Interaction between tumor stage and age on survival outcomes of patients with anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive, rare malignancy associated with rapid growth and metastasis, and a very poor prognosis. We investigated the clinical characteristics, survival outcomes and independent prognostic factors associated with anaplastic thyroid cancer. AIM: To assess to what extent the interaction between age and tumor stage affects mortality. METHODS: A total of 622 patients diagnosed with anaplastic thyroid cancer, between 2010 and 2017 were enrolled in our study by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We analyzed demographics, clinical characteristics, overall mortality (OM) and cancer specific mortality (CSM) of ATC. Variables with a P value < 0.1 were incorporated into the multivariate cox model to determine the independent prognostic factors. Furthermore, we analyzed the interaction between age and tumor stage on mortality. RESULTS: In the multivariate analyses, the divorced/separated population had a lower OM [hazard ratio (HR) = 0.63, 95%CI: 0.42-0.94, P < 0.05] and CSM (HR = 0.61, 95%CI: 0.40-0.92, P < 0.05). OM was higher in tumors with direct extension only (HR = 6.26, 95%CI: 1.29-30.42, P < 0.05) and tumors with distant spread (HR = 5.73, 95%CI: 1.34-24.51, P < 0.05). CSM was also higher in tumors with direct extension (HR = 5.05, 95%CI: 1.05-24.19, P < 0.05) and tumors with distant spread (HR = 4.57, 95%CI: 1.08-19.29, P < 0.05). Mortality was not adversely affected by lymph node involvement. OM was lower in patients who received radiation (HR = 0.66, 95%CI: 0.53-0.83, P < 0.01), chemotherapy (HR = 0.63, 95%CI: 0.50-0.79, P < 0.01) or surgery (HR = 0.53, 95%CI: 0.43-0.66, P < 0.01). CSM was also lower in patient who received radiation (HR = 0.64, 95%CI: 0.51-0.81, P < 0.01), chemotherapy (HR = 0.62, 95%CI: 0.50-0.78, P < 0.01) or surgery (HR = 0.51, 95%CI: 0.41-0.63, P < 0.01). There was no significant interaction between age and tumor stage that affected mortality. CONCLUSION: In this large US SEER database retrospective study, we found the mortality to be higher in advanced stage tumors with direct extension and distant metastasis. However, patients who received aggressive therapy showed a better overall survival. The aim of our study is to emphasize the importance of detecting ATC at an early stage and provide aggressive therapy to these patients. Since advanced stage ATC is associated with a dismal prognosis, we emphasize the need for randomized control trials and development of novel therapies that will be used to treat ATC.

Trends in Mortality for Anaplastic Thyroid Cancer: Have We Made Progress?

INTRODUCTION: Anaplastic thyroid cancer (ATC) has one of the highest mortality rates of all human malignancies, accounting for two-thirds of all thyroid cancer deaths. Despite multimodal treatment, ATC still has a reported median survival period of 6 mo. Recent single-center studies have reported improved survival with the approval of new treatments for ATC. In this study, we sought to investigate whether the approval of new treatments and use of multimodal treatments was associated with reduced risk of mortality over time nationally. METHODS: Eight hundred and seventy four patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results database that were diagnosed with ATC from 1990 to 2020 were included in this study. Cox proportional hazards models were used to assess the change in 2-y survival over time and to identify characteristics associated with survival. Overall survival (OS) and cancer specific survival (CSS) were both evaluated. RESULTS: The OS within 2 y of diagnosis was 14% and the CSS was 19%. For every 3-y increase in diagnosis year from 1990 to 2020, there was no significant change in the CSS (adjusted hazard ratio [95% confidence interval]: 0.98 [0.94, 1.01]). Patients who received treatment (surgery, chemotherapy, and/or radiation) had an increased CSS (adjusted hazard ratio [95% confidence interval]: 0.42 [0.32, 0.55]). CONCLUSIONS: We observed no significant change in OS or CSS after adjusting for confounders by year of diagnosis. Though receiving treatment was associated with increased CSS, more effective treatments are needed in the future to increase survival time in patients with ATC.

C5AR1-induced TLR1/2 pathway activation drives proliferation and metastasis in anaplastic thyroid cancer.

This study aimed to elucidate the role and mechanisms of Complement C5a receptor 1 (C5AR1) in driving the malignant progression of anaplastic thyroid carcinoma (ATC). C5AR1 expression was assessed in ATC tissues and cell lines. Functional assays evaluated the effects of C5AR1 knockdown on the malignant features of ATC cells. The interaction between C5AR1 and miR-335-5p was confirmed using a luciferase reporter assay and Fluorescence in situ hybridization, and the impact of C5AR1 knockdown on the Toll-like receptor (TLR) 1/2 signaling pathway was examined. In vivo studies evaluated the effects of C5AR1 modulation on tumor growth and metastasis. C5AR1 levels were elevated in ATC tumor samples and associated with poor survival in ATC patients. C5AR1 knockdown impeded ATC cell proliferation, migration, and invasion in vitro. MiR-335-5p was identified as an upstream regulator of C5AR1, which negatively modulates C5AR1 expression. C5AR1 knockdown diminished TLR1, TLR2, and myeloid differentiation primary response 88 (MyD88) levels, while C5AR1 overexpression activated this pathway. Blocking TLR1/2 signaling abrogated the oncogenic effects of C5AR1 overexpression. C5AR1 silencing inhibited tumor growth and lung metastasis of ATC cells in nude mice. C5AR1 contributes to ATC tumorigenesis and metastasis by activating the TLR1/2 pathway, and is negatively regulated by miR-335-5p. Targeting the miR-335-5p/C5AR1/TLR1/2 axis represents a potential therapeutic strategy for ATC.

Disparities in Presentation, Treatment, and Survival in Anaplastic Thyroid Cancer.

BACKGROUND: Disparities have been previously described in the presentation, management, and outcomes of other thyroid cancer subtypes; however, it is unclear whether such disparities exist in anaplastic thyroid cancer (ATC). METHODS: We identified patients with ATC from the National Cancer Database (2004-2020). The primary outcomes were receipt of surgery, chemotherapy, and radiation. The secondary outcome was 1-year survival. Multivariable logistic and Cox proportional hazards regressions were used to assess the associations between sex, race/ethnicity, and the outcomes. RESULTS: Among 5359 patients included, 58% were female, and 80% were non-Hispanic white. Median tumor size was larger in males than females (6.5 vs. 6.0 cm; p < 0.001) and in patients with minority race/ethnicity than in white patients (6.5 vs. 6.0 cm; p < 0.001). After controlling for tumor size and metastatic disease, female patients were more likely to undergo surgical resection (odds ratio [OR]: 1.20; p = 0.016) but less likely to undergo chemotherapy (OR: 0.72; p < 0.001) and radiation (OR: 0.76; p < 0.001) compared with males. Additionally, patients from minority racial/ethnic backgrounds were less likely to undergo chemotherapy (OR: 0.69; p < 0.001) and radiation (OR: 0.71; p < 0.001) than white patients. Overall, unadjusted, 1-year survival was 23%, with differences in treatment receipt accounting for small but significant differences in survival between groups. CONCLUSIONS: There are disparities in the presentation and treatment of ATC by sex and race/ethnicity that likely reflect differences in access to care as well as patient and provider preferences. While survival is similarly poor across groups, the changing landscape of treatments for ATC warrants efforts to address the potential for exacerbation of disparities.

2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Since the guidelines for the management of ATC by the American Thyroid Association were first published in 2012, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, and researchers on published evidence relating to the diagnosis and management of ATC. Methods: The specific clinical questions and topics addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of the Task Force members (authors of the guideline). Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, targeted/systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues, including end of life. The guidelines include 31 recommendations and 16 good practice statements. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of ATC. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with ATC.

Outcomes of multimodal therapy in a large series of patients with anaplastic thyroid cancer.

BACKGROUND: The role of radiotherapy (RT) in the treatment of patients with anaplastic thyroid cancer (ATC) for local tumor control is critical because mortality often is secondary to complications of tumor volume rather than metastatic disease. Herein, the authors report the long-term outcomes of RT for patients with ATC. METHODS: A total of 104 patients with histologically confirmed ATC were identified who presented to the study institution between 1984 and 2017 and who received curative-intent or postoperative RT. Locoregional progression-free survival (LPFS), overall survival (OS), and distant metastasis-free survival were assessed. RESULTS: The median age of the patients was 63.5 years. The median follow-up was 5.9 months (interquartile range, 2.7-17.0 months) for the entire cohort and 10.6 months (interquartile range, 5.3-40.0 months) for surviving patients. Thirty-one patients (29.8%) had metastatic disease prior to the initiation of RT. Concurrent chemoradiation was administered in 99 patients (95.2%) and 53 patients (51.0%) received trimodal therapy. Systemic therapy included doxorubicin (73.7%), paclitaxel with or without pazopanib (24.3%), and other systemic agents (2.0%). The 1-year OS and LPFS rates were 34.4% and 74.4%, respectively. On multivariate analysis, RT ≥60 Gy was associated with improved LPFS (hazard ratio [HR], 0.135; P = .001) and improved OS (HR, 0.487; P = .004), and trimodal therapy was associated with improved LPFS (HR, 0.060; P = .017). The most commonly observed acute grade 3 adverse events included dermatitis (20%) and mucositis (13%), with no grade 4 subacute or late adverse events noted (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). CONCLUSIONS: RT appears to demonstrate a dose-dependent, persistent LPFS and OS benefit in patients with locally advanced ATC with an acceptable toxicity profile. Aggressive RT should be strongly considered for the treatment of patients with ATC as part of a trimodal treatment approach.

Baicalein induced apoptosis and autophagy of undifferentiated thyroid cancer cells by the ERK/PI3K/Akt pathway.

Thyroid cancer is the most common endocrine system malignancy, and undifferentiated thyroid cancer is one of the most invasive tumors. Studies have found that baicalein, a major flavonoid separated from the root of Scutellaria baicalensis Georgi, has an inhibitory effect on a variety of malignant tumor cells. However, the effect of baicalein on undifferentiated thyroid cancer has not yet been investigated. In the present study, follicular undifferentiated thyroid cancer cells (FRO) were treated with different concentrations of baicalein (10 µM, 20 µM, 40 µM, 80 µM) for 12 h, 24 h, 36 h, or 48 h; then, the cell viability and clonogenicity were measured. Cell cycles and cell apoptosis were measured by flow cytometer after FRO cells were treated with baicalein for 36 h or 48 h. After FRO cells were treated with baicalein for 48 h, the expression of apoptosis-related proteins (Bcl-2, Bax, Caspase-3 and Caspase-8), autophagy-related proteins (Beclin-1, p62, Atg5 and Atg12) and the phosphorylation levels of ERK and Akt in FRO cells were measured by Western blot. The results showed that baicalein reduced the cell viability and cell colony numbers of FRO cells in a dose- and time-dependent manner. Baicalein also induced cell apoptosis and arrested the cell cycles of FRO cells. Baicalein decreased the ratio of Bcl-2/Bax but increased the expression of Caspase-3 and Caspase-8. Furthermore, baicalein induced autophagy in FRO cells. It significantly increased the expression of Beclin-1, Atg5, p62 and Atg12. Baicalein significantly decreased the ratios of p-ERK/ERK and p-Akt/Akt, indicating that it suppressed the ERK and PI3K/Akt pathways. In conclusion, baicalein could suppress the growth of undifferentiated thyroid cancer cells by inducing apoptosis and autophagy. The inhibition of the ERK and PI3K/Akt pathways may be involved in the mechanism.

Oncogenesis of Thyroid Cancer

Thyroid neoplasms encompass a variety of lesions that range from benign adenomas to malignancies. These latter can be well-differentiated, poorly differentiated or undifferentiated (anaplastic) carcinomas. More than 95% of thyroid cancers are derived from thyroid follicular cells, while 2-3% (medullary thyroid cancers, MTC) originate from calcitonin producing C-cells. Over the last decade, investigators have developed a clearer understanding of genetic alterations underlying thyroid carcinogenesis. A number of point mutations and translocations are involved, not only in its tumorigenesis, but also as have potential use as diagnostic and prognostic indicators and therapeutic targets. Many occur in genes for several important signaling pathways, in particular the mitogen-activated protein kinase (MAPK) pathway. Sporadic (isolated) lesions account for 75% of MTC cases, while inherited MTC, often in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, constitute the remainder. However, non-MEN familial MTC may also occur. Advances in genetic testing have revolutionized the management of MTC, with prospects of genetic screening, testing and early prophylactic thyroidectomy. Ethical concerns of these advances are addressed.