{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:30:15Z","timestamp":1793374215068,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T00:00:00Z","timestamp":1550016000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Development Center for Medical Science and Technology, National Health and Family Planning Commission of the People\u2019s Republic of China","award":["2018ZX09721003-008"],"award-info":[{"award-number":["2018ZX09721003-008"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2019,12]]},"DOI":"10.1186\/s13023-019-1012-x","type":"journal-article","created":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T09:05:43Z","timestamp":1550048743000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis"],"prefix":"10.1186","volume":"14","author":[{"given":"Min","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,13]]},"reference":[{"issue":"1","key":"1012_CR1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1749-6632.1991.tb37754.x","volume":"615","author":"JP Osborne","year":"2010","unstructured":"Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 2010;615(1):125\u20137.","journal-title":"Ann N Y Acad Sci"},{"issue":"5327","key":"1012_CR2","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1126\/science.277.5327.805","volume":"277","author":"SM Van","year":"1997","unstructured":"Van SM, De HR, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277(5327):805\u20138.","journal-title":"Science"},{"issue":"7","key":"1012_CR3","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","volume":"75","author":"Consortium E C","year":"1993","unstructured":"Consortium E C. 1 T S. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75(7):1305\u201315.","journal-title":"Cell"},{"issue":"4","key":"1012_CR4","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.devcel.2007.03.020","volume":"12","author":"PT Bhaskar","year":"2007","unstructured":"Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007;12(4):487\u2013502.","journal-title":"Dev Cell"},{"issue":"4","key":"1012_CR5","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.001","volume":"49","author":"N Hope","year":"2013","unstructured":"Hope N, Krueger Darcy A, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243\u201354.","journal-title":"Pediatr Neurol"},{"issue":"4","key":"1012_CR6","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.002","volume":"49","author":"DA Krueger","year":"2013","unstructured":"Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49(4):243.","journal-title":"Pediatr Neurol"},{"issue":"8","key":"1012_CR7","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nrd2062","volume":"5","author":"S Faivre","year":"2006","unstructured":"Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671.","journal-title":"Nat Rev Drug Discov"},{"key":"1012_CR8","volume-title":"Rapamune (sirolimus) oral solution and tablets [package insert]","author":"Wyeth Pharmaceuticals Inc","year":"2012","unstructured":"Wyeth Pharmaceuticals Inc. Rapamune (sirolimus) oral solution and tablets [package insert]. Philadelphia: Wyeth Pharmaceuticals Inc; 2012."},{"issue":"2","key":"1012_CR9","doi-asserted-by":"publisher","first-page":"83","DOI":"10.2165\/00003088-200443020-00002","volume":"43","author":"DGI Kirchner","year":"2004","unstructured":"Kirchner DGI, Meierwiedenbach I, Manns MP. Clinical pharmacokinetics of Everolimus. Clin Pharmacokinet. 2004;43(2):83\u201395.","journal-title":"Clin Pharmacokinet"},{"issue":"8","key":"1012_CR10","doi-asserted-by":"publisher","first-page":"573","DOI":"10.2165\/00003088-200140080-00002","volume":"40","author":"K Mahalati","year":"2001","unstructured":"Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet. 2001;40(8):573\u201385.","journal-title":"Clin Pharmacokinet"},{"issue":"7448","key":"1012_CR11","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature12122","volume":"497","author":"H Yang","year":"2013","unstructured":"Yang H, Rudge DG, Koos JD, et al. mTOR kinase structure, mechanism and regulation by the rapamycin-binding domain. Nature. 2013;497(7448):217\u201323.","journal-title":"Nature"},{"issue":"10","key":"1012_CR12","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1111\/iju.13168","volume":"23","author":"T Hatano","year":"2016","unstructured":"Hatano T, Chikaraishi K, Inaba H, et al. Outcomes of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: a single institution experience in Japan. Int J Urol. 2016;23(10):833.","journal-title":"Int J Urol"},{"issue":"4","key":"1012_CR13","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/pbc.25368","volume":"62","author":"J Trelinska","year":"2015","unstructured":"Trelinska J, Dachowska I, Kotulska K, et al. Factors affecting response to everolimus therapy for subependymal giant cell astrocytomas associated with tuberous sclerosis. Pediatr Blood Cancer. 2015;62(4):616\u201321.","journal-title":"Pediatr Blood Cancer"},{"issue":"1","key":"1012_CR14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4103\/0378-6323.190844","volume":"83","author":"SL Cinar","year":"2017","unstructured":"Cinar SL, Kartal D, Bayram AK, et al. Topical sirolimus for the treatment of angiofibromas in tuberous sclerosis. Indian J Dermatol Venereol Leprol. 2017;83(1):27.","journal-title":"Indian J Dermatol Venereol Leprol"},{"issue":"4","key":"1012_CR15","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1002\/ana.21331","volume":"63","author":"LH Zeng","year":"2008","unstructured":"Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63(4):444\u201353.","journal-title":"Ann Neurol"},{"issue":"1","key":"1012_CR16","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s13023-016-0530-z","volume":"11","author":"S Samueli","year":"2016","unstructured":"Samueli S, Abraham K, Dressler A, et al. Efficacy and safety of Everolimus in children with TSC - associated epilepsy \u2013 pilot data from an open single-center prospective study. Orphanet J Rare Dis. 2016;11(1):145.","journal-title":"Orphanet J Rare Dis"},{"key":"1012_CR17","volume-title":"RxList: The internet drug index","author":"Rapamune","year":"2013","unstructured":"Rapamune. RxList: The internet drug index. 2013."},{"issue":"1","key":"1012_CR18","doi-asserted-by":"publisher","first-page":"51","DOI":"10.5152\/tpa.2015.2138","volume":"50","author":"\u0130 Erol","year":"2015","unstructured":"Erol \u0130, Sava\u015f T, \u015eekerci S, et al. Tuberous sclerosis complex; single center experience. T\u00fcrk Pediatri Ar\u015fivi. 2015;50(1):51.","journal-title":"T\u00fcrk Pediatri Ar\u015fivi"},{"issue":"6","key":"1012_CR19","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.pediatrneurol.2010.01.016","volume":"42","author":"SP Sparagana","year":"2010","unstructured":"Sparagana SP, Wilkes DC, Thompson CE, et al. Optic nerve tumor in tuberous sclerosis complex is not responsive to sirolimus. Pediatr Neurol. 2010;42(6):443.","journal-title":"Pediatr Neurol"},{"issue":"7","key":"1012_CR20","first-page":"CD011272","volume":"7","author":"TH Sasongko","year":"2016","unstructured":"Sasongko TH, Ismail NFD, Zabidi-Hussin Z. Rapamycin and rapalogs for tuberous sclerosis complex. Cochrane Database Syst Rev. 2016;7(7):CD011272.","journal-title":"Cochrane Database Syst Rev"},{"issue":"10056","key":"1012_CR21","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1016\/S0140-6736(16)31419-2","volume":"388","author":"JA French","year":"2016","unstructured":"French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153.","journal-title":"Lancet"},{"issue":"10","key":"1012_CR22","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1212\/WNL.0000000000003077","volume":"87","author":"IE Overwater","year":"2016","unstructured":"Overwater IE, Rietman AB, Bindelsde HK, et al. Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. Neurology. 2016;87(10):1011\u20138.","journal-title":"Neurology"},{"key":"1012_CR23","unstructured":"Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Cochrane Collaboration:2011 Available from https:\/\/training.cochrane.org\/handbook ."},{"issue":"9861","key":"1012_CR24","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0140-6736(12)61134-9","volume":"381","author":"DN Franz","year":"2013","unstructured":"Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125\u201332.","journal-title":"Lancet"},{"key":"1012_CR25","doi-asserted-by":"crossref","unstructured":"Bissler John J, Kingswood J Christopher, Radzikowska El\u017cbieta et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet, 2013;381(9869): 817\u2013824.","DOI":"10.1016\/S0140-6736(12)61767-X"},{"issue":"12","key":"1012_CR26","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1002\/acn3.494","volume":"4","author":"DA Krueger","year":"2017","unstructured":"Krueger DA, Sadhwani A, Byars AW, et al. Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders. Ann Clin Transl Neurol. 2017;4(12):877\u201387.","journal-title":"Ann Clin Transl Neurol"},{"key":"1012_CR27","doi-asserted-by":"publisher","first-page":"e0204646","DOI":"10.1371\/journal.pone.0204646","volume":"13","author":"A Zonnenberg Bernard","year":"2018","unstructured":"Zonnenberg Bernard A, Neary Maureen P, Sheng DM, et al. Observational study of characteristics and clinical outcomes of Dutch patients with tuberous sclerosis complex and renal angiomyolipoma treated with everolimus. Plos One. 2018;13:e0204646.","journal-title":"Plos One"},{"issue":"12","key":"1012_CR28","doi-asserted-by":"publisher","first-page":"e0189132","DOI":"10.1371\/journal.pone.0189132","volume":"12","author":"S Brakemeier","year":"2017","unstructured":"Brakemeier S, Vogt L, Adams L, et al. Treatment effect of mTOR-inhibition on tissue composition of renal angiomyolipomas in tuberous sclerosis complex (TSC). PLoS One. 2017;12(12):e0189132.","journal-title":"PLoS One"},{"issue":"1","key":"1012_CR29","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13023-018-0781-y","volume":"13","author":"Y Cai","year":"2018","unstructured":"Cai Y, Guo H, Wang W, et al. Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial. Orphanet J Rare Dis. 2018;13(1):43.","journal-title":"Orphanet J Rare Dis"},{"issue":"23","key":"1012_CR30","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1212\/WNL.0000000000003400","volume":"87","author":"DA Krueger","year":"2016","unstructured":"Krueger DA, Wilfong AA, Mays M, Talley CM, Agricola K, Tudor C, Capal J, Holland-Bouley K, Franz DN. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016;87(23):2408\u201315.","journal-title":"Neurology"},{"issue":"17","key":"1012_CR31","first-page":"31969","volume":"S1090\u20133798","author":"DA Krueger","year":"2018","unstructured":"Krueger DA, Capal JK, Paolo C, et al. Short-term Safety of mTOR Inhibitors in infants and very young children with Tuberous Sclerosis Complex (TSC): Multicentre Clinical Experience. Eur J Paediatr Neurol. 2018;S1090\u20133798(17):31969\u20134.","journal-title":"Eur J Paediatr Neurol"},{"issue":"4","key":"1012_CR32","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.oraloncology.2012.11.008","volume":"49","author":"F Martins","year":"2013","unstructured":"Martins F, de Oliveira MA, Wang Q, et al. A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol. 2013;49(4):293\u20138.","journal-title":"Oral Oncol"},{"issue":"1\u20132","key":"1012_CR33","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/odi.12795","volume":"24","author":"L Lo Muzio","year":"2018","unstructured":"Lo Muzio L, Arena C, Troiano G, et al. Oral stomatitis and mTOR inhibitors: a review of current evidence in 20,915 patients. Oral Dis. 2018;24(1\u20132):144\u201371.","journal-title":"Oral Dis"},{"issue":"3","key":"1012_CR34","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1111\/odi.12616","volume":"23","author":"S Sonis","year":"2017","unstructured":"Sonis S, Andreotta PW, Lyng G. On the pathogenesis of mTOR inhibitor-associated stomatitis (mIAS)-studies using an organotypic model of the oral mucosa. Oral Dis. 2017;23(3):347\u201352.","journal-title":"Oral Dis"},{"issue":"5","key":"1012_CR35","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1007\/s40265-016-0552-9","volume":"76","author":"P Curatolo","year":"2016","unstructured":"Curatolo P, Bj\u00f8rnvold M, Dill PE, et al. The role of mTOR inhibitors in the treatment of patients with tuberous sclerosis complex: evidence-based and expert opinions. Drugs. 2016;76(5):551\u201365.","journal-title":"Drugs"},{"key":"1012_CR36","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1002\/ajmg.c.31655","volume":"178","author":"FD Neal","year":"2018","unstructured":"Neal FD, Andrew KD. mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018;178:365\u201373.","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"3","key":"1012_CR37","first-page":"121","volume":"12","author":"MK Koenig","year":"2012","unstructured":"Koenig MK, Hebert AA, Roberson J, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs. 2012;12(3):121\u20136.","journal-title":"Drugs"},{"issue":"7","key":"1012_CR38","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1001\/jamadermatol.2018.0464","volume":"154","author":"MK Koenig","year":"2018","unstructured":"Koenig MK, Bell CS, Hebert AA, et al. Efficacy and safety of topical rapamycin in patients with facial Angiofibromas secondary to tuberous sclerosis complex: the TREATMENT randomized clinical trial. JAMA Dermatol. 2018;154(7):773\u201380.","journal-title":"JAMA Dermatol"},{"issue":"1","key":"1012_CR39","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1186\/s13063-016-1446-6","volume":"17","author":"E Randell","year":"2016","unstructured":"Randell E, Mcnamara R, Davies DM, et al. The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial. Trials. 2016;17(1):398.","journal-title":"Trials"},{"key":"1012_CR40","unstructured":"Yan X. Clinical effect and safety analysis of rapamycin in the treatment of tuberous sclerosis with epilepsy in children. World Latest Med Inf Dig. 2016;16(72):176."},{"issue":"7","key":"1012_CR41","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1001\/jamadermatol.2018.1408","volume":"154","author":"M Wataya-Kaneda","year":"2018","unstructured":"Wataya-Kaneda M, Ohno Y, Fujita Y, et al. Sirolimus gel treatment vs placebo for facial Angiofibromas in patients with tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2018;154(7):781\u20138.","journal-title":"JAMA Dermatol"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-019-1012-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13023-019-1012-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-019-1012-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,14]],"date-time":"2024-07-14T19:14:13Z","timestamp":1720984453000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-019-1012-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,13]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1012"],"URL":"https:\/\/doi.org\/10.1186\/s13023-019-1012-x","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,13]]},"assertion":[{"value":"10 April 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Publisher\u2019s Note"}}],"article-number":"39"}}