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Henri J L M Timmers
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Anne-Paule Gimenez-Roqueplo Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, INSERM, Endocrinology Unit, Reproductive and Adult Endocrinology Program, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, INSERM, Endocrinology Unit, Reproductive and Adult Endocrinology Program, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, INSERM, Endocrinology Unit, Reproductive and Adult Endocrinology Program, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

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Massimo Mannelli Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, INSERM, Endocrinology Unit, Reproductive and Adult Endocrinology Program, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

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Karel Pacak Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, INSERM, Endocrinology Unit, Reproductive and Adult Endocrinology Program, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

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Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [18F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.

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Anne-Paule Gimenez-Roqueplo Université Paris Cité, PARCC, INSERM, Paris, France
Département de Médecine Génomique des Tumeurs et des Cancers, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France

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Mercedes Robledo Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain

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Patricia L M Dahia Division of Hematology and Medical Oncology, Department Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, USA
Mays Cancer Center at UTHSCSA, San Antonio, Texas, USA

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Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.

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Patricia L M Dahia Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

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Roderick Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, Northern Clinical School, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia

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Anne-Paule Gimenez-Roqueplo AP-HP, Hôpital Européen Georges Pompidou, Genetics Department, Paris, France
Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain

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Mercedes Robledo AP-HP, Hôpital Européen Georges Pompidou, Genetics Department, Paris, France
Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain

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Camilo Jimenez Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients with large pheochromocytomas, sympathetic paragangliomas, and norepinephrine-secreting tumors. Older subjects, those with larger tumors and synchronous metastases, advance more rapidly. Germline mutations of SDHB, FH, and possibly SLC25A11, or somatic MAML3 disruptions relate to a higher risk for metastatic disease. However, it is unclear whether these mutations predict outcome. Once diagnosed, there are no well-established predictors of outcome in mPPGLs, and aggressive tumors have few therapeutic options and limited response. High-specific activity (HSA) metaiodine-benzyl-guanidine (MIBG) is the first FDA approved treatment and shows clinical effectiveness for MIBG-avid mPPGLs. Ongoing and future investigations should involve validation of emerging candidate outcome biomarkers, including somatic ATRX, TERT, and microRNA disruptions and identification of novel prognostic indicators. Long-term effect of HSA-MIBG and the role of other radiopharmaceuticals should be investigated. Novel trials targeting molecular events prevalent in SDHB/FH mutant tumors, such as activated hypoxia inducible factor 2 (HIF2), angiogenesis, or other mitochondrial defects that might confer unique vulnerability to these tumors should be developed and initiated. As therapeutic options are anticipated to expand, multi-institutional collaborations and well-defined clinical and molecular endpoints will be critical to achieve higher success rates in improving care for patients with mPPGLs.

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Sophie Moog Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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Betty Salgues PARCC INSERM UMR970, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France

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Yasmine Braik-Djellas Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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Thomas Viel Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France

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Daniel Balvay Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France

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Gwennhael Autret Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France

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Estelle Robidel Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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Anne-Paule Gimenez-Roqueplo Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Plateforme d’Imageries du Vivant, Université de Paris Cité, Faculté de Médecine, Paris, France

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Bertrand Tavitian Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France

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Charlotte Lussey-Lepoutre PARCC INSERM UMR970, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France

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Judith Favier Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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Therapies for metastatic SDHB-dependent pheochromocytoma and paraganglioma (PPGL) are limited and poorly efficient. New targeted therapies and identification of early non-invasive biomarkers of response are thus urgently needed for these patients. We characterized an in vivo allograft model of spontaneously immortalized murine chromaffin cells (imCC) with inactivation of the Sdhb gene by dynamic contrast-enhanced MRI (DCE-MRI) and 18FDG-PET. We evaluated the response to several therapies: IACS-010759 (mitochondrial respiratory chain complex I inhibitor), sunitinib (tyrosine kinase inhibitor with anti-angiogenic activity), talazoparib (poly ADP ribose polymerase (PARP) inhibitor) combined or not to temozolomide (alkylating agent), pharmacological inhibitors of HIF2a (PT2385 and PT2977 (belzutifan)) and molecular inactivation of HIF2a (imCC Sdhb−/− shHIF2a). Multimodal imaging was performed, including magnetic resonance spectroscopy (1H-MRS) to monitor the level of succinate in vivo. The allografted model of Sdhb−/− imCC reflected SDHB-deficient tumors, with increased angiogenesis and a particular avidity for 18FDG. After 14 days of treatment, IACS-010759, sunitinib and talazoparib at high doses allowed a significant reduction of the tumor volumes. In contrast to the tumor growth inhibition observed in Sdhb−/− shHIF2a imCC tumors, pharmacological inhibitors of HIF2a (PT2385 and belzutifan) showed no antitumor action in this model, alone or in combination with sunitinib. 1H-MRS, but not DCE-MRI, enabled the monitoring response to sunitinib, which was the best treatment in this study, promoting a decrease in succinate levels detected in vivo. This study paves the way for new therapeutic options and reveals a potential new early biomarker of response to treatment in SDHB-dependent PPGL.

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Thibault Bahougne Service d’Endocrinologie et Diabétologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Institut des Neurosciences Cellulaires et Intégratives, CNRS (UPR 3212), Strasbourg, France

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Alessio Imperiale Service de Biophysique et de Médecine Nucléaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
ICube, UMR 7357 Université de Strasbourg/CNRS et FMTS, Faculté de Medécine, Strasbourg, France

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Gerlinde Averous Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

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Gerard Chabrier Service d’Endocrinologie et Diabétologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

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Nelly Burnichon Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France

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Anne Paule Gimenez-Roqueplo Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France
Centre Expert National COMETE-Cancer de la surrénale, Paris, France

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Nassim Dali-Youcef Laboratoire de Biochimie et de Biologie Moléculaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/Université de Strasbourg, Illkirch, France

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Rossella Libe Centre Expert National COMETE-Cancer de la surrénale, Paris, France
Endocrinology Department, Cochin Hospital, Paris, France
Département de Médecine Nucléaire et de Tumeurs Endocrines, Institut Gustave Roussy, Université Paris Sud, Villejuif, France

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Eric Baudin Département de Médecine Nucléaire et de Tumeurs Endocrines, Institut Gustave Roussy, Université Paris Sud, Villejuif, France

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Catherine Roy Service de Radiologie B, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

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Herve Lang Service d’Urologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

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Laurence Kessler Service d’Endocrinologie et Diabétologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

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Francesca Branzoli Paris Brain Institute - Institut du Cerveau (ICM), Center for Neuroimaging Research (CENIR), Paris, France
Sorbonne University, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France

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Betty Salgues Sorbonne University, nuclear medicine department, Pitié-Salpêtrière Hospital, Assistance -Publique Hôpitaux de Paris, Paris, France
Paris Cardiovascular Research Center (PARCC), Inserm, Paris, France

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Małgorzata Marjańska Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, Minnesota, USA

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Marie Laloi-Michelin Endocrinology department, Lariboisière Hospital, Assistance -Publique Hôpitaux de Paris, Paris, France

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Philippe Herman ENT unit, Lariboisière Hospital, Assistance -Publique Hôpitaux de Paris, Paris-Cité University, INSERM U1141, Paris, France

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Lauriane Le Collen Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, University of Lille, Lille, France
Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France
Department of Genetic, University Hospital Center of Reims, Reims, France

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Brigitte Delemer Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France
CRESTIC EA 3804, University of Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Moulin de La Housse, BP 1039, Reims, France

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Julien Riancho AP-HP, Hôpital Européen Georges Pompidou, Hypertension Unit, and Reference centre for rare adrenal diseases, Paris, France

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Emmanuelle Kuhn Pituitary Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France

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Christel Jublanc Pituitary Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France

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Nelly Burnichon Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Laurence Amar AP-HP, Hôpital Européen Georges Pompidou, Hypertension Unit, and Reference centre for rare adrenal diseases, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Judith Favier Université Paris Cité, Inserm, PARCC, Paris, France

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Anne-Paule Gimenez-Roqueplo Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Alexandre Buffet Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Charlotte Lussey-Lepoutre Sorbonne University, nuclear medicine department, Pitié-Salpêtrière Hospital, Assistance -Publique Hôpitaux de Paris, Paris, France
Paris Cardiovascular Research Center (PARCC), Inserm, Paris, France

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Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the ‘3PAs’ syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

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