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Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT , AKT1 , PIK3CA , and EIF1AX were frequently co-mutated with driver genes ( BRAF V600E and RAS ) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A ) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS -positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs. Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) come with a dismal prognosis. Here, Yoo and colleagues reveal the genomic and transcriptomic landscape of ATC and DTC, highlighting potential therapeutic vulnerabilities.

Background Anaplastic thyroid carcinoma (ATC) is a rare but aggressive malignancy, which accounts for only 1–2% of all thyroid cancers. The median overall survival (OS) time for all stages patients is at about 5 months. The benefit of surgery combined with adjuvant radiation and chemotherapy in stage IVC anaplastic thyroid cancer is still controversial. The aim of this study is to investigating surgery combined with adjuvant radiation and chemotherapy and survival outcomes in stage IVC ATC patients. Method Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 2004 to 2016 were used to conduct a cross-sectional study in the analysis. The endpoint of this study was overall survival. Results The median OS of the overall population was 2.0 months. Multivariate analysis showed that age (<67 vs. ≥67 years old, P  = 0.017, HR = 1.355, 95% CI: 1.057–1.738), tumor size (<7 cm vs. ≥7 cm, P  = 0.001, HR = 1.579, 95% CI: 1.202–2.073), Surgery (thyroidectomy vs. non-surgery, P  < 0.001, HR = 0.554, 95% CI: 0.401–0.766), radiation therapy ( P  < 0.001, HR = 0.571, 95% CI: 0.445–0.733) and chemotherapy ( P  = 0.003, HR = 0.684, 95% CI: 0.531–0.881) were independent prognostic factor for worse OS in stage IVC ATC patients. Surgery combined with adjuvant radiation and chemotherapy exhibited the better overall survival time for 4 months. Conclusions Surgery combined with adjuvant radiation and chemotherapy can improve overall survival in stage IVC ATC patients. We recommend surgical approach with fully evaluation combined with radiation therapy and chemotherapy for selected stage IVC ATC patients.

TERT promoter mutation is associated with poor prognosis in differentiated thyroid carcinoma, with US features varying by mutation status. However, this correlation in anaplastic thyroid carcinoma (ATC) is understudied. We investigated the association between clinicopathological characteristics and US features of ATC with TERT mutation status and prognosis. From November 1994 to May 2022, 58 ATC nodules from 58 patients were analyzed. Two radiologists retrospectively reviewed US features based on the revised K-TIRADS and ACR-TIRADS. Of all 58 ATC nodules, 32 nodules were tested for TERT promoter mutation and detected in 11. TERT promoter-mutated ATC was larger than TERT wild-type ATC ( p  = 0.032); however, no other differences were observed. ATC with survival period of less than 12 months were more likely to have lymph node metastasis ( p  = 0.012) or distant metastasis at diagnosis ( p  < 0.001), larger size on US ( p  = 0.005), and suspicion for gross extrathyroidal extension on US ( p  = 0.04) compared to ATC with survival period of 12 months or more. Advanced disease at diagnosis was a critical factor associated with 1-year survival in patients with ATC, whereas the TERT promoter mutation status was not.

Background Anaplastic thyroid cancer (ATC) is a highly lethal disease, often diagnosed with advanced locoregional and distant metastases, resulting in a median survival of just 3–5 months. This study determines the stratified effectiveness of baseline treatments in all combinations, enabling precise prognoses prediction and establishing benchmarks for advanced therapeutic options. Methods The study extracted a cohort of pathologically confirmed ATC patients from the Surveillance, Epidemiology, and End Results program. Overall, 1879 patients from 2000 to 2018 were identified from the database. Kaplan–Meier survival curve estimation and Cox proportional hazard regression were applied. Results Overall, compared with no treatment, surgery raised 1-year overall survival (OS) from 0.6% to 30% and median survival from <1 month to 3 months in ATC patients. For stage IVa, surgery increased 1-year OS from 21.5% to 71.8% and median survival from 2 to 23.5 months, and in stage IVb, surgery increased 1-year OS from 9.4% to 41.3% and median survival from 2 to 7 months; however, in stage IVc, the benefits of surgery were not markedly different from non-surgical approaches. When combined with surgery, other effective non-surgical ATC treatments demonstrated a surgery-dominant synergistic effect, particularly for stages IVa and IVb ATC, but not for stage IVc ATC. Conclusions Our study provides insights into stratified baseline treatments for patients with ATC in all stages, emphasizing surgery’s vital role in a multimodal approach.

Anaplastic thyroid cancer (ATC) is highly aggressive with a poor prognosis. Adjuvant systemic therapy and radiation post-surgery are endorsed by NCCN and ATA guidelines. Our study aimed to identify those at risk of forgoing postoperative adjuvant treatment and to determine survival predictors. We used the National Cancer Database (NCDB) to identify ATC patients who underwent upfront thyroidectomy from 2010 to 2017, excluding those opting for palliative care. We compared demographics, characteristics, treatments, and outcomes between those who received adjuvant therapy and those who did not. Predictors of receiving adjuvant therapy were identified using logistic regression, while Cox regression identified survival factors. Of 563 patients, 160 received no adjuvant treatment, 82 received radiation only, 16 received systemic therapy only, and 305 received combination therapy. Notably, over 75 ​% of patients who did not receive adjuvant treatment had it excluded from their treatment plan, not due to refusal. Older age (OR 0.92) and non-white race/ethnicity (OR 0.33) were significant predictors of not receiving adjuvant therapy. Undergoing a total thyroidectomy, an R0 or R1 resection, and radiation or combination therapy were associated with better survival, while non-metropolitan location, primary tumor size >7.5 ​cm, and stage IVC disease were negative factors. Total thyroidectomy, R0/R1 resection, and adjuvant therapy reduce mortality in ATC patients. However, older patients and minorities are less likely to receive adjuvant therapy, underscoring disparities in treatment adherence. •Total thyroidectomy, R0 resection, and adjuvant therapy reduce mortality in ATC patients.•Older patients and minorities are less likely to receive adjuvant therapy in ATC.•Most patients that did not receive adjuvant therapy did not cite refusal as the reason for not receiving it, suggesting possible poor provider adherence to guidelines.

Background The prognosis of patients with anaplastic thyroid cancer (ATC) remains dismal. A small portion of patients experience longterm survival and need to be identified before treatment allocation. Survival scores may guide clinicians making more informed decisions about treatment options and improve the understanding of patients’ prognosis. The aim of this study was to validate two prognostic scores using an independent dataset to analyze which prognostic index is superior in discriminating survival. Methods Thirty-four patients with histologically confirmed ATC diagnosed between January 2009 and December 2019 were consecutively treated at our department and evaluated. Next generation sequencing was performed in 7 (21%) patients, but no druggable mutation was found. 50% of all patients received surgery and 56% were treated with chemoradiotherapy. The median radiation dose in equivalent dose in 2 Gy fractions (EQD2) was 50 Gy (SD:21 Gy). The study compared the discrimination of the Sugitani Prognostic Index (SPI) and the Marchand-Crety Prognostic Score (MCPS) using concordance statistics, area under the receiver-operating characteristics curve (AUC), net reclassification index, and integrated discrimination improvement for 6-month survival. Results The median survival of the entire cohort was 5 months (range: 1-133). The AUC for 6-month survival was 0.85 (95% confidence interval [CI]:0.72–0.97) for SPI and 0.69 (95% CI: 0.56–0.83) for MCPS ( p  < 0.0001). Using the net reclassification index (NRI), 73% of patients were correctly reclassified using SPI instead of MCPS for 6-month survival ( p  = 0.0237). Conclusion The SPI was more accurate than the MCPS to determine patients’ life expectancies and should be recommended for clinical guidance and treatment allocation. In the last decade, comprehensive genetic profiling of actionable mutations in ATC has become vital to guide targeted therapy.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy characterized by nearly 100% mortality and significant therapeutic challenges. This study investigated the tumour microenvironment (TME) in ATC, focusing on immune checkpoint molecules (PD-L1/PD-1), tumour-associated macrophages (TAMs), and E-cadherin expression. A retrospective cohort of 22 ATC patients treated at a tertiary care centre in India, between January 2017 and August 2022, was analysed. Immunohistochemical evaluation revealed PD-L1 expression in 68.2% of cases, with a median tumour proportion score (TPS) of 50. PD-1 expression was limited to inflammatory cells. E-cadherin loss was observed in over 69% of cases, suggesting disrupted cell adhesion. TAM infiltration was elevated in 58.8% of patients and correlated significantly with PD-L1 expression ( p  = 0.02). Survival analysis demonstrated a significantly lower survival in patients with a high TAM density (0.015). Although not significant but patients expressing PD-L1 had a mean survival of 2.4 months compared to 4.1 months for those without PD-L1 expression ( p 0.129). Similarly, high PD-1 expression in inflammatory cells and E cadherin expression in tumor cells correlated with poorer outcomes. These findings underscore the critical role of immune markers within the TME in influencing ATC prognosis. The findings highlight the potential of targeted immunotherapeutic strategies to improve outcomes in ATC. Further research is warranted to clarify the predictive value of these markers in guiding treatment 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.

Background The prognostic value of nutritional status in anaplastic thyroid carcinoma (ATC) remains unclear. The Prognostic Nutritional Index (PNI) is a reliable indicator of overall nutritional and immune status, and it has emerged as a significant prognostic factor in various malignancies. This study aimed to explore the utility of PNI in ATC. Methods We systematically reviewed ATC patients in our institute from January 2000 to June 2023 and categorized them into high and low PNI groups based on the median PNI value. Kaplan–Meier analysis and Cox regression were employed to assess the impact of PNI on overall survival, while ROC curve analysis evaluated the predictive value of PNI. Mimics software was used for three-dimensional reconstruction of pre- and post-immunotherapy tumor volumes, enabling the assessment of treatment response. Results A total of 77 ATC patients were included in this study. Low baseline PNI was associated with significantly shorter overall survival (1-year survival rate: 5.26% vs 30.77%; median survival time: 5.30 months vs 8.87 months). The 1-year, 2-year, and 3-year AUC values for PNI were 0.82, 0.79, and 0.77, respectively. In the multivariate analysis, both PNI and tumor size emerged as independent prognostic factors for patient overall survival. Among ATC patients receiving 2–3 cycles of immunotherapy, an increase in post-treatment PNI levels was positively correlated with a reduction in tumor volume. Conclusion PNI is an independent predictor of overall survival and holds the potential to serve as a valuable indicator for assessing and predicting immunotherapy efficacy in ATC patients.