{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:56:34Z","timestamp":1785214594978,"version":"3.55.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Developmental Synaptopathies Consortium","award":["U54NS092090"],"award-info":[{"award-number":["U54NS092090"]}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016650","name":"Rare Diseases Clinical Research Network","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016650","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Data Management and Coordinating Center","award":["U2CTR002818"],"award-info":[{"award-number":["U2CTR002818"]}]},{"name":"Rare Diseases Research"},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 HD105351"],"award-info":[{"award-number":["P50 HD105351"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23NS119666"],"award-info":[{"award-number":["K23NS119666"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with\/without autism. We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5\u00a0mg\/m2) in individuals (5\u201345\u00a0years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners\u2019 Continuous Performance Test hit reaction time and Purdue Pegboard Test score. Forty-six participants underwent 1:1 randomization: n\u2009=\u200924 (everolimus) and n\u2009=\u200922 (placebo). Gastrointestinal adverse events were more common in the everolimus group (P\u2009&amp;lt;\u20090.001). Changes in the primary endpoint between groups from baseline to Month 6 were not apparent (Cohen\u2019s d\u2009=\u2009\u22120.10, P\u2009=\u20090.518). However, several measures were associated with modest effect sizes (\u22650.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior and global improvement. There was a significant difference in EEG central alpha power (P\u2009=\u20090.049) and central beta power (P\u2009=\u20090.039) 6\u00a0months after everolimus treatment. Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6\u00a0months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.<\/jats:p>","DOI":"10.1093\/hmg\/ddac111","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T21:03:41Z","timestamp":1653080621000},"page":"3393-3404","source":"Crossref","is-referenced-by-count":35,"title":["A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7008-1879","authenticated-orcid":false,"given":"Siddharth","family":"Srivastava","sequence":"first","affiliation":[{"name":"Department of Neurology , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Booil","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Frazier","sequence":"additional","affiliation":[{"name":"Department of Psychology , John Carroll University, , OH 44118 , USA"},{"name":"University Heights , John Carroll University, , OH 44118 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Snow","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleming","family":"Peck","sequence":"additional","affiliation":[{"name":"Department of Neurology , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April R","family":"Levin","sequence":"additional","affiliation":[{"name":"Department of Neurology , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeeta","family":"Mondal","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zetan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajna","family":"Filip-Dhima","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Geisel","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira A","family":"Dies","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Diplock","sequence":"additional","affiliation":[{"name":"Department of Neurology , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charis","family":"Eng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabi","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hematology, Oncology, Blood and Marrow Transplantation, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Neurology , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston Children\u2019s Hospital, , Boston, MA 02115 , USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center , Boston Children\u2019s Hospital, , Boston, MA 02115 , 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