Search Results (177)

Background/Objectives: Medullary thyroid carcinoma (MTC) is a rare and aggressive endocrine malignancy frequently associated with RET alterations and dysregulation of RET-associated signaling pathways. In previous studies, first-generation nitro-substituted thieno[3,2-c]quinolines 1 showed promising antiproliferative activity in TT(RET^C634R) cells, while subsequent imidazole-based optimization generated second-generation derivatives 2 with broad-spectrum antiproliferative activity in the NCI-60 human tumor cell line panel. Since thyroid cancer models are not included in the NCI-60 platform, the present study aimed to evaluate the antiproliferative potential of these optimized derivatives in clinically relevant MTC cellular models. Methods: Imidazole-functionalized thieno[3,2-c]quinoline derivatives (2a–j) were evaluated against TT(RET^C634R) and MZ-CRC-1(RET^M918T) cells. The most active compounds were further characterized through induced fit docking (IFD), MM-GBSA calculations, and molecular dynamics (MD) simulations on representative molecular targets. In silico ADME/Toxicity profiling was also performed to assess their developability. Results: Several derivatives exhibited potent activity in both MTC cell models, with multiple compounds achieving submicromolar potency. Compounds 2b and 2g emerged as the most active derivatives in TT(RET^C634R) cells, whereas compounds 2d and 2i displayed the most favorable profile in the aggressive MZ-CRC-1(RET^M918T) model, thereby extending the biological applicability of the scaffold to an additional clinically relevant RET-mutant context. Computational studies supported RET as the most plausible molecular target for all selected lead compounds, while favorable PI3Kα interaction profiles were predicted for selected derivatives, suggesting distinct target engagement profiles within the series. The most promising derivatives also exhibited an overall favorable predicted ADME/Toxicity profile. Conclusions: The present findings support the success of imidazole-based optimization of the thieno[3,2-c]quinoline scaffold and identify thieno[3,2-c]quinolines 2 as promising lead structures for the future development of novel anti-MTC agents. Further biological and mechanistic investigations will be necessary to better clarify the molecular mechanisms underlying their antiproliferative activity and to guide future lead optimization studies. Full article

Background: Several factors have been reported to influence the prognosis of medullary thyroid cancer (MTC). This study aimed to identify prognostic variables associated with progression-free survival (PFS) and overall survival (OS) in a cohort of patients treated at our institution. Patients and Methods: We performed a retrospective analysis of 107 consecutive patients with histologically confirmed MTC who were followed for at least 12 months. Demographic, clinical, and pathological data were retrieved from medical records. The association between baseline variables and survival outcomes was evaluated using univariate Cox proportional hazards regression models. The study was approved by the local ethics committee. Results: The median age at diagnosis was 56 years (range, 10–80 years), and 63% of the patients were female. Germline REarranged during Transfection (RET) mutations were identified in 10% of cases. The median follow-up duration was 100 months (range, 12–464 months). At diagnosis, disease stages were distributed as follows: stage I, 52%; stage II, 12%; stage III, 17%; and stage IV, 19%. Female patients showed significantly longer PFS compared with males (Hazard Ratio (HR) = 0.41, 95% Confidence Interval (CI) (0.21–0.82); p = 0.012). Factors associated with PFS by Cox regression models were post-operative serum calcitonin (CT) values after 1 and 3 months of surgery (HR = 0.08, 95% CI (0.03–0.20); p < 0.001; HR = 0.03, 95% CI (0.01–0.11); p < 0.001, respectively), Tumor, Node, and Metastasis (TNM) stage III–IV (HR = 16.86, 95% CI (5.87–48.44); p < 0.001), presence of lymph nodes metastasis at diagnosis (HR = 9.6, 95% CI (3.59–25.63); p < 0.001), multifocal disease (HR = 2.37, 95% CI (1.07–5.28); p = 0.034) and capsular invasion (HR = 10.72, 95% CI (4.45–25.87); p < 0.001). Factors associated with OS by Cox regression models were age at diagnosis (HR = 1.07, 95% CI (1.01–1.12); p = 0.019) and TNM Classification of Malignant Tumours stage III-IV (HR = 6.69, 95% CI (1.42–31.62); p = 0.016). Although lymph node metastasis and capsular invasion were not significantly associated with overall survival (p = 0.178 and p = 0.094, respectively), both variables showed a trend toward an association with OS. Conclusions: The study confirmed that post-operative serum CT values, male sex, lymph nodes metastasis at diagnosis, TNM stage III and IV and capsular invasion were all associated with a lower PFS. Factors associated with OS were age at diagnosis, presence of lymph nodes metastasis, TNM stage III–IV and capsular invasion. 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

Background: The clinical impact of familial history on the prognosis of non-medullary thyroid cancer (NMTC) remains controversial. This study aimed to investigate whether familial NMTC (fNMTC) is associated with different patterns of response-to-therapy evolution over time compared to sporadic NMTC (sNMTC), using a dynamic risk stratification (DRS) approach. Methods: We analyzed 665 sNMTC cases and 130 fNMTC cases. Response to therapy was assessed at the first follow-up (6–12 months after initial therapy) and at the last outcome. Univariate and multivariate analyses were used to assess the role of family history as a modifier of response reclassification, independently of established prognostic factors. Results: A significant difference in the dynamic pattern of response evolution was observed between fNMTC and sNMTC (p = 0.003), with familial cases showing higher response variability. Among patients with an initial excellent response (n = 558), familial status remained the only independent predictor of losing excellent response (OR 3.3, 95% CI 1.54–7.12; p = 0.002). The worsening in fNMTC was primarily driven by transitions to indeterminate or biochemical incomplete responses (12.3% vs. 4.2%, p = 0.006), while structural progression remained rare and similar between groups (2.5% vs. 1.3%, p = 0.33). Regarding recovery, 50.2% of patients with an initial non-excellent response achieved an excellent response, with no significant difference between familial and sporadic cases (61.2% vs. 47.3%, p = 0.1). An intermediate-to-high ATA risk class was independently associated with a lower probability of achieving an excellent response (OR 0.45, 95% CI 0.25–0.91; p = 0.01). Conclusions: These findings suggest that “Excellent Response” is more fragile in a familial context. Familial NMTC might require prolonged and vigilant biochemical surveillance, even when cases appear to be in full remission. Full article

The proto-oncogene Rearranged During Transfection (RET) encodes a receptor tyrosine kinase that is essential for neural, renal, and thyroid development. Pathogenic RET alterations, including mutations and fusions, drive oncogenesis, most notably medullary and papillary thyroid carcinomas and non-small cell lung cancer, by constitutively activating downstream RAS–MAPK, PI3K–AKT, and JAK–STAT signaling. Early multi-kinase inhibitors such as vandetanib and cabozantinib demonstrated modest efficacy with significant toxicity, whereas the selective RET inhibitors selpercatinib and pralsetinib have achieved improved response rates and tolerability. However, resistance remains a key clinical challenge, arising from secondary RET mutations and bypass signaling via MET or EGFR pathways. Continued investigation into next-generation inhibitors and rational combination therapies aims to overcome resistance and optimize treatment sequencing, advancing precision oncology for RET-altered malignancies. Nonetheless, resistance, driven by secondary mutations and bypass signaling, presents a major therapeutic challenge. Ongoing development of next-generation inhibitors and combination strategies aims to overcome resistance and improve patient outcomes. Full article

Objectives: Medullary thyroid carcinoma (MTC) is a rare but biologically aggressive neuroendocrine tumor for which reliable preoperative prognostic biomarkers are still lacking. This study aimed to evaluate the association between preoperative blood immunological markers and disease recurrence in patients with MTC undergoing curative surgery. Methods: We conducted a retrospective cohort study at a single tertiary academic center including 52 consecutive patients who underwent curative surgery for MTC between January 1999 and December 2023. The study size was determined by including all eligible consecutive patients meeting predefined inclusion/exclusion criteria within the study period. Preoperative inflammatory indices (MLR, NLR, PLR, SII, SIRI) were calculated from standardized complete blood count tests performed within 30 days before surgery. Disease-free survival (DFS) was calculated using the Kaplan–Meier method. Cox proportional hazards regression analysis with a backward stepwise selection based on the Akaike Information Criterion was used to identify independent predictors of recurrence, adjusting for potential confounders. Results: The mean age was 55.0 years (range 31–75), and 73% of patients were female. The ROC-derived cut-off for preCT was 181 pg/mL. Locally advanced disease (T3-T4) was observed in 12% of cases, and cervical node metastases in 27%. With a mean follow-up of 75.48 months, the 3- and 5-year DFS rates were 91% and 86%, respectively. On multivariable Cox regression, a high monocyte-to-lymphocyte ratio (MLR ≥0.37), positive surgical margins, and pathological nodal involvement remained independently associated with worse DFS after confounder adjustment (HR 9.73, 10.78, and 17.71, respectively). Conclusions: Elevated MLR, histological node metastases, and positive surgical margins independently predict recurrence in MTC after curative treatment. Preoperative MLR may represent a simple, inexpensive, and reproducible biomarker to improve preoperative risk stratification and personalize surgical and follow-up strategies: patients with MLR ≥0.37 may benefit from more aggressive management and/or closer follow-up. Full article

Introduction: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has demonstrated unprecedented efficacy in the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, its rapid clinical widespread use has ignited a debate regarding long-term safety, particularly concerning the risk of specific neoplasms and its ability to modulate cardiovascular health, not only as primary prevention but also as a potential agent to mitigate cardiotoxicity. Objectives: This narrative review aims to analyze the most recent evidence from clinical trials and post-marketing surveillance to evaluate the correlation between semaglutide use and the incidence of cancer, as well as the drug’s efficacy in reducing cardiotoxicity induced by anticancer therapies. Results and Discussion: While preclinical rodent models suggested a link to medullary thyroid carcinoma, human epidemiological data remain reassuring, though caution is advised in patients with genetic predisposition. Regarding pancreatic cancer, current meta-analyses do not confirm a significant increase in risk, suggesting that metabolic benefits outweigh potential concerns. Conclusions: Semaglutide is confirmed as a therapeutic tool with a highly favorable benefit–risk profile. While oncological monitoring must continue, the drug’s cardioprotective and anti-inflammatory properties open new frontiers not only in metabolic management but also in safeguarding cardiovascular integrity in complex clinical scenarios. 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

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

Artificial intelligence (AI) and machine learning (ML) are reshaping cancer research and care. In pediatric oncology, early evidence—most robust in imaging—suggests value for diagnosis, risk stratification, and assessment of treatment response. Pediatric endocrine tumors are rare and heterogeneous, including intra- and extra-adrenal paraganglioma (PGL), adrenocortical tumors (ACT), differentiated and medullary thyroid carcinoma (DTC/MTC), and gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Here, we provide a pediatric-first, entity-structured synthesis of AI/ML applications in endocrine tumors, paired with a methods-for-clinicians primer and a pediatric endocrine tumor guardrails checklist mapped to contemporary reporting/evaluation standards. We also outline a realistic EU-anchored roadmap for translation that leverages existing infrastructures (EXPeRT, ERN PaedCan). We find promising—yet preliminary—signals for early non-remission/recurrence modeling in pediatric DTC and interpretable survival prediction in pediatric ACT. For PGL and GEP-NEN, evidence remains adult-led (biochemical ML screening scores; CT/PET radiomics for metastatic risk or peptide receptor radionuclide therapy response) and serves primarily as methodological scaffolding for pediatrics. Cross-cutting insights include the centrality of calibration and validation hierarchy and the current limits of explainability (radiomics texture semantics; saliency ≠ mechanism). Translation is constrained by small datasets, domain shift across age groups and sites, limited external validation, and evolving regulatory expectations. We close with pragmatic, clinically anchored steps—benchmarks, multi-site pediatric validation, genotype-aware evaluation, and equity monitoring—to accelerate safe, equitable adoption in pediatric endocrine oncology. 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/Objective: To comprehensively characterize the genetic landscape of medullary thyroid carcinoma (MTC) in a Romanian cohort. Methods: Germline and somatic RET testing were performed in 164 MTC patients (105 sporadic, 59 hereditary) consecutively enrolled at a single tertiary center (2021–2024) using genomic DNA or DNA extracted from fresh surgical or paraffin-embedded pathology specimens. Results: Hereditary MTC (hMTC) accounted for 59/164 (35.9%) cases. Among hMTC, 58/59 (98.3%) had MEN2 (72.4% classic, 5.2% with cutaneous lichen amyloidosis, 5.2% with Hirschsprung disease, and 17.2% with familial medullary thyroid carcinoma), and 1/59 (1.7%) had MEN3. Codon 634 mutations were the most prevalent (33/59, 55.9%). Extracellular cysteine-rich domain mutations were significantly more prevalent in syndromic cases (p = 0.006), while non-cysteine mutations were predominant in apparently sporadic cases (p = 0.006). In advanced MTC (stage III/IV or metastatic), the somatic M918T mutation was the most common (15/20, 75% cases). Conclusions: Germline RET screening is mandatory for all MTC cases. Somatic testing is critical in advanced disease, where M918T prevails in 75% of cases and guides tyrosine kinase inhibitor therapy. Codon 634 is the most frequent mutation in Romanian MTC, highlighting regional variation warranting population-adjusted screening and earlier prophylactic thyroidectomy. Full article

The thyroid cancer incidence has been continuously rising over the last decades. Recently, intelligent cancer detection software are gaining popularity, due to their high diagnostic accuracy and subsequent direct benefits in avoiding unnecessary surgical interventions. This study introduces a novel hybrid computer-aided diagnosis (CAD) system that combines convolutional neural networks (CNNs) and molecular data analysis to achieve comprehensive and reliable thyroid cancer diagnostics. The system consists of two key modules: The first is a CNN-based model leveraging transfer learning, processes ultrasound images to classify patients as either “healthy” or “with a thyroid nodule.” In cases where a nodule is detected, the second module utilizes molecular data to predict the malignancy risk, providing a probability score for clinical decision support. Different image augmentation techniques (traditional ones as well as novels) were carried out to enhance the robustness of the system. The combination of two independent modules makes it possible to use them decoupled, while used together they provide a powerful, in-depth diagnosis of thyroid cancer. The proposed system demonstrates strong performance: the ultrasound-based CNN module achieves an accuracy of 93.65%, with a sensitivity of 100% and a specificity of 69.23%. For the gene analysis component, the model achieves a training mean squared error (MSE) of 4.24 × 10⁻⁵ and a testing MSE 6.31 × 10⁻³. These results underscore the system’s competitive performance with existing thyroid cancer detection CAD systems in both diagnostic performance and the depth of insights provided, supporting clinicians in making informed, reliable decisions in thyroid cancer management. Full article

Background/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated RET mutation database. Methods: RET mutation database is built through the integration and curation of data from two major RET mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. Results: To date, 78 pathogenic RET mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10–11, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. Conclusions: Aberrant RET activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the RET gene plays a fundamental role in molecular diagnostics and personalized medicine. 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