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International audience; Aims: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromestreated with metreleptin in a national reference network, in a real-life setting.Patients and Methods: Clinical and metabolic data from patients receiving metreleptin in France wereretrospectively collected, at baseline, one year and at the latest follow-up during treatment.Results: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD, n=28) andpartial lipodystrophy (PLD, n=19) received metreleptin over the last decade. At baseline, age was 29.3[16.6-47.6] (years, median [interquartile range]); BMI 23.8 kg/m2 [21.2-25.7]; serum leptin 3.2 [1.0-4.9] ng/mL); 94% of patients had diabetes (66% insulin-treated), 53% hypertension, and 87%dyslipidemia. Metreleptin therapy, administered during 31.7 [14.2-76.0] months, was ongoing in 77%of patients at the latest follow-up. In patients with GLD, HbA1c (%) and fasting triglycerides (mmol/L)significantly decreased from baseline to one year-metreleptin treatment, from 8.4 [6.5-9.9] to 6.8 [5.6-7.4], and 3.6 [1.7-8.5] to 2.2 [1.1-3.7] respectively (p

Purpose Bone metastases (BM) from differentiated thyroid carcinoma (DTC) impact negatively the quality of life and the life expectancy of patients. The aim of the study was (a) to evaluate the overall survival (OS) and prognostic factors of OS and (b) to assess predictive factors of complete BM response (C-BM-R) using radioiodine treatment (RAI) either alone or in association with focal treatment modalities. Methods A total of 178 consecutive DTC patients harbouring BM, treated between 1989 and 2015, were enrolled in this retrospective study conducted in two tertiary referral centers. OS analysis was performed for the whole cohort, and only the 145 considered non-RAI refractory patients at BM diagnosis were evaluated for C-BM-R following RAI. Results The median OS from BM diagnosis was 57 months (IQR: 24–93). In multivariate analysis, OS was significantly reduced in the case of T4 stage, 18FDG uptake by the BM and RAI refractory status. Among the 145 DTC considered non-RAI refractory patients at BM diagnosis, 46 patients (31.7%) achieved a C-BM-R following RAI treatment, either alone in 32 (18%) patients or in association with focal BM treatment modalities in 14. The absence of extra-skeletal distant metastasis and of 18FDG uptake in BM were predictive for C-BM-R. Conclusions In nearly one-third of DTC patients with RAI avid BM, RAI alone or in combination with BM focal treatment can induce C-BM-R. The presence of 18FDG uptake in BM is associated with an absence of C-BM-R and with a poor OS. 18FDG PET-CT should be performed when BM is suspected.

The natriuretic peptide family consists of three biologically active peptides: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP, secreted by the heart, act as cardiac hormones, whereas CNP is an endothelial peptide. The aim of this manuscript is to review the production, action mechanisms, effects and clinical applications of natriuretic peptides.

Background: Lymph node dissection (LND) in primary treatment of differentiated thyroid carcinoma is controversial. The aim of our retrospective study was to analyse the risk factors of post-thyroidectomy complications and to assess the morbidity of lymph node dissection, especially in the central neck compartment, since prophylactic central lymph node dissection has not been proven to bring an overall survival benefit. Methods: We performed a retrospective analysis of postoperative complications from 1547 consecutive patients with differentiated thyroid carcinoma in an academic department of endocrine surgery over a period of 10 years. Results: A total of 535 patients underwent lymph node dissection, whereas the other 1012 did not. The rate of postoperative hypoparathyroidism was higher in patients with LND (17.6% vs. 11.4%, p = 0.001). No significant difference in the rate of permanent hypoparathyroidism (2.4% vs. 1.3%, p = 0.096) was observed between these two groups. A multivariate analysis was performed. Female gender, ipsilateral and bilateral central LND (CLND), parathyroid autotransplantation, and the presence of the parathyroid gland on the resected thyroid were associated with transient hypoparathyroidism. Bilateral CLND and the presence of the parathyroid gland on specimen were associated with permanent hypoparathyroidism. The rate of transient recurrent laryngeal nerve (RLN) injury (15.3% vs. 5.4%, p < 0.001) and permanent RLN injury (6.5% vs. 0.9%, p < 0.001) were higher in the LND group. In multivariate analysis, ipsilateral and bilateral lateral LND (LLND) were the main predictive factors of transient and permanent RLN injury. Bilateral RLN injury (2.6% vs. 0.4%, p < 0.001), chyle leakage (2.4% vs. 0%, p < 0.001), other nerve injuries (2.2% vs. 0%, p < 0.001), and abscess (2.4% vs. 0.5%, p = 0.001) were higher in the patients with LND. Conclusions: The surgical technique and the extent of lymph node dissection during surgery for thyroid carcinoma increase postoperative morbidity. A wider knowledge of lymph-node-dissection-related complications associated with thyroid surgery could help surgeons to carefully evaluate the surgical and medical therapeutic options.

Chest wall resections for lung cancer treatment remain difficult to plan using standard 2-dimensional computed tomography. Although virtual reality headsets have been used in many medical contexts, they have not been used in chest wall resection planning.We compared preoperative planning of a chest wall surgical resection for lung cancer treatment between senior and resident surgeons who used an immersive virtual reality device and a 2-dimensional computed tomography.Chest wall resection planning was more accurate when surgeons used virtual reality vs computed tomography analysis (28.6% vs 18.3%, P = .018), and this was particularly true in the resident surgeon group (27.4% vs 8.3%, P = .0025). Predictions regarding the need for chest wall substitutes were also more accurate when they were made using virtual reality vs computed tomography analysis in all groups (96% vs 68.5%, P.0001). Other studied parameters were not affected by the use of the virtual reality tool.Virtual reality may offer enhanced accuracy for chest wall resection and reconstruction planning for lung cancer treatment.

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Lipomas are the most common soft tissue tumors and are malignant in only 1% of cases. Lipomatosis is defined as the presence of multiple benign lipomas on the body, without lipoatrophy. Their impact on quality of life is significant. Different entities have been described such as symmetrical multiple lipomatosis (MSL), also called Madelung's disease and familial multiple lipomatosis (FML). MSL occurs preferentially in men (but also women) who are alcohol abuser. There are different subtypes of the disease, the most classic of which affects the upper body and the nuchal region with a buffalo hump appearance. A metabolic component with obesity is frequent. In contrast to Dercum's disease, there is no pain. SAOS, complications of the metabolic syndrome and of alcohol abuse including cancers, may be associated and should be screened. FML has been little described in the literature since Brodie's first report in 1846. FML occurs preferentially in the third decade but equally in women and men. Its autosomal dominant component is classically accepted with variable penetrance within the same family. Association with naevi, angiomas, polyneuropathies and with gastrointestinal comorbidities has been reported. Interestingly, and in contrast with most lipodystrophy disorders, the patients show an insulin sensitivity profile. A better understanding of the underlying pathophysiological mechanisms would open up avenues on therapeutic research, since treatments are only symptomatic to date.

In order to explore pituitary adenoma (PA), magnetic resonance imaging (MRI) remains the cornerstone. However, there are some limitations and MRI can be non-conclusive. The development of additional imaging modalities like nuclear medicine explorations may help to confirm PA diagnosis, guide management and follow up. Nuclear medicine uses radiopharmaceuticals for imaging with single photon emission computed tomography (SPECT), or positron emission tomography (PET), coupled to CT scan. Radiopharmaceuticals products target specific cellular elements which allow to explore several biological pathways. Nuclear medicine may also be used for therapeutic purposes and recent developments of approach based on Peptide Receptor Radionuclide Therapy (PRRT) for treatment of aggressive PA and pituitary carcinoma will be reviewed. Several radiotracers have been studied in the context of PA, and the aim of this paper is to discuss their respective performances and clinical interest.

Context Dercum’s disease (DD) and Roch-Leri mesosomatic lipomatosis (LMS) are rare and poorly characteri -zed diseases. The clinical presentation combines multiple lipomas, painful in DD in contrast with LMS, without lipoatrophy. ObjectiveTo identify any specific metabolic and immune phenotype of DD and LMS with the aim to improve their treatment.Design & PatientsThis monocentric retrospective study included 38 patients: 9 DD, 11 LMS and 18 healthy controls. Metabolic and immunohematological characteristics of each group were compared.Results The median age of the patients was similar in the 3 groups (31 years). The number of women, and of basophils, and CD3+, CD4+ and CD8 + T lymphocytes was significantly higher in the DD versus the LMS group, without any difference of the metabolic parameters. Weight, BMI, blood pressure, gamma-GT, leptin, fasting insulin and C-peptide levels, fat mass percentage, and intra/total abdominal fat ratio were significantly higher in each lipomatosis group compared with the control group. Compared with the control group, the DD group had significantly higher fasting blood glucose, LDL-cholesterol, platelets, leukocytes, basophils, and a lower NK cell count, whereas the LMS group had a significantly lower rate of CD3, CD4, and CD8 lymphocytes.ConclusionDD and LMS show a common background of obesity and metabolic phenotype, but a distinct immunohematological profile characterized by a higher number of platelets, leukocytes and basophils in DD patients, an inflammatory profile that could contribute to pain. T lymphocyte depletion was present in LMS. These findings could offer specific therapeutic opportunities, especially for painful DD.NCT0178428

Objectif Evaluer la prevalence et l’evolution des comorbidites cardiovasculaires, metaboliques et osseuses dans les HBMS. Patients et methodes Etude retrospective monocentrique en soins courants de 25 patients suivis pour HBMS (V0), dont 15 ont ete revus a 5 ans (V5). Resultats Le diagnostic d’HBMS etait porte a 58 ans (Mediane), decouvert fortuitement dans 88 % des cas, avec un hypercortisolisme modere (cortisol apres test de freinage minute : 2,55 μg/dL, superieur chez les patients operes (egalement plus jeunes) : 5,2 μg/dL, que non operes 2,4 μg/dL. Cette valeur etait stable a V5 chez les non-operes. Un total de 20 % des patients ont beneficie d’une surrenalectomie, unilaterale dans 80 % des cas. A V0, un diabete, une dyslipidemie et une hypertension arterielle etaient presents chez 32 %, 40 % et 76 % des patients respectivement. Deux nouveaux cas de diabete et 5 nouveaux cas d’intolerance au glucose ont ete observes a V5. Les parametres lipidiques et tensionnels sont restes stables. Les comorbidites cardio-metaboliques etaient similaires entre les groupes operes ou non a V0 ; 26 % des patients avaient presente au moins un evenement cardiovasculaire a V5. 8 % des patients presentaient une osteoporose densitometrique et 28 % une osteopenie a V0, et 20 % a V5 en lien avec la realisation entre V0 et V5 de la premiere absorptiometrie. Discussion Dans cette serie de 25 patients, la secretion infra-clinique de cortisol au diagnostic d’HBMS, modeste, restait stable a 5 ans mais etait associee a une prevalence initiale et une incidence a 5 ans de comorbidites cardio-metaboliques elevees malgre le traitement symptomatique.

Several molecules are being investigated for their ability to enhance the anti-tumor effect of radiotherapy. The widely prescribed antidiabetic drug metformin has been suggested to possess anti-cancer activity; data indicate that metformin could also enhance radiation sensitivity. The purpose of this review is to summarize current knowledge on the specific effect of metformin in the field of RT, while also discussing the many unknowns that persist. Preclinical models point to multiple mechanisms involved in the radiosensitizing effects of metformin that are mainly linked to mitochondrial complex I inhibition and AMP-activated protein kinase. Transposition of results from bench to bedside will be discussed through the lens of the drug concentration, its potential limits in human settings, and possible alternatives. Clinical data suggest metformin improves progression-free and overall survival in patients for many different cancers treated with RT; nevertheless, the results are not always consistent. The main limitations of the reviewed literature are the retrospective nature of studies, and most of the time, a lack of information on MTF treatment duration and the administered dosages. Despite these limitations, the possible mechanisms of the role of metformin and its utility in enhancing radiotherapy treatments are analyzed. Ongoing clinical trials are also discussed.

Anaplastic thyroid carcinoma (ATC) is a rare and undifferentiated form of thyroid cancer. Its prognosis is poor: the median overall survival (OS) of patients varies from 4 to 10 months after diagnosis. However, a doubling of the OS time may be possible owing to a more systematic use of molecular tests for targeted therapies and integration of fast-track dedicated care pathways for these patients in tertiary centers. The diagnostic confirmation, if needed, requires an urgent biopsy reread by an expert pathologist with additional immunohistochemical and molecular analyses. Therapeutic management, defined in multidisciplinary meetings, respecting the patient’s choice, must start within days following diagnosis. For localized disease diagnosed after primary surgical treatment, adjuvant chemo-radiotherapy is recommended. In the event of locally advanced or metastatic disease, the prognosis is very poor. Treatment should then involve chemotherapy or targeted therapy and decompressive cervical radiotherapy. Here we will review current knowledge on ATC and provide perspectives to improve the management of this deadly disease.

Objectifs Decrire les caracteristiques cliniques, pathologiques et pronostiques des patients traites en France pour TNE renale. Materiel et methodes Nous avons collecte les donnees cliniques et pathologiques des patients traites pour une TNE renale histologiquement prouvee dans les centres de reference entre 1995 et 2019. Resultats 27 patients ont ete inclus, l’âge median etait de 52 ans. Les TNEs etaient toutes sporadiques, se developpaient sur malformation renale en fer a cheval dans 22 %, etaient kystiques dans 26 %. Aucune n’etait fonctionnelle, 58 % ont ete diagnostiquees fortuitement. La taille tumorale mediane etait de 60 mm, une extension metastatique a ete observee dans 29 %. Les TNEs etaient de grade 1 et 2 dans 50 % et 50 %. Apres un suivi median de 74,5 mois, 9 (33 %) recidives ont ete reportees. 9 (33 %) deces ont ete notes. Les survies sans rechute et survie globales medianes etaient de 102 et 109 mois. La rechute etait significativement associee avec des tumeurs plus volumineuses. Une moins bonne survie etait associee a des tumeurs symptomatiques et la presence de metastase au diagnostic. En cas de maladie avancee, une reponse partielle a ete observee chez 3 des 4 patients traites par radiotherapie interne vectorisee et 2 des 9 patients traites par chimiotherapie. Conclusions Il s’agit de la plus grande serie de TNEs renales. Ces tumeurs semblent etre sporadiques, non fonctionnelles, et G1 ou G2. Le pronostic reste correct avec une survie mediane proche de 10 ans. La taille tumorale et la presence de metastase semblent pronostiques.

La maladie de Dercum et la lipomatose mesosomatique de Roch-Leri, de physiopathologie inconnue, associent des lipomes sans lipoatrophie, douloureux dans le Dercum. Objectif Identifier le phenotype metabolique et immunitaire de ces lipomatoses rares. Materiels et methodes Etude transversale comparant les caracteristiques metaboliques et immunohematologiques de 46 patients: 9 Dercum, 11 Roch-Leri, 18 temoins minces et 8 temoins obeses (NCT0178428). Resultats L’âge median des 4 groupes etait similaire (31 ans). Le nombre de femmes, de lymphocytes basophiles et T (LT) CD3+, CD4+ et CD8+ etait significativement plus eleve chez les « Dercum » compares aux « Roch-Leri », sans difference metabolique. Le poids, l’IMC, la pression arterielle, les medianes de gamma-GT, leptine, insuline a jeun, le pourcentage de graisse et le rapport de graisse intra-abdominale/abdominale totale etaient significativement plus eleves dans les groupes lipomatoses compares aux temoins minces. Les « Dercum » presentaient une glycemie, un cholesterol-LDL, des plaquettes, leucocytes et basophiles significativement plus eleves et un nombre de cellules NK plus faible, que les temoins minces, tandis que les « Roch-Leri » presentaient un taux de LT plus faible. Les basophiles restaient plus eleves chez les Dercum, et les LT plus bas chez les Roch-Leri, que chez les temoins obeses. Discussion Ces lipomatoses partagent un phenotype metabolique commun avec l’obesite mais s’en distinguent au plan immuno-hematologique. L’activation des basophiles, forme mature des mastocytes susceptibles de liberer de la serotonine, pourrait ouvrir de nouvelles perspectives therapeutiques tout particulierement dans le Dercum (Yabut Nat Commun 2020).

Gene therapy represents a feasible strategy to treat inherited monogenic diseases and intramuscular (i.m.) injection of recombinant adeno-associated viral (AAV) vector is now recognized as a convenient and safe method of gene transfer. However, this approach is hampered by immune responses directed against the vector and against the transgenic protein. We used here to reproduce this situation a mouse model where robust immune responses are induced following injection of an AAV vector coding for an immunogenic transgenic protein. We show that prophylactic oral administration of the immunogenic protein before AAV-mediated gene transfer completely prevented antibody formation and cytotoxic CD8(+) T-cell response. Consistently, prophylactic oral-tolerization considerably improved long-term transgene persistence and expression. Mechanistically, inhibition of the cytotoxic immune response involved abortive proliferation of antigen-specific cytotoxic CD8(+) T cells, upregulation of the PD-1 immunoregulatory molecule, downregulation of the Bcl-2 antiapoptotic factor, and their deletion in the context of AAV-mediated gene transfer. Hence, gene therapy may represent an ideal situation where oral-tolerization can be adopted before or at the same time as vector injection to efficiently prevent deleterious immune responses directed against the transgenic protein.

We present the case of a caseous calcification of the mitral annulus, responsible for two strokes, in a 72-year-old female patient. The brain computed tomography (CT) scan confirmed the presence of a calcific embolus. The echocardiography showed a liquidy, pseudotumoral mass combined with numerous calcifications located in the posterior part of the mitral annulus and extending toward the inferior surface of the left ventricle. During surgery, we found a direct communication between the caseous necrosis and the lumen of the left ventricle at the level of its inferior wall. We performed a valve repair procedure and excision of the caseous necrosis, combined with injection of bioglue into the cavity, to avoid recurrence. Six months after the procedure, the patient was in good health, and had no recurrence of stroke with a satisfactory echocardiography. This is the first description of spontaneous fistulization of a caseous necrosis in the lumen of the left ventricle, explaining a new mechanism for cerebral embolism during the course of calcifying diseases of the mitral annulus.

Objectifs : Faire un état des lieux de l’incidence des différentes complications respiratoires postoesophagectomie (CRPO) par voie trans-thoracique pour cancer par des équipes de chirurgie thoracique françaises, en rechercher les facteurs de risque de survenue pré-, per- et post-opératoires et en étudier l’impact sur la survie globale et sur la survie sans récidive. Matériel et Méthodes : Il s’agit d’une étude de cohorte rétrospective bicentrique comprenant 334 patients opérés d’une œsophagectomie pour cancer entre janvier 2007 et juillet 2013. Une analyse multivariée a été réalisée pour déterminer les facteurs de risque de CRPO. Résultats : 41% des malades ont présenté une complication respiratoire après leur œsophagectomie (34% une pneumopathie, 15% un SDRA et 9% une pleurésie infectieuse). Les facteurs de risque indépendants sont le sexe masculin (p=0.03), une perte de poids > 12% (p=0.03), un tabagisme actif (p=0.03), un score de Charlson ajusté à l’âge ≥ 4 (p=0.002), un VEMS ≤ 80% de la théorique (p=0.002), une histologie de type carcinome épidermoïde (p=0.003) et un saignement per-opératoire de plus de 400 ml (p=0.03). La médiane de la durée d’hospitalisation est allongée en cas de complications respiratoires (30 vs 18 jours, p