There is strong association between inflammatory processes and their main metabolic mediators, such as leptin, adiponectin secretion, and low/high-density lipoproteins, with the cancer risk and aggressive behavior of solid tumors. In this scenario, cancer cells (CCs) and cancer stem cells (CSCs) have important roles. These cellular populations, which come from differentiated cells and progenitor stem cells, have increased metabolic requirements when it comes to maintaining or expanding the tumors, and they serve as links to some inflammatory mediators. Although the molecular mechanisms that are involved in these associations remain unclear, the two following cellular pathways have been suggested: 1) the mesenchymal-epithelial transition (MET) process, which permits the differentiation of adult stem cells throughout the acquisition of cell polarity and the adhesion to epithelia, as well to new cellular lineages (CSCs); and, 2) a reverse process, termed the epithelial-mesenchymal transition (EMT), where, in pathophysiological conditions (tissue injury, inflammatory process, and oxidative stress), the differentiated cells can acquire a multipotent stem cell-like phenotype. The molecular mechanisms that regulate both EMT and MET are complex and poorly understood. Especially, in the thyroid gland, little is known regarding MET/EMT and the role of CCs or CSCs, providing an exciting, new area of knowledge to be investigated. This article reviews the progress to date in research on the role of inflammatory mediators and metabolic reprogramming during the carcinogenesis process of the thyroid gland and the EMT pathways.

Background: Lenvatinib, a tyrosine kinase inhibitor (TKI) approved for the treatment of progressive and radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), is associated with significant adverse effects that can be partially mitigated through the development of novel drug formulations. The utilization of nanoparticles presents a viable option, as it allows for targeted drug delivery, reducing certain side effects and enhancing the overall quality of life for patients. This study aimed to produce and assess, both in vitro and in vivo, the cytotoxicity, biodistribution, and therapeutic efficacy of lenvatinib-loaded PLGA nanoparticles (NPs), both with and without decoration using antibody conjugation (cetuximab), as a novel therapeutic approach for managing aggressive thyroid tumors. Methods: Poly(lactic-co-glycolic acid) nanoparticles (NPs), decorated with or without anti-EGFR, were employed as a lenvatinib delivery system. These NPs were characterized for size distribution, surface morphology, surface charge, and drug encapsulation efficiency. Cytotoxicity was evaluated through MTT assays using two cellular models, one representing normal thyroid cells (Nthy-ori 3-1) and the other representing anaplastic thyroid cells (CAL-62). Additionally, an in vivo xenograft mouse model was established to investigate biodistribution and therapeutic efficacy following intragastric administration. Results: The NPs demonstrated success in terms of particle size, polydispersity index (PDI), zeta potential, morphology, encapsulation efficiency, and cetuximab distribution across the surface. In vitro analysis revealed cytotoxicity in both cellular models with both formulations, but only the decorated NPs achieved an ID50 value in CAL-62 cells. Biodistribution analysis following intragastric administration in xenografted thyroid mice demonstrated good stability in terms of intestinal barrier function and tumor accumulation. Both formulations were generally well tolerated without inducing pathological effects in the examined organs. Importantly, both formulations increased tumor necrosis; however, decorated NPs exhibited enhanced parameters related to apoptotic/karyolytic forms, mitotic index, and vascularization compared with NPs without decoration. Conclusions: These proof-of-concept findings suggest a promising strategy for administering TKIs in a more targeted and effective manner.

We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.

Summary: Objective: Ultrasonography and cytology obtained by fine‐needle aspiration are part of the basic study of the thyroid nodule. Although they are not diagnostic in every case, they are cost‐effective methods that inform surgical treatment and its extent. The purpose of this study was to evaluate the accuracy of ultrasonography associated with fine‐needle aspiration to predict malignancy in nodular thyroid pathology.Design and patients: We collected prospective data from patients undergoing thyroidectomy by single nodule or multinodular goitre between 2006 and 2016. A total of 417 patients were included. Ultrasounds were classified as suspected of malignancy if they had 2 or more of the following characteristics: hypoechogenicity, microcalcifications, intranodular central hypervascularization, irregular margins and poorly defined edges.Measurements: Ultrasound and fine‐needle aspiration accuracy.Results: In the postoperative study, 40% presented malignant pathology. 33% of patients with nonsuspicious ultrasound and 73% of those with suspicious ultrasound had malignant disease. Among patients with single nodule and suspicious ultrasound, the malignancy rate reached 80%. As for cytology, 100% of BethesdaVIpatients, 88% of V, 63% ofIV, 31% ofIIIand 12% ofIIwere found to have carcinoma. The combination of the 2 tests showed a high predictive value, particularly in cases of BethesdaIVcytology.Conclusions: Thyroid cytology provides high predictive value of the presence of carcinoma. The predictive value of ultrasound is also high, mainly in the study of isolated nodules. The combination of the 2 tests results in increased diagnostic accuracy.

The deregulation of microRNAs (miRNAs) is associated with the various steps of the metastatic process. In addition, circulating miRNAs are remarkably stable in peripheral blood, making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to determine whether tumor-tissue-derived miRNAs are traceable to plasma in ER-positive early breast cancer patients. We performed RNA-sequencing on 30 patients for whom plasma, sentinel lymph nodes (SLNs) and tumor tissue were available. We carried out differential expression, gene ontology and enrichment analyses. Our results show that circulating miRNAs are inversely expressed compared with tumor tissue or SLNs obtained from the same patients. Our differential expression analysis shows the overall downregulation of circulating miRNAs. However, the expression of miR-643a-3p and miR-223 was up-regulated in patients with positive SLNs. Furthermore, gene ontology analysis showed the significant enrichment of biological processes associated with the regulation of epithelial cell proliferation and transcriptional regulation commonly involved in the promotion of metastases. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further preclinical and clinical studies are required to understand the biological significance of the most significant miRNAs and to validate our results in a larger cohort of patients.

The most frequent cause of suboptimal results in a parathyroid adenoma resection is an ectopic location, mainly in the anterior mediastinum. These cases may not always be resected through a traditional cervical access. We present 2 cases of primary hyperparathyroidism who underwent an unsuccessful bilateral cervical exploration due to parathyroid tissue located inside the thymic gland. A video-assisted thoracoscopic surgery thymectomy with intraoperative determination of blood parathormone levels was performed. A 50% reduction of intraoperatory parathyroid hormone blood from the highest basal level at 5 and 10 min after resection was obtained. Final pathological results showed an intra-thymic parathyroid adenoma in the first patient and an intra-thymic focus of parathyroid hyperplasia in the second patient. In conclusion, video-assisted thoracoscopic surgery thymectomy could be the optimal approach to resect ectopic parathyroid adenomas located in the anterior mediastinum.