Treatment of diabetic macular edema in real-world clinical practice: The effect of aging.

AIMS/INTRODUCTION: In older patients, the management of diabetic macular edema (DME) can be complicated by comorbidities, geriatric syndrome, and socioeconomic status. This study aims to evaluate the effects of aging on the management of DME. MATERIALS AND METHODS: This is a real-world clinical study including 1,552 patients with treatment-naïve center-involved DME. The patients were categorized into 4 categories by age at baseline (C1, <55; C2, 55-64; C3, 65-74; and C4, ≥75 years). The outcomes were the change in logarithm of the minimum angle of resolution best-corrected visual acuity (logMAR BCVA) and central retinal thickness (CRT), and the number of treatments from baseline to 2 years. RESULTS: From baseline to 2 years, the mean changes in logMAR BCVA from baseline to 2 years were -0.01 in C1, -0.06 in C2, -0.07 in C3, and 0.01 in C4 (P = 0.016), and the mean changes in CRT were -136.2 µm in C1, -108.8 µm in C2, -100.6 µm in C3, and -89.5 µm in C4 (P = 0.008). Treatments applied in the 2 year period exhibited decreasing trends with increasing age category on the number of intravitreal injections of anti-VEGF agents (P = 0.06), selecting local corticosteroid injection (P = 0.031), vitrectomy (P < 0.001), and laser photocoagulation outside the great vascular arcade (P < 0.001). CONCLUSIONS: Compared with younger patients with DME, patients with DME aged ≥75 years showed less frequent treatment, a lower BCVA gain, and a smaller CRT decrease. The management and visual outcome in older patients with DME would be unsatisfactory in real-world clinical practice.

Real-world management of treatment-naïve diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study.

BACKGROUND/AIMS: To investigate real-world outcomes for best-corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve, centr-involving diabetic macular oedema (DME). METHODS: Retrospective analysis of longitudinal medical records obtained from 27 institutions specialising in retinal diseases in Japan. A total of 2049 eyes with treatment-naïve DME commencing intervention between 2010 and 2015 who were followed for 2 years were eligible. Interventions for DME included anti-vascular endothelial growth factor (VEGF) therapy, local corticosteroid therapy, macular photocoagulation and vitrectomy. Baseline and final BCVA (logMAR) were assessed. Eyes were classified by the treatment pattern, depending on whether anti-VEGF therapy was used, into an anti-VEGF monotherapy group (group A), a combination therapy group (group B) and a group without anti-VEGF therapy (group C). RESULTS: The mean 2-year improvement of BCVA was -0.04±0.40 and final BCVA of >20/40 was obtained in 46.3% of eyes. Based on the treatment pattern, there were 427 eyes (20.9%) in group A, 807 eyes (39.4%) in group B and 815 eyes (39.8%) in group C. Mean improvement of BCVA was -0.09±0.39, -0.02±0.40 and -0.05±0.39, and the percentage of eyes with final BCVA of >20/40 was 49.4%, 38.9%, and 52.0%, respectively. CONCLUSION: Following 2-year real-world management of treatment-naïve DME in Japan, BCVA improved by 2 letters. Eyes treated by anti-VEGF monotherapy showed a better visual prognosis than eyes receiving combination therapy. Despite treatment for DME being selected by specialists in consideration of medical and social factors, a satisfactory visual prognosis was not obtained, but final BCVA remained >20/40 in half of all eyes.

Dynamics of soluble vascular endothelial growth factor receptors and their ligands in aqueous humour during ranibizumab for age-related macular degeneration.

BACKGROUND: Intravitreal ranibizumab injection (IRI) is effective for patients with exudative age-related macular degeneration (AMD) and decreases intraocular levels of vascular endothelial growth factor (VEGF), but VEGF receptor intraocular dynamics after IRI are unclear. Therefore, we evaluated changes in the aqueous humor levels of soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2, and their ligands for these receptors (VEGF) patients with AMD receiving IRI. METHODS: The subjects were 24 patients with AMD (24 eyes) who received 3 doses of IRI at monthly intervals. Aqueous humor samples were obtained when each IRI dose was given (visits 0, 1, and 2 at 4-week intervals). Then the suspension array method was employed to measure sVEGFR-1, sVEGFR-2, VEGF, and placental growth factor (PlGF) in aqueous humor samples from the 24 AMD patients and 13 cataract patients (as controls). Best corrected visual acuity (BCVA; logMAR) chart and central macular thickness (CMT; optical coherence tomography) were also assessed over time. RESULTS: At baseline, the aqueous humor levels of sVEGFR-1, sVEGFR-2, VEGF, and PlGF were significantly higher in the AMD group than in the control group. There was a significant correlation between VEGF and PlGF or between sVEGFR-1 and sVEGFR-2. BCVA and CMT both improved significantly after IRI, and the aqueous humor levels of VEGF, PlGF, and sVEGFR-1 also decreased significantly. CONCLUSIONS: VEGFRs may be involved in the pathogenesis of AMD. IRI improves clinical parameters in AMD patients by suppressing intraocular levels of VEGF, PlGF, and sVEGFR-1.

Comparing Cytokine Kinetics between Ranibizumab and Aflibercept in Central Retinal Vein Occlusion with Macular Edema.

PURPOSE: To investigate dynamic changes in aqueous humor levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and inflammatory factors in patients receiving intravitreal ranibizumab injection (IRI) or intravitreal aflibercept injection (IAI) to treat central retinal vein occlusion (CRVO) with macular edema. METHODS: In 22 CRVO patients scheduled to receive 3 doses of ranibizumab (11 eyes) or aflibercept (11 eyes) at monthly intervals, aqueous samples were collected at the time of intravitreal injection. The concentrations of VEGF, PlGF, soluble intercellular adhesion molecule-1, monocyte chemotactic protein (MCP)-1 (CCL2), platelet-derived growth factor-AA, interleukin (IL)-6, IL-8 (CXCL8), IL-12(p70) (IL12B), and IL-13 in aqueous samples were measured by the suspension array method. RESULTS: Visual acuity and foveal thickness improved significantly in both the IRI group and the IAI group. In addition, aqueous levels of VEGF and PlGF as well as MCP-1 and IL-6 decreased significantly over time in both groups. These parameters did not significantly differ between both groups. CONCLUSIONS: In CRVO patients, both ranibizumab and aflibercept achieved similar improvement in clinical parameters and similar reductions in aqueous VEGF, PlGF, MCP-1, and IL-6 levels.

Dynamics of Inflammatory Factors in Aqueous Humor during Ranibizumab or Aflibercept Treatment for Age-Related Macular Degeneration.

PURPOSE: To evaluate the dynamic changes of the aqueous humor levels of inflammatory factors between patients receiving intravitreal ranibizumab injection (IRI) and aflibercept injection (IAI) in patients with exudative age-related macular degeneration (AMD). METHODS: The study was performed on 30 eyes with AMD that were scheduled to receive 3 doses of IRI (15 eyes) or IAI (15 eyes) at monthly intervals. Aqueous humor samples were collected when injection was done. The concentrations of VEGF, monocyte chemoattractant protein 1 (MCP-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, and IL-8 were measured in aqueous humor samples from the 30 AMD patients and 10 cataract patients (as controls) by the suspension array method. RESULTS: Aqueous levels of the inflammatory factors (MCP-1, PDGF-AA, IL-6, and IL-8) were significantly correlated with each other. In both the IRI-treated eyes and the IAI-treated eyes, visual acuity and central macular thickness improved significantly, and the aqueous level of VEGF showed a significant decrease. In IAI-treated eyes, the aqueous levels of MCP-1 and PDGF-AA were significantly decreased at 2 months. CONCLUSIONS: These findings suggest that the inflammatory factors are involved in the pathogenesis of AMD and also the possibility that the interaction between these inflammatory factors and IRI or IAI is different.

Aqueous Humor Levels of Soluble Vascular Endothelial Growth Factor Receptor and Inflammatory Factors in Diabetic Macular Edema.

Aqueous levels of soluble vascular endothelial growth factor receptor (sVEGFR) and inflammatory factors were measured in 35 patients (37 eyes) with diabetic macular edema (DME) receiving anti-vascular endothelial growth factor (VEGF) therapy. Aqueous levels of growth factors (VEGF, placental growth factor [PlGF], and platelet-derived growth factor AA [PDGF-AA]), sVEGFR-1 and -2, soluble intercellular adhesion molecule 1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, -8, -12, and -13, and interferon-inducible 10-kDa protein (IP-10) were significantly higher in the DME group than in the nondiabetic control group. The sVEGFR-2 level was significantly correlated with the neurosensory retinal thickness, as well as with the levels of growth factors (VEGF and PDGF-AA) and inflammatory factors (MCP-1, IL-6, and IL-8). Three growth factors (VEGF, PlGF, and PDGF-AA) were also significantly correlated with each other, as were sVEGFR-1 or -2 and the inflammatory factors (MCP-1, IL-6, IL-8, and IP-10). These findings suggest that sVEGFRs and growth/inflammatory factors have an important role in DME.

Aqueous cytokine and growth factor levels indicate response to ranibizumab for diabetic macular oedema.

BACKGROUND/AIMS: To investigate the relations between aqueous humour levels of cytokines/growth factors and treatment response to intravitreal ranibizumab (IVR) for diabetic macular oedema (DME) METHODS: Sixty-eight eyes of 68 patients with treatment-naïve centre-involved DME, central macular thickness (CMT) greater than 400 µm and visual acuity (VA) worse than logMAR 0.3 were recruited. Each patient received monthly IVR injection (0.5 mg/0.05 mL) until CMT was reduced to below 300 µm. Additional IVR was given to maintain CMT below 300 µm during the clinical course of 6 months with monthly follow-up. Aqueous concentrations of cytokines/chemokines and growth factors were measured using samples obtained just before first IVR injection. CMT and VA were monitored monthly for up to 6 months. The number of monthly IVR injections given during the 6-month study period was also recorded. RESULTS: Twenty-four eyes showed CMT <300 µm soon after the first IVR injection (good responders), while 12 eyes did not reach the goal after six consecutive injections (poor responders). Baseline CMT and VA were not significantly different between the two groups. However, the good responders showed significant increases in baseline aqueous concentrations of vascular endothelial growth factor (VEGF), placenta growth factor, soluble VEGF receptor-1 (sVEGFR1), monocyte chemoattractant protein-1, intercellular adhesion molecule-1, interleukin 6 and inducible protein-10, but not of sVEGFR2, compared with poor responders. CONCLUSIONS: Response to ranibizumab treatment for DME appears to be associated with aqueous concentrations of VEGFR1 family and certain inflammatory cytokines, but not with clinical parameters.

Optic neuritis and acute anterior uveitis associated with influenza A infection: a case report.

BACKGROUND: A few reports have described ocular complications of influenza A infection, such as impaired ocular movement, parasympathetic ocular nerve, keratitis, macular lesion, and frosted branch angiitis. We encountered a rare case of acute anterior uveitis and optic neuritis associated with influenza A infection. CASE PRESENTATION: A 70-year-old man presented with symptoms of upper respiratory tract infection. A rapid diagnostic test showed a positive result for influenza A. At the same time, he developed ocular symptoms including blurred vision with optic disk edema and hemorrhage in the left eye, and bilateral red eyes. Multiplex polymerase chain reaction performed on aqueous humor sample detected no viral infection. Visual field testing with a Goldmann perimeter showed central and paracentral scotomas in the left eye. In addition to antiviral agent (oseltamivir phosphate 75 mg), the patient was prescribed topical prednisolone acetate ophthalmic suspension eye drops every 5 hours and high-dose intravenous methylprednisolone 1,000 mg daily for 3 days. Two months later, his best-corrected visual acuity improved to 20/50 with regression of visual field defects in his left eye. CONCLUSION: We report a case of bilateral acute anterior uveitis and unilateral optic neuritis concomitant with influenza A infection. Topical and systemic corticosteroids were effective to resolve acute anterior uveitis and neuritis. Analysis of aqueous humor sample suggested that acute anterior uveitis and optic neuritis in this case were not caused by influenza A virus infection per se but by autoimmune mechanism.

A Case of Choroidal Melanoma Resulted in Eyeball Enucleation 2 Years after Carbon Ion Radiotherapy Due to Local Recurrence.

Background: Recently, carbon ion radiotherapy (CIR) has become the standard therapy for choroidal melanoma to preserve the eyeballs in Japan. We report a case of choroidal melanoma resulting in eyeball enucleation 2 years after carbon ion radiotherapy due to local recurrence. Case: A 64-year-old man was referred to Tokyo Medical University hospital with a diagnosis of choroidal tumor. Intraocular tumor was located at the equator of temporal area in ocular fundus. After systemic work-up, clinical diagnosis of choroidal melanoma was made and CIR was applied. After CIR, the intraocular tumor was stable for 2 years. However, 2 years and 3 months after CIR, local recurrence of the tumor was detected. Eventually, the eyeball was enucleated. Histopathologically, the original lesion was composed of melanoma cells containing abundant melanin pigments, and these cells were positive for HMB-45, Melan-A and S-100 protein. In contrast, the recurrent lesion showed lack of melanin pigment and proved less positive for HMB-45, Melan-A and S-100 protein. Four months after enucleation, the patient developed liver metastasis and received the appropriate supportive care. Conclusions: Even after CIR with remission, choroidal melanoma can recur. Recurrent lesions of the tumor may reveal alternative histopathological findings compared to the original lesion.

Cytokines and Recurrence of Macular Edema after Intravitreal Ranibizumab in Patients with Branch Retinal Vein Occlusion.

The aqueous humor levels of cytokines and growth/inflammatory factors were measured in 46 branch retinal vein occlusion (BRVO) patients with macular edema (ME) who were treated with intravitreal ranibizumab injection (IRI). Patients with recurrence of ME received further IRI as needed. The number of IRIs was significantly correlated with age, baseline best-corrected visual acuity, and baseline central macular thickness (CMT), as well as the baseline aqueous levels of 5 cytokines/factors (soluble vascular endothelial growth factor receptor-1, platelet-derived growth factor-AA [PDGF-AA], soluble intercellular adhesion molecule-1, interleukin-6 [IL-6], and IL-8). Multivariate linear regression analysis with stepwise selection confirmed that age, baseline CMT, and baseline PDGF-AA level were independent determinants of the number of IRIs. These findings suggest that inflammatory factors may influence the recurrence of ME in BRVO patients, and that PDGF-AA might be a useful indicator of the number of IRIs required to control ME.

Comparative Effects of Topical Diclofenac and Betamethasone on Inflammation After Vitrectomy and Cataract Surgery in Various Vitreoretinal Diseases.

PURPOSE: To compare the effects of topical diclofenac and betamethasone on postoperative inflammation after combined sutureless cataract and vitreoretinal surgery in patients with macular hole (MH), epiretinal membrane (ERM), diabetic macular edema (DME), and rhegmatogenous retinal detachment (RRD). METHODS: The study involved 180 eligible eyes that underwent the combined surgery, followed by treatment with topical diclofenac (n = 100) or betamethasone (n = 80) for 12 weeks. Maximum postoperative inflammation index (maxPOI), assessed by laser flare-cell meter, and intraocular pressure (IOP) were monitored. The relationships between maxPOI and total operation time or number of endophotocoagulations during surgery were investigated. RESULTS: Postoperative inflammation peaked at 2 weeks and decreased thereafter in all 4 diseases, without significant differences between 2 treated groups. Postoperative IOP in MH and ERM was significantly higher in the betamethasone group. In DME and RRD, a greater number of endophotocoagulations increased maxPOI in both diclofenac and betamethasone groups, while longer operation time increased maxPOI only in diclofenac groups. CONCLUSIONS: In MH and ERM, topical diclofenac and betamethasone equally suppressed postoperative inflammation after the combined surgery, although diclofenac better controlled postoperative IOP. In DME and RRD, both drugs were equally effective in suppressing inflammation and controlling IOP, but diclofenac showed weaker suppression following longer operation.

Intravitreal Ranibizumab and Aqueous Humor Factors/Cytokines in Major and Macular Branch Retinal Vein Occlusion.

Aqueous humor levels of cytokines and growth/inflammatory factors were measured in 38 patients with macular edema who had major branch retinal vein occlusion (BRVO) or macular BRVO and were treated with intravitreal ranibizumab injection (IRI). Patients with recurrence of macular edema received further IRI as needed. Aqueous humor levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1), and other cytokines/factors were measured. Compared with major BRVO, macular BRVO was associated with lower aqueous humor levels of sVEGFR-1, its ligands (VEGF and placental growth factor), and other growth/inflammatory factors (platelet-derived growth factor-AA, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, interleukin-6, and interleukin-8). The mean number of IRI over 6 months was significantly lower in the macular BRVO group than in the major BRVO group. These findings suggest that macular BRVO requires fewer IRI than major BRVO and is associated with lower aqueous humor levels of various growth/inflammatory factors and cytokines.

'Niigata S3' is a new strawberry cultivar suitable for forcing culture under low temperature and insolation conditions.

'Niigata S3' is a new strawberry (Fragaria × ananassa Duch.) cultivar that is early flowering and possesses high soluble solid content and good coloration. It was selected from a cross between Kei812 (seed parent) and 'Asuka-Ruby' (pollen parent). The first harvest date of 'Niigata S3' was December 27, 34 days earlier than 'Echigohime' and 9 days earlier than 'Asuka-Ruby' (means of 2007 and 2008). The marketable yield of 'Niigata S3' was 85% of 'Echigohime', 107% of 'Asuka-Ruby', while the early yield was 145% of 'Echigohime', 85% of 'Asuka-Ruby' (based on 2007 and 2008 means). The shape of the fruit is long conical, and its skin color medium-red. The fruit skin hardness of 'Niigata S3' was 31.5 g/mm(2), which was harder than 'Echigohime', and its average soluble solid content was 11.4%, which was higher than the values for 'Echigohime' and 'Asuka-Ruby' (2008). Furthermore, 'Niigata S3' did not bear apical overripe fruit. This new cultivar is adaptable to the climatic conditions of Niigata, as well as other regions that experience low winter temperatures and insolation.