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Marie-Lise Jaffrain-Rea Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Mariolina Angelini Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Donatella Gargano Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Maria A Tichomirowa Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Adrian F Daly Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Jean-François Vanbellinghen Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Emanuela D'Innocenzo Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Anne Barlier Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Felice Giangaspero Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Vincenzo Esposito Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Luca Ventura Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Antonietta Arcella Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Marily Theodoropoulou Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Luciana A Naves Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Carmen Fajardo Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Sabina Zacharieva Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Vincent Rohmer Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Thierry Brue Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Alberto Gulino Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Giampaolo Cantore Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Edoardo Alesse Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Albert Beckers Department of Experimental Medicine, Neuromed Institute, Fondazione ‘Carlo Ferri’ per la prevenzione e la cura dei tumori, Departments of Endocrinology, Molecular Genetics, Department of Endocrinology, Department of Experimental Medicine and Pathology, Pathology, Max Planck Institute of Psychiatry, Endocrinology Unit, Department of Endocrinology, Department of Endocrinology, Endocrinology, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Germline mutations of the aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated PA. To provide further insights into the possible role of AIP in pituitary tumour pathogenesis, the expression of AIP and AHR was determined by real-time RT-PCR and/or immunohistochemistry (IHC) in a large series of PA (n=103), including 17 with AIP mutations (AIP mut). Variable levels of AIP and AHR transcripts were detected in all PA, with a low AHR expression (P<0.0001 versus AIP). Cytoplasmic AIP and AHR were detected by IHC in 84.0 and 38.6% of PA respectively, and significantly correlated with each other (P=0.006). Nuclear AHR was detected in a minority of PA (19.7%). The highest AIP expression was observed in somatotrophinomas and non-secreting (NS) PA, and multivariate analysis in somatotrophinomas showed a significantly lower AIP immunostaining in invasive versus non-invasive cases (P=0.019). AIP expression was commonly low in other secreting PA. AIP immunostaining was abolished in a minority of AIP mut PA, with a frequent loss of cytoplasmic AHR and no evidence of nuclear AHR. In contrast, AIP overexpression in a subset of NS PA could be accompanied by nuclear AHR immunopositivity. We conclude that down-regulation of AIP and AHR may be involved in the aggressiveness of somatotrophinomas. Overall, IHC is a poorly sensitive tool for the screening of AIP mutations. Data obtained on AHR expression suggest that AHR signalling may be differentially affected according to PA phenotype.

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Patrick Petrossians Department of Endocrinology CHU de Liège, University of Liège, Belgium

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Adrian F Daly Department of Endocrinology CHU de Liège, University of Liège, Belgium

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Emil Natchev Clinical Centre of Endocrinology and Gerontology Medical University, Sofia, Bulgaria

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Luigi Maione APHP Endocrinology and Reproductive Diseases Paris Sud University, Le Kremlin-Bicêtre, France

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Karin Blijdorp Section of Endocrinology Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

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Mona Sahnoun-Fathallah Department of Endocrinology Centre de Référence des Maladies Rares d’Origine Hypophysaire, Hôpital de la Timone, Marseille, France

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Renata Auriemma Dipartimento Di Medicina Clinica e Chirurgia Sezione di Endocrinologia, University “Federico II”, Naples, Italy

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Alpha M Diallo Department of Endocrinology CHU de Reims, France

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Anna-Lena Hulting Department of Molecular Medicine and Surgery Karolinska University Hospital, Stockholm, Sweden

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Diego Ferone Department of Internal Medicine University of Genoa, Genova, Italy

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Vaclav Hana Jr Third Department of Internal Medicine 1st Faculty of Medicine, Charles University, Prague, Czech Republic

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Silvia Filipponi Department of Biotechnological and Applied Clinical Sciences University of L’Aquila, L’Aquila, Italy and Neuromed, IRCCS, Pozzilli, Italy

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Caroline Sievers Department of Internal Medicine Endocrinology and Clinical Chemistry, Max Planck Institute of Psychiatry, Munich, Germany

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Claudia Nogueira Department of Internal Medicine Endocrinology, Diabetes and Metabolism Unit, Centro Hospitalar de Trás-os-Montes e Alto Douro, Portugal

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Carmen Fajardo-Montañana Department of Endocrinology Hospital Universitario de la Ribera, Alzira, Spain

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Davide Carvalho Department of Endocrinology Diabetes and Metabolism, Centro Hospitalar S. João, Faculty of Medicine, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal

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Vaclav Hana Third Department of Internal Medicine 1st Faculty of Medicine, Charles University, Prague, Czech Republic

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Günter K Stalla Department of Internal Medicine Endocrinology and Clinical Chemistry, Max Planck Institute of Psychiatry, Munich, Germany

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Marie-Lise Jaffrain-Réa Department of Biotechnological and Applied Clinical Sciences University of L’Aquila, L’Aquila, Italy and Neuromed, IRCCS, Pozzilli, Italy

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Brigitte Delemer Department of Endocrinology CHU de Reims, France

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Annamaria Colao Dipartimento Di Medicina Clinica e Chirurgia Sezione di Endocrinologia, University “Federico II”, Naples, Italy

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Thierry Brue Department of Endocrinology Centre de Référence des Maladies Rares d’Origine Hypophysaire, Hôpital de la Timone, Marseille, France

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Sebastian J C M M Neggers Section of Endocrinology Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

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Sabina Zacharieva Clinical Centre of Endocrinology and Gerontology Medical University, Sofia, Bulgaria

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Philippe Chanson APHP Endocrinology and Reproductive Diseases Paris Sud University, Le Kremlin-Bicêtre, France

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Albert Beckers Department of Endocrinology CHU de Liège, University of Liège, Belgium

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Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P < 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P < 0.001). Tumors were larger in males than females (P < 0.001); tumor size and invasion were inversely related to patient age (P < 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (P < 0.001). GH was inversely related to age in both sexes (P < 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6–4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.

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Manel Puig-Domingo Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, Badalona, Spain
Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain
Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain

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Joan Gil Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain

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Miguel Sampedro-Nuñez Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
Department of Endocrinology, Hospital de la Princesa, Universidad Autónoma de Madrid, Instituto Princesa, Madrid, Spain

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Mireia Jordà Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain

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Susan M Webb Department of Endocrinology/Medicine, CIBERER U747, ISCIII, Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-SPau, Universitat Autònoma de Barcelona, Barcelona, Spain

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Guillermo Serra Department of Endocrinology, Son Espases University Hospital, Palma de Mallorca, Balearic Islands, Spain

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Laura Pons Department of Pathology, Germans Trias i Pujol University Hospital, Badalona, Spain

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Isabel Salinas Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, Badalona, Spain

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Alberto Blanco Department of Neurosurgery, Germans Trias i Pujol University Hospital, Badalona, Spain

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Montserrat Marques-Pamies Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, Badalona, Spain

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Elena Valassi Department of Endocrinology/Medicine, CIBERER U747, ISCIII, Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-SPau, Universitat Autònoma de Barcelona, Barcelona, Spain

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Antonio Picó Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
Hospital General Universitario de Alicante-Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
Department of Clinical Medicine, Miguel Hernández University, Elche, Spain

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Araceli García-Martínez Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
Hospital General Universitario de Alicante-Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain

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Cristina Carrato Department of Pathology, Germans Trias i Pujol University Hospital, Badalona, Spain

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Raquel Buj Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA

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Carlos del Pozo Department of Endocrinology, Hospital Universitari Mutua Terrassa, Terrassa, Spain

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Gabriel Obiols Department of Endocrinology, Hospital General Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

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Carles Villabona Department of Endocrinology, Hospital Universitari de Bellvitge, Barcelona, Spain

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Rosa Cámara Endocrinology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain

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Carmen Fajardo-Montañana Endocrinology Department, Hospital Universitario de La Ribera, Alzira, Spain

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Clara V Alvarez Neoplasia & Endocrine Differentiation P0L5, Centro de Investigacion en Medicina Molecular y Enfermedades Cronicas (CIMUS), Instituto de Investigacion Sanitaria de Santiago (IDIS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain

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Ignacio Bernabéu Endocrinology Division, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain

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Mónica Marazuela Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
Department of Endocrinology, Hospital de la Princesa, Universidad Autónoma de Madrid, Instituto Princesa, Madrid, Spain

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Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.

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Maria A Tichomirowa Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Misu Lee Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Anne Barlier Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium
Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Adrian F Daly Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Ilaria Marinoni Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Marie-Lise Jaffrain-Rea Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium
Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Luciana A Naves Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Patrice Rodien Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Vincent Rohmer Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Fabio Rueda Faucz Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Philippe Caron Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Bruno Estour Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Pierre Lecomte Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Françoise Borson-Chazot Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Alfred Penfornis Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Maria Yaneva Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Mirtha Guitelman Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Emily Castermans Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Catherine Verhaege Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Jean-Louis Wémeau Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Antoine Tabarin Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Carmen Fajardo Montañana Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Brigitte Delemer Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Veronique Kerlan Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Jean-Louis Sadoul Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Christine Cortet Rudelli Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Françoise Archambeaud Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Sabine Zacharieva Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Marily Theodoropoulou Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Thierry Brue Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Alain Enjalbert Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium
Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Vincent Bours Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Natalia S Pellegata Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Albert Beckers Departments of, Endocrinology, Molecular Genetics, Institute of Pathology, Laboratory of Biochemistry and Molecular Biology, CRN2M, Department of Experimental Medicine, Neuromed, Division of Endocrinology, Department of Endocrinology, Group for Advanced Molecular Investigation, Service d'Endocrinologie, Department of Endocrinology, Unit of Endocrinology, Department of Endocrinology, Department of Endocrinology, Clinical Center of Endocrinology and Gerontology, Faculty of Medicine, Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Endocrinology, Department of Internal Medicine and Endocrinology, Department of Endocrinology, Service d'Endocrinologie, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart‐Tilman, University of Liège, 4000 Liège, Belgium

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Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15–25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27I119T shows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

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Marta Araujo-Castro Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain & Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain

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Betina Biagetti Department of Endocrinology and Nutrition, Hospital Universitario Vall de Hebrón, CIBERER U747 (ISCIII), ENDO-ERN, Barcelona, Spain

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Edelmiro Menéndez Torre Department of Endocrinology and Nutrition, Hospital Universitario Central de Asturias & Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain

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Iría Novoa-Testa Department of Endocrinology and Nutrition, Hospital Universitario de A Coruña, A Coruña, Spain

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Fernando Cordido Department of Endocrinology and Nutrition, Hospital Universitario de A Coruña, A Coruña, Spain

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Eider Pascual-Corrales Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain & Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain

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Víctor Rodríguez Berrocal Department of Neurosurgery, Hospital Universitario Ramón y Cajal, Madrid, Spain

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Fernando Guerrero-Pérez Department of Endocrinology and Nutrition, Hospital Universitario de Bellvitge, Cataluña L’Hospitalet de Llobregat, Spain

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Almudena Vicente Department of Endocrinology and Nutrition, Hospital Universitario de Toledo, Toledo, Spain

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Juan Carlos Percovich Hualpa Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, Madrid, Spain

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Rogelio García-Centeno Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, Madrid, Spain

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Laura González-Fernández Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, Madrid, Spain

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María Dolores Ollero García Department of Endocrinology and Nutrition, Hospital Universitario Navarra, Pamplona, Spain

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Ana Irigaray Echarri Department of Endocrinology and Nutrition, Hospital Universitario Navarra, Pamplona, Spain

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María Dolores Moure Rodríguez Department Endocrinology and Nutrition, Hospital Universitario de Cruces, Bilbao, Spain

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Cristina Novo-Rodríguez Department of Endocrinology and Nutrition, Hospital Universitario Virgen de las Nieves, Granada, Spain

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María Calatayud Department of Endocrinology and Nutrition, Hospital Universitario Doce de Octubre, Madrid, Spain

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Rocío Villar-Taibo Department of Endocrinology and Nutrition, Hospital Universitario de Santiago de Compostela, Madrid, Spain

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Ignacio Bernabéu Department of Endocrinology and Nutrition, Hospital Universitario de Santiago de Compostela, Madrid, Spain

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Cristina Alvarez-Escola Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid, Spain

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Pamela Benítez Valderrama Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid, Spain

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Carmen Tenorio-Jiménez Department of Endocrinology and Nutrition, Hospital Universitario Virgen de las Nieves, Granada, Spain

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Pablo Abellán Galiana Department of Endocrinology and Nutrition, Hospital General Universitario de Castellón, Castellón, Spain
Department of Medicine and Surgery, Universidad Cardenal Herrera-CEU, CEU Universities, Castellón, Spain

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Eva Venegas Department of Endocrinology and Nutrition, Hospital Universitario Virgen del Rocío, Sevilla, Spain

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Inmaculada González-Molero Endocrinology and Nutrition Department, Hospital Regional Universitario de Málaga, IBIMA Plataforma Bionand, Málaga, Spain

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Pedro Iglesias Department of Endocrinology and Nutrition, Hospital Universitario Puerta de Hierro, Madrid, Spain

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Concepción Blanco-Carrera Department of Endocrinology and Nutrition, Hospital Universitario Príncipe de Asturias, Madrid, Spain

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Fernando Vidal-Ostos De Lara Department of Endocrinology and Nutrition, Hospital Universitario Príncipe de Asturias, Madrid, Spain

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Paz de Miguel Novoa Department of Endocrinology and Nutrition, Hospital Clínico San Carlos, Madrid, Spain

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Elena López Mezquita Department of Endocrinology and Nutrition, Hospital Universitario Clínico San Cecilio, Granada, Spain

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Felicia Alexandra Hanzu Department of Endocrinology and Nutrition, Hospital Clinic de Barcelona, Barcelona, Spain

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Iban Aldecoa Biomedical Diagnostic Center, Department of Pathology, Hospital Clinic - University of Barcelona, Barcelona, Spain
Neurological Tissue Bank of the Biobank, FCRB-IDIBAPS-Hospital Clinic Barcelona, Barcelona, Spain

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Silvia Aznar Department of Endocrinology and Nutrition, Hospital Universitario De Albacete, Albacete, Spain

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Cristina Lamas Department of Endocrinology and Nutrition, Hospital Universitario De Albacete, Albacete, Spain

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Anna Aulinas Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, IR-SANT PAU, CIBERER U747 (ISCIII), Barcelona, Spain
Department of Medicine, Universitat de Vic-Universitat Central de Catalunya, Vic, Spain

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Queralt Asla Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, IR-SANT PAU, CIBERER U747 (ISCIII), Barcelona, Spain
Department of Medicine, Universitat de Vic-Universitat Central de Catalunya, Vic, Spain

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Paola Gracia Gimeno Department of Endocrinology and Nutrition, Hospital Royo Villanova, Zaragoza, Spain

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José María Recio-Córdova Department of Endocrinology and Nutrition, Hospital Royo Villanova, Zaragoza, Spain

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María Dolores Avilés-Pérez Department of Endocrinology and Nutrition, Hospital Universitario Clínico San Cecilio, Granada, Spain

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Diego Asensio-Wandosell Department of Endocrinology and Nutrition, Hospital Universitario Germans Trias i Pujol, Cataluña, Spain

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Miguel Sampedro-Núñez Department of Endocrinology and Nutrition, Hospital Universitario La Princesa Madrid, Spain

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Rosa Cámara Department of Endocrinology and Nutrition, Hospital Universitario y Politécnico La Fe, Valencia, Spain

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Miguel Paja Fano Department of Endocrinology and Nutrition, OSI Bilbao-Basurto, Hospital Universitario de Basurto & University of the Basque Country UPV/EHU, Bilbao, Spain

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Ignacio Ruz-Caracuel Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS & CIBER Cáncer (CIBERONC), Madrid, Spain

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Carmen Fajardo Department of Endocrinology and Nutrition, Hospital Universitario La Ribera, Valencia, Spain

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Mónica Marazuela Department of Endocrinology and Nutrition, Hospital Universitario La Princesa Madrid, Spain

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Manel Puig-Domingo Department of Endocrinology and Nutrition, Hospital Universitario Germans Trias i Pujol, Cataluña, Spain

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The objective of the study was to evaluate the efficacy of second-line therapies in patients with acromegaly caused by a growth hormone (GH) and prolactin (PRL) co-secreting pituitary neuroendocrine tumor (GH&PRL-Pit-NET) compared to their efficacy in patients with acromegaly caused by a GH-secreting pituitary neuroendocrine tumor (GH-Pit-NET). This is a multicenter retrospective study of patients with acromegaly on treatment with pasireotide and/or pegvisomant. Patients were classified in two groups: GH&PRL-Pit-NETs when evidence of hyperprolactinemia and immunohistochemistry (IHC) for GH and PRL was positive or if PRL were >200 ng/dL regardless of the PRL-IHC and GH-Pit-NETs when the previously mentioned criteria were not met. A total of 28 cases with GH&PRL-Pit-NETs and 122 with GH-Pit-NETs met the inclusion criteria. GH&PRL-Pit-NETs presented at a younger age, caused hypopituitarism, and were invasive more frequently than GH-Pit-NETs. There were 124 patients treated with pegvisomant and 49 with pasireotide at any time. The efficacy of pegvisomant for IGF-1 normalization was of 81.5% and of pasireotide of 71.4%. No differences in IGF-1 control with pasireotide and with pegvisomant were observed between GH&PRL-Pit-NETs and GH-Pit-NETs. All GH&PRL-Pit-NET cases treated with pasireotide (n = 6) and 82.6% (n = 19/23) of the cases treated with pegvisomant normalized PRL levels. No differences in the rate of IGF-1 control between pegvisomant and pasireotide were detected in patients with GH&PRL-Pit-NETs (84.9% vs 66.7%, P = 0.178). We conclude that despite the more aggressive behavior of GH&PRL-Pit-NETs than GH-Pit-NETs, no differences in the rate of IGF-1 control with pegvisomant and pasireotide were observed between both groups, and both drugs have shown to be effective treatments to control IGF-1 and PRL hypersecretion in these tumors.

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