Impact of Injection Protocol Selection by Retina Specialists on Clinical Outcomes in Patients with Diabetic Macular Edema

Intravitreal anti-VEGF injections are the current gold standard for treating diabetic macular edema (DME). However, injection practice patterns of retina specialists have varied markedly based on physician discretion. This retrospective study analyzes the impact of injection protocol selection on change in best-corrected visual acuity (BCVA) and central macular thickness (CMT) in 170 eyes treated by 4 retina specialists practicing a pro re nata (PRN) strategy between 2010 and 2020. DME patients received an average of 7.25 injections every 6.24 weeks over 56.6 weeks. There were significant differences between retina specialists in mean number of injections (p = 0.0001) and mean length of treatment (p = 0.0007) but not in mean interval between injections. Over the treatment period, average change in BCVA was −0.053 logMAR, and average change in CMT was −51.1 µm, neither of which had significant differences between retina specialists. BCVA and CMT at initial visit were found to be significantly associated with improved BCVA and CMT over the treatment period (p < 0.001). Number of injections administered and interval between injections were not found to be significant factors affecting change in BCVA or CMT. Despite significant differences in injection dosing regimen, retina specialists achieved similar outcomes in change in BCVA and CMT over the treatment period.

Safety and Immunogenicity of a Shigella Bivalent Conjugate Vaccine (ZF0901) in 3-Month- to 5-Year-Old Children in China

No licensed Shigella vaccine is presently available globally. A double-blinded, randomized, placebo-controlled, age descending phase II clinical trial of a bivalent conjugate vaccine was studied in China. The vaccine ZF0901 consisted of O-specific polysaccharides purified and detoxified from lipopolysaccharide (LPS) of S. flexneri 2a and S. sonnei and covalently bonded to tetanus toxoid. A total of 224, 310, and 434 children, consented by parents or guardians, aged 3 to 6 and 6 to 12 months and 1 to 5 years old, respectively, were injected with half or full doses, with or without adjuvant or control Hib vaccine. There were no serious adverse reactions in all recipients of ZF0901 vaccine independent of age, dosage, number of injections, or the adjuvant status. Thirty days after the last injection, ZF0901 induced robust immune responses with significantly higher levels of type-specific serum antibodies (geometric mean concentrations (GMCs) of IgG anti-LPS) against both serotypes in all age groups compared with the pre-immune or the Hib control (p < 0.0001). Here, we demonstrated that ZF0901 bivalent Shigella conjugate vaccine is safe and immunogenic in infants and young children and is likely suitable for routine immunization.

Efficacy and Safety of Anti–Vascular Endothelial Growth Factor Monotherapies for Neovascular Age-Related Macular Degeneration: A Mixed Treatment Comparison

Background: We aimed to evaluate the comparative efficacy and safety of anti–vascular endothelial growth factor (anti-VEGF) monotherapy to identify its utilization and prioritization in patients with neovascular age-related macular degeneration (nAMD).Methods: Eligible studies included randomized controlled trials comparing the recommended anti-VEGF agents (ranibizumab, bevacizumab, aflibercept, brolucizumab, and conbercept) under various therapeutic regimens. Outcomes of interest included the mean change in best-corrected visual acuity (BCVA), serious adverse events, the proportion of patients who gained ≥15 letters or lost &lt;15 letters in BCVA, the mean change in central retinal thickness, and the number of injections within 12 months.Results: Twenty-seven trials including 10,484 participants and eighteen treatments were identified in the network meta-analysis. The aflibercept 2 mg bimonthly, ranibizumab 0.5 mg T&amp;E, and brolucizumab 6 mg q12w/q8w regimens had better visual efficacy. Brolucizumab had absolute superiority in anatomical outcomes and a relative advantage of safety, as well as good performance of aflibercept 2 mg T&amp;E. The proactive regimens had slightly better efficacy but a slightly increased number of injections versus the reactive regimen. Bevacizumab had a statistically non-significant trend toward a lower degree of efficacy and safety.Conclusion: The visual efficacy of four individual anti-VEGF drugs is comparable. Several statistically significant differences were observed considering special anti-VEGF regimens, suggesting that brolucizumab 6 mg q12w/q8w, aflibercept 2 mg bimonthly or T&amp;E, and ranibizumab 0.5 mg T&amp;E are the ideal anti-VEGF regimens for nAMD patients. In the current landscape, based on the premise of equivalent efficacy and safety, the optimal choice of anti-VEGF monotherapies seems mandatory to obtain maximal benefit.

Intravitreal aflibercept following treat and extend protocol versus fixed protocol for treatment of neovascular age-related macular degeneration

Background To assess the morphological and functional outcome of intravitreal aflibercept following the treat and extend protocol compared to the fixed protocol for treatment of eyes with neovascular age-related macular degeneration. Methods This retrospective study included 126 eyes of 113 patients with primary onset neovascular age-related macular degeneration who were followed for 12 months. All eyes were treated with 2 mg/0.05 mL aflibercept. All eyes received an upload with three monthly aflibercept injections. We subsequently studied two groups of eyes. For group 1, 54 eyes were treated following the treat and extend protocol. For group 2, 72 eyes were treated following the fixed protocol (fixed 2-monthly interval). Main outcome measures included: best corrected visual acuity (BCVA), central macular thickness (CMT) and number of injections. Results BCVA (logMAR) in group 1 vs group 2 was (0.61 ± 0.3 vs 0.72 ± 0.3, p = 0.09) before treatment and (0.48 ± 0.3 vs 0.51 ± 0.3, p = 0.6) after one year of treatment. CMT in group 1 vs group 2 was (371 ± 101 μm vs 393 ± 116 μm, p = 0.5) before treatment and (284 ± 60 μm vs 290 ± 67 μm, p = 0.1) after one year of treatment. Number of injections/eye in group 1 vs group 2 was (8.5 ± 2.2 vs 7.0 ± 0, p < 0.001). Conclusions Significant differences regarding BCVA and central macular thickness were not found between both treatment protocols during the first year of treatment using aflibercept. However, a significantly higher number of injections was needed for eyes in the treat and extend group during the first year of treatment. This might suggest that aflibercept should better not be extended past an 8 weeks interval during the first year of treatment. Study registration This study was approved by the Ethics Committee of the Medical Association of Saarland, Germany (Nr. 123/20, Date: 16.06.2020). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Nanomedicine for Treating Diabetic Retinopathy Vascular Degeneration

The incidence of diabetes and the pathological conditions associated with chronic hyperglycemia is increasing worldwide. Among them, diabetic retinopathy represents a leading cause of vision loss, causing a significant structural and functional impairment of the retinal and choroidal capillary network. Current therapies include anti-angiogenic and anti-inflammatory drugs administered through repetitive and invasive intraocular injections, and associated with significant adverse effects. The presence of ocular barriers affects the efficiency of topically administered therapeutics for treating the posterior segment of the eye. In this scenario, nanomedicine could improve current therapies for diabetic retinopathy by providing tools that can decrease the number of injections thanks to their controlled release properties, while some materials showed a natural ability to mitigate pathological neo-angiogenesis. Moreover, specific surface modifications could open new scenarios for the development of topical treatments. This review describes current advances in generating nanomedicine for diabetic retinopathy, focusing on the properties of the different materials tested explicitly for this purpose.

Progression of macular atrophy in patients receiving long-term anti-VEGF therapy for age-related macular degeneration; Real Life Data

Purpose To evaluate the progression of macular atrophy (MA) based on near-infrared reflectance (NIR) and optical coherence tomography (OCT) images, in patients with age-related macular degeneration (AMD), receiving anti-vascular endothelial growth factor (anti-VEGF) treatment for at least a 6-year period. Materials and Methods This retrospective study included 53 naïve patients (53 eyes) with neovascular AMD from two centers, who were treated with anti-VEGF intravitreal injections and had no MA at baseline. MA was evaluated in an annual basis using NIR images, while all available OCT images were used to confirm that the atrophic area fulfilled the criteria proposed by the Classification of Atrophy Meetings (CAM) group for complete retinal pigment epithelium RPE and outer retinal atrophy (cRORA). Incidence and progression of MA were evaluated. Associations with best-corrected visual acuity (BCVA) and total number of injections were also studied. Results Treatment duration of our patients was 7.34 ± 1.54 years. The mean number of anti-VEGF injections was 24.4 ± 13.6. BCVA at baseline was 0.38 ± 0.27 logMAR while at final visit it was 0.60 ± 0.35 logMAR (p=0.731). The cumulative incidence of new MA at years 1, 2, 3, 4, 5, and 6 was 1.89%, 18.87% 32.08%, 39.62%, 49.06% and 50.94% respectively. In patients who developed MA, mean MA area increased from zero at baseline to 5.66 ± 7.18 mm2 at final visit. The estimated annual enlargement of MA was 0.45 mm/year based on square root transformation (1.12 mm2/year, untransformed data). MA progression does not appear to be significantly associated with age (R=0.055; p=0.784), gender (R=0.113; p=0.576), BCVA (R=0.168; p=0.404) and total number of injections (R=0.133; p=0.255). Conclusion In this real-life setting, half of neovascular AMD patients under anti-VEGF treatment, without MA at therapy initiation, developed MA over a period of at least 6 years. In this work, the number of injections did not seem to have a significant association with MA progression.

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.

Factors for Visual Acuity Improvement After Anti-VEGF Treatment of Wet Age-Related Macular Degeneration in China: 12 Months Follow up

Purpose: To evaluate the treatment solutions and effectiveness of intravitreal ranibizumab (RBZ) or conbercept in patients with wet age-related macular degeneration (wAMD) in a real-life setting in China.Methods: The medical records of 368 patients with wAMD who started RBZ or conbercept treatment between 1 May 2014 and 30 April 2018 were evaluated. All patients were defined on fundus angiography at baseline to determine the subtype of AMD (PCV or CNV). We report visual acuity (VA) and central retinal thickness (CRT) measurements at baseline and 12 months.Results: The average number of anti-VEGF injections was 2.1 ± 1.2. The BCVA improvement of these two groups was similar with a difference of 1.00 letter (95% CI: −1.4~3.4, p = 0.8505). At the end of the study, a BCVA increase of at least 5 letters was determined to be a satisfactory efficacy endpoint. Several factors were related to the possible improvement in the satisfactory efficacy endpoint, including female sex (OR 2.07, 95% CI 1.22~3.51), number of injections (OR 1.40, 95% CI 1.12~1.75) and VA change at the first month (OR 13.75, 95% CI 7.41~25.51). Additionally, some factors were related to the possible reduction in the satisfactory efficacy endpoint, including diabetes (OR 0.27, 95% CI 0.10~0.73) and disease history (OR 0.75, 95% CI 0.57~0.98).Conclusion: Our study demonstrates that anti-VEGF drugs can effectively improve BCVA and reduce CRT in AMD patients. Sex, number of injections, VA change at the first month, diabetes and disease history are the most important factors affecting visual acuity.

Febrile neutropenia prophylaxis, G-CSF physician preferences: discrete-choice experiment

ObjectivesFebrile neutropenia (FN) commonly occurs during cancer chemotherapy. Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is known to reduce the severity and incidence of FN and infections in patients with cancer. Despite the proven efficacy, G-CSFs are not always prescribed as recommended. We performed a discrete-choice experiment (DCE) to determine what factors drive the physician preference for FN prophylaxis in patients with cancer undergoing chemotherapy.MethodsAttributes for the DCE were selected based on literature search and on expert focus group discussions and comprised pain at the injection site, presence of bone pain, associated fever/influenza syndrome, efficacy of prophylaxis, biosimilar availability, number of injections per chemotherapy cycle and cost. Oncologists, in a national database, were solicited to participate in an online DCE. The study collected the responses to the choice scenarios, the oncologist characteristics and their usual prescriptions of G-CSFs in the context of breast, lungs and gastrointestinal cancers.ResultsOverall, the responses from 205 physicians were analysed. The physicians were mainly male (61%), with ≤20 years of experience (76%) and working only in public hospitals (73%). The physicians prescribe G-CSF primary prophylaxis for 32% of patients: filgrastim in 46% and pegfilgrastim in 54%. The choice of G-CSF for primary and secondary prophylaxis was driven by cost and number of injections. Biosimilars were well accepted.ConclusionCost and convenience of G-CSF drive the physician decision to prescribe or not G-CSF for primary and secondary FN prophylaxes. It is important that these results be incorporated in the optimisation of G-CSF prescription in the clinical setting.

Association between Vortex Vein Engorgement and Treatment Outcomes of Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy

Purpose: To investigate the influence of the number of engorged vortex veins on treatment outcomes in eyes with treatment-naïve polypoidal choroidal vasculopathy (PCV) undergoing intravitreal aflibercept monotherapy.Methods: The medical charts of 65 patients with PCV who underwent intravitreal aflibercept injection were reviewed retrospectively. The number of quadrants of vortex vein engorgement was evaluated in the middle phase of ultra-widefield indocyanine green angiography, which was classified as extended engorgement if the dilated choroidal vessels expanded the macula. Associations between treatment outcomes with age, subfoveal choroidal thickness (SFCT), central retinal thickness, and vortex vein engorgement were investigated using univariate and multivariate analyses.Results: There were no significant differences in best-corrected visual acuity (BCVA), SFCT, and central retinal thickness at baseline and 12 months, according to the number of vortex vein engorgement. However, an increase in the number of vortex vein engorgement extending to the macula was associated with a thick SFCT (p = 0.038), a greater number of injections (p = 0.041), low BCVA at 12 months (p = 0.038), and a less dry macula at 12 months (p = 0.026). In the multivariate analysis, the number of quadrants with vortex vein engorgement extending to the macula was significantly associated with BCVA changes at 12 months, total number of injections, and a dry macula at 12 months (p = 0.030, p = 0.030, p = 0.020, respectively).Conclusions: More quadrants with vortex vein engorgement extending to the macula in PCV was associated with unfavorable visual outcomes, a less dry macula at 12 months, and a greater number of injections at 1 year after intravitreal aflibercept injection. Clinicians should keep in mind that vortex vein engorgement extending to the macula may be a new biomarker in predicting treatment outcomes in PCV.