SGLT2 inhibitors and diabetic retinopathy progression.

PURPOSE: To evaluate whether sodium-glucose co-transporter 2 (SGLT2) inhibitors affect progression of non-proliferative diabetic retinopathy (NPDR) compared to standard of care. METHODS: A retrospective cohort study compared subjects enrolled in a commercial and Medicare Advantage medical claims database who filled a prescription for a SGLT2 inhibitor between 2013 and 2020 to unexposed controls, matched up to a 1:3 ratio. Patients were excluded if they were enrolled for less than 2 years in the plan, had no prior ophthalmologic exam, had no diagnosis of NPDR, had a diagnosis of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), had received treatment for vision-threatening diabetic retinopathy (VTDR), or were younger than 18 years. To balance covariates of interest between the cohorts, an inverse probability treatment weighting (IPTW) propensity score for SGLT2 inhibitor exposure was used. Multivariate Cox proportional hazard regression modeling was employed to assess the hazard ratio (HR) for VTDR, PDR, or DME relative to SGLT2 exposure. RESULTS: A total of 6065 patients who initiated an SGLT2 inhibitor were matched to 12,890 controls. There were 734 (12%), 657 (10.8%), and 72 (1.18%) cases of VTDR, DME, and PDR, respectively, in the SGLT2 inhibitor cohort. Conversely, there were 1479 (11.4%), 1331 (10.3%), and 128 (0.99%) cases of VTDR, DME, and PDR, respectively, among controls. After IPTW, Cox regression analysis showed no difference in hazard for VTDR, PDR, or DME in the SGLT2 inhibitor-exposed cohort relative to the unexposed group [HR = 1.04, 95% CI 0.94 to 1.15 for VTDR; HR = 1.03, 95% CI 0.93 to 1.14 for DME; HR = 1.22, 95% CI 0.89 to 1.67 for PDR]. CONCLUSION: Exposure to SGLT2 inhibitor therapy was not associated with progression of NPDR compared to patients receiving other diabetic therapies.

ONE-YEAR OUTCOMES OF A NOVEL TECHNIQUE FOR RESCUING AND SCLERAL FIXATING A POSTERIOR DISLOCATED INTRAOCULAR LENS-BAG COMPLEX WITHOUT CONJUNCTIVAL OPENING (HOFFMAN POCKETS).

PURPOSE: To present the 1-year follow-up of a novel surgical technique that allows for suture fixation of a posteriorly dislocated lens-bag complex without the need for conjunctival incision. METHODS: A retrospective chart review of 19 patients who underwent posterior chamber intraocular lens rescue using the novel surgical technique was performed. Data were collected 1 year after surgery for all patients. RESULTS: Average preoperative vision was 20/500, whereas 3 months and 12 months postoperatively, the vision was 20/65 and 20/54, respectively. Three of 15 eyes had decentration of the sutured intraocular lens, 2 of which required additional surgical repair. CONCLUSION: Outcome data at 1 year support this novel technique as a viable option for the surgical repair of a dislocated lens-capsular bag complex.

Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion.

Squamous cell cancers comprise the most common type of human epithelial cancers. One subtype, esophageal squamous cell carcinoma (ESCC), is an aggressive cancer with poor prognosis due to late diagnosis and metastasis. Factors derived from the extracellular matrix (ECM) create an environment conducive to tumor growth and invasion. Specialized cancer-associated fibroblasts (CAFs) in the ECM influence tumorigenesis. We have shown previously that the nature and activation state of fibroblasts are critical in modulating the invasive ability of ESCC in an in vivo-like organotypic 3D cell culture, a form of human tissue engineering. Dramatic differences in invasion of transformed esophageal epithelial cells depended on the type of fibroblast in the matrix. We hypothesize that CAFs create an environment primed for growth and invasion through the secretion of factors. We find that fibroblast secretion of hepatocyte growth factor (HGF) fosters the ability of transformed esophageal epithelial cells to invade into the ECM, although other unidentified factors may cooperate with HGF. Genetic modifications of both HGF in fibroblasts and its receptor Met in epithelial cells, along with pharmacologic inhibition of HGF and Met, underscore the importance of this pathway in ESCC invasion and progression. Furthermore, Met activation is increased upon combinatorial overexpression of epidermal growth factor receptor (EGFR) and p53(R175H), two common genetic mutations in ESCC. These results highlight the potential benefit of the therapeutic targeting of HGF/Met signaling in ESCC and potentially other squamous cancers where this pathway is deregulated.

OPHTHALMIC ARTERY OCCLUSION AS THE PRESENTING SIGN OF ACQUIRED IMMUNODEFICIENCY SYNDROME.

BACKGROUND/PURPOSE: The purpose of this study was to describe a case of severe occlusive vasculitis that led to a diagnosis of AIDS in a previously healthy middle-aged man. METHODS: Multimodal imaging including widefield fundus photography, spectral domain optical coherence tomography, and widefield fluorescein angiography was performed. RESULTS: A healthy 46-year-old man presented with sudden onset vision loss in his left eye with an afferent pupillary defect. His examination revealed signs of retinal vascular disease in both eyes, with an ophthalmic artery occlusion in his affected left eye and a hemiretinal vein occlusion in his asymptomatic right eye. An extensive medical workup was significant for HIV positivity; he was ultimately diagnosed with AIDS, and ocular findings were attributed to an associated occlusive vasculitis. He developed anterior segment neovascularization in the left eye for which he received intravitreal bevacizumab and panretinal photocoagulation. He ultimately required cyclophotocoagulation in the left eye for poorly controlled intraocular pressure in the setting of neovascular glaucoma. CONCLUSION: Although HIV is most classically associated with a retinal microangiopathy, testing should be considered in cases of occlusive retinal vasculitis because it is a rare cause of such findings.

Vitreoretinal lymphoma presenting as frosted branch angiitis in a patient with diffuse large B-cell lymphoma.

Purpose: To describe the evaluation, diagnosis, and treatment of vitreoretinal lymphoma presenting as frosted branch angiitis in a patient with diffuse large B-cell lymphoma (DLBCL). Observations: A 57-year-old woman with a history of non-Hodgkin lymphoma and recent DLBCL relapse presented with frosted branch angiitis that raised suspicion for an infectious retinitis but was found to be vitreoretinal lymphoma. Conclusions and Importance: This case primarily highlights the importance of considering vitreoretinal lymphoma on the differential diagnosis of etiologies of frosted branch angiitis. Despite suspicion for vitreoretinal lymphoma, it is also important to treat empirically for infectious etiologies of retinitis in cases of frosted branch angiitis. In this case where the diagnosis was ultimately vitreoretinal lymphoma, weekly alternating intravitreal injections of methotrexate and rituximab led to improvement in visual acuity and retinal infiltration.

OUTER RETINOPATHY AND MICROANGIOPATHY IN ACUTE MYELOGENOUS LEUKEMIA.

PURPOSE: To describe a patient with acute myelogenous leukemia who presented with a recurrent, bilateral, outer retinopathy, before and after consolidative peripheral blood stem cell transplantation complicated by chronic graft-versus-host disease. METHODS: This is a retrospective review of records from a 23-year-old woman with acute myelogenous leukemia who underwent comprehensive ophthalmic evaluations for over a year including chromatic perimetry and multifocal electroretinograms, imaging with spectral domain optical coherence tomography, near-infrared and short-wavelength fundus reflectance and autofluorescence, fluorescein and optical coherence tomography angiography. RESULTS: The patient presented with recurrent, unilateral paracentral scotomas. There was localized loss of inner segment ellipsoid (EZ) and photoreceptor outer segment signals (IZ) in the pericentral retina of both eyes co-localizing with hyperreflective lesions on near-infrared reflectance. She subsequently lost vision (visual acuity = 20/200) in the right eye a year after consolidative peripheral blood stem cell transplantation complicated by steroid-resistant-chronic graft-versus-host disease. There was loss of the EZ and IZ signals corresponding to a dense central cone scotoma and multifocal electroretinograms depression. Near-infrared autofluorescence, fluorescein and optical coherence tomography angiography were within normal limits. Visual acuity (20/20) and retinal sensitivities improved with restoration of the EZ/IZ signals after oral prednisone and intravenous rituximab, but left a residual photoreceptor loss and paracentral scotoma. CONCLUSION: We propose that an immune-mediated microangiopathy may explain the protracted, recurrent course of primary photoreceptor abnormalities in our patient, which was further complicated by manifestations of chronic graft-versus-host disease following consolidative peripheral blood stem cell transplantation. Outer retinal findings previously documented in leukemia may be explained by a similar mechanism.

UTILITY OF OCULAR ß- d -GLUCAN TESTING IN PATIENTS WITH FUNGAL ENDOPHTHALMITIS.

PURPOSE: To assess the diagnostic utility of (1→3)-ß- d -glucan (BDG) in ocular fluid of patients with fungal endophthalmitis. METHODS: This prospective pilot single-center study evaluated aqueous and vitreous humor BDG levels of suspected fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls with the standard Fungitell assay and the Fungitell STAT assay. ß- d -Glucan levels were compared using generalized linear models followed by post hoc pairwise comparisons. RESULTS: Seven fungal endophthalmitis, 6 bacterial endophthalmitis, and 17 noninfectious ocular samples were evaluated. Mean aqueous BDG concentrations were 204, 11.0, and 9.6 pg/mL for fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls, respectively ( P = 0.01, fungal vs. bacterial; P = 0.0005, fungal vs. noninfectious controls). Mean vitreous BDG concentrations were 165, 30.3, and 5.4 pg/mL, respectively ( P = 0.001 for fungal vs. bacterial; P < 0.0001 for fungal vs. noninfectious controls). Mean vitreous BDG index (Fungitell STAT) values were 1.7, 0.4, and 0.3, respectively ( P = 0.001, fungal vs. bacterial; P = 0.0004, fungal vs. noninfectious controls). The Pearson correlation between BDG levels and BDG index was high (correlation coefficient = 0.99, P < 0.001). CONCLUSION: Significantly elevated ocular BDG levels were found in fungal endophthalmitis compared with bacterial endophthalmitis and noninfectious controls. Our study suggests a potential utility for BDG testing in the diagnosis of fungal endophthalmitis, and a larger study is warranted.

A large meta-analysis identifies genes associated with anterior uveitis.

Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.

Implications of fibrotic extracellular matrix in diabetic retinopathy.

Fibrosis is an accumulation of extracellular matrix (ECM) proteins and fibers in a disordered fashion, which compromises cell and tissue functions. High glucose-induced fibrosis, a major pathophysiological change of diabetic retinopathy (DR), severely affects vision by compromising the retinal vasculature and ultimately disrupting retinal tissue organization. The retina is a highly vascularized, stratified tissue with multiple cell types organized into distinct layers. Chronically high blood glucose stimulates certain retinal cells to increase production and assembly of ECM proteins resulting in excess ECM deposition primarily in the capillary walls on the basal side of the endothelium. This subendothelial fibrosis of the capillaries is the earliest histological change in the diabetic retina and has been linked to the vascular dysfunction that underlies DR. Proteins that are not normally abundant in the capillary basement membrane (BM) matrix, such as the ECM protein fibronectin, are assembled in significant quantities, disrupting the architecture of the BM and altering its properties. Cell culture models have identified multiple mechanisms through which elevated glucose can stimulate fibronectin matrix assembly, including intracellular signaling pathways, alternative splicing, and non-enzymatic glycation of the ECM. The fibrotic subendothelial matrix alters cell adhesion and supports further accumulation of other ECM proteins leading to disruption of endothelial cell-cell junctions. We review evidence supporting the notion that these molecular changes in the ECM contribute to the pathogenesis of DR, including vascular leakage, loss of endothelial cells and pericytes, changes in blood flow, and neovascularization. We propose that the accumulation of ECM, especially fibronectin matrix, first around the vasculature and later in extravascular locations, plays a critical role in DR and vision loss. Strategies for DR prevention and treatment should consider the ECM a potential therapeutic target.

A NOVEL APPROACH TO SCLERAL FIXATION OF POSTERIOR CHAMBER INTRAOCULAR LENSES AND CAPSULAR TENSION RINGS AND SEGMENTS IN DEEP-SET EYES.

PURPOSE: To demonstrate a novel approach to scleral fixation of posterior chamber intraocular lenses and capsular tension rings and segments in deep-set eyes using the Finesse FlexLoop (Alcon Laboratories). METHODS: The technique described herein, based on previous approaches to scleral fixation of posterior chamber intraocular lenses, uniquely employs the FlexLoop to "lasso" Gore-Tex sutures that have already been threaded through the eyelets of a CZ70BD (Alcon Laboratories) IOL and externalize them. RESULTS: All patients who underwent surgery with this technique experienced visual improvement. The only complication was of mild hyphema in the patient who had a capsular tension segment placed, which resolved with medical therapy. CONCLUSION: The advantages of this procedure include a smaller diameter instrument (FlexLoop) as compared to the 25-gauge forceps typically employed, an easier to perform surgical maneuver that alleviates the need for both precise placement and constant tension to be exerted by the surgeon to grasp the sutures, as well as an instrument that can function when bent up to 45° to help accommodate deep-set eyes requiring this procedure.

Efficacy of Maribavir in Valganciclovir-Resistant Cytomegalovirus Retinitis.

PURPOSE: To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis. METHODS: Retrospective case report of a lung transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs. RESULTS: A 72-year-old lung transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the un-injected eye. CONCLUSIONS: This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.

The antibiotic dehydrophos is converted to a toxic pyruvate analog by peptide bond cleavage in Salmonella enterica.

The metabolic processing of dehydrophos, a broad-spectrum peptide antibiotic containing an unusual vinyl-phosphonate moiety, was examined by using a panel of Salmonella enterica mutants deficient in peptide uptake and catabolism. Dehydrophos bioactivity is lost in opp tpp double mutants, demonstrating a requirement for uptake via nonspecific oligopeptide permeases. Dehydrophos bioactivity is also abolished in a quadruple Salmonella mutant lacking the genes encoding peptidases A, B, D, and N, showing that hydrolysis of the peptide bond is required for activity. (31)P nuclear magnetic resonance spectroscopy was used to assess the fate of dehydrophos following in vitro digestion of the antibiotic with purified PepA. The results suggest that the initial product of peptidase processing is 1-aminovinyl-phosphonate O-methyl ester. This phosphonate analogue of dehydroalanine undergoes rearrangement to the more stable imine, followed by spontaneous hydrolysis to yield O-methyl-acetylphosphonate, a structural analogue of pyruvate. This compound is a known inhibitor of pyruvate dehydrogenase and pyruvate oxidase and is probably the active species responsible for dehydrophos bioactivity.

Central Retinal Vein Occlusion in a 46-Year-Old Man with COVID-19: Case Report and Review of the Literature.

A 46-year-old man with a history of well-controlled hypertension presented with a central retinal vein occlusion (CRVO) in his right eye, which was complicated by cystoid macular edema. When the patient noted new visual symptoms, he was also experiencing muscle aches and easy fatiguability. A standard hypercoagulability panel failed to identify an etiology for his CRVO. However, the patient underwent COVID-19 antibody testing, which returned positive. The patient received a series of aflibercept injections for his macular edema, and his vision improved. Further study is warranted to determine if there is any association between mild infection with COVID-19 and the development of CRVO.

The Proteome of Preretinal Tissue in Proliferative Vitreoretinopathy.

BACKGROUND AND OBJECTIVE: Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment repair failure. However, the molecular pathogenesis remains incompletely understood. Determining the proteome of PVR will help to identify novel therapeutic targets. MATERIALS AND METHODS: Preretinal tissue samples, delaminated during surgery from six PVR cases and one idiopathic epiretinal membrane (ERM) were analyzed by mass spectrometry. Tandem mass spectra were extracted using the UniProt database, generating a list of 896 proteins, which were subjected to pathway set and fold-change (ERM vs PVR) analyses. RESULTS: Two pathways were enriched in PVR: extracellular matrix (ECM) organization and extracellular structure organization. A fold-change analysis comparing mean total spectral counts from PVR to an ERM control identified fibronectin, the ECM glycoprotein, as the protein most significantly elevated in PVR compared to ERM. CONCLUSION: These data identify pathwayskey to PVR progression, including thoseinvolved in cell-mediated ECM assembly and thus tractional force generation at the cellular level. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:S5-S12.].

Tobacco smoke induces urokinase-type plasminogen activator and cell invasiveness: evidence for an epidermal growth factor receptor dependent mechanism.

Multiple tobacco smoke-related premalignant and malignant lesions develop synchronously or metachronously in various organ sites, including the oral cavity. Both field cancerization and clonal migration seem to contribute to the occurrence of multiple tumors. Although the importance of endogenous factors (e.g., oncogenes) in regulating clonal migration is well established, little is known about the role of exogenous factors. Hence, the main objective of this study was to elucidate the mechanism by which tobacco smoke stimulated the migration of cells through extracellular matrix (ECM). Treatment of MSK-Leuk1 cells with a saline extract of tobacco smoke induced the migration of cells through ECM. Tobacco smoke induced the expression of urokinase-type plasminogen activator (uPA), resulting in plasmin-dependent degradation of ECM and increased cell migration. AG1478, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, a neutralizing antibody to EGFR, or an antibody to amphiregulin, an EGFR ligand, also blocked tobacco smoke-mediated induction of uPA and cell migration through ECM. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase activity, caused similar inhibitory effects. Taken together, these results suggest that tobacco smoke activated the EGFR-->extracellular signal-regulated kinase 1/2 MAPK pathway, causing induction of uPA. This led, in turn, to increased plasmin-dependent degradation of matrix proteins and enhanced cell migration through ECM. These data strongly suggest that chemicals in tobacco smoke can mimic the effects of oncogenes in regulating uPA-dependent cell invasion through ECM. These findings also strengthen the rationale for determining whether inhibitors of EGFR tyrosine kinase reduce the risk of tobacco smoke-related second primary tumors.

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity.

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.