{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:37:15Z","timestamp":1784954235488,"version":"3.55.0"},"reference-count":52,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","theclinics.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Dermatologic Clinics"],"published-print":{"date-parts":[[2022,4]]},"DOI":"10.1016\/j.det.2021.12.009","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T17:22:08Z","timestamp":1646414528000},"page":"127-136","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Systemic Therapy for Vascular Anomalies and the Emergence of Genotype-Guided Management"],"prefix":"10.1016","volume":"40","author":[{"given":"Cynthia L.","family":"Nicholson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheilagh M.","family":"Maguiness","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cps.2010.08.004","article-title":"Vascular anomalies: current overview of the field","volume":"38","author":"Greene","year":"2011","journal-title":"Clin Plast Surg"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib2","doi-asserted-by":"crossref","first-page":"e203","DOI":"10.1542\/peds.2014-3673","article-title":"Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies","volume":"136","author":"Wassef","year":"2015","journal-title":"Pediatrics"},{"key":"10.1016\/j.det.2021.12.009_bib3","unstructured":"ISSVA Classification of Vascular Anomalies \u00a9. Published 2018. Available at: https:\/\/www.issva.org\/classification. Accessed 02\/15\/2020."},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib4","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1177\/1358863X20918941","article-title":"Emerging importance of molecular pathogenesis of vascular malformations in clinical practice and classifications","volume":"25","author":"Pang","year":"2020","journal-title":"Vasc Med"},{"issue":"8","key":"10.1016\/j.det.2021.12.009_bib5","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.bbamcr.2006.10.001","article-title":"Roles of the Raf\/MEK\/ERK pathway in cell growth, malignant transformation and drug resistance","volume":"1773","author":"McCubrey","year":"2007","journal-title":"Biochim Biophys Acta"},{"issue":"7","key":"10.1016\/j.det.2021.12.009_bib6","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/sj.leu.2402945","article-title":"Signal transduction mediated by the Ras\/Raf\/MEK\/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention","volume":"17","author":"Chang","year":"2003","journal-title":"Leukemia"},{"key":"10.1016\/j.det.2021.12.009_bib7","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ejmech.2016.01.012","article-title":"PI3K\/Akt\/mTOR and Ras\/Raf\/MEK\/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives","volume":"109","author":"Asati","year":"2016","journal-title":"Eur J Med Chem"},{"issue":"9","key":"10.1016\/j.det.2021.12.009_bib8","doi-asserted-by":"crossref","first-page":"954","DOI":"10.18632\/oncotarget.652","article-title":"Mutations and deregulation of Ras\/Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR cascades which alter therapy response","volume":"3","author":"McCubrey","year":"2012","journal-title":"Oncotarget"},{"issue":"3","key":"10.1016\/j.det.2021.12.009_bib9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.18632\/oncotarget.240","article-title":"Ras\/Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health","volume":"2","author":"Chappell","year":"2011","journal-title":"Oncotarget"},{"issue":"6","key":"10.1016\/j.det.2021.12.009_bib10","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.jhep.2010.12.013","article-title":"PI(3)K\/PTEN\/AKT pathway","volume":"54","author":"Piguet","year":"2011","journal-title":"J\u00a0Hepatol"},{"issue":"7711","key":"10.1016\/j.det.2021.12.009_bib11","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41586-018-0217-9","article-title":"Targeted therapy in patients with PIK3CA-related overgrowth syndrome","volume":"558","author":"Venot","year":"2018","journal-title":"Nature"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib12","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1053\/j.sempedsurg.2014.07.002","article-title":"Lymphatic malformations: diagnosis and management","volume":"23","author":"Elluru","year":"2014","journal-title":"Semin Pediatr Surg"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib13","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1097\/MOP.0000000000000518","article-title":"Update on classification and diagnosis of vascular malformations","volume":"29","author":"McCuaig","year":"2017","journal-title":"Curr Opin Pediatr"},{"issue":"7","key":"10.1016\/j.det.2021.12.009_bib14","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/S0022-3468(99)90590-0","article-title":"25 years' experience with lymphangiomas in children","volume":"34","author":"Alqahtani","year":"1999","journal-title":"J\u00a0Pediatr Surg"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib15","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1089\/lrb.2017.0062","article-title":"Treatment of lymphatic malformations with the mTOR inhibitor sirolimus: a systematic review","volume":"16","author":"Wiegand","year":"2018","journal-title":"Lymphat Res Biol"},{"issue":"3","key":"10.1016\/j.det.2021.12.009_bib16","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1097\/MOP.0000000000000209","article-title":"Management of lymphatic malformations in children","volume":"27","author":"Bagrodia","year":"2015","journal-title":"Curr Opin Pediatr"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib17","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/lio2.241","article-title":"Clinical application of molecular genetics in lymphatic malformations","volume":"4","author":"Padia","year":"2019","journal-title":"Laryngoscope Investig Otolaryngol"},{"issue":"7","key":"10.1016\/j.det.2021.12.009_bib18","doi-asserted-by":"crossref","first-page":"e0200343","DOI":"10.1371\/journal.pone.0200343","article-title":"PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations","volume":"13","author":"Blesinger","year":"2018","journal-title":"PLoS One"},{"key":"10.1016\/j.det.2021.12.009_bib19","doi-asserted-by":"crossref","first-page":"110013","DOI":"10.1016\/j.ijporl.2020.110013","article-title":"Surgical resection of macrocystic lymphatic malformations of the head and neck: short and long-term outcomes","volume":"134","author":"Bonilla-Velez","year":"2020","journal-title":"Int J Pediatr Otorhinolaryngol"},{"issue":"3","key":"10.1016\/j.det.2021.12.009_bib20","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s00431-020-03811-4","article-title":"Lymphatic malformations in children: treatment outcomes of sclerotherapy in a large cohort","volume":"180","author":"Bouwman","year":"2021","journal-title":"Eur J Pediatr"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib21","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jpeds.2012.06.044","article-title":"Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals","volume":"162","author":"Croteau","year":"2013","journal-title":"J\u00a0Pediatr"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib22","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13023-020-1320-1","article-title":"Kaposiform hemangioendothelioma: current knowledge and future perspectives","volume":"15","author":"Ji","year":"2020","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib23","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.jpeds.2013.03.080","article-title":"Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma","volume":"163","author":"Drolet","year":"2013","journal-title":"J\u00a0Pediatr"},{"issue":"2","key":"10.1016\/j.det.2021.12.009_bib24","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.ajhg.2016.06.010","article-title":"GNA14 somatic mutation causes congenital and sporadic vascular tumors by MAPK activation","volume":"99","author":"Lim","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"6","key":"10.1016\/j.det.2021.12.009_bib25","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1111\/pde.13979","article-title":"Tufted angioma with associated Kasabach-Merritt phenomenon caused by somatic mutation in GNA14","volume":"36","author":"Lim","year":"2019","journal-title":"Pediatr Dermatol"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib26","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s12887-020-02093-x","article-title":"Effective surgical treatment of life-threatening huge vascular anomalies associated with thrombocytopenia and coagulopathy in infants unresponsive to drug therapy","volume":"20","author":"Wu","year":"2020","journal-title":"BMC Pediatr"},{"issue":"6","key":"10.1016\/j.det.2021.12.009_bib27","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1002\/pbc.23124","article-title":"Sirolimus for the treatment of complicated vascular anomalies in children","volume":"57","author":"Hammill","year":"2011","journal-title":"Pediatr Blood Cancer"},{"issue":"2","key":"10.1016\/j.det.2021.12.009_bib28","doi-asserted-by":"crossref","first-page":"e20153257","DOI":"10.1542\/peds.2015-3257","article-title":"Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies","volume":"137","author":"Adams","year":"2016","journal-title":"Pediatrics"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib29","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.jvs.2019.06.217","article-title":"Efficacy and safety of sirolimus in the treatment of vascular anomalies: a systematic review","volume":"71","author":"Freixo","year":"2020","journal-title":"J\u00a0Vasc Surg"},{"issue":"5","key":"10.1016\/j.det.2021.12.009_bib30","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1089\/lrb.2018.0068","article-title":"Oral sirolimus: an option in the management of neonates with life-threatening upper airway lymphatic malformations","volume":"17","author":"Triana","year":"2019","journal-title":"Lymphat Res Biol"},{"issue":"11","key":"10.1016\/j.det.2021.12.009_bib31","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1111\/1346-8138.15076","article-title":"Sirolimus therapy for Kaposiform hemangioendothelioma with long-term follow-up","volume":"46","author":"Wang","year":"2019","journal-title":"J\u00a0Dermatol"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib32","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1002\/ijc.30775","article-title":"Sirolimus for the treatment of progressive Kaposiform hemangioendothelioma: a multicenter retrospective study","volume":"141","author":"Ji","year":"2017","journal-title":"Int J Cancer"},{"issue":"9","key":"10.1016\/j.det.2021.12.009_bib33","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1111\/jpc.14370","article-title":"Vincristine and sirolimus in the treatment of Kaposiform haemangioendothelioma","volume":"55","author":"Peng","year":"2019","journal-title":"J\u00a0Paediatr Child Health"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib34","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1186\/s13063-018-2725-1","article-title":"Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design","volume":"19","author":"Maruani","year":"2018","journal-title":"Trials"},{"issue":"2","key":"10.1016\/j.det.2021.12.009_bib35","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/ajmg.a.36836","article-title":"PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation","volume":"167a","author":"Keppler-Noreuil","year":"2015","journal-title":"Am J Med Genet A"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib36","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/cge.12832","article-title":"CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS)","volume":"91","author":"Martinez-Lopez","year":"2017","journal-title":"Clin Genet"},{"issue":"6","key":"10.1016\/j.det.2021.12.009_bib37","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/j.ajhg.2012.05.006","article-title":"Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome","volume":"90","author":"Kurek","year":"2012","journal-title":"Am J Hum Genet"},{"issue":"3 Suppl","key":"10.1016\/j.det.2021.12.009_bib38","doi-asserted-by":"crossref","first-page":"7s","DOI":"10.1016\/S0041-1345(03)00211-2","article-title":"Sirolimus: its discovery, biological properties, and mechanism of action","volume":"35","author":"Sehgal","year":"2003","journal-title":"Transplant Proc"},{"issue":"5","key":"10.1016\/j.det.2021.12.009_bib39","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/s41436-018-0297-9","article-title":"Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum","volume":"21","author":"Parker","year":"2019","journal-title":"Genet Med"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib40","doi-asserted-by":"crossref","first-page":"e0123092","DOI":"10.1371\/journal.pone.0123092","article-title":"Molecular and functional characterization of three different postzygotic mutations in PIK3CA-related overgrowth spectrum (PROS) patients: effects on PI3K\/AKT\/mTOR signaling and sensitivity to PIK3 inhibitors","volume":"10","author":"Loconte","year":"2015","journal-title":"PLoS One"},{"issue":"6","key":"10.1016\/j.det.2021.12.009_bib41","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.jpag.2019.07.003","article-title":"Alpelisib treatment for genital vascular malformation in a patient with congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal\/skeletal anomalies and\/or scoliosis (CLOVES) syndrome","volume":"32","author":"L\u00f3pez Guti\u00e9rrez","year":"2019","journal-title":"J\u00a0Pediatr Adolesc Gynecol"},{"issue":"2","key":"10.1016\/j.det.2021.12.009_bib42","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.bbrc.2020.06.022","article-title":"Endothelial MAP2K1 mutations in arteriovenous malformation activate the RAS\/MAPK pathway","volume":"529","author":"Smits","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1053\/j.sempedsurg.2014.07.005","article-title":"Arteriovenous malformations","volume":"23","author":"Uller","year":"2014","journal-title":"Semin Pediatr Surg"},{"issue":"3","key":"10.1016\/j.det.2021.12.009_bib44","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.ajhg.2017.01.018","article-title":"Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation","volume":"100","author":"Couto","year":"2017","journal-title":"Am J Hum Genet"},{"issue":"3","key":"10.1016\/j.det.2021.12.009_bib45","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1056\/NEJMoa1709449","article-title":"Somatic activating KRAS mutations in arteriovenous malformations of the brain","volume":"378","author":"Nikolaev","year":"2018","journal-title":"N\u00a0Engl J Med"},{"issue":"2","key":"10.1016\/j.det.2021.12.009_bib46","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1001\/jamadermatol.2018.4653","article-title":"Genotype-guided medical treatment of an arteriovenous malformation in a child","volume":"155","author":"Lekwuttikarn","year":"2019","journal-title":"JAMA Dermatol"},{"issue":"3","key":"10.1016\/j.det.2021.12.009_bib47","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2019-3206","article-title":"Monitoring arteriovenous malformation response to genotype-targeted therapy","volume":"146","author":"Edwards","year":"2020","journal-title":"Pediatrics"},{"issue":"1","key":"10.1016\/j.det.2021.12.009_bib48","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/abbs\/gmx123","article-title":"TGF-\u03b2 signaling in cancer metastasis","volume":"50","author":"Xie","year":"2018","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib49","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s11684-018-0646-8","article-title":"Intracellular and extracellular TGF-\u03b2 signaling in cancer: some recent topics","volume":"12","author":"Miyazono","year":"2018","journal-title":"Front Med"},{"issue":"4","key":"10.1016\/j.det.2021.12.009_bib50","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/ajmg.c.31531","article-title":"Somatic overgrowth disorders of the PI3K\/AKT\/mTOR pathway & therapeutic strategies","volume":"172","author":"Keppler-Noreuil","year":"2016","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"2","key":"10.1016\/j.det.2021.12.009_bib51","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s10048-018-0540-1","article-title":"In\u00a0vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS)","volume":"19","author":"Ranieri","year":"2018","journal-title":"Neurogenetics"},{"issue":"28","key":"10.1016\/j.det.2021.12.009_bib52","doi-asserted-by":"crossref","first-page":"45470","DOI":"10.18632\/oncotarget.17566","article-title":"The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K\/AKT\/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS)","volume":"8","author":"Suzuki","year":"2017","journal-title":"Oncotarget"}],"container-title":["Dermatologic Clinics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0733863521000991?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0733863521000991?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T10:46:10Z","timestamp":1760006770000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0733863521000991"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4]]},"references-count":52,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["S0733863521000991"],"URL":"https:\/\/doi.org\/10.1016\/j.det.2021.12.009","relation":{},"ISSN":["0733-8635"],"issn-type":[{"value":"0733-8635","type":"print"}],"subject":[],"published":{"date-parts":[[2022,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Systemic Therapy for Vascular Anomalies and the Emergence of Genotype-Guided Management","name":"articletitle","label":"Article Title"},{"value":"Dermatologic Clinics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.det.2021.12.009","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}