{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:36:17Z","timestamp":1772030177254,"version":"3.50.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002342","name":"Suomalainen Tiedeakatemia","doi-asserted-by":"publisher","award":["Kliininen tutkija"],"award-info":[{"award-number":["Kliininen tutkija"]}],"id":[{"id":"10.13039\/501100002342","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["R01 NS034949 (H.K.)"],"award-info":[{"award-number":["R01 NS034949 (H.K.)"]}]},{"name":"National Institute of Health","award":["U54 NS065705 (H.K., M.F., M.T.L)."],"award-info":[{"award-number":["U54 NS065705 (H.K., M.F., M.T.L)."]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neurochir"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>COX2 expression was found in 78% (109\/139) of the bAVMs and localized to the vessels\u2019 lumen or medial layer in 70% (95\/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (<jats:italic>r<\/jats:italic>\u2009=\u2009.231, <jats:italic>p<\/jats:italic>\u2009=\u2009.007, Spearman rank correlation). COX2 expression did not associate with haemorrhage.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00701-021-04895-z","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T04:02:35Z","timestamp":1624939355000},"page":"2503-2514","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cyclo-oxygenase 2, a putative mediator of vessel remodeling, is expressed in the brain AVM vessels and associates with inflammation"],"prefix":"10.1007","volume":"163","author":[{"given":"Sara","family":"Ker\u00e4nen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santeri","family":"Suutarinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul","family":"Mallick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna P.","family":"Laakkonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludmila","family":"Pawlikowska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Behnam Rezai","family":"Jahromi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuomas","family":"Rauramaa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seppo","family":"Yl\u00e4-Herttuala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doug","family":"Marchuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timo","family":"Krings","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timo","family":"Koivisto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Lawton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Radovanovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie E.","family":"Faughnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juhana","family":"Fr\u00f6sen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"4895_CR1","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1227\/NEU.0000000000000686","volume":"76","author":"AA Abla","year":"2015","unstructured":"Abla AA, Nelson J, Kim H, Hess CP, Tihan T, Lawton MT (2015) Silent arteriovenous malformation hemorrhage and the recognition of \u201cunruptured\u201d arteriovenous malformation patients who benefit from surgical intervention. Neurosurgery 76:592\u2013600","journal-title":"Neurosurgery"},{"key":"4895_CR2","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1093\/brain\/124.10.1900","volume":"124","author":"R Al-Shahi","year":"2001","unstructured":"Al-Shahi R, Warlow C (2001) A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 124:1900\u20131926","journal-title":"Brain"},{"key":"4895_CR3","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aah6037","author":"T Aoki","year":"2017","unstructured":"Aoki T, Fr\u00f6sen J, Fukuda M, Bando K, Shioi G, Tsuji K, Ollikainen E, Nozaki K, Laakkonen J, Narumiya S (2017) Prostaglandin E2-EP2-NF-\u03baB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. Sci Signal. https:\/\/doi.org\/10.1126\/scisignal.aah6037","journal-title":"Sci Signal"},{"key":"4895_CR4","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1111\/j.1476-5381.2011.01358.x","volume":"163","author":"T Aoki","year":"2011","unstructured":"Aoki T, Nishimura M, Matsuoka T, Yamamoto K, Furuyashiki T, Kataoka H, Kitaoka S, Ishibashi R, Ishibazawa A, Miyamoto S, Morishita R, Ando J, Hashimoto N, Nozaki K, Narumiya S (2011) PGE(2)-EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-\u03baB. Br J Pharmacol 163:1237\u20131249","journal-title":"Br J Pharmacol"},{"key":"4895_CR5","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1111\/bph.13457","volume":"173","author":"MS Avenda\u00f1o","year":"2016","unstructured":"Avenda\u00f1o MS, Mart\u00ednez-Revelles S, Aguado A, Sim\u00f5es MR, Gonz\u00e1lez-Amor M, Palacios R, Guillem-Llobat P, Vassallo DV, Vila L, Garc\u00eda-Puig J, Beltr\u00e1n LM, Alonso MJ, Cachofeiro MV, Salaices M, Briones AM (2016) Role of COX-2-derived PGE2 on vascular stiffness and function in hypertension. Br J Pharmacol 173:1541\u20131555","journal-title":"Br J Pharmacol"},{"key":"4895_CR6","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1227\/NEU.0b013e3181fa00f1","volume":"67","author":"MM Aziz","year":"2010","unstructured":"Aziz MM, Takagi Y, Hashimoto N, Miyamoto S (2010) Activation of nuclear factor \u03baB in cerebral arteriovenous malformations. Neurosurgery 67:1669\u20131680","journal-title":"Neurosurgery"},{"key":"4895_CR7","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1093\/cvr\/cvp411","volume":"86","author":"EJ Belin de Chantem\u00e8le","year":"2010","unstructured":"Belin de Chantem\u00e8le EJ, Vessi\u00e8res E, Guihot AL, Toutain B, Loufrani L, Henrion D (2010) Cyclooxygenase-2 preserves flow-mediated remodelling in old obese Zucker rat mesenteric arteries. Cardiovasc Res 86:516\u2013525","journal-title":"Cardiovasc Res"},{"key":"4895_CR8","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1038\/jcbfm.2012.84","volume":"32","author":"N Chalouhi","year":"2012","unstructured":"Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Koch WJ, Dumont AS (2012) Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab 32:1659\u20131676","journal-title":"J Cereb Blood Flow Metab"},{"key":"4895_CR9","doi-asserted-by":"publisher","first-page":"2881","DOI":"10.1161\/STROKEAHA.117.017785","volume":"48","author":"X Chen","year":"2017","unstructured":"Chen X, Cooke DL, Saloner D, Nelson J, Su H, Lawton MT, Hess C, Tihan T, Zhao Y, Kim H (2017) Higher flow is present in unruptured arteriovenous malformations with silent intralesional microhemorrhages. Stroke 48:2881\u20132884","journal-title":"Stroke"},{"key":"4895_CR10","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1227\/01.neu.0000333306.64683.b5","volume":"62","author":"Y Chen","year":"2008","unstructured":"Chen Y, Zhu W, Bollen AW, Lawton MT, Barbaro NM, Dowd CF, Hashimoto T, Yang GY, Young WL (2008) Evidence of inflammatory cell involvement in brain arteriovenous malformations. Neurosurgery 62:1340\u20131350","journal-title":"Neurosurgery"},{"key":"4895_CR11","doi-asserted-by":"publisher","unstructured":"Fr\u00f6sen J, Bj\u00f6rkman J, Ollikainen E, Kurtelius A, Tulamo R, Huttunen J, Huttunen T, Niemel\u00e4 M, Hernesniemi J, Fraunberg M, J\u00e4\u00e4skel\u00e4inen J, Koivisto T, Yl\u00e4-Herttuala S, Aoki T, Lindgren A (2017) Use of COX-2 inhibitor medication reduces the progression of intracranial aneurysms in patients https:\/\/doi.org\/10.1159\/000471872","DOI":"10.1159\/000471872"},{"key":"4895_CR12","doi-asserted-by":"publisher","DOI":"10.3171\/2019.5.FOCUS19234","author":"J Fr\u00f6sen","year":"2019","unstructured":"Fr\u00f6sen J, Cebral J, Robertson AM, Aoki T (2019) Flow-induced, inflammation mediated wall remodeling in the formation and progression of intracranial aneurysms. Neurosurg Focus. https:\/\/doi.org\/10.3171\/2019.5.FOCUS19234","journal-title":"Neurosurg Focus"},{"key":"4895_CR13","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1093\/cvr\/cvy002","volume":"114","author":"J Fr\u00f6sen","year":"2018","unstructured":"Fr\u00f6sen J, Joutel A (2018) Smooth muscle cells of intracranial vessels: from development to disease. Cardiovasc Res 114:501\u2013512","journal-title":"Cardiovasc Res"},{"key":"4895_CR14","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1161\/01.STR.0000140636.30204.da","volume":"35","author":"J Fr\u00f6sen","year":"2004","unstructured":"Fr\u00f6sen J, Piippo A, Paetau A, Kangasniemi M, Niemel\u00e4 M, Hernesniemi J, J\u00e4\u00e4skel\u00e4inen J (2004) Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 35:2287\u20132293","journal-title":"Stroke"},{"key":"4895_CR15","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.cardiores.2006.10.015","volume":"73","author":"JM Gitlin","year":"2007","unstructured":"Gitlin JM, Trivedi DB, Langenbach R, Loftin CD (2007) Genetic deficiency of cyclooxygenase-2 attenuates abdominal aortic aneurysm formation in mice. Cardiovasc Res 73:227\u2013236","journal-title":"Cardiovasc Res"},{"key":"4895_CR16","first-page":"1072","volume":"27","author":"GJ Hademenos","year":"1996","unstructured":"Hademenos GJ, Massoud TF (1996) Risk of intracranial arteriovenous malformation rupture due to venous drainage impairment. A theoretical analysis Stroke 27:1072\u20131083","journal-title":"A theoretical analysis Stroke"},{"key":"4895_CR17","doi-asserted-by":"publisher","first-page":"3156","DOI":"10.1161\/STROKEAHA.111.619411","volume":"42","author":"DM Hasan","year":"2011","unstructured":"Hasan DM, Mahaney KB, Brown RD Jr, Meissner I, Piepgras DG, Huston J, Capuano AW, Torner JC (2011) Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 42:3156\u20133162","journal-title":"Stroke"},{"key":"4895_CR18","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1161\/01.STR.0000061888.71524.DF","volume":"34","author":"T Hashimoto","year":"2003","unstructured":"Hashimoto T, Wen G, Lawton MT, Boudreau NJ, Bollen AW, Yang GY, Barbaro NM, Higashida RT, Dowd CF, Halbach VV, Young WL (2003) Abnormal expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in brain arteriovenous malformations. Stroke 34:925\u2013931","journal-title":"Stroke"},{"key":"4895_CR19","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1093\/brain\/awy307","volume":"142","author":"T Hong","year":"2019","unstructured":"Hong T, Yan Y, Li J, Radovanovic I, Ma X, Shao YW, Yu J, Ma Y, Zhang P, Ling F, Huang S, Zhang H, Wang Y (2019) High prevalence of KRAS\/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain 142:23\u201334","journal-title":"Brain"},{"key":"4895_CR20","doi-asserted-by":"publisher","first-page":"639","DOI":"10.18388\/abp.2014_1825","volume":"61","author":"J Korbecki","year":"2014","unstructured":"Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D (2014) Cyclooxygenase pathways. Acta Biochim Pol 61:639\u2013649","journal-title":"Acta Biochim Pol"},{"key":"4895_CR21","first-page":"793","volume":"46","author":"HJ Meisel","year":"2000","unstructured":"Meisel HJ, Mansmann U, Alvarez H, Rodesch G, Brock M, Lasjaunias P (2000) Cerebral arteriovenous malformations and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery 46:793\u2013802","journal-title":"Neurosurgery"},{"key":"4895_CR22","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1056\/NEJMoa1709449","volume":"378","author":"SI Nikolaev","year":"2018","unstructured":"Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B, Khyzha N, DiStefano PV, Suutarinen S, Kiehl TR, Mendes Pereira V, Herman AM, Krings T, Andrade-Barazarte H, Tung T, Valiante T, Zadeh G, Tymianski M, Rauramaa T, Yl\u00e4-Herttuala S, Wythe JD, Antonarakis SE, Fr\u00f6sen J, Fish JE, Radovanovic I (2018) Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain. N Engl J Med 378:250\u2013261","journal-title":"N Engl J Med"},{"key":"4895_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2019.03.105","author":"M Oka","year":"2019","unstructured":"Oka M, Kushamae M, Aoki T, Yamaguchi T, Kitazato K, Abekura Y, Kawamata T, Mizutani T, Miyamoto S, Takagi Y (2019) KRAS G12D or G12V mutation in human brain arteriovenous malformations. World Neurosurg. https:\/\/doi.org\/10.1016\/j.wneu.2019.03.105","journal-title":"World Neurosurg"},{"key":"4895_CR24","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.prostaglandins.2017.03.003","volume":"133","author":"G Ozen","year":"2017","unstructured":"Ozen G, Norel X (2017) Prostanoids in the pathophysiology of human coronary artery. Prostaglandins Other Lipid Mediat 133:20\u201328","journal-title":"Prostaglandins Other Lipid Mediat"},{"key":"4895_CR25","doi-asserted-by":"publisher","DOI":"10.3171\/2014.7.FOCUS14214","author":"L Rangel-Castilla","year":"2014","unstructured":"Rangel-Castilla L, Russin JJ, Martinez-Del-Campo E, Soriano-Baron H, Spetzler RF, Nakaji P (2014) Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment. Neurosurg Focus. https:\/\/doi.org\/10.3171\/2014.7.FOCUS14214","journal-title":"Neurosurg Focus"},{"key":"4895_CR26","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s00380-011-0148-y","volume":"27","author":"JN Roan","year":"2012","unstructured":"Roan JN, Tsai YC, Chen IW, Chang SW, Huang CC, Lam CF (2012) Inhibition of cyclooxygenase-2 modulates phenotypic switching of vascular smooth muscle cells during increased aortic blood flow. Heart Vessels 27:307\u2013315","journal-title":"Heart Vessels"},{"key":"4895_CR27","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1161\/01.RES.0000170888.11669.28","volume":"96","author":"RD Rudic","year":"2005","unstructured":"Rudic RD, Brinster D, Cheng Y, Fries S, Song WL, Austin S, Coffman TM, FitzGerald GA (2005) COX-2-derived prostacyclin modulates vascular remodeling. Circ Res 96:1240\u20131247","journal-title":"Circ Res"},{"key":"4895_CR28","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00035.2016","author":"S Russell-Puleri","year":"2017","unstructured":"Russell-Puleri S, Dela Paz NG, Adams D, Chattopadhyay M, Cancel L, Ebong E, Orr AW, Frangos JA, Tarbell JM (2017) Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38. Am J Physiol Heart Circ Physiol. https:\/\/doi.org\/10.1152\/ajpheart.00035.2016","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"4895_CR29","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1007\/s12975-014-0351-0","volume":"5","author":"WC Rutledge","year":"2017","unstructured":"Rutledge WC, Ko NU, Lawton MT, Kim H (2017) Hemorrhage rates and risk factors in the natural history course of brain arteriovenous malformations. Transl Stroke Res 5:538\u2013542","journal-title":"Transl Stroke Res"},{"key":"4895_CR30","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1227\/01.NEU.0000210248.39504.B5","volume":"58","author":"J Tu","year":"2006","unstructured":"Tu J, Stoodley MA, Morgan MK, Storer KP (2006) Ultrastructure of perinidal capillaries in cerebral arteriovenous malformations. Neurosurgery 58:961\u2013970","journal-title":"Neurosurgery"},{"key":"4895_CR31","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1161\/01.CIR.100.1.48","volume":"100","author":"LJ Walton","year":"1999","unstructured":"Walton LJ, Franklin IJ, Bayston T, Brown LC, Greenhalgh RM, Taylor GW, Powell JT (1999) Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation 100:48\u201354","journal-title":"Circulation"}],"container-title":["Acta Neurochirurgica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00701-021-04895-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00701-021-04895-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00701-021-04895-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T05:10:04Z","timestamp":1628658604000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00701-021-04895-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,29]]},"references-count":31,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["4895"],"URL":"https:\/\/doi.org\/10.1007\/s00701-021-04895-z","relation":{},"ISSN":["0001-6268","0942-0940"],"issn-type":[{"value":"0001-6268","type":"print"},{"value":"0942-0940","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,29]]},"assertion":[{"value":"30 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 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":"This study was approved by the Ethics Committee of the Hospital District of Northern Savo (KUH). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"For the patients of KUH, the Ethics Committee of the Hospital District of Northern Savo waived the need for an informed consent, since this study was of retrospective nature and the patients involved were not contacted in anyway. For the patients of TWH and UCSF, signed informed consent was obtained prior to sample collection at surgery.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}