{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T22:29:30Z","timestamp":1773786570301,"version":"3.50.1"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Singapore ministry of health\u2019s national medical research council","award":["Centre Grant (CG) Programme (CGAug16M005)"],"award-info":[{"award-number":["Centre Grant (CG) Programme (CGAug16M005)"]}]},{"name":"Singapore ministry of health\u2019s national medical research council","award":["Clinician Scientist Award (SI Category"],"award-info":[{"award-number":["Clinician Scientist Award (SI Category"]}]},{"name":"Singapore ministry of health\u2019s national medical research council","award":["C\/CSASI\/0004\/2015)"],"award-info":[{"award-number":["C\/CSASI\/0004\/2015)"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer Res Treat"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can \u201cnormalize\u201d the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin\/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001 and 0.001) along with decrease in LVD post-C1 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.006 for Sunitinib vs\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.004).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registry<\/jats:title>\n                    <jats:p>ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10549-021-06470-7","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T03:04:52Z","timestamp":1639969492000},"page":"131-142","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin\/cyclophosphamide chemotherapy in HER2-negative breast cancer"],"prefix":"10.1007","volume":"192","clinical-trial-number":[{"clinical-trial-number":"nct02790580","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Kritika","family":"Yadav","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joline","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan","family":"Choo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel Guan Wei","family":"Ow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matilda","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching Wan","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikael","family":"Hartman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siew Eng","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Ngoi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siau Wei","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvonne","family":"Ang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan Qin","family":"Chong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hon Lyn","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sing Huang","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boon Cher","family":"Goh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-6419","authenticated-orcid":false,"given":"Soo Chin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"6470_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 68:394\u2013424. https:\/\/doi.org\/10.3322\/caac.21492","journal-title":"CA: Cancer J Clin"},{"key":"6470_CR2","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1200\/JCO.2005.12.017","volume":"23","author":"BP Schneider","year":"2005","unstructured":"Schneider BP, Miller KD (2005) Angiogenesis of breast cancer. J Clin Oncol 23:1782\u20131790. https:\/\/doi.org\/10.1200\/JCO.2005.12.017","journal-title":"J Clin Oncol"},{"key":"6470_CR3","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1186\/bcr1796","volume":"9","author":"SB Fox","year":"2007","unstructured":"Fox SB, Generali DG, Harris AL (2007) Breast tumour angiogenesis. Breast Cancer Res 9:216. https:\/\/doi.org\/10.1186\/bcr1796","journal-title":"Breast Cancer Res"},{"key":"6470_CR4","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1056\/NEJMoa1111097","volume":"366","author":"HD Bear","year":"2012","unstructured":"Bear HD, Tang G, Rastogi P et al (2012) Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310\u2013320. https:\/\/doi.org\/10.1056\/NEJMoa1111097","journal-title":"N Engl J Med"},{"key":"6470_CR5","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1200\/JCO.2011.38.5492","volume":"30","author":"HS Rugo","year":"2012","unstructured":"Rugo HS (2012) Inhibiting angiogenesis in breast cancer: the beginning of the end or the end of the beginning? J Clin Oncol 30:898\u2013901. https:\/\/doi.org\/10.1200\/JCO.2011.38.5492","journal-title":"J Clin Oncol"},{"key":"6470_CR6","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.3892\/ijo.2016.3709","volume":"49","author":"E Maj","year":"2016","unstructured":"Maj E, Papiernik D, Wietrzyk J (2016) Antiangiogenic cancer treatment: the great discovery and greater complexity (Review). Int J Oncol 49:1773\u20131784. https:\/\/doi.org\/10.3892\/ijo.2016.3709","journal-title":"Int J Oncol"},{"key":"6470_CR7","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1126\/science.1104819","volume":"307","author":"RK Jain","year":"2005","unstructured":"Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58\u201362. https:\/\/doi.org\/10.1126\/science.1104819","journal-title":"Science"},{"key":"6470_CR8","doi-asserted-by":"publisher","first-page":"547","DOI":"10.4161\/cam.23332","volume":"6","author":"M Perrot-Applanat","year":"2012","unstructured":"Perrot-Applanat M, Di Benedetto M (2012) Autocrine functions of VEGF in breast tumor cells. Cell Adh Migr 6:547\u2013553. https:\/\/doi.org\/10.4161\/cam.23332","journal-title":"Cell Adh Migr"},{"key":"6470_CR9","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.5858\/arpa.2018-0902-SA","volume":"142","author":"AC Wolff","year":"2018","unstructured":"Wolff AC, Hammond MEH, Allison KH et al (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology\/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 142:1364\u20131382. https:\/\/doi.org\/10.5858\/arpa.2018-0902-SA","journal-title":"Arch Pathol Lab Med"},{"key":"6470_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1918-1","author":"JV Gaustad","year":"2015","unstructured":"Gaustad JV, Simonsen TG, Smistad R et al (2015) Early effects of low dose bevacizumab treatment assessed by magnetic resonance imaging. BMC Cancer. https:\/\/doi.org\/10.1186\/s12885-015-1918-1","journal-title":"BMC Cancer"},{"key":"6470_CR11","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11596","author":"ALA Wong","year":"2016","unstructured":"Wong ALA, Sundar R, Wang TT et al (2016) Phase Ib\/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer. Oncotarget. https:\/\/doi.org\/10.18632\/oncotarget.11596","journal-title":"Oncotarget"},{"key":"6470_CR12","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1093\/jnci\/92.3.205","volume":"92","author":"P Therasse","year":"2000","unstructured":"Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. JNCI J Natl Cancer Inst 92:205\u2013216. https:\/\/doi.org\/10.1093\/jnci\/92.3.205","journal-title":"JNCI J Natl Cancer Inst"},{"key":"6470_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/261750","volume":"2012","author":"E Fakhrejahani","year":"2012","unstructured":"Fakhrejahani E, Toi M (2012) Tumor angiogenesis: pericytes and maturation are not to be ignored. J Oncol 2012:1\u201310. https:\/\/doi.org\/10.1155\/2012\/261750","journal-title":"J Oncol"},{"key":"6470_CR14","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/sj.bjc.6604921","volume":"100","author":"XB Trinh","year":"2009","unstructured":"Trinh XB, Tjalma WAA, Vermeulen PB et al (2009) The VEGF pathway and the AKT\/mTOR\/p70S6K1 signalling pathway in human epithelial ovarian cancer. Br J Cancer 100:971\u2013978. https:\/\/doi.org\/10.1038\/sj.bjc.6604921","journal-title":"Br J Cancer"},{"key":"6470_CR15","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djk020","author":"M Dowsett","year":"2007","unstructured":"Dowsett M, Smith IE, Ebbs SR et al (2007) Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. https:\/\/doi.org\/10.1093\/jnci\/djk020","journal-title":"J Natl Cancer Inst"},{"key":"6470_CR16","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1200\/JCO.20.6.1456","volume":"20","author":"IC Smith","year":"2002","unstructured":"Smith IC (2002) Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20:1456\u20131466. https:\/\/doi.org\/10.1200\/JCO.20.6.1456","journal-title":"J Clin Oncol"},{"key":"6470_CR17","doi-asserted-by":"publisher","first-page":"3731","DOI":"10.1158\/0008-5472.CAN-04-0074","volume":"64","author":"RT Tong","year":"2004","unstructured":"Tong RT, Boucher Y, Kozin SV et al (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Can Res 64:3731\u20133736. https:\/\/doi.org\/10.1158\/0008-5472.CAN-04-0074","journal-title":"Can Res"},{"key":"6470_CR18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.ccr.2004.10.011","volume":"6","author":"F Winkler","year":"2004","unstructured":"Winkler F, Kozin SV, Tong RT et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation. Cancer Cell 6:553\u2013563. https:\/\/doi.org\/10.1016\/j.ccr.2004.10.011","journal-title":"Cancer Cell"},{"key":"6470_CR19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.28.0982","author":"NJ Robert","year":"2011","unstructured":"Robert NJ, Di\u00e9ras V, Glaspy J et al (2011) RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. https:\/\/doi.org\/10.1200\/JCO.2010.28.0982","journal-title":"J Clin Oncol"},{"key":"6470_CR20","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1309\/2HGNJ1GU57JMBJAQ","volume":"129","author":"YM El-Gohary","year":"2008","unstructured":"El-Gohary YM, Metwally G, Saad RS et al (2008) Prognostic significance of intratumoral and peritumoral lymphatic density and blood vessel density in invasive breast carcinomas. Am J Clin Pathol 129:578\u2013586. https:\/\/doi.org\/10.1309\/2HGNJ1GU57JMBJAQ","journal-title":"Am J Clin Pathol"},{"key":"6470_CR21","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1093\/neuonc\/noy103","volume":"20","author":"SR Michaelsen","year":"2018","unstructured":"Michaelsen SR, Staberg M, Pedersen H et al (2018) VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro Oncol 20:1462\u20131474. https:\/\/doi.org\/10.1093\/neuonc\/noy103","journal-title":"Neuro Oncol"},{"key":"6470_CR22","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1634\/theoncologist.2014-0465","volume":"20","author":"Y Zhao","year":"2015","unstructured":"Zhao Y, Adjei AA (2015) Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist 20:660\u2013673. https:\/\/doi.org\/10.1634\/theoncologist.2014-0465","journal-title":"Oncologist"},{"key":"6470_CR23","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1158\/1535-7163.MCT-10-1124","volume":"10","author":"G Aparicio-Gallego","year":"2011","unstructured":"Aparicio-Gallego G, Blanco M, Figueroa A et al (2011) New insights into molecular mechanisms of sunitinib-associated side effects. Mol Cancer Ther 10:2215\u20132223. https:\/\/doi.org\/10.1158\/1535-7163.MCT-10-1124","journal-title":"Mol Cancer Ther"},{"key":"6470_CR24","first-page":"1225","volume":"31","author":"Y Tanaka","year":"2011","unstructured":"Tanaka Y, Shibata MA, Morimoto J, Otsuki Y (2011) Sunitinib suppresses tumor growth and metastases in a highly metastatic mouse mammary cancer model. Anticancer Res 31:1225","journal-title":"Anticancer Res"},{"key":"6470_CR25","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1186\/s12885-020-07616-4","volume":"20","author":"YLE Ang","year":"2020","unstructured":"Ang YLE, Ho GF, Soo RA et al (2020) A randomized phase II trial evaluating the addition of low dose, short course sunitinib to docetaxel in advanced solid tumours. BMC Cancer 20:1118. https:\/\/doi.org\/10.1186\/s12885-020-07616-4","journal-title":"BMC Cancer"},{"key":"6470_CR26","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1200\/JCO.2005.03.4645","volume":"24","author":"SB Wedam","year":"2006","unstructured":"Wedam SB, Low JA, Yang SX et al (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24:769\u2013777. https:\/\/doi.org\/10.1200\/JCO.2005.03.4645","journal-title":"J Clin Oncol"},{"key":"6470_CR27","doi-asserted-by":"publisher","first-page":"4163","DOI":"10.2147\/CMAR.S174712","volume":"10","author":"W Li","year":"2018","unstructured":"Li W, Quan YY, Li Y et al (2018) Monitoring of tumor vascular normalization: the key points from basic research to clinical application. Cancer Manag Res 10:4163\u20134172. https:\/\/doi.org\/10.2147\/CMAR.S174712","journal-title":"Cancer Manag Res"}],"container-title":["Breast Cancer Research and Treatment"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10549-021-06470-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10549-021-06470-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10549-021-06470-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T11:05:59Z","timestamp":1644750359000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10549-021-06470-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,20]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["6470"],"URL":"https:\/\/doi.org\/10.1007\/s10549-021-06470-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-820044\/v1","asserted-by":"object"}]},"ISSN":["0167-6806","1573-7217"],"issn-type":[{"value":"0167-6806","type":"print"},{"value":"1573-7217","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,20]]},"assertion":[{"value":"16 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"SGWO served on advisory boards and had speaker\u2019s engagement with Pfizer, Novartis, Eli Lilly, AstraZeneca and Roche, and has received support to attend conference\/travel from Pfizer, Novartis and AstraZeneca. AW has served on advisory board of Pfizer and Astra Zeneca. NN has received honoraria from Astra Zeneca, Janssen, Thermofisher and support to attend conferences from Astra Zeneca, Eisai. WQC has received conference sponsorship by MSD (ASCO 2021). GBC has been on advisory boards of MSD, AstraZeneca and Novartis and served as consultant to Adagene. He has received research support from BMS, MSD, Adagene and Taiho and has stock ownership of Merus and Gilead Sciences. SCL served on advisory boards and had speaker\u2019s engagement with Pfizer, Novartis, Eli Lilly, Astra Zeneca, Roche, and ACT genomics, received research grants\/ grants to support clinical trials from Eisai, Taiho, Pfizer, and Karyopharm, and has received support to attend conference\/travel from Amgen, Pfizer, Novartis, Roche and ACT Genomics.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the National Healthcare Group Domain Specific Ethics Review Board in 2016 (DSRB 2016\/00327).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Signed written informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}