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      French Endocrine Society Guidance on endocrine side effects of immunotherapy

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          Abstract

          The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using ‘common terminology criteria for adverse events’ (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

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          Most cited references39

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          Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses.

          Distinct genes encode 6 human receptors for IgG (hFcgammaRs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFcgammaRs for the 4 human IgG subclasses is unknown. This information is critical for antibody-based immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3, and IgG4 to FcgammaRI; FcgammaRIIA, IIB, and IIC; FcgammaRIIIA and IIIB; and all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found that (1) IgG1 and IgG3 bind to all hFcgammaRs; (2) IgG2 bind not only to FcgammaRIIA(H131), but also, with a lower affinity, to FcgammaRIIA(R131) and FcgammaRIIIA(V158); (3) IgG4 bind to FcgammaRI, FcgammaRIIA, IIB and IIC and FcgammaRIIIA(V158); and (4) the inhibitory receptor FcgammaRIIB has a lower affinity for IgG1, IgG2, and IgG3 than all other hFcgammaRs. We also identified parameters that determine the specificity and affinity of hFcgammaRs for IgG subclasses. These results document how hFcgammaR specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFcgammaRs in the therapeutic and pathogenic effects of antibodies in disease.
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            Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.

            Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.
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              Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review

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                Author and article information

                Journal
                Endocr Relat Cancer
                Endocr. Relat. Cancer
                ERC
                Endocrine-Related Cancer
                Bioscientifica Ltd (Bristol )
                1351-0088
                1479-6821
                February 2019
                08 October 2018
                : 26
                : 2
                : G1-G18
                Affiliations
                [1 ]Aix-Marseille Université , Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), and Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’Hypophyse HYPO, Marseille, France
                [2 ]Service de Médecine Interne B – Endocrinologie , Limoges Cedex, France
                [3 ]Hôpital Cochin , Service d’Endocrinologie et Maladies Métaboliques, Paris Cedex 14, France
                [4 ]CHU Dijon , Hôpital François Mitterrand, Service d’Endocrinologie, Diabétologie, Maladies Métaboliques, Dijon Cedex, France
                [5 ]Unité INSERM LNC-UMR 1231 , Université de Bourgogne, Dijon, France
                [6 ]Institut MITOVASC , INSERM U1083, Angers University, Department of Endocrinology, Diabetology and Nutrition, University Medical Center, Angers, France
                [7 ]Department of Endocrinology , L’Institut du Thorax, CHU Nantes, Nantes, France
                [8 ]CHU de Toulouse – Hôpital Larrey – Service d’Endocrinologie – Maladies métaboliques – Nutrition , TSA 30030, Toulouse Cedex 9, France
                [9 ]CHU de Grenoble – Hôpital Albert Michallon , Service d’Endocrinologie-Diabétologie-Nutrition, Grenoble Cedex 9, France
                [10 ]Assistance Publique-Hôpitaux de Paris (AP-HP) , Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, et UMR S-1185 Faculté de Médecine Paris-Sud, University of Paris-Saclay, Le Kremlin-Bicêtre, France
                [11 ]CHRU de Lille – Hopital Huriez , Service d’Endocrinologie, Lille Cedex, France
                [12 ]CHU de Bordeaux – Hôpital du Haut Lévêque , Service d’Endocrinologie-Diabétologie et Maladies Métaboliques, Pessac Cedex, France
                [13 ]Institut Curie , Oncologie Endocrinienne, Saint Cloud, France
                [14 ]Department of Endocrinology , Diabetes and Nutrition, Reference Centre of Rare Thyroid Disease, Hospital of Angers, Angers Cedex 09, France
                [15 ]Département d’Hormonologie Spécialisée , BPR-AS, Pannes, France
                [16 ]Hospices Civils de Lyon , Laboratoire d’Hormonologie, Service de Biochimie et Biologie Moléculaire, Groupement Hospitalier Est, Lyon, France
                [17 ]Hospices Civils de Lyon , Fédération d’Endocrinologie, Université Claude Bernard Lyon 1, Lyon, France
                Author notes
                Correspondence should be addressed to F Castinetti: frederic.castinetti@ 123456ap-hm.fr
                Article
                ERC-18-0320
                10.1530/ERC-18-0320
                6347286
                30400055
                711ab163-48da-4ee6-8c87-7ec0b68cef20
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 10 September 2018
                : 08 October 2018
                Categories
                Guidelines and Guidance

                Oncology & Radiotherapy
                immune checkpoint inhibitor,ctla-4,pd-1,pd-l1,hypothyroidism,thyrotoxicosis,hypophysitis,diabetes,adrenal insufficiency

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