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Keywords = metastatic thyroid cancer

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24 pages, 7718 KiB  
Article
Integration of Single-Cell Analysis and Bulk RNA Sequencing Data Using Multi-Level Attention Graph Neural Network for Precise Prognostic Stratification in Thyroid Cancer
by Langping Tan, Zhenjun Huang, Yongjian Chen, Zehua Wang, Zijia Lai, Xinzhi Peng, Cheng Zhang, Ruichong Lin, Wenhao Ouyang, Yunfang Yu and Miaoyun Long
Cancers 2025, 17(14), 2411; https://doi.org/10.3390/cancers17142411 - 21 Jul 2025
Viewed by 529
Abstract
Background: The prognosis management of thyroid cancer remains a significant challenge. This study highlights the critical role of T cells in the tumor microenvironment and aims to improve prognostic precision by integrating bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data, providing a more comprehensive [...] Read more.
Background: The prognosis management of thyroid cancer remains a significant challenge. This study highlights the critical role of T cells in the tumor microenvironment and aims to improve prognostic precision by integrating bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data, providing a more comprehensive view of tumor biology at the single-cell level. Method: 15 thyroid cancer scRNA-seq samples were analyzed from GEO and 489 patients from TCGA. A multi-level attention graph neural network (MLA-GNN) model was applied to integrate T-cell-related differentially expressed genes (DEGs) for predicting disease-free survival (DFS). Patients were divided into training and validation cohorts in an 8:2 ratio. Result: We systematically characterized the immune microenvironment of metastatic thyroid cancer by using single-cell transcriptomics and identified the important role of T-cell subtypes in the development of thyroid cancer. T-cell-based DEGS between tumor tissues and normal tissues were also identified. Subsequently, T-cell-based risk signatures were selected for establishing a risk model using MLA-GNN. Finally, our MLA-GNN-based model demonstrated an excellent ability to predict the DFS of thyroid cancer patients (1-year AUC: 0.965, 3-years AUC: 0.979, and 5-years AUC: 0.949 in training groups, and 1-year AUC: 0.879, 3-years AUC: 0.804, and 5-years AUC: 0.804 in validation groups). Conclusions: Risk features based on T-cell genes have demonstrated the effectiveness in predicting the prognosis of thyroid cancer. By conducting a comprehensive characterization of T-cell features, we aim to enhance our understanding of the tumor’s response to immunotherapy and uncover new strategies for the treatment of cancer. Full article
(This article belongs to the Section Methods and Technologies Development)
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12 pages, 1025 KiB  
Article
Inhibitory Effects of Vandetanib on Catecholamine Synthesis in Rat Pheochromocytoma PC12 Cells
by Yoshihiko Itoh, Kenichi Inagaki, Tomohiro Terasaka, Eisaku Morimoto, Takahiro Ishii, Kimitomo Yamaoka, Satoshi Fujisawa and Jun Wada
Int. J. Mol. Sci. 2025, 26(14), 6927; https://doi.org/10.3390/ijms26146927 - 18 Jul 2025
Viewed by 311
Abstract
Gain-of-function gene alterations in rearranged during transfection (RET), a receptor tyrosine kinase, are observed in both sporadic and hereditary medullary thyroid cancers (MTCs) and pheochromocytomas and paragangliomas (PPGLs). Several tyrosine kinase inhibitors (TKIs) that target RET have been proven to be effective on [...] Read more.
Gain-of-function gene alterations in rearranged during transfection (RET), a receptor tyrosine kinase, are observed in both sporadic and hereditary medullary thyroid cancers (MTCs) and pheochromocytomas and paragangliomas (PPGLs). Several tyrosine kinase inhibitors (TKIs) that target RET have been proven to be effective on MTCs and PCCs. Recently, TKIs, namely, sunitinib and selpercatinib, which were clinically used to target PPGLs, have been reported to decrease catecholamine levels without reducing tumor size. Our clinical case of metastatic medullary thyroid cancer, which is associated with RET mutations undergoing treatment with vandetanib, also suggests that vandetanib can decrease catecholamine levels. Therefore, we investigated the effect of vandetanib, a representative multi-targeted TKI for RET-related MTC, on cell proliferation and catecholamine synthesis in rat pheochromocytoma PC12 cells. Vandetanib reduced viable cells in a concentration-dependent manner. The dopamine and noradrenaline levels of the cell lysate were reduced in a concentration-dependent manner. They also decreased more prominently at lower concentrations of vandetanib compared to the inhibition of cell proliferation. The RNA knockdown study of Ret revealed that this inhibitory effect on catecholamine synthesis is mainly mediated by the suppression of RET signaling. Next, we focused on two signaling pathways downstream of RET, namely, ERK and AKT signaling. Treatment with vandetanib reduced both ERK and AKT phosphorylation in PC12 cells. Moreover, both an MEK inhibitor U0126 and a PI3K/AKT inhibitor LY294002 suppressed catecholamine synthesis without decreasing viable cells. This study in rat pheochromocytoma PC12 cells reveals the direct inhibitory effects of vandetanib on catecholamine synthesis via the suppression of RET-ERK and RET-AKT signaling. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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11 pages, 1124 KiB  
Article
Next-Generation Sequencing Reveals the Potential Role of RET Protooncogene in Metastasis Progression in Medullary Thyroid Cancer
by Maurice Klein, Anna Julia Claudia Klein, Arnold M. Raem, Nicklas Garrelfs, Henrike J. Fischer, Frank Hölzle and Kai Wermker
Curr. Issues Mol. Biol. 2025, 47(7), 560; https://doi.org/10.3390/cimb47070560 - 18 Jul 2025
Viewed by 314
Abstract
Background: Medullary thyroid carcinoma (MTC) has a high rate of local and distant metastases. In particular, the RET protooncogene appears to be the predominant driver mutation for oncogenesis. The German S3 thyroid carcinoma guidelines recommend molecular genetic analysis of the tumour without specifying [...] Read more.
Background: Medullary thyroid carcinoma (MTC) has a high rate of local and distant metastases. In particular, the RET protooncogene appears to be the predominant driver mutation for oncogenesis. The German S3 thyroid carcinoma guidelines recommend molecular genetic analysis of the tumour without specifying the site of the tissue sampling. Whether there is difference in RET protooncogene between the primary tumour, lymph node, and distant metastasis has not yet been investigated. However, differences could be important with regard to biopsy localization, and also, thus, the choice of single- or multi-tyrosine-kinase-inhibitor therapy. Methods: In a case of sporadic MTC, Cancer Hotspot panel diagnostics were performed on the primary tumour, lymph node metastasis, and distant metastasis. Mutations were classified using different gene databases, and the different stages of metastasis were compared. Results: RET protooncogene (chr10:43609933, c.1886_1891delTGTGCG, p.Leu629_Asp631delinsHis) was found to be present in the MTC tissue of the primary tumour, lymph node, and distant metastasis in the Cancer Hotspot Panel diagnostic, while the other investigated therapy-relevant mutational profiles were not consistently found. Conclusions: Further longitudinal studies in larger patient cohorts are required to elucidate the role of the RET protooncogene in the metastatic progression of MTC and to determine its impact on the selection of biopsy sites and the subsequent decision-making regarding single- versus multi-tyrosine kinase inhibitor therapy. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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12 pages, 1044 KiB  
Article
Therapeutic Efficacy of a Very Low/Low Dose of Lenvatinib in Advanced Radioiodine-Refractory Thyroid Cancer: A Real-World Series from a Single Center
by Vittorio Oteri, Fiorenza Gianì, Giulia Sapuppo, Stefania Panebianco, Ilenia Marturano, Giusi Blanco, Pasqualino Malandrino, Marco Russo, Francesco Frasca and Gabriella Pellegriti
Cancers 2025, 17(14), 2372; https://doi.org/10.3390/cancers17142372 - 17 Jul 2025
Viewed by 410
Abstract
Background: Lenvatinib is a receptor tyrosine kinase inhibitor indicated for advanced radioiodine-refractory thyroid cancer (RAI-RTC). It is recommended to start at 24 mg per day; however, in patients who are at risk of severe adverse events, it may be reasonable to start at [...] Read more.
Background: Lenvatinib is a receptor tyrosine kinase inhibitor indicated for advanced radioiodine-refractory thyroid cancer (RAI-RTC). It is recommended to start at 24 mg per day; however, in patients who are at risk of severe adverse events, it may be reasonable to start at lower doses. Patients and Methods: We included 15 patients with RAI-RTC who started lenvatinib at a very low/low dose and evaluated the efficacy and safety. Results: Eight patients (53.3%) did not show progression of the disease, and about half of the patients (53.3%) were alive at the last follow-up visit. Up to 26.6% of patients achieved a partial response to therapy, with a notable volume reduction in the local and metastatic lesions. However, 80% of patients experienced adverse events, mainly of a moderate grade. Conclusions: Although these findings are based on a small sample size and a single-center study, treatment with lenvatinib at very low/low doses in fragile patients seems to be a promising strategy for the management of RAI-RTC, balancing effective disease control with a favorable safety profile. Full article
(This article belongs to the Section Cancer Pathophysiology)
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16 pages, 831 KiB  
Article
Mutational Profiling of Medullary Thyroid Carcinoma via a Large-Scale Genomic Repository
by Beau Hsia, Elijah Torbenson, Nigel Lang and Peter T. Silberstein
DNA 2025, 5(3), 35; https://doi.org/10.3390/dna5030035 - 17 Jul 2025
Viewed by 270
Abstract
Background: Medullary thyroid cancer (MTC), a neuroendocrine tumor originating from thyroid parafollicular C-cells, presents therapeutic challenges, particularly in advanced stages. While RET proto-oncogene mutations are known drivers, a comprehensive understanding of the broader somatic mutation landscape is needed to identify novel therapeutic targets [...] Read more.
Background: Medullary thyroid cancer (MTC), a neuroendocrine tumor originating from thyroid parafollicular C-cells, presents therapeutic challenges, particularly in advanced stages. While RET proto-oncogene mutations are known drivers, a comprehensive understanding of the broader somatic mutation landscape is needed to identify novel therapeutic targets and improve prognostication. This study leveraged the extensive AACR Project GENIE dataset to characterize MTC genomics. Methods: A retrospective analysis of MTC samples from GENIE examined recurrent somatic mutations, demographic/survival correlations, and copy number variations using targeted sequencing data (significance: p < 0.05). Results: Among 341 samples, RET mutations predominated (75.7%, mostly M918T), followed by HRAS (10.0%) and KRAS (5.6%), with mutual exclusivity between RET and RAS alterations. Recurrent mutations included KMT2D (5.3%), CDH11 (5.3%), ATM (5.0%), and TP53 (4.1%). NOTCH1 mutations were enriched in metastatic cases (p = 0.023). Preliminary associations included sex-linked mutations (BRAF/BRCA1/KIT in females, p = 0.028), and survival (ATM associated with longer survival, p = 0.016; BARD1/BLM/UBR5/MYH11 with shorter survival, p < 0.05), though limited subgroup sizes warrant caution. Conclusions: This large-scale genomic analysis confirms the centrality of RET and RAS pathway alterations in MTC and their mutual exclusivity. The association of NOTCH1 mutations with metastasis suggests a potential role in disease progression. While findings regarding demographic and survival correlations are preliminary, they generate hypotheses for future validation. This study enhances the genomic foundation for understanding MTC and underscores the need for integrated clinico-genomic datasets to refine therapeutic approaches. Full article
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12 pages, 241 KiB  
Review
Recombinant Human TSH Versus Thyroid Hormone Withdrawal: The Role in the Preparation for RAI Therapy in Differentiated Thyroid Cancer: A Comprehensive Evidence-Based Review
by Motaz Daraghma and Michael M. Graham
J. Clin. Med. 2025, 14(14), 5000; https://doi.org/10.3390/jcm14145000 - 15 Jul 2025
Viewed by 406
Abstract
Radioactive iodine (RAI) therapy plays a fundamental role in the management of differentiated thyroid cancer (DTC) following appropriate surgical intervention. High levels of TSH are required in order to achieve maximum RAI uptake in residual thyroid tissue or metastatic cells. The two techniques [...] Read more.
Radioactive iodine (RAI) therapy plays a fundamental role in the management of differentiated thyroid cancer (DTC) following appropriate surgical intervention. High levels of TSH are required in order to achieve maximum RAI uptake in residual thyroid tissue or metastatic cells. The two techniques that are most commonly used are thyroid hormone withdrawal (THW), which induces endogenous TSH elevation by creating a hypothyroid state, and exogenous stimulation with recombinant human TSH (rhTSH). This review compares both approaches over a range of DTC risk categories. Extensive evidence demonstrates that rhTSH and THW yield equivalent oncological outcomes, including remnant ablation success, recurrence-free survival, and overall survival, in low-, intermediate-, and high-risk disease. Additionally, rhTSH maintains quality of life by avoiding hypothyroid symptoms. While THW continues to be an excellent option when there is a lack of availability of rhTSH, its disadvantages, particularly the transient hypothyroid state, must be carefully weighed against the demonstrated equivalence in efficacy. In current clinical practice, rhTSH is frequently the preferred option for its convenience, safety, and patient-centered benefits; however, the selection of the optimal approach should be based on individual clinical circumstances and patients’ preferences, as well as resource considerations. Full article
(This article belongs to the Section Nuclear Medicine & Radiology)
5 pages, 809 KiB  
Case Report
Mild SARS-CoV-2 Infection with the Omicron Variant Mimicking Metastatic Cancer on Whole-Body 18-F FDG PET/CT Imaging
by Gunnhild Helmsdal, Sissal Clemmensen, Jann Mortensen, Marnar Fríðheim Kristiansen, Maria Skaalum Petersen and Herborg L. Johannesen
COVID 2025, 5(7), 98; https://doi.org/10.3390/covid5070098 - 29 Jun 2025
Viewed by 263
Abstract
We present a case with unusual findings on nuclear imaging after mild SARS-CoV-2 infection. During evaluation for an incidentaloma, 18F-Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography imaging showed activity in the thyroid gland, in the lower thoracic spinal column, in portal lymph nodes, and in [...] Read more.
We present a case with unusual findings on nuclear imaging after mild SARS-CoV-2 infection. During evaluation for an incidentaloma, 18F-Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography imaging showed activity in the thyroid gland, in the lower thoracic spinal column, in portal lymph nodes, and in the terminal ileum and surrounding lymph nodes, all suspicious for metastatic cancer. The patient underwent extensive invasive and non-invasive diagnostic procedures, including biopsies of all the suspicious foci, only showing a small low-grade thyroid cancer that would often be followed and not immediately operated on. Three months later, the findings had either disappeared or were considered reactive. The patient later recalled having had mild COVID-19 seven days prior to the PET/CT. Full article
(This article belongs to the Section COVID Clinical Manifestations and Management)
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16 pages, 401 KiB  
Review
The Impact of Radioiodine (131I) Therapy of Thyroid Disease on Salivary Glands Function and Inflammation: A Comprehensive Review
by Pietro Bellini, Francesco Dondi, Carlo Cappelli, Elisa Gatta, Davide Lombardi, Claudio Casella, Riccardo Morandi, Gianluca Viganò, Luca Camoni, Michela Cossandi, Valentina Zilioli and Francesco Bertagna
Biomedicines 2025, 13(6), 1404; https://doi.org/10.3390/biomedicines13061404 - 7 Jun 2025
Viewed by 887
Abstract
Radioactive iodine therapy has been a well-established treatment for various thyroid conditions since the 1940s, targeting both benign diseases and malignancies. Treatment for benign conditions typically involves low doses of 131I, often requiring no more than two treatments, with the dose either fixed [...] Read more.
Radioactive iodine therapy has been a well-established treatment for various thyroid conditions since the 1940s, targeting both benign diseases and malignancies. Treatment for benign conditions typically involves low doses of 131I, often requiring no more than two treatments, with the dose either fixed or personalized based on thyroid tissue mass and iodine uptake. In contrast, differentiated thyroid cancer treatment often requires higher doses and multiple administrations, especially for metastatic cases. Recent guidelines and studies have proposed more conservative management strategies, including careful follow-up, due to concerns over the high risk–benefit ratio in selected cases with a low risk of disease recrudescence. Despite its possible efficacy, radioiodine therapy is associated with dose-dependent side effects, the most common of which is salivary gland dysfunction or inflammation, affecting approximately 30% of adult patients. These effects pose significant challenges in nuclear medicine practice. This review aims to summarize the latest evidence on the incidence, impact on quality of life, prevention strategies and the role of these side effects in the decision-making process regarding RAI therapy. Full article
(This article belongs to the Special Issue Thyroid Disease: From Mechanism to Therapeutic Approaches)
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11 pages, 1620 KiB  
Review
Super-Superselective Level VB Neck Dissection for Papillary Thyroid Cancer
by Dana M. Hartl, Davide Lombardi, Ricard Simo, Radu Mihai, Aleix Rovira, Enyi Ofo and Iain J. Nixon
Cancers 2025, 17(9), 1497; https://doi.org/10.3390/cancers17091497 - 29 Apr 2025
Viewed by 753
Abstract
Objective: Therapeutic lateral neck dissection is recommended for papillary thyroid cancer with metastatic lymph nodes detected on palpation or on preoperative imaging. Current guidelines recommend systematic dissection of levels IIA, III, IV and VB in these patients. Despite this recommendation, management of level [...] Read more.
Objective: Therapeutic lateral neck dissection is recommended for papillary thyroid cancer with metastatic lymph nodes detected on palpation or on preoperative imaging. Current guidelines recommend systematic dissection of levels IIA, III, IV and VB in these patients. Despite this recommendation, management of level V remains controversial due to a varying degree of clinical and occult lymph node involvement reported in published retrospective studies, but also due to the functional risk involved in level V dissection in which the spinal accessory nerve may be temporarily or permanently injured. The aim of this review was to address the issues involved in level VB dissection and to provide our view of surgical management of level VB. Method: Narrrative review. Result: We propose a new concept of a partial or “super-superselective” level VB dissection in patients with clinical disease in levels IIA, III and IV. Full article
(This article belongs to the Special Issue Thyroid Cancer: Diagnosis, Prognosis and Treatment (2nd Edition))
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17 pages, 2342 KiB  
Article
Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration
by Faisal A. Hassan, Camryn Slone, Robert J. McDonald, Julie C. Dueber, Adeel M. Ashraf, Melina J. Windon, Oliver J. Fackelmayer, Cortney Y. Lee, Therese J. Bocklage and Derek B. Allison
Curr. Oncol. 2025, 32(4), 224; https://doi.org/10.3390/curroncol32040224 - 11 Apr 2025
Viewed by 854
Abstract
Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations—one [...] Read more.
Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations—one germline and one somatic—and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN’s role in thyroid cancer pathogenesis. Full article
(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)
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24 pages, 1931 KiB  
Article
Real-World Evaluation of Immune-Related Endocrinopathies in Metastatic NSCLC Patients Treated with ICIs in Romania
by Simona Coniac, Mariana Cristina Costache-Outas, Ionuţ-Lucian Antone-Iordache, Ana-Maria Barbu, Victor Teodor Bardan, Andreea Zamfir, Andreea-Iuliana Ionescu and Corin Badiu
Cancers 2025, 17(7), 1198; https://doi.org/10.3390/cancers17071198 - 31 Mar 2025
Cited by 1 | Viewed by 864
Abstract
(1) Background: Exploring real-world data (RWD) regarding immune-related adverse events (irAEs) is crucial to better understand the efficacy and safety of immunotherapy in cancer patient populations excluded from clinical trials. An analysis was conducted to evaluate the presumptive predictive causality between endocrine irAEs [...] Read more.
(1) Background: Exploring real-world data (RWD) regarding immune-related adverse events (irAEs) is crucial to better understand the efficacy and safety of immunotherapy in cancer patient populations excluded from clinical trials. An analysis was conducted to evaluate the presumptive predictive causality between endocrine irAEs and the efficacy of immune check-point inhibitors (ICIs) in metastatic non-small-cell lung cancer (mNSCLC) patients treated in daily practice in Romania. (2) Methods: This was a retrospective cohort study of mNSCLC patients treated with ICIs in a tertiary level hospital in Romania for a period of almost seven years, from November 2017 till July 2024. Endocrine irAEs were well defined as any occurring autoimmune endocrinopathy during ICIs and related to immunotherapy. The hospital endocrinologist (M.C.C.O) diagnosed, treated, and followed these endocrine irAEs in a multidisciplinary approach. We investigated multiple medical variables to assess their impact on ICI effectiveness. Descriptive and statistical analyses were performed. (3) Results: Of 487 cancer patients treated with ICIs, we identified 215 mNSCLC patients who were evaluated for endocrine irAEs and co-medications during ICI therapy. Forty-seven (21.8%) patients experienced endocrine irAEs, thyroiditis being the most frequent and prevalent autoimmune endocrinopathy in 60% of cases. Endocrine irAEs were statistically significant, correlated with ICI efficacy (p = 0.002) for survival analysis. Steroids and proton-pump inhibitors used as co-medication during ICIs had a negative impact on response to therapy. (4) Conclusions: Endocrine irAEs might be considered predictive biomarkers for successful immunotherapy in mNSCLC patients. Co-medication during ICIs had a major influence on the effectiveness of these cutting-edge therapies. RWD plays an important role for oncology daily practice whenever clinical trial evidence is not available to guide decision. Full article
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26 pages, 2875 KiB  
Systematic Review
Modern Therapeutic Approaches in Anaplastic Thyroid Cancer: A Meta-Analytic Review of Randomised and Single Arm Studies on Efficacy and Survival
by Mutahar A. Tunio, Donna Hinder, Blaise Emery, Muhammad H. Riaz, Yusef A. Ibraheem, Krishnendu Kumar Nayak and Wael Mohamed
Cancers 2025, 17(5), 777; https://doi.org/10.3390/cancers17050777 - 24 Feb 2025
Viewed by 1616
Abstract
Background: Meta-analyses aimed to assess the effectiveness and safety of targeted and contemporary therapies utilised in locally advanced and metastatic anaplastic thyroid cancer (ATC). Methods: Employing PRISMA and MOOSE guidelines, PubMed, Scopus, Cochrane Library and Web of Science were explored from the inception [...] Read more.
Background: Meta-analyses aimed to assess the effectiveness and safety of targeted and contemporary therapies utilised in locally advanced and metastatic anaplastic thyroid cancer (ATC). Methods: Employing PRISMA and MOOSE guidelines, PubMed, Scopus, Cochrane Library and Web of Science were explored from the inception of targeted therapy until December 2024. A meta-analysis was performed to evaluate the effectiveness, toxicity and survival outcomes of various mutationally directed agents, chemotherapy and radiotherapy in locally advanced/metastatic ATC cases. Results: A total of 47 studies (26 prospective phase II trials and 21 retrospective studies) involving 980 patients met the inclusion criteria. The pooled results showed an overall response rate (ORR) of 29.7% (95% CI: 25.4–34.2%; I2 = 42.4%; p < 0.0001). A total of 49.9% deaths were reported, although a significant number remained alive compared to baseline (mean difference [MD]: 2.07, 95% CI: 1.90–2.24; I2 = 88.6%; p < 0.0001). The pooled median progression-free survival (PFS) was 5.4 months (95% CI: 4.0–6.7 months; I2 = 97.9%; p < 0.0001). Dabrafenib/trametinib (DT) with and without pembrolizumab and lenvatinib plus pembrolizumab (LP) were associated with higher ORR rates and improved OS and PFS. About 51.% of studies mentioned bio-marker analysis (BRAFV600 [14.7%], PDL1 [9.2%], RAS [1.1%], PIK3CA [1.0%] and NTRK1/3 [0.7%]). Toxicity was reported in 94.7% of patients. Conclusions: This meta-analysis found that DT could be a promising first-line treatment option for BRAFV600-mutated ATC, with or without immunotherapy. Alternatively, LP shows potential in BRAFV600 wild-type and PDL1-overexpressing cases. Routine biomarker analysis remains critical for optimising ATC management strategies. Full article
(This article belongs to the Section Cancer Therapy)
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10 pages, 899 KiB  
Article
Clinical and Pathologic Characteristics of Cytologically Indeterminate Thyroid Nodules with Non-V600E BRAF Alterations
by Ryan Instrum, Christina E. Swartzwelder, Ronald A. Ghossein, Bin Xu, Babak Givi, Richard J. Wong, Brian R. Untch and Luc G. T. Morris
Cancers 2025, 17(5), 741; https://doi.org/10.3390/cancers17050741 - 22 Feb 2025
Cited by 1 | Viewed by 944
Abstract
Background: Molecular assays serve as a potential risk stratification tool for cytologically indeterminate thyroid nodules (ITNs). BRAF V600E mutations are nearly always associated with thyroid cancer. However, the malignancy risk for ITNs with other less common BRAF alterations is less well understood. In this [...] Read more.
Background: Molecular assays serve as a potential risk stratification tool for cytologically indeterminate thyroid nodules (ITNs). BRAF V600E mutations are nearly always associated with thyroid cancer. However, the malignancy risk for ITNs with other less common BRAF alterations is less well understood. In this retrospective cohort study, we examine the risk of malignancy (ROM), histopathologic diagnoses, and clinical outcomes for non-V600E BRAF-altered ITNs. Methods: Genomic profiling data obtained from 1034 pre-operative fine-needle aspiration samples from 955 patients were reviewed. Nodules harboring BRAF V600E were excluded. Clinical, radiographic, and histopathologic data were analyzed retrospectively from BRAF-altered ITNs managed surgically at one comprehensive cancer center (2014–2024). Diagnoses were subdivided based on American Thyroid Association (ATA) risk categories. Results: Thirty-seven patients (3.9%) with non-V600E BRAF-altered ITNs were identified (isolated BRAF mutation: n = 29 [78.4%], BRAF + other mutation: n = 3 [8.1%], BRAF fusion: n = 4 [10.8%], BRAF-like gene expression: n = 1 [2.7%]). All BRAF mutations identified in the cohort were class II (RAS-independent, intermediate to high kinase activity). Nodules had a median pre-operative diameter of 1.8 cm (interquartile range [IQR] 1.4–2.5). Patients presented with nodal metastases in 2.7% (n = 1) of cases, and local invasion was not identified in any patients in the cohort. Approximately half of patients (54.1%) were initially treated with a partial thyroidectomy (lobectomy: n = 17 [45.9%], isthmusectomy: n = 3 [8.1%]), and the remaining patients underwent total thyroidectomy (n = 17 [45.9%]). Median post-operative follow-up was 28 months (IQR 17.8–45.5). ROM for BRAF alterations was 73% (95%CI 59–87%; ATA low risk: 64.9%/ATA int risk: 5.4%/ATA high risk: 2.7%). There were no high-risk cancers identified in patients with isolated BRAF mutation (benign: n = 10 [34.5%], ATA low risk: n = 19 [65.5%]), and the most common isolated mutation was K601E (n = 17, 45.9%) which had a 58.8% ROM (all ATA low risk). Patients with isolated BRAF mutations had a significantly lower rate of ATA intermediate or high risk pathology when compared to all other BRAF alterations (0% vs. 37.5%, p = 0.0072). Only three patients were treated with radioactive iodine post-operatively (8.1%), and no completion thyroidectomy procedures were performed in those who did not initially undergo total thyroidectomy. No patients in the cohort were found to have distant metastatic disease or recurrence, and there were no deaths during the follow-up interval. Conclusions: ITNs harboring non-V600E BRAF alterations were rare (3.9% of patients) and typically malignant (73%). Nearly all nodules were benign or ATA low-risk cancers. Only 8% of such nodules were ATA intermediate or high risk cancers. In ITNs with isolated non-V600E BRAF and no other genetic alterations, one-third were non-malignant, and all cancers were ATA low risk. In the appropriate clinical context, thyroid lobectomy or active surveillance can be considered for initial management of non-V600E BRAF-altered ITNs. Full article
(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)
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18 pages, 1894 KiB  
Article
Effect of Hemoglobin, Albumin, Lymphocyte Count, and Platelet (HALP) Score on Survival of Patients with Metastatic Thyroid Cancer Treated with Tyrosine Kinase Inhibitors
by Hikmet Öztop, Fazıl Çağrı Hunutlu, Selin İldemir Ekizoğlu, Özen Öz Gül, Soner Cander and Ahmet Bilgehan Şahin
J. Clin. Med. 2025, 14(4), 1306; https://doi.org/10.3390/jcm14041306 - 16 Feb 2025
Cited by 1 | Viewed by 866
Abstract
Tyrosine kinase inhibitors (TKIs) are crucial for improving the survival rates of individuals with metastatic thyroid cancer. Moreover, systemic inflammation and malnutrition are known to negatively affect metastatic thyroid cancer prognosis. Evaluating nutritional status at the start of treatment can improve survival rates. [...] Read more.
Tyrosine kinase inhibitors (TKIs) are crucial for improving the survival rates of individuals with metastatic thyroid cancer. Moreover, systemic inflammation and malnutrition are known to negatively affect metastatic thyroid cancer prognosis. Evaluating nutritional status at the start of treatment can improve survival rates. Purpose: This study investigated the correlation between the hemoglobin, albumin, lymphocyte count, and platelet (HALP) score and prognosis of patients with metastatic thyroid cancer undergoing first-line TKI therapy. Methods: We retrospectively analyzed data from 44 patients between January 2010 and June 2024. The primary outcomes evaluated in the study were time to treatment failure (TTF) and overall survival (OS); HALP scores were categorized as low (≤29.21) and high (>29.21) based on receiver operating characteristic analysis. Results: The 1-year survival rate was significantly lower in the low HALP score group compared to the high HALP score group (50% vs. 96.3%). Multivariate Cox regression analysis revealed that low HALP scores, elevated leukocyte counts, and lymphopenia were independent predictors of shorter TTF (HR = 0.272, p = 0.011) and OS (HR = 0.208, p = 0.028). Conclusions: The results obtained in the present study demonstrate that the HALP score has prognostic significance for patients with metastatic thyroid cancer who are undergoing first-line TKI treatment. In metastatic thyroid cancer patients, interventions focused on improving nutritional status at the start, during initiation, and throughout the TKI treatment may enhance treatment effectiveness. However, further prospective studies involving larger patient cohorts are necessary to validate our results. Full article
(This article belongs to the Section Oncology)
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Article
Long-Term Results of Intensity Modulated Radiotherapy (IMRT) with Helical Tomotherapy in Non-Metastatic Breast Cancer Patients: Final Analysis
by Pierre Loap, Abdelkarim Uakkas, Sofiane Allali, Jihane Bouziane, Alain Fourquet and Youlia Kirova
Cancers 2025, 17(3), 544; https://doi.org/10.3390/cancers17030544 - 6 Feb 2025
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Abstract
Background: Intensity modulated radiotherapy with helical tomotherapy (IMRT-HT) is used in the breast cancer (BC) treatment for years now to obtain homogeneous dose distribution in the treated volumes and reduce the doses to organs at risk. The purpose of this study was to [...] Read more.
Background: Intensity modulated radiotherapy with helical tomotherapy (IMRT-HT) is used in the breast cancer (BC) treatment for years now to obtain homogeneous dose distribution in the treated volumes and reduce the doses to organs at risk. The purpose of this study was to evaluate our experience in terms of local control, overall survival, progression free survival and adverse events in BC patients treated with IMRT-HT with long term follow-up. Methods: This study is a retrospective data analysis of patients irradiated with IMRT-HT. Overall survival (OS) and progression free survival (PFS) curves were plotted with Kaplan-Meier method. We also analyzed the OS and PFS data by molecular subgroups of the population. Long-term toxicities including skin, cardiac and pulmonary complications were also evaluated. Multivariant logistic regression analysis was performed to determine the independent predictors of the side effects. Results: Between 2009 and 2015, a total of 194 breasts in 179 women with nonmetastatic breast cancer were treated. Most of the tumors were grade III and N+. With a median follow-up of 10 years, we observed 9 local recurrences, 2 loco-regional recurrences, and 29 patients experienced metastatic disease. Only 18 patients are dear, of them 7 cases with breast cancer death. At 10 years, the Local recurrence free survival was 95.3% [95%CI: 92.1–98.5], the loco-regional relapse free survival was 94.5% [91.1–98.1]. The metastases free survival was 82.9% [76.9–89.3]. The progression free survival was 79.9 [73.6–86.7]. The cancer specific survival was 94.3%, and the overall survival 88% [82.8–93.5]. At long term, there were no cardiac, lung, thyroid, digestive radio induced toxicities. A small number of patients experienced grade I or II fibrosis. Conclusions: IMRT-HT could be safely used for adjuvant breast cancer irradiation in patients with complex anatomy. IMRT-HT provides favourable long-term prognosis, while late toxicity is acceptable. Full article
(This article belongs to the Special Issue Advances in Invasive Breast Cancer: Treatment and Prognosis)
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