Publications by authors named "Charlotte Lussey-Lepoutre"

29 Publications

  • Page 1 of 1

Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate.

Cancer Res 2021 Jul 14;81(13):3480-3494. Epub 2021 Jun 14.

PARCC, INSERM UMR970, Equipe Labellisée par la Ligue Contre le Cancer, Paris, France.

Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an knockout chromaffin cell line and compared it with deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in -deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers. SIGNIFICANCE: Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2936DOI Listing
July 2021

International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.

Nat Rev Endocrinol 2021 Jul 21;17(7):435-444. Epub 2021 May 21.

INSERM, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
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http://dx.doi.org/10.1038/s41574-021-00492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205850PMC
July 2021

Recurrence-free survival analysis in locally advanced pheochromocytoma: first appraisal.

J Clin Endocrinol Metab 2021 Mar 30. Epub 2021 Mar 30.

Endocrine oncology unit, Gustave Roussy, F-94805, Villejuif, France.

Context: Locally advanced pheochromocytoma (LAP) behavior remains unknown.

Objective: To characterize this population and its recurrence-free survival (RFS).

Design: A retrospective multicentric study run within the ENDOCAN-COMETE network and GTE from 2003 to 2018.

Setting: 11 French Referral centers.

Patients: Patients with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis.

Main Outcome Measures: Recurrence was defined as the reappearance of the tumor, including local site and/or distant metastasis. The primary endpoint was RFS analysis. The secondary endpoints were characterization, overall survival (OS) and prognostic factors of recurrence.

Results: Among 950 patients, 90 exhibited LAP criteria (9%). 55 met the inclusion criteria (median age: 53 years-old, 61% males, 14% with a germline mutation, 84% with a catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes and 22 (40%) vascular invasions. After a median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of a metastatic disease. Median RFS was 115 months (range, 6-168). The recurrences were local in 2 patients, distant in 2 and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5cm (p=0.019) and Ki-67>2% (p=0.028) were identified as independent significant prognostic factors in multivariate analysis.

Conclusions: LAP represents 9% of pheochromocytoma's population and is characterized by a metastatic behavior. This study paved the way of a future pathological TNM classification.
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http://dx.doi.org/10.1210/clinem/dgab202DOI Listing
March 2021

Therapeutic Plasma Exchange in Refractory Hyperthyroidism.

Eur Thyroid J 2021 Mar 28;10(1):86-92. Epub 2020 Apr 28.

Thyroid and Endocrine Tumors Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France.

Introduction: Hyperthyroid patients who are unresponsive to medical treatment remain a challenging clinical problem.

Objective: The goal of our study was to evaluate the use of therapeutic plasma exchange (TPE) in hyperthyroid patients and their outcome after TPE.

Method: We retrospectively reviewed 22 patients who underwent TPE for refractory thyrotoxicosis in our institution: 13 with Graves' disease, 7 with amiodarone-induced thyrotoxicosis (AIT), 1 with toxic goiter, and 1 pregnant patient with familial nonautoimmune thyrotoxicosis.

Results: Before TPE, all patients had severe hyperthyroidism, and antithyroid drugs were either contraindicated or not sufficiently effective to restore euthyroidism promptly. After all the TPEs, free T (fT4) decreased significantly by 48% ( = 0.001) and fT3 by 52% ( = 0.0001). The median number of TPE sessions per patient was 4 (range: 1-10). There were no complications during the 91 TPE sessions. Total thyroidectomy with no severe side effects was performed on 16/22 patients and 1 other patient was treated with radioactive iodine. One patient died from severe thyrotoxicosis during medical care. The remaining 4 patients were followed up without any radical treatment. For all 7 patients with AIT, iterative TPE led to a significant clinical improvement, and amiodarone was continued for 1 patient. Available treatments were continued between TPE sessions (cholestyramine for 13 patients [60%] and glucocorticoids for 16 patients [73%]).

Conclusion: TPE allowed a safe decrease of 50% in thyroid hormone levels, and it should be considered for refractory hyperthyroid patients when medical treatments are contraindicated or have failed to restore euthyroidism, irrespective of the etiology of the thyrotoxicosis.
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http://dx.doi.org/10.1159/000507019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983568PMC
March 2021

Screening of a Large Cohort of Asymptomatic SDHx Mutation Carriers in Routine Practice.

J Clin Endocrinol Metab 2021 Mar;106(3):e1301-e1315

Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols.

Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.

Design And Setting: Retrospective multicentric study in 6 referral centers.

Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled.

Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.

Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data.
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http://dx.doi.org/10.1210/clinem/dgaa888DOI Listing
March 2021

Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas.

Endocr Relat Cancer 2020 12;27(12):R451-R463

PARCC, INSERM UMR970, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla or extra-adrenal paraganglia. Around 40% of all cases are caused by a germline mutation in a susceptibility gene, half of which being found in an SDHx gene (SDHA, SDHB, SDHC, SDHD or SDHAF2). They encode the four subunits and assembly factor of succinate dehydrogenase (SDH), a mitochondrial enzyme involved both in the tricarboxylic acid cycle and electron transport chain. SDHx mutations lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting iron(II) and alpha-ketoglutarate-dependent dioxygenases thereby regulating the cell's hypoxic response and epigenetic processes. Moreover, SDHx mutations induce cell metabolic reprogramming and redox imbalance. Major discoveries in PPGL pathophysiology have been made since the initial discovery of SDHD gene mutations in 2000, improving the understanding of their biology and patient management. It indeed provides new opportunities for diagnostic tools and innovative therapeutic targets in order to improve the prognosis of patients affected by these rare tumors, in particular in the context of metastatic diseases associated with SDHB mutations. This review first describes an overview of the pathophysiology and then focuses on clinical implications of the epigenetic and metabolic reprogramming of SDH-deficient PPGL.
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http://dx.doi.org/10.1530/ERC-20-0346DOI Listing
December 2020

Solitary Breast Metastasis From Thyroid Papillary Carcinoma Revealed on Whole-Body Radioactive 131I Scan.

Clin Nucl Med 2020 Sep;45(9):687-688

From the Sorbonne Université, Department of Nuclear Medicine, AP-HP, Pitie-Salpêtrière Hospital.

Breast metastasis from thyroid papillary carcinoma is an exceptional situation. Here, we present the diagnostic approach and the management of a 19-year-old woman with single breast metastasis from thyroid carcinoma. There was no extra thyroidal extension, neoplastic emboli, or lymph node invasion. The metastasis was revealed by whole-body radioactive I scan, explored by a fine-needle aspiration, and confirmed by elevated thyroglobulin in situ.
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http://dx.doi.org/10.1097/RLU.0000000000003115DOI Listing
September 2020

Utility of a Second Tc-MIBI Scintigraphy Before Reoperation for Patients With Persistent Sporadic Primary Hyperparathyroidism: Results of a Retrospective Multicenter Study.

Ann Surg Oncol 2020 Oct 3;27(10):3831-3839. Epub 2020 Apr 3.

Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire de Nantes, Nantes, France.

Background: Persistent primary hyperparathyroidism (PHPT) occurs in 2.5% to 15% of cases after parathyroidectomy. Few studies have evaluated the best pre-reoperative imaging approaches for persistent sporadic PHPT. This retrospective multicenter study aimed to evaluate the benefit of a second pre-reoperative Tc-methoxy-isobutyl-isonitrile (MIBI) scintigraphy for patients with persistent PHPT who had a Tc-MIBI before their initial surgery.

Methods: The study enrolled 50 patients with persistent sporadic PHPT who had reoperation between 2006 and 2016 in three French University Hospitals (Angers, Nantes, and La Pitié Salpêtrière-Paris). Preoperative Tc-MIBI scan was performed before each operation.

Results: After the reoperation, 42 patients (84%) were cured. By the second Tc-MIBI, 31 patients (62%) had a removed gland identified. A new pathologic gland was identified by a second Tc-MIBI in 25 patients (50%), and this imaging permitted correction of an initial surgical error in six patients (12%). A second Tc-MIBI showed a sensitivity of 63%, a specificity of 89%, a positive predictive value (PPV) of 78%, and a negative predictive value (NPV) of 80%. A concordant second Tc-MIBI and ultrasonography (17 patients) showed a sensitivity of 70%, a specificity of 81%, a PPV of 70%, and an NPV of 81%.

Conclusions: Performing a second Tc-MIBI scan permitted 62% of the persistent PHPT patients to be cured, allowing identification of new pathologic glands in 50% of the cases and correction of an initial surgical error in 12% of the cases, with high specificity and PPV. These results reinforce the fact that a second Tc-MIBI scan should be performed at first intention before reoperation of patients with persistent PHPT, regardless of the result from the initial Tc-MIBI scan.
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http://dx.doi.org/10.1245/s10434-020-08428-3DOI Listing
October 2020

Concurrent imaging of vascularization and metabolism in a mouse model of paraganglioma under anti-angiogenic treatment.

Theranostics 2020 10;10(8):3518-3532. Epub 2020 Feb 10.

Université de Paris, PARCC, INSERM, F-75015 Paris, France.

: Deregulation of metabolism and induction of vascularization are major hallmarks of cancer. Using a new multimodal preclinical imaging instrument, we explored a sequence of events leading to sunitinib-induced resistance in a murine model of paraganglioma (PGL) invalidated for the expression of succinate dehydrogenase subunit B ( ). : Two groups of tumors bearing mice were treated with sunitinib (6 weeks) or vehicle (3 weeks). Concurrent Positron Emission Tomography (PET) with 2' -deoxy-2'-[F]fluoro-D-glucose (FDG), Computed Tomography (CT) and Ultrafast Ultrasound Imaging (UUI) imaging sessions were performed once a week and ex vivo samples were analyzed by western blots and histology. : PET-CT-UUI enabled to detect a rapid growth of tumors with increased glycolysis and vascular development. Sunitinib treatment prevented tumor growth, vessel development and reduced FDG uptake at week 1 and 2 (W1-2). Thereafter, imaging revealed tumor escape from sunitinib treatment: FDG uptake in tumors increased at W3, followed by tumor growth and vessel development at W4-5. Perfused vessels were preferentially distributed in the hypermetabolic regions of the tumors and the perfused volume increased during escape from sunitinib treatment. Finally, initial changes in total lesion glycolysis and maximum vessel length at W1 were predictive of resistance to sunitinib. : These results demonstrate an adaptive resistance of tumors to six weeks of sunitinib treatment. Early metabolic changes and delayed vessel architecture changes were detectable and predictable early during anti-angiogenic treatment. Simultaneous metabolic, anatomical and functional imaging can monitor precisely the effects of anti-angiogenic treatment of tumors.
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http://dx.doi.org/10.7150/thno.40687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069082PMC
April 2021

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

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

When Graves' disease resists to surgery: A rare case of an association with follicular thyroid cancer in struma ovarii.

Ann Endocrinol (Paris) 2019 Nov 18;80(5-6):329-331. Epub 2019 Oct 18.

Department of nuclear medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France; Inserm, UMR970, Paris-Cardiovascular Research Center, 75015 Paris, France; GRC n(o) 16, GRC tumeurs thyroïdiennes, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.ando.2019.09.002DOI Listing
November 2019

Transcriptome Analysis of lncRNAs in Pheochromocytomas and Paragangliomas.

J Clin Endocrinol Metab 2020 03;105(3)

Paris University, PARCC, INSERM, Equipe labellisée par la Ligue contre le cancer, Paris, France.

Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness.

Objective: We aimed at identifying long noncoding RNAs (lncRNAs) specific for PPGL molecular groups and metastatic progression.

Design And Methods: To analyze the expression of lncRNAs, we used a mining approach of transcriptome data from a well-characterized series of 187 tumor tissues. Clustering consensus analysis was performed to determine a lncRNA-based classification, and informative transcripts were validated in an independent series of 51 PPGLs. The expression of metastasis-related lncRNAs was confirmed by RT-qPCR. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive accuracy of potential markers.

Main Outcome Measure: Univariate/multivariate and metastasis-free survival (MFS) analyses were carried out for the assessment of risk factors and clinical outcomes.

Results: Four lncRNA-based subtypes strongly correlated with mRNA expression clusters (chi-square P-values from 1.38 × 10-32 to 1.07 × 10-67). We identified one putative lncRNA (GenBank: BC063866) that accurately discriminates metastatic from benign tumors in patients with SDHx mutations (area under the curve 0.95; P = 4.59 × 10-05). Moreover, this transcript appeared as an independent risk factor associated with poor clinical outcome of SDHx carriers (log-rank test P = 2.29 × 10-05).

Conclusion: Our findings extend the spectrum of transcriptional dysregulations in PPGL to lncRNAs and provide a novel biomarker that could be useful to identify potentially metastatic tumors in patients carrying SDHx mutations.
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http://dx.doi.org/10.1210/clinem/dgz168DOI Listing
March 2020

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma.

Theranostics 2019 9;9(17):4946-4958. Epub 2019 Jul 9.

Department of Internal Medicine, Radboud University Medical Centre, 6525 HP Nijmegen, The Netherlands.

: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through models, and define specific therapeutic options according to tumor genomic features. : We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized . : A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, =4.67·10), and was found associated with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated a repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. : Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.
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http://dx.doi.org/10.7150/thno.35458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691382PMC
August 2020

Emerging molecular markers of metastatic pheochromocytomas and paragangliomas.

Ann Endocrinol (Paris) 2019 Jun 11;80(3):159-162. Epub 2019 Apr 11.

Inserm, UMR970, équipe labellisée Ligue Contre le Cancer, Paris-Cardiovascular Research Center, 75015 Paris, France; Faculté de médecine, PRES Sorbonne Paris-Cité, Paris-Descartes University, 75006 Paris, France. Electronic address:

Metastatic pheochromocytoma/paraganglioma (PPGL) represents a major clinical challenge due to limitations in accurate diagnostic tools and effective treatments. Currently, patients classified at high-risk by means of clinical, biochemical and genetic criteria, require a lifelong monitoring, while it remains difficult to determine the metastatic potential of PPGL only on the basis of histopathological features. Thus, tumor molecular markers that improve the risk stratification of these patients are needed. In the past few years, we have witnessed an unprecedented molecular characterization of PPGL, which led to the emergence of promising candidate biomarkers predictive of metastatic behavior. Here, we briefly discuss these breakthroughs and provide some insights for the prospective implementation of molecular markers of metastatic PPGL in the clinical setting in years to come.
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http://dx.doi.org/10.1016/j.ando.2019.04.003DOI Listing
June 2019

Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.

J Med Genet 2019 08 15;56(8):513-520. Epub 2019 Mar 15.

Genetics department, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France.

Background: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS).

Methods: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours.

Results: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available.

Conclusion: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.
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http://dx.doi.org/10.1136/jmedgenet-2018-105714DOI Listing
August 2019

Novel PET tracers: added value for endocrine disorders.

Endocrine 2019 04 14;64(1):14-30. Epub 2019 Mar 14.

Sorbonne University, Nuclear Medicine Department, Pitié-Salpêtrière Hospital, 47-83 Bd de l'Hôpital, 75013, Paris, France.

Nuclear medicine has been implicated in the diagnosis and treatment of endocrine disorders for several decades. With recent development of PET tracers, functional imaging now plays a major role in endocrine tumors enabling with high performance to their localization, characterization, and staging. Besides F-FDG, which may be used in the management and follow-up of endocrine tumors, new tracers have emerged, such as F-DOPA for neuroendocrine tumors (NETs) (medullary thyroid carcinoma, pheochromocytomas and paragangliomas and well-differentiated NETs originating from the midgut) and F-Choline in the field of primary hyperparathyroidism. Moreover, some peptides such as somatostatin analogs can also be used for peptide receptor radionuclide therapy. In this context, Gallium-68 labeled somatostatin analogs (Ga-SSA) can help to tailor therapeutic choices and follow the response to treatment in the so-called "theranostic" approach. This review emphasizes the usefulness of these three novel PET tracers (F-Choline, F-FDOPA, and Ga-SSA) for primary hyperparathyroidism and neuroendocrine tumors.
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http://dx.doi.org/10.1007/s12020-019-01895-zDOI Listing
April 2019

18F-Fluorocholine PET/CT and Parathyroid 4D Computed Tomography for Primary Hyperparathyroidism: The Challenge of Reoperative Patients.

World J Surg 2019 05;43(5):1232-1242

Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Background: To evaluate FCH-PET/CT and parathyroid 4D-CT so as to guide surgery in patients with primary hyperparathyroidism (pHPT) and prior neck surgery.

Methods: Medical records of all patients referred for a FCH-PET/CT in our institution were systematically reviewed. Only patients with pHPT, a history of neck surgery (for pHPT or another reason) and an indication of reoperation were included. All patients had parathyroid ultrasound (US) and Tc-99m-sestaMIBI scintigraphy, and furthermore, some patients had 4D-CT. Gold standard was defined by pathological findings and/or US-guided fine-needle aspiration with PTH level measurement in the washing liquid.

Results: Twenty-nine patients were included in this retrospective study. FCH-PET/CT identified 34 abnormal foci including 19 ectopic localizations. 4D-CT, performed in 20 patients, detected 11 abnormal glands at first reading and 6 more under FCH-PET/CT guidance. US and Tc-99m-sestaMIBI found concordant foci in 8/29 patients. Gold standard was obtained for 32 abnormal FCH-PET/CT foci in 27 patients. On a per-lesion analysis, sensitivity, specificity, positive and negative predictive values were, respectively, 96%, 13%, 77% and 50% for FCH-PET/CT, 75%, 40%, 80% and 33% for 4D-CT. On a per-patient analysis, sensitivity was 85% for FCH-PET/CT and 63% for 4D-CT. FCH-PET/CT results made it possible to successfully remove an abnormal gland in 21 patients, including 12 with a negative or discordant US/Tc-99m-sestaMIBI scintigraphy result, with a global cure rate of 73%.

Conclusion: FCH-PET/CT is a promising tool in the challenging population of reoperative patients with pHPT. Parathyroid 4D-CT appears as a confirmatory imaging modality.
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http://dx.doi.org/10.1007/s00268-019-04910-6DOI Listing
May 2019

NIFT-P: Are they indolent tumors? Results of a multi-institutional study.

Surgery 2019 01 9;165(1):12-16. Epub 2018 Nov 9.

Sorbonne Université, Pitié Salpêtrière Hospital, Paris, France.

Background: Encapsulated follicular variant of papillary thyroid carcinoma has recently been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the basis of its highly indolent behavior, as proposed by an international group of experienced thyroid pathologists.

Methods: All patients from 9 high-volume endocrine surgery departments who underwent surgery between 2005 and 2015 and whose final surgical pathology revealed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (>10 mm) were included in this study. The primary outcome was to determine the potential for recurrent disease in these patients.

Results: Among the 363 patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features, 76% were female with a median age of 50 years (5-86 years); 345 patients (95%) underwent total thyroidectomy. A total of 65 patients had an associated micropapillary thyroid carcinoma. In the group of 133 patients who underwent prophylactic lymph node dissection (37%), 1 patient had a micrometastasis but with an associated micropapillary thyroid carcinoma. Over a median follow-up period of 5 years, 1 patient with an associated micropapillary thyroid carcinoma had recurrent disease at 6 years. All patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features without micropapillary thyroid carcinoma had no lymph node metastasis or recurrent disease.

Conclusion: We found that noninvasive follicular thyroid neoplasm with papillary-like nuclear features presents with indolent behavior. However, the identification of an associated micropapillary thyroid carcinoma should be carefully evaluated because it could be a factor for lymph node metastasis and/or of recurrence.
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http://dx.doi.org/10.1016/j.surg.2018.04.089DOI Listing
January 2019

Treatment of adult Graves' disease.

Ann Endocrinol (Paris) 2018 Dec 16;79(6):618-635. Epub 2018 Aug 16.

Service de médecine nucléaire, Inserm U970, Sorbonne université, groupe hospitalier Pitié-Salpétrière, 75013 Paris, France.

Treatment strategy in Graves' disease firstly requires recovery of euthyroid status by antithyroid therapy. Treatment modalities, precautions, advantages and side-effects are to be discussed with the patient. No particular treatment modality has demonstrated superiority. Pregnancy or pregnancy project affects choice of treatment and monitoring. Graves' orbitopathy is liable to be aggravated by iodine-131 treatment and requires pre-treatment assessment. Iodine-131 treatment aims at achieving hypothyroidism. Thyroid surgery for Graves' disease should preferably be performed by an expert team. In case of recurrence of hyperthyroidism, the various treatment options should be discussed with the patient. Empiric treatment of thyroid dermopathy uses local corticosteroids in occlusive dressing.
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http://dx.doi.org/10.1016/j.ando.2018.08.003DOI Listing
December 2018

Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier Gene Confer a Predisposition to Metastatic Paragangliomas.

Cancer Res 2018 04 5;78(8):1914-1922. Epub 2018 Feb 5.

INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.

Comprehensive genetic analyses have identified germline and gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an -like molecular profile in the absence of or mutations and identified a germline mutation in the gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in - and -related tumors were observed both in tumors with mutated and in immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation. A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2463DOI Listing
April 2018

Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis.

Cell Tissue Res 2018 05 9;372(2):379-392. Epub 2018 Feb 9.

INSERM UMR970, Paris-Cardiovascular Research Center, Equipe Labellisée Ligue Contre le Cancer, 56 rue Leblanc, F-75015, Paris, France.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors characterized by a large spectrum of hereditary predisposition. Based on gene expression profiling classification, they can be classically assigned to either a hypoxic/angiogenic cluster (cluster 1 including tumors with mutations in SDHx, VHL and FH genes) or a kinase-signaling cluster (cluster 2 consisting in tumors related to RET, NF1, TMEM127 and MAX genes mutations, as well as most of the sporadic tumors). The past 15 years have seen the emergence of an increasing number of genetically engineered and grafted models to investigate tumorigenesis and develop new therapeutic strategies. Among them, only cluster 2-related predisposed models have been successful but grafted models are however available to study cluster 1-related tumors. In this review, we present an overview of existing rodent models targeting predisposition genes involved or not in human pheochromocytoma/paraganglioma susceptibility and their contribution to the improvement of pheochromocytoma experimental research.
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http://dx.doi.org/10.1007/s00441-018-2797-yDOI Listing
May 2018

Simultaneous positron emission tomography and ultrafast ultrasound for hybrid molecular, anatomical and functional imaging.

Nat Biomed Eng 2018 02 6;2(2):85-94. Epub 2018 Feb 6.

Inserm, UMR970, Paris Cardiovascular Research Center, Paris, France.

Positron emission tomography-computed tomography (PET-CT) is the most sensitive molecular imaging modality, but it does not easily allow for rapid temporal acquisition. Ultrafast ultrasound imaging (UUI)-a recently introduced technology based on ultrasonic holography-leverages frame rates of up to several thousand images per second to quantitatively map, at high resolution, haemodynamic, biomechanical, electrophysiological and structural parameters. Here, we describe a pre-clinical scanner that registers PET-CT and UUI volumes acquired simultaneously and offers multiple combinations for imaging. We demonstrate that PET-CT-UUI allows for simultaneous images of the vasculature and metabolism during tumour growth in mice and rats, as well as for synchronized multi-modal cardiac cine-loops. Combined anatomical, functional and molecular imaging with PET-CT-UUI represents a high-performance and clinically translatable technology for biomedical research.
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http://dx.doi.org/10.1038/s41551-018-0188-zDOI Listing
February 2018

Diffusion-weighted MRI is not superior to FDG-PET/CT for the detection of neck recurrence in well-differentiated thyroid carcinoma.

Q J Nucl Med Mol Imaging 2019 Sep 3;63(3):311-320. Epub 2017 May 3.

Department of Nuclear Medicine and Radiology, Henri Becquerel Centre & Quant.I.F - LITIS (Equipe d'Accueil) 4108 - Fédération de Recherche CNRS 3638, Faculty of Medicine, University of Rouen, Rouen, France.

Background: Management of patients with well-differentiated thyroid carcinoma (WDTC) and positive thyroglobulin (Tg)/negative iodine-131 whole body scintigraphy (WBS) remains challenging. Here, we investigate the specific role of diffusion-weighted magnetic resonance imaging of the neck (DW-MRI) as compared to rhTSH stimulated FDG-PET/CT in such patients.

Methods: Patients with WDTC, positive Tg/negative WBS were prospectively enrolled in the study. FDG-PET/CT and neck DW-MRI were performed on the same day after rhTSH stimulation. Neck-US was performed 24 hours after FDG-PET/CT and MRI to guide fine-needle aspiration (FNA). Patients with positive FNA underwent surgery. Patient with negative workup underwent new explorations at 6 and 18 months.

Results: A total of 86 FDG-PET/CT and 83 DW-MRI tests were performed in 40 patients (23 females; 17 males; 52±16 years). For detection of neck recurrences, sensitivity was equivalent for FDG-PET/CT and to DW-MRI at baseline (46% vs. 43%), at 6 months (30% vs. 20%) and at 18 months (11 vs. 10%). The comparison with a non-weighted Kappa test shows significant concordance between FDG-PET/CT and DW-MRI (K=0.741±0.062; P<0.0001). A relationship was observed between Tg and results of FDG-PET/CT, but not for DW-MRI. FDG-PET/CT permitted to detect iodine-refractory distant metastasis in 4 patients.

Conclusions: In Tg-positive/WBS-negative DTC patients, low tumour burden, neck DW-MRI does not provide additional information compared to rhTSH-stimulated FDG-PET/CT. FDG-PET/CT has the best sensitivity, is acceptable for patients, allows whole body exploration and distant metastasis detections, and is correlated with Tg levels.
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http://dx.doi.org/10.23736/S1824-4785.17.02961-2DOI Listing
September 2019

Mitochondrial Deficiencies in the Predisposition to Paraganglioma.

Metabolites 2017 May 4;7(2). Epub 2017 May 4.

INSERM UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumours with a very strong genetic component. It is estimated that around 40% of all cases are caused by a germline mutation in one of the 13 predisposing genes identified so far. Half of these inherited cases are intriguingly caused by mutations in genes encoding tricarboxylic acid enzymes, namely , , , , and genes, encoding succinate dehydrogenase and its assembly protein, encoding fumarate hydratase, and encoding malate dehydrogenase. These mutations may also predispose to other type of cancers, such as renal cancer, leiomyomas, or gastro-intestinal stromal tumours. SDH, which is also the complex II of the oxidative respiratory chain, was the first mitochondrial enzyme to be identified having tumour suppressor functions, demonstrating that 80 years after his initial proposal, Otto Warburg may have actually been right when he hypothesized that low mitochondrial respiration was the origin of cancer. This review reports the current view on how such metabolic deficiencies may lead to cancer predisposition and shows that the recent data may lead to the development of innovative therapeutic strategies and establish precision medicine approaches for the management of patients affected by these rare diseases.
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http://dx.doi.org/10.3390/metabo7020017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487988PMC
May 2017

Heterogeneous Prognoses for pT3 Papillary Thyroid Carcinomas and Impact of Delayed Risk Stratification.

Thyroid 2017 06 24;27(6):778-786. Epub 2017 Apr 24.

1 Thyroid and Endocrine Tumors Unit, Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Paris VI University , Cancer Institute, Paris, France .

Background: Papillary thyroid carcinomas (PTC) in the pT3 category constitute a heterogeneous group of tumors with a variable risk of recurrence. The objectives of this study were (i) to estimate disease-free survival (DFS) and identify prognostic factors associated with recurrence in a cohort of pT3 PTC, and (ii) to evaluate the concept of delayed risk stratification in a cohort of pT3 tumors.

Methods: A total of 560 patients with pT3 PTC, treated and followed at the authors' institution, were studied. They were divided into three groups: group 1, pT3 ≤10 mm; group 2, pT3 >10 mm with extrathyroidal invasion (ETI); and group 3, pT3 due to a tumor size >4 cm. DFS was estimated using the Kaplan-Meier method, and associated prognostic features were studied in univariate and multivariate Cox model-based analyses in each group. Then, DFS was studied for each group according to the six- to eight-month status (remission or not).

Results: DFS at 10 years was 75% for the entire cohort and was 89%, 67%, and 82% in groups 1, 2, and 3, respectively (p < 0.0001). Multivariate analysis identified three factors significantly associated with reduced DFS: lymph node (LN) involvement, male sex, and group 2 (>1 cm with ETI). A trend toward a worse prognosis in patients with pT3 N0/Nx PTC >10 mm with ETI was found in comparison with the other pT3 N0/Nx patients. When the six- to eight-month checkup was normal, the DFS at 10 years increased to 98%, 96%, and 91% in groups 1-3, respectively. Furthermore, in this case, initial LN involvement no longer seemed to affect the prognosis in those groups.

Conclusion: PTC ≤10 mm with ETI and large tumors >4 cm without ETI both have a low-recurrence risk when there are no adverse associated prognostic features such as LN involvement. LN involvement, especially in the lateral compartment (N1b), is a strong prognostic factor of recurrence in pT3 PTC. Delayed risk stratification can be applied in pT3 PTC patients. Those cured at the first checkup, including those with limited LN involvement, have excellent outcomes, which should prompt clinicians to adapt subsequent management accordingly.
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http://dx.doi.org/10.1089/thy.2016.0512DOI Listing
June 2017

MANAGEMENT OF ENDOCRINE DISEASE: Recurrence or new tumors after complete resection of pheochromocytomas and paragangliomas: a systematic review and meta-analysis.

Eur J Endocrinol 2016 Oct 14;175(4):R135-45. Epub 2016 Apr 14.

Faculty of MedicineSorbonne Universités, UPMC Univ Paris 06, Paris, France INSERMU1142, LIMICS, Paris, France Department of Internal MedicineAP-HP, Hôpital Tenon, Paris, France

Objectives: To systematically review the incidence and factors associated with recurrences or new tumors after apparent complete resection of pheochromocytoma or thoraco-abdomino-pelvic paraganglioma.

Design: A systematic review and meta-analysis of published literature was performed.

Methods: Pubmed and Embase from 1980 to 2012 were searched for studies published in English on patients with non-metastatic pheochromocytoma or thoraco-abdomino-pelvic paraganglioma, complete tumor resection, postoperative follow-up exceeding 1 month, and recurrence or new tumor documented by pathology, hormonal dosages, or imaging tests. Incidence rates of new events after curative surgery were calculated for each study that had sufficient information and pooled using random-effect meta-analysis.

Results: In total, 38 studies were selected from 3518 references, of which 36 reported retrospective cohorts from the USA, Europe, and Asia. Patient follow-up was neither standardized nor exhaustive in the included studies. A clear description of patient retrieval methods was available for nine studies and the follow-up protocol and patient flow for four studies. Only two studies used multivariable methods to assess potential predictors of postoperative events.The overall rate of recurrent disease from 34 studies was 0.98 events/100 person-years (95% confidence interval 0.71, 1.25). Syndromic diseases and paragangliomas were consistently associated with a higher risk of a new event in individual studies and in meta-regression analysis.

Conclusions: The risk of recurrent disease after complete resection of pheochromocytoma may be lower than that previously estimated, corresponding to five events for 100 patients followed up for 5 years after complete resection. Risk stratification is required to tailor the follow-up protocol after complete resection of a pheochromocytoma or paraganglioma. Large multicenter studies are needed to this end.
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http://dx.doi.org/10.1530/EJE-16-0189DOI Listing
October 2016

Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.

Nat Commun 2015 Nov 2;6:8784. Epub 2015 Nov 2.

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.
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http://dx.doi.org/10.1038/ncomms9784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632646PMC
November 2015

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma.

Clin Cancer Res 2016 Mar 21;22(5):1120-9. Epub 2015 Oct 21.

INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.

Purpose: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy.

Experimental Design: A pulsed proton magnetic resonance spectroscopy ((1)H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb(-/-) or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors.

Results: A succinate peak was observed at 2.44 ppm by (1)H-MRS in all Sdhb(-/-)-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, (1)H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene.

Conclusions: Detection of succinate by (1)H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1576DOI Listing
March 2016
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