anti-VEGF Therapy Research Articles

Reduction of pathological retinal neovascularization, vessel obliteration, and artery tortuosity by PEDF protein in an oxygen-induced ischemic retinopathy rat model.

Retinopathy of prematurity (ROP) is a severe retinal disease in premature infants characterized by pathological neovascularization, obliteration of retinal vessels and increased vessel tortuosity. Currently, there are no completely satisfactory treatments for ROP. Pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, appears late in gestation and its deficiency may be linked to development of ROP. This study investigates the preclinical efficacy of PEDF protein alone or in combination with VEGF antagonists for treating ROP. The safety of PEDF protein in the rat eye was assessed using functional invivo measurements and histology. The efficacy of intravitreal injections (IVI) of various treatments was evaluated in a rat oxygen-induced retinopathy (OIR) model using invivo imaging and flatmount analyses. No functional or histological side-effects were found in rat eyes after intravitreal PEDF protein injection. PEDF protein alone or combined with anti-VEGF drugs significantly reduced pathological neovascularization and vessel obliteration, comparable to the effects of anti-VEGF drugs alone. Regarding arterial tortuosity, treatment with a combination of PEDF, and VEGF antagonist was more effective than treatment with anti-VEGF alone. IVI of PEDF protein is safe. PEDF protein alone or combined with VEGF antagonists shows similar efficacy in reducing pathological neovascularization and vessel obliteration as anti-VEGF agents. Furthermore, only treatments involving PEDF protein, alone or with VEGF antagonists, significantly improved the quality of retinal vasculature. Thus, PEDF protein alone or combined with anti-VEGF agents presents a promising alternative to current anti-VEGF treatments for ROP.

Cellular and Molecular Mechanisms of Neuronal Degeneration in Early-Stage Diabetic Retinopathy.

Studies on the early retinal changes in Diabetic Retinopathy (DR) have demonstrated that neurodegeneration precedes vascular abnormalities like microaneurysms or intraretinal hemorrhages. Therefore, there is a growing field of study to analyze the cellular and molecular pathways involved to allow for the development of novel therapeutics to prevent the onset or delay the progression of DR. Molecular Mechanisms: Oxidative stress and mitochondrial dysfunction contribute to neurodegeneration through pathways involving polyol, hexosamine, advanced glycation end products, and protein kinase C. Potential interventions targeting these pathways include aldose reductase inhibitors and protein kinase C inhibitors. Neurotrophic factor imbalances, notably brain-derived neurotrophic factor and nerve growth factor, also play a role in early neurodegeneration, and supplementation of these neurotrophic factors show promise in mitigating neurodegeneration. Cellular Mechanisms: Major cellular mechanisms of neurodegeneration include caspase-mediated apoptosis, glial cell reactivity, and glutamate excitotoxicity. Therefore, inhibitors of these pathways are potential therapeutic avenues. Vascular Component: The nitric oxide pathway, critical for neurovascular coupling, is disrupted in DR due to increased reactive oxygen species. Vascular Endothelial Growth Factor (VEGF), a long-known angiogenic factor, has demonstrated both damaging and neuroprotective effects, prompting a careful consideration of long-term anti-VEGF therapy. Current DR treatments primarily address vascular symptoms but fall short of preventing or halting the disease. Insights into the mechanisms of retinal neurodegeneration in the setting of diabetes mellitus not only enhance our understanding of DR but also pave the way for future therapeutic interventions aimed at preventing disease progression and preserving vision.

Visual and Anatomic Responses in Patients With Neovascular Age-Related Macular Degeneration and a Suboptimal Response to Anti-VEGF Therapy Switched to Faricimab

Purpose: To determine the efficacy of switching to intravitreal (IVT) faricimab in patients with treatment-resistant neovascular age-related macular degeneration (nAMD) and determine the rates of reversion to original antivascular endothelial growth factor (anti-VEGF) therapy. Methods: A retrospective chart review was performed of patients with nAMD and persistent fluid on optical coherence tomography previously treated with anti-VEGF injections who received at least 1 IVT faricimab injection between March 1, 2022, and January 31, 2023. Results: The study comprised 135 eyes of 119 patients. Before switching to IVT faricimab, the mean number of anti-VEGF injections in the previous 12 months was 10.7 ± 2.6 (SD) with a mean interval of 4.8 ± 1.3 weeks (range, 2-8). The mean follow-up was 11.6 ± 2 months. Thirty eyes (22.2%) switched to IVT faricimab returned to the original therapy. Of 105 eyes remaining on IVT faricimab, 66 (62.9%) had no fluid at the last follow-up. Compared with the original treatment, there was a significant improvement in logMAR visual acuity at the last follow-up in eyes on IVT faricimab (0.42 vs 0.38; P < .01) and in central subfield thickness (286 µm vs 246 µm; P < .0001). There was also a significant increase in the dosing interval after the third injection vs before IVT faricimab was prescribed (4.8 weeks vs 5.5 weeks; P < .001). Conclusions: Faricimab has a potent drying effect and potential for increasing the injection interval in many eyes with nAMD and persistent fluid on other anti-VEGF agents. Although nearly 25% of eyes reverted to the original therapy because of an insufficient response or adverse events, the majority did not achieve fluid resolution after reversion.

Topographical Quantification of Retinal Fluid in Type 3 MNV and Associations With Short-Term Visual Outcomes

PurposeThis study aims to quantify the volume of intraretinal fluid (IRF), subretinal fluid (SRF), and sub-retinal pigment epithelium (sub-RPE) fluid in treatment-naïve Type 3 macular neovascularization (MNV) eyes with age-related macular degeneration (AMD) and to investigate the correlation of these fluid volumes with visual acuity (VA) outcomes at baseline and following anti-vascular endothelial growth factor (VEGF) treatment. DesignRetrospective, clinical cohort study. MethodsIn this study, we analyzed patients diagnosed with exudative AMD and treatment-naïve Type 3 MNV undergoing a loading dose of anti-VEGF therapy. Using a validated deep-learning segmentation strategy, we processed optical coherence tomography (OCT) B-scans to segment and quantify IRF (i.e., both in the inner and outer retina), SRF, and sub-RPE fluid volumes at baseline. The study correlated baseline fluid volumes with baseline and short-term VA outcomes post-loading dose of anti-VEGF injections. ResultsForty-six eyes from 46 patients were included in this study. Visual acuity was 0.51±0.30 LogMAR at baseline and 0.33±0.20 LogMAR after the loading dose of anti-VEGF (p=0.001). Visual acuity at the follow-up visit was 0.40±0.17 LogMAR in patients with no complete resolution of retinal fluid and 0.31±0.20 LogMAR in eyes without retinal fluid after treatment (P=0.225). In the multivariable analysis, the IRF volume in the inner retina (P=0.032) and the distance of the MNV from the fovea (P=0.037) were predictors of visual acuity at baseline. The baseline IRF volume in the inner retina also predicted the visual acuity at follow-up (p=0.023). ConclusionThe present study highlights the fluid volume in the inner retina as a crucial predictor of short-term visual outcomes in Type 3 MNV, underscoring the detrimental effect of IRF on neuroretinal structures.

Recurrent Bilateral Chronic Central Serous Chorioretinopathy Treated with Anti-VEGF

Introduction: After diabetic retinopathy, branch retinal vein occlusion, and age-related macular degeneration, central serous chorioretinopathy (CSC) is the fourth most frequent retinopathy. Males in their 20s to 50s who have acute or subacute central vision loss or distortion are usually the ones who develop CSC, males more than females. Localized serous macula detachment is its defining feature. Within three to six months, the majority of instances resolve on their own and return to normal vision, but in certain situations, laser or medication treatment may be necessary. Case: A 45-year-old male came with a chief complaint of gradually blurred vision in his right eye since a month ago. Optical computed tomography (OCT) examination showed an accumulation of sub-retinal fluid (SRF) suggestive of CSC. His visual acuity was declining even after being given oral spironolactone for 1 month, so he was scheduled for intravitreal injection Anti-Vascular Endothelial Growth Factor Therapy (Anti-VEGF). After three times in injection right eye the visual acuity improved. One month later he had a chief complaint of gradually blurred vision in his left eye. After three times in injection left eye, CSC in both eyes resolved and the visual acuity improved. Three years later he came back with a chief complaint on both eyes like three years ago. Conclusion: Normally resolution of symptoms from CSC takes several months, treatment with anti- VEGF injection an efficient way to treat CSC resolution time and improve vision.

Dual pathway inhibition with faricimab for previously treated neovascular age-related macular degeneration and diabetic macular oedema: guidance from a UK panel of retina specialists.

Some eyes with neovascular age-related macular degeneration (nAMD) and centre-involving diabetic macular oedema (DMO) fail to respond sufficiently or lose response over time to standard of care intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. This paper explores clinical scenarios for switching to dual action angiopoietin-2 (Ang-2)/VEGF-A inhibitor faricimab (Vabysmo, Roche Products Limited) in previously anti-VEGF-treated patients. A national steering group meeting of UK retina specialists was held in London on 27 October 2023. Clinician practice and experience were reviewed together with pivotal clinical trial data and early findings from real-world settings. Roche Products Limited facilitated and funded the meeting. While there is no standardised protocol for identifying suboptimal response, the authors review relevant clinical biomarkers of disease activity used in routine clinical practice to determine patient response and guide treatment decisions. Common reasons identified for considering a change of treatment were lack of efficacy demonstrated by suboptimal anatomic or visual improvement and insufficient durability of response. The panel outline strategies for switching to faricimab among eligible patients with a prior anti-VEGF treatment history, with initial monthly loading doses or maintaining the previous treatment interval before attempting to extend, that may be integrated into current treat-and-extend (T&E) clinical pathways for treating patients with nAMD and DMO. General considerations for switching between treatments are also reviewed. Clinicians may consider a treatment switch to faricimab in nAMD and DMO patients who have suboptimal disease control or insufficient durability of response on initial anti-VEGF therapy.

Investigation of the effect of intravitreal bevacizumab treatment on left heart function using speckle tracking echocardiography

Introduction and objectivesVascular endothelial growth factor (VEGF) inhibitors are widely used in oncology and ophthalmology. Although these agents have been shown to increase the risk of cardiovascular events in systemic use, the effect of local applications is unclear. In our study, we aimed to investigate the effects of anti-VEGF agents on left heart functions after intravitreal injection using speckle tracking echocardiography. MethodsIn this prospectively designed study, 44 patients who were going to start intravitreal anti-VEGF treatment were included in the study. Patients were evaluated with speckle tracking echocardiography before the first anti-VEGF administration and at three months of anti-VEGF treatment. ResultsGlobal longitudinal strain (GLS) values at three months were lower in the patients who participated in the study and this was statistically significant (−18.77±2.17, −18.60±2.01, p=0.001). Also, there was a statistically significant decrease in the mean values of GLS (GLS4CH) obtained from apical four space image, GLS (GLSAPLAX) obtained from apical long axis image and GLS (GLS2CH) obtained from apical 2 space image at month 0 and month 3 (−19.08±2.39, −18.93±2.26, p=0.004; −18.81±2.29, −18.60±2.12, p=0.001; −18.44±2.31, −18.27±2.12, p=0.013, respectively). ConclusionThe slight decrease in GLS in our study suggests that the use of intravitreal anti-VEGF agents may have cardiac effects.

Comparison of ranibizumab and conbercept treatment in type 1 prethreshold retinopathy of prematurity in zone II

PurposeThe treatment with anti-VEGF for Retinopathy of prematurity (ROP) has already been widely applied in clinics even though there are still many concerns about this treatment. In this project we investigated the clinical outcomes of intra-vitreous conbercept (IVC) and ranibizumab (IVR) injection for treating type 1 prethreshold ROP in Zone II.MethodsThe data of ROP infants receiving IVR or IVC from January 2017 to March 2020 who were followed up for at least 12 months in our hospital was studied in the present retrospective study. Regression, reactivation, complications, and ocular biological parameters were evaluated.ResultsOne hundred twenty-five eyes (64 infants) in IVC group and 229 eyes (117 infants) in IVR group were observed in the study. All infants showed good response to the two anti-VEGF agents. No eyes deteriorated during the observation. No significant difference was found between the two groups as to the regression within one week and one month, the reactivation rate, and the retreatment interval (p > 0.05) whereas retinal complete vascularization rate at 6 mons after the initial treatment and mean completion time of retinal vascularization after initial injection showed significant difference (p < 0.05). At 12 mons PMA the ocular parameters also presented no statistical difference between the two treated groups (p > 0.05). However, the ocular showed slight myopic tendency with the anti-VEGF treatment when compared to the control group (p < 0.05) whereas there was no statistical difference revealed between the two treated groups (p > 0.05).ConclusionsBoth conbercept and ranibizumab for treating type 1 prethreshold ROP in Zone II are safe and effective. They had little effect on the development of ocular whereas there was a slight tendency of myopia after the treatment.

High-Dose Brolucizumab for Refractory Neovascular Age-Related Macular Degeneration Resistant to Standard-Dose Brolucizumab.

The aim of this study was to evaluate the efficacy and safety of escalating the dosage of intravitreal brolucizumab in patients with refractory neovascular age-related macular degeneration (AMD). This retrospective study included 17 eyes of 17 patients with refractory AMD treated with high-dose brolucizumab (12mg/0.1ml) for over 12months. Patients initially received at least one anti-vascular endothelial growth factor (anti-VEGF) agent and were switched to standard-dose brolucizumab (6mg/0.05ml). Those who showed a suboptimal response to standard-dose treatment had their dosage of brolucizumab escalated. Visual acuity was maintained from 68.3 ± 3.4 letters to 70.7 ± 3.2 letters after 12months of high-dose treatment (P = 0.128). Central subfield thickness was 343.7 ± 17.0μm before high-dose treatment and 316.7 ± 18.5μm at 12months (P = 0.083). The proportions of patients with subretinal fluid and serous pigment epithelial detachment significantly decreased from 82.4% to 41.2% and from 52.9% to 17.6%, respectively, after high-dose treatment (P = 0.039 and P = 0.031, respectively). The treatment interval extended from 7.2 ± 2.4weeks to 10.2 ± 2.2weeks after switching to standard-dose brolucizumab (P < 0.001) and was maintained at 13.5 ± 2.8weeks after increasing the dose (P = 0.154). No severe ocular adverse events were observed. High-dose brolucizumab was effective in patients who did not respond to standard-dose brolucizumab after switching from previous anti-VEGF agents. Increasing the dosage could offer sustained disease control and reduce the treatment burden for patients with refractory AMD.

Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications.

Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.

Pachychoroid neovascular membrane in a patient with sickle cell disease trait.

To describe a rare presentation of pachychoroid neovascular membrane in a patient with sickle cell trait and the accuracy of ruling out hemoglobinopathies in the presentation of pachychoroid spectrum. The patient was subjected to physical examinations, multimodal images (fluorescein angiography, optical coherence tomography), hemoglobin electrophoresis, and peripheral blood smear, documenting sickle cell trait. The management included laser treatment to target non-perfusion areas, along with a single dose of anti-VEGF. A 45-year-old male patient with diagnosis of pachychoroid neovascularization treated for 6 years with multiple anti VEGF injections in the left eye. A detailed clinical evaluation included hypochromic conjunctiva, peripheral vascular occlusion with non-perfusion areas led us to suspect sickle cell disease retinopathy. The images of fluorescein angiography showed peripheral arteriovenous anastomosis with non-perfusion areas; the optical coherence tomography revealed a thinner neuroepithelium with a thicker choroid; also, hemoglobin electrophoresis and peripheral blood smear documenting sickle cell trait. The chosen management was photocoagulation of the peripheral retina on the non-perfusion areas and anti VEGF without neovascular activity recurrence in the follow up period. Although sickle cell trait is considered a mild form of this pathology without serious retinal manifestations, it has to be noted that in the context of pachychoroid spectrum diseases is a trigger that could perpetuate retinal ischemia and neovascular activity.

Real-World Efficacy of Intravitreal Faricimab for Diabetic Macular Edema: A Systematic Review.

Diabetic macular edema (DME) is a prevalent exudative maculopathy, and anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line choice for treatment. Faricimab, a novel anti-VEGF and anti-angiopoietin-2 bispecific agent, has recently been approved for the treatment of DME. In this study, we systematically reviewed the real-world evidence of the efficacy of faricimab for the treatment of DME. We searched 11 databases for eligible studies. Study selection and data extraction were made independently by two authors in duplicate. Eligible studies were reviewed qualitatively. We identified 10 eligible studies that summarized data from a total of 6054 eyes with a mean follow-up of between 55 days and 12 months. Five studies reported outcomes in a population of both treatment-naïve and previously treated eyes, and five studies reported outcomes exclusively in relation to eyes that were previously treated. Faricimab improved the best-corrected visual acuity and macular thickness. The extension of the treatment interval was possible in 61-81% of treatment-naïve eyes and 36-78% of previously treated eyes. Faricimab for DME yields clinical outcomes similar to those known from previous anti-VEGF treatments but with extended treatment intervals, thus lowering the burden of therapy for patients. Long-term real-world studies are warranted.

Fibrosis in age-related neovascular macular degeneration in the anti-VEGF era.

The natural history of neovascular age-related macular degeneration (nAMD) leads to scarring and loss of vision. Since the advent of anti-VEGF therapies, which are very effective for controlling exudation, large disciform scars are rarely encountered in the clinic. However long term studies show that smaller and less severe fibrotic scars are not uncommon and develop over time despite optimal treatment. This means that additional mechanisms of action may be required to completely address this condition. To permit new treatments, a proper understanding of the clinical impact of fibrosis is required. This review is focused on clinical aspects of fibrosis and summarises recent data on biomarkers, prevalence, causes, consequences, and therapies, highlighting the most important and urgent topics to tackle in order to advance in the treatment of fibrosis.

Prediction of treatment outcome for branch retinal vein occlusion using convolutional neural network-based retinal fluorescein angiography

Deep learning techniques were used in ophthalmology to develop artificial intelligence (AI) models for predicting the short-term effectiveness of anti-VEGF therapy in patients with macular edema secondary to branch retinal vein occlusion (BRVO-ME). 180 BRVO-ME patients underwent pre-treatment FFA scans. After 3 months of ranibizumab injections, CMT measurements were taken at baseline and 1-month intervals. Patients were categorized into good and poor prognosis groups based on macular edema at the 4th month follow-up. FFA-Net, a VGG-based classification network, was trained using FFA images from both groups. Class activation heat maps highlighted important locations. Benchmark models (DesNet-201, MobileNet-V3, ResNet-152, MansNet-75) were compared for training results. Performance metrics included accuracy, sensitivity, specificity, F1 score, and ROC curves. FFA-Net predicted BRVO-ME treatment effect with an accuracy of 88.63% and an F1 score of 0.89, with a sensitivity and specificity of 79.40% and 71.34%, respectively.The AUC of the ROC curve for the FFA-Net model was 0.71. The use of FFA based on deep learning technology has feasibility in predicting the treatment effect of BRVO-ME. The FFA-Net model constructed with the VGG model as the main body has good results in predicting the treatment effect of BRVO-ME. The typing of BRVO in FFA may be an important factor affecting the prognosis.

Overview of the Use of Optical Coherence Tomography Angiography in Neovascular Age-Related Macular Degeneration.

The aim of this review is to present and discuss the use of optical coherence tomography angiography (OCTA) in age-related macular degeneration (AMD). OCTA is a non-invasive imaging procedure that gives a detailed indirect view of physiological and pathological vessels in the retina and choroid membrane. Compared with dye-based imaging, OCTA provides a segmented presentation of the individual vascular layers and plexuses, thus enabling previously unattainable differentiation and classification of pathological vascular changes within or underneath the retina. In particular, OCTA facilitates early detection of exudative macular neovascularizations (MNV) so that treatment with anti-VEGF medication can be initiated. Moreover, in the context of both screening and therapy monitoring, it is hoped that OCTA can provide more detailed data to enable greater personalization of treatment and follow-up. The image quality of OCTA is, however, susceptible to artifacts, and validation of the results by studies is required. Recent developments have shown constant improvement both in the algorithms for image calculation and avoidance of artifacts and in image quality, so the scope of OCTA will certainly expand with time.

Association between time to treatment and outcome in branch retinal vein occlusion.

To investigate the association between the time from onset to initial treatment and changes in visual acuity or the number of treatments in patients with branch retinal vein occlusion (BVO). Retrospective. Thirty-nine eyes of 39 consecutive patients with untreated acute-phase BVO who visited the University of Tokyo Hospital and were followed up for at least one year were included. The patients were initially treated with anti-vascular endothelial growth factor (VEGF) therapy and additional pro re nata therapy within six months of onset. The patients were classified according to the time from disease onset to the first treatment (group A: 28days or less, group B: over 28days). The mean (SD) age was 73 ± 8years, and 19 patients were male. The mean (SD) time to the first treatment was 31.6 ± 17.9days. The mean (SD) logMAR visual acuity at first treatment was 0.37 ± 0.30. After 12months of treatment, the mean (SD) logMAR change was -0.15 ± 0.23, and the mean number (SD) of treatments was 3.1 ± 1.7. No significant association was observed between the timing of treatment initiation and changes in logMAR visual acuity. Patients in group A and central macular thickness at the initial visit were independently associated with the greater number of treatments at one year (p = 0.03 and p = 0.01, respectively). At one year, the time between onset and the start of anti-VEGF therapy for BVO was not associated with subsequent visual acuity changes. Meanwhile, it may have significant association with the number of treatments.

VEGF-A165a and angiopoietin-2 differently affect the barrier formed by retinal endothelial cells

Exposure to VEGF-A165a over several days leads to a persistent dysfunction of the very tight barrier formed by immortalized endothelial cells of the bovine retina (iBREC). Elevated permeability of the barrier is indicated by low cell index values determined by electric cell-substrate impedance measurements, by lower amounts of claudin-1, and by disruption of the homogenous and continuous staining of vascular endothelial cadherin at the plasma membrane. Because of findings that suggest modulation of VEGF-A's detrimental effects on the inner blood-retina barrier by the angiogenic growth factor angiopoietin-2, we investigated in more detail in vitro whether this growth factor indeed changes the stability of the barrier formed by retinal endothelial cells or modulates effects of VEGF-A. In view of the clinical relevance of anti-VEGF therapy, we also studied whether blocking VEGF-A-driven signaling is sufficient to prevent barrier dysfunction induced by a combination of both growth factors. Although angiopoietin-2 stimulated proliferation of iBREC, the formed barrier was not weakened at a concentration of 3 nM: Cell index values remained high and expression or subcellular localization of claudin-1 and vascular endothelial cadherin, respectively, were not affected. Angiopoietin-2 enhanced the changes induced by VEGF-A165a and this was more pronounced at lower concentrations of VEGF-A165a. Specific inhibition of the VEGF receptors with tivozanib as well as interfering with binding of VEGF-A to its receptors with bevacizumab prevented the detrimental effects of the growth factors; dual binding of angiopoietin-2 and VEGF-A by faricimab was marginally more efficient. Uptake of extracellular angiopoietin-2 by iBREC can be efficiently prevented by addition of faricimab which is also internalized by the cells. Exposure of the cells to faricimab over several days stabilized their barrier, confirming that inhibition of VEGF-A signaling is not harmful to this cell type. Taken together, our results confirm the dominant role of VEGF-A165a in processes resulting in increased permeability of retinal endothelial cells in which angiopoietin-2 might play a minor modulating role.

Topical bromfenac in VEGF-driven maculopathies: topical review and meta-analysis

BackgroundTopical non-steroidal anti-inflammatory drugs have the potential to reduce treatment burden and improve outcomes of anti-VEGF therapy for a number of retinal disorders, including neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. In this review, we focused on the advantages of topical bromfenac as an adjunct to intravitreal anti-VEGF therapy in VEGF-driven maculopathies.MethodsCochrane Library, PubMed, and EMBASE were systematically reviewed to identify the relevant studies of neovascular age-related macular degeneration, diabetic macular edema, macular edema associated with retinal vein occlusion, myopic choroidal neovascularization, and radiation maculopathy which reported changes in central retinal thickness, visual acuity, and the number of anti-VEGF injections needed when anti-VEGF therapy was combined with topical bromfenac.ResultsIn total, ten studies evaluating bromfenac as an adjunct to anti-VEGF therapy were identified. Five studies were included in meta-analysis of the number of injections and five studies were included in the analysis of changes in central retinal thickness. A statistically significantly lower number of intravitreal injections (p = 0.005) was required when bromfenac was used as an adjunct to anti-VEGF therapy compared to anti-VEGF monotherapy with pro re nata regimen. At the same time, eyes receiving bromfenac as an adjunct to anti-VEGF therapy demonstrated non-inferior outcomes in central retinal thickness (p = 0.07). Except for one study which reported better visual outcomes with combined treatment, no difference in visual acuity or clinically significant adverse effects were reported.ConclusionsThis literature review and meta-analysis showed that topical bromfenac can be considered as a safe adjunct to anti-VEGF therapy with a potential to reduce the treatment burden with anti-VEGF drugs requiring frequent injections without compromising improvement of central retinal thickness or visual acuity.

Extracellular vesicle-bound VEGF in oral squamous cell carcinoma and its role in resistance to Bevacizumab Therapy

BackgroundVascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn’t improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue.MethodsExpression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell’s conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF.ResultsThe most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo.ConclusionAntagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.

Intravitreal Dexamethasone Implant Switch after Anti-VEGF Treatment in Patients Affected by Retinal Vein Occlusion: A Review of the Literature.

Nowadays, retinal vein occlusion (RVO) is the second most prevalent cause of vision loss associated with retinal vascular disease. Intravitreal injections are currently known as a major advancement in ophthalmology, particularly in the treatment of RVO and other retinal disorders. Particularly, the first line of therapy is usually anti-vascular endothelial growth factor (VEGF) drugs. Notably, for RVO eyes that have not responded to anti-VEGF therapy, an intravitreal dexamethasone (DEX) implant 0.7 mg (Ozurdex®, AbbVie Inc., North Chicago, IL, USA) is considered a suitable therapeutical substitute. Actually, investigations carried out in the real world and clinical trials have shown the safety and the efficacy of intravitreal DEX implants for treating this retinal disease. For this reason, choosing patients carefully may thus be essential to reduce the number of injections that clinics and hospitals have to do to manage RVO and its complications. The primary aim of this review is to summarize the pathophysiology of this retinal vascular disease, as well as the clinical and ocular imaging features that may support a switch from prior anti-VEGF treatment to intravitreal DEX implant, to provide the RVO patients with the best possible treatment to ensure maximum visual recovery.