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      MEK Inhibitor-Associated Central Retinal Vein Occlusion Associated with Hyperhomocysteinemia and MTHFR Variants

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          Abstract

          Background: Central retinal vein occlusion (CRVO) is a visually threatening event that has rarely been observed in patients taking MEK1/2 inhibitors and that may necessitate permanent discontinuation of a potentially efficacious therapy. We investigated the clinical characteristics of CRVO in patients on mitogen-activated protein kinase kinase (MEK) inhibition to better understand their predisposing factors and clinical course. Case Series: This was a single-center, retrospective cohort study (between December 2006 and September 2018). Three of 546 patients enrolled in 46 prospective trials involving treatment with MEK inhibitors at Memorial Sloan Kettering Cancer Center were identified as having CRVO. Clinical examination and course, multimodal ophthalmic imaging, and serum laboratory results (including homocysteine levels and genetic variants of methylene tetrahydrofolate reductase [MTHFR]) were reviewed for the 3 affected patients. All 3 patients with MEK inhibitor-associated CRVO had elevated serum homocysteine and gene variants of MTHFR (1 homozygous for A1298C, 1 heterozygous for A1298C, and 1 homozygous for C677T). Following intravitreous injections of anti-VEGF and discontinuation of drug, all patients regained vision to their baseline. Discussion: MEK inhibitor-associated CRVO is a rare event which can exhibit visual recovery after drug cessation and intravitreous anti-VEGF injections. In this cohort, it was associated with hyperhomocysteinemia and genetic mutations in MTHFR, suggesting a potential role for hyperhomocysteinemia screening prior to initiation of MEK inhibitor therapy.

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          Most cited references 16

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          Is Open Access

          MEK and the inhibitors: from bench to bedside

          Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clinical trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clinical development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518), and AZD8330.
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            Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase.

            Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms of the human enzyme have been identified: 677C>T, which leads to the substitution of Ala-222 by valine, and 1298A>C, which leads to the replacement of Glu-429 by alanine; the former polymorphism is the most frequent genetic cause of mild hyperhomocysteinemia, a risk factor for cardiovascular disease. By using a baculovirus expression system, recombinant human MTHFR has been expressed at high levels and purified to homogeneity in quantities suitable for biochemical characterization. The Glu429Ala protein has biochemical properties that are indistinguishable from the wild-type enzyme. The Ala222Val MTHFR, however, has an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution; the resulting loss of activity is slowed in the presence of methyltetrahydrofolate or adenosylmethionine. This biochemical phenotype is in good agreement with predictions made on the basis of studies comparing wild-type Escherichia coli MTHFR with a mutant, Ala177Val, homologous to the Ala222Val mutant human enzyme [Guenther, B. D., et al. (1999) Nat. Struct. Biol. 6, 359-365].
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              Natural history of visual outcome in central retinal vein occlusion.

              To investigate systematically the natural history of visual outcome in central retinal vein occlusion (CRVO). Cohort study. Six hundred sixty-seven consecutive patients (30 patients had both eyes involved resulting in 697 eyes) with CRVO first seen in the authors' clinic from 1973 through 2000. At the first visit, all patients underwent a detailed ophthalmic and medical history and a comprehensive ophthalmic evaluation. Visual evaluation was carried out by recording visual acuity, using the Snellen visual acuity chart, and assessing visual fields with a Goldmann perimeter. The same ophthalmic evaluation was performed at each follow-up visit. Central retinal vein occlusion was classified into nonischemic (588 eyes) and ischemic (109 eyes) types at the initial visit based on functional and morphologic criteria. Visual acuity and visual fields. Of the eyes first seen within 3 months, visual acuity was 20/100 or better in 78% with nonischemic CRVO and in only 1% with ischemic CRVO (P < 0.0001), and visual field defects were minimal or mild in 91% and 8%, respectively (P < 0.0001). Final visual acuity, on resolution of macular edema, was 20/100 or better in 83% with nonischemic CRVO and in only 12% with ischemic CRVO (P < 0.0001), and visual field defects were minimal or mild in 95% and 18%, respectively (P < 0.0001). On resolution of macular edema, in eyes with initial visual acuity of 20/70 or worse, visual acuity improved in 59% with nonischemic CRVO, with no significant (P = 0.55) improvement in ischemic CRVO. Similarly, on resolution of macular edema, in eyes with moderate to severe initial visual field defect, improvement was seen in 86% of nonischemic CRVO eyes, but no significant (P = 0.83) improvement was seen in eyes with ischemic CRVO. In nonischemic CRVO, development of foveal pigmentary degeneration, epiretinal membrane, or both, was the main cause of poor final visual acuity. This shows that initial presentation and the final visual outcome in the 2 types of CRVO are entirely different. A clear differentiation of CRVO into nonischemic and ischemic types, based primarily on functional criteria, is crucial and fundamental in determining visual outcome. Visual outcome is good in nonischemic CRVO and poor in ischemic CRVO. Copyright © 2011. Published by Elsevier Inc.
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                Author and article information

                Journal
                OOP
                OOP
                10.1159/issn.2296-4657
                Ocular Oncology and Pathology
                S. Karger AG
                2296-4681
                2296-4657
                2020
                May 2020
                21 October 2019
                : 6
                : 3
                : 159-163
                Affiliations
                aOphthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                bWeill Cornell Medical Center, New York, New York, USA
                cDepartment of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                dDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                eHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
                Author notes
                *Jasmine H. Francis, MD, Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065 (USA), E-Mail francij1@mskcc.org
                Article
                501155 Ocul Oncol Pathol 2020;6:159–163
                10.1159/000501155
                © 2019 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 2, Pages: 5
                Categories
                Novel Insights from Clinical Practice

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