Search Results (182)

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: The role of surgery in advanced thyroid cancer remains controversial, particularly in the setting of aggressive tumor behavior, local invasion, and limited therapeutic windows. Advanced thyroid cancer represents a heterogeneous clinical entity that includes anaplastic thyroid carcinoma as well as differentiated and poorly differentiated carcinomas with aggressive features. Methods: We conducted a retrospective case series of 10 consecutive patients who underwent surgical management for advanced thyroid cancer at a tertiary referral center over a 30-month period. Clinical presentation, surgical strategy, postoperative complications, adjuvant therapies, and outcomes were analyzed. Results: The cohort included 2 papillary, 5 poorly differentiated, and 3 anaplastic thyroid carcinomas. Most patients presented with locally invasive disease and compressive symptoms, including dysphonia and dyspnea. Complete resection (R0) was achieved in five patients and was associated with favorable outcomes, while patients with anaplastic histology experienced poor survival despite palliative interventions. Surgery provided meaningful symptom control in selected patients, particularly those with airway compromise. No perioperative mortality occurred. Conclusions: Surgical management of advanced thyroid cancer should be highly individualized and guided by tumor extent, symptom burden, and patient performance status. While surgery alone is insufficient as a standalone treatment, it plays a pivotal role when integrated within a multimodal strategy, offering both oncologic and palliative benefits. Early identification of candidates for surgical intervention and integration with systemic therapies represent key elements in the management of these complex malignancies. Full article

Anaplastic thyroid carcinoma (ATC) represents the most aggressive thyroid malignancy, characterized by rapid progression, therapeutic resistance, and poor prognosis. Conventional treatments remain largely ineffective, highlighting the need for novel therapies. Metabolic reprogramming, particularly the Warburg effect (WE), has emerged as a promising area of investigation. This review synthesizes current evidence on the role of WE in ATC and PDTC, integrating data from molecular profiling, preclinical studies, and emerging therapeutic strategies. Oncogenic alterations frequently observed in ATC, including mutations in BRAF, RAS, TP53, and activation of PI3K/AKT/mTOR and HIF-1α signaling, converge to promote glycolytic reprogramming. This metabolic shift supports tumor proliferation, immune evasion, and metastasis through increased glucose uptake, lactate production, and microenvironmental remodeling. Key metabolic nodes, including glucose transporters, hexokinase, and monocarboxylate transporters, are regarded as promising targets. Preclinical studies suggest that pharmacological inhibition of these pathways reduces tumor growth, enhances radiosensitivity, and improves response to targeted therapies. Future efforts should focus on combination therapies, biomarker-driven patient stratification, and the development of targeted delivery systems to overcome toxicity and resistance. A deeper understanding of tumor metabolic heterogeneity will be essential for translating these approaches into clinical practice. Full article

Background and Clinical Significance: Thyroid cancer is increasing, particularly the differentiated type, with decreasing incidence of the anaplastic type. Anaplastic thyroid carcinoma (ATC) is a rare, aggressive, and often lethal form. It frequently presents with metastatic disease, regional and systemic, with common distant metastasis to the lung, bone, brain, and adrenal, and rarely to other places; Case presentation: A 74-year-old Arab male presented with symptomatic anemia and melena and was admitted for investigation of the cause. The patient was found to have a large retrosternal goiter and gastric tumor. CT scan showed a pedunculated, nonobstructive mass, suggestive of a GIST or leiomyoma. The neck mass presented with compressive symptoms. He underwent a combined neck and abdominal surgical resection based on a multidisciplinary team decision, as prior biopsies were not conclusive. The final pathology report identified similar tumors in the two specimens and suggested an anaplastic thyroid carcinoma as the primary tumor with metastasis to the stomach. Furthermore, the workup, including a PET scan 2 weeks post-surgery, revealed widespread metastases in the bone, lung, and liver, and the treatment was palliative. He was followed up in the outpatient clinic for 4 and a half months post-operatively. The patient developed sepsis and cardiopulmonary arrest and died; Conclusions: ATC can metastasize to many places in the body, including the stomach (as shown in our case), which can cause significant upper gastrointestinal bleeding and anemia. Metastatic ATC carries a poor prognosis; thus, physicians need to keep a high index of suspicion in approaching similar cases. A multidisciplinary approach for the management is of utmost importance for appropriate treatment. This disease’s pathology, behavior, and targeted new treatment modalities must be explored further. Full article

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive malignancy characterized by rapid progression, early metastasis, and extremely poor survival outcomes. Effective therapeutic options remain limited, highlighting the need for efficient and biologically relevant preclinical drug-discovery platforms. In this study, high-throughput compound screening using human ATC cell lines identified ANC-3 as a potential anticancer candidate. Its antitumor activity was evaluated through cytotoxicity and functional assays, zebrafish xenograft validation with live fluorescence imaging, colony-formation assays, and bulk RNA sequencing with pathway enrichment analyses. ANC-3 demonstrated consistent antitumor effects by significantly inhibiting cell viability, migration, invasion, and clonogenic survival, while also suppressing tumor growth in zebrafish xenograft models. Transcriptomic analyses revealed modulation of multiple oncogenic pathways, including MAPK, Ras, and NF-κB signaling. Collectively, these findings support zebrafish xenograft-based screening as a rapid and scalable platform for ATC drug discovery and suggest ANC-3 as a promising multi-pathway inhibitor warranting further preclinical 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

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

Differentiated thyroid cancer (DTC), including papillary and follicular subtypes, is generally associated with favorable prognosis; however, a subset of patients develops recurrent, metastatic, or radioiodine-refractory diseases with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a biologically relevant process in thyroid cancer, yet its role in differentiated disease remains incompletely defined. Unlike many other malignancies, thyroid cancer arises within an organ intrinsically shaped by iodine-dependent redox reactions required for thyroid hormone biosynthesis. This unique oxidative environment imposes selective pressure on tumor cells to adapt redox balance, lipid metabolism, and antioxidant defenses, all of which are central regulators of ferroptosis. Accumulating evidence indicates that ferroptosis susceptibility in DTC is dynamically modulated by differentiation status, oncogenic signaling, metabolic rewiring, and tumor microenvironmental interactions. Notably, progression toward radioiodine-refractory disease is accompanied by dedifferentiation and reinforcement of anti-ferroptotic programs, linking ferroptosis resistance to therapeutic failure. In this review, we synthesize recent original studies and contemporary reviews to provide a focused overview of ferroptosis in DTC, excluding anaplastic disease. We discuss thyroid-specific redox and iodine metabolism, genetic and metabolic determinants of ferroptosis sensitivity, lipid remodeling, and immune–microenvironmental interactions, and highlight translational opportunities for targeting ferroptosis in radioiodine-refractory DTC. By reframing ferroptosis as a context-dependent vulnerability rather than a universal death pathway, this review outlines a conceptual roadmap for integrating ferroptosis modulation into existing therapeutic strategies for DTC. Full article

Background: Riedel’s thyroiditis is a rare fibrosing thyroid disorder that remains one of the most difficult to diagnose, often being initially interpreted as malignant due to its clinical, radiological, and histopathological similarities with anaplastic carcinoma or other infiltrative thyroid diseases. Preoperative investigations, including fine-needle aspiration cytology (FNAC), may be misleading and contribute to an erroneous diagnosis of cancer. Methods: We report the case of a 44-year-old woman presenting with a rapidly enlarging, hard goiter associated with compressive symptoms and cytological findings suspicious for papillary thyroid carcinoma (Bethesda V). Based on these findings and the multidisciplinary team’s assessment, surgical intervention was undertaken. Intraoperatively, the thyroid gland was densely fibrotic and adherent to adjacent structures, prompting frozen-section analysis that revealed a benign fibroinflammatory process consistent with Riedel’s thyroiditis. This intraoperative finding guided the surgical team toward a near-total thyroidectomy, preventing unnecessary radical excision. Results: The paraffin-embedded section confirmed the diagnosis. Postoperative recovery was favorable, with complete resolution of compressive symptoms. Conclusions: This case highlights the persistent diagnostic challenges of Riedel’s thyroiditis and illustrates how intraoperative frozen-section examination can contribute to differentiating it from malignancy when preoperative findings remain inconclusive. A multidisciplinary approach and surgical expertise are essential in tailoring the extent of resection, preventing complications, and achieving both diagnostic confirmation and symptom relief. Full article

In recent years, several studies have highlighted the ability of malignant cells to use acetate as an alternative energy and biosynthetic source to glucose. In this context, the present study aimed at characterizing the expression profile of genes involved in acetate metabolism in thyroid carcinomas. To this end, we analyzed molecular and clinical data from 496 papillary thyroid cancers (PTCs) and 59 normal thyroid tissues from The Cancer Genome Atlas (TGCA). In addition, we examined 57 PTCs and matched normal tissues, and six anaplastic thyroid carcinomas (ATCs) collected in our institutions, using real time RT-PCR. The results show a downregulation of ACSS1, ACSS2, ACACB, PDHA1, SLC16A3 and SLC16A7 genes in PTCs compared with normal tissues, some of which were significantly lower in BRAF-mutated tumors, the more aggressive tall cell variant, and larger and/or metastatic PTCs. Overall, these findings point to a reduction in mitochondrial oxidative pathways that was more evident in advanced or aggressive disease forms. In ATCs, ACSS2 was the only upregulated gene, suggesting further tumor adaptation to the metabolic stress of rapidly growing cancers. In conclusion, our study demonstrates a dysregulated expression pattern of multiple genes involved in acetate metabolism, which could be exploited for the development of new therapeutic strategies. Full article

Anaplastic thyroid carcinoma (ATC) is an aggressive and lethal malignancy that carries a poor prognosis. Moreover, there are limited therapeutic options for managing ATC. There is increasing evidence that implicates the role of cancer stem cells (CSCs) in the processes of dedifferentiation in the progression, therapeutic resistance, and metastatic potential of ATC. In this review, we integrate the molecular and cellular insights into the CSCs paradigm in ATC to highlight the role of stemness-associated markers that include CD44, CD133, and ALDH1. We put special emphasis on the role of CD44 and its variant isoforms (CD44v), which play a role in the interface of cancer stemness, tumour microenvironment crosstalk, modulation of epithelial–mesenchymal transition (EMT), chemoresistance, and metastasis. The contribution of signalling pathways (PI3K/AKT/mTOR, MAPK, Notch, Wnt/β-catenin, and Hedgehog) to hypoxia, cancer-associated fibroblasts (CAFs), and tumour-associated macrophages (TAMs) in sustaining CSC niches will be discussed. The review explores advances in molecular diagnostics, imaging technologies, and targeted therapeutic strategies with the potential to disrupt CSC-driven tumour maintenance. Through integration of multigenic, epigenetic, and microenvironmental perspectives, this review highlights the potential necessity of CSC-targeted and combination therapies to improve disease outcomes in ATC. Full article

Positive surgical margins (PSMs) are a major predictor of recurrence in thyroid cancer; however, their intraoperative detection remains challenging, particularly for microscopic PSMs. This study aimed to demonstrate that a sprayable pH-sensitive near-infrared fluorescent probe (PH10) could specifically and robustly label thyroid tumors in orthotopic mouse models. The pH sensitivity, cytotoxicity, and cellular uptake mechanisms of PH10 were evaluated in papillary thyroid carcinoma (K1) and anaplastic thyroid carcinoma (8505C) cell lines in vitro. Orthotopic thyroid cancer mouse models were then established using both K1 and 8505C cells. In vivo fluorescence following topical spraying of PH10 was quantified after sequential washes to assess tumor-to-background ratios. Fluorescence-guided surgery (FGS) was performed to determine whether PH10 could facilitate complete resection of orthotopically grown thyroid tumors. Complete resection was validated by hematoxylin and eosin histology. PH10 demonstrated low cytotoxicity at clinically relevant concentrations in vitro and showed selective uptake into thyroid cancer cells, predominantly via organic anion transporting polypeptide-mediated transport. Topical spraying of PH10 in orthotopic thyroid cancer mouse models established from K1 and 8505C cell lines generated strong tumor-specific fluorescence. Tumor-to-background ratios were significantly higher than background and remained distinguishable after multiple washes. In both models, PH10 enabled visualization of macroscopic residual tumors and detection of microscopic PSMs, with fluorescence patterns closely corresponding to histologic findings. FGS enabled complete tumor resection, as confirmed by fluorescence and histology. In conclusion, topical application of PH10 provides rapid, tumor-specific fluorescence suitable for identifying PSMs and facilitating complete tumor resection by FGS in thyroid cancer. Full article

Pulmonary arterial hypertension (PAH) and cancer share high mortality and complex prognoses. Due to PAH’s rarity, these parallels may be underrecognized by healthcare stakeholders. This study explored similarities between PAH and cancer across epidemiological, clinical, therapeutic, and healthcare resource utilization (HCRU) considerations. A four-step approach was employed: (1) inclusion/exclusion criteria were applied to identify potential PAH cancer analogs; (2) characteristics for comparison were categorized as epidemiologic, clinical, therapeutic landscape, and HCRU; (3) a targeted literature review extracted data on disease characteristics; (4) a similarity ranking was calculated as the absolute difference between each cancer’s and PAH’s characteristics. Fourteen cancers met the inclusion criteria. Well-differentiated thyroid cancer (WDTC) had the highest number (5) of characteristics closest to PAH. WDTC and medullary thyroid cancer were most similar to PAH in epidemiology; gastrointestinal stromal tumor was most similar in clinical and HCRU characteristics, and anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer and renal cell carcinoma were most similar in therapeutic landscape. Although no single cancer fully mirrors PAH, the identification of multiple analogs underscores PAH’s multidimensional complexity and confirms its overlap with oncological conditions. Cancer analogs could serve as a valuable framework for enhancing recognition of PAH’s clinical, therapeutic, and HRCU implications among healthcare stakeholders. Full article

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

Background and Clinical Significance: Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with a poor prognosis, where median survival typically ranges from 4 to 10 months. Advances in genetic profiling, particularly the identification of BRAF mutations, offer new opportunities for targeted therapy. Case Presentation: This case report details the journey of a woman in her late 50s diagnosed with symptomatic ATC. Initial immunohistochemistry (IHC) testing for BRAF mutations returned negative results, leaving the patient with limited treatment options and prompting her to pursue medical assistance in dying (MAiD). However, next-generation sequencing (NGS) confirmed a ^V600EBRAF mutation, and a basis for targeted therapy. The patient began treatment with dabrafenib-trametinib, followed by pembrolizumab as second-line therapy, ultimately extending her life by nearly seven months. Conclusions: This case underscores the importance of rapid and comprehensive diagnostic approaches, particularly the higher sensitivity of NGS over IHC for detecting BRAF mutations. The complexities of accessing newer therapies in Canada’s single-payer healthcare system are also emphasized. The utilization of newer rapid diagnostic technologies can have a direct impact on directing treatment for ATC and other aggressive malignancies. Full article