Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

Doxycycline Ameliorates the Severity of Experimental Proliferative Vitreoretinopathy in Mice.

After successful surgeries for patients with rhegmatogenous retinal detachment, the most common cause of retinal redetachment is proliferative vitreoretinopathy (PVR), which causes severe vision impairment and even blindness worldwide. Until now, the major treatment for PVR is surgical removal of the epiretinal membrane, while effective treatment to prevent PVR is still unavailable. Therefore, we investigated the potential of doxycycline, an antibiotic in the tetracycline class, to treat PVR using a mouse model. We used the human retinal pigment epithelial cell line, ARPE-19, for in vitro and in vivo studies to test doxycycline for PVR treatment. We found that doxycycline suppressed the migration, proliferation, and contraction of ARPE-19 cells with reduced p38 MAPK activation and total MMP activity. Intravitreal doxycycline and topical tetracycline treatment significantly ameliorated the PVR severity induced by ARPE-19 cells in mice. PVR increased the expression of MMP-9 and IL-4 and p38 MAPK phosphorylation and modestly decreased IL-10. These effects were reversed by doxycycline and tetracycline treatment in the mouse retina. These results suggest that doxycycline will be a potential treatment for PVR in the future.

Changes in choroidal vascular structure from vitreoretinal lymphoma and the intraocular cytokine level associated with clinical resolution after intravitreal methotrexate treatment.

PURPOSE: To evaluate changes in choroidal vascular structure and aqueous cytokine levels in eyes with vitreoretinal lymphoma (VRL) after intravitreal methotrexate (MTX) treatment. METHODS: In this retrospective study, VRL patients who visited our hospital between October 2018 and July 2020 were reviewed. Aqueous samples were obtained before treatment and at clinical resolution after intravitreal MTX therapy. Interleukin (IL)-6 and IL-10 levels and the IL-10-to-IL-6 ratio were evaluated. Swept-source optical coherence tomographic images were obtained along with the aqueous samples. Subfoveal choroidal thickness (SFCT), total vascular area of the choroid (TCA), stromal area (SA), luminal area (LA), and choroidal vascularity index (CVI) were assessed. RESULTS: Twelve patients were enrolled (female:male-5:7). The mean age (± standard deviation) at diagnosis was 60.9±8.5 years. In the 16 eyes diagnosed with VRL, values of SFCT, TCA, LA, and SA significantly decreased after treatment (all p-values <0.05). Additionally, the aqueous cytokine IL-10 level and IL-10-to-IL-6 ratio were significantly decreased (p = 0.001 and p = 0.003, respectively). The choroidal structure in the non-treated fellow eyes did not show any significant difference. There were no further changes in SFCT, TCA, LA, or CVI that occurred during maintenance therapy. For clinical remission, the patients received 7.7±5.5 intravitreal MTX injections. The required number of injections for clinical remission was positively correlated with best-corrected visual acuity, IL-10, and IL-6 levels in the active phase (p = 0.035, p = 0.009, and p = 0.031, respectively). CONCLUSION: Eyes with active VRL exhibited choroidal thickening with increased vascular and stromal areas that decreased after remission following MTX treatment. Higher aqueous IL-10 and IL-6 levels and lower visual acuity in the active phase may indicate the number of injections required for remission; this should be considered in the treatment of patients with VRL.

Comparative Molecular Analysis of Primary Central Nervous System Lymphomas and Matched Vitreoretinal Lymphomas by Vitreous Liquid Biopsy.

Primary Central Nervous System Lymphoma (PCNSL) is a lymphoid malignancy of the brain that occurs in ~1500 patients per year in the US. PCNSL can spread to the vitreous and retina, where it is known as vitreoretinal lymphoma (VRL). While confirmatory testing for diagnosis is dependent on invasive brain tissue or cerebrospinal fluid sampling, the ability to access the vitreous as a proximal biofluid for liquid biopsy to diagnose PCNSL is an attractive prospect given ease of access and minimization of risks and complications from other biopsy strategies. However, the extent to which VRL, previously considered genetically identical to PCNSL, resembles PCNSL in the same individual with respect to genetic alterations, diagnostic strategies, and precision-medicine based approaches has hitherto not been explored. Furthermore, the degree of intra-patient tumor genomic heterogeneity between the brain and vitreous sites has not been studied. In this work, we report on targeted DNA next-generation sequencing (NGS) of matched brain and vitreous samples in two patients who each harbored VRL and PCSNL. Our strategy showed enhanced sensitivity for molecular diagnosis confirmation over current clinically used vitreous liquid biopsy methods. We observed a clonal relationship between the eye and brain samples in both patients, which carried clonal CDKN2A deep deletions, a highly recurrent alteration in VRL patients, as well as MYD88 p.L265P activating mutation in one patient. Several subclonal alterations, however, in the genes SETD2, BRCA2, TERT, and broad chromosomal regions showed heterogeneity between the brain and the eyes, between the two eyes, and among different regions of the PCNSL brain lesion. Taken together, our data show that NGS of vitreous liquid biopsies in PCNSL patients with VRL highlights shared and distinct genetic alterations that suggest a common origin for these lymphomas, but with additional site-specific alterations. Liquid biopsy of VRL accurately replicates the findings for PCNSL truncal (tumor-initiating) genomic alterations; it can also nominate precision medicine interventions and shows intra-patient heterogeneity in subclonal alterations. To the best of our knowledge, this study represents the first interrogation of genetic underpinnings of PCNSL with matched VRL samples. Our findings support continued investigation into the utility of vitreous liquid biopsy in precision diagnosis and treatment of PCNSL/VRL.

Indications and outcomes for intravitreal injection of C3F8 gas for symptomatic vitreomacular traction.

To evaluate the indications and outcomes of perfluoropropane (C3F8) gas injection for symptomatic vitreomacular traction (VMT). A retrospective analysis of eyes with VMT treated with 0.3 mL of C3F8 gas was performed. Patients were not asked to posture after gas injection. In phakic patients, cataract surgery was performed simultaneously. Patients were examined after one week and one month postoperatively. Twenty-nine consecutive eyes of 26 patients with symptomatic VMT who underwent pneumatic vitreolysis were included. A complete posterior vitreous detachment was achieved in 18 eyes (62.1%) after a single gas injection at the final visit. The rate of posterior vitreous detachment was reduced significantly with the presence of epiretinal membrane (ERM) (p = 0.003). Three eyes formed a macular hole (MH) postoperatively and another eye developed a retinal detachment. Mean visual acuity increased significantly after one month (p < 0.008). Pneumatic vitreolysis is a viable option for treating VMT with few adverse events. Patient with concomitant ERM had a significantly lower success rate.

Green Light-Triggered Intraocular Drug Release for Intravenous Chemotherapy of Retinoblastoma.

Retinoblastoma is one of the most severe ocular diseases, of which current chemotherapy is limited to the repetitive intravitreal injections of chemotherapeutics. Systemic drug administration is a less invasive route; however, it is also less efficient for ocular drug delivery because of the existence of blood-retinal barrier and systemic side effects. Here, a photoresponsive drug release system is reported, which is self-assembled from photocleavable trigonal small molecules, to achieve light-triggered intraocular drug accumulation. After intravenous injection of drug-loaded nanocarriers, green light can trigger the disassembly of the nanocarriers in retinal blood vessels, which leads to intraocular drug release and accumulation to suppress retinoblastoma growth. This proof-of-concept study would advance the development of light-triggered drug release systems for the intravenous treatment of eye diseases.

Agonist of growth hormone-releasing hormone enhances retinal ganglion cell protection induced by macrophages after optic nerve injury.

Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes Il1b, Il6, and Tnf Moreover, agonist MR-409 further enhanced the promotion of RGC survival by lens injury or zymosan-induced macrophage activation, whereas antagonist MIA-602 attenuated the enhancement in RGC survival. Our findings reveal the protective effect of agonistic analogs of GHRH on RGCs in rats after optic nerve injury and its additive effect to macrophage activation, indicating a therapeutic potential of GHRH agonists for the protection of RGCs against optic neuropathies especially in glaucoma.

REVISED PREDICTIVE BIOMARKER FOR OCRIPLASMIN THERAPY IN VITREOMACULAR TRACTION DISORDERS.

PURPOSE: To determine a statistically optimal limit of adhesion size in vitreomacular traction (VMT) syndrome for ocriplasmin treatment. METHODS: In this retrospective, consecutive, interventional study, we included 106 patients treated with ocriplasmin injection because of VMT between July 2013 and January 2018. A univariate and multivariate risk analysis was performed with grouped factors and continuous factors. We used a receiver operating characteristic curve to measure the prognostic relevance of each continuous factor for therapy success and determined the statistically optimal cutoff value at which specificity and sensitivity are simultaneously maximized. RESULTS: Among the grouped factors, only a phakic lens status showed a highly significant positive influence on the resolution of the VMT. For the continuous factors, only the adhesion diameter before injection was a good predictor of anatomical success. The statistically optimal threshold value for the adhesion size was calculated to be 480 µm. Eyes below this limit had a 6.84-fold better chance of VMT resolution compared with eyes with a larger adhesion diameter. CONCLUSION: The threshold value of the VMT diameter for ocriplasmin therapy could be statistically defined as 480 µm and may thus be a new quantitative biomarker to predict treatment success.

CLINICAL FEATURES, DIAGNOSTIC SIGNIFICANCE, AND PROGNOSIS OF VITREORETINAL LYMPHOMA IN YOUNG PATIENTS.

PURPOSE: To investigate the clinical features, diagnostic approaches, and outcomes of young patients with vitreoretinal lymphoma. METHODS: Fifty-one vitreoretinal lymphoma patients (97 eyes) referred to the Eye and ENT Hospital of the Fudan University from 2011 to 2020 were grouped based on their onset age (age ≤50 years and age >50 years). Complete eye examinations, evaluation of systemic conditions, and biological analysis of intraocular fluids were performed. RESULTS: Young patients accounted for 31.4% (n = 16) of the cohort. More eyes had retinal/subretinal pigment epithelial infiltration (20 [64.5%] vs. 23 [34.8%]; P = 0.018) in young patients than in elderly ones. The mutation rate of Myeloid Differentiation Factor 88 gene (MYD88) was significantly lower in young patients than in elderly ones (5 [50%] vs. 21 [91.3%]; P = 0.016). The median time to new onset of central nervous system lymphoma was significantly shorter in young patients (11.7 vs. 36.2 months; P = 0.012). However, mean overall survival did not differ between the 2 groups (64.9 vs. 57.5 months; P = 0.871). CONCLUSION: Early diagnosis and central nervous system evaluation are crucial for young vitreoretinal lymphoma patients with rapid central nervous system involvement. Meanwhile, young vitreoretinal lymphoma patients have some unique features, including more retinal/subretinal pigment epithelial infiltrations and lower MYD88 mutation rates.

Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders.

Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.

Enzymatic vitreolysis using reengineered Vibrio mimicus-derived collagenase.

Purpose: Collagen is a key player contributing to vitreoelasticity and vitreoretinal adhesions. Molecular reorganization causes spontaneous weakening of these adhesions with age, resulting in the separation of the posterior hyaloid membrane (PHM) from the retina in what is called complete posterior vitreous detachment (PVD). Incomplete separation of the posterior hyaloid or tight adherence or both can lead to retinal detachment, vitreomacular traction syndrome, or epiretinal membrane formation, which requires surgical intervention. Pharmacological vitrectomy has the potential of avoiding surgical vitrectomy; it is also useful as an adjunct during retinal surgery to induce PVD. Previously studied enzymatic reagents, such as collagenase derived from Clostridium histolyticum, are nonspecific and potentially toxic. We studied a novel collagenase from Vibrio mimicus (VMC) which remains active (VMA), even after deletion of 51 C-terminal amino acids. To limit the activity of VMA to the vitreous cavity, a fusion construct (inhibitor of hyaluronic acid-VMA [iHA-VMA]) was made in which a 12-mer peptide (iHA, which binds to HA) was fused to the N-terminus of VMA. The construct was evaluated in the context of PVD. Methods: VMA and iHA-VMA were expressed in Escherichia coli, purified, and characterized with gelatin zymography, collagen degradation assay, fluorescamine-based assay, and cell-based assays. Two sets of experiments were performed in New Zealand albino rabbits. Group A (n = 10) received iHA-VMA, while group B (n = 5) received the equivalent dose of VMA. In both groups, saline was injected as a control in the contralateral eyes. Animals were monitored with indirect ophthalmoscopy, optical coherence tomography (OCT), and B-scan ultrasonography. Retinal toxicity was assessed with hematoxylin and eosin (H&E) staining of retinal tissue. Results: The activity of iHA-VMA and VMA was comparable and 65-fold lower than that of C. histolyticum collagenase Type IV. In the iHA-VMA group, all the rabbits (n = 10) developed PVD, with complete PVD seen in six animals. No statistically significant histomorphological changes were seen. In the VMA group, four of the five rabbits developed complete PVD; however, retinal morphological changes were seen in two animals. Conclusions: iHA-VMA displays targeted action confined to the vitreous and shows potential for safe pharmacologic vitreolysis.

B-SCAN ULTRASONOGRAPHY OF VITREOUS DYNAMICS DURING INTRAVITREAL ADMINISTRATION OF ANTIANGIOGENICS.

PURPOSE: To study the distribution of angiogenesis inhibitors (anti-Vascular Endothelial Growth Factor) injected into the vitreous cavity by means of simultaneous ultrasonography. METHODS: Three hundred and thirty-two B-scan ultrasound sequences of 121 eyes from 95 patients were recorded simultaneously to the intravitreal anti-Vascular Endothelial Growth Factor administration. The dynamics of the injected substance and the presence of reflux were studied, associating them with the presence/absence of total posterior vitreous detachment. RESULTS: Three well-defined patterns were distinguished. Pattern A: the medication penetrates the vitreous in a linear manner until reaching the retina (3.6%, n = 12). Pattern B: the medication adopts a globular shape and then moves down reaching the retrohyaloid space (37%, n = 123). Pattern C: the medication remains in a globular form (54%, n = 180). The pattern was not identified in 17 (5.1%) injections. Pattern A was only observed in vitrectomized eyes. The reflux (7.8%) was exclusive in eyes showing a C pattern. A relationship (P < 0.001) was observed between the presence/absence of total posterior vitreous detachment, the patterns, and the presence of reflux. CONCLUSION: This study document for the first time the behavior of antiangiogenic medication injected into the vitreous cavity and how its distribution and the presence of reflux is conditioned by the previous state of the vitreous body.

Non-invasive evaluation of toxicity in vitreoretinal domain following insertion of sustained release methotrexate micro-implant.

PURPOSE: To evaluate the safety and toxicity profile of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based sustained release methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes using non-invasive testing that included electroretinography (ERG), ultrasound biomicroscopy (US), slit-lamp biomicroscopy (SLB), funduscopy, and intraocular pressure (IOP). METHODS: PLGA-coated CS-based micro-implants containing 400 µg of MTX and placebo (without drug) micro-implants were surgically-implanted in the vitreous of the right and the left eyes, respectively, in each of the thirty New Zealand rabbits. ERG, US, SLB, funduscopy, and IOP were assessed in both eyes at pre-determined time points (days: 1, 3, 7, 14, 28 and 56). The safety of micro-implants was assessed by analyzing the ERG data using different statistical models, to quantify and compare the functional integrity of the retina. Further, US, funduscopy, SLB and IOP determined the condition of the retina, the micro-implant and associated intraocular features. RESULTS: Statistical analyses of the ERG data showed unchanged functional integrity of retina between eyes with the PLGA-coated CS-based MTX micro-implant and the placebo micro-implant. US analysis showed that micro-implants were stationary throughout the study. SLB, funduscopy and IOP further confirmed that there were no abnormalities in the intraocular physiology. CONCLUSION: The findings from ERG, US, SLB, funduscopy, and IOP showed no detectable adverse effects caused by our biodegradable micro-implants. These non-invasive techniques appeared to show lack of significant ocular toxicity over time in spite of degradation and changes in morphology of the micro-implants following intraocular implantation.

Statins for the prevention of proliferative vitreoretinopathy: cellular responses in cultured cells and clinical statin concentrations in the vitreous.

Proliferative vitreoretinopathy (PVR) with rhegmatogenous retinal detachment (RRD) is a complex inflammatory ocular disease. Statins are widely used cholesterol-lowering drugs with putative anti-inflammatory properties. In this study, we have explored their efficacy in controlling post-surgical PVR formation. Simvastatin (SIM), atorvastatin (ATV), or rosuvastatin (RSV) were added to cultures of human retinal pigment epithelial cells (ARPE-19) prior to exposure with the bacterial lipopolysaccharide (LPS), and the production of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) was examined using an enzyme-linked immunosorbent assay. In addition, the concentrations of simvastatin, atorvastatin, rosuvastatin, and their metabolites were measured from the vitreal samples of 20 patients undergoing vitrectomy (16 of them receiving oral statin therapy) using an ultra-performance liquid chromatography-tandem mass spectrometer technique. All statins alleviated LPS-induced inflammation at 5 µM concentration in the ARPE-19 cell cultures. Statin levels in the vitreous samples ranged from 6 to 316 pg/mL (ca. 0.1-7 M-10). Vitreal statin concentrations were similar to the typical steady-state unbound statin concentrations in plasma, indicating that only the unbound drug distributes from the blood circulation into the vitreous. Pharmacokinetic simulations of the intravitreal delivery of statins indicate that the measured clinical statin concentrations could be maintained with existing drug delivery technologies for months. Our results suggest that intravitreal statin therapy may have the potential in alleviating the risk of post-surgical PVR.

Dropless cataract surgery: modernizing perioperative medical therapy to improve outcomes and patient satisfaction.

PURPOSE OF REVIEW: Advances in pharmacology offer freedom from topical medical therapy without compromise of anti-inflammatory and antimicrobial coverage in the perioperative period. In this review, we describe the basis for dropless cataract surgery with the goal of improving outcomes and the patient experience. RECENT FINDINGS: Phacoemulsification outcomes depend largely on surgeon skill but also on adherence to a complex multidrug regimen of perioperative anti-inflammatory and antimicrobial therapy to prevent sight-threatening complications such as cystoid macular edema or endophthalmitis. Successful administration of this regimen can be limited by noncompliance, difficulty administering eye drops, bioavailability, and side effects, among others. The recent development of sustained-release formulations of dexamethasone - one an intracanalicular insert and the other an intraocular suspension - can provide sustained tapering doses of dexamethasone while reducing or eliminating the need for anti-inflammatory eye drop therapy. Similarly, mounting evidence compellingly demonstrates that intracameral antibiotic use intraoperatively is at least as effective as topical antibiotics in preventing endophthalmitis. SUMMARY: Sustained-release dexamethasone coupled with intracameral antibiotics at the time of phacoemulsification can provide antimicrobial and anti-inflammatory prophylaxis without the need for topical eye drop medications. This approach has the potential to improve compliance with therapy, visual acuity outcomes, and the overall patient experience.

Ocular and systemic pharmacokinetics of brimonidine and brinzolamide after topical administration in rabbits: comparison between fixed-combination and single-drug formulations.

AIM: The aim of this study was to compare the ocular and systemic absorption of brimonidine (BMD) and brinzolamide (BZM) in rabbits after the topical administration of a fixed-combination ophthalmic suspension of 0.1% BMD tartrate and 1% BZM (FCBB) with that after the administration of the respective single-drug formulations. MATERIALS AND METHODS: Ocular and systemic drug absorption was estimated by determining BMD and BZM concentrations in the aqueous humor, retina/choroid, vitreous body, and blood/plasma by liquid chromatography/tandem mass spectrometry after the administration of FCBB, 0.1% BMD tartrate ophthalmic solution (0.1% BMD), or 1% BZM ophthalmic suspension (1% BZM) to rabbits. RESULTS: In concomitant administration, instilling 0.1% BMD and 1% BZM successively without interval lowered aqueous humor concentrations of both drugs compared to those observed with a 5-min interval. After FCBB administration, BMD and BZM concentrations in the aqueous humor were comparable with those observed after the administration of 0.1% BMD and 1% BZM, whereas BMD concentrations in posterior ocular tissues were equal to or higher than those observed after 0.1% BMD. Plasma BMD concentrations following the administration of FCBB were 0.8-fold lower than those after 0.1% BMD; no remarkable differences were observed in blood BZM concentrations for both formulations. CONCLUSIONS: FCBB achieved drug distribution in the aqueous humor and systemic exposure that were comparable to those for the single-drug formulations. The viscosity of FCBB may increase BMD distribution in the retina/choroid. The administration interval affects ocular drug absorption with the concomitant administration of 0.1% BMD and 1% BZM, which can be overcome by using the fixed-combination of both drugs.

INTRAVITREAL MELPHALAN FOR TREATMENT OF VITREOUS SEEDING FROM CHOROIDAL MELANOMA.

PURPOSE: To report treatment of vitreous seeding of choroidal melanoma with monthly injections of intravitreal melphalan. METHODS: Case report. RESULTS: A 70-year-old white woman noted floaters in her left eye, and further examination revealed visual acuity of 20/30 in both eyes. Funduscopically, there was a mushroom-shaped choroidal melanoma in her left eye, measuring 9 mm in basal dimension and 4.8 mm in thickness. Notably, there was apical retinal invasion of melanoma with mild vitreous hemorrhage, without vitreous seeding. The tumor was treated with iodine-125 plaque radiotherapy using an apex dose of 70 Gy over 99 hours, designed to include the retinal invasion. The melanoma demonstrated complete regression into a nearly flat scar of 1 mm and remained stable over 4 years. Five years after radiotherapy, there were diffuse vitreous pigmented seeds of presumed melanoma origin, emanating from the site of retinal necrosis. This progressively worsened over the following 18 months, suspicious for viable melanoma cells, as visual acuity concurrently declined to 20/100. Treatment with intravitreal melphalan (10 µg/0.05 mL) was delivered on a monthly basis for 12 cycles, resulting in vitreous seeds regression, and preservation of the eye. Final visual acuity was 20/200. There were no treatment-related complications. CONCLUSION: Intravitreal melphalan can be considered in cases of vitreous seeding from uveal melanoma.

SHP-1 suppresses endotoxin-induced uveitis by inhibiting the TAK1/JNK pathway.

We investigated how Src-homology 2-domain phosphatase-1 (SHP-1) regulates the inflammatory response in endotoxin-induced uveitis (EIU), and the signalling pathways involved. One week after intravitreal injection of short hairpin RNA targeting SHP-1 or SHP-1 overexpression lentivirus in rats, we induced ocular inflammation with an intravitreal injection of lipopolysaccharide (LPS). We then assessed the extent of inflammation and performed full-field electroretinography. The concentrations and retinal expression of various inflammatory mediators were examined with enzyme-linked immunosorbent assays and Western blotting, respectively. SHP-1 overexpression and knockdown were induced in Müller cells to study the role of SHP-1 in the LPS-induced inflammatory response in vitro. Retinal SHP-1 expression was up-regulated by LPS. SHP-1 knockdown exacerbated LPS-induced retinal dysfunction and increased the levels of proinflammatory mediators in the retina, which was abrogated by a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). SHP-1 overexpression had the opposite effects. In Müller cells, the LPS-induced inflammatory response was enhanced by SHP-1 knockdown and suppressed by SHP-1 overexpression. SHP-1 negatively regulated the activation of the transforming growth factor-ß-activated kinase-1 (TAK1)/JNK pathway, but not the nuclear factor-κB pathway. These results indicate that SHP-1 represses EIU, at least in part, by inhibiting the TAK1/JNK pathway and suggest that SHP-1 is a potential therapeutic target for uveitis.

Endophthalmitis after cataract surgery: an update on recent advances.

PURPOSE OF REVIEW: Prevention and management of postcataract endophthalmitis remain quite relevant for anterior segment and vitreoretinal surgeons. Although the Endophthalmitis Vitrectomy Study, published in 1996, remains the only level 1 evidence for the management of postcataract endophthalmitis, recent advances have resulted in an evolution of practice patterns. The aim of this review is to summarize the literature regarding postcataract endophthalmitis with a focus on the last 18 months. RECENT FINDINGS: The IRIS registry indicates the rates of endophthalmitis are decreasing in the United States, and the outcomes appear to be improving. Intracameral moxifloxacin has become more widely accepted and intracameral vancomycin has been shown to be associated with retinal vasculitis. The role of systemic antibiotics and vitrectomy is unclear and practice patterns vary widely. SUMMARY: Although practice patterns vary, prevention and treatment of endophthalmitis after cataract surgery continues to improve. More uniform guidelines regarding surgical and medical therapy are necessary but the standard of prompt referral to a vitreoretinal specialist for immediate intravitreal antibiotics remains the most important intervention in the management of postcataract endophthalmitis.

Novel use of a chemically modified siRNA for robust and sustainable in vivo gene silencing in the retina.

Despite efficient and specific in vitro knockdown, more reliable and convenient methods for in vivo knockdown of target genes remain to be developed particularly for retinal research. Using commercially available and chemically modified siRNA so-called Accell siRNA, we established a novel in vivo gene silencing approach in the rat retina. siRNA designed for knockdown of the house keeping gene Gapdh or four retinal cell type-specific genes (Nefl, Pvalb, Rho and Opn1sw) was injected into the vitreous body, and their retinal mRNA levels were quantified using real-time PCR. Intravitreal injection of siRNA for Gapdh resulted in approximately 40-70% reduction in its retinal mRNA levels, which lasted throughout a 9-day study period. Furthermore, all the selected retinal specific genes were efficiently down-regulated by 60-90% following intravitreal injection, suggesting injected siRNA penetrated into major retinal cell types. These findings were consistent with uniform distribution of a fluorescence-labeled siRNA injected into the vitreous body. Interestingly, gene silencing of Grin1, a core subunit of NMDA receptor, was accompanied by significant prevention from NMDA-induced retinal ganglion cell death. Thus, we provide single intravitreal injection of Accell siRNA as a versatile technique for robust and sustainable in vivo retinal gene silencing to characterize their biological functions under physiological and pathophysiological conditions.