{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:20:44Z","timestamp":1780467644655,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: There has been speculation that IOP-lowering medication, which increases aqueous humor outflow, increases the risk of metastatic uveal melanoma (UM). This hypothesis has not been studied previously but is relevant for UM patients who use IOP-lowering medication. The aim of the current study is to assess the association between the use of intraocular pressure (IOP)-lowering medication and the risk of metastatic UM, and mortality. Methods: A retrospective cohort study, in which patients from the Rotterdam Ocular Melanoma Study were included from 1986 onwards. Medical records were evaluated for use of IOP-lowering medication at baseline (i.e., before diagnosis). For each IOP-lowering medication, we divided patients into two groups for comparison (e.g., patients with alpha2-agonist use and patients without alpha2-agonist use). All patients underwent regular ophthalmic examinations and routine screening for metastasis. Survival analyses were initiated to compare groups in each IOP-lowering medication group. In addition, secondary analyses were performed to examine the association between IOP and the development of metastatic UM, and mortality. Results: A total of 707 patients were included of whom 13 patients used prostaglandin or pilocarpine at baseline. For alpha2-agonist, beta-blocker, carbonic anhydrase inhibitor, and oral IOP-lowering medication these were 4, 14, 11, and 12 patients, respectively. The risk of metastatic UM (choroid and ciliary body melanoma) among the prostaglandin\/pilocarpine users was significantly higher than controls (HR [95% CI]: 4.840 [1.452\u201316.133]). Mortality did not differ significantly among the IOP-lowering medications groups, except for the prostaglandin or pilocarpine group (HR [95% CI]: 7.528 [1.836\u201330.867]). If we combined all IOP-lowering medication that increase aqueous humor outflow, the risk (HR [95% CI]) of metastatic UM and mortality was 6.344 (1.615\u201324.918) and 9.743 (2.475\u201338.353), respectively. There was an association between IOP and mortality, but not for the onset of metastatic UM. Conclusion: The use of topical prostaglandin or pilocarpine may increase the risk of metastatic UM and mortality compared to patients without prostaglandin or pilocarpine use. Therefore, use of IOP-lowering medication which increases aqueous humor outflow, should be avoided in patients with (presumed) UM.<\/jats:p>","DOI":"10.3390\/cancers13225657","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T08:10:22Z","timestamp":1636704622000},"page":"5657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Effect of Intraocular Pressure-Lowering Medication on Metastatic Uveal Melanomas"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8523-5471","authenticated-orcid":false,"given":"Jan","family":"Pals","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanneke W.","family":"Mensink","sequence":"additional","affiliation":[{"name":"The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-4010","authenticated-orcid":false,"given":"Erwin","family":"Brosens","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1437-214X","authenticated-orcid":false,"given":"Robert M.","family":"Verdijk","sequence":"additional","affiliation":[{"name":"Department of Pathology, Section Ophthalmic Pathology, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"},{"name":"Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole C.","family":"Naus","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dion A.","family":"Paridaens","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"},{"name":"The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emine","family":"Kilic","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1780-5281","authenticated-orcid":false,"given":"Wishal D.","family":"Ramdas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Erasmus University Medical Center, 3015 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1001\/archophthalmol.2009.208","article-title":"Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes","volume":"127","author":"Shields","year":"2009","journal-title":"Arch. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/j.ophtha.2011.01.040","article-title":"Uveal melanoma: Trends in incidence, treatment, and survival","volume":"118","author":"Singh","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8076","DOI":"10.1200\/JCO.2005.02.6534","article-title":"Variates of survival in metastatic uveal melanoma","volume":"23","author":"Rietschel","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1167\/iovs.03-0538","article-title":"Very long-term prognosis of patients with malignant uveal melanoma","volume":"44","author":"Kujala","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/BF01606450","article-title":"The biology of haematogenous metastasis in human uveal malignant melanoma","volume":"422","author":"McLean","year":"1993","journal-title":"Virchows. Arch. A Pathol. Anat. Histopathol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Van Beek, J.G.M., Van den Bosch, Q.C.C., Naus, N., Paridaens, D., de Klein, A., Kilic, E., and Verdijk, R.M. (2019). Absence of intraocular lymphatic vessels in uveal melanomas with extrascleral growth. Cancers, 11.","DOI":"10.3390\/cancers11020228"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1158\/1078-0432.CCR-06-2630","article-title":"Molecular pathways mediating liver metastasis in patients with uveal melanoma","volume":"14","author":"Bakalian","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jochems, A., Van der Kooij, M.K., Fiocco, M., Schouwenburg, M.G., Aarts, M.J., van Akkooi, A.C., Van den Berkmortel, F., Blank, C.U., van den Eertwegh, A.J.M., and Franken, M.G. (2019). Metastatic uveal melanoma: Treatment strategies and survival-results from the dutch melanoma treatment registry. Cancers, 11.","DOI":"10.3390\/cancers11071007"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00280-019-03860-z","article-title":"Uveal melanoma: Physiopathology and new in situ-specific therapies","volume":"84","author":"Souto","year":"2019","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.ophtha.2016.01.023","article-title":"Uveal melanomas with sf3b1 mutations: A distinct subclass associated with late-onset metastases","volume":"123","author":"Yavuzyigitoglu","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/ICU.0000000000000550","article-title":"Glaucoma secondary to intraocular tumors: Mechanisms and management","volume":"30","author":"Camp","year":"2019","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0161-6420(87)33537-7","article-title":"Prevalence and mechanisms of secondary intraocular pressure elevation in eyes with intraocular tumors","volume":"94","author":"Shields","year":"1987","journal-title":"Ophthalmology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.ophtha.2005.01.042","article-title":"Intraocular pressure-lowering effects of all commonly used glaucoma drugs: A meta-analysis of randomized clinical trials","volume":"112","author":"Webers","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.1016\/j.survophthal.2008.08.010","article-title":"Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction","volume":"53","author":"Toris","year":"2008","journal-title":"Surv. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/0002-9394(57)93136-7","article-title":"Studies on the mode of action of pilocarpine on aqueous outflow","volume":"44","author":"Flocks","year":"1957","journal-title":"Am. J. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1001\/jamaophthalmol.2016.1881","article-title":"Effect of pilocarpine hydrochloride on the schlemm canal in healthy eyes and eyes with open-angle glaucoma","volume":"134","author":"Skaat","year":"2016","journal-title":"JAMA Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1001\/archopht.1995.01100120044006","article-title":"Effects of brimonidine on aqueous humor dynamics in human eyes","volume":"113","author":"Toris","year":"1995","journal-title":"Arch. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/0039-6257(79)90231-5","article-title":"Longterm timolol therapy","volume":"23","author":"Lin","year":"1979","journal-title":"Surv. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S1350-9462(99)00006-3","article-title":"Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors","volume":"19","author":"Sugrue","year":"2000","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/00061198-200202000-00013","article-title":"Management of iris melanoma with secondary glaucoma","volume":"11","author":"Girkin","year":"2002","journal-title":"J. Glaucoma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0161-6420(00)00449-8","article-title":"Iris melanoma: Risk factors for metastasis in 169 consecutive patients","volume":"108","author":"Shields","year":"2001","journal-title":"Ophthalmology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1038\/modpathol.2014.43","article-title":"Clinical significance of immunohistochemistry for detection of bap1 mutations in uveal melanoma","volume":"27","author":"Koopmans","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/modpathol.2017.187","article-title":"Combined mutation and copy-number variation detection by targeted next-generation sequencing in uveal melanoma","volume":"31","author":"Smit","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"(2017). European glaucoma society terminology and guidelines for glaucoma, 4th edition\u2014Chapter 3: Treatment principles and options supported by the egs foundation: Part 1: Foreword; introduction; glossary; chapter 3 treatment principles and options. Br. J. Ophthalmol., 101, 130\u2013195.","DOI":"10.1136\/bjophthalmol-2016-EGSguideline.003"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3109\/13816810.2016.1164193","article-title":"Prostaglandins in the eye: Function, expression, and roles in glaucoma","volume":"38","author":"Doucette","year":"2017","journal-title":"Ophthalmic. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1136\/bjo.76.4.210","article-title":"Localisation of prostaglandin f2 alpha and e2 binding sites in the human eye","volume":"76","author":"Matsuo","year":"1992","journal-title":"Br. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1006\/bbrc.2000.2969","article-title":"Prostaglandins up-regulate vascular endothelial growth factor production through distinct pathways in differentiated u937 cells","volume":"273","author":"Bamba","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/15569527.2021.1874009","article-title":"Effects of topical prostaglandin drops on angiogenesis in an in ovo chick chorioallantoic membrane model","volume":"40","author":"Sabaner","year":"2021","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7707","DOI":"10.1158\/0008-5472.CAN-05-0101","article-title":"A novel angiogenic role for prostaglandin f2alpha-fp receptor interaction in human endometrial adenocarcinomas","volume":"65","author":"Sales","year":"2005","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.vph.2006.02.009","article-title":"Relationship between prostaglandin e2 and vascular endothelial growth factor (vegf) in angiogenesis in human vascular endothelial cells","volume":"44","author":"Tamura","year":"2006","journal-title":"Vascul. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1111\/bph.12815","article-title":"Multiple roles of the pge2 -ep receptor signal in vascular permeability","volume":"171","author":"Omori","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","first-page":"1514","article-title":"Increased human scleral permeability with prostaglandin exposure","volume":"42","author":"Kim","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1254\/jphs.FP0061061","article-title":"Intravenously administered vasodilatory prostaglandins increase retinal and choroidal blood flow in rats","volume":"103","author":"Mori","year":"2007","journal-title":"J. Pharmacol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1084\/jem.20021408","article-title":"Host prostaglandin e(2)-ep3 signaling regulates tumor-associated angiogenesis and tumor growth","volume":"197","author":"Amano","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/pcmr.12455","article-title":"Microsomal pge2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression","volume":"29","author":"Kim","year":"2016","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1002\/cam4.2594","article-title":"Beta-blockers exert potent anti-tumor effects in cutaneous and uveal melanoma","volume":"8","author":"Bustamante","year":"2019","journal-title":"Cancer Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1215\/15228517-2007-001","article-title":"Carbonic anhydrase ii in the endothelium of glial tumors: A potential target for therapy","volume":"9","author":"Haapasalo","year":"2007","journal-title":"Neuro. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8201","DOI":"10.1158\/1078-0432.CCR-05-0816","article-title":"Carbonic anhydrase ii is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy","volume":"11","author":"Yoshiura","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2165\/00002512-199914050-00006","article-title":"Prostaglandin analogues in the treatment of glaucoma","volume":"14","author":"Linden","year":"1999","journal-title":"Drugs Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1442-9071.2011.02718.x","article-title":"Lower eyelid melanoma during bimatoprost (lumigan) therapy","volume":"40","author":"Sun","year":"2012","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_41","first-page":"60","article-title":"[melanoma during latanoprost therapy: Three cases] melanomes associes au latanoprost: Trois cas","volume":"136","author":"Esteve","year":"2009","journal-title":"Ann. Dermatol. Venereol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/22\/5657\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:29:04Z","timestamp":1760167744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/22\/5657"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,12]]},"references-count":41,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cancers13225657"],"URL":"https:\/\/doi.org\/10.3390\/cancers13225657","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,12]]}}}