Search Results (160)

Triphenyl phosphate (TPhP) is a ubiquitous environmental contaminant and endocrine disruptor potentially associated with an increased risk of thyroid cancer (TC). However, whether TPhP directly contributes to TC remains unclear. This study integrated network toxicology and machine learning to investigate potential molecular associations between TPhP exposure and thyroid oncogenesis. By integrating multi-source databases and transcriptomic data, we constructed a TPhP–TC interaction network and established a TC risk prediction model using 127 machine learning algorithm combinations, identifying ten candidate hub genes. GO and KEGG enrichment analyses indicated that these genes are predominantly enriched in phosphorus metabolism, purine metabolism, and nuclear receptor signaling pathways, implying that TPhP may be linked to tumorigenesis through the disruption of metabolic reprogramming. SHAP analysis highlighted AHR and SLC20A2 as critical contributors to model performance. Molecular docking predicted stable binding between TPhP and all hub proteins in silico, with binding energies ranging from −9.2 to −6.6 kcal/mol. This study offers two computational contributions: (1) a quantifiable framework for predicting pollutant-associated TC risk and (2) systematic computational evidence for potential TPhP thyroid toxicity. These findings address a critical gap in understanding potential links between endocrine-disrupting chemical exposure and thyroid carcinogenesis, generating hypotheses for future experimental validation. Full article

Thyroid cancer (TC) is the most common endocrine malignancy, with incidence increasing worldwide. Although most differentiated TCs have a favorable prognosis, radioiodine (RAI)-refractory differentiated thyroid cancer (DTC), BRAF inhibitor-resistant papillary thyroid cancer, and anaplastic thyroid cancer (ATC) remain major areas of unmet clinical need. The sirtuin (SIRT) family of NAD⁺-dependent enzymes has emerged as a multifaceted regulator of TC biology, with isoform-specific dichotomous roles: SIRT1, SIRT6, and SIRT7 act as tumor promoters through engagement of BRAF/MAPK, PI3K/AKT, epithelial–mesenchymal transition (EMT), and Hippo pathways, while SIRT3 and SIRT4 function as tumor suppressors via mitochondrial metabolic regulation. This review synthesizes recent developments that expand the therapeutic landscape: (i) the recognition that SIRT7 functions as a desuccinylase with preclinically identified oncogenic substrates, modifying KIF23 in ATC and LATS1 in PTC; (ii) the emerging roles of isoform-specific SIRT axes, including the NAMPT–SIRT1–PD-L1 axis, SIRT6-associated regulatory T-cell biology, and SIRT2 as a T-cell metabolic checkpoint, as determinants of immune microenvironment state and potential modulators of immune checkpoint inhibitor response; and (iii) the SIRT6–nuclear receptor coactivator 4 (NCOA4) ferritinophagy axis as a supported ferroptosis vulnerability in ATC, with potential but still hypothesis-generating relevance to dedifferentiated and RAI-refractory DTC. Importantly, the therapeutic logic for SIRT6 is disease-state-specific rather than contradictory: SIRT6 inhibition is rationalized in BRAF-driven aggressive PTC and DTC contexts where SIRT6 supports MAPK signaling, EMT, and ferroptosis resistance, whereas in SIRT6-high ATC, the same enzyme’s NCOA4-dependent ferritinophagy activity may instead be exploited to enhance ferroptosis sensitivity. We review the current SIRT modulator pharmacological toolkit—including EX-527, OSS_128167, and emerging SIRT7-selective inhibitors—and identify the substantial clinical translation gap, with no SIRT-targeted clinical trial yet conducted in TC, despite strong preclinical rationale. We outline biomarker-stratified combination strategies with BRAF/MEK inhibitors, multikinase inhibitors, immune checkpoint inhibitors, and ferroptosis inducers, prioritizing biomarker-driven preclinical validation and, where supported by efficacy and safety data, subsequent early-phase evaluation in BRAF V600E-mutant and SIRT6-high thyroid cancer. Sirtuins thus represent a mechanistically promising and potentially biomarker-stratifiable therapeutic hypothesis for difficult-to-treat thyroid cancer; however, clinical translation remains at an early stage and requires validated biomarkers, isoform-selective compounds, and disease-specific in vivo evidence. Full article

Objective: Our objectives were to describe molecular profiling in a real-life cohort of patients with radioiodine-resistant (RAI-R) differentiated or poorly differentiated thyroid cancer (DTC or PDTC) treated with lenvatinib and to focus on factors potentially influencing the quality of tissue samples for molecular analysis, including the impact of storage time, defined as the interval between tissue collection and molecular testing. Design: We retrospectively included all lenvatinib-treated RAI-R DTC or PDTC patients tested with DNA- and/or RNA-based next-generation sequencing (NGS) in our center, also analyzing the results of fluorescence in situ hybridization (FISH) for RET fusions if the sample did not satisfy quality criteria for RNA-based NGS analysis. We investigated differences in terms of histotype, biopsy site, or storage time between adequate and inadequate samples for RNA-based NGS. Results: At least one gene alteration was detected in 50% of the cohort (18 out of 36 patients); RAS and BRAF were the most frequent mutations, while gene fusions accounted for 5.6% of cases. Tissue samples were more frequently adequate for DNA-based NGS compared to RNA-NGS analysis (93.9% vs. 58.3%, p < 0.001). The median storage time was significantly longer in the case of inadequate samples for RNA-based NGS compared with adequate specimens (41.5 vs. 9.5 months, p = 0.016); samples archived for ≥3 years led more frequently to an inadequate result. Conclusions: Advanced RAI-R TC candidates for systemic therapy often harbor gene alterations. An adequate result was less frequently achieved in cases of RNA-based NGS than in DNA-based NGS, especially if the interval between tissue collection and molecular analysis was longer; nevertheless, the limited cohort size precludes definitive conclusions. Full article

Objectives: Endocrine neoplasms, as a general rule, show systemic, neuro-inflammatory and metabolic consequences, known as paraneoplastic syndrome. The comorbidity of thyroid tumors with neurological and autoimmune diseases prompt looking for common neuro-immuno-endocrine mechanisms of these disorders. While most TCs are well described, there is a gap in the literature after the isolation of oncocytic/Hürthle cell carcinoma (HCC), as a unique type due to immunoendocrine and metabolic features (low TSH-receptor expression and radioiodine avidity). The aim of this study was to collect clearly defined reports of HCC (as a separate entity) and to attempt determining common clinical symptoms and the usefulness of various diagnostic techniques (comprehensive critical review). This may be an introduction to modern treatment (patient-centered care) since the main cause of mortality is not local progression or metastases. Results: Until now, due to misnomenclature and data misinterpretation, HCC has been treated according to general standards (with overuse of TSH-ST and RIA). High thyroglobulin level, decreased total thyroxin (with normal FT3 and spontaneous decrease in TSH), hypercalcemia, as well as the “reverse flip-flop” phenomenon, as common symptoms, indicate the neuroendocrine origin of HCC. Sparse, well-documented lymph node metastases are another feature, although from few studies. Most studies omit the N stage. Whole-body ¹³¹iodine and ¹⁸F-fluorodeoxyglucose scintigraphy may be useful before FNAB. Fine-needle aspiration biopsy (FNAB), as a “gold standard” in early diagnosis of thyroid nodules, delays HCC diagnosis because of the inability to determine a benign/malignant nature. Conclusions: Final HCC outcome may be affected by various overlapping immunoendocrine factors (paraneoplastic effects). Due to very few thyroid function tests performed in HCC, we have proposed a set of basic laboratory analyses, core biopsy in HCC differentiation, and diagnostic chain for standardization. According to the review, adaptation and treatment of HCC based on existing standards for other thyroid cancers seem to be insufficient, and the risks outweigh the benefits. The key recommendations resulting from the 5th edition of the WHO Classification of Endocrine Neoplasms are only the beginning of refuting many myths and biases. Full article

Thyroid cancer (TC) is the most common endocrine malignancy, with a steadily rising global incidence. Despite most cases having a favorable prognosis, a subset of patients develops aggressive, recurrent, or radioiodine-refractory disease, demonstrating the need for improved molecular biomarkers and targeted therapies. The Forkhead box P (FOXP) transcription factors (FOXP1–FOXP4) have appeared as important regulators of tumor biology, yet their roles in thyroid cancer remain incompletely defined. This review summarizes current bioinformatic, experimental, and clinical evidence regarding FOXP expression patterns, molecular mechanisms, and clinical relevance in TC. FOXP3 and FOXP4 are mainly associated with aggressive clinicopathological features, including extrathyroidal invasion, lymph node metastasis, and distant metastases, and may serve as markers of poor prognosis. The most explored FOXP3 contributes to immune evasion and radioiodine resistance by suppressing sodium iodide symporter expression and regulating tumor-associated immune responses. FOXP4 promotes tumor progression by activating key oncogenic signaling pathways and regulating non-coding RNAs. In contrast, evidence indicates that FOXP2 primarily acts as a tumor suppressor in TC by inhibiting cell proliferation and promoting apoptosis, although it may show context-dependent functions. FOXP1, though less well studied, is also suggested to have tumor-suppressive effects in some studies, and demands additional investigation in TC. Collectively, current evidence suggests that FOXP family members may represent promising diagnostic, prognostic, and therapeutic biomarkers in thyroid cancer, although further validation in large clinical cohorts and mechanistic studies is still required. Full article

Thyroid cancer (TC) is an endocrine malignant tumor with the fastest-growing incidence worldwide. It has complex pathological types and significant heterogeneity, with great differences in clinical prognosis among different subtypes. Among them, aggressive subtypes, such as radioiodine-refractory (RAI-R) TC and anaplastic thyroid cancer (ATC), have become a major challenge in current clinical diagnosis and treatment, due to limited treatment options and high risks of recurrence and metastasis. Tumor metabolic reprogramming is one of the characteristics of cancer, among which the Warburg effect plays a driving role. As a rate-limiting enzyme in the glycolytic pathway, pyruvate kinase M2 (PKM2), with its unique functional plasticity, has become a linchpin of glycolytic metabolism and malignant phenotypes of tumor cells. This article will systematically review the functional regulatory mechanisms of PKM2, its specific role in TC, and explore the targeted therapeutic strategies and research prospects of TC with PKM2, providing a new theoretical basis and potential plans for the clinical diagnosis and treatment. Full article

Background and Objectives: Doxorubicin is an antineoplastic drug used to treat cancer. However, side effects limit its use. Edaravone (EDO) is a recently discovered, powerful drug with antioxidant properties. The aim of the present study was to show the negative effects of doxorubicin and the protective effect of EDO on the thyroid gland using scintigraphic and biochemical methods. Materials and Methods: Thirty-five male Wistar rats were randomly divided into five groups (n = 7) to establish the following study groups: control, doxorubicin, and 1, 10, or 30 mg/kg EDO. DOX (18 mg/kg cumulative intraperitoneal injection (i.p.) was performed on the 19th, 20th, and 21st days of the experiment. EDO (1, 10, and 30 mg/kg) was administered on the first day of the trial and continued for 21 days. These groups also received i.p. injections of DOX (18 mg/kg) on the 19th, 20th, and 21st days of the experiment. On the 22nd day of the experiment, scintigraphic imaging of the thyroid glands of rats was performed using ^99mTc pertechnetate as the radiopharmaceutical. Serum levels of T3, T4, TSH, NLRP3, IL-1β, and IL-18, as well as thyroid tissue levels of MDA, TNF-α, and IL-6, were determined using the ELISA method. Results: DOX significantly reduced ^99mTc pertechnetate uptake in the thyroid gland compared to the control group (p < 0.001). It reduced plasma levels of thyroid hormones T3 (p < 0.001) and T4 (p < 0.001) while increasing TSH levels (p < 0.01). Additionally, NLRP3, IL-1β, IL-18, MDA, TNF-α, and IL-6 levels were significantly increased in the DOX group compared with the control group (all p < 0.001). Pretreatment with EDO significantly attenuated doxorubicin-induced abnormalities in the thyroid gland (p < 0.001). Conclusions: The data from scintigraphic and biochemical analyses revealed the development of hypothyroidism after doxorubicin administration in rats. It was shown that pretreatment with EDO could partially prevent hypothyroidism caused by doxorubicin. Full article

Background: Thyroid cancer (TC) represents the most common endocrine malignancy worldwide, with incidence increasing rapidly across diverse geographic regions. However, population-based evidence from North Africa remains limited, and comprehensive longitudinal analyses examining sex-specific incidence patterns, histological subtypes, and trends in tumor extension are lacking in Tunisia. Aim: This study aimed to (i) quantify TC incidence trends by sex and age group, (ii) characterize histological subtype-specific temporal patterns and tumor extension at diagnosis in northern Tunisia between 2000 and 2018, and (iii) to address projections in incidence by sex until 2040. Methods: A retrospective, population-based registry study was conducted using data from the Northern Tunisia Cancer Registry (NTCR), covering 11 governorates with a population of 5,233,700 in 2018. All primary invasive TC cases diagnosed between 2000 and 2018 were included (n = 3639). Age-standardized incidence rates (ASIRs) were calculated using the WHO standard population. Temporal trends were assessed using Joinpoint regression to estimate average annual percentage change (AAPC) with 95% confidence intervals. Projections of TC incidence to 2040 were generated using Bayesian autoregressive age–period–cohort models. Results: TC incidence increased significantly between 2000 and 2018, with overall ASIR rising from 2.8 to 5.0 per 100,000 person-years (AAPC = 3.8%, p < 0.001). In males, ASIR increased from 0.9 to 2.4 (AAPC = 3.0%, p < 0.001), while in females it rose from 3.7 to 7.8 (AAPC = 4.3%, 95% CI: 3.0–5.7; p < 0.001). The increase was predominantly driven by papillary thyroid carcinoma (PTC) (AAPC = 6.4% in males; 5.8% in females; both p < 0.001), whereas follicular thyroid carcinoma (FTC) remained stable. Notably, the proportion of metastatic cases decreased significantly in females (AAPC = −7.2%, p = 0.033), and the proportion of regionally advanced disease decreased in males (AAPC = −5.0%, p = 0.034). Conclusions: This population-based study demonstrates a sustained rise in TC incidence in northern Tunisia, disproportionately affecting women and largely driven by papillary histology. The concurrent increase in TC incidence alongside a reduction in regional and metastatic extension at diagnosis occurred. These findings have important implications for cancer prevention and control, highlighting the need for risk-adapted screening strategies and rationalized diagnostic practices. Full article

Thyroid cancer (TC) is the most common endocrine malignancy, and challenges persist in preoperative diagnosis of indeterminate nodules and postoperative monitoring when thyroglobulin (Tg) assays are compromised by interfering anti-Tg antibodies (Tg-Ab). Extracellular vesicles (EVs) carry molecular cargo reflective of cells of origin and are increasingly explored as biomarker sources. In this study, we investigated whether thyroid-derived EVs retain the expression of thyroid-specific thyrotropin-receptor (TSHR), a suitable target in immunoaffinity-based EV isolation, and explored the presence of Tg in EV cargo as potential surrogate for serum Tg. EVs from thyroid cell lines (Nthy-Ori 3-1, TPC-1, OCUT2) and plasma of patients with benign, malignant tumors and recurrent TC were isolated by differential ultracentrifugation and characterized via nanoparticle tracking and Dot and Western blot analyses. EVs derived from Nthy-Ori 3-1 and TPC-1 cell lines were positive for surface TSHR and vesicular Tg, but not OCUT2. All plasma-derived EVs were positive for TSHR and Tg, while their electrophoretic profiles from vesicles differed compared to tissue lysate. Tg was detectable in EVs isolated from recurrent TC samples, even in Tg-Ab positive cases. Together, these results support the use of TSHR for targeted EV isolation and point to vesicular Tg as a potential recurrence marker. Full article

Background/Objectives: Thyroid cancer (TC) is among the most common endocrine malignancies, with incidence rates increasing worldwide. However, careful inferential analysis based on refined data is needed to provide a sharper clinical and epidemiological description of this serious condition in a biologically and technologically evolving society. This study presents an exploratory statistical analysis of data from 1470 patients who underwent thyroid surgery for differentiated TC. Methods: The analysis combines bivariate exploration of associations between variables with univariate and multivariate analyses stratified by histological subtype. We examined pathological characteristics (tumor location, nodal metastases, distant metastases, margin involvement, lymphovascular invasion, vascular invasion, and perineural invasion), clinical characteristics (clinical stage), biochemical markers (thyroglobulin, anti-thyroglobulin antibodies, and thyroid-stimulating hormone), and demographic variables (sex assigned at birth and age). In addition, exploratory multivariable models were used to investigate factors associated with lymph node metastasis and margin involvement in papillary microcarcinoma, the diffuse sclerosing variant, and the classical variant of papillary thyroid carcinoma. Results: Notably, moderate to high effect size correlations highlight the interdependence of invasive histopathological features in thyroid cancer and their collective link to adverse surgical outcomes and prognosis. Conclusions: This study provides an analysis of associations between the variables and subtype-specific descriptive estimates, serving as a foundation for future work in tailoring personalized medicine. Full article

Background and aim: Recent preclinical studies have confirmed that inhibiting the MAP kinase pathway can induce the re-differentiation of radioiodine (RAI)-refractory (RAIR) follicular cell thyroid cancers (TCs). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myo-inositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells. Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into two groups: (1) a control group in which patients are treated with KIs (subgroup a: trametinib plus dabrafenib; subgroup b: lenvatinib); (2) a group in which patients (divided into the two subgroups) are treated with the same KIs in addition to MI. After 30 days of MI treatment, all patients, treated with levothyroxine (L-T4) at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). On day 35, the patients will be subjected to whole-body scintigraphy, with hybrid imaging where possible (SPECT/CT), after the administration of diagnostic activity (185–222 MBq of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0); after 30 days of MI therapy; and then on days 31, 32, 33, 34, and 35 after MI therapy. Quality of life (QoL) will be assessed at the beginning of the MI treatment and at the end of its administration. The primary endpoint is the restoration of 123-I uptake in RAIR-TC patients already on KI therapy alone and on KI therapy plus MI. The restoration of 123-I uptake in target lesions will be evaluated. Conclusions: MI may have a synergistic effect at the cellular level, and the possible increase in the re-differentiation of RAIR-TC in patients treated with KIs plus MI may have great clinical relevance. The re-uptake of RAI will be evaluated as the primary endpoint, and Tg values and QoL will be evaluated as the secondary endpoints. The main limitation of this study is that we do not investigate any clinical effects. We will have to postpone the clinical analysis to a later date after the administration of RAI for therapeutic purposes. Full article

Background: BCAR3 has been implicated in various cancers, yet its role in thyroid cancer (TC) remains unclear. This study aimed to investigate the methylation status, functional effects, and underlying mechanisms of BCAR3 in TC. Methods: BCAR3 methylation was analyzed using matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF) mass spectrometry in 422 TC and 371 benign thyroid nodule samples. Expression levels were assessed via immunohistochemistry, qPCR, and Western blot. Functional assays including proliferation, migration, and invasion were performed after BCAR3 knockdown. Rescue experiments using a PI3K activator were conducted to examine pathway mechanisms. Results: BCAR3 was significantly hypomethylated in TC compared to benign tissues (p < 0.001), with CpG_6 most strongly associated with TC risk (odds ratio, OR = 1.73, p < 0.001). Notably, BCAR3 hypomethylation was more pronounced in cases with larger tumor size and advanced disease stage. Furthermore, BCAR3 methylation showed differential patterns across TC subtypes, with medullary thyroid carcinoma exhibiting the lowest methylation levels. BCAR3 expression was upregulated in TC tissues and cell lines (p < 0.05). Mechanistically, BCAR3 knockdown reduced phosphorylation of AKT/mTOR and altered expression of epithelial-to-mesenchymal transition (EMT) marker, characterized by an increase in E-cadherin and decreases in Vimentin and N-cadherin, and consequently suppressed proliferation, migration, and invasion (p < 0.05). Rescue experiments with a PI3K activator showed a trend towards restoration of these effects, although not to the level of the control groups. Conclusions: BCAR3 hypomethylation contributes to TC cells’ proliferation, migration, and invasion by promoting AKT/mTOR activation and EMT. These findings highlight the potential of BCAR3 methylation as both a biomarker and a therapeutic target in TC. Full article

Thyroid cancer (TC) incidence is rising, necessitating a refined understanding of its complex biology, particularly for advanced forms. This review synthesizes the state-of-the-art knowledge, guided by the WHO 5th Classification (2022), which incorporates molecular findings and introduces categories like Differentiated High-Grade Thyroid Carcinoma (DHGTC) to better stratify prognosis. The review summarizes the molecular changes in thyroid cancer (TC) by establishing a clear link between specific oncogenic alterations and the resulting tumor phenotype, prognosis, risk stratification and therapeutic vulnerabilities. The central importance of the review lies in its comprehensive integration of these molecular changes with the resulting immunological microenvironment and the rationale for novel, personalized therapies. Moreover, high-level genomic instability within aggressive thyroid malignancies promotes an immunosuppressive tumor microenvironment via the selection and recruitment of suppressive immune components, contributing to immune evasion and poor prognosis. This characteristic immunosuppression identifies the aggressive tumors as prime candidates for targeted immunotherapies. The review implicitly argues that understanding the molecular drivers of this immunosuppression is essential for designing effective clinical trials using these novel agents. Diagnostic advancements, including molecular testing for high-risk mutations (BRAF, TERT) and the integration of Artificial Intelligence (AI) for refined risk stratification, are enabling personalized treatment. The evolving molecular and clinical understanding allows for a paradigm shift toward individualized therapies that balance optimal disease control with minimizing morbidity, especially in the context of high-risk disease. Full article

Chronic inflammation plays a key role in cancer pathogenesis. Aggressive thyroid cancer is associated with immune infiltration and systemic inflammation. Long pentraxin 3 (PTX3) is an inflammatory protein implicated in tumor progression. This study evaluates PTX3 plasma levels in patients with non-medullary thyroid cancer (TC) compared to benign thyroid disease and investigates its tissue expression. We prospectively included 55 TC patients: 42 papillary, 3 follicular, 4 oncocytic, 4 anaplastic (ATC), and 2 poorly differentiated (PDTC). The control group consisted of 32 patients with benign thyroid disease. PTX3 plasma concentrations were measured by ELISA, and tissue expression of PTX3 and CD68 was analyzed using immunohistochemistry. PTX3 plasma levels did not significantly differ between TC and controls, but patients with PDTC and ATC had markedly higher concentrations. Tissue analysis showed strong PTX3 expression in three of four ATC cases in tumor and stromal cells, whereas benign and differentiated thyroid tissues exhibited minimal staining. CD68 expression was positive in ATC, indicating tumor-associated macrophage infiltration, but a few cells were double-positive for PTX3 and CD68. Our findings suggest a possible association between PTX3 and aggressive TC, particularly ATC. Further studies are needed to validate these findings and elucidate the cellular origin and functional role of PTX3. Full article

Background: Suspicious ultrasound patterns are essential for the accurate preoperative assessment of thyroid cancer (TC). The number of tumor foci may serve as an additional parameter, particularly when considered in association with ultrasound patterns and the reoperation rate. Methods: We conducted a retrospective analysis of 665 well-differentiated TC (WDTC) patients treated between 2008 and 2024. The analysis included preoperative data, ultrasound patterns (hypoechogenicity, microcalcifications, high vascularity, and irregular tumor shape or margins), and histopathological findings regarding the number of tumor foci and reoperation rates, additionally stratified by TNM stage and sex. Results: A statistically significant association was observed between the number of tumor foci and the mean number of ultrasound patterns (p < 0.05). The highest mean number of patterns was found with ≥4 foci (SD: 2.50 ± 1.20). However, this relationship was not linear, as in each focus category (1, 2, 3, and ≥4), the greatest number of ultrasound patterns consistently predominated. No significant association was found between a higher number of foci and a complete set of ultrasound patterns (p = 0.273) or the reoperation rate (p = 0.469). Analyses stratified by TNM stage and sex also did not reveal any significant differences (p > 0.05). Conclusions: Although the number of tumor foci demonstrates an association with ultrasound patterns, the lack of a consistent linear correlation and the absence of an impact on reoperation rates suggest that this parameter may provide limited additional clinical value beyond the general concept of multifocality. Full article