demonstrated high-grade microscopic features, neither the PTC nor follicular thyroid carcinoma (FTC) components expressed TIGT in any composite ATCs. Conclusion TIGIT was immunohistochemically found in MTC with high frequency and partially in high-grade TC. TIGIT expression in cancer cells may be beneficial for a potential utility in MTC and a subset of high-grade TC, especially ATC therapy.

It is still of great challenge for anaplastic thyroid carcinoma (ATC) treatment since ATC is an extremely destructive and lethal thyroid malignancy. Herein, a kind of multifunctional nanoplatform (denoted as PDA-dsCpG-DOX NP) has been prepared and applied for tri-modal ATC therapy including photothermal therapy (PTT), chemotherapy, and immunotherapy. Polydopamine nanoparticle (PDA NP) serves as a photothermal agent to generate PTT, as well as a carrier of doxorubicin (DOX) and immunotherapeutic DNA (i.e., oligonucleotide comprising unmethylated cytosine-phosphate-guanine dinucleotide (CpG ODN)). The high temperature induced by PTT results in the release of CpG ODNs for immunotherapy and the liberation of DOX for chemotherapy. PDA-dsCpG-DOX NPs exhibit a phenomenal collaborative therapy effect contrasted with a corresponding single therapy or dual-modal treatment. By use of mice bearing C643 thyroid tumors as a model, PDA-dsCpG-DOX NPs have been demonstrated to realize nearly complete tumor growth suppression with good biocompatibility. Hence, PDA-dsCpG-DOX NPs introduce a synergistic scheme for ATC treatment and foreground the congregate effects of tri-modal therapy.

Background and Aim: Programmed cell death ligand‑1 (PD‑L1) immunoexpression status determines the response to immunotherapy in many cancers. Limited data exist on PD‑L1 status in aggressive thyroid tumors. We investigated PD‑L1 expression across thyroid cancers and correlated it with their molecular profile. Materials and Methods: Sixty‑five cases of differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) were assessed for PD‑L1 expression (clone SP263, VENTANA). The differentiated cases encompassed the aggressive hobnail and tall cell subtypes of papillary thyroid carcinoma (PTC) besides classical PTC and follicular thyroid carcinoma (FTC). Ten nodular goiters (NG) were also evaluated. Tumor proportion score (TPS) and H‑score were calculated. BRAFV600E and H‑/K‑/N‑RAS were assessed using allele‑specific real‑time polymerase chain reaction (PCR). Fisher’s exact and Kruskal–Wallis tests were used to investigate the associations between the categorical variables and compare PD‑L1 scores with the mutation status. Results: Most PTC (87%) and ATC (73%) cases were PD‑L1 positive (TPS ≥1%), with significantly higher positivity rates than NG (20%). TPS >50% was seen in 60% ATC and 7% PTC cases. The median TPS and H‑score of ATC were 56 (0–96.6) and 168 (0–275), respectively, and of PTC were 9.6 (4–16.8) and 17.8 (6.6–38.6), respectively. The scores were similar across the PTC subtypes. Only one case each of FTC and PDTC was PD‑L1 positive. PD‑L1 expression correlated significantly with BRAFV600E, but not with RAS mutation. Conclusions: ATC showed intense and diffuse PD‑L1 staining. Although most PTCs were PD‑L1 positive, the expression was weaker and patchy, irrespective of the histological subtype. Results of this pilot study indicate that ATC is most likely to respond to immunotherapy. PTC, FTC, and PDTC may be less amenable to immunotherapy. PD‑L1 expression correlated significantly with BRAFV600E, allowing for combined targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid carcinoma. Lenvatinib, a multikinase inhibitor, is rarely used in preoperative settings due to adverse effects including delayed wound healing and fistula formation. Herein, we report the use of lenvatinib treatment prior to conversion surgery for the treatment of ATC. Case presentation: A 71-year-old woman was referred to our hospital with suspected thyroid cancer with recurrent laryngeal nerve invasion and cervical lymph node metastasis based on the results of ultrasonography. Computed tomography demonstrated the presence of a thyroid tumor invading the trachea and esophagus with no evidence of distant metastasis. Fine needle aspiration of the left cervical lymph node indicated the lymph node metastasis of ATC. As the tumor had widely invaded the trachea and esophagus, unresectable ATC was diagnosed and treatment with lenvatinib was initiated at a dose of 24 mg/day. On day 13 of lenvatinib treatment, the primary tumor and lymph node metastases demonstrated a partial response to therapy. As the tumor was now considered resectable, the decision was made to perform conversion surgery. Total thyroidectomy and left lateral neck node dissection were performed 7 days after the withdrawal of lenvatinib. The patient was discharged on postoperative day 5 with no complications. Histopathological examination demonstrated that the tumor contained the component of papillary thyroid carcinoma, squamoid ATC cells, and granulation tissue. In areas of granulation tissue, atypical cells with spindle-shaped or polygonal morphology, pyknotic nuclei, and scant cytoplasm were observed. Immunohistochemically, these cells were positive for cytokeratin AE1/AE3, TTF-1, and p53 and negative for thyroglobulin and PAX8. Therefore, the areas of granulation tissue observed within tumor samples were also considered ATC that were affected by lenvatinib treatment. In total, approximately 50% of resected tumor comprised ATC, and 70% of them had been changed to granulation tissue. Conclusions: The findings in the present case indicate that lenvatinib may have significant antitumor effects in preoperative settings. Lenvatinib may represent a promising candidate therapy for unresectable ATC by increasing tumor resectability. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies, representing less than 5% of all thyroid carcinomas. Τhe median survival is limited to months due to the resistance of ATC to surgery, radioiodine therapy, radiotherapy and chemotherapy. This review will cover novel agents involving several cellular signaling pathways including the BRAF pathway. The BRAF inhibitor vemurafenib improves survival among patients with metastatic melanoma, hairy-cell leukemia and intracranial neoplasms with BRAF gene mutations. The frequency of a BRAF (V600E) mutation in ATC is about 25%. Case presentation: We report the first case of a marked partial response to adjuvant first line monotherapy with vemurafenib in BRAF V600E-mutated ATC. The 78-year-old man showed a sustained response for 7 months, thereafter scans revealed progressive disease and the patient died 10 months after first diagnosis. This case report is accompanied by a comprehensive review of current strategies and tools for ATC treatment. Conclusions: This case and the review of current data confirm the benefit of BRAF inhibition in BRAF-mutated ATC, limited by acquired resistance to targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. Results: In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin–proteasome pathway. Conclusion: Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma (ATC) is a rare cancer accounting for 40% of thyroid cancer-specific deaths. In the last 5 years, improved insights into molecular pathways led the Food and Drug Administration to license BRAF/MEK inhibitors (B/Mi) in BRAF V600E -mutant ATC, and pembrolizumab in solid cancer with high tumour mutational burden (TMB-H) (≥10 mutations/megabase) (mut/Mb). In Europe, clinicians face challenges in prescribing novel treatments, as the European Medical Association (EMA) has not licensed B/Mi nor immunotherapy (IO) for ATC so far. Some patients manage to receive these drugs through alternative ways. We investigated the extent of this phenomenon launching an online survey from March 12th to 19th 2021 open to 239 Institutions in the EORTC Endocrine and Head & Neck Cancer Groups. Questions enquired about the number of ATC patients evaluated/year, feasibility of BRAF assessment, accessibility to B/Mi-IO, availability of clinical trials and interest in new studies. Colleagues from 94 Institutions (20 Countries) joined: 30 centres evaluated ≥5 ATC patients/year, with an overall incidence >200 patients/year. 80.8% tested BRAF status, 43.6% by next-generation sequencing. 62.7% and 70% of responders reported limitations in prescribing B/Mi and IO, respectively: either the impossibility of offering them, or drugs accessibility exclusively under certain conditions (e.g. health insurance, clinical trials, compassionate use, off-label). Only 13.8% had clinical trials ongoing while 91.5% of sites claimed ATC-dedicated trials. Disparities in access to novel treatments are diffuse. Access to cutting-edge therapies is an urgent issue in this setting, and clinical trials seem feasible within an appropriate network. • Anaplastic thyroid carcinoma is poorly responsive to chemotherapy and highly lethal. • BRAF/MEKi and immunotherapy have shown promising results in certain subsets of ATC. • International guidelines recommend molecular testing to address appropriate therapy. • In Europe, no innovative treatments have been approved recently for advanced ATC. • This survey captures the diversified scenario of ATC diagnosis/therapy across E.U. [ABSTRACT FROM AUTHOR]

The clinical utilities of paclitaxel in anaplastic thyroid carcinoma (ATC) have been reported. The current study investigated the outcomes in ATC patients treated by paclitaxel as neoadjuvant setting. Furthermore, the prognostic factor for overall survival (OS) and predictive marker for response to paclitaxel were investigated. Records of ATC patients treated by paclitaxel as neoadjuvant setting in our hospital were reviewed. The median OS for the patients with (n = 43) and without (n = 23) resection were 14.7 (95% CI, 11.0–21.7) and 4.2 (95% CI, 3.0–5.4) months, respectively (p < 0.001). Univariate analysis identified the factors of stage (p = 0.028), prognostic index (PI) ≥2 (p < 0.001), response to paclitaxel (p = 0.007), resection (p < 0.001), and radiotherapy (p < 0.001) to be associated with OS, and multivariate analysis revealed that the factors of PI ≥2 [hazard ratio (HR), 2.406 (95% CI, 1.096–5.281), p = 0.029], response to paclitaxel [HR, 0.423 (95% CI, 0.193–0.930), p = 0.032], resection [HR, 0.316 (95% CI, 0.129–0.773), p = 0.012], and radiotherapy [HR, 0.229 (95% CI, 0.100–0.526), p < 0.001] were independent prognostic factors of OS. There were no significant predictive factors for response to paclitaxel in baseline characteristics. PI ≥2, response to paclitaxel, resection, and radiotherapy were independent prognostic factors in ATC patients treated with paclitaxel as neoadjuvant setting. It is important to investigate predictor for response to paclitaxel for improving resectability and prognosis in ATC. [ABSTRACT FROM AUTHOR]

Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid‐peptide‐mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase‐free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10‐fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (131I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine‐rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine. [ABSTRACT FROM AUTHOR]

Diallyl trisulfide (DATS), a natural sulfide present in allicin, has been documented as an effective anti-cancer agent against various carcinomas. Anaplastic thyroid carcinoma (ATC) is the most lethal histologic type of thyroid carcinoma. Over 80% of patients are found to have metastasis when they are diagnosed with ATC. Our previous researches indicated that DATS could induce apoptosis and compromise the stem cell phenotype of thyroid carcinoma. However, the effect of DATS on ATC metastasis is still unclear. The present study demonstrated that DATS could inhibit the migration, invasion, cell adhesion and spreading of ATC cells. Mechanistically, the process of epithelial-mesenchymal transition (EMT) was reversed by DATS treatment, evidenced as the decreased Slug expression. Integrins are the major receptors of extracellular matrix (ECM) components which regulate the migration and proliferation of cells. We found that integrin α2β1 was upregulated in ATC tissues. DATS could downregulate both the expression and membrane localization of integrin α2β1 in ATC cells. Our results suggested that DATS was capable of suppressing ATC cells metastasis. Besides, the expression of integrin α2β1 in ATC cells triggered by TGF-β were further inhibited after DATS treatment. These findings suggested that DATS showed bioactivity to serve as a plant intervention ingredient. [Display omitted] • Diallyl trisulfide inhibited metastasis of anaplastic thyroid carcinoma cells. • Integrin α2β1 is overexpressed in anaplastic thyroid carcinoma. • Diallyl trisulfide reduced the expression and membrane location of integrin α2β1. • TGF-β-Smad3 pathway was associated with expression of integrin α2β1. [ABSTRACT FROM AUTHOR]

Abstract Exosomes are nanoscale monolayer membrane vesicles that are actively endogenously secreted by mammalian cells. Currently, multifunctional exosomes with tumor-targeted imaging and therapeutic potential have aroused widespread interest in cancer research. Herein, we developed a multifunctional HEK-293T exosome-based targeted delivery platform by engineering HEK-293T cells to express a well-characterized exosomal membrane protein (Lamp2b) fused to the αv integrin-specific iRGD peptide and tyrosine fragments. This platform was loaded with doxorubicin (Dox) and labeled with radioiodine-131 (131I) using the chloramine-T method. iRGD exosomes showed highly efficient targeting and Dox delivery to integrin αvβ3-positive anaplastic thyroid carcinoma (ATC) cells as demonstrated by confocal imaging and flow cytometry in vitro and an excellent tumor-targeting capacity confirmed by single-photon emission computed tomography-computed tomography after labeling with 131I in vivo. In addition, intravenous injection of this vehicle delivered Dox and 131I specifically to tumor tissues, leading to significant tumor growth inhibition in an 8505C xenograft mouse model, while showing biosafety and no side effects. These as-developed multifunctional exosomes (denoted as Dox@iRGD-Exos-131I) provide novel insight into the current treatment of ATC and hold great potential for improving therapeutic efficacy against a wide range of integrin αvβ3-overexpressing tumors. Graphical Abstract

• Combination TKIs with immunotherapy are safe and effective for unresectable ATC. • More than one-third of ATC patients could convert to operable status. • Most patients response well, including more than a quarter complete response. • Longer survival was observed in ATC patients with BRAF V600E mutations. Anaplastic thyroid carcinoma (ATC) is rare but has a very poor prognosis. New therapeutic options such as multikinase inhibitors and selective tyrosine kinase inhibitors have revolutionized the treatment of ATC, with immunotherapy also showing encouraging effects. This study evaluated the efficacy and safety of kinase inhibitors combined with an anti-PD-1 inhibitor as first-line treatment, as well as in the neoadjuvant setting for patients with unresectable ATC. This retrospective single-center study recruited consecutive patients with stage IVB and IVC ATC who received first-line kinase inhibitors plus immunotherapy between June 2021 and June 2023. The patients were treated with either selective or multi-kinase inhibitors (dabrafenib/trametinib, lenvatinib, or anlotinib) in combination with one immune checkpoint inhibitor (pembrolizumab, sintilimab, or camrelizumab). The endpoints included overall survival (OS), progression-free survival (PFS), response evaluation, and feasibility of R0/R1 resection. Eighteen patients were included in this analysis. The median OS (mOS) was 14.0 months and the 12-month survival rate was 55.6 %. The mOS in BRAF V600E mutated ATC was not reached, significantly longer than non-BRAF V600E mutated ATC (4.0 months [95 %CI, 1.1–6.9], p = 0.049). Among evaluable patients, 5 achieved a complete response (CR) and 6 patients achieved partial response (PR). The best ORR was 61.1 %. Surgical resection was feasible in 7/18 (38.9 %) patients. One grade 5 adverse event (AE) occurred. Most AEs were well tolerated. Combination kinase inhibitors with immunotherapy as first-line therapy are safe and effective for the treatment of unresectable ATC, especially with BRAF V600E mutation. [ABSTRACT FROM AUTHOR]