{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T22:10:30Z","timestamp":1760825430568,"version":"build-2065373602"},"reference-count":27,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"unspecified","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Triticum Exploitatie BV"},{"name":"Zuyderland Research and Innovation Fund"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,6,24]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>High-grade squamous intraepithelial lesions are caused by persistent high-risk human papillomavirus (hr-HPV) infections and are subdivided into cervical intraepithelial neoplasia (CIN) lesions: CIN II (moderate) and CIN III (severe). Current treatment options for CIN II include large loop excision of the transformation zone, imiquimod and expectant management. Each treatment option has its drawbacks, and therefore, a non-invasive treatment is desirable. Preliminary evidence shows that medical-grade honey (MGH) has antiviral activity and might be able to modulate the vaginal microbiome, reduce local inflammation or directly influence the intralesional immune response within cervical tissues. Therefore, this study aims to investigate the possible effect of MGH on hr-HPV clearance and to investigate the possible underlying mechanisms contributing to the regression of CIN II lesions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and analysis<\/jats:title>\n                  <jats:p>This study is performed in the Zuyderland Medical Centre and Maastricht University Medical Centre+. A total of 60 eligible women with newly histologically confirmed CIN II will receive MGH (L-Mesitran Soft) for intravaginal use for 6 months. The primary objective is to investigate the effect of MGH on the hr-HPV clearance after 6 months. Secondary aims are the effect of MGH on the regression of CIN II lesions, clearance of hr-HPV at 12 and 24 months and the role of the vaginal microbiome, local immune system and intravaginal inflammatory status in response to MGH. Moreover, data on quality of life, side effects and compliance will be collected.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Ethics and dissemination<\/jats:title>\n                  <jats:p>Ethical approval from the Medical Ethics Review Committee of the Zuyderland Medical Centre Heerlen has been obtained (NL86044.096.24 on 24 April 2024). The results will be presented to researchers and healthcare professionals through conferences, meetings and publications in international journals.<\/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\" specific-use=\"clinicaltrial pre-results\" xlink:href=\"NCT06219018\">NCT06219018<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-104585","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T08:40:37Z","timestamp":1753346437000},"page":"e104585","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of medical-grade honey (L-Mesitran) for cervical intraepithelial neoplasia II: protocol for a multicentre cohort pilot study (HONEY FOR CIN II study)"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"nct06219018","registry":"10.18810\/clinical-trials-gov","type":"preResults"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8506-5797","authenticated-orcid":false,"given":"Jasmijn","family":"Prop","sequence":"first","affiliation":[{"name":"Obstetrics and Gynaecology, Zuyderland Medical Centre Heerlen, Heerlen, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peggy","family":"De Vos van Steenwijk","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Maastricht University Medical Centre+, Maastricht, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line M J G","family":"Lardenoije","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Maastricht University Medical Centre+, Maastricht, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-8987","authenticated-orcid":false,"given":"Niels A J","family":"Cremers","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Maastricht University Medical Centre+, Maastricht, Netherlands"},{"name":"Research, Triticum Exploitatie BV, Maastricht, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9953-0495","authenticated-orcid":false,"given":"S A","family":"Morre","sequence":"additional","affiliation":[{"name":"GROW - Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, Netherlands"},{"name":"Institute of Public Health Genomics, Department of Genetics & Cell Biology, Maastricht University, Maastricht, Netherlands"},{"name":"Dutch Chlamydia trachomatis Reference Laboratory, Department of Medical Microbiology, Infectious Diseases and Infection Prevention, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Centre+, Maastricht, Netherlands"},{"name":"Department of Molecular and Cellular Engineering, Jacob Institute of Biotechnology and Bioengineering, Sam Higginbottom University of Agriculture Technology and Sciences, Allahabad, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordy","family":"Mongula","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynaecology, Zuyderland Medical Centre Heerlen, Heerlen, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"2025101814275394000_15.7.e104585.1","unstructured":"IKNL\/ NVOG guideline . CIN, AIS en VAIN NVOG guideline. 2021."},{"key":"2025101814275394000_15.7.e104585.2","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2019.03116","article-title":"Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy","volume":"10","author":"Pal","year":"2019","journal-title":"Front Microbiol"},{"key":"2025101814275394000_15.7.e104585.3","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000604"},{"key":"2025101814275394000_15.7.e104585.4","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/ijgo.14953","article-title":"The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia: A systematic review and meta-analysis","volume":"164","author":"van de Sande","year":"2024","journal-title":"Int J Gynaecol Obstet"},{"key":"2025101814275394000_15.7.e104585.5","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1002\/pon.5897","article-title":"Psychosocial impact of testing human papillomavirus positive in Australia\u2019s human papillomavirus-based cervical screening program: A cross-sectional survey","volume":"31","author":"Chadwick","year":"2022","journal-title":"Psychooncology"},{"key":"2025101814275394000_15.7.e104585.6","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/j.1471-0528.2007.01609.x","article-title":"A 2-year follow-up study of anxiety and depression in women referred for colposcopy after an abnormal cervical smear","volume":"115","author":"Hellsten","year":"2008","journal-title":"BJOG"},{"key":"2025101814275394000_15.7.e104585.7","doi-asserted-by":"crossref","DOI":"10.3390\/jcm11051432","article-title":"Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy","volume":"11","author":"Muntinga","year":"2022","journal-title":"J Clin Med"},{"key":"2025101814275394000_15.7.e104585.8","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-005288","article-title":"Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous intraepithelial lesions","volume":"10","author":"Abdulrahman","year":"2022","journal-title":"J Immunother Cancer"},{"key":"2025101814275394000_15.7.e104585.9","doi-asserted-by":"crossref","DOI":"10.1038\/srep16865","article-title":"Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity","volume":"5","author":"Mitra","year":"2015","journal-title":"Sci Rep"},{"key":"2025101814275394000_15.7.e104585.10","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000646"},{"key":"2025101814275394000_15.7.e104585.11","doi-asserted-by":"crossref","first-page":"00487","DOI":"10.1128\/IAI.00487-20","article-title":"The Complex Link between the Female Genital Microbiota, Genital Infections, and Inflammation","volume":"89","author":"Dabee","year":"2021","journal-title":"Infect Immun"},{"key":"2025101814275394000_15.7.e104585.12","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-023-02965-w","article-title":"Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies","volume":"21","author":"Bowden","year":"2023","journal-title":"BMC Med"},{"key":"2025101814275394000_15.7.e104585.13","doi-asserted-by":"crossref","DOI":"10.1186\/s12906-020-03170-5","article-title":"Honey and its nutritional and anti-inflammatory value","volume":"21","author":"Ranneh","year":"2021","journal-title":"BMC Complement Altern Med"},{"key":"2025101814275394000_15.7.e104585.14","doi-asserted-by":"crossref","DOI":"10.1186\/1472-6882-10-47","article-title":"Comparison of the antimicrobial activity of Ulmo honey from Chile and Manuka honey against methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa","volume":"10","author":"Sherlock","year":"2010","journal-title":"BMC Complement Altern Med"},{"key":"2025101814275394000_15.7.e104585.15","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.2174\/1381612828666220928110103","article-title":"Antiviral Activity of Bee Products","volume":"28","author":"Kontogiannis","year":"2022","journal-title":"Curr Pharm Des"},{"key":"2025101814275394000_15.7.e104585.16","doi-asserted-by":"crossref","DOI":"10.3390\/nu14173579","article-title":"General Nutritional Profile of Bee Products and Their Potential Antiviral Properties against Mammalian Viruses","volume":"14","author":"Asma","year":"2022","journal-title":"Nutrients"},{"key":"2025101814275394000_15.7.e104585.17","doi-asserted-by":"crossref","DOI":"10.3390\/nu13041269","article-title":"The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer","volume":"13","author":"Masad","year":"2021","journal-title":"Nutrients"},{"key":"2025101814275394000_15.7.e104585.18","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.3390\/molecules19022497","article-title":"Effects of honey and its mechanisms of action on the development and progression of cancer","volume":"19","author":"Erejuwa","year":"2014","journal-title":"Molecules"},{"key":"2025101814275394000_15.7.e104585.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2010.12.010"},{"key":"2025101814275394000_15.7.e104585.20","doi-asserted-by":"crossref","first-page":"957932","DOI":"10.3389\/fnut.2022.957932","article-title":"The potential of honey as a prebiotic food to re-engineer the gut microbiome toward a healthy state","volume":"9","author":"Schell","year":"2022","journal-title":"Frontiers in Nutrition (Lausanne)"},{"key":"2025101814275394000_15.7.e104585.21","doi-asserted-by":"crossref","DOI":"10.3390\/jof7010050","article-title":"Antifungal Activity of a Medical-Grade Honey Formulation against Candida auris","volume":"7","author":"de Groot","year":"2021","journal-title":"J Fungi (Basel)"},{"key":"2025101814275394000_15.7.e104585.22","doi-asserted-by":"crossref","DOI":"10.1186\/s12866-021-02149-7","article-title":"The profiling of microbiota in vaginal swab samples using 16S rRNA gene sequencing and IS-pro analysis","volume":"21","author":"Singer","year":"2021","journal-title":"BMC Microbiol"},{"key":"2025101814275394000_15.7.e104585.23","unstructured":"NVOG . Nederlandse Vereniging voor Obstetrie & Gynaecologie. Keuzekaart CIN2 na onderzoek van je baarmoederhals, 2022. Available: https:\/\/www.degynaecoloog.nl\/wp-content\/uploads\/2022\/08\/keuzekaart-CIN2-2022.pdf"},{"key":"2025101814275394000_15.7.e104585.24","doi-asserted-by":"crossref","DOI":"10.3390\/antibiotics13040368","article-title":"Medical-Grade Honey as a Potential New Therapy for Bacterial Vaginosis","volume":"13","author":"Lardenoije","year":"2024","journal-title":"Antibiotics (Basel)"},{"key":"2025101814275394000_15.7.e104585.25","doi-asserted-by":"crossref","DOI":"10.3390\/jof7080664","article-title":"Treating (Recurrent) Vulvovaginal Candidiasis with Medical-Grade Honey-Concepts and Practical Considerations","volume":"7","author":"van Riel","year":"2021","journal-title":"J Fungi (Basel)"},{"key":"2025101814275394000_15.7.e104585.26","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/0140-6736(93)90527-N","article-title":"Honey for wounds, ulcers, and skin graft preservation","volume":"341","author":"Postmes","year":"1993","journal-title":"The Lancet"},{"key":"2025101814275394000_15.7.e104585.27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/00218839.2019.1693713","article-title":"Defining the standards for medical grade honey","volume":"59","author":"Hermanns","year":"2020","journal-title":"J Apic Res"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-104585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T21:28:00Z","timestamp":1760822880000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-104585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":27,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7,24]]},"published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1136\/bmjopen-2025-104585"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-104585","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2025,7]]}}}