Publications by authors named "Christine Cugnet-Anceau"

12 Publications

  • Page 1 of 1

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up.

J Clin Med 2020 Oct 13;9(10). Epub 2020 Oct 13.

Service d'Endocrinologie, Diabète, Nutrition, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France.

Hypophysitis, secondary to programmed cell death 1 protein (PD1) and programmed cell death 1 ligand 1 (PDL1) inhibitors, were thought to be rare, with only a few studies describing more than one case with long-term follow-up. The aim of the present study was to describe the clinical, laboratory, and morphological characteristics of PD1/PDL1 inhibitor-induced hypophysitis, and its long-term course. This cohort study was conducted at the University Hospital of Lyon, France, with longitudinal follow-up of patients. Seventeen cases of PD1/PDL1 inhibitor-induced hypophysitis were included. The median time to onset of hypophysitis was 28 weeks (range: 10-46). At diagnosis, 16 patients complained of fatigue, 12 of nausea or loss of appetite, while headache was rare. We found no imaging pituitary abnormality. All patients presented adrenocorticotropic hormone (ACTH) deficiency; other pituitary deficiencies were less common ( = 7). At last follow-up (median: 13 months), ACTH deficiency persisted in all but one patient and one patient recovered from gonadotropic deficiency. PD1/PDL1 inhibitor-induced hypophysitis is a clinical entity different from those associated to cytotoxic T-lymphocyte antigen-4 (CTLA4) inhibitors, with less obvious clinical and radiological signs, and probably a different mechanism. The paucity of symptoms demonstrates the need for systematic hormonal follow-up for patients receiving PD1/PDL1 inhibitors.
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http://dx.doi.org/10.3390/jcm9103280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601962PMC
October 2020

Poorly differentiated thyroid carcinoma with pleomorphic giant cells-a case report.

Virchows Arch 2020 Oct 1;477(4):597-601. Epub 2020 Apr 1.

Pathology Department, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.

Poorly differentiated thyroid carcinoma (PDTC) refers to a malignant tumour that displays an intermediate prognosis between well-differentiated carcinomas and anaplastic thyroid carcinomas (ATC). In the thyroid, pleomorphic giant cells are observed in ATC or in some non-neoplastic thyroid diseases. We described the case of a 43-year-old woman with a 34-mm nodule in her thyroid right lobe. Microscopic examination revealed an encapsulated tumour with a main solid growth pattern and extensive capsular invasion. Multiple images of angioinvasion were observed. There was neither necrosis nor inflammation. Most of the tumour cells were medium-sized and intermingled with pleomorphic giant tumour cells with bizarre features. The immunoprofile (keratins +, TTF1+, Pax 8+) proved their thyroid origin. By NGS, no molecular alteration was identified. The patient was treated by surgery and radioiodine therapy and she has no recurrence after a follow-up of 24 months. Our case meets all the histological criteria of the Turin proposal for PDTC but with pleomorphic giant cells and is very different from ATC according to clinical, histological and immunohistochemical features. Pleomorphic tumour giant cells in thyroid carcinomas could be present in PDTC and do not always represent dedifferentiation and more aggressive carcinoma, thyroid neoplasm.
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http://dx.doi.org/10.1007/s00428-020-02807-7DOI Listing
October 2020

[Checkpoint inhibitors-induced hypophysitis].

Bull Cancer 2020 Apr 19;107(4):490-498. Epub 2020 Mar 19.

Hospices civils de Lyon, fédération d'endocrinologie, 28, avenue Doyen-Lépine, 69677 Bron cedex, France; ImmuCare, institut de cancérologie des hospices civils de Lyon (IDCRC-HCL), Lyon, France; Université de Lyon, université Claude-Bernard-Lyon-1, Lyon, France.

Checkpoint inhibitors immunotherapy is more and more prescribed in oncology, causing new immune related endocrine adverse events. Hypophysitis occurs in approximately 10 % of patients treated with anti-CTLA4. It occurs two to three months after initiation of the immunotherapy. The initial presentation is characterized, in typical forms, by the association of headache, asthenia and hyponatremia. Hormonal exploration usually shows ACTH, gonadotropic and thyrotropic deficiencies. ACTH deficiency may be life-threatening and requires urgent supplementation, without awaiting for biological results. MRI is warranted in order to exclude differential diagnoses, such as pituitary metastases. Hypophysitis induced by anti-PD1/PDL1 seems to be a different nosologic entity characterized by a later onset and a less symptomatic presentation. Biologically ACTH deficiency seems to be constant and permanent, and often isolated. Treatment requires high-dose steroids only in case of severe tumor syndrome (resistant headache, visual disturbance) or acute decompensation of ACTH deficiency. Patients always need lifelong hormonal supplementation of pituitary deficits and must be followed and educated specifically. Immunotherapy can be delayed during the acute phase, but can be secondarily continued if there is an oncological benefit. As it is a pauci-symptomatic but potentially life-threatening complication, biological screening must be systematic in patients treated with checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.bulcan.2020.01.012DOI Listing
April 2020

[Thyroid dysfunctions secondary to cancer immunotherapy].

Bull Cancer 2020 Feb 24;107(2):262-271. Epub 2019 Dec 24.

Hospices civils de Lyon, hôpital Lyon Sud, service d'endocrinologie diabète nutrition, 165, chemin du Grand Revoyet, 69310 Pierre-Bénite, France; ImmuCare, Institut de cancérologie des hospices civils de Lyon (IDCRC-HCL), 69003 Lyon, France; Université de Lyon, université Claude Bernard Lyon 1, 69100 Lyon, France.

The immune checkpoint inhibitors (CPI) such as anti-PD(L)1 or anti-CTLA4 had improved long-term patients' outcomes in different malignancies. Thyroid disorders are the most frequent endocrine side effects from CPI reported in clinical trials and in clinical routine practice. The incidence of thyroid dysfunction is variable according to ICP used (more frequent under anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1)). Most thyroid dysfunctions have been reported to occur 2 to 4 courses after CPI initiation. The clinical symptoms are generally nonspecific (asthenia, weight change, rarely cardiac rhythm disorder). These thyroid dysfunctions are commonly painless thyroiditis with a biphasic evolution: thyrotoxicosis followed by a secondary hypothyroidism frequently definitive. Diagnosis is made on a thyroid test (TSH and FT4). In most cases, no further exam is necessary. Beta blockers therapy is recommended in symptomatic thyrotoxicosis with palpitations. Thyroid hormones therapy will be introduced quickly in case of hypothyroidism. Thyroid dysfunctions are not a contra-indication to the continuation of immunotherapy. Due to the high frequency of these complications, close monitoring of the thyroid status is recommended under CPI.
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http://dx.doi.org/10.1016/j.bulcan.2019.10.005DOI Listing
February 2020

Acquired Generalized Lipodystrophy: A New Cause of Anti-PD-1 Immune-Related Diabetes.

Diabetes Care 2019 10 21;42(10):2008-2010. Epub 2019 Aug 21.

French Network of Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS) and FIRENDO Network, Paris and Lyon, France

Objective: Anti-programmed cell death-1 (anti-PD-1) antibodies have revolutionized advanced cancer therapy. Anti-PD-1 therapy is responsible for immune-related adverse events, with frequent endocrine manifestations, including acute-onset type 1 diabetes. Acquired generalized lipodystrophy (AGL) is a rare disease, believed to be immune mediated, characterized by loss of adipose tissue and insulin resistance-associated complications.

Research Design And Methods: We describe the first reported case of AGL induced by immune checkpoint therapy.

Results: A 62-year-old woman with metastatic melanoma treated with nivolumab was referred for major hyperglycemia, hypertriglyceridemia, and nonalcoholic steatohepatitis. She had presented with a rapidly progressive generalized loss of subcutaneous adipose tissue. Diabetes was associated with severe insulin resistance and undetectable plasma leptin. Subcutaneous biopsy revealed atrophic adipose tissue infiltrated with cytotoxic CD8 T lymphocytes and fibrosis.

Conclusions: AGL is an additional immune-related adverse event of anti-PD-1 therapy that leads to severe insulin resistance-associated complications.
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http://dx.doi.org/10.2337/dc18-2535DOI Listing
October 2019

The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors.

Acta Diabetol 2019 Dec 19;56(12):1239-1245. Epub 2019 Aug 19.

Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.
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http://dx.doi.org/10.1007/s00592-019-01402-wDOI Listing
December 2019

Fulminant diabetes induced by PD-1 and PD-L1 inhibitors: what about glucose variability?

Acta Diabetol 2019 03 1;56(3):377-378. Epub 2018 Dec 1.

Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, 165 chemin du Grand Revoyet, 69310, Pierre-Bénite, France.

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http://dx.doi.org/10.1007/s00592-018-1262-4DOI Listing
March 2019

Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype.

Acta Diabetol 2019 Apr 4;56(4):441-448. Epub 2018 Oct 4.

Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, 165 chemin du Grand Revoyet, Pierre-Bénite, 69310, France.

Aims: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors.

Methods: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes.

Results: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up.

Conclusions: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.
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http://dx.doi.org/10.1007/s00592-018-1234-8DOI Listing
April 2019

Homozygous leptin receptor mutation due to uniparental disomy of chromosome 1: response to bariatric surgery.

J Clin Endocrinol Metab 2013 Feb 28;98(2):E397-402. Epub 2012 Dec 28.

Institut National de la Santéet de la Recherche Médicale (INSERM), Unité (U)872, Team 7, Nutriomique, Universite´ Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers, 75006 Paris, France.

Context: Severe early-onset obesity with major hyperphagia associated with hypogonadotropic hypogonadism is recognized as the main clinical presentation of leptin (LEP) or LEP receptor (LEPR) gene complete deficiency. In a few reported cases, homozygous mutations have been found in patients from consanguineous families. Care of LEPR-deficient patients is complicated because they cannot benefit from LEP treatment. Furthermore, gastric surgery may not be recommended in such genetic hypothalamic obesity.

Objective: We investigated in a morbidly obese patient the genetic origin of his obesity and evaluated the benefit of bariatric surgery in this case.

Subject And Methods: The patient exhibited severe early-onset obesity with hyperphagia and delayed puberty in a nonobese family. He had clinical and hormonal follow-up from 3 to 26 years of age. Gastroplasty procedures were undertaken when he was 16 and 18 years old. LEPR genetic analysis of the patient and his relatives was performed.

Results: A new homozygous LEPR sequence frameshift, predicted to generate a truncated protein from a premature stop codon in exon 14, was identified in the proband inherited from two paternal copies of chromosome 1 (isodisomy). Vertical ring gastroplasty was sufficient to induce and maintain a 40-kg weight loss into adulthood.

Conclusion: We described the first case of a patient with chromosome 1 uniparental isodisomy revealed by molecular analysis of LEPR. In this case, gastroplasty may be partially effective for weight control as illustrated.
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http://dx.doi.org/10.1210/jc.2012-2779DOI Listing
February 2013

[Hypertriglyceridemia: therapeutic strategy].

Rev Prat 2011 Oct;61(8):1110-6

Fédération d'endocrinologie, maladies métaboliques, diabète, nutrition, Hôpital Louis-Pradel, GHE HCL, CHU de Lyon, Université Lyon-1, 69677 Bron Cedex.

Causes of hypertriglyceridemia (HTG) vary according to their severity and to their character pure or mixed. Environmental factors including caloric intake excess, fructose overload, alcohol consumption, metabolic syndrom, diabetes, and drug exposure are mostly involved in pure, mild HTG. In contrast, the main etiology of mixed HTG (combined dyslipidemia) is familial combined hyperlipidemia which is commonly associated with metabolic syndrome. Major HTG (> 10 g/L) results mostly from genetic disorder in lipid metabolism with a variable contribution of environmental factors. The complications of HTG are an increased risk of acute pancreatitis (TG > 10 g/L) and a controversial atherogenic risk. Lifestyle modification is the treatment cornerstone. Nevertheless, statins are generally considered as the first drug if a medication is necessary for mixed hyperlipidemia. Fibrates may be used in combination with statin for patient with high atherogenic risk and simultaneous residual hypertriglycéridémie and low HDLc or in high risk patient with severe pure hypertriglyceridemia.
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October 2011

Increased lipid peroxidation in LDL from type-2 diabetic patients.

Lipids 2010 Aug 12;45(8):723-31. Epub 2010 Aug 12.

Université de Lyon, 69622, Lyon, France.

Increased oxidative stress is associated with type-2 diabetes and related cardiovascular diseases, but oxidative modification of LDL has been partially characterized. Our aim was to compare the lipid and fatty acid composition as well as the redox status of LDL from diabetic patients and healthy subjects. First, to ensure that isolation of LDL by sequential ultracentrifugation did not result in lipid modifications, lipid composition and peroxide content were determined in LDL isolated either by ultracentrifugation or fast-protein liquid chromatography. Both methods resulted in similar concentrations of lipids, fatty acids, hydroxy-octadecadienoic acid (HODE) and malondialdehyde (MDA). Then, LDLs were isolated by ultracentrifugation from eight type-2 diabetic patients and eight control subjects. Compared to control LDL, diabetic LDL contained decreased cholesteryl esters and increased triglyceride concentrations. Ethanolamine plasmalogens decreased by 49%. Proportions of linoleic acid decreased in all lipid classes, while proportions of arachidonic acid increased in cholesteryl esters. Total HODE concentrations increased by 56%, 12- and 15-hydroxy-eicosatetraenoic acid by 161 and 86%, respectively, and MDA levels increased by twofold. alpha-Tocopherol concentrations, expressed relative to triglycerides, were lower in LDL from patients compared to controls, while gamma-tocopherol did not differ. Overall, LDL from type-2 diabetic patients displayed increased oxidative stress. Determination of hydroxylated fatty acids and ethanolamine plasmalogen depletion could be especially relevant in diabetes.
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http://dx.doi.org/10.1007/s11745-010-3453-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944870PMC
August 2010

A controlled study of consumption of beta-glucan-enriched soups for 2 months by type 2 diabetic free-living subjects.

Br J Nutr 2010 Feb 28;103(3):422-8. Epub 2009 Sep 28.

Centre de Recherche en Nutrition Humaine de Rhône-Alpes, F-69495 Pierre-Bénite, France.

Type 2 diabetes is associated with a higher cardiovascular risk and there has been a growing interest in using dietary intervention to improve lipid profile and glucose control. The present work aims at analysing the effects of the enrichment of a normal diet with beta-glucan (3.5 g/d) in free-living type 2 diabetic subjects for 2 months, using a palatable soup. This trial was a parallel, placebo-controlled, double-blinded randomised study performed in fifty-three type 2 diabetic subjects. During a 3-week run-in period, subjects daily consumed a ready meal control soup (without beta-glucan). For the following 8 weeks, subjects were randomly assigned to consume daily either a control soup or a beta-glucan soup. Changes in lipid profile (total cholesterol (TC), HDL- and LDL-cholesterol (HDLc and LDLc), apo B and TAG) and in glucose control (HbA1c and fasting glucose) were measured. There was no significant alteration in lipid profile in the two groups (TC, HDLc, LDLc and apo B). TAG decreased significantly in the beta-glucan group compared with the control group ( - 0.12 (SD 0.38) v. 0.12 (SD 0.44) mmol/l, P = 0.03). HbA1c and fasting glucose were not reduced in any group. A single daily ingestion of 3.5 g beta-glucan, as required by official dietary recommendations, for 8 weeks did not change the lipid profile and HbA1c in type 2 diabetic subjects. To improve the metabolic profile of type 2 diabetic subjects in the long term, the quantity, the food vectors and the tolerability of beta-glucan products may be re-evaluated.
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http://dx.doi.org/10.1017/S0007114509991875DOI Listing
February 2010