RON receptor tyrosine kinase regulates glycolysis through MAPK/CREB signaling to affect ferroptosis and chemotherapy sensitivity of thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is one of the deadliest and most aggressive human malignancies for which there is currently no effective treatment. Tyrosine kinase receptor RON is highly expressed in various cancer types, including colon, pancreatic and thyroid cancer. However, its underlying role in ATC is not fully understood. The present study investigated the therapeutic potential and molecular mechanism of RON in ATC. RON expression in thyroid cancer cells was detected by western blotting. Glycolysis was assessed by measuring the extracellular acidification rate, glucose uptake, lactate concentration, and expression levels of glucose transporter 1, hexokinase 2 and pyruvate kinase M1/2. In addition, ferroptosis was assessed by detecting the levels of total iron, lipid peroxide and reactive oxygen species, and the expression levels of ferroptosis­related proteins. Furthermore, mitochondrial function were assessed by JC­1 staining and detection kits, respectively. The results demonstrated that RON was highly expressed in thyroid cancer cell lines. Furthermore, RON interference inhibited glycolysis, promoted ferroptosis, elevated cell sensitivity to chemotherapy and affected mitochondrial function in thyroid cancer cells. Further experiments demonstrated that RON interference affected the ferroptosis levels in thyroid cancer cells by inhibiting the glycolysis process. Mechanistically, the present results indicated that RON may affect ferroptosis, glycolysis and chemotherapy sensitivity by regulating MAPK/cAMP­response element binding protein (CREB) signaling in thyroid cancer cells. In conclusion, the present study demonstrated that RON affected ferroptosis, glycolysis and chemotherapy sensitivity in thyroid cancer cells by regulating MAPK/CREB signaling, demonstrating its potential as a therapeutic target in thyroid cancer cells.

A case of selpercatinib treatment for anaplastic thyroid carcinoma resulting in abscess formation.

Rearranged during transfection (RET) gene abnormality is a driver gene mutation that causes thyroid cancer, and selpercatinib has been shown to be useful for treating thyroid cancer with RET gene abnormalities. Anaplastic thyroid cancer is a disease with an extremely poor prognosis with no standard treatment established, and there are only one case reports of the efficacy of selpercatinib for RET fusion gene-positive anaplastic thyroid cancer. We herein report our experience treating an old Japanese woman with unresectable anaplastic thyroid cancer with selpercatinib. Surgical resection was initially attempted but was not possible due to adhesion to the common carotid artery. Postoperative genetic testing was positive for the RET fusion gene, and selpercatinib was administered. However, the administration had to be stopped due to the formation of an abscess on day 14 and a pharyngeal fistula on day 17, after which the tumor grew rapidly, and the patient died on day 65. Although selpercatinib has been reported to have a high safety profile with few adverse events, this case suggests that caution should be exercised when treating anaplastic thyroid cancer with invasion to vital organs.

Attenuation of aggressive tumor progression of anaplastic thyroid cancer by p53.

Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer, with very limited treatment options. Mutations of p53 are associated with lethal outcomes of ATC. In this study, we tested the hypothesis that wild type p53 (WTp53) mitigates its aggressive progression. We used human 8505C cells (from human ATC tumors) as a model, harboring a BRAFV600E mutation and single of mutated p53C742G allele. We exogenously expressed WTp53 or mutant p53C742G into 8505C cells (8505C-WTp53 or 8505C-MTp53, respectively). The expressed WTp53 inhibited cell proliferation, decreased cell migration, and induced apoptosis via induction of proapoptotic WTp53 target BAX and PUMA genes in vitro. Mouse xenograft studies showed suppression of tumors induced by 8505C-WTp53 but not by 8505C-MTp53 cells. Consistent with in vitro findings, WTp53 inhibited proliferation of tumor cells, evidenced by decreased proliferation marker Ki-67 in tumors. WTp53 also induced apoptosis in xenograft tumors as shown by increased cleaved caspase-3 proteins and pro-apoptotic regulators, BAX and PUMA. Single cells RNA-sequencing (scRNA-seq) of tumors induced by 8505C, 8505C-WTp53, and 8505C-MTp53 cells demonstrated differential expression gene (DEG) patterns between 8505C-WTp53 and 8505C tumors. DEGs analysis identified alteration of multiple pathways, leading to attenuating the oncogenic actions of mutant p53. The discovery of the suppression of TNFα via NFκB pathway topped the pathways list, resulting in subduing the deleterious inflammatory responses caused by mutant p53. Our findings that exogenously expressed WTp53 could counter act the oncogenic actions of p53 has heightened the feasibility of using CRISPR/Cas9 genome editing to modify the p53 alleles for potential treatment of ATC.

Predicting overall survival in anaplastic thyroid cancer using machine learning approaches.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is a highly aggressive and lethal thyroid cancer subtype with a poor prognosis. Recent advancements in machine learning (ML) have the potential to improve survival predictions. This study aimed to develop and validate ML models using the SEER database to predict 3-month, 6-month, and 12-month (overall survival) OS in ATC patients. METHODS: Clinical and demographic data for patients with ATC from the SEER database (2004-2015) were utilized. Five ML algorithms-AdaBoost, support vector machines, gradient boosting classifiers, random forests, and naive Bayes-were evaluated. The data were split into training and testing sets (7:3 ratio), and the models were tuned using fivefold cross-validation. Model performance was assessed using the concordance index (C-index) and Brier score, with 95% confidence intervals reported. RESULTS: The gradient boosting model achieved the greatest performance for 3-month survival (C-index: 0.8197, 95% CI 0.7682-0.8689; Brier score: 0.1802), and the AdaBoost model achieved the greatest performance in 6-month survival (C-index: 0.8473, 95% CI 0.7979-0.8933; Brier score: 0.1775). The SVC model showed superior performance for 12-month survival (C-index: 0.8347, 95% CI 0.7866-0.8816; Brier score: 0.1476). Using SHAP with a gradient boosting model, the top five features affecting 6-month OS were identified: surgery, the presence of stage IVC, radiation, chemotherapy, and tumor size. Treatment improved survival, while higher stages reduced survival, with smaller tumors generally linked to better outcomes. CONCLUSION: ML algorithms can accurately predict short-term survival in ATC patients. These models can potentially guide clinical decision-making and individualized treatment strategies.

Study on the mechanism of 17-Hydroxy-jolkinolide B on anaplastic thyroid cancer cell.

BACKGROUND: Anaplastic thyroid cancer (ATC) has a dismal prognosis, and the optimal treatment has not yet been confirmed. Euphorbia fischeriana Steud has been proven to exhibit pharmacological properties, including various antitumor effects, that can be used to treat numerous diseases and has been used to treat cancer. 17-Hydroxy-jolkinolide B (17-HJB) is one of the major diterpenoids produced from plants, but little research has investigated how it affects cancer. METHODS: MTT assays, glucose and lactate concentration detection, Annexin V-FITC detection via cytometry, and Western blotting were performed to research the mechanism of 17-HJB. RESULTS: Cell viability was inhibited in a concentration-dependent manner after 17-HJB treatment. 17-HJB inhibited glucose consumption and lactate production, and the expression of the glucose transporter GLUT1 and proteins associated with glycolysis, HK2, PFK1, and PKM2, was significantly downregulated. 17-HJB induced apoptosis, and the expression of signaling proteins related to apoptosis, such as Caspase-3 and cleaved Caspase-3, was upregulated. In vivo, 17-HJB effectively inhibited the growth of ATC tumors. The results of the expression of glycolysis-related enzyme proteins and apoptosis signaling proteins were consistent with those in vitro. CONCLUSIONS: 17-HJB inhibited the growth of ATCs both in vivo and in vitro. The mechanism may be related to the effects on glucose metabolism and the inhibition of aerobic glycolysis. 17-HJB also induced ATC apoptosis.

Single-Institution Experience of Larotrectinib Therapy for Patients With NTRK Fusion-Positive Thyroid Carcinoma.

Context: The real world efficacy and tolerabiltiy of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results. Objective: We report a retrospective analysis of patients with thyroid cancer harboring NTRK fusions who underwent treatment with larotrectinib. Methods: A single-institution, retrospective case series of patients with NTRK fusion-positive thyroid cancers treated with neurotrophic tyrosine receptor kinase (NTRK) inhibitors from January 1, 2007, to January 1, 2023, was performed. This study was conducted at a single academic tertiary referral center. Patients with confirmed NTRK-fusion thyroid cancer who received larotrectinib were included. Larotrectinib was administered in accordance with clinical judgment from oncology providers. The primary end point was progression-free survival (PFS). Results: Eight patients with NTRK fusion-positive thyroid cancer treated with larotrectinib were identified: 4 with papillary thyroid cancer (PTC) (50%), 3 with poorly differentiated thyroid cancer (PDTC) (38%), and 1 with anaplastic thyroid cancer (ATC) (12%). The median PFS (mPFS) for all patients was 24.7 months (95% CI, 11.3-38.1). mPFS in PTC was higher than PDTC (34.6 months [24.7-48.7 months] vs 17.5 [7.1-21.1 months]; P = .017). The median overall survival (OS) was 43.8 months (29.8-56.8 months) overall. The single patient with ATC had a PFS and OS of 23 months. Two patients remained on treatment/alive at data cutoff, with a duration of response of 33.5 months and a median follow-up of 52 months. Patients achieved 1 complete response (12%), 6 partial responses (75%), and 1 stable disease (12%). Conclusion: In this single-institution cohort of patients with NTRK fusion-positive thyroid cancer, NTRK inhibition led to an mPFS of 25 months, with survival surpassing historic benchmarks for ATC and PDTC.

Anaplastic thyroid cancer cell-secreted TGFß1 plays a key role in inducing macrophage polarization of human monocytes.

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 ß1 (TGFß1) 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 TGFß1 induced M2-like macrophage polarization, showing high CD163 and Dectin1 expression. Moreover, we showed that TGFß1 induced the messenger RNA (mRNA) and protein expression of the transcription factors SNAIL and SLUG. Accordingly, increased TGFß1 secretion from ATC cells was confirmed by enzyme-linked immunosorbent assay (ELISA). Addition of SB431542, a TGFß 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 TGFß 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 TGFß ligands, TGFß1 and TGFß3, 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 TGFß1 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.

Ophiopogonin D' inhibited tumour growth and metastasis of anaplastic thyroid cancer by modulating JUN/RGS4 signalling.

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.

Improved Survival of Advanced-Stage Anaplastic Thyroid Cancer With Systemic Therapy.

OBJECTIVES: 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. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Development of a novel dynamic nomogram for predicting overall survival in anaplastic thyroid cancer patients with distant metastasis: a population-based study based on the SEER database.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Neoadjuvant treatment with lenvatinib and pembrolizumab in a BRAF V600E-mutated anaplastic thyroid cancer: a case report.

Background: 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. Case presentation: 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. Conclusion: 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.

Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies.

Background: 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. Methods: 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). Results: 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%). Conclusion: 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.

A novel mutation in PTEN in anaplastic thyroid carcinoma: A case report.

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.

Anaplastic thyroid cancer: Unveiling advances in diagnosis and 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.

Combined radiation and chemotherapy versus monotherapy for anaplastic thyroid cancer: A SEER retrospective analysis.

Background: The effect of combined radiation and chemotherapy (combination therapy) versus monotherapy on anaplastic thyroid carcinoma (ATC) has not yet been clear. Methods: 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. Results: 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). Conclusion: 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.

Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.

OPINION STATEMENT: Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

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.

Recent Trends and Potential of Radiotherapy in the Treatment of Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy characterized by advanced disease at diagnosis and a poor prognosis. Despite multimodal therapeutic approaches that include surgery, radiotherapy, and chemotherapy, an optimal treatment strategy remains elusive. Current developments in targeted therapies and immunotherapy offer promising avenues for improved outcomes, particularly for BRAF-mutant patients. However, challenges remain regarding overcoming drug resistance and developing effective treatments for BRAF-wild-type tumors. This comprehensive review examines the clinical and biological features of ATC, outlines the current standards of care, and discusses recent developments with a focus on the evolving role of radiotherapy. Moreover, it emphasizes the necessity of a multidisciplinary approach and highlights the urgent need for further research to better understand ATC pathogenesis and identify new therapeutic targets. Collaborative efforts, including large-scale clinical trials, are essential for translating these findings into improved patient outcomes.

Efficacy and safety of BRAF/MEK inhibitors in BRAFV600E-mutated anaplastic thyroid cancer: a systematic review and meta-analysis.

PURPOSE: Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAFV600E mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAFV600E ATC patients. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAFV600E ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs). RESULTS: Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I2 = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I2 = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I2 = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I2 = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found. CONCLUSIONS: Our study demonstrated BRAFi/MEKi have a decent activity for BRAFV600E ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.