Publications by authors named "Lionel Groussin"

109 Publications

Rapid control of severe ectopic Cushing's syndrome by oral osilodrostat monotherapy.

Eur J Endocrinol 2021 May;184(5):L13-L15

Department of Endocrinology, Polyclinic of Saint Côme, Compiegne, France.

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http://dx.doi.org/10.1530/EJE-21-0147DOI Listing
May 2021

Authors' Reply: 18F-fluorocholine PET/CT in MEN1 Patients with Primary Hyperparathyroidism.

World J Surg 2021 04 1;45(4):1256. Epub 2021 Jan 1.

Hopital Cochin - Université de Paris, Paris, France.

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http://dx.doi.org/10.1007/s00268-020-05896-2DOI Listing
April 2021

Correction to: A pheochromocytoma wrapped in an IgG4-related disease.

Eur J Nucl Med Mol Imaging 2021 Mar;48(3):949-950

Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, Paris, France.

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http://dx.doi.org/10.1007/s00259-020-05067-4DOI Listing
March 2021

Genomic classification of benign adrenocortical lesions.

Endocr Relat Cancer 2021 Jan;28(1):79-95

Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.
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http://dx.doi.org/10.1530/ERC-20-0128DOI Listing
January 2021

Larotrectinib-Enhanced Radioactive Iodine Uptake in Advanced Thyroid Cancer.

N Engl J Med 2020 10;383(17):1686-1687

Hôpital Cochin, Paris, France.

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http://dx.doi.org/10.1056/NEJMc2023094DOI Listing
October 2020

Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients.

Horm Res Paediatr 2020 5;93(3):182-196. Epub 2020 Aug 5.

INSERM U1185, Bicêtre Paris Sud - Paris Saclay University, Le Kremlin-Bicêtre, France.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
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http://dx.doi.org/10.1159/000508985DOI Listing
August 2020

Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma.

Endocr Connect 2020 Jul;9(7):705-714

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).

Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were 'Noisy' (numerous and anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.
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http://dx.doi.org/10.1530/EC-20-0228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424337PMC
July 2020

F-fluorocholine PET/CT in MEN1 Patients with Primary Hyperparathyroidism.

World J Surg 2020 Nov 17;44(11):3761-3769. Epub 2020 Jul 17.

Université de Paris, Paris, France.

Background: Primary hyperparathyroidism (HPT1) is the most frequent endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Its surgical management is challenging. We aimed to describe and compare the imaging findings of parathyroid ultrasound (US), sestaMIBI scintigraphy (sestaMIBI), and F-fluorocholine (FCH) PET/CT in a series of MEN1 patients with HPT1.

Methods: Retrospective analysis of a cohort of MEN1 patients with HPT1 assessed by parathyroid US, sestaMIBI scintigraphy and SPECT/CT, and FCH-PET/CT for potential surgery between 2015 and 2019.

Results: Twenty-two patients with a confirmed diagnosis of MEN1 who presented with HPT1 and were assessed by the 3 imaging modalities were included. After imaging workups, 11 patients were operated on for the first time, 4 underwent a redo surgery, and 7 did not undergo an operation. The overall patient-based positivity rate of imaging was 91% (20 of 22) for parathyroid US and 96% (21 of 22) for both sestaMIBI and FCH-PET/CT. The 3 imaging modalities demonstrated negative findings in 1/22 patient who did not undergo surgery. Overall, 3 pathologic glands were not detected by any imaging technique. SestaMIBI and FCH-PET/CT both resulted in the same 3 false-positive results in ectopic areas with a significant uptake on two thymic carcinoid tumors and one inflammatory lymph node. FCH-PET/CT provided more surgically relevant data than sestaMIBI in 4/11 patients with initial surgery and in 1/4 patient who underwent redo surgery.

Conclusions: Compared to sestaMIBI scintigraphy, FCH-PET/CT provides additional information regarding the number of pathologic parathyroid glands and their localization in MEN1 patients with HPT1.
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http://dx.doi.org/10.1007/s00268-020-05695-9DOI Listing
November 2020

A pheochromocytoma wrapped in an IgG4-related disease.

Eur J Nucl Med Mol Imaging 2021 Mar 15;48(3):929-930. Epub 2020 Jul 15.

Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, Paris, France.

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http://dx.doi.org/10.1007/s00259-020-04959-9DOI Listing
March 2021

Management of thyroid dysfunctions in the elderly. French Endocrine Society consensus 2019 guidelines. Short version.

Ann Endocrinol (Paris) 2020 10 21;81(5):511-515. Epub 2020 May 21.

Service d'endocrinologie et maladies métaboliques, CHU de Larrey, 31059 Toulouse, France. Electronic address:

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http://dx.doi.org/10.1016/j.ando.2020.05.002DOI Listing
October 2020

Amiodarone-induced thyrotoxicosis.

Ann Endocrinol (Paris) 2020 Apr 29. Epub 2020 Apr 29.

Service endocrinologie, AP-HP, hôpital Cochin, 75014 Paris, France; Université de Paris, 75014 Paris, France; Institut Cochin, Inserm Unité 1016, CNRS UMR 8104, 75014 Paris, France. Electronic address:

Amiodarone-induced thyrotoxicosis (AIT) are not uncommon endocrinopathies. Clinicians are sometimes faced with difficult diagnostic and therapeutic situations. The disease pathophysiology is partially understood, explaining the lack of predictive factors for occurrence. Different international recommendations for their management have been published: the most recent in 2018 by the European Thyroid Association (ETA) (Ross et al., 2016; Bartalena et al., 2018). The purpose of this paper is to present the essential concepts for their management and to review the literature since 2018.
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http://dx.doi.org/10.1016/j.ando.2020.04.009DOI Listing
April 2020

Redifferentiation of radioiodine-refractory thyroid cancers.

Endocr Relat Cancer 2020 05;27(5):R113-R132

Sorbonne Université Service de Médecine Nucléaire, Groupe de Recherche Clinique n°16 Tumeurs Thyroïdiennes, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.

The management of radioiodine refractory thyroid cancers (RAIR TC) is challenging for the clinician. Tyrosine kinase inhibitors classically prescribed in this setting can fail due to primary or acquired resistance or the necessity of drug withdrawal because of serious or moderate but chronic and deleterious adverse effects. Thus, the concept of redifferentiation strategy, which involves treating patients with one or more drugs capable of restoring radioiodine sensitivity for RAIR TC, has emerged. The area of redifferentiation strategy leads to the creation of new definitions of RAIR TC including persistent non radioiodine-avid patients and 'true' RAIR TC patients. The latter group presents a restored or increased radioiodine uptake in metastatic lesions but with no radiological response on conventional imaging, that is, progression of a metastatic disease, thus proving that they are 'truly' resistant to the radiation delivered by radioiodine. Unlike these patients, metastatic TC patients with restored radioiodine uptake offer the hope of prolonged remission or even cure of the disease as for radioiodine-avid metastatic TC. Here, we review the different redifferentiation strategies based on the underlying molecular mechanism leading to the sodium iodide symporter (NIS) and radioiodine uptake reinduction, that is, by modulating signaling pathways, NIS transcription, NIS trafficking to the plasma membrane, NIS post-transcriptional regulation, by gene therapy and other potential strategies. We discuss clinical trials and promising preclinical data of potential future targets.
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http://dx.doi.org/10.1530/ERC-19-0491DOI Listing
May 2020

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

J Clin Endocrinol Metab 2020 03;105(3)

INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris.

Introduction: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.

Methods: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.

Results: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.

Conclusion: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
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http://dx.doi.org/10.1210/clinem/dgaa002DOI Listing
March 2020

Succinate detection using in vivo H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas.

Eur J Nucl Med Mol Imaging 2020 06 13;47(6):1510-1517. Epub 2019 Dec 13.

Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France.

Purpose: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients.

Methods: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor.

Results: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%.

Conclusions: Detection of succinate using H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.
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http://dx.doi.org/10.1007/s00259-019-04633-9DOI Listing
June 2020

Genetics of Human Thyroid Cancer Cell Lines-Letter.

Clin Cancer Res 2019 11;25(22):6882

INSERM Unité 1016, Institut Cochin, Paris, France.

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http://dx.doi.org/10.1158/1078-0432.CCR-19-2107DOI Listing
November 2019

Prolonged response to Lu-DOTATATE therapy of a bone marrow infiltration in a refractory thymic neuro endocrine tumor.

Invest New Drugs 2020 08 24;38(4):1196-1199. Epub 2019 Oct 24.

Department of Nuclear Medicine, Cochin Hospital, AP-HP, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France.

Thymic neuro endocrine tumor (tNET) are extremely rare malignancies with poor prognosis, requiring investigation of novel therapeutic approaches. Lu-DOTATATE is a successful systemic treatment modality in patients with metastatic gastroenteropancreatic but it role in tNET is not yet well established. Here we report a case of a 39-year-old man with refractory bone marrow infiltration of a tNET, treated by 4 cycles of peptide receptor radionuclide therapy (PRRT) with Lu DOTATATE. Since the first cycle, clinical symptoms were substantially decreased, without any severe subacute haematological toxicity. Three months after the end of PRRT, both Ga-DOTATOC and F-FDG PET confirmed a partial response, already suggested by Lu-DOTATATE treatment scan with a significant decrease of the bone marrow uptake between the first and fourth cycle. This report highlights that PRRT could be an effective therapeutic option for advanced bone metastatic disease tNET, with the significant benefit of alleviation of bone pain and radiologic response, without severe or irreversible haematotoxicity.
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http://dx.doi.org/10.1007/s10637-019-00865-6DOI Listing
August 2020

Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma.

JAMA Oncol 2019 Jul 11. Epub 2019 Jul 11.

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, France.

Importance: The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome.

Objective: To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors.

Design, Setting, And Participants: In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018.

Exposures: Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts.

Main Outcomes And Measures: Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model.

Results: Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC.

Conclusions And Relevance: The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.
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http://dx.doi.org/10.1001/jamaoncol.2019.1558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624825PMC
July 2019

A Hungry Bone Syndrome Predicted by 18F-Fluorocholine PET/CT.

Clin Nucl Med 2019 Nov;44(11):903-904

From the Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University.

Predicting hungry bone syndrome (HBS) after surgical cure of primary hyperparathyroidism (PHPT) can be challenging. A 57-year-old man diagnosed with PHPT was assessed preoperatively by F-fluorocholine PET/CT. An intense and diffuse tracer uptake of the axial and peripheral skeleton was visualized, in addition to a pathologic uptake suggestive of hyperfunctioning parathyroid gland. After the removal of a parathyroid adenoma, a severe and prolonged HBS requiring high doses of calcium and active metabolites of vitamin D was observed. This observation suggests that intense and diffuse bone uptake on F-fluorocholine PET/CT could be a predictive factor for HBS in patients with PHPT.
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http://dx.doi.org/10.1097/RLU.0000000000002676DOI Listing
November 2019

MET overexpression and activation favors invasiveness in a model of anaplastic thyroid cancer.

Oncotarget 2019 Mar 19;10(23):2320-2334. Epub 2019 Mar 19.

INSERM Unité 1016, Institut Cochin, Paris, France.

In thyroid cancers, MET receptor overexpression has been associated with higher risk of metastatic progression. In this study, it was shown that the anaplastic thyroid cancer (ATC)-derived TTA1 cell line overexpressed MET. By using FISH and relative quantification by qPCR, it was demonstrated that this overexpression resulted from a amplification with more than 20 copies. As expected, MET overexpression led to its constitutive activation and upregulated signaling towards the MAPK, PI3K/AKT, STAT3 and NF-κB pathways. Since the usual feature of -amplified cell lines is the "MET addiction" for their cell proliferation, the effect of the highly selective ATP competitive MET inhibitor PHA665752 was analyzed. While PHA665752 strongly inhibited the MAPK pathway, it did not reduce cell proliferation in TTA1 cells (IC = 4100 nM). This resistance to PHA665752 of the TTA1 cell line was demonstrated to be related to EGFR-MET functional cross-talk and PI3K/AKT and NF-κB signaling. Nevertheless, PHA665752 suppressed the anchorage-independent growth capacity of the TTA1 cell line and reduced cell migration and invasion in a transwell assay. The role of activated MET in these neoplastic properties of the TTA1 cells was also proved with si-MET-RNA targeting. Thus, this work highlights the TTA1 cell line as the first model of amplification in an ATC cell line, which leads to MET constitutive activation and underlies its neoplastic properties. Besides being a useful model for MET inhibitors screening, the TTA1 cell line also supports the argument for searching for amplification in ATC, as it could have therapeutic implications.
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http://dx.doi.org/10.18632/oncotarget.26798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481343PMC
March 2019

Visualization of Macroprolactinoma by F-Fluorocholine PET/CT in a Patient With Multiple Endocrine Neoplasia Type 1.

J Endocr Soc 2018 Oct 13;2(10):1170-1172. Epub 2018 Sep 13.

Department of Nuclear Medicine, Tenon Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1210/js.2018-00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169461PMC
October 2018

18F-FDG PET reveals an adrenocortical carcinoma in a bilateral adrenal multinodular disease.

Endocrine 2019 01 24;63(1):188-189. Epub 2018 Sep 24.

COMETE Cancer Network for Adrenal Cancers, Department of Endocrinology, Cochin Hospital, Paris, France.

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http://dx.doi.org/10.1007/s12020-018-1757-3DOI Listing
January 2019

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.

Nat Rev Endocrinol 2018 08;14(8):476-500

APHP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Platform of Expertise Paris-Sud for Rare Diseases and Filière OSCAR, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.
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http://dx.doi.org/10.1038/s41574-018-0042-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541219PMC
August 2018

Polyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma.

J Endocr Soc 2017 Jun 28;1(6):646-649. Epub 2017 Apr 28.

Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.

Introduction: Checkpoint inhibitors have significantly improved the prognosis of patients with advanced melanoma. These cancer immunotherapy drugs have specific endocrine autoimmune toxicity. We describe a case of an adrenal insufficiency secondary to pembrolizumab, an anti-programmed cell death-1 monoclonal antibody. Moreover, this case of polyendocrinopathy resulting from a pembrolizumab as the adrenal insufficiency occurred after a thyroiditis.

Participant: A 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma. Five months after initiation, she suffered from thyrotoxicosis. A thyroiditis was diagnosed by iodine-123 thyroid scintigraphy and ultrasonography. Pembrolizumab therapy was maintained. Two weeks later, without any other treatment given, she patient developed hypothyroidism and levothyroxine substitution was started. Pembrolizumab proved to be ineffective and was stopped 9 months after initiation. One month following its discontinuation, the patient was hospitalized in the intensive care unit. Severe hyponatremia (115 mmol/L) associated with hyperkalemia (5.7 mmol/L) led to the early recognition and treatment of an acute adrenal insufficiency. Positive results for adrenal cortex and 21-hydroxylase antibodies were in favor of autoimmune toxicity.

Conclusion: This case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Because acute adrenal crisis may be associated with substantial morbidity and mortality, physicians must be aware of these rare adverse events to allow an early diagnosis.
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http://dx.doi.org/10.1210/js.2017-00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686573PMC
June 2017

Restoring Radioiodine Uptake in Mutated Papillary Thyroid Cancer.

J Endocr Soc 2017 Apr 21;1(4):285-287. Epub 2017 Feb 21.

Department of Endocrinology, Hôpital Cochin, 75014, Paris, France, and.

This image illustrates a multimodal therapeutic strategy for an iodine-refractory -mutated metastatic papillary thyroid carcinoma with reversed radioiodine resistance using BRAF inhibitors.
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http://dx.doi.org/10.1210/js.2016-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686703PMC
April 2017

Pituitary Lesion of Unknown Origin: Think Epithelioid Angiosarcoma.

J Endocr Soc 2017 Jan 12;1(1):72-74. Epub 2017 Jan 12.

Departments of Endocrinology.

We report the unusual etiology of a sellar aggressive mass, an epithelioid angiosarcoma, the diagnosis of which was made from positive epithelial and vascular markers.
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http://dx.doi.org/10.1210/js.2016-1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677211PMC
January 2017

Reversal of a Blunted Follicle-Stimulating Hormone by Chemotherapy in an Inhibin B-Secreting Adrenocortical Carcinoma.

J Endocr Soc 2017 Jan 12;1(1):46-50. Epub 2017 Jan 12.

Departments of Endocrinology.

Context: Adrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion.

Case Description: We describe a 60-year-old man with a right adrenal mass. Hormonal evaluation showed an ACTH-independent Cushing syndrome. Surprisingly, follicle-stimulating hormone (FSH) levels were suppressed and blunted during gonadotropin-releasing hormone stimulation, despite normal luteinizing hormone levels. Levels of inhibin B, which negatively regulates the pituitary FSH, were very high. Given the atypical hormonal findings, an adrenal mass biopsy was performed, which allowed the diagnosis of an adrenocortical tumor (positive for steroidogenic factor-1 immunostaining). Moreover, an intense -inhibin subunit immunostaining was observed. Because of the presence of metastases, the patient received mitotane and chemotherapy (etoposide and cisplatin). After 2 cycles, the inhibin B dropped. After 5 cycles, tumor size was reduced by 15%. Inhibin B levels remained low, and basal and gonadotropin-releasing hormone-stimulated FSH levels normalized. The patient underwent tumor resection, and pathology confirmed the ACC diagnosis (Weiss score of 9). The intensity of the -inhibin subunit immunostaining was significantly decreased.

Conclusions: We report the case of an inhibin B-secreting ACC in which the response to chemotherapy and mitotane was associated with a normalization of inhibin B secretion, allowing the reversal of the blunted FSH secretion. Inhibin B should be measured in case of suppressed FSH levels despite normal luteinizing hormone levels and may be considered a tumoral marker in some ACCs, even during treatment follow-up.
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http://dx.doi.org/10.1210/js.2016-1009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677210PMC
January 2017

DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers.

PLoS One 2017 14;12(9):e0184861. Epub 2017 Sep 14.

INSERM, U1016, Institut Cochin, Paris, France.

Background: Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis.

Methods: MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RASV12 or BRAFV600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAFV600E carcinoma cell lines.

Results: BRAFV600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAFV600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAFV600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion.

Conclusions: Our results are in favor of a stronger activation of the MAPK pathway in BRAFV600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAFV600E PTC cell line models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184861PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599027PMC
October 2017