Giant cardiac lesion in anaplastic thyroid cancer.
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ABSTRACT:
SUBMITTER: Guerra G
PROVIDER: S-EPMC9735418 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
Publications
Giant cardiac lesion in anaplastic thyroid cancer.
Guerra Giulia G Fabozzo Assunta A Ragona Rosario Marchese RM Gerosa Gino G
JTCVS techniques 20220929
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Project description:Anaplastic thyroid cancer (ATC) is one of the worst human malignancies, with an associated median survival of only 5 months. It is resistant to conventional thyroid cancer therapies, including radioiodine and thyroid-stimulating hormone suppression. Cancer immunotherapy has emerged over the past few decades as a transformative approach to treating a wide variety of cancers. However, immunotherapy for ATC is still in the experimental stage. This review will cover several strategies of immunotherapy and discuss the possible application of these strategies in the treatment of ATC (such as targeted therapy for tumor-associated macrophages, cancer vaccines, adoptive immunotherapy, monoclonal antibodies and immune checkpoint blockade) with the hope of improving the prognosis of ATC in the future.
| S-EPMC7137046 | biostudies-literature
Project description:BackgroundLenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need.Patients and methodsThis phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate.ResultsAt data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%.ConclusionIn this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC.ClinicaltrialsgovNCT01728623.
| S-EPMC5331066 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) represents one of the most lethal human cancers and although this tumor type is rare, ATC accounts for the majority of deaths from thyroid cancer. Due to the rarity of ATC, a comprehensive genomic characterization of this tumor type has been challenging, and thus the development of new therapies has been lacking. To date, there is only one mutation-driven targeted therapy for BRAF-mutant ATC. Recent genomic studies have used next generation sequencing to define the genetic landscape of ATC in order to identify new therapeutic targets. Together, these studies have confirmed the role of oncogenic mutations of MAPK pathway as key drivers of differentiated thyroid cancer (BRAF, RAS), and that additional genetic alterations in the PI3K pathway, TP53, and the TERT promoter are necessary for anaplastic transformation. Recent novel findings have linked the high mutational burden associated with ATC with mutations in the Mismatch Repair (MMR) pathway and overactivity of the AID/APOBEC family of cytidine deaminases. Additional novel mutations include cell cycle genes, SWI/SNF chromatin remodeling complex, and histone modification genes. Mutations in RAC1 were also identified in ATC, which have important implications for BRAF-directed therapies. In this review, we summarize these novel findings and the new genetic landscape of ATC. We further discuss the development of therapies targeting these pathways that are being tested in clinical and preclinical studies.
| S-EPMC7117889 | biostudies-literature
Project description:BackgroundAnaplastic thyroid cancer (ATC) is rare, accounting for 1-2% of thyroid malignancies. Median survival is only 3-10 months, and the optimal therapeutic approach has not been established. This study aimed to evaluate outcomes in ATC based on treatment modality.MethodsRetrospective review was performed for patients treated at a single institution between 1990 and 2015. Demographic and clinical covariates were extracted from the medical record. Overall survival (OS) was modeled using Kaplan Meier curves for different treatment modalities. Univariate and multivariate analyses were conducted to assess the relationships between treatment and disease characteristics and OS.Results28 patients with ATC were identified (n = 16 female, n = 12 male; n = 22 Caucasian, n = 6 African-American; median age 70.9). Majority presented as Stage IVB (71.4%). Most patients received multimodality therapy. 19 patients underwent local surgical resection. 21 patients received locoregional external beam radiotherapy (EBRT) with a median cumulative dose of 3,000 cGy and median number of fractions of 16. 14 patients received systemic therapy (n = 11 concurrent with EBRT), most commonly doxorubicin (n = 9). 16 patients were never disease free, 11 patients had disease recurrence, and 1 patient had no evidence of disease progression. Median OS was 4 months with 1-year survival of 17.9%. Regression analysis showed that EBRT (HR: 0.174; 95% CI: 0.050-0.613; p=0.007) and surgical resection (HR: 0.198; 95% CI: 0.065-0.598; p=0.004) were associated with improved OS. Administration of chemotherapy was not associated with OS.ConclusionsAnaplastic thyroid cancer patients receiving EBRT to the thyroid area/neck and/or surgical resection had better OS than patients without these therapies, though selection bias likely contributed to improved outcomes since patients who can undergo these therapies tend to have better performance status. Prognosis remains poor overall, and new therapeutic approaches are needed to improve outcomes.
| S-EPMC6556325 | biostudies-literature
Project description:Differentiated thyroid cancer (DTC) has one of the lowest cancer mutational burdens, while anaplastic thyroid cancer (ATC) has a much higher mutation frequency. A fraction of ATC has an associated differentiated component, which suggests the coevolution of both cancers. Here, we aimed to compare mutation frequency in coexisting ATC and DTC diagnosed concurrently in the same thyroid gland (3 cases) as well as in archetypal DTC and ATC alone (5 cases each). Single-nucleotide variations (SNV) and copy number variations (CNV) were analyzed in each case based on the next-generation sequencing data. We found a similar extent of mutational events, both SNV and CNV, in undifferentiated and differentiated components of thyroid cancers coexisting in one patient. The magnitude of these mutations was comparable to the level of mutations observed in ATC alone; yet, it was much higher than in archetypal DTC. This suggested that, despite histopathological features of differentiated tumors, molecular characteristics of such cancers coexisting with ATC and archetypal DTC could be significantly different. Pairwise comparison of mutational profiles of coexisting cancers enabled assumption on the possible evolution of both components, which appeared distinct in 3 analyzed cases. This included independent development of ATC and DTC diagnosed concurrently in two lobes of the same thyroid, as well as the development of anaplastic and differentiated cancer from the common ancestor that putatively gained a key driver mutation (BRAFV600E or KRASQ61R), which was followed either by early or late molecular separation of both cancers.
| S-EPMC7822790 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC), accounting for less than 2% of all thyroid cancer, is responsible for the majority of death from all thyroid malignancies and has a median survival of 6 months. The resistance of ATC to conventional thyroid cancer therapies, including radioiodine and thyroid-stimulating hormone suppression, contributes to the very poor prognosis of this malignancy. This review will cover several cellular signaling pathways and mechanisms, including RET/PTC, RAS, BRAF, Notch, p53, and histone deacetylase, which are identified to play roles in the transformation and dedifferentiation process, and therapies that target these pathways. Lastly, novel approaches and agents involving the Notch1 pathway, nuclear factor κB, Trk-fused gene, cancer stem-like cells, mitochondrial mutation, and tumor immune microenvironment are discussed. With a better understanding of the biological process and treatment modality, the hope is to improve ATC outcome in the future.
| S-EPMC4221369 | biostudies-literature
Project description:Spontaneous pneumothorax is rarely associated with cancer. We describe a 73 year old man who presented with recurrent tumor in the right neck, mediastinal lymphadenopathy and bilateral pulmonary nodules after thyroidectomy. He was treated with lenvatinib and presented with bilateral pneumothoraces. Anaplastic thyroid cancer is an aggressive subtype of thyroid cancer that has limited response to cytotoxic chemotherapy and poor prognosis. Recent reports show that targeted therapy with a multiple receptor tyrosine kinase inhibitor, lenvatinib, may have improvement in progression-free survival, but rarely pneumothorax has been reported in those with lung metastases. Various mechanisms have been postulated, but necrosis of pulmonary lesions and/or subpleural micrometastases leading to bilateral pleural defects likely resulted in the development of pneumothoraces for our patient.
| S-EPMC6348391 | biostudies-literature
Project description:Wee1 is a kinase that regulates the G2/M progression by the inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either a single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.
| S-EPMC8197631 | biostudies-literature
Project description:BackgroundThe staging system for patients with anaplastic thyroid cancer (ATC) was updated in the 8th edition of the American Joint Committee on Cancer Staging Manual. A cut-off age of 55 years was stipulated as a prognostic factor for differentiated thyroid cancer; however, age was not considered for ATC patients. To this end, this study investigated the relationship between age at diagnosis and prognosis of ATC patients.MethodsThe clinical information on ATC patients was acquired from the Surveillance, Epidemiology, and End Results Program public database. Youden's index and X-tile analyses were used to calculate the high-point age at diagnosis associated with prognosis. Cox proportional hazards models, Kaplan-Meier curves, and 1000-person-year were then used for verifying the accuracy of the high-point age.ResultsAfter inclusion/exclusion criteria was applied, 586 patients were included in this study. The high-point age was determined to be 70 years by both the Youden's index and X-tile plot methods. The hazard ratio was 1.662 (95% confidence interval [CI]: 1.321-2.092), indicating that there was an increased risk of poor prognosis for patients > 70 years of age. The cancer-specific mortality rates per 1000-person-years for patients ≤ and > 70 years-old were 949.980 (95% CI: 827.323-1090.822) and 1546.667 (95% CI: 1333.114-1794.428), respectively. P-values were < 0.001 for the results shown above.ConclusionOur study found that age influenced the prognosis of ATC patients. Furthermore, we determined that the high-point age at diagnosis was 70 years and that > 70 years of age was associated with a poor prognosis. These results provide a useful addition to the staging manual and can improve the diagnosis, treatment strategies and prognosis of ATC patients.
| S-EPMC8353231 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive human malignancies, with no effective treatment currently available. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. TAZ is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal TAZ expression in ATC remains to be characterized. In the present study, we identified USP26, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of TAZ in ATC. USP26 was shown to interact with, deubiquitylate, and stabilize TAZ in a deubiquitylation activity-dependent manner. USP26 depletion significantly decreased ATC cell proliferation, migration, and invasion. The effects induced by USP26 depletion could be rescued by further TAZ overexpression. Depletion of USP26 decreased the TAZ protein level and the expression of TAZ/TEAD target genes in ATC, including CTGF, ANKRD1, and CYR61. In general, our findings establish a previously undocumented catalytic role for USP26 as a deubiquitinating enzyme of TAZ and provides a possible target for the therapy of ATC.
| S-EPMC8994751 | biostudies-literature