Abstract Background Studies focusing on mediastinal paragangliomas are limited. In this study, we describe the clinical, pathological, and genetic characteristics of mediastinal paragangliomas. Methods Clinical data from all patients with extrapericardial mediastinal paragangliomas at a single center were retrospectively analyzed. Germline variants were assessed using next-generation sequencing and Sanger sequencing of blood samples. Patients were grouped according to genetic variants and tumor location, and clinical characteristics were compared. Results 22 patients (male:female ratio, 8:14) were included in the study, with a mean age of 41.4 years. Hypertension was present in 16 patients (72.7%), and 13 (59.1%) exhibited typical catecholamine-related symptoms. Tumors were located in the anterior, middle, and posterior mediastinum in 1 (4.5%), 4 (18.2%), and 17 (77.3%) cases, with an average size of 5.3±1.7 cm. Multiple tumors were identified in 6 patients. Catecholamine-producing tumors were observed in 17/21 (81.0%) patients. Surgical resection was performed in 20 (90.9%) patients. No postoperative local recurrences were observed. Metastasis occurred in 2/18 (11.1%) cases. Eleven patients underwent genetic testing; six harbored SDHx mutations. Compared with anterior and middle mediastinal tumors, posterior mediastinal tumors were associated with higher rates of typical symptoms (12/17 vs. 1/5, p = 0.043) and catecholamine-producing function (17/17 vs. 0/4, p < 0.001), as well as higher levels of 24-hour urinary norepinephrine (5.10 × ULN vs. 0.56 × ULN, p = 0.037). Conclusion Mediastinal paragangliomas are rare and are frequently associated with SDHx variants. Posterior mediastinal tumors are predominantly functional and noradrenergic; recognizing these features may facilitate diagnosis.
Abstract Background Multiple endocrine neoplasia (MEN) syndromes involve tumors in multiple endocrine organs. Distinguishing MEN1 from rarer MEN-like syndromes, including MEN4 caused by pathogenic germline CDKN1B variants, can be challenging. Methods We describe four individuals from two families, integrating clinical, biochemical and imaging findings with germline whole-exome sequencing, evolutionary conservation, in silico variant-effect prediction, structural modeling and molecular dynamics. Tumor tissue was unavailable for somatic sequencing or loss-of-heterozygosity analysis. Results Proband 1, initially suspected of MEN1 because of a nonfunctioning pituitary microadenoma, bilateral adrenal hyperplasia and primary hyperparathyroidism, carried a pathogenic germline CDKN1B frameshift variant, p.Lys96GlnfsTer29. Proband 2 carried the CDKN2C p.Leu107Val variant, classified as a variant of uncertain significance, and had hyperthyroidism, primary hyperaldosteronism, nephrolithiasis, primary hyperparathyroidism, a nonfunctioning pituitary microadenoma and a pancreatic mucinous cystic neoplasm. The variants showed distinct predicted mechanisms. The CDKN1B frameshift preserves the kinase-inhibitory domain but removes the C-terminal regulatory region of p27Kip1 and is predicted to trigger nonsense-mediated decay. In contrast, CDKN2C Leu107 is evolutionarily invariant and buried within the hydrophobic core of ankyrin repeat 4; substitution by valine reduced local hydrophobic packing, consistent with partial destabilization rather than protein loss. The two variant-positive sons of Proband 2 were asymptomatic, and no variant-positive individual carried a MEN1 mutation. Conclusions These findings support CDKN1B testing in MEN1-negative patients with MEN features and highlight CDKN2C as a candidate contributor to MEN-like phenotypes. Integrated clinical, genetic, conservation and structural data may support future re-evaluation of p.Leu107Val while preserving its current VUS classification.
BACKGROUND Indeterminate cytology results (Bethesda categories III and IV) from fine-needle aspiration (FNA) create challenges in clinical decision-making. This study evaluated the expression and diagnostic utility of selected long non-coding RNAs (lncRNAs) in cell-free plasma from patients with indeterminate thyroid nodules. DESIGN Prospective, single-center study. METHODS Nine candidate long non-coding RNA were selected from a curated disease database. A total of 126 individuals with solitary thyroid nodules were enrolled. RNA was extracted from plasma, FNA, and tissue samples and expression levels were measured using quantitative real-time PCR. In the discovery cohort, patients with benign and malignant nodules confirmed by histopathology, were used to determine optimal cut-off values through receiver operating characteristic analysis. Spearman correlation analyses were performed to assess concordance between plasma and FNA/tissue expression. In the validation phase, significantly altered markers were applied to indeterminate nodules to assess diagnostic performance. RESULTS In the discovery cohort, PVT1, MALAT1, and BANCR were significantly upregulated in malignant compared with benign nodules (P < 0.0001). Significant positive correlations were observed between plasma and FNA expression for PVT1 (r = 0.7095), MALAT1 (r = 0.5487), and BANCR (r = 0.6792), and between plasma and tissue expression for PVT1 (r = 0.7673), MALAT1 (r = 0.5284), and BANCR (r = 0.6864) (P < 0.0001). In the Bethesda III/IV validation cohort, only PVT1 retained diagnostic utility, with 76% sensitivity, 87.5% specificity, 85% positive predictive value, and 80% negative predictive value, whereas MALAT1 and BANCR did not demonstrate significant diagnostic performance. CONCLUSIONS Circulating PVT1 expression in plasma may serve as a useful non-invasive biomarker for distinguishing benign from malignant indeterminate thyroid nodules.
Abstract To determine whether Yes-associated protein (YAP), a transcriptional coactivator frequently activated in cancer, coordinates lipid and cholesterol metabolism in papillary thyroid cancer (PTC), YAP was overexpressed or silenced in BCPAP and TPC-1 cells, and transcriptomic, biochemical and functional analyses were performed. Glucose deprivation and the AMP-activated protein kinase (AMPK) activator metformin suppressed YAP nuclear localization and lipogenic programs, whereas AMPK inhibition by Compound C or YAP overexpression (OE) restored them. Mechanistically, YAP associated with TEA domain family member 1 (TEAD1), occupied canonical TEAD-binding motifs in the SREBF1 and SREBF2 promoters, and activated their transcription in a TEAD1-dependent manner: TEAD1 knockdown abolished YAP-induced SREBF promoter activity, while eight-group genetic epistasis experiments showed that TEAD1 or SREBP1/2 depletion was required for YAP-driven proliferation, clonogenic growth, neutral-lipid and cholesterol accumulation, and expression of FASN, SCD, HMGCR and HMGCS1. Pharmacological SREBP blockade by fatostatin or AMPK activation by metformin reversed YAP-driven phenotypes in vitro and restrained xenograft growth in vivo, with comparable tumor-weight inhibition between the two treatments and no effect on body weight.Clinically, YAP1 expression correlated with lipogenic genes and with shorter disease-free survival in the TCGA-THCA cohort and with SREBP expression in 200 paired PTC specimens. These findings support a model in which glucose–AMPK signaling gates a YAP–TEAD1–SREBP1/2 axis that promotes lipid and cholesterol metabolism and PTC growth, and suggest metformin and SREBP-targeting strategies as candidate therapeutic approaches.
Abstract This narrative review evaluates the clinical rationale for integrating incretin-based therapies as therapeutic adjuncts for men with advanced prostate cancer undergoing androgen axis suppression. Androgen deprivation therapy combined with potent androgen receptor pathway inhibitors significantly prolongs survival but induces severe, progressive metabolic toxicities, including sarcopenic obesity, profound insulin resistance, dyslipidemia, and heightened cardiovascular mortality. To address this unmet need, this study reviews published preclinical mechanisms, epidemiological data, and emerging clinical datasets examining glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists. The compiled evidence indicates that these agents provide robust metabolic protection by counteracting treatment-induced metabolic syndrome and cardiovascular risk. Furthermore, incretins may exert indirect antitumor effects by attenuating systemic hyperinsulinemia and visceral adiposity-driven chronic inflammation. Direct antitumor activity is also supported by preclinical evidence demonstrating that receptor engagement on malignant cells downregulates oncogenic signaling pathways, which correlates with recent retrospective clinical database trends showing a numerical reduction in metastatic stage migration among men with localized disease. However, dual receptor agonism introduces mechanistic uncertainty due to potential proliferative signaling cascades in neuroendocrine tumor phenotypes. In conclusion, incretin-based therapies offer a highly rational dual-action strategy for metabolic rescue and potential tumor suppression in advanced prostate cancer. Although several early-phase prospective clinical trials are currently underway to evaluate safety and metabolic efficacy, routine clinical implementation cannot be recommended until rigorously designed randomized controlled trials definitively establish long-term safety, optimal patient selection, and durable oncological outcomes.
