Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum

Purpose PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS

Pharmacokinetics, pharmacodynamics and clinical efficacy of omalizumab for the treatment of asthma.

IF 2.598International audienceOmalizumab 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

Efficacy of a Novel Prefilled, Single-Use, Needle-Free Device (Zeneo®) in Achieving Intramuscular Agent Delivery: An Observational Study

International audienceIt 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(A (R)) 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. 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 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/m(2) (range 21.2-30.8 kg/m(2)). 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/m(2) 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. Use of the Zeneo(A (R)) 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. Crossject

An update on the latest chemical therapies for reflux esophagitis in children

IF 3.475 (2017)International audienceGastroesophageal 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). Areas covered: 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. Expert opinion: 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

Small Molecule Drugs in Inflammatory Bowel Diseases

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

Dermoscopy of small and medium congenital melanocytic nevi in infants and children

IF 3.528International audienc

Continuous Anti-TNFα Use Throughout Pregnancy: Possible Complications For the Mother But Not for the Fetus. A Retrospective Cohort on the French National Health Insurance Database (EVASION)

International audienceOBJECTIVES: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

Antiplatelet and anticoagulant agents in vitreoretinal surgery: a prospective multicenter study involving 804 patients

Publication for the CFSR Research NetInternational audiencePURPOSE: To assess the rate of hemorrhagic complications after vitreoretinal surgery and the influence of antithrombotic agents. METHODS: Hemorrhagic complications of vitreoretinal procedures performed in seven ophthalmologic centers on patients treated or not treated with antiplatelet (AP) or anticoagulant (AC) agents were prospectively collected. Patients' characteristics, surgical techniques, and complications were recorded during surgery and for 1 month after. RESULTS: Eight hundred four procedures were performed between January 2015 and April 2015. Among them, 18.4% were treated with AP agents (n = 148) and 7.8% with AC agents (n = 63), with 18 of them treated with NOACS (new oral anticoagulants). AP or AC agents were continued in 96.5% and 80.7% of cases, respectively. Fifty-three patients (6.6%) developed one or more hemorrhagic complications in one eye during this period. In univariate analysis, AC agents were not associated with hemorrhagic complications (P = 0.329) in contrast to AP (P = 0.005). However, in multivariate analysis, AP agents were no longer associated with hemorrhagic complications and the intraoperative use of endodiathermy was the only factor associated with hemorrhagic complications (P = 0.001). CONCLUSIONS: This study showed that AP and AC agents were not a factor associated with hemorrhagic complications during vitreoretinal surgery. The continuation of these treatments should be considered without risk of severe hemorrhagic complications