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Theo S Plantinga Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands

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Mirela S Petrulea Department of Endocrinology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

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Marije Oosting Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Leo A B Joosten Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Doina Piciu Oncology Institute, Cluj-Napoca, Romania

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Johannes W Smit Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Romana T Netea-Maier Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Carmen E Georgescu Department of Endocrinology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

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The NF-κB inflammatory pathway plays a major role in cancer development and clinical progression. Activation of NF-κB signaling is promoted by NFKB1 and inhibited by NFKBIA. The present study aimed to determine the relevance of NFKB1 rs4648068 and NFKBIA rs2233406 genetic variants for non-medullary thyroid cancer (NMTC) susceptibility, progression and clinical outcome. This case–control and cohort study consists of a Romanian discovery cohort (157 patients and 258 controls) and a Dutch validation cohort (138 patients and 188 controls). In addition, patient cohorts were analyzed further for the association of genetic variants with clinical parameters. Functional studies were performed on human peripheral blood mononuclear cells. No associations were observed between the studied genetic variants and TC susceptibility. Although no statistically significant associations with clinical parameters were observed for NFKB1 rs4648068, the heterozygous genotype of NFKBIA rs2233406 was correlated with decreased radioactive iodide sensitivity requiring higher cumulative dosages to achieve clinical response. These findings were discovered in the Romanian cohort (P < 0.001) and confirmed in the Dutch cohort (P = 0.01). Functional studies revealed that this NFKBIA rs2233406 genotype was associated with elevated TLR4-mediated IL-1β production. In conclusion, genetic variation in NFKBIA, an inhibitor of NF-κB signaling, is associated with clinical response to RAI therapy and with increased production of the pro-inflammatory cytokine IL-1β, providing a potential mechanism for the observed clinical associations. These data suggest that NF-κB signaling is involved in NMTC pathogenesis and that the inflammatory tumor microenvironment could contribute to RAI resistance.

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Meggie M C M Drissen Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

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Janet R Vos Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

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Romana T Netea-Maier Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands

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Martin Gotthardt Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Nicoline Hoogerbrugge Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

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Thyroid cancer surveillance (TCS) with ultrasound (US) is advised for PTEN hamartoma tumour syndrome (PHTS) patients due to increased thyroid cancer (TC) risk. However, data supporting TCS guidelines are scarce. We aimed to assess the detection and yield of annual TCS with US in adult PHTS patients without a TC history and to evaluate the impact of a reduced US interval on the TCS yield. A retrospective cohort study was conducted, including adult PHTS patients and medical record data between 2005 and 2021. The yield from annual TCS was compared with hypothetical biennial and triennial TCS after two initial US with annual interval by counting delayed detection of nodular growth, thyroid adenoma, and TC. During 279 follow-up years, 84 patients (median age 40 years) underwent 349 US. Thyroidectomy was performed in 6/84 (7%) patients, revealing a minimally invasive follicular TC in one patient aged 22 and a thyroid adenoma in two patients aged 21 and 53. Multiple thyroid nodules were diagnosed in 73/84 (87%) patients (median age 36 years). Nodular growth was detected in 9/56 (16%) patients, and its detection would have been delayed in 4–7% US rounds with biennial TCS, and in 2–6% US rounds with triennial TCS. US-based thyroiditis and indeterminate non-malignant lymph nodes were found in 8/74 (11%) and 7/72 (10%) patients, respectively. Following our findings combined with the literature, we propose starting TCS before age 18 and reducing the follow-up frequency after the initial two US from annual to biennial if no suspicious findings are detected.

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Angelique Huijbers Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Theo S Plantinga Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE
Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Leo A B Joosten Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE
Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Katja K H Aben Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE
Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Julius Gudmundsson Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Martin den Heijer Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Lambertus A L M Kiemeney Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE
Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE
Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Mihai G Netea Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE
Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Ad R M M Hermus Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Romana T Netea-Maier Department of Endocrinology, Department of Internal Medicine, Nijmegen Institute of Infection, Department of Epidemiology, Department of Urology, Department of Cancer Registry and Research, deCODE

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Elena Valassi IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona, Spain
Universitat Internacional de Catalunya (UIC), Barcelona, Spain

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Frédéric Castinetti Department of Endocrinology, Aix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Marseille, France

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Amandine Ferriere Department of Endocrinology, Diabetes and Nutrition, University of Bordeaux, Bordeaux, France

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Stylianos Tsagarakis Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece

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Richard A Feelders Erasmus Medical Center, Division of Endocrinology, Department of Internal Medicine, Rotterdam, The Netherlands

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Romana T Netea-Maier Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Michael Droste Praxis für Endokrinologie Dr. med. Michael Droste, Oldenburg, Germany

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Christian J Strasburger Division of Clinical Endocrinology, Department of Medicine CCM, Charité-Universitätsmedizin, Berlin, Germany

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Dominique Maiter Service d’Endocrinologie et Nutrition, Cliniques universitaires Saint Luc, Brussels, Belgium

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Darko Kastelan Department of Endocrinology, University Hospital Zagreb, Zagreb, Croatia

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Philippe Chanson Institut National de la Santé et de la Recherche Médicale, U1185, Le Kremlin, Bicêtre, Paris, France

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Susan M Webb IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona, Spain
Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

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Frank Demtröder Zentrum für Endokrinologie, Diabetologie, Rheumatologie Dr. Demtröder & Kollegen, Dortmund, Germany

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Valdis Pirags Paula Stradiņa klīniskā universitātes slimnīca, Riga, Latvia

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Olivier Chabre Hospitalier Universitaire, Grenoble, France

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Holger Franz Lohmann & Birkner Health Care Consultimg GmbH, Berlin, Germany

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Alicia Santos IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona, Spain
Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

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Martin Reincke Medizinische Klinik UND Poliklinik IV, Campus Innestadt, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany

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Corticotroph tumor progression after bilateral adrenalectomy/Nelson’s syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing’s disease (CD) included in the European Registry on Cushing’s Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2–9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5–6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1–5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

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