Lymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical interventions. Moreover, despite the recent discovery of PIK3CA mutations in lymphatic endothelial cells of LM patients, the full spectrum of molecular pathways involved in LM pathogenesis is poorly understood. Here, we performed RNA sequencing on blood samples obtained from ten LM patients and nine healthy subjects and found 421 differentially expressed genes that stratify LM subjects from healthy controls. Using this LM gene signature, we identified novel pathway alterations in LM, such as oxidative phosphorylation, MEK/ERK, bone morphogenetic protein (BMP), and Wnt/β-catenin pathways, in addition to confirming the known alterations in cell cycle and the PI3K/AKT pathway. Furthermore, we performed computational drug repositioning analysis to predict existing therapies (e.g. sirolimus) and novel classes of drugs for LM. These findings deepen our understanding of LM pathogenesis and may facilitate non-invasive diagnosis, pathway analysis and therapeutic development.

This is the first report of long-term follow-up of pediatric LM patients treated with sildenafil. Our findings suggest that sildenafil is beneficial for the symptomatic treatment of LMs. Additional analysis on the role of sildenafil as adjuvant therapy is necessary to optimize the use of this medication in the management of complex LMs.

The objective of this study was to describe adults initiating dupilumab for AD, in terms of sociodemographics, comorbidity burden, AD treatment patterns, and persistence on dupilumab. From Truven US MarketScan data, we identified adults with AD with 1 dupilumab dispensation (Rx) between 28 March 2017 (US market launch) and 31 January 2018 with continuous enrolment during the baseline period (12 months prior to index Rx). Patients were followed from first dupilumab Rx until 31 July 2018 or disenrollment. Kaplan-Meier curves were used to estimate persistence at 6 and 12 months, using a 30-day grace period and assuming 14-day injection frequency. 1,637 adults initiated dupilumab (mean[SD] age 42.2[15.8]; 49.9% women, 94.7% commercially insured) and 53.2% had 1 atopic comorbidity (allergic rhinitis [33.7%] and asthma [26.8%] were most prevalent). AD treatments during baseline included: systemic corticosteroids (71.9%), PDE-4 inhibitors (15.8%), phototherapy (10.1%), immunosuppressants (24.7%; 10.8% cyclosporine), topical corticosteroids (81.1%). Over a mean (SD) follow-up of 287.5 (106.2) days, dupilumab persistence (95% CI) at 6 and 12 months was 92.2% (90.9-93.6%) and 78.5% (75.9-81.1%), respectively. Among patients discontinuing dupilumab, 66.9% reinitiated treatment within a mean of 111.5 (65.5) days. Most dupilumab initiators were persistent at 12 months; among those discontinuing, a majority reinitiated treatment. We conclude that 12month persistence on dupilumab in AD is higher than reported persistence for the most commonly used first-line biologic treatment for psoriasis, adalimumab (53.4% 1 ). These findings suggest patient satisfaction with dupilumab effectiveness and tolerability. 1

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