{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T16:21:01Z","timestamp":1785687661890,"version":"3.56.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008792","name":"Novartis Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008792","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Esophagus"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>PI3K\/AKT\/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K inhibitor with promising activity in several cancers. We prospectively investigated efficacy, safety, and biomarkers of BKM120 in advanced ESCC. We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>BKM120 (100\u00a0mg\/day) was administered orally in a 28-day cycle. The primary end point was disease control rate (DCR). Tumor samples for all patients were collected for gene alteration analysis in a comprehensive genomic profiling assay.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Of 42 patients enrolled, 20 had stable disease and two had confirmed partial response. One ineligible patient was excluded from the primary analysis, which met the primary end point (DCR 51.2%; 95% confidence interval [CI], 35.1\u201367.1). In the 42 patients, median progression-free survival and overall survival were 2.3 (95% CI 1.8\u20133.2) and 9.0 (95% CI 6.5\u201311.4) months, respectively. Common grade 3 or 4 adverse events were rash, anorexia, hyponatremia, and abnormal hepatic function; profiles of these events in this study were similar to those in previous studies of BKM120 monotherapy. No treatment-related deaths occurred. PI3K pathway activation was observed in patients with good clinical response.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>BKM120 monotherapy showed promising efficacy and a manageable toxicity profile even in patients with pretreated advanced ESCC. This study showed the potential target PI3K for ESCC, and further confirmatory trial will be necessary to confirm it. Unique ID issued by UMIN: UMIN 000011217.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10388-022-00928-3","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T07:06:27Z","timestamp":1659078387000},"page":"702-710","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303)"],"prefix":"10.1007","volume":"19","author":[{"given":"Takashi","family":"Kojima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Muro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Nishina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Wakabayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ohtsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Doi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"928_CR1","doi-asserted-by":"publisher","first-page":"E359","DOI":"10.1002\/ijc.29210","volume":"136","author":"J Ferlay","year":"2015","unstructured":"Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359\u201386.","journal-title":"Int J Cancer"},{"key":"928_CR2","first-page":"172","volume":"22","author":"T Iizuka","year":"1992","unstructured":"Iizuka T, Kakegawa T, Ide H, et al. Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japanese Esophageal Oncology Group Trial. Jpn J Clin Oncol. 1992;22:172\u20136.","journal-title":"Jpn J Clin Oncol"},{"key":"928_CR3","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1093\/jjco\/hye090","volume":"31","author":"K Hayashi","year":"2001","unstructured":"Hayashi K, Ando N, Watanabe H, et al. Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407). Jpn J Clin Oncol. 2001;31:419\u201323.","journal-title":"Jpn J Clin Oncol"},{"key":"928_CR4","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1093\/annonc\/mdp069","volume":"20","author":"S Lorenzen","year":"2009","unstructured":"Lorenzen S, Schuster T, Porschen R, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009;20:1667\u201373.","journal-title":"Ann Oncol"},{"key":"928_CR5","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/S1470-2045(13)70136-0","volume":"14","author":"T Crosby","year":"2013","unstructured":"Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2\/3 randomised trial. Lancet Oncol. 2013;14:627\u201337.","journal-title":"Lancet Oncol"},{"key":"928_CR6","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1001\/jamaoncol.2017.1598","volume":"3","author":"M Suntharalingam","year":"2017","unstructured":"Suntharalingam M, Winter K, Ilson D, et al. Effect of the addition of Cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: the NRG oncology RTOG 0436 phase 3 Randomized Clinical Trial. JAMA Oncol. 2017;3:1520\u20138.","journal-title":"JAMA Oncol"},{"key":"928_CR7","first-page":"84","volume":"20","author":"F Perrone","year":"2009","unstructured":"Perrone F, Lampis A, Orsenigo M, et al. PI3KCA\/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Nncol. 2009;20:84\u201390.","journal-title":"Ann Nncol"},{"key":"928_CR8","doi-asserted-by":"publisher","first-page":"2530","DOI":"10.1158\/1078-0432.CCR-14-2368","volume":"21","author":"A de la Rochefordiere","year":"2015","unstructured":"de la Rochefordiere A, Kamal M, Floquet A, et al. PIK3CA pathway mutations predictive of poor response following standard radiochemotherapy +\/\u2212cetuximab in cervical cancer patients. Clin Cancer Res. 2015;21:2530\u20137.","journal-title":"Clin Cancer Res"},{"key":"928_CR9","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.1038\/onc.2008.245","volume":"27","author":"TL Yuan","year":"2008","unstructured":"Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497\u2013510.","journal-title":"Oncogene"},{"key":"928_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0103021","volume":"9","author":"L Wang","year":"2014","unstructured":"Wang L, Shan L, Zhang S, et al. PIK3CA gene mutations and overexpression: implications for prognostic biomarker and therapeutic target in Chinese esophageal squamous cell carcinoma. PLoS\u00a0One. 2014;9: e103021.","journal-title":"PLoS\u00a0One"},{"key":"928_CR11","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s12885-016-3041-3","volume":"17","author":"K Hatogai","year":"2017","unstructured":"Hatogai K, Fujii S, Kojima T, et al. Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma. BMC Cancer. 2017;17:36.","journal-title":"BMC Cancer"},{"key":"928_CR12","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1158\/1078-0432.CCR-12-3559","volume":"19","author":"H Shigaki","year":"2013","unstructured":"Shigaki H, Baba Y, Watanabe M, et al. PIK3CA mutation is associated with a favorable prognosis among patients with curatively resected esophageal squamous cell carcinoma. Clin Cancer Res. 2013;19:2451\u20139.","journal-title":"Clin Cancer Res"},{"key":"928_CR13","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.jss.2007.03.044","volume":"145","author":"R Mori","year":"2008","unstructured":"Mori R, Ishiguro H, Kimura M, et al. PIK3CA mutation status in Japanese esophageal squamous cell carcinoma. J Surg Res. 2008;145:320\u20136.","journal-title":"J Surg Res"},{"key":"928_CR14","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1158\/1535-7163.MCT-11-0474","volume":"11","author":"SM Maira","year":"2012","unstructured":"Maira SM, Pecchi S, Huang A, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317\u201328.","journal-title":"Mol Cancer Ther"},{"key":"928_CR15","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1111\/cas.12350","volume":"105","author":"Y Ando","year":"2014","unstructured":"Ando Y, Inada-Inoue M, Mitsuma A, et al. Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105:347\u201353.","journal-title":"Cancer Sci"},{"key":"928_CR16","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1200\/JCO.2011.36.1360","volume":"30","author":"JC Bendell","year":"2012","unstructured":"Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30:282\u201390.","journal-title":"J Clin Oncol"},{"key":"928_CR17","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1007\/s10637-014-0082-9","volume":"32","author":"J Rodon","year":"2014","unstructured":"Rodon J, Bra\u00f1a I, Siu LL, et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2014;32:670\u201381.","journal-title":"Invest New Drugs"},{"key":"928_CR18","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.celrep.2013.12.035","volume":"6","author":"F Janku","year":"2014","unstructured":"Janku F, Hong DS, Fu S, et al. Assessing PIK3CA and PTEN in early-phase trials with PI3K\/AKT\/mTOR inhibitors. Cell Rep. 2014;6:377\u201387.","journal-title":"Cell Rep"},{"key":"928_CR19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1093\/jjco\/hyp120","volume":"40","author":"I Okamoto","year":"2010","unstructured":"Okamoto I, Doi T, Ohtsu A, et al. Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol. 2010;40:17\u201323.","journal-title":"Jpn J Clin Oncol"},{"key":"928_CR20","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/S1470-2045(17)30064-5","volume":"18","author":"D Soulieres","year":"2017","unstructured":"Soulieres D, Faivre S, Mesia R, et al. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017;18:323\u201335.","journal-title":"Lancet Oncol"},{"key":"928_CR21","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/bjc.2016.430","volume":"116","author":"PE Heudel","year":"2017","unstructured":"Heudel PE, Fabbro M, Roemer-Becuwe C, et al. Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group. Br J Cancer. 2017;116:303\u20139.","journal-title":"Br J Cancer"},{"key":"928_CR22","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/nature20805","volume":"541","author":"The Cancer Genome Atlas Research Network","year":"2017","unstructured":"The Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541:169\u201375.","journal-title":"Nature"},{"key":"928_CR23","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.ctrv.2012.11.002","volume":"39","author":"AM Gonzalez-Angulo","year":"2013","unstructured":"Gonzalez-Angulo AM, Blumenschein GR Jr. Defining biomarkers to predict sensitivity to PI3K\/Akt\/mTOR pathway inhibitors in breast cancer. Cancer Treat Rev. 2013;39:313\u201320.","journal-title":"Cancer Treat Rev"},{"key":"928_CR24","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1158\/1535-7163.MCT-10-0994","volume":"10","author":"F Janku","year":"2011","unstructured":"Janku F, Tsimberidou AM, Garrido-Laguna I, et al. PIK3CA mutations in patients with advanced cancers treated with PI3K\/AKT\/mTOR axis inhibitors. Mol Cancer Ther. 2011;10:558\u201365.","journal-title":"Mol Cancer Ther"},{"key":"928_CR25","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1200\/JCO.2011.36.1196","volume":"30","author":"F Janku","year":"2012","unstructured":"Janku F, Wheler JJ, Westin SN, et al. PI3K\/AKT\/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012;30:777\u201382.","journal-title":"J Clin Oncol"},{"key":"928_CR26","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1097\/JTO.0000000000000607","volume":"10","author":"JF Vansteenkiste","year":"2015","unstructured":"Vansteenkiste JF, Canon JL, De Braud F, et al. Safety and efficacy of Buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the Phase II BASALT-1 Study. J Thoracic Oncol. 2015;10:1319\u201327.","journal-title":"J Thoracic Oncol"},{"key":"928_CR27","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ccr.2004.06.007","volume":"6","author":"RJ Shaw","year":"2004","unstructured":"Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6:91\u20139.","journal-title":"Cancer Cell"},{"key":"928_CR28","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.ccr.2010.04.026","volume":"17","author":"J Carretero","year":"2010","unstructured":"Carretero J, Shimamura T, Rikova K, et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell. 2010;17:547\u201359.","journal-title":"Cancer Cell"},{"key":"928_CR29","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1093\/hmg\/ddi139","volume":"14","author":"C Forcet","year":"2005","unstructured":"Forcet C, Etienne-Manneville S, Gaude H, et al. Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity. Hum Mol Genet. 2005;14:1283\u201392.","journal-title":"Hum Mol Genet"}],"container-title":["Esophagus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10388-022-00928-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10388-022-00928-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10388-022-00928-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T03:28:03Z","timestamp":1662089283000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10388-022-00928-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,29]]},"references-count":29,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["928"],"URL":"https:\/\/doi.org\/10.1007\/s10388-022-00928-3","relation":{},"ISSN":["1612-9059","1612-9067"],"issn-type":[{"value":"1612-9059","type":"print"},{"value":"1612-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,29]]},"assertion":[{"value":"11 December 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Takahashi Kojima has received grants from MSD, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Astellas Amgen BioPharma, Taiho Pharmaceutical, Chugai Pharmaceutical Co. Ltd., and Shionogi; and honoraria from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, MSD, Astellas Pharma, Merck, and Oncolys BioPharma. Ken Kato has received grants from Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., MSD, BeiGene, Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical, AstraZeneca, BAYER, Shionogi, and Novartis; consulting fees from BMS, ONO, and BeiGene; honoraria from Bristol Myers Squibb and ONO; and Participation on advisory board from Daiichi Sankyo. Hiroki Hara has received grants from Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Elevar Therapeutics, GSK, Incyte, Merck Biopharma, MSD K. K., Ono, Pfizer, and Taiho Pharmaceutical; consulting fees from Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Lilly, MSD K. K., and Ono; and honoraria from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD K. K., Ono, Sanofi, Taiho Pharmaceutical, Takeda, and Yakult Honsha. Shunji Takahashi has received grants from Eisai, Novartis, and Taiho Pharmaceutical; and honoraria from Eisai, Novartis, and Taiho Pharmaceutical. Kei Muro has received all support for the present manuscript from Novartis Pharma K.K.; grants from Astellas, Amgen, Sanofi K.K., Daiichi Sankyo, Parexel International, Taiho, MSD, Merck Biopharma Co., Ltd., Pfizer Inc., Eisai Co., Ltd., Solasia Pharma K.K., and Ono Pharmaceutical Co., Ltd.; consulting fees from Amgen, Ono Pharmaceutical Co., Ltd., and AstraZeneca; honoraria from Eli Lilly, Chugai Pharmaceutical Co. Ltd., Takeda, Ono Pharmaceutical Co., Ltd., Taiho, Sanofi, Bristol Myers Squibb, and Bayer. Tomohiro Nishina has received honoraria from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo, and Bristol Myers Squibb. Shogo Nomura has received a grant for Amgen, and AstraZeneca; and Honoraria from AstraZeneca, Pfizer, Taiho, and Chugai. Akihiro Sato has received a grant from Novartis pharma. Toshihiko Doi has received grants from Lilly, MSD, Daiichi Sankyo, Sumitomo Dainippon, Taiho, Novartis, Merck Serono, Janssen Pharma, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, AbbVie, IQVIA, and Eisai; consulting fees from Sumitomo Dainippon, Taiho, Takeda, Chugai Pharmaceutical Co. Ltd. Pharma, AbbVie, Bayer, Rakuten Medical, and Otsuka Pharma; honoraria from Bristol Myers Squibb, Rakuten Medical, Ono Pharma, Oncolys BioPharma, and Taiho; and advises on the boards of MSD, Daiichi Sankyo, Amgen, Novartis, Boehringer Ingelheim, Janssen Pharma, AbbVie, Bayer, and Astellas Pharma. Masashi Wakabayashi and Atsushi Ohtsu report no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. The study protocol was approved by the institutional review board at each study site.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical statement"}}]}}