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Item does not contain fulltext, The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.

© 2020 © Gland Surgery. All rights reserved. Background: Recent guidelines for the treatment of hypoparathyroidism emphasize the need for long-term disease control, avoiding symptoms and hypocalcaemia. Our aim has been to analyze the prevalence of poor disease control in a national cohort of patients with hypoparathyroidism, as well as to evaluate predictive variables of inadequate disease control. Methods: From a nation-wide observational study including a cohort of 1792 patients undergoing total thyroidectomy, we selected 260 subjects [207 women and 53 men, aged (mean ± SD) 47.2±14.8 years] diagnosed with permanent hypoparathyroidism. In every patient demographic data and details on surgical procedure, histopathology, calcium (Ca) metabolism, and therapy with Ca and calcitriol were retrospectively collected. A patient was considered not adequately controlled (NAC) if presented symptoms of hypocalcemia or biochemical data showing low serum Ca levels or high urinary Ca excretion. Results: Two hundred and twenty-one (85.0%) patients were adequately controlled (AC) and 39 (15.0%) were NAC. Comparison between AC and NAC patients did not show any significant difference in demographic, surgical, and pathological features. Rate of hospitalization during follow-up was significantly higher among NAC patients in comparison with AC patients (35.9% vs. 10.9%, P<0.001). Dose of oral Ca and calcitriol were also significantly higher in NAC subjects. In a subgroup of 129 patients with serum parathyroid hormone (PTH) levels available, we found that NAC patients exhibited significantly lower postoperative PTH concentrations than AC patients [median (interquartile range) 3 (1.9–7.8) vs. 6.9 (3.0–11) pg/mL; P=0.009]. Conclusions: In a nation-wide cohort of 260 subjects with definitive hyp

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.