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Laura Moonen Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands

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Jules L Derks Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands

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Lisa M Hillen Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands

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Robert Jan van Suylen Pathology-DNA, Jeroen Bosch Hospital, s’Hertogenbosch, The Netherlands

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Michael A den Bakker Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

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Jan H von der Thüsen Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands

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Ronald A Damhuis Department of Research, Comprehensive Cancer Association, Utrecht, The Netherlands

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Wieneke A Buikhuisen Department of Thoracic Oncology, Netherlands Cancer Institute Amsterdam, The Netherlands

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Esther C van den Broek PALGA (Dutch Nationwide Pathology Databank), Houten, The Netherlands

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Jos Maessen Department of Cardiothoracic Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands

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Alexander P W M Maat Department of Cardiothoracic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

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Paul van Schil Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Antwerp, Belgium

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Ernst J M Speel Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands

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A-M C Dingemans Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands

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The predictive value of the extent of peri-operative lymph node (LN) sampling in relation to disease relapse in patients with pulmonary carcinoid (PC) is unknown. Furthermore, post-surgery follow-up recommendations rely on institutional retrospective studies with short follow-ups. We aimed to address these shortcomings by examining the relation between LN sampling and relapse in a population-based cohort with long-term follow-up. By combining the Dutch nationwide pathology and cancer registries, all patients with surgically resected PC (2003–2012) were included in this analysis (last update 2020). The extent of surgical LN dissection was scored for the number of LN samples, location (hilar/mediastinal), and completeness of resection according to European Society of Thoracic Surgeons (ESTS) guidelines. Relapse-free interval (RFI) was evaluated using Kaplan Meier and multivariate regression analysis. 662 patients were included. The median follow-up was 87.5 months. Relapse occurred in 10% of patients, mostly liver (51.8%) and locoregional sites (45%). The median RFI was 48.1 months (95% CI 36.8–59.4). Poor prognostic factors were atypical carcinoid, pN1/2, and R1/R2 resection. In 546 patients LN dissection data could be retrieved; at least one N2 LN was examined in 44% and completeness according to ESTS in merely 7%. In 477 cN0 patients, 5.9% had pN1 and 2.5% had pN2 disease. In conclusion, relapse occurred in 10% of PC patients with a median RFI of 48.1 months thereby underscoring the necessity of long-term follow-up. Extended mediastinal LN sampling was rarely performed but systematic nodal evaluation is recommended as it provides prognostic information on distant relapse.

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Fredrika Svahn Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Karolina Solhusløkk Höse Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Adam Stenman Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Yaxuan Liu Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China

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Jan Calissendorff Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Emma Tham Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

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Ákos Végvári Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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Roman A Zubarev Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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Na Wang Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden

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Reju Korah Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA

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Tobias Carling Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
Carling Adrenal Center, Tampa, Florida, USA

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Jan Zedenius Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Robert Bränström Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital Stockholm, Sweden

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Catharina Larsson Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here, we re-analyzed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and from analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in six PCC cases. Three of these were constitutional, and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak or negative staining. Reduced CACNA1H gene expression was especially pronounced in PCC compared to aPGL and in PPGL with cluster 2 kinase signaling phenotype. Furthermore, CACNA1H levels correlated with HIF1A and HIF2A. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles, determined by mass spectrometry, as well as a shift in the membrane potential where maximum calcium currents were observed, as determined by electrophysiology. The findings suggest the involvement of CACNA1H/CaV3.2 in pheochromocytoma development and establish a potential link between the etiology of adrenomedullary and adrenocortical tumor development.

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Paul Benjamin Loughrey Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Brian Herron Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK

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Stephen Cooke Department of Neurosurgery, Belfast Health and Social Care Trust, Belfast, UK

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Philip Weir Department of Neurosurgery, Belfast Health and Social Care Trust, Belfast, UK

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Jayna Elizabeth Smyth Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Karen R Mullan Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Estelle G Healy Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK

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Jane Evanson Department of Radiology, Barts Health NHS Trust, London, UK

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Stephanie G Craig Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK

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Jacqueline A James Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
Northern Ireland Biobank, Belfast Health and Social Care Trust, Belfast, UK

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Márta Korbonits Department of Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Steven J Hunter Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Cushing’s disease is a rare condition that occurs due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing’s disease in Northern Ireland (NI) from 2000 to 2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing’s disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing’s disease of 1.39–1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤ 50 nmol/L (1.8 µg/dL) and ≤ 138 nmol/L (5 µg/dL), respectively, in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer-term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing’s disease had a significantly higher mortality rate compared to the NI general population (standardised mortality ratio 8.10, 95% CI 3.3–16.7, P < 0.001). Annual incidence of Cushing’s disease in NI is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population.

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Judith Favier Université Paris Cité, Inserm UMR970 PARCC, Equipe Labellisée par la Ligue contre le cancer, Paris, France

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Roderick Clifton-Bligh Department of Endocrinology Royal North Shore Hospital, University of Sydney, Sydney, Australia

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Giulia Vocino Trucco Pathology Unit, SS. Annunziata Hospital, Savigliano, Italy

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Marco Volante Department of Oncology, University of Turin, Orbassano, Turin, Italy

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Graphical abstract

Abstract

The 5th edition of the World Health Organization (WHO) classification of neuroendocrine neoplasms (NENs) is built to achieve a uniform terminology and to define a similar diagnostic scheme across different anatomic locations. Since the 4th edition, a chapter discussing NENs in nonneuroendocrine organs has been introduced, which proposes a binary system for classification segregating well-differentiated neoplasms, termed neuroendocrine tumors (NETs), and poorly differentiated neoplasms, termed neuroendocrine carcinomas (NECs). A grading system for NETs is based on mitotic index and/or Ki-67 index and/or necrosis, depending on the different locations. Although this approach has been already well established in the digestive system, it modifies and homogenizes the classification of NENs in the urinary tract, in female genital organs, and in the male genital system. In the lung and thymus, the double terminology of carcinoid/NET, already introduced in the 5th edition of the WHO classification of thoracic tumors, is endorsed. This approach undoubtedly helps the multidisciplinary approach for the diagnosis and clinical management of patients affected by these neoplasms, without losing site-specific characteristics that influence the clinical and biological behavior of tumors in different anatomical sites. Other major advances of the new WHO scheme are the homogenization of epidemiological data and the correct integration of data from prospective future studies aimed at the definition of molecular profiles and at the identification of tumor type-specific and patient-specific therapeutic approaches.

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Ali S Alzahrani Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Meshael Alswailem Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Alexandre Buffet Université Paris Cité, Inserm, Paris Centre de Recherche Cardiovasculaire (PARCC), Equipe Labellisée Ligue contre le Cancer, Paris, France
Département de Médecine Génomique des Tumeurs et des Cancers, Fédération de Génétique et de Médecine Génomique, Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Paris, France

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Balgees Alghamdi Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Lulu Alobaid Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Osamah Alsagheir Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Hindi Al-Hindi Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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In 2012, somatic EPAS1 pathogenic variants were found to cause a triad of pheochromocytoma/paragangliomas (PPGLs), polycythemia, and somatostatinoma. Since then, a limited number of studies on this subject have been reported, and data on the long-term outcome of metastatic disease are not available on this rare syndrome. We comprehensively reviewed EPAS1-related PPGL and describe an unusual patient who has been living with an EPAS1-related metastatic PPGL for 47 years. The results of this work show that EPAS1 pathogenic variants are rare, more in females and patients without pathogenic variants in other PPGL susceptibility genes. PPGLs are the most common manifestation followed by polycythemia and somatostatinoma. The EPAS1 pathogenic variants are often postzygotic, and the timing of their acquirement during embryonic development seems to correlate with the number and timing of development of the disease manifestations. Although recurrent and multifocal disease is common in EPAS1-related PPGL, distant metastases are uncommon and usually indolent. This is illustrated by a case of a man who was diagnosed at the age of 9 years and is currently 56 years old, alive, and well for 47 years with these metastases. He was found to have a somatic EPAS1 pathogenic variant (c.1592C>A, p.Pro531His) in bilateral pheochomocytoma and a pancreatic NET (somatostatinoma) but not in genomic DNA isolated from peripheral leukocytes. This and previous reports suggest that distant metastases are uncommon and less aggressive in EPAS1-related PPGLs compared to those found in other hereditary PPGLs.

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Mijin Kim Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
Biomedical Research Institute, Pusan National University Hospital, Busan, Korea

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Chae Hwa Kwon Biomedical Research Institute, Pusan National University Hospital, Busan, Korea

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Bo Hyun Kim Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
Biomedical Research Institute, Pusan National University Hospital, Busan, Korea

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The genetic alterations currently identified in papillary thyroid microcarcinomas (PTMCs) are insufficient for distinguishing tumors with aggressive features. We aimed to identify candidate markers associated with lateral lymph node metastasis (LLNM, N1sb disease) in patients with PTMC using transcriptomic analysis. RNA sequencing was performed on 26 matched tumor and normal thyroid tissue samples (N0, n = 14; N1b, n = 12), followed by functional enrichment analyses of differentially expressed genes (DEGs). EcoTyper was used to explore the distinct tumor microenvironment (TME). We identified 631 DEGs (213 upregulated and 418 downregulated) between N1b and N0 PTMCs. The most significantly upregulated genes in N1b were associated with tumorigenesis, adhesion, migration, and invasion. DEGs were mainly enriched in the pathways of idiopathic pulmonary fibrosis, TME, wound healing, and inhibition of matrix metalloproteases. We predicted the activation of these pathways in N1b PTMCs. N1b PTMCs had a unique TME with abundant fibroblasts and epithelial cells, associated with an increased risk of disease progression. Fibroblast marker genes, including POSTN, MMP11, TNFAIP6,and FN1, and epithelial cell marker genes, including NOX4, MFAP2, TGFVBI,and TNC, were selected. POSTN and FN1, fibroblast cell-specific genes, and NOX4 and TNC, epithelial cell-specific genes, were promising biomarkers for predicting LLNM development and recurrence in patients with PTMC. We delineated the cellular ecotypes within the TME of patients with N1b PTMC and revealed potential markers for predicting LLNM and the prognosis of PTMC. These findings provide valuable insights into the contributions of cancer-associated fibroblasts and epithelial cells to PTMC progression and metastasis.

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Marcia S Brose Department of Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania, USA

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Jaume Capdevila Gastrointestinal and Endocrine Tumor Unit, Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Rossella Elisei Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Lars Bastholt Department of Clinical Oncology, Odense University Hospital, Odense, Denmark

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Dagmar Führer-Sakel Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, University Hospital Essen, Essen, Germany

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Sophie Leboulleux Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France
Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Hôpitaux Universitaires de Genève, Geneve, Switzerland

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Iwao Sugitani Department of Endocrine Surgery, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

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Matthew H Taylor Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA

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Zhuoying Wang Department of Head Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
Department of Head Neck Surgery, Renji Hospital Affiliated to Jiaotong University School of Medicine, Shanghai, China

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Lori J Wirth Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Francis P Worden Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

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John Bernard Sanofi, Cambridge, Massachusetts, USA

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Paolo Caferra Sanofi, Amsterdam, The Netherlands
Department of Pharmacy, University of Pisa, Pisa, Italy

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Raffaella M Colzani Sanofi, Cambridge, Massachusetts, USA

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Shiguang Liu Sanofi, Cambridge, Massachusetts, USA

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Martin Schlumberger Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France

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The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55–1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

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Vicente Rodrigues Marczyk V Marczyk, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

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Ana Luiza Maia A Maia, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

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Iuri Martin Goemann I Goemann, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

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TERT promoter mutations C228T and C250T are associated with disease aggressiveness and poor clinical outcomes in patients with papillary thyroid carcinomas. However, very little is known about the transcriptional consequences of these mutations and whether they both carry similar oncogenic potential. Here we characterized the transcriptional disturbances and clinical outcomes associated with the presence of each of these two mutations using data derived from The Cancer Genome Atlas. We observed that tumors harboring the C228T mutation (n=27) exhibited a 16-fold increase in TERT mRNA levels (P=5.3x10-42), whereas C250T tumors (n=8) showed only a 2-fold increase in expression (P=0.034). The C228T mutation was associated with the activation of signaling pathways controlling the cell cycle, cellular division, and extracellular matrix degradation. Univariate analysis demonstrated that the C228T mutation was associated with older age at diagnosis, large tumor size, lymph node invasion, and distant metastases at diagnosis. The C228T mutation was also associated with worse progression-free interval (PFI) in comparison to WT tumors (HR=5,04; P<0.001). This association remained significant in a multivariate analyses (HR=3.74, P=0.003) adjusting for BRAF-V600E status and ATA risk group. Our data indicate that TERT promoter mutations C228T and C250T have distinct transcriptional consequences in PTC, suggesting a greater oncogenic potential for the C228T mutation. TERT promoter mutation C228T may be a useful prognostic marker to identify patients at high risk of distant recurrence. Clinical data for the C250T mutation is still limited, with no evidence up to date to confirm its prognostic significance.

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Takuya Mikoshiba T Mikoshiba, Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinjuku-ku, 1608582, Japan

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Mariko Sekimizu M Sekimizu, Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinjuku-ku, Japan

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Shin Saito S Saito, Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinjuku-ku, Japan

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Shintaro Nakamura S Nakamura, Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinjuku-ku, Japan

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Ryoto Nagai R Nagai, Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinjuku-ku, Japan

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Miho Kawaida M Kawaida, Division of Diagnostic Pathology, Keio University Hospital, Shinjuku-ku, Japan

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Isao Kurihara I Kurihara, Division of Medical Education Improvement and Planning, Medical Education and Clinical Training Center, National Defense Medical College, Tokorozawa, Japan

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Sakiko Kobayashi S Kobayashi, Endocrinology, Metabolism and Nephrology, Keio University, School of medicine, Shinjuku-ku, Japan

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Hiroyuki Ozawa H Ozawa, Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, Shinjuku-ku, Japan

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Olfactory neuroblastomas rarely secrete adrenocorticotropic hormone, leading to ectopic adrenocorticotropic hormone syndrome. However, the prevalence, timing, and triggers of ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastomas remain unclear. This study aimed to investigate these factors and conduct a literature review. Fifteen patients with olfactory neuroblastomas who underwent surgery at our institution were included. The prevalence of ectopic adrenocorticotropic hormone syndrome development was assessed by evaluating adrenocorticotropic hormone expression using immunohistochemistry. Furthermore, 26 patients with olfactory neuroblastomas who developed ectopic adrenocorticotropic hormone syndrome from previous reports were reviewed. Among the 15 patients, three (20%) showed adrenocorticotropic hormone-positive tumor cells at the time of initial surgery, and two (13%) developed ectopic adrenocorticotropic hormone syndrome. The timing of developing ectopic adrenocorticotropic hormone syndrome was 2.5 and 10 years following initial treatment of olfactory neuroblastoma. Based on the literature review, nine patients with recurrent and metastatic olfactory neuroblastoma developed ectopic adrenocorticotropic hormone syndrome after the initial surgery, of whom, three had confirmed disease after developing ectopic adrenocorticotropic hormone syndrome, three developed during disease progression, two developed after receiving chemotherapy, and one developed after undergoing a biopsy. The timing of ectopic adrenocorticotropic hormone syndrome was 2.5–15 years after initial treatment. Our study revealed that acknowledging olfactory neuroblastomas can manifest as ectopic adrenocorticotropic hormone syndrome with a certain low prevalence is crucial. Moreover, our study speculated that tumor stimulation, such as biopsy or chemotherapy, as well as disease progression, could trigger ectopic adrenocorticotropic hormone syndrome onset. Thus, olfactory neuroblastomas can develop into ectopic adrenocorticotropic hormone syndrome, even long after the initial treatment.

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