{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:52:57Z","timestamp":1790776377232,"version":"4.1.0"},"reference-count":41,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"unspecified","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Interreg consortium Changing Cancer Care, funded by the European Regional Development Fund","award":["094-1.1-18"],"award-info":[{"award-number":["094-1.1-18"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,5,14]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Skin malignancy is a distressing problem for many patients, and clinical management is challenging. This article describes the protocol for the Calcium Electroporation Response Study (CaEP-R) designed to investigate tumour response to calcium electroporation and is a descriptive guide to calcium electroporation treatment of malignant tumours in the skin. Calcium electroporation is a local treatment that induces supraphysiological intracellular calcium levels by intratumoural calcium administration and application of electrical pulses. The pulses create transient membrane pores allowing diffusion of non-permeant calcium ions into target cells. High calcium levels can kill cancer cells, while normal cells can restore homeostasis. Prior trials with smaller cohorts have found calcium electroporation to be safe and efficient. This trial aims to include a larger multiregional cohort of patients with different cancer diagnoses and also to investigate treatment areas using MRI as well as assess impact on quality of life.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This non-randomised phase II multicentre study will investigate response to calcium electroporation in 30 patients with cutaneous or subcutaneous malignancy. Enrolment of 10 patients is planned at three centres: Zealand University Hospital, University Hospital of Southern Denmark and University Hospital Schleswig-Holstein. Response after 2 months was chosen as the primary endpoint based on short-term response rates observed in a prior clinical study. Secondary endpoints include response to treatment using MRI and change in quality of life assessed by questionnaires and qualitative interviews.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The trial is approved by the Danish Medicines Agency and The Danish Regional Committee on Health Research Ethics. All included patients will receive active treatment (calcium electroporation). Patients can continue systemic treatment during the study, and side effects are expected to be limited. Data will be published in a peer-reviewed journal and made available to the public.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration numbers<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04225767\">NCT04225767<\/jats:ext-link>\n                      and EudraCT no: 2019-004314-34.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2020-046779","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T13:04:06Z","timestamp":1623848646000},"page":"e046779","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Study protocol designed to investigate tumour response to calcium electroporation in cancers affecting the skin: a non-randomised phase II clinical trial"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct04225767","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Mille","family":"Vissing","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde and N\u00e6stved, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Ploen","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital of Southern Denmark, Vejle, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mascha","family":"Pervan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital Schleswig Holstein, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitt","family":"Vestergaard","sequence":"additional","affiliation":[{"name":"University College Absalon, Sor\u00f8, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazen","family":"Schnefeldt","sequence":"additional","affiliation":[{"name":"Department of Radiology, University Hospital of Southern Denmark, Vejle, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stine Krog","family":"Frandsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde and N\u00e6stved, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren Rafael","family":"Rafaelsen","sequence":"additional","affiliation":[{"name":"Department of Radiology, University Hospital of Southern Denmark, Vejle, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Louise","family":"Lindhardt","sequence":"additional","affiliation":[{"name":"University College Absalon, Sor\u00f8, Denmark"},{"name":"Clinical Institute, University of Southern Denmark, Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars Henrik","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital of Southern Denmark, Vejle, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Rody","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital Schleswig Holstein, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3829-0210","authenticated-orcid":false,"given":"Julie","family":"Gehl","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde and N\u00e6stved, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"2025121221211475000_11.6.e046779.1","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1053\/ejso.1999.0931","article-title":"Educational tips in the treatment of malignant ulcerating tumours of the skin","volume":"26","author":"van Leeuwen","year":"2000","journal-title":"Eur J Surg Oncol"},{"key":"2025121221211475000_11.6.e046779.2","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2017.1355109"},{"key":"2025121221211475000_11.6.e046779.3","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12010179","article-title":"Evaluation of calcium electroporation for the treatment of cutaneous metastases: a double blinded randomised controlled phase II trial","volume":"12","author":"\u00c1goston","year":"2020","journal-title":"Cancers"},{"key":"2025121221211475000_11.6.e046779.4","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(88)90251-0"},{"key":"2025121221211475000_11.6.e046779.5","first-page":"3450","article-title":"Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice","volume":"55","author":"Sersa","year":"1995","journal-title":"Cancer Res"},{"key":"2025121221211475000_11.6.e046779.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0305-7372(03)00073-2"},{"key":"2025121221211475000_11.6.e046779.7","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.ejso.2019.11.509","article-title":"Electrochemotherapy for the treatment of primary basal cell carcinoma; a randomised control trial comparing electrochemotherapy and surgery with five year follow up","volume":"46","author":"Clover","year":"2020","journal-title":"Eur J Surg Oncol"},{"key":"2025121221211475000_11.6.e046779.8","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1982.tb01257.x"},{"key":"2025121221211475000_11.6.e046779.9","doi-asserted-by":"publisher","DOI":"10.1097\/00008390-200012000-00010"},{"key":"2025121221211475000_11.6.e046779.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-015-1724-2"},{"key":"2025121221211475000_11.6.e046779.11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3782"},{"key":"2025121221211475000_11.6.e046779.12","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0122973","article-title":"Dose-Dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength","volume":"10","author":"Hansen","year":"2015","journal-title":"PLoS One"},{"key":"2025121221211475000_11.6.e046779.13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1611"},{"key":"2025121221211475000_11.6.e046779.14","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12020290","article-title":"A comprehensive review of calcium electroporation -A novel cancer treatment modality","volume":"12","author":"Frandsen","year":"2020","journal-title":"Cancers"},{"key":"2025121221211475000_11.6.e046779.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.02.050"},{"key":"2025121221211475000_11.6.e046779.16","doi-asserted-by":"publisher","DOI":"10.3390\/biom2010165"},{"key":"2025121221211475000_11.6.e046779.17","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3412"},{"key":"2025121221211475000_11.6.e046779.18","doi-asserted-by":"publisher","DOI":"10.4161\/cc.23599"},{"key":"2025121221211475000_11.6.e046779.19","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12020425","article-title":"Calcium delivery by electroporation induces in vitro cell death through mitochondrial dysfunction without DNA damages","volume":"12","author":"Gibot","year":"2020","journal-title":"Cancers"},{"key":"2025121221211475000_11.6.e046779.20","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.bbagen.2013.12.003","article-title":"Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions","volume":"1840","author":"Frandsen","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"2025121221211475000_11.6.e046779.21","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0144028","article-title":"Calcium electroporation: evidence for differential effects in normal and malignant cell lines, evaluated in a 3D spheroid model","volume":"10","author":"Frandsen","year":"2015","journal-title":"PLoS One"},{"key":"2025121221211475000_11.6.e046779.22","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-27728-z","article-title":"Effect of calcium electroporation on tumour vasculature","volume":"8","author":"Staresinic","year":"2018","journal-title":"Sci Rep"},{"key":"2025121221211475000_11.6.e046779.23","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ejcsup.2006.08.002","article-title":"Electrochemotherapy \u2013 an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European standard operating procedures of electrochemotherapy) study","volume":"4","author":"Marty","year":"2006","journal-title":"European Journal of Cancer Supplements"},{"key":"2025121221211475000_11.6.e046779.24","doi-asserted-by":"publisher","DOI":"10.2217\/fon.13.235"},{"key":"2025121221211475000_11.6.e046779.25","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2017.1290274"},{"key":"2025121221211475000_11.6.e046779.26","doi-asserted-by":"crossref","first-page":"11604","DOI":"10.18632\/oncotarget.24352","article-title":"Calcium electroporation for treatment of sarcoma in preclinical studies","volume":"9","author":"Szewczyk","year":"2018","journal-title":"Oncotarget"},{"key":"2025121221211475000_11.6.e046779.27","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/lio2.233","article-title":"Calcium electroporation for recurrent head and neck cancer: a clinical phase I study","volume":"4","author":"Plaschke","year":"2019","journal-title":"Laryngoscope Investig Otolaryngol"},{"key":"2025121221211475000_11.6.e046779.28","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ejcsup.2006.08.003","article-title":"Standard operating procedures of the electrochemotherapy: Instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes","volume":"4","author":"Mir","year":"2006","journal-title":"European Journal of Cancer Supplements"},{"key":"2025121221211475000_11.6.e046779.29","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2018.1454602"},{"key":"2025121221211475000_11.6.e046779.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"2025121221211475000_11.6.e046779.31","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-019-41188-z","article-title":"Calcium electroporation and electrochemotherapy for cancer treatment: importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy","volume":"9","author":"Hoejholt","year":"2019","journal-title":"Sci Rep"},{"key":"2025121221211475000_11.6.e046779.32","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1301332"},{"key":"2025121221211475000_11.6.e046779.33","unstructured":"Glesne C . Becoming qualitative researchers. An introduction. ed: Pearson, 2016."},{"key":"2025121221211475000_11.6.e046779.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2011.01.004"},{"key":"2025121221211475000_11.6.e046779.35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ejca.2020.06.020","article-title":"Electrochemotherapy in the treatment of cutaneous malignancy: outcomes and subgroup analysis from the cumulative results from the pan-European international network for sharing practice in electrochemotherapy database for 2482 lesions in 987 patients (2008-2019)","volume":"138","author":"Clover","year":"2020","journal-title":"Eur J Cancer"},{"key":"2025121221211475000_11.6.e046779.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-6111(00)00083-5"},{"key":"2025121221211475000_11.6.e046779.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-011-9351-0"},{"key":"2025121221211475000_11.6.e046779.38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3109\/0284186X.2014.991045","article-title":"Detection of electroporation-induced membrane permeabilization states in the brain using diffusion-weighted MRI","volume":"54","author":"Mahmood","year":"2015","journal-title":"Acta Oncol"},{"key":"2025121221211475000_11.6.e046779.39","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/bjd.19298","article-title":"Current measures are not sufficient: an Interview-Based qualitative assessment of quality of life in cutaneous T-cell lymphoma","volume":"184","author":"Bhat","year":"2021","journal-title":"Br J Dermatol"},{"key":"2025121221211475000_11.6.e046779.40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042817"},{"key":"2025121221211475000_11.6.e046779.41","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0304-4165(99)00094-X","article-title":"In vivo electroporation of skeletal muscle: threshold, efficacy and relation to electric field distribution","volume":"1428","author":"Gehl","year":"1999","journal-title":"Biochim Biophys Acta"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2020-046779","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T05:21:27Z","timestamp":1765603287000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2020-046779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,16]]},"published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1136\/bmjopen-2020-046779"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2020-046779","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6]]}}}