PMID- 30373605 OWN - NLM STAT- MEDLINE DCOM- 20190416 LR - 20190416 IS - 1750-1172 (Electronic) IS - 1750-1172 (Linking) VI - 13 IP - 1 DP - 2018 Oct 29 TI - Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. PG - 191 LID - 10.1186/s13023-018-0934-z [doi] LID - 191 AB - BACKGROUND: Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations. METHODS: Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire. RESULTS: Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event. CONCLUSIONS: Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated. FAU - Hammer, Jennifer AU - Hammer J FAU - Seront, Emmanuel AU - Seront E AD - Center for Vascular Anomalies, Institut Roi Albert II, Department of Medical Oncology, Cliniques universitaires Saint Luc, University of Louvain, Brussels, Belgium. FAU - Duez, Steven AU - Duez S AD - Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint Luc, University of Louvain, 10 avenue Hippocrate, B-1200, Brussels, Belgium. FAU - Dupont, Sophie AU - Dupont S AD - Department of Pediatric Hemato-oncology, Cliniques universitaires Saint Luc, University of Louvain, Brussels, Belgium. FAU - Van Damme, An AU - Van Damme A AD - Center for Vascular Anomalies, Department of Pediatric Hemato-oncology, Cliniques universitaires Saint Luc, University of Louvain, Brussels, Belgium. FAU - Schmitz, Sandra AU - Schmitz S AD - Center for Vascular Anomalies, Department of Head and Neck Surgery, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium. FAU - Hoyoux, Claire AU - Hoyoux C AD - Department of Pediatric Hemato-oncology, CHR Citadelle, Liege, Belgium. FAU - Chopinet, Caroline AU - Chopinet C AD - Department of Pediatric Cardiology, CHRU Lille, Lille, France. FAU - Clapuyt, Philippe AU - Clapuyt P AD - Division of Pediatric Radiology, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium. FAU - Hammer, Frank AU - Hammer F AD - Division of Interventional Radiology, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium. FAU - Vikkula, Miikka AU - Vikkula M AD - Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium. FAU - Boon, Laurence M AU - Boon LM AD - Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint Luc, University of Louvain, 10 avenue Hippocrate, B-1200, Brussels, Belgium. laurence.boon@uclouvain.be. AD - Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium. laurence.boon@uclouvain.be. LA - eng GR - T.0146.16/Fonds de la Recherche Scientifique - FNRS/International GR - T.0026.14/Fonds de la Recherche Scientifique - FNRS/International GR - WELBIO-CR-2015A/WELBIO/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181029 PL - England TA - Orphanet J Rare Dis JT - Orphanet journal of rare diseases JID - 101266602 RN - 0 (Immunosuppressive Agents) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adolescent MH - Adult MH - Child MH - Child, Preschool MH - Drug Administration Schedule MH - Female MH - Humans MH - Immunosuppressive Agents/administration & dosage/*therapeutic use MH - Male MH - Middle Aged MH - Sirolimus/administration & dosage/*therapeutic use MH - Treatment Outcome MH - Vascular Malformations/*drug therapy MH - Young Adult PMC - PMC6206885 OTO - NOTNLM OT - Complex vascular malformation OT - Extensive vascular anomaly OT - Lymphatic malformation OT - Rapamycin OT - Sirolimus OT - Slow-flow anomaly OT - Venous malformation COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study (NCT01811667; EudraCT 2012-001262-15) was approved by the Ethics Committee of the Cliniques universitaires Saint-Luc, Brussels, Belgium. Each patient or patient's parent signed an informed consent after receiving a summary explaining the procedure of the study. The trial was also registered at clinicaltrials.gov under the name VASCA-LM. CONSENT FOR PUBLICATION: Each patient or patient's parent signed a consent for publication. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/10/31 06:00 MHDA- 2019/04/17 06:00 PMCR- 2018/10/29 CRDT- 2018/10/31 06:00 PHST- 2018/06/19 00:00 [received] PHST- 2018/10/11 00:00 [accepted] PHST- 2018/10/31 06:00 [entrez] PHST- 2018/10/31 06:00 [pubmed] PHST- 2019/04/17 06:00 [medline] PHST- 2018/10/29 00:00 [pmc-release] AID - 10.1186/s13023-018-0934-z [pii] AID - 934 [pii] AID - 10.1186/s13023-018-0934-z [doi] PST - epublish SO - Orphanet J Rare Dis. 2018 Oct 29;13(1):191. doi: 10.1186/s13023-018-0934-z.