{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:35:55Z","timestamp":1793748955694,"version":"4.6.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Surg Oncol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Currently, sentinel lymph node biopsy (SLNB) is considered standard staging for patients with stage IB\u2013II melanomas. Owing to recent systemic therapy advances, SLNB is once again being scrutinized. The aim of the current study was to validate the diagnostic accuracy of the clinicopathological gene expression profile (CP-GEP) for risk of sentinel node metastases and recurrence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and Methods<\/jats:title>\n                    <jats:p>\n                      Samples and clinical data of 252 patients with newly diagnosed clinical stage I\/II melanoma between 2007 and 2015 were obtained. CP-GEP included eight target genes associated with tumor development (i.e.,\n                      <jats:italic>MLANA, GDF15, CXCL8, LOXL4, TGFBR1, ITGB3, PLAT<\/jats:italic>\n                      , and\n                      <jats:italic>SERPINE2<\/jats:italic>\n                      ) and two housekeeping genes in combination with clinicopathological variables, age, and Breslow thickness.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The median age was 57 years old, and 51.4% were female. The median Breslow thickness was 1.8 mm, and 53 patients (21.8%) had a positive SLNB. The median follow-up was 91 months. CP-GEP identified 68 (28%) patients as CP-GEP low risk and 175 (72%) as high risk. The sensitivity of CP-GEP was 92.5%, specificity was 33.7%, positive predictive value (PPV) was 28.0%, and negative predictive value (NPV) was 94.1% for all (T1\u2013T4). The CP-GEP had the best performance in T1, with an NPV of 95.2% and an SLNB reduction rate (RR) of 80.8%. In the pT1b\u2013pT2a melanomas with an NPV of 93.3% and a SLNB RR of 45.5% in terms of long-term survival, the 5-year recurrence-free survival (RFS) of CP-GEP low risk was 89.6% versus 76.8% for CP-GEP high-risk patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CP-GEP demonstrated good prognostic performance, particularly for patients with pT1b\u2013pT2a melanoma and thus could be considered a noninvasive alternative for a SLNB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1245\/s10434-025-18928-9","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T18:52:54Z","timestamp":1766083974000},"page":"3991-3999","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Independent Dutch Validation Study of CP-GEP (Merlin Assay) for the Prediction of Nodal Metastasis and Long-Term Outcome in Patients with Primary Cutaneous Melanoma"],"prefix":"10.1245","volume":"33","author":[{"given":"Lisanne P.","family":"Zijlker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Verwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart A.","family":"van der Wiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke M. J.","family":"Kuijpers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel W. J. M.","family":"Wouters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winan J.","family":"van Houdt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3262-6935","authenticated-orcid":false,"given":"Alexander C. J.","family":"van Akkooi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"18928_CR1","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1093\/annonc\/mdz411","volume":"30","author":"O Michielin","year":"2019","unstructured":"Michielin O, van Akkooi ACJ, Ascierto PA, et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Ann Oncol. 2019;30:1884\u2013901.","journal-title":"Ann Oncol"},{"key":"18928_CR2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.ejca.2022.12.022","volume":"182","author":"ACJ van Akkooi","year":"2023","unstructured":"van Akkooi ACJ, Schadendorf D, Eggermont AMM. Alternatives and reduced need for sentinel lymph node biopsy (SLNB) staging for melanoma. Eur J Cancer. 2023;182:163\u20139.","journal-title":"Eur J Cancer"},{"key":"18928_CR3","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1056\/NEJMoa1310460","volume":"370","author":"DL Morton","year":"2014","unstructured":"Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599\u2013609.","journal-title":"N Engl J Med"},{"key":"18928_CR4","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.ejca.2005.10.023","volume":"42","author":"AC van Akkooi","year":"2006","unstructured":"van Akkooi AC, de Wilt JH, Verhoef C, et al. High positive sentinel node identification rate by EORTC melanoma group protocol. Prognostic indicators of metastatic patterns after sentinel node biopsy in melanoma. Eur J Cancer. 2006;42:372\u201380.","journal-title":"Eur J Cancer"},{"key":"18928_CR5","first-page":"472","volume":"67","author":"JE Gershenwald","year":"2017","unstructured":"Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472\u201392.","journal-title":"CA Cancer J Clin"},{"key":"18928_CR6","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1056\/NEJMoa1602253","volume":"375","author":"F Cardoso","year":"2016","unstructured":"Cardoso F, van\u2019t Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016;375:717\u201329.","journal-title":"N Engl J Med"},{"key":"18928_CR7","doi-asserted-by":"crossref","unstructured":"Mulder E, Johansson I, Grunhagen DJ, et al: Using a clinicopathologic and gene expression (CP-GEP) model to identify stage I\u2013II melanoma patients at risk of disease relapse. Cancers (Basel) 14, 2022","DOI":"10.3390\/cancers14122854"},{"key":"18928_CR8","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1001\/jamadermatol.2020.1729","volume":"156","author":"D Grossman","year":"2020","unstructured":"Grossman D, Okwundu N, Bartlett EK, et al. Prognostic gene expression profiling in cutaneous melanoma: identifying the knowledge gaps and assessing the clinical benefit. JAMA Dermatol. 2020;156:1004\u201311.","journal-title":"JAMA Dermatol"},{"key":"18928_CR9","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1200\/PO.19.00206","volume":"4","author":"D Bellomo","year":"2020","unstructured":"Bellomo D, Arias-Mejias SM, Ramana C, et al. Model combining tumor molecular and clinicopathologic risk factors predicts sentinel lymph node metastasis in primary cutaneous melanoma. JCO Precis Oncol. 2020;4:319\u201334.","journal-title":"JCO Precis Oncol"},{"key":"18928_CR10","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.ejca.2022.12.021","volume":"182","author":"T Amaral","year":"2023","unstructured":"Amaral T, Sinnberg T, Chatziioannou E, et al. Identification of stage I\/II melanoma patients at high risk for recurrence using a model combining clinicopathologic factors with gene expression profiling (CP-GEP). Eur J Cancer. 2023;182:155\u201362.","journal-title":"Eur J Cancer"},{"key":"18928_CR11","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ejca.2019.10.027","volume":"125","author":"TMS Amaral","year":"2020","unstructured":"Amaral TMS, Hoffmann MC, Sinnberg T, et al. Clinical validation of a prognostic 11-gene expression profiling score in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma. Eur J Cancer. 2020;125:38\u201345.","journal-title":"Eur J Cancer"},{"key":"18928_CR12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2023.107249","volume":"49","author":"RC Stassen","year":"2023","unstructured":"Stassen RC, Mulder E, Mooyaart AL, et al. Clinical evaluation of the clinicopathologic and gene expression profile (CP-GEP) in patients with melanoma eligible for sentinel lymph node biopsy: a multicenter prospective Dutch study. Eur J Surg Oncol. 2023;49:107249.","journal-title":"Eur J Surg Oncol"},{"key":"18928_CR13","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1200\/JCO.2017.75.7724","volume":"36","author":"SL Wong","year":"2018","unstructured":"Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice guideline update. J Clin Oncol. 2018;36:399\u2013413.","journal-title":"J Clin Oncol"},{"key":"18928_CR14","doi-asserted-by":"crossref","unstructured":"van der Ploeg IM, Madu MF, van der Hage JA, et al: Blue dye can be safely omitted in most sentinel node procedures for melanoma. Melanoma Res, 2016","DOI":"10.1097\/CMR.0000000000000271"},{"key":"18928_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejca.2019.03.010","volume":"114","author":"MG Cook","year":"2019","unstructured":"Cook MG, Massi D, Szumera-Cieckiewicz A, et al. An updated European Organisation for Research and Treatment of Cancer (EORTC) protocol for pathological evaluation of sentinel lymph nodes for melanoma. Eur J Cancer. 2019;114:1\u20137.","journal-title":"Eur J Cancer"},{"key":"18928_CR16","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1002\/(SICI)1097-0258(19980430)17:8<857::AID-SIM777>3.0.CO;2-E","volume":"17","author":"RG Newcombe","year":"1998","unstructured":"Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 1998;17:857\u201372.","journal-title":"Stat Med"},{"key":"18928_CR17","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1097\/SLA.0b013e3181b07ffd","volume":"250","author":"S Mocellin","year":"2009","unstructured":"Mocellin S, Thompson JF, Pasquali S, et al. Sentinel node status prediction by four statistical models: results from a large bi-institutional series (n = 1132). Ann Surg. 2009;250:964\u20139.","journal-title":"Ann Surg"},{"key":"18928_CR18","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.ejso.2021.11.010","volume":"48","author":"I Johansson","year":"2022","unstructured":"Johansson I, Tempel D, Dwarkasing JT, et al. Validation of a clinicopathological and gene expression profile model to identify patients with cutaneous melanoma where sentinel lymph node biopsy is unnecessary. Eur J Surg Oncol. 2022;48:320\u20135.","journal-title":"Eur J Surg Oncol"},{"key":"18928_CR19","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1111\/ijd.15594","volume":"60","author":"A Yousaf","year":"2021","unstructured":"Yousaf A, Tjien-Fooh FJ, Rentroia-Pacheco B, et al. Validation of CP-GEP (Merlin Assay) for predicting sentinel lymph node metastasis in primary cutaneous melanoma patients: a US cohort study. Int J Dermatol. 2021;60:851\u20136.","journal-title":"Int J Dermatol"},{"key":"18928_CR20","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1111\/bjd.19499","volume":"184","author":"E Mulder","year":"2021","unstructured":"Mulder E, Dwarkasing JT, Tempel D, et al. Validation of a clinicopathological and gene expression profile model for sentinel lymph node metastasis in primary cutaneous melanoma. Br J Dermatol. 2021;184:944\u201351.","journal-title":"Br J Dermatol"},{"key":"18928_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00354-5","volume":"22","author":"AMM Eggermont","year":"2021","unstructured":"Eggermont AMM, Suciu S, Robert C. Adjuvant therapy in stage IIIA melanoma - Authors\u2019 reply. Lancet Oncol. 2021;22:e300.","journal-title":"Lancet Oncol"},{"key":"18928_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00346-6","volume":"22","author":"E Hindie","year":"2021","unstructured":"Hindie E. Adjuvant therapy in stage IIIA melanoma. Lancet Oncol. 2021;22:e299.","journal-title":"Lancet Oncol"},{"key":"18928_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcskn.2024.100021","volume":"2","author":"ACJ van Akkooi","year":"2024","unstructured":"van Akkooi ACJ, Mandala M, Nathan P, et al. Adjuvant systemic therapy in melanoma: Relative versus absolute benefit; the number needed to treat (NNT) versus the number needed to harm (NNH)? EJC Skin Cancer. 2024;2:100021.","journal-title":"EJC Skin Cancer"},{"key":"18928_CR24","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/S1470-2045(24)00076-7","volume":"25","author":"RC Stassen","year":"2024","unstructured":"Stassen RC, Maas C, van der Veldt AAM, et al. Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis. Lancet Oncol. 2024;25:509\u201317.","journal-title":"Lancet Oncol"},{"key":"18928_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.114327","volume":"211","author":"AM Eggermont","year":"2024","unstructured":"Eggermont AM, Kicinski M, Blank CU, et al. Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 \/ KEYNOTE-054 trial. Eur J Cancer. 2024;211:114327.","journal-title":"Eur J Cancer"},{"key":"18928_CR26","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1093\/annonc\/mdl176","volume":"17","author":"AC van Akkooi","year":"2006","unstructured":"van Akkooi AC, de Wilt JH, Verhoef C, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol. 2006;17:1578\u201385.","journal-title":"Ann Oncol"},{"key":"18928_CR27","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ejca.2013.08.023","volume":"50","author":"AP van der Ploeg","year":"2014","unstructured":"van der Ploeg AP, van Akkooi AC, Haydu LE, et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer. 2014;50:111\u201320.","journal-title":"Eur J Cancer"},{"key":"18928_CR28","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.1200\/JCO.2010.31.6760","volume":"29","author":"AP van der Ploeg","year":"2011","unstructured":"van der Ploeg AP, van Akkooi AC, Rutkowski P, et al. Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria. J Clin Oncol. 2011;29:2206\u201314.","journal-title":"J Clin Oncol"},{"key":"18928_CR29","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1097\/CMR.0000000000000643","volume":"30","author":"MF Madu","year":"2020","unstructured":"Madu MF, Franke V, van de Wiel BA, et al. External validation of the American Joint Committee on Cancer 8th edition melanoma staging system: who needs adjuvant treatment? Melanoma Res. 2020;30:185\u201392.","journal-title":"Melanoma Res"},{"key":"18928_CR30","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1002\/jso.22043","volume":"104","author":"OE Nieweg","year":"2011","unstructured":"Nieweg OE, Veenstra HJ. False-negative sentinel node biopsy in melanoma. J Surg Oncol. 2011;104:709\u201310.","journal-title":"J Surg Oncol"},{"key":"18928_CR31","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.ejso.2016.08.007","volume":"43","author":"MF Madu","year":"2017","unstructured":"Madu MF, Wouters MW, van Akkooi AC. Sentinel node biopsy in melanoma: Current controversies addressed. Eur J Surg Oncol. 2017;43:517\u201333.","journal-title":"Eur J Surg Oncol"},{"key":"18928_CR32","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nrclinonc.2010.100","volume":"7","author":"AC van Akkooi","year":"2010","unstructured":"van Akkooi AC, Verhoef C, Eggermont AM. Importance of tumor load in the sentinel node in melanoma: clinical dilemmas. Nat Rev Clin Oncol. 2010;7:446\u201354.","journal-title":"Nat Rev Clin Oncol"},{"key":"18928_CR33","doi-asserted-by":"crossref","unstructured":"Hieken TJ, Egger ME, Angeles CV, et al: Gene expression profile-based test to predict melanoma sentinel node status: the MERLIN_001 study. JAMA Surg, 2025","DOI":"10.1001\/jamasurg.2025.4399"},{"key":"18928_CR34","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1056\/NEJMoa1613210","volume":"376","author":"MB Faries","year":"2017","unstructured":"Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376:2211\u201322.","journal-title":"N Engl J Med"},{"key":"18928_CR35","first-page":"835","volume":"157","author":"JS Crystal","year":"2022","unstructured":"Multicenter Selective Lymphadenectomy Trials Study G, Crystal JS, Thompson JF, et al. Therapeutic value of sentinel lymph node biopsy in patients with melanoma: a randomized clinical trial. JAMA Surg. 2022;157:835\u201342.","journal-title":"JAMA Surg"},{"key":"18928_CR36","unstructured":"Blank CU, Lucas MW, Scolyer RA, et al: Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. N Engl J Med, 2024"},{"key":"18928_CR37","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1056\/NEJMoa2211437","volume":"388","author":"SP Patel","year":"2023","unstructured":"Patel SP, Othus M, Chen Y, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388:813\u201323.","journal-title":"N Engl J Med"},{"key":"18928_CR38","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ejca.2023.01.004","volume":"182","author":"ACJ van Akkooi","year":"2023","unstructured":"van Akkooi ACJ, Blank C, Eggermont AMM. Neo-adjuvant immunotherapy emerges as best medical practice, and will be the new standard of care for macroscopic stage III melanoma. Eur J Cancer. 2023;182:38\u201342.","journal-title":"Eur J Cancer"}],"container-title":["Annals of Surgical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1245\/s10434-025-18928-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1245\/s10434-025-18928-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1245\/s10434-025-18928-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T12:26:41Z","timestamp":1776256001000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1245\/s10434-025-18928-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,18]]},"references-count":38,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["18928"],"URL":"https:\/\/doi.org\/10.1245\/s10434-025-18928-9","relation":{},"ISSN":["1068-9265","1534-4681"],"issn-type":[{"value":"1068-9265","type":"print"},{"value":"1534-4681","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,18]]},"assertion":[{"value":"30 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}