RESUMEN
Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.
Asunto(s)
Progresión de la Enfermedad , Homeostasis , Magnesio , Carcinoma Anaplásico de Tiroides , Animales , Femenino , Humanos , Ratones , Apoptosis , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Magnesio/metabolismo , Ratones Desnudos , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer, and it has a poor prognosis and high probability of metastatic recurrence. The long-term survival of cancer cells depends on their ability to settle in a favorable environment. Cancer cells interact with other cells in the tumor microenvironment to shape the "soil" and make it suitable for cell growth by forming an extremely complex tumor ecosystem. The extracellular matrix (ECM) is an essential component of the tumor ecosystem, and its biological and mechanical changes strongly affect tumor invasion, metastasis, immune escape and drug resistance. Compared to normal tissues, biological processes, such as collagen synthesis and ECM signaling, are significantly activated in ATC tissues. However, how ATC triggers changes in the properties of the ECM and its interaction with the ECM remain poorly characterized. Therefore, an in-depth study of the regulatory mechanism of the abnormal activation of ECM signaling in ATC is highly important for achieving the therapeutic goal of exerting antitumor effects by destroying the "soil" in which cancer cells depend for survival. In this research, we revealed the aberrant activation state of ECM signaling in ATC progression and attempted to uncover the potential mechanism of action of ECM components in ATC, with the aim of providing new drug targets for ATC therapy.
Asunto(s)
Matriz Extracelular , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Microambiente Tumoral , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Humanos , Matriz Extracelular/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Transducción de SeñalRESUMEN
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.
Asunto(s)
Apoptosis , Proliferación Celular , Proteínas RGS , Saponinas , Transducción de Señal , Espirostanos , Carcinoma Anaplásico de Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Saponinas/farmacología , Proteínas RGS/metabolismo , Proteínas RGS/genética , Proliferación Celular/efectos de los fármacos , Animales , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Espirostanos/farmacología , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratones Desnudos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Metástasis de la NeoplasiaRESUMEN
Anaplastic thyroid carcinoma (ATC) is a highly aggressive human malignancy without effective treatment. Yes-associated protein (YAP) is a critical effector of the Hippo pathway, which is essential in thyroid carcinogenesis. However, the underlying mechanisms of aberrant YAP expression in ATC are not completely understood. Ubiquitylation-related enzyme siRNA screening identified the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) as a stabilizer of YAP in ATC cells. UBR1 deficiency reduced YAP protein levels and its target gene expression. UBR1 directly interacted with YAP and promoted its monoubiquitylation, competitively suppressing its polyubiquitylation and resulting in extended protein half-life. UBR1 depletion reduced ATC cell proliferation and migration in vitro. Xenograft tumor studies also suggested that UBR1 knockdown suppressed ATC cell growth in vivo. Furthermore, exogenous YAP expression partially reversed the inhibitive effects of UBR1 depletion on ATC cell proliferation and migration. Our studies demonstrated that UBR1 directly interacts with YAP and stabilized it in a monoubiquitylation-dependent manner, consequently promoting ATC tumorigenesis, suggesting that UBR1 might be a potentially therapeutic target for ATC treatment.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Movimiento Celular , Proliferación Celular , Carcinoma Anaplásico de Tiroides , Factores de Transcripción , Ubiquitinación , Proteínas Señalizadoras YAP , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones , Estabilidad Proteica , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Progresión de la Enfermedad , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica , Fosfoproteínas/metabolismo , Fosfoproteínas/genéticaRESUMEN
BACKGROUND: Thyroid cancer is a common thyroid malignancy. The majority of thyroid lesion needs intraoperative frozen pathology diagnosis, which provides important information for precision operation. As digital whole slide images (WSIs) develop, deep learning methods for histopathological classification of the thyroid gland (paraffin sections) have achieved outstanding results. Our current study is to clarify whether deep learning assists pathology diagnosis for intraoperative frozen thyroid lesions or not. METHODS: We propose an artificial intelligence-assisted diagnostic system for frozen thyroid lesions that applies prior knowledge in tandem with a dichotomous judgment of whether the lesion is cancerous or not and a quadratic judgment of the type of cancerous lesion to categorize the frozen thyroid lesions into five categories: papillary thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid tumor, and non-cancerous lesion. We obtained 4409 frozen digital pathology sections (WSI) of thyroid from the First Affiliated Hospital of Sun Yat-sen University (SYSUFH) to train and test the model, and the performance was validated by a six-fold cross validation, 101 papillary microcarcinoma sections of thyroid were used to validate the system's sensitivity, and 1388 WSIs of thyroid were used for the evaluation of the external dataset. The deep learning models were compared in terms of several metrics such as accuracy, F1 score, recall, precision and AUC (Area Under Curve). RESULTS: We developed the first deep learning-based frozen thyroid diagnostic classifier for histopathological WSI classification of papillary carcinoma, medullary carcinoma, follicular tumor, anaplastic carcinoma, and non-carcinoma lesion. On test slides, the system had an accuracy of 0.9459, a precision of 0.9475, and an AUC of 0.9955. In the papillary carcinoma test slides, the system was able to accurately predict even lesions as small as 2 mm in diameter. Tested with the acceleration component, the cut processing can be performed in 346.12 s and the visual inference prediction results can be obtained in 98.61 s, thus meeting the time requirements for intraoperative diagnosis. Our study employs a deep learning approach for high-precision classification of intraoperative frozen thyroid lesion distribution in the clinical setting, which has potential clinical implications for assisting pathologists and precision surgery of thyroid lesions.
Asunto(s)
Aprendizaje Profundo , Secciones por Congelación , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugía , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/diagnóstico , Cáncer Papilar Tiroideo/cirugía , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Carcinoma Papilar/diagnóstico , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/cirugía , Glándula Tiroides/patología , Glándula Tiroides/cirugía , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/cirugía , Femenino , Masculino , Persona de Mediana Edad , Adulto , Periodo Intraoperatorio , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/diagnóstico , Carcinoma Anaplásico de Tiroides/cirugíaRESUMEN
The objective of this study was to explore the effects and mechanisms of the combination of isobavachalcone (IBC) and doxorubicin (DOX) on the progression of anaplastic thyroid cancer (ATC). Cell viability of 8505C and CAL62 cells was observed by CCK-8 assay. Kits were used to detect the presence of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and cellular iron. Protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was detected using western blot, and CD31 was detected through immunofluorescence. Tumor xenograft models of 8505C cells were constructed to observe the effect of IBC and DOX on ATC growth in vivo. The co-administration of IBC and DOX exhibited a synergistic effect of suppressing the growth of 8505C and CAL62 cells. The concurrent use of IBC and DOX resulted in elevated iron, ROS, and MDA levels, while reducing GSH levels and protein expression of SLC7A11 and GPX4. However, the Fer-1 ferroptosis inhibitor effectively counteracted this effect. In vitro and in vivo, the inhibitory effect on ATC cell proliferation and tumor growth was significantly enhanced by the combination of IBC and DOX. The combination of IBC and DOX can inhibit the growth of ATC by activating ferroptosis, and might prove to be a potent chemotherapy protocol for addressing ATC.
Asunto(s)
Chalconas , Doxorrubicina , Sinergismo Farmacológico , Ferroptosis , Especies Reactivas de Oxígeno , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Ferroptosis/efectos de los fármacos , Doxorrubicina/farmacología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/metabolismo , Animales , Humanos , Chalconas/farmacología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Progresión de la Enfermedad , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Supervivencia Celular/efectos de los fármacos , Glutatión/metabolismo , Glutatión/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismoRESUMEN
BACKGROUND: The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events. METHODS: Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events. RESULTS: Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common gradeâ ≥â 3 treatment-related adverse events. CONCLUSION: Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies.
Asunto(s)
Inhibidores de la Angiogénesis , Inhibidores de Proteínas Quinasas , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Prospectivos , Sorafenib/uso terapéutico , Sorafenib/efectos adversos , Indazoles/uso terapéutico , Indazoles/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Supervivencia sin Progresión , Pirimidinas , Quinolinas , SulfonamidasRESUMEN
PURPOSE: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are rare, aggressive thyroid cancers with poor prognosis. At present, there are a limited number of research reports on PDTC and ATC. The study aimed to analysis the predictive value of hematologic parameters and clinicopathological features of PDTC and ATC. METHODS: This study retrospectively analyzed 67 patients at Tianjin Medical University Cancer Hospital from 2007 to 2019. We analyzed the clinicopathological features and survival outcomes of PDTC and ATC. RESULTS: This study showed that positive D-dimer, a high NLR, and a high PLR were more common in death patients. At the end of follow-up, 22 (32.8%) patients were alive at the time of study and 45 (67.2%) patients died from thyroid carcinoma. Disease-related death rates were 93.8% in ATC and 42.9% in the PDTC group. The median overall survival (OS) was 2.5 (0.3-84) months for patients with ATC, and 56 (3-113) months of PDTC patients. Univariate analysis showed that age at diagnosis and surgery were associations with OS in ATC patients, what's more, age at diagnosis, a high NLR, a high PLR, and positive D-dimer were associations with OS in PDTC patients. Multivariate analysis revealed that age at diagnosis was an independent association with OS in ATC patients. CONCLUSIONS: The hematologic parameters and clinicopathological features may provide predictive value of prognosis for patients with PTDC and ATC.
Asunto(s)
Valor Predictivo de las Pruebas , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Masculino , Femenino , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/cirugía , Persona de Mediana Edad , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/mortalidad , Carcinoma Anaplásico de Tiroides/sangre , Estudios Retrospectivos , Anciano , Adulto , Pronóstico , Tasa de Supervivencia , Anciano de 80 o más AñosRESUMEN
Anaplastic thyroid cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase-ATP6V1A, ATP6V1B2, and ATP6V0C-resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA's anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent pyroptosis in cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.
Asunto(s)
Lisosomas , Piroptosis , Carcinoma Anaplásico de Tiroides , ATPasas de Translocación de Protón Vacuolares , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Humanos , Piroptosis/efectos de los fármacos , ATPasas de Translocación de Protón Vacuolares/metabolismo , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Animales , Línea Celular Tumoral , Sapogeninas/farmacología , Ratones , Ratones Desnudos , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , GasderminasRESUMEN
Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive thyroid cancer with poor prognosis. Killing cancer cells by inducing DNA damage or blockage of DNA repair is a promising strategy for chemotherapy. It is reported that aldehyde-reactive alkoxyamines can capture the AP sites, one of the most common DNA lesions, and inhibit apurinic/apyrimidinic endonuclease 1(APE1)-mediated base excision repair (BER), leading to cell death. Whether this strategy can be employed for ATC treatment is rarely investigated. The aim of this study is to exploit GSH-responsive AP site capture reagent (AP probe-net), which responses to the elevated glutathione (GSH) levels in the tumor micro-environment (TME), releasing reactive alkoxyamine to trap AP sites and block the APE1-mediated BER for targeted anti-tumor activity against ATC. In vitro experiments, including MTT andγ-H2AX assays, demonstrate their selective cytotoxicity towards ATC cells over normal thyroid cells. Flow cytometry analysis suggests that AP probe-net arrests the cell cycle in the G2/M phase and induces apoptosis. Western blotting (WB) results show that the expression of apoptotic protein increased with the increased concentration of AP probe-net. Further in vivo experiments reveal that the AP probe-net has a good therapeutic effect on subcutaneous tumors of the ATC cells. In conclusion, taking advantage of the elevated GSH in TME, our study affords a new strategy for targeted chemotherapy of ATC with high selectivity and reduced adverse effects.
Asunto(s)
Apoptosis , Glutatión , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/metabolismo , Humanos , Glutatión/metabolismo , Animales , Ratones , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Reparación del ADN/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Daño del ADN/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
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.
Asunto(s)
Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Prospectivos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidadRESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Terapia Neoadyuvante , Compuestos de Fenilurea , Proteínas Proto-Oncogénicas B-raf , Quinolinas , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Masculino , Proteínas Proto-Oncogénicas B-raf/genética , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Quinolinas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Anciano , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
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.
Asunto(s)
Nomogramas , Programa de VERF , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Masculino , Femenino , Persona de Mediana Edad , Carcinoma Anaplásico de Tiroides/mortalidad , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/terapia , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Anciano , Pronóstico , Metástasis de la Neoplasia , Adulto , Tasa de Supervivencia , Curva ROCRESUMEN
BACKGROUND: Anaplastic thyroid carcinoma(ATC) is a rare pathological type of thyroid malignancy. Primary squamous cell carcinoma of thyroid(PSCCT) is now considered as a subtype of ATC, hereinafter referred to as ATC-SCC subtype. ATC-SCC subtype combined with follicular thyroid carcinoma is exceedingly rare, with fewer cases reported. The ATC-SCC subtype is a highly invasive tumor with a poor prognosis for patients after metastasis occurs, and current treatment of this type of tumor is tricky. CASE PRESENTATION: A 68-year-old female patient presented with a gradually growing swelling of right cervical region. Comprehensive auxiliary examinations and postoperative pathology confirmed the diagnosis of ATC-SCC subtype with follicular thyroid carcinoma, and the metastasis squamous cell carcinoma of the right cervical lymph nodes originates from ATC-SCC subtype. The patient received chemoradiotherapy postoperative. However, the residual cervical lymph nodes metastasis with squamous cell carcinoma still infiltrated surrounding structures in the neck extensively after palliative resection. The patient died 7 months after surgery. CONCLUSION: Our case highlights that cervical lymph node metastasis may be a significant factor in the poor prognosis of ATC-SCC subtype. This malignancy should be detected and treated early.
Asunto(s)
Adenocarcinoma Folicular , Metástasis Linfática , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Femenino , Anciano , Neoplasias de la Tiroides/patología , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/secundario , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/diagnóstico , Carcinoma Anaplásico de Tiroides/terapia , Pronóstico , Resultado Fatal , Cuello/patología , Ganglios Linfáticos/patología , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/diagnósticoRESUMEN
Thyroid carcinoma of follicular cell origin exists on a histopathologic and clinical spectrum. The authors focus on the category of tumors that fall between the very favorable well-differentiated thyroid carcinomas and the very unfavorable anaplastic thyroid carcinomas. These intermediately aggressive tumors include poorly differentiated thyroid carcinoma and the newly defined differentiated high-grade thyroid carcinoma. Both diagnoses require certain histopathologic requirements be met in order to accurately identify these tumors post-operatively. Management remains primarily surgical though adjunctive treatments such as molecular targeted therapies (eg, tyrosine kinase inhibitors) and differentiation therapy (to restore tumor response to radioactive iodine) are also becoming available.
Asunto(s)
Neoplasias de la Tiroides , Tiroidectomía , Humanos , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Tiroidectomía/métodos , Clasificación del Tumor , Adenocarcinoma Folicular/terapia , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/diagnóstico , Carcinoma Anaplásico de Tiroides/terapia , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/diagnósticoRESUMEN
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.
Asunto(s)
Terapia Molecular Dirigida , Recurrencia Local de Neoplasia , Carcinoma Anaplásico de Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/terapia , Carcinoma Anaplásico de Tiroides/diagnóstico , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Biomarcadores de Tumor , Manejo de la Enfermedad , Mutación , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Metástasis de la Neoplasia , Resultado del Tratamiento , Susceptibilidad a EnfermedadesRESUMEN
OBJECTIVE: Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications. DESIGN, PATIENTS AND MESUREMENT: A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ2 tests, were employed for survival analysis and gene mutation comparisons. RESULTS: Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data. CONCLUSIONS: Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling.
Asunto(s)
Mutación , Proteínas Proto-Oncogénicas B-raf , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Proteínas Proto-Oncogénicas B-raf/genética , Masculino , Femenino , Estudios Retrospectivos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Persona de Mediana Edad , Anciano , Neoplasias de la Tiroides/genética , Neurofibromina 1/genética , Anciano de 80 o más Años , Adulto , Japón/epidemiología , Genómica/métodos , Proteínas ras/genéticaRESUMEN
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.
Asunto(s)
Quinasa de Linfoma Anaplásico , Apoptosis , Proliferación Celular , Crizotinib , Inhibidores de Proteínas Quinasas , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Crizotinib/farmacología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Masculino , Femenino , Antineoplásicos/farmacología , Persona de Mediana Edad , Movimiento Celular/efectos de los fármacos , Anciano , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Células Tumorales Cultivadas , Línea Celular Tumoral , Proteínas de Unión a Calmodulina , Proteínas de la Membrana , Proteínas del Tejido NerviosoRESUMEN
The differential diagnosis of a rapidly enlarging neck mass consists of many different benign ((haemorrhagic) cyst) and malignant (anaplastic thyroid cancer (ATC) and lymphoma) causes. ATC is a rare disease with a median survival of 6 months. As early diagnosis and management are key for fast-growing cancers, in our centre we have implemented a dedicated short-stay in-hospital fast-track diagnostic work-up for patients with a rapid growing mass in the neck. The goal of this track is to have a fast diagnostic and therapeutic plan for this disease. Based on three clinical cases we discuss our experience with this fast-track diagnostic work-up for rapidly growing mass in the neck and illustrate the additional value in this clinical entity.