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Sen S, Khalid H, Udaya P, Raman R, Rajendram R, ElHousseini Z, Nicholson L, Kannan NB, Ramasamy K, Kumaragurupari T. Ultrastructural imaging biomarkers in diabetic macular edema: A major review. Indian J Ophthalmol 2025; 73:S7-S23. [PMID: 39723865 PMCID: PMC11834929 DOI: 10.4103/ijo.ijo_878_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 10/02/2024] [Accepted: 10/10/2024] [Indexed: 12/28/2024] Open
Abstract
Diabetic macular edema (DME) is a vision-threatening complication of diabetic retinopathy and causes significant morbidity in patients. Anti-vascular endothelial growth factor (VEGF) agents are the mainstay of treatment for DME, with steroid implants being used for the treatment of anti-VEGF resistant eyes. Over the years, several classification systems have been devised to describe the patterns of DME using optical coherence tomography (OCT). With the advent of effective treatments, it has become imperative that imaging cues are not merely used for classifying the disease but also as biomarkers for prognostication of disease activity and treatment response. In this aspect, newer imaging findings such as hyperreflective dots, photoreceptor integrity, and disorganization of retinal inner layers have been characterized in detail by several authors. Macular perfusion analysis using OCT angiography is the latest in the armamentarium for imaging DME. In this narrative review, we have summarized all relevant literature related to the ultrastructural imaging-based biomarkers of DME and their correlation to treatment.
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Affiliation(s)
- Sagnik Sen
- Department of Medical Retina, Moorfields Eye Hospital, London, UK
- Department of Vitreoretina, St Thomas Hospital, London, UK
- UCL Institute of Ophthalmology, London, UK
- Department of Vitreoretina, Aravind Eye Hospital, Madurai, India
| | - Hagar Khalid
- Department of Medical Retina, Moorfields Eye Hospital, London, UK
- Department of Ophthalmology, Tanta University, Egypt
| | - Prithviraj Udaya
- Department of Vitreoretina, Aravind Eye Hospital, Madurai, India
| | - Rajiv Raman
- Department of Vitreoretina, Sankara Nethralaya, Chennai, Tamil Nadu, India
| | - Ranjan Rajendram
- Department of Medical Retina, Moorfields Eye Hospital, London, UK
| | - Zein ElHousseini
- Department of Ophthalmology, Royal Free London NHS Foundation Trust, London, UK
| | - Luke Nicholson
- Department of Medical Retina, Moorfields Eye Hospital, London, UK
| | | | - Kim Ramasamy
- Department of Vitreoretina, Aravind Eye Hospital, Madurai, India
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Singh RP, Tabano D, Kuo BL, LaPrise A, Leng T, Kim E, Hatfield M, Garmo V. How intravitreal anti-vascular endothelial growth factor initial dosing impacts patient outcomes in diabetic macular oedema. BMC Ophthalmol 2024; 24:552. [PMID: 39736584 DOI: 10.1186/s12886-024-03797-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 12/02/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Intravitreal anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular oedema (DME) may begin with several initial monthly doses. Characteristics, treatment patterns and outcomes were compared for eyes with DME that did and did not receive such initial doses. METHODS This was a retrospective database study using American Academy of Ophthalmology Intelligent Research in Sight® Registry data (01/01/15-31/12/20; index period). Eligible adults had documented DME within 2 months of first anti-VEGF treatment (index date), data available for 12 months beforehand, and ≥ 1 visual acuity (VA) recording ≤ 60 days before index date. Eyes must have received intravitreal anti-VEGF injections during the index period, but none in the prior 12 months. Characteristics and outcomes for eyes with initial doses (three injections within 100 days of index date) were compared with those without. Multivariate Cox Proportional Hazards modelling estimated predictors for treatment discontinuation, re-initiation, or switch; Generalized Estimating Equations-adjusted modelling estimated characteristics associated with receiving initial doses. Demographics and characteristics were summarised. Injection frequency and number, and VA were determined annually for ≤ 6 years. Discontinuations, reinitiations and switches were compared. RESULTS Included were 217,696 eyes (n = 77,769 initial; n = 139,927 non-initial) from 166,868 patients. Mean (SD) baseline VA was numerically higher for eyes with versus without initial doses (63.0 [18.1] vs. 62.5 [19.8] letters); this remained during follow-up. Based on modelling results, Eyes with initial doses received more injections (mean [standard deviation (SD)] 11.6 [8.9] vs. 6.1 [6.8] injections) more frequently (interval 7.6 [2.8] vs. 12.6 [7.7] weeks) than eyes without. These differences occurred across follow-up years. Discontinuation (45.7% vs. 63.8%), re-initiation (17.2% vs. 25.0%), and switch (24.5% vs. 31.5%) were less common with initial doses. Asian, Black, and patients of other/unknown race were less likely (P < 0.01) to receive initial doses than White patients, as were Medicare/Medicaid-insured patients versus commercially insured patients (P < 0.01). CONCLUSIONS Various sociodemographic factors associate with initial anti-VEGF doses, including race, ethnicity and insurance. Although eyes with frequent initial doses maintained higher VA than those without, they also receive more injections over time. Further research may elucidate the impact of frequent initial doses versus total injection number on DME outcomes.
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Affiliation(s)
- Rishi P Singh
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, 44106, USA.
| | | | - Blanche L Kuo
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | - Theodore Leng
- Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Eunice Kim
- Genentech, Inc, South San Francisco, CA, USA
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Mahaling B, Baruah N, Dinabandhu A. Nanomedicine in Ophthalmology: From Bench to Bedside. J Clin Med 2024; 13:7651. [PMID: 39768574 PMCID: PMC11678589 DOI: 10.3390/jcm13247651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 11/28/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Ocular diseases such as cataract, refractive error, age-related macular degeneration, glaucoma, and diabetic retinopathy significantly impact vision and quality of life worldwide. Despite advances in conventional treatments, challenges like limited bioavailability, poor patient compliance, and invasive administration methods hinder their effectiveness. Nanomedicine offers a promising solution by enhancing drug delivery to targeted ocular tissues, enabling sustained release, and improving therapeutic outcomes. This review explores the journey of nanomedicine from bench to bedside, focusing on key nanotechnology platforms, preclinical models, and case studies of successful clinical translation. It addresses critical challenges, including pharmacokinetics, regulatory hurdles, and manufacturing scalability, which must be overcome for successful market entry. Additionally, this review highlights safety considerations, current marketed and FDA-approved nanomedicine products, and emerging trends such as gene therapy and personalized approaches. By providing a comprehensive overview of the current landscape and future directions, this article aims to guide researchers, clinicians, and industry stakeholders in advancing the clinical application of nanomedicine in ophthalmology.
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Affiliation(s)
- Binapani Mahaling
- Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
| | - Namrata Baruah
- Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA;
| | - Aumreetam Dinabandhu
- Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;
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Wu X, Zhu H, Liu J, Ouyang S, Lyu Z, Jin Y, Chen X, Meng Q. Jagged1-Notch1 Signaling Pathway Induces M1 Microglia to Disrupt the Barrier Function of Retinal Microvascular Endothelial Cells. Curr Eye Res 2024; 49:1098-1106. [PMID: 38783634 DOI: 10.1080/02713683.2024.2357601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/28/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE Microglia-related inflammation is closely linked to the pathogenesis of retinal diseases. The primary objective of this research was to investigate the impact and mechanism of M1 phenotype microglia on the barrier function of retina microvascular endothelial cells. METHODS Quantitative polymerase chain reactions and western blot techniques were utilized to analysis the mRNA and protein expressions of M1 and M2 markers of human microglial clone 3 cell line (HMC3), as well as the levels of Notch ligands and receptors under the intervention of lipopolysaccharide (LPS) or interleukin (IL)-4. ELISA was utilized to detect the pro-inflammatory and anti-inflammatory cytokines from HMC3 cells. The cellular tight junction and apoptosis of human retinal microvascular endothelial cells (HRMECs) were assessed by western blot and fluorescein isothiocyanate-dextran permeability assay. The inhibitors of Notch1 and RNA interference (RNAi) targeting Jagged1 were used to assess their contribution to the barrier function of vascular endothelial cells. RESULTS Inducible nitric oxide synthase (iNOS) and IL-1β were considerably elevated in LPS-treated HMC3, while CD206 and Arg-1 markedly elevated under IL-4 stimulation. The conditioned medium derived from LPS-treated HMC3 cells promoted permeability, diminished the expression of zonula occludens-1 and Occludin, and elevated the expression of Cleaved caspase-3 in HRMECs. RNAi targeting Jagged1 or Notch1 inhibitor could block M1 HMC3 polarization and maintain barrier function of HRMECs. CONCLUSION Our findings suggest that Jagged1-Notch1 signaling pathway induces M1 microglial cells to disrupt the barrier function of HRMECs, which may lead to retinal diseases.
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Affiliation(s)
- Xiyu Wu
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Haoxian Zhu
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Junbin Liu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Shuyi Ouyang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zheng Lyu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yeanqi Jin
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xinyu Chen
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Qianli Meng
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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Glassman AR, Elmasry MA, Baskin DE, Brigell M, Chong V, Davis Q, Lesmes L, Levin LA, Maddess T, Taylor LJ, Wenzel A. Visual Function Measurements in Eyes With Diabetic Retinopathy: An Expert Opinion on Available Measures. OPHTHALMOLOGY SCIENCE 2024; 4:100519. [PMID: 38881606 PMCID: PMC11179417 DOI: 10.1016/j.xops.2024.100519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/18/2024] [Accepted: 03/18/2024] [Indexed: 06/18/2024]
Abstract
Clinical Relevance Visual function impairment from diabetic retinopathy can have a considerable impact on patient's quality of life. Best-corrected visual acuity (BCVA) is most commonly used to assess visual function and guide clinical trials. However, BCVA is affected late in the disease process, is not affected in early disease, and does not capture some of the visual disturbances described by patients with diabetes. The goal of this report is to evaluate the relationship between diabetic retinal disease (DRD) and visual function parameters to determine which if any of them may be used in a future DRD staging system. Methods The visual functions working group was 1 of 6 areas of DRD studied as part of the DRD staging system update, a project of the Mary Tyler Moore Vision Initiative. The working group identified 12 variables of possible interest, 7 of which were judged to have sufficient preliminary data to suggest an association with DR to warrant further review: microperimetry, static automated perimetry, electroretinogram (ERG) oscillatory potentials, flicker ERG, low luminance visual acuity (LLVA), contrast sensitivity (CS), and BCVA. The objective field analyzer (OFA) was added after subsequent in-person workshops. Results Currently, the only visual function test available for immediate use is BCVA; the remaining tests are either promising (within 5 years) or have potential (>5 years) use. Besides BCVA, most visual function tests had a limited role in current clinical care; however, LLVA, CS, flicker ERG, and OFA demonstrated potential for screening and research purposes. Conclusions Although current visual function tests are promising, future prospective studies involving patients with early and more advanced retinopathy are necessary to determine if these tests can be used clinically or as endpoints for clinical studies. Financial Disclosures Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
| | - Mohamed Ashraf Elmasry
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
- Joslin Diabetes Center, Boston, Massachusetts
| | - Darrell E Baskin
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | | | | | | | - Luis Lesmes
- Adaptive Sensory Technology, San Diego, California
| | - Leonard A Levin
- Departments of Ophthalmology & Visual Sciences and Neurology & Neurosurgery, McGill University, Montreal, Canada
| | - Ted Maddess
- John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
| | - Laura J Taylor
- Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Andreas Wenzel
- Roche Pharma Research & Early Development, F. Hoffmann - La Roche Ltd, Basel, Switzerland
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Shimura M, Oh H, Ueda T, Kitano S, Mitamura Y, Sato J, Iwasaki K, Hirakata A. Efficacy, durability, and safety of faricimab with extended dosing up to every 16 weeks in diabetic macular edema: 2-year results from the Japan subgroup of the phase 3 YOSEMITE trial. Jpn J Ophthalmol 2024; 68:511-522. [PMID: 39083147 PMCID: PMC11420323 DOI: 10.1007/s10384-024-01078-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 05/29/2024] [Indexed: 09/26/2024]
Abstract
PURPOSE To evaluate the 2-year efficacy, durability, and safety of faricimab in patients with diabetic macular edema (DME) in the YOSEMITE Japan subgroup. STUDY DESIGN YOSEMITE/RHINE (NCT03622580/NCT03622593) subgroup analysis: global, multicenter, randomized, double-masked, active-comparator-controlled, phase 3 faricimab trials. METHODS Patients were randomized 1:1:1 to intravitreal faricimab 6.0 mg every 8 weeks (Q8W) and per treat-and-extend (T&E) dosing, or aflibercept 2.0 mg Q8W. Outcomes were assessed through year 2 for the YOSEMITE Japan subgroup (N = 60) and the pooled YOSEMITE/RHINE global cohort (N = 1891). RESULTS In the YOSEMITE Japan subgroup, 21, 19, and 20 patients were randomized to faricimab Q8W, faricimab T&E, and aflibercept Q8W, respectively (632, 632, and 627 patients in the pooled YOSEMITE/RHINE cohort). Vision gains and anatomic improvements with faricimab at year 1 were maintained over 2 years and were generally consistent between groups. Mean best-corrected visual acuity changes from baseline at year 2 (weeks 92-100 average) for the YOSEMITE Japan subgroup were +12.5, +9.0, and +5.0 letters in the faricimab Q8W, faricimab T&E and aflibercept Q8W arms, respectively (+10.8, +10.4, and +10.3 letters in the pooled YOSEMITE/RHINE cohort). At week 96, 61.1% of the YOSEMITE Japan subgroup and 78.1% of the pooled YOSEMITE/RHINE cohort were on ≥ Q12W dosing. Faricimab was well-tolerated with a safety profile comparable with aflibercept. CONCLUSION Faricimab up to Q16W offered durable vision gains and anatomic improvements up to 2 years in patients with DME in the YOSEMITE Japan subgroup. Outcomes were generally consistent with the pooled YOSEMITE/RHINE cohort.
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Affiliation(s)
- Masahiko Shimura
- Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji-shi, Tokyo, 193-0998, Japan.
| | - Hideyasu Oh
- Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
| | - Tetsuo Ueda
- Nara Medical University Hospital, Nara, Japan
| | | | | | - Junko Sato
- Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
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Ammari W, Chaabene H, Messaoud R. [Anatomical and functional outcomes of the "3+PRN" therapeutic protocol in the treatment of diabetic macular edema]. J Fr Ophtalmol 2024; 47:104234. [PMID: 38875945 DOI: 10.1016/j.jfo.2024.104234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 02/04/2024] [Accepted: 03/12/2024] [Indexed: 06/16/2024]
Abstract
PURPOSE To evaluate the anatomical and functional results of the "3+PRN" protocol in the treatment of diabetic macular edema (DME), determine the predictive factors for good final visual acuity, and compare it to other protocols. MATERIALS AND METHODS We conducted a retrospective, descriptive, comparative, cross-sectional study of patients with DME, which we dubbed HTSM. All patients were treated with three monthly initial intravitreal injections (IVT) of 1.25mg bevacizumab and followed according to the pro re nata (PRN) protocol for a period of 3years. The protocol was based on a monthly monitoring schedule for the first 3months, then increasingly spaced out over time. "On-demand" treatment was indicated with resumption of bevacizumab IVT in the event of worsening of DME. RESULTS A total of 52 patients were included. The mean age was 65years. Type 2 was the most frequently observed type of diabetes. The mean duration of the PRN protocol was 6months, and the mean number of injections was 6. The mean visual acuity (VA), initially 1/10, improved to 3/10 by the conclusion of the 3+PRN protocol, with an improvement of more than 5 letters in 77.6% of cases. The mean initial central macular thickness (CMT) was 451.5μm. The final mean EMC decreased to 298.5μm, which corresponds to a reduction of 153μm compared to the initial value. The mean subfoveal choroidal thickness, initially 304.2μm, decreased to a mean of 284.5μm at completion. Comparative analysis of the results before and after the PRN protocol confirmed the existence of a statistically significant correlation between VA and CMT (P<0.05). No correlation was observed between age and visual acuity or between initial and final VA. The analysis of the various tomographic parameters and VA revealed a significantly better visual improvement in the group in whom the external limiting membrane (MLE) and ellipsoid zone (ZE) were intact (P=0.04), as well as in the group in whom serous retinal detachment (SRD) was absent (P<0.001). Posterior vitreous detachment (PVD) was the most frequently observed vitreomacular anomaly. The final VA was similar in the groups with and without PVD (P=0.04). CONCLUSION The 3+PRN protocol is effective both functionally and tomographically in the treatment of DME. Various tomographic parameters might influence therapeutic efficacy. However, further in-depth studies are needed to better investigate these parameters.
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Affiliation(s)
- W Ammari
- Service d'ophtalmologie, hôpital universitaire Taher Sfar Mahdia, Jbel Dar Waja 5100, Tunisie; Faculté de médecine de Monastir, Monastir, Tunisie.
| | - H Chaabene
- Service d'ophtalmologie, hôpital universitaire Taher Sfar Mahdia, Jbel Dar Waja 5100, Tunisie; Faculté de médecine de Monastir, Monastir, Tunisie
| | - R Messaoud
- Service d'ophtalmologie, hôpital universitaire Taher Sfar Mahdia, Jbel Dar Waja 5100, Tunisie; Faculté de médecine de Monastir, Monastir, Tunisie
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Limon DU, Kaplan FB, Saygın I, Önder Tokuç E, Kutlutürk Karagöz I, Kanar HS, Sevik MO, Yayla U, Çelik E, Sönmez A, Aykut A, Kumral Türkseven E, Erçalık NY, Oncu Aydın Ö, Bozkurt E, Aydoğan T, Emengen EB, Özkaya A, Açıkalın Öncel B, Yenerel NM, Şahin Ö, Karabaş L. One-Year Functional and Morphological Prognosis After Intravitreal Injection Treatments According to Different Morphological Patterns of Diabetic Macular Edema in Real-Life: MARMASIA Study Group Report No.13. Semin Ophthalmol 2024; 39:460-467. [PMID: 39087722 DOI: 10.1080/08820538.2024.2324450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE To evaluate the responses of different optical coherence tomography (OCT) patterns of diabetic macular edema (DME) to intravitreal injection therapy. METHODS In this retrospective, comparative, and multicenter study, patients who had previously untreated DME, who received intravitreal ranibizumab (IVR) or aflibercept (IVA) and/or steroid treatment with the pro re nata (PRN) treatment regimen after a 3-month loading dose, and had a 12-month follow-up in the MARMASIA Study Group were included. Morphological patterns of DME were divided into four groups based on OCT features diffuse/spongious edema (Group 1), cystoid edema (Group 2), diffuse/spongious edema+subretinal fluid (SRF) (Group 3), and cystoid edema+SRF (Group 4). Changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA) at months 3, 6, and 12, and the number of injections at month 12 were compared between the DME groups. RESULTS 455 eyes of 299 patients were included in the study. The mean baseline BCVAs [Logarithm of the Minimum Angle of Resolution (logMAR)] in groups 1, 2, 3, and 4 were 0.54 ± 0.24, 0.52 ± 0.25, 0.55 ± 0.23, and 0.57 ± 0.27, respectively. There was no significant difference between the baseline mean BCVAs between the groups (p = .35). The mean BCVAs were significantly improved to 0,47 ± 0,33 in group 1, 0,42 ± 0,33 in group 2, 0,47 ± 0,31 in group 3, and 0,45 ± 0,43 at month 12. There was no significant difference between the groups in terms of BCVA change at month 12 (p = .71). The mean baseline CMTs in groups 1, 2, 3, and 4 were 387,19 ± 128,19, 447,02 ± 132,39, 449,12 ± 109,24, and 544,19 ± 178,61, respectively. At baseline, the mean CMT was significantly higher in Group 4 than in the other groups (p = .000). The mean CMTs were significantly decreased to 325,16 ± 97,55, 334,94 ± 115,99, 324,33 ± 79,20, and 332,08 ± 150,40 in four groups at month 12 respectively (p > .05). The groups had no significant difference in mean CMT at month 12 (p = .835). The change in CMT was significantly higher in Group 4 than in the other groups at month 12 (p = .000). The mean number of intravitreal anti-VEGF injections at month 12 was 4.51 ± 1.57 in Group 1, 4.63 ± 1.54 in Group 2, 4.88 ± 1.38 in Group 3, and 5.07 ± 1.49 in Group 4. The mean number of anti-VEGF injections in Group 1 and Group 2 was significantly lower than in Group 4 (p = 0,014 and p = 0,017). CONCLUSIONS In real life, there was no significant difference between the DME groups in terms of visual improvement at month 12. However, better anatomical improvement was achieved in Group 4 than in the other DME groups.
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Affiliation(s)
- Dr Utku Limon
- Ümraniye Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Fatih Bilgehan Kaplan
- Fatih Sultan Mehmet Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Işılay Saygın
- Ümraniye Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Ecem Önder Tokuç
- Derince Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Kocaeli, Turkey
| | - Işıl Kutlutürk Karagöz
- Şişli Hamidiye Etfal Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Hatice Selen Kanar
- Kartal Dr. Lütfi Kırdar City Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Mehmet Orkun Sevik
- Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey
| | - Uğur Yayla
- Derince Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Kocaeli, Turkey
| | - Erkan Çelik
- Department of Ophthalmology, Sakarya University School of Medicine, Sakarya, Turkey
| | - Ayşe Sönmez
- Fatih Sultan Mehmet Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Aslan Aykut
- Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey
| | - Esra Kumral Türkseven
- Haydarpaşa Numune Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Nimet Yeşim Erçalık
- Haydarpaşa Numune Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Özlem Oncu Aydın
- Haydarpaşa Numune Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Erdinç Bozkurt
- Ümraniye Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Tuğba Aydoğan
- Ümraniye Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Ece Başaran Emengen
- Department of Ophthalmology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Abdullah Özkaya
- Department of Ophthalmology, Memorial Şişli Hospital, Istanbul, Turkey
| | - Banu Açıkalın Öncel
- Fatih Sultan Mehmet Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Nursal Melda Yenerel
- Haydarpaşa Numune Education and Research Hospital, Department of Ophthalmology, University of Health Sciences, Istanbul, Turkey
| | - Özlem Şahin
- Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey
| | - Levent Karabaş
- Department of Ophthalmology, Kocaeli University School of Medicine, Kocaeli, Turkey
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Toto L, Romano A, Pavan M, Degl'Innocenti D, Olivotto V, Formenti F, Viggiano P, Midena E, Mastropasqua R. A deep learning approach to hard exudates detection and disorganization of retinal inner layers identification on OCT images. Sci Rep 2024; 14:16652. [PMID: 39030181 PMCID: PMC11271624 DOI: 10.1038/s41598-024-63844-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 06/03/2024] [Indexed: 07/21/2024] Open
Abstract
The purpose of the study was to detect Hard Exudates (HE) and classify Disorganization of Retinal Inner Layers (DRIL) implementing a Deep Learning (DL) system on optical coherence tomography (OCT) images of eyes with diabetic macular edema (DME). We collected a dataset composed of 442 OCT images on which we annotated 6847 HE and the presence of DRIL. A complex operational pipeline was defined to implement data cleaning and image transformations, and train two DL models. The state-of-the-art neural network architectures (Yolov7, ConvNeXt, RegNetX) and advanced techniques were exploited to aggregate the results (Ensemble learning, Edge detection) and obtain a final model. The DL approach reached good performance in detecting HE and classifying DRIL. Regarding HE detection the model got an AP@0.5 score equal to 34.4% with Precision of 48.7% and Recall of 43.1%; while for DRIL classification an Accuracy of 91.1% with Sensitivity and Specificity both of 91.1% and AUC and AUPR values equal to 91% were obtained. The P-value was lower than 0.05 and the Kappa coefficient was 0.82. The DL models proved to be able to identify HE and DRIL in eyes with DME with a very good accuracy and all the metrics calculated confirmed the system performance. Our DL approach demonstrated to be a good candidate as a supporting tool for ophthalmologists in OCT images analysis.
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Affiliation(s)
- Lisa Toto
- Ophthalmology Clinic, Department of Medicine and Ageing Science, University "G. D'Annunzio" of Chieti-Pescara, Via Dei Vestini Snc, 66100, Chieti, Italy
| | - Anna Romano
- Ophthalmology Clinic, Department of Medicine and Ageing Science, University "G. D'Annunzio" of Chieti-Pescara, Via Dei Vestini Snc, 66100, Chieti, Italy.
| | - Marco Pavan
- Datamantix S.R.L. Artificial Intelligence Company, Via Paolo Sarpi, 14/15, 33100, Udine, Italy
| | - Dante Degl'Innocenti
- Datamantix S.R.L. Artificial Intelligence Company, Via Paolo Sarpi, 14/15, 33100, Udine, Italy
| | - Valentina Olivotto
- Datamantix S.R.L. Artificial Intelligence Company, Via Paolo Sarpi, 14/15, 33100, Udine, Italy
| | - Federico Formenti
- Ophthalmology Clinic, Department of Medicine and Ageing Science, University "G. D'Annunzio" of Chieti-Pescara, Via Dei Vestini Snc, 66100, Chieti, Italy
| | - Pasquale Viggiano
- Ophthalmology Clinic, Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Edoardo Midena
- Department of Ophthalmology, University of Padova, 35128, Padova, Italy
- IRCCS- Fondazione Bietti, 00198, Roma, Italy
| | - Rodolfo Mastropasqua
- Ophthalmology Clinic, Department of Neuroscience, Imaging and Clinical Science, "G. D'Annunzio" University of Chieti-Pescara, Via Dei Vestini Snc, 66100, Chieti, Italy
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Pessoa B, Leite J, Ferreira A, Ramalhão J, Poças J, José D, Coelho C, Figueira J, Meireles A, Beirão JM. Oct biomarkers for early prognosis in diabetic macular edema treatment with ranibizumab. Eur J Ophthalmol 2024; 34:1141-1148. [PMID: 37919940 DOI: 10.1177/11206721231210753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2023]
Abstract
BACKGROUND Diabetic macular edema is the main cause of vision loss in patients with diabetic retinopathy. In this work, we aimed to assess the role of Optical Coherence Tomography (OCT) biomarkers in patients treated with ranibizumab. METHODS A prospective study enrolling 46 eyes with DME under ranibizumab intravitreal therapy with 12 months of follow-up. The primary endpoint was to assess the association between OCT biomarkers at baseline and the type of treatment response. RESULTS Good responders, compared with partial/non responders, had lower number of inner nuclear layer cysts (INLc) at baseline, (26.5% vs 73.5%, p = 0.035) and presented, at 12 months of follow-up, lower percentage of disorganization of retinal inner layers (12.0% vs 88.0%, p = 0.001), lower disruption of outer plexiform layer (8.7% vs 91.3%, p < 0.001) and lower outer nuclear layer cysts (17.4% vs 82.6%, p = 0.013). At the end of follow-up, it was observed a higher frequency of inner nuclear layer cysts in patients with higher glycated haemoglobin (p = 0.028). CONCLUSION This study showed the value and importance of OCT parameters, such as absence of INLc, as a prognostic therapeutic response. A normalization of the macular anatomy with ranibizumab is more likely to happen in early complete responders. The association between INLc and higher glycated haemoglobin levels showed the importance of systemic metabolic control in systemic diabetic manifestations. Clinicaltrials.gov NCT04387604.
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Affiliation(s)
- Bernardete Pessoa
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
- Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - João Leite
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| | - André Ferreira
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
- Unit of Anatomy, Department of Biomedicine, Faculty of Medicine of University of Porto, Portugal
| | - João Ramalhão
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| | - João Poças
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| | - Diana José
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| | - Constança Coelho
- Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - João Figueira
- Faculty of Medicine of the University of Coimbra, Coimbra, Portugal
- Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal
| | - Angelina Meireles
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
- Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - João Melo Beirão
- Department of Ophthalmology, Centro Hospitalar Universitário de Santo António, Porto, Portugal
- Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
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Wong TY, Haskova Z, Asik K, Baumal CR, Csaky KG, Eter N, Ives JA, Jaffe GJ, Korobelnik JF, Lin H, Murata T, Ruamviboonsuk P, Schlottmann PG, Seres AI, Silverman D, Sun X, Tang Y, Wells JA, Yoon YH, Wykoff CC. Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials. Ophthalmology 2024; 131:708-723. [PMID: 38158159 DOI: 10.1016/j.ophtha.2023.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024] Open
Abstract
PURPOSE To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
- Tien Y Wong
- Tsinghua Medicine, Tsinghua University, Beijing, China, and Singapore National Eye Centre, Singapore, Republic of Singapore.
| | | | - Kemal Asik
- Genentech, Inc., South San Francisco, California
| | | | - Karl G Csaky
- Retina Foundation of the Southwest, Dallas, Texas
| | - Nicole Eter
- Department of Ophthalmology, University of Münster, Münster, Germany
| | - Jane A Ives
- Roche Products Ltd., Welwyn Garden City, United Kingdom
| | - Glenn J Jaffe
- Department of Ophthalmology, Duke University, Durham, North Carolina
| | - Jean-François Korobelnik
- Centre Hospitalier Universitaire (CHU) de Bordeaux, Service d'Ophtalmologie, Université de Bordeaux, INSERM, BPH, UMR1219, Bordeaux, France
| | - Hugh Lin
- Genentech, Inc., South San Francisco, California
| | | | - Paisan Ruamviboonsuk
- Department of Ophthalmology, College of Medicine, Rangsit University, Rajavithi Hospital, Bangkok, Thailand
| | | | | | | | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yannan Tang
- Genentech, Inc., South San Francisco, California
| | - John A Wells
- Palmetto Retina Center, Retina Consultants of America, Columbia, South Carolina
| | - Young Hee Yoon
- Department of Ophthalmology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea
| | - Charles C Wykoff
- Retina Consultants of Texas, Retina Consultants of America, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas
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Choi J, Kim SJ, Kang SW, Hwang S, Son KY. Biomarkers determining treatment interval of diabetic macular edema after initial resolution by anti-vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 2024; 262:421-429. [PMID: 37843565 DOI: 10.1007/s00417-023-06269-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/20/2023] [Accepted: 09/27/2023] [Indexed: 10/17/2023] Open
Abstract
PURPOSE To identify predictive factors that help determine the interval of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection after the initial resolution of diabetic macular edema (DME). METHODS This retrospective case-control study enrolled treatment-naïve DME patients who had achieved DME resolution after intravitreal anti-VEGF injections. Patients were classified into the recurrence and no-recurrence groups, depending on the development of recurrent DME after deferring intravitreal anti-VEGF injection. The demographics and clinical features, including optical coherence tomography findings, were compared between the two groups. RESULTS We enrolled 105 eyes. Sixty eyes (57.1%) belonged to the no-recurrence group, and 45 (42.9%), belonged to the recurrence group. The severity of diabetic retinopathy at baseline was related to early DME recurrence (P = 0.009). At the treatment deferring point, the non-recurrence group had both thinner central subfield thickness (289.5 ± 27.2 μm vs. 307.0 ± 38.2 μm, P = 0.011) and thinner central retinal thickness (214.9 ± 41.4 μm vs. 231.8 ± 41.2 μm, P = 0.043) compared to the recurrence group. Intraretinal cyst was observed in 34 eyes (56.7%) in the no-recurrence group and 42 eyes (93.3%) in the recurrence group at the deferring point (P < 0.001). CONCLUSION A low risk of early DME recurrence is anticipated in the eyes with foveal thinning and no intraretinal cyst when anti-VEGF injection is deferred. These predictive biomarkers can be useful for patient monitoring and determining treatment strategies for DME patients.
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Affiliation(s)
- Jaehwan Choi
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sang Jin Kim
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Se Woong Kang
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Sungsoon Hwang
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ki Young Son
- Department of Ophthalmology, Chungnam National University Sejong Hospital, Sejong, South Korea
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Rennie C, Lotery A, Payne J, Singh M, Ghanchi F. Suboptimal outcomes and treatment burden of anti-vascular endothelial growth factor treatment for diabetic macular oedema in phakic patients. Eye (Lond) 2024; 38:215-223. [PMID: 37542174 PMCID: PMC10764926 DOI: 10.1038/s41433-023-02667-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 06/27/2023] [Accepted: 07/14/2023] [Indexed: 08/06/2023] Open
Abstract
OBJECTIVES In England and Wales, treatment options were limited for patients with diabetic macular oedema (DMO) with phakic eyes that failed anti-vascular endothelial growth factor (anti-VEGF) treatment pre-2022. This study aimed to quantify the response to, and treatment burden of, anti-VEGF treatment in phakic eyes. METHODS Retrospective, cohort study using electronic patient record data from two UK centres between 2015 and 2020. Primary objective was proportion of phakic eyes with a suboptimal response after initial 6 months of anti-VEGF treatment. Data were available for 500 eyes from 399 patients. RESULTS At 6 months significantly more eyes had a suboptimal response to anti-VEGF treatment: 65.8% (95% CI 61.5-70.0%) vs 34.2% (95% CI 30.0-38.5%), p < 0.0001. Baseline visual acuity (VA) predicted VA outcome, however, despite greater gains in eyes with poorer VA, such eyes did not achieve the same VA levels as those who started treatment with better VA. Only 53.6% of eyes had more than three injections in the first 6 months indicating difficulties in delivering high volume/high frequency treatment. Treatment and review burden were similar over the following years regardless of response to anti-VEGF treatment. CONCLUSIONS Data confirm previous real world evidence around response to anti-VEGF treatment, importance of baseline VA and frequency of injections in predicting outcomes in a UK setting. Continuing treatment beyond 6 months in suboptimal responders imposes unnecessary treatment burden without significant change in VA. In suboptimal responders, consideration of early switch to longer acting steroid treatments may help to reduce treatment burden, whilst maintaining or improving vision.
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Affiliation(s)
- Christina Rennie
- University Hospital Southampton NHS Foundation Trust, Southampton, UK.
| | - Andrew Lotery
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Jo Payne
- AbbVie Ltd, AbbVie House, Vanwall Business Park, Maidenhead, UK
| | - Moushmi Singh
- AbbVie Ltd, AbbVie House, Vanwall Business Park, Maidenhead, UK
| | - Faruque Ghanchi
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
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Hein M, Vukmirovic A, Constable IJ, Raja V, Athwal A, Freund KB, Balaratnasingam C. Angiographic biomarkers are significant predictors of treatment response to intravitreal aflibercept in diabetic macular edema. Sci Rep 2023; 13:8128. [PMID: 37208427 DOI: 10.1038/s41598-023-35286-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023] Open
Abstract
This prospective single-center study aims to identify biomarkers that predict improvement in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at 6 months, in 76 eyes with diabetic macular edema (DME) treated monthly with intravitreal aflibercept. At baseline, all patients underwent standardized imaging with color photography, optical coherence tomography (OCT), fluorescein angiography (FA) and OCT angiography (OCTA). Glycosylated hemoglobin, renal function, dyslipidemia, hypertension, cardiovascular disease and smoking were recorded. Retinal images were graded in a masked fashion. Baseline imaging, systemic and demographic variables were investigated to detect associations to BCVA and CRT change post aflibercept. Predictors of BCVA improvement included greater macular vessel density quantified using OCTA (p = 0.001) and low-density lipoprotein (LDL) ≥ 2.6 mmol/L (p = 0.017). Lower macular vessel density eyes showed a significant reduction in CRT but no BCVA improvement. Predictors of CRT reduction included peripheral non-perfusion seen on ultrawide-field FA (p = 0.005) and LDL ≥ 2.6 mmol/L (p < 0.001). Retinal angiographic biomarkers derived from OCTA and ultrawide-field FA may help predict functional and anatomic response to anti-vascular endothelial growth factor (VEGF) therapy in patients with DME. Elevated LDL is associated with treatment response in DME. These results may be used to better-select patients who will benefit from intravitreal aflibercept for treatment of DME.
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Affiliation(s)
- Martin Hein
- Lions Eye Institute, Perth, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Aleksandar Vukmirovic
- Lions Eye Institute, Perth, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Ian J Constable
- Lions Eye Institute, Perth, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Australia
| | - Vignesh Raja
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Australia
- Joondalup Eye Clinic, Perth, Australia
| | - Arman Athwal
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada
- Department of Medical Physics and Biomedical Engineering, University College London, London, England
| | - K Bailey Freund
- Vitreous Retina Macula Consultants of New York, New York, USA
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA
| | - Chandrakumar Balaratnasingam
- Lions Eye Institute, Perth, Australia.
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia.
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Australia.
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Costanzo E, Giannini D, De Geronimo D, Fragiotta S, Varano M, Parravano M. Prognostic Imaging Biomarkers in Diabetic Macular Edema Eyes Treated with Intravitreal Dexamethasone Implant. J Clin Med 2023; 12:jcm12041303. [PMID: 36835839 PMCID: PMC9968175 DOI: 10.3390/jcm12041303] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 01/31/2023] [Accepted: 02/04/2023] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND The aim was to evaluate predictive value of baseline optical coherence tomography (OCT) and OCT angiography (OCTA) parameters in diabetic macular edema (DME) treated with dexamethasone implant (DEXi). METHODS OCT and OCTA parameters were collected: central macular thickness (CMT), vitreomacular abnormalities (VMIAs), intraretinal and subretinal fluid (mixed DME pattern), hyper-reflective foci (HRF), microaneurysms (MAs) reflectivity, ellipsoid zone disruption, suspended scattering particles in motion (SSPiM), perfusion density (PD), vessel length density, and foveal avascular zone. Responders' (RES) and non-responders' (n-RES) eyes were classified considering morphological (CMT reduction ≥ 10%) and functional (BCVA change ≥ 5 ETDRS letters) changes after DEXi. Binary logistic regression OCT, OCTA, and OCT/OCTA-based models were developed. RESULTS Thirty-four DME eyes were enrolled (18 treatment-naïve). OCT-based model combining DME mixed pattern + MAs + HRF and OCTA-based model combining SSPiM and PD showed the best performance to correctly classify the morphological RES eyes. In the treatment-naïve eyes, VMIAs were included with a perfect fit for n-RES eyes. CONCLUSION The presence of DME mixed pattern, a high number of parafoveal HRF, hyper-reflective MAs, SSPiM in the outer nuclear layers, and high PD represent baseline predictive biomarkers for DEXi treatment responsiveness. The application of these models to treatment-naïve patients allowed a good identification of n-RES eyes.
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Affiliation(s)
| | | | | | - Serena Fragiotta
- Ophthalmology Unit, Department NESMOS, Sant’ Andrea Hospital, University of Rome “La Sapienza”, Rome, Italy
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Chen X, Jiang Y, Duan Y, Zhang X, Li X. Mesenchymal-Stem-Cell-Based Strategies for Retinal Diseases. Genes (Basel) 2022; 13:genes13101901. [PMID: 36292786 PMCID: PMC9602395 DOI: 10.3390/genes13101901] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 12/04/2022] Open
Abstract
Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies. However, hindered by the retinal barriers, the initial vision for the stem cell replacement strategy fails to achieve the anticipated effect and has now been questioned. Accumulating evidence now suggests that the paracrine effect may play a dominant role in MSC-based treatment, and MSC-derived extracellular vesicles emerge as a novel compelling alternative for cell-free therapy. This review summarizes the therapeutic potential and current strategies of this fascinating class of cells in retinal degeneration and other retinal dysfunctions.
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Horozoglu F, Sener H, Polat OA, Temizyurek O, Evereklioglu C. Predictive impact of optical coherence tomography biomarkers in anti-vascular endothelial growth factor resistant macular edema treated with dexamethasone implant. Photodiagnosis Photodyn Ther 2022; 42:103167. [PMID: 36261095 DOI: 10.1016/j.pdpdt.2022.103167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/16/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022]
Abstract
PURPOSE To perform a longitudinal analysis of the effect of optic coherence tomography (OCT) biomarkers on macular thickness in patients with persistent macular edema secondary to diabetes mellitus and retinal vein occlusion who recieved intravitreal dexamethasone (DEX) implant. METHODS Eighty-nine patients were included in the retrospective study. Patients with anti-VEGF-resistant macular edema were included in the study. The effect of the presence or absence of OCT biomarkers before intravitreal DEX implant therapy on central foveal thickness (CFT) was evaluated. In addition, the change in biomarkers from the baseline visit to the final visit was evaluated. The evaluated OCT biomarkers were as follows: ellipsoid zone and external limiting membrane (ELM) integrity, hyperreflective foci (HRF), disorganization of inner retinal layers (DRIL), hard exudates, serous macular detachment (SMD), pearl necklace, posterior vitreous detachment and the epiretinal membrane (ERM). RESULTS The mean age of the overall sample in the study was 64.4 ± 9.6. CFT decreased significantly from 625.3 ± 22.3 μm at baseline to 365.0 ± 21.7 μm in the 1st month but increased significantly to 430.2 ± 22.6 μm in the 3rd month. In the presence of HRF and SMD, recurrence of macular edema was significant in the 3rd month. The percentage of ELM disruption, DRIL, and ERM deteriorated significantly and the percentage of SMD improved significantly at the final visit. CONCLUSIONS DEX implant therapy resulted in a satisfactory reduction in CFT in patients with DME and RVO. The presence of HRF and SMD is a negative predictor of recurrence in CFT in short term. DEX implant therapy resulted in satisfactory improvement in SMD.
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Affiliation(s)
- Fatih Horozoglu
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey
| | - Hidayet Sener
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey.
| | - Osman Ahmet Polat
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey
| | - Ozge Temizyurek
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey
| | - Cem Evereklioglu
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey
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Huang H, Jansonius NM, Chen H, Los LI. Hyperreflective Dots on OCT as a Predictor of Treatment Outcome in Diabetic Macular Edema: A Systematic Review. Ophthalmol Retina 2022; 6:814-827. [PMID: 35367382 DOI: 10.1016/j.oret.2022.03.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/24/2022] [Accepted: 03/24/2022] [Indexed: 06/14/2023]
Abstract
TOPIC This review aims to evaluate the role of hyperreflective dots (HRDs), detected using OCT, as a predictor of the treatment outcome in patients with diabetic macular edema (DME). CLINICAL RELEVANCE The treatment of DME is possible, but its results are often unsatisfactory. Thus, it is important to develop biomarkers that can help to predict the treatment response to optimize the treatment's effect for individual patients. METHODS PubMed, Embase, Web of science, and Cochrane library were searched (final search date on May 5, 2021). Participants were patients diagnosed with DME and provided with treatment. The predictor was HRDs, detected using OCT, before treatment. The outcomes were best-corrected visual acuity (BCVA) and central macular thickness (CMT), detected using OCT, after treatment. Two reviewers independently screened the titles and abstracts as well as full text. The refined Quality in Prognosis Studies tool was used to assess the risk of bias for each included study. Because of the clinical heterogeneity of the studies, a meta-analysis was not performed. RESULTS Thirty-six studies were included. The Quality in Prognosis Studies assessment showed that most studies had a low or moderate risk of bias in 6 domains. Six studies could not find any correlation between baseline HRDs (either the presence or absence of HRDs [n = 1] or baseline HRD number [n = 5]) and outcome (BCVA or CMT), whereas 12 studies found a significant correlation between these variables. Eight studies reported that baseline HRDs could predict a poor visual outcome (n = 4 on prescence or abscence of HRD and n = 4 on HRD number), and 4 studies (n = 1 on prescence or abscence of HRD and n = 3 on HRD number) found that HRDs were predictive of visual improvement. Fifteen out of 17 studies found that the HRD number decreased after treatment. CONCLUSION Based on the current literature, the HRD numbers decrease with treatment, but it is not clear whether HRDs predict the treatment outcome in patients with DME. Future investigations with more uniform approaches are needed to confirm the nature of this biomarker and its effect on DME treatment outcome.
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Affiliation(s)
- Haifan Huang
- Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Joint Shantou International Eye Center, Shantou University & The Chinese University of Hong Kong, Shantou, China
| | - Nomdo M Jansonius
- Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Graduate School of Medical Sciences (Research School of Behavioural and Cognitive Neurosciences), University of Groningen, Groningen, The Netherlands
| | - Haoyu Chen
- Joint Shantou International Eye Center, Shantou University & The Chinese University of Hong Kong, Shantou, China
| | - Leonoor I Los
- Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Graduate School of Medical Sciences (W.J. Kolff Institute), University of Groningen, Groningen, The Netherlands.
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Hui VWK, Szeto SKH, Tang F, Yang D, Chen H, Lai TYY, Rong A, Zhang S, Zhao P, Ruamviboonsuk P, Lai CC, Chang A, Das T, Ohji M, Huang SS, Sivaprasad S, Wong TY, Lam DSC, Cheung CY. Optical Coherence Tomography Classification Systems for Diabetic Macular Edema and Their Associations With Visual Outcome and Treatment Responses - An Updated Review. Asia Pac J Ophthalmol (Phila) 2022; 11:247-257. [PMID: 34923521 DOI: 10.1097/apo.0000000000000468] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Optical coherence tomography (OCT) is an invaluable imaging tool in detecting and assessing diabetic macular edema (DME). Over the past decade, there have been different proposed OCT-based classification systems for DME. In this review, we present an update of spectral-domain OCT (SDOCT)-based DME classifications over the past 5 years. In addition, we attempt to summarize the proposed OCT qualitative and quantitative parameters from different classification systems in relation to disease severity, risk of progression, and treatment outcome. Although some OCT-based measurements were found to have prognostic value on visual outcome, there has been a lack of consensus or guidelines on which parameters can be reliably used to predict treatment outcomes. We also summarize recent literatures on the prognostic value of these parameters including quantitative measures such as macular thickness or volume, central subfield thickness or foveal thickness, and qualitative features such as the morphology of the vitreoretinal interface, disorganization of retinal inner layers, ellipsoid zone disruption integrity, and hyperreflec-tive foci. In addition, we discuss that a framework to assess the validity of biomarkers for treatment outcome is essentially important in assessing the prognosis before deciding on treatment in DME. Finally, we echo with other experts on the demand for updating the current diabetic retinal disease classification.
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Affiliation(s)
- Vivian W K Hui
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, china
- Hong Kong Eye Hospital, Hong Kong, China
| | - Simon K H Szeto
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, china
- Hong Kong Eye Hospital, Hong Kong, China
| | - Fangyao Tang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, china
| | - Dawei Yang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, china
| | - Haoyu Chen
- Joint Shantou International Eye Centre of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Timothy Y Y Lai
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, china
- 2010 Retina & Macula Center, Kowloon, Hong Kong
| | - Ao Rong
- Department of Ophthalmology, Tongji Hospital Affiliated to Tongji University, Shanghai, China
- Shanghai Xin Shi Jie Eye Hospital, Shanghai, China
| | | | - Peiquan Zhao
- Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Paisan Ruamviboonsuk
- Department of Ophthalmology, College of Medicine, Rangsit University, Rajavithi Hospital, Bangkok, Thailand
| | - Chi-Chun Lai
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Andrew Chang
- Sydney Retina Clinic, Sydney Eye Hospital, University of Sydney, Sydney, NSw, Australia
| | - Taraprasad Das
- Smt. Kanuri Santhamma Center for Vitreoretinal Diseases, Kallam Anji Reddy Campus, LV Prasad Eye Institute, Hyderabad, India
| | - Masahito Ohji
- Department of Ophthalmology, Shiga University of Medical Science, Otsu, Japan
| | - Suber S Huang
- Retina Center of Ohio, Cleveland, OH, US
- Bascom Palmer Eye Institute, University of Miami, Miami, FL, US
| | - Sobha Sivaprasad
- NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital, London, UK
| | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Duke-NUS Medical School, Singapore
| | - Dennis S C Lam
- C-MER International Eye Research Center of The Chinese University of Hong Kong (Shenzhen), Shenzhen, China
- C-MER Dennis Lam & Partners Eye Center, C-MER International Eye Care Group, Hong Kong, China
| | - Carol Y Cheung
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, china
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20
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Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema. Int J Mol Sci 2022; 23:ijms23074042. [PMID: 35409401 PMCID: PMC8999697 DOI: 10.3390/ijms23074042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/30/2022] [Accepted: 04/03/2022] [Indexed: 02/06/2023] Open
Abstract
Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.
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SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS OF RETINAL HYPERPERMEABILITY AND CHOROIDAL INFLAMMATION AS PREDICTORS OF SHORT-TERM FUNCTIONAL AND ANATOMICAL OUTCOMES IN EYES WITH DIABETIC MACULAR EDEMA TREATED WITH INTRAVITREAL BEVACIZUMAB. Retina 2022; 42:760-766. [PMID: 35350050 DOI: 10.1097/iae.0000000000003361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE To assess spectral domain optical coherence tomography biomarkers of short-term outcomes in eyes with diabetic macular edema treated with intravitreal bevacizumab. METHODS In a prospective interventional case series, 66 eyes with diabetic macular edema underwent 3 monthly intravitreal bevacizumab injections. Best-corrected visual acuity measurement and spectral domain optical coherence tomography were performed at baseline and at 3 months. Multivariate regression analysis was performed to investigate the baseline spectral domain optical coherence tomography parameters as predictors of functional and anatomical outcomes. RESULTS Patients with diabetic nephropathy had greater subfoveal choroidal thickness (300.8 ± 35.54 vs. 253.0 ± 50.07 µm, P < 0.01) and were more likely to have subretinal fluid (r = 0.26, P = 0.03) at baseline. Multivariate analysis showed that the extent of external limiting membrane disruption (P = 0.03) and the extent of disorganization of retinal inner layers (P = 0.03) at baseline were predictors of best-corrected visual acuity at 3 months, whereas the extent of disorganization of retinal inner layers (P = 0.04) and duration of diabetes mellitus (P = 0.03) were predictors of central subfield thickness at 3 months. CONCLUSION External limiting membrane disruption and disorganization of retinal inner layers, as the spectral domain optical coherence tomography biomarkers of retinal hyperpermeability, can predict short-term outcomes in diabetic macular edema eyes treated with intravitreal bevacizumab.
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22
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Sharma S, Karki P, Joshi SN, Parajuli S. Optical coherence tomography patterns of diabetic macular edema and treatment response to bevacizumab: a short-term study. Ther Adv Ophthalmol 2022; 14:25158414221074519. [PMID: 35387237 PMCID: PMC8977703 DOI: 10.1177/25158414221074519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/03/2022] [Indexed: 11/29/2022] Open
Abstract
Background: The purpose of this study was to evaluate the short-term response of
intravitreal bevacizumab in diabetic macular edema (DME) and assess the
variation in treatment outcomes in different morphology patterns using
spectral domain–optical coherence tomography (SD-OCT). Objective: To study different morphological patterns of DME based on OCT and compare
their treatment response to bevacizumab. Methods: Hundred and twelve eyes of 112 patients with DME were included and treated
with intravitreal bevacizumab (1.25 mg/0.05 ml monthly for 3 months). The
morphological patterns of DME were classified on the basis of OCT into three
groups – diffuse retinal thickening (DRT), cystoid macular edema (CME), and
serous retinal detachment (SRD) – and changes in central macular thickness
(CMT) and best corrected visual acuity (BCVA) after treatment were
compared. Results: A total of 112 eyes with DME were included and consisted of 40 DRT, 37 CME,
and 35 SRD. Treatment with bevacizumab resulted in decrease in central
macular thickness and improvement in BCVA in all three groups. The baseline
visual acuity and CMT of DRT group was better than that of the other two
groups. The treatment outcome was measured in terms of CMT and BCVA. Change
in CMT was statistically significant among three groups and was found to be
better in DRT group (p < 0.05, 95% confidence interval).
However, there was statistically no significant variation between the three
groups regarding the change in BCVA (p = 0.169, 95%
confidence interval). Conclusion: Anatomic and visual improvement can be achieved by bevacizumab in all
patterns of DME. However, individual pattern may respond differently. DRT,
which appears to be the earliest form of DME, responds better than other
types. Thus, the pattern of macular edema shown by OCT may provide an
objective guideline in predicting the response of bevacizumab injection in
DME.
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Affiliation(s)
| | - Pratap Karki
- Department of Retina, B.P. Koirala Lions Center for Ophthalmic Studies (BPKLCOS), Institute of Medicine, Kathmandu, Nepal
| | - Sagun Narayan Joshi
- Department of Retina, B.P. Koirala Lions Center for Ophthalmic Studies (BPKLCOS), Institute of Medicine, Kathmandu, Nepal
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Carpi-Santos R, de Melo Reis RA, Gomes FCA, Calaza KC. Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation. Antioxidants (Basel) 2022; 11:617. [PMID: 35453302 PMCID: PMC9027671 DOI: 10.3390/antiox11040617] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood-retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.
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Affiliation(s)
- Raul Carpi-Santos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (R.C.-S.); (F.C.A.G.)
| | - Ricardo A. de Melo Reis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil;
| | - Flávia Carvalho Alcantara Gomes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (R.C.-S.); (F.C.A.G.)
| | - Karin C. Calaza
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niteroi 24210-201, RJ, Brazil
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24
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YOSEMITE and RHINE. OPHTHALMOLOGY SCIENCE 2022; 2:100111. [PMID: 36246184 PMCID: PMC9559760 DOI: 10.1016/j.xops.2021.100111] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 12/22/2021] [Accepted: 12/22/2021] [Indexed: 12/02/2022]
Abstract
Purpose Faricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Design Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Participants Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. Methods These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. Main Outcome Measures We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. Results YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. Conclusions YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.
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25
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Wykoff CC, Abreu F, Adamis AP, Basu K, Eichenbaum DA, Haskova Z, Lin H, Loewenstein A, Mohan S, Pearce IA, Sakamoto T, Schlottmann PG, Silverman D, Sun JK, Wells JA, Willis JR, Tadayoni R. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet 2022; 399:741-755. [PMID: 35085503 DOI: 10.1016/s0140-6736(22)00018-6] [Citation(s) in RCA: 253] [Impact Index Per Article: 84.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/29/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING F Hoffmann-La Roche.
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Affiliation(s)
- Charles C Wykoff
- Retina Consultants of Texas, Retina Consultants of America, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA.
| | | | | | - Karen Basu
- Roche Products (Ireland), Dublin, Ireland
| | - David A Eichenbaum
- Retina Vitreous Associates of Florida, St Petersburg, FL, USA; Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | | | - Hugh Lin
- Genentech, South San Francisco, CA, USA
| | - Anat Loewenstein
- Tel Aviv Medical Center and Tel Aviv University, Tel Aviv, Israel
| | | | - Ian A Pearce
- Royal Liverpool University Hospital, Liverpool, UK
| | - Taiji Sakamoto
- Department of Ophthalmology, Kagoshima University, Kagoshima, Japan
| | | | | | - Jennifer K Sun
- Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology, Boston, MA, USA
| | - John A Wells
- Palmetto Retina Center, Retina Consultants of America, Columbia, SC, USA
| | | | - Ramin Tadayoni
- Université de Paris, AP-HP, Lariboisière, Saint Louis, Paris, France; Fondation Adolphe de Rothschild Hospitals, Paris, France
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Alryalat SA, Al-Antary M, Arafa Y, Azad B, Boldyreff C, Ghnaimat T, Al-Antary N, Alfegi S, Elfalah M, Abu-Ameerh M. Deep Learning Prediction of Response to Anti-VEGF among Diabetic Macular Edema Patients: Treatment Response Analyzer System (TRAS). Diagnostics (Basel) 2022; 12:diagnostics12020312. [PMID: 35204404 PMCID: PMC8870773 DOI: 10.3390/diagnostics12020312] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/16/2022] [Accepted: 01/24/2022] [Indexed: 02/01/2023] Open
Abstract
Diabetic macular edema (DME) is the most common cause of visual impairment among patients with diabetes mellitus. Anti-vascular endothelial growth factors (Anti-VEGFs) are considered the first line in its management. The aim of this research has been to develop a deep learning (DL) model for predicting response to intravitreal anti-VEGF injections among DME patients. The research included treatment naive DME patients who were treated with anti-VEGF. Patient’s pre-treatment and post-treatment clinical and macular optical coherence tomography (OCT) were assessed by retina specialists, who annotated pre-treatment images for five prognostic features. Patients were also classified based on their response to treatment in their post-treatment OCT into either good responder, defined as a reduction of thickness by >25% or 50 µm by 3 months, or poor responder. A novel modified U-net DL model for image segmentation, and another DL EfficientNet-B3 model for response classification were developed and implemented for predicting response to anti-VEGF injections among patients with DME. Finally, the classification DL model was compared with different levels of ophthalmology residents and specialists regarding response classification accuracy. The segmentation deep learning model resulted in segmentation accuracy of 95.9%, with a specificity of 98.9%, and a sensitivity of 87.9%. The classification accuracy of classifying patients’ images into good and poor responders reached 75%. Upon comparing the model’s performance with practicing ophthalmology residents, ophthalmologists and retina specialists, the model’s accuracy is comparable to ophthalmologist’s accuracy. The developed DL models can segment and predict response to anti-VEGF treatment among DME patients with comparable accuracy to general ophthalmologists. Further training on a larger dataset is nonetheless needed to yield more accurate response predictions.
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Affiliation(s)
- Saif Aldeen Alryalat
- Department of Ophthalmology, The University of Jordan Hospital, The University of Jordan, Amman 11942, Jordan; (M.E.); (M.A.-A.)
- Correspondence: or ; Tel.: +962-798914594
| | - Mohammad Al-Antary
- School of Computing and Mathematical Sciences, University of Greenwich, London SE10 9LS, UK; (M.A.-A.); (Y.A.); (C.B.)
| | - Yasmine Arafa
- School of Computing and Mathematical Sciences, University of Greenwich, London SE10 9LS, UK; (M.A.-A.); (Y.A.); (C.B.)
| | - Babak Azad
- School of Computer Engineering, Iran University of Science and Technology, Tehran 13114-16846, Iran;
| | - Cornelia Boldyreff
- School of Computing and Mathematical Sciences, University of Greenwich, London SE10 9LS, UK; (M.A.-A.); (Y.A.); (C.B.)
| | - Tasneem Ghnaimat
- Department of Computer Science, Princess Sumaya University for Technology, Amman 11941, Jordan;
| | | | - Safa Alfegi
- Tripoli Central Hospital, Tripoli 22131, Libya;
| | - Mutasem Elfalah
- Department of Ophthalmology, The University of Jordan Hospital, The University of Jordan, Amman 11942, Jordan; (M.E.); (M.A.-A.)
| | - Mohammed Abu-Ameerh
- Department of Ophthalmology, The University of Jordan Hospital, The University of Jordan, Amman 11942, Jordan; (M.E.); (M.A.-A.)
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Zhang Y, Xu F, Lin Z, Wang J, Huang C, Wei M, Zhai W, Li J. Prediction of Visual Acuity after anti-VEGF Therapy in Diabetic Macular Edema by Machine Learning. J Diabetes Res 2022; 2022:5779210. [PMID: 35493607 PMCID: PMC9042629 DOI: 10.1155/2022/5779210] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 12/05/2022] Open
Abstract
PURPOSE To predict visual acuity (VA) 1 month after anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema (DME) by using machine learning. METHODS This retrospective study included 281 eyes with DME receiving intravitreal anti-VEGF treatment from January 1, 2019, to April 1, 2021. Eighteen features from electronic medical records and measurements data from OCT images were extracted. The data obtained from January 1, 2019, to November 1, 2020, were used as the training set; the data obtained from November 1, 2020, to April 1, 2021, were used as the validation set. Six different machine learning algorithms were used to predict VA in patients after anti-VEGF therapy. After the initial detailed investigation, we designed an optimization model for convenient application. The VA predicted by machine learning was compared with the ground truth. RESULTS The ensemble algorithm (linear regression + random forest regressor) performed best in VA and VA variance predictions. In the validation set, the mean absolute errors (MAEs) of VA predictions were 0.137-0.153 logMAR (within 7-8 letters), and the mean square errors (MSEs) were 0.033-0.045 logMAR (within 2-3 letters) for the 1-month VA predictions, respectively. For the prediction of VA variance at 1 month, the MAEs were 0.164-0.169 logMAR (within 9 letters), and the MSEs were 0.056-0.059 logMAR (within 3 letters), respectively. CONCLUSIONS Our machine learning models could accurately predict VA and VA variance in DME patients receiving anti-VEGF therapy 1 month after, which would be much valuable to guide precise individualized interventions and manage expectations in clinical practice.
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Affiliation(s)
- Ying Zhang
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Qidu Pharmaceutical Co. Ltd., Shandong Provincial Key Laboratory of Neuroprotective Drugs, Zibo, China
| | - Fabao Xu
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhenzhe Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
| | - Jiawei Wang
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chao Huang
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Min Wei
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weibin Zhai
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianqiao Li
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Luengas-Martinez A, Paus R, Young HS. A novel personalised treatment approach for psoriasis: anti-VEGF-A therapy. Br J Dermatol 2021; 186:782-791. [PMID: 34878645 PMCID: PMC9313866 DOI: 10.1111/bjd.20940] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/01/2021] [Accepted: 12/04/2021] [Indexed: 12/25/2022]
Abstract
Chronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK’s population and is associated with extracutaneous morbidities and a reduced quality of life. A complex crosstalk between innate and adaptive immunity, the epithelia and the vasculature maintain the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient’s goals. Vascular endothelial growth factor‐A (VEGF‐A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF‐A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF‐A in in vivo models of psoriasis‐like inflammation resulted in disease clearance. Anti‐angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF‐A inhibitors who have experienced Psoriasis Area and Severity Index improvement. Existing psoriasis treatments downregulate VEGF‐A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF‐A, who may be most likely to benefit from anti‐VEGF‐A therapy, offering an opportunity to personalize treatment in psoriasis. Anti‐VEGF‐A therapies may offer an alternative to existing anticytokine strategies or be complementary to standard treatments for the management of psoriasis.
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Affiliation(s)
- A Luengas-Martinez
- Centre for Dermatology Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - R Paus
- Centre for Dermatology Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.,Dr. Philip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - H S Young
- Centre for Dermatology Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
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29
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Zhang CL, Wang HL, Li PC, Hong CD, Chen AQ, Qiu YM, Zeng AP, Zhou YF, Hu B, Li YN. Mfsd2a overexpression alleviates vascular dysfunction in diabetic retinopathy. Pharmacol Res 2021; 171:105755. [PMID: 34229049 DOI: 10.1016/j.phrs.2021.105755] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 11/30/2022]
Abstract
Diabetic retinopathy (DR) is one of the common complications in diabetic patients. Nowadays, VEGF pathway is subject to extensive research. However, about 27% of the patients have a poor visual outcome, with 50% still having edema after two years' treatment of diabetic macular edema (DME) with ranibizumab. Docosahexaenoic acid (DHA), the primary ω-3 long-chain polyunsaturated fatty acid (LC-PUFA), reduces abnormal neovascularization and alleviates neovascular eye diseases. A study reported that fish oil reduced the incidence of retinopathy of prematurity (ROP) by about 27.5% in preterm infants. Although ω-3 LC-PUFAs protects against pathological retinal neovascularization, the treatment effectiveness is low. It is interesting to investigate why DHA therapy fails in some patients. In human vitreous humor samples, we found that the ratio of DHA and DHA-derived metabolites to total fatty acids was higher in vitreous humor from DR patients than that from macular hole patients; however, the ratio of DHA metabolites to DHA and DHA-derived metabolites was lower in the diabetic vitreous humor. The expression of Mfsd2a, the LPC-DHA transporter, was reduced in the oxygen-induced retinopathy (OIR) model and streptozotocin (STZ) model. In vitro, Mfsd2a overexpression inhibited endothelial cell proliferation, migration and vesicular transcytosis. Moreover, Mfsd2a overexpression in combination with the DHA diet obviously reduced abnormal retinal neovascularization and vascular leakage, which is more effective than Mfsd2a overexpression alone. These results suggest that DHA therapy failure in some DR patients is linked to low expression of Mfsd2a, and the combination of Mfsd2a overexpression and DHA therapy may be an effective treatment.
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Affiliation(s)
- Chun-Lin Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hai-Ling Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Peng-Cheng Li
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Can-Dong Hong
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - An-Qi Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan-Mei Qiu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ai-Ping Zeng
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yi-Fan Zhou
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Ya-Nan Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Ţălu Ş, Nicoara SD. Malfunction of outer retinal barrier and choroid in the occurrence and progression of diabetic macular edema. World J Diabetes 2021; 12:437-452. [PMID: 33889289 PMCID: PMC8040083 DOI: 10.4239/wjd.v12.i4.437] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/23/2021] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic macular edema (DME) is the most common cause of vision loss in diabetic retinopathy, affecting 1 in 15 patients with diabetes mellitus (DM). The disruption of the inner blood-retina barrier (BRB) has been largely investigated and attributed the primary role in the pathogenesis and progression in DME, but there is increasing evidence regarding the role of outer BRB, separating the RPE from the underlying choriocapillaris, in the occurrence and evolution of DME. The development of novel imaging technologies has led to major improvement in the field of in vivo structural analysis of the macula allowing us to delve deeper into the pathogenesis of DME and expanding our vision regarding this condition. In this review we gathered the results of studies that investigated specific outer BRB optical coherence tomography parameters in patients with DM with the aim to outline the current status of its role in the pathogenesis and progression of DME and identify new research pathways contributing to the advancement of knowledge in the understanding of this condition.
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Affiliation(s)
- Ştefan Ţălu
- Directorate of Research, Development and Innovation Management (DMCDI), Technical University of Cluj-Napoca, Cluj-Napoca 400020, Romania
| | - Simona Delia Nicoara
- Department of Ophthalmology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
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Koc F, Güven YZ, Egrilmez D, Aydın E. Optical Coherence Tomography Biomarkers in Bilateral Diabetic Macular Edema Patients with Asymmetric anti-VEGF Response. Semin Ophthalmol 2021; 36:444-451. [PMID: 33780313 DOI: 10.1080/08820538.2021.1907423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: This study aimed to identify optical coherence tomography (OCT) biomarkers for predicting response to anti-VEGF treatment in diabetic macular edema (DME)Methods: Bilateral DME patients with asymmetric response to a loading dose of anti-VEGF (ranibizumab/aflibercept) treatment were retrospectively studied. The morphologic response criterion was central subfield thickness (CST) ≤300 µm; asymmetric response was defined as ≥10% difference in CST reduction between the eyes. The functional response criterion was an increase in logMAR acuity of ≥3 lines, with an increase below this threshold in the fellow eye considered asymmetric response. Relationships between final morphologic and functional responses to anti-VEGF therapy and baseline values of the following OCT-derived biomarkers were evaluated: DME subtype, CST, vitreoretinal interface anomalies, disorganization of the inner retinal layers (DRIL), external limiting membrane (ELM) disruption, ellipsoid zone (EZ) disruption, and subretinal fluid (SRF).Results: After a loading dose of anti-VEGF, 31 eyes that met both morphologic and functional response criteria were classified as responders (RR) and 27 eyes that did not respond morphologically or functionally based on the defined criteria were classified as resistant (RT). Eyes that showed only functional (n = 5) or morphological response (n = 1) were excluded due to their small number. The presence of SRF or simple epiretinal membrane (ERM) was not associated with any difference in treatment responses (p > .05), while tractional ERM, extensive DRIL (≥500 µm), and ELM and EZ disruptions in the fovea-centered 1000-µm zone were important OCT biomarkers in predicting resistance (p < .001). A multilayer perceptron model ranked predictive power as 100% for ELM disruption, 51.7% for tractional ERM, 25.4% for DRIL, and 24.5% for EZ disruption.Conclusion: Extensive ELM disruption was the strongest OCT biomarker to predict anti-VEGF resistance, followed by tractional ERM. EZ disruption and DRIL had relatively lower predictive value.
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Affiliation(s)
- Feray Koc
- Medicine, Department of Ophthalmology, Izmir Katip Celebi University, Izmir, Turkey
| | - Yusuf Ziya Güven
- Medicine, Department of Ophthalmology, Izmir Katip Celebi University, Izmir, Turkey
| | - Deniz Egrilmez
- Department of Ophthalmology, Ataturk Education and Research HospitalEye Clinic, Izmir, Turkey
| | - Erdinç Aydın
- Medicine, Department of Ophthalmology, Izmir Katip Celebi University, Izmir, Turkey
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Pessoa B, Ferreira A, Leite J, Figueira J, Meireles A, Beirão JM. Optical Coherence Tomography Biomarkers: Vitreous Status Influence in Outcomes for Diabetic Macular Edema Therapy with 0.19-mg Fluocinolone Acetonide Implant. Ophthalmic Res 2021; 64:639-647. [PMID: 33601389 DOI: 10.1159/000515306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/14/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND The 0.19-mg fluocinolone acetonide (FAc) implant (ILUVIEN®; Alimera Sciences Ltd., Hampshire, UK) was approved for the treatment of vision impairment associated with chronic and refractory diabetic macular edema (DME). OBJECTIVES To quantitatively assess functional and structural features in nonvitrectomized and vitrectomized DME patients after being treated with an FAc implant. METHODS Retrospective review of patients with DME receiving a single intravitreal injection of the FAc implant. The study was designed to analyze the presence of quantitative structural OCT biomarkers at baseline and 12 months after FAc therapy according to vitreous status. RESULTS A total of 41 eyes from 30 patients were included in this study. At 12 months after injection, vitrectomized patients had a lower central foveal thickness (p = 0.017) and fewer hyperreflective dots (p = 0.028) compared with nonvitrectomized. Thirty (73%) patients presented a significant functional improvement with 17 (42%) increasing at least 15 ETDRS letters. Overall, 22 (54%) eyes had a complete resolution of DME at the 12-month visit. Patients who needed additional therapy had a higher prevalence of subretinal fluid (42 vs. 3%, p = 0.005) at baseline. CONCLUSIONS This study supports the effectiveness of the FAc implant and reports significant changes at 12 months after FAc injection.
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Affiliation(s)
- Bernardete Pessoa
- Department of Ophthalmology, Centro Hospitalar Universitário do Porto, Porto, Portugal.,Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - André Ferreira
- Department of Ophthalmology, Centro Hospitalar Universitário do Porto, Porto, Portugal.,Unit of Anatomy, Department of Biomedicine, Faculty of Medicine of University of Porto, Porto, Portugal
| | - João Leite
- Department of Ophthalmology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - João Figueira
- Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.,Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal
| | - Angelina Meireles
- Department of Ophthalmology, Centro Hospitalar Universitário do Porto, Porto, Portugal.,Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - João Melo Beirão
- Department of Ophthalmology, Centro Hospitalar Universitário do Porto, Porto, Portugal.,Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
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Pessoa B, Malheiro L, Carneiro I, Monteiro S, Coelho J, Coelho C, Figueira J, Meireles A, Melo Beirão JN. Intravitreal Ranibizumab or Aflibercept After Bevacizumab in Diabetic Macular Edema: Exploratory Retrospective Analysis. Clin Ophthalmol 2021; 15:253-260. [PMID: 33519187 PMCID: PMC7837538 DOI: 10.2147/opth.s280644] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/05/2020] [Indexed: 11/23/2022] Open
Abstract
Aim To evaluate the efficacy of switching from bevacizumab to ranibizumab or aflibercept in eyes with diabetic macular edema (DME) unresponsive to bevacizumab. Methods Single-center retrospective comparative study of patients with DME unresponsive to intravitreal bevacizumab that was switched to ranibizumab or aflibercept. Best-corrected visual acuity (BCVA) and central foveal thickness (CFT) were analysed prior to and 4 months after the switch. Ocular coherence tomography (OCT) biomarkers were also analysed. Results Fifty-six eyes from 40 patients were included in the study, 33 eyes switched to ranibizumab and 23 to aflibercept. A significant median CFT decrease was observed in both groups (p<0.001), with no between-group differences. BCVA gain was only significant in the ranibizumab group (p<0.001). None of the pre-baseline or baseline parameters were associated with the response to ranibizumab or aflibercept. Conclusion In persistent DME unresponsive to bevacizumab, both anatomical and functional improvements were observed with ranibizumab whereas aflibercept only showed an anatomical improvement. Clinicaltrials.gov NCT04018833.
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Affiliation(s)
- Bernardete Pessoa
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Luísa Malheiro
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Inês Carneiro
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Sílvia Monteiro
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - João Coelho
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Constança Coelho
- Genetics Laboratory, Institute of Environmental Health, Lisbon Medical School, University of Lisbon, Porto, Portugal
| | - João Figueira
- Centro Hospitalar e Universitário de Coimbra, Porto, Portugal.,Faculty of Medicine of the University of Coimbra, Porto Portugal.,Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal
| | - Angelina Meireles
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - João Nuno Melo Beirão
- Ophthalmology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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Giannakaki-Zimmermann H, Behrndt A, Hoffmann L, Guichard MM, Türksever C, Prünte C, Hatz K. Predictors for 2-Year Functional and Morphological Outcomes of a Treat-and-Extend Regimen with Ranibizumab in Patients with Diabetic Macular Edema. Ophthalmic Res 2021; 64:465-475. [PMID: 33498045 DOI: 10.1159/000514721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 01/14/2021] [Indexed: 01/12/2023]
Abstract
PURPOSE The purpose of the study was to investigate longer term functional and morphological outcomes and their predictors in diabetic macular edema (DME) following a treat-and-extend regimen (TER) without loading dose under ranibizumab. METHODS Patient data were reviewed and analyzed retrospectively over a period of 24 months after initiation of TER. Best-corrected visual acuity (BCVA), treatment frequency, and quantitative and qualitative spectral-domain optical coherence tomography parameters were assessed. RESULTS 118 eyes of 87 patients were included. A mean of 9.74 ± 2.13 injections in the first and 7.63 ± 2.29 in the second year were applied. There were significant gains of BCVA and reductions in central retinal thickness from baseline to 12 and 24 months (all p < 0.001). Percentage of eyes with an intact inner segment/outer segment (IS/OS) junction increased from 15.3% at baseline to 42.1% at 24 months (p < 0.001). An intact IS/OS junction at baseline increased the probability of having a dry retina after 12 months by 79.3% (p = 0.017) and after 24 months by 88.1% (p = 0.040). Less IS/OS disruption at baseline predicted longer maximum recurrence-free treatment intervals at 2 years (r = -0.345, p < 0.001) and better BCVA at 1 year (r = -0.347, p < 0.001). Baseline bigger intraretinal cysts were associated with more IS/OS disruption at 24 months (r = 0.305, p = 0.007). Younger age and lower BCVA at baseline were predictive for a higher BCVA gain at 24 months (p = 0.046, p < 0.001). CONCLUSION Ranibizumab applied in a TER without loading dose in DME significantly improves visual acuity and retinal anatomical structure throughout 2 years. The evaluated predictors might help guide routine clinical treatment in DME.
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Affiliation(s)
| | - Alexandra Behrndt
- Vista Klinik, Binningen, Switzerland.,Faculty of Medicine, University of Basel, Basel, Switzerland
| | | | | | | | - Christian Prünte
- Faculty of Medicine, University of Basel, Basel, Switzerland.,Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.,Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
| | - Katja Hatz
- Vista Klinik, Binningen, Switzerland, .,Faculty of Medicine, University of Basel, Basel, Switzerland,
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Liu B, Zhang B, Hu Y, Cao D, Yang D, Wu Q, Hu Y, Yang J, Peng Q, Huang M, Zhong P, Dong X, Feng S, Li T, Lin H, Cai H, Yang X, Yu H. Automatic prediction of treatment outcomes in patients with diabetic macular edema using ensemble machine learning. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:43. [PMID: 33553336 PMCID: PMC7859823 DOI: 10.21037/atm-20-1431] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background This study aimed to predict the treatment outcomes in patients with diabetic macular edema (DME) after 3 monthly anti-vascular endothelial growth factor (VEGF) injections using machine learning (ML) based on pretreatment optical coherence tomography (OCT) images and clinical variables. Methods An ensemble ML system consisting of four deep learning (DL) models and five classical machine learning (CML) models was developed to predict the posttreatment central foveal thickness (CFT) and the best-corrected visual acuity (BCVA). A total of 363 OCT images and 7,587 clinical data records from 363 eyes were included in the training set (304 eyes) and external validation set (59 eyes). The DL models were trained using the OCT images, and the CML models were trained using the OCT images features and clinical variables. The predictive posttreatment CFT and BCVA values were compared with true outcomes obtained from the medical records. Results For CFT prediction, the mean absolute error (MAE), root mean square error (RMSE), and R2 of the best-performing model in the training set was 66.59, 93.73, and 0.71, respectively, with an area under receiver operating characteristic curve (AUC) of 0.90 for distinguishing the eyes with good anatomical response. The MAE, RMSE, and R2 was 68.08, 97.63, and 0.74, respectively, with an AUC of 0.94 in the external validation set. For BCVA prediction, the MAE, RMSE, and R2 of the best-performing model in the training set was 0.19, 0.29, and 0.60, respectively, with an AUC of 0.80 for distinguishing eyes with a good functional response. The external validation achieved a MAE, RMSE, and R2 of 0.13, 0.20, and 0.68, respectively, with an AUC of 0.81. Conclusions Our ensemble ML system accurately predicted posttreatment CFT and BCVA after anti-VEGF injections in DME patients, and can be used to prospectively assess the efficacy of anti-VEGF therapy in DME patients.
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Affiliation(s)
- Baoyi Liu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Bin Zhang
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Yijun Hu
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Dan Cao
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Dawei Yang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Qiaowei Wu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yu Hu
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Jingwen Yang
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Qingsheng Peng
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Manqing Huang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Pingting Zhong
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xinran Dong
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Songfu Feng
- Department of Ophthalmology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Tao Li
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Haotian Lin
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Hongmin Cai
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Xiaohong Yang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Honghua Yu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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Campos A, Oliveira N, Martins J, Arruda H, Sousa J. The Paradigm Shift of Ophthalmology in the COVID-19 Era. Clin Ophthalmol 2020; 14:2625-2630. [PMID: 32982155 PMCID: PMC7500830 DOI: 10.2147/opth.s267427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/06/2020] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE To describe how a fixed regimen of intravitreal injections (IVI) was helpful to continue activity during the COVID-19 outbreak and lockdown and to address basic conditions to resume activity. METHODS A fixed regimen of IVI was conceived to significantly reduce the number of visits while keeping a number of injections related to the best outcomes. We retrospectively collected data of surgeries performed in 2019 and in the first seven months of 2020 and from OCTs in the first semester of 2020. RESULTS IVI per month, from January to July 2020, were 304, 291, 256, 204, 276, 297 and 322, respectively. Phacoemulsification surgeries in the same period were 397, 408, 171, 0, 304, 391 and 389. Posterior vitrectomies were 23, 21, 17, 10, 21, 28 and 25. Laser sessions were 44, 26, 33, 17, 23 and 33, respectively. OCTs dropped from a mean of 25.7 per day in the first half of March 2020 to 5.8 per day in the second half of March. A mean of 6.5 OCTs per day was made in April, rising to 19.1 in May and 39.5 in June. CONCLUSION It was possible to keep the ophthalmological activity during the pandemic outbreak due to the existence of a pre-scheduled fixed regimen for IVI and to the availability of personal protective equipment. The air-borne nature of the peril we are facing addresses the need to evaluate the physical conditions of health facilities, including ventilation, size of waiting and consult rooms and the need to avoid elevators.
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Affiliation(s)
- António Campos
- Department of Ophthalmology, Centro Hospitalar de Leiria EPE, Leiria2410-197, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra3000-548, Portugal
- ciTechCare, Center for Innovative Care and Health Technology, Polytechnic Institute of Leiria, Leiria2411-901, Portugal
| | - Nuno Oliveira
- Department of Ophthalmology, Centro Hospitalar de Leiria EPE, Leiria2410-197, Portugal
| | - Joana Martins
- Department of Ophthalmology, Centro Hospitalar de Leiria EPE, Leiria2410-197, Portugal
| | - Henrique Arruda
- Department of Ophthalmology, Centro Hospitalar de Leiria EPE, Leiria2410-197, Portugal
| | - João Sousa
- Department of Ophthalmology, Centro Hospitalar de Leiria EPE, Leiria2410-197, Portugal
- ciTechCare, Center for Innovative Care and Health Technology, Polytechnic Institute of Leiria, Leiria2411-901, Portugal
- Medical Sciences Department, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
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Chan HW, Yang B, Wong W, Blakeley P, Seah I, Tan QSW, Wang H, Bhargava M, Lin HA, Chai CHC, Mangunkusumo EA, Thet N, Yuen YS, Sethi R, Wang S, Hunziker W, Lingam G, Su X. A Pilot Study on MicroRNA Profile in Tear Fluid to Predict Response to Anti-VEGF Treatments for Diabetic Macular Edema. J Clin Med 2020; 9:E2920. [PMID: 32927780 PMCID: PMC7564365 DOI: 10.3390/jcm9092920] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
(1) Background: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) is an established treatment for center-involving diabetic macular edema (ci-DME). However, the clinical response is heterogeneous. This study investigated miRNAs as a biomarker to predict treatment response to anti-VEGF in DME. (2) Methods: Tear fluid, aqueous, and blood were collected from patients with treatment-naïve DME for miRNA expression profiling with quantitative polymerase chain reaction. Differentially expressed miRNAs between good and poor responders were identified from tear fluid. Bioinformatics analysis with the miEAA tool, miRTarBase Annotations, Gene Ontology categories, KEGG, and miRWalk pathways identified interactions between enriched miRNAs and biological pathways. (3) Results: Of 24 participants, 28 eyes received bevacizumab (15 eyes) or aflibercept (13 eyes). Tear fluid had the most detectable miRNA species (N = 315), followed by serum (N = 309), then aqueous humor (N = 134). MiRNAs that correlated with change in macular thickness were miR-214-3p, miR-320d, and hsa-miR-874-3p in good responders; and miR-98-5p, miR-196b-5p, and miR-454-3p in poor responders. VEGF-related pathways and the angiogenin-PRI complex were enriched in good responders, while transforming growth factor-β and insulin-like growth factor pathways were enriched in poor responders. (4) Conclusions: We reported a panel of novel miRNAs that provide insight into biological pathways in DME. Validation in larger independent cohorts is needed to determine the predictive performance of these miRNA candidate biomarkers.
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Affiliation(s)
- Hwei Wuen Chan
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Binxia Yang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; (B.Y.); (Q.S.W.T.); (H.W.); (R.S.); (W.H.)
| | - Wendy Wong
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
| | - Paul Blakeley
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Ivan Seah
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
| | - Queenie Shu Woon Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; (B.Y.); (Q.S.W.T.); (H.W.); (R.S.); (W.H.)
| | - Haofei Wang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; (B.Y.); (Q.S.W.T.); (H.W.); (R.S.); (W.H.)
| | - Mayuri Bhargava
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
| | - Hazel Anne Lin
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Charmaine HC Chai
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Erlangga Ariadarma Mangunkusumo
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
| | - Naing Thet
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
| | - Yew Sen Yuen
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Raman Sethi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; (B.Y.); (Q.S.W.T.); (H.W.); (R.S.); (W.H.)
| | - Si Wang
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Walter Hunziker
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; (B.Y.); (Q.S.W.T.); (H.W.); (R.S.); (W.H.)
| | - Gopal Lingam
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
| | - Xinyi Su
- Department of Ophthalmology, National University Hospital, Singapore S118177, Singapore; (H.W.C.); (W.W.); (I.S.); (M.B.); (H.A.L.); (C.H.C.); (E.A.M.); (N.T.); (Y.S.Y.); (G.L.)
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (P.B.); (S.W.)
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore; (B.Y.); (Q.S.W.T.); (H.W.); (R.S.); (W.H.)
- Singapore Eye Research Institute (SERI), Singapore National Eye Centre, Singapore 169856, Singapore
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Parravano M, Costanzo E, Querques G. Profile of non-responder and late responder patients treated for diabetic macular edema: systemic and ocular factors. Acta Diabetol 2020; 57:911-921. [PMID: 32114642 DOI: 10.1007/s00592-020-01496-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/04/2020] [Indexed: 12/12/2022]
Abstract
Diabetic macular edema (DME) treatment represents a challenge for the ophthalmologists, and several aspects of real treatment expectancy are still being discussed and not yet fully elucidated. A univocal definition of responsiveness to treatment has not been reached. How the clinicians can evaluate the therapeutic success? The evaluation of systemic and ocular factors should help in this complex management. The age influences the long-term outcomes, and the role of glycemic control is confounded by contrasting correlations between hemoglobin glycated A1c and DME. Long-term treatment success is influenced by baseline best-corrected visual acuity (BCVA), central macular thickness (CMT) and early BCVA response. Also baseline diabetic retinopathy severity scale score is useful to evaluate the chances of improvement before and during treatments. The time-switching was influenced by early BCVA response, however considering a delayed response in a percentage of patients. Several structural optical coherence tomography (OCT) findings could predict long-term success, as the presence of serous retinal detachment, hyperreflective retinal spots, the disruption of external limiting membrane and ellipsoid zone, the disorganization of inner retinal layers and continued increase in CMT were considered predictors of poor response to treatment. Foveal avascular zone enlargement, high number of microaneurysms (Mas), lower vessel density (VD) in deep capillary plexus and lower parafoveal VD in superficial capillary plexus were considered as OCT angiography biomarkers of poor responsiveness. The aim of this review is to report the factors that could influence the response to treatment of DME patients.
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Affiliation(s)
| | | | - Giuseppe Querques
- Department of Ophthalmology, IRCCS Ospedale San Raffaele, University Vita-Salute, Milan, Italy
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Vitrectomy with internal limiting membrane peeling versus nonsurgical treatment for diabetic macular edema with massive hard exudates. PLoS One 2020; 15:e0236867. [PMID: 32735583 PMCID: PMC7394381 DOI: 10.1371/journal.pone.0236867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose To compare the anatomical and functional outcomes of severe diabetic macular edema (DME) with massive hard exudates managed by pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling or nonsurgical treatment. Methods We retrospectively reviewed 40 eyes with DME and massive hard exudates treated with either PPV with ILM peeling (vitrectomy group, 21 eyes) or nonsurgical treatment with anti-vascular endothelium growth factor (VEGF) and/or steroids (nonsurgical group, 19 eyes). Changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) and resolution of macular hard exudates were compared between the two groups. Results After treatment, CRT decreased steadily in the vitrectomy group but fluctuated in the nonsurgical group. Compared with eyes in the nonsurgical group, eyes in the vitrectomy group had better visual improvement (P < 0.05 at 6 and 12 months and the final visit) and greater decrease in CRT (P < 0.05 at 3 and 6 months and the final visit) after adjustment for baseline BCVA. Hard exudates resolved more rapidly in the vitrectomy group than in the nonsurgical group, with 94.1% versus 47.4% eyes showing significant absorption after 6 months of the treatment (P = 0.003). In the vitrectomy group, 62% eyes did not require any further injections for treating DME after the operation. Conclusions PPV with ILM peeling resulted in rapid resolution of hard exudates with significant anatomical and functional improvement in DME with massive hard exudates.
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40
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The role of semaphorins in small vessels of the eye and brain. Pharmacol Res 2020; 160:105044. [PMID: 32590102 DOI: 10.1016/j.phrs.2020.105044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 06/19/2020] [Accepted: 06/19/2020] [Indexed: 12/20/2022]
Abstract
Small vessel diseases, such as ischemic retinopathy and cerebral small vessel disease (CSVD), are increasingly recognized in patients with diabetes, dementia and cerebrovascular disease. The mechanisms of small vessel diseases are poorly understood, but the latest studies suggest a role for semaphorins. Initially identified as axon guidance cues, semaphorins are mainly studied in neuronal morphogenesis, neural circuit assembly, and synapse assembly and refinement. In recent years, semaphorins have been found to play important roles in regulating vascular growth and development and in many pathophysiological processes, including atherosclerosis, angiogenesis after stroke and retinopathy. Growing evidence indicates that semaphorins affect the occurrence, perfusion and regression of both the macrovasculature and microvasculature by regulating the proliferation, apoptosis, migration, barrier function and inflammatory response of endothelial cells, vascular smooth muscle cells (VSMCs) and pericytes. In this review, we concentrate on the regulatory effects of semaphorins on the cell components of the vessel wall and their potential roles in microvascular diseases, especially in the retina and cerebral small vessel. Finally, we discuss potential molecular approaches in targeting semaphorins as therapies for microvascular disorders in the eye and brain.
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Tessier M, Meillon C, Creuzot-Garcher C, Bron AM, Nguyen P. Efficacy and follow-up of anti-VEGF injections in diabetic macular edema in real-life practice at the Dijon university medical centre through the Save Sight Registries. J Fr Ophtalmol 2020; 43:618-625. [PMID: 32473741 DOI: 10.1016/j.jfo.2019.10.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 10/18/2019] [Indexed: 01/14/2023]
Abstract
PURPOSE To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections (IVT) in diabetic macular edema (DME) in real-life practice using the Save Sight Registries (SSR). MATERIAL AND METHODS We conducted an observational, single-centre, retrospective study in the department of ophthalmology of the Dijon University Hospital. We included treatment-naive patients who presented with DME between January 2016 and December 2017. Demographic and clinical data, follow-up visits, and treatments administered were entered into the SSR, an international online ophthalmic registry. Primary endpoints were the change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to 12 and 24 months. RESULTS Fifty-eight eyes of 43 patients with a mean [standard deviation (SD)] age of 67.1 [9.5] years were included. Forty-one eyes completed 12 months of follow-up, and 17 eyes completed 24 months of follow up. Median [SD] baseline BCVA was 56.1 [22.9] ETDRS letters and the median [95% confidence interval (95% CI)] baseline CST was 447.9 [161.0] micrometers (μm). Median [95% CI] improvement in BCVA from baseline to months 12 and 24 were respectively, +5.6 [+0.5; +10.7] ETDRS letters and +7.7 [-2.8; +18.2] ETDRS letters. The median [95% CI] decrease in CST from baseline to months 12 and 24 were respectively, -110.9 [-154.5; -67.3] μm and -125.5 [-198.0; -53.0] μm. CONCLUSION Our clinical practice can be evaluated easily with the SSR system. In real life, anti-VEGF IVT are an effective treatment for DME, which result in improved BCVA and decreased CST.
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Affiliation(s)
- M Tessier
- Service d'ophtalmologie, CHU de Dijon, Dijon, France.
| | - C Meillon
- Service d'ophtalmologie, CHU de Dijon, Dijon, France
| | - C Creuzot-Garcher
- Service d'ophtalmologie, CHU de Dijon, Dijon, France; Eye and Nutrition Research Group, CSGA, UMR1324 INRA, 6265 CNRS, Université Bourgogne Franche-Comté, Dijon, France
| | - A M Bron
- Service d'ophtalmologie, CHU de Dijon, Dijon, France; Eye and Nutrition Research Group, CSGA, UMR1324 INRA, 6265 CNRS, Université Bourgogne Franche-Comté, Dijon, France
| | - P Nguyen
- The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
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Jiang W, Chen H, Tai Z, Li T, Luo L, Tong Z, Zhu W. Apigenin and Ethaverine Hydrochloride Enhance Retinal Vascular Barrier In Vitro and In Vivo. Transl Vis Sci Technol 2020; 9:8. [PMID: 32821505 PMCID: PMC7409011 DOI: 10.1167/tvst.9.6.8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 03/11/2020] [Indexed: 12/28/2022] Open
Abstract
Purpose This study aims to develop an impedance-based drug screening platform that will help identify drugs that can enhance the vascular barrier function by stabilizing vascular endothelial cell junctions. Methods Changes in permeability of cultured human retinal microvascular endothelial cells (HRMECs) monolayer were monitored in real-time with the xCELLigence RTCA system. Using this platform, we performed a primary screen of 2100 known drugs and confirmed hits using two additional secondary permeability assays: the transwell permeability assay and the XPerT assay. The cellular and molecular mechanisms of action and in vivo therapeutic efficacy were also assessed. Results Eleven compounds blocked interleukin 1 beta (IL-1β) induced hyperpermeability in the primary screen. Two of 11 compounds, apigenin and ethaverine hydrochloride, reproducibly blocked multiple cytokines induced hyperpermeability. In addition to HRMEC monolayers, the two compounds stabilized three other types of primary vascular endothelial cell monolayers. Preliminary mechanistic studies suggest that the two compounds stabilize the endothelium by blocking ADP-ribosylation factor 6 (ARF6) activation, which results in enhanced VE-cadherin membrane localization. The two compounds showed in vivo efficacy in an animal model of retinal permeability. Conclusions We developed an impedance-based cellular phenotypic drug screening platform that can identify drugs that enhance vascular barrier function. We found apigenin and ethaverine hydrochloride stabilize endothelial cell junctions and enhance the vascular barrier by blocking ARF6 activation and increasing VE-cadherin membrane localization. Translational Relevance The drugs identified from the phenotypic screen would have potential therapeutic efficacy in retinal vascular diseases regardless of the underlying mechanisms that promote vascular leak.
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Affiliation(s)
- Weiwei Jiang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Huan Chen
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Zhengfu Tai
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Tian Li
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ling Luo
- Department of Ophthalmology, the 306th Hospital of PLA, Beijing, China
| | - Zongzhong Tong
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.,Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA.,Navigen Inc., Salt Lake City, UT, USA
| | - Weiquan Zhu
- Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA.,Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA
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Wu JH, Li YN, Chen AQ, Hong CD, Zhang CL, Wang HL, Zhou YF, Li PC, Wang Y, Mao L, Xia YP, He QW, Jin HJ, Yue ZY, Hu B. Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy. EMBO Mol Med 2020; 12:e10154. [PMID: 31943789 PMCID: PMC7005627 DOI: 10.15252/emmm.201810154] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022] Open
Abstract
Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR.
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Affiliation(s)
- Jie-Hong Wu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ya-Nan Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - An-Qi Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Can-Dong Hong
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun-Lin Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hai-Ling Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Fan Zhou
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng-Cheng Li
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Wang
- Aier School of Ophthalmology, Wuhan Aier Eye Hospital, Central South University, Wuhan, China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan-Peng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Quan-Wei He
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui-Juan Jin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhen-Yu Yue
- Department of Neurology and Department of Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Gurung RL, FitzGerald LM, McComish BJ, Verma N, Burdon KP. Identifying Genetic Risk Factors for Diabetic Macular Edema and the Response to Treatment. J Diabetes Res 2020; 2020:5016916. [PMID: 33274237 PMCID: PMC7683113 DOI: 10.1155/2020/5016916] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/31/2020] [Accepted: 11/05/2020] [Indexed: 12/23/2022] Open
Abstract
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). DR is complex and the term encompasses several clinical subtypes of diabetic eye disease, including diabetic macular edema (DME), the most frequent cause of central vision loss in DR patients. Both genetic and environmental factors contribute to the pathophysiology of DR and its subtypes. While numerous studies have identified several susceptibility genes for DR, few have investigated the impact of genetics on DME susceptibility. This review will focus on the current literature surrounding genetic risk factors associated with DME. We will also highlight the small number of studies investigating the genetics of response to antivascular endothelial growth factor (anti-VEGF) injection, which is used to treat DME.
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Affiliation(s)
- Rajya L. Gurung
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Liesel M. FitzGerald
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Bennet J. McComish
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Nitin Verma
- School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Kathryn P. Burdon
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
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Augustin AJ, Feltgen N, Haritoglou C, Hoerauf H, Maier MM, Mardin CY, Schargus M. [Clinical Decision Making for Treatment of Diabetic Macular Oedema with DEX Implant: a Consensus Paper]. Klin Monbl Augenheilkd 2019; 238:73-84. [PMID: 31770786 DOI: 10.1055/a-1024-4089] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Currently two intravitreally applied corticosteroids (dexamethasone and fluocinolone) are licensed in Germany for treatment of diabetic macular oedema (DME). The use of DEX implant for DME in daily clinical practice has not been defined in detail. Following a Delphi panel survey, a group of retina experts set out to come up with a consensus for use of the DEX implant in DME. MATERIAL AND METHODS International and national treatment recommendations were identified from the literature. A steering group generated a catalogue of 72 statements on the aetiology and pathogenesis of DME, therapy with DEX implant, use of DEX implant in patients previously treated with VEGF-inhibitors, use of DEX implant in combination therapy, safety of DME therapies as well as patients' burden of treatment. Twenty-two ophthalmologists from private practice and 6 hospital ophthalmologists participated in the Delphi panel via Survey Monkey. Consensus was reached if at least 75% of participants agreed or disagreed with a statement. Statements for which consensus was not reached were discussed once more during the expert consensus meeting and a vote was taken. Based on these results a treatment algorithm for foveal DME was proposed. RESULTS If a patient does not show sufficient response after 3 - 6 months of anti-VEGF treatment (visual acuity gain of < 5 ETDRS letters or reduction of central retinal thickness ≤ 20%), a switch to DEX implant should take place. DEX implant is also suitable in eyes with longer presentation of DME, showing e.g. massive lipid exudates. DEX implant is suitable as first-line therapy especially in pseudophakic patients, patients unwilling or able to comply with tight anti-VEGF injection intervals or patients with known vascular diseases. With fixed control visits every 4 - 8 weeks, use of DEX implant is flexible and individual. Decision parameters for repeated use should be visual acuity, retinal thickness and intraocular pressure. Treatment of both eyes on the same day should not take place. CONCLUSION The algorithm presented reflects survey as well as expert discussion results and may differ from recommendations issued by the German professional society. The consensus recommendations for the treatment of DME generated during the survey and meeting of retina experts are intended to guide use of DEX implant in daily practice.
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Affiliation(s)
| | | | | | | | | | | | - Marc Schargus
- Augenklinik, Asklepios Kliniken GmbH, Hamburg.,Universitäts-Augenklinik, Heinrich-Heine-Universität, Düsseldorf
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Factors influencing clinical outcomes in patients with diabetic macular edema treated with intravitreal ranibizumab: comparison between responder and non-responder cases. Sci Rep 2019; 9:10952. [PMID: 31358777 PMCID: PMC6662817 DOI: 10.1038/s41598-019-47241-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 06/20/2019] [Indexed: 12/31/2022] Open
Abstract
Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus. A retrospective study was conducted to investigate the factors influencing the clinical outcomes in 73 patients (94 eyes) with DME treated with intravitreal ranibizumab therapy. Baseline demographic, systemic, and ocular data were assessed for the association with visual and anatomic outcomes after treatment. The mean best corrected visual acuity (BCVA) improved from 0.92 ± 0.45 to 0.61 ± 0.43 logarithm of the minimum angle of resolution (LogMAR) (p < 0.001) after treatment. The mean central subfield macular thickness (CST) decreased from 425.2 ± 127.4 to 328.6 ± 99.4 μm (p < 0.001). The treatment response was significantly influenced by Age (p = 0.003) and baseline BCVA (p = 0.001). In addition, glycosylated hemoglobin (HbA1c) (p = 0.013) and proliferative diabetic retinopathy (PDR) (p = 0.019) were the prognostic factors for the visual outcome in the responders and non-responders, respectively. Moreover, baseline CST was the strongest predictor of anatomic outcome in all subjects (p < 0.001). Intravitreal ranibizumab for DME resulted in significant improvement in clinical outcomes. Younger age and better baseline BCVA were associated with better visual outcome after the treatment. In addition, glycemic control in the treatment of patients with DME is crucial to achieve better visual outcomes, especially in the responders to ranibizumab treatment.
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Eski Yucel O, Birinci H, Sullu Y. Outcome and Predictors for 2-Year Visual Acuity in Eyes with Diabetic Macular Edema Treated with Ranibizumab. J Ocul Pharmacol Ther 2019; 35:229-234. [PMID: 30896316 DOI: 10.1089/jop.2018.0082] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Purpose: To determine the role of baseline characteristics in predicting visual outcome in patients with diabetic macular edema (DME) treated with ranibizumab. Methods: A review was carried out of the charts of 97 eyes that received pro re nata (PRN) intravitreal ranibizumab (IR) 0.5 mg treatment for DME. The change in the mean best-corrected visual acuity (BCVA) was analyzed. The baseline demographics and ocular and optic coherence tomography findings were analyzed to determine the association with the 2-year visual acuity (VA). Results: BCVA increased from 0.54 ± 0.2 (0.05-1.0) to 0.41 ± 0.3 (0.0-1.0) log of the minimum angle of resolution (P < 0.001). Age (P = 0.012), gender (P = 0.018), baseline BCVA (P < 0.001), presence of leaking microaneurysms (MA) (P = 0.018), development of vitreomacular traction (VMT) (P = 0.001), development of posterior vitreous detachment (PVD) (P = 0.040), and disruption of ellipsoid zone (EZ) (P = 0.007) were found as predictors of 2-year VA. There was no association between visual outcome and the other characteristics. Conclusions: PRN treatment of IR provides significant benefits in VA gain and anatomic improvement in eyes with DME. Older age, female sex, lower baseline VA, VMT development, and EZ disruption are predictors for the poor final VA. Development of PVD and leaking MA are predictors for the good final VA.
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Affiliation(s)
- Ozlem Eski Yucel
- Department of Ophthalmology, Medical Faculty, Ondokuz Mayis University, Samsun, Turkey
| | - Hakki Birinci
- Department of Ophthalmology, Medical Faculty, Ondokuz Mayis University, Samsun, Turkey
| | - Yuksel Sullu
- Department of Ophthalmology, Medical Faculty, Ondokuz Mayis University, Samsun, Turkey
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Anti-Vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema in a Real-World Clinical Setting. Am J Ophthalmol 2018; 195:209-222. [PMID: 30098350 DOI: 10.1016/j.ajo.2018.08.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 07/29/2018] [Accepted: 08/02/2018] [Indexed: 12/30/2022]
Abstract
PURPOSE To report the long-term outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME) in a real-world clinical setting and to assess the efficacy of subsequent alternative treatments in eyes with suboptimal response to anti-VEGF. DESIGN Retrospective interventional case series. METHODS The medical records of consecutive eyes with center-involving DME, treated between August 2008 and June 2015 with 3 monthly intravitreal anti-VEGF injections-with or without prompt or deferred laser-followed by pro re nata re-treatment, were reviewed. A subgroup of eyes that were unresponsive to the treatment received subsequent alternative therapeutic options, including switching to another anti-VEGF drug, intravitreal injection of dexamethasone, and vitrectomy. RESULTS A total of 170 eyes of 129 patients were included in the study. The mean follow-up (FU) was 45.6 months (SD 18; minimum 12-maximum 81). The change in mean best-corrected visual acuity (BCVA) at 1-year FU was +5 ETDRS letters (P < .0001). Improvement in BCVA was statistically significant up to 5 years. Improvement in central macular thickness (CMT) was statistically significant up to the last FU visit. In eyes with suboptimal response, no significant visual improvement was found by switching to another anti-VEGF (P =.4347). Twenty-four eyes treated with intravitreal dexamethasone and 14 with vitrectomy exhibited a significant reduction in CMT with variable functional responses. In these eyes, better BCVA gain was found in cases with an early change of the treatment strategy. CONCLUSION The results support treatment with intravitreal anti-VEGF for DME in real-world clinical settings and suggest that an early change of the therapeutic strategy should be considered for eyes unresponsive to the treatment.
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Campos A, Campos EJ, do Carmo A, Caramelo F, Martins J, Sousa JP, Ambrósio AF, Silva R. Evaluation of markers of outcome in real-world treatment of diabetic macular edema. EYE AND VISION 2018; 5:27. [PMID: 30386806 PMCID: PMC6198537 DOI: 10.1186/s40662-018-0119-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 09/26/2018] [Indexed: 12/29/2022]
Abstract
Objective To evaluate short-term markers of outcome in diabetic macular edema (DME). Methods Prospective interventional case series included 122 eyes of 122 patients with recently diagnosed DME. Eyes were treated with a 3-monthly loading dose of ranibizumab or aflibercept and pro re nata thereafter. Serial enhanced deep imaging SD-OCT high resolution scans were used to measure subfoveal choroidal thickness (SFCT) and central retinal thickness (CRT). Anatomic (10% CRT decrease) and functional responses (best corrected visual acuity, BCVA gain ≥5 letters) were assessed at 3 months and 6 months using univariate and multivariate analyses. Parameters tested were gender, duration of diabetes, HbA1c, hypertension, CRT, SFCT, BCVA, ellipsoid zone (EZ) status, subfoveal neuroretinal detachment (SND), anti-VEGF used and laser naivety. A logistic regression model was applied to find independent markers outcome. Results BCVA increased, CRT and SFCT decreased at 3 months and 6 months. Good metabolic control (p = 0.003), intact baseline EZ (p = 0.030), EZ re-grading at 3 M (p < 0.001) and laser naivety (p = 0.001) were associated with better functional outcome. The multivariate linear regression model showed that baseline SND and CRT are predictors of anatomic response, while lower baseline BCVA and intact EZ are predictors of functional response. Conclusion The presence of SND predicts anatomic response only, while an intact EZ is critical to achieve a good functional outcome in DME. Electronic supplementary material The online version of this article (10.1186/s40662-018-0119-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- António Campos
- 1Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.,2CNC.iCBR Consortium, University of Coimbra, Coimbra, Portugal.,Department of Ophthalmology, Leiria Hospital, Leiria, Portugal
| | - Elisa J Campos
- 1Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.,2CNC.iCBR Consortium, University of Coimbra, Coimbra, Portugal
| | - Anália do Carmo
- 2CNC.iCBR Consortium, University of Coimbra, Coimbra, Portugal.,4Clinical Pathology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal
| | - Francisco Caramelo
- 1Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.,5Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - João Martins
- 1Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.,2CNC.iCBR Consortium, University of Coimbra, Coimbra, Portugal
| | - João P Sousa
- Department of Ophthalmology, Leiria Hospital, Leiria, Portugal.,6Medical Sciences Department, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
| | - António Francisco Ambrósio
- 1Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.,2CNC.iCBR Consortium, University of Coimbra, Coimbra, Portugal
| | - Rufino Silva
- 1Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.,7Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, Portugal.,8Department of Ophthalmology, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal
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Wu D, Kanda A, Liu Y, Kase S, Noda K, Ishida S. Galectin-1 promotes choroidal neovascularization and subretinal fibrosis mediated via epithelial-mesenchymal transition. FASEB J 2018; 33:2498-2513. [PMID: 30277820 DOI: 10.1096/fj.201801227r] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
VEGFA and TGF-β are known major angiogenic and fibrogenic factors. Galectin-1, encoded by lectin, galactoside-binding, soluble ( LGALS) 1, has attracted growing attention for its facilitatory role in angiogenesis and fibrosis through its modification of VEGFA and TGF-β receptor signaling pathways. We reveal galectin-1 involvement in the mouse model of laser-induced choroidal neovascularization (CNV) and subretinal fibrosis, both of which represent the pathogenesis of age-related macular degeneration (AMD). Neither deletion nor overexpression of Lgals1 affected physiologic retinal development or visual function. Galectin-1/ Lgals1 was upregulated by CNV induction, whereas deletion of Lgals1 suppressed CNV together with downstream molecules of VEGF receptor (VEGFR)2. Loss of Lgals1 also attenuated subretinal fibrosis, expression of epithelial-mesenchymal transition (EMT) markers including Snai1, and phosphorylation of SMAD family member 2. Supporting these in vivo findings, silencing of LGALS1 in human retinal pigment epithelial (RPE) cells inhibited TGF-β1-induced EMT-related molecules and cell motilities. Conversely, overexpression of Lgals1 enhanced CNV and subretinal fibrosis. Specimens from patients with AMD demonstrated colocalization of galectin-1 with VEGFR2 in neovascular endothelial cells and with phosphorylated SMAD2 in RPE cells. These results suggested a biologic significance of galectin-1 as a key promotor for both angiogenesis and fibrosis in eyes with AMD.-Wu, D., Kanda, A., Liu, Y., Kase, S., Noda, K., Ishida, S. Galectin-1 promotes choroidal neovascularization and subretinal fibrosis mediated via epithelial-mesenchymal transition.
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Affiliation(s)
- Di Wu
- Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Atsuhiro Kanda
- Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ye Liu
- Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Satoru Kase
- Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kousuke Noda
- Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Susumu Ishida
- Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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