{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:29:00Z","timestamp":1779920940675,"version":"3.53.1"},"reference-count":37,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Association of Danish Laboratory Scientists","award":["9987"],"award-info":[{"award-number":["9987"]}]},{"DOI":"10.13039\/100008363","name":"Kr\u00e6ftens Bek\u00e6mpelse","doi-asserted-by":"publisher","award":["R248-A14476"],"award-info":[{"award-number":["R248-A14476"]}],"id":[{"id":"10.13039\/100008363","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hospital Units of Central Denmark Region"},{"DOI":"10.13039\/501100008262","name":"Harboefonden","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008262","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,6,16]]},"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      may be valuable for risk assessment of CIN2. However, data on HPV E4\/p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      as a predictor for CIN2 regression is lacking.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      We will conduct a historical cohort study including 500\u2009women aged 23\u201340 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000\u20132010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&amp;E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05049252\">NCT05049252<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-059593","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T12:20:36Z","timestamp":1657110036000},"page":"e059593","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Performance of HPV E4 and p16\n                    <sup>INK4a<\/sup>\n                    biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct05049252","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05049252","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9400-662X","authenticated-orcid":false,"given":"Rikke Kamp","family":"Damgaard","sequence":"first","affiliation":[{"name":"Dep. 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Pathology, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Doorbar","sequence":"additional","affiliation":[{"name":"Dep. Pathology, Division of Virology, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Kahlert","sequence":"additional","affiliation":[{"name":"Dep. Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patti E","family":"Gravitt","sequence":"additional","affiliation":[{"name":"National Cancer Institute, University of Virginia Cancer Center, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Steiniche","sequence":"additional","affiliation":[{"name":"Dep. Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"name":"Dep. 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