Search Results (305)

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

Background: Sorafenib remains an important treatment option for patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). This study evaluated real-world outcomes and prognostic factors in patients treated with sorafenib. Materials and Methods: This retrospective multicenter study included 176 patients with RAI-R DTC treated with sorafenib between 2000 and 2024 across sixteen centers. Clinical, pathological and treatment-related variables, including metastatic sites, radiotherapy, dose reduction, inflammatory markers (neutrophil-to-lymphocyte ratio [NLR] and platelet-to-lymphocyte ratio [PLR]) and pretreatment thyroglobulin (Tg), were analyzed. Progression-free survival (PFS) was evaluated using Kaplan–Meier analysis. Prognostic factors were assessed using univariate and multivariate Cox regression analyses. Results: The median follow-up duration was 24 months and the median PFS was 21 months (95% CI: 15.5–26.5). Partial response was observed in 82 patients (46.6%), stable disease in 55 (31.3%) and progressive disease in 35 (19.9%). Patients who underwent dose reduction had longer PFS than those without dose reduction (42 vs. 19 months, p = 0.030), and absence of dose reduction remained independently associated with progression risk. Patients who received radiotherapy had shorter PFS than those who did not receive radiotherapy (16 vs. 37 months, p = 0.002), and radiotherapy-related variables remained independent predictors of progression. Patients with PLR values >138.2 had shorter PFS than those with PLR values ≤ 138.2 (19 vs. 34 months, p = 0.047), although this association was not maintained in Cox regression analysis. Similarly, associations between NLR and Tg values and PFS did not reach statistical significance (p = 0.112 and p = 0.072, respectively). Hand–foot syndrome was the most common toxicity, occurring in 59 patients (33.5%), while Grade 3 hand–foot syndrome was observed in 7 patients (4.0%). Conclusions: Sorafenib provided meaningful disease control with a median PFS of 21 months in this real-world cohort. Dose reduction was associated with longer PFS, whereas radiotherapy requirement appeared to reflect a higher-risk subgroup. Toxicities were generally manageable. 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

Background: Radioiodine (Na[¹³¹I]I) therapy is the cornerstone of systemic treatment for differentiated thyroid cancer (DTC), exploiting sodium–iodide symporter (NIS) expression for durable control. Up to 30–40% of advanced cases develop radioiodine-refractory disease (RAI-R DTC), marked by impaired iodine uptake, aggressive behavior, and poor response to Na[¹³¹I]I. Locoregional treatments, multikinase inhibitors (MKIs), and selective targeted agents improve progression-free survival but are not curative and carry cumulative toxicity, motivating precision-based alternatives. The primary objective of this review is to clarify the evolving theranostic paradigm in RAI-R DTC; the secondary objectives are to appraise redifferentiation and iodine-based theranostics for restoring or exploiting iodine avidity and to evaluate non-iodine theranostic strategies for cases where iodine biology is absent, impaired, or unreliable. Methods: This narrative review synthesizes contemporary evidence on theranostic strategies in RAI-R DTC, drawn from available studies, clinical trials, and current guidelines, with an emphasis on redifferentiation and non-iodine approaches; a systematic search protocol was not applied. Results: Theranostics couples target-specific molecular imaging with matched radionuclide therapy and response-adapted sequencing. Its most transformative application is redifferentiation, in which pharmacologic modulation of oncogenic signaling can restore iodine avidity and enable renewed, dosimetry-guided Na[¹³¹I]I treatment. Beyond iodine, somatostatin receptor (SSTR) imaging and peptide receptor radionuclide therapy (PRRT) have re-emerged in very selected cases, whereas alpha emitters remain investigational. Refractoriness is increasingly viewed as a reversible continuum rather than a fixed state. Conclusions: Theranostics can individualize RAI-R DTC treatment, restoring or exploiting iodine biology where possible and shifting to non-iodine targets where it is unreliable. Patient selection, timing, and integration with systemic therapy are central, and prospective validation is needed. 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

Dicarbadodecaboranes (12) (carboranes) are versatile molecular building blocks with unique properties, which allow the expansion of classical medicinal-chemical space. To enable single-photon emission computed tomography (SPECT) imaging of cyclooxygenase-2 (COX-2), we investigated the feasibility of introducing iodine-123 into nido-indoborin 1, a nido-carborane analog of indomethacin with potent and selective cyclooxygenase-2 inhibitory activity. An electrophilic iodination strategy afforded two regioisomers, 2a and 2b, bearing the iodine at the carborane cluster. Compared to nido-indoborin, a reduced COX-2 inhibition potency and selectivity were observed, with 2b exhibiting the more favorable inhibition profile. Radiosynthesis of [¹²³I]2b was achieved by N-chlorosuccinimide–mediated electrophilic substitution of 1, and conditions were optimized, leading to an isolated radiochemical yield of 4%. While the radiotracer displayed high stability in phosphate buffer, ester hydrolysis was observed in human plasma and murine liver microsomes with no significant deiodination in vitro. Cell uptake studies indicated partial COX-2–dependent accumulation but also revealed substantial non-specific uptake and unexpected enhancement of radiotracer uptake in the presence of carborane-based blocking agents. In vivo pilot imaging studies in mice bearing U87 xenografts showed renal and hepatobiliary clearance without measurable tumor accumulation but evidence of deiodination over time. Overall, iodination was feasible, but the resulting compounds lacked the required COX-2-selective tumor accumulation for further radiotracer development. Full article

Thyroid cancer comprises biologically diverse entities ranging from largely indolent differentiated thyroid cancer (DTC) to aggressive poorly differentiated/anaplastic thyroid cancer and medullary thyroid cancer, generating a need for minimally invasive biomarkers that can be repeatedly sampled. This review summarizes recent advances in liquid biopsy for thyroid cancer, focusing on analytes and technologies spanning circulating tumor DNA (ctDNA)/cell-free DNA, circulating microRNAs (miRNAs), extracellular vesicles (EVs), and circulating tumor cells (CTCs). For ctDNA, we contrast qPCR/ddPCR and next-generation sequencing, tumor-informed versus tumor-agnostic strategies, the impact of low tumor fraction in DTC, clonal hematopoiesis confounding, and emerging methylation-based multi-cancer detection paradigms. For miRNAs, we highlight that bulk serum/plasma and EV-enriched compartments are not interchangeable and that regulated EV loading supports fraction-resolved biomarker development. We review recent translational EV-miRNA studies, including externally validated classifiers for metastatic disease and follicular-patterned/indeterminate nodules, and summarize the evolution of CTC research from enumeration to preoperative risk stratification and postoperative or radioiodine-related kinetics. We conclude with an indications-first framework that pairs analyte choice with clinical intent (preoperative diagnosis, initial risk stratification, response to treatment and minimal residual disease and identification of actionable alterations and resistance mechanisms) and prioritizes standardized workflows and prospective multicenter validation. Multi-analyte integration, epigenetic/fragmentomic cfDNA signals, and higher-resolution EV analytics are likely to accelerate clinical adoption, particularly in advanced thyroid cancer where circulating signal and therapeutic actionability are highest. Full article

Objectives: The response to radioiodine therapy (RAI) in differentiated thyroid cancer (DTC) patients is one of the most important factors that determines the treatment outcome and overall prognosis. The objective of this study is to determine the correlation between BRAF^V600E and TERT promoter (TERTp) mutation in tumor samples of DTC patients with the response to RAI as well as correlation with clinical and pathohistological features. Methods: Samples of 110 DTC patients (80 with intermediate and high risk of disease recurrence-IHR and 30 with distant metastases) were analyzed for BRAF^V600E and TERTp mutation (BRAF/TERT) and 89 patients were assessed for the response to RAI. Results: Sixty-one (55.5%) patients had BRAF^V600E mutation, 30 (27.3%) had TERTp mutation, while 21 (19.1%) patients had both mutations. In the IHR group, the study showed a statistically significant association between genotype BRAF/TERTp and treatment outcome (p = 0.04). IHR DTC patients with BRAF-/TERT- finding showed in general an excellent response to RAI, while patients with BRAF/TERT co-mutation had a predominantly incomplete or indeterminate response. In DTC patients with BRAF/TERT co-mutation that presented with distant metastases, a tendency to a higher frequency of RAI-refractory (RAI-R) disease was recorded, but without statistical significance. The pathohistological and clinical features that significantly correlated with BRAF/TERT status are age at diagnosis, locoregional lymph node involvement, the largest positive lymph node diameter, tumor angioinvasion and the presence of distant metastases. Conclusions: BRAF/TERT co-mutation may be associated with a less favorable disease course and poorer response to RAI. However, findings in patients with distant metastases should be considered exploratory due to the limited sample size. 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

Hypoxia is a hallmark feature of solid tumors and is increasingly recognized as an important factor in tumor progression, aggressiveness, and therapeutic resistance. In the tumor microenvironment, hypoxia is associated with genetic instability, abnormal angiogenesis, metabolic reprogramming, and crosstalk with oncogenic signaling pathways, thereby potentially enhancing tumor invasiveness and metastatic potential. Furthermore, hypoxia may impair the sensitivity of tumor cells to conventional therapies and contribute to treatment resistance. This article reviews current evidence on the role of hypoxia in thyroid cancer, focusing on its biological effects, clinical implications, and therapeutic relevance. Available studies suggest that hypoxia may affect thyroid cancer progression and treatment tolerance by modulating hypoxia-inducible factor (HIF) signaling, epithelial–mesenchymal transition (EMT), angiogenesis, metabolic adaptation, cancer stem-like properties, extracellular matrix remodeling, and stress-adaptive responses. However, the strength of evidence varies across these pathways, and many hypoxia-targeted strategies remain under preclinical investigation. Approaches such as HIF inhibition, redifferentiation therapy, and vascular modulation may offer potential therapeutic directions for advanced and refractory thyroid cancer. Given the marked heterogeneity of thyroid cancer, further thyroid cancer-specific studies are needed to clarify the prognostic and therapeutic significance of hypoxia. Full article

Background: Iodinated contrast media are essential for oncologic imaging but raise specific safety concerns because cancer patients are often exposed to repeated contrast-enhanced computed tomography, nephrotoxic drugs, immune-modulating therapies, and, in selected cases, radioiodine-dependent diagnostic or therapeutic pathways. Methods: We performed a narrative review based on an exploratory search followed by a focused search targeting iodinated contrast use in oncology-related settings. Studies were included if they addressed renal risk and post-contrast acute kidney injury, hypersensitivity and acute adverse reactions, or thyroid dysfunction with radioiodine-related implications. We also considered clinically relevant studies on drug interactions, isotope studies, and laboratory confounding. Results: The evidence base was methodologically heterogeneous, with renal safety as the predominant domain. Kidney injury after contrast-enhanced imaging in cancer patients appeared frequently multifactorial, supporting the broader concept of post-contrast acute kidney injury rather than automatic attribution to contrast alone. Hypersensitivity reactions to modern nonionic iodinated contrast media were generally uncommon, with severe reactions rare, although immune-modulating therapies may alter risk. Thyroid-related effects were usually transient but relevant in patients with thyroid autonomy and in differentiated thyroid carcinoma, where contrast exposure may affect scintigraphy and radioiodine planning. Conclusions: In oncology, iodinated contrast use requires individualized, field-specific risk stratification instead of reflexive avoidance. Full article

This study investigated cytogenetic damage in peripheral blood lymphocytes of 10 differentiated thyroid cancer patients who received multiple ¹³¹I radioiodine (RAI) treatments following total thyroidectomy. Blood samples were collected before the RAI therapy course and 2–3 days after the course for a few selected courses (from 1 to 3) for each patient. The cumulative average number of chromosome aberrations (CAs) per cell and its increment due to a selected RAI course were evaluated using the multiplex fluorescence in situ hybridization method (mFISH). An increase in the number of CAs was observed with the accumulation of RAI activity. The yield of these CAs per unit of accumulated RAI activity was, however, approximately three-fold lower than the respective yield for the incremented number of CAs in a selected course, thus demonstrating the elimination of CAs and/or aberrant cells with time. Biological dosimetry was performed based on the number of all types of CAs and in vitro mFISH calibration curves. With an average administered RAI activity of 3.40 ± 0.39 GBq, the average absorbed blood dose was 0.61 Gy (0.31–0.89:95% CI). Our results demonstrate that one-time administration of such activities of RAI was safe, since the commonly accepted threshold of 2 Gy for the blood dose was not exceeded. Full article

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and is generally associated with an excellent prognosis. Historically, treatment strategies were uniform and frequently aggressive, including total thyroidectomy and routine radioiodine ablation, even in low-risk cases. Current Perspective: Over the past decade, the management of PTC has shifted toward a de-escalation paradigm. This transition is driven by high evidence showing that the majority of PTCs follow an indolent course, with low recurrence and mortality rates. As a result, there is increasing emphasis on tailoring the extent of surgery and adjuvant therapy to individual patient risk profiles. Active surveillance, hemithyroidectomy, and selective use of radioiodine now represent valid alternatives to traditional radical approaches, particularly for low-risk tumors. Clinical Implications: The goal of this evolution is to balance oncologic safety with quality of life, reducing overtreatment and minimizing long-term complications such as hypoparathyroidism or recurrent laryngeal nerve injury. Personalized treatment decisions are now guided by tumor biology, molecular markers, and refined risk stratification systems. Conclusions: This article will review the current evidence supporting this shift, highlight the challenges of implementation in clinical practice, and discuss future trends in the management of papillary thyroid carcinoma. Full article

Background: Papillary thyroid cancer (PTC) is the most common form of thyroid malignancy, with an incidence that has been steadily rising globally. Early and accurate diagnosis remains crucial for effective treatment and improved outcomes. MicroRNAs (miRNAs), small non-coding RNA molecules that regulate gene expression, have emerged as promising biomarkers in cancer research due to their stability and accessibility in serum. In this pilot study we compared the expression of 84 consistently reported, malignancy-associated serum miRNAs in patients with PTC (PTC group) and benign thyroid disease (Control group) as potential PTC markers. Methods: A focused panel containing primer assays for 84 human miRNAs that are consistently reported in the literature as being detectable and differentially expressed in serum in various organ-specific cancers was used to measure miRNA levels in serum samples from PTC (n = 8) and benign thyroid disease (n = 6) patients prior to thyroidectomy. Results: Among the 84 miRNAs analyzed, a panel of ten miRNAs showed numerical trends of differential expression between the two groups, including three upregulated (hsa-miR-150-5p, hsa-miR-21-5p, hsa-miR-23a-3p) and seven downregulated miRNAs (hsa-miR-17-5p, hsa-miR-17-3p, hsa-miR-200c-3p, hsa-miR-296-5p, hsa-miR-574-3p, hsa-miR-885-5p, hsa-miR-130-3p). The serum expression levels of hsa-miR-23a-3p were markedly elevated in patients with malignant nodules compared with those with benign lesions, while hsa-miR-574-3p was significantly downregulated in the PTC group. Conclusions: These findings warrant further investigation of hsa-miR-23a-3p and hsa-miR-574-3p in larger cohorts of patients with PTC to validate their potential clinical relevance. Full article