Three-year outcomes of vascular endothelial growth factor inhibitors in naïve branch retinal vein occlusion: Fight Retinal Blindness!

PURPOSE: To evaluate the 3-year outcomes of vascular endothelial growth factor (VEGF) inhibitors in the treatment of cystoid macular oedema (CME) due to branch retinal vein occlusion (BRVO) in an international multicenter cohort of eyes. DESIGN: Multicenter, international, BRVO database study. SUBJECTS: Seven hundred forty-seven patients (760 eyes) undergoing intravitreal therapy for BRVO for 3 years in a multicenter international setting. METHODS: Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters, central subfield thickness (CST), treatments, number of injections and visits data was collected using a validated web-based tool. MAIN OUTCOME MEASURES: Visual acuity (VA) gain at 3 years in LogMAR letters. Secondary outcome measures included anatomical results, treatment pattern and percentage of completers. A subgroup analysis by study drug was conducted for clinical outcomes. RESULTS: Mean adjusted VA change was +11 letters (95% CI 9,13), mean adjusted change in CST was -176µm (-193, -159). Median number of injections/visits was 16/24 at 3 years of follow-up. Most eyes received VEGF inhibitors exclusively (89%, n=677) and as a monotherapy in 71% (n=538). Few eyes were switched to steroids (11%, n=83). Suspensions in treatment >180 days occurred in 26% of study eyes. Aflibercept showed greater CST reductions (-147 vs -128 vs -114µm; p< 0.001) and significantly lower switching rates (14% vs 38% vs 33%, p< 0.001) compared with ranibizumab and bevacizumab, respectively. CONCLUSIONS: This international study of 3-year BRVO outcomes after starting treatment with VEGF inhibitors found adequate visual and anatomical results in routine clinical care. Visual outcomes were similar amongst the different initiating VEGF inhibitors, although eyes starting with aflibercept had better anatomical outcomes and a lower switching rate.

Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach.

Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI's MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors' predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI's MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood-retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition.

Artificial intelligence-based fluid quantification and associated visual outcomes in a real-world, multicentre neovascular age-related macular degeneration national database.

AIM: To explore associations between artificial intelligence (AI)-based fluid compartment quantifications and 12 months visual outcomes in OCT images from a real-world, multicentre, national cohort of naïve neovascular age-related macular degeneration (nAMD) treated eyes. METHODS: Demographics, visual acuity (VA), drug and number of injections data were collected using a validated web-based tool. Fluid compartment quantifications including intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelial detachment (PED) in the fovea (1 mm), parafovea (3 mm) and perifovea (6 mm) were measured in nanoliters (nL) using a validated AI-tool. RESULTS: 452 naïve nAMD eyes presented a mean VA gain of +5.5 letters with a median of 7 injections over 12 months. Baseline foveal IRF associated poorer baseline (44.7 vs 63.4 letters) and final VA (52.1 vs 69.1), SRF better final VA (67.1 vs 59.0) and greater VA gains (+7.1 vs +1.9), and PED poorer baseline (48.8 vs 57.3) and final VA (55.1 vs 64.1). Predicted VA gains were greater for foveal SRF (+6.2 vs +0.6), parafoveal SRF (+6.9 vs +1.3), perifoveal SRF (+6.2 vs -0.1) and parafoveal IRF (+7.4 vs +3.6, all p<0.05). Fluid dynamics analysis revealed the greatest relative volume reduction for foveal SRF (-16.4 nL, -86.8%), followed by IRF (-17.2 nL, -84.7%) and PED (-19.1 nL, -28.6%). Subgroup analysis showed greater reductions in eyes with higher number of injections. CONCLUSION: This real-world study describes an AI-based analysis of fluid dynamics and defines baseline OCT-based patient profiles that associate 12-month visual outcomes in a large cohort of treated naïve nAMD eyes nationwide.

Macular Neovascularization Type Influence on Anti-VEGF Intravitreal Therapy Outcomes in Age-Related Macular Degeneration.

PURPOSE: To evaluate the influence of macular neovascularization (MNV) lesion type on 12-month clinical outcomes in treatment-naive eyes with neovascular age-related macular degeneration (nAMD) treated with anti-VEGF drugs nationwide. DESIGN: Multicenter national nAMD database observational study. SUBJECTS: One thousand six hundred six treatment-naive nAMD eyes (1330 patients) undergoing anti-VEGF therapy for 12 months nationwide. METHODS: Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution letters, number of injections and visits were was collected using a validated web-based tool. Neovascular lesion phenotype was classified as type 1 (T1, n = 711), type 2 (T2, n = 505), type 3 (T3, n = 315), and aneurysmal type 1 (A-T1, n = 75), according to the new proposed consensus classification. MAIN OUTCOME MEASURES: Mean VA change at 12 months, final VA at 12 months, number of injections, time to lesion inactivation. RESULTS: A total of 1606 treatment-naive nAMD eyes (1330 patients) received a median of 7 injections over 12 months. Mean (± standard deviation) baseline VA was significantly lower for T2 (49.4 ± 23.5 letters) compared with T1 (57.8 ± 20.8) and T3 (58.2 ± 19.4) (both P < 0.05) lesions. Mean VA change at 12 months was significantly greater for A-T1 (+9.5 letters) compared with T3 (+3.1 letters, P < 0.05). Patients with T3 lesions had fewer active visits (24.9%) than those with other lesion types (T1, 30.5%; T2, 32.6%; A-T1, 27.5%; all P < 0.05). Aflibercept was the most used drug in A-T1 lesions (70.1%) and ranibizumab in T1 (40.7%), T2 (57.7%), and T3 (47.6%) lesions. CONCLUSIONS: This study highlights the relevance of MNV type on clinical outcomes in nAMD and reports significant differences in baseline VA, VA change, and lesion activity at 12 months. This report provides data about lesion-specific clinical features, which may guide the management of nAMD cases and potentially support personalized clinical decision making for these patients. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Corneal Endothelial Cell Cultures from Organotypic Preservation of Older Donor Corneas Are Suitable for Advanced Cell Therapy.

INTRODUCTION: The purpose of this work was to evaluate the in vitro growth capacity and functionality of human corneal endothelial cells (hCEC) expanded from corneas of elderly (>60 years) donors that were preserved using an organotypic culture method (>15 days, 31°C) and did not meet the clinical criteria for keratoplasty. METHODS: Cell cultures were obtained from prior descemetorhexis (≥10 mm) and a controlled incubation with collagenase type I followed by recombinant trypsin. Cells were seeded on coated plates (fibronectin-albumin-collagen I) and cultures were expanded using the dual supplemented medium approach (maintenance medium and growth medium), in the presence of a 10 µm Rho-associated protein kinase inhibitor (Y-27632). Cell passages were obtained at culture confluency (∼2 weeks). A quantitative colorimetric WST-1 cell growth assay was performed at different time points of the culture. Morphometric analysis (area assessment and circularity), immunocytochemistry (ZO-1, Na+/K+-ATPase α, Ki67), and transendothelial electrical resistance (TEER) were performed on confluent monolayers. RESULTS: There was no difference between the cell growth profiles of hCEC cultures obtained from corneas older than 60 years, whether preserved cold or cultivated organotypic corneas. Primary cultures were able to maintain a certain cell circularity index (around 0.8) and morphology (hexagonal) similar to corneal endothelial mosaic. The ZO-1 and Na+/K+-ATPase pump markers were highly positive in confluent cell monolayers at 21 days after isolation (passage 0; P0), but significantly decreased in confluent monolayers after the first passage (P1). A weak expression of Ki67 was observed in both P0 and P1 monolayers. The P0 monolayers showed a progressive increase in TEER values between days 6 and 11 and remained stable until day 18 of culture, indicating a state of controlled permeability in monolayers. The P1 monolayers also showed some functional ability but with decreased TEER values compared to monolayers at P0. CONCLUSIONS: Our results indicate that it is possible to obtain functional hCEC cultures in eye banks, using simplified and standardized protocols, from older donor corneas (>60 years of age), previously preserved under organotypic culture conditions. This tissue is more readily available in our setting, due to the profile of the donor population or due to the low endothelial count (<2,000 cells/mm2) of the donated cornea.

Oxidative Stress, Inflammatory, Angiogenic, and Apoptotic molecules in Proliferative Diabetic Retinopathy and Diabetic Macular Edema Patients.

The aim of this study is to evaluate molecules involved in oxidative stress (OS), inflammation, angiogenesis, and apoptosis, and discern which of these are more likely to be implicated in proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) by investigating the correlation between them in the plasma (PLS) and vitreous body (VIT), as well as examining data obtained from ophthalmological examinations. Type 2 diabetic (T2DM) patients with PDR/DME (PDRG/DMEG; n = 112) and non-DM subjects as the surrogate controls (SCG n = 48) were selected according to the inclusion/exclusion criteria and programming for vitrectomy, either due to having PDR/DME or macular hole (MH)/epiretinal membrane (ERM)/rhegmatogenous retinal detachment. Blood samples were collected and processed to determine the glycemic profile, total cholesterol, and C reactive protein, as well as the malondialdehyde (MDA), 4-hydroxynonenal (4HNE), superoxide dismutase (SOD), and catalase (CAT) levels and total antioxidant capacity (TAC). In addition, interleukin 6 (IL6), vascular endothelial growth factor (VEGF), and caspase 3 (CAS3) were assayed. The VITs were collected and processed to measure the expression levels of all the abovementioned molecules. Statistical analyses were conducted using the R Core Team (2022) program, including group comparisons and correlation analyses. Compared with the SCG, our findings support the presence of molecules involved in OS, inflammation, angiogenesis, and apoptosis in the PLS and VIT samples from T2DM. In PLS from PDRG, there was a decrease in the antioxidant load (p < 0.001) and an increase in pro-angiogenic molecules (p < 0.001), but an increase in pro-oxidants (p < 0.001) and a decline in antioxidants (p < 0.001) intravitreally. In PLS from DMEG, pro-oxidants and pro-inflammatory molecules were augmented (p < 0.001) and the antioxidant capacity diminished (p < 0.001), but the pro-oxidants increased (p < 0.001) and antioxidants decreased (p < 0.001) intravitreally. Furthermore, we found a positive correlation between the PLS-CAT and the VIT-SOD levels (rho = 0.5; p < 0.01) in PDRG, and a negative correlation between the PSD-4HNE and the VIT-TAC levels (rho = 0.5; p < 0.01) in DMEG. Integrative data of retinal imaging variables showed a positive correlation between the central subfield foveal thickness (CSFT) and the VIT-SOD levels (rho = 0.5; p < 0.01), and a negative correlation between the CSFT and the VIT-4HNE levels (rho = 0.4; p < 0.01) in PDRG. In DMEG, the CSFT displayed a negative correlation with the VIT-CAT (rho = 0.5; p < 0.01). Exploring the relationship of the abovementioned potential biomarkers between PLS and VIT may help detecting early molecular changes in PDR/DME, which can be used to identify patients at high risk of progression, as well as to monitor therapeutic outcomes in the diabetic retina.

Creation of a neovascular age-related macular degeneration national database using a web-based platform: Fight Retinal Blindness Spain. Report 1: Visual outcomes.

BACKGROUND: To study the visual outcomes of neovascular AMD (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs at national level. METHODS: Multicenter national database of nAMD eyes treated with anti-VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) in fixed bimonthly (FB) or treat-and-extend (TAE) regimens. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) ETDRS letters at baseline and subsequent visits, number of injections and visits data were collected using a validated web-based tool (Fight Retinal Blindness!). RESULTS: 1273 eyes (1014 patients) were included, 971 treatment naïve (TN) and 302 previously treated (PT). Baseline VA (mean ± SD) was 57.5 (±19.5) and 62.2 (±17) (p > 0.001), and 24 months final VA was 60.4 (±21.2) and 58.8 (±21.1) (p = 0.326), respectively. Mean VA change at 12/24 months was +4.2/+2.9 letters in TN eyes and +0.1/-3.4 letters in PT eyes (p < 0.001/p < 0.001). The percentage of ≥15 letters gainers/losers at 24 months was 24.8%/14.5% in TN, and 10.3%/15.7% in PT eyes. The median number of injections/visits at 12 months was 7/9 in TN and 6/8 in PT (p = 0.002/p < 0.001) and at 24 months was 11/16 in TN and 11/14 in PT (p = 0.329/p < 0.001). Study drugs included ranibizumab (39.5%), aflibercept (41.2%) and bevacizumab (19.3%). CONCLUSION: Independent, large-scale national audits are feasible if committed health care professionals are provided with efficient information technology systems to do them. The results described here represent an adequate measurement of the quality of care delivered nationwide and benchmark the clinical management of nAMD at a country level compared to other real-world international cohorts.

Intraocular pressure after myopic laser refractive surgery measured with a new Goldmann convex prism: correlations with GAT and ORA.

BACKGROUND: The purpose of this study is to describe measurements using a newly developed modified Goldmann convex tonometer (CT) 1 year after myopic laser refractive surgery. Intraocular pressure (IOP) measurements were compared with IOP values obtained by Goldmann applanation tonometer (GAT), and Ocular Response Analyzer (ORA). METHODS: Prospective double-masked study performed on thirty eyes of thirty patients that underwent laser in situ keratomileusis (LASIK; n = 19) or photorefractive keratectomy (PRK; n = 11). IOP was measured before and 3 and 12 months after surgery. Intraclass correlation coefficient (ICC) and Bland-Altman plot were calculated to assess the agreement between GAT, CT, IOPg (Goldmann-correlated IOP) and IOPcc (corneal-compensated IOP) from ORA. RESULTS: Twelve months after LASIK, IOP measured with CT showed the best correlation with IOP measured with GAT before surgery (GATpre) (ICC = 0.886, 95% CI: 0.703-0.956) (15.60 ± 3.27 vs 15.80 ± 3.22; p < 0.000). However, a moderate correlation was found for IOP measured with IOPcc and CT 12 months after LASIK (ICC = 0.568, 95% CI: - 0.185 - 0.843) (15.80 ± 3.22 vs 12.87 ± 2.77; p < 0.004). Twelve months after PRK, CT showed a weak correlation (ICC = - 0.266, 95% CI: - 3.896 - 0.663), compared to GATpre (17.30 ± 3.47 vs 16.01 ± 1.45; p < 0.642), as well as poor correlation (ICC = 0.256, 95% CI: - 0.332 - 0.719) with IOPcc (17.30 ± 3.47 vs 13.38 ± 1.65; p < 0.182). CONCLUSIONS: Twelve months after LASIK, IOP measured with CT strongly correlated with GAT before surgery and could therefore provide an alternative method for measuring IOP after this surgery. More studies regarding this new convex prism are needed to assess its accuracy.

Lyophilized amniotic membrane graft for primary pterygium surgery: preliminary results.

The aim of this study was to investigate the tolerability, safety and efficacy of new lyophilized amniotic membrane (LAM) presentation for ocular use. A prospective case-series cohort of four patients with primary nasal pterygium which undergone excision and LAM implantation was evaluated for complications and clinical outcomes. Surgical manipulation of LAM was also assessed. LAM was stiff and easy to manipulate as well as no tearing occurred during surgery or suturing. Ocular comfort was checked and similar among those patients with LAM glued or sutured. After 12 months, there were no issues about tolerability or adverse events. Lower cosmetic outcomes (recurrence) were stated in 3 patients. Our study showed that LAM could be an effective alternative to cryopreserved amniotic membrane for graft after pterygium excision surgery. Its main advantage, storage at room temperature, can make it of immediate availability. Further studies comparing clinical outcomes of pterygium surgery with cryopreserved amniotic membrane versus LAM would confirm the benefits of the last.

Vascular endothelial growth factor inhibitors for predominantly Caucasian myopic choroidal neovascularization: 2-year treatment outcomes in clinical practice: data from the Fight Retinal Blindness! Registry.

PURPOSE: To report the 24-month outcomes of vascular endothelial growth factor (VEGF) inhibitors for myopic choroidal neovascularization (mCNV) in predominantly Caucasian eyes in routine clinical practice. METHODS: Retrospective analysis of treatment-naïve eyes starting intravitreal injection of VEGF inhibitors of either bevacizumab (1.25 mg) or ranibizumab (0.5 mg) for mCNV from 1 January 2006 to 31 May 2018 that were tracked in the Fight Retinal Blindness! registry. RESULTS: We identified 203 eyes (bevacizumab-85 and ranibizumab-118) of 189 patients. The estimated mean (95% CI) change in VA over 24 months for all eyes using longitudinal models was +8 (5, 11) letters with a median (Q1, Q3) of 3 (2, 5) injections given mostly during the first year. The estimated mean change in VA at 24 months was similar between bevacizumab and ranibizumab [+9 (5, 13) letters for bevacizumab versus +9 (6, 13) letters for ranibizumab; p = 0.37]. Both agents were also similar in the mCNV activity outcomes, treatment frequency and visit frequency. CONCLUSIONS: The 24-month treatment outcomes of VEGF inhibitors for mCNV were favourable in this largest series yet reported of predominantly Caucasian eyes in routine clinical practice, with approximately two lines of visual gain and a median of three injections given mostly during the first year. These outcomes are similar to those reported for predominantly Asian eyes. Bevacizumab appeared to be as safe and effective as ranibizumab.

Twelve-month outcomes of ranibizumab versus aflibercept for macular oedema in branch retinal vein occlusion: data from the FRB! registry.

BACKGROUND/AIMS: To compare the efficacy of ranibizumab (0.5 mg) with aflibercept (2 mg) in the treatment of cystoid macular oedema due to branch retinal vein occlusion (BRVO) over 12 months. METHODS: A multicentre, international, database observational study recruited 322 eyes initiating therapy in real-world practice over 5 years. The main outcome measure was mean change in EDTRS letter scores of visual acuity (VA). Secondary outcomes included anatomic outcomes, percentage of eyes with VA >6/12 (70 letters), number of injections and visits, time to first inactivity, switching or non-completion. RESULTS: Generalised mixed effect models demonstrated that mean (95% CI) adjusted 12-month VA changes for ranibizumab and aflibercept were similar (+10.8 (8.2 to 13.4) vs +10.9 (8.3 to 13.5) letters, respectively, p=0.59). The mean adjusted change in central subfield thickness (CST) was greater for aflibercept than ranibizumab (-170 (-153 to -187) µm vs -147 (-130 to -164) µm, respectively, p=0.001). The overall median (Q1, Q3) of 7 (4, 8) injections and 9 (7, 11) visits was similar between treatment groups. First grading of inactivity occurred sooner with aflibercept (p=0.01). Switching was more common from ranibizumab (37 eyes, 23%) than from aflibercept (17 eyes, 11%; p=0.002). CONCLUSION: Visual outcomes at 12 months in this direct comparison of ranibizumab and aflibercept for BRVO in real-world practice were generally good and similar for the 2 drugs, despite a greater effect of aflibercept on CST and time to first grading of inactivity.

38†Lyophilized amniotic membrane for pterygium surgery: long-term outcomes.

PURPOSE: To investigate the tolerability, security and long-term efficacy of lyophilized amniotic membrane (LAM) as an alternative to cryopreserved amniotic membrane in pterygium surgery. MATERIAL AND METHODS: Prospective case series of patients with primary nasal pterygium who undergone pterygium surgery and LAM implant either with sutures or glue. Postoperative follow-up was until month 24. Clinical and cosmetic outcomes, quality of life (as ocular comfort), and complications were evaluated. RESULTS: LAM was stiff and easy to manipulate as well as no tearing occurred during surgery or suturing. 4 patients (3 males) had pterygium surgery and LAM implant two with sutures and the other two with glue. Ocular comfort was checked and similar among those patients with LAM glued or sutured. After 24 months, there were no issues about tolerability or adverse events. Lower cosmetic outcomes (recurrence) were stated in 3 patients. CONCLUSION: Our study showed that LAM could be an effective alternative to cryopreserved amniotic membrane for graft after pterygium excision surgery. Its main advantage, storage at room temperature, can make it of immediate availability. Further studies comparing clinical outcomes of pterygium surgery with cryopreserved amniotic membrane versus LAM would confirm the benefits of the last.

Transplantation of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium in a Swine Model of Geographic Atrophy.

BACKGROUND: The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). METHODS: Well-delimited selective outer retinal damage was induced by subretinal injection of NaIO3 into one eye in minipigs (n = 10). Thirty days later, a suspension of hiPSC-derived RPE cells expressing green fluorescent protein was injected into the subretinal space, into the healthy margins, and within areas of degenerative retina. In vivo follow-up was performed by multimodal imaging. Post-mortem retinas were analyzed by immunohistochemistry and histology. RESULTS: In vitro differentiated hiPSC-RPE cells showed a typical epithelial morphology, expressed RPE-related genes, and had phagocytic ability. Engrafted hiPSC-RPE cells were detected in 60% of the eyes, forming mature epithelium in healthy retina extending towards the border of the atrophy. Histological analysis revealed RPE interaction with host photoreceptors in the healthy retina. Engrafted cells in the atrophic zone were found in a patchy distribution but failed to form an epithelial-like layer. CONCLUSIONS: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and therefore slow down the progression of GA.

Cord blood and amniotic membrane extract eye drop preparations display immune-suppressive and regenerative properties.

Diseases and injuries that compromise the ocular surface cause considerable patient distress and have long term consequences for their quality of life. Treatment modalities that can address the delicate balance of tissue regeneration, inflammation and maintenance of corneal transparency are therefore needed. We have recently formulated two novel eye drops from placental tissues: cord blood platelet lysate (CBED) and amniotic membrane extract eye drops (AMED), which can be used to treat severe ocular disorders. Here we characterise these two preparations by measuring: (a) growth factors (GF) and cytokines composition, (b) promotion of human corneal epithelial cell (HCEC) growth and (c) effects on immune cells in a lymphocyte culture assay. Finally, their bioavailability was assayed in an ex vivo porcine corneal model. We show that both preparations contain GF and cytokines that were able to promote the in vitro growth of HCEC and support repair in an in vitro scratch test. When assessed in a lymphocyte culture, both favoured immune suppression reducing the cellular expression of NKG2D and CD107a as well as the production of interferon gamma (IFN-γ) in natural killer, NKT and T cells. Regarding bioavailability, CBED active molecules were found mainly in the pre-corneal fraction with some penetration into the corneal fraction, in an ex vivo model. In summary, both placental-derived allogeneic preparations, CBED and AMED, display regenerative and immunomodulatory capabilities. These results will help define mechanisms of action and the best indications and doses of each product for use in a particular patient and support the development of off-the-shelf therapies for ocular surface pathologies in which wound healing defects and inflammatory events are contributing factors.

Searching for the Antioxidant, Anti-Inflammatory, and Neuroprotective Potential of Natural Food and Nutritional Supplements for Ocular Health in the Mediterranean Population.

Adherence to a healthy diet offers a valuable intervention to compete against the increasing cases of ocular diseases worldwide, such as dry eye disorders, myopia progression, cataracts, glaucoma, diabetic retinopathy, or age macular degeneration. Certain amounts of micronutrients must be daily provided for proper functioning of the visual system, such as vitamins, carotenoids, trace metals and omega-3 fatty acids. Among natural foods, the following have to be considered for boosting eye/vision health: fish, meat, eggs, nuts, legumes, citrus fruits, nuts, leafy green vegetables, orange-colored fruits/vegetables, olives-olive oil, and dairy products. Nutritional supplements have received much attention as potential tools for managing chronic-degenerative ocular diseases. A systematic search of PubMed, Web of Science, hand-searched publications and historical archives were performed by the professionals involved in this study, to include peer-reviewed articles in which natural food, nutrient content, and its potential relationship with ocular health. Five ophthalmologists and two researchers collected the characteristics, quality and suitability of the above studies. Finally, 177 publications from 1983 to 2021 were enclosed, mainly related to natural food, Mediterranean diet (MedDiet) and nutraceutic supplementation. For the first time, original studies with broccoli and tigernut (chufa de Valencia) regarding the ocular surface dysfunction, macular degeneration, diabetic retinopathy and glaucoma were enclosed. These can add value to the diet, counteract nutritional defects, and help in the early stages, as well as in the course of ophthalmic pathologies. The main purpose of this review, enclosed in the Special Issue "Health Benefits and Nutritional Quality of Fruits, Nuts and Vegetables," is to identify directions for further research on the role of diet and nutrition in the eyes and vision, and the potential antioxidant, anti-inflammatory and neuroprotective effects of natural food (broccoli, saffron, tigernuts and walnuts), the Mediterranean Diet, and nutraceutic supplements that may supply a promising and highly affordable scenario for patients at risk of vision loss. This review work was designed and carried out by a multidisciplinary group involved in ophthalmology and ophthalmic research and especially in nutritional ophthalmology.

Priming human adipose-derived mesenchymal stem cells for corneal surface regeneration.

Limbal stem cells (LSC) maintain the transparency of the corneal epithelium. Chemical burns lead the loss of LSC inducing an up-regulation of pro-inflammatory and pro-angiogenic factors, triggering corneal neovascularization and blindness. Adipose tissue-derived mesenchymal stem cells (AT-MSC) have shown promise in animal models to treat LSC deficiency (LSCD), but there are not studies showing their efficacy when primed with different media before transplantation. We cultured AT-MSC with standard medium and media used to culture LSC for clinical application. We demonstrated that different media changed the AT-MSC paracrine secretion showing different paracrine effector functions in an in vivo model of chemical burn and in response to a novel in vitro model of corneal inflammation by alkali induction. Treatment of LSCD with AT-MSC changed the angiogenic and inflammatory cytokine profile of mice corneas. AT-MSC cultured with the medium that improved their cytokine secretion, enhanced the anti-angiogenic and anti-inflammatory profile of the treated corneas. Those corneas also presented better outcome in terms of corneal transparency, neovascularization and histologic reconstruction. Priming human AT-MSC with LSC specific medium can potentiate their ability to improve corneal wound healing, decrease neovascularization and inflammation modulating paracrine effector functions in an in vivo optimized rat model of LSCD.

Clinical evaluation of allogeneic eye drops from cord blood platelet lysate.

BACKGROUND: Current treatments for several corneal lesions show limited efficacy. Here we report the clinical evaluation of the efficacy of a novel eye drop preparation produced in a public cord blood (CB) bank. MATERIALS AND METHODS: In a multicentre, retrospective, consecutive case study we evaluated 33 patients (46 eyes) unresponsive to conventional treatments who required urgent intervention. The patients were given allogeneic eye drops obtained from cord blood platelet lysate (CBED) to treat severe ocular surface lesions under a compassionate use protocol. The CBED were prepared from CB units donated for haematopoietic stem cell transplantation that did not contain the minimum stem cell dose required for this use. Patients were grouped by acute conditions (neurotrophic ulcers: group I; other corneal ulcers: group II; corneal burns: group III), and chronic conditions (ocular graft-versus-host disease: group IV; severe dry eye syndrome: group V). The patients received one or two drops of the product to the affected eye four to six times per day for 19 days. A further 19-day cycle of treatment could be repeated according to the initial clinical response. RESULTS: Patients received a median of 19 CBED vials (interquartile range 19-57, range 19-442) to complete the therapy. Group I-II-III patients showed full and partial ulcer recovery in 25 (78%) and six (19%) eyes respectively. One eye (3%) did not respond to treatment. For groups IV-V improvement was reported for 12 (85%) eyes and lesions worsened on treatment in both eyes (15%) of one patient. No severe adverse events were directly attributed to CBED. DISCUSSION: Promptly available CBED resulted in a well-tolerated allogeneic treatment that showed evidence of efficacy in this cohort of patients. These positive results support further studies on CBED from platelet lysate as a novel product of CB banks. A prospective clinical trial in neurotrophic keratitis (NCT03084861) is ongoing to confirm these preliminary data.

Postoperative treatment compliance rate and complications with two different protocols after pterygium excision and conjunctival autografting.

AIM: To evaluate compliance rate to pterygium postoperative treatment with two different protocols. METHODS: Review of clinical data of patients submitted to pterygium excision and conjunctival autografting in a single centre (and a single surgeon) in Barcelona between March 2014 and December 2017. Initial postoperative protocol (protocol 1) consisted of 4 months of topical steroids in a tapering fashion. Protocol 2 consisted of topical steroids tapered over 5 weeks. Compliance rate, complications and clinical outcomes were evaluated, and statistical comparisons were made. RESULTS: 120 surgeries were performed in 99 patients. Protocol 1 was applied in 63 cases and the next 57 followed protocol 2. Compliance with protocol 1 (57.6%) was lower than with protocol 2 (84.9%) (p = 0.002). Intraoperative complications (graft tear, corneal thinning, corneal perforation and bleeding) were found in 10 cases of protocol 1 and three cases of protocol 2, p = 0.08. Postoperative complications (graft dislocation, graft haematoma, ocular hypertension and recurrence) were found in 31 cases of protocol 1 (46.2%) and eight cases of protocol 2 (14%), p = 0.001. Six weeks after surgery, ocular hypertension was detected in eight cases corresponding to protocol 1 (13.6%) and two cases of protocol 2 (3.8%), p = 0.099. Recurrence rate during first year was higher in protocol 1 (26.3%) compared to protocol 2 (7.6%), p = 0.011. No cases of visual acuity worsening or infection were registered. CONCLUSION: Protocol 2 has shown to have higher compliance rate than protocol 1 and less postoperative complications, proving to be a safe and effective postoperative treatment after pterygium surgery.

Treat-and-extend versus fixed bimonthly treatment regimens for treatment-naive neovascular age-related macular degeneration: real world data from the Fight Retinal Blindness registry.

PURPOSE: To compare the outcomes of two different antivascular endothelial growth factor treatment regimens for treatment-naive eyes with neovascular age-related macular degeneration in routine clinical care at 12 and 24 months in Spain. METHODS: Observational study using the Fight Retinal Blindness (FRB) outcomes registry platform. Eyes were treated with fixed bimonthly (FB) aflibercept group at one center and a treat-and-extend (TAE) regimen using either aflibercept or ranibizumab at the other center. RESULTS: We included 192 eyes. Of these, 160 eyes (83%) completed 12 months (86 TAE and 74 FB) and 79 (41%) completed 24 months (46 for TAE and 33 for FB) of follow-up. No statistically significant differences (p > 0.05) were found regarding mean visual acuity (VA, logMAR letters) at baseline (12 month cohort TAE 59.6 vs FB 57.9; 24 month cohort TAE 61.7 vs FB 62.6), final mean VA (12 month cohort TAE 61.1 vs FB 63.0; 24 month cohort TAE 64.8 vs FB 66.4), and median number of injections (12 months TAE 7 vs FB 7; 24 months TAE 11 vs FB 12). However, the distribution of injection frequencies for the TAE group was larger, with 35% of TAE eyes receiving ≤ 6 injections at 12 months compared with only 19% of FB eyes (p = 0.024). CONCLUSION: Similar VA results were observed with TAE and FB regimens, with no differences in the median number of injections. However, the TAE approach seemed to deliver a wider distribution of injection frequencies due to its individualized approach, which may help reduce the burden of injections in some eyes.