Acta Dermato-Venereologica 99-12CompleteContent

CLINICAL REPORT Efficacy and Tolerance of Sirolimus (Rapamycin) for Extracranial Arteriovenous Malformations in Children and Adults Romain GABEFF 1–3# , Olivia BOCCARA 4# , Véronique SOUPRE 5 , Gérard LORETTE 1–3 , Christine BODEMER 4 , Denis HERBRETEAU 1,2,6 , Elsa TAVERNIER 7,8 and Annabel MARUANI 1–3,8 1 University of Tours, 2 Department of Dermatology, Unit of Pediatric Dermatology, 6 Department of Neuroradiology and Interventional Radiology, CHRU Tours, 3 Center of reference for genodermatoses and rare skin diseases (MAGEC), Tours, 4 Department of Dermatology and Center of reference for genodermatoses and rare skin diseases (MAGEC), University Paris Descartes – Sorbonne Paris Cité, Institute Imagine, 5 Department of Maxillo-Facial Surgery and Stomatology, University Hospital Necker-Enfants Malades, Paris, 7 Clinical Investigation Center-INSERM 1415, Tours, and 8 INSERM 1246-SPHERE, University of Tours and Nantes, France # These authors contributed equally and should be considered as first authors. Managing extracranial arteriovenous malformations is challenging. Sirolimus (rapamycin) is increasingly be- ing used when surgery and embolization are not advi- sed. Because of its anti-angiogenic properties, here we report all extracranial arteriovenous malformation ca- ses treated with sirolimus in 2 French tertiary centers for vascular anomalies. The outcomes were efficacy (complete, partial, no response) based on arteriove- nous malformation volume and necrosis/hemorrhage and side effects. We retrospectively included 10 pa- tients (7 children). The sirolimus dose ranged from 0.6 to 3.5 mg/m 2 . Median (interquartile range [IQR]) treat ment time was 24.5 (4.5; 35) months. Five pa- tients showed no response, and 5 showed partial re- sponse at a median (IQR) of 3 (1; 5) months, followed in 2 cases by therapeutic resistance (i.e., progres- sive disease after 9 and 24 months of treatment). The most frequent side effect was mouth ulcers. This study shows poor efficacy of sirolimus for treating extracra- nial arteriovenous malformations. Key words: vascular anomaly; arteriovenous malformation; si- rolimus; rapamycin. Accepted Aug 6, 2019; E-published Aug 6, 2019 1105 Acta Derm Venereol 2019; 99: 1105–1109. Corr: Prof. Annabel Maruani, CHRU Tours, Clocheville Hospital, 9 Boule- vard Béranger, FR-37044 Tours, France. E-mail: annabel.maruani@univ- tours.fr E xtracranial arteriovenous malformations (AVMs) are rare, potentially aggressive, congenital, fast- flow vascular anomalies (1). They are characterized by a red, warm, pulsative swelling, mostly located on the extremities and head and neck and that might be asymp- tomatic or painful (2). The degree of severity is classified by Schöbinger stages: stage I, quiescent forms; stage II, growing phase; stage III, tissue destruction, ulceration, pain and hemorrhage; and stage IV, cardiac overload (3). Management of extracranial AVMs is challenging, and we lack guidelines for treatment. The evolution of AVMs is unpredictable, even though trauma and hormonal changes during life are risk factors for rapid aggrava- tion (2). When AVMs are not complicated, the “wait and SIGNIFICANCE Managing extracranial arteriovenous malformations is chal- lenging. Sirolimus (rapamycin) is increasingly being used in all kinds of vascular anomalies. In this study, we report the largest series of arteriovenous malformations treated with sirolimus, which included 10 patients (7 children). Re- sults suggest a poor efficacy of sirolimus for this condition, with only partial response in 50% of patients, which was transient and lasted several months in 2 of 5 patients, with further worsening. see” attitude might be relevant. If necessary, therapeutic management results, at best, after multidisciplinary consultations (4, 5), considering arterial embolization alone or followed by radical surgery of the lesion (5, 6). In some cases, embolization and surgical intervention are not possible or are not sufficiently effective, and we lack efficient background drugs. Sirolimus (rapamycin) is an inhibitor of mammalian target of rapamycin (mTOR), a serine/threonine kinase regulated by phosphoinositide-3-kinase (PI3K) and AKT. Once activated, the PI3K-AKT-mTOR pathway stimula- tes protein synthesis, cell proliferation and angiogenesis (7, 8). Sirolimus was tried in almost 170 published cases of vascular anomalies, mainly lymphatic and/or venous malformations and also tumors complicated by Kasabach–Merritt phenomenon (9–11). Sirolimus was efficient in most cases. Very few cases of AVMs treated with sirolimus have been reported, with controversial results (9, 10, 12). In this study, we assessed the efficacy and tolerance of oral sirolimus for extracranial superficial AVMs in children and adults. METHODS Study design and setting This retrospective, observational study was performed in 2 French tertiary centers for vascular anomalies (university hospitals of Paris-Necker and Tours) and was conducted according to the Declaration of Helsinki ethical guidelines. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3273 Acta Derm Venereol 2019; 99: 1105–1109

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