{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:02:50Z","timestamp":1791291770172,"version":"4.1.0"},"reference-count":19,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during \u201coff\u2010label use\u201d for vascular anomalies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a retrospective, multicenter chart review for SAEs during \u201coff\u2010label\u201d sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (<jats:italic>n<\/jats:italic>\u00a0=\u00a04), Gorham\u2013Stout disease (<jats:italic>n<\/jats:italic>\u00a0=\u00a02), central conducting lymphatic anomaly (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), lymphatic malformation (<jats:italic>n<\/jats:italic>\u00a0=\u00a04), tufted angioma (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), kaposiform hemangioendothelioma (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), and venous malformation in a patient with CLOVES syndrome (<jats:italic>n<\/jats:italic>\u00a0=\u00a01). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2\u00a0years (<jats:italic>n<\/jats:italic>\u00a0=\u00a05), 2\u20136\u00a0years (<jats:italic>n<\/jats:italic>\u00a0=\u00a05), and older than 12\u00a0years (<jats:italic>n<\/jats:italic>\u00a0=\u00a04). SAEs occurred during the first 3\u00a0months of sirolimus therapy (<jats:italic>n<\/jats:italic>\u00a0=\u00a07), between 3 and 12\u00a0months (<jats:italic>n<\/jats:italic>\u00a0=\u00a07) and after 1\u00a0year of therapy (<jats:italic>n<\/jats:italic>\u00a0=\u00a03). The most frequent SAE was viral pneumonia (<jats:italic>n<\/jats:italic>\u00a0=\u00a08) resulting in one death due to a metapneumovirus infection in a 3\u00a0months old and a generalized adenovirus infection in a 28\u2010month\u2010old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21\u00a0ng\/L. Five patients were on antibiotic prophylaxis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.28936","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T17:12:32Z","timestamp":1613322752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Severe adverse events during sirolimus \u201coff\u2010label\u201d therapy for vascular anomalies"],"prefix":"10.1002","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4022-4917","authenticated-orcid":false,"given":"Jochen","family":"R\u00f6ssler","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology, Department of Pediatrics, Inselspital Bern University Hospital, University of Bern  Bern Switzerland"},{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine Medical Center \u2010 University of Freiburg, Faculty of Medicine, University of Freiburg  Freiburg Germany"},{"name":"VASCERN VASCA European Reference Centre"},{"name":"Department of Vascular Medicine University Hospital of Montpellier, FAVA\u2010MULTI Reference Centre for Lymphedema and Lymphatic Anomalies, University of Montpellier  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eulalia","family":"Baselga","sequence":"additional","affiliation":[{"name":"Department of Dermatology Hospital Sant Joan de Deu  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Davila","sequence":"additional","affiliation":[{"name":"Department of Dermatology Hospital Sant Joan de Deu  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Celis","sequence":"additional","affiliation":[{"name":"Department of Oncology Hospital Sant Joan de Deu  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Diociaiuti","sequence":"additional","affiliation":[{"name":"VASCERN VASCA European Reference Centre"},{"name":"Dermatology Unit, Bambino Ges\u00f9 Children Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"El Hachem","sequence":"additional","affiliation":[{"name":"VASCERN VASCA European Reference Centre"},{"name":"Dermatology Unit, Bambino Ges\u00f9 Children Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Mestre","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine University Hospital of Montpellier, FAVA\u2010MULTI Reference Centre for Lymphedema and Lymphatic Anomalies, University of Montpellier  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Haeberli","sequence":"additional","affiliation":[{"name":"Division of Angiology, Swiss Cardiovascular Center, Inselspital Bern University Hospital, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aram","family":"Prokop","sequence":"additional","affiliation":[{"name":"Pediatric Hematology and Oncology Children's Hospital  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Hanke","sequence":"additional","affiliation":[{"name":"Diakonie Klinikum Children's Hospital  Schw\u00e4bisch Hall Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Loichinger","sequence":"additional","affiliation":[{"name":"Pediatric Hematology and Oncology University Hospital of Ulm  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Qu\u00e9r\u00e9","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine University Hospital of Montpellier, FAVA\u2010MULTI Reference Centre for Lymphedema and Lymphatic Anomalies, University of Montpellier  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Division of Angiology, Swiss Cardiovascular Center, Inselspital Bern University Hospital, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte M.","family":"Niemeyer","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine Medical Center \u2010 University of Freiburg, Faculty of Medicine, University of Freiburg  Freiburg Germany"},{"name":"VASCERN VASCA European Reference Centre"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-6177","authenticated-orcid":false,"given":"Friedrich G.","family":"Kapp","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine Medical Center \u2010 University of Freiburg, Faculty of Medicine, University of Freiburg  Freiburg Germany"},{"name":"VASCERN VASCA European Reference Centre"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2340\/00015555-3262"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23124"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2015-3257"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0934-z"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27614"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpc.14345"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.15076"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.11.011"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2014.12.069"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200343"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nephro.2017.02.004"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2017-1044"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2016-2919"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0297-9"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-1345(03)00223-9"},{"issue":"5","key":"e_1_2_10_17_1","first-page":"631","article-title":"Use of Sirolimus in five pediatric patients undergoing solid organ transplantation","volume":"136","author":"Roque EJ","year":"2008","journal-title":"Rev Med Chil"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-07-657981"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-015-2572-y"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0217-9"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.28936","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pbc.28936","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.28936","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T08:57:21Z","timestamp":1693213041000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.28936"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,13]]},"references-count":19,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1002\/pbc.28936"],"URL":"https:\/\/doi.org\/10.1002\/pbc.28936","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"value":"1545-5009","type":"print"},{"value":"1545-5017","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,13]]},"assertion":[{"value":"2020-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e28936"}}