{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T09:27:50Z","timestamp":1774171670280,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T00:00:00Z","timestamp":1531699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acad Dermatol Venereol"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Tuberous sclerosis complex (<jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010associated lesions because they act on the underlying disease pathophysiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We evaluated the long\u2010term effect of oral everolimus on <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010associated skin lesions as a secondary objective in the phase <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content> studies <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20101 (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00789828) and <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20102 (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00790400) after approximately 4 years of treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Everolimus was dosed 4.5 mg\/m<jats:sup>2<\/jats:sup>\/day (titrated to trough 5\u201315 ng\/<jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content>) in patients with <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010associated subependymal giant cell astrocytoma in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20101, and 10 mg\/day initially in adult patients with <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010 or sporadic lymphangioleiomyomatosis\u2013associated renal angiomyolipoma in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20102. Following positive results from the core phase, remaining patients were offered open\u2010label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 105 patients in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20101 and 107 in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20102 received everolimus and had \u22651 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1\u201367.7%) in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20101 and 68.2% (58.5\u201376.9%) in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20102; most were partial responses. At week 192 (<jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20101: <jats:italic>n<\/jats:italic> = 55; <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20102: <jats:italic>n<\/jats:italic> = 56), 69% and 66% had a response. Most common drug\u2010related adverse event was stomatitis (41\u201345%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Oral everolimus improved <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010related skin lesions, with responses sustained over 4 years of treatment in <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20101 and <jats:styled-content style=\"fixed-case\">EXIST<\/jats:styled-content>\u20102.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdv.14964","type":"journal-article","created":{"date-parts":[[2018,3,23]],"date-time":"2018-03-23T10:42:56Z","timestamp":1521801776000},"page":"1796-1803","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4\u2010year results from the randomized <scp>EXIST<\/scp>\u20101 and <scp>EXIST<\/scp>\u20102 studies"],"prefix":"10.1111","volume":"32","author":[{"given":"D.N.","family":"Franz","sequence":"first","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.","family":"Budde","sequence":"additional","affiliation":[{"name":"Charit\u00e9 Universit\u00e4tsmedizin Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.C.","family":"Kingswood","sequence":"additional","affiliation":[{"name":"Royal Sussex County Hospital Brighton UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Belousova","sequence":"additional","affiliation":[{"name":"Moscow Research Institute of Pediatrics &amp; Pediatric Surgery Moscow Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Sparagana","sequence":"additional","affiliation":[{"name":"Texas Scottish Rite Hospital for Children Dallas TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.J.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Division of Child and Adolescent Psychiatry University of Cape Town Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Berkowitz","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Ridolfi","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals S.A.S. 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