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International audience; ABSTRACT Purpose PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Methods Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Results Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort ( n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Proton pump inhibitors (PPIs) block the gastric H/K-ATPase, therefore inhibiting acid gastric secretion, leading to an increased pH (4). They account for an extremely high number of prescriptions worldwide. Numerous drug-drug interactions have been described with PPIs, but all the described interactions do not have clinical significance.This review will discuss the latest updates on drug-drug interactions with PPIs, focusing on the last 10-year publications in the following areas: anti-infective agents, anticancer drugs, antiplatelet agents and anticoagulants, and antidiabetics.Although pharmacokinetic interactions of PPIs have been described with many drugs, their clinical relevance remains controversial. However, given the extremely high number of people being treated with PPIs, clinicians should remain vigilant for interactions that may be clinically significant and require dose adjustment or therapeutic monitoring. Interestingly, not all PPIs have the same pharmacokinetic and pharmacodynamic profile, with some having a strong potential to inhibit CYP2C19, such as omeprazole, esomeprazole, and lansoprazole, while others, pantoprazole, rabeprazole, and dexlansoprazole, are weak CYP2C19 inhibitors. These may be preferred depending on co-prescribed treatments.In addition, new formulations have been developed to prevent some of the gastric pH-dependent drug interactions and should be evaluated in further large-scale prospective comparative studies.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS-like disorders and suggest vascular imaging is indicated in these patients.

ObjectiveTo pilot test the feasibility and acceptability of Simulation in Therapeutic Patient Education (S-TPE), in both adult patients with diabetes and educators.ConceptionAdult patients with insulin-dependent diabetes and who participated in a full TPE programme for the implementation of a FreeStyle were included in this monocentric pilot study. S-TPE intervention was based on a consensus conference determining the conditions and objectives of S-TPE. Main outcomes were the patients’ and educators’ perception of the usefulness of S-TPE and the patient’s satisfaction level at the conclusion of the simulation sequence, measured on validated scales. Secondary outcomes were organisational, human, material and temporal, facilitating and limiting factors for patients and educators, patient self-efficacy and anxiety scores.InterventionsThe final session of TPE used the simulation. For each group, one patient volunteered to be the simulated patient. Intervention was divided into three steps: (1) a pre-briefing, (2) a simulation of hypoglycaemia and (3) a debriefing with the group of patients and educators. The whole intervention lasted about 2 hours.ResultsWe included 23 patients (mean age ±SD 63±15 years, 14 men) and 3 educators. After S-TPE intervention, patients’ and educators’ perceived usefulness score were 20.6/25 and 37.5/40, respectively. Patient’s satisfaction score was 51.9/60. Qualitative analysis revealed no limiting factors to implementing S-TPE. Self-efficacy was stable. Decrease in anxiety score after S-TPE reached statistical significance in women (from 35.1±4.5 to 32.7±5.5, p=0.04) but not in men.ConclusionNo limiting factors that could prevent the conduct of clinical trials to assess S-TPE efficacy in patients with diabetes were identified. S-TPE appears as a promising technique to improve diabetes management.Trial registration numberRegistration N°: 2019-A00773-54 and NTC: 03956927.

With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispose carriers to a preventable or treatable disease in childhood/adulthood and genes for genetic counselling issues). We also focused on the 59 PharmGKB class IA/IB pharmacogenetic variants. We also compared the results in different gene lists. We identified variants (likely) affecting protein function in genes for care in 26 cases (3.7%) and heterozygous variants in genes for genetic counselling in 29 cases (3.8%). Mean time for the 700 patients was about 6.3 min/patient for medically actionable genes and 1.3 min/patient for genes for genetic counselling, and a mean time of 37 min/patients for the reinterpreted variants. These results would lead to all 700 pre-test counselling sessions being longer, to 55 post-test genetic consultations and to 27 secondary specialised medical evaluations. ES also detected 42/59 pharmacogenetic variants or combinations of variants in the majority of cases. An extremely low metabolizer status in genes relevant for neurodevelopmental disorders (CYP2C9 and CYP2C19) was found in 57/700 cases. This study provides information regarding the need to anticipate the implementation of genomic medicine, notably the work overload at various steps of the process.

International audience; Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an "in house" pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytointreated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10-23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.

To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size.DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known.The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d'étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases.Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared.DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.

The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.

BACKGROUND Children born to mothers with IBD may be exposed to anti-TNFα agents antenatally. Current European guidelines recommend postponing live vaccines until after 6 months of life in this population. Data on the safety of live vaccines administration in the first year of life of these children are sparse with one reported fatality following bacillus Calmette-Guerin (BCG) administration. AIMS To describe the use and safety of vaccines administered in children born to mothers with IBD and exposed antenatally to anti-TNFα agents METHODS: Data from children born to mothers with IBD between 2013 and 2014 were collected retrospectively from the French Health Insurance Database. Vaccines recommended before or at 1 year of age were considered. RESULTS Among 4741 children, 670 (14.1%) were exposed to anti-TNFα agents antenatally, with concomitant thiopurines in 16.0% (n = 107) and steroids in 19.3% (n = 214). Among these 670 children, 315 (47%) were exposed up to delivery. Exposed children were less likely than non-exposed to receive BCG (88/670, 13.1% vs 780/4071, 19.2% respectively, P

Inflammatory bowel diseases (IBDs), mainly represented by Crohn’s disease (CD) and Ulcerative Colitis (UC), are chronic disorders with an unclear pathogenesis. This incurable and iterative intestinal mucosal inflammation requires the life-long use of anti-inflammatory drugs to prevent flares or relapses, which are the major providers of complications, such as small bowel strictures and intestinal perforations. The introduction of tumor necrosis factor (TNF)-alpha inhibitors and other compounds, such as anti-IL12/23 and anti-alpha4/beta7 integrin monoclonal antibodies, has considerably improved the clinical management of IBDs. They are now the standard of care, being the first-line therapy in patients with aggressive disease and in patients with moderate to severe disease with an inadequate response to conventional therapy. However, for approximately one third of all patients, their efficacy remains insufficient by a lack or loss of response due to the formation of anti-drug antibodies or compliance difficulties with parenteral formulations. To address these issues, orally administered Small Molecules Drugs (SMDs) that use a broad range of novel pharmacological pathways, such as JAK inhibitors, sphingosine-1-phosphate receptor modulators, and phosphodiesterase 4 inhibitors, have been developed for CD and UC. This article provides an updated and complete review of the most recently authorized SMDs and SMDs in phase II/III development.

Gastroesophageal reflux (GER), and its complicated form gastroesophageal reflux disease (GERD) is a common condition in infants and children. As GERD is often considered to cause extra-oesophageal symptoms in children and in the absence of standardized diagnostic and treatment algorithm, many children are inappropriately exposed to empirical anti-reflux treatments, with Acid-Suppressive Medications (ASM); mostly proton pump inhibitors (PPIs).The authors summarize the pharmacological management of pediatric GERD and discuss the efficacy of PPIs as randomized controlled trials have failed to demonstrate their clinical efficacy in the pediatric population. They consider the controversies surrounding the use of PPIs in the pediatric population as increasing evidence suggests of, although controversially, an increased risk of adverse events such as infection of the respiratory or gastrointestinal tract. Esophagitis is a complication that has a significant impact on weight gain and growth, as well as on the quality of life, and in such case, the benefit of treatment largely outweighs the risk.Clinicians should reserve ASM use for infants and children with proven esophagitis and avoid their routine use in patients with merely symptoms of GER. Treatment need and options must be frequently re-evaluated to reduce the risks associated with ongoing therapy.

International audience; OBJECTIVES:Inflammatory bowel diseases (IBD) need long-term treatment, which can influence pregnancies in young women. Uncontrolled IBD is associated with poor pregnancy outcomes. Despite the labeling of Anti-tumor necrosis factor (TNF) antibodies (anti-TNFα) which indicates that their use is not recommended during pregnancy, anti-TNFα are increasingly being used during pregnancy and may expose women and their fetuses to treatment-related complications. Existing recommendations on the timing of treatment during pregnancy are inconsistent. We aimed to assess the safety of anti-TNFα treatment in pregnant women with IBD, and up to the first year of life for their children.METHODS:An exposed/non exposed retrospective cohort was conducted on the French national health system database SNIIRAM (Système National d'Information Inter-Régimes de l'Assurance Maladie). All IBD women who became pregnant between 2011 and 2014 were included. Women with concomitant diseases potentially treated with anti-TNFα were excluded. Anti-TNFα exposure (infliximab, adalimumab, golimumab or certolizumab pegol) during pregnancy was retrieved from the exhaustive prescription database in SNIIRAM. The main judgment criterion was a composite outcome of disease-, treatment- and pregnancy-related complications during pregnancy for the mother, and infections during the first year of life for children.RESULTS:We analyzed data from 11,275 pregnancies (8726 women with IBD), among which 1457 (12.9%) pregnancies were exposed to anti-TNFα, mainly infliximab or adalimumab, with 1313/7722 (17.0%) suffering from Crohn's disease and 144/3553 (4.1%) from ulcerative colitis. After adjusting for disease severity, steroid use, age, IBD type, and duration and concomitant 6-mercaptopurine use, anti-TNFα treatment was associated with a higher risk of overall maternal complications (adjusted Odds Ratio (aOR) = 1.49; 95% confidence interval (CI): 1.31-1.67) and infections (aOR = 1.31; 95% CI: 1.16-1.47). Maintaining anti-TNFα after 24 weeks did not increase the risk of maternal complication, but interrupting the anti-TNFα increased relapse risk. No increased risk for infection was found in children (aOR = 0.89; 95% CI: 0.76-1.05) born to mother exposed to anti-TNFα during pregnancy.CONCLUSIONS:Anti-TNFα treatment during pregnancy increased the risk of maternal complications compared to unexposed; however, discontinuation before week 24 increased the risk of disease flare. There was no increased risk for children exposed to anti-TNFα up to 1 year of life.

Background: To assess the association between final polytetrafluoroethylene (PTFE)-covered stent transjugular intrahepatic portosystemic shunt (TIPS) angiographic parameters and free shunt revision survey. Methods: Series of two comparison groups were generated with persistence of varices or not, the 25 th , 50 th , and 75th percentile as cutoff for each angle and a 15-mm distance as cutoff for distance D. Kaplan Meier free shunt revision curves were then created and compared with Log Rank test. Results: Mean follow-up was 455 days. Thirteen (19.4%) patients had shunt revision. Significant free shunt revision survey difference was found between post-procedural angiographic persistent varices group and the group without varices (P=0.0001). Shunt revision rate at 3, 12 and 24 months was respectively 13%, 29%, and 39% in the group with varices versus 0%, 2.7% and 2.7% in the group without. No difference was found between groups for angles A, B, C and distance D. Conclusions: Persistence of gastric or esophageal varices on final trans-TIPS angiography increases TIPS revision rate after PTFE-covered stent shunt creation whereas geometric parameters have no influence.

Introduction Les syndromes de Klippel-Trenaunay et CLOVES font partie du spectre hypertrophique lie a PIK3CA (PROS). Ils sont dus a des mutations activatrices du gene PIK3CA codant la sous-unite alpha de la phosphatidyl-inositol-3-kinase, qui activent la voie MTOR, dont l’inhibition represente donc une possibilite de traitement. Nous avons rapporte une reduction partielle de l’hypertrophie ou des douleurs sous sirolimus, inhibiteur de MTOR. De plus, une reponse jugee importante sur la reduction des malformations lymphatiques ou de l’hypertrophie des tissus mous a ete rapportee sous alpelisib, inhibiteur specifique de la sous-unite alpha de la PI3 K, en cours d’evaluation dans le cancer du sein, mais peu de donnees de tolerance sont disponibles. Nous avons mis en place un essai de phase I/II pour evaluer la tolerance et l’efficacite dans le PROS d’un autre inhibiteur de PI3 K, le taselisib. Materiel et methodes Essai ouvert a un seul bras multicentrique de phase IB/IIA evaluant la tolerance de faibles doses de taselisib sur 6 mois, prevu chez 30 adultes PROS, avec schema d’augmentation progressive des doses : 1 mg/j chez les 6 premiers patients, puis 2 mg/j chez le reste des participants. Le critere de jugement principal etait la survenue de toxicite de grade ≥ 3 limitant la dose, voire motivant l’arret de l’essai a partir d’un nombre important d’evenements indesirables (EI) graves, suspectes (5) ou inattendus (SUSAR, 2). L’efficacite a ete evaluee par mesure du volume des zones hypertrophiques par IRM ou absorptiometrie (DEXA) en comparant les sites atteints et indemnes, et sur l’aspect des malformations vasculaires, la coagulopathie, et la qualite de vie. Resultats Au total, 19 patients ont ete inclus dont 17 ont recu taselisib, parmi lesquels 11 ont recu les 6 mois de traitement. Bien qu’aucun EI grave ne soit survenu a 1 mg/j (6 patients), l’etude a ete arretee apres l’inclusion de 11 patients a 2 mg, dont 5 avaient termine l’essai, en raison de 2 SUSAR (ileite aigue et pachymeningite). Tous les patients traites ont presente au moins un EI (113 au total), et 3 ont presente un EI de grade 3 (2 SUSAR et 1 infection a parvovirus). Les troubles gastro-intestinaux, du systeme nerveux et les infections representaient respectivement 43 %, 17 % et 12 % des 113 EI. Une amelioration de la qualite de vie, une reduction de la douleur, ou l’arret d’un saignement chronique ont ete observes mais la reduction de l’hypertrophie etait modeste ou nulle. Conclusion Ce premier essai therapeutique d’un inhibiteur de PI3 K dans le PROS a montre un profil de tolerance insuffisant du taselisib, malgre un certain degre de reponse, motivant l’arret de son developpement dans cette indication. D’autres inhibiteurs de PI3 K restent a evaluer dans des essais cliniques, en particulier l’alpelisib, mais les EI observes ici motivent une surveillance attentive de la tolerance de cette classe de medicaments.

IF 2.004 (2017); International audience; With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice» is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.

Objective To determine the prognostic impact of the nuclear status at the two-cell stage on intracytoplasmic sperm injection (ICSI) outcomes. Design Retrospective study. Setting Hospital. Patient(s) Only ICSI cycles with time-lapse monitoring of transferred embryos with known implantation/delivery data from November 2012 to December 2014 were included. A total of 2,449 embryos were assessed for multinucleation rates at the two- and four-cell stage, and 608 transferred embryos were studied for ICSI outcomes. Intervention(s) None. Main Outcome Measure(s) Implantation rate (IR) and live birth rate (LBR) according to the number of multinucleated blastomeres at the two-cell stage: none (Without-MNB 2cell ), one (MNB 1/2cell ), and two (MNB 2/2cell ); morphokinetics of MNB 2cell embryos. Result(s) Embryos with MNB 1/2cell led to lower IR (27.7%) and LBR (22.7%) than embryos Without-MNB 2cell (33.4% and 29.8%, respectively). The MNB 2/2cell embryos led to significantly lower IR (18.3%) and LBR (13.4%) than embryos Without-MNB 2cell . This difference remained significant in multivariate analysis for implantation (odds ratio 0.57; 95% confidence interval 0.34–0.94) and birth (odds ratio 0.46; 95% confidence interval 0.26–0.80), independently of the other significant parameters (women's age, time of two-cell formation, and multinucleation at the four-cell stage). Among implanted MNB 2cell , if cleavage into four cells occurred later than 37 hours after insemination, embryos were significantly more likely to lead to birth. Conclusion(s) The presence of multinucleation at the two-cell stage and more specifically in both blastomeres had a significant negative impact on birth potential. Thus, embryo multinucleation at the two-cell stage should be used as an additional noninvasive criterion for embryo selection.

Introduction Les maladies inflammatoires chroniques intestinales (MICI) necessitent un traitement chronique, pouvant interferer avec le desir de grossesse chez les jeunes femmes. Une MICI non controlee en debut de grossesse est un facteur de mauvais pronostic maternel et fœtal. L’utilisation, hors autorisation, des antagonistes du « Tumor Necrosis Factor α » (anti-TNFα) durant la grossesse, augmente actuellement, et peuvent exposer la femme et le fœtus a des complications iatrogenes. Les recommandations actuelles sur les anti-TNFα dans cette population sont discordantes. Cette etude visait a evaluer, les modalites d’utilisation et le rapport benefice-risque des anti-TNFα pendant la grossesse chez les patientes atteintes de MICI, et durant la premiere annee de vie chez les enfants exposes in utero. Methodes Il s’agit d’une cohorte retrospective incluant 11 275 grossesses chez 8726 femmes atteintes de MICI enceintes entre 2011 et 2014, identifiees dans le Systeme national d’information inter-regimes de l’assurance maladie. Le critere de jugement principal composite regroupait les complications liees au traitement, a la maladie et a la grossesse. Le risque etait analyse par regression logistique, ajuste sur l’âge au debut de grossesse, les caracteristiques de la MICI (type, severite et anciennete) et la prise concomitante de thiopurines. Resultats Au total, 1457 grossesses (12,9 %) ont ete exposees aux anti-TNFα, principalement l’infliximab et l’adalimumab, dont 1313/7722 (17,0 %) maladies de Crohn et 144/3553 (4,1 %) rectocolites hemorragiques. Les anti-TNFα etaient associes a un risque accru de complications maternelles (Odds Ratio ajuste (aOR) = 1,45 ; IC 95 % [1,29–1,64]) et d’infections (aOR = 1,35 ; [1,19–1,50]). Aucun risque infectieux n’a ete retrouve chez l’enfant (aOR = 0,90 [0,77–1,06]). Discussion/Conclusion L’utilisation des anti-TNFα durant la grossesse est associee a un risque de complications maternelles, mais semble sure chez l’enfant durant la premiere annee de vie. Un suivi plus long chez l’enfant ainsi que d’autres analyses chez la mere ajustees sur les traitements concomitants et les facteurs environnementaux, sont necessaires pour estimer plus precisement le rapport benefice–risque des anti-TNFα durant la grossesse.

IF 2.598; International audience; Omalizumab is a subcutaneously administrated monoclonal anti-IgE antibody indicated in adults, adolescents and children 6 years of age and older with moderate to severe allergic asthma uncontrolled by conventional pharmacological treatments and sensitization to at least one perennial allergen. Area covered: This drug evaluation summarizes published data on pharmacokinetic and pharmacodynamic properties of omalizumab, on clinical efficacy and safety, including real-world evidence, and provides a medico-economic evaluation of the drug. Expert opinion: Omalizumab represents an efficient therapeutic option for the management of patients with uncontrolled moderate/severe allergic asthma. It provides a significant reduction in the asthma exacerbation rate with a steroid-sparing effect, an improvement in quality of life in adults and adolescents, despite a lack of evidence about its efficacy specifically in severe allergic asthma. Clinical trials have demonstrated its efficacy in the pediatric population but further real-life evidence is expected to better characterize long-term effects in this population. There is still some debate about the optimal treatment duration but, to date, it is recommended not to stop the treatment as cessation has resulted in symptom recurrence. Omalizumab is an expensive treatment, but a key therapeutic option when used for uncontrolled severe allergic asthma.

Introduction Les mutations en mosaiques de PIK3CA activant la voie mTOR sont responsables d’un syndrome hypertrophique en mosaique appele congenital lipomatous overgrowth with vascular, epidermal or skeletal anomalies (CLOVES) ou PIK3CA-related overgrowth spectrum (PROS). Nous evaluons le traitement de l’hypertrophie par sirolimus et rapportons nos donnees preliminaires de tolerance dans la cohorte francaise. Materiel et methodes L’etude PROMISE ( NCT02443818 ) est un essai pilote multicentrique en cours aux Etats-Unis, au Royaume-Uni et en France, ouvert, non randomise, evaluant l’efficacite et la tolerance du sirolimus dans le PROS incluant 30 patients de 3 a 65 ans. Le critere d’evaluation principal est la variation de volume des parties molles a 6 mois de traitement, evalue par IRM volumetrique, mesure de la masse grasse par absorptiometrie biphotonique (DEXA), mensurations cliniques et photographies lors de l’inclusion (M0), apres 6 mois de surveillance sans traitement (M6), puis apres 6 mois de traitement (M12). Le sirolimus est administre a la dose de 0,8 mg/m2/j (1 a 2 mg/j) pour obtenir des taux plasmatiques residuels entre 2 et 6 ng/mL. Les effets indesirables font l’objet d’un suivi bimensuel par un comite local et mensuel par un comite international de surveillance. Resultats Entre decembre 2015 (date de debut du traitement chez le premier patient inclus) et juin 2016, 9 enfants (âge median : 10,6 ans) et 4 adultes (âge median : 26,3 ans) ont ete inclus dans la cohorte francaise. Dans cette periode, 54 effets indesirables ont ete recenses, dont 18 consideres comme lies au traitement chez 9 patients (69,0 %) : 8 infections, 4 episodes thromboemboliques ou hemorragiques, 4 perturbations biologiques isolees, 1 surdose sans consequences et 1 fievre prolongee revelatrice d’un syndrome de Still. Le delai moyen de survenue depuis l’instauration du sirolimus etait de 34,6 jours. Chez 4 patients, il s’agissait d’un effet indesirable grave (grade ≥ 3) motivant l’arret definitif du traitement dans 3 cas, mais ceci n’a pas justifie d’interrompre prematurement l’essai clinique. L’efficacite ne sera evaluee que lorsque les 30 patients auront ete inclus a l’international. Discussion Bien que les precedentes observations rapportees d’utilisation du sirolimus dans les malformations vasculaires ne fassent pas etat de problemes majeurs de tolerance, notre essai a montre chez les patients atteints de PROS un taux preoccupant d’effets indesirables potentiellement lies au traitement. Conclusion Ceci justifie d’effectuer une selection prudente des indications et une surveillance rigoureuse chez les patients PROS traites par sirolimus hors AMM.

Background It is recognized that, as a result of variation in tissue anatomy, current auto-injectors may have insufficient needle length to achieve successful intramuscular agent delivery in a number of patients. The Zeneo® auto-injector is a novel prefilled, single-use, needle-free device currently in development for intradermal, subcutaneous, and intramuscular agent delivery across a variety of clinical indications. We aimed to evaluate delivery depth of the device calibrated at pressure appropriate for intramuscular (IM) administration. Methods This was a prospective single-center study in healthy adult volunteers, in whom each received a single injection of saline into the anterolateral thigh. Using sequential MRI scans, we measured skin-to-muscle distance (STMD) agent delivery depth, and the success of IM agent penetration. Device dynamic pressure measurements were also recorded. Results Results are reported for 37 subjects with evaluable MRI scans; 19 men, 18 women; mean age 38 years (range 20–58); mean BMI 27.0 kg/m2 (range 21.2–30.8 kg/m2). Mean STMD values were 18.6 mm (range 13.4–23.6 mm) in women and 10.0 mm (range 5.0–21.7 mm) in men, with gender differences due primarily to greater subcutaneous thickness in women. A trend for greater STMD in subjects with BMI greater than 25 kg/m2 was seen. Mean injectate penetration depths of 30.1 mm (range 20.2–45.6 mm) were observed with values similar in male and female subjects. Successful IM delivery was reported in 95% of subjects. When failure occurred, this was not due to inadequate injection depth. Device pressure (P max) had the greatest influence on injectate muscle penetration. Conclusion Use of the Zeneo® auto-injector achieves delivery depth that ensures intramuscular delivery in both men and women, regardless of BMI. Consistent with other reported data, STMD is greater in women. Funding Crossject.