Analysis of telomere maintenance related genes reveals NOP10 as a new metastatic-risk marker in pheochromocytoma/paraganglioma

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAMOne of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.This work was supported by Project PI17/01796 and PI20/01169 to M.R. [Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofinanciado a través del Fondo Europeo de Desarrollo Regional (FEDER)], Paradifference Foundation [no grant number applicable to M.R.] and Pheipas Association [no grant number applicable to M.R.]. Research in the M.A.B. lab was funded by the Spanish State Research Agency (AEI), Ministry of Science and Innovation, cofounded by the European Regional Development Fund (ERDF) (SAF2017-82623-R and SAF2015-72455-EXP), the Comunidad de Madrid Project (S2017/BMD-3770), the World Cancer Research (WCR) Project (16-1177), the European Research Council (ERC-AvG Shelterines GA882385) and the Fundación Botín (Spain). International collaborators research has been supported by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease” to F.B., S.N., M.F.-C., N.B. and G.E. and by the Immuno-TargET project under the umbrella of the University Medicine Zurich to F.B. and S.N. M.M. was supported by the Spanish Ministry of Science, Innovation and Universities “Formación del Profesorado Universitario—FPU” fellowship with ID number FPU18/00064. L.J.L.-G. was supported both by the Banco Santander Foundation and La Caixa Postdoctoral Junior Leader Fellowship (LCF/BQ/PI20/11760011). C.M.-C. was supported by a grant from the AECC Foundation (AIO15152858 MONT). A.M.M.-M. was supported by CAM (S2017/BMD-3724; TIRONET2-CM). B.C. was supported by the Rafael del Pino Foundation (Becas de Excelencia Rafael del Pino 2017) and currently by the ISCIII project PI17/01796. A.D.-T. is supported by the Centro de Investigacion Biomédica en Red de Enfermedades Raras (CIBERER). We thank the Spanish National Tumor Bank Network (RD09/0076/00047) for the support in obtaining tumor samples and all patients, physicians and tumor biobanks involved in the stud

Predictive model of pheochromocytoma based on the imaging features of the adrenal tumours

The purpose of our study was to develop a predictive model to rule out pheochromocytoma among adrenal tumours, based on unenhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) features. We performed a retrospective multicentre study of 1131 patients presenting with adrenal lesions including 163 subjects with histological confirmation of pheochromocytoma (PHEO), and 968 patients showing no clinical suspicion of pheochromocytoma in whom plasma and/or urinary metanephrines and/or catecholamines were within reference ranges (non-PHEO). We found that tumour size was significantly larger in PHEO than non-PHEO lesions (44.3 ± 33.2 versus 20.6 ± 9.2 mm respectively; P < 0.001). Mean unenhanced CT attenuation was higher in PHEO (52.4 ± 43.1 versus 4.7 ± 17.9HU; P < 0.001). High lipid content in CT was more frequent among non-PHEO (83.6% versus 3.8% respectively; P < 0.001); and this feature alone had 83.6% sensitivity and 96.2% specificity to rule out pheochromocytoma with an area under the receiver operating characteristics curve (AUC-ROC) of 0.899. The combination of high lipid content and tumour size improved the diagnostic accuracy (AUC-ROC 0.961, sensitivity 88.1% and specificity 92.3%). The probability of having a pheochromocytoma was 0.1% for adrenal lesions smaller than 20 mm showing high lipid content in CT. Ninety percent of non-PHEO presented loss of signal in the “out of phase” MRI sequence compared to 39.0% of PHEO (P < 0.001), but the specificity of this feature for the diagnosis of non-PHEO lesions low. In conclusion, our study suggests that sparing biochemical screening for pheochromocytoma might be reasonable in patients with adrenal lesions smaller than 20 mm showing high lipid content in the CT scan, if there are no typical signs and symptoms of pheochromocytom

MEN1-associated primary hyperparathyroidism in the Spanish Registry: Clinical characterictics and surgical outcomes

Primary hyperparathyroidism is the most frequent manifestation of multiple endocrine neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). Eighty-nine patients (49 men and 40 women, 34.2 ± 13 years old) were included. Sixtyfour out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs 7/12, P < 0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypopar athyroidism and patients with different mutated exons, but a second surgery was more freq uent after a less than subtotal parathyroidectomyThe Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytmas and Paragangliomas is supported by IPSEN Pharmaceutical

MEN1-associated primary hyperparathyroidism in the Spanish Registry: clinical characterictics and surgical outcomes

Primary hyperparathyroidism is the most frequent manifestation of multiple endocrine neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). Eighty-nine patients (49 men and 40 women, 34.2 ± 13 years old) were included. Sixty-four out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs 7/12, P < 0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypoparathyroidism and patients with different mutated exons, but a second surgery was more frequent after a less than subtotal parathyroidectom

Diagnosis, treatment and follow-up of patients with acromegaly in a clinical practice setting in Spain: the ACROPRAXIS program Delphi survey

The ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance. Methods: Ninety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus &gt; 66.6% of response in the same tertile). Results: Ninety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. Diagnosis: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1–1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. Treatment: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1–3 months after surgery. Disease remission is considered if random GH levels are &lt; 1 µg/L or OGTT is &lt; 1 or ≤ 0.4 µg/L, depending on the assay’s sensitivity. Conclusion: Current clinical management for acromegaly is homogeneous across Spain and generally follows clinical guideline

Pasireotide in the Personalized Treatment of Acromegaly

The delay in controlling the disease in patients who do not respond to first-line treatment with first generation somatostatin receptor ligands (first-generation SRLs) can be quantified in years, as every modification in the medical therapy requires some months to be fully evaluated. Considering this, acromegaly treatment should benefit from personalized medicine therapeutic approach by using biomarkers identifying drug response. Pasireotide has been positioned mostly as a compound to be used in first-generation SRLs resistant patients and after surgical failure, but sufficient data are now available to indicate it is a first line therapy for patients with certain characteristics. Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI signal is shown and in those depicting low SST2 and high expression of SST5, low or mutated AIP condition and sparsely granulated immunohistochemical pattern. This combination of clinical and pathological characteristics is unique for certain patients and seems to cluster in the same cases, strongly suggesting an etiopathogenic link. Thus, in this paper we propose to include this clinico-pathologic phenotype in the therapeutic algorithm, which would allow us to use as first line medical treatment those compounds with the highest potential for achieving the fastest control of GH hypersecretion as well as a positive effect upon tumor shrinkage, therefore accelerating the implementation of precision medicine for acromegaly. Moreover, we suggest the development, validation and clinical use of a pasireotide acute test, able to identify patients responsive to pasireotide LAR as the acute octreotide test is able to do for SRLs

Effectiveness of lanreotide autogel 120 mg at extended dosing intervals for acromegaly

Purpose: Recent data indicate that extended dosing intervals (EDIs) with lanreotide autogel 120 mg are effective and well-received among patients with acromegaly who have achieved biochemical control with monthly injections of long-acting somatostatin analogues (SSAs). We further evaluated the effectiveness of lanreotide autogel 120 mg delivered at EDIs (&gt;4 weeks) in routine clinical practice. Methods: Cross-sectional, multicentre, observational study conducted to determine the effectiveness—measured by control of serum insulin-like growth factor 1 (IGF-1)—of lanreotide autogel 120 mg at dosing intervals &gt;4 weeks for ≥6 months in selected patients with acromegaly treated in routine clinical practice (NCT02807233). Secondary assessments included control of growth hormone (GH) levels, treatment adherence, patient satisfaction, and quality of life (QoL) using validated questionnaires (EQ-5D, AcroQoL, and TSQM-9). Patients who received radiotherapy within the last 6 months were excluded. Results: Among 109 patients evaluated, mean (SD) age was 59.1 (13.2) years. IGF-1 values were normal (mean [SD]: 175.0 [74.5], 95% CI: 160.8 –189.1) in 91.7% of cases and normal in 91.4% of patients without previous radiotherapy treatment (n = 81). GH levels were ≤2.5 and ≤1 ng/mL, respectively, in 80.6% and 58.3%. Most patients were treated either every 5–6 (57.8%) or 7–8 weeks (38.5%), with 2.8% treated greater than every 8 weeks. The mean AcroQoL score was 63.0 (20.1). The mean global treatment satisfaction score (TSQM-9) was 75.1 (16.6). Treatment adherence (defined as no missed injections) was 94.5%. Conclusion: Lanreotide autogel 120 mg at intervals of &gt;4 weeks provided IGF-1 control in more than 90% of patients with acromegaly. Treatment satisfaction and adherence were good. These findings support use of extended dosing intervals in patients who have achieved good biochemical control with long-acting SSAs

Data mining analyses for precision medicine in acromegaly: a proof of concept

Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients

Observational, multicentre study to evaluate the effectiveness in routine clinical practice of Lanreotide Autogel 120 mg at extended dosing intervals (>4 weeks) for the treatment of acromegaly: SOMACROL study

Guided posterThis is not the definitive version of record of this article. This manuscript has been accepted for publication in Endocrine Abstracts, but the version presneted here has not yet been copy-edited, formatted or proofed. Consequently, Bioscientifca accepts no responsability for any errors or omissions it may contain. The definitive version in now freely avaliable at Bioscientifica web page

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma

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 models, and define specific therapeutic options according to tumor genomic features. : 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 . : 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, =4.67·10), and was found associated 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 a repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. : 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