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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Satoshi Endo United Graduate School of Medical Information Sciences, Gifu University, Gifu, Japan
Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan

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Shigehiro Tsukahara Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Tokiyoshi Tanegashima Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Satoshi Kobayashi Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Matsumoto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and posttranscriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant, has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3βHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3βHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer.

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Cassia Michael Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA

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Juliana Moreira Mendonça-Gomes Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA

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Clinton Walton DePaolo Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA

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Antonio Di Cristofano Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA
Department of Medicine (Oncology), Albert Einstein College of Medicine, Bronx, New York, USA
Montefiore-Einstein Comprehensive Cancer Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
Cancer Dormancy Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, New York, USA

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Sofia de Oliveira Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA
Montefiore-Einstein Comprehensive Cancer Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
Cancer Dormancy Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, New York, USA
Department of Medicine (Hepatology), Albert Einstein College of Medicine, Bronx, New York, USA
Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA

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Anaplastic thyroid cancer (ATC) is of the most aggressive thyroid cancer. While ATC is rare, it accounts for a disproportionately high number of thyroid cancer-related deaths. Here, we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo. Using both mouse (T4888M) and human (C643)-derived fluorescently labeled ATC cell lines, we show these cell lines display different engraftment rates, mass volume, proliferation, cell death, angiogenic potential, and neutrophil and macrophage recruitment and infiltration. Next, using a PIP-FUCCI reporter to track proliferation in vivo, we observed cells in each phase of the cell cycle. Additionally, we performed long-term non-invasive intravital microscopy over 48 h to understand cellular dynamics in the tumor microenvironment at the single-cell level. Lastly, we tested two drug treatments, AZD2014 and a combination therapy of dabrafenib and trametinib, to show our model could be used as an effective screening platform for new therapeutic compounds for ATC. Altogether, we show that zebrafish xenotransplants make a great model to study thyroid carcinogenesis and the tumor microenvironment, while also being a suitable model to test new therapeutics in vivo.

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Erin Gibbons Department of Microbiology and Immunology University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

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Manisha Taya Division of Hematology and Oncology, UT Southwestern, Dallas, Texas, USA

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Huixing Wu Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA

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Samia H Lopa Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA

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Joel Moss Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA

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Elizabeth P Henske Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Francis X McCormack Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA

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Stephen R Hammes Department of Microbiology and Immunology University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

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Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here, we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

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Bin Li Department of Neurosurgery, Peking University People’s Hospital, Beijing, China

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Sida Zhao Department of Cell and Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

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Yiyuan Chen Department of Cell and Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

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Hua Gao Department of Cell and Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

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Weiyan Xie Department of Cell and Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

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Hongyun Wang Department of Cell and Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

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Peng Zhao Department of Neurosurgical, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Chuzhong Li Department of Neurosurgical, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Yazhuo Zhang Department of Neurosurgical, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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The clinical diagnosis and treatment of pituitary neuroendocrine tumors (PitNETs) that invade the cavernous sinus are fraught with difficulties and challenges. Exploring the biological characteristics involved in the occurrence and development of PitNETs that invade the cavernous sinus will help to elucidate the mechanism of cavernous sinus invasion. There are differences between intrasellar tumors (IST) and cavernous sinus-invasion tumors (CST) in ultramicrostructure, tumor microenvironment (TME), gene expression, and signaling pathways. The microvascular endothelial cell is increased in CST. The VEGFR signaling pathway, VEGF signaling pathway, and chemokine signaling pathway are activated in CST. HSPB1 is upregulated in CST and promotes cell proliferation, cell viability, and migration. HSPB1 promotes the release of VEGF from GT1-1 cells and activates the VEGF signaling pathway in bEnd.3 cells. HSPB1 promotes the migration of bEnd.3 cells to GT1-1 cells and promotes the formation of blood vessels of bEnd.3 cells. bEnd.3 cells can release CCL3 and CCL4 and promote the vitality, proliferation, and migration of GT1-1 cells. HSPB1 promotes the formation of blood vessels of bEnd.3 cells and ultimately leads to tumor growth in vivo. HSPB1 acts as a key gene for invasion of the cavernous sinus in PitNETs, remodeling TME by promoting the formation of blood vessels of brain microvascular endothelial cells. The synergistic effect of tumor cells and microvascular endothelial cells promotes tumor progression. The mechanism by which HSPB1 promotes tumor invasion by inducing angiogenesis in PitNETs may be a new target for the treatment of PitNETs invading the cavernous sinus.

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Laura Gerard Service de Gastroentérologie et d’Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Céline Patte Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Laurence Chardon Service de Biochimie Biologie Moléculaire, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France

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Valérie Hervieu Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France
Service Central d’Anatomie et Cytologie Pathologiques, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France

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Léa Payen Institut de Cancérologie des Hospices Civils de Lyon, CIRculating CANcer Program (CIRCAN), Lyon, France

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Marion Allio Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Claire Marx Service d'Endocrinologie-Diabète-Nutrition, Hospices Civils de Lyon, Hôpital Lyon Sud, Lyon, France

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Hugo Clermidy Service de Chirurgie Thoracique, Vidéothoracoscopie et Transplantation Pulmonaire, Hospices Civils de Lyon, Hôpital Louis Pradel, Lyon, France

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Alice Durand Service de Gastroentérologie et d’Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France

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Patrick Mehlen Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Julien Bollard Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Gilles Poncet Service de Chirurgie Digestive, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France

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Colette Roche Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Benjamin Gibert Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Thomas Walter Service de Gastroentérologie et d’Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Neuropilin 2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers and particularly in neuroendocrine neoplasms (NENs). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN. NRP2 expression was studied by immunochemistry on tissue microarrays (n = 437) and on circulating tumour cells (CTCs, n = 5 patients with neuroendocrine carcinoma, NEC). We described the levels of sNRP2 in 229 patients with NEN using the ELISA method to identify the factors associated with sNRP2 levels and to evaluate its prognostic role; 90 blood donors represented the healthy control group. NRP2 was found in 97% of neuroendocrine tumours (396/410) and in 74% of NEC (20/27). NRP2 was also expressed in CTC of all the studied patients. The receiver operating characteristic (ROC) analysis showed that sNRP2 had a weak capacity to discriminate between NEN patients and healthy controls (area under curve (AUC) = 0.601, P = 0.053). Abnormal sNRP2 levels were associated with inflammatory syndrome, bone and peritoneal metastases, and abnormal chromogranin A levels. Patients with high sNRP2 levels (sNRP2Q3–Q4) had significantly poorer overall survival in multivariate analysis (HR 0.16, 95% CI (0.04–0.67), P = 0.015). In conclusion, the present study found that sNRP2 and NRP2 could represent a new prognostic biomarker and a therapeutic target, respectively, particularly in aggressive NEN.

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Katherine I Wolf Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Linda Rose-Krasnor Pheo Para Alliance and Psychology Department, Brock University, St. Catharines, Ontario, Canada

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Stephanie Alband Pheo Para Alliance, Alexandria, Virginia, USA

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Jacques W M Lenders Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands

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Lauren Fishbein Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, and Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, Colorado, USA

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Pheochromocytoma and paragangliomas (PPGLs) originate from the chromaffin cells of the adrenal medulla or neural crest progenitors outside the adrenal gland, respectively. The estimated annual incidence of PPGL is between 2.0 and 8.0/million adults. Minimal data exist on the impact of PPGL from the patient’s perspective. Therefore, a survey was adapted from a previously published study on gastroenteropancreatic neuroendocrine tumors to explore the voice of patients with PPGL and learn ways to improve clinical care while understanding the current gaps to direct future research. A self-reported online survey was available to patients with PPGL and those with genetic predisposition even without PPGL from June to July 2022. Survey questions captured sociodemographic and clinical characteristics, the diagnostic workup, treatment and monitoring, quality and access to care, and financial impact. Here, we report the most relevant findings on patient experience of disease burden following diagnosis. A total of 270 people responded, the majority of whom were from the USA (79%), Caucasian (88%), and female (81%). The results of this survey highlight the burden of disease on a patient’s daily life, resulting in moderate to severe financial distress, increased travel time to specialized facilities resulting in loss of work and wages, and significant delays in care. Respondents reported being unheard and unacknowledged. With a median time to diagnosis just over 2 years, the physical, mental, and emotional toll are substantial. Increasing access to PPGL specialists and centers could lead to faster diagnoses and better management, which may reduce the burden on both patients and healthcare centers.

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Judith Favier J Favier, UMR970, Paris Cardiovascular Research Center, INSERM, Paris, France

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Karel Pacak K Pacak, Section on Medical Neuroendocrinology, NIH, Bethesda, United States

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Roderick J. Clifton-Bligh R Clifton-Bligh, Endocrinology, Royal North Shore Hospital, Sydney, 2065, Australia

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The endocrine community has witnessed significant advances in understanding and management of pheochromocytoma and paraganglioma, thanks to continuous and relentless efforts of healthcare professionals and researchers worldwide. The 6th International Symposium on Pheochromocytoma (ISP) held in Prague, Czech Republic in September 2022 brought together experts from various disciplines underscoring the importance of unity in pursuit of clinical and basic research progress in these challenging endocrine tumors (Pacak and Clifton-Bligh 2023). It also provided Endocrine-Related Cancer the unique opportunity for a special collection of articles as testament to this progress and showcasing the latest developments in clinical management and research.

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Giulia Vocino Trucco G Vocino Trucco, Pathology, Hospital SS Annunziata Savigliano, Savigliano, Italy

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Marco Volante M Volante, Oncology, University of Turin and San Luigi Hospital, Orbassano, Italy

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The 5th Edition of WHO classification of neuroendocrine neoplasms is built to achieve a uniform terminology and to define a similar diagnostic scheme across different anatomical locations. At variance with the 4th edition, a chapter discussing neuroendocrine neoplasms in non-neuroendocrine organs has been introduced, that proposes a binary system for classification segregating well differentiated neoplasms, termed neuroendocrine tumors (NET), and poorly differentiated neoplasms, termed neuroendocrine carcinomas (NEC). A grading system for NET is based on mitotic index and/or Ki-67 index and/or necrosis, depending on the different location. If already well-established in the digestive system, this approach modifies and homogenize the classification of neuroendocrine neoplasms 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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Isabel Heidegger Department of Urology, Medical University Innsbruck, Innsbruck, Austria

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Zoran Culig Department of Urology, Medical University Innsbruck, Innsbruck, Austria

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Ali S Alzahrani A Alzahrani, Department of Medicine, KFSH&RC, Riyadh, Saudi Arabia

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Meshael Alswailem M Alswailem, Molecualr Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Alexandre Buffet A Buffet, Sorbonne Paris-Cité, Université Paris Descartes, Sorbonne PAris-Cité, Paris, France

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Balgees Alghamdi B Alghamdi, Molecular Oncology, King Faisal Specialist Hospital and Research Center’s General Organization, Riyadh, Saudi Arabia

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Lulu Alobaid L Alobaid, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Osamah Alsagheir O Alsagheir, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Hindi Al-Hindi H Al-Hindi, Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Karel Pacak K Pacak, Section on Medical Neuroendocrinology, NIH, Bethesda, United States

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In 2012, somatic EPAS1 pathogenic variants were found to cause a triad of pheochromocytoma/paragangliomas (PPGL), 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 seem 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 indolent. This is illustrated by a case of a man who was diagnosed at age 9 years and is currently 56-year-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 pheochomoctoma and 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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